JP-2026514427-A - Cyclohexyl or heterocycloalkyl β-hydroxyalkylamines for use in the treatment of hyperglycemia and disorders characterized by hyperglycemia

Abstract

Compounds of formula I are provided herein. [Chemical formula 1] In the formula, Q1 to Q5 , R1 , rings A, Z, and n have the meanings defined herein. Its medical uses are also provided herein. [Selection Diagram] None

Inventors

• ムトゥレ，イルガ
• シュミツ，ギンツ

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, R 1 represents H or C 1-6 alkyl, Each of Q1 to Q5 independently represents a carbon atom, a heteroatom, or a direct bond, and the ring containing Q1 to Q5 is Represents a phenyl which may be optionally substituted with one or more Y1s , or a five-membered or six-membered heteroaryl which may be optionally substituted with one or more Y2s , Each Y1 independently represents Halo, Ra1 , -CN, -N3 , -N( Rb1 ) Rc1 , or -ORd1 . Each Y 2 independently represents Halo, Ra a2 , -CN, -N 3 , -N(R b2 )R c2 , or -OR d2 . Ring A represents a 4- to 7-membered cycloalkyl or 4- to 7-membered heterocycloalkyl containing one or two heteroatoms selected from N or O. n represents a value between 0 and 5. When each Z is present on a carbon atom, it independently represents halo, Ra3 , -CN, -N3 , -N( Rb3 ) Rc3 , -ORd3 , -S(O) pRe3 , -S(O)qN( Rf3 ) Rg3 , -N ( Rh3 ) S (O) tRi3 , or =O. When each Z is present on a nitrogen atom, it independently represents R a3 , -S(O) p Re e3 , or -S(O) q N(R f3 )R g3 . Each R a1 and R a2 represents a C1-6 alkyl which may be independently and optionally substituted with one or more halos. Each R a1 and R a2 represents a C1-6 alkyl which may be independently and optionally substituted with one or more halos. Each R a3 , R e3 , and R i3 independently represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl which may be optionally substituted by 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 which may be optionally substituted with H, or one or more groups independently selected from halo and G2 , Alternatively, R b3 and R c3 , and/or R f3 and R g3 may bond together to form a 4- to 6-membered ring with the nitrogen atom to which they are bonded, the ring of which may optionally contain one further heteroatom, and the ring of which may optionally be substituted with one or more groups independently selected from a halo, a C1-3 alkyl which may optionally be substituted with 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 , -N(R h4 )S(O) r Ri i4 , or =O, Each R a4 independently represents phenyl or a 5-membered or 6-membered heteroaryl, each of which may be optionally substituted with one or more groups selected from halo, R a5 , -CN, -N3 , -N(R b5 )R c5 , -OR d5 , -S(O) p R e5 , -S(O) q N(R f5 )R g5 , or -N(R h5 )S(O) t R i5 . Each R b4 , R c4 , R d4 , R f4 , R h4 , and R g4 independently represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl which may be optionally substituted with H or one or more halos, -CN, or =O. Each R e4 and R i4 independently represents a C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl which may be optionally substituted with one or more halos or -CNs. Alternatively, R b4 and R c4 , and/or R f4 and R g4 may be bonded together with the nitrogen atom to which they are bonded to form a 4- to 6-membered ring, which may optionally contain one further heteroatom, which may optionally be substituted with one or more groups independently selected from a halo, a C1-3 alkyl which may optionally be substituted with 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, and each of these C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl may be optionally substituted with one or more groups independently selected from a halo, a C1-3 alkyl which may be optionally substituted with one or more halos, and =O. Each of R b5 , R c5 , R d5 , R f5 , R g5 , and R h5 is independent of the others. H, or C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl may be optionally substituted with one or more groups independently selected from a halo, a C1-3 alkyl which may be optionally substituted with one or more halos, and =O. Alternatively, R b5 and R c5 , and/or R f5 and R g5 may be bonded together with the nitrogen atom to which they are bonded to form a 4- to 6-membered ring, which may optionally contain one further heteroatom, which may optionally be substituted with one or more groups independently selected from a halo, a C1-3 alkyl which may optionally be substituted with one or more halos, and =O. Each p independently represents 0, 1, or 2. Each q independently represents either 1 or 2. Each r independently represents either 1 or 2, Each t independently represents either 1 or 2, However, the compound of formula I is subject to the following conditions (A) to (C): 4-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]cyclohexane-1-ol, (B) (αR)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclobutyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-4-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]benzenemethanol, (αS)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, (αR)-α-[[(3-methylcyclopentyl)amino]methyl]benzenemethanol, α-[[(trans-4-methylcyclohexyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclopentyl)aminomethyl]benzenemethanol, α-[[(3-methylcyclopentyl)aminomethyl]benzenemethanol, α-[[(3-methylcyclohexyl)aminomethyl]benzenemethanol, α-[[(3-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(4-aminocyclohexyl)amino]methyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-3-pyridinemethanol, (αR)-α-[[(3-fluorocyclobutyl)amino]methyl]benzenemethanol, α-[[(4-methylcycloheptyl)aminomethyl]benzenemethanol, (αR)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)aminomethyl]benzenemethanol, (αS)-α-[[(1-methyl-3-azetidinyl)amino]methyl]benzenemethanol, α-[[(4-hydroxycyclohexyl)amino]methyl]benzenemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-3-pyridinemethanol, α-[[(3-methylcyclopentyl)amino]methyl]-4-pyridinemethanol, α-[[(3-hydroxycyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(4-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, α-[[(3-methylcyclohexyl)amino]methyl]-4-pyridinemethanol, (αR)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, (αS)-α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]benzenemethanol, α-[[(1-methyl-3-pyrrolidinyl)aminomethyl]benzenemethanol, 5-[(2-hydroxy-2-phenylethyl)amino]cyclooctanol, α-[[(3-fluorocyclobutyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-3-piperidinyl)aminomethyl]benzenemethanol, α-[[(1-methyl-3-azetidinyl)amino]methyl]-3-pyridinemethanol, α-[[(Hexahydro-1-methyl-1H-azepine-4-yl)aminomethyl]benzenemethanol, α-[[(3-fluorocyclobutyl)amino]methyl]-2-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-4-pyridinemethanol, α-[[(1-methyl-3-pyrrolidinyl)amino]methyl]-3-pyridinemethanol, α-[[(1-methyl-4-piperidinyl)aminomethyl]benzenemethanol hydrochloride, α-[[(1-methyl-3-azetidinyl)amino]methyl]-2-pyridinemethanol, (C) α-[[(1-methyl-4-piperidinyl)aminomethyl]benzenemethanol, 2-((1-benzylpiperidine-4-yl)amino)-1-phenylethanol, 4-(1-hydroxy-2-((1-methylpiperidine-4-yl)aminoethyl)phenol, 4-(2-((1-benzylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 4-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, 3-(2-((1-butylpiperidine-4-yl)amino)-1-hydroxyethyl)phenol, A compound that is not one of the following: 4-(1-hydroxy-2-((1-(2-methoxyethyl)piperidine-4-yl)amino)ethyl)phenol or 4-(1-hydroxy-2-((1-phenethylpiperidine-4-yl)amino)ethyl)phenol.
2. Furthermore, according to the following conditions (D) to (M), the compound of formula I is as follows (D) (E) (F) (G) (H) (J) (K) (L) (M) The compound according to claim 1, which does not fall under any of the above.
3. The ring including Q1 to Q5 is Phenyls which may be optionally substituted with one or more Y1s , The compound according to claim 1 or 2, comprising pyridyl which may be optionally substituted with one or more Y2s .
4. The compound according to any one of the preceding claims, wherein each Y1 independently represents Ra1 , halo, or -CN.
5. The compound according to any one of the preceding claims, wherein each Y2 independently represents Ra2 , halo, or -CN.
6. The compound according to any one of the preceding claims, wherein each Y1 and Y2 represents F.
7. The compound according to any one of the preceding claims 1, wherein each Z, when present on a carbon atom, independently represents halo, R a3 , -CN, -N(R b3 )R c3 , -OR d3 , or -N(R h3 )S(O) tR i3 .
8. The compound according to any one of the preceding claims, wherein each Z, when present on a carbon atom, independently represents Ra a3 , -N(R b3 )R c3 , -OR d3 , or -N(R h3 )S(O) tR i3 , for example, Ra a3 .
9. A compound according to any one of the preceding claims, wherein t represents 2.
10. A compound according to any one of the preceding claims, wherein n represents 1.
11. The compound of formula I is the compound of formula IX, During the ceremony, Q1 to Q5 , R1 , n, and Z are as defined in any of the preceding claims, X represents C or N, The compound according to any one of the preceding claims, wherein m1 and m2 independently represent 0 to 2.
12. The compound of formula IX is the compound of formula IE, The compound according to claim 11, wherein Q1 to Q5 , R1 , and Z are as defined in any of the preceding claims, and X is as defined in claim 11.
13. A compound defined in any one of claims 1 to 12, for use in medical applications.
14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, and one or more pharmaceutically acceptable adjuvants, diluents, and/or carriers, optionally selected from among them.
15. A compound as defined in any one of claims 1 to 12, for use in the treatment of hyperglycemia or a disorder characterized by hyperglycemia.
16. Use of a compound defined in any one of claims 1 to 12 for the manufacture of a pharmaceutical product for the treatment of hyperglycemia or a disorder characterized by hyperglycemia.
17. A method for treating hyperglycemia or a disorder characterized by hyperglycemia, comprising administering a therapeutically effective amount of a compound defined in any one of claims 1 to 12 to a patient in need thereof.
18. A compound, method, or use according to any one of claims 15 to 17, wherein hyperglycemia or a disorder characterized by hyperglycemia is characterized by or in a patient exhibiting severe insulin resistance.
19. A compound, method, or use for use according to any one of claims 15 to 18, wherein the disorder characterized by hyperglycemia is selected from the group consisting of type 2 diabetes mellitus, Rabson-Mendenhall syndrome, Donahue syndrome (fairy syndrome), insulin-resistant type A and B syndromes, HAIR-AN (hyperandrogenism, insulin resistance, and acanthosis nigricans) syndrome, pseudoacromegaly, and lipodystrophy.
20. A compound as defined in any one of claims 1 to 12, for use in the treatment of non-alcoholic fatty liver disease.

Description

This invention relates to novel compounds and compositions, and their use in medicine, for example, in the treatment of hyperglycemia and disorders characterized by hyperglycemia (e.g., type 2 diabetes). 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 via significant cAMP release. Such compounds are also used in the treatment of other diseases or disorders, which are also performed through activation of β2 adrenergic receptors. Any listing or discussion of previously published literature in this specification should not necessarily be construed as an endorsement that such literature is part of cutting-edge technology or common general knowledge. Hyperglycemia, or high blood sugar, 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, non-significant) response to insulin. Several syndromes exist that are characterized by SIR, including Rabson-Mendenhall syndrome, Donahue syndrome (Fairy syndrome), 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 of 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. Thus, 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 (i.e., insulin-dependent diabetes mellitus) and type 2 (insulin-independent diabetes mellitus), 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 inhibiting glucose production from the liver, but many of these treatments have several drawbacks and side effects. Therefore, there is considerable 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 and insulin injections or oral medications to regulate glucose homeostasis. Individuals with late-stage type 2 diabetes develop "beta-cell dysfunction," meaning 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