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EP-4734985-A1 - PREVENTION, INHIBITION OR TREATMENT OF CONDITIONS OR DISORDERS MEDIATED BY UROCANATE REDUCTASE

EP4734985A1EP 4734985 A1EP4734985 A1EP 4734985A1EP-4734985-A1

Abstract

The invention provides compounds of formula (I), stereoisomers, tautomers, or pharmaceutically acceptable salts thereof for use in preventing, inhibiting or treating a condition or disorder which is mediated by urocanate reductase: (I) wherein A is a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and in which at least one of said heteroatoms is nitrogen; R 1 and R 2 are independently selected from: -H; C 1-6 alkyl; C 1-6 haloalkyl; C 1-6 alkoxy; halogen; and -CN; when present, each R 3 is independently selected from: C 1-6 alkyl; C 1-6 haloalkyl; C 1-6 alkoxy; halogen; -OH; -CN; -NO 2 ; -NR 5 R 6 wherein R 5 and R 6 are independently selected from H and C 1-3 alkyl; and -C(=NR 7 )(NR 8 R 9 ) wherein each of R 7 , R 8 and R 9 is independently selected from H and C 1-3 alkyl; R 4 is selected from: -OH; -SH; C 1-6 alkoxy; and -NR 10 R 11 wherein R 10 and R 11 are independently selected from H and C 1-3 alkyl; and n is an integer from 0 to 2. Such compounds are particularly suitable for use in preventing, inhibiting or treating gastrointestinal disorders or conditions, cardiovascular diseases or disorders, and metabolic disorders, such as but not limited to primary sclerosing cholangitis (PSC), myocardial fibrosis, heart failure, type 2 diabetes and pre-diabetes. The invention further provides certain novel compounds, methods for their preparation and pharmaceutical compositions containing such compounds.

Inventors

  • Beck, Katharina
  • BÄCKHED, Fredrik
  • WESTERLUND, CHRISTER

Assignees

  • IMPLEXION PHARMA AB

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. 1 . A compound of formula (I), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof for use in preventing, inhibiting or treating a condition or disorder which is mediated by urocanate reductase: wherein: A is a 5-membered heteroaromatic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and in which at least one of said heteroatoms is nitrogen; R 1 and R 2 are independently selected from: -H; C1-6 alkyl, preferably C1-3 alkyl, e.g. -CH3; C1-6 haloalkyl, preferably C1-3 haloalkyl, e.g. -CF3; C1-6 alkoxy, preferably C1-3 alkoxy, e.g. -OCH3; halogen, preferably F, Cl, Br or I; and -CN; when present, each R 3 is independently selected from: C1-6 alkyl, preferably C1-3 alkyl, e.g. -CH3; C1-6 haloalkyl, preferably C1-3 haloalkyl, e.g. -CF3; C1-6 alkoxy, preferably C1-3 alkoxy, e.g. -OCH3; halogen, preferably F, Cl, Br or I; -OH; -CN; -NO2; -NR 5 R 6 wherein R 5 and R 6 are independently selected from H and C1-3 alkyl, preferably selected from H and -CH3; and -C(=NR 7 )(NR 8 R 9 ) wherein each of R 7 , R 8 and R 9 is independently selected from H and C1-3 alkyl, preferably selected from H and -CH3; R 4 is selected from: -OH -SH C1-6 alkoxy, preferably C1-3 alkoxy; and -NR 10 R 11 wherein R 10 and R 11 are independently selected from H and C1-3 alkyl, preferably selected from H and -CH3; and n is an integer from O to 2.
  2. 2. A compound for use as claimed in claim 1 , wherein said condition or disorder is a gastrointestinal disorder or condition, a cardiovascular disease or disorder, or a metabolic disorder.
  3. 3. A compound for use as claimed in claim 1 , wherein said condition or disorder is primary sclerosing cholangitis (PSC), myocardial fibrosis, heart failure, type 2 diabetes or pre-diabetes.
  4. 4. A compound for use as claimed in any one of claims 1 to 3, wherein in formula (I), A is a 5- membered heteroaromatic ring containing 1 to 3 heteroatoms selected from nitrogen and sulphur, preferably 1 or 2 heteroatoms selected from nitrogen and sulphur.
  5. 5. A compound for use as claimed in any one of claims 1 to 3, wherein in formula (I), A is a 5- membered heteroaromatic ring containing 1 to 3 nitrogen atoms, preferably 1 or 2 nitrogen atoms.
  6. 6. A compound for use as claimed in any one of claims 1 to 3, wherein in formula (I), A is imidazolyl, pyrazolyl, pyrrolyl, or thiazolyl, preferably 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 3-pyrrolyl, or 4-thiazolyl.
  7. 7. A compound for use as claimed in any one of the preceding claims, wherein in formula (I), n is 0 or 1.
  8. 8. A compound for use as claimed in any one of claims 1 to 6, wherein in formula (I), n is other than 0, and R 3 is selected from C1-3 alkyl (e.g. -CH3 or -CH2CH3), C1-3 haloalkyl (e.g. CF3), C1-3 alkoxy (e.g. -OCH3), F, Cl, -NH2 and -OH.
  9. 9. A compound for use as claimed in any one of the preceding claims, wherein in formula (I), R 1 and R 2 are independently selected from -H, C1-3 alkyl (e.g. -CH3 or -CH2CH3), C1-3 haloalkyl (e.g. -CF3), F and Cl.
  10. 10. A compound for use as claimed in any one of claims 1 to 9, wherein in formula (I), R 1 is H, -CH3, -CH2CH3 or F.
  11. 11. A compound for use as claimed in any one of claims 1 to 9, wherein R 1 is H.
  12. 12. A compound for use as claimed in any one of claims 1 to 11 , wherein in formula (I), R 2 is H, -CH3, -CH2CH3 or F, preferably H, -CH3 or -CH2CH3.
  13. 13. A compound for use as claimed in claim 12, wherein R 2 is H, -CH3 or -CH2CH3.
  14. 14. A compound for use as claimed in claim 13, wherein R 2 is -CH3 or -CH2CH3, preferably -CH3.
  15. 15. A compound for use as claimed in any one of claims 1 to 11 , wherein R 2 is other than H.
  16. 16. A compound for use as claimed in any one of the preceding claims, wherein in formula (I), R 4 is -OH or C1-3 alkoxy, preferably -OH.
  17. 17. A compound for use as claimed in any one of the preceding claims, wherein in formula (I), the heteroaromatic ring A and the group -C(O)R 4 are trans to one another.
  18. 18. A compound for use as claimed in any one of claims 1 to 3, wherein said compound is a compound of formula (II), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: wherein: R 1 is as defined in any one of claims 1 and 9 to 11 ; R 2 is as defined in any one of claims 1 , 9 and 12-15; R 3 is as defined in claim 1 or claim 8; R 4 is as defined in claim 1 or claim 16; and m is an integer from 0 to 2, preferably 0 or 1 .
  19. 19. A compound for use as claimed in claim 18, wherein said compound is a compound of formula (II) in which the imidazolyl ring and the group -C(O)R 4 are trans to one another, a tautomer or pharmaceutically acceptable salt thereof.
  20. 20. A compound for use as claimed in any one of claims 1 to 3, wherein said compound is a compound of formula (III), a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: wherein: R 1 is as defined in any one of claims 1 and 9 to 11 ; R 2 is as defined in any one of claims 1 , 9 and 12-15; R 3 is as defined in claim 1 or claim 8; R 4 is as defined in claim 1 or claim 16; and p is an integer from 0 to 2, preferably 0 or 1 .

Description

PREVENTION, INHIBITION OR TREATMENT OF CONDITIONS OR DISORDERS MEDIATED BY UROCANATE REDUCTASE TECHNICAL FIELD The present invention relates to the use of compounds in preventing, inhibiting or treating conditions which are mediated by urocanate reductase, more specifically conditions which are mediated by urocanate reductase present in the gut microbiota of a subject. In particular, it relates to the use of such compounds in preventing, inhibiting or treating conditions which arise from and/or are associated with the production of imidazole propionate, such as metabolic disorders, cardiovascular disorders, and disorders of the gastrointestinal system. The invention further relates to certain novel compounds, to pharmaceutical compositions containing them, and to their use in such treatment. BACKGROUND Urocanate reductase is a bacterial enzyme which catalyses the conversion of urocanate to imidazole propionate (ImP) in the microbial histidine degradation pathway. Elevated ImP levels have been linked to a wide range of conditions, diseases and disorders. These include metabolic disorders, such as type 2 diabetes (T2D), a range of cardiovascular disorders such as cardiovascular disease (CVD), heart failure (HF) and myocardial fibrosis, and various gastrointestinal conditions such as inflammatory bowel disease (IBD). Metabolic disorders may be associated with altered gut microbiota structure and function. The microbial metabolite ImP is present at higher concentrations in individuals with T2D and impaired glucose tolerance (IGT) as compared to healthy individuals with normal glucose tolerance (NGT) (Koh et al., Cell 175, 947-961, e17, 2018; and Molinaro et al., Nat. Commun. 11 , 5881 , 2020). Microbially produced ImP reduces insulin receptor substrate (IRS) protein levels and impairs insulin signaling through the alternative p38y mitogen-activated protein kinase (MAPK) activation pathway of mechanistic target of the rapacymin complex 1 (mTORCI). ImP thus contributes to the pathogenesis of T2D and IGT. Furthermore, elevated ImP levels are also associated with the inability of metformin to lower blood glucose levels by interfering with AMPK phosphorylation through a p38y/Akt dependent pathway (Koh et al., Cell Metabolism 32(4): 643-653, 2020). It has been shown that plasma ImP concentrations are positively correlated with diastolic blood pressure (Son et al., Nutrients 13, 2021). Pharmacological inhibition of p38y, the molecular target of ImP, has also been found to reduce myocardial fibrosis in patients with HFpEF (Lewis et al., Nature Medicine 27, 1477-1482, 2021), and the activation of p38y/5 has been shown to induce cardiac hypertrophy and thus potentially contribute to diabetic cardiomyopathy (DCM) (Gonzalez-Teran et al., Nat. Commun. 7:10477, 2016). More recently, it has been demonstrated that ImP levels are associated with CVD and HF in human subjects, independently of T2D and other established cardiovascular risk factors, and that ImP levels are an independent risk factor for overall mortality (Molinaro et al., JACC Heart Fail. 2023 Apr 1 ; S2213-1779(23) 00138-5, doi: 10.1016/j.jchf.2023.03.008). Specifically, elevated ImP levels were found to be associated with reduced left ventricular systolic ejection fraction and a predictor of 5 years mortality. Increased levels of the gut microbial metabolite ImP thus contribute to CVD and HF, and are a predictor of overall survival. An earlier study reported that ImP is excreted from patients with intestinal disorders but is almost absent in faeces and urine from healthy subjects (Van Der Heiden et al., Clinica Chimica Acta 39, 201 - 214, 1972). ImP is associated with inflammatory bowel disease and rectal ImP administration has also been shown to induce intestinal inflammation, impair the intestinal barrier, and affect the proliferation of goblet cells (Vich Vila et al., Gut 0:1-14, 2023; and Wu et al., Mol. Nutr. Food Res. 66, e2101175, 2022). ImP is also associated with colorectal cancer (Gao et al., Gastroenterology 163(4): P1024- 1037, 2022). Previous studies have also shown that the mTORC pathway, which includes p38y, the molecular target of ImP, is activated in patients with primary sclerosing cholangitis (PSC) which is a long-term progressive disease of the liver and gallbladder (Panzitt et al., J. Hepatol. 72, 1122-1131 , 2020). PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer and cholangiocarcinoma. For example, it has been shown that ImP is increased in patients with colon carcinoma (Gao et al., Gastroenterology 163: 1024-1037, e1029, 2022). Increased ImP levels have also been shown to be associated with a NASH Gottingen Minipig model (Liitzhoft et al., BMC Microbiol. 22, 287, 2020). These studies suggest that decreasing ImP levels is a therapeutic target in the treatment of various gastrointestinal disorders and associated conditions. SUMMARY ImP is a known microbial histidine degradation pro