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EP4646195A2 - Compositions et méthodes de régulation de niveaux de glucose - Google Patents

Compositions et méthodes de régulation de niveaux de glucose

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Publication number
EP4646195A2
EP4646195A2 EP24738905.9A EP24738905A EP4646195A2 EP 4646195 A2 EP4646195 A2 EP 4646195A2 EP 24738905 A EP24738905 A EP 24738905A EP 4646195 A2 EP4646195 A2 EP 4646195A2
Authority
EP
European Patent Office
Prior art keywords
group
methyl
optionally substituted
substituents selected
different
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24738905.9A
Other languages
German (de)
English (en)
Inventor
Kelly J. ABERNATHY
Michael Friedrich ACKERMANN
Stephen E. Butts
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sirtsei Pharmaceuticals Inc
Original Assignee
Sirtsei Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sirtsei Pharmaceuticals Inc filed Critical Sirtsei Pharmaceuticals Inc
Publication of EP4646195A2 publication Critical patent/EP4646195A2/fr
Pending legal-status Critical Current

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Classifications

    • 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
    • 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
    • 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

  • one aspect of the invention relates to a method of improving glucose homeostasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby improving glucose homeostasis.
  • Another aspect of the invention relates to a method of lowering plasma glucose levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby lowering plasma glucose levels.
  • a further aspect of the invention relates to a method of treating hyperglycemia, prediabetes, or diabetes (e.g., Type I, Type II or gestational) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the hyperglycemia, prediabetes, or diabetes.
  • a SIRT6 activator e.g., Type I, Type II or gestational
  • the present invention also contemplates that in some embodiments of the invention, any feature or combination of features set forth herein can be excluded or omitted.
  • the term “about,” as used herein when referring to a measurable value such as an amount of a compound or agent of this invention, dose, time, temperature, and the like, is meant to encompass variations of ⁇ 10%, ⁇ 5%, ⁇ 1%, ⁇ 0.5%, or even ⁇ 0.1% of the specified amount.
  • the transitional phrase “consisting essentially of” is to be interpreted as encompassing the recited materials or steps and those that do not materially affect the basic and novel characteristic(s) of the claimed invention.
  • the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising.”
  • the terms “treating”, “treatment”, “treat” and the like mean affecting a subject (e.g., a patient), tissue or cell to obtain a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing, or reducing the severity of, a disease or associated symptom, and/or may be therapeutic in terms of a partial or complete cure of a disease.
  • a reference to “treating” diabetes therefore encompasses: (a) arresting the progress of the disease, e.g., preventing worsening of a symptom (e.g., hyperglycemia) or complication over time; (b) relieving or ameliorating the effects of diabetes, i.e., causing an improvement of at least one symptom or complication of diabetes; (c) preventing or delaying additional symptoms or complications of diabetes from developing; (d) preventing or delaying diabetes or a symptom or complication associated with diabetes from occurring in a Attorney Docket No.1512.7.WO subject with prediabetes or insulin resistance; and/or (e) preventing or delaying an increased risk of developing a disease, e.g., preventing the increase of a risk factor for diabetes, such as by reducing blood glucose levels following glucose administration.
  • a symptom e.g., hyperglycemia
  • complication e.g., hyperglycemia
  • administering refers to providing a pharmaceutical composition to a subject suffering from or at risk of the disease(s) and/or condition(s) to be treated.
  • effective amount it is meant an amount sufficient that, when administered to the subject, an amount of the drug is provided to achieve an effect. In the case of a therapeutic method, this effect may be the treatment of hyperglycemia, prediabetes, diabetes or an associated disease, condition and/or disorder. Therefore, the “effective amount” may be a “therapeutically effective amount”.
  • therapeutically effective amount it is meant an amount sufficient that when administered to the subject an amount of active ingredient is provided to treat the disease or a symptom of the disease.
  • composition relates to a composition comprising at least one active ingredient that is in a pharmaceutically acceptable form.
  • pharmaceutically acceptable it is meant that the material is compatible with other ingredients included in the pharmaceutical composition and is suitable for administration to a subject based on avoidance of deleterious effects upon or following administration and any regulatory considerations. The material would naturally be selected to minimize any degradation of the active ingredient and to minimize any adverse side effects in the subject, as would be well known to one of skill in the art (see, e.g., Remington's Pharmaceutical Science; 21 st ed. 2005).
  • Exemplary pharmaceutically acceptable carriers for compositions of this invention include, but are not limited to, sterile pyrogen-free water and sterile pyrogen-free physiological saline solution.
  • SIRT6 is an NAD + -dependent protein deacylase. SIRT6 efficiently deacetylates nucleosomal histones in vitro and nucleosomes as well as proteins involved in DNA repair in cells.
  • SIRT6-activating compounds or “SIRT6 activators” increase the cellular function of SIRT6. SIRT6 activators may bind in the acyl binding channel, stimulate SIRT6 deacetylation activity, and/or increase SIRT6 expression.
  • One aspect of the invention relates to a method of improving glucose homeostasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby improving glucose homeostasis.
  • the term "glucose homeostasis” refers to the balance of insulin and glucagon to maintain blood glucose levels within normal levels (i.e., about 70 mg/dL (3.9 mmol/L) to about 100 mg/dL (5.6 mm/L)).
  • the subject being treated has elevated glucose levels, e.g., plasma glucose levels above about 100 mg/dL.
  • a SIRT6 activator that "improves glucose homeostasis” preferably reduces blood glucose levels down to, but not below, normal levels.
  • Another aspect of the invention relates to a method of lowering plasma glucose levels in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby lowering plasma glucose levels.
  • the subject being treated has a plasma glucose level above the normal level (e.g., above about 100 mg/dL).
  • the SIRT6 activator reduces the subject’s glucose level by at least about 1% or more (e.g., 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or more) relative to a baseline plasma glucose level determined by, e.g., a standard fasting glucose test, prior to treatment with the SIRT6 activator.
  • the SIRT6 activator reduces the subject’s plasma glucose level by at least about 5%, preferably by at least about 10%, or more preferably by at least about 15% relative to a baseline plasma glucose level.
  • the SIRT6 activator does not reduce the plasma glucose level to a level substantially below normal levels, e.g., below about 70 mg/dL.
  • a further aspect of the invention relates to methods of treating hyperglycemia, prediabetes, or diabetes in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SIRT6 activator, thereby treating the hyperglycemia, prediabetes, or diabetes.
  • hyperglycemia refers to a higher than normal blood glucose concentration, usually 125 mg/dL or greater while fasting and greater than 180 mg/dL two hours postprandial.
  • diabetes relates to a disease characterized by insulin resistance and disordered glucose metabolism, and is often accompanied by complications including dyslipidemia, inflammation, retinopathy, neuropathy, nephropathy, macrovascular disease and cognitive impairment.
  • Diabetes includes Type I, Type II and gestational diabetes and symptoms and/or complications thereof.
  • Type I diabetes is characterized by a lack of insulin production and Type II diabetes is characterized by insulin resistance.
  • Gestational diabetes is a type of diabetes that can develop during pregnancy in women who do not already have diabetes.
  • the diabetes being treated in accordance with the methods herein is Type I diabetes, Type II diabetes or gestational diabetes.
  • Prediabetes refers to the condition where blood sugar levels are higher than normal, but not high enough yet to be diagnosed as Type II diabetes.
  • blood tests that can diagnose prediabetes. The most common ones are the fasting plasma glucose (FPG) test, which measures blood sugar at a single point in time and the A1C test, which measures average blood sugar over the past 3 months.
  • FPG fasting plasma glucose
  • A1C test measures average blood sugar over the past 3 months.
  • a result of 100 to 125 mg/dL glucose in the FPG test is indicative Attorney Docket No.1512.7.WO of prediabetes, whereas 126 and above is indicative of diabetes.
  • A1C test a percentage of between 5.7% to 6.4% is indicative of prediabetes, whereas above 6.5% is indicative of diabetes.
  • SIRT6 activators include, without limitation, quercetin, isoquercetin, kaempferol, luteolin, cyanidin, fisetin, delphinidin, icariin, N-acetylethanolamines, oleic acid, linoleic acid, fucoidan, MDL-800 (CAS No. 2275619-53-7), MDL-811 (CAS No. 2275619-98-0), UBCS038 (CAS No. 358721-70-7; You et al. (2017) Angew. Chem. Int. Ed.
  • UBCS039 (CAS No. 358721-70-7), UBCS040 (1-(4,5-Dihydropyrrolo[1,2- a]quinoxalin-4-yl)naphthalen-2-ol), UBCS058 (4-(Pyridin-3-yl)pyrrolo[1,2-a]quinoxaline), UBCS060 (4-(Pyridin-2-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline), UBCS068 (1-(5-((3- (Trifluoromethyl)phenyl)sulfonyl)-4,5-dihydropyrrolo[1,2-a]quinoxalin-4-yl)naphthalen-2-ol), myristic acid, oleoylethanolamide (OEA), CL5D (CAS No.2488745-53-3), 10b (2-(1-benzofuran- 2-yl)-N-(diphenylmethyl) quinoline
  • a further example of a SIRT6 activator is a compound of Formula 1 or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof: Attorney Docket No.1512.7.WO wherein: R 1 is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from a substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; R 2 is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered
  • the compound of Formula 1 is any compound selected from the following group: (2S,5’R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5-tetrahydropyran-4-yl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-[5-(1-methyl-4-piperidyl)-1,3,4-oxadiazol-2- yl] spiro [benzofuran
  • the compound of Formula 1 is a compound of Formula 1′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof: Attorney Docket No.1512.7.WO wherein: R 1 is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated heterocyclic group optionally substituted with the same or different one to two substituents selected from the substituent group X; R 2 is a C1-C6 alkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, a C3-C6 cycloalkyl group optionally substituted with the same or different one to two substituents selected from the substituent group X, or a 4-7 membered saturated
  • R 1 is a C1-C6 alkyl group
  • R 2 is a C1-C6 alkyl group
  • A is a 5-membered aromatic heterocyclic ring
  • R 3 and R 3’ are each independently a hydrogen or a C1-C6 alkyl group.
  • R 1 is a methyl group, an ethyl group, or a hydroxyethyl group.
  • R 2 is a methyl group.
  • A is a 5-membered aromatic heterocyclic ring
  • R 3 is a methyl group, an ethyl group, a hydroxy C1-C3 alkyl group, or a methoxy C1-C3 alkyl group
  • R 3’ is a hydrogen atom
  • the compound of Formula 1 is a compound of a Formula 1′′ or a pharmaceutically acceptable salt, racemate, stereoisomer, or prodrug thereof: wherein Attorney Docket No.1512.7.WO R 1 is a methyl group or an ethyl group; R 2 is a methyl group; A is any ring selected from the following group: R 3 is a methyl group or an ethyl group.
  • the compound of Formula 1′ is any compound selected from the following group: (2S,5’R)-7-chloro-6-(2-hydroxyethoxy)-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-6-(2-methoxyethoxy)-5’-methyl-spiro [benzofuran-2,4’- cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(1-methylpyrazol-3-yl) spiro [benzofuran- 2,4’-cyclohex-2-ene]-1’,3-dione; (2S,5’R)-7-chloro-6-(1-ethylpyrazol
  • the compound is (2S,5’R)-7-chloro-6-(1-ethylpyrazol-3-yl)-3’,4- dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmacologically acceptable salt thereof.
  • the compound is (2S,5’R)-7-chloro-3’,4-dimethoxy-5’-methyl-6-(5- methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmacologically acceptable salt thereof.
  • the compound is (2S,5’R)-7-chloro-6-(5-ethyl-1,3,4-oxadiazol-2-yl)- 3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmacologically acceptable salt thereof.
  • the compound is (2S,5’R)-7-chloro-6-[3-(1-hydroxy-1-methyl- ethyl)-1,2,4-oxadiazol-5-yl]-3’,4-dimethoxy-5’-methyl-spiro [benzofuran-2,4’-cyclohex-2-ene]- 1’,3-dione or a pharmacologically acceptable salt thereof.
  • the compound is (2S,5’R)-7-chloro-4-ethoxy-3’-methoxy-5’-methyl- 6-(5-methyl-1,3,4-oxadiazol-2-yl) spiro [benzofuran-2,4’-cyclohex-2-ene]-1’,3-dione or a pharmacologically acceptable salt thereof.
  • Attorney Docket No.1512.7.WO [0046]
  • the 5-membered aromatic heterocyclic ring for A is the same as described above, but more preferably, it represents the following 5-membered ring.
  • the “5-membered aromatic heterocyclic ring” is a monocyclic 5-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • rings such as those shown below are included.
  • N N N N N N N 6-membered aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom For example, rings such as those shown below are included.
  • the “8-10 membered condensed aromatic heterocyclic ring” is an 8-10 membered condensed aromatic heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • rings such as those shown below are included.
  • N N N N N N N N N N N N N N N N is a ring in which a monocyclic 5-7 membered saturated heterocyclic ring is partially oxidized or a ring in which an aromatic heterocyclic ring is partially reduced containing one to four atoms selected from Attorney Docket No.1512.7.WO the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • rings such as those shown below are included.
  • O S NH N O HN S N N . is a monocyclic 4-7 membered saturated heterocyclic ring containing one to four atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • rings such as those shown below are included.
  • H N O S NH O S a bromine atom, or an iodine atom, and is preferably a fluorine atom or a chlorine atom.
  • Cyano refers to the group -CN. Attorney Docket No.1512.7.WO
  • Hydroxy or “hydroxyl” refers to the group -OH.
  • Carboxyl or “carboxy” refers to -COOH or salts thereof.
  • phenoxy refers to a group of the formula -O-R, where R is phenyl.
  • Cx-Cy indicates that the following group has from x to y carbon atoms.
  • C1-C6 alkyl indicates that the alkyl group has from 1 to 6 carbon atoms.
  • the “C1-C6 alkyl group” in the present specification is a linear or branched alkyl group having one to six carbon atoms.
  • Examples thereof include a methyl group, an ethyl group, a 1- propyl group, an isopropyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl- 1-pentyl group, a 3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butyl group, and a 2,3-dimethyl-1-butyl group, and it is preferably a methyl group or an ethyl group.
  • an alkyl group comprises from 1 to 2 carbon atoms, 1 to 3 carbon atoms, 1 to 4 carbon atoms, 1 to 5 carbon atoms, 1 to 6 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.
  • the “C2-C6 alkenyl group” in the present specification is a linear or branched alkenyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon double bonds.
  • an alkenyl group comprises from Attorney Docket No.1512.7.WO 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.
  • the “C2-C6 alkynyl group” in the present specification is a linear or branched alkynyl group having two to six carbon atoms, and it may have one or two or more carbon-carbon triple bonds.
  • it is an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-butynyl group, a 1-pentynyl group, a 2-pentynyl group, or 1-hexynyl group, and it is preferably an ethynyl group or a 1-propynyl group.
  • an alkynyl group comprises from 2 to 3 carbon atoms, 2 to 4 carbon atoms, 2 to 5 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, 4 to 6 carbon atoms, or 5 to 6 carbon atoms.
  • the “C1-C6 alkoxy group” in the present specification is a group in which an oxygen atom is bonded to a C1-C6 alkyl group.
  • Examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group, a 2-propoxy group, a 1-butoxy group, a 2-butoxy group, a 2-methyl-1- propoxy group, a 2-methyl-2-propoxy group, a 1-pentyloxy group, a 2-pentyloxy group, a 3- pentyloxy group, a 2-methyl-2-butoxy group, a 3-methyl-2-butoxy group, a 1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a 2-methyl-1-pentyloxy group, and a 3-methyl-1- pentyloxy group.
  • the “C3-C6 cycloalkyl group” in the present specification is a cyclic alkyl group having three to six carbon atoms, and it is preferably a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.
  • the “hydroxy C1-C6 alkyl group” in the present specification is a group in which a hydroxyl group is bonded to a C1-C6 alkyl group.
  • the “C1-C6 alkoxy C1-C6 alkyl group” in the present specification is a group in which a C1-C6 alkoxy is bonded to a C1-C6 alkyl group. Examples thereof include a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, and an ethoxyethyl group.
  • the “C1-C6 haloalkyl group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkyl group.
  • Examples thereof include a fluoromethyl group, a difluoromethyl group, a dichloromethyl group, a dibromomethyl group, a trifluoromethyl group, a trichloromethyl group, a 2-fluoroethyl group, a 2-bromoethyl group, a 2-chloroethyl group, a 2- iodoethyl group, a 2,2-difluoroethyl group, a 2,2,2-trifluoroethyl group, a trichloroethyl group, a pentafluoroethyl group, a 3-fluoropropyl group, a 3-chloropropyl group, and a 4-fluorobutyl group.
  • C3-C6 halocycloalkyl group in the present specification is a group in which a halogen atom is bonded to a C3-C6 cycloalkyl group, and examples thereof include a fluorocyclopropyl group, a fluorocyclobutyl group, a fluorocyclopentyl group, and a fluorocyclohexyl group.
  • the “C1-C6 haloalkoxy group” in the present specification is a group in which a halogen atom is bonded to a C1-C6 alkoxy group, and examples thereof include a fluoromethoxy group, a difluoromethoxy group, a dichloromethoxy group, a dibromomethoxy group, a trifluoromethoxy group, a trichloromethoxy group, a 2-fluoroethoxy group, a 2-bromoethoxy group, a 2- chloroethoxy group, a 2-iodoethoxy group, a 2,2-difluoroethoxy group, a 2,2,2-trifluoroethoxy group, a trichloroethoxy group, a pentafluoroethoxy group, a 3-fluoropropoxy group, a 3- chloropropoxy group, and a 4-fluorobutoxy group.
  • C3-C6 cycloalkoxy group in the present specification is a group in which a C3-C6 cycloalkyl group is bonded to an oxygen atom, and it is preferably a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, or a cyclohexyloxy group.
  • the “C3-C6 halocycloalkoxy group” in the present specification is a group in which a C3-C6 halocycloalkyl group is bonded to an oxygen atom, and examples thereof include a fluorocyclopropoxy group, a fluorocyclobutoxy group, a fluorocyclopentyloxy group, and a fluorocyclohexyloxy group.
  • the “5-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 5-membered aromatic heterocyclic ring is bonded to an oxygen atom.
  • the “6-membered aromatic heterocyclic oxy group” in the present specification is a group in which a 6-membered aromatic heterocyclic ring is bonded to an oxygen atom.
  • the “4-7 membered saturated heterocyclic oxy group” in the present specification is a group in which a 4-7 membered saturated heterocyclic ring is bonded to an oxygen atom.
  • C3-C6 cycloalkylcarbonyl group refers to a cycloalkyl group having 3 to 6 carbon atoms in which one hydrogen atom is replaced by a carbonyl group.
  • C1-C6 alkoxycarbonyl group in the present specification is a group in which a C1- C6 alkoxy group is bonded to a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.
  • C3-C6 cycloalkoxycarbonyl group in the present specification is a group in which a C3-C6 cycloalkoxy group is bonded to a carbonyl group, and it is preferably a cyclopropyloxycarbonyl group, a cyclobutyloxycarbonyl group, a cyclopentyloxycarbonyl group, or a cyclohexyloxycarbonyl group.
  • the “C1-C6 alkyl carbonyl group” in the present specification is a group in which a C1- C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methyl carbonyl group, an ethyl carbonyl group, or a propyl carbonyl group.
  • An “amino group” refers to the group -NH 2 or -NH-R, where each R is independently alkyl, aryl, or cycloalkyl.
  • the “mono (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminocarbonyl group, and it is preferably a methylaminocarbonyl group, an ethylaminocarbonyl group, or a propylaminocarbonyl group.
  • the “di (C1-C6 alkyl) aminocarbonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of an aminocarbonyl group, and it is preferably a dimethylaminocarbonyl group, a diethylaminocarbonyl group, or a dipropylaminocarbonyl group.
  • the “mono (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which one C1-C6 alkyl group is bonded to the amino group of an aminosulfonyl group, and it is Attorney Docket No.1512.7.WO preferably a methylaminosulfonyl group, an ethylaminosulfonyl group, or a propylaminosulfonyl group
  • the “di (C1-C6 alkyl) aminosulfonyl group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to the amino group of the aminosulfonyl group, and it is preferably a dimethylaminosulfonyl group, a diethylaminosulfonyl group, or a dipropylaminosulfonyl group.
  • the “mono (C1-C6 alkyl) amino group” in the present specification is a group in which one C1-C6 alkyl group is bonded to an amino group, and it is preferably a methylamino group, an ethylamino group, or a propylamino group.
  • the “di (C1-C6 alkyl) amino group” in the present specification is a group in which two C1-C6 alkyl groups are bonded to an amino group, and it is preferably a dimethylamino group, a diethylamino group, or a dipropyl amino group.
  • C1-C6 alkoxycarbonylamino group in the present specification is a group in which a C1-C6 alkoxycarbonyl group is bonded to an amino group, and for example, it is a methoxycarbonylamino group, an ethoxycarbonylamino group, or a propoxycarbonylamino group.
  • the “mono (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a mono (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably a methylaminocarbonylamino group, an ethylaminocarbonylamino group, or a propylaminocarbonylamino group.
  • the “di (C1-C6 alkyl) aminocarbonylamino group” in the present specification is a group in which a di (C1-C6 alkyl) aminocarbonyl group is bonded to an amino group, and it is preferably Attorney Docket No.1512.7.WO a dimethylaminocarbonylamino group, a diethylaminocarbonylamino group, or a dipropylaminocarbonylamino group.
  • the “5-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 5-membered aromatic heterocyclic carbonyl group is bonded to an amino group.
  • the “6-membered aromatic heterocyclic carbonylamino group” in the present specification is a group in which a 6-membered aromatic heterocyclic carbonyl group is bonded to an amino group.
  • the “C1-C6 alkylsulfonylamino group” in the present specification is a group in which a C1-C6 alkyl group is bonded to the sulfonyl group of a sulfonylamino group, and it is preferably a methylsulfonylamino group, an ethylsulfonylamino group, or a propylsulfonylamino group.
  • Substituted refers to a group wherein one or more hydrogens have been independently replaced with one or more substituents including, but not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, guanidino, halo, heteroalkyl, heteroaryl, heterocycloalkyl, hydroxy, hydrazino, hydroxyl, imino, oxo, nitro, sulfonamide, sulfonic acid, thiocyanate, thiol, thione, or a combination thereof.
  • the “pharmaceutically acceptable salt” indicates a salt that can be used as a pharmaceutical.
  • the compound has an acidic group or a basic group it can be converted to a basic salt or an acidic salt by reacting with a base or an acid to form a salt thereof.
  • the pharmaceutically acceptable “basic salt” of the compound preferably includes an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt; an alkaline earth metal salt such as a magnesium salt and a calcium salt; organic base salts such as an N-methyl morpholine salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, and a picoline salt; and an amino acid salt such as glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamate, and an aspartate, and it is preferably an alkali metal salt.
  • an alkali metal salt such as a sodium salt, a potassium salt, and a lithium salt
  • an alkaline earth metal salt such as a
  • the pharmaceutically acceptable “acidic salt” of the compound preferably includes an inorganic acid salt such as a hydrohalide such as a hydrofluoride, a hydrochloride, a hydrobromide, and a hydroiodide, a nitrate, a perchlorate, a sulfate, and a phosphate; an organic salt such as a lower alkanesulfonate such as methanesulfonate, trifluoromethanesulfonate, and ethanesulfonate, an aryl sulfonate such as a benzenesulfonates, and a p-toluene sulfonate, an acetate, a malate, a fumarate, a succinate, a citrate, an ascorbate, a tartrate, an oxalate, a maleate, and the like; and an amino acid salt such as glycine salt, a lycine salt,
  • Pharmaceutically acceptable salts also include ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutically acceptable salts can be found in Berge et al. (1977) J. Pharma Sci.66(1):1-19, and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA (2005) p.732, Table 38-5, each of which are hereby incorporated by reference herein. [0101] The compound of the present invention or the pharmaceutically acceptable salt thereof may absorb moisture, adhere to adsorbed water, or become a hydrate by leaving in the air or Attorney Docket No.1512.7.WO recrystallization.
  • the present invention also encompasses compounds of such various hydrates, solvates, and crystalline polymorphs.
  • the compounds of the present invention, their pharmaceutically acceptable salts or solvates thereof, depending on the type and combination of substituents, may have various isomers such as geometric isomers including a cis isomer and a trans isomer, tautomers, or optical isomers such as a D isomer and an L isomer.
  • the invention includes such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio unless otherwise specified. Mixtures of these isomers may be resolved by known resolution means.
  • the compounds of the present invention also include labels, that is, a compound in which one or more atoms of the compounds are substituted with an isotope (for example, 2 H, 3 H, 13 C, 14 C, 35 S, and the like).
  • the present invention also encompasses a prodrug.
  • the prodrug is a compound having a group which can be converted to an amino group, a hydroxyl group, a carboxyl group, or the like of the compound by hydrolysis or under physiological conditions, and as a group forming such a prodrug, it is a group described in Rautio et al. (2016) Nature Rev. Drug Discov.17(8):559– 587; Markovic et al.
  • a compound in which the amino group is acylated, alkylated, or phosphorylated for example, it is a compound in which the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4- yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidinyl methylated, pivaloyloxymethylatied, or tert-butylated, or the like) and the like are included, and when a hydroxyl group is present in the compound, a compound in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, it is a compound in which the hydroxyl group Attorney Docket No.1512.7.
  • a carboxy group when a carboxy group is present in the compound, a compound in which the carboxy group is esterified or amidated (for example, it is a compound in which the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated, or methylamidated, or the like), and the like are included.
  • Particularly favored prodrugs are those that increase the bioavailability of the compounds of the embodiments when such compounds are administered to a subject (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment relative to the parent species.
  • the compounds of the present invention may be produced by synthetic methods known in the art and as described in WO 2017/170623 and WO 2019/065928, incorporated by reference herein in their entirety.
  • Administration of the compounds of the present invention may be carried out by any form of oral administration by a tablet, a pill, a capsule, a granule, a powder, a solution, or the like, or by any form of parenteral administration by an injection for intra-articular, intravenous, intramuscular, or the like, a suppository, an eye drop, an eye ointment, a transdermal solution, an ointment, a transdermal patch, a transmucosal solution, a transmucosal patch, an inhalant, or the like.
  • a solid composition for oral administration a tablet, a powder, a granule, and the like are used as a solid composition for oral administration.
  • Such a solid composition is composed of one or more active ingredients and at least one inert excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline Attorney Docket No.1512.7.WO cellulose, starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate, and/or the like.
  • the solid composition may contain, according to a conventional method, one or more of an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, a stabilizer, and a solubilizer.
  • the tablet or pill may be coated with a sugar coating or a film of a substance soluble in the stomach or intestine, if necessary.
  • a liquid composition for oral administration a pharmaceutically acceptable emulsion, solution, suspension, syrup, elixir, or the like is used.
  • a generally used inert diluent such as purified water or ethanol.
  • the liquid composition may contain, in addition to an inert diluent, one or more of a solubilizer, an adjuvant such as a wetting agent, a sweetening agent, a flavoring agent, a fragrance, and a preservative.
  • a sterile aqueous or non-aqueous solution, a suspension or an emulsion, and the like are used as an injection for parenteral administration.
  • the aqueous solvent includes, for example, distilled water for injection, physiological saline, and the like.
  • the non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, and vegetable oil such as olive oil, alcohols such as ethanol, Polysorbate 80, and the like.
  • Such an injection composition may further contain a one or more of a tonicity agent, a preservative, a wetting agent, an emulsion, a dispersing agent, a stabilizer, or a solubilizer.
  • These injection compositions can be sterilized by, for example, filtration through a bacteria retention filter, application of a bactericide, or irradiation.
  • these injection compositions may be used by producing a sterile solid composition and dissolved or suspended in sterile water or a sterile solvent for injection prior to use.
  • an ointment a plaster, a cream, a jelly, a cataplasm, a spray, a lotion, an eye drop, an eye ointment, and the like are used.
  • These external preparations include generally used ointment bases, lotion bases, aqueous or non-aqueous solutions, suspensions, Attorney Docket No.1512.7.WO emulsions, and the like.
  • polyethylene glycol, propylene glycol, white petrolatum, bleached beeswax, polyoxyethylene hydrogenated castor oil, glycerin monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like are used as an ointment or lotion base.
  • a transmucosal agent such as an inhalant and a transnasal agent are used in solid, liquid, or semisolid form, and it may be produced according to a conventionally known method.
  • a known excipient and furthermore, one or more of a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, a thickener, and the like may be added as appropriate.
  • devices appropriate for inhalation or insufflation may be used as the method of administration.
  • the compound may be administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using known devices and nebulizers, such as metered dose inhalation devices.
  • a dry powder inhaler or the like may be for single or multiple administration, and a dry powder or powder containing capsule may be also used.
  • an appropriate ejector may be used.
  • it may be in the form of a pressurized aerosol spray or the like using a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
  • a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, or carbon dioxide.
  • the appropriate daily dose of a SIRT6 activator is about 0.001 mg/kg to 100 mg/kg, preferably 0.1 mg/kg to 30 mg/kg, and more preferably 0.1 mg/kg to 10 mg/kg of body weight.
  • the daily dose of a SIRT6 activator is about 0.001, 0.002, 0.003, 0.004, 0.005, 0.006, 0.007, 0.008, 0.009, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 mg/kg to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, Attorney Docket No.1512.7.WO 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,
  • the appropriate daily dose of a SIRT6 activator is about 0.0001 mg/kg to 10 mg/kg (e.g., about 0.0001, 0.0005, 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, or 10 mg/kg or any range or value therein) of body weight, which is administered once or separated into several times a day.
  • transmucosal agent about 0.001 mg/kg to 100 mg/kg (e.g., about 0.001, 0.005, 0.01, 0.05, 0.1, 0.5, 1, 5, 10, 50, or 100 mg/kg or any range or value therein) of body weight is administered once or separated into several times a day.
  • the dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like.
  • the SIRT6 activator may be administered daily, e.g., in the morning and/or evening, and/or before, during or after one or more daily meals, e.g., breakfast, lunch, and/or dinner.
  • Improvements in glucose homeostasis, reduction in plasma glucose levels, and/or treatment of hyperglycemia, prediabetes, and/or diabetes may be assessed by one or more conventional tests (e.g., a glycated hemoglobin (A1C) test, a fasting plasma glucose test, an oral glucose tolerance test) and/or a decrease in one or more symptoms associated with therewith (e.g., thirst, appetite, fatigue, weight loss, and/or blurred vision).
  • the period of time following treatment may be at least about 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 300 minutes or longer.
  • treatment with the SIRT6 activator reduces plasma glucose levels for an extended period of time, e.g., at least 2 weeks, at least 4 weeks, or more.
  • the plasma glucose levels are reduced without significantly affecting the insulin and/or C-peptide concentration(s).
  • the SIRT6 activator may be administered in combination with various therapeutic agents or preventive agents of use in subjects with elevated glucose plasma levels, hyperglycemia, prediabetes, and/or diabetes.
  • the therapeutic agent may be, for example, one that treats elevated glucose plasma levels, hyperglycemia, prediabetes, and/or diabetes or one that treats a disease, condition and/or disorder associated with elevated glucose plasma levels, hyperglycemia, prediabetes, and/or diabetes.
  • diseases, conditions and/or disorders include prediabetes, glycosuria, hyperglycemia, hyperinsulinemia, insulin resistance, and combinations thereof.
  • a SIRT6 activator may be used in combination with insulin (e.g., a short-acting insulin that reaches the bloodstream 30 minutes after injection and peaks 2-3 hours afterward, a rapid acting insulin that works within 15 minutes and peaks 1 to 2 hours after use, an intermediate-acting insulin that works about 2-4 hours after use with an average peak time of 12 hours, a long-acting insulin that lower your blood glucose levels for up to 24 hours or longer, or combinations thereof), an amylinomimetic (e.g., pramlintide), an alpha-glucosidase inhibitor (e.g., acarbose or miglitol), a biguanide (e.g., metformin), a dopamine-2 agonist, a dipeptidyl peptidase-4 inhibitor (e.g., alogliptin, linagliptin, saxagliptin or sitagliptin),a glucagon-like peptide-1 receptor agonist
  • the combination may be administered simultaneously, separately, concurrently, and continuously or at desired time intervals.
  • the co-administered agents may be blended or formulated separately.
  • Attorney Docket No.1512.7.WO [0115]
  • the methods of the present invention find use in both veterinary and medical applications. Suitable subjects include avians, reptiles, amphibians, fish, and mammals.
  • the term “mammal” as used herein includes, but is not limited to, humans, primates, non-human primates (e.g., monkeys and baboons), cattle, sheep, goats, pigs, horses, cats, dogs, rabbits, rodents (e.g., rats, mice, hamsters, and the like), etc.
  • Human subjects include neonates, infants, juveniles, and adults.
  • the subject is “in need of” the methods of the present invention, e.g., because the subject has or is believed to be at risk for aberrant glucose homeostasis, elevated plasma glucose levels, hyperglycemia, prediabetes, and/or diabetes or that would benefit from treatment with a compound as described herein.
  • the subject can be a laboratory animal and/or an animal model of disease.
  • the subject is a human.
  • SIRT6 Activators Normalize Elevated Glucose Levels [0117] SIRT6 is principal regulator of glucose homeostasis (Zhong et al. (2010) Cell 140(2):280- 93). Thus, it was determined whether the SIRT6 activators disclosed herein could reduce fasting glucose levels in subjects with baseline elevated fasting glucose. [0118] Following the successful completion of a Screening Phase, subjects were randomized to one of two treatment groups in an approximately 1:1 ratio and received Compound 1 (SP-624) or placebo over a treatment period of four weeks (Treatment Group #1: SP-62420 mg/day; Treatment Group #2: Placebo).

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Abstract

La présente invention concerne des méthodes d'amélioration de l'homéostasie du glucose et/ou de réduction des niveaux de plasma de glucose par l'administration d'un activateur de SIRT6. La présente invention concerne également des méthodes de traitement de l'hyperglycémie, du prédiabète et du diabète comprenant le diabète de type I, le diabète de type II ou le diabète gestationnel par administration d'un activateur de SIRT6.
EP24738905.9A 2023-01-06 2024-01-04 Compositions et méthodes de régulation de niveaux de glucose Pending EP4646195A2 (fr)

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