Use of (s)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid in treatment of diabetes and prediabetes

Abstract

Methods and compositions for treating diabetes or prediabetes comprise administering (S)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject diagnosed as having diabetes or prediabetes. In an embodiment, administration of (s)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject diagnosed with diabetes or prediabetes is effective in reducing HbA1c levels, fasting plasma glucose levels, 2-hour oral glucose tolerance test (OGTT) one or more of a resulting level and a random plasma glucose level. (S)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, may optionally be administered in combination with a hypoglycemic agent.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 485,624, filed February 17, 2023, and which is incorporated herein by reference in its entirety. Technical Field

[0002] Treatment of diabetes and prediabetes with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. background

[0003] According to the World Health Organization, diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. Insulin regulates (lowers) the concentration of blood sugar (glucose). It is a peptide hormone produced by the beta cells of the pancreas. Insulin regulates the metabolism of carbohydrates, fats, and proteins by promoting the absorption of glucose from the blood into fat, liver, and skeletal muscle cells. Pancreatic beta cells (beta cells) are sensitive to the concentration of glucose in the blood. In non-diabetic patients, when the concentration of glucose in the blood is high, the pancreatic beta cells secrete insulin into the blood; when the glucose level is low, the secretion of insulin is suppressed. Pancreatic alpha cells secrete another peptide hormone, glucagon, into the blood, which increases the concentration of glucose in the blood in an opposite way, that is, secretion increases when blood glucose is low and secretion decreases when the glucose concentration is high. The secretion of insulin and glucagon into the blood in response to blood glucose concentration is the main mechanism responsible for keeping the glucose level in the extracellular fluid within a narrow range.

[0004] Hyperglycemia, or high blood sugar, is a common effect of uncontrolled diabetes and, over time, can lead to serious damage to many body systems, especially to the nerves and blood vessels. According to the World Health Organization, the number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. In 2014, 8.5% of adults aged 18 and over had diabetes. In 2012, diabetes was the direct cause of 1.5 million deaths, and high blood sugar was responsible for another 2.2 million deaths. Diabetes is a leading cause of blindness, kidney failure, heart attack, stroke, and lower limb amputation. Adults with diabetes have a 2-3 times increased risk of heart attack and stroke. Combined with reduced blood flow, neuropathy (nerve damage) in the feet increases the chances of foot ulcers, infection, and ultimately the need for amputation. Diabetes is one of the leading causes of kidney failure.

[0005] Type 1 diabetes (formerly known as insulin-dependent, juvenile-onset, or childhood-onset diabetes) is characterized by insufficient insulin production and typically requires daily insulin administration. Most cases of type 1 diabetes are due primarily to destruction of pancreatic beta cells. People with type 1 diabetes are prone to ketoacidosis. Symptoms of type 1 diabetes include excessive urine excretion (polyuria), thirst (polydipsia), constant hunger, weight loss, vision changes, and fatigue. These symptoms may appear suddenly. Type 2 diabetes (formerly known as non-insulin-dependent or adult-onset diabetes) is caused by the body's ineffective use of insulin. Most people with diabetes worldwide have type 2 diabetes. Type 2 diabetes is associated with being overweight and lacking exercise. Symptoms may be similar to those of type 1 diabetes but are usually less obvious. Sleep apnea is associated with an increased risk of developing type 2 diabetes. See, Botros et al., Amer. J. Med. , 122(12), 1122-1127 (2009). More than 50% of people with type 2 diabetes have sleep apnea. Until recently, type 2 diabetes was seen only in adults, but it is now occurring more and more frequently in children. In type 1 diabetes, 70% of pancreatic beta cells are destroyed, while in type 2 diabetes, 40%-60% of pancreatic beta cells are destroyed at the time of diagnosis. Al-Kuraishy et al., Int J Prev Med. 2021 Feb 24;12:19.

[0006] Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) (collectively referred to herein as "prediabetes") are intermediate conditions that transition between normal and diabetes. IFG and IGT are not interchangeable and represent different glucose regulation abnormalities, one in the fasting state and one after a meal. People with IGT or IFG are at high risk of developing type 2 diabetes, although this is not inevitable.

[0007] According to the American Diabetes Association guidelines, the criteria for diagnosing diabetes involve four options: a fasting plasma glucose level greater than or equal to 126 mg / dL, a 2-hour oral glucose tolerance test (OGTT) with a plasma glucose value greater than or equal to 200 mg / dL, an HbA1c value greater than or equal to 6.5%, or a random plasma glucose level greater than or equal to 200 mg / dL in individuals with symptoms of hyperglycemia or hyperglycemic crisis. Prediabetes is defined as a fasting plasma glucose level between 100 mg / dL and 125 mg / dL, a 2-hour OGTT plasma glucose level between 140 mg / dL and 199 mg / dL, or an HbA1c value between 5.7% and 6.4%. Prediabetes may be considered a major risk factor for the development of type 2 diabetes, cardiovascular disease, and mortality.

[0008] In monitoring the treatment of diabetes, the HbA1c value, which is a non-enzymatic glycation product of the hemoglobin B chain, can be considered an important parameter. The HbA1c value depends on the blood glucose level and the life span of the red blood cells in the blood. The HbA1c value is generally reflected in the average blood glucose level of 4 weeks to 12 weeks before the patient's blood is taken out and tested. Diabetic patients whose HbA1c levels are well controlled (i.e., total hemoglobin in the sample <6.5%) during long-term treatment are generally better protected from diabetic microangiopathy. Available diabetes treatments can improve the HbA1c levels of diabetic patients by an average of about 1.0-1.5%. However, this reduction in HbA1c levels may not be enough to achieve the desired target range of <7.0%, preferably <6.5%, and more preferably <6% HbA1c for all diabetic patients.

[0009] In addition to improving HbA1c levels within the glycemic control range, other recommended treatment goals for patients with type 2 diabetes are to improve fasting plasma glucose (FPG) levels and postprandial plasma glucose (PPG) levels to normal or as close to normal as possible. The desired target range for pre-prandial (fasting) plasma glucose can be, for example, 90-130 mg / dL or <110 mg / dL, and the desired target range for two-hour post-prandial plasma glucose can be, for example, <180 mg / dL or <140 mg / dL.

[0010] Diet therapy and exercise therapy are generally considered to be essential in the treatment of diabetes. When these therapies are not sufficient to control the patient's condition (especially its blood sugar level), oral or non-oral antidiabetic agents can be used to treat diabetes. Conventional antidiabetic drugs or hypoglycemic agents include but are not limited to biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, meglitinides (also known as glinides), alpha-glucosidase blockers, GLP-1 and GLP-1 analogs and insulin and insulin analogs.

[0011] Although intensive treatment of hyperglycemia can reduce the incidence of chronic damage, many patients with diabetes remain undertreated, in part because of limitations in the long-term efficacy, tolerability, and inconvenience of administration of existing antihyperglycemic therapies. The use of conventional hypoglycemic agents may be associated with various adverse reactions. For example, metformin may be associated with lactic acidosis or gastrointestinal side effects; sulfonylureas, meglitinides (glitinides), and insulin or insulin analogs may be associated with hypoglycemia or weight gain; thiazolidinediones may be associated with edema, fractures, weight gain, or heart failure / cardiac reactions; and α-glucosidase blockers and GLP-1 or GLP-1 analogs may be associated with gastrointestinal adverse reactions (e.g., dyspepsia, flatulence or diarrhea, or nausea or vomiting). In the treatment of metabolic diseases, there is a continuing need for improved antihyperglycemic therapies.

[0012] Vigabatrin is a γ-aminobutyric acid transaminase (GABA-AT) inhibitor that has been used to treat intractable epilepsy and infantile spasms. Vigabatrin is associated with some potentially serious side effects. Its use is limited due to potential retinal toxicity and subsequent visual field defects. (1S, 3S) -3-amino + difluoromethylene-1-cyclopentanoic acid (also known as CPP-115) is a GABA-AT inhibitor that is 186 times more efficient at inactivating GABA-AT than vigabatrin. It is reported that preclinical data for CPP-115 show that when compared with vigabatrin, significantly lower drug doses provide comparable pharmacokinetics, improved tolerability, and a more favorable toxicity profile. See, Prescot et al., Neuropsychopharmacology (2018) 43, 646–654. See also U.S. Patent No. 9,993,449, which is incorporated herein by reference. (S)-3-Amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (also known as OV329) is a GABA-AT inhibitor that has shown to be 9.8 times more efficient than CPP-115 as a GABA-AT inactivator. Same as above . Overview

[0013] Provided are methods and compositions for treating diabetes and prediabetes. In embodiments, the method for treating diabetes or prediabetes includes administering an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need. In embodiments, a composition for treating diabetes or prediabetes comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need. In embodiments, the method for treating diabetes or prediabetes includes administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need, to provide improvement of one or more symptoms of diabetes or prediabetes in the subject. In an embodiment, a method for treating diabetes or prediabetes comprises administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof to provide an improvement in the symptoms of diabetes or prediabetes in the subject the day after administration of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In an embodiment, the effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is between about 0.01 mg and about 750 mg. In an embodiment, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to the subject once, twice, three times, or four times a day.

[0014] In embodiments, a method of treating diabetes or prediabetes comprises administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof to reduce one or more of HbA1c levels, fasting plasma glucose levels, 2-hour oral glucose tolerance test (OGTT) result levels, and random plasma glucose levels. In embodiments, the diabetes is type 2 diabetes. In embodiments, the diabetes is type 1 diabetes. In embodiments, the HbA1c levels are reduced by an amount greater than 0.25%. In embodiments, the HbA1c levels are reduced by an amount greater than 0.5%. In embodiments, the HbA1c levels are reduced by an amount greater than 0.75%. In embodiments, the HbA1c levels are reduced by an amount greater than 1.0%. In embodiments, the HbA1c levels are reduced by an amount greater than 1.5%. In an embodiment, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more hypoglycemic agents, such as biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, meglitinides (glinids), alpha-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs. In an embodiment, the combination of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, and one or more hypoglycemic agents provides a therapeutic benefit that is greater than the additive effect of the same doses of each of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, and the hypoglycemic agent administered alone.

[0015] In an embodiment, a method of treating diabetes and sleep apnea comprises administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject diagnosed with diabetes and sleep apnea in an amount effective to reduce episodes of sleep apnea. Details

[0016] Provided herein are methods and compositions for use in treating diabetes, including Type 1 diabetes, Type 2 diabetes, and prediabetes. In an embodiment, administration of an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, alone or optionally in combination with one or more hypoglycemic agents such as a biguanide, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a sulfonylurea, a thiazolidinedione, a meglitinide (glitinide-like drug), an alpha-glucosidase blocker, a glucagon-like peptide-1 receptor agonist, insulin or an insulin analog, can alleviate the symptoms of, prevent, slow the progression of, or delay a metabolic disorder, such as, for example, type 1 diabetes, type 2 diabetes, prediabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), hyperglycemia and / or postprandial hyperglycemia.

[0017] Methods and compositions for use in treating diabetes (including type 1 diabetes, type 2 diabetes, and prediabetes as disclosed herein) involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are used to improve glycemic control. "Improvement of glycemic control," "improving glycemic control," or "glycemic control" refers to improving glucose tolerance, improving postprandial plasma glucose concentration, improving fasting plasma glucose concentration, improving HbA1c values, or / and improving fasting plasma insulin concentration.

[0018] The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof improve, reduce, or alleviate symptoms or conditions associated with diabetes or prediabetes. Conditions associated with diabetes or prediabetes can include, for example, sleep apnea, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, non-alcoholic fatty liver disease (NAFLD), retinopathy, neurological disease, nephropathy, and / or metabolic syndrome. The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can improve glycemic control, such as lowering fasting plasma glucose, lowering postprandial plasma glucose, and / or lowering HbA1c. The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can prevent, slow, delay or reverse the progression from impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance to type 2 diabetes due to metabolic syndrome.

[0019] The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can prevent, reduce the risk of, slow the progression of, delay or treat complications of diabetes or prediabetes, such as microvascular and macrovascular disease, including nephropathy, micro- or macroalbuminuria, proteinuria, retinopathy, cataracts, neurological disease, learning or memory impairment, neurodegenerative or cognitive disorders, cardiovascular or cerebrovascular disease, tissue ischemia, diabetic foot ulcers, atherosclerosis, hypertension, endothelial dysfunction, myocardial infarction, acute coronary syndrome, unstable angina, stable angina, peripheral arterial occlusive disease, cardiomyopathy, heart failure, arrhythmias, vascular restenosis and / or stroke. The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can prevent type 2 diabetes that has failed primarily or secondary to conventional (oral) hypoglycemic monotherapy or combination therapy, slow the progression of the type 2 diabetes, delay or treat the type 2 diabetes. The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can achieve a reduction in the dose of conventional hypoglycemic drugs required for sufficient therapeutic effect, thereby reducing the risk of adverse reactions associated with conventional hypoglycemic drugs. The methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can maintain and / or improve insulin sensitivity and / or treat or prevent hyperinsulinemia and / or insulin resistance.

[0020] In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are used to treat inadequate or insufficient glycemic control in a subject with diabetes or prediabetes. Inadequate or insufficient glycemic control can be considered a condition in which a patient exhibits an HbA1c value above 6.0%, such as an HbA1c value above 6.5%, above 7.0%, above 7.5%, above 8%, above 8.5%, above 9%, above 9.5%, above 10%, above 10.5%, above 11%, or any value between 6.0% and 11.0%. For example, a patient with inadequate or insufficient glycemic control may include a patient with an HbA1c value of from 6.5% to 7.0%, 7.0% to 7.5%, 7.5% to 10%, or from 7.5% to 11%. For example, an inadequately controlled patient may refer to a patient with poor glycemic control, including but not limited to a patient having an HbA1c value ≥ 9%.

[0021] In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by an amount greater than 0.25%. In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by an amount greater than 0.5%. In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by an amount greater than 0.75%. In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by an amount greater than 1.0%. In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by an amount greater than 1.25%. In embodiments, the methods and compositions disclosed herein for use in treating diabetes or prediabetes involving an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, reduce HbA1c levels by an amount greater than 1.5%.

[0022] The structure of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid can be represented as follows:

[0023] In embodiments, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid can be provided as an acid addition salt, a zwitterion hydrate, a zwitterion anhydrate, a hydrochloride or a hydrobromide salt, or as a zwitterion monohydrate. Acid addition salts include, but are not limited to, addition salts of maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bismethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, acetic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, malic acid, mandelic acid, cinnamic acid, citraconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, pantothenic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, or theophylline acetate, and 8-halotheophyllines such as 8-bromotheophylline. In embodiments, inorganic acid addition salts may be used, including but not limited to hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, or nitric acid addition salts.

[0024] The pathogenesis of diabetes and prediabetes can begin with an inflammatory cascade. Autoimmunity in diabetes and prediabetes can begin at the molecular and cellular levels. For example, serum cytokine levels can increase. Some patients eventually transition from autoimmunity to immune-mediated inflammation primarily focused on the pancreas. The pancreas is infiltrated by immune cells, including innate immune cells (monocytes, dendritic cells, mast cells) and adaptive immune cells (T helper cell 1, Th1; T helper cell 17, Th17), B cells, and plasma cells. Neutrophils may not normally be present in the pancreas, but rather flow into the pancreas from the blood. Cytokines and chemokines such as tumor necrosis factor (TNF), interleukin-6 (IL-6), and granulocyte-monocyte colony-stimulating factor (GM-CSF) can activate endothelial cells and attract immune cells within the pancreas.

[0025] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature mammalian central nervous system (CNS). Outside the brain, GABA is produced by pancreatic β cells, as well as T cells and macrophages, which express all components of the GABAergic system, including its receptors, transporters, and metabolic enzymes. GABA acts as a negative regulator of inflammatory cytokine production and T cell activation by macrophages by blocking calcium signaling and NFκB activity.

[0026] Many different types of murine and human immune cells express various GABA receptors (GABA-Rs). See Tian et al., Sci Rep11, 5402 (2021). https: / / doi.org / 10.1038 / s41598-021-84751-3. GABA has been shown to restrict the production of IL-21, IFNγ2-4, TNFα3, and IL-123 by murine T cells, while promoting TGFβ and Treg responses. Same as above Antigen presenting cells (APCs) such as macrophages also express GABA A -R, and their activation inhibits their inflammatory activity. Same as above For example, GABA or GABA A -R agonists reduce the secretion of IL-6, IL-1β, IL-12 and / or TNFα from LPS-stimulated murine macrophages. Same as above .

[0027] Pancreatic β-cells synthesize GABA from glutamate via glutamate decarboxylase (GAD). See Al-Kuraishy et al., Int J Prev Med. 2021 Feb 24;12:19. Potential roles of GABA in pancreatic islets include regulating hormone secretion, suppressing immune responses, improving β-cell survival, and transforming α cells into β cells. Same as above Notably, autoantibodies against GAD are associated with the development of type 1 diabetes, in which β-cell mass is reduced and eventually lost. Same as above Glucagon-like peptide-1 (GLP-1) activates pancreatic GAD and leads to elevated β-cell GABA concentrations, which increases insulin synthesis and secretion. Same as above Due to its immunomodulatory and anti-inflammatory effects, GABA, through its two receptors, preserves beta-cell mass and prevents the progression of both type 1 and type 2 diabetes. Same as above GABA exerts a trophic effect on β cells through activation of the PI3K / Akt pathway. Same as above In pancreatic islets from patients with type 1 and type 2 diabetes, GABA content in β cells is depleted and secretion is impaired, suggesting that loss of GABA, a synchronization signal for hormone output, may be relevant to diabetic pathogenesis. Menegaz et al., Nat Metab 1, 1110–1126 (2019) Abstract.

[0028] (S)-3-Amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid is a γ-aminobutyric acid transaminase (GABA-AT) inhibitor. GABA-AT is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. Compared to CPP-115, (S)-3-Amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid has a higher binding affinity for GABA-AT (K values ​​of 1 and CPP-115 have been found to be similar). I values ​​were 9.7 μM and 59 μM, respectively), and (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid inactivated GABA-AT at a greater rate than CPP-115 (k values ​​for (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid and CPP-115 were 9.7 μM and 59 μM, respectively). 无活性 The values ​​were 3.32 min -1 and 2.05 min -1 ). See U.S. Patent No. 9,993,449. In general, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (k 无活性 / K I =342 mM -1 min -1 ) is the efficiency constant of CPP-115(k 无活性 / K I =34.9 mM -1 min -1 ); thus, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid is 9.8 times more efficient as an inactivator of GABA-AT than CPP-115. Unlike vigabatrin, CPP-115 has been reported not to inactivate or inhibit off-target enzymes such as aspartate aminotransferase (Asp-AT) and alanine aminotransferase (Ala-AT), which may contribute to its greater safety margin than vigabatrin. (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid is a very weak reversible inhibitor of both Asp-AT and Ala-AT, with an IC 50 >4 mM. CPP-115 is a moderate inactivator of OAT with a KI value of 0.116 mM and a k 无活性 The value is 0.097 min -1 (S)-3-Amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid is an effective inactivator of OAT, wherein K I The value is 0.0033 mM and k 无活性 The value is 0.025 min -1By comparing (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (7.6 mM -1 min -1 ) and CPP-115 (0.84 mM -1 min -1 ) of k 无活性 / K I The results showed that (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid was 9.0 times more efficient as an inactivator of OAT than CPP-115, which is consistent with its higher efficiency as an inactivator of GABA-AT.

[0029] Without wishing to be bound by any particular theory, the selective inhibition of GABA-AT by (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases the concentration of GABA where GABA is normally present. By increasing the concentration of GABA, GABA A -R is activated, which inhibits the inflammatory activity of lymphocytes and macrophages in the pancreas, while also reducing the production of inflammatory cytokines, thereby inhibiting the disease process. In addition, reduced GABA levels and the altered GABA signaling system contribute to the pathogenesis of diabetes and prediabetes. Administration of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases GABA concentration, leading to increased insulin secretion, suppression of immune response, improved β cell survival, promotion of changes in α cells to β cells in the pancreas, and regulation of the GABA signaling system, thereby treating and improving the symptoms of type 1 diabetes, type 2 diabetes, and prediabetes.

[0030] In embodiments, the terms "effective amount" or "therapeutically effective amount" may be used interchangeably and refer to an amount of a compound, material, composition, drug, or other material effective to achieve the reduction, elimination, or prevention of Diabetes or pre-Diabetes while minimizing side effects typically associated with hypoglycemic agents or other GABA-AT inhibitors.

[0031] In embodiments, an "effective amount" herein may range from about 0.01 mg to about 750 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, administered once to four or more times per day. For example, a pharmaceutical composition comprising an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can contain from about 0.01 mg to about 0.1 mg, about 0.1 mg to about 1 mg, 1 mg to about 5 mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mg to about 20 mg, about 20 mg to about 25 mg, about 25 mg to about 30 mg, about 30 mg to about 35 mg, about 35 mg to about 40 mg, about 40 mg to about 45 mg, about 45 mg to about 50 mg, about 50 mg to about 55 mg, about 55 mg to about 60 mg, about 60 mg to about 65 mg, about 65 mg to about 70 mg, about 70 mg to about 75 mg, about 75 mg to about 80 mg, about 80 mg to about 85 mg, about 85 mg to about 90 mg, about 90 mg to about 95 mg, about 95 mg to about 100 mg. mg, about 100 mg to about 105 mg, about 105 mg to about 110 mg, about 110 mg to about 115 mg, about 115 mg to about 120 mg, about 120 mg to about 125 mg, about 125 mg to about 130 mg, about 130 mg to about 135 mg, about 135 mg to about 140 mg, about 140 mg to about 145 mg, about 145 mg to about 150, about 150 mg to about 155 mg, about 155 mg to about 160 mg, about 160 mg to about 165 mg, about 165 mg to about 170 mg, about 170 mg to about 175 mg, about 175 mg to about 180 mg, about 180 mg to about 185 mg, about 185 mg to about 190 mg, about 190 mg to about 195 mg, about 195 mg to about 200 mg, about 200 mg to about 205 mg, about 205 mg to about 210 mg, about 210 mg to about 215 mg, about 215 mg to about 220 mg, about 220 mg to about 225 mg, about 225 mg to about 230 mg, about 230 mg to about 235 mg, about 235 mg to about 240 mg, about 240 mg to about 245 mg, about 245 mg to about 250 mg, about 250 mg to about 255 mg, about 255 mg to about 260 mg, about 260 mg to about 265 mg, about 265 mg to about 270mg, about 270 mg to about 275 mg, about 275 mg to about 280 mg, about 280 mg to about 285 mg, about 285 mg to about 290 mg, about 290 mg to about 295 mg, about 295 mg to about 300 mg, about 300 mg to about 305 mg, about 305 mg to about 310 mg, about 310 mg to about 315 mg, about 315 mg to about 320 mg, about 320 mg to about 325 mg, about 325 mg to about 330 mg, 330 mg to about 335 mg, about 335 mg to about 340 mg, about 340 mg to about 345 mg, about 345 mg to about 350 mg, about 350 mg to about 355 mg, about 355 mg to about 360 mg, about 360 mg to about 365 mg, about 365 mg to about 370 mg, about 370 mg to about 375 mg, about 375 mg to about 380 mg, about 380 mg to about 385 mg, about 385 mg to about 390 mg, about 390 mg to about 395 mg, about 395 mg to about 400 mg, about 400 mg to about 405 mg, about 405 mg to about 410 mg, about 410 mg to about 415 mg, about 415 mg to about 420 mg, about 420 mg to about 425 mg, about 425 mg to about 430 mg, about 430 mg to about 435 mg, about 435 mg to about 440 mg, about 440 mg to about 445 mg, about 445 mg to about 450 mg, about 450 mg to about 455 mg, about 455 mg to about 460 mg, about 460 mg to about 465 mg, about 465 mg to about 470 mg, about 470 mg to about 475 mg, about 475 mg to about 480 mg, about 480 mg to about 485 mg, about 485 mg to about 490 mg, about 490 mg to about 495 mg, or about 495 mg to about 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0032] In an embodiment, a pharmaceutical composition comprising an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, comprises 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, 86 mg, 87 mg, 88 mg, 89 mg, 90 mg, 91 mg, 92 mg, 93 mg, 94 mg, 95 mg, 96 mg, 97 mg, 98 mg, 99 mg, 100 mg, 101 mg, 102 mg, 103 mg, 104 mg, 105 mg, 106 mg, 107 mg, 108 mg, 109 mg, 110 mg, 111mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144mg, 145 mg, 146 mg, 147 mg, 148 mg, 149 mg, 150 mg, 151mg, 152mg、153 mg、154 mg、155mg、156 mg、157 mg、158 mg、159 mg、160 mg、161 mg、162 mg、163 mg、164 mg、165 mg、166mg、167 mg、168 mg、169 mg、170 mg、171 mg、172 mg、173 mg、174 mg、175 mg、176 mg、177mg、178 mg、179 mg、180 mg、181 mg、182 mg、183 mg、184 mg、185 mg、186 mg、187 mg、188mg、189 mg、190 mg、191 mg、192mg、193 mg、194 mg、195 mg、196 mg、197 mg、198 mg、199mg、200 mg、201 mg、202 mg、203 mg、204 mg、205 mg、206 mg、207 mg、208 mg、209 mg、210mg、211 mg、212 mg、213 mg、214 mg、215 mg、216 mg、217 mg、218 mg、219 mg、220 mg、221mg、222 mg、223 mg、224 mg、225 mg、226 mg、227 mg、228 mg、229 mg、230 mg、231 mg、232mg、233 mg、234 mg、235 mg、236 mg、237 mg、238 mg、239 mg、240 mg、241 mg、242 mg、243mg、244 mg、245 mg、246 mg、247 mg、248 mg、249 mg、250 mg、251mg、252 mg、253 mg、254mg、255 mg、256 mg、257 mg、258 mg、259 mg、260 mg、261 mg、262 mg、263 mg、264 mg、265mg、266 mg、267 mg、268 mg、269 mg、270 mg、271 mg、272 mg、273 mg、274 mg、275 mg、276mg、277 mg、278 mg、279 mg、280 mg、281 mg、282 mg、283 mg、284 mg、285 mg、286 mg、287mg、288 mg、289 mg、290 mg、291 mg、292mg、293 mg、294 mg、295 mg、296 mg、297mg、298mg、299 mg、300 mg、301 mg、302 mg、303 mg、304 mg、305 mg、306 mg、307 mg308 mg、309mg、310 mg、311 mg、312 mg、313 mg、314 mg、315 mg、316 mg、317 mg、318 mg、319 mg、320mg、321 mg、322 mg、323 mg、324 mg、325 mg、326 mg、327 mg、328 mg、329 mg、230 mg、331mg、332 mg、333 mg、334 mg、335 mg、336 mg、337 mg、338 mg、339 mg、340 mg、241 mg、342mg、343 mg、344 mg、345 mg、346 mg、347 mg、348 mg、349 mg、350 mg、351mg、352 mg、353mg、354 mg、355 mg、356 mg、357 mg、358 mg、359 mg、360 mg、361 mg、362 mg、363 mg、364mg、365 mg、366 mg、367 mg、368 mg、369 mg、370 mg、371 mg、372 mg、373 mg、374 mg、375mg、376 mg、377 mg、378 mg、379 mg、380 mg、381 mg、382 mg、383 mg、384 mg、385 mg、386mg、387 mg、388 mg、389 mg、390 mg、391 mg、392mg、393 mg、394 mg、395 mg、396 mg、397mg、398 mg、399 mg、400 mg、401 mg、402 mg、403 mg、404 mg、405 mg、406 mg、407 mg、408mg、409 mg、410 mg、411 mg、412 mg、413 mg、414 mg、415 mg、416 mg、417 mg、418 mg、419mg、420 mg、421 mg、422 mg、423 mg、424 mg、425 mg、426 mg、427 mg、428 mg、429 mg、430mg、431 mg、432 mg、433 mg、434 mg、435 mg、436 mg、237 mg、438 mg、439 mg、440 mg、441mg、442mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, 450 mg, 451 mg, 452mg, 453 mg, 454 mg, 455 mg, 456 mg, 457 mg, 458 mg, 459 mg, 460 mg, 461 mg, 462 mg, 463mg, 464 mg, 465 466 mg mg, 489 mg, 490 mg, 491 mg, 492 mg, 493 mg, 494 mg, 495 mg, 496 mg, 497 mg, 498 mg, 499 mg or 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0033] In an embodiment, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to the subject at from about 0.01 mg / day to about 750 mg / day. For example, in embodiments, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, is administered at about 0.01 mg / day, about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 5 mg / day, about 10 mg / day, about 15 mg / day, about 20 mg / day, about 25 mg / day, about 30 mg / day, about 35 mg / day, about 40 mg / day, about 45 mg / day, about 50 mg / day, about 60 mg / day, about 65 mg / day, about 70 mg / day, about 75 mg / day, about 80 mg / day, about 85 mg / day, about 90 mg / day, about 95 mg / day, about 100 mg / day, about 105 mg / day, about 110 mg / day, about 115 mg / day, about 120 mg / day, about 125 mg / day, about 130 mg / day, about 135 mg / day, about 140 mg / day, about 145 mg / day, about 150 mg / day, about 155 mg / day, about 160 mg / day, about 165 mg / day, about 170 mg / day, about 175 mg / day, about 180 mg / day, about 185 mg / day, about 190 mg / day, about 195 mg / day, about 200 mg / day, about 205 mg / day, about 210 mg / day, about 215 mg / day, about 220 mg / day, about 225 mg / day, about 230 mg / day, about 235 mg / day, about 240 mg / day, about 245 mg / day, about 250 mg / day, about 255 mg / day, about 260 mg / day, about 265 mg / day, about 270 mg / day, about 275 mg / day, about 280 mg / day, about 285 mg / day, about 290 mg / day, about 295 mg / day, about 300 mg / day, about 305 mg / day, about 310 mg / day, about 315 mg / day, about 320 mg / day, about 325 mg / day, about 330 mg / day, about 335 mg / day, about 340 mg / day, about 345 mg / day, about 350 mg / day, about 355 mg / day, about 360 mg / day, about 365 mg / day, about 370 mg / day, about 375 mg / day, about 380 mg / day, about 385 mg / day, about 390 mg / day, about 395 mg / day, about 400 mg / day, about 405 mg / day, about 410 mg / day, about 415 mg / day, about 420 mg / day, about 425 mg / day, about 430 mg / day, about 435mg / day, about 440 mg / day, about 445 mg / day, about 450 mg / day, about 455 mg / day, about 460 mg / day, about 465 mg / day, about 470 mg / day, about 475 mg / day, about 480 mg / day, about 485 mg / day, about 490 mg / day, about 495 mg / day, about 500 mg / day, about 505 mg / day, about 510 mg / day, about 515 mg / day, about 520 mg / day, about 525 mg / day, about 530 mg / day, about 535 mg / day, about 540 mg / day, about 545 mg / day, about 550 mg / day, about 555 mg / day, about 560 mg / day, about 565 mg / day, about 570 mg / day, about 575 mg / day, about 580 mg / day, about 585 mg / day, about 590 mg / day, about 595 mg / day, about 600 mg / day, about 605 mg / day, about 610 mg / day, about 615 mg / day, about 620 mg / day, about 625 mg / day, about 630 mg / day, about 635 mg / day, about 640 mg / day, about 645 mg / day, about 650 mg / day, about 655 mg / day, about 660 mg / day, about 665 mg / day, about 670 mg / day, about 675 mg / day, about 680 mg / day, about 685 mg / day, about 690 mg / day, about 695 mg / day, about 700 mg / day, about 705 mg / day, about 710 mg / day, about 715 mg / day, about 720 mg / day, about 725 mg / day, about 730 mg / day, about 735 mg / day, about 740 mg / day, about 745 mg / day, or about 750 mg / day, administered to a subject in one, two, three, four, or more doses. In embodiments, a subject may start with a low dose and the dose may be increased over time.

[0034] In embodiments, (S) -3-amino-4- (difluoromethylene) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt is administered to a subject diagnosed with diabetes or prediabetes via a pharmaceutical composition. Pharmaceutical compositions herein encompass dosage forms. Dosage forms herein encompass unit doses. In embodiments, as discussed below, various dosage forms including conventional formulations and modified release formulations can be administered once, twice, three times, four times or more daily. In embodiments, (S) -3-amino-4- (difluoromethylene) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt is administered to a subject once or twice daily (e.g., morning and / or evening). In embodiments, (S) -3-amino-4- (difluoromethylene) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt is administered to a subject three times daily (e.g., morning, afternoon and bedtime, or every 8 hours). In embodiments, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to the subject four times a day (e.g., morning, afternoon, evening, and bedtime, or every 6 hours). In embodiments, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to the subject via continuous infusion. In embodiments, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to the subject at the onset of diabetes or prediabetes symptoms (whenever they may occur). Any suitable route of administration may be utilized, such as oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, epidural, intramuscular, intraperitoneal, and subcutaneous routes. Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, transdermal forms such as topical liquids, patches, creams and ointments, parenteral formulations and suppositories. In an embodiment, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for treating diabetes or prediabetes.

[0035] In embodiments, a method of treating diabetes or prediabetes is provided, comprising administering a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the composition provides an improvement in the symptoms of diabetes or prediabetes that persists for more than 1 hour after administration to the subject. In embodiments, a method of treating diabetes or prediabetes is provided, comprising administering a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the composition provides an improvement in the symptoms of diabetes or prediabetes that persists for more than 2 hours after administration to the subject. In embodiments, a method of treating diabetes or prediabetes is provided, comprising administering a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the composition provides an improvement in the symptoms of diabetes or prediabetes that persists for more than 3 hours after administration to the subject. In embodiments, a method of treating diabetes or prediabetes is provided, comprising administering a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the composition provides an improvement in the symptoms of diabetes or prediabetes that persists for more than 4 hours after administration to the subject. In embodiments, a method for treating diabetes or prediabetes is provided, the method comprising administering a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the composition provides an improvement in the symptoms of diabetes or prediabetes that persists for more than 6 hours after administration to the subject. In embodiments, a method for treating diabetes or prediabetes is provided, the method comprising administering a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, to a subject in need thereof, wherein the composition provides an improvement in the symptoms of diabetes or prediabetes that persists for more than 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours after administration to the subject. In embodiments, the pharmaceutical composition provides an improvement in next-day function in a subject diagnosed with diabetes or prediabetes. For example, the pharmaceutical composition can provide improvement in symptoms of diabetes or prediabetes that persists for more than about, e.g., 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours after administration and waking from a night's sleep.

[0036] In embodiments, as previously mentioned, the pharmaceutical compositions herein can be provided with conventional release profiles or modified release profiles. Pharmaceutical compositions can be prepared using a pharmaceutically acceptable "carrier" comprising a material that is considered to be safe and effective. A "carrier" includes all components present in the pharmaceutical formulation except for one or more active ingredients (active ingredient or ingredients). The term "carrier" includes, but is not limited to, diluents, binders, lubricants, disintegrants, fillers, and coating compositions. Those skilled in the art are familiar with such pharmaceutical carriers and methods for compounding pharmaceutical compositions using such carriers.

[0037] In an embodiment, the pharmaceutical composition herein is a modified release dosage form providing a modified release profile. The modified release profile can present an immediate release profile, a delayed release profile, or an extended release profile. Conventional (or unmodified) release oral dosage forms such as tablets, capsules, suppositories, syrups, solutions, and suspensions typically release the drug into the mouth, stomach, or intestine as the tablet, capsule shell, or suppository dissolves, or in the case of syrups, solutions, and suspensions, when they are swallowed. In order to achieve the desired therapeutic purpose and / or better patient compliance, the pattern of drug release from a modified release (MR) dosage form is intentionally changed from the pattern of drug release of a conventional dosage form. Types of MR drug products include orally disintegrating dosage forms (ODDF) providing immediate release, extended release dosage forms, delayed release dosage forms (e.g., enteric coated), and pulsatile release dosage forms.

[0038] ODDF is a solid dosage form comprising a pharmaceutical substance or active ingredient, which typically disintegrates rapidly within a few seconds when placed on the tongue. The disintegration time of ODDF is typically in the range of from one or two seconds to about one minute. ODDF is designed to disintegrate rapidly or dissolve after contact with saliva. This mode of administration may be beneficial to people who may have problems swallowing tablets, whether the problem is essentially from physical weakness or mental illness. Subjects suffering from diabetes or prediabetes can show such behavior. ODDF can provide rapid delivery of medicine to the bloodstream through the mucous membrane, resulting in rapid onset. The example of ODDF includes orally disintegrating tablets, capsules, and rapidly dissolving films and wafers.

[0039] Extended-release dosage form (ERDF) has extended release profile, and is compared with the administration frequency presented by conventional dosage form such as solution or unmodified release dosage form, allows those dosage forms of reduction of administration frequency.ERDF provides the drug action duration that continues.Providing suitable formulations for extended release profile is well known in the art.For example, the slowly released pearls or granules (" pearls " and " granules " are used interchangeably in this article) of coating, wherein (S)-3-amino-4-(difluoromethylene) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt are applied to pearls, for example sugar granules (confectionersnonpareil) pearls, and then coated with conventional release delaying materials such as wax, enteric coating and the like.In embodiments, pearls can be formed, wherein (S)-3-amino-4-(difluoromethylene) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt are mixed with material, to provide the agglomerate that medicine is leached from therein. In embodiments, the beads can be engineered to provide different release rates by varying the properties of the coating or mass, such as thickness, porosity, using different materials, etc. Beads with different release rates can be combined into a single dosage form to provide variable or continuous release. The beads can be contained in a capsule or compressed into a tablet.

[0040] In embodiments, the modified dosage form herein includes a delayed release dosage form with a delayed release overview. The delayed release dosage form can include delayed release tablets or delayed release capsules. The delayed release tablet is a solid dosage form, which releases a drug (or drugs) different from the time of immediate release after administration, such as (S)-3-amino-4-(difluoromethylene) cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. The delayed release capsule is a solid dosage form, in which the drug is encapsulated in a hard or soft soluble container made of gelatin of suitable form, and the solid dosage form releases a drug (or drugs) different from the time of immediate release after administration. For example, enteric-coated tablets, capsules, granules and pearls are examples known to delayed release dosage forms. Enteric-coated tablets, capsules and granules and pearls pass through the stomach and release medicine in the intestine. In an embodiment, a delayed-release tablet is a solid dosage form comprising agglomerates of pharmaceutically acceptable particles that release a drug (or more drugs) at a time different from immediate release after administration. In an embodiment, the agglomerates of pharmaceutically acceptable particles are covered with a coating that delays the release of the drug. In an embodiment, a delayed-release capsule is a solid dosage form comprising agglomerates of pharmaceutically acceptable particles that release a drug (or more drugs) at a time different from immediate release after administration. In an embodiment, the agglomerates of pharmaceutically acceptable particles are covered with a coating that delays the release of the drug.

[0041] Delayed release dosage form is well known to those skilled in the art.For example, the delayed release pearl or granule of coating, wherein (S)-3-amino-4-(difluoromethylene) cyclopent-1-alkene-1-carboxylic acid or its pharmaceutically acceptable salt is applied to pearl, for example sugar granule pearl, and then with conventional release delay material such as wax, enteric coating and analogue come coating.In embodiments, pearl can be formed, wherein (S)-3-amino-4-(difluoromethylene) cyclopent-1-alkene-1-carboxylic acid or its pharmaceutically acceptable salt is mixed with material, to provide the agglomerate that medicine is leached from therein.In embodiments, pearl can be engineered to provide different release rates by changing the characteristic such as thickness, porosity of coating or agglomerate, using different materials etc. In an embodiment, enteric coated granules of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can be contained in enteric coated capsules or tablets that release the granules in the small intestine. In an embodiment, the granules have a coating that remains intact until the coated granules reach at least the ileum and thereafter provides delayed release of the drug in the colon. Suitable enteric coating materials are well known in the art, for example Eudragit® coatings, such as methacrylic acid and methyl methacrylate polymers and others. The granules can be contained in capsules or compressed into tablets.

[0042] In an embodiment, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into a porous inert carrier that provides a delayed release profile. In an embodiment, the porous inert carrier is incorporated into a channel or passage from which the drug diffuses into the surrounding fluid. In an embodiment, (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into an ion exchange resin to provide a delayed release profile. When the drug-resin complex contacts gastrointestinal fluid and the ionic components dissolved therein, the drug is released from the resin at a predetermined rate and can cause a delayed effect. In an embodiment, a membrane is used to control the rate of release from a reservoir containing the drug. In an embodiment, a liquid product can also be used to provide a delayed release profile. For example, a liquid product composed of solid particles dispersed throughout a liquid phase, the particles being insoluble in the liquid phase. The suspension is formulated to at least allow for a reduction in the frequency of dosing of the drug compared to a conventional dosage form (e.g., a solution or a conventional solid dosage form for rapid release of the drug), for example, a suspension of an ion exchange resin composition or microbeads.

[0043] In embodiments, pharmaceutical composition described herein is suitable for parenteral administration, including, for example, intramuscular (im), intravenous (iv), subcutaneous (sc), intraperitoneal (ip), epidural or intrathecal (it). Parenteral compositions should be sterile, for use by injection, infusion or implantation into the body, and can be packaged in single-dose containers or multi-dose containers. In embodiments, the liquid pharmaceutical composition for parenteral administration to the subject comprises the active substance of any corresponding amount described above, for example, (S)-3-amino-4-(difluoromethylene) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt. In embodiments, the pharmaceutical composition for parenteral administration is formulated into a cumulative volume of about, for example, 10 ml, 20 ml, 25 ml, 50 ml, 100 ml, 200 ml, 250 ml or 500 ml. In embodiments, compositions is contained in bag, glass bottle, plastic bottle or bottle.

[0044] The pharmaceutical composition for parenteral administration provided herein can include one or more excipients, such as solvents, solubility enhancers, suspending agents, buffers, isotonic agents, stabilizers or antimicrobial preservatives. When used, the excipient of parenteral composition will not adversely affect the stability, bioavailability, safety and / or effectiveness of the (S)-3-amino-4-(difluoromethylene) cyclopent-1-alkene-1-carboxylic acid or its pharmaceutically acceptable salt used in the composition. Therefore, parenteral composition is provided, wherein there is no incompatibility between any components of the dosage form.

[0045] In an embodiment, the parenteral composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof comprises a stabilizing amount of at least one excipient. For example, the excipient can be selected from the group consisting of a buffer, a solubilizer, a tonicity agent, an antioxidant, a chelating agent, an antimicrobial agent, and a preservative. It will be understood by those skilled in the art that an excipient can have more than one function and be classified into one or more defined groups.

[0046] In embodiments, parenteral compositions comprise (S) -3- amino -4- (difluoromethylene) cyclopent- 1- alkene -1- carboxylic acid or its pharmaceutically acceptable salt and excipient, wherein excipient is with less than about such as 10%, 5%, 2.5%, 1% or 0.5% weight percent (w / v) existence. In embodiments, excipient is with about such as 1.0% to 10%, 10% to 25%, 15% to 35%, 0.5% to 5%, 0.001% to 1%, 0.01% to 1%, 0.1% to 1% or 0.5% to 1% weight percent existence. In embodiments, excipient is with about such as 0.001% to 1%, 0.01% to 1%, 1.0% to 5%, 10% to 15% or 1% to 15% weight percent existence.

[0047] In an embodiment, a parenteral composition of an active substance is provided, such as (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the pH of the composition is between about 4.0 and about 8.0. In an embodiment, the pH of the composition is, for example, between about 5.0 and about 8.0, about 6.0 and about 8.0, about 6.5 and about 8.0. In an embodiment, the pH of the composition is, for example, between about 6.5 and about 7.5, about 7.0 and about 7.8, about 7.2 and about 7.8, or about 7.3 and about 7.6. In an embodiment, the pH of the aqueous solution is, for example, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.7, about 7.8, about 8.0, about 8.2, about 8.4, or about 8.6.

[0048] It should be understood that the dosage amounts of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof provided herein are applicable to all dosage forms described herein, including conventional dosage forms, modified dosage forms, and parenteral formulations described herein. A person skilled in the art will determine the appropriate amount depending on criteria such as dosage form, route of administration, subject tolerance, efficacy, therapeutic goals, and therapeutic benefits, as well as other pharmaceutically acceptable criteria.

[0049] The clinical efficacy of treatment can be monitored using any method known in the art. The measurable parameters for monitoring efficacy will depend on the condition being treated. To monitor the state or improvement of diabetes or prediabetes, both subjective parameters (e.g., patient report) and objective parameters (e.g., fasting blood glucose levels, HbA1c, 2-hour oral glucose tolerance test (OGTT) results, and random plasma glucose levels) can be used.

[0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0051] As used herein, the term "about" or "approximately" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, according to practice in the art, "about" can mean within 3 or more standard deviations. Alternatively, "about" can mean a range of at most 20%, at most 10%, at most 5%, and / or at most 1% of a given value.

[0052] "Amelioration" refers to treatment of Diabetes or pre-Diabetes, including treatment of all symptoms normally associated with Diabetes or pre-Diabetes.

[0053] "Improvement in next-day function" or "wherein there is an improvement in next-day function" refers to an improvement after waking from an overnight sleep period, wherein the beneficial effects of administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are applicable to symptoms of diabetes or prediabetes and are sustained for a period of time after waking, e.g., 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc., as discernible subjectively by the subject or objectively by an observer.

[0054] "Treating," "treatment," or "treat" may refer to reducing, improving, alleviating, ameliorating, alleviating, suppressing, reversing, and / or alleviating diabetes or prediabetes in a subject, or delaying the onset of symptoms of diabetes or prediabetes in a subject (prevention). In embodiments, "treating," "treatment," or "treatment" may refer to preventing the onset of clinical symptoms of a disease or condition in a subject who may be suffering from or susceptible to a disease or condition but has not yet experienced or displayed clinical symptoms or subclinical symptoms of the disease or condition. "Treating," "treatment," or "treatment" also refers to suppressing or alleviating diabetes or prediabetes, e.g., causing regression of diabetes or prediabetes or at least one of its clinical or subclinical symptoms. The benefit to the subject being treated may be statistically significant, mathematically significant, or at least perceptible to the subject and / or physician. Nonetheless, prophylactic (preventive) treatment and therapeutic (curative) treatment are two separate embodiments of the disclosure herein.

[0055] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally recognized as safe," e.g., they are physiologically tolerable and typically do not produce allergic reactions or similar adverse reactions such as gastric upset and the like when administered to humans. In embodiments, the term refers to molecular entities and compositions that are approved by a regulatory agency of the Federal or state government as being on the GRAS list under sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act, or a similar list, that has undergone premarket review and approval by the FDA; or are set forth in the U.S. Pharmacopeia or another generally recognized pharmacopoeia for use in animals, and more particularly in humans.

[0056] "Co-administered with," "administered in combination with," "combination of," or "administered together with" may be used interchangeably and mean the administration of two or more agents in a course of treatment. The agents may be administered together at the same time or separately at spaced intervals. The agents may be administered in a single dosage form or in separate dosage forms.

[0057] "Subjects in need thereof" include individuals who have been diagnosed with diabetes or prediabetes. Individuals include mammals. Methods and compositions comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can be provided to any individual, including, for example, where the subject is a neonate, infant, pediatric subject (6 months to 12 years of age), adolescent subject (age 12-18 years of age), or adult (over 18 years of age). Subjects include mammals. "Patient" and "subject" are used interchangeably herein.

[0058] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds defined herein, wherein the parent compound is modified by preparing an acid salt or a basic salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali metal or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. Such conventional non-toxic salts include, but are not limited to, those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid; and salts prepared from following organic acids: such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid and hydroxyethanesulfonic acid. Pharmaceutically acceptable salts can be synthesized by conventional chemical methods from the parent compound comprising a basic or acidic moiety.

[0059] It should be understood that the examples and embodiments provided herein are illustrative examples and embodiments. Those skilled in the art will envision various modifications of the examples and embodiments consistent with the scope of the present disclosure. Such modifications are intended to be covered by the claims.

Claims

1. A method for treating diabetes, comprising administering an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof.

2. The method for treating diabetes according to claim 1, wherein the diabetes is type 2 diabetes. The method for treating diabetes according to claim 1 , wherein the diabetes is type 1 diabetes.

4. The method for treating diabetes according to claim 1, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount effective to reduce one or more of HbA1c level, fasting plasma glucose level, 2-hour oral glucose tolerance test (OGTT) result level, and random plasma glucose level.

5. The method for treating diabetes according to claim 4, wherein the HbA1c level is reduced by an amount greater than 0.5%.

6. The method of treating diabetes according to claim 4, wherein the HbA1c level is reduced by an amount greater than 1.0%.

7. The method for treating diabetes according to claim 1, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.01 mg to about 750 mg.

8. The method for treating diabetes according to claim 1, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in combination with one or more hypoglycemic agents selected from the group consisting of biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, glinides, α-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs.

9. A method for treating prediabetes, comprising administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

10. The method for treating prediabetes according to claim 9, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof in an amount effective to reduce one or more of HbA1c level, fasting plasma glucose level, 2-hour oral glucose tolerance test (OGTT) result level, and random plasma glucose level.

11. The method of treating prediabetes according to claim 10, wherein the HbA1c level is reduced by an amount greater than 0.5%.

12. The method of treating prediabetes according to claim 10, wherein the HbA1c level is reduced by an amount greater than 1.0%.

13. The method of treating prediabetes according to claim 9, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.01 mg to about 750 mg.

14. The method for treating prediabetes according to claim 9, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in combination with one or more hypoglycemic agents selected from the group consisting of biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, glinides, α-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs.

15. A method of treating diabetes and sleep apnea, comprising administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject diagnosed with diabetes and sleep apnea in an amount effective to reduce episodes of sleep apnea.

16. The method for treating diabetes and sleep apnea according to claim 15, wherein the diabetes is type 2 diabetes.

17. The method for treating diabetes and sleep apnea according to claim 15, wherein the diabetes is type 1 diabetes.

18. The method for treating diabetes and sleep apnea according to claim 15, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount ranging from about 0.01 mg to about 750 mg.

19. The method for treating diabetes and sleep apnea according to claim 15, wherein the (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in combination with one or more hypoglycemic agents selected from the group consisting of biguanides, dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, thiazolidinediones, glinides, α-glucosidase blockers, glucagon-like peptide-1 receptor agonists, insulin, and insulin analogs.

20. The method of treating diabetes and sleep apnea according to claim 15, wherein the administration is effective to reduce one or more of the subject's HbA1c level, fasting plasma glucose level, 2-hour oral glucose tolerance test (OGTT) result level, and random plasma glucose level.

21. The method of treating diabetes and sleep apnea according to claim 20, wherein the HbA1c level is reduced by an amount greater than 0.5%.

22. The method of treating diabetes and sleep apnea according to claim 20, wherein the HbA1c level is reduced by an amount greater than 1%.

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