Β-lactam compounds or salts thereof for use in long-acting prevention or treatment of glucose metabolism disorder

Abstract

To provide a β-lactam compound or a pharmaceutically acceptable salt thereof that exhibits a long-acting effect to prevent or treat glucose metabolism disorders.SOLUTION: Provided is a long-acting method for preventing or treating glucose metabolism disorders that includes administering a β-lactam compound or a pharmaceutically acceptable salt thereof to a subject in need thereof. The method for preventing or treating glucose metabolism disorders has a long-acting effect that lasts for at least two days even after medication has been stopped.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to methods for preventing or treating glucose metabolism disorders, and in particular, to methods for long-acting prevention or treatment of glucose metabolism disorders by administering a β-talactam compound or a pharma- ceutically acceptable salt thereof to a subject in need thereof. [Background technology]

[0002] The body's organs require energy to function normally. Many tissues use fats and proteins as energy sources, while other tissues, such as the brain and red blood cells, use glucose exclusively. Glucose is therefore the most important cellular energy source, and its metabolism is therefore highly regulated.

[0003] High blood glucose levels stimulate the secretion of insulin, which is produced by the beta cells of the pancreas. Insulin secreted into the blood activates glucose uptake by muscle and fat cells, leading to storage of glycogen and triglycerides and protein synthesis, thus maintaining blood glucose levels within an appropriate range. Disruption of this regulatory network can lead to diabetes and its associated syndromes.

[0004] Disorders of glucose metabolism can lead to hyperglycemia, hyperinsulinemia, or impaired glucose tolerance. An example of a disorder that is usually associated with abnormal glucose levels is insulin resistance, in which liver, fat, and muscle cells lose the ability to respond to normal blood insulin levels. Obesity and insulin resistance have a complex relationship that leads to the development of various types of metabolic disorders, such as type 2 diabetes. Both triglycerides stored in adipocytes and free fatty acids released by said cells are cholesterol precursors that play an important role in the development and progression of diabetes and its associated disorders.

[0005] Before the final clinical diagnosis of diabetes, patients may be considered to have prediabetes for a period of time. Impaired fasting glucose (IFG, 100-126 mg / dL) and impaired glucose tolerance (IGT, 140-200 mg / dL) are the two main tests for diagnosing prediabetes. A prediabetic patient has a higher blood glucose level than normal, but not high enough to be considered diabetic. Prediabetes puts a person at higher risk of developing diabetes and heart disease in the future. Prediabetes may be controlled by diet and exercise; for example, a 5-10% weight loss through diet and exercise may significantly reduce the risk of developing diabetes in the future. Medical intervention may also be required to prevent the onset of diabetes.

[0006] To maintain blood glucose levels at a constant level throughout the day, for example, before and after meals and during sleep with extended fasting periods, drugs with different onset, peak, and duration of therapeutic effect have been used. For example, according to the U.S. Food and Drug Administration (FDA), there are four types of insulin therapy, including (i) fast-acting insulin, which starts working just 15 minutes after taking it, peaks within 30-90 minutes, and lasts for 3-5 hours, (ii) short-acting insulin, which takes about 30-60 minutes to activate, peaks within 2-4 hours, and lasts for 5-8 hours, (iii) intermediate-acting insulin, which takes 1-3 hours to start working, peaks within 8 hours, and lasts for 12-16 hours, and (iv) long-acting insulin, which takes the longest time to start working but lasts for up to 24 hours.

[0007] Despite the availability of various treatment options, managing glucose metabolism disorders remains problematic. Patients do not always reach glycemic targets and adhere to treatment regimens that rely on specific frequency and meal dosing, leaving room for human error. Long-acting treatments are preferred for controlling blood glucose levels, as they require fewer injections in treatment, improving patients' quality of life and compliance with treatment. However, the longest acting insulin currently available is 42 hours, still requiring daily injections.

[0008] Thus, there remains an unmet need for compositions and methods useful for the long-acting treatment of glucose metabolism disorders. Summary of the Invention [Problem to be solved by the invention]

[0009] Based on the above, the present disclosure provides a β-lactam compound or a pharma- ceutically acceptable salt thereof, which has a long-acting effect and can prevent or treat glucose metabolism disorders. [Means for solving the problem]

[0010] In one embodiment of the disclosure, there is provided a method for the long-acting prevention or treatment of glucose metabolism disorders in a subject in need thereof, comprising administering to the subject an effective amount of a β-lactam compound or a pharma- ceutical acceptable salt thereof.

[0011] In one embodiment of the present disclosure, the β-lactam compound for use in the long-acting prevention or treatment of glucose metabolism disorders is a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.

[0012] [ka] (I)

[0013] wherein R1 and R3 are independently H or a substituted or unsubstituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, fluoroalkyl, chloroalkyl, bromoalkyl, iodoalkyl, perfluoroalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, carboxyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocyclyl, acyl, benzyl, phenyl, aminocarbonyl, aminoalkyl, amino, hydroxyl, alkoxy, acyloxy, silyloxy, amido, imidoyl, carbamoyl, halogen, thio, thioether, sulfo, sulfonic acid, sulfamoyl, thiazolyl, thiazolidinyl, pyrrolyl, pyrrolidinyl, triazolyl, azetidinyl, and sulfonamide; R2 is H or a (C1-C6)-alkyl group; R4 is H, a (C1-C6)-alkyl group, an alkali metal or an alkaline earth metal, the alkali metal or alkaline earth metal being sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium.

[0014] In one embodiment of the present disclosure, the compound of formula (I) may be a compound represented by the following formula (II):

[0015] [ka] (II)

[0016] wherein R is defined as R1 above, and R2 and R3 are as defined above.

[0017] In one embodiment of the present disclosure, in formula (I) or (II), R3 can be represented by any one of the following formulas (Ia) to (I-1).

[0018] [ka] JPEG2024177198000004.jpg133170

[0019] wherein R9 and R13 are independently H, a (C1-C6)-alkyl group, an alkali metal or an alkaline earth metal, the alkali metal or alkaline earth metal being sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; R 10 and R 11 are independently H, a halogen, a cyano group, a (C1-C6)-alkyl group, a nitro group, a hydroxy group, a carboxy group, a (C1-C6)-alkoxy group, a (C1-C6)-alkoxycarbonyl group, an aminosulfonyl group, a (C1-C6)-alkylaminosulfonyl group, a di-(C1-C6)-alkylaminosulfonyl group, a carbamoyl group, a (C1-C6)-alkylcarbamoyl group, a di-(C1-C6)-alkylcarbamoyl group, a trifluoromethyl group, a sulfonic acid group, an amino group, a (C1-C6)-alkylamino group, a di-(C1-C6)-alkylamino group, a (C1-C6)-alkanoylamino group, a (C1-C6)-alkanoyl(N-(C1-C6)-alkyl)amino group, a (C1-C6)-alkanesulfonamido group, or a (C1-C6)-alkyl-S(O) n (wherein n is 0 to 2.) R 12 is H or a (C1-C6)-alkyl group.

[0020] In one embodiment of the present disclosure, the compound of formula (II) may be a compound represented by the following formula:

[0021] [ka] (IIA), TIFF2024177198000006.tif4574(IIB), TIFF2024177198000007.tif4678(IIC), or TIFF2024177198000008.tif5476(IID)

[0022] R is defined as R1 above.

[0023] In one embodiment of the present disclosure, the compound for use in the long-acting prevention or treatment of glucose metabolism disorders is a compound represented by formula (III) or a pharma- ceutically acceptable salt thereof.

[0024] [ka] (III)

[0025] In the formula, R' represents H, or an alkyl group, an alkenyl group, an alkynyl group, a hydroxyalkyl group, a fluoroalkyl group, a chloroalkyl group, a bromoalkyl group, an iodoalkyl group, a perfluoroalkyl group, an aryl group, a phenyl group, a phenoxyl group, a benzyl group, a naphthalenyl group, an isoxazolyl group, a piperazinyl group, an oxopiperazinyl group, a pyrrolidinyl group, a pyrazolyl group, a pyridiazinyl group, a heteroaryl group, a pyridinyl group, a cyclopentapyridinyl group, a quinolinyl group, a cycloalkyl group, a cycloalkenyl group, a carboxyl group, an aralkyl group, an aralkenyl group, an aralkynyl group, a heteroaralkyl group, a heteroaralken ... a substituted or unsubstituted moiety selected from the group consisting of alkynyl, heterocyclyl, acyl, aminocarbonyl, aminoalkyl, amino, imino, alkylamino, imidazolyl, oxoimidazolidinyl, cyano, furanyl, hydroxyl, alkoxy, acyloxy, silyloxy, amido, imidoyl, carbamoyl, triazinanyl, triazolyl, tetrazolyl, halogen, thio, thioether, thienyl, thietanyl, thiophenyl, thiazolyl, thiadiazolyl, sulfo, sulfanyl, sulfonyl, phosphonic acid, sulfonic acid, and sulfonamide; R5 is H or a substituted or unsubstituted alkoxy group; R6 and R7 are joined to form a substituted or unsubstituted 5- or 6-membered heterocycle.

[0026] In one embodiment of the present disclosure, the compound of formula (III) may be a compound represented by the following formula:

[0027] [ka] (IIIA), or TIFF2024177198000011.tif4752(IIIB)

[0028] wherein R' and R5 are as defined above and R8 is defined as R'.

[0029] In one embodiment of the present disclosure, in formula (IIIA), R' is a substituted moiety selected from the group consisting of an alkyl group, a hydroxyalkyl group, an aryl group, a heteroaryl group, and an aralkyl group.

[0030] In one embodiment of the present disclosure, in formula (IIIB), R5 is H or a methoxy group, and R8 is a substituted moiety selected from the group consisting of a heteroaryl group, a heterocyclyl group, an alkoxy group, and a thio group.

[0031] In one embodiment of the present disclosure, the β-lactam compound for use in the long-acting prevention or treatment of glucose metabolism disorders can be one or more of penicillins, cephalosporins, and carbapenems. In another embodiment, the β-lactam compound is ertapenem, doripenem, imipenem, meropenem, biapenem, panipenem, tomopenem, lenapenem, tebipenem, razupenem, thienpenem, penicillin G ... Penicillin O, penicillin N, penicillin K, penicillin V, phenethicillin, propacillin, ampicillin, amoxicillin, azlocillin, carbenicillin, epicillin, methicillin, mezlocillin, oxacillin cillin, piperacillin, cloxacillin, dicloxacillin, flucloxacillin, sulbenicillin, ticarcillin, nafcillin, metampicillin, oxacillin, ceftriaxone ne), cefalotin, cefoxitin, cefotetan, ceftazidime, cefotaxime, cefepime, cefacetrile, cefadroxil, cefalexin, cefaloglycin, cefalonium,Cephaloridine, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefradine, cefroxadine, ceftezole, cefaclor, cefonicid, cefprozil, cefuroxime furoxime, cefuzonam, cefmetazole, cefbuperazone, cefminox, cefotiam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, Cefodizime, cefovecin, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, cefoperazone, cefclidine, cefiderocol, Selected from the group consisting of cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane, cefaparole, cefmatilen, cefsumide, and combinations thereof.

[0032] In one embodiment of the disclosure, long-acting prevention or treatment of glucose metabolism disorders is preventing or treating symptoms of glucose metabolism disorders for more than 2 days after administration of the compound (i.e., after administration of the compound is stopped). In another embodiment, the long-acting effect of preventing or treating glucose metabolism disorders persists for at least 1 week after administration of the compound. In yet another embodiment, the long-acting effect persists for at least 6 weeks after administration of the compound. In yet another embodiment, the long-acting effect persists for 6 to 10 weeks after administration of the compound.

[0033] In one embodiment of the present disclosure, the glucose metabolic disorder is obesity, overweight, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, type 1 diabetes or type 2 diabetes.In another embodiment, the glucose metabolic disorder is hyperglycemia, and administering the compound reduces the subject's plasma glucose level.In yet another embodiment, the glucose metabolic disorder is impaired glucose tolerance, and administering the compound increases the subject's glucose tolerance.

[0034] In one embodiment of the disclosure, the subject is a mammal, hi another embodiment, the subject is a human.

[0035] In one embodiment of the disclosure, the subject suffers from diabetes mellitus type 1. In another embodiment, the subject suffers from diabetes mellitus type 2. [Brief description of the drawings]

[0036] [Figure 1] Figure 1 shows blood glucose concentrations three weeks after ertapenem treatment. See below for details. [Diagram 2] Figure 2 shows the histology of different tissues after ertapenem treatment, see below for details. [Diagram 3] Figure 3 shows a scheme of treatment times, mouse ages and data acquisition times, see below for details. [Figure 4] Figure 4 shows blood glucose concentrations at 6, 12, 16, and 18 weeks after treatment. See below for details. [Diagram 5]Figure 5 shows the histology of the four different tissues after treatment, see below for details. [Figure 6] Figures 6A and 6B show blood glucose concentrations at 6 weeks (Figure 6A) and 9 weeks (Figure 6B) after treatment. See below for details. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] JPEG2024177198000012.jpg26150 JPEG2024177198000013.jpg26150 JPEG2024177198000014.jpg27152 JPEG2024177198000015.jpg45150 JPEG2024177198000016.jpg51150 JPEG2024177198000017.jpg64150The following examples are used to illustrate the present disclosure. Those skilled in the art can easily imagine other advantages and effects of the present disclosure based on the disclosure herein. Also, the present disclosure can be implemented or applied as described in different examples. For different embodiments and applications, the following examples can be modified or changed to implement the present disclosure without violating the spirit and scope thereof.

[0038] Additionally, it should be noted that, as used in this disclosure, the singular forms "a," "an," and "the" include plural referents unless expressly and unambiguously limited to one referent. The term "or" is used interchangeably with the term "and / or" unless the context clearly dictates otherwise.

[0039] In the context of therapy, the terms "patient" or "subject", used interchangeably herein, refer to a human or non-human animal that is the recipient of therapeutic or preventative care.

[0040] The term "glucose tolerance" as used herein refers to the ability of a subject to control plasma glucose and / or plasma insulin levels when glucose intake fluctuates.For example, glucose tolerance includes the ability to return plasma glucose levels to the level before glucose intake within about 120 minutes or so.

[0041] The term "prediabetes" as used herein refers to a condition that may be determined by using either a fasting plasma glucose (FPG) test or an oral glucose tolerance test (OGTT). Both require the subject to fast overnight. In an FPG test, the subject's blood glucose level is first measured in the morning before eating a meal. In an OGTT, the subject's blood glucose level is checked after fasting and two hours after drinking a glucose-rich drink. In a healthy individual, a normal test result for an FPG will show a blood glucose level of less than about 100 mg / dL. A subject with prediabetes will have an FPG level of about 100 mg / dL to about 125 mg / dL. If the blood glucose level rises to about 126 mg / dL or higher, the subject is determined to have "diabetes." In an OGTT, the subject's blood glucose level is measured after fasting and two hours after drinking a glucose-rich drink. A normal blood glucose level for a healthy individual is less than about 140 mg / dL two hours after drinking. In a pre-diabetic subject, the 2-hour blood glucose level is between about 140 mg / dL and about 199 mg / dL. If the 2-hour blood glucose level rises to 200 mg / dL or higher, the subject is considered to have "diabetes."

[0042] The present disclosure provides methods for treating patients suffering from hyperglycemia, hyperinsulinemia, impaired glucose tolerance, etc. These conditions are also commonly associated with many other glucose metabolic disorders. Thus, patients with glucose metabolic disorders may be candidates for treatment with the methods of the present disclosure.

[0043] The term "glucose metabolism disorder" encompasses any disorder characterized by a clinical symptom or combination of clinical symptoms associated with elevated glucose levels and / or elevated insulin levels in a subject compared to a healthy individual. Elevated glucose and / or insulin levels may be manifested in disorders and / or conditions such as type 2 diabetes (e.g., insulin-resistant diabetes), gestational diabetes, insulin resistance, impaired glucose tolerance, hyperinsulinemia, impaired glucose metabolism, prediabetes, metabolic disorders (such as metabolic syndrome, also known as metabolic syndrome X), obesity, or obesity-related disorders.

[0044] An example of a suitable patient may be one who suffers from hyperglycemia and / or hyperinsulinemia and who has also been diagnosed with diabetes mellitus (e.g., type 2 diabetes). "Diabetes" refers to a progressive disease of carbohydrate metabolism involving inadequate production or utilization of insulin, and is characterized by hyperglycemia and glycosuria.

[0045] As used herein, the term "hyperglycemia" is a condition in which elevated amounts of glucose circulate in the plasma compared to healthy individuals, and can be diagnosed using methods known in the art. For example, hyperglycemia can be diagnosed as fasting blood glucose levels between 5.6 mM and 7 mM (prediabetes) or above 7 mM (diabetes).

[0046] The term "hyperinsulinemia" as used herein is a condition in which blood glucose levels are elevated or may remain normal while circulating insulin levels are elevated. Hyperinsulinemia may be caused by insulin resistance associated with dyslipidemia, such as high triglycerides, high cholesterol, high low-density lipoprotein (LDL) and low high-density lipoprotein (HDL), high uric acid, polycystic ovarian syndrome, type 2 diabetes, and obesity. Hyperinsulinemia may be diagnosed when plasma insulin levels exceed about 2 μU / mL.

[0047] Patients with any of the above disorders may be suitable candidates for treatment according to the present disclosure to treat their glucose metabolism disorder. By administering to such subjects a beta-lactam compound according to the present disclosure, glucose homeostasis can be restored and one or more symptoms associated with the disorder can be reduced.

[0048] Candidates for treatment using the methods of the present disclosure can be determined using diagnostic methods known in the art, for example, by analyzing plasma glucose and / or insulin levels. Candidates for treatment include those who have demonstrated or have demonstrated higher than normal plasma glucose / insulin levels. Such patients include those with fasting blood glucose concentrations (tested after 8-10 hours of fasting) greater than about 100 mg / dL, e.g., greater than about 110 mg / dL, greater than about 120 mg / dL, between about 150 mg / dL and about 200 mg / dL, or more. Individuals suitable for treatment also include those with 2-hour postprandial blood glucose concentrations or post-glucose tolerance test concentrations (e.g., 2 hours after ingestion of a glucose-rich drink) greater than about 140 mg / dL, e.g., between about 150 mg / dL and 200 mg / dL, or more. Glucose concentrations can also be expressed in mmol / L, which can be obtained by dividing mg / dL by 18.

[0049] Subjects having, suspected of having, or at risk of developing a glucose metabolism disorder are contemplated for use in the treatments described herein.

[0050] The term "treatment" as used herein refers to a situation in which at least an improvement in symptoms associated with a condition afflicting a subject is achieved, where improvement refers to at least a decrease in parameters associated with the condition being treated, e.g., the magnitude of symptoms. Thus, treatment includes situations in which a condition, or at least symptoms associated therewith, are alleviated or avoided. Treatment includes (i) reducing the risk of developing clinical symptoms, which is interchangeable with prevention, including not developing clinical symptoms, e.g., preventing disease progression to harmful or other undesirable conditions, and (ii) inhibiting, i.e., preventing the occurrence or further development of clinical symptoms, e.g., reducing or completely inhibiting active disease (e.g., reducing insulin and / or glucose levels in blood, increasing glucose tolerance to minimize glucose level fluctuations, and / or protecting against illness caused by disruption of glucose homeostasis).

[0051] The method related to glucose metabolism disorder described herein includes, for example, the use of the above-mentioned β-lactam compound for treatment alone or in combination with other types of treatment.The method includes administering the β-lactam compound of the present disclosure to a subject (e.g., subcutaneously, intramuscularly, or intravenously).As described above, the method is useful in the context of treating or preventing various disorders related to glucose metabolism.

[0052] The disclosed methods include administering to a subject having a glucose metabolism disorder a β-lactam compound of the disclosed invention. The disclosed methods include administering a compound of formula (I), (II), or (III) disclosed above in the context of a variety of conditions (both prophylactic and post-diagnostic treatment), including the disorders exemplified above.

[0053] In one embodiment, the β-lactam compound of the present disclosure for use in the long-acting prevention or treatment of glucose metabolism disorders may be a carbapenem represented by formula (IIA), (IIB), (IIC), or (IID), such as ertapenem, doripenem, imipenem, meropenem, biapenem, and panipenem.

[0054] In one embodiment, the β-lactam compound of the present disclosure for use in the long-acting prevention or treatment of glucose metabolism disorders may be a penicillin represented by formula (IIIA), such as penicillin G, penicillin O, penicillin N, penicillin K, penicillin V, phenethicillin, propacillin, ampicillin, amoxicillin, azlocillin, carbenicillin, epicillin, methicillin, mezlocillin, oxacillin, piperacillin, cloxacillin, dicloxacillin, flucloxacillin, sulbenicillin, ticarcillin, nafcillin, methampicillin, and oxacillin.

[0055] In one embodiment, the β-lactam compound of the present disclosure for use in the long-acting prevention or treatment of glucose metabolism disorders can be a cephalosporin represented by formula (IIIB), such as ceftriaxone, cephalothin, cefoxitin, cefotetan, ceftazidime, cefotaxime, cefepime, cephacetrile, cefadroxil, cephalexin, cephaloglycin, cephalonium, cephaloridine, cephapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cephradine, cefroxadine, ceftezole, cefaclor, cefonicid, cefprozil, cef cefotiam, cefcapene, cefdaloxime, cefdinir, cefditoren, cefetamet, cefixime, cefmenoxime, cefodizime, cefovecin, cefpimizole, cefpodoxime, cefteram, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, cefoperazone, cefclidin, cefiderocol, cefluprenam, cefoselis, cefozopran, cefpirome, cefquinome, ceftobiprole, ceftaroline, ceftolozane, cefaparol, cefmatilen, and cefsumide.

[0056] In the methods of the present disclosure, the β-lactam compound may be administered in the form of a pharmaceutical composition. The pharmaceutical composition may include one or more of the β-lactam compounds described herein and / or additional therapeutic agents for the disorders exemplified above. The pharmaceutical composition may be administered to a subject (e.g., a human patient) to, for example, achieve and / or maintain glucose homeostasis, e.g., lower glucose levels in the bloodstream and / or lower insulin levels to a certain range in healthy individuals. Subjects for treatment include those with glucose metabolism disorders described herein.

[0057] In one embodiment, the pharmaceutical composition of the present disclosure can further comprise pharmaceutically acceptable carrier, diluent, excipient or solvate, and can be prepared into suitable dosage form.The examples of suitable dosage forms include tablets, capsules, coated tablets, granules, solutions and syrups for oral administration; medicinal salves, pastes, creams and ointments for transdermal administration; suppositories for rectal administration; sterile solutions for administration via injection or aerosol route.

[0058] Other examples of suitable dosage forms include those based on, for example, liposomes, that have sustained release properties, for administration via either oral or injection routes.

[0059] The dosage forms may also contain other conventional ingredients such as preservatives, stabilizers, surfactants, buffers, salts for regulating osmolarity, emulsifiers, sweeteners, colorants, flavoring agents, and the like.

[0060] Additionally, where specific treatments are indicated, the pharmaceutical compositions of the present disclosure may also contain other pharmacologically active ingredients whose co-administration is useful.

[0061] The amount of the β-lactam compound according to the present disclosure can vary within a wide range, depending, for example, on the type of disease being treated, the severity of the disease, the weight of the patient, the dosage form, the selected route of administration, the number of daily doses, and the efficacy of the selected β-lactam compound, however, those skilled in the art can determine the optimal amount in a simple and routine manner, if necessary, based on the present disclosure.

[0062] In the disclosed methods, a therapeutically effective amount of a beta-lactam compound is administered to a subject in need thereof, i.e., to a patient who did not have normal levels of glucose and insulin compared to healthy individuals prior to the treatment, an effective amount of the beta-lactam compound is delivered to the bloodstream to restore plasma glucose and / or insulin levels to normal levels compared to healthy individuals. The dosage will vary depending on the purpose of administration, the health, physical condition and age of the individual being treated, the activity of the compound used, the evaluation of the disease state by the treating clinician, the condition of the subject, the weight of the subject, the severity of the glucose and insulin dysregulation, and the stage of the disease, as well as other relevant factors. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that may accompany the administration of the compound.

[0063] The amount is expected to fall within a relatively wide range that can be determined by routine testing.For example, the amount of compound used to restore glucose homeostasis does not exceed the amount that can be irreversibly toxic to subjects (i.e., the maximum tolerated dose).In other cases, the amount is near or well below the toxicity threshold, but still within the effective concentration range or as low as the threshold dose.

[0064] Also, the appropriate dose and dosing regimen can be determined by comparison with indicators of glucose metabolism. Such doses include, for example, doses that result in stable levels of glucose and insulin that are comparable to healthy individuals without significant side effects. Dosage treatment can be a single dose schedule or a multiple dose schedule (e.g., including ramp and maintenance doses). As shown below, the pharmaceutical composition can be administered in combination with other agents, so the dose and dosing regimen can be varied in this situation to suit the needs of the subject.

[0065] Each dose is usually equal to or greater than the amount required to produce a measurable effect in a subject, and can be determined based on the pharmacokinetics and pharmacology of the absorption, distribution, metabolism, and excretion (hereinafter collectively referred to as "ADME") of the compound or its by-products, and therefore based on the disposition of the composition in the subject. This includes consideration of the route of administration and dosage, which can be adjusted for enteral (applied systemically or locally via the digestive tract by being retained in a portion of the digestive tract) or parenteral (applied by a route other than the digestive tract). For example, administration of the compound is typically by injection, usually intravenously, intramuscularly, or a combination thereof.

[0066] The term "effective amount" means that there is a detectable difference between the levels of indicators measured before and after administration of a particular therapeutic amount. Indicators include, but are not limited to, glucose and insulin. For example, it can mean that administration to an individual in that amount, either as part of a series of the same or different compositions or in a single dose, effectively contributes to the restoration of glucose metabolic homeostasis as assessed by the subject's glucose and / or insulin levels. As mentioned above, the therapeutically effective amount can be adjusted in conjunction with the dosing regimen and diagnostic analysis of the subject's condition (e.g., monitoring the glucose and / or insulin levels in plasma), etc.

[0067] The dosage forms of the pharmaceutical compositions according to the present disclosure can be prepared according to techniques well known to medicinal chemists, including mixing, granulating, compressing, dissolving, sterilizing, and the like.

[0068] The terms "long-acting" or "long-acting effect", as used interchangeably herein, refer to an effect in preventing or treating a glucose metabolism disorder that persists for at least 24 hours, at least 48 hours, at least 72 hours, at least 96 hours, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks after administration of the beta-lactam compound has ceased. In one embodiment, the beta-lactam compounds of the present disclosure are not only useful in preventing or treating a glucose metabolism disorder, but also exhibit a long-acting effect in preventing or treating a glucose metabolism disorder after administration to a subject in need thereof, said long-acting effect may persist for at least 2 days, at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, at least 10 weeks, at least 11 weeks, or at least 12 weeks. EXAMPLES

[0069] The following examples are presented to provide one of ordinary skill in the art with a complete disclosure and description of how to make and use the present disclosure, and are not intended to limit the scope of the invention, nor do they represent that the following experiments are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, weights, temperature, etc.), but some experimental error and deviation should be accounted for.

[0070] material and method The materials and methods used in the following examples are described in detail below. Materials used in this disclosure but not annotated herein are commercially available.

[0071] (1)Animals In the following examples, the effects of candidate compounds in regulating blood glucose homeostasis are investigated using leptin receptor gene (Lepr)-deficient db / db mice, which exhibit insulin resistance similar to that of type 2 diabetes patients.

[0072] Four to five week old db / db mice (BKS.Cg-Dock 7m + / +Lepr db / JNarl) and m / m mice (BKS.Cg-Dock 7m + / Dock 7m +) were obtained from the Taiwan National Laboratory Animal Center (Nangang, Taipei, Taiwan). The animals were housed in a facility with a 12-h dark-light cycle at 24 ± 2 °C and 65 ± 5% humidity and were provided with food (No. 5001; PMI Nutrition International, Brentwood, MO) and water ad libitum. In the experiments, the average body weight of the m / m mice was approximately 20 g, and the average body weight of the db / db mice was approximately 30 g. Mouse body weight (bw) and water and food intake were recorded weekly throughout the study period.

[0073] (2) Fasting plasma glucose (FPG) measurement For each mouse, blood was sampled from the tail vein at the designated time points, and FPG levels were measured using a glucometer (OneTouch UltraEasy, Johnson & Johnson, USA).

[0074] (3) Oral glucose tolerance test (OGTT) For OGTT, all mice were fasted for 16 h before the test but had water available ad libitum. Blood was collected from the tail vein, and FPG values ​​were measured and recorded as basal blood glucose levels. After FPG measurement, mice were orally administered 2 mg / g glucose (20% glucose solution), and blood glucose levels were measured at 15, 30, 60, and 120 min after feeding. The area under the curve (AUC) of OGTT was plotted and calculated by Area Under Coordinates Program (StatsToDo Server, Department of Obstetrics and Gynecology, Chinese University of Hong Kong).

[0075] (4) Other analyses Inflammatory markers such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine (Cr), and hemoglobin A1c (HbA1c) in serum were measured using a BMC-Hitachi 717 automated chemistry analyzer.

[0076] For histopathological evaluation, all mice were sacrificed by 95% CO2 asphyxiation at the end of the study period. Their brains, livers, kidneys, pancreas, and epididymal fat pads were removed, fixed in 10% phosphate-buffered formalin, and embedded in paraffin. Paraffin-embedded tissues were cut into 4 μm-thick sections and stained with hematoxylin-eosin (i.e., H&E staining).

[0077] (5) Statistical analysis Results calculated from at least six mice in each experimental group were shown as mean ± SEM. P values ​​< 0.05 were considered significant (ANOVA followed by Duncan's test). Medical treatment was considered effective (P value < 0.05) in lowering blood glucose levels if FPG levels after treatment were significantly lower than before treatment or if oral glucose tolerance test (OGT) values ​​after treatment were significantly higher than before treatment.

[0078] Example 1: Effect of Ertapenem Treatment on Glucose Metabolism Disorders This example investigates the effect of ertapenem (hereinafter also abbreviated as "DMH") on impaired glucose metabolism in comparison with metformin (Met), a known first-line pharmacological therapy for treating type 2 diabetes.

[0079] Twelve 7- or 8-week-old db / db mice were randomly divided into two groups and intraperitoneally (ip) injected with or without ertapenem (i.e., DB+DMH group or DB group, respectively). The treatments for each group are specifically described in Table 1 below.

[0080] Mice were divided into two groups for different treatments. [Table 1]

[0081] Each mouse was treated intraperitoneally with either saline or ertapenem once daily, and such treatment lasted a total of three weeks.

[0082] (1-1) Ertapenem treatment reduced food and water intake As shown in Table 2 below, mice treated with ertapenem (i.e., DB+DMH group) were found to have decreased food and water intake throughout the study period (P<0.05). This result clearly indicates that ertapenem is effective in controlling food and water intake in diabetic mice.

[0083] Average food and water intake among mouse groups [Table 2]

[0084] (1-2) Ertapenem treatment increased oral glucose tolerance OGTT was performed at week 3, i.e., at the end of ertapenem treatment. As shown in Figure 1, the glucose concentrations in the DB+DMH group were significantly lower than those in the DB group at 90 and 120 min.

[0085] In addition, the total area under the curve (AUC) of OGTT was plotted and calculated, as shown in Table 3. The results showed that the AUC of ertapenem-treated mice (DB+DMH group) was significantly smaller than that of untreated mice (DB group) (P<0.05).

[0086] OGTT AUC in two mouse groups [Table 3]

[0087] (1-3) Plasma biochemical parameter analysis AST and ALT, previously called serum glutamic oxaloacetic transaminase (GOT) and serum glutamic pyruvic transaminase (GPT), respectively, are inflammatory markers in the liver. BUN and Cr are inflammatory markers in the kidney. These markers and HbA1c were measured at week 3, i.e., at the end of ertapenem treatment. The results are reported in Table 4. The levels of AST, ALT, BUN and HbA1c in diabetic mice were found to be significantly decreased by treatment with ertapenem.

[0088] Plasma biochemical parameters of the two mouse groups [Table 4]

[0089] (1-4) Histological changes after ertapenem treatment At the end of the study period, all mice were sacrificed and their brains, livers, kidneys, pancreas, and epididymal fat pads (EFP) were collected and examined histologically for damage.

[0090] As shown in FIG. 2, the results showed that the pancreas, epididymal fat pads, and brain of all mice were free of histological changes.

[0091] Furthermore, very slight to slight levels of glycogen storage were observed in the cytoplasm of hepatocytes around the central vein area in liver tissues of the two groups, with the severity and incidence of such glycogen storage in the DB+DMH group being less than that in the DB group.

[0092] In kidney tissue, degeneration and necrosis of tubular epithelial cells, calcified deposits, and hyaline casts were observed in some mice, but the severity and incidence of such histological changes were not significantly different between the two groups.

[0093] Overall, no significant damage was observed in the brain, liver, kidney, pancreas, and epididymal fat pads after ertapenem treatment.

[0094] Example 2: Effect of ertapenem treatment on glucose metabolic disorders after cessation of treatment To examine the effects of ertapenem and metformin (Met) treatment after treatment cessation, eight 8-week-old m / m mice were used as normal controls (G1) and 40 8-week-old db / db mice were randomly divided into five groups (G2–G6). Each group received a different treatment, as described in Table 5 below.

[0095] Mice were divided into six groups for different treatments. [Table 5]

[0096] Treatment lasted a total of 6 weeks, and all administration was discontinued after 6 weeks. The studies were performed at the corresponding mouse age time points, as shown in the scheme in Figure 3. The studies and results were described as follows:

[0097] (2-1) Ertapenem treatment caused weight loss As shown in Table 6 below, the body weight of G1 mice was the lowest (P<0.05) throughout the study period. No significant changes in body weight were observed between mice treated with metformin (G3) and the other test mouse groups.

[0098] However, G4 mice weighed significantly less than G2 and G3 mice during weeks 2–9, and G6 mice weighed less than G2 (weeks 3–7 and 9) and G3 (weeks 3–9). These data indicate that ertapenem treatment (0.1 mg / g body weight and 0.4 mg / g body weight) had a positive effect on weight loss in db / db mice. This effect occurred because db / db mice reduced their food and water intake under ertapenem treatment.

[0099] Body weights between mouse groups [Table 6] TIFF2024177198000024.tif134162

[0100] In Table 6, the mean ± SEM values ​​of body weight for each group are presented, and the differences in values ​​were significant (P<0.05) between different italicized letters. For example, when comparing the values ​​represented by a and b, there was statistical significance (P<0.05) between the body weights of the two. Also, when comparing the values ​​represented by b and c, there was statistical significance (P<0.05) between the body weights of the two. Furthermore, the values ​​represented by bc were significantly different from the values ​​represented by "a" or "d".

[0101] (2-2) Ertapenem treatment lowered blood glucose levels FPG measurements were performed in mice at 8, 11, 14, 17, 20, 24, and 26 weeks of age, and the FPG levels in 8-week-old mice were set as the levels at week 0. Thus, the FPG levels in 11, 14, 17, 20, 24, and 26-week-old mice were the levels at weeks 3, 6, 9, 12, 16, and 18 after treatment, respectively. The FPG levels in mice in each group were reported in Table 7 below.

[0102] Average FPG levels in mice [Table 7]

[0103] Table 7 shows the mean ± SEM values ​​of FPG levels in each group, and as explained above, the differences in values ​​were significant (P < 0.05).

[0104] As shown in Table 7 above, G1 mice showed the lowest FPG levels at all measurement points (P<0.05).

[0105] At week 3, the FPG levels in G3, G4, and G6 mice were significantly lower than those in G2 mice ( P < 0.05), suggesting that ertapenem treatment (0.1 mg / g body weight and 0.4 mg / g body weight) was as effective as metformin (0.3 mg / g body weight) in lowering blood glucose levels in db / db mice.

[0106] At week 6, the FPG levels in G3, G4, G5, and G6 mice were all significantly lower than those in G2 mice (P<0.05), indicating that all concentrations of ertapenem had similar effects as metformin (0.3 mg / g body weight) on blood glucose levels in spontaneously type 2 diabetic db / db mice.

[0107] At weeks 9, 12, 16, and 18, FPG levels in metformin-treated mice (G3) were similar to those in untreated db / db mice (G2), likely because metformin has a plasma half-life of only about 6 hours and is cleared from the blood within 24 hours.

[0108] Surprisingly, at week 9, the FPG levels in G6 mice were significantly lower than those in G2 (P<0.05) and G3 (P=0.0059) mice, and the FPG levels in G4 and G5 mice were also lower than those in G3 mice (P<0.05). At week 12, the FPG levels in G4, G5, and G6 mice were still lower than those in G2 mice, and there was no significant difference in the FPG levels among G4, G5, and G6 mice. These results clearly indicate that the effect of ertapenem is long-acting and long-lasting.

[0109] These results clearly demonstrate that ertapenem is as effective as metformin in controlling blood glucose levels, and the blood glucose-lowering effect of ertapenem persisted for at least 6 weeks in mice, even when ertapenem treatment was discontinued.

[0110] (2-3) Ertapenem treatment increased oral glucose tolerance OGTTs were performed 6, 12, 16, and 18 weeks after treatment (mice were 14, 20, 24, and 26 weeks old).

[0111] As shown in Table 8 and Figure 4, ertapenem significantly increased oral glucose tolerance (OGT) in db / db mice at most time points at weeks 6 and 12. However, no significant changes in OGT were observed in mice treated with metformin at most time points, and only small changes were observed between groups of db / db mice at most time points at weeks 16 and 18.

[0112] Levels of OGTT among groups at 6, 12, 16, and 18 weeks [Table 8] TIFF2024177198000027.tif104164

[0113] The mean ± SEM values ​​of OGTT levels of the groups are shown in Table 8. As explained above, when the superscript italicized letters did not overlap, the difference in values ​​was significant (P < 0.05).

[0114] The total area under the curve (AUC) of OGTT was then plotted and calculated, as shown in Table 9 below. The results show that the AUC of ertapenem-treated mice (G4 and G5) was significantly smaller (P<0.05) than that of metformin-treated mice (G3) and untreated db / db mice (G2) at weeks 6, 12, and 16. There was no statistical significance in the AUC between the G2 and G3 groups at any measurement point.

[0115] AUC of OGTT in six mouse groups [Table 9]

[0116] Table 9 above lists the mean ± SEM values ​​of AUC for OGTT for the groups, and as explained above, when the superscript italicized letters did not overlap, the difference in values ​​was significant (P<0.05).

[0117] These results indicate that ertapenem effectively increases oral glucose tolerance in db / db mice, even after 10 weeks of cessation of treatment.

[0118] (2-4) Inflammatory marker levels after DMH treatment Levels of inflammatory markers were measured at week 19. Blood glucose (GLU) and creatinine (Cr) were similar among mice in the test groups (G2–G6) but higher than in G1. No significant changes in other inflammatory markers were observed in mice in the test groups (G2–G6).

[0119] (2-5) Histological changes after DMH treatment The liver, kidney, pancreas, and epididymal fat pads of mice were examined histologically for damage.

[0120] The results showed that there were no histological changes in the pancreas of all mice, as shown in Figure 5. Trace amounts of glycogen were found to accumulate in the hepatocytes around the central vein in db / db mice, but not in m / m mice.

[0121] No histological changes were observed in the kidneys of m / m mice, but some db / db mice showed degeneration and necrosis of tubular epithelial cells, calcified deposits, and hyaline casts. These histological changes were more evident in mice treated with metformin than in mice treated with ertapenem.

[0122] In the epididymal fat pads, oil droplets were larger in db / db mice than in m / m mice, and no histological differences were observed between the groups.

[0123] No significant damage was observed in the liver, kidney, pancreas, and epididymal fat pads after ertapenem treatment.

[0124] Example 3: Effect of β-lactam compound treatment on impaired glucose metabolism after cessation of treatment To examine the effects of β-lactam compounds after treatment cessation, six 8-week-old m / m mice were used as normal controls (G7), and 42 7- or 8-week-old db / db mice were randomly divided into seven groups (G8–G14). Each group received a different treatment, as described in Table 10 below.

[0125] Mice were divided into eight groups for different treatments. [Table 10]

[0126] Specifically, the treatments each group received were as follows: G7:m / m mice, with free access to water, were given saline intraperitoneally daily (10 μL / g body weight) G8:db / db mice, with free access to water, were given saline intraperitoneally daily (10 μL / g body weight). G9: db / db mice, given daily intraperitoneal injections of ertapenem (DMH) (0.41 mg / g body weight, equivalent to 0.033 g / kg in humans) G10: db / db mice, given daily intraperitoneal injections of meropenem hydrate (MER) (0.205 mg / g body weight, equivalent to 0.017 g / kg in humans) G11:db / db mice, given daily intraperitoneal injections of ceftriaxone (CEFT) (0.82 mg / g body weight, equivalent to 0.067 g / kg in humans) G12: db / db mice, given daily intraperitoneal injections of penicillin G (PEN) (1.473 mg / g body weight, equivalent to 0.12 g / kg in humans) G13:db / db mice, given Tienum (TIE) intraperitoneally daily (0.41 mg / g body weight, equivalent to 0.033 g / kg in humans) G14:db / db mice, orally administered metformin (MET) daily (0.3 mg / g body weight)

[0127] Treatment lasted a total of 3 weeks; that is, all treatments were discontinued after 3 weeks. Tests or measurements were performed at predefined time points, including the start of treatment (also annotated as baseline or week 0), when treatment had been administered for 3 weeks (also annotated as week 3), when treatment had been stopped for 3 weeks (also annotated as week 6), and when treatment had been stopped for 6 weeks (also annotated as week 9). Tests and results were described as follows:

[0128] (3-1) Effect of β-lactam compound treatment on body weight As shown in Table 11 below, except for the control group, G12 mice exhibited the lowest body weight throughout the study period (P<0.05).

[0129] Body weights between mouse groups [Table 11]

[0130] In Table 11 above, the mean ± SEM values ​​of body weight for each group are presented, and as explained above, when the superscript italicized letters do not overlap, the difference in values ​​was significant (P<0.05).

[0131] (3-2) Effect of β-lactam compound treatment on food and water intake As shown in Table 12 below, it was found that treatment with DMH, CEFT and PEN significantly decreased (P<0.05) the food intake of db / db mice, and treatment with DMH, CEFT, TIE and PEN significantly decreased (P<0.05) the water intake of db / db mice.

[0132] Mean food and water intake among mouse groups [Table 12]

[0133] In Table 12 above, the mean ± SEM values ​​of food and water intake for each group are presented, and as explained above, when the superscript italicized letters do not overlap, the difference in values ​​was significant (P<0.05).

[0134] (3-3) Effect of β-lactam compound treatment on oral glucose tolerance test OGTTs were performed at weeks 6 and 9, i.e., when treatment had been stopped for 3 and 6 weeks, respectively.

[0135] As shown in Figure 6A, the glucose concentrations in the G9 and G12 groups were significantly lower than that in the G8 group at 30 and 60 min, and as shown in Figure 6B, the glucose concentrations in the G9 and G12 groups were significantly lower than that in the G8 group at 30, 60, and 120 min, suggesting that DMH and PEN are still effective in regulating blood glucose homeostasis even if administration is discontinued for at least 3 weeks.

[0136] Additionally, the total AUC of the OGTT was plotted and calculated, as shown in Table 13 below. The results show that the AUC of mice treated with β-lactam compounds (i.e., G9-G13 groups) was smaller (P<0.05) than that of untreated mice (G8 group), even after treatment was stopped for at least 3 weeks.

[0137] OGTT AUC in eight mouse groups [Table 13]

[0138] Table 13 above lists the mean ± SEM values ​​of AUC for OGTT for each group, and as explained above, when the superscript italicized letters did not overlap, the difference in values ​​was significant (P<0.05).

[0139] (3-4) Plasma biochemical parameter analysis The concentrations of AST, ALT, BUN, Cr, and HbA1c in the plasma of mice from each group were measured at week 9, i.e., 6 weeks after treatment was stopped. The results are summarized in Table 14 below.

[0140] The results showed that the levels of AST, ALT, BUN, Cr and HbA1c in diabetic mice were reduced by treatment with β-lactam compounds. For example, DMH could reduce the levels of AST, ALT and HbA1c, MER could reduce the levels of AST, CEFT could reduce the levels of AST, ALT, BUN, Cr and HbA1c, PEN could reduce the levels of ALT, BUN, Cr and HbA1c, and TIE could reduce the levels of HbA1c, even after 6 weeks of treatment.

[0141] Plasma biochemical parameters in mice of each group [Table 14]

[0142] Table 14 above lists the mean ± SEM values ​​for each parameter in each group, and as explained above, when the superscript italicized letters do not overlap, the differences in values ​​were significant (P<0.05).

[0143] In conclusion, the β-lactam compounds of the present disclosure exhibit long-acting efficacy in improving glucose metabolic disorders and can therefore help improve patients' quality of life and compliance with treatment of glucose metabolic disorders.

[0144] Although several embodiments of the present disclosure have been described in detail above, those skilled in the art may make various modifications and changes to the specific embodiments shown without substantially departing from the teachings and advantages of the present disclosure. Such modifications and changes are within the spirit and scope of the present disclosure as set forth in the appended claims.

Claims

1. 1. A compound for use in the long-acting prevention or treatment of glucose metabolism disorders in a subject in need thereof, comprising: the compound is administered to the subject in an effective amount; The compound has the formula (I): 【Chemistry 1】 (In the formula, R 1 and R 3 are independently H or a substituted or unsubstituted moiety selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyalkyl, fluoroalkyl, chloroalkyl, bromoalkyl, iodoalkyl, perfluoroalkyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, carboxyl, aralkyl, aralkenyl, aralkynyl, heteroaralkyl, heteroaralkenyl, heteroaralkynyl, heterocyclyl, acyl, benzyl, phenyl, aminocarbonyl, aminoalkyl, amino, hydroxyl, alkoxy, acyloxy, silyloxy, amido, imidoyl, carbamoyl, halogen, thio, thioether, sulfo, sulfonic acid, sulfamoyl, thiazolyl, thiazolidinyl, pyrrolyl, pyrrolidinyl, triazolyl, azetidinyl, and sulfonamido; R 2 is H or a (C1-C6)-alkyl group, R 4 is H, a (C1-C6)-alkyl group, an alkali metal or an alkaline earth metal, the alkali metal or alkaline earth metal being sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium. or a pharma- ceutically acceptable salt thereof, The long-acting prevention or treatment of glucose metabolism disorders refers to preventing or treating symptoms of glucose metabolism disorders for more than two days after administration of the compound. Compound for use.

2. R 3 are represented by the following formulas (I-a) to (I-l): 【Chemistry 2】 【change】 (In the formula, R 9 and R 13 are independently H, a (C1-C6)-alkyl group, an alkali metal or an alkaline earth metal, the alkali metal or alkaline earth metal being sodium, potassium, lithium, cesium, rubidium, barium, calcium or magnesium; R 10 and R 11 are independently H, a halogen, a cyano group, a (C1-C6)-alkyl group, a nitro group, a hydroxy group, a carboxy group, a (C1-C6)-alkoxy group, a (C1-C6)-alkoxycarbonyl group, an aminosulfonyl group, a (C1-C6)-alkylaminosulfonyl group, a di-(C1-C6)-alkylaminosulfonyl group, a carbamoyl group, a (C1-C6)-alkylcarbamoyl group, a di-(C1-C6)-alkylcarbamoyl group, a trifluoromethyl group, a sulfonic acid group, an amino group, a (C1-C6)-alkylamino group, a di-(C1-C6)-alkylamino group, a (C1-C6)-alkanoylamino group, a (C1-C6)-alkanoyl(N-(C1-C6)-alkyl)amino group, a (C1-C6)-alkanesulfonamido group, or a (C1-C6)-alkyl-S(O) n (wherein n is 0 to 2), R 12 is H or a (C1-C6)-alkyl group.

2. The compound for use according to claim 1, which is represented by any one of the following:

3. The compound has the following formula (II): 【Chemistry 3】 (Wherein, R is R in claim 1 1 is defined as R 2 and R 3 is as defined in claim 1. A compound for use according to claim 1, represented by

4. 4. The compound for use according to claim 3, wherein said compound is a carbapenem.

5. The compound has the following formula: 【Chemistry 4】 【change】 (Wherein, R is R in claim 1 1 5. The compound for use according to claim 4, which is represented by the formula:

6. 5. The compound for use according to claim 4, wherein the compound is ertapenem, doripenem, imipenem, meropenem, biapenem, panipenem, tomopenem, lenapenem, tebipenem, razupenem, or thienpenem.

7. 2. The compound for use according to claim 1, wherein said glucose metabolism disorder is selected from the group consisting of obesity, overweight, hyperglycemia, hyperinsulinemia, impaired glucose tolerance, type 1 diabetes, and type 2 diabetes.

8. The glucose metabolism disorder is hyperglycemia, 8. The compound for use according to claim 7, wherein said administration reduces plasma glucose levels in a subject.

9. The glucose metabolic disorder is impaired glucose tolerance, 8. The compound for use according to claim 7, wherein said administration increases the glucose tolerance of the subject.

10. 2. The compound for use according to claim 1, wherein said long-acting prevention or treatment lasts for at least one week after administration.

11. 2. The compound for use according to claim 1, wherein said long-acting prevention or treatment lasts for at least 6 weeks after administration.

12. The compound for use according to claim 1, wherein said long-acting prevention or treatment lasts for 6 to 10 weeks after administration.

13. 2. The compound for use according to claim 1, wherein the subject is a mammal.

14. The compound for use according to claim 1, wherein the subject is a human.

15. 2. The compound for use according to claim 1, wherein the subject is suffering from type 1 or type 2 diabetes.

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