WO2023223257A1 - Composés amino-hétéroaromatiques - Google Patents

Composés amino-hétéroaromatiques Download PDF

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WO2023223257A1
WO2023223257A1 PCT/IB2023/055126 IB2023055126W WO2023223257A1 WO 2023223257 A1 WO2023223257 A1 WO 2023223257A1 IB 2023055126 W IB2023055126 W IB 2023055126W WO 2023223257 A1 WO2023223257 A1 WO 2023223257A1
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compound
pharmaceutically acceptable
disclosure
acceptable salt
nash
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PCT/IB2023/055126
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Kyle Denton
Takashi Satoh
Sana BAZZAZ
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X-Chem Inc.
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Publication of WO2023223257A1 publication Critical patent/WO2023223257A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical

Definitions

  • This specification relates to certain amino heteroaromatic compounds and pharmaceutically acceptable salts thereof that inhibit 17P hydroxy steroid dehydrogenase 13 (17PHSD13 or HSD17B13), and their use in treating diseases such as liver disease.
  • This specification also relates to processes and intermediate compounds involved in the preparation of the amino heteroaromatic compounds and to pharmaceutical compositions containing them.
  • Non-alcoholic fatty liver disease represents a spectrum of liver disease ranging from simple steatosis (non-alcoholic fatty liver), to non-alcoholic steatohepatitis (NASH) with or without fibrosis, to cirrhosis.
  • Hepatic steatosis is defined as excess fat accumulation in the liver with greater than 5% induced by causes other than alcohol intake.
  • NASH is defined by hepatic steatosis with inflammation and hepatocyte injury, with or without fibrosis. It is estimated that approximately 25% of the global population has NAFLD, and mortality due to NAFLD-related disease is expected to increase significantly through 2030.
  • a variant in the 17PHSD13 gene was associated in an allele dose-dependent manner with decreased serum aminotransferases levels, as well as a lower risk of liver disease, including alcoholic and non-alcoholic liver disease, cirrhosis and hepatocellular carcinoma (HCC) (Abul-Husn et al, N Engl J Med. 2018, 378(12), 1096-106, Wang et al, Eur Rev Med Pharmacol Sci, 2020, 24(17), 8997-9007).
  • HCC hepatocellular carcinoma
  • the 17PHSD13 splice variant results in a truncated, unstable and enzymatically inactive protein and has thus been characterized as an 17PHSD13 Loss of Function (LoF) variant (Ma et al, Hepatology 2019, 69(4), 1504-19).
  • LoF Loss of Function
  • LoF 17PHSD13 rs72613567:TA
  • decreased disease severity has been replicated in additional cohorts with histologically proven NAFLD and was also associated with lower plasma transaminases, reduced risk of cirrhosis, HCC and liver related mortality in a study of 111612 individuals from the Danish general population (Gellert-Kristensen et al, Hepatology, 2020, 71(1), 56-66).
  • the protective effect of the LoF 17PHSD13 (rs72613567:TA) variant on plasma transaminases levels appears to be amplified by several key risk factors of liver disease such as obesity, alcohol consumption, as well as established genetic risk factors such as, but not limited to, the (rs738409 C>G) variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3).
  • PNPLA3 patatin-like phospholipase domain-containing protein 3
  • two additional 17PHSD13LoF variants (rs62305723) and (rsl43404524) were also reported to confer protection from chronic liver disease progression (Kozlitina et al, N Engl J Med, 2018, 379(19), 1876-7).
  • the LoF 17PHSD13 protective variants has a stronger association with fibrosis and progression to advance liver disease but is not associated with steatosis.
  • liver diseases such as NAFLD (for example NASH, liver fibrosis, cirrhosis and isolated steatosis), liver inflammation, alcoholic steatohepatitis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC), such as in individuals harbouring several key risk factors of liver disease such as obesity, alcohol consumption, as well as established genetic risk factors such as the (rs738409 C>G) variant in PNPLA3.
  • NAFLD for example NASH, liver fibrosis, cirrhosis and isolated steatosis
  • ASH alcoholic steatohepatitis
  • HCV hepatitis C virus
  • HCC hepatocellular carcinoma
  • the compounds of the disclosure provide an anti-liver disease effect by, as a minimum, acting as 17PHSD13 inhibitors. Further, compounds of the disclosure may selectively inhibit 17PHSD13 over 17PHSD4 and/or 17PHSD9.
  • 17PHSD Fifteen 17PHSD (HSD17B) members have been identified in human. The sequence homology among the different members is rather low, but the overall structure seems conserved. 17P-Hydroxysteroid dehydrogenases are mainly involved in sex hormone metabolism. Some 17PHSD enzymes also play key roles in cholesterol and fatty acid metabolism (Labrie et al. Journal of Molecular Endocrinology, 2000, 25, 1-16, Wen Su et al. Molecular and Cellular Endocrinology, 2019, 489, 119-125). A clean off-target profile is an advantage for a 17PHSD13 inhibitor to avoid potential toxicity caused by off- target activity. This includes selectivity to other 17PHSD members.
  • 17PHSD4/ D-bifunctional protein is involved in fatty acid p-oxidation and steroid metabolism. 17PHSD4 is ubiquitously expressed and play an important role in the inactivation of estrogens in a large series of peripheral tissues. Mutations in 17PHSD4 are known to cause DBP deficiency, an autosomal-recessive disorder of peroxisomal fatty acid p-oxidation that is generally fatal within the first two years of life.
  • a homozygous missense variant in 17PHSD4 has been identified in Perrault syndrome, a recessive disorder characterized by ovarian dysgenesis in females, sensorineural deafness in both males and females, and in some patients, neurological manifestations (Pierce et al. Am. J. Hum. Genet., 2010, 87, 282-8; and Chen et al. BMC Med Genet., 2017, 18, 91).
  • 17PHSD9/ RDH5 (retinol dehydrogenase 5) is involved in retinoid metabolism.
  • the enzyme is mainly expressed in the retinal pigment epithelium.
  • the RDH5 gene encodes the enzyme that is a part of the visual cycle, the 11-cis retinol dehydrogenase, catalysing the reduction of 11-cis-retinol to 11-cis- retinal.
  • RDH5 gene mutations cause a progressive cone dystrophy or macular dystrophy as well as night blindness.
  • Fundus albipunctatus is a rare, congenital form of night blindness with rod system impairment, characterised by the presence of numerous small, white-yellow retinal lesions.
  • the compounds of the specification may also exhibit advantageous physical properties (for example, lower lipophilicity, higher aqueous solubility, higher permeability, lower plasma protein binding, and/or greater chemical stability), and/or favourable toxicity profiles (for example a decreased activity at hERG), and/or favourable metabolic or pharmacokinetic profiles, in comparison with other known 17PHSD13 inhibitors.
  • Such compounds may therefore be especially suitable as therapeutic agents, such as for the treatment of liver disease.
  • a compound, or a pharmaceutically acceptable salt thereof wherein the compound is 2-(difluoromethoxy)-5-(5-((5-fluoroadamantan-2- yl)(methyl)amino)-l,3,4-oxadiazol-2-yl)phenol or 5-(3-(((l-cyclohexyl-lH-tetrazol-5- yl)methyl)(methyl)amino)-l,2,4-oxadiazol-5-yl)-2-fluorophenol.
  • composition comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a compound of the disclosure or a pharmaceutically acceptable salt thereof for use in the treatment of liver disease.
  • a method of treating liver disease in a patient comprising administering to the patient an effective amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof.
  • Units, prefixes, and symbols are denoted in their International System of Units (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.
  • the is provided 2-(difluoromethoxy)-5-(5-((5-fluoroadamantan-2- yl)(methyl)amino)-l,3,4-oxadiazol-2-yl)phenol, or a pharmaceutically acceptable salt thereof.
  • the is provided 5-(3-(((l-cyclohexyl-lH-tetrazol-5-yl)methyl)(methyl)amino)-l,2,4- oxadiazol-5-yl)-2-fluorophenol, or a pharmaceutically acceptable salt thereof.
  • the compounds of the disclosure, and pharmaceutically acceptable salts thereof may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form and any given compound of the disclosure, or pharmaceutically acceptable salt thereof, may be capable of being formed into more than one crystalline / polymorphic form, including hydrated (e.g. hemi hydrate, a mono hydrate, a di hydrate, a tri hydrate or other stoichiometry of hydrate) and/or solvated forms. It is to be understood that the present specification encompasses any and all such solid forms of the compound of the disclosure, and pharmaceutically acceptable salts thereof.
  • isotopes will be understood to include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • isotopes of carbon include 13 C and 14 C.
  • Isotopes of nitrogen include 15 N.
  • Isotopes of fluorine include 18 F.
  • a suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, a base addition salt.
  • a base addition salt of a compound of the disclosure may be formed by bringing the compound into contact with a suitable inorganic or organic base under conditions known to the skilled person.
  • a base addition salt may for example be an alkali metal salt (such as a sodium, potassium, or lithium salt) or an alkaline earth metal salt (such as a calcium salt), which may be formed using an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide).
  • a base addition salt may also be formed using a suitably basic organic amine (e.g., a choline or meglumine salt).
  • a further suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, a salt formed within a patient's body after administration of a compound of the disclosure to the patient.
  • the compound of the disclosure, or pharmaceutically acceptable salt thereof may be prepared as a co-crystal solid form. It is to be understood that a pharmaceutically acceptable co-crystal of an compound of the disclosure, or pharmaceutically acceptable salts thereof, form an aspect of the present specification.
  • composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • composition refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a patient to which the composition would be administered. Such compositions can be sterile.
  • a pharmaceutical composition according to the present specification will comprise a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • Such compositions may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • An effective amount of the compound of the disclosure, or a pharmaceutically acceptable salt thereof, will normally be present in the composition.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and/or nasal route and/or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible.
  • the compositions may be administered at varying doses.
  • compositions of the compound of the disclosure, described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.
  • compositions of the compound of the disclosure may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
  • compositions suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifying agents; and preservatives Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of the disclosure, and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.
  • SEG soft elastic gelatin
  • the compounds of the disclosure, and pharmaceutically acceptable salts thereof are expected to be useful in therapy, for example in the treatment of diseases or medical conditions mediated at least in part by 17BHSD13, including liver disease, such as NASH.
  • the liver disease is selected from alcoholic liver disease, non-alcoholic liver disease, NAFLD (such as NASH, liver fibrosis, cirrhosis, and isolated steatosis), liver inflammation, alcoholic steatoheptatis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC).
  • NAFLD such as NASH, liver fibrosis, cirrhosis, and isolated steatosis
  • liver inflammation alcoholic steatoheptatis (ASH), hepatitis C virus (HCV) and hepatocellular carcinoma (HCC).
  • ASH alcoholic steatoheptatis
  • HCV hepatitis C virus
  • HCC hepatocellular carcinoma
  • the term “therapy” is intended to have its normal meaning of dealing with a disease in order to entirely or partially relieve one, some or all of its symptoms, or to correct or compensate for the underlying pathology.
  • the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary.
  • the terms “therapeutic” and “therapeutically” should be interpreted in a corresponding manner.
  • prophylaxis is intended to have its normal meaning and includes primary prophylaxis to prevent the development of the disease and secondary prophylaxis whereby the disease has already developed and the patient is temporarily or permanently protected against exacerbation or worsening of the disease or the development of new symptoms associated with the disease.
  • treatment is used synonymously with “therapy”.
  • treat can be regarded as “applying therapy” where “therapy” is as defined herein.
  • a compound of the disclosure for use in providing an inhibitory effect on 17PHSD13.
  • a compound of the disclosure for use in the treatment of a disease mediated by 17PHSD13, such as liver disease (e.g. NASH).
  • a disease mediated by 17PHSD13 such as liver disease (e.g. NASH).
  • a compound of the disclosure for use in the treatment of fatty liver disease.
  • a compound of the disclosure for use in the treatment of nonalcoholic Fatty Liver Disease (NAFLD), such as isolated steatosis, Nonalcoholic Steatohepatitis (NASH), liver fibrosis or cirrhosis.
  • NAFLD nonalcoholic Fatty Liver Disease
  • NASH Nonalcoholic Steatohepatitis
  • liver fibrosis or cirrhosis.
  • the liver disease is end stage liver disease.
  • a compound of the disclosure for use in the treatment of liver disease, such as NASH, wherein the patient is also suffering from or susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, Type 2 diabetes, and renal insufficiency.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of liver disease, such as NASH wherein the patient has a body mass index (BMI) of 27 kg/m 2 to 40 kg/m 2 .
  • BMI body mass index
  • the subject has a BMI of 30 kg/m 2 to 39.9 kg/m 2 .
  • the patient has a BMI of at least 40 kg/m 2 .
  • the patient is overweight.
  • the patient is obese.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of liver disease, such as NASH wherein the patient is also suffering from or susceptible to dyslipidemia.
  • a compound of the disclosure for use in the treatment of liver disease, such as NASH, wherein the patient is also suffering from or susceptible to insulin resistance.
  • a compound of the disclosure for use in the treatment of liver disease, such as NASH, wherein the patient is also suffering from or susceptible to Type 2 diabetes.
  • a compound of the disclosure for use in the treatment of liver disease, such as NASH, wherein the patient is also suffering from or susceptible to renal insufficiency.
  • the patient is (i) suffering from or susceptible to liver fibrosis, and (ii) suffering from or susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, Type 2 diabetes, and renal insufficiency.
  • the patient is (i) suffering from or susceptible to cirrhosis, and (ii) suffering from or susceptible to one or more conditions selected from the group consisting of obesity, dyslipidemia, insulin resistance, Type 2 diabetes, and renal insufficiency.
  • the NAFLD is Stage 1 NAFLD.
  • the NAFLD is Stage 2 NAFLD.
  • the NAFLD is Stage 3 NAFLD.
  • the NAFLD is Stage 4 NAFLD. See, e.g., "The Diagnosis and Management of Nonalcoholic Fatty Liver Disease: Practice Guidance From the American Association for the Study of Liver Diseases," Hepatology, Vol. 67, No. 1, 2018.
  • NAFLD such as NASH.
  • the patient is obese.
  • the patient has alcoholic liver disease.
  • the patient has a genetic risk factor for liver disease, such as the (rs738409 C>G) variant in PNPLA3.
  • the NASH is Stage 1 NASH.
  • the NASH is Stage 2 NASH.
  • the NASH is Stage 3 NASH.
  • the NASH is Stage 4 NASH.
  • the patient is also suffering from or susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, Type 2 diabetes, and renal insufficiency.
  • liver fibrosis is Stage 3 liver fibrosis.
  • the patient is also suffering from or susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, Type 2 diabetes, and renal insufficiency.
  • a compound of the disclosure for use in the treatment of cirrhosis.
  • the cirrhosis is stage F4 cirrhosis.
  • the patient is also suffering from or susceptible to one or more conditions selected from obesity, dyslipidemia, insulin resistance, Type 2 diabetes, and renal insufficiency.
  • a compound of the disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment of liver inflammation is chronic inflammation.
  • the chronic inflammation is selected from the group consisting of rheumatoid arthritis, osteoarthritis, and Crohn's disease.
  • the chronic inflammation is rheumatoid arthritis.
  • a compound of the disclosure for use in the treatment of hepatocellular carcinoma (HCC).
  • HCC hepatocellular carcinoma
  • a compound of the disclosure for use in the treatment of alcoholic steatoheptatis (ASH).
  • HCV hepatitis C virus
  • a method of treating disease such as NASH, in a patient comprising administering to the patient an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof.
  • treating refers to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and/or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and/or slow the development of a targeted pathologic condition or disorder.
  • those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented.
  • an effective amount means an amount of an active ingredient which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response).
  • the effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.
  • patient refers to any animal (e.g., a mammal), including, but not limited to humans, nonhuman primates, rodents, and the like, which is to be the recipient of a particular treatment.
  • the term "patient” refers to a human subject.
  • a method of treating disease in a patient comprising administering to the patient an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, wherein the disease is selected from isolated steatosis, NASH, liver fibrosis and cirrhosis.
  • a method of treating a 17PHSD13 mediated disease in a patient comprising administering to the patient an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, such as NASH.
  • the compounds of the present disclosure may be used in the methods described above as either as single pharmacological agents or in combination with other pharmacological agents or techniques. Such combination therapies may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. These combination therapies (and corresponding combination products) employ the compounds of the present disclosure and the other pharmacological agent(s).
  • a combination for use in the treatment of liver disease comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a sodium-glucose transport protein 2 (SGLT2) inhibitor.
  • the SGLT2 inhibitor is selected from canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, ipragliflozin, luseogliflozin, and remogliflozin.
  • a combination for use in the treatment of liver disease comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and metformin, or a pharmaceutically acceptable salt thereof.
  • a combination for use in the treatment of liver disease comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a glucagon-like peptide-1 receptor (GLP1) agonist.
  • GLP1 agonist is selected from exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and semaglutide.
  • a combination for use in the treatment of liver disease comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a dipeptidyl peptidase 4 (DPP4) inhibitor agonist.
  • the DPP4 inhibitor is selected sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, omarigliptin, evogliptin, gosogliptin, and dutogliptin.
  • a combination for use in the treatment of liver disease comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a PPAR agonist.
  • the PPAR agonist is a PPARa agonist.
  • the PPAR agonist is a PPARy agonist.
  • the PPAR agonist is a PPARa/y agonist.
  • the PPAR agonist is selected from clofibrate, gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate.
  • the PPAR agonist is a thiazolidinedione.
  • the thiazolidinedione is selected from pioglitazone, rosiglitazone, lobeglitazone, and rivoglitazone.
  • the PPAR agonist stimulates liver expression of FGF21.
  • the compounds of the disclosure are primarily of value as therapeutic agents for use in patients, they are also useful whenever it is required to inhibit 17PHSD13. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • reactions refer to being degassed or purged
  • this can be performed for example by purging the reaction solvent with a constant flow of nitrogen for a suitable period of time (for example 5 to 10 min) or by repeatedly evacuating the vessel and backfill with appropriate inert atmosphere (for example nitrogen (g) or argon (g));
  • organic solutions were dried over anhydrous MgSCU or NajSC , or by using ISOLUTE Phase Separator, and workup procedures were carried out using traditional phase separating techniques.
  • a drying agent such as e.g. MgSO4 or Na2SO4 is used for drying an organic layer, it is understood that said organic layer is filtered before concentration of said layer.
  • flash column chromatography was performed on straight phase silica, using either MERCK Silica Gel (Art. 9385) or prep-packed cartridges such as BIOTAGE SNAP cartridges (40-63 pm silica, 4-330 g), BIOTAGE SFAR Silica HC D cartridges (20 pm, 10-100 g), INTERCHIM PURIFLASH cartridges (25 pm, 4-120 g), INTERCHIM PURIFLASH cartridges (50 pm, 25-330 g), GRACE GRACE RESOLV Silica Flash Cartridges (4-120 g) or AGELA FLASH Colum Silica-CS cartridges (80- 330g), or on reversed phase silica using AGELA TECHNOLOGIES C-18, spherical cartridges (20-35pm, 100A, 80-330g), manually or automated using a GRACE REVELERIS X2 Flash system or similar system;
  • the structures of the end-products of the disclosure might appear as rotamers in the NMR-spectrum, in which instances only peaks of the major rotamer are reported.
  • the structures of the intermediates and/or the end-products of the disclosure might appear as rotamers in the NMR-spectrum, in which instances peaks of all rotamers are reported, and only the total number of protons are reported.
  • Electrospray mass spectral data were obtained using a WATERS ACQUITY UPLC coupled to a Waters single quadrupole mass spectrometer or similar equipment, acquiring both positive and negative ion data, and generally, only ions relating to the parent structure are reported; high resolution electrospray mass spectral data were obtained using a WATERS XEVO qToF mass spectrometer or similar equipment, coupled to a WATERS ACQUITY UPLC, acquiring either positive and negative ion data, and generally, only ions relating to the parent structure are reported; (xi) intermediates were not necessarily fully purified but their structures and purity were assessed by TLC, analytical HPLC/UPLC, and/or NMR analysis and/or mass spectrometry;
  • Example 1 2-(Difluoromethoxy)-5-(5-((5-fluoroadamantan-2-yl)(methyl)amino)-l,3,4-oxadiazol-2- yl)phenol h (56 mg, 0.2 mmol) followed by DBU (33 mg, 0.2 mmol) was added to a solution of (Ej-2-(4- (difluoromethoxy)-3-hydroxybenzylidene)-/V-(5-fluoroadamantan-2-yl)-/ ⁇ /-methylhydrazine-l- carboxamide Intermediate 3 (45 mg, 0.1 mmol) in MeOH (1 mL) and the reaction mixture was stirred at rt for 1 h.
  • SCIEX LC-MS/MS system Sample was injected with CTC analytical injector, SHIMATZU LC pumps LC20 and analyzed on the SCIEX API 5000 LCMSMS system with the following settings. Samples were chromatographed on a WATERS, SYMMETRY, C8, 3.5 pm, 2. lx 50 mm) column at constant flow rate of 0.5 mL/min. The mobile phases consist of A (water with 0.2% formic acid) and B (acetonitrile with 0.2% formic acid). The LC gradient profile is as follows: 50% B during 0 to 0.5 min, a linear increase to 100% B during 0.5 to 1 min, hold at 100% B during 1 to 1.6 min then back to 50% B from 1.6 to 2 min.
  • the run time was 2 min with retention times of approximately 0.8 and 1.07 min for Estradiol and Estrone, respectively.
  • Detection was performed on a API 5000 LC/MS/MS system with a triple quadrupole mass spectrometer, a TURBO V ion source, in multiple reaction monitoring (MRM) mode at positive polarity with APCI probe.
  • MRM pairs were m/z 273.1 to m/z 107.0 and m/z 271.3 to 107.0. for Estradiol and Estrone, respectively.
  • the dwell times were 100 ms for each transition and a depolarization and collision energy of 100 and 40, respectively.
  • Data from MS signals was using area under curve (AUC).
  • Ratio Estrone/(Estrone + Estradiol)
  • GENEDATA SCREENER was used for curve fitting and calculation of IC 5 o values.
  • Compound % effect -100 x ((X-min)/(max-min)) where X represents the effect in the presence of test compound, min is DMSO and max is the maximum inhibition of enzyme using a known inhibitor as control.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La description concerne le 2-(difluorométhoxy)-5-(5-((5-fluoroadamantan-2-yl)(méthyl) amino)-1,3,4-oxadiazol-2-yl) phénol ou le 5-(3-(((1-cyclohexyl -1H-tétrazol-5-yl)méthyl)(méthyl)amino)-1,2,4-oxadiazol-5-yl)-2-fluorophénol, et des sels pharmaceutiquement acceptables de ceux-ci, des procédés et des intermédiaires utilisés pour leur préparation, des compositions pharmaceutiques les contenant et leur utilisation dans le traitement de maladies telles qu'une maladie du foie.
PCT/IB2023/055126 2022-05-19 2023-05-18 Composés amino-hétéroaromatiques WO2023223257A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021050555A1 (fr) * 2019-09-10 2021-03-18 X-Chem, Inc. Compositions et leurs utilisations
US20220127258A1 (en) * 2019-01-31 2022-04-28 The National Institutes of Pharmaceutical R&D Co., Ltd. Aromatic ring or heteroaromatic ring compounds, preparation method therefor and medical use thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220127258A1 (en) * 2019-01-31 2022-04-28 The National Institutes of Pharmaceutical R&D Co., Ltd. Aromatic ring or heteroaromatic ring compounds, preparation method therefor and medical use thereof
WO2021050555A1 (fr) * 2019-09-10 2021-03-18 X-Chem, Inc. Compositions et leurs utilisations

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE [online] 13 January 2016 (2016-01-13), ANONYMOUA: "SID 282670940", XP093113721, retrieved from PUBCHEM Database accession no. 282670940 *
DATABASE PUBCHEM SUBSTANCE [online] 25 May 2018 (2018-05-25), ANONYMOUS: "SID 365202679", XP093113720, retrieved from PUBCHEM Database accession no. 365202679 *
DATABASE PUBCHEM SUBSTANCE [online] 3 June 2015 (2015-06-03), ANONYMOUS: "SID 251931991", XP093113713, retrieved from PUBCHEM Database accession no. 251931991 *

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