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JP-2026514428-A - Heterocycloalkylbeta-hydroxyalkylamines for use in the treatment of hyperglycemia and disorders characterized by hyperglycemia

JP2026514428AJP 2026514428 AJP2026514428 AJP 2026514428AJP-2026514428-A

Abstract

This specification provides for compounds of formula (I) in which Q1 to Q5 , rings A, Z, n, m, and r have the meanings provided in the description. Their use in medicine is also provided herein. [Chemical formula 1] [Selection Diagram] None

Inventors

  • ムトゥレ，イルガ
  • スペ，リンダ

Assignees

  • アトロジー アーベー

Dates

Publication Date
20260511
Application Date
20240328
Priority Date
20230329

Claims (20)

  1. Compound of formula I or a pharmaceutically acceptable salt thereof, in the formula, Each of Q1 to Q5 independently represents a carbon atom, a heteroatom, or a direct bond, and therefore the ring containing Q1 to Q5 is This represents a phenyl molecule optionally substituted with one or more Y1 molecules , or a five-membered or six-membered heteroaryl molecule optionally substituted with one or more Y2 molecules . Each Y1 independently represents Halo, Ra1 , -CN, -N3 , -NRb1 , Rc1 , or -ORd1 . Each Y 2 independently represents Halo, Ra a2 , -CN, -N 3 , -NR b2 R c2 , or -OR d2 . Ring A represents a 4- to 7-membered heterocycloalkyl group containing one or two heteroatoms selected from N and O. When present on a carbon atom of ring A, each Z independently represents halo, Ra a3 , CN, -N3 , -N(R b3 )R c3 , -OR d3 , -S(O) p Re e3 , -S(O) q N(R f3 )R g3 , -N(R h3 )S(O) t Ri3 , or =O. When present on the nitrogen atom of ring A, each Z independently represents R a3 , -S(O) p Re e3 , or -S(O) q N(R f3 )R g3 . Each R a1 , R a2 , R a3 , R e3 , and R i3 represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted with one or more groups independently selected from the halo and G 1 . Each of R b1 , R b2 , R b3 , R c1 , R c2 , R c3 , R d1 , R d2 , R d3 , R f3 , R g3 , and R h3 independently, Represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl molecule, each optionally substituted by one or more groups independently selected from H, halo, and G2 . Alternatively, any of R b1 and R c1 , R b2 and R c2 , R b3 and R c3 , and/or R f3 and R g3 may be linked together to form a 4- to 6-membered ring with the nitrogen atom to which they are linked, the ring optionally containing one further heteroatom, the ring optionally substituted with one or more groups independently selected from a halo, a C1-3 alkyl group optionally substituted by one or more halos, and =O. Each G1 and G2 independently represents Ra a4 , -CN, -N3 , -N(R b4 )R c4 , -OR d4 , -S(O) p Re e4 , -S(O) q N(R f4 )R g4 , or =O, Each R a4 independently represents a phenyl or a 5-membered or 6-membered heteroaryl, each optionally substituted with one or more groups selected from halo, R a5 , -CN, -N3 , -N(R b5 )R c5 , -OR d5 , -S(O) p Re e5 , -S(O) q N(R f5 ) R g5 , or -N(R h5 )S(O) t Ri5 . Each of R b4 , R c4 , R d4 , R f4 , and R g4 independently represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl which is optionally substituted with H or one or more halos or -CNs. Each R e4 independently represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted by one or more halos or -CNs. Alternatively, R b4 and R c4 and/or any of R f4 and R g4 may be linked together to form a 4- to 6-membered ring with the nitrogen atom to which they are linked, the ring optionally containing one further heteroatom, the ring optionally substituted with one or more groups independently selected from a halo, a C1-3 alkyl group optionally substituted by one or more halos, and =O. Each R a5 , R e5 , and R i5 independently represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted by a halo, a C1-3 alkyl group optionally substituted by one or more halos, and one or more groups independently selected from =O. Each of R b5 , R c5 , R d5 , R f5 , R g5 , and R h5 is independent, Represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each optionally substituted by H, a halo, one or more halos, and one or more groups independently selected from = O , Alternatively, R b5 and R c5 , and/or any of R f5 and R g5 , may be linked together to form a 4- to 6-membered ring with the nitrogen atom to which they are linked, wherein the ring optionally contains one further heteroatom, and the ring optionally substituted with one or more groups independently selected from a halo, a C1-3 alkyl group optionally substituted by one or more halos, and =O. Each p independently represents 0, 1, or 2. Each q independently represents either 1 or 2. Each t independently represents either 1 or 2. m represents a value between 0 and 3. n represents a value between 0 and 2. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein r represents 0 to 6.
  2. The compound according to claim 1, wherein each Y1 and Y2 independently represents Ra1 , halo, or -CN.
  3. The compound according to any one of the prior claims, wherein each Y1 and Y2 independently represents F.
  4. The ring including Q1 to Q5 is A compound according to any one of the prior claims, representing a phenyl or a six-membered heteroaryl that is optionally substituted with one or more Y1 groups .
  5. The ring including Q1 to Q5 is A compound according to any one of the prior claims, representing a phenyl atom optionally substituted with one or more Y1 atoms , or a pyridyl atom optionally substituted with one or more Y2 atoms .
  6. A compound according to any one of the prior claims, wherein r represents 0.
  7. A compound according to any one of the prior claims, wherein n represents 1.
  8. A compound according to any one of the prior claims, wherein m represents 1.
  9. A compound according to any one of claims 1 to 8, for use in medical applications.
  10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, and one or more pharmaceutically acceptable adjuvants, diluents, and/or carriers, optionally selected from among them.
  11. A compound according to any one of claims 1 to 8, for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.
  12. Use of the compound according to any one of claims 1 to 8 for the manufacture of a drug for the treatment of hyperglycemia or a disorder characterized by hyperglycemia.
  13. A method for treating hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 8 to a patient in need thereof.
  14. The compound, method, or use according to any one of claims 11 to 13, wherein the hyperglycemia or disorder characterized by hyperglycemia is in a patient exhibiting severe insulin resistance, or is characterized by a patient exhibiting severe insulin resistance.
  15. The compound, method, or use for use according to any one of claims 11 to 14, wherein the disorder characterized by hyperglycemia is selected from the group consisting of type 2 diabetes mellitus, Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.
  16. A compound according to any one of claims 1 to 8, for use in the treatment of non-alcoholic fatty liver disease.
  17. Use of the compound according to any one of claims 1 to 8 in the manufacture of a drug for the treatment or prevention of non-alcoholic fatty liver disease.
  18. A method for treating or preventing non-alcoholic fatty liver disease, comprising administering a therapeutically effective amount of a compound described in any one of claims 1 to 8 to a patient in need thereof.
  19. A compound according to any one of claims 1 to 8, for use in the treatment of a disease or disorder in which the treatment is mediated by the activation of β2 -adrenergic receptors.
  20. Use of the compound according to any one of claims 1 to 8 in the manufacture of a drug for use in the treatment of a disease or disorder in which the treatment is mediated by the activation of β2 adrenergic receptors.

Description

This invention relates to novel compounds and compositions in medical applications, such as the treatment of hyperglycemia and disorders characterized by hyperglycemia, including type 2 diabetes, and to their use. In particular, this invention relates to novel compounds, compositions, and methods for the treatment of conditions such as type 2 diabetes by activation of β2 -adrenergic receptors. Importantly, such compounds are thought to have a beneficial side effect profile because they do not exert their effects through significant cAMP release. Such compounds are also useful for the treatment of other diseases or disorders in which therapies are mediated by activation of β2- adrenergic receptors. Any list or discussion of previously published documents in this specification should not be construed as an endorsement that such documents represent part of cutting-edge technology or common general knowledge. Hyperglycemia, or hyperglycemia, is a condition in which an excess amount of glucose circulates in the plasma. If left untreated, hyperglycemia can become a serious problem and potentially develop into life-threatening conditions such as ketoacidosis. For example, chronic hyperglycemia can cause cardiac damage and is strongly associated with heart attacks and death in individuals without coronary heart disease or a history of heart failure. The causes of hyperglycemia are diverse, including diabetes and severe insulin resistance. Severe insulin resistance (SIR) is a condition in which patients experience a very low level (or, in extreme cases, no significant) response to insulin. Several syndromes exist that are characterized by SIR, including Rabson-Mendenhall syndrome, Donahue syndrome (dwarfism), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy. The majority of these conditions have genetic causes, such as mutations in the insulin receptor gene. Reported prevalences for Donahue syndrome, Rabson-Mendenhall syndrome, and insulin-resistant type A syndromes have been reported to vary from 50 to 1 per 100,000 cases. However, because some of these conditions are severe and extremely rare, many patients are likely to go undiagnosed before death, especially in developing regions of the world. Therefore, it is difficult to estimate the exact number of patients with these syndromes. The current standard of treatment for hyperglycemia in patients with SIR is a controlled diet supplemented with insulin receptor-sensitive drugs such as metformin, or insulin replacement therapy. However, this treatment has proven insufficient and ultimately unsuccessful, particularly for disorders caused by mutations in the insulin receptor gene. Diabetes encompasses two distinct diseases: type 1 (or insulin-dependent diabetes) and type 2 (insulin-independent diabetes), both of which involve dysfunction of glucose homeostasis. Type 2 diabetes affects over 400 million people worldwide, and its numbers are rapidly increasing. Complications of type 2 diabetes include severe cardiovascular problems, renal failure, peripheral neuropathy, and blindness, and in the later stages of the disease, limb loss and ultimately even death. Type 2 diabetes is characterized by insulin resistance in skeletal muscle and adipose tissue, and there is currently no definitive cure. Most treatments used today focus on improving dysfunctional insulin signaling or suppressing glucose production from the liver, but many of these treatments have several drawbacks and side effects. Therefore, there is great interest in identifying novel insulin-independent methods for treating type 2 diabetes. In type 2 diabetes, the insulin signaling pathway becomes blunted in peripheral tissues such as adipose tissue and skeletal muscle. Treatment methods for type 2 diabetes typically include lifestyle modifications, as well as insulin injections or oral medications to regulate glucose homeostasis. Individuals with late-stage type 2 diabetes develop "beta-cell dysfunction," a disorder in which the pancreas is unable to release insulin in response to high blood glucose levels. In the later stages of the disease, patients often require insulin injections in combination with oral medications to manage diabetes. Furthermore, the most common medications have side effects, including downregulation or desensitization of the insulin pathway, and/or increased lipid uptake in adipose tissue, the liver, and skeletal muscle. Therefore, there is considerable interest in identifying novel methods for treating metabolic diseases, including type 2 diabetes, that do not involve these side effects. After a meal, the increase in blood glucose concentration stimulates insulin release from the pancreas. Insulin mediates the normalization of blood glucose concentration. Important effects of insulin on glucose metabolism include increased glucose uptake into skeletal muscle and adipocytes, a