WO1998004521B1 - Potassium channel inhibitors - Google Patents

Abstract

Compounds of general formula (I) wherein R1 is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl; R2 is selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl; R3 is hydrogen or methyl; R4 is hydrogen or methyl; X1 is C=O, C=S, or SO¿2; X?2 is C=O or SO¿2; Y?1 is O, (CH¿2?)p, CH2O, HC=CH or NH; wherein p is 0, 1 or 2; Y?2¿ is O, (CH¿2?)q, HC=CH or NH; wherein q is 0 or 1; Z is H, OR?5 or NR6R7¿; wherein R5 is H, (CH¿2)m-R?8; or C(O)-(CH¿2)m-R?8; m = 1 to 5; R?8 is N(R9)¿2, N(R9)3L or CO2R9; wherein each R9 is independently selected from H or alkyl; and L is a counter ion; R6 is H or alkyl; R7 is H, alkyl or CO¿2R?10; wherein R10 is alkyl; or pharmaceutically acceptable salts or prodrugs thereof are useful as potassium channel inhibitors and useful for the treatment of cardiac arrhythmias and cell proliferative disorders.

Claims

AMENDED CLAIMS

[received by the International Bureau on 9 February 1998 (09.02.98); original claims 1 and 5 amended; remaining claims unchanged (3 pages)]

1. A compound having potassium channel inhibitory activity of the formula:

wherein, R¹ is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;

R² is selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;

R³ is hydrogen or methyl;

R⁴ is hydrogen or methyl;

X¹ is C=0, C=S, or S0₂;

X² is C=0 or S0₂; Y¹ is O, (CH₂)_p, CH₂0, HC=CH or NH; wherein p is 0, 1 or 2;

Y² is O, (CH₂)_q, HC=CH or NH; wherein q is 0 or 1;

Z is H, OR⁵ or NR⁶R⁷; wherein R⁵ is H, (CH₂)_m-R⁸; or C(0)-(CH₂)_m-R⁸; m = 1 to 5; R⁸ is N(R⁹)₂, N(R⁹)₃L or C0₂R⁹; wherein each R⁹ is independently selected from H or alkyl; and L is a counter ion;

R⁶ is H or alkyl;

R⁷ is H, alkyl or C0₂R¹⁰; wherein R¹⁰ is alkyl; or a pharmaceutically acceptable salt or prodrug thereof with the proviso that when Z is H, then X¹ and X² cannot both be C=0 while Y¹ is (CH₂)_p with p=0, while Y² is (CH₂)_q with q=0, and while R¹ and R² are both methyl. R¹ is H or an optionally substituted aryl selected from the group of phenyl and β-naphthyl;

R² is selected from the group of an optionally substituted phenyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl and an optionally substituted carbocycloalkyl; m is 0 or 1;

X is O or S ; and

Y is selected from one of (CHJ-,, (CH_jO), and (NH).; where p is 0, 1 or 2; q is O or 1, and r is O or 1; or a pharmaceutically acceptable salt or prodrug thereof.

4. A compound according to claim 3 having the formula:

wherein R¹, R² and p have the same meanings recited in claim 3; or a pharmaceutically acceptable salt or prodrug thereof.

5. A pharmaceutical composition comprising a compound of the following formula:

wherein, R¹ is H, alkyl or is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl;

R² is selected from the group consisting of alkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl and an optionally substituted carbocycloalkyl; R³ is hydrogen or methyl; R⁴ is hydrogen or methyl; X¹ is C=0, C=S, or S0₂; X² is C=0 or S0₂;

Y¹ is O, (CH₂)_p, CH₂0, HC=CH orNH; wherein p is 0, 1 or 2; Y² is O, (CH₂)_q, HC=CH or NH; wherein q is 0 or 1; Z is H, OR⁵ or NR⁶R⁷; wherein R⁵ is H, (CH₂)_m-R⁸; or C(0)-(CH₂)_m-R⁸; m = l to 5;

R⁸ is N(R N(R⁹)₃L or C0₂R⁹; wherein each R⁹ is independently selected from H or alkyl; and L is a counter ion; R⁶ is H or alkyl;

R⁷ is H, alkyl or C0₂R¹⁰; wherein R¹⁰ is alkyl; or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable diluent or carrier with the proviso that when Z is H, then X¹ and X² cannot both be C=0 while Y¹ is (CH₂)_p with p=0, while Y² is (CH₂)_q with q=0, and while R¹ and R² are both methyl. 6. A pharmaceutical composition comprising a compound of the following formula:

wherein,