Use of (s)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid for gastrointestinal disorders and as immunomodulators

Abstract

Provided are methods for effecting immune modulation and treating gastrointestinal disorders, comprising administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid, or a pharmaceutically acceptable salt thereof. In an embodiment, a composition comprising (S)-3-amino-4-(difluoromethylene) cyclopent-1-en-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, for effecting immune modulation and treating gastrointestinal disorders is administered to a subject in need thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 485,620, filed February 17, 2023, and which is incorporated herein by reference in its entirety. Technical Field

[0002] Gastrointestinal disorders are treated with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. background

[0003] Gastrointestinal disorders include irritable bowel syndrome (IBS), Crohn's disease, celiac disease, ulcerative colitis and microscopic colitis. According to the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), IBS is a group of symptoms that occur simultaneously, including changes in cramping, recurrent abdominal pain, bloating and bowel movements, which can be diarrhea, constipation or both. These symptoms may occur in the absence of any obvious damage or signs of disease in the digestive tract. IBS is classified into three types, 1) constipation-type IBS (IBS-C), 2) diarrhea-type IBS (IBS-D), and 3) mixed bowel habit-type IBS (IBS-M). One or more causes of IBS are unclear. The imbalance of GABA signaling and inflammation is relevant to the pathogenesis of IBS-D. See, e.g., Aggarwal et al., Journal of Neurogastroenterology and Motility, 2018; 24(3): 422-430. Some cases of IBS may be triggered by infection, known as post-infectious IBS. Dietary changes, lifestyle changes, probiotics, mental health therapies, and medications are used to treat IBS. Antidiarrheal medications such as loperamide are used to treat IBS-D. Fiber supplements and laxatives such as lubiprostone are used to treat IBS-C. Antispasmodics such as dicyclomine or peppermint oil and antidepressants such as tricyclines, SSRIs can be used to treat the overall symptoms, cramping, and abdominal pain associated with IBS. There is a continuing need for effective therapies to treat IBS.

[0004] According to the NIDDK, Crohn's disease is an inflammatory bowel disease that most commonly affects the small intestine and the beginning of the large intestine. However, it can affect any part of the digestive tract, such as the mouth, esophagus, stomach, and anus. The cause or causes of Crohn's disease are unknown. In some cases, it may be inherited. In others, it may be an autoimmune reaction that causes inflammation. Other possible causes include smoking, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, and oral contraceptives. A high-fat diet may also contribute to the development of Crohn's disease. Symptoms of Crohn's disease include diarrhea, cramping, abdominal pain, anemia, fever, and nausea. Complications caused by Crohn's disease include intestinal obstruction, fistulas, abscesses, anal fissures, ulcers, malnutrition, and inflammation in other parts of the body. There is no single treatment that works for all cases of Crohn's disease. Dietary changes and medications can be used to treat Crohn's disease. Medications include aminosalicylates, which can reduce inflammation; corticosteroids, which reduce immune system activity and inflammation; and immunomodulators, which reduce immune system activity. Monoclonal antibodies have also been used to reduce immune system activity, thereby reducing inflammation. The aforementioned drugs can be associated with severe side effects.There is a continuing need for effective therapies to treat Crohn's disease.

[0005] According to the NIDDK, celiac disease is a digestive disorder that damages the small intestine. It is triggered by the intake of foods containing gluten, a protein found, for example, in wheat, barley, and rye, which causes an autoimmune reaction. Celiac disease appears to be hereditary in nature. Symptoms are more common in children and include bloating, chronic diarrhea, constipation, flatulence, nausea, pale, foul-smelling stools, stomach pain, and malabsorption of nutrients that can cause damage to tooth enamel, delayed puberty, stagnation of growth in infants, slow growth, and weight loss. Adults are less likely to have digestive symptoms, but may experience anemia, red, shiny tongue, bone or joint pain, depression, headache, dermatitis herpetiformis, infertility, mouth sores, seizures, fatigue and weakness, and brittle bones. Gastrointestinal (GI) symptoms in adults include abdominal pain, bloating, intestinal obstruction, ulcers on the stomach or intestinal lining. Treatment typically involves avoiding foods containing gluten. There is a continuing need for effective therapies that reduce or eliminate the symptoms of celiac disease.

[0006] According to the NIDDK, ulcerative colitis is a chronic inflammatory bowel disease characterized by inflammation and ulcers in the lining of the large intestine. Ulcerative colitis most often begins gradually and can worsen over time. Symptoms can range from mild to severe. Most people experience periods of remission—times when symptoms disappear—that can last from weeks to years. The goal of care is to keep people in remission long-term. The exact cause of ulcerative colitis is unknown. The following factors may play a role in causing ulcerative colitis: genetic predisposition, an abnormal immune response targeting the lining of the intestine, nonsteroidal anti-inflammatory drugs, antibiotics, and oral contraceptives. Symptoms include an urgent need to have a bowel movement, fatigue, nausea, loss of appetite, weight loss, fever, anemia, joint pain, and rash. About 10% of people may have severe symptoms, such as frequent bloody bowel movements; fever; and severe abdominal cramping. Treatment of ulcerative colitis symptoms typically involves medications such as aminosalicylates, which can reduce inflammation; corticosteroids, which reduce the activity of the immune system and reduce inflammation; and immunomodulators, which reduce the activity of the immune system. Monoclonal antibodies have also been used to reduce the activity of the immune system, thereby reducing inflammation. These drugs can be associated with serious side effects. There is a continuing need for effective therapies to treat ulcerative colitis.

[0007] According to the NIDDK, microscopic colitis is an inflammatory condition that can only be seen with a microscope. There are two types of microscopic colitis: collagenous colitis and lymphocytic colitis. In both types of microscopic colitis, an increase in the number of lymphocytes can be seen in the colon's epithelium. The two types of colitis affect the colon tissue in slightly different ways. In lymphocytic colitis, the number of lymphocytes is higher, and the tissue and lining of the colon have a normal thickness. In collagenous colitis, the collagen layer beneath the epithelium accumulates and becomes thicker than normal. Although the exact cause of microscopic colitis is unknown, it is believed that it may be caused by an abnormal immune response to bacteria that normally live in the colon. Several other factors may play a role in causing microscopic colitis, including autoimmune diseases, medications, infections, genetic factors, and bile acid malabsorption. The most common symptom of microscopic colitis is chronic, watery, non-bloody diarrhea. Episodes of diarrhea may last for weeks, months, or even years. However, many people with microscopic colitis may not have diarrhea for long periods of time. Other signs and symptoms of microscopic colitis can include an intense urgency to have a bowel movement or the need to go to the bathroom quickly, pain, cramping, or bloating in the abdomen (usually mild), weight loss, nausea, fecal incontinence (the unintentional passing of stool or fluid from the rectum), especially at night, and dehydration from not consuming enough fluids to replace fluids lost through diarrhea. Treatment of ulcerative colitis symptoms typically involves medications such as anti-diarrheal drugs such as bismuth subsalicylate, diphenoxylate / atropine, and loperamide, corticosteroids such as budesonide and prednisone, anti-inflammatory drugs such as mesalamine and sulfasalazine, cholestyramine resin (a drug that blocks bile acids), antibiotics such as metronidazole and erythromycin, immunomodulators such as mercaptopurine, azathioprine, and methotrexate, and anti-TNF therapies such as infliximab and adalimumab. Some of the aforementioned drugs may be associated with serious side effects. There is a continuing need for effective therapies for treating microscopic colitis.

[0008] 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 been shown to be 9.8 times more efficient as a GABA-AT inactivator than CPP-115. Overview

[0009] Methods and compositions for treating gastrointestinal disorders are provided. In embodiments, the methods described herein for treating irritable bowel syndrome comprise 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. In embodiments, a composition for treating irritable bowel syndrome 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 thereof. In embodiments, the method for treating irritable bowel syndrome 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 one or more symptoms of irritable bowel syndrome in the subject. In an embodiment, a method of treating irritable bowel syndrome 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 subject's irritable bowel syndrome symptoms 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, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating irritable bowel syndrome 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 a subject with irritable bowel syndrome once, twice, three times, or four times a day. In embodiments, described herein are methods of treating irritable bowel syndrome, 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, in combination with a drug selected from the group consisting of an anti-diarrhea drug, an antispasmodic drug, and an antidepressant, wherein the method provides improvement in irritable bowel syndrome.

[0010] In embodiments, the methods described herein for treating Crohn's disease comprise 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. In embodiments, a composition for treating Crohn's disease 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 thereof. In embodiments, the methods for treating Crohn's disease comprise 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 one or more symptoms of Crohn's disease in the subject. In an embodiment, a method for treating Crohn's disease 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 subject's Crohn's disease symptoms 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, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating Crohn's disease 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 for treating Crohn's disease is administered to the subject once, twice, three times, or four times daily. In embodiments, described herein are methods of treating Crohn's disease, comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a drug selected from the group consisting of an anti-diarrheal drug, an antispasmodic drug, an aminosalicylate, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method provides improvement in Crohn's disease.

[0011] In embodiments, the methods described herein for treating celiac disease comprise 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. In embodiments, a composition for treating celiac disease 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 thereof. In embodiments, a method for treating celiac disease 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 one or more symptoms of celiac disease in the subject. In one embodiment, a method of treating celiac disease 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 celiac disease symptoms 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 one embodiment, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, for treating celiac disease is between about 0.01 mg and about 750 mg. In one embodiment, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, for treating celiac disease is administered to the subject once, twice, three times, or four times daily. In embodiments, described herein are methods of treating celiac disease, comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a drug selected from the group consisting of an anti-diarrheal drug, an antispasmodic drug, an aminosalicylate, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method provides improvement in celiac disease.

[0012] In embodiments, the methods described herein for treating ulcerative colitis comprise 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. In embodiments, a composition for treating ulcerative colitis 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 thereof. In embodiments, the methods for treating ulcerative colitis comprise 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 one or more symptoms of ulcerative colitis in the subject. In an embodiment, a method of treating ulcerative colitis 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 subject's ulcerative colitis symptoms 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, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating ulcerative colitis 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 for treating ulcerative colitis is administered to the subject once, twice, three times, or four times daily. In embodiments, described herein are methods of treating ulcerative colitis comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a drug selected from the group consisting of an anti-diarrheal agent, an antispasmodic agent, an aminosalicylate, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method provides improvement in ulcerative colitis.

[0013] In embodiments, the methods described herein for treating microscopic colitis comprise 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. In embodiments, a composition for treating microscopic colitis 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 thereof. In embodiments, the methods for treating microscopic colitis comprise 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 one or more symptoms of microscopic colitis in the subject. In embodiments, a method for treating microscopic colitis 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 subject's symptoms of microscopic colitis the day after administration of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating microscopic colitis is between about 0.01 mg and about 750 mg. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating microscopic colitis is administered to the subject once, twice, three times, or four times daily. In embodiments, described herein are methods of treating microscopic colitis comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with an agent selected from the group consisting of an anti-diarrheal agent, an antispasmodic agent, an aminosalicylate, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method provides improvement in microscopic colitis. Details

[0014] Methods of treating irritable bowel syndrome with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are described herein. As used herein, "irritable bowel syndrome" includes IBS-C, IBS-D, and IBS-M. Methods of treating Crohn's disease with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are also described herein. Methods of treating celiac disease with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are also described herein. Methods of treating ulcerative colitis with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are also described herein. Methods of treating microscopic colitis with (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof are also described herein. As used herein, "microscopic colitis" includes collagenous colitis and lymphocytic colitis.

[0015] Methods and compositions for treating irritable bowel syndrome are provided. According to the present disclosure, methods and compositions for treating irritable bowel syndrome are provided, which alleviate the symptoms of irritable bowel syndrome without certain undesirable side effects associated with commonly prescribed medications or other GABA-AT inhibitors for irritable bowel syndrome. In an embodiment, the method for treating irritable bowel syndrome comprises 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. In an embodiment, a composition for treating irritable bowel syndrome 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 thereof. In an embodiment, the method for treating irritable bowel syndrome 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 improvement in one or more symptoms of irritable bowel syndrome in the subject. In an embodiment, a method of treating irritable bowel syndrome 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 subject's irritable bowel syndrome symptoms 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, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating irritable bowel syndrome 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 a subject with irritable bowel syndrome once, twice, three times, or four times a day.

[0016] Methods and compositions for treating Crohn's disease are provided. According to the present disclosure, methods and compositions for treating Crohn's disease are provided, which alleviate the symptoms of Crohn's disease without certain undesirable side effects associated with commonly prescribed drugs or other GABA-AT inhibitors for Crohn's disease. In an embodiment, the method for treating Crohn's disease comprises 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. In an embodiment, a composition for treating Crohn's disease 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 thereof. In an embodiment, the method for treating Crohn's disease 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 improvement in one or more symptoms of Crohn's disease in the subject. In an embodiment, a method for treating Crohn's disease 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 subject's Crohn's disease symptoms 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, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating Crohn's disease 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 a subject with Crohn's disease once, twice, three times, or four times a day.

[0017] Methods and compositions for treating celiac disease are provided. According to the present disclosure, methods and compositions for treating celiac disease are provided that alleviate the symptoms of celiac disease without certain undesirable side effects associated with commonly prescribed medications or other GABA-AT inhibitors for celiac disease. In embodiments, the method for treating celiac disease comprises 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. In embodiments, a composition for treating celiac disease 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 thereof. In embodiments, the method for treating celiac disease 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 one or more symptoms of celiac disease in the subject. In one embodiment, a method of treating celiac disease 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 celiac disease symptoms 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 one embodiment, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, for treating celiac disease is between about 0.01 mg and about 750 mg. In one 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 a subject with celiac disease once, twice, three times, or four times daily.

[0018] Provided are methods and compositions for treating ulcerative colitis. According to the present disclosure, provided are methods and compositions for treating ulcerative colitis, which alleviate the symptoms of ulcerative colitis without certain undesirable side effects associated with commonly prescribed drugs or other GABA-AT inhibitors for ulcerative colitis. In embodiments, the method for treating ulcerative colitis 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 thereof. In embodiments, a composition for treating ulcerative colitis 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 thereof. In embodiments, a method of treating ulcerative colitis 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 one or more symptoms of ulcerative colitis in the subject. In embodiments, a method of treating ulcerative colitis 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 subject's ulcerative colitis symptoms the day after administration of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, for treating ulcerative colitis 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 a subject with ulcerative colitis once, twice, three times, or four times daily.

[0019] Methods and compositions for treating microscopic colitis are provided. According to the present disclosure, methods and compositions for treating microscopic colitis are provided, which alleviate the symptoms of microscopic colitis without certain undesirable side effects associated with commonly prescribed drugs or other GABA-AT inhibitors for microscopic colitis. In embodiments, the method for treating microscopic colitis 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 microscopic colitis 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 microscopic colitis 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 in one or more symptoms of microscopic colitis in the subject. In embodiments, a method of treating microscopic colitis 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 subject's symptoms of microscopic colitis the day after administration of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating microscopic colitis is between about 0.01 mg and about 750 mg. In embodiments, an effective amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject suffering from microscopic colitis once, twice, three times, or four times daily.

[0020] The structure of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid can be represented as follows:

[0021] 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.

[0022] The pathogenesis of inflammatory gastrointestinal disorders may begin with an inflammatory cascade. Autoimmunity in inflammatory gastrointestinal disorders can begin at the molecular and cellular levels. For example, serum cytokine levels may increase. Some patients eventually transition from autoimmunity to immune-mediated inflammation that is primarily localized in the digestive tract. The digestive tract is infiltrated by immune cells, including innate immune cells (monocytes, dendritic cells, mast cells) and adaptive immune cells (T helper 1, Th1; T helper 17, Th17), B cells, and plasma cells. Neutrophils may not normally be present in the digestive tract, but rather shed from the blood to the lining of the digestive tract. 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 in the digestive tract.

[0023] 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.

[0024] Many different types of murine and human immune cells express various GABA receptors (GABA-Rs). See Tian et al., Sci Rep 11, 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 aboveAntigen presenting cells (APCs) such as macrophages also express GABA A -R, and their activation inhibits their inflammatory activity. same superior 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 .

[0025] (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 K I The value is 0.116 mM and 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 -1 By 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.

[0026] 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 the GI tract lining of lymphocytes and macrophages, while also reducing the production of inflammatory cytokines, thereby inhibiting the disease process. In addition, reduced GABA levels and altered GABA signaling systems contribute to the pathogenesis of gastrointestinal disorders described herein. Administration of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases GABA concentration, leading to the regulation of both motility and secretory gastrointestinal activity, thereby alleviating the symptoms of gastrointestinal disorders described herein.

[0027] Advantageously disclosed herein are methods for treating IBS by administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating IBS is provided, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising 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, wherein the composition provides an improvement that persists for more than 6 hours after administration to the subject.

[0028] Advantageously disclosed herein are methods for treating Crohn's disease by administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating Crohn's disease is provided, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising 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, wherein the composition provides an improvement that persists for more than 6 hours after administration to the subject.

[0029] Advantageously disclosed herein are methods for treating ulcerative colitis by administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating ulcerative colitis is provided, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising 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, wherein the composition provides an improvement that persists for more than 6 hours after administration to the subject.

[0030] Advantageously disclosed herein are methods for treating celiac disease by administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating celiac disease is provided, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising 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, wherein the composition provides improvement that persists for more than 6 hours after administration to the subject.

[0031] Advantageously disclosed herein are methods for treating microscopic colitis by administering (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in an embodiment, a method for treating microscopic colitis is provided, the method comprising administering to a subject in need thereof a pharmaceutical composition comprising 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, wherein the composition provides an improvement that persists for more than 6 hours after administration to the subject.

[0032] 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 reduction, elimination, or prevention of a gastrointestinal disorder as described herein while minimizing side effects typically associated with drugs or other GABA-AT inhibitors administered for gastrointestinal disorders.

[0033] 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.

[0034] 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.

[0035] 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.

[0036] 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 a gastrointestinal disorder herein 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 acute symptoms of gastrointestinal disturbances (e.g., cramps, nausea, diarrhea) (whenever this may occur). Any suitable route of administration can 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 to prepare a medicament for treating a gastrointestinal disorder herein.

[0037] In embodiments, methods of treating a gastrointestinal disorder described herein are 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 a gastrointestinal disorder described herein that persists for more than 1 hour after administration to the subject. In embodiments, methods of treating a gastrointestinal disorder described herein are 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 a gastrointestinal disorder described herein that persists for more than 2 hours after administration to the subject. In embodiments, methods of treating a gastrointestinal disorder described herein are 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 a gastrointestinal disorder described herein that persists for more than 3 hours after administration to the subject. In embodiments, methods of treating a gastrointestinal disorder described herein are 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 a gastrointestinal disorder described herein that persists for more than 4 hours after administration to the subject. In embodiments, a method of treating a gastrointestinal disorder described herein 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 a gastrointestinal disorder described herein that persists for more than 6 hours after administration to the subject. In embodiments, a method of treating a gastrointestinal disorder described herein 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 a gastrointestinal disorder described herein 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 herein with a gastrointestinal disorder. For example, the pharmaceutical compositions can provide improvement in symptoms of a gastrointestinal disorder herein 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.

[0038] 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.

[0039] 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.

[0040] ODDF is a solid dosage form comprising a pharmaceutical substance or active ingredient, which disintegrates rapidly in a few seconds when placed on the tongue. The disintegration time of ODDF is generally 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 can be useful to people who may have the problem of swallowing tablets, whether the problem is in essence from physical weakness or mental illness. Subjects suffering from gastrointestinal disorders herein may show such behavior. ODDF can provide the 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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. In order to monitor the status or improvement of the gastrointestinal disorders herein, both subjective parameters (e.g., patient report) and objective parameters (e.g., endoscopy, allodynia, hyperalgesia, physical examination, nerve conduction velocity, electrophysiology, etc.) can be used.

[0052] In an embodiment, provided herein are methods for treating IBS, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of IBS. Symptoms of IBS may include, but are not limited to, cramping, recurrent abdominal pain, bloating, and changes in bowel movements, which may be diarrhea, constipation, or both.

[0053] In an embodiment, provided herein are methods for treating Crohn's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of Crohn's disease. Symptoms of Crohn's disease may include, but are not limited to, diarrhea, cramping, abdominal pain, anemia, fever, and nausea.

[0054] In an embodiment, provided herein are methods for treating celiac disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of celiac disease. Symptoms of celiac disease can include, but are not limited to, abdominal bloating, chronic diarrhea, constipation, flatulence, nausea, pale, foul-smelling stools, stomach pain, and malabsorption of nutrients, delayed puberty, failure to thrive in infants, slowed growth, and weight loss.

[0055] In an embodiment, provided herein are methods of treating ulcerative colitis, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition provides an improvement in at least one symptom of ulcerative colitis. Symptoms of ulcerative colitis may include, but are not limited to, an urgent need to defecate, bloody stools, fever, severe abdominal cramping, fatigue, nausea, loss of appetite, weight loss, fever, anemia, joint pain, and rash.

[0056] In an embodiment, provided herein are methods for treating microscopic colitis, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition provides improvement in at least one symptom of microscopic colitis. Symptoms of microscopic colitis may include, but are not limited to, chronic watery, non-bloody diarrhea, intense urgency to defecate, pain, cramping, bloating, weight loss, nausea, and fecal incontinence.

[0057] In embodiments, provided herein are methods for treating IBS, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a second pharmaceutically active agent. In embodiments, provided herein are methods for treating Crohn's disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a second pharmaceutically active agent. In embodiments, provided herein are methods for treating celiac disease, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a second pharmaceutically active agent. In embodiments, provided herein are methods of treating ulcerative colitis comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a second pharmaceutically active agent. In embodiments, provided herein are methods of treating microscopic colitis comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid, or a pharmaceutically acceptable salt thereof, in combination with a second pharmaceutically active agent.

[0058] When the symptom includes diarrhea, the second pharmaceutically active agent may include an anti-diarrhea drug such as diphenoxylate / atropine, loperamide, paregoric, bismuth subsalicylate. When constipation is the symptom, the second pharmaceutically active agent may include a laxative, such as a bulk-forming agent, such as fiber; a stool softener, such as docusate; a lubricant, such as mineral oil; a hypertonic agent, such as sorbitol, mannitol, polyethylene glycol; a stimulant, such as bisacodyl; or a chloride channel activator, such as lubiprostone. The second pharmaceutically active agent may include an antispasmodic drug, such as dicyclomine, promethazine, or peppermint oil. The second pharmaceutically active agent can include an antidepressant, for example, a tricycline such as amitriptyline, desipramine, doxepin, imipramine, nortryptyline, and protriptyline; an SSRI such as citalopram, escitalopram, fluoxetine, paroxetine, sertraline, and vilazodone; an SNRI such as duloxetine, venlafaxine, and desvenlafaxine; and an NDRI such as bupropion. The second pharmaceutically active agent can include an anti-inflammatory drug such as aminosalicylate, for example 4-aminosalicylic acid, balsalazide, olsalazine, sulfasalazine or mesalazine; or a corticosteroid such as cortisol, cortisone, prednisone, prednisolone, methylprednisolone, dexamethasone, betamethasone, triamcinolone or fludrocortisone acetate. The second pharmaceutically active agent can include an immunomodulator such as azathioprine, 6-mercaptopurine, cyclosporin A, methotrexate and tacrolimus. The second pharmaceutically active agent can include an anti-TNF antibody such as certolizumab, adalimumab, infliximab or natalizumab. The second pharmaceutically active agent can include cholestyramine.The second pharmaceutically active agent can include an antibiotic such as penicillin G, ampicillin, amoxicillin, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, carbenicillin, mezlocillin, clavulanic acid, sulbactam, cefacetin, cefadroxil, cephalexin, cefazolin, cephradine, loracarbef, cefoxitin, cefdinir, azithromycin, clarithromycin, erythromycin, fidaxomicin, sulfacetamide, sulfadiazine, sulfisoxazole, sulfamethoxazole, sulfadimethoxine, sulfadoxine, lincomycin, clindamycin, streptomycin, kanamycin, gentamicin, doxycycline, chlortetracycline, minocycline, tetracycline, oxytetracycline, chloramphenicol. The second pharmaceutically active agent may include an antiemetic, such as prochloroperazine, dimenhydrinate, or meclizine.The foregoing second active agents are representative and should not be considered limiting.

[0059] 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.

[0060] 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.

[0061] "Gastrointestinal disorder herein" refers to irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis and / or microscopic colitis.

[0062] "Amelioration" herein refers to treating a gastrointestinal disorder, ie, irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, and / or microscopic colitis, including some or all of the corresponding symptoms typically associated with the aforementioned disorders.

[0063] "Improvement in next-day function" or "wherein there is an improvement in next-day function" refers to 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 the symptoms of the gastrointestinal disorders herein (i.e., irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, and microscopic colitis), and persist 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.

[0064] "Treating," "treatment," or "treat" may refer to the following: reducing, improving, alleviating, ameliorating, alleviating, inhibiting, reversing, and / or alleviating a gastrointestinal disorder herein, i.e., irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, and microscopic colitis, in a subject, or delaying the appearance of symptoms of a gastrointestinal disorder herein in a subject (prevention). In embodiments, "treating," "treatment," or "treatment" may refer to preventing the appearance 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 inhibiting or alleviating a gastrointestinal disorder herein, e.g., causing regression of at least one of the gastrointestinal disorder herein or its corresponding clinical symptoms or subclinical symptoms. The benefit to the subject being treated can be statistically significant, mathematically significant, or at least perceptible to the subject and / or physician. Nevertheless, prophylactic (preventive) treatment and therapeutic (curative) treatment are two separate embodiments of the disclosure herein.

[0065] By "effective amount" or "therapeutically effective amount" is meant a dosage sufficient to alleviate one or more symptoms of the disorder, disease or condition being treated, e.g., IBS, Crohn's disease, celiac disease, ulcerative colitis, or microscopic colitis, or to otherwise provide the desired pharmacological and / or physiological effect.

[0066] "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.

[0067] "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.

[0068] "Subjects in need thereof" include individuals who have been diagnosed with a gastrointestinal disorder described herein. Individuals include mammals. The 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.

[0069] 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.

[0070] 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 irritable bowel syndrome, 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, wherein the method provides an improvement in one or more symptoms of irritable bowel syndrome in the subject.

2. The method of claim 1, wherein the improvement is provided for more than 6 hours after administration.

3. The method of claim 1, wherein the subject is administered a composition comprising 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.

4. The method of claim 3, wherein the subject is administered a composition comprising about 1 mg to about 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

5. The method of claim 3, wherein the subject is administered a composition comprising about 5 mg to about 250 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

6. The method of claim 1, wherein the method provides improvement in at least one symptom selected from the group consisting of cramping, recurrent abdominal pain, bloating, diarrhea, and constipation.

7. The method of claim 3, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 400 mg.

8. The method of claim 3, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 200 mg.

9. The method of claim 1, wherein (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times per day.

10. The method of claim 1, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal, and parenteral.

11. A method for treating Crohn's disease, 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, wherein the method provides an improvement in one or more symptoms of the Crohn's disease in the subject.

12. The method of claim 11, wherein the improvement is provided for more than 6 hours after administration.

13. The method of claim 11, wherein the subject is administered a composition comprising 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.

14. The method of claim 13, wherein the subject is administered a composition comprising about 1 mg to about 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

15. The method of claim 13, wherein the subject is administered a composition comprising about 5 mg to about 250 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

16. The method of claim 11, wherein the method provides improvement in at least one symptom selected from the group consisting of diarrhea, cramping, abdominal pain, anemia, fever, and nausea.

17. The method of claim 13, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 400 mg.

18. The method of claim 13, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 200 mg.

19. The method of claim 11, wherein (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times per day.

20. The method of claim 11, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal, and parenteral.

21. A method of treating celiac disease 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, wherein the method provides an improvement in one or more symptoms of celiac disease in the subject.

22. The method of claim 21, wherein the improvement is provided for more than 6 hours after administration.

23. The method of claim 21, wherein the subject is administered a composition comprising 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.

24. The method of claim 23, wherein the subject is administered a composition comprising about 1 mg to about 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

25. The method of claim 23, wherein the subject is administered a composition comprising about 5 mg to about 250 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

26. The method of claim 21, wherein the method provides improvement in at least one symptom selected from the group consisting of diarrhea, cramping, abdominal pain, anemia, fever, and nausea.

27. The method of claim 23, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 400 mg.

28. The method of claim 23, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 200 mg.

29. The method of claim 21, wherein (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times per day.

30. The method of claim 21, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ophthalmic, vaginal, and parenteral.

31. A method of treating ulcerative colitis 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, wherein the method provides an improvement in one or more symptoms of the ulcerative colitis in the subject.

32. The method of claim 31 , wherein the improvement is provided for more than 6 hours after administration.

33. The method of claim 31, wherein the subject is administered a composition comprising 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.

34. The method of claim 33, wherein the subject is administered a composition comprising about 1 mg to about 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

35. The method of claim 33, wherein the subject is administered a composition comprising about 5 mg to about 250 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

36. The method of claim 31 , wherein the method provides improvement in at least one symptom selected from the group consisting of diarrhea, cramping, abdominal pain, anemia, fever, and nausea.

37. The method of claim 33, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 400 mg.

38. The method of claim 33, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 200 mg.

39. The method of claim 31, wherein (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times per day.

40. The method of claim 31, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ocular, vaginal, and parenteral.

41. A method of treating microscopic colitis 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, wherein the method provides an improvement in one or more symptoms of the microscopic colitis in the subject.

42. The method of claim 41, wherein the improvement is provided for more than 6 hours after administration.

43. The method of claim 41, wherein the subject is administered a composition comprising 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.

44. The method of claim 43, wherein the subject is administered a composition comprising about 1 mg to about 500 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

45. The method of claim 43, wherein the subject is administered a composition comprising about 5 mg to about 250 mg of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

46. ​​The method of claim 41, wherein the method provides improvement in at least one symptom selected from the group consisting of diarrhea, cramping, abdominal pain, anemia, fever, and nausea.

47. The method of claim 43, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 400 mg.

48. The method of claim 43, wherein the total amount of (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject over a twenty-four hour period is between 1 mg and 200 mg.

49. The method of claim 41, wherein (S)-3-amino-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered from one to four times per day.

50. The method of claim 41, wherein administering is accomplished via a route selected from the group consisting of oral, buccal, sublingual, rectal, topical, intranasal, ocular, vaginal, and parenteral.

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