Naphthilidinone derivatives for the treatment of diseases or disorders

Abstract

This disclosure is based on formula (I): [Case 1] JPEG2026519489000060.jpg50170 (In the formula, A, L, and R3 are as described herein.) This invention relates to compounds that are phosphate ester derivatives of the compound, as well as compositions and methods for using such compounds.

Claims

1. Equation (I): 【Chemistry 1】 (In the formula, L is optionally substituted with one or more -OH groups (C １ ~C ６ ) is alkylene, A is -OR ２ or -SO ２ (C １ ~C ４ )alkyl, -NHC(O)R ｂ and -C(O)NHR ｃ and is optionally substituted with one or more substituents independently selected from １ (C ６ ~C )alkyl R ２ is -NHC(O)R ｄ and -C(O)NHR ｅ Substituted with one or more substituents independently selected from (C １ ~C ６ ) is alkyl, and the above (C １ ~C ６ The alkyl group is further optionally substituted with one or more substituents independently selected from halogens, -OH, and -CN. R ａ , R ｂ , R ｃ , R ｄ and R ｅ Each of these is independently and optionally substituted with H and one or more -OH groups (C １ ~C ６ ) Selected from alkyl, and R ３ is, (C １ ~C ４ (It is alkyl.) A compound that is a phosphate ester derivative of the compound, or a pharmaceutically acceptable salt thereof.

2. L is -CH ２ CH ２ -ien-CH ２ -CH(CH ３ ) - and - CH ２ C (CH ３ ) ２ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the following.

3. Formula (II): 【Chemistry 2】 (In the formula, L is optionally substituted with one or more -OH groups (C １ ~C ６ ) is alkylene, A is -OR ２ or -SO ２ (C １ ~C ４ ) Alkyl, -NHC(O)R ａ and -C(O)NHR ｂ It is optionally substituted with one or more substituents independently selected from (C １ ~C ６ ) is alkyl, R ２ is -NHC(O)R ｃ and -C(O)NHR ｄ Substituted with one or more substituents independently selected from (C １ ~C ６ ) is alkyl, and the above (C １ ~C ６ The alkyl group is further optionally substituted with one or more substituents independently selected from halogens, -OH, and -CN. R ａ , R ｂ , R ｃ and R ｄ Each of these is independently and optionally substituted with H and one or more -OH groups (C １ ~C ６ ) Selected from alkyl, and R ３ is, (C １ ~C ４ (It is alkyl.) A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the above.

4. A is -OR ２ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. Formula (IV): 【Transformation 3】 (In the formula, L is optionally substituted with one or more -OH groups (C １ ~C ６ ) is alkylene, R ｄ (C) is optionally substituted with H and one or more -OH groups. １ ~C ６ ) Selected from alkyl, and R ３ is, (C １ ~C ４ (It is alkyl.) A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the above.

6. R ３ is, -CH ３ The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. 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-methylpropanamide, 2-((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-hydroxyethyl)acetamide, 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)oxy)-N-methylpropanamide, 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)oxy)-N-methylacetamide, 2-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-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)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-yl)oxy)ethyl)acetamide, (S)-3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxypropoxy)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)phenyl)-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-methylpropoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)oxy)-2-hydroxy-N-methylpropanamide, 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)oxy)-2,2-difluoro-N-methylpropanamide, 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)oxy)propanamide, N-(3-(8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)propyl)acetamide, 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonyl)ethyl)-1,6-naphthyridine-4(1H)-one, 8-Chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-5-(2-(methylsulfonyl)propyl)-1,6-naphthyridine-4(1H)-one, and 8-Chloro-1-(2,6-dichloro-4-(2-hydroxy-2-methylpropoxy)phenyl)-2-methyl-5-(3-(methylsulfonyl)propyl)-1,6-naphthyridine-4(1H)-one The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is a phosphate ester derivative of a compound of formula (I) selected from the group consisting of the following.

8. 2-(3,5-dichloro-4-(8-chloro-5-(2-hydroxy-3-(methylamino)-3-oxopropoxy)-2-methyl-4-oxo-1,6-naphthyridine-1(4H)-yl)phenoxy)ethyl dihydrogen phosphate, (R)-2-(3,5-dichloro-4-(8-chloro-5-(2-hydroxy-3-(methylamino)-3-oxopropoxy)-2-methyl-4-oxo-1,6-naphthyridine-1(4H)-yl)phenoxy)ethyl dihydrogen phosphate, and (S)-2-(3,5-dichloro-4-(8-chloro-5-(2-hydroxy-3-(methylamino)-3-oxopropoxy)-2-methyl-4-oxo-1,6-naphthyridine-1(4H)-yl)phenoxy)ethyl dihydrogen phosphate A compound according to any one of claims 1 to 4, 6, or 7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

9. 3-((8-chloro-1-(2,6-dichloro-4-(2-hydroxyethoxy)phenyl)-2-methyl-4-oxo-1,4-dihydro-1,6-naphthyridine-5-yl)oxy)-1-(methylamino)-1-oxopropane-2-yl dihydrogen phosphate, (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)-1-(methylamino)-1-oxopropane-2-yl dihydrogen phosphate, and (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)-1-(methylamino)-1-oxopropane-2-yl dihydrogen phosphate A compound according to any one of claims 1, 2, or 4-7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of the above.

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

11. Class I antiarrhythmic agents, Class II antiarrhythmic agents, Class III antiarrhythmic agents, Class IV antiarrhythmic agents, Class V antiarrhythmic agents, cardiac glycosides and other drugs acting on the atrial refractory period; hemostatic modifiers, antithrombotic agents; thrombin inhibitors; factor Vila inhibitors; anticoagulants, factor Xa inhibitors and direct thrombin inhibitors; antiplatelet agents, cyclooxygenase inhibitors, adenosine diphosphate (ADP) receptor inhibitors, phosphodiesterase inhibitors, glycoprotein IIB / IIA, adenosine reuptake inhibitors; anti-dyslipidemia agents, HM G-CoA reductase inhibitors, other cholesterol-lowering agents; bile acid adsorbents; cholesterol absorption inhibitors; cholesteryl ester transfer protein (CETP) inhibitors; ileal bile acid transport system inhibitors (IBAT inhibitors); bile acid binding resins; nicotinic acid and its analogues; antioxidants; ω-3 fatty acids; antihypertensive drugs including adrenergic receptor antagonists, β-blockers, α-blockers, and mixed α / β-blockers; adrenergic receptor agonists, α-2 agonists; angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers; angio Tensin II receptor antagonists; aldosterone receptor antagonists; central adrenergic agonists, central alpha agonists; and diuretics; anti-obesity agents, pancreatic lipase inhibitors, microsomal transport protein (MTP) modulators, diacylglycerol acyltransferase (DGAT) inhibitors, cannabinoid (CBI) receptor antagonists; insulin and insulin analogs; insulin secretagogues; incretin enhancers, dipeptidyl peptidase IV (DPP-4) inhibitors, glucagon-like peptide-I (GL) P-1) Agonists; insulin sensitizers, peroxisome proliferator-activated receptor gamma (PPARγ) agonists, drugs that regulate hepatic glucose balance, fructose 1,6-bisphosphatase inhibitors, glycogen phosphorylase inhibitors, glycogen synthase kinase inhibitors, glucokinase activators; drugs designed to reduce / delay glucose absorption from the intestines, α-glucosidase inhibitors; drugs that antagonize the action of glucagon or reduce glucagon secretion, amylin analogs;The pharmaceutical composition according to claim 10, further comprising at least one further pharmaceutically active agent selected from agents that prevent glucose reabsorption by the kidneys and sodium-dependent glucose transporter 2 (SGLT-2) inhibitors.

12. A method for treating or preventing a disease or disorder in response to inhibition of GIRK1 / 4 receptors, wherein the disease or disorder in response to inhibition of GIRK1 / 4 receptors is selected from cardiac arrhythmias, atrial fibrillation, bradyarrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosteronism, hypotension, and vasovagal syncope, and the method comprises administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11.

13. A method for maintaining sinus rhythm after electrical cardioversion in a patient having persistent or recently onset atrial fibrillation, or for preventing recurrence in a patient having paroxysmal atrial fibrillation, comprising administering to a patient in need a therapeutically effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11.

14. The method according to claim 12 or 13, wherein the administration of the compound or the pharmaceutical composition is by oral ingestion.

15. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, for use as a pharmaceutical agent.

16. For use in the treatment of a disease or disorder responding to inhibition of the GIRK1 / 4 receptor, wherein the disease or disorder responding to inhibition of the GIRK1 / 4 receptor is selected from cardiac arrhythmias, atrial fibrillation, bradyarrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosteronism, hypotension, and vasovagal syncope, the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 or 11.

17. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, for use in maintaining sinus rhythm after electrical cardioversion in patients with persistent or recently onset atrial fibrillation, or in preventing recurrence in patients with paroxysmal atrial fibrillation.

18. For use in the manufacture of a drug for treating a disease or disorder in response to inhibition of the GIRK1 / 4 receptor, wherein the disease or disorder in response to inhibition of the GIRK1 / 4 receptor is selected from cardiac arrhythmias, atrial fibrillation, bradyarrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosteronism, hypotension, and vasovagal syncope, the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 or 11.

19. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in the manufacture of a pharmacopoeia for treating a disease or disorder in response to inhibition of the GIRK1 / 4 receptor, wherein the disease or disorder in response to inhibition of the GIRK1 / 4 receptor is selected from cardiac arrhythmias, atrial fibrillation, bradyarrhythmia, bradycardia, heart block, sick sinus syndrome, parasympathetic hyperreaction, primary aldosteronism, hypotension, and vasovagal syncope.

20. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 or 11, in maintaining sinus rhythm after electrical cardioversion in patients with persistent or recently onset atrial fibrillation, or in preventing recurrence in patients with paroxysmal atrial fibrillation.

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