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US-20260125347-A1 - l,2-SUBSTITUTED 3-OXOPYRAZOLIDINE DERIVATIVES AS PROSTAGLANDIN E2 RECEPTOR 4 (EP4) AGONISTS FOR THE TREATMENT OF GASTROINTESTINAL AND PULMONARY DISEASES

US20260125347A1US 20260125347 A1US20260125347 A1US 20260125347A1US-20260125347-A1

Abstract

The present invention relates to compounds of formula I as prostaglandin E2 receptor 4 (EP4) agonists for use in methods of treatment of gastrointestinal and pulmonary dis-cases or disorders. An exemplary compound is e.g. 4-(2-(2-(3-hydroxy-3-(4′-hydroxy-2′-methyl-[1,1′-biphenyl]-3-yl) propyl)-5-oxopyrazolidin-1-yl)ethyl)benzoic acid (Example 1) Pharmacological data is provided, e.g.

Inventors

  • Nigel Alan Swain
  • Benjamin Whitehurst
  • Miles Stuart Congreve
  • Giles Albert Brown

Assignees

  • NXERA PHARMA UK LIMITED

Dates

Publication Date
20260507
Application Date
20230802
Priority Date
20220802

Claims (20)

  1. 1 . A compound of the Formula I: or a pharmaceutically acceptable salt solvate, hydrate, tautomer or optical isomer thereof, wherein; A is OR′, C(O)R′, CO 2 R′, C(O)N(R′) 2 , C(O)N(R′)S(O) 2 R 3 , S(O) 2 R′, S(O) 2 OR′, SO 2 N(R′) 2 , C 1-8 alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; X is halo, OR′, COOR′, or C 1-6 alkyl; L and L′are each independently a C 2-4 alkylene; R 1 is H, halo, CN, NO 2 , OR′, SR′, COOR′, C 1-6 alkoxy, or C 1-6 alkyl; R 2 is OR′, OC(O)R 3 , OC(O)OR 3 , CO 2 R′, CON(R′) 2 , SO 2 N(R′) 2 , SO 2 R 3 , OSO 2 R 3 , or OSO 2 N(R′) 2 ; R 3 is C 1-6 alkyl, C 3-6 cycloalkyl, or a phenyl; R′ is H, C 1-6 alkyl, or C 3-6 cycloalkyl; and n is 0, 1, 2, or 3; wherein at each occurrence, alkyl, alkylene, alkoxy, and cycloalkyl are each optionally and independently substituted with up to 3 instances of OH, SH, CN, NO 2 , COOH, halo, or COOC 1-4 alkyl; wherein at each occurrence, heterocycloalkyl, aryl, and heteroaryl are each optionally and independently substituted with up to 3 instances of OR′, SR′, CN, NO 2 , CO 2 R′, halo, C 1-4 alkyl, or oxo.
  2. 2 . The compound according to claim 1 , wherein (i) L′ is the group and/or (ii) L is the group
  3. 3 . The compound according to claim 1 , wherein the compound is a compound of Formula (1): Or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof, wherein A, X, R 1 , R 2 and n are the same as defined in claim 1 .
  4. 4 . The compound according to claim 1 , wherein A is selected from C(O)OR′, C(O)N(R′)S(O) 2 R 3 , S(O) 2 OR′, C 1-8 alkyl, heterocycloalkyl, or heteroaryl, wherein the heterocycloalkyl, and heteroaryl are each optionally and independently substituted with up to 3 instances of OR′, SR′, halo, C 1-4 alkyl, or oxo.
  5. 5 . The compound according to claim 1 , wherein A is selected from the group consisting of: preferably wherein A is: more preferably wherein A is
  6. 6 . The compound according to claim 1 , wherein X is halo or OR′, preferably wherein X is F or OH.
  7. 7 . The compound according to claim 6 , wherein X is F or OH, and n is 1, or 2.
  8. 8 . The compound according to claim 1 wherein n is 0.
  9. 9 . The compound according to claim 1 , wherein R 1 is H, OH, halo, CN, C 1-6 alkoxy optionally substituted with 1-3 fluorine atoms or C 1-6 alkyl optionally substituted with 1-3 fluorine atoms; preferably wherein R 1 is C 1-6 alkyl optionally substituted with 1-3 fluorine atoms.
  10. 10 . The compound according to claim 9 , wherein R 1 is methyl.
  11. 11 . The compound according to claim 1 , wherein R 2 is OR′, CON(R′) 2 , SO 2 N(R′) 2 , or OSO 2 N(R′) 2 , preferably wherein R 2 is OH, CONH 2 , SO 2 NH 2 , or OSO 2 NH 2 .
  12. 12 . The compound according to claim 1 , wherein R 2 is CON(R′) 2 , SO 2 N(R′) 2 , OSO 2 R 3 , or OSO 2 N(R′) 2 ; preferably wherein R 2 is CONH 2 , SO 2 NH 2 , or OSO 2 NH 2 .
  13. 13 . The compound according to claim 1 which is a compound of Formula (2a), (2b), (2c), or (2d): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof, wherein X, R 1 , R 2 and n are the same as defined in any preceding claim .
  14. 14 . The compound according to claim 1 , which is a compound of Formula (5), (5a), (5b), (6), (6a), (6b): or a pharmaceutically acceptable salt, solvate, hydrate or tautomer thereof.
  15. 15 . The compound according to claim 1 , wherein the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or optical isomer thereof.
  16. 16 . A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, solvate, hydrate, or tautomer, according to claim 1 and a pharmaceutically acceptable excipient.
  17. 17 . The pharmaceutical composition according to claim 16 , wherein the composition further comprises at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators and combinations thereof.
  18. 18 . A kit comprising a compound, pharmaceutically acceptable salt, solvate, hydrate, tautomer or optical isomer according to claim 1 and at least one additional therapeutic agent selected from the group consisting of aminosalicylates, corticosteroids, immunomodulators and combinations thereof.
  19. 19 . (canceled)
  20. 20 . A method of treating an EP 4 receptor mediated disease, the method comprising administering an effective therapeutic amount of a compound according to claim 1 to a patient in need thereof.

Description

This application relates to novel compounds and their use as prostaglandin E2 receptor 4 (EP4) agonists. Compounds described herein may be useful in the treatment or prevention of diseases in which EP4 receptors are involved. The application is also directed to pharmaceutical compositions comprising these compounds and the manufacture and use of these compounds and compositions in the prevention or treatment of such diseases in which EP4 receptors are involved. BACKGROUND OF THE INVENTION Prostanoids including prostaglandins and thromboxanes are metabolite derivatives of arachidonic acid that play key roles in cellular physiological function. Arachidonic acid is an integral component of membrane phospholipids which is released via the activity of phospholipase A2 (PLA2). The biosynthesis of prostaglandins is mediated via cyclooxygenase (COX) which catalyses conversion of arachidonic acid to an unstable intermediate (PGH2) and leads to the generation of prostaglandins including PGE2. PGE2 represents the most widely produced prostanoid whose activity is mediated through action at 4 functionally distinct subtypes of receptors, EP1-4. EP receptors belong to a family of G protein coupled receptors (GPCR) which are integral membrane proteins with seven-transmembrane domains. This receptor class can broadly be classified according to their signaling pathways: i) Gs coupled receptors (adenylate cyclase activation and cyclic adenosine monophosphate (cAMP) production), EP2 and EP4 ii) Gq coupled receptor (PLC activation), EP1 and iii) Gi coupled receptor (inhibition of adenylate cyclase), EP3. EP4 receptor signals through Gs and couples positively to adenylate cyclase to increase CAMP levels. The receptor was originally described in 1993 with the identification of an EP2 like receptor which couples positively to adenylate cyclase but does not bind butaprost (A Honda et al. J. Biol. Chem. 1993, 268, 7759-7762). The EP4 receptor plays key roles in diverse physiological functions including gastrointestinal homeostasis, regulation of vascular tone, renal function, inflammation, fever and carcinogenesis. The potent biological action of PGE2 has fuelled interest in developing subtype selective EP4 agonists and antagonists for the treatment of a broad range of indications. Functional gastrointestinal diseases (FGIDs), including chronic constipation, are common gastrointestinal conditions encountered by primary care physicians and gastroenterologists. The prevalence of chronic constipation ranges from 1% to 8% and can negatively impact the quality of life (QoL), resulting in major social and economic burden. Chronic constipation can bring discomfort to patients and affect their daily lives. Symptoms include hard and lumpy stools, straining during defecation and a sensation of incomplete evacuation. The use of laxatives and stool softners remains high, despite many patients not obtaining substantial benefit. There remains a need for treatments that can provide complete and sustainable symptomatic relief. The intestinal mucosa plays an important role in the homeostasis of anion and body fluid maintenance. These functions are mediated through coordinated ion transport via membrane bound transporters and channels localized on the apical and basolateral membrane of intestinal epithelial cells. PGE2 is a well established secretagogue that may directly promote chloride secretion from intestinal epithelial cells. The secretory effects of PGE2 are in part mediated via the EP4 receptor which can stimulate anion chloride secretion across the gut mucosa. Lubiprostone, a bicyclic fatty acid derivative of PGE1 clinically approved for the treatment of chronic constipation and IBS-C has been shown to promote fluid secretion and gastrointestinal tract motility through the activation of prostaglandin (EP4) receptors. EP4 selective agonists may have therapeutic value in promoting intestinal fluid homeostasis in chronic constipation conditions. Inflammatory bowel disease (IBD) is a chronic debilitating gastrointestinal disorder that includes ulcerative colitis and Crohn's disease. Patients with IBD commonly present with symptoms that include diarrhoea, abdominal pain, weight loss, rectal bleeding and fever. Clinical management involves strategies to control the abnormal dysregulated immune response in the intestinal mucosa. A wide range of agents are employed to induce and maintain remission, depending on the severity of the disease. These include aminosalicylates, corticosteroids, immunosuppressive agents, antibiotics and biologic agents. This may be given in a stepwise approach, with intensification of therapy according to the severity and progression of the disease. It is clear, however, that some patients are refractory to medical therapy or fail to tolerate it due to systemic side effects. Only a subset of patients achieve long term remission with current therapeutic strategies, suggesting the need for improved therapies. Intestinal barrie