CN116003387B

CN116003387B - Deuterated indazole propionamide compound, pharmaceutical composition and application

Info

Publication number: CN116003387B
Application number: CN202211451461.1A
Authority: CN
Inventors: 郭炳华; 闫海磊; 温杰
Original assignee: Yaokang Zhongtuo Beijing Pharmaceutical Technology Co ltd
Current assignee: Yaokang Zhongtuo Beijing Pharmaceutical Technology Co ltd
Priority date: 2022-11-20
Filing date: 2022-11-20
Publication date: 2024-03-26
Anticipated expiration: 2042-11-20
Also published as: CN116003387A

Abstract

The invention discloses a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, a pharmaceutical composition and application. The compound shown in the formula I provided by the invention has good inhibitory activity on CGRP receptors and good therapeutic effect on diseases related to abnormal CGRP receptor activity.

Description

Deuterated indazole propionamide compound, pharmaceutical composition and application

Technical Field

The invention belongs to the field of innovative pharmaceutical chemistry, and relates to a deuterated indazole propionamide compound, a pharmaceutical composition and application.

Background

Calcitonin Gene Related Peptide (CGRP) is an early discovered neuropeptide consisting of 37 amino acids, which belongs to a family of bioactive peptides consisting of calcitonin, adrenomedullin, amylin, etc. The peptides are widely distributed in the peripheral and central nervous systems, mainly in sensory afferents and central neurons. CGRP binds to specific cell surface G protein-coupled receptors and exerts its biological effects primarily by activating intracellular adenylate cyclase. CGRP plays multiple roles in migraine, including dilation of cranial blood vessels, degranulation of mast cells exacerbates neurogenic inflammation, and effects on central sensitization. Studies have shown elevated CGRP levels at the onset of migraine. Thus, antagonizing CGRP or CGRP receptors may alleviate migraine symptoms. Small molecule receptor antagonists or monoclonal antibodies act directly on CGRP receptors or CGRP, and have recently been approved for prophylactic treatment of migraine. In addition to its clinical use in the prophylactic treatment of migraine, the FDA has recently proposed that CGRP receptor antagonists that would otherwise enter phase III clinical for the treatment of migraine initiate a randomized II clinical trial for alleviating lung inflammation, impending oxygen saturation, acute respiratory distress syndrome, supplemental oxygen requirements, artificial ventilation and death in covd-19 hospitalized patients. BHV-3500 is a small molecule CGRP receptor antagonist currently undergoing regulatory scrutiny in the united states as an intranasal acute treatment for adult migraine. BHV-3500 is currently being used as an oral formulation in the phase II/III clinical evaluation for migraine prophylaxis. In addition, the compound was used in phase II/III clinical trials in hospitalized COVID-19 patients requiring oxygen supplementation, and in phase I clinical trials in asthmatic patients.

Deuterated drugs refer to the replacement of part of the hydrogen atoms in the drug molecule with deuterium. Deuterated drugs generally retain the biological activity and selectivity of the original drug due to the shape and volume of deuterium in the drug molecule, which is similar to hydrogen. Because the C-D bond is more stable than the C-H bond, the C-D bond is less likely to break during the chemical reaction of the deuterated drug, and the half-life period of the deuterated drug is prolonged. Since 2000, deuteration strategies have been widely used in drug research.

Disclosure of Invention

The invention provides a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof, which has the following structure:

wherein R is ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Or R is ₇ Independently selected from the group consisting of hydrogen and deuterium,

at the same time, R ₁ 、R ₂ 、R ₃ 、R ₄ 、R ₅ 、R ₆ Or R is ₇ At least one of which is deuterium.

In some embodiments, the compound is represented by any one of the following structural formulas:

the invention provides an application of a compound shown in a formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in preparing a CGRP receptor antagonist.

The invention provides a use of a compound shown as I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof in the preparation of a medicament for the treatment and/or prevention of diseases in which CGRP receptor activity is involved.

In some embodiments, the disorder involving CGRP receptor activity is selected from migraine, asthma, acute respiratory syndrome, covd-19, chronic obstructive pulmonary disease.

The invention provides a pharmaceutical composition, which contains a compound shown in a formula I, or pharmaceutically acceptable salts, isomers, metabolites, prodrugs, solvates or hydrates thereof, and pharmaceutically acceptable carriers or auxiliary materials.

In the pharmaceutical composition, the compound shown in the formula I or pharmaceutically acceptable salt, isomer, metabolite, prodrug, solvate or hydrate thereof is used in an amount which is effective in treatment.

The invention provides an application of a pharmaceutical composition in preparing CGRP receptor antagonist.

The present invention provides the use of a pharmaceutical composition for the manufacture of a medicament for the treatment and/or prophylaxis of diseases in which CGRP receptor activity is involved.

The pharmaceutical excipients can be those which are widely used in the field of pharmaceutical production. Adjuvants are used primarily to provide a safe, stable and functional pharmaceutical composition, and may also provide means for allowing the subject to dissolve at a desired rate after administration, or for promoting effective absorption of the active ingredient after administration of the composition. The pharmaceutical excipients may be inert fillers or provide a function such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition. The pharmaceutical excipients can comprise one or more of the following excipients: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, sizing agents, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption retarders, dissolution inhibitors, enhancing agents, adsorbents, buffering agents, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared in accordance with the disclosure using any method known to those of skill in the art. For example, conventional mixing, dissolving, granulating, emulsifying, levigating, encapsulating, entrapping or lyophilizing processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular). The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, soft capsules, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations which may be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic formulations; aerosol: such as nasal sprays or inhalants; a liquid dosage form suitable for parenteral administration; suppositories and lozenges.

The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention prepared from the compounds of the present invention which have the specified substituents found herein with relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts may be obtained by contacting the free form of such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid (forming carbonates or bicarbonates), phosphoric acid (forming phosphates, monohydrogenphosphates, dihydrogenphosphates, sulfuric acid (forming sulfates or bisulphates), hydroiodic acid, phosphorous acid, and the like, and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, salts of amino acids (such as arginine and the like), and salts of organic acids such as glucuronic acid.

The "pharmaceutically acceptable salts" of the present invention can be synthesized from the parent compound containing an acid or base by conventional chemical methods. In general, the preparation of such salts is as follows: prepared via reaction of these compounds in free acid or base form with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

The term "isomer" refers to compounds of the same chemical formula but having different arrangements of atoms.

The term "metabolite" refers to a pharmaceutically active product of a compound of formula I or a salt thereof produced by in vivo metabolism. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, glucuronidation, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds produced by a method of contacting a compound of the present invention with a mammal for a period of time sufficient to obtain the metabolites thereof.

Identification of metabolites typically occurs by preparing a radiolabeled isotope of a compound of the invention, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, in a detectable dose (e.g., greater than about 0.5 mg/kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion product from urine, blood, or other biological samples. These products are easy to isolate because they are labeled (others are isolated by using antibodies that are capable of binding to epitopes present in the metabolite). The metabolite structures are determined in a conventional manner, for example by MS, LC/MS or NMR analysis. In general, the analysis of metabolites is performed in the same manner as conventional drug metabolism studies known to those skilled in the art. So long as the metabolite products are not otherwise undetectable in vivo, they are useful in assays for therapeutic dosing of the compounds of the invention. The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more of the atoms comprising the compounds. For example, compounds can be labeled with radioisotopes, such as tritium @, for example ³ H) Iodine-125% ¹²⁵ I) Or C-14% ¹⁴ C) A. The invention relates to a method for producing a fibre-reinforced plastic composite All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

In addition to salt forms, the compounds provided herein exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert to the compounds of the invention. Any compound that can be converted in vivo to provide a biologically active substance (i.e., a compound of formula I) is a prodrug within the scope and spirit of the invention. For example, compounds containing a carboxyl group can form a physiologically hydrolyzable ester that acts as a prodrug by hydrolyzing in vivo to give the compound of formula I itself. The prodrugs are preferably administered orally, as hydrolysis occurs in many cases primarily under the influence of digestive enzymes. Parenteral administration may be used when the ester itself is active or hydrolysis occurs in the blood.

The invention has the positive progress effects that:

(1) The compound has good inhibitory activity on CGRP.

(2) The oral bioavailability of the compound of the invention is obviously improved, and the oral administration is supported.

(3) The compound has good therapeutic effect on migraine, asthma, acute respiratory syndrome, COVID-19 and chronic obstructive pulmonary disease.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

Example 1: synthesis of Compound I-1

Step one: synthesis of Compound 2

To a solution of Compound 1 (110 mg,0.47 mmol) in N, N-dimethylformamide (15 mL) was added potassium hydroxide (105.5 mg,1.88 mmol) and elemental iodine (239 mg,0.94 mmol), reacted at room temperature for 3 hours, and TLC was monitored for completion of the reaction, and the saturated solution of sodium sulfite was added to quench the reaction, and the aqueous phase was extracted with ethyl acetate (10 mL. Times.2), washed with water (20 mL. Times.2) and saturatedAnd brine (20 mL) were washed with water, dried over anhydrous sodium sulfate, and concentrated column chromatography was performed to obtain iodo compound 2 (51 mg, 46%). MS (ESI, M/z): 360 (M) ⁺ +1).

Step two: synthesis of Compound 3

To a deuterated acetic acid solution (8 mL) of compound 2 (129 mg,0.36 mmol) was added sodium acetate (97.9 mg,0.72 mmol), and after completion of the 2-hour drop, the reaction was performed at room temperature for 24 hours, TLC detection was complete, and concentration under reduced pressure, column chromatography separation and purification were performed to obtain compound 3 (51 mg, 60%). MS (ESI, M/z): 235 (M) ⁺ +1).

Step three: synthesis of Compound 4

Raw material 6 (274 mg,1.2 mmol) was dissolved in anhydrous THF (10 mL), CDI (243 mg,1.5 mmol) and TEA (0.21 mL,1.5 mmol) were added to the above solution at 0deg.C, and then transferred to room temperature and reacted for 1h with stirring. The THF was removed by swirling, extraction with ethyl acetate was performed 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in anhydrous DMF, and to the above solution were added compound 3 (, 1 mmol) and TEA (0.28 mL,2 mmol), and the reaction was stirred at room temperature for 3h. After the reaction was completed, the reaction was quenched with water, extracted with ethyl acetate 3 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography to give compound 4 (418 mg, 85%). MS (ESI, M/z): 489 (M) ⁺ +1).

Step four: synthesis of Compound 5

Raw material 4 (400 mg,0.82 mmol) was dissolved in methanol (5 mL), and an aqueous sodium hydroxide solution (2 mL,1.64 mmol) was added to the above solution, and the temperature was raised to 45℃to react for 3h. After the reaction is completed, transferring to 0 ℃, regulating the pH to be acidic by dilute hydrochloric acid, carrying out suction filtration, and carrying out vacuum drying to obtain the compound 5, and directly putting into the next reaction.

Step four: synthesis of Compound I-1

Compound 5 (47.4 mg,0.1 mmol) was dissolved in DMF (2 mL), and to the solution were added compound 7 (20 mg,0.11 mmol), EDCI (33 mg,0.17 mmol), HOBT (18 mg,0.13 mmol) and TEA (42. Mu.L, 0.3 mmol), and the reaction was stirred at room temperature for 3h. The reaction was quenched with water, extracted with ethyl acetate (5 mL. Times.3), the organic phases combined, dried over anhydrous sodium sulfate, filtered and concentratedCompound I-1 (57 mg, 89%) was obtained. ¹ H NMR(500MHz,DMSO-d ₆ )δ7.67–7.61(m,1H),7.50(d,J＝2.2Hz,1H),7.40(ddd,J＝7.7,7.0,1.8Hz,1H),7.38–7.28(m,2H),7.15–7.11(m,1H),7.08(d,J＝2.0Hz,1H),7.00(d,J＝9.3Hz,1H),4.61(dt,J＝9.3,7.8Hz,1H),3.91–3.75(m,4H),3.47(ddd,J＝6.0,4.8,1.4Hz,4H),3.03(dd,J＝14.0,7.8Hz,1H),2.97–2.86(m,3H),2.81–2.68(m,4H),2.56(s,4H),2.39–2.21(m,6H),2.12–1.95(m,4H),1.81–1.66(m,6H).MS(ESI,m/z):640(M ⁺ +1).

Example 2: synthesis of Compound I-2

¹ H NMR(500MHz,DMSO-d ₆ )δ7.67–7.61(m,1H),7.60(s,1H),7.50(d,J＝2.2Hz,1H),7.40(ddd,J＝7.7,7.0,1.8Hz,1H),7.38–7.28(m,2H),7.15–7.11(m,1H),7.08(d,J＝2.0Hz,1H),7.00(d,J＝9.3Hz,1H),4.61(dt,J＝9.3,7.8Hz,1H),3.91–3.75(m,4H),3.47(ddd,J＝6.0,4.8,1.4Hz,4H),3.03(dd,J＝14.0,7.8Hz,1H),2.97–2.86(m,3H),2.81–2.68(m,4H),2.56(s,4H),2.39–2.21(m,3H),2.12–1.95(m,4H),1.81–1.66(m,6H).MS(ESI,m/z):641(M ⁺ +1).

Example 3: synthesis of Compound I-3

Step one: synthesis of Compound 8

The synthesis was as in step three of example 1.

Step two: synthesis of Compound 9

The synthesis was as in step four of example 1.

Step three: synthesis of Compound 10

The synthesis is as in step five of example 1.

Step four: synthesis of Compound 11

Compound 10 (200 mg,0.28 mmol) was dissolved in ethyl acetate (5 mL), and to the above solution was added ethyl acetate/HCl solution (0.56 mL), and the reaction was stirred at room temperature for 4h. After the reaction is completed, suction filtration is carried out, filter cakes are collected, and the compound 11 is prepared by vacuum drying.

Step five: synthesis of Compound I-3

Compound 11 (100 mg,0.16 mmol) was dissolved in acetone (5 mL), methyl iodide (0.24 mmol) and potassium carbonate (33 mg,0.24 mmol) were added to the above solution, the reaction was stirred at room temperature, and after the completion of the reaction, the mixture was filtered off with suction, concentrated under reduced pressure, and separated and purified by column chromatography to give Compound I-3. ¹ H NMR(500MHz,DMSO-d ₆ )δ7.67–7.61(m,1H),7.60(s,1H),7.50(d,J＝2.2Hz,1H),7.40(ddd,J＝7.7,7.0,1.8Hz,1H),7.38–7.28(m,2H),7.15–7.11(m,1H),7.08(d,J＝2.0Hz,1H),7.00(d,J＝9.3Hz,1H),4.61(dt,J＝9.3,7.8Hz,1H),3.91–3.75(m,1H),3.47(ddd,J＝6.0,4.8,1.4Hz,4H),3.03(dd,J＝14.0,7.8Hz,1H),2.97–2.86(m,3H),2.81–2.68(m,4H),2.56(s,4H),2.39–2.21(m,6H),2.12–1.95(m,4H),1.81–1.66(m,6H).MS(ESI,m/z):642(M ⁺ +1).

Example 4: synthesis of Compound I-4

The synthesis method is as in examples 1 and 3, only the corresponding raw materials need to be replaced. ¹ H NMR(500MHz,DMSO-d ₆ )δ7.67–7.61(m,1H),7.50(d,J＝2.2Hz,1H),7.40(ddd,J＝7.7,7.0,1.8Hz,1H),7.38–7.28(m,2H),7.15–7.11(m,1H),7.08(d,J＝2.0Hz,1H),7.00(d,J＝9.3Hz,1H),4.61(dt,J＝9.3,7.8Hz,1H),3.91–3.75(m,1H),3.47(ddd,J＝6.0,4.8,1.4Hz,4H),3.03(dd,J＝14.0,7.8Hz,1H),2.97–2.86(m,3H),2.81–2.68(m,4H),2.56(s,4H),2.39–2.21(m,6H),2.12–1.95(m,4H),1.81–1.66(m,6H).MS(ESI,m/z):643(M ⁺ +1).

Example 5: competitive binding assay for CGRP receptor

Human neuroblastoma SK-N-MC cells have a sequence identical to the cloned human CGRP receptor due to their endogenous expression, and thus a competitive binding assay to the CGRP receptor is hereinIn cells. Determination of test Compounds with radioelement labeling Using radioligands ¹²⁵ I]CGRP competes for binding to CGRP receptors. For specific methods of operation reference is made to the experimental methods disclosed in WO 2011/123232.

TABLE 1 binding Capacity of test Compounds to CGRP receptor

Names of Compounds	(Ki pM)
		I-1	8.5
I-2	8.6
		I-3	8.7
I-4	8.9
		BHV-3500	26.2

As shown in Table 1, the compounds I-1 to I-4 were inhibited in a concentration-dependent manner ¹²⁵ I]The CGRP and the CGRP receptor in the SK-N-MC cell membrane are combined, and the inhibition activity is obviously better than that of positive control BHV-3500.

Example 6: cAMP assay

The CGRP receptor complex is coupled to Gs class G proteins. Binding of CGRP to this complex results in cAMP production by Gs-dependent activation of adenylate cyclase. Using the amount of CGRP mediated cAMP production in SK-NMC cells as a detection indicator, the functional antagonism of the compounds to CGRP receptors is detected by detecting the extent of inhibition of cAMP production. For specific experimental methods reference is made to the experimental methods disclosed in WO 2011/123232.

TABLE 2 inhibitory Activity of test Compounds against CGRP receptor mediated cAMP production

As shown in Table 2, compounds I-1 to I-4 inhibited CGRP stimulated cAMP production in the attached whole SK-N-MC cells in a dose-dependent manner, and the observed inhibition of about 100% indicated that the compounds had complete antagonism at the CGRP receptor. And, the inhibition effect of the compounds I-1 to I-4 on cAMP generation is superior to that of a positive control.

Example 7: test compound pharmacokinetic property detection

Male BABL/c mice are selected for oral administration (10 mg/kg) or intravenous injection (2 mg/kg), 5min,15min,30min,1h,2h,4h,8h,10h and 24h after administration, blood is continuously taken from the eyeground venous plexus and placed into an EP tube containing heparin, and LC-MS/MS analysis is carried out on centrifugation and upper plasma, and according to blood concentration-time data obtained by testing, pharmacokinetic parameters are calculated by adopting WinNonlin software, and the oral bioavailability is calculated.

The research result shows that the oral bioavailability of BHV-3500 in mice is extremely low and is only 2.5%, and the BHV-3500 cannot be orally administered, and can only be administered intranasally at present; the oral bioavailability of the compound I-1 is improved to 15%, and the compound I-1 can be orally administered or intranasally administered, has a more flexible administration mode and can provide better choices for more patients.

The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized by a structure selected from the group consisting of:

。

2. a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or adjuvant.

3. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for the preparation of a CGRP receptor antagonist.

4. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 2, for the manufacture of a medicament for the treatment and/or prophylaxis of diseases in which CGRP receptor activity is involved.

5. The use according to claim 4, wherein the disease involving CGRP receptor activity is selected from migraine, asthma, acute respiratory syndrome, covd-19, chronic obstructive pulmonary disease.