Ion channel modulating activity I
AssigneeCardiome Pharma Corp.
InventorsDavid Fedida, Gregory Beatch, Alan Ezrin, Peter Orth, Christian Hesketh
Life of this patent
Estimating the term…
Abstract
Methods, compositions, dosing regimes, and routes of administration for the treatment or prevention of arrhythmias. In these methods, early afterdepolarizations and prolongation of QT interval may be reduced or eliminated by administering ion channel modulating compounds to a subject in need thereof. The ion channel modulating compounds may be cycloalkylamine ether compounds, particularly cyclohexylamine ether compounds. Also described are compositions of ion channel modulating compounds and drugs which induce early afterdepolarizations, prolongation of QT interval and/or Torsades de Pointes.
Claims98
A composition comprising
- an ion channel modulating compound that blocks a late component of a cardiac sodium channel current approximately as much as or more than it blocks an early component of a cardiac sodium channel current;
- wherein the ion channel modulating compound further blocks the early component of a cardiac sodium channel current approximately as much as or more than it blocks a sustained component of a cardiac sodium channel current;
- and
- a compound which prolongs QT interval.
A composition comprising:
- an ion channel modulating compound that blocks a late component of a cardiac sodium channel current approximately as much as or more than it blocks an early component of a cardiac sodium channel current;
- wherein the ion channel modulating compound further blocks the early component of a cardiac sodium channel current approximately as much as or more than it blocks a sustained component of a cardiac sodium channel current;
- and
- a compound which induces Torsades de Pointes.
A composition comprising:
- an ion channel modulating compound of formula
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy;
- and
- a compound which prolongs QT interval.
A composition comprising
- an ion channel modulating compound of formula:
- or solvates or pharmaceutically acceptable salts thereof, wherein,
- n=1, 2, 3, or 4;
- X is a direct bond, —C(R6,R14)—Y—, or —C(R13)═CH—, with the proviso that when X is a direct bond and A is formula (III) then at least one of R7, R8 and R9 is not hydrogen;
- Y is a direct bond, O, S, or C1-C4alkylene;
- R13 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, aryl, or benzyl;
- R1 and R2 are independently hydrogen, C1-C8alkyl, C3-C8alkoxyalkyl, C1-C8hydroxyalkyl, or C7-C12aralkyl;
- or
- R1 and R2, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), form a ring denoted by formula (II):
- wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently carbon, nitrogen, oxygen, or sulfur;
- where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from the group consisting of hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, C2-C4acyl, C1-C3alkyl, C2-C4alkylcarboxy, C1-C3alkoxy, and C1-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms of oxygen or sulfur;
- and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents of hydrogen, C1-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl or C3-C8alkoxyalkyl;
- or
- R1 and R2, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), may form a bicyclic ring system of 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, or 3-azabicyclo[3.2.0]heptan-3-yl;
- R3 and R4 are independently attached to the cyclohexane ring shown in formula (Ia) at the 3-, 4-, 5- or 6-positions and are independently hydrogen, hydroxy, C1-C6alkyl, or C1-C6alkoxy, and, when both R3 and R4 are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms of oxygen or sulfur;
- R5, R6 and R14 are independently hydrogen, C1-C6alkyl, aryl or benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl;
- A is C5-C12alkyl, a C3-C13carbocyclic ring, or ring systems comprising formulae (III), (IV), (V), (VI), (VII) or (VIII):
- where R7, R8 and R9 are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- where R10 and R11 are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- where R12 is bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- and Z is CH, CH2, O, N or S, where Z may be directly bonded to “X” as shown in formula (Ia) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, aryl or benzyl;
- and
- a compound which prolongs QT interval.
A method of reducing or eliminating the prolongation of QT interval by a drug in a subject given a therapeutically effective amount of a drug capable of prolonging QT interval comprising:
- administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound that blocks a late component of a cardiac sodium channel current approximately as much as or more than it blocks an early component of a cardiac sodium channel current, and blocks the early component of a cardiac sodium channel current approximately as much as or more than it blocks a sustained component of a cardiac sodium channel current.
A method of reducing or eliminating the prolongation of QT interval by a drug in a subject given a therapeutically effective amount of a drug capable of prolonging QT interval, the method comprising:
- administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound having the formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
A method of reducing or eliminating the prolongation of QT interval by a drug in a subject given a therapeutically effective amount of a drug capable of prolonging QT interval, the method comprising:
- administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or solvates or pharmaceutically acceptable salts thereof;
- wherein,
- n=1, 2, 3, or 4;
- X is a direct bond, —C(R6,R14)—Y—, or —C(R13)═CH—, with the proviso that when X is a direct bond and A is formula (III) then at least one of R7, R8 and R9 is not hydrogen;
- Y is a direct bond, O, S, or C1-C4alkylene;
- R13 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, aryl, or benzyl;
- R1 and R2 are independently hydrogen, C1-C8alkyl, C3-C8alkoxyalkyl, C1-C8hydroxyalkyl, or C7-C12aralkyl;
- or
- R1 and R2, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), form a ring denoted by formula (II):
- wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently carbon, nitrogen, oxygen, or sulfur;
- where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from the group consisting of hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, C2-C4acyl, C1-C3alkyl, C2-C4alkylcarboxy, C1-C3alkoxy, and C1-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms of oxygen or sulfur;
- and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents of hydrogen, C1-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl or C3-C8alkoxyalkyl;
- or
- R1 and R2, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), may form a bicyclic ring system of 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, or 3-azabicyclo[3.2.0]heptan-3-yl;
- R3 and R4 are independently attached to the cyclohexane ring shown in formula (Ia) at the 3-, 4-, 5- or 6-positions and are independently hydrogen, hydroxy, C1-C6alkyl, or C1-C6alkoxy, and, when both R3 and R4 are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms of oxygen or sulfur;
- R5, R6 and R14 are independently hydrogen, C1-C6alkyl, aryl or benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl;
- A is C5-C12alkyl, a C3-C13carbocyclic ring, or ring systems selected from the group consisting of formulae (III), (IV), (V), (VI), (VII) and (VIII):
- where R7, R8 and R9 are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- where R10 and R11 are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- where R12 is bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- and Z is CH, CH2, O, N or S, where Z may be directly bonded to “X” as shown in formula (Ia) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, aryl or benzyl;
A method of treating chemically-induced Torsades de Pointes comprising administering to a subject in need thereof an ion channel modulating compound in an amount effective to block the late component of a cardiac sodium channel current approximately as much as or more than it blocks the early component of a cardiac sodium channel current, and also to block the early component of a cardiac sodium channel current approximately as much as or more than it blocks the sustained component of a cardiac sodium channel current.
A method of preventing chemically-induced Torsades de Pointes comprising administering to a subject in need thereof an ion channel modulating compound in an amount effective to block the late component of a cardiac sodium channel current approximately as much as or more than it blocks the early component of a cardiac sodium channel current, and also to block the early component of a cardiac sodium channel current approximately as much as or more than it blocks the sustained component of a cardiac sodium channel current.
A method of treating and preventing chemically-induced Torsades de Pointes comprising administering to a patient in need thereof an ion channel modulating compound in an amount effective to block the late component of a cardiac sodium channel current approximately as much as or more than it blocks the early component of a cardiac sodium channel current, and also to block the early component of a cardiac sodium channel current approximately as much as or more than it blocks the sustained component of a cardiac sodium channel current.
A method of terminating early afterdepolarization comprising administering to a subject in need thereof an ion channel modulating compound in an amount effective to block the late component of a cardiac sodium channel current approximately as much as or more than it blocks the early component of a cardiac sodium channel current, and also to block the early component of a cardiac sodium channel current approximately as much as or more than it blocks the sustained component of a cardiac sodium channel current.
A method of preventing early afterdepolarization comprising administering to a patient in need thereof an ion channel modulating compound in an amount effective to block the late component of a cardiac sodium channel current approximately as much as or more than it blocks the early component of a cardiac sodium channel current, and also to block the early component of a cardiac sodium channel current approximately as much as or more than it blocks the sustained component of a cardiac sodium channel current.
A method of terminating and preventing early afterdepolarization comprising administering to a subject in need thereof an ion channel modulating compound in an amount effective to block the late component of a cardiac sodium channel current approximately as much as or more than it blocks the early component of a cardiac sodium channel current, and also to block the early component of a cardiac sodium channel current approximately as much as or more than it blocks the sustained component of a cardiac sodium channel current.
A method of treating chemically-induced Torsades de Pointes comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
A method of preventing chemically-induced Torsades de Pointes comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
A method of treating and preventing chemically-induced Torsades de Pointes comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
The method of claim 83 wherein the ion channel modulating compound comprises a monohydrochloride salt of the formula:
A method of terminating early afterdepolarization comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
A method of preventing early afterdepolarization comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
A method of terminating and preventing early afterdepolarization comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or a solvate or pharmaceutically acceptable salt thereof;
- wherein R22 and R23 are independently hydrogen, hydroxy or C1-C6alkoxy.
A method of terminating or preventing early afterdepolarization comprising administering to a subject in need thereof a therapeutically effective amount of an ion channel modulating compound of formula:
- or solvates or pharmaceutically acceptable salts thereof;
- wherein,
- n=1, 2, 3, or 4;
- X is a direct bond, —C(R6,R14)—Y—, or —C(R13)═CH—, with the proviso that when X is a direct bond and A is formula (III) then at least one of R7, R8 and R9 is not hydrogen;
- Y is a direct bond, O, S, or C1-C4alkylene;
- R13 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, aryl, or benzyl;
- R1 and R2 are independently hydrogen, C1-C8alkyl, C3-C8alkoxyalkyl, C1-C8hydroxyalkyl, or C7-C12aralkyl;
- or
- R1 and R2, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), form a ring denoted by formula (II):
- wherein the ring of formula (II) is formed from the nitrogen as shown as well as three to nine additional ring atoms independently carbon, nitrogen, oxygen, or sulfur;
- where any two adjacent ring atoms may be joined together by single or double bonds, and where any one or more of the additional carbon ring atoms may be substituted with one or two substituents selected from the group consisting of hydrogen, hydroxy, C1-C3hydroxyalkyl, oxo, C2-C4acyl, C1-C3alkyl, C2-C4alkylcarboxy, C1-C3alkoxy, and C1-C20alkanoyloxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms of oxygen or sulfur;
- and any two adjacent additional carbon ring atoms may be fused to a C3-C8carbocyclic ring, and any one or more of the additional nitrogen ring atoms may be substituted with substituents of hydrogen, C1-C6alkyl, C2-C4acyl, C2-C4hydroxyalkyl or C3-C8alkoxyalkyl;
- or
- R1 and R2, when taken together with the nitrogen atom to which they are directly attached in formula (Ia), may form a bicyclic ring system of 3-azabicyclo[3.2.2]nonan-3-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.1.0]hexan-3-yl, or 3-azabicyclo[3.2.0]heptan-3-yl;
- R3 and R4 are independently attached to the cyclohexane ring shown in formula (Ia) at the 3-, 4-, 5- or 6-positions and are independently hydrogen, hydroxy, C1-C6alkyl, or C1-C6alkoxy, and, when both R3 and R4 are attached to the same cyclohexane ring atom, may together form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms of oxygen or sulfur;
- R5, R6 and R14 are independently hydrogen, C1-C6alkyl, aryl or benzyl, or R6 and R14, when taken together with the carbon to which they are attached, may form a spiro C3-C5cycloalkyl;
- A is C5-C12alkyl, a C3-C13carbocyclic ring, or ring systems selected from the group consisting of formulae (III), (IV), (V), (VI), (VII) and (VIII):
- where R7, R8 and R9 are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- where R10 and R11 are independently bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- where R12 is bromine, chlorine, fluorine, carboxy, hydrogen, hydroxy, hydroxymethyl, methanesulfonamido, nitro, sulfamyl, trifluoromethyl, C2-C7alkanoyloxy, C1-C6alkyl, C1-C6alkoxy, C2-C7alkoxycarbonyl, C1-C6thioalkyl, or N(R15,R16) where R15 and R16 are independently hydrogen, acetyl, methanesulfonyl, or C1-C6alkyl;
- and Z is CH, CH2, O, N or S, where Z may be directly bonded to “X” as shown in formula (Ia) when Z is CH or N, or Z may be directly bonded to R17 when Z is N, and R17 is hydrogen, C1-C6alkyl, C3-C8cycloalkyl, aryl or benzyl;
Dependencies are inferred from the claim text.