Heterocyclo inhibitors of potassium channel function

• US 7,005,436 B2
• Filed: 04/16/2003
• Issued: 02/28/2006
• Est. Priority Date: 04/19/2002
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company, Icagen, Inc.
• Original Assignee: Bristol Myers Squibb Co., Icagen, Inc.
• Inventors: Finlay, Heather, Lloyd, John, Yan, Lin, Gross, Michael F., Beaudoin, Serge, Jeon, Yoon T.
• Primary Examiner(s): DESAI, RITA J
• Application Number:
  US10/417,355
• Publication Number:
  US 20040110793A1
• Time in Patent Office: 1,049 Days
• Field of Search: 546/188, 546/191, 544/336, 514/317, 514/252.1
• US Class Current: 514/317
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 Antiarrhythmics
• CPC Class Codes: C07D 211/26 with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 211/64 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 211/96 Sulfur atom
• CPC Class Codes: C07D 223/04 with only hydrogen atoms, halogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

Abstract

Novel heterocyclo compounds useful as inhibitors of potassium channel function (especially inhibitors of the K_v1 subfamily of voltage gated K⁺ channels, especially inhibitors K_v1.5 which has been linked to the ultra-rapidly activating delayed rectifier K⁺ current I_Kur), methods of using such compounds in the prevention and treatment of arrhythmia and I_Kur-associated conditions, and pharmaceutical compositions containing such compounds.

Claims

1. A compound of formula I

including enantiomers, diastereomers, salts and solvates thereof wherein

mn and p are independently 0, 1, or 2, provided that the sum of m and p is 2;

Q is NR¹;

J is a bond or C_1-4 alkylene optionally substituted with one or more groups T^1a, T^2a or T^3a;

R¹ is selected from

R² is aryl, which may be optionally independently substituted with one or more groups T¹, T² or T³;

R³ is

R⁵ is optionally substituted heteroaryl or (heteroaryl)alkyl wherein the hetero is pyrazine or pyridine, and either of these may be optionally independently substituted with one or more groups T^1c, T^2c or T^3c;

R⁶, R⁷, R⁸ and R^8a are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, —

C(O)R⁹, —

CO₂R⁹, —

C(O)—

NR⁹R¹⁰, or —

NR⁹R¹⁰, any of which may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R^8b is H, alkyl, aryl, cyano, nitro, acyl or —

SO₂(alkyl) wherein the alkyl and aryl groups may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R^8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy or aryloxy, any of which may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R⁹ and R¹⁰ are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl (alkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or (aryl)alkyl, any of which may be optionally independently substituted with one or more groups T^1f, T^2f or T^3f;

Z¹ is ═

O;

R^x is one or more optional substituents attached to any available ring carbon atom, each of which is independently selected from T^1g, T^2g or T^3g;

T^1-1g, T^2-2g, and T^3-3g are independently

(1) hydrogen or T⁶, where T⁶ is

(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, or (aryl)alkyl;

(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);

or

(iii) B group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13);

(2) —

OH or —

OT⁶,

(3) —

SH or —

ST⁶,

(4) —

C(O)_tH, —

C(O)_tT⁶, or —

O—

C(O)T⁶, where t is 1 or 2;

(5) —

SO₃H, —

S(O)_tT⁶, or S(O)_tN(T⁹)T⁶,

(6) halo,

(7) cyano,

(8) nitro,

(9) -T⁴-NT⁷T⁶,

(10) -T⁴-N(T⁹)-T⁵-NT⁷T⁸,

(11) -T⁴-N(T¹⁰)-T⁵-T⁶,

(12) -T⁴-N(T¹⁰)-T⁵-H,

(13) oxo;

T⁴ and T⁵ are independently

(1) a single bond,

(2) -T¹¹-S(O)_t-T¹²-,

(3) -T¹¹-C(O)-T¹²-,

(4) -T¹¹-C(S)-T¹²-,

(5) -T¹¹-O-T¹²-,

(6) -T¹¹-S-T¹²-,

(7) -T¹¹-O—

C(O)-T¹²-,

(8) -T¹¹-C(O)—

O-T¹²-,

(9) -T¹¹-C(═

NT^9a)-T¹²-, or

(10) -T¹¹-C(O)—

C(O)-T¹²-;

T⁷, T⁸, T⁹, T^9a and T¹⁰

(1) are independently hydrogen or a group provided in the definition of T⁶; and

T¹¹ and T¹² are independently

(1) a single bond,

(2) alkylene,

(3) alkenylene, or

(4) alkynylene.

2. A compound of claim 1 wherein

Q is NR¹;

R¹ is

 

J is a bond or methylene; and

R³ is

3. A compound of claim 1 wherein

R⁵ is

R⁶ and R⁷ are independently H, alkyl, alkenyl, alkynyl, aryl, (aryl)alkyl, (alkoxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, (hydroxy)alkyl, (aryloxy)alkyl, —

C(O)R⁹, —

CO₂R⁹, or —

C(O)—

NR⁹R¹⁰ any of which may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R^8a is H, alkyl, or (aryl)alkyl where the alkyl and aryl groups may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R^8c is

(a) alkyl or aryl, any of which may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

or

(b) —

NR⁹R¹⁰; and

Z¹ is ═

O.

4. A compound of claim 3 wherein T¹, T^1b, T^1c, T^1d, T², T^2b, T^2c, T^2d, T³, T^3b, T^3c and T^3d are independently halo, cyano, alkyl, aryl, (aryl)alkyl, haloalkyl, —

OH, —

OT⁶, —

C(O)_tT⁶, —

SO₂T⁶, -T⁴NT⁷T⁸, or -T⁴N(T¹⁰)T⁵-T⁶.

5. A compound of claims 1 having the structure:

8. A pharmaceutical composition comprising at least one compound of claim 1 together with a suitable vehicle or carrier therefor.

9. A pharmaceutical composition of claim 8 further comprising at least one additional therapeutic agent selected from anti-arrhythmic agents, calcium channel blockers, anti-platelet agents, anti-hypertensive agents, anti-thrombotic/anti-thrombolytic agents, anti-coagulants, HMG-CoA reductase inhibitors, anti-diabetic agents, thyroid mimetics, mineralocorticoid receptor antagonists, or cardiac glycosides.

10. The pharmaceutical composition of claim 9 wherein

(a) the additional anti-arrhythmic agent is selected from sotalol, dofetilide, diltiazem and verapamil;

(b) the anti-platelet agent is selected from clopidogrel, ifetroban and aspirin;

(c) the anti-hypertensive agent is selected from beta adrenergic blockers, ACE inhibitors, A II antagonists, ET antagonists, Dual ET/A II antagonists, and vasopepsidase inhibitors;

(d) the anti-thrombotic/anti-thrombolytic agent is selected from tPA, recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa inhibitors and thrombin inhibitors;

(e) the anti-coagulant is selected from warfarin and heparins;

(f) the HMG-CoA reductase inhibitor is selected from pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 and ZD-4522;

(g) the anti-diabetic agent is selected from biguanides and biguanide/glyburide combinations;

(h) the mineralocorticoid receptor antagonist is selected from spironalactone and eplerinone; and

(i) the cardiac glycoside is selected from digitalis and ouabain.

11. The pharmaceutical composition of claim 10 wherein

(a) the ACE inhibitor is selected from captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, and lisinopril;

and

(b) the vasopepsidase inhibitor is selected from omapatrilat and gemopatrilat.

6. A compound having the structure:

wherein

R^8c is selected from H or alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy, aryloxy, any of which may be optionally independently substituted with one or more groups T^1b, T^2d or T^3d as defined hereinabove;

T¹, T² and T³ may each be present or absent and each may be selected from halo or —

CN; and

T¹⁰ is selected from H or —

NH₂.

7. The compound of claim 6 wherein any of T¹, T² and T³ is selected from Cl, F, or CF₃.

12. A method of treating arrhythmia comprising administering to a patient in need thereof an effective amount of a compound of the formula I:

including enantiomers, diastereomers, salts and solvates thereof wherein

m and p are independently 0, 1, or 2, provided that the sum of m and p is 2;

Q is NR^t;

J is a bond or C_1-4 alkylene optionally substituted with one or more groups T^1a, T^2a or T^3a;

R¹ is selected from

R² is aryl, which may be optionally independently substituted with one or more groups T¹, T² or T³;

R³ is

R⁵ is optionally substituted heteroaryl or (heteroaryl)alkyl wherein the hetero is pyrazine or pyridine, and either of these may be optionally independently substituted with one or more groups T^1c, T^2c or T^3c;

R⁶, R⁷, R⁸ and R^8a are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, (cyano)alkyl, (alkenyl)alkyl, (alkynyl)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, —

C(O)R⁹, —

CO₂R⁹, —

C(O)—

NR⁹R¹⁰, or —

NR⁹R¹⁰, any of which may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R^8b is H, alkyl, aryl, cyano, nitro, acyl or —

SO₂(alkyl) wherein the alkyl and aryl groups may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R^8c is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, alkoxy or aryloxy, any of which may be optionally independently substituted with one or more groups T^1d, T^2d or T^3d;

R⁹ and R¹⁰ are independently H, alkyl, hydroxy, alkoxy, aryloxy, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or (aryl)alkyl, any of which may be optionally independently substituted with one or more groups T^1f, T^2f or T^3f;

Z¹ is ═

O;

R^x is one or more optional substituents attached to any available ring carbon atom, each of which is independently selected from T^1g, T^2g or T^3g;

T^1-1g, T^2-2g, and T^3-3g are independently

(1) hydrogen or T⁶, where T⁶ is

(i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl, or (aryl)alkyl;

(ii) a group (i) which is itself substituted by one or more of the same or different groups (i);

or

(iii) a group (i) or (ii) which is independently substituted by one or more of the following groups (2) to (13);

(2) —

OH or —

OT⁶,

(3) —

SH or —

ST⁶,

(4) —

C(O)_tH, —

C(O)_tT⁶, or —

O—

C(O)T⁶, where t is 1 or 2;

(5) —

SO₃H, —

S(O)_tT⁶, or S(O)_tN(T⁹)T⁶,

(6) halo,

(7) cyano,

(8) nitro,

(9) -T⁴-NT⁷T⁸,

(10) -T⁴-N(T⁹)-T⁶-NT⁷T⁸,

(11) -T⁴-N(T¹⁰)-T⁵-T⁶,

(12) -T⁴-N(T¹⁰)-T⁵-H,

(13) oxo;

T⁴ and T⁵ are independently

(1) a single bond,

(2) -T¹¹-S(O)_t-T¹²-,

(3) -T¹¹-C(O)-T¹²-,

(4) -T¹¹-C(S)-T¹²-,

(5) -T¹¹-O-T¹²-,

(6) -T¹¹-S-T¹²-,

(7) -T¹¹-O—

C(O)-T¹²-,

(8) -T¹¹-C(O)—

O-T¹²-,

(9) -T¹¹-C(═

NT^9a)-T¹²-, or

(10) -T¹¹-C(O)—

C(O)-T¹²-;

T⁷, T⁸, T⁹, T^9a and T¹⁰

(1) are independently hydrogen or a group provided in the definition of T⁶; and

T¹¹ and T¹² are independently

(1) a single bond,

(2) alkylene,

(3) alkenylene, or

(4) alkynylene.

13. The method of claim 12 wherein the arrhythmia is a supraventricular arrhythmia.

14. The method of claim 13 wherein the supraventricular arrhythmia is atrial fibrillation.

15. The method of claim 14 wherein the supraventricular arrhythmia is atrial flutter.