Naphthilidinone derivatives for the treatment of diseases or disorders
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- NOVARTIS AG
- Filing Date
- 2026-02-25
- Publication Date
- 2026-06-23
AI Technical Summary
を示す のを可能にする、組み合わされた投与のいずれかを指す。組み合わせの有益な効果として は、限定されないが、治療剤の組み合わせから得られる、協働効果、例えば相乗効果及び /又は薬物動態学的若しくは薬力学的相互作用又はそれらの任意の組み合わせが挙げられ る。一実施形態では、組み合わせにおけるこれらの治療剤の投与は、規定の期間(例えば 、選択された組み合わせに応じて、数分間、数時間、数日間又は数週間)にわたって行わ れる。
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Abstract
Claims
1. Equation (I): 【Chemistry 1】 (In the formula, R １ is -OH, -C(O)NHR ａ and optionally substituted with one or more -OH groups Substituted with one or more substituents independently selected from the 4-membered to 6-membered heterocycles. ru (C １ ~C ６ ) is alkyl; A is -OR ２ or -SO ２ (C １ ~C ４ )alkyl, -NHCO(R) ｂ and -C( O) NHR ｃ Optionally substituted with one or more substituents independently selected from ru (C １ ~C ６ ) is alkyl; R ２ is -NHC(O)R ｄ and -C(O)NHR ｅ One or one selected independently from Substituted with multiple substituents (C １ ~C ６ ) is alkyl, and the above (C １ ~C ６ ) Al Kill is further selected from one or more substituents independently of halo, -OH, and -CN. It is optionally substituted; R ａ , R ｂ , R ｃ , R ｄ and R ｅ Each of these is independently H and one or more -OH groups. It is optionally replaced by (C １ ~C ６ ) selected from alkyl; and R ３ is, (C １ ~C ４ (It is alkyl.) A compound of or a pharmaceutically acceptable salt thereof.
2. R １ teeth, 【Chemistry 2】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the above.
3. A is -OR ２ The compound according to claim 1 or 2, or the pharmaceutically acceptable thereof Salt.
4. R ｅ (C) is optionally substituted with H and one or more -OH groups. １ ~C ４ )a A compound selected from Lukil, according to any one of claims 1 to 3, or a compound thereof pharmaceutically acceptable Tolerable salt.
5. R ２ は、-NHC(O)CH ３ 、-C(O)NHCH ３ 、-C(O)NHCH ２ CH ２ OH and -C(O)NH ２ Substituted with one or more substituents independently selected from ru (C １ ~C ４ ) is alkyl, and the above (C １ ~C ４ ) Alkyl is a halo, -OH and - The molecule is further optionally substituted with one or more substituents independently selected from the CN. , the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
6. R ２ teeth, 【Transformation 3】 A compound selected from any one of claims 1 to 5 or the pharmaceutically acceptable compound thereof Salt.
7. R ３ is, -CH ３ The compound or the pharmaceutically acceptable chemical of the compound described in any one of claims 1 to 6. A salt that is acceptable for this purpose.
8. 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phen Nyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl )oxy)-N-methylpropanamide; 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phen (L)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl) oxy)-N-(2-hydroxyethyl)acetamide; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpro Poxyphenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthilidi N-5-yl)oxy)-N-methylpropanamide; 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpro Poxyphenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthilidi N-5-yl)oxy)-N-methylacetamide; 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phen (L)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl) oxy)-N-methylacetamide; (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy (C)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine- 5-yl)oxy)-N-methylpropanamide; (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy )phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5 -yl)oxy)-N,2-dimethylpropanamide; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy )phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5 -yl)oxy)-N,2-dimethylpropanamide; N-(2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy) Phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5- Iyl(oxy)ethyl(acetamide); (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy (C)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine- 5-yl)oxy)-N-methylpropanamide; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phen (L)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl) oxy)-N,2,2-trimethylpropanamide; (R)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy )phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5 -yl)oxy)-2-hydroxy-N-methylpropanamide; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy )phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5 -yl)oxy)-2-hydroxy-N-methylpropanamide; (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methyl (Tylpropoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-na Futilizin-5-yl)oxy)-2-hydroxy-N-methylpropanamide; 3-((8-chloro-1-(2,6-dichloro-4-((3-hydroxyoxetane-3 -yl)methoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6- Naphthyridine-5-yl)oxy)-N-methylpropanamide; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phen (L)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl) oxy)-2,2-difluoro-N-methylpropanamide; 2-(4-(5-(2-amino-2-oxoethoxy)-8-chloro-2-methyl-4- Oxo-1,6-naphthyridine-1(4H)-yl)-3,5-dichlorophenoxy)- N-methylacetamide; 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phen (L)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl) Oxypropanamide; N-(3-(8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)f (enyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-i (L)propyl)acetamide; 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2 -methyl-5-(2-(methylsulfonyl)ethyl)-1,6-naphthyridine-4(1H )-on; 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2 -methyl-5-(2-(methylsulfonyl)propyl)-1,6-naphthyridine-4(1 H) -on; and 8-Chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy) Phenyl)-2-methyl-5-(3-(methylsulfonyl)propyl)-1,6-naphthyl Lysine-4(1H)-one A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.
9. Its free form, hydrate, solvate, polymorph, and cocrystal are selected crystalline forms. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.
10. The following crystal forms: (i) Cu having a wavelength of 1.5418 Å in a free crystalline form called transformation A-1 When measured using Kα radiation at a temperature of approximately 22°C, select from the 2θ values shown in the table below. The X-ray powder diffraction pattern is characterized by having four or more selected 2θ values (±0.1°). Characteristic free crystal form: Table 1 (ii) In the hydrate crystal form called transformation A-2, which has a wavelength of 1.5418 Å When measured using CuKα radiation at a temperature of approximately 22°C, the 2θ values shown in the table below are... The X-ray powder diffraction pattern has four or more 2θ values (±0.1°) selected from these values. Hydrate crystal forms characterized by: Table 2 (iii) In the hydrate crystal form called transformation A-3, it has a wavelength of 1.5418 Å. When measured using CuKα radiation at a temperature of approximately 22°C, the 2θ values shown in the table below are The X-ray powder diffraction pattern has four or more 2θ values (±0.1°) selected from the above. Hydrate crystal forms characterized by: Table 3 (iv) In the hydrate crystal form called transformation A-4, it has a wavelength of 1.5418 Å. When measured using CuKα radiation at a temperature of approximately 22°C, the 2θ values shown in the table below are... The X-ray powder diffraction pattern has four or more 2θ values (±0.1°) selected from these values. Hydrate crystal forms characterized by: Table 4 (v) In the hydrate crystal form called transformation A-5, C has a wavelength of 1.5418 Å. When measured using uKα radiation at a temperature of approximately 22°C, the 2θ values shown in the table below The X-ray powder diffraction pattern has four or more selected 2θ values (±0.1°). Characteristic hydrate crystal form: Table 5 3-((8-chloro-1-(2,6-dichloro-4-(2-hydrox (Theethoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyl The compound according to claim 9 is lysine-5-yl)oxy)-N-methylpropanamide thing.
11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and one A pharmaceutical composition comprising or a plurality of pharmaceutically acceptable carriers.
12. Class I antiarrhythmics, Class II antiarrhythmics, Class III antiarrhythmics, Class IV antiarrhythmics Arrhythmic agents, Class V antiarrhythmic agents, cardiac glycosides, and other drugs that act on the atrial refractory period; hemostatic agents Anticoagulants, antithrombotic agents; thrombin inhibitors; factor VIla inhibitors; anticoagulants, factor Xa inhibitors Drugs and direct thrombin inhibitors; antiplatelet agents, cyclooxygenase inhibitors, adenosine dihydrogenase inhibitors Phosphate (ADP) receptor inhibitors, phosphodiesterase inhibitors, glycoprotein IIB / I IA, adenosine reuptake inhibitors; anti-dyslipidemia agents, HMG-CoA reductase inhibitors Cholesterol-lowering agents; other cholesterol-lowering agents; bile acid adsorbents; cholesterol absorption inhibitors; cholesterol Luester transfer protein (CETP) inhibitors; Ileal bile acid transport system inhibitors (IBAT inhibitors) Harmful agents); bile acid binding resins; nicotinic acid and its analogues; antioxidants; ω-3 fatty acids; adrenal Antihypertensive drugs including narin receptor antagonists, beta-blockers, alpha-blockers, and mixed alpha / beta-blockers; Adrenalin α-2 receptor agonists; angiotensin-converting enzyme (ACE) inhibitors; calcium Mucochannel blockers; angiotensin II receptor antagonists; aldosterone receptor antagonists; Central adrenergic agonists, central alpha agonists; and diuretics; anti-obesity agents, pancreatic lipase inhibitors Microsomal transport protein (MTP) regulator, diacylglycerol acyltrans Ferrase (DGAT) inhibitors, cannabinoid (CBI) receptor antagonists; insulin and Insulin analogs; insulin secretagogues; drugs that enhance incretin activity, Peptidyl peptidase IV (DPP-4) inhibitor, glucagon-like peptide-I (GLP) -1) Agonists; insulin sensitizers, peroxisome proliferator-activated receptor γ (PPAR) γ) Agonists, drugs that regulate liver glucose balance, fructose 1,6-bisphosphonate Atase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinases Inhibitors, glucokinase activators; reduce / slow down glucose absorption from the gut. Drugs designed to do so, α-glucosidase inhibitors; antagonizing the action of glucagon or Drugs that reduce glucagon secretion, such as amylin analogs; inhibit the reabsorption of glucose by the kidneys. From preventive drugs and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors Claim 11 further comprises at least one further pharmaceutically active agent selected A listed pharmaceutical composition.
13. A method for treating or preventing a disease or disorder, which is therapeutically effective for patients who need it. A quantity of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. Or a method comprising administering the pharmaceutical composition described in claim 11 or 12.
14. The aforementioned disease or disorder is a disease or disorder that responds to inhibition of the GIRK1 / 4 receptor. The method described in item 13.
15. The aforementioned diseases or disorders that respond to inhibition of GIRK1 / 4 receptors include cardiac arrhythmias, atrial fibrillation, and dysregulation. Pulsational arrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosterone The present invention according to claim 13 or 14, selected from Rons syndrome, hypotension, and vasovagal syncope. method.
16. Sinus rhythm after electrical cardioversion in patients with persistent or recently onset atrial fibrillation A method for maintaining or preventing recurrence in patients with paroxysmal atrial fibrillation, To patients who require it, a therapeutically effective amount of the compound according to any one of claims 1 to 10 A substance or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in claim 11 or 12. A method that includes administering the substance.
17. The administration of the compound or the pharmaceutical composition is by oral in the cases of claims 13 to 16. The method described in any one of the items.
18. A compound or the compound described in any one of claims 1 to 10 for use as a pharmaceutical agent. A pharmaceutically acceptable salt of or the pharmaceutical composition according to claim 11 or 12.
19. It is intended for use in the treatment of diseases or disorders that respond to inhibition of GIRK1 / 4 receptors. Furthermore, the aforementioned diseases or disorders that respond to inhibition of GIRK1 / 4 receptors include cardiac arrhythmias, atrial fibrillation, Bradyarrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosterone Any one of claims 1 to 10, selected from Therons syndrome, hypotension, and vasovagal syncope. The compound described in paragraph 1 or a pharmaceutically acceptable salt thereof, or the compound described in claim 11 or 12 A listed pharmaceutical composition.
20. Sinus rhythm after electrical cardioversion in patients with persistent or recently onset atrial fibrillation To maintain or prevent recurrence in patients with paroxysmal atrial fibrillation The compound described in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. Or the pharmaceutical composition according to claim 11 or 12.
21. Used in the manufacture of drugs for treating diseases or disorders that respond to inhibition of GIRK1 / 4 receptors. It is intended for use, and the disease or disorder that responds to inhibition of the GIRK1 / 4 receptor is Cardiac arrhythmia, atrial fibrillation, bradyarrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic nervous system overactivity A diagnosis is made by selecting from the following: reaction, primary aldosteronism, hypotension, and vasovagal syncope. The compound described in any one of items 1 to 10 or a pharmaceutically acceptable salt thereof, or claim The pharmaceutical composition described in 11 or 12.
22. In the manufacture of drugs for treating diseases or disorders that respond to inhibition of GIRK1 / 4 receptors The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof. Alternatively, the use of the pharmaceutical composition according to claim 11 or 12, wherein the GIRK1 / 4 receptor The diseases or disorders that respond to inhibition of include cardiac arrhythmias, atrial fibrillation, bradyarrhythmias, bradycardia, and cardiac Block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosteronism, hypotension and blood Selected for use in vagal syncope.
23. Sinus rhythm after electrical cardioversion in patients with persistent or recently onset atrial fibrillation Claims 1 to 10 relating to the maintenance of or prevention of recurrence in patients with paroxysmal atrial fibrillation The compound described in any one of the claims or a pharmaceutically acceptable salt thereof, or claim 11 or Use of the pharmaceutical composition described in 12.