Novel therapeutic molecules

Abstract

The present invention relates to a compound of structural formula (I), or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of unsubstituted or substituted 1. straight chain aliphatic alkyl carboxylic acid, 2. branched aliphatic alkyl carboxylic acid, 3. straight chain aliphatic alkenyl / alkynyl carboxylic acid, 4. branched aliphatic alkenyl / alkynyl carboxylic acid, 5. aromatic carboxylic acid, and 6. heteroaryl carboxylic acid; and Y is unsubstituted or substituted 1. straight chain aliphatic alkoxy group, 2. branched aliphatic alkoxy group, 3. straight chain aliphatic alkenyl / alkynyloxy group. , 4. a branched aliphatic alkenyl / alkynyloxy group, 5. an aryloxy group, and 6. a heteroaryloxy group; and Z is unsubstituted or substituted, and is selected from the group comprising 1. a straight chain aliphatic alkyl hydroxyl group, 2. a branched aliphatic alkyl hydroxyl group, 3. a straight chain aliphatic alkenyl / alkynyl hydroxyl group, 4. a branched aliphatic alkenyl / alkynyl hydroxyl group, 5. an aromatic hydroxyl group, and 6. a heteroaryl hydroxyl group, or a pharmaceutically acceptable salt thereof. JPEG2025533301000014.jpg2528

Description

[Technical Field]

[0001] The present invention relates generally to pharmaceuticals, and more particularly to novel therapeutic agents. More specifically, the present invention relates to novel therapeutic compounds for the prevention, treatment and management of type 2 diabetes and its associated complications. [Background technology]

[0002] The global prevalence of type 2 diabetes is increasing at an alarming rate. By the end of this decade, the number of patients with type 2 diabetes is predicted to increase to more than 320 million [1]. Various pharmacological agents are used to improve glucose homeostasis through various modes of action. Biguanides (e.g., metformin) promote glucose utilization and reduce hepatic glucose production, sulfonylureas induce insulin secretion, alpha-glucosidase inhibitors (e.g., acarbose) delay carbohydrate absorption from the intestine, and thiazolidinediones enhance the cellular action of insulin on glucose metabolism [2]. Insulin replacement therapy is also necessary when patients experience reduced insulin production due to poor glycemic control [3]. In recent years, treatment strategies have required increased attention to the development of novel alternatives to insulin therapy. In type 2 diabetes, the reduced ability of insulin to stimulate glucose disposal and reduced glucose uptake into muscle or adipose tissue in response to insulin result in a condition known as insulin resistance [4]. Although the molecular basis of type 2 diabetes is not fully understood, it is well known that insulin signaling, including activation of IR tyrosine kinase activity, is impaired in most patients with type 2 diabetes [5]. Various small molecule compounds, such as demethylasteriquinone-B1 and TLK19780, have been identified as potent insulin mimetics, but they have low bioavailability and poor receptor specificity [6][7]. As a result, the search for new oral, dynamic insulin mimetics with strict receptor selectivity is rather necessary. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Rao YK,Lee M,Chen K, Lee Y,Wu W,Tzeng Y.Insulin-Mimetic Action of Rhoifolin and Cosmosiin Isolated from Citrus grandis (L.) Osbeck Leaves: Enhanced Adiponectin Secretion and Insulin Receptor Phosphorylation in 3T3-L1 Cells.2011;2011. [Non-patent document 2] He K, Chan CB, Liu X, et al.Identification of a molecular activator for insulin receptor with potent anti-diabetic effects.J Biol Chem 2011;286:37379-37388. [Non-patent document 3] Jung D,Ha H, Zheng X,Chang Y,Williams DR.Novel use of fluorescent glucose analogues to identify a new class of triazine-based insulin mimetics possessing useful secondary effects w.2011:346-358. [Non-patent document 4] Kim EY, Anderson M, Dryer SE. Insulin increases surface expression of TRPC6 channels in podocytes:role of NADPH oxidases and reactive oxygen species.AJP Ren Physiol 2012;302:F298-F307. [Non-Patent Document 5] Jung SH, Ha YJ, Shim EK, et al. Insulin-mimetic and insulin-sensitizing activities of a pentacyclic triterpenoid insulin receptor activator.Biochem J 2007;403:243-250. [Non-patent document 6] Qiang G, Xue S, Yang JJ, et al.Identification of a small molecular insulin receptor agonist with potent antidiabetes activity.Diabetes 2014;63:1394-1409. [Non-Patent Document 7] Qiang G, Xue S, Yang JJ, et al.Identification of a Small Molecular Insulin Receptor Agonist With Potent Antidiabetes Activity.2014;63:1394-1409. Summary of the Invention

[0004] Objectives of the present invention: The main object of the present invention relates to novel small molecules for use in the prevention, treatment and management of type 2 diabetes and its associated complications.

[0005] Another object of the present invention is to synthesize novel small molecules for use in the prevention, treatment and management of type 2 diabetes and its associated complications.

[0006] Yet another object of the present invention is to synthesize small molecule drugs that act by producing insulin-dependent activation of the IR tyrosine kinase domain and that are potentially attractive for the treatment of type 2 diabetes.

[0007] Yet another object of the present invention is to synthesize small molecule drugs that have insulin-dependent activity in controlling hyperglycemia by modulating their effects as insulin levels change in response to physiological stimuli.

[0008] It is yet another object of the present invention to synthesize small molecule drugs that increase IR autophosphorylation in the presence of insulin and also enhance downstream signaling events, including phosphorylation of IRS-1 and GLUT4 translocation.

[0009] Yet another object of the present invention is to synthesize small molecule drugs that significantly lower blood glucose levels in two animal models of type 2 diabetes.

[0010] A further object of the present invention is to utilize synthetic small molecule drugs for subjects suffering from type 2 diabetes and its associated complications.

[0011] Brief description of the drawings: The foregoing and following information, as well as other features of the present disclosure, will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings, in which: The present disclosure will be described with additional specificity and detail through the use of the accompanying drawings, with the understanding that these drawings depict only some embodiments in accordance with the present disclosure and therefore are not to be considered limiting of its scope. [Brief explanation of the drawings]

[0012] [Figure 1] FIG. 1 shows the C NMR spectrum of compound I of the present invention. [Figure 2] FIG. 2 shows the 1H NMR spectrum of compound I of the present invention. [Figure 3] FIG. 3 shows the IR spectrum of compound I of the present invention. [Figure 4a]FIG. 4 shows the effect of Compound I on (a) body weight, (b) plasma glucose, (c) total cholesterol, and (d) triglyceride levels in HFD+STZ type II diabetic mice. [Figure 4b] Same as above. [Figure 4c] Same as above. [Figure 4d] Same as above. [Figure 5a] FIG. 5 shows the effect of Compound I on (a) body weight, (b) plasma glucose, (c) total cholesterol, and (d) triglyceride levels in db / db diabetic mice. [Figure 5b] Same as above. [Figure 5c] Same as above. [Figure 5d] Same as above. [Figure 6] FIG. 6 shows gene expression levels in different groups of mice in both liver and skeletal muscle of C57BL / 6J-db / db mice. [Figure 7a] Figure 7 shows the insulinomimetic effects of Compound I in the liver and skeletal muscle of HFD+STZ type II diabetic mice. a. Insulinomimetic effects b. Inflammatory mediators [Figure 7b] Same as above. [Figure 8] FIG. 8 shows the effect of Compound I on hepatic insulin resistance in C57BL / 6J-db / db mice. [Figure 9] FIG. 9 shows the insulin-mimetic effects of Compound I in skeletal muscle and liver of db / db mice. DETAILED DESCRIPTION OF THE INVENTION

[0013] Summary of the invention: The present invention provides compounds of structural formula I: [ka] A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: X is, 1. Unsubstituted or substituted straight chain aliphatic alkyl carboxylic acids, 2. Unsubstituted or substituted branched aliphatic alkyl carboxylic acids, 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyl carboxylic acids, 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyl carboxylic acids, 5. Unsubstituted or substituted aromatic carboxylic acids and 6. selected from the group comprising unsubstituted or substituted heteroaryl carboxylic acids, Y is, 1. Unsubstituted or substituted straight-chain aliphatic alkoxy groups, 2. Unsubstituted or substituted branched aliphatic alkoxy groups, 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyloxy groups, 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyloxy groups, 5. Unsubstituted or substituted aryloxy groups and 6. selected from the group comprising unsubstituted or substituted heteroaryloxy groups; Z, 1. Unsubstituted or substituted straight chain aliphatic alkyl hydroxyl groups, 2. Unsubstituted or substituted branched aliphatic alkyl hydroxyl groups; 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyl hydroxyl groups; 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyl hydroxyl groups, 5. Unsubstituted or substituted aromatic hydroxyl groups and 6. Disclosed is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group comprising an unsubstituted or substituted heteroaryl hydroxyl group.

[0014] DETAILED DESCRIPTION OF THE INVENTION Definition: "Alkyl" means saturated carbon chains which may be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Other groups having the prefix "alk," such as alkoxy and alkanoyl, may also be linear or branched, or combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like. In one embodiment of the present invention, the alkyl is methyl.

[0015] "Alkenyl," unless otherwise defined, means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like. In one embodiment of the present invention, the alkenyl is 2-methyl-1-propenyl.

[0016] "Alkynyl," unless otherwise defined, means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like. In one embodiment, alkynyl is -C2alkyne-CH3.

[0017] "Aryl" means a monocyclic, bicyclic, or tricyclic carbocyclic aromatic ring or ring system containing 5 to 14 carbon atoms, wherein at least one of the rings is aromatic. Examples of aryl include phenyl and naphthyl. In one embodiment of the present invention, aryl is phenyl.

[0018] "Heteroaryl" means a monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 carbon atoms and at least one ring heteroatom selected from N, NH, S (including SO and SO), and O, wherein at least one of the heteroatom-containing rings is aromatic. Examples of heteroaryl include pyrrolyl, indole, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzopyrazole (or indazole), benzothiophenyl (including the S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and isoquinolyl. In one embodiment of the invention, heteroaryl is selected from pyridine, pyrazole, thiazole, thiophene, pyrrole, triazole, indazole, and indole. In another embodiment of the invention, heteroaryl is selected from pyrazole, thiazole, thiophene, pyrrole, triazole, indazole, and indole. In another embodiment of the invention, heteroaryl is pyridine.

[0019] In selecting compounds of the present invention, one of skill in the art will recognize that the various substituents are selected according to well-known principles of connectivity and stability of chemical structures.

[0020] The term "substituted" shall be deemed to include multiple degrees of substitution by a named substituent. Where multiple substituent moieties are disclosed or claimed, the substituted compound may be singly or multiply independently substituted with one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents may be the same or different.

[0021] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, salts, and / or dosage forms that are safe and suitable for administration to humans or animals using sound medical judgment and in accordance with all applicable government regulations.

[0022] It will be understood that, as used herein, references to the compounds of the invention are meant to include pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable, when they are used as precursors to the free compounds or their pharmaceutically acceptable salts, or in other synthetic operations.

[0023] The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids. The salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, hydrogensulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, and lactate. Salts include lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate. Furthermore, when the compound of the present invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, potassium, sodium, zinc, etc. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.

[0024] Additionally, for carboxylic acid (—COOH) or alcohol groups present in the compounds of the invention, pharmaceutically acceptable esters of the carboxylic acid derivatives, such as methyl, ethyl, or pivaloyloxymethyl, or acyl derivatives of the alcohol, such as O-acetyl, O-pivaloyl, O-benzoyl, and O-aminoacyl, can be used. Included are esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations.

[0025] The term "therapeutically effective" as applied to a dose or amount refers to that amount of a compound or pharmaceutical preparation sufficient to result in a desired clinical benefit following administration to a patient in need thereof.

[0026] In the following detailed description, reference is made to the accompanying drawings, which form a part hereof. In the drawings, like symbols typically identify like elements unless context dictates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not intended to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented herein. It will be readily understood that aspects of the present disclosure, as generally described herein and illustrated in the figures, can be arranged, substituted, combined, separated, and designed in a wide variety of different configurations, all of which are expressly contemplated herein.

[0027] Generally, the present invention discloses novel therapeutic compounds for the treatment of diabetes that directly sensitize the insulin receptor.

[0028] In one preferred embodiment, the present invention provides a compound of formula I: [ka] A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: X is, 1. Unsubstituted or substituted straight chain aliphatic alkyl carboxylic acids, 2. Unsubstituted or substituted branched aliphatic alkyl carboxylic acids, 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyl carboxylic acids, 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyl carboxylic acids, 5. Unsubstituted or substituted aromatic carboxylic acids and 6. selected from the group comprising unsubstituted or substituted heteroaryl carboxylic acids, Y is, 1. Unsubstituted or substituted straight-chain aliphatic alkoxy groups, 2. Unsubstituted or substituted branched aliphatic alkoxy groups, 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyloxy groups, 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyloxy groups, 5. Unsubstituted or substituted aryloxy groups and 6. selected from the group comprising unsubstituted or substituted heteroaryloxy groups; Z, 1. Unsubstituted or substituted straight chain aliphatic alkyl hydroxyl groups, 2. Unsubstituted or substituted branched aliphatic alkyl hydroxyl groups; 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyl hydroxyl groups; 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyl hydroxyl groups, 5. Unsubstituted or substituted aromatic hydroxyl groups and 6. Disclosed is a compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group comprising an unsubstituted or substituted heteroaryl hydroxyl group.

[0029] According to the present invention, in the compound of formula I, X is an unsubstituted branched aliphatic alkenyl carboxylic acid having at least 1 carbon atom or a pharmaceutically acceptable salt thereof.

[0030] According to the present invention, in the compound of formula I, X is 1-methylprop-1-enoic acid.

[0031] According to the present invention in compounds of formula I, Y is an unsubstituted straight chain aliphatic alkoxy group having at least 1 carbon atom or a pharmaceutically acceptable salt thereof.

[0032] According to the present invention, in the compound of formula I, Y is a methoxy group.

[0033] According to the present invention, in the compound of formula I, Z is an unsubstituted straight chain aliphatic alkylhydroxyl group having at least 1 carbon atom or a pharmaceutically acceptable salt thereof.

[0034] According to the present invention, in the compound of formula I, Z is a hydroxylmethyl group.

[0035] According to the present invention, the compound of formula I comprises the structure of Compound I. [ka] Compound I.

[0036] In a further preferred embodiment, the present invention is intended to disclose a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a therapeutically effective amount of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0037] In a further preferred embodiment, the present invention discloses a pharmaceutical composition comprising a therapeutically effective amount of Compound I and a pharmaceutically acceptable carrier.

[0038] In one embodiment, compound I can be prepared according to the reaction scheme provided below.

[0039] Stage 1: Manufacturing process overview: Upon esterification with methanol and thionyl chloride, 4-amino-3-methoxybenzoic acid is obtained, which is subsequently reacted with bis(pyridine)iodonium tetrafluoroborate to give methyl 4-amino-3-iodo-5-methoxybenzoate. Synthetic Route: [ka]

[0040] Stage-2: Manufacturing process overview: N-acetylation of methyl 4-amino-3-iodo-5-methoxybenzoate with acetic anhydride in the presence of sulfuric acid and dichloromethane gives methyl 4-acetamido-3-iodo-5-methoxybenzoate. Synthetic Route: [ka]

[0041] Stage-3: Manufacturing process overview: Methyl 4-acetamido-3-iodo-5-methoxybenzoate is reacted with phenylboronic acid in the presence of palladium diacetate and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl to give methyl 6-acetamido-5-methoxy-[1,1'-biphenyl]-3-carboxylate. Synthetic Route: [ka]

[0042] Stage-4: Manufacturing process overview: Methyl 6-acetamido-5-methoxy-[1,1'-biphenyl]-3-carboxylate is cyclized in the presence of cupric acetate, oxygen, and palladium acetate to give methyl 1-methoxy-9H-carbazole-3-carboxylate. Synthetic Route: [ka]

[0043] Stage-5: Manufacturing process overview: Methyl 1-methoxy-9H-carbazole-3-carboxylate is reacted with acetyl chloride to give methyl 8-acetyl-1-methoxy-9H-carbazole-3-carboxylate. Synthetic Route: [ka]

[0044] Stage-6: Manufacturing process overview: Methyl 8-acetyl-1-methoxy-9H-carbazole-3-carboxylate Reaction with ethyl (triphenylphosphoranylidene)acetate in the presence of sodium hydroxide and hydrochloric acid gives (E)-3-(8-methoxy-6-(methoxycarbonyl)-9H-carbazol-1-yl)but-2-enoic acid, followed by carboxylic acid protection with 2-yl-methyl-1,3-dithiane, reduction with LiAlH4, and finally carboxylic acid deprotection with sodium periodate / potassium carbonate to form (2E)-3-[6-(hydroxymethyl)-8-methoxy-9H-carbazol-1-yl]but-2-enoic acid (compound 1). Synthetic Route: [ka]

[0045] Synthesized compound I was then subjected to molecular characterization to confirm the structure of the compound.

[0046] Molecular characterization: Purity of Synthesized Compound I Confirmed by Melting Point, Thin Layer Chromatography, HPLC, IR, Mass Spectrometry and NMR Analysis From Figures 1 to 3, the structure of Synthesized Compound I is revealed as shown below. [ka] Compound I.

[0047] In some embodiments, Compound I may include both cis and trans isomers. In some embodiments, Compound I may be a mixture of cis and trans isomers. In some embodiments, Compound I may be a cis isomer. In some embodiments, Compound I may be a trans isomer.

[0048] In some embodiments, Compound I can include either the R or S stereoisomer and mixtures of stereoisomers. In some embodiments, Compound I can include both racemic and enantiomeric isomers.

[0049] Compounds I of the present invention can be used to perform or provide any of the biological functions described herein.

[0050] Pharmaceutical Composition The present disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of the herein disclosed Compound I. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof.

[0051] In various embodiments, the amount of Compound I or a pharmaceutically acceptable salt thereof can be administered in an amount of from about 0.001 mg / kg to about 100 mg / kg of body weight (e.g., from about 0.01 mg / kg to about 10 mg / kg or from about 0.1 mg / kg to about 5 mg / kg).

[0052] The concentration of the disclosed compounds in a pharmaceutically acceptable mixture will vary depending on several factors, including the dose of the compound administered, the pharmacokinetic characteristics of the compound(s) used, and the route of administration. The agent may be administered in a single dose or multiple doses. The administration regimen utilizing the compounds of the present invention is selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition being treated, the route of administration, the patient's renal and hepatic function, and the specific compound or salt thereof used. Treatment may be administered once daily or more frequently, depending on numerous factors, including the patient's overall health and the formulation and route of administration of the selected compound(s).

[0053] The compounds or pharmaceutical compositions of the disclosure may be prepared and / or administered in single or multiple unit dosage forms.

[0054] In some embodiments, Compound I of the present disclosure is administered to patients with type 2 diabetes and its associated complications.

[0055] In certain embodiments, the compounds and compositions described herein are administered in combination with one or more antidiabetic agents. Compound I of the present invention may be used in combination with other drugs that may also be useful in treating or ameliorating diseases or conditions for which the compounds of the present invention are useful. Such other drugs may be administered simultaneously or sequentially with the compounds of the present invention, by routes and in amounts commonly used therefor. In treating patients with type 2 diabetes, insulin resistance, obesity, metabolic syndrome, and comorbidities associated with these diseases, two or more drugs are typically administered. Compounds of the present invention may generally be administered to patients already taking one or more other drugs for these conditions. In many cases, the compounds are administered to patients already being treated with one or more antidiabetic compounds, such as metformin, sulfonylureas, and / or PPARγ agonists, when the patient's blood glucose levels do not adequately respond to treatment.

[0056] When compound I of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of the present invention is preferred.However, combination therapy also includes therapy in which compound I of the present invention and one or more other drugs are administered on different overlapping schedules.It is also contemplated that when used in combination with one or more other active ingredients, the compound of the present invention and the other active ingredients may be used in lower doses than when each is used alone.Therefore, the pharmaceutical composition of the present invention includes pharmaceutical compositions containing one or more other active ingredients in addition to the compound of the present invention.

[0057] Examples of other active ingredients that may be administered in combination with Compound I described herein, separately, or in the same pharmaceutical composition include, but are not limited to, other dipeptidyl peptidase-IV (DPP-4) inhibitors, insulin sensitizers, insulin or insulin analogs, leptin derivatives and leptin derivatives and agonists, amylin and amylin analogs, sulfonylureas and non-sulfonylurea insulin secretagogues, α-glucosidase inhibitors, glucagon receptor antagonists, incretin mimetics, LDL cholesterol lowering agents, HDL raising agents, anti-obesity compounds, anti-inflammatory agents, antihypertensive agents, glucokinase activators, inhibitors of 11β-hydroxysteroid dehydrogenase type 1, CETP inhibitors, fructose 1,6-bis(2-hydroxybenzoates), benzodiazepines, benzocaine, ... and inhibitors of acetyl-CoA carboxylase-1 or -2, AMP-activated protein kinase (AMPK) activators, other agonists of G protein-coupled receptors, SSTR3 antagonists, neuromedin U receptor agonists, SCD inhibitors, GPR-105 antagonists, SGLT inhibitors, inhibitors of acyl-coenzyme A, inhibitors of fatty acid synthase, inhibitors of acyl-coenzyme A, agonists of TGR5 receptor, ileal bile acid transporter inhibitors, PACAP, PACAP mimetics and PACAP receptor 3 agonists, PPAR agonists, protein tyrosine phosphatase-1B (PTP-1B) inhibitors, IL-1b antibodies, bromocriptine mesylate and its rapid release formulation, GPR 120 agonists, antidiabetic agents, antilipemic agents, antihypertensive agents, antiobesity agents and appetite suppressants.

[0058] The present invention also provides a method for the treatment or prevention of type 2 diabetes and its associated complications, which method comprises administering to a patient in need of such treatment or at risk of developing type 2 diabetes and its associated complications a therapeutically effective amount of Compound I of the present invention and one or more active ingredients, which together provide effective relief.

[0059] In a further aspect of the present invention, there is provided a pharmaceutical composition comprising Compound I of the present invention together with at least one pharmaceutically acceptable carrier or excipient.

[0060] Thus, according to a further aspect of the present invention there is provided the use of compound I of the present invention for the manufacture of a medicament for the treatment or prevention of type 2 diabetes and its associated complications. Thus, in a further or alternative aspect of the present invention there is provided a product comprising compound I of the present invention and one or more active ingredients as a combined preparation for simultaneous, separate or sequential use in the treatment or prevention of type 2 diabetes and its associated complications.

[0061] It will be appreciated that for the treatment or prevention of diabetes and its associated complications, the compounds of the present invention may be used in conjunction with another pharmaceutical agent effective in treating that disorder.

[0062] The present invention also provides a method for the treatment or prevention of diabetes and its associated complications, which method comprises administering to a patient in need of such treatment an amount of Compound I of the present invention and an amount of another pharmaceutical agent effective to treat the disorder, so that together they provide effective relief. The present invention also provides a method for the treatment or prevention of diabetes and its associated complications, which method comprises administering to a patient in need of such treatment an amount of Compound I of the present invention and an amount of another pharmaceutical agent useful for treating the particular condition, so that together they provide effective relief. [Example]

[0063] Biological Examples: Example 1: Effects of Compound I on body weight, total cholesterol, plasma glucose, and triglyceride levels in HFD+STZ type II diabetic mice: Eight weeks of dietary manipulation using a high-fat diet increased body weight in all groups compared with the NPD group. Administration of low-dose STZ significantly reduced body weight in the HFD + STZ diabetic group compared with the body weight on day 0 of the experiment (p<0.05). When Compound I (100 mg / kg and 200 mg / kg b.wt) of the present invention was administered to C57BL / 6J mice fed a high-fat diet for 14 days, the food intake of the induced mice was significantly lower than that of the control mice (p<0.001). Furthermore, body weight was significantly reduced in Compound I-treated mice compared with control mice. Administration of standard metformin (250 mg / kg b.wt) significantly reduced glucose, total cholesterol, and triglyceride rates compared with the diabetic group. Low and high doses of Compound I showed approximately two-fold reductions in plasma glucose and triglyceride levels, while total cholesterol levels were reduced 2.5-fold compared with the diabetic group. Fasting plasma glucose, insulin, and triglyceride levels were significantly reduced in Compound I-treated mice compared with control mice at 14 days post-treatment in a dose-dependent manner (Figure 4a, b, c, d).

[0064] Example 2: Effects of Compound I on body weight, total cholesterol, plasma glucose, and triglyceride levels in db / db diabetic mice When compound I (100 mg / kg and 200 mg / kg b.wt) was administered to db / db mice for two weeks, the drug-induced food intake of the mice was significantly lower than that of the control mice (p>0.05). Body weight was also significantly reduced in the treated mice compared with the control mice (p>0.05). It is well known that serum lipid levels are elevated in people with diabetes. As shown in Figure 5, the db / db mice used in this study had significantly higher triglyceride and total cholesterol levels compared with control mice (P<0.01, P<0.05). Serum triglyceride and total cholesterol levels in the metformin-treated group were lower than those in the model group (P<<0.05). Compound I-treated mice showed a dose-dependent reduction in total cholesterol and triglyceride levels, with the high-dose treatment group exhibiting a better lipid-lowering profile than the other dose groups (P<0.05). Fasting plasma glucose, triglyceride levels, and insulin were significantly lower in Compound I-treated mice compared with control mice on day 7 after treatment (P>0.001). These data suggest that Compound I can restore serum glucose, insulin, and lipid abnormalities without significant weight gain.

[0065] Example 3: Effect of Compound I on the expression of diabetes-related gene transcripts in streptozotocin-induced diabetic rats: One of the mechanisms by which glucose uptake in cells can be stimulated or enhanced is increased translocation of glucose transporter 4 (GLUT4) from intracellular sites to the plasma membrane. This effect is mediated through the insulin signaling pathway, as suggested by gene expression profiles. The expression of diabetes-related, gluconeogenic, and glycolytic genes in streptozotocin-induced diabetic mice treated with Compound I was determined using semiquantitative RT-PCR. As an internal control, GAPDH was used, with the band density of each target gene normalized to the band density of GAPDH in the sample. Figure 6 shows the levels of gene expression in different groups of mice, both in liver and skeletal muscle. Based on fold-change analysis with STZ-35 mg / kg, the expression of genes involved in the insulin signaling pathway, such as IRS-1, IRS-2, PI3K, Glut4, and Akt, was significantly decreased in both liver and skeletal muscle compared with controls. The metformin-treated group showed a significant increase in the level of insulin signaling gene expression in both skeletal muscle and liver tissues (p<0.05). However, treatment with 100 mg / kg of Compound I enhanced the expression of all gene transcripts, with an approximately 3.5-fold change in skeletal muscle and an approximately 2.5-fold increase in expression in liver tissue. These results suggest that Compound I stimulates genes involved in the insulin signaling pathway, which may be responsible for the antihyperglycemic effect. Treatment with all tested preparations helps overcome insulin resistance by restoring the above-mentioned insulin-dependent signaling gene expression levels to normal.

[0066] Example 4: Insulin-mimetic effects of Compound I in liver and skeletal muscle of HFD+STZ type II diabetic mice In the insulin signaling pathway, protein tyrosine phosphatase 1B (PTP1B) has been implicated as playing a crucial role in intracellular signaling processes and metabolism. Consequently, there is compelling evidence that PTP1B is primarily involved in the dephosphorylation of insulin receptor (IR-β), resulting in the blockade of the insulin signaling pathway. This study investigated whether Compound I possesses insulin-mimetic activity in HFD + STZ-induced mice by PCR analysis. As shown in Figure 7, the diabetic group exhibited increased PTP1B activity in the liver and skeletal muscle. Treatment with Compound I (p<0.05) significantly decreased PTP1B expression in a dose-dependent manner, accompanied by a concomitant increase in IR-β levels, thereby demonstrating the insulin-mimetic properties of Compound I. Treatment with Compound I significantly reduced the expression of inflammatory parameters (Figure 7, a and b).

[0067] Example 5: Effect of Compound I on hepatic insulin resistance in C57BL / 6J-db / db mice The expression of insulin signaling genes, such as IRS-1, IRS-2, PI3K, Glut4, and Akt, in the livers of db / db mice was significantly reduced compared to that of normal mice. In the C57BL / 6J-db / db treated group, there was a significant increase in the activation of all genes examined compared to that of the normal control group (Figure 8). Supplementation with Compound I notably enhanced the expression of all genes involved in the insulin signaling pathway compared to that of the C57BL / 6J-db / db control group (p<0.05).

[0068] Example 6: Insulin-mimetic effects of compound I in skeletal muscle and liver of db / db mice To further exploit the insulin-mimetic effect of Compound I, key proteins in the PTP1B and PI3K / Akt signaling pathways were evaluated using Western blot and PCR analysis of Compound I after treatment with Compound I. Western blot and PCR analysis were performed to verify the expression of PTP1B and IRβ in skeletal muscle and liver and establish the inhibitory effect of Compound I on PTP1B. PTP1B in the Compound I-treated group was substantially downregulated compared to the control group (p<0.01) (Figure 9). Furthermore, p-IRβ in skeletal muscle and liver was significantly increased in the Compound I-treated group compared to the untreated control group (p<0.0). This information suggested a mechanism for Compound I to inhibit PTP1B and trigger insulin receptor signaling in vivo.

[0069] Discussion of Biological Examples 1-6: Type 2 diabetes and its associated complications have emerged as serious health problems in modern society. The cutting edge of drug development is identifying small molecule drugs that can help control both diabetes and obesity. In this study, we evaluated the effects of the small molecule compound I, which has insulin-mimetic effects by inhibiting PTP-1B and activating IR-β phosphorylation in insulin-sensitive tissues, in an in vivo animal model. Streptozotocin selectively destroys splenic insulin-secreting B cells, leaving less active cells and resulting in a diabetic state (Szkudelski 2001). In this study, intraperitoneal administration of streptozotocin efficiently induced diabetes in mice. The induction of diabetes in mice was confirmed by elevated fasting plasma glucose levels. Plasma glucose levels were measured in normal and experimental mice. STZ-treated diabetic mice showed significantly increased blood glucose levels compared to normal mice. Oral administration of compound I at 100 mg / kg and 200 mg / kg b.wt showed highly significant effects by reducing plasma glucose levels (Figure 4, a-d). Furthermore, insulin and triglyceride levels were significantly reduced in compound I-treated mice compared with normal control mice on day 14 of treatment in a dose-dependent manner (Figure 4a-d). When compound I (100 mg / kg and 200 mg / kg b.wt) was administered to C57BL / 6J mice fed a high-fat diet for 7 days, food intake in treated mice was significantly reduced compared with that in control mice. Furthermore, body weight was also significantly reduced in compound I-treated mice compared with normal control mice. Insulin levels, fasting plasma glucose levels, and triglyceride levels were significantly reduced in compound I-treated mice compared with control mice 7 days after injection.

[0070] The db / db mouse is a genetically obese diabetic animal model generated with the aid of leptin receptor deficiency. The pathological features of T2DM in db / db mice are similar to those in human type 2 diabetes, including hyperglycemia, obesity, and insulin resistance. In recent years, db / db mice have been widely used in animal experiments to establish a T2DM model. We investigated whether compound I contains an IR activator with insulin-mimetic and insulin-sensitizing activity by assessing its effects on IR signaling. Seven-day treatment with compound I (100 mg / kg and 200 mg / kg b.wt) reduced food consumption and body weight in db / db mice, a genetically obese animal model (Figure 5, a-d). Treatment further reduced insulin levels, fasting plasma glucose levels, free fatty acid levels, and triglyceride levels in db / db mice compared with normal controls. Based on these findings, further studies on compound I were conducted in subsequent experiments to explore its inhibitory activity against PTP1B.

[0071] Defects in the IR and its signaling pathway have been found in patients with insulin resistance, including reduced insulin receptor and insulin receptor substrate (IRS)-1 phosphorylation and reduced PI3K activity. Inhibition of insulin signaling leads to hyperglycemia and various other metabolic disorders. Therefore, pharmacological agents that enhance IRβ tyrosine kinase receptor activity may be useful in treating type 2 diabetes, which is considered to be due to irregular insulin secretion caused by reduced β-cell function and insulin resistance in target tissues.

[0072] The progression of tyrosine phosphorylation and dephosphorylation is a central mechanism for cell proliferation and differentiation, and the balance of this process is maintained by protein tyrosine phosphatases (PTP1b) and protein tyrosine kinases (PTKs). Protein tyrosine phosphatase 1B (PTP1B), a key member of the PTP1B family, is a negative regulator of insulin signaling and a potential target for the treatment of type 2 diabetes. Furthermore, PTP1B dephosphorylated activated JAK2 and STAT3, preventing leptin signaling. Increased expression of PTP1B affected PTK activity, resulting in insulin refractory to IR, inducing insulin resistance and leptin resistance, leading to type 2 diabetes and obesity.

[0073] Next, we investigated the effects of compound ion PTP-1B inhibition and activation of IR-β phosphorylation by PCR and Western blotting. In this study, we evaluated the antihyperglycemic properties of type 2 diabetic C57BL / 6J STZ, HFD+STZ C57BL / 6J, and db / db mouse models. Figures 6 and 8 show increased PTP1B expression in induced animals by Western blotting and PCR analysis. As shown in Figures 6 and 8, there was a decrease in the tyrosine phosphorylation level of IR-β in the skeletal muscle and liver of diabetic mice, implicating PTP1B function in all diabetic-treated mice. Tagami et al. reported upregulated PTP1B activity in skeletal muscle and adipose tissue in Otsuka Long-Evans Tokush-type adipose rats. Haj et al. established liver-specific PTP1B expression, confirming that insulin resistance in PTP1B knockout mice was no longer limited to the liver but also in other tissues. Thus, PTP1B plays a key role in diabetic mice. Activation of PTP1B blocks the insulin signaling pathway, disrupting plasma glucose levels and subsequently increasing plasma glucose levels. As shown in Figure 6, phosphorylated forms of insulin signaling molecules, such as p-IRβ and IR, were dramatically reduced in the muscle and liver of the diabetic group compared with the normal group. However, oral administration of Compound I significantly enhanced the protein expression levels in a dose-dependent manner. Furthermore, GLUT4 mRNA expression was significantly elevated in the Compound I-treated group compared with that of the normal control group (Figure 4). The increased tyrosine phosphorylated expression levels of the IR β subunit in the skeletal muscle and liver of diabetic mice treated with Compound I indicates enhanced insulin sensitivity across all animal models tested.

[0074] PI3K, a key molecule in the insulin-dependent signaling pathway, has been found to play an important role in diabetes. In this study, we also confirmed that Compound I can enhance PI3K expression in skeletal muscle and liver tissues and improve insulin transmission via the PI3K / Akt signaling pathway. These findings were based on a study of liver tissue from diabetic mice, showing that PI3K was reduced in diabetic rats compared with normal rats. Furthermore, increased p13K led to enrichment of GLUT4. The mechanism of Compound I's protection against T2DM was examined by analyzing the expression levels of genes in the PI3K / Akt signaling cascade. Gene expression studies showed that PI3K and GLUT4 expression levels were significantly enhanced with Compound I treatment, in contrast to diabetic mice. These results were consistent with the following report: Shih et al. found that GLUT4 in skeletal muscle was greater in the indicated group than in the diabetic group.

[0075] Therefore, we propose that Compound I reduces the expression profile and activity of PTP1B in insulin-sensitive tissues, such as liver and skeletal muscle. This reduction in both expression and relative activity is crucial for the increased expression of tyrosine phosphorylation levels of the IR β subunit and the development of insulin sensitivity. To date, PTP1B inhibitors, including Compound I, have not been found to be effective in multiple tissues in vivo.

[0076] In conclusion, this study demonstrated that compound I possesses insulin-mimetic biological activity and improves glucose tolerance in all mouse models of diabetes, with and without obesity. These include male C57BL / 6J mice fed a normal diet (standard model), mice fed a high-fat diet (a diabetic animal model with mild obesity), db / db mice (a genetic model of diabetes with severe obesity), and STZ-diabetic mice (a lean model of insulin-deficient diabetes). In this report, we identified a novel small molecule, compound I, that mimics insulin's ability to inhibit PTP-1B and activate the insulin receptor and its downstream signaling molecules in vitro and in vivo. This study is the first to demonstrate that compound I specifically binds to IR and increases its kinase activity, resulting in antidiabetic results that lower blood glucose in both normal and insulin-resistant mice. Thus, compound I mimics the biological action of insulin by improving glucose uptake in insulin-sensitive tissues through IRβ phosphorylation. Therefore, compound I is a suitable candidate for the management of diabetes and related metabolic disorders.

[0077] From the foregoing, it will be understood that various embodiments of the present disclosure have been described herein for purposes of illustration, and that various modifications thereof can be made without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed herein are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

1. A compound of structural formula I: 【Chemistry 11】 A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: X is, 1. Unsubstituted or substituted straight chain aliphatic alkyl carboxylic acids, 2. Unsubstituted or substituted branched aliphatic alkyl carboxylic acids, 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyl carboxylic acids, 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyl carboxylic acids, 5. Unsubstituted or substituted aromatic carboxylic acids and 6. selected from the group comprising unsubstituted or substituted heteroaryl carboxylic acids, Y, 1. Unsubstituted or substituted straight-chain aliphatic alkoxy groups, 2. Unsubstituted or substituted branched aliphatic alkoxy groups, 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyloxy groups; 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyloxy groups; 5. Unsubstituted or substituted aryloxy groups and 6. selected from the group comprising unsubstituted or substituted heteroaryloxy groups; Z is, 1. Unsubstituted or substituted straight chain aliphatic alkyl hydroxyl groups, 2. Unsubstituted or substituted branched aliphatic alkyl hydroxyl groups; 3. Unsubstituted or substituted straight chain aliphatic alkenyl / alkynyl hydroxyl groups; 4. Unsubstituted or substituted branched aliphatic alkenyl / alkynyl hydroxyl groups; 5. Unsubstituted or substituted aromatic hydroxyl groups and 6. A compound or a pharmaceutically acceptable salt thereof selected from the group comprising an unsubstituted or substituted heteroaryl hydroxyl group.

2. 2. The compound of claim 1, wherein X is an unsubstituted branched aliphatic alkenyl carboxylic acid having at least 1 carbon atom, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein X is 1-methylprop-1-enoic acid.

4. 2. The compound of claim 1, wherein Y is an unsubstituted straight chain aliphatic alkoxy group having at least 1 carbon atom, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein Y is a methoxy group.

6. 2. The compound of claim 1, wherein Z is an unsubstituted straight chain aliphatic alkylhydroxyl group having at least 1 carbon atom, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein Z is a hydroxylmethyl group.

8. The compound of claim 1, comprising the structure of Compound I. 【Chemistry 12】 Compound I.

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

10. 10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 8 and a pharmaceutically acceptable carrier.

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