3-(piperidine-4-yl) quinoline-2 (1H)-ketone derivative and application thereof

Abstract

The invention discloses a 3-(piperidine-4-yl) quinoline-2 (1H)-ketone derivative and application thereof, the compound provided by the invention has CGRP antagonistic activity, and the compound has an application prospect in treatment of migraine.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and provides a class of 3-(piperidin-4-yl)quinolin-2(1H)-one derivatives, their preparation methods and pharmaceutical uses. Such compounds are CGRP antagonists and have application prospects for treating migraine headaches. Background Art

[0002] Migraine is a common chronic episodic brain dysfunction disease. Long-term recurrent attacks can lead to serious health losses, reduced quality of life, and productivity losses, and it has now become one of the major problems in global public health. Migraine is a common primary headache in clinical practice, manifested as recurrent pulsating moderate to severe headaches, often accompanied by symptoms such as nausea or vomiting, photophobia, and phonophobia; Migraine has a high incidence and a long course, ranking second in the burden of neurological diseases.

[0003] Calcitonin gene-related peptide (CGRP) is a neuropeptide containing 37 amino acids. It was discovered 30 years ago and is produced during the alternative RNA processing of the calcitonin gene. CGRP is a potent vasodilator and thus has protective mechanisms that are very important for physiological and pathological conditions such as the cardiovascular system and wound healing. CGRP is mainly released by sensory nerves and is thus related to the pain pathway. It has been confirmed that CGRP antagonists can relieve migraine. Summary of the Invention

[0004] Technical Problem to be Solved: The present invention provides a class of 3-(piperidin-4-yl)quinolin-2(1H)-one compounds, which are CGRP antagonists and have the effect of relieving migraine.

[0005] Technical Solution: A class of 3-(piperidin-4-yl)quinolin-2(1H)-one compounds of formula I or pharmaceutically acceptable salts thereof,

[0006]

[0007] wherein,

[0008] R1, R2, R3, R4 and R5 are each independently selected from H, F or Cl.

[0009] Preferably, wherein,

[0010] R1, R2, R3, R4 and R5 are each independently selected from H or F.

[0011] Preferably, wherein,

[0012] R1 and R2 are independently selected from H or F;

[0013] R3, R4 and R5 are selected from F.

[0014] Preferably, the compound is:

[0015]

[0016] Compound 1: as shown in S1;

[0017]

[0018] Compound 2: as shown in S2.

[0019] The present invention provides an application of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating migraine.

[0020] The present invention provides a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. Detailed implementation manners

[0021] The present invention discloses a class of 3-(piperidin-4-yl)quinolin-2(1H)-one compounds and their uses. Those skilled in the art can draw on the content of this article and appropriately improve process parameters to achieve. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all regarded as included in the present invention. The methods and applications of the present invention have been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate modifications and combinations to the methods and applications described herein without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0022] The following examples can enable those skilled in the art to understand the present invention more comprehensively, but do not limit the present invention in any way.

[0023] Example 1: Synthesis of Compound S1

[0024] Synthesis route:

[0025]

[0026] Synthesis process:

[0027] Intermediate A1:

[0028]

[0029] Dissolve tert-butyl (5-hydroxypentyl)carbamate (5 g, 24.60 mmol, 1 eq) and triethylamine (3.73 g, 5.14 mL, 36.89 mmol, 1.5 eq) in dichloromethane (20 mL). Dropwise add p-toluenesulfonyl chloride (3.66 g, 2.44 mL, 31.98 mmol, 1.3 eq) with stirring in an ice bath. Stir at 20 °C for 1 h. Add 20 mL of saturated sodium bicarbonate solution and extract with dichloromethane (50 mL×2). Combine the organic phases, wash the organic phase with 50 mL of brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain 7.10 g of a light yellow gum (crude product), which is directly used in the next step.

[0030] 1 H NMR (400 MHz, CDCl3) δ 4.54 (s, 1H), 4.22 (t, J = 6.4 Hz, 2H), 3.19 - 3.07 (m, 2H), 3.00 (s, 3H), 1.81 - 1.74 (m, 2H), 1.59 - 1.37 (m, 15H).

[0031] Intermediate A2:

[0032]

[0033] Mix water (40 mL) and 1,4-dioxane (200 mL). Under nitrogen protection, add tert-butyl (piperidin-4-ylmethyl)carbamate (13.22 g, 61.71 mmol), 4-bromopyridine hydrochloride (10.00 g, 51.42 mmol), sodium tert-butoxide (7.41 g, 77.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (2.35 g, 2.57 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (4.80 g, 7.71 mmol), and stir at 80 °C for 16 h. Concentrate, and purify the crude product by silica gel column chromatography (dichloromethane:methanol = 10:1) to obtain 10.0 g of a yellow oil, with a yield of 66.7% and a purity of 50%.

[0034] LCMS (ESI): tR = 0.780, m / z, 292.4 [M+H]+

[0035] Intermediate A3:

[0036]

[0037] A2 (10 g, 17.16 mmol) was mixed with HCl (20.41 ml, 81.63 mmol, 4 M dioxane). The mixture was stirred at 25 °C for 16 h and monitored by TLC until the reaction was complete. Ethyl acetate (100 mL) and water (100 mL) were added, and the mixture was extracted with ethyl acetate (50 ml × 3). The aqueous phase was adjusted to pH 8 with 2 M aqueous sodium hydroxide and freeze-dried to obtain 4.9 g of a yellow solid (crude product).

[0038] 1 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 2H), 8.20 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 4.26 - 4.21 (m, 2H), 3.18 - 3.11 (m, 2H), 2.72 - 2.67 (m, 2H), 2.08 - 1.99 (m, 1H), 1.92 - 1.87 (m, 2H), 1.26 - 1.16 (m, 2H).

[0039] Intermediate A4:

[0040]

[0041] A3 (1.69 g, 8.84 mmol), 5-((tert-butoxycarbonyl)amino)pentyl methanesulfonate (2.49 g, 8.84 mmol) and cesium carbonate (3.66 g, 26.51 mmol) were mixed in 80 ml of acetonitrile and stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by preparative HPLC (water (0.1% FA)-ACN). The HPLC eluate containing the product was rotary evaporated to remove the organic solvent and then lyophilized to obtain 200 mg of a white solid with a yield of 70.8%.

[0042] LCMS (ESI): tR = 0.628, m / z, 377.4 [M+H]+

[0043] Intermediate A5:

[0044]

[0045] Under ice bath stirring, 2-amino-tert-butyldimethylsilyloxyethane (10.50 g, 59.88 mmol, 1 eq) and triethylamine (7.88 g, 10.82 mL, 77.84 mmol, 1.3 eq) were successively added to a mixed solution of ethyl bromoacetate (10.2 g, 98%, 6.78 mL, 59.88 mmol, 1 eq) and tetrahydrofuran (100 mL). Stir at 10 °C for 16 h. Add 100 ml of water and extract with ethyl acetate (100 ml × 2). The combined organic phases were washed with 100 ml of brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain 13 g of a colorless liquid with a yield of 83.0%.

[0046] 1 1H NMR (400 MHz, CDCl3) δ 4.13 (q, J = 7.2 Hz, 2H), 3.70 - 3.61 (m, 2H), 3.37 (s, 2H), 2.70 - 2.62 (m, 2H), 1.21 (t, J = 7.2 Hz, 3H), 0.84 (s, 9H), 0.03 (s, 6H).

[0047] Intermediate A6:

[0048]

[0049] A5 (2 g, 7.65 mmol, 1 eq) and 3,4,5-trifluorobenzyl bromide (1.72 g, 7.65 mmol, 1 eq) were dissolved in 20 ml of N,N-dimethylformamide, and potassium carbonate (2.11 g, 15.30 mmol, 2 eq) was added. Stir at 50 °C for 16 h. The reaction mixture was filtered, and the filtrate was added to 30 ml of saturated ammonium chloride aqueous solution. Extract with ethyl acetate (30 ml × 2). The combined organic phases were washed with water (30 mL) and brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.55 g of a pale yellow oil with a yield of 82.2%, which was directly used for the next step.

[0050] 1 1H NMR (400 MHz, CDCl3) δ 7.09 - 6.97 (m, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.81 (s, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.44 (s, 2H), 2.79 (t, J = 5.6 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H), 0.88 (s, 9H), 0.04 (s, 6H).

[0051] Intermediate A7:

[0052]

[0053] Dissolve A6 (2.50 g, 6.16 mmol, 1 eq) in 50 ml of ethanol. Add p-toluenesulfonic acid·H2O (3.52 g, 4.85 mL, 18.49 mmol, 3 eq) to the solution and stir at 20 °C for 5 hours. Then quench with saturated aqueous sodium bicarbonate and adjust the pH to 7 - 8. Extract with ethyl acetate (80 ml × 2). Combine the organic phases, wash with 80 ml of brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 1.78 g of a colorless gum, with a yield of 99.1%, which is directly used in the next step. 1 HNMR (400 MHz, CDCl3) δ 6.98 - 6.81 (m, 2H), 4.08 (q, J = 7.2 Hz, 2H), 3.67 (s, 2H), 3.51 (t, J = 5.2 Hz, 2H), 3.24 (s, 2H), 2.79 - 2.71 (m, 2H), 1.18 (t, J = 7.2, 3H). LCMS (ESI): t R = 0.666, m / z, 291.9 [M + H] + .

[0054] Intermediate A8:

[0055]

[0056] Dropwise add a solution of (COCl)2 (3.92 g, 2.65 mL, 30.90 mmol, 6 eq) in dichloromethane (1 mL) to a solution of dimethyl sulfoxide (3.22 g, 2.93 mL, 41.20 mmol, 8 eq) in dichloromethane (50 mL) at -70 °C and stir at -70 °C for 30 minutes. Dropwise add a solution of A7 (1.50 g, 5.15 mmol, 1 eq) in dichloromethane (10 mL) and stir at -70 °C for 1 hour. Dropwise add triethylamine (5.21 g, 7.16 mL, 51.50 mmol, 10 eq) at -70 °C and stir at -70 °C for 30 minutes. Slowly heat the system to 0 °C. Add 50 ml of water and extract with dichloromethane (50 ml × 2). Combine the organic phases, wash the organic phase with 100 ml of brine, dry over anhydrous sodium sulfate, filter, and concentrate to obtain 1.49 g of a pale yellow gum (crude product), which is directly used in the next step.

[0057] LCMS (ESI): tR = 1.371, m / z, 308.2 [M + H2O]+

[0058] Intermediate A9:

[0059]

[0060] Dissolve A8 (1.49 g, 5.15 mmol, 1 eq) and A4 (1.94 g, 5.15 mmol, 1 eq) in 100 mL of ethanol, and add three drops of acetic acid. Stir at 25 °C for 2 hours. Add sodium triacetoxyborohydride (3.28 g, 15.45 mmol, 3 eq), and stir at 25 °C for 16 hours. Concentrate, add the solid to a solution of DCM / MeOH = 10 / 1. Filter and concentrate the filtrate. Purify the crude product by silica gel column chromatography (dichloromethane:methanol = 10:1, 0.1 N NH₃·H₂O) to obtain 760 mg of a pale yellow gum (yield: 22.7%).

[0061] LCMS(ESI): t R = 0.811, m / z, 650.4 [M+H] +

[0062] Intermediate A10:

[0063]

[0064] Dissolve A9 (760 mg, 1.17 mmol, 1 eq) in a mixed solution of tetrahydrofuran (5 mL) and water (1 mL), and add LiOH·H₂O (147 mg, 3.51 mmol, 3 eq). Stir at 25 °C for 16 hours. Concentrate to obtain 727 mg of a pale yellow gum, which is directly used for the next step.

[0065] LCMS(ESI): t R = 1.623, m / z, 622.3 [M+H] +

[0066] Intermediate A11:

[0067]

[0068] Dissolve A10 (727 mg, 1.17 mmol, 1 eq) and 3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride (309 mg, 1.17 mmol, 1 eq) in 10 ml of N,N-dimethylformamide, and add 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridin-3-ium hexafluorophosphate (667 mg, 1.75 mmol, 1.5 eq) and N,N-diisopropylethylamine (453 mg, 0.58 ml, 3.51 mmol, 3 eq). Stir at 25 °C for 16 hours and rotary evaporate. Purify the crude product by silica gel column chromatography (dichloromethane:methanol = 5:1, 1% NH₃·H₂O) and preparative thin layer chromatography (DCM / MeOH = 8 / 1, 1% NH₃·H₂O) to obtain 57 mg of a white solid with a yield of 5.8%.

[0069] LCMS (ESI): tR = 1.934, m / z, 832.4 [M+H]+

[0070] Compound S1:

[0071]

[0072] Dissolve A11 in 2 ml of methanol, and add HCl / 1,4-dioxane (1 mL, 4 M). Stir at 25 °C for 5 hours. Concentrate to obtain the crude product, purify by preparative HPLC (water (0.05% HCl)-ACN), and lyophilize to obtain 72.8 mg of pale yellow gum S1, yield: 60.0%, purity: 99.3%.

[0073] 1 H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 11.80 (s, 1H), 10.23 (s, 1H), 8.22 (dd, J = 5.6, 7.4 Hz, 2H), 8.07 (s, 2H), 7.71 - 7.57 (m, 2H), 7.51 - 7.39 (m, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.27 - 7.08 (m, 3H), 4.49 (d, J = 12.4 Hz, 1H), 4.27 (d, J = 13.6 Hz, 2H), 4.00 (s, 2H), 3.83 (d, J = 13.6 Hz, 2H), 3.37 (d, J = 12.8 Hz, 3H), 3.27 - 2.90 (m, 10H), 2.85 - 2.57 (m, 4H), 2.36 - 2.18 (m, 2H), 2.12 - 1.98 (m, 2H), 1.88 (t, J = 12.8 Hz, 2H), 1.74 (d, J = 9.6 Hz, 2H), 1.62 (m, 2H), 1.36 (m, 6H). LCMS (ESI): tR = 1.981, m / z, 732.4 [M+H]+.

[0074] Example 2: Synthesis of Compound S2

[0075] Synthesis process:

[0076] Intermediate B11:

[0077]

[0078] A10 (727 mg, 1.17 mmol, 1 eq) and difluoroquinolinone hydrochloride (309 mg, 1.17 mmol, 1 eq) were dissolved in 10 ml of N,N-dimethylformamide. 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazole[4,5-b]pyridin-3-ium hexafluorophosphate (667 mg, 1.75 mmol, 1.5 eq) and N,N-diisopropylethylamine (453 mg, 0.58 ml, 3.51 mmol, 3 eq) were added. The mixture was stirred at 25 °C for 16 h and then concentrated by rotary evaporation. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 5:1, 1% NH₃·H₂O) and preparative thin layer chromatography (DCM / MeOH = 8 / 1, 1% NH₃·H₂O) to give 57 mg of a white solid with a yield of 5.8%.

[0079] LCMS (ESI): tR = 2.232, m / z, 868.4 [M+H]+

[0080] Compound S2:

[0081]

[0082] B11 was dissolved in 2 ml of methanol. HCl / 1,4-dioxane (1 mL, 4 M) was added. The mixture was stirred at 25 °C for 5 h. The mixture was concentrated to obtain the crude product, which was purified by preparative HPLC (water (0.05% HCl)-ACN), lyophilized to give 172.8 mg of a pale yellow gum with a yield of 60.0% and a purity of 99.3%.

[0083] 11H NMR (400 MHz, DMSO-d6) δ 13.53 (s, 1H), 11.80 (s, 1H), 10.23 (s, 1H), 8.22 (dd, J = 5.6, 7.4 Hz, 2H), 8.07 (s, 2H), 7.71 - 7.57 (m, 1H), 7.51 - 7.39 (m, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.27 - 7.08 (m, 3H), 4.49 (d, J = 12.4 Hz, 1H), 4.27 (d, J = 13.6 Hz, 2H), 4.00 (s, 2H), 3.83 (d, J = 13.6 Hz, 2H), 3.37 (d, J = 12.8 Hz, 3H), 3.27 - 2.90 (m, 10H), 2.85 - 2.57 (m, 4H), 2.36 - 2.18 (m, 2H), 2.12 - 1.98 (m, 2H), 1.88 (t, J = 12.8 Hz, 2H), 1.74 (d, J = 9.6 Hz, 2H), 1.62 (m, 2H), 1.36 (m, 6H). LCMS (ESI): tR = 1.789, m / z, 768.4 [M + H]+。

[0084] Example 3: Activity Detection of the Compound

[0085] Experimental Method: Using a stably expressed CGRP cell line (CALCRL / RAMP1 / CRCP combination), the activity of the test substance was detected with a FlexStation3 Multi-Mode Microplate Reader (Molecular Devices). Detection of compound concentration settings: 10 detection concentrations for each sample, duplicate wells, 3-fold serial dilution, and the starting detection concentration was 10 μM.

[0086] Table 1 Results of the CGRP Activity of the Compound

[0087]

[0088] Note: "++" indicates that the compound activity is 200 nM

Claims

1. A class of 3-(piperidin-4-yl)quinolin-2(1H)-one compounds of formula I or a pharmaceutically acceptable salt thereof, characterized in that, wherein, R1, R2, R3, R4 and R5 are each independently selected from H, F or Cl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein wherein, R1, R2, R3, R4 and R5 are each independently selected from H or F.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, wherein, R1 and R2 are independently selected from H or F; R3, R4 and R5 are selected from F.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, The compound is: Compound 1: as shown in S1; Compound 2: as shown in S2.

5. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 in the preparation of a medicament for treating migraine.

6. A pharmaceutical composition, characterized in that, Comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

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