N-phenyl terephthalamide derivatives and their medical use

Abstract

The present application relates to the formula shown with BCA Tm agonist effect 2- (amino carbonyl) -1H-indole-5-carboxamide derivatives, its racemate or optical isomer, its solvate, or its pharmaceutically acceptable salt, and its use in the preparation of treating metabolic syndrome or obesity drugs and the use of pharmaceutical compositions containing them. Wherein, R1 is the following substituent group amide, methanol, methyl sulfonamide.

Description

Technical Field

[0001] This invention relates to N-phenylterephthalamide derivatives having BCATm agonist activity, their racemic or optical isomers, their solvates, or pharmaceutically acceptable salts thereof, and their use in the preparation of medicaments for treating metabolic syndrome or obesity and pharmaceutical compositions containing them. Background Technology

[0002] Branched-chain aminotransferases (BCATs) are classified as folded type IV transaminases and are pyridoxal 5'-phosphate (PLP)-dependent enzymes. BCATs typically bind to the cofactor PLP in dimer form. They are divided into two types: BCATc, mainly distributed in the central nervous system and kidney cytoplasm; and BCATm, mainly found in the mitochondria of skeletal muscle, pancreas, stomach, and colon. Their main function is to catalyze the conversion of branched-chain amino acids (BCAAs) leucine, isoleucine, and valine into their respective α-keto acids. α-keto acids are further converted into succinyl-CoA and acetyl-CoA, participating in the tricarboxylic acid cycle and glycolysis, thereby contributing to energy metabolism in the body. BCATm plays a crucial role in BCAA metabolism. The relationship between BCAAs and obesity was noted decades ago; they exhibit complex interactions with obesity by influencing energy metabolism, insulin resistance, and lipid metabolism. Studies have shown that knocking out or inhibiting BCATm in mice results in metabolic phenotypes such as low body fat, high energy expenditure, high insulin sensitivity and glucose tolerance, and resistance to obesity induced by a high-fat diet, similar to the outcomes of a high-protein diet. Therefore, BCATm is a suitable peripheral target for treating obesity and holds promise as a potential target for metabolic diseases. Currently, there are no drugs marketed targeting this target. Summary of the Invention

[0003] The technical problem solved by this invention is to provide a compound of formula I with BCATm agonist activity, its stereoisomer, its prodrug and pharmaceutically active metabolite, its pharmaceutically acceptable salt, solvate, and hydrate, and to provide its use in the preparation of medicaments for treating metabolic-related diseases.

[0004] The first aspect of this invention relates to compounds of Formula I, their stereoisomers, their prodrugs and pharmaceutically active metabolites, their pharmaceutically acceptable salts, solvates, and hydrates.

[0005]

[0006] in,

[0007] R1 can be one of the following substituents: acetamide, methanol, or methanesulfonamide.

[0008] In one specific embodiment of the invention, the compound of Formula 1, its racemic or optical isomer, its solvate, or a pharmaceutically or physiologically acceptable salt thereof, wherein the compound is selected from:

[0009] 4-({[2-(formamidomethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 1)

[0010] 4-({[3-(formamidomethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 2)

[0011] 4-({[2-(2-hydroxyethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (compound 3)

[0012] 4-({[3-(2-hydroxyethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (compound 4)

[0013] 4-[({2-[methanesulfonylamino]phenyl}amino)carbonyl]benzene-1-carboxamide (compound 5)

[0014] Another aspect of the invention relates to pharmaceutical compositions comprising a racemic or optical isomer of a compound of the invention and at least one pharmaceutically acceptable carrier, which are suitable for in vivo treatment and are biocompatible. The pharmaceutical compositions can be prepared in various forms depending on the route of administration. The compounds mentioned in the invention can also be prepared as various pharmaceutically acceptable salts, and the pharmaceutical compositions of the invention can be used in remedies for metabolic diseases.

[0015] The pharmaceutical composition involved in this invention refers to a composition comprising an effective dose of a compound of Formula I of the invention or a pharmaceutically acceptable salt or hydrate thereof and one or more suitable pharmaceutically acceptable carriers. Pharmaceutical carriers herein include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycerol, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose materials, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, and lanolin.

[0016] The pharmaceutical compositions of the compounds of the present invention can be administered in any of the following ways: orally, by spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, and intracranial injection or infusion, or by means of an external implantation device.

[0017] When taken orally, the compounds of this invention can be formulated into any orally acceptable dosage form, including but not limited to tablets, capsules, aqueous solutions, or aqueous suspensions. Tablets typically use carriers including lactose and corn starch, and lubricants such as magnesium stearate may also be added. Capsule formulations typically use diluents including lactose and dried corn starch. Aqueous suspension formulations usually involve mixing the active ingredient with suitable emulsifiers and suspending agents. If desired, sweeteners, flavorings, or colorings may also be added to the above oral dosage forms.

[0018] When used topically, especially for treating affected areas or organs easily accessible by topical application, such as the eyes, skin, or lower gastrointestinal neurological disorders, the compounds of this invention can be formulated into different topical formulations depending on the affected area or organ, as detailed below:

[0019] When applied topically to the eyes, the compounds of this invention can be formulated as a micronized suspension or solution, using an isotonic sterile saline solution of a specific pH as the carrier, with or without preservatives such as benzyl alkyl chloride. For ophthalmic use, the compounds can also be formulated as an ointment, such as petrolatum.

[0020] When applied topically to the skin, the compounds of the present invention can be formulated into suitable ointment, lotion, or cream formulations, wherein the active ingredient is suspended or dissolved in one or more carriers. Carriers that can be used in ointment formulations include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsified wax, and water; carriers that can be used in lotions or creams include, but are not limited to, mineral oil, sorbitan monostearate, Tween 60, hexadecyl ester wax, hexadecene aromatic alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0021] The compounds of this invention can also be administered in sterile injectable formulations, including sterile injectable water or oil suspensions or sterile injectable solutions. The carriers and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils, such as monoglycerides or diglycerides, can also be used as solvents or suspension media.

[0022] It should also be noted that the dosage and method of administration of the compounds of this invention depend on many factors, including the patient's age, weight, sex, natural health condition, nutritional status, the activity intensity of the compound, the duration of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The preferred dosage is between 0.01 and 100 mg / kg body weight / day, with the optimal dosage being between 1 mg / kg and 50 mg / kg body weight / day. Detailed Implementation

[0023] The following will further illustrate the essence and beneficial effects of the present invention with reference to embodiments. These embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0024] The melting point of the compound was determined using an RY-1 melting point apparatus; the thermometer was not calibrated. Specific rotation was determined using an OA Polar 3005 precision automatic polarimeter, and mass spectrometry was performed using a Micromass ZabSpec high-resolution mass spectrometer (1000 Å resolution). 1 HNMR was measured using a BRUKER-ADV600 superconducting NMR spectrometer, operating frequency 1 H NMR 600MHz, 13 C NMR 100MHz.

[0025] In a preferred embodiment of the present invention, the compound of formula I, its racemic or optical isomer, its pharmaceutically acceptable salt, solvate, or hydrate can be prepared, by way of example, via the following reaction route:

[0026] The technical solution of the present invention will be described in detail below with reference to the specific embodiments. However, it should be understood that the present invention is not limited to the specific examples described below.

[0027] Example 1: 4-({[2-(formamidomethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 1)

[0028] 4-Cyanobenzic acid (0.3 g, 2.04 mmol) was dissolved in 10 mL of DMF, and HOBT (0.41 g, 3.06 mmol) and EDCI (1.17 g, 6.12 mmol) were added. The reaction was allowed to proceed for 0.5 h. (2-Aminophenyl)acetonitrile (0.27 g, 2.04 mmol) was then added to the system, and the reaction was allowed to proceed for 4 h. After the reaction was complete, 50 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium bicarbonate, followed by separation by column chromatography with petroleum ether:ethyl acetate at a ratio of 5:1. The solution was concentrated under reduced pressure to obtain 0.19 g of a pink solid, which was directly added to the next step.

[0029] The crude product from the previous step was dissolved in a mixed solvent of DMSO / H2O2 (5:1), and 0.2 g of potassium carbonate was added under ice bath conditions. The reaction was allowed to proceed for 0.5 h, followed by overnight reaction at room temperature. After the reaction was complete, 30 mL of water was added to the system, and a solid precipitated. The solid was filtered and washed with 20 mL of water to give 0.1 g of a white solid. Yield: 16.7%. ESI-MS (m / z): 298.12 ([M+H]+). 1H NMR (600MHz, DMSO) δ11.34 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.2Hz, 2H), 8.03-7.99 (m, 2H), 7.96 (d, J = 2.6Hz, 1H), 7.90 (d, J =8.2Hz, 1H), 7.55 (s, 1H), 7.38-7.33 (m, 1H), 7.30 (ddd, J=7.2, 4.2, 2.6Hz, 2H), 7.15 (td, J=7.5, 1.3Hz, 1H), 3.58 (s, 2H).

[0030] Example 2: 4-({[3-(formamidomethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 2)

[0031] Following the method described above for synthesizing target compound 1, (2-aminophenyl)acetonitrile in the reaction system was replaced with (3-aminophenyl)acetonitrile, yielding 0.11 g of a white solid, with a yield of 18.3%. ESI-MS (m / z): 298.12 ([M+H]+). 1H NMR (600MHz, DMSO) 610.32 (s, 1H), 8.12 (s, 1H), 8.06-7.97 (m, 4H), 7.70 (t, J=1.9Hz, 1H), 7.65 (ddd, J=8.2, 2.2, 1.1H z, 1H), 7.53 (s, 1H), 7.48 (s, 1H), 7.28 (t, J=7.8Hz, 1H), 7.02 (dt, J=7.7, 1.3Hz, 1H), 6.94-6.87 (m, 1H), 3.38 (s, 2H).

[0032] Example 3: 4-({[2-(2-hydroxyethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 3)

[0033] Following the method described above for synthesizing target compound 1, the (2-aminophenyl)acetonitrile in the reaction system was replaced with 2-(2-aminophenyl)ethyl-1-ol, yielding 0.12 g of a white solid, with a yield of 20.7%. ESI-MS (m / z): 283.11 ([MH]+). 1HNMR (600MHz, DMSO) δ10.35 (s, 1H), 8.13 (s, 1H), 8.01 (s, 4H), 7.60 (d, J=7.9Hz, 1H), 7.55 (s, 1H), 7.31 (dd, J=7.6, 1.6Hz, 1H), 7 .26 (td, J=7.6, 1.6Hz, 1H), 7.18 (td, J=7.4, 1.4Hz, 1H), 5.35 (t, J=4.4Hz, 1H), 3.68 (td, J=6.4, 4.4Hz, 2H), 2.81 (t, J=6.4Hz, 2H).

[0034] Example 4: 4-({[3-(2-hydroxyethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 4)

[0035] Following the method described above for synthesizing target compound 1, the (2-aminophenyl)acetonitrile in the reaction system was replaced with 2-(3-aminophenyl)ethyl-1-ol, yielding 0.1 g of a white solid, with a yield of 17.2%. ESI-MS (m / z): 283.11 ([MH]+). 1HNMR (600MHz, DMSO) δ10.28 (s, 1H), 8.13 (s, 1H), 8.00 (d, J=2.4Hz, 4H), 7.62 (d, J=8.4Hz, 2H), 7.53 (s, 1H), 7.26 (t, J= 7.7Hz, 1H), 6.97 (dt, J=7.6, 1.5Hz, 1H), 4.70 (td, J=5.3, 1.8Hz, 1H), 3.62 (td, J=7.1, 5.2Hz, 2H), 2.72 (t, J=7.1Hz, 2H).

[0036] Example 5: 4-[({2-[methanesulfonylamino]phenyl}amino)carbonyl]benzene-1-carboxamide (Compound 5)

[0037] Following the method described above for synthesizing target compound 1, the (2-aminophenyl)acetonitrile in the reaction system was replaced with 2-methanesulfonylaminoaniline, yielding 50 mg of a white solid in 8.8% yield. ESI-MS (m / z): 283.11 ([MH]+). ¹H NMR (600 MHz, DMSO) δ 9.90 (s, 1H), 9.17 (s, 1H), 8.14 (s, 1H), 8.03 (s, 4H), 7.73 (dd, J = 7.8, 1.8 Hz, 1H), 7.55 (s, 1H), 7.46 (dd, J = 7.7, 1.8 Hz, 1H), 7.29 (dtd, J = 19.9, 7.5, 1.7 Hz, 2H), 2.98 (s, 3H).

[0038] Example 6: Determination of BCATm inhibitory effect at the molecular level

[0039] The assay was performed in 384-well plates with a final volume of 10 μL per well. Before adding the assay components, the test compound was added to the plate as a 50 nL DMSO solution using an ultrasonic dispenser. Additionally, two wells contained 50 nL DMSO or an appropriate concentration of the control inhibitor compound, respectively, to generate 100% activity and 100% inhibition control. Single-concentration assays were performed at a 10 μM compound concentration. For pIC50 assays, the compounds were tested using an 11-point 3-fold dilution series. 4 μL of enzyme-PLP solution containing standard concentrations of BCATm and PLP in assay buffer was added to these plates. Subsequently, 4 μL of a coupling solution containing 3 mM L-leucine, 0.5 mM α-ketoglutarate, 10 units / mL HRP, and 80 μM Amplex red was added to initiate the reaction. The coupling solution was incubated at room temperature in a 15 mL tube with 1 mL of agarose-immobilized catalase / 10 mL of coupling solution to “wash” the coupling solution and remove background levels of hydrogen peroxide before adding Amplex Red. After incubation for a specified time, 2 μL of 100 mM 4-methyl-2-oxovalerate was added to stop the reaction. The final determination concentrations were 10 nM BCATm, 20 nM PLP, 5 units / mL HRP, 1.5 mM L-leucine, 0.25 mM α-ketoglutarate, and 40 μM Amplex Red. The plate was transferred to a fluorescence plate reader (excitation filter 525 / 20 nm; emission filter 598 / 25 nm) to read the data, and the IC50 was calculated by tabulation and graphing.

[0040] Table 1. Activity evaluation results of the compounds

[0041]

Claims

1. Compounds of Formula I, their stereoisomers, their prodrugs and active metabolites, their pharmaceutically acceptable salts, solvates, and hydrates. in, R1 can be one of the following substituents: acetamide, methanol, or methanesulfonamide.

2. The use according to claim 1, wherein the compound of formula 1, its racemic or optical isomer, its solvate, or a pharmaceutically or physiologically acceptable salt thereof, is selected from: 4-({[2-(formamidomethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 1) 4-({[3-(formamidomethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (Compound 2) 4-({[2-(2-hydroxyethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (compound 3) 4-({[3-(2-hydroxyethyl)phenyl]amino}carbonyl)benzene-1-carboxamide (compound 4) 4-[({2-[methanesulfonylamino]phenyl}amino)carbonyl]benzene-1-carboxamide (compound 5).

3. The use of the compound according to claims 1-2, or its stereoisomers, its prodrugs and pharmaceutically active metabolites, its pharmaceutically acceptable salts, solvates, and hydrates, in the preparation of medicaments for treating metabolic syndrome and pharmaceutical compositions containing them.

4. The metabolic syndrome described in claim 4 includes obesity, diabetes, atherosclerosis, dyslipidemia, hypertension, multiple sclerosis, etc.

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