Use of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid for gastrointestinal disorders and as an immunomodulator

Abstract

Provided is a method for effecting immunomodulation and treating gastrointestinal disorders, comprising administering to the subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt.In some embodiments, the composition for effecting immunomodulation and treating gastrointestinal disorders, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, is administered to the subject in need thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 485,620, filed February 17, 2023, the entire contents of which are incorporated herein by reference.

[0002] Technical Field Treatment of gastrointestinal disorders with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. [Background technology]

[0003] background 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 co-occurring symptoms including cramping, recurring abdominal pain, bloating, and altered bowel motility, which may be diarrhea, constipation, or both. These symptoms may occur without visible signs of damage or disease in the gastrointestinal tract. IBS is classified into three types: 1) IBS with constipation (IBS-C), 2) IBS with diarrhea (IBS-D), and 3) IBS with mixed bowel habits (IBS-M). The cause of IBS is unclear. Dysregulation of GABAergic signaling and inflammation have been implicated in the pathogenesis of IBS-D. See, for example, Aggarwal et al., Journal of Neurogastroenterology and Motility, 2018; 24(3):422-430. Some IBS cases may be triggered by infection and referred to 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 tricyclics and SSRIs, may be used to treat the general symptoms, cramps, and abdominal pain associated with IBS. There is a continuing need for effective therapies to treat IBS.

[0004] According to the National Institutes of Digestive Diseases (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, including the mouth, esophagus, stomach, and anus. The cause of Crohn's disease is unclear. It may be genetic in some cases. In certain cases, it may be an autoimmune reaction that causes inflammation. Other possible causes are smoking, nonsteroidal anti-inflammatory drugs, 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, cramps, abdominal pain, anemia, fever, and nausea. Complications resulting from Crohn's disease include intestinal obstruction, fistulas, abscesses, anal fissures, ulcers, nutritional disorders, and inflammation in other parts of the body. No single treatment is effective 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 reduce inflammation; and immunomodulators, which reduce immune system activity. Monoclonal antibodies have also been used to reduce the activity of the immune system, thereby reducing inflammation. Such drug therapies can be associated with serious side effects. There is a continuing need for effective therapies to treat Crohn's disease.

[0005] According to the National Institutes of Diseases and Diseases (NIDDK), celiac disease is a digestive disorder that damages the small intestine. It is caused by the ingestion of foods containing gluten, a protein found in wheat, barley, and rye, which results in an autoimmune response. Celiac disease appears to be genetic in nature. Symptoms are more common in children and include abdominal bloating, chronic diarrhea, constipation, gas, nausea, pale, foul-smelling stools, stomach pain, and impaired nutrient absorption, which can lead to tooth enamel damage, delayed puberty, poor growth in infants, and weight loss. Adults are less likely to experience digestive symptoms, but may present with anemia, a red, shiny tongue, bone or joint pain, depression, headaches, dermatitis herpetiformis, infertility, mouth ulcers, seizures, fatigue, and weak, brittle bones. Gastrointestinal (GI) symptoms in adults include abdominal pain, bloating, intestinal blockage, and ulcers in the stomach or intestinal lining. Treatment generally involves avoiding foods containing gluten. There is a continuing need for effective treatments to reduce or eliminate the symptoms of celiac disease.

[0006] According to the National Institutes of Diseases (NIDDK), ulcerative colitis is a chronic inflammatory bowel disease characterized by inflammation and ulcers in the lining of the large intestine. Ulcerative colitis often begins gradually and can worsen over time. Symptoms can range from mild to severe. Many people experience periods of remission, or symptom-free periods, that can last weeks or years. The goal of treatment is to maintain people in long-term remission. The exact cause of ulcerative colitis is unknown. The following factors may contribute to the development of ulcerative colitis: genetic predisposition, an abnormal immune response targeting the intestinal lining, nonsteroidal anti-inflammatory drugs, antibiotics, and oral contraceptives. Symptoms include bowel urgency, fatigue, nausea, loss of appetite, weight loss, fever, anemia, joint pain, and rash. Approximately 10 percent of people may experience severe symptoms, such as frequent bloody stools, fever, and severe abdominal cramps. Treatment of ulcerative colitis symptoms generally includes drug therapy 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.Said drug therapy may be accompanied by serious side effects.There is a continuing need for an effective therapy for treating ulcerative colitis.

[0007] According to the NIDDK, microscopic colitis is inflammation visible only under a microscope. Two types of microscopic colitis are collagenous colitis and lymphocytic colitis. In both types of microscopic colitis, an increased number of lymphocytes can be seen in the colonic epithelium. The two types of colitis affect colonic tissue in slightly different ways. In lymphocytic colitis, the lymphocyte count is high and the colonic tissue and lining are normal in thickness. In collagenous colitis, the collagen layer below the epithelium accumulates and becomes thicker than normal. The exact cause of microscopic colitis is unknown, but it is thought to result from an abnormal immune response to bacteria normally present in the colon. Several other factors, including autoimmune diseases, medications, infections, genetic factors, and bile acid malabsorption, may contribute to the development of microscopic colitis. The most common symptom of microscopic colitis is chronic watery, non-bloody diarrhea. Episodes of diarrhea can last for weeks, months, or years. However, many people with microscopic colitis may experience long periods without diarrhea. Other signs and symptoms of microscopic colitis may include a strong urgency to defecate or the need to rush to the toilet, pain, cramps, or abdominal distension, which is usually mild, weight loss, nausea, fecal incontinence, which is the involuntary loss of stool or liquid from the rectum, especially at night, and dehydration due to not consuming enough fluids to replace the fluid lost through diarrhea. Treatment for ulcerative colitis symptoms generally includes medications such as antidiarrheals (e.g., bismuth subsalicylate, diphenoxylate / atropine, and loperamide), corticosteroids (e.g., budesonide and prednisone), anti-inflammatory medications (e.g., mesalamine and sulfasalazine), bile-blocking medications (e.g., cholestyramine resin), antibiotics (e.g., metronidazole and erythromycin), immunomodulators (e.g., mercaptopurine, azathioprine, and methotrexate), and anti-TNF therapies (e.g., infliximab and adalimumab). Some of these medications may be associated with serious side effects. There is a continuing need for effective therapies for treating microscopic colitis.

[0008] Vigabatrin is a gamma-aminobutyric acid aminotransferase (GABA-AT) inhibitor used to treat treatment-resistant epilepsy and infantile spasms. Vigabatrin is associated with several potentially serious side effects. Its use is limited due to the possibility of retinal toxicity and subsequent visual field loss. (1S,3S)-3-aminodifluoromethylenyl-1-cyclopentanoic acid (also known as CPP-115) is a GABA-AT inhibitor that inactivates GABA-AT 186-fold more efficiently than vigabatrin. Preclinical data on CPP-115 have reportedly demonstrated comparable pharmacokinetics, improved tolerability, and a more favorable toxicity profile compared to vigabatrin at significantly lower drug doses. See Prescot et al., Neuropsychopharmacology (2018) 43, 646-654. See also U.S. Patent No. 9,993,449, incorporated herein by reference. (S)-3-amino-4-(difluoromethylenyl)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 effective as a GABA-AT inactivator than CPP-115. Id. Summary of the Invention

[0009] overview Provided are methods and compositions for treating gastrointestinal disorders.In some embodiments, the method for treating irritable bowel syndrome described herein comprises administering to a subject in need thereof, and comprises administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof.In some embodiments, the composition for treating irritable bowel syndrome, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, is administered to a subject in need thereof.In some embodiments, the method for treating irritable bowel syndrome comprises administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, thereby causing the subject to improve one or more symptoms of irritable bowel syndrome. In some embodiments, the method for treating irritable bowel syndrome comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, so that the subject experiences an improvement in the symptoms of irritable bowel syndrome the day after administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating irritable bowel syndrome is about 0.01 mg to about 750 mg. In certain embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject suffering from irritable bowel syndrome once daily, twice daily, three times daily, or four times daily.In certain embodiments, a method for treating irritable bowel syndrome is described herein, comprising administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical agent selected from the group consisting of an antidiarrheal, an antispasmodic, and an antidepressant, wherein the method results in improvement of irritable bowel syndrome.

[0010] In some embodiments, the method for treating Crohn's disease described herein comprises administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, a composition for treating Crohn's disease, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof. In some embodiments, the method for treating Crohn's disease comprises administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, resulting in the improvement of one or more symptoms of Crohn's disease in the subject. In one embodiment, the method for treating Crohn's disease comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting in an improvement in the symptoms of Crohn's disease in the subject the day after administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating Crohn's disease is about 0.01 mg to about 750 mg. In certain embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating Crohn's disease is administered to a subject once daily, twice daily, three times daily, or four times daily.In certain embodiments, a method of treating Crohn's disease is described herein, comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical agent selected from the group consisting of an antidiarrheal, an antispasmodic, an aminosalicylic acid, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method results in improvement of Crohn's disease.

[0011] In some embodiments, the method for treating celiac disease described herein comprises administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, a composition for treating celiac disease comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In some embodiments, the method for treating celiac disease comprises administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, resulting in the improvement of one or more symptoms of celiac disease in the subject. In one embodiment, the method for treating celiac disease comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting in an improvement in the symptoms of celiac disease in the subject the day after administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating celiac disease is about 0.01 mg to about 750 mg. In certain embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating celiac disease is administered to a subject once daily, twice daily, three times daily, or four times daily.In certain embodiments, a method of treating celiac disease is described herein, comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical agent selected from the group consisting of an antidiarrheal, an antispasmodic, an aminosalicylic acid, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method results in improvement of the celiac disease.

[0012] In some embodiments, the method for treating ulcerative colitis described herein comprises administering to a subject in need thereof, and comprises administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt.In some embodiments, the composition for treating ulcerative colitis, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, is administered to a subject in need thereof.In some embodiments, the method for treating ulcerative colitis comprises administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, thereby causing the subject to improve one or more symptoms of ulcerative colitis. In some embodiments, the method for treating ulcerative colitis comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, so that the subject experiences an improvement in the symptoms of ulcerative colitis the day after administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating ulcerative colitis is about 0.01 mg to about 750 mg. In certain embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating ulcerative colitis is administered to a subject once daily, twice daily, three times daily, or four times daily.In certain embodiments, a method of treating ulcerative colitis is described herein, comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical agent selected from the group consisting of an antidiarrheal, an antispasmodic, an aminosalicylic acid, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method results in improvement of the ulcerative colitis.

[0013] In some embodiments, the method for treating microscopic colitis described herein comprises administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, a composition for treating microscopic colitis, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof. In some embodiments, the method for treating microscopic colitis comprises administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, resulting in the improvement of one or more symptoms of microscopic colitis in the subject. In one embodiment, the method for treating microscopic colitis comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting in an improvement in the symptoms of microscopic colitis in the subject the day after administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating microscopic colitis is about 0.01 mg to about 750 mg. In certain embodiments, an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating microscopic colitis is administered to a subject once daily, twice daily, three times daily, or four times daily.In certain embodiments, a method of treating microscopic colitis is described herein, comprising administering to a subject in need thereof (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof in combination with a pharmaceutical agent selected from the group consisting of an antidiarrheal, an antispasmodic, an aminosalicylic acid, a corticosteroid, an immunomodulator, and an antidepressant, wherein the method results in improvement of the microscopic colitis. DETAILED DESCRIPTION OF THE INVENTION

[0014] Detailed Description A method for treating irritable bowel syndrome with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is described herein.As used herein, "irritable bowel syndrome" includes IBS-C, IBS-D, and IBS-M.A method for treating Crohn's disease with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is also described herein.A method for treating celiac disease with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is also described herein.A method for treating ulcerative colitis with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is also described herein. Also described herein is a method for treating microscopic colitis with (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. 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 the specific undesirable side effects associated with medications or other GABA-AT inhibitors that are commonly prescribed for irritable bowel syndrome.In some embodiments, the method for treating irritable bowel syndrome comprises administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt.In some embodiments, the composition for treating irritable bowel syndrome, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, is administered to a subject in need thereof. In some embodiments, the method for treating irritable bowel syndrome comprises administering (S)-3-amino-4- (difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof, thereby improving one or more symptoms of irritable bowel syndrome in the subject.In some embodiments, the method for treating irritable bowel syndrome comprises administering (S)-3-amino-4- (difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof, thereby improving the symptoms of irritable bowel syndrome in the subject the next day after administering (S)-3-amino-4- (difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating irritable bowel syndrome is about 0.01 mg to about 750 mg. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject suffering from irritable bowel syndrome once daily, twice daily, three times daily, or four times daily.

[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 the undesirable side effects associated with medications or other GABA-AT inhibitors commonly prescribed for Crohn's disease. In some embodiments, the method for treating Crohn's disease comprises administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, a composition for treating Crohn's disease comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In some embodiments, the method for treating Crohn's disease comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting in the improvement of one or more symptoms of Crohn's disease in the subject. In one embodiment, the method for treating Crohn's disease comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, resulting in an improvement in the symptoms of Crohn's disease in the subject the day after administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In one embodiment, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating Crohn's disease is about 0.01 mg to about 750 mg. In one embodiment, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject suffering from Crohn's disease once a day, twice a day, three times a day, 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, which alleviate the symptoms of celiac disease without the undesirable side effects associated with medications or other GABA-AT inhibitors commonly prescribed for celiac disease. In some embodiments, the method for treating celiac disease comprises administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, a composition for treating celiac disease comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. In some embodiments, the method for treating celiac disease comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby improving one or more symptoms of celiac disease in the subject.In some embodiments, the method for treating celiac disease comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby improving one or more symptoms of celiac disease in the subject the day after administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating celiac disease is about 0.01 mg to about 750 mg. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject with celiac disease once daily, twice daily, three times daily, or four times daily.

[0018] Methods and compositions for treating ulcerative colitis are provided. According to the present disclosure, methods and compositions for treating ulcerative colitis are provided, which alleviate the symptoms of ulcerative colitis without the specific undesirable side effects associated with medications or other GABA-AT inhibitors that are commonly prescribed for ulcerative colitis.In some embodiments, the method for treating ulcerative colitis comprises administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof.In some embodiments, the composition for treating ulcerative colitis, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, is administered to a subject in need thereof. In some embodiments, the method for treating ulcerative colitis comprises administering (S)-3-amino-4- (difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof, thereby improving one or more symptoms of ulcerative colitis in the subject.In some embodiments, the method for treating ulcerative colitis comprises administering (S)-3-amino-4- (difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt to a subject in need thereof, thereby improving the symptoms of ulcerative colitis in the subject the next day after administering (S)-3-amino-4- (difluoromethylenyl) cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating ulcerative colitis is about 0.01 mg to about 750 mg. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject suffering from ulcerative colitis once daily, twice daily, three times daily, 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 the specific undesirable side effects associated with medications or other GABA-AT inhibitors that are commonly prescribed for microscopic colitis. In some embodiments, the method for treating microscopic colitis comprises administering an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof. In some embodiments, a composition for treating microscopic colitis, comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, is administered to a subject in need thereof. In some embodiments, the method for treating microscopic colitis comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby improving one or more symptoms of microscopic colitis in the subject.In some embodiments, the method for treating microscopic colitis comprises administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby improving the symptoms of microscopic colitis in the subject the day after administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof for treating microscopic colitis is about 0.01 mg to about 750 mg. In some embodiments, the effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject suffering from microscopic colitis once daily, twice daily, three times daily, or four times daily.

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

[0021] In certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid can be provided as an acid addition salt, zwitterion hydrate, zwitterion anhydrate, hydrochloride or hydrobromide salt, or in the form of a zwitterion monohydrate. Acid addition salts include but are not limited to maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, oxalic acid, bis-methylenesalicylic acid, methanesulfonic acid, ethane-disulfonic 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 acetic acid addition salt, and 8-halotheophylline, for example, 8-bromo-theophylline.In some embodiments, inorganic acid addition salts can be used, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid or nitric acid addition salts.

[0022] The pathogenesis of inflammatory gastrointestinal disorders can begin with an inflammatory cascade. Autoimmunity in inflammatory gastrointestinal disorders can be initiated at the molecular and cellular levels. For example, serum cytokine concentrations can be elevated. In some patients, autoimmunity eventually transitions to immune-mediated inflammation, primarily focused on the gastrointestinal tract. The gastrointestinal 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, although not normally present in the gastrointestinal tract, migrate from the blood to the lining of the gastrointestinal 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 into the gastrointestinal tract.

[0023] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature mammalian 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 macrophage inflammatory cytokine production and T cell activation by blocking calcium signaling and NFκB activity.

[0024] Diverse types of mouse 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 is known to limit mouse T cell production of IL-21, IFNγ2-4, TNFα3, and IL-123, while promoting TGFβ and Treg responses. Ibid. Antigen-presenting cells (APCs), such as macrophages, also express GABA. A GABA or GABA receptors express GABA-R, and their activation inhibits their inflammatory activity. A-R agonists reduced the secretion of IL-6, IL-1β, IL-12, and / or TNFα from LPS-stimulated mouse macrophages. Id.

[0025] (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a γ-aminobutyric acid aminotransferase (GABA-AT) inhibitor. GABA-AT is a pyridoxal 5'-phosphate-dependent enzyme responsible for the degradation of the inhibitory neurotransmitter GABA. (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid has a higher binding affinity to GABA-AT compared to CPP-115 (K of 1 and CPP-115). I values ​​were found to be 9.7 μM and 59 μM, respectively), (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid inactivates GABA-AT at a higher rate than CPP-115 (k values ​​for (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid and CPP-115 inact The values ​​are 3.32 minutes, respectively. -1 and 2.05 mm -1 See U.S. Patent No. 9,993,449. Overall, the efficiency constant (k inact / K I =342 mM -1 minutes -1 ) is the efficiency constant (k inact / K I =34.9 mM -1 minutes -1) is 9.8 times greater than CPP-115; therefore, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is 9.8 times more efficient as a GABA-AT inactivator 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 have contributed to its greater safety compared to vigabatrin. (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid exhibited IC values ​​of 1.25 and 1.5% for both Asp-AT and Ala-AT. 50 CPP-115 is a very weak reversible inhibitor of K I The value is 0.116 mM, and k inact The value is 0.097 minutes -1 (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a moderate OAT inactivator. I The value is 0.0033 mM, and k inact The value is 0.025 minutes -1 (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is a potent OAT inactivator. inact / K I value (7.6 mM -1 minutes -1 ) CPP-115 k inact / K I value (0.84 mM -1 minutes -1 ), (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid is 9.0 times more efficient as an inactivator of OAT than CPP-115, which is consistent with its greater efficiency as a GABA-AT inactivator.

[0026] Without wishing to be bound by any particular theory, selective inhibition of GABA-AT by (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases GABA concentrations at sites where GABA is normally present. A This activates the GABA receptor, which inhibits the inflammatory activity of lymphocytes and macrophages that damages the gastrointestinal lining, simultaneously reducing the production of inflammatory cytokines, thereby suppressing the disease process. Furthermore, decreased GABA levels and alterations in the GABAergic signaling system contribute to the pathogenesis of the gastrointestinal disorders described herein. Administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof increases GABA levels, resulting in the regulation of both gastrointestinal motor and secretory activity, thereby alleviating the symptoms of the gastrointestinal disorders described herein.

[0027] Advantageously disclosed herein is a method for treating IBS by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt.For example, in one embodiment, a method for treating IBS is provided, which comprises administering to a subject in need thereof a pharmaceutical composition comprising about 0.01 mg to about 750 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition causes improvement for more than 6 hours after administration to the subject.

[0028] Advantageously disclosed herein is a method for treating Crohn's disease by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in one embodiment, a method for treating Crohn's disease is provided, comprising administering to a subject in need thereof about 0.01 mg to about 750 mg of a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition causes improvement for more than 6 hours after administration to the subject.

[0029] Advantageously disclosed herein is a method for treating ulcerative colitis by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in one embodiment, a method for treating ulcerative colitis is provided, comprising administering to a subject in need thereof a pharmaceutical composition comprising about 0.01 mg to about 750 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition causes improvement for more than 6 hours after administration to the subject.

[0030] Advantageously disclosed herein is a method for treating celiac disease by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in one embodiment, a method for treating celiac disease is provided, comprising administering to a subject in need thereof about 0.01 mg to about 750 mg of a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition results in improvement for more than 6 hours after administration to the subject.

[0031] Advantageously disclosed herein is a method for treating microscopic colitis by administering (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof. For example, in one embodiment, a method for treating microscopic colitis is provided, comprising administering to a subject in need thereof about 0.01 mg to about 750 mg of a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition causes improvement for more than 6 hours after administration to the subject.

[0032] In certain embodiments, the terms "effective amount" or "therapeutically effective amount" may be used interchangeably and refer to an amount of a compound, substance, composition, medicament, or other substance that is effective to achieve reduction, elimination, or prevention of a gastrointestinal disorder herein and minimize side effects typically associated with drugs or other GABA-AT inhibitors administered for a gastrointestinal disorder.

[0033] In certain embodiments, an "effective amount" herein can range from about 0.01 mg to about 750 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, administered one to four or more times per day. For example, a pharmaceutical composition containing an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof may 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 100 mg, about 100 mg to about 150 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 100 mg to about 150 mg, about mg~95 mg, 95 mg~100 mg, 100 mg~105 mg, 105 mg~110 mg, 110 mg~115 mg, 115 mg~120 mg, 120 mg~125 mg, 125 mg~130 mg, 130 mg~135 mg, 135 mg~140 mg, approx. 140 mg ~ approx. 145 mg, approx. 145 mg ~ approx. 150, approx. 150 mg ~ approx. 155 mg, approx. 155 mg ~ approx. 160 mg, approx. 160 mg ~ approx. 165 mg, approx. mg ~ approx. 190 mg, approx. 190 mg ~ approx. 195 mg, approx. 195 mg ~ approx. 200 mg, approx. 200 mg ~ approx. 205 mg, approx. 205 mg ~ approx. 210 mg, approx. 210 mg ~ approx. 215 mg, approx. 215 mg ~ approx. 220 mg, approx. mg ~ approx. 245 mg, approx. 245 mg ~ approx. 250, approx. 250mg~255 mg, 255 mg~260 mg, 260 mg~265 mg, 265 mg~270 mg, 270 mg~275 mg, 275 mg~280 mg, 280 mg~285 mg, 285 mg~290 mg, 290 mg~295 mg, 295 mg~300 300 mg to 305 mg, 305 mg to 310 mg, 310 mg to 315 mg, 315 mg to 320 mg, 320 mg to 325 mg, 325 mg to 330 mg, 335 mg to 340 mg, 340 mg to 345 mg, 345 mg ~ approx. 350, approx. 350 mg ~ approx. 355 mg, approx. 355 mg ~ approx. 360 mg, approx. 360 mg ~ approx. 365 mg, approx. 365 mg ~ approx. 370 mg, approx. 370 mg ~ approx. 375 mg, approx. mg ~ 405 mg, 405 mg ~ 410 mg, 410 mg ~ 415 mg, 415 mg ~ 420 mg, 420 mg ~ 425 mg, 425 mg ~ 430 mg, 430 mg ~ 435 mg, 435 mg ~ 440 mg, 440 mg ~ 445 mg, 445 mg ~ approx. 450, approx. 450 mg ~ approx. 455 mg, approx. 455 The compound may contain from about 460 mg to about 465 mg, from about 465 mg to about 470 mg, from about 470 mg to about 475 mg, from about 475 mg to about 480 mg, from about 480 mg to about 485 mg, from about 485 mg to about 490 mg, from about 490 mg to about 495 mg, or from about 495 mg to about 500 mg of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0034] In certain embodiments, the pharmaceutical composition comprising an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered in an amount of 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, 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, 74 mg, 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 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, 74 mg, 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, 111 mg, 112 mg, 113 mg, 114 mg, 115 mg, 116 mg, 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 141 mg, 142 mg, 143 mg, 144 mg, 145 mg, 146 mg, 147mg、148 mg、149 mg、150 mg、151mg、152 mg、153 mg、154 mg、155 mg、156 mg、157 mg、158 mg、159 mg、160 mg、161 mg、162 mg、163 mg、164 mg、165 mg、166 mg、167 mg、168 mg、169 mg、170 mg、171 mg、172 mg、173 mg、174 mg、175 mg、176 mg、177 mg、178 mg、179 mg、180 mg、181 mg、182 mg、183 mg、184 mg、185 mg、186 mg、187 mg、188 mg、189 mg、190 mg、191 mg、192mg、193 mg、194 mg、195 mg、196 mg、197 mg、198 mg、199 mg、200 mg、201 mg、202 mg、203 mg、204 mg、205 mg、206 mg、207 mg、208 mg、209 mg、210 mg、211 mg、212 mg、213 mg、214 mg、215 mg、216 mg、217 mg、218 mg、219 mg、220 mg、221 mg、222 mg、223 mg、224 mg、225 mg、226 mg、227 mg、228 mg、229 mg、230 mg、231 mg、232 mg、233 mg、234 mg、235 mg、236 mg、237 mg、238 mg、239 mg、240 mg、241 mg、242 mg、243 mg、244 mg、245 mg、246 mg、247 mg、248 mg、249 mg、250 mg、251mg、252 mg、253 mg、254 mg、255 mg、256 mg、257 mg、258 mg、259 mg、260 mg、261 mg、262 mg、263 mg、264 mg、265 mg、266 mg、267 mg、268 mg、269 mg、270 mg、271 mg、272 mg、273 mg、274 mg、275 mg、276 mg、277 mg、278 mg、279 mg、280 mg、281 mg、282 mg、283 mg、284 mg、285 mg、286 mg、287 mg、288 mg、289 mg、290mg、291 mg、292mg、293 mg、294 mg、295 mg、296 mg、297 mg、298 mg、299 mg、300 mg、301 mg、302 mg、303 mg、304 mg、305 mg、306 mg、307 mg308 mg、309 mg、310 mg、311 mg、312 mg、313 mg、314 mg、315 mg、316 mg、317 mg、318 mg、319 mg、320 mg、321 mg、322 mg、323 mg、324 mg、325 mg、326 mg、327 mg、328 mg、329 mg、230 mg、331 mg、332 mg、333 mg、334 mg、335 mg、336 mg、337 mg、338 mg、339 mg、340 mg、241 mg、342 mg、343 mg、344 mg、345 mg、346 mg、347 mg、348 mg、349 mg、350 mg、351mg、352 mg、353 mg、354 mg、355 mg、356 mg、357 mg、358 mg、359 mg、360 mg、361 mg、362 mg、363 mg、364 mg、365 mg、366 mg、367 mg、368 mg、369 mg、370 mg、371 mg、372 mg、373 mg、374 mg、375 mg、376 mg、377 mg、378 mg、379 mg、380 mg、381 mg、382 mg、383 mg、384 mg、385 mg、386 mg、387 mg、388 mg、389 mg、390 mg、391 mg、392mg、393 mg、394 mg、395 mg、396 mg、397 mg、398 mg、399 mg、400 mg、401 mg、402 mg、403 mg、404 mg、405 mg、406 mg、407 mg、408 mg、409 mg、410 mg、411 mg、412 mg、413 mg、414 mg、415 mg、416 mg、417 mg、418 mg、419 mg、420 mg、421 mg、422 mg、423 mg、424 mg、425 mg、426 mg、427 mg、428 mg、429 mg、430 mg、431 mg、432 mg、433mg, 434 mg, 435 mg, 436 mg, 237 mg, 438 mg, 439 mg, 440 mg, 441 mg, 442 mg, 443 mg, 444 mg, 445 mg, 446 mg, 447 mg, 448 mg, 449 mg, 450 mg, 451 mg, 452 mg, 453 mg, 454 mg, 455 mg, 456 mg, 457 mg, 458 mg, 459 mg, 460 mg, 461 mg, 462 mg, 463 mg, 464 mg, 465 mg, 466 mg, 467 mg, 468 mg, 469 mg, 470 mg, 471 mg, 472 mg, 473 mg, 474 mg, 475 mg, 476 mg, 477 mg, 478 mg, 479 mg, 480 mg, 481 mg, 482 mg, 483 mg, 484 mg, 485 mg, 486 mg, 487 mg, 488 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

[0035] In certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at about 0.01 mg / day to about 750 mg / day. For example, in certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at a dose of 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 2 130 mg / day, 135 mg / day, 140 mg / day, 145 mg / day, 150 mg / day, 155 mg / day, 160 mg / day, 165 mg / day, 170 mg / day, 175 mg / day, 180 mg / day, 185 mg / day, 190 mg / day, 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, approx. 270 mg / day, approx. 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 405mg / day, about 410 mg / day, about 415 mg / day, about 420 mg / day, about 425 mg / day, about 430 mg / day, about 435 mg / 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, approx. 480 mg / day, approx. 485 mg / day, approx. 490 mg / day, approx. 495 mg / day, approx. 500 mg / day, approx. 505 mg / day, approx. 510 mg / day, approx. 515 mg / day, approx. mg / day, approx. 550 mg / day, approx. 555 mg / day, approx. 560 mg / day, approx. 565 mg / day, approx. 570 mg / day, approx. 575 mg / day, approx. 580 mg / day, approx. 585 mg / day, approx. 590 mg / day, approx. 595 mg / day, approx. 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, approx. 700 mg / day, approx. 705 The dose may be administered in one, two, three, four or more divided doses, such as 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. In certain embodiments, subjects may be started on a low dose, and the dose may be gradually increased over time.

[0036] In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject diagnosed with a gastrointestinal disorder herein via a pharmaceutical composition. The pharmaceutical composition herein encompasses dosage forms. The dosage form herein encompasses unit doses. In some embodiments, various dosage forms, including conventional formulations and modified-release formulations, can be administered once, twice, three times, four times, or more times per day, as described below. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject once or twice per day (e.g., morning and / or evening). In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject three times per day (e.g., morning, midday, and bedtime, or every 8 hours). In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject four times a day (for example, morning, noon, evening, and bedtime, or every 6 hours). In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject via continuous infusion. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered to a subject at the onset of acute gastrointestinal disorder symptoms, such as cramps, nausea, diarrhea, whenever they occur. Any suitable administration route, such as oral, rectal, nasal, pulmonary, vaginal, sublingual, transdermal, intravenous, intraarterial, epidural, intramuscular, intraperitoneal, and subcutaneous, may be used. Suitable dosage forms include tablets, capsules, oral liquids, powders, aerosols, topical liquids, patches, transdermal modalities such as creams and ointments, parenteral formulations and suppositories.In certain embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is used to manufacture a medicament for the treatment of a gastrointestinal disorder herein.

[0037] In some embodiments, provided herein is a method for treating gastrointestinal disorders, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition improves the symptoms of the gastrointestinal disorders described herein for more than 1 hour after administration to the subject.In some embodiments, provided herein is a method for treating gastrointestinal disorders, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition improves the symptoms of the gastrointestinal disorders described herein for more than 2 hours after administration to the subject. In some embodiments, provided herein is a method for treating gastrointestinal disorders, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition improves the symptoms of the gastrointestinal disorders described herein for more than 3 hours after administration to the subject.In some embodiments, provided herein is a method for treating gastrointestinal disorders, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition improves the symptoms of the gastrointestinal disorders described herein for more than 4 hours after administration to the subject. In certain embodiments, provided herein is a method for treating a gastrointestinal disorder, comprising administering to a subject in need thereof a pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, wherein the composition results in improvement of symptoms of the gastrointestinal disorder herein for more than 6 hours after administration to the subject.In some embodiments, provided herein is a method for treating gastrointestinal disorders, comprising administering to a subject in need thereof pharmaceutical compositions comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition is administered to the subject and causes the symptom improvement of the gastrointestinal disorders herein for more than 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours or 24 hours.In some embodiments, the pharmaceutical composition causes the improvement of the next day function of the subject diagnosed with gastrointestinal disorders herein.For example, the pharmaceutical composition can cause the symptom improvement of the gastrointestinal disorders herein for more than about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours or about 24 hours after administration and waking up from a night's sleep.

[0038] In some embodiments, as described above, the pharmaceutical compositions herein can be provided with a conventional release profile or a modified release profile. Pharmaceutical compositions can be prepared using a pharmaceutically acceptable "carrier" made of a material that is considered safe and effective. "Carrier" includes all ingredients present in a pharmaceutical formulation other than the active ingredient. 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 formulating pharmaceutical compositions using such carriers.

[0039] In some embodiments, the pharmaceutical composition herein is a modified release dosage form that provides a modified release profile. The modified release profile can be an immediate release, delayed release, or sustained release profile. Conventional (or non-modified) release oral dosage forms, such as tablets, capsules, suppositories, syrups, solutions, and suspensions, generally release drugs into the oral cavity, stomach, or intestines when the tablet, capsule shell, or suppository dissolves, or in the case of syrups, solutions, and suspensions, they are swallowed. The drug release pattern from modified release (MR) dosage forms is intentionally changed from that of conventional dosage forms to achieve desired therapeutic goals and / or better patient compliance. MR pharmaceuticals include orally disintegrating dosage forms (ODDFs) that provide immediate release, sustained release dosage forms, delayed release dosage forms (e.g., enteric-coated), and pulsed release dosage forms.

[0040] ODDF is a solid dosage form containing a pharmaceutical substance or active ingredient that rapidly disintegrates upon placement on the tongue, typically within a few seconds. ODDF disintegration times generally range from one or two seconds to approximately one minute. ODDF is designed to rapidly disintegrate or dissolve upon contact with saliva. This administration method can be beneficial for people who may have difficulty swallowing tablets, whether due to physical weakness or psychological reasons. Subjects suffering from gastrointestinal disorders may exhibit such behavior. ODDF can rapidly deliver drugs to the bloodstream via the mucosa, resulting in a rapid onset of action. Examples of ODDF include orally disintegrating tablets, capsules, and rapidly dissolving films and wafers.

[0041] An extended-release dosage form (ERDF) has a sustained-release profile, allowing for reduced dosing frequency compared to that exhibited by conventional dosage forms, such as solutions or non-modified-release dosage forms. ERDFs provide a sustained duration of drug action. Suitable formulations providing extended-release profiles are well known in the art. For example, coated extended-release beads or granules ("beads" and "granules" are used interchangeably herein) are well known in the art, in which (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is loaded onto beads, e.g., nonpareil confectionery beads, and then coated with a conventional release-retarding material, such as wax or an enteric coating. In an embodiment, the beads can be formed by mixing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof with a material to provide a mass from which the drug can be leached. In some embodiments, beads can be designed to provide different release rates by varying coating or bulk properties, such as thickness, porosity, the use of different materials, etc. Beads with different release rates can be combined into a single dosage form to provide variable or sustained release. The beads can be placed in capsules or compressed into tablets.

[0042] In some embodiments, the modified dosage form herein incorporates a delayed-release dosage form with a delayed-release profile. The delayed-release dosage form can include delayed-release tablets or delayed-release capsules. A delayed-release tablet is a solid dosage form that releases a drug (or drugs), such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, at a time other than immediately after administration. A delayed-release capsule is a solid dosage form in which a drug is enclosed in a hard or soft soluble container made of a suitable form of gelatin, and the drug is released at a time other than immediately after administration. For example, enteric-coated tablets, capsules, particles, and beads are well-known examples of delayed-release dosage forms. Enteric-coated tablets, capsules, particles, and beads pass through the stomach and release the drug in the intestine. In some embodiments, the delayed-release tablet is a solid dosage form containing a collection of pharmaceutical particles that releases a drug (or drugs) at a time other than immediately after administration. In some embodiments, the collection of pharmaceutical particles is covered with a coating that delays the release of the drug. In some embodiments, a delayed-release capsule is a solid dosage form containing a collection of pharmaceutical particles that releases a drug (or drugs) at a time other than immediately after administration. In some embodiments, the collection of pharmaceutical particles is covered with a coating that delays the release of the drug.

[0043] Delayed-release dosage forms are well known to those skilled in the art. For example, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt is loaded onto beads, such as nonpareil confectionery beads, and then coated with conventional release-delaying materials, such as wax, enteric coating, etc., to form delayed-release beads or granules. In some embodiments, beads can be formed by mixing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt with materials to provide a mass from which the drug is leached. In some embodiments, beads can be designed to provide different release rates by varying the properties of the coating or mass, such as thickness, porosity, the use of different materials, etc. In some embodiments, the enteric-coated granules of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salts can be contained in an enteric-coated capsule or tablet that releases the granules in the small intestine. In some embodiments, the granules have a coating that keeps the coated granules intact until they reach at least the ileum, and then provides delayed release of the drug in the colon. Suitable enteric coating materials, such as Eudragit® coatings, such as methacrylic acid and methyl methacrylate polymers, are well known in the art. The granules can be placed in capsules or compressed into tablets.

[0044] In some embodiments, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is incorporated into a porous inert carrier to provide a delayed-release profile. In some embodiments, the porous inert carrier incorporates channels or passageways through which the drug diffuses into the surrounding fluid. In some embodiments, (S)-3-amino-4-(difluoromethylenyl)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. The delayed effect may be due to a predetermined release rate of the drug from the resin when the drug-resin complex contacts gastrointestinal fluid and the ionic components dissolved therein. In some embodiments, a membrane is utilized to control the release rate from the drug-containing reservoir. In some embodiments, liquid formulations may also be utilized to provide a delayed-release profile. For example, liquid formulations comprise solid particles dispersed throughout a liquid phase in which the particles do not dissolve. The suspensions of the present invention are formulated to allow for at least reduced dosing frequency compared to drugs presented in conventional dosage forms (e.g., as solutions or conventional solid dosage forms that rapidly release the drug), e.g., suspensions of ion exchange resin components or microbeads.

[0045] In some embodiments, the pharmaceutical compositions described herein are suitable for parenteral administration, including, for example, intramuscular (im), intravenous (iv), subcutaneous (sc), intraperitoneal (ip), epidural, or intrathecal (it) administration. Parenteral compositions should be sterile for administration by injection, infusion, or implantation into the body and may be packaged in either single-dose or multi-dose containers. In some embodiments, a liquid pharmaceutical composition for parenteral administration to a subject contains an active substance, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, in any of the amounts described above. In some embodiments, the pharmaceutical composition for parenteral administration is formulated, for example, in a total volume of about 10 ml, about 20 ml, about 25 ml, about 50 ml, about 100 ml, about 200 ml, about 250 ml, or about 500 ml. In some embodiments, the composition is contained in a bag, glass vial, plastic vial, or bottle.

[0046] The pharmaceutical compositions for parenteral administration provided herein may contain one or more additives, such as solvents, solubility enhancers, suspending agents, buffers, isotonicity agents, stabilizers, or antimicrobial preservatives.When used, the additives of the parenteral composition do not adversely affect the stability, bioavailability, safety, and / or efficacy of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salts used in the composition.Therefore, a parenteral composition is provided in which there is no incompatibility between any of the components of the dosage form.

[0047] In some embodiments, the parenteral composition (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt comprises a stabilizing amount of at least one additive.For example, the additive can be selected from the group consisting of buffering agents, solubilizing agents, isotonicity agents, antioxidants, chelating agents, antibacterial agents and preservatives.Those skilled in the art will understand that additives can have one or more functions and can be classified into one or more defined groups.

[0048] In some embodiments, in the parenteral composition comprising (S)-3-amino-4-difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof and an additive, the additive is present in a weight percent (w / v) of, for example, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5%. In some embodiments, the additive is present in a weight percent of, for example, about 1.0% to about 10%, about 10% to about 25%, about 15% to about 35%, about 0.5% to about 5%, about 0.001% to about 1%, about 0.01% to about 1%, about 0.1% to about 1%, or about 0.5% to about 1%. In some embodiments, the additive is present in a weight percentage of, for example, about 0.001% to about 1%, about 0.01% to about 1%, about 1.0% to about 5%, about 10% to about 15%, or about 1% to about 15%.

[0049] In some embodiments, a parenteral composition of an active substance, such as (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof, is provided, wherein the pH of the composition is about 4.0 to about 8.0. In some embodiments, the pH of the composition is, for example, about 5.0 to about 8.0, about 6.0 to about 8.0, or about 6.5 to about 8.0. In some embodiments, the pH of the composition is, for example, about 6.5 to about 7.5, about 7.0 to about 7.8, about 7.2 to about 7.8, or about 7.3 to about 7.6. In some embodiments, 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 is understood that the dosage of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt provided herein is applicable to all dosage forms described herein, including conventional dosage forms, modified dosage forms, and parenteral formulations described herein. Those 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 effect, among other pharmaceutically acceptable criteria.

[0051] The clinical effectiveness of treatment can be monitored by any method known in the art.The measurable parameters for monitoring effectiveness depend on the condition being treated.To monitor the condition or improvement of 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 some embodiments, the present invention provides a method for treating IBS, comprising administering to a subject in need thereof the pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition causes the improvement of at least one IBS symptom.IBS symptom can include but is not limited to cramps, repeated abdominal pain, abdominal distension, and the change in intestinal motility, which can be diarrhea, constipation, or both.

[0053] In some embodiments, the present invention provides a method for treating Crohn's disease, comprising administering to a subject in need thereof the pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition causes the improvement of at least one symptom of Crohn's disease.The symptom of Crohn's disease can include but is not limited to diarrhea, cramps, abdominal pain, anemia, fever and nausea.

[0054] In some embodiments, the present invention provides a method for treating celiac disease, comprising administering to a subject in need thereof the pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition causes the improvement of at least one symptom of celiac disease.The symptom of celiac disease can include but is not limited to abdominal distension, chronic diarrhea, constipation, gas, nausea, pale and foul-smelling stool, stomach pain and nutrient malabsorption, delayed puberty, poor infant growth, growth retardation and weight loss.

[0055] In some embodiments, the present invention provides a method for treating ulcerative colitis, comprising administering to a subject in need thereof the pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition causes at least one symptom improvement of ulcerative colitis.The symptom of ulcerative colitis can include but is not limited to: urgency to defecate, bloody stool, fever, severe abdominal cramps, fatigue, nausea, loss of appetite, weight loss, fever, anemia, joint pain and rash.

[0056] In some embodiments, the present invention provides a method for treating microscopic colitis, comprising administering to a subject in need thereof the pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or its pharmaceutically acceptable salt, wherein the composition causes the improvement of at least one symptom of microscopic colitis.The symptom of microscopic colitis can include but is not limited to chronic watery non-bloody diarrhea, strong urgency to defecate, pain, cramps, abdominal distension, weight loss, nausea and fecal incontinence.

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

[0058] When the symptom includes diarrhea, the second pharmaceutically active agent can include antidiarrheals such as diphenoxylate / atropine, loperamide, paregoric, bismuth subsalicylate, etc. When the symptom includes constipation, the second pharmaceutically active agent can include laxatives, such as bulking agents, such as fiber; stool softeners, such as docusate; lubricants, such as mineral oil; hyperosmolar agents, such as sorbitol, mannitol, polyethylene glycol; stimulants, such as bisacodyl; or chloride channel activators, such as lubipostone. The second pharmaceutically active agent can include antispasmodics, such as dicyclomine, promethazine, or peppermint oil. The second pharmaceutically active agent may include an antidepressant, such as a tricyclic agent such as amitriptyline, desipramine, doxepin, imipramine, nortriptyline, 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 may include an anti-inflammatory agent, such as an aminosalicylates, such as 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 may include an immunomodulatory agent such as azathioprine, 6-mercaptopurine, cyclosporine A, methotrexate, and tacrolimus. The second pharmaceutically active agent may include an anti-TNF antibody such as certolizumab, adalimumab, infliximab, or natalizumab. The second pharmaceutically active agent may include cholestyramine.The second pharmaceutically active agent may include an antibiotic such as penicillin G, ampicillin, amoxicillin, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, carbenicillin, mezlocillin, clavulanic acid, sulbactam, cephacetrile, 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, or chloramphenicol. The second pharmaceutically active agent may include an antiemetic agent such as prochlorperazine, dimenhydrinate, or meclizine. The above second pharmaceutically active agents are representative and should not be considered limiting.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0060] As used herein, the term "about" or "approximately" refers to within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 3 standard deviations or more than 3 standard deviations, in accordance with the practice in the art. Alternatively, "about" can refer to a range of up to 20%, up to 10%, up to 5%, and / or up to 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 the treatment of gastrointestinal disorders, namely irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis and / or microscopic colitis, including some or all of the respective symptoms normally associated with said disorders.

[0063] "Improved next day function" or "experiencing improved next day function" refers to an improvement after awakening from a night's sleep period, wherein the beneficial effects of administration of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof apply to symptoms of gastrointestinal disorders herein, i.e., irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, and microscopic colitis, are discernible subjectively by the subject or objectively by an observer over a period of time after awakening, such as 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, etc.

[0064] "Treating," "treatment," or "treat" can refer to reducing, improving, alleviating, ameliorating, pacifying, suppressing, reversing, and / or alleviating the symptoms of a gastrointestinal disorder herein, i.e., irritable bowel syndrome, Crohn's disease, celiac disease, ulcerative colitis, and microscopic colitis, in a subject, or delaying (preventing) the onset of symptoms of a gastrointestinal disorder herein in a subject. In certain embodiments, "treating," "treat," or "treatment" can refer to preventing the onset of clinical symptoms of a disease or condition in a subject who may be suffering from or predisposed to a disease or condition, but who has not yet experienced or exhibited clinical or subclinical symptoms of the disease or condition. "Treating," "treat," or "treatment" also refers to inhibiting or alleviating a gastrointestinal disorder herein, for example, causing regression of a gastrointestinal disorder herein, or at least one of its respective clinical or subclinical symptoms. The benefit to a treated subject may be statistically significant, mathematically significant, or at least perceptible to the subject and / or physician. Nevertheless, preventative (prophylactic) treatment and therapeutic (curative) treatment are two separate embodiments of the present disclosure.

[0065] By "effective amount" or "therapeutically effective amount" is meant a dose 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 otherwise produce the desired pharmacological and / or physiological effect.

[0066] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe," e.g., physiologically tolerated, and generally do not produce allergic or similar undesirable reactions, such as stomach upset, when administered to humans. In certain embodiments, the term refers to molecular entities and compositions that have been approved by a federal or state regulatory agency as a GRAS listed under Sections 204(s) and 409 of the Federal Food, Drug, and Cosmetic Act, and are subject to premarket review and approval by the FDA or similar listing, the United States Pharmacopoeia, or other generally recognized pharmacopeia for use in animals, more particularly in humans.

[0067] "Administered simultaneously," "administered in combination," "combination of," or "administered together" can be used interchangeably and mean that two or more agents are administered during the course of treatment. The agents can be administered simultaneously or separately at intervals. The agents can be administered in a single dosage form or in separate dosage forms.

[0068] A "subject in need thereof" includes an individual diagnosed with a gastrointestinal disorder herein. An individual includes a mammal. Methods and compositions comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof can be provided to any individual, including, for example, when the subject is a newborn, infant, pediatric subject (6 months to 12 years), adolescent subject (12 to 18 years), or adult (18 years or older). A subject includes a mammal. The terms "patient" and "subject" are used interchangeably herein.

[0069] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of compounds defined herein, which are modified by making acid or base salts of the parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, 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 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 isethionic acid. Pharmaceutically acceptable salts can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods.

[0070] It is understood that the examples and embodiments provided herein are exemplary examples and embodiments. Those skilled in the art will envision various modifications of the examples and embodiments that are consistent with the scope of the disclosure herein. Such modifications are intended to be encompassed by the claims.

Claims

1. 1. A method of treating irritable bowel syndrome, comprising: administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof; wherein the method results in improvement of one or more symptoms of irritable bowel syndrome in the subject. The method.

2. 10. The method of claim 1, wherein the improvement occurs more than 6 hours after administration.

3. 10. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

4. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

5. 4. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

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

7. 4. The method of claim 3, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 400 mg.

8. 4. The method of claim 3, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 200 mg.

9. 10. The method of claim 1, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered 1 to 4 times daily.

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

11. 1. A method of treating Crohn's disease, comprising: administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof; wherein the method results in amelioration of one or more symptoms of Crohn's disease in the subject. The method.

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

13. 12. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

14. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

15. 14. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

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

17. 14. The method of claim 13, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 400 mg.

18. 14. The method of claim 13, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 200 mg.

19. 12. The method of claim 11, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered 1 to 4 times daily.

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

21. 1. A method of treating celiac disease, comprising: administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof; wherein the method results in amelioration of one or more symptoms of celiac disease in the subject. The method.

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

23. 22. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

24. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

25. 24. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

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

27. 24. The method of claim 23, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 400 mg.

28. 24. The method of claim 23, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 200 mg.

29. 22. The method of claim 21, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered 1 to 4 times daily.

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

31. 1. A method of treating ulcerative colitis, comprising: administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof; wherein the method results in amelioration of one or more symptoms of ulcerative colitis in the subject. The method.

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

33. 32. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

34. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

35. 34. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

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

37. 34. The method of claim 33, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 400 mg.

38. 34. The method of claim 33, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 200 mg.

39. 32. The method of claim 31, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered 1 to 4 times daily.

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

41. 1. A method of treating microscopic colitis, comprising: administering to a subject in need thereof an effective amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof; wherein the method results in amelioration of one or more symptoms of microscopic colitis in the subject. The method.

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

43. 42. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

44. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

45. 44. 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-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof.

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

47. 44. The method of claim 43, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 400 mg.

48. 44. The method of claim 43, wherein the total amount of (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof administered to the subject in a 24-hour period is 1 mg to 200 mg.

49. 42. The method of claim 41, wherein (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid or a pharmaceutically acceptable salt thereof is administered 1 to 4 times daily.

50. 42. The method of claim 41, wherein administration 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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