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US-20260124194-A1 - VELUSETRAG FOR USE IN THE TREATMENT OF CHRONIC INTESTINAL PSEUDO-OBSTRUCTION (CIPO)

US20260124194A1US 20260124194 A1US20260124194 A1US 20260124194A1US-20260124194-A1

Abstract

The invention relates to 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide (velusetrag) or a pharmaceutically acceptable salt thereof for use in a method of treating idiopathic chronic intestinal pseudo-obstruction (CIPO), neuropathic chronic intestinal pseudo-obstruction, or chronic intestinal pseudo-obstruction being secondary to neurodegeneration or to demyelinating conditions in a patient suffering from said diseases or conditions.

Inventors

  • Loredana Vesci
  • Maria Grimaldi
  • Fabrizio Giorgi
  • Roberto Giovannini
  • Michelangelo BARONE

Assignees

  • ALFASIGMA S.P.A.

Dates

Publication Date
20260507
Application Date
20230920
Priority Date
20220920

Claims (18)

  1. 1 . A method for the treatment of a condition selected from the group consisting of a) idiopathic chronic intestinal pseudo-obstruction (CIPO), b) neuropathic chronic intestinal pseudo-obstruction, c) chronic intestinal pseudo-obstruction being secondary to neurodegeneration or being secondary to autoimmune conditions or being secondary to connective tissue disorders or being secondary to demyelinating conditions, comprising administering an effective amount of 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide (velusetrag) or a pharmaceutically acceptable salt thereof to a patient in need thereof.
  2. 2 . The method of claim 1 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.
  3. 3 . The method of claim 1 , wherein velusetrag is in crystalline form and/or hydrated form.
  4. 4 . The method of claim 1 , wherein the idiopathic CIPO, the neuropathic CIPO or CIPO being secondary to neurodegeneration or being secondary to autoimmune conditions or being secondary to connective tissue disorders or being secondary to demyelinating conditions is one caused by diseases of the autonomic nervous system such as stroke, encephalitis, calcification of basal ganglia, orthostatic hypotension, one caused by diseases of intestinal wall nervous system such as paraneoplastic syndrome, viral infections, iatrogenic disorders, Hirschsprung's disease, Chagas' disease, Von Recklinghausen's disease, one caused by diseases of the intestinal wall muscle layer such as myotonic dystrophy, progressive systemic sclerosis or one caused by diseases of the mixed enteric nervous system and smooth muscle layer such as scleroderma, dermatomyositis, amyloidosis, Ehler-Danlos syndrome or one caused by an unknown mechanism such as hypothyroidism, hypoparathyroidism, pheochromocytoma, antidepressants drugs, antineoplastics or bronchodilatators or one caused by immune-mediated and connective tissue disorder or disease such as paraneoplastic disease (CNS neoplasms, lung microstoma, bronchial carcinoid, leyomyosarcomas, systemic lupus erythematosus.
  5. 5 . The method of claim 1 , wherein the patient is an adult or a pediatric patient.
  6. 6 . The method of claim 5 , wherein the patient is one having a history of chronic CIPO or of CIPO secondary to neurodegenerative disease or demyelinating disease.
  7. 7 . The method of claim 1 , wherein at least one of the symptoms of CIPO selected from abnormal gastrointestinal motility, increased dilatation of the proximal colon and/or of the distal small intestine, modified intestinal contractility, ulceration, inflammation of the proximal colon and/or of the distal small intestine, pseudo-obstructive episode, vomiting, bloating, abdominal pain, mental health, quality of life and lethality is alleviated and/or ameliorated and/or wherein the number and/or frequency of CIPO-related and/or CIPO-caused hospitalizations is reduced.
  8. 8 . The method of claim 1 , wherein the velusetrag is administered in a dosage of 0.5 to 30 mg/day based on the weight of the free base.
  9. 9 . The method of claim 1 , wherein the velusetrag is administered for a period of two to twelve weeks.
  10. 10 . The method of claim 1 , wherein the velusetrag is administered orally, parenterally, buccally, sublingually, rectally, intraperitoneally, or endotracheally.
  11. 11 . The method of claim 10 , wherein the percutaneous administration is subcutaneous, intramuscular, intravenous, transdermal, or by implantation.
  12. 12 . The method of claim 10 , wherein the velusetrag is administered orally in the form of a liquid, capsule, tablet, chewable tablet, dissolvable film, pill, lozenge, cachet, dragee, powder, granules, a solution, a suspension, an oil-in-water or water-in-oil liquid emulsion, an elixir or a syrup.
  13. 13 . The method of claim 10 , wherein the velusetrag is administered parentally in the form of a liquid, solid or gel.
  14. 14 . The method of claim 1 , wherein the velusetrag is taken orally with or without food.
  15. 15 . The method of claim 8 , wherein the velusetrag is administered 5 to 15 mg/day, based on the weight of the free base.
  16. 16 . The method of claim 8 , wherein the velusetrag is administered 15 mg/day, based on the weight of the free base.
  17. 17 . The method of claim 9 , wherein the velusetrag is administered for a period of two to six weeks.
  18. 18 . The method of claim 14 , wherein the velusetrag is taken in a once daily administration.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 371 of PCT/EP2023/075925, filed Sep. 20, 2023, which claims the benefit of European Patent Application No. 22196573.4, filed Sep. 20, 2022. FIELD OF THE INVENTION The present invention relates to velusetrag (1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid {(1S,3R,5R)-8-[(R)-2-hydroxy-3-(methanesulfonyl-methyl-amino)propyl]-8-azabicyclo[3.2.1]oct-3-yl}amide), pharmaceutically acceptable salts thereof as well as compositions comprising said compound(s) for use in the treatment of chronic intestinal pseudo-obstruction (CIPO), particularly neuropathic CIPO or idiopathic CIPO. Hence, the present invention is in the field of methods of treating altered gastrointestinal motility conditions and disorders, such as chronic intestinal pseudo-obstruction (or colonic pseudo-obstruction) and disorders and conditions associated with constipation, for example constipation associated with the use of opiate painkillers, constipation post-surgery and constipation associated with neuropathic disorders and other conditions. BACKGROUND OF THE INVENTION Pseudo-intestinal obstruction is a rare and severe condition characterized by disordered peristalsis with symptoms of intestinal obstruction, but without signs of mechanical obstruction. The disorder is caused by abnormalities of the enteric neuromusculature and/or its autonomic innervation; it represents the most severe form of gastrointestinal dysmotility with debilitating and life-threatening consequences. When the condition persists for more than 6 months, chronic intestinal pseudo-obstruction (CIPO) occurs, one of the most important causes of chronic intestinal failure in both pediatric (15%) and adult (20%) cases. As affected individuals are often unable to sustain a normal oral diet and maintain a proper body weight, a severe clinical picture characterized by disabling digestive symptoms is established in the patient, which contributes to the severe deterioration of the patient's quality of life, leading to death. A distinction is made between primary and secondary forms of CIPO. Primary CIPO is due to an intrinsic defect (congenital or acquired) and can be classified according to the type of damage (that could be associated): visceral myopathy (linked to muscle damage; e.g. MNGIE: mitochondrial neuro-gastrointestinal neuropathy, MMIHS: megacystis-microcolon-intestinal hypoperistalsis syndrome, idiopathic), visceral neuropathy (linked to damage to the autonomic nerves; e.g.: developmental anomaly of the myenteric plexus, Hirschsprung's disease, sequel of necrosing enterocolitis, idiopathic) or mesenchymopathy (linked to damage to Cajal cells in the digestive tract). The etiological classification of CIPO has been evolving with the discovery of new genetic entities, in particular through the study of familial forms. Examples of involved genes are TYMP gene (mutated in MNGIE), ACTG2 gene (mutated in megacystis-microcolon-hypoperistalsis syndrome, MMIHS), SGOL1 gene (mutated in chronic atrial and intestinal arrhythmia syndrome, CAID), POLG gene (mutated in Alpers' disease). Despite that, the etiology of the majority of cases of CIPO is currently unknown and these cases are called idiopathic. They are thus included in the primary CIPO grouping. Secondary CIPO is linked to an underlying systemic neurological, endocrine and connective tissue diseases or malignancies. In these diseases the intestinal motility could be affected due to the involvement of the autonomic nervous system (stroke, encephalitis, orthostatic hypotension), the nervous system of the intestinal wall (paraneoplastic syndromes, viral infections, iatrogenic, diabetes, Chagas' disease, Von Recklinghausen's disease), the muscular layer of the intestinal wall (myotonic dystrophy, progressive systemic sclerosis), the mixed enteric nervous system and the smooth muscle layer (scleroderma, dermatomyositis, amyloidosis, Ehlers-Danlos syndrome, jejunal diverticulosis, radiation enteritis) and finally unknown mechanisms (hypothyroidism, hypoparathyroidism, pheochromocytoma, antidepressants, anti-neoplastics, bronchodilators) [Antonucci A. et al. Chronic intestinal pseudo-obstruction.” World journal of gastroenterology 2008; 14:2953-61; Zhu C. Z. et al. Latest developments in chronic intestinal pseudo-obstruction. World J Clin Cases. 2020; 8:5852-5865; Billiauws L. et al. Small intestine motility disorders: Chronic intestinal pseudo-obstruction. J Visc Surg. 2022; 159(1S):S22-S27]. There are no clear epidemiological data; it has been estimated that in the USA about 100 infants per year are affected by intestinal pseudo-obstruction; the incidence among adults is 0.2 (male) and 0.24 (female) per 100.000 patients/year and its prevalence in adults has been estimated to be 0.2 to 0.9/100,000 population [Di Nardo G. et al. Pharmacological and nutritional therapy of children and adults with chronic intestinal pseudo-obstruction. Expert Review of Gastroenterolog