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US-12622891-B2 - AMP-activated protein kinase activator

US12622891B2US 12622891 B2US12622891 B2US 12622891B2US-12622891-B2

Abstract

The present invention aims to provide a novel AMP-activated protein kinase activator. The present invention relates to a compound represented by the formula (I): wherein each symbol is as described in the specification, or a salt thereof, or a hydrate thereof. In addition, the present invention relates to an AMP-activated protein kinase activator containing the aforementioned compound, and a medicament containing the aforementioned compound for the prophylaxis and/or treatment of cancer.

Inventors

  • Susumu Nakata
  • Naoto Kojima

Assignees

  • KYOTO PHARMACEUTICAL UNIVERSITY

Dates

Publication Date
20260512
Application Date
20220603
Priority Date
20210604

Claims (11)

  1. 1 . A compound represented by the formula (I): wherein R 1 is a propyl group or a C 8-10 alkyl group, each of which is optionally substituted by a hydroxy group or a C 2-6 alkynyl group; R 2 is a thienyl group or a pyrazolyl group, each of which is optionally substituted by a substituent selected from the group consisting of a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 6-10 aryl group, a cyano group, a nitro group, a carboxy group, a C 1-6 alkoxy-carbonyl group, and an acyl group, L 1 is a C 1-20 alkylene group optionally substituted by a hydroxy group, L 2 is a divalent group represented by the formula: *NHC(═O)** or the formula: *NHS(O) 2 ** wherein * represents a bonding position to L 1 ; and ** represents a bonding position to R 2 ; and n is an integer of 1 to 8, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  2. 2 . The compound according to claim 1 , wherein R 1 is a C 8-10 alkyl group optionally substituted by a hydroxy group or an ethynyl group, R 2 is a 2-thienyl group, a 3-thienyl group, or a 5-pyrazolyl group, each of which is optionally substituted by a substituent selected from the group consisting of a halogen atom, a C 1-6 alkyl group, a cyano group, a nitro group, a carboxy group, and a C 1-6 alkoxy-carbonyl group, L 1 is a C 6-12 alkylene group, and n is an integer of 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate thereof.
  3. 3 . The compound according to claim 1 , wherein the compound of the formula (I) is any of the following a to k, or a pharmaceutically acceptable salt thereof: a. N-(13,16,19,22-tetraoxapentacosan-1-yl)thiophene-3-carboxamide, b. N-(13,16,19,22-tetraoxahentriacontan-1-yl)thiophene-3-carboxamide, c. N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-3-carboxamide, d. N-(13,16,19,22-tetraoxa-33-tetratriacontyn-1-yl)thiophene-3-carboxamide, e. N-(13,16,19,22-tetraoxa-32-tritriacontyn-1-yl)thiophene-3-carboxamide, f. N-(13,16,19,22,25-pentaoxadotriacontan-1-yl)thiophene-3-carboxamide, g. N-(10,13,16,19,22-pentaoxadotriacontan-1-yl)thiophene-3-carboxamide, h. N-(13,16,19,22-tetraoxadotriacontan-1-yl)-1-methylpyrazole-5-carboxamide, i. N-(13,16,19,22-tetraoxadotriacontan-1-yl)thiophene-2-carboxamide, j. N-(13,16,19,22,25-pentaoxapentatriacontan-1-yl)thiophene-3-carboxamide, and k. N-(13,16,19,22,25,28-hexaoxaoctatriacontan-1-yl)thiophene-3-carboxamide.
  4. 4 . A pharmaceutical composition comprising (a) the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and (b) a pharmaceutically acceptable carrier.
  5. 5 . A pharmaceutical composition comprising (a) the compound according to claim 2 , or a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and (b) a pharmaceutically acceptable carrier.
  6. 6 . A method of treating a disease caused by decreased activity of AMP-activated protein kinase in a subject, comprising administering an effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient to the subject.
  7. 7 . A method of treating a disease caused by decreased activity of AMP-activated protein kinase in a subject, comprising administering an effective amount of the compound according to claim 2 , or a pharmaceutically acceptable salt thereof, or a hydrate thereof, as an active ingredient to the subject.
  8. 8 . The method of claim 6 , wherein the disease caused by decreased activity of AMP-activated protein kinase is diabetes, obesity, or cancer.
  9. 9 . The method of claim 7 , wherein the disease caused by decreased activity of AMP-activated protein kinase is diabetes, obesity, or cancer.
  10. 10 . The method of claim 6 , wherein the disease caused by decreased activity of AMP-activated protein kinase is cancer.
  11. 11 . The method of claim 7 , wherein the disease caused by decreased activity of AMP-activated protein kinase is cancer.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a U.S. national stage of International Patent Application No. PCT/JP2022/023390, filed Jun. 3, 2022, which claims the benefit of Japanese Patent Application No. 2021-094481, filed Jun. 4, 2021, the entire contents of each of which are fully incorporated herein by reference. TECHNICAL FIELD The present invention relates to a novel polyether compound having an AMP-activated protein kinase activating action and useful for the prophylaxis and/or treatment of diseases caused by a decrease in AMP-activated protein kinase activity. The present invention also relates to a pharmaceutical composition containing the aforementioned novel polyether compound. BACKGROUND ART In recent years, hyperglycemia and hyperinsulinemia have been clarified to increase the risk of development, proliferation, and recurrence of cancer cells. One of the causes thereof is insulin resistance. As a factor that improves insulin resistance, AMP-activated protein kinase (AMPK) has been attracting attention recently (NPL 1). AMPK is a type of serine threonine kinase (serine threonine phosphorylase) present in eukaryotic cells of from humans to yeasts, plays an important role as a sensor for intracellular energy, and is a protein kinase activated with AMP (adenosine Monophosphate: adenosine-1-phosphate) produced using adenosine triphosphate as energy. That is, AMPK is activated in response to an increase in AMP under conditions where ATP delivery is depleted in cells in low glucose, hypoxia, ischemia, heat shock, and the like. When AMPK is activated, the synthesis of sugars, fats, and proteins is suppressed, and the degradation (catabolism) of sugars, fats, and proteins is enhanced to produce ATP. As a result, the same effect as exercise can be obtained, which is known to be effective in the treatment of obesity and diabetes (NPL 2). Furthermore, it has been reported in recent years that metabolic syndrome, in which the activity of AMPK decreases, is a risk factor for cancer, that the activity of AMPK is suppressed even in cancer cells, and further that activation of AMPK makes it possible to suppress the proliferation of cancer cells. Thus, AMPK is considered to be promising as a target for the prophylaxis and/or treatment of cancer (NPL 3). Metformin, cordicepin, resveratrol, oleanolic acid, cryptotansinone, verberine, and the like have been so far reported as activators of AMPK (NPL 4). Under such circumstances, there is a demand for the development of a novel AMPK activator as an effective prophylactic and/or therapeutic agent for cancer as well as obesity and type 2 diabetes. CITATION LIST Non Patent Literature [NPL 1] J. Clin. Invest., 2013, July; 123(7):2764-72. [NPL 2] Diabetes Metab. J., 2013, February; 37(1):1-21. [NPL 3] J. Physiol., 2006, Jul. 1; 574(Pt 1):63-71. [NPL 4] Exp. Mol. Med., 2016, Apr. 1; 48(4): e224. SUMMARY OF INVENTION Technical Problem An object of the present invention is to develop a novel AMPK activator that exhibits an excellent AMPK activating action, that can be easily synthesized, and that is stable and easy to handle. Another object of the present invention is to provide a prophylactic and/or therapeutic agent for cancer, containing the AMPK activator as an active ingredient. Solution to Problem The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problems and found that a compound represented by the formula (I): whereinR1 is a hydrogen atom or an optionally substituted C1-20 alkyl group;R2 is an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group;L1 is a C1-20 alkylene group optionally substituted by a hydroxy group;L2 is a divalent group represented by the formula: *N(R3)C(═O)** or the formula: *N(R3)S(O)2** wherein R3 is a hydrogen atom or a C1-6 alkyl group; * represents a bonding position to L1; and ** represents a bonding position to R2; andn is an integer of 1 to 10(hereinafter sometimes to be abbreviated as “compound (I)”) or a pharmaceutically acceptable salt thereof shows a superior AMP-activated protein kinase activating action, which resulted in the completion of the present invention. That is, the present invention provides the following. [1] An AMP-activated protein kinase activator comprising a compound represented by the formula (I): whereinR1 is a hydrogen atom or an optionally substituted C1-20 alkyl group;R2 is an optionally substituted 5- or 6-membered monocyclic aromatic heterocyclic group;L1 is a C1-20 alkylene group optionally substituted by a hydroxy group;L2 is a divalent group represented by the formula: *N(R3)C(═O)** or the formula: *N(R3)S(O)2** wherein R3 is a hydrogen atom or a C1-6 alkyl group; * represents a bonding position to L1; and ** represents a bonding position to R2; andn is an integer of 1 to 10,or a pharmaceutically acceptable salt thereof as an active ingredient.[2] The AMP-activated protein kinase activator of the above-mention