WO2017042380A1 - Nouveaux composés 5-amino-2-thio-imidazoles et leur utilisation - Google Patents

Nouveaux composés 5-amino-2-thio-imidazoles et leur utilisation Download PDF

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WO2017042380A1
WO2017042380A1 PCT/EP2016/071415 EP2016071415W WO2017042380A1 WO 2017042380 A1 WO2017042380 A1 WO 2017042380A1 EP 2016071415 W EP2016071415 W EP 2016071415W WO 2017042380 A1 WO2017042380 A1 WO 2017042380A1
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phenyl
mmol
methyl
integer
difluoro
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PCT/EP2016/071415
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English (en)
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Julie Charton
Benoit Deprez
Vanessa HOGUET
Manuel LASALLE
Florence Leroux
Bart Staels
Anne MUHR-TAILLEUX
Nathalie HENNUYER
Loïc BELLOY
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Universite De Lille 2 Droit Et Sante
Institut Pasteur De Lille
INSERM (Institut National de la Santé et de la Recherche Médicale)
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Publication of WO2017042380A1 publication Critical patent/WO2017042380A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to novel compounds including their pharmaceutically acceptable salts and solvates, which are agonists of TGR5 (G protein-coupled bile acid receptor 1, also named Gpbarl or M-BAR) and are useful as therapeutic compounds, particularly in the treatment and/or prevention of TGR5 related diseases, such as Type 2 diabetes (T2D) also known as diabetes mellitus and conditions that are often associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • TGR5 G protein-coupled bile acid receptor 1
  • T2D Type 2 diabetes
  • lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • Type 2 diabetes also known as diabetes mellitus is a growing health problem. Recent estimates indicate there were 171 million people in the world with diabetes in the year 2000 and this is projected to increase to 366 million by 2030 (Wild S, Roglic G, Green A, Sicree R, King H. Global Prevalence of Diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care. 2004, 27, 1047- 1053).
  • the classical treatment for type 2 diabetes developed over the past 20 years has been based on 2 types of oral anti-hyperglycemic drugs; sulfonylureas that stimulate insulin secretion and the biguanides that have a broad spectrum of effects, but act primarily on hepatic insulin resistance.
  • alpha glucosidase inhibitors i.e. acarbose
  • acarbose alpha glucosidase inhibitors
  • TGD nuclear receptor peroxisome proliferator- activated receptor gamma
  • PARy nuclear receptor peroxisome proliferator- activated receptor gamma
  • GLP- 1 is an incretin hormone causing enhanced post-prandial insulin secretion, but also known to have a range of additional effects including reduced gastric motility and appetite suppression, which indirectly impact on glucose metabolism in vivo (Drucker, D. J.; Sherman, S. I.; Bergenstal, R. M.; Buse, J. B., The safety of incretin-based therapies— review of the scientific evidence. J Clin Endocrinol Metab 2011, 96, 2027-2031. Baggio, L. L.; Drucker, D. J., Biology of Incretins: GLP-1 and GIP. Gastroenterology 2007, 132, 2131-2157).
  • the bile acid receptor TGR5 appears as an emerging and promising therapeutic target (Chen X Fau - Lou, G.; Lou G Fau - Meng, Z.; Meng Z Fau - Huang, W.; Huang, W., TGR5: A Novel Target for Weight Maintenance and Glucose Metabolism. Exp Diabetes Res. 2011, 201 1 : 853501. Pols Tw Fau - Noriega, L. G.; Noriega Lg Fau - Nomura, M.; Nomura M Fau - Auwerx, J.; Auwerx J Fau - Schoonjans, K.; Schoonjans, K., The bile acid membrane receptor TGR5: a valuable metabolic target. Dig. Dis.
  • TGR5 also named Gpbarl or M-BAR
  • M-BAR Maruyama, T.; Miyamoto, Y.; Nakamura, T.; Tamai, Y.; Okada, H.; Sugiyama, E.; Nakamura, T.; Itadani, H.; Tanaka, K., Identification of membrane-type receptor for bile acids (M-BAR). Biochem. Biophys. Res. Commun 2002, 298, 714-719.
  • TGR5 is highly expressed in adipose tissue, muscle and enteroendocrine cells.
  • a body of evidence supports a role for TGR5 in energy homeostasis. Indeed, administration of bile acids to mice increased energy expenditure in the brown adipose tissue and prevented diet-induced obesity and insulin-resistance. This effect was ascribed to a cAMP dependant intra-cellular induction of the type 2 iodothyronine deiodase (D2) enzyme, which converts inactive thyroxine (T4) into active 3,5,5'-tri-iodothyronine (T3).
  • D2 iodothyronine deiodase
  • T4 inactive thyroxine
  • T3 3,5,5'-tri-iodothyronine
  • bile acids increase energy expenditure in part through activation of mitochondrial function in brown adipose tissue and skeletal muscle, hence preventing obesity and resistance to insulin (Watanabe, M.; Houten, S. M.; Mataki, C; Christoffolete, M. A.; Kim, B. W.; Sato, H.; Messaddeq, N.; Harney, J. W.; Ezaki, O.; Kodama, T.; Schoonjans, K.; Bianco, A. C; Auwerx, J., Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature 2006, 439, (7075), 484-489).
  • oleanolic acid a component of olive oil that binds to and activates TGR5
  • mice fed with a high fat diet and enhances glucose tolerance Sato, H.; Genet, C; Strehle, A.; Thomas, C; Lobstein, A.; Wagner, A.; Mioskowski, C; Auwerx, J.; Saladin, R., Anti-hyperglycemic activity of a TGR5 agonist isolated from Olea europaea. Biochem. Biophys. Res. Commun 2007, 362, 793-798).
  • bile acids and compounds that affect TGR5 activity have been shown to increase GLP-1 secretion from enteroendocrine intestinal cells (Katsuma, S.; Hirasawa, A.; Tsujimoto, G. Bile acids promote glucagon-like peptide- 1 secretion through TGR5 in a murine enteroendocrine cell line STC-1 Biochem. Biophys. Res. Commun. 2005, 329, 386-390). More recently, using a combination of pharmacological and genetic gain- and loss-of- function studies in vivo, Thomas et al.
  • TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.
  • TGR5 has also been shown to be expressed in inflammatory cells and its activation leads to anti-inflammatory effects and to anti-atherosclerotic effects in mouse.
  • TGR5 agonists including natural or semi-synthetic bile acids
  • TGR5 stimulation in skin by systemic agonists triggers intense pruritus, comparable to the effect of the naturally occurring bile acids during cholestasis (Alemi, F.; Kwon, E.; Poole, D.
  • TGR5 related diseases such as T2D
  • conditions that are associated with this disease including, lipid disorders such as dyslipidemia, hypertension, obesity, atherosclerosis and its sequelae.
  • the invention thus encompasses compounds of general Formula I, their pharmaceutically acceptable salts and solvates as well as methods of use of such compounds or compositions comprising such compounds as agonists of TGR5 activity.
  • the invention provides compounds of general
  • R 1 and R 2" are independently H, Cl-C2-alkoxy or halo
  • R 3 is H, Cl-C4-alkyl or allyl
  • R is H or Cl-C6-alkyl unsubstituted or substituted by a group selected from - OOCH 3 , -N + R 3 Q wherein Q is a counter anion wherein q is an integer from 1 to 6;
  • R 5 is phenyl substituted by one or more groups selected from halo, Cl-C4-alkyl, Cl-C2-alkoxy, haloalkyl;
  • R 6 and R 7 are independently H, Cl-C2-alkyl or halo;
  • L 1 is -CO-, -(CH 2 ) t - wherein t is an integer from 0 to 4,
  • L 2 is -0-, -C ⁇ C-
  • p is an integer from 0 to 4,
  • R is H or CH 3 ;
  • n is an integer from 0 to 4.
  • A is selected from the group consisting of: wherein m 1 is an integer from 3 to 500, with the proviso that
  • Q + is a counter cation, wherein R is CH 2 OH, CH 2 OS0 3 ⁇ Q + or COOH,
  • R 8 is H or CH 3 and R* is CH 2 OH
  • R 8 is H or CH 3 and R 9 is CH 2 OH, CH 2 OS0 3 " Q + or COOH, wherein R 9 is CH 2 OH, CH 2 OS0 3 ⁇ Q + or COOH, R 8 is H or CH 3 ; R 9 is CH 2 OH,
  • n is an integer from 0 to 3;
  • X is CH 2 , NH, O or -CH(OH)- CH(OH)-,
  • Suitable, generally pharmaceutically acceptable, counter anions Q " are well known to those skilled in the art.
  • suitable counter anions include acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, halides such as fluoride, chloride, bromide, iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharide,
  • Non-limiting examples of suitable counter cations include sodium, ammonium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminium or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, cyclic amines or basic ion exchange resins.
  • Preferred counter cations Q + are selected from sodium, ammonium, potassium, lithium, calcium, magnesium.
  • Preferred compounds of Formula I are those, wherein one or more of L , L , n and A are as defined as follows: L 1 is -CO-, -(CH 2 )t- wherein t is an integer from 0 to 4, L 2 is -0-, -C ⁇ C-
  • p is an integer from 0 to 4,
  • R is H or CH 3 , n is an integer from 0 to 4;
  • A is selected from the group consisting of: wherein m 1 is an integer from 3 to 500, with the proviso that not -O- or -C ⁇ C- when L 1 is -(CH 2 ) t - with t
  • m is an integer from 3 to 500, wherein m 3 is an integer from 3 to 500 and Q " is a counter anion, wherein Q + is a counter cation, wherein R is CH 2 OH, CH 2 OS0 3 Q + or COOH,
  • R 9 is CH 2 OH, CH 2 OS0 3 " Q + or COOH
  • R 8 is H or CH 3 ;
  • R 9 is CH 2 OH,
  • r is an integer from 1 to 4,
  • n 4 is an integer from 3 to 50, wherein m 5 is an integer from 0 to 11; n 1 is an integer from 0 to 3; X is CH 2 , NH, O or -CH(OH)- CH(OH)-,
  • the present inventors believe that the L -(CH 2 ) n -A moiety as defined herein and not being H limits the absorption of the compounds of the invention in the intestine and thus decreases their systemic action.
  • the resulting compounds are thus topical agonists which have the advantage of promoting GLP- 1 secretion in intestine without side effects due to TGR5 activation in other organs.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt or solvate thereof.
  • the invention also relates to the use of the above compounds or their pharmaceutically acceptable salts and solvates as modulators of TGR5, preferably as agonists of TGR5 and more preferably as agonists of TGR5 exerting their action locally in the intestine with low or even without systemic exposure.
  • the preferred agonists of the invention have the advantage of enhancing safety and the therapeutic index for potential chronic administration.
  • the invention further provides the use of a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof as a medicament.
  • the medicament is used for the treatment and/or prevention of TGR5 related diseases, such as metabolic diseases, gastrointestinal diseases and/or hepato-biliary diseases.
  • Metabolic diseases within the meaning of the present invention include, but are not limited to, type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and their sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis.
  • dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia
  • the metabolic disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its sequelae, preferably the disease is type II diabetes.
  • Gastrointestinal diseases within the meaning of the present invention include, but are not limited to, Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD), and Irritable Bowel Syndrome (IBS), intestinal injury disorders such as short-bowel syndrome, diseases involving intestinal barrier dysfunction such as proctitis and pouchitis, and gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility, including but not limited to any type of diarrhea.
  • IBD Inflammatory Bowel Diseases
  • UC Ulcerative colitis
  • CD Crohn's Disease
  • IBS Irritable Bowel Syndrome
  • intestinal injury disorders such as short-bowel syndrome
  • diseases involving intestinal barrier dysfunction such as proctitis and pouchitis
  • the gastrointestinal disease is Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD).
  • IBD Inflammatory Bowel Diseases
  • UC Ulcerative colitis
  • CD Crohn's Disease
  • Hepato-biliary diseases within the meaning of the present invention include, but are not limited to, fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), secondary cholangiopathies in which the inflammatory and fibrosing biliary disease is the consequence of other conditions.
  • fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC)
  • PSC primary sclerosing cholangitis
  • PBC primary biliary cirrhosis
  • secondary cholangiopathies in which the inflammatory and fibrosing biliary disease is the consequence of other conditions.
  • Preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein one or more of, R 1 -R7', L , n, and A are defined as follows:
  • R 1 and R 2" are independently H, methoxy, chloro or fluoro, preferably methoxy or chloro, and more preferably both of R 1 and R 2 are methoxy;
  • R 3 is H, Cl-C2-alkyl, or allyl, preferably R 3 is methyl;
  • R 4 is H or Cl-C6-alkyl unsubstituted or substituted by a group selected from - -COOCH3, -N + R 3 Q wherein Q is a counter anion and wherein q is an integer from 1 to 6; preferably R 4 is H, methyl, 4-aminobutyl or 3-carboxypropyl; more preferably R 4 is H;
  • R 5 is phenyl substituted by one or more groups selected from the group consisting of fluoro, chloro, halomethyl, and Cl-C2-alkoxy; preferably R 5 is phenyl substituted by one or more groups selected from the group consisting of fluoro, chloro, trifluoromethyl, and methoxy; more preferably R 5 is phenyl substituted by one or more groups selected from the group consisting of fluoro and methoxy;
  • R 6 and R 7 are independently H, fluoro, chloro, or methyl; preferably R 6 and R 7 are both halo, and more preferably R 6 and R 7 are both fluoro; L 1 is -CO- or -(CH 2 ) t - wherein t is an integer from 0 to 4; preferably L 1 is -CO- or -(CH 2 ) t - wherein t is 0 or 1; more preferably L 1 is-(CH 2 ) t - wherein t is 0;
  • A is selected from the group consisting of wherein m 1 is an integer from 3 to 500, with the proviso that
  • L 2 is not -O- or -C ⁇ C- wherein m 2 is an integer from 3 to 500, wherein m is an integer from 3 to 500 and Q " is a counter anion,
  • Q + is a counter cation, herein R is CH 2 OH, CH 2 OS0 3 " Q + or COOH,
  • Particularly preferred compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are those wherein L - (CH 2 ) n -A is not H. Indeed, without wanting to be bound to any theory, the present inventors believe that the L -(CH 2 ) n -A moiety as defined herein and not being H limits the absorption of the compounds of the invention in the intestine and thus decrease their systemic action.
  • the compounds of Formula I are those of Formula II
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , L 2 , n, and A are as defined above with respect to Formula I.
  • Preferred compounds of Formula II and pharmaceutically acceptable salts and solvates thereof are those wherein R 5 is phenyl substituted by one or more groups selected from the group consisting of fluoro, chloro, halomethyl, and Cl-C2-alkoxy; preferably, fluoro, chloro, trifluoromethyl, and methoxy.
  • R is H or CH 3 ,
  • n 0 and A is
  • L is -0-, n is 3 and A is wherein m 1 is an integer
  • Q " is a counter anion, wherein Q + is a counter cation; L is ethynylene, n is 0 and A is ; or
  • n is 1 or COOH, preferably R 9 is CH 2 OH; or , n is 0 and A is wherein m is an integer from 3 to 50.
  • compounds of Formula II and pharmaceutically acceptable salts and solvates thereof as described above are those wherein R is methyl.
  • the compounds of Formula II are those of Formula III
  • R 1 , R 2, R 3, R 6°, R 7', L 2, n, and A are as defined above with respect to Formula I;
  • R 10 , and R 11 are independently selected from the group consisting of H, fluoro, chloro, halomethyl, and Cl-C2-alkoxy; preferably H, fluoro, chloro, trifluoromethyl, and methoxy, with the proviso that at least one of R 10 , and R 11 is not H, preferably R 10 is fluoro and R 11 is H or methoxy.
  • L 2 is erein R is H or CH 3
  • n is 0 and A is wherein m 1 is an integer from 3 to 500;
  • L is -0-, n is 3 and A is wherein m 2 is an integer
  • Q " is a counter anion, wherein Q + is a counter cation
  • L is ethynylene, n is 0 and A is L 2 is s H, n is 1
  • R 9 is CH 2 OH; or , n is 0 and A is wherein m is an integer from 3 to 50 ; and/or wherein R 1 and R 2 are preferably both methoxy and wherein R 6 and R 7 are both fluoro; and/or wherein preferably R 10 is fluoro and R 11 is H or methoxy.
  • compounds of Formula III as described above are those of Formula Ilia
  • the compounds of Formula I are those of
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and L 1 are as defined above with respect to Formula I.
  • Preferred compounds of Formula IV and pharmaceutically acceptable salts and solvates thereof are those wherein R 1 and R 2 are both
  • L is -CO- or -(CH 2 ) t - wherein t is 0 or 1; and/or R is methyl or allyl; and/or R 4 is H, methyl, 4-aminobutyl or 3-carboxypropyl and/or R 5 is 4- fluorophenyl; and/or R 6 and R 7 are both fluoro, with the proviso that R 4 is not H when R 3 is methyl and L 1 is -(CH 2 ) t - wherein t is 0.
  • the compounds of Formula I are those of Formula V
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above with respect to Formula I, and wherein L -(CH 2 ) n -A is phenyl unsubstituted or substituted with a group selected from OH, COOH, NH 2 , Cl-C4-alkoxy.
  • Preferred compounds of Formula V and pharmaceutically acceptable salts and solvates thereof as defined above are those wherein R 1 and R 2 are both methoxy; and/or R 3 is methyl; and/or R 6 and R 7 are both fluoro.
  • Particularly preferred compounds of Formulae I, II, III, IV and V, and pharmaceutically acceptable salts and solvates thereof are those wherein R 1 and R 2 are both methoxy and R 6 and R 7 are both fluoro.
  • the invention further provides the use of the compounds of the invention or pharmaceutically acceptable salts, or solvates thereof as agonists of TGR5, preferably agonists of TGR5 having low or no systemic activity.
  • the invention relates to the use of compounds of formula I and subformulae or pharmaceutically acceptable salts and solvates thereof, in particular those of table 1 above, as TGR5 agonists, in particular agonists of TGR5 having low or no systemic activity.
  • the compounds of the invention are therefore useful in the prevention and/or the treatment of TGR5 related diseases, such as metabolic and/or gastrointestinal diseases.
  • the invention thus also relates to the use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in treating and/or preventing a TGR5 related disease, in particular a metabolic and/or a gastrointestinal disease.
  • the invention also releates to a method of treating and/or preventing TGR5 related diseases, in particular metabolic diseases, gastrointestinal diseases, hepato-biliary diseases, comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of the invention, to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • Metabolic diseases within the meaning of the present invention include, but are not limited to, type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and their sequelae including angina, claudication, heart attack, stroke, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, and nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis.
  • the metabolic disease is type II diabetes, a lipid disorder such as dyslipidemia, hypertension, obesity, or atherosclerosis and its
  • the diseases are type II diabetes and a lipid disorder such as dyslipidemia, preferably type II diabetes.
  • Gastrointestinal diseases within the meaning of the present invention include, but are not limited to, Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD), and Irritable Bowel Syndrome (IBS), intestinal injury disorders such as short-bowel syndrome, diseases involving intestinal barrier dysfunction such as proctitis and pouchitis, and gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility, including but not limited to any type of diarrhea.
  • IBD Inflammatory Bowel Diseases
  • UC Ulcerative colitis
  • CD Crohn's Disease
  • IBS Irritable Bowel Syndrome
  • intestinal injury disorders such as short-bowel syndrome
  • diseases involving intestinal barrier dysfunction such as proctitis and pouchitis
  • gastrointestinal disorders characterized by hypermotilenemia or gastrointestinal hypermotility including but not limited to any type of diarrhea.
  • the gastrointestinal disease is Inflammatory Bowel Diseases (IBD) including but not limited to colitis, Ulcerative colitis (UC) and Crohn's Disease (CD).
  • IBD Inflammatory Bowel Diseases
  • UC Ulcerative colitis
  • CD Crohn's Disease
  • Hepato-biliary diseases within the meaning of the present invention include, but are not limited to, fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC), secondary cholangiopathies in which the inflammatory and fibrosing biliary disease is the consequence of other conditions.
  • fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC)
  • PSC primary sclerosing cholangitis
  • PBC primary biliary cirrhosis
  • secondary cholangiopathies in which the inflammatory and fibrosing biliary disease is the consequence of other conditions.
  • the invention also provides for a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for use in delaying the onset of a TGR5 related disease, such as a metabolic and/or a gastrointestinal disease.
  • the invention also provides for a method for delaying in patient the onset of a TGR5 related diseases, such as a metabolic and/or a gastrointestinal disease comprising the administration of a therapeutically effective amount of a compound or pharmaceutically acceptable salt or solvate of the invention, to a patient in need thereof.
  • the patient is a warm-blooded animal, more preferably a human.
  • the metabolic and/or gastrointestinal diseases are preferably those defined above.
  • the invention further provides the use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for use in treating and/or preventing TGR5 related diseases, in particular metabolic and/or gastrointestinal diseases.
  • TGR5 related diseases in particular metabolic and/or gastrointestinal diseases.
  • the metabolic diseases, gastrointestinal diseases and/or hepato-biliary diseases are those defined above.
  • the invention also provides a method for modulating TGR5 receptor activity, in a patient, in need of such treatment, which comprises administering to said patient an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof.
  • the patient is a warm blooded animal, and even more preferably a human.
  • the compounds of the invention may be administered as part of a combination therapy.
  • compositions and medicaments which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Such multiple drug regimens may be used in the treatment and/or prevention of any of the diseases or conditions related to with TGR5 receptor modulation, particularly type II diabetes, obesity, dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia, hypertriglyceridemia, hypoglycemia, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia hypertension, hyperlipoproteinemia, metabolic syndrome, syndrome X, thrombotic disorders, cardiovascular disease, atherosclerosis and its sequelae including angina, claudication, heart attack, stroke and others, kidney diseases, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, nonalcoholic fatty liver diseases such as steatosis or nonalcoholic steatohepatitis (NASH), liver cirrhosis, liver fibrosis, liver hepato-carcinogenesis.
  • NASH nonalcoholic steatohepatitis
  • Suitable supplementary therapeutic agents used for the purpose of auxiliary treatment include drugs which, instead of directly treating or preventing a disease or condition related to TGR5 receptor modulation, treat diseases or conditions which directly result from or indirectly accompany the basic or underlying TGR5 receptor related disease or condition.
  • the methods of treatment and pharmaceutical compositions of the present invention may employ the compounds of the invention or their pharmaceutical acceptable salts or solvates thereof in the form of monotherapy, but said methods and compositions may also be used in the form of multiple therapy in which one or more compounds of the invention or their pharmaceutically acceptable salts or solvates are coadministered in combination with one or more other therapeutic agents.
  • the invention also provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.
  • the invention also covers pharmaceutical compositions which contain, in addition to a compound of the present invention, a pharmaceutically acceptable salt or solvate thereof as active ingredient, additional therapeutic agents and/or active ingredients.
  • Another object of this invention is a medicament comprising at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient.
  • the compounds of the inventions may be formulated as a pharmaceutical preparation comprising at least one compound of the invention and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds.
  • such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc.
  • parenteral administration such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion
  • topical administration including ocular
  • suitable administration forms - which may be solid, semi-solid or liquid, depending on the manner of administration - as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.
  • any reference to compounds of the invention herein means the compounds as such as well as there pharmaceutically acceptable salts and solvates.
  • halo or halogen means fluoro, chloro, bromo, or iodo. Preferred halo groups are fluoro and chloro, fluoro being particularly preferred.
  • alkyl by itself or as part of another substituent refers to a hydrocarbyl radical of Formula C n H2 n +i wherein n is a number greater than or equal to 1.
  • haloalkyl alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen as defined above.
  • haloalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,1, 1-trifluoroethyl and the like.
  • a preferred haloalkyl radical is trifluoromethyl.
  • the compounds of the invention containing a basic functional group and/or an acidic functional group may be in the form of pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts of the compounds of the invention containing one or more basic functional groups include in particular the acid addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosy
  • Compounds containing one or more acidic functional groups may be capable of forming pharmaceutically acceptable salts with a pharmaceutically acceptable base, for example and without limitation, inorganic bases based on alkaline metals or alkaline earth metals or organic bases such as primary amine compounds, secondary amine compounds, tertiary amine compounds, cyclic amines or basic ion exchange resins.
  • Compounds containing one or more basic functional groups may be capable of forming pharmaceutically acceptable salts, e.g. amine groups may be transformed into ammonium groups by reacting the amine group with an inorganic or organic base or an alkylating agent such as e.g. an alkylhalide (e.g. methyliodide).
  • an alkylating agent such as e.g. an alkylhalide (e.g. methyliodide).
  • the compounds of the invention may also form internal salts, and such compounds are within the scope of the invention.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the salt may vary from completely ionized to almost non-ionized.
  • solvate is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, water or ethanol.
  • solvent molecules for example, water or ethanol.
  • 'hydrate' is employed when said solvent is water.
  • All references to compounds of Formula I include references to salts and solvates thereof.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) and isotopically- labeled compounds of Formula I.
  • salts of the compounds of the invention are preferred, it should be noted that the invention in its broadest sense also includes non- pharmaceutically acceptable salts, which may for example be used in the isolation and/or purification of the compounds of the invention.
  • non- pharmaceutically acceptable salts which may for example be used in the isolation and/or purification of the compounds of the invention.
  • salts formed with optically active acids or bases may be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of Formula I above.
  • patient refers to a warm-blooded animal, more preferably a human, who/which is awaiting or receiving medical care or is or will be the object of a medical procedure.
  • human refers to subjects of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). In one embodiment, the human is an adolescent or adult, preferably an adult.
  • treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms.
  • prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient's risk of acquiring a condition or disease.
  • terapéuticaally effective amount means the amount of active agent or active ingredient (e. g. TGR5 agonist) which is sufficient to achieve the desired therapeutic or prophylactic effect in the individual to which it is administered.
  • administration means providing the active agent or active ingredient (e. g. a TGR5 agonist), alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented.
  • active agent or active ingredient e. g. a TGR5 agonist
  • pharmaceutically acceptable is meant that the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the patient thereof.
  • agonist means a ligand that activates an intracellular response when it binds to a receptor.
  • pharmaceutical vehicle means a carrier or inert medium used as solvent or diluent in which the pharmaceutically active agent is formulated and/or administered.
  • pharmaceutical vehicles include creams, gels, lotions, solutions, and liposomes.
  • lipid disorder means any plasma lipid disorder including but not limited to dyslipidemia such as mixed or diabetic dyslipidemia, hypercholesterolemia, low HDL cholesterol, high LDL cholesterol, hyperlipidemia and hypertriglyceridemia.
  • Solvents, reagents and starting materials were purchased from well known chemical suppliers such as for example Sigma Aldrich, Acros Organics, Fluorochem, Eurisotop, VWR International, and the following abbreviations are used:
  • ACN Acetonitrile
  • TFA Trifluoroacetic acid
  • Procedure B In a microwave tube were introduced the isothioureido-acetamide derivative (1 eq), ethyl acetate (QS 0.1 M), diisopropylethylamine (6 eq), and T3P ® (3 eq). Reaction mixture was heated under microwave irradiation at 150°C for 10 min. Reaction mixture was then diluted with ethyl acetate, washed with a saturated aqueous solution of NaHC0 3 , and brine. Organic phase was then dried over Na 2 S0 4 and evaporated. Residue was purified by flash chromatography (cHex/EtOAc).
  • reaction mixture was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHC0 3 , brine, and the organic phases were dried over Na 2 S0 4 and evaporated to dryness to give 4.33 g of tert-butyl N-[2-(3,4-dimethoxy-N-methyl- anilino)-2-oxo-ethyl]carbamate as a yellow powder, leading to a 100 % yield. It was used without further purification in the next step of the synthesis.
  • EXAMPLE la 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzoic acid
  • the titled product was obtained as a white powder, after precipitation in EtOH (194 mg, 35%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (40 mg) and 4- boronobenzoic acid (70 mg).
  • the titled product was obtained as a white powder, after precipitation in EtOH (194 mg, 35%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (40 mg) and 4- boronobenzoic acid (70 mg).
  • the titled product was obtained as a white powder, after purification by preparative HPLC (465 mg, 67%), following Procedure C, using 4-[4-[[5-(3,4- dimethoxy-N-methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2- yl]sulfanylmethyl]-3,5-difluoro-phenyl]benzoic acid (80 mg) and 2-[2- methoxypolyethyleneglycoxy]ethanamine (614 mg).
  • the titled product was obtained as a yellow oil, after purification by flash chromatography (150 mg, 73%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (200 mg) and 4- (4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol (74.04 mg).
  • the titled product was obtained as a yellow oil, after purification by flash chromatography (150 mg, 73%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3- methoxy-phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (200 mg) and 4- (4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenol (74.04 mg).
  • reaction mixture was evaporated to dryness, diluted in ethyl acetate, washed with water, brine, dried over MgS0 4 and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (97/3) gave 30 mg of the product not clean.
  • the titled product was obtained as a white powder, after precipitation in EtOH (194 mg, 35%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (250 mg) and 4- boronobenzoic acid (70 mg).
  • Reaction mixture was evaporated to dryness and purified by flash chromatography using as eluent a mixture of cHex/EtOAc (6/4), to give 3.2 g of N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4-fluorophenyl)-C- sulfanyl-carbonimidoyl] amino] -N-methyl-acetamide as a yellowish powder, leading to a 68 % yield.
  • N-(3,4-dimethoxyphenyl)-2-[[(Z)-N-(4- fluorophenyl)-C-sulfanyl-carbonimidoyl] amino] -N-methyl-acetamide (1 g, 2.54 mmol), K 2 C0 3 (0.35 g, 2.54 mmol), Nal (0.19 g, 1.27 mmol), and 13 mL of acetonitrile (QS 0.1 M).
  • the titled product was obtained as a yellow oil, after purification by flash chromatography (70 mg, 70%), following Procedure C, using 2-[(4-bromo-2,6- difluoro-phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluorophenyl)-N- methyl-imidazol-4-amine (Intermediate 10) (100 mg) and phenylboronic acid
  • Residue was then purified by flash chromatography using as eluent a mixture of cHex/EtOAc (7/3) to give 1040 mg of 2-[[(Z)-C-[[4-(3-chloropropoxy)-2,6-difluoro- phenyl]methylsulfanyl]-N-(4-fluorophenyl)carbonimidoyl]amino]-N-(3,4- dimethoxyphenyl)-N-methyl-acetamide as a yellowish solid, leading to a 75% yield.
  • Residue was then purified by flash chromatography using as eluent a mixture of cHex/EtOAc (7/3) to give 915 mg of 2-(chloromethyl)-5-(3-chloropropoxy)-l,3-difluoro-benzene as a yellowish solid, leading to a 73 %.
  • Residue was then purified by flash chromatography using as eluent a mixture of cHex/EtOAc (6/4) to give 300 mg of tert-butyl N-tert-butoxycarbonyl-N-[3-[4- [[(Z)-N-[2-(3,4-dimethoxy-N-methyl-anilino)-2-oxo-ethyl]-N'-(4- fluorophenyl)carbamimidoyl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate as a yellowish oil, leading to a 35%. It was used without further purification in the next step of the synthesis.
  • Residue was purified by flash chromatography using as eluent a mixture of DCM/MeOH (99/1) to give 183 mg of tert-butyl N- tert-butoxycarbonyl-N-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)- 1-(4- fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenoxy]propyl]carbamate as an orange oil, leading to a 62% yield.
  • Step 11 diammonium;2-[3-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4- fluorophenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenoxy]propyl-(2- sulfonatoethyl)amino]ethanesulfonate
  • 1,3-dibromopropane (950.87 ⁇ , 9.37 mmol), 3,5-difluoro-4- (hydroxymethyl)phenol (Intermediate 12c) (300 mg, 1.87 mmol) and potassium carbonate (258.95 mg, 1.87 mmol) were added in acetonitrile (6 mL, QS 0.3 M) and the reaction mixture was stirred at reflux for 3 hours. The solvent was removed under reduced pressure. The crude was dissolved in ethyl acetate and washed with water. The aqueous phase was extracted with ethyl acetate and washed with brine, dried under Na 2 S0 4 .
  • reaction mixture was diluted with ethyl acetate, washed with water, saturated aqueous solution of NaHC0 3 and brine, and the organic phase was dried over Na 2 S0 4 and evaporated to give 523 mg of tert-butyl N-[2-(3,4-dimethoxy-N-methyl-anilino)- l-methyl-2- oxo-ethyl] carbamate as a yellow powder, leading to a 66 % yield.
  • T P ® (3 eq.) and DIEA (6 eq.) were added after 4, 19, and 24 hours.
  • T 3 P ® (1.5 eq.) and DIEA (3 eq.) were added after 42 hours.
  • Reaction mixture was then diluted with EtOAc, washed with water, a saturated aqueous solution of NaHC0 3 , and brine. Organic phase was then dried over Na 2 S0 4 and evaporated.
  • Residue was then purified by preparative HPLC (pH 3.8) to give 4.5 mg of [2-(2,6-difluoro-benzylsulfanyl)-3- (4-fluoro-phenyl)-5-methyl-3H-imidazol-4-yl]-(3,4-dimethoxy-phenyl)-methyl- amine as a yellowish solid, leading to a 6 % yield.
  • Residue was purified by flash chromatography using as eluent a mixture of cHex/EtOAc (8/2) to give 587 mg of N-allyl-3,4-dimethoxy-aniline as a pale yellowish oil, leading to a 51% yield.
  • reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NaHC0 3 and with brine, and the organic phase was dried over Na 2 S0 4 and evaporated to give 1.07 g of tert- butyl N-[2-(N-allyl-3,4-dimethoxy-anilino)-2-oxo-ethyl]carbamate as a yellowish viscous oil, leading to a 100 % yield.
  • N-Allyl-N-(3,4-dimethoxy-phenyl)-2-[3-(4-fluoro- phenyl)-isothioureido]-acetamide 400 mg, 0.99 mmol
  • potassium carbonate 137 mg, 0.99 mmol
  • sodium iodide 74 mg, 0.50 mmol
  • 2-(bromomethyl)- 1,3-difluoro-benzene 205 mg, 0.99 mmol
  • Reaction mixture was then diluted with EtOAc, washed with water, with a saturated aqeous solution of NaHC0 3 , and with brine. Organic phase was then dried over Na 2 S0 4 and evaporated. Residue was then purified by flash chromatography using as eluent a mixture of CHCl 3 /MeOH (99: 1) to give 192 mg of allyl-[2-(2,6-difluoro-benzylsulfanyl)-3-(4-fluoro-phenyl)-3H-imidazol-4-yl]- (3,4-dimethoxy-phenyl)-amine as an orange solid, leading to a 53 % yield.
  • the titled product was obtained as a dark oil (1.05 g, 87%), following Procedure A, using methyl 2-(bromomethyl)- l,3-difluoro-benzene (419.82 mg) and methyl (4S)-5-(3,4-dimethoxy-N-methyl-anilino)-4-[(4- fluorophenyl)carbamothioylamino]-5-oxo-pentanoate (940 mg).
  • the reaction mixture was diluted in EtOAc and washed with water, brine, and dried over MgS0 4 and evaporated to dryness. The conversion was not complete. The residue was dissolved in 17 mL of AcOEt. T 3 P (3.01 mL, 5.1 mmol), DIEA (1.88 mL, 10.21 mmol) were added at the reaction mixture and it was stirred at 80°C for 24 h. The reaction mixture was diluted in EtOAc, washed with water and brine. Organic phase was dried over MgS0 4 and evaporated. The crude was purified by flash chromatography using as eluent a mixture of Cy/EA (70/30) to give 265 mg of the desired product not clean.
  • Methyl 3-[2-[(2,6-difluorophenyl)methylsulfanyl]-5-(3,4-dimethoxy-N-methyl- anilino)-l-(4-fluorophenyl)imidazol-4-yl]propanoate (104.6 mg, 0.18 mmol) was dissolved in MeOH (1.83 mL) and NaOH 1 N (640 ⁇ , 0.64 mmol) was added. The mixture was stirred overnight at room temperature and evaporated to dryness. The residue was dissolved in DCM and washed with HCl 1 N, water and brine.
  • reaction mixture was diluted in ethyl acetate, washed with a saturated aqueous solution of NaHC0 3 and with brine, and the organic phase was dried over MgS0 4 and evaporated to dryness to give 1.85 g of 9H-fluoren-9-ylmethyl N-[(5S)-5-(tert- butoxycarbonylamino)-6-(3,4-dimethoxy-N-methyl-anilino)-6-oxo- hexyl] carbamate as a dark red oil, leading to a 100% yield. It was used without further purification in the next step of the synthesis.
  • l-fluoro-4-isothiocyanato-benzene (0.46 g, 2.99 mmol) and TEA (0.4 mL, 2.99 mmol) were added in a 500 mL flask in 20 mL of ethanol.
  • the titled product was obtained as an oily residue (207 mg, 58%), following Procedure A, using N-(3,4-dimethoxy-benzyl)-2-[3-(4-fluoro-phenyl)-thioureido]- N-methyl-acetamide (19b) (0.300 g) and 2-bromomethyl-l,3-difluoro-benzene (77 mg).
  • the titled product was obtained as a yellowish powder (91 mg, 47 %) following procedure B using 2-[2-(2,6-difluoro-benzyl)-3-(4-fluoro-phenyl)-isothioureido]- N-(3,4-dimethoxy-benzyl)-N-methyl-acetamide (19c) (200 mg).
  • EXAMPLE 21 4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro-phenyl]-N-
  • the titled product was obtained as a white powder, after precipitation in EtOH (194 mg, 35%), following Procedure C, using 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (250 mg) and 4- boronobenzoic acid (70 mg).
  • EXAMPLE 22 3-[[4-[4-[[5-(3,4-dimethoxy-N-methyl-anilino)-l-(4-fluoro-3- methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5-difluoro- phenyl]phenyl]methylamino]propanoic acid
  • the reaction mixture was heated under microwave irradiation at 100°C for 10 min.
  • the reaction mixture was filtrated and evaporated to dryness.
  • the crude was diluted in DCM and filtrated on Celite. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH (95/5) gave 330 mg of the desired compound as a yellow oil, leading to a 67 % yield.
  • the aqueous phase was extracted by EtOAc and washed with brine, dried over MgS0 4 .
  • the solvents were removed under reduced pressure.
  • the crude was purified by flash chromatography using as eluent a mixture of Cy/EA (50/50) to give 150 mg of the titled compound as yellow oil, leading to a 94% yield.
  • Step 1 In a microwave tube were added 2-[(4-bromo-2,6-difluoro- phenyl)methylsulfanyl]-N-(3,4-dimethoxyphenyl)-3-(4-fluoro-3-methoxy- phenyl)-N-methyl-imidazol-4-amine (Intermediate 2) (1000 mg, 1.682 mmol), [4- [(tert-butoxycarbonylamino)methyl]phenyl]boronic acid (422.39 mg, 1.68 mmol), 1M Cs 2 C0 3 (5.047 mL), and PdCl 2 (dppf) (274.54 mg, 0.34 mmol) in 8.4 mL of DMF.
  • Intermediate 2 1000 mg, 1.682 mmol
  • [4- [(tert-butoxycarbonylamino)methyl]phenyl]boronic acid (422.39 mg, 1.68 mmol)
  • 1M Cs 2 C0 3 5.047 mL
  • the reaction mixture was heated under microwave irradiation at 100°C for 10 min.
  • the reaction mixture was filtrated and evaporated to dryness.
  • the crude was diluted in EtOAc and washed with IN aqueous solution of HC1, with brine, dried over MgS0 4 and evaporated to dryness. Purification of the crude by flash chromatography using as eluent a mixture of DCM/MeOH gave 740 mg of the desired compound as yellow oil, leading to a 61 % yield.
  • Step 2 In a 25 mL flask was diluted tert-butyl N-[[4-[4-[[5-(3,4-dimethoxy-N- methyl-anilino)-l-(4-fluoro-3-methoxy-phenyl)imidazol-2-yl]sulfanylmethyl]-3,5- difluoro-phenyl]phenyl]methyl]carbamate (740 mg, 1.03 mmol) in 4 mL of DCM. 1.2 mL of TFA was added at the reaction mixture and it was stirred at room temperature for 30 min.
  • reaction mixture was diluted in DCM and washed with a saturated aqueous solution of NaHC0 3 , with brine, dried over MgS0 4 and evaporated to dryness to give 590 mg of the desired product as a yellow solid, leading to 93% yield.
  • HEK 293 cells were transiently co-transfected with pCMV tag4b-TGR5h (to follow hTGR5 activation) or pCMV AC6-TGR5m (to follow mTGR5 activation) expression plasmids and the pCRE TA-Lucif erase reporter plasmid using the JET PEI reagent (Polyplus transfection). Transfected cells were seeded in 96-well plates and incubated overnight with the test compounds at increasing concentrations tested in duplicate.

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Abstract

La présente invention concerne de nouveaux composés de formule (I), des sels ou des solvates pharmaceutiquement acceptables de ces composés, ainsi que leur utilisation.
PCT/EP2016/071415 2015-09-11 2016-09-12 Nouveaux composés 5-amino-2-thio-imidazoles et leur utilisation WO2017042380A1 (fr)

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EP4212515A1 (fr) 2017-12-21 2023-07-19 Ribon Therapeutics Inc. Quinazolinones en tant qu'inhibiteurs de parp14

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