Deuterated piperidone acid amide azaindan type CGRP inhibitor medicine and application

Abstract

The invention discloses a deuterated piperidone acid amide aza-indan indan compound as well as a stereoisomer, a tautomer and pharmaceutically acceptable salt thereof as shown in a formula I. The invention relates to a deuterated CGRP inhibitor as well as a pharmaceutical composition and application of the deuterated CGRP inhibitor.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and in particular relates to deuterated piperidone acid amide azaindan CGRP inhibitor drugs and uses thereof. Background Art

[0002] Migraine is a common neurological disease that can cause severe pain on one or both sides of the head. Related symptoms include nausea, vomiting, and sensitivity to light, sound or smell. If left untreated, an attack can last 4 to 72 hours and will recur, seriously affecting the patient's work and life. The pathogenesis of migraine is not yet very clear, but it is affected by environmental and genetic factors and is closely related to family history. More than 1 billion people suffer from migraine worldwide, and the World Health Organization lists migraine as one of the ten most serious disabling medical diseases.

[0003] A leading hypothesis for the pathogenesis of migraine is currently based on activation of the trigeminovascular system. Several neuropeptides are involved in this activation, among which calcitonin gene-related peptide (CGRP) plays a key role. CGRP exerts a variety of different biological effects through the peripheral and central nervous system (CNS). Functional CGRP-receptor (CGRP-R) complexes

[0004] The compounds have been well characterized, and new therapeutic approaches target both CGRP itself and its receptor.

[0005] Deuterated drugs, that is, new drug molecules in which one or more carbon-hydrogen bonds of a drug molecule are replaced with carbon-deuterium bonds, can improve the pharmacokinetic properties of the original drugs, thereby overcoming the original defects of the drugs such as easy metabolism and large side effects.

[0006] The present invention relates to a class of deuterated piperidone acid amide azaindane CGRP inhibitor drugs, which can further improve the pharmacokinetic properties of current piperidone acid amide azaindane CGRP inhibitor drugs, and reduce the dosage and possible toxic side effects. Summary of the invention

[0007] The present invention provides deuterated compounds of deuterated piperidone acid amide azaindane CGRP inhibitors, stereoisomers, tautomers and pharmaceutically acceptable salts thereof, which can further improve the pharmacokinetic properties of deuterated compounds of deuterated piperidone acid amide azaindane CGRP inhibitors and pharmaceutically acceptable salts thereof, and reduce the dosage and possible toxic side effects.

[0008] In order to achieve the above-mentioned object, the present invention provides a deuterated compound of a deuterated piperidone acid amide azaindane CGRP inhibitor as shown in the following formula I, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof:

[0009]

[0010] The piperidone acid amide azaindan indane compound, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof of the present invention are selected from the following structures:

[0011]

[0012] The deuterated compounds of the deuterated piperidone acid amide azaindane CGRP inhibitors of the present invention, their stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein the pharmaceutically acceptable salts thereof are selected from methanesulfonate, maleate, hydrochloride or phosphate.

[0013] The deuterated compound and pharmaceutically acceptable salt thereof of the present invention include their use in preparing CGRP inhibitor drugs.

[0014] The deuterated compound and the pharmaceutically acceptable salt thereof of the present invention comprise the deuterated compound and the pharmaceutically acceptable salt thereof as active ingredients and a pharmaceutically acceptable carrier.

[0015] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures and other mixtures. In addition, asymmetric carbon atoms may represent substituents, such as alkyl. All isomers and their mixtures are included in the present invention.

[0016] According to the present invention, the ratio of isomers contained in the mixture of isomers can be various. For example, in the mixture of only two isomers, there can be the following combinations: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0, and all ratios of isomers are within the scope of the present invention. Similar ratios that are easily understood by ordinary technicians in this profession, and ratios for more complex mixtures of isomers are also within the scope of the present invention.

[0017] The pharmaceutical composition of the deuterated compound and the pharmaceutically acceptable salt thereof of the present invention is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches. Beneficial effects: Compared with the prior art, the present invention has the following advantages:

[0018] The present invention provides a class of deuterated piperidone acid amide azaindane CGRP inhibitor drugs, which further improve the pharmacokinetic properties of piperidone acid amide azaindane CGRP inhibitors and reduce the dosage and possible toxic side effects. DETAILED DESCRIPTION

[0019] The present invention will be further described below in conjunction with the examples. The present invention will be further described below in conjunction with the specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

[0020] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0021] Example 1

[0022] Synthesis method

[0023]

[0024] Add cesium carbonate (2 mmol, 4 eq) to a solution of intermediate 1-A (0.5 mmol) in N,N-dimethylformamide (10 mL), react at room temperature for 1 hour, add 1-B (0.75 mmol), and continue to react overnight. Filter, add water to the filtrate, extract with ethyl acetate (100 mL*2), wash with water (20 mL*2), wash with saturated salt (20 mL), dry over anhydrous sodium sulfate, concentrate and chromatograph to obtain intermediate 1-C.

[0025] Dissolve intermediate 1-C (0.5 mmol), 2,2,2-trifluoroethylamine (2 mmol), acetic acid (2.5 mmol) and sodium triacetoxyborohydride (2 mmol) in 1,2-dichloroethane and stir at room temperature for 10 hours. After TLC monitoring, the reaction is complete, water is added, and the mixture is extracted with dichloromethane. Intermediate 1-D can be obtained by silica gel column chromatography and chiral separation.

[0026] Intermediate 1-E can be prepared by referring to the method of patent CN103328478;

[0027] The intermediate 1-E (3 mmol) was dissolved in DMF (20 mL), HATU (4 mmol) was added and stirred for half an hour, and then the intermediate 1-D (3 mmol) and DIPEA (6 mmol) were added. The reaction was continued overnight. The reaction was complete when detected by TLC. The mixture was filtered, and the solid was washed with water and dried to obtain Example 1. 1H NMR (500 MHz, Chloroform-d) δ 9.12 (d, J = 3.2 Hz, 1H), 8.11 – 8.09 (m, 2H), 7.47 (dd, J = 3.1, 2.1 Hz, 1H), 7.39 – 7.36 (m, 2H), 7.29 – 7.23 (m, 3H), 6.94 (q, J = 6.2 Hz, 1H), 4.71 – 4.52 (m, 2H), 3.89 – 3.77 (m, 2H), 3.38 (d, J = 8.0 Hz, 1H), 3.43 – 3.36 (m, 3H), 3.34 – 3.21 (m, 1H), 2.76 – 2.66(m, 1H), 2.08 – 2.03 (m, 1H).

[0028] Example 2

[0029]

[0030] The synthesis method of Example 2 refers to the synthesis of Example 1, and Example 2 can be prepared by replacing the intermediate 1-A with 1-(deuterated phenyl-d5)acetone. 1 H NMR (500 MHz, Chloroform-d) δ 9.11 (d, J = 3.2Hz, 1H), 8.14 – 8.10 (m, 2H), 7.45 (d, J = 3.3 Hz, 1H), 6.96 (t, J = 5.3 Hz,1H), 4.70 – 4.54 (m, 2H), 3.90 – 3.81 (m, 2H), 3.40 (d, J = 6.4 Hz, 1H), 3.44– 3.38 (m, 3H), 3.32 – 3.20 (m, 1H), 2.72 – 2.61 (m, 1H), 2.03 – 2.00 (m,1H), 1.02 (d, J = 5.2 Hz, 3H).

[0031] Example 3

[0032] The synthesis method of Example 3 refers to the synthesis of Example 1, and Example 3 can be prepared by replacing the intermediate 1-A with 1-(deuterated phenyl-d5)acetone-3,3,3-d3. 1H NMR (500 MHz, Chloroform-d) δ 9.12(d, J =3.2 Hz, 1H), 8.10 – 8.08(m, 2H), 7.48(d, J = 4.1 Hz, 1H), 6.97(t, J = 5.1 Hz, 1H), 4.73 – 4.55(m, 2H), 3.86 – 3.74 (m, 2H), 3.35 (d, J = 7.5 Hz, 1H), 3.43 – 3.35 (m, 3H), 3.31 – 3.23 (m, 1H), 2.76 – 2.67 (m, 1H), 2.05 – 1.99 (m, 1H).

[0033] Test Example 1: CGRP binding activity test

[0034] The compound was dissolved in DMSO at a concentration of 100 mM and diluted with 10 mM HEPES (20 mM NaCl, pH 8.5) buffer, and 16 concentration gradients were prepared by 2-fold dilution. The prepared concentration gradient samples were mixed with dye-labeled CGRP protein in a 1:1 ratio, incubated at room temperature in the dark for 10 min, loaded into Monolith NT.115, tested using NanoTemper monolith NT.115 interaction analyzer, and the compound Ki value was calculated using Nano Temper software.

[0035] Compound No. Ki (nM) Example 1 3.6 Example 2 4.7 Example 3 5.1 Ubrelvy 12

[0036] Experimental Example 2: Pharmacokinetics of Compounds

[0037] 1. Experimental instruments and materials

[0038] High-speed refrigerated centrifuge, vortex oscillator (Vortex Genius3), high-speed centrifuge (Eppendorf5415D), disposable syringes, pipettes (Eppendorf), SD male rats used in the experiment were purchased from Yangzhou University, EDTA-K2 vacuum blood collection tubes, and normal saline. All rats in the oral group fasted for 12 hours before administration, and had free access to water and food during administration.

[0039] (II) Experimental steps

[0040] Example 1 or bozitinib was dissolved in DMSO / solutol / water (10 / 10 / 80) to prepare a clear solution. The intranasal administration dose of the compound was 25 mg / kg, and the tail vein administration dose of the compound was 5 mg / kg. At 2 min, 10 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after tail vein administration, 0.5 mL of blood was continuously collected from the venous plexus of the fundus into a heparin tube. At 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after intranasal administration, 0.5 mL of blood was continuously collected from the venous plexus of the fundus into a heparin tube. The samples were heated at 8000 r, 4 0 After centrifugation at -20 °C for 10 min, 0.15 mL of the upper plasma was collected and 0 The samples were stored at 4 °C and then analyzed by LC-MS / MS. The data were analyzed by WinNolin non-compartmental model to obtain key pharmacokinetic parameters.

[0041] (III) Experimental results

[0042] Table 1 Pharmacokinetic parameters

[0043]

[0044] Compared with Ubrelvy, the half-life and peak concentration of Example 1 after oral administration are significantly improved, which can effectively improve the dosage, thereby reducing the toxic and side effects of high-dose administration.

Claims

1. A deuterated piperidone acid amide azaindan compound of formula I, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, and R6 are independently selected from hydrogen or deuterium, but are not all deuterium.

2. A deuterated piperidone acid amide azaindane compound, its stereoisomers, tautomers and pharmaceutically acceptable salts as described in claim 1, characterized in that the deuterated piperidone acid amide azaindane CGRP inhibitor is selected from the following structures: 。 3. The deuterated piperidone acid amide azaindan compound, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof according to claim 1 or 2, characterized in that The pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

4. Use of the deuterated piperidone acid amide azaindan compound according to claim 1 or 2, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof in the preparation of CGRP inhibitor drugs.

5. A pharmaceutical composition, characterized in that The pharmaceutical composition is composed of the deuterated piperidone acid amide azaindane compound according to claim 1 or 2, its stereoisomers, tautomers and pharmaceutically acceptable salts thereof as active ingredients and a pharmaceutically acceptable carrier.

6. The pharmaceutical composition according to claim 5, characterized in that The pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral solutions, inhalants, ointments, suppositories or patches.

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