US 10,328,075 B2Granted

Method of treatment and compounds for use therein

AssigneesBaker Heart and Diabetes Institute, Monash University

InventorsRebecca Helen Ritchie, Cheng Xue Qin, Arthur Christopoulos, Patrick Michael Sexton, Jonathan Bayldon Baell

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Abstract

The present invention relates generally to a method of therapeutically or prophylactically treating ischaemia-induced myocardial tissue damage, in particular ischaemia-reperfusion-induced myocardial tissue damage. More particularly, the present invention relates to a method of reducing the extent of ischaemia-induced myocardial tissue damage in a mammal by selectively upregulating FPR1-mediated ERK signalling. The method of the present invention is useful, inter alia, in reducing the extent and/or severity of myocardial tissue damage associated with conditions characterized by myocardial ischaemia or myocardial ischaemia and reperfusion, such as acute myocardial infarction caused by atherosclerotic artery occlusion or blood clot-induced artery occlusion.

Claims22

Dependent claims

A method of minimising the extent of ischaemia-induced myocardial tissue damage or ischaemia-reperfusion-induced myocardial tissue damage in a mammal comprising administering to said mammal an effective amount of a compound of structure (I):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein
(a) X is CH2;
Y is CH2CONH, (CH2)2CONH, CH(CH3)CONH, CH2, CH2CO, CH2NHCONH, CH2NHCO, (CH2)2O, (CH2)2NH, (CH2)2NHCONH, (CH2)2NHCO, CH2CSNH, or C(R6R7)CONH;
wherein R6 is H;
R7 is CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, or C6H5;
or
R6 is CH3;
R7 is C2H5 or CH3;
and
R1 is CH3;
or
(b) X is CH2;
Y is CH2CONH;
and
R1 is CH3, H, CH2CH3, CH(CH3)2, C6H11, C6H5, 2-Thienyl, C6H4—OCH3, C6H4—Cl, C6H4—CH3, C6H4—F, or CH2—C6H5;
or
(c) X is NHCO or NHCONH;
Y is CH2;
and
R1 is CH3;
or
(d) X is NH;
Y is CH2CONH;
and
R1 is CH3;
or
(e) X is NHCO or CO;
Y is CH2CONH;
and
R1 is CH3;
or
(f) X is CH2;
Y is CH2CO;
wherein the phenyl group substituted with R2 and R3 and bonded to Y of structure (I) is replaced with N-methyl piperazine, N(CH3)—C6H4—Br, NHCH2—C6H4—Br, or O—C6H4—Br;
and
R1 is CH3;
or
(g) X is NHCONH, NHCO, or NH;
Y of structure (I) is not present and instead the phenyl group substituted with R2 and R3 is directly bonded to the N2 of the pyridazinone ring;
and
R1 is CH3;
or
(h) X is CH2;
Y is CH2CONH;
the phenyl group substituted with R4 and R5 and bonded to X of structure (I) is replaced with 3-Furyl, 3-Thienyl, 2-Thienyl, 1-Naphthyl, or 3-Pyridyl;
and
R1 is CH3;
or
(i) X and the phenyl group substituted with R4 and R5 are not present;
Y is CH2CONH;
and
R1 is CH3;
or
(j) X and the phenyl group substituted with R4 and R5 are not present;
Y is CH2CONH;
R1 is CH3;
and
the bond between C4 and C5 of the pyridazinone ring is a single bond;
or
(k) X is NH2 and the phenyl group substituted with R4 and R5 is not present;
Y is CH2CONH;
and
R1 is CH3;
or
(I) X of structure (I) is not present and instead the phenyl group substituted with R4 and R5 is directly bonded to C4 of the pyridazinone ring;
Y is CH2CONH;
and
R1 is CH3;
or
(m) X is NH;
Y is CH2CONH;
R1 is CH3;
and
C5 is additionally substituted with COCH3;
wherein R2, R3, R4 and R5 are independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfide, cyano, nitro, or R2 and R3 and/or R4 and R5 is a bridged di-alkoxy group;
and
wherein said compound is administered for a time and under conditions sufficient for said compound to induce cardiomyocyte FPR1 activation.

74 more elements

A method of therapeutically or prophylactically treating a condition characterised by ischaemia-induced myocardial tissue damage or ischaemia-reperfusion-induced myocardial tissue damage in a mammal comprising administering to said mammal an effective amount of the compound of structure (I):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein
(a) X is CH2;
Y is CH2CONH, (CH2)2CONH, CH(CH3)CONH, CH2, CH2CO, CH2NHCONH, CH2NHCO, (CH2)2O, (CH2)2NH, (CH2)2NHCONH, (CH2)2NHCO, CH2CSNH, or C(R6R7)CONH;
wherein R6 is H;
R7 is CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, or C6H5;
or
R6 is CH3;
R7 is C2H5 or CH3;
and
R1 is CH3;
or
(b) X is CH2;
Y is CH2CONH;
and
R1 is CH3, H, CH2CH3, CH(CH3)2, C6H11, C6H5, 2-Thienyl, C6H4—0CH3, C6H4—Cl, C6H4—CH3, C6H4—F, or CH2—C6H5;
or
(c) X is NHCO or NHCONH;
Y is CH2;
and
R1 is CH3;
or
(d) X is NH;
Y is CH2CONH;
and
R1 is CH3;
or
(e) X is NHCO or CO;
Y is CH2CONH;
and
R1 is CH3;
or
(f) X is CH2;
Y is CH2CO;
wherein the phenyl group substituted with R2 and R3 and bonded to Y of structure (I) is replaced with N-methyl piperazine, N(CH3)—C6H4—Br, NHCH2—C6H4—Br, or O—C6H4—Br;
and
R1 is CH3;
or
(g) X is NHCONH, NHCO, or NH;
Y of structure (I) is not present and instead the phenyl group substituted with R2 and R3 is directly bonded to the N2 of the pyridazinone ring;
and
R1 is CH3;
or
(h) X is CH2;
Y is CH2CONH;
the phenyl group substituted with R4 and R5 and bonded to X of structure (I) is replaced with 3-Furyl, 3-Thienyl, 2-Thienyl, 1-Naphthyl, or 3-Pyridyl;
and
R1 is CH3;
or
(i) X and the phenyl group substituted with R4 and R5 are not present;
Y is CH2CONH;
and
R1 is CH3;
or
(j) X and the phenyl group substituted with R4 and R5 are not present;
Y is CH2CONH;
R1 is CH3;
and
the bond between C4 and C5 of the pyridazinone ring is a single bond;
or
(k) X is NH2 and the phenyl group substituted with R4 and R5 is not present;
Y is CH2CONH;
and
R1 is CH3;
or
(I) X of structure (I) is not present and instead the phenyl group substituted with R4 and R5 is directly bonded to C4 of the pyridazinone ring;
Y is CH2CONH;
and
R1 is CH3;
or
(m) X is NH;
Y is CH2CONH;
R1 is CH3;
and
C5 is additionally substituted with COCH3;
wherein R2, R3, R4 and R5 are independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfide, cyano, nitro, or R2 and R3 and/or R4 and R5 is a bridged di-alkoxy group;
and
wherein said compound is administered for a time and under conditions sufficient for said compound to induce cardiomyocyte FPR1 activation.

74 more elements

A method of treating ischaemia-induced myocardial tissue damage or ischaemia-reperfusion-induced myocardial tissue damage in a mammal comprising administering to said mammal an effective amount of a compound of structure (I):

or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein
(a) X is CH2;
Y is CH2CONH, (CH2)2CONH, CH(CH3)CONH, CH2, CH2CO, CH2NHCONH, CH2NHCO, (CH2)2O, (CH2)2NH, (CH2)2NHCONH, (CH2)2NHCO, CH2CSNH, or C(R6R7)CONH;
wherein R6 is H;
R7 is CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, or C6H5;
or
R6 is CH3;
R7 is C2H5 or CH3;
and
R1 is CH3;
or
(b) X is CH2;
Y is CH2CONH;
and
R1 is CH3, H, CH2CH3, CH(CH3)2, C6H11, C6H5, 2-Thienyl, C6H4—OCH3, C6H4—Cl, C6H4—CH3, C6H4—F, or CH2—C6H5;
or
(c) X is NHCO or NHCONH;
Y is CH2;
and
R1 is CH3;
or
(d) X is NH;
Y is CH2CONH;
and
R1 is CH3;
or
(e) X is NHCO or CO;
Y is CH2CONH;
and
R1 is CH3;
or
(f) X is CH2;
Y is CH2CO;
wherein the phenyl group substituted with R2 and R3 and bonded to Y of structure (I) is replaced with N-methyl piperazine, N(CH3)—C6H4—Br, NHCH2—C6H4—Br, or O—C6H4—Br;
and
R1 is CH3;
or
(g) X is NHCONH, NHCO, or NH;
Y of structure (I) is not present and instead the phenyl group
substituted with R2 and R3 is directly bonded to the N2 of the pyridazinone ring;
and
R1 is CH3;
or
(h) X is CH2;
Y is CH2CONH;
the phenyl group substituted with R4 and R5 and bonded to X of structure (I) is replaced with 3-Furyl, 3-Thienyl, 2-Thienyl, 1-Naphthyl, or 3-Pyridyl;
and
R1 is CH3;
or
(i) X and the phenyl group substituted with R4 and R5 are not present;
Y is CH2CONH;
and
R1 is CH3;
or
(j) X and the phenyl group substituted with R4 and R5 are not present;
Y is CH2CONH;
R1 is CH3;
and
the bond between C4 and C5 of the pyridazinone ring is a single bond;
or
(k) X is NH2 and the phenyl group substituted with R4 and R5 is not present;
Y is CH2CONH;
and
R1 is CH3;
or
(I) X of structure (I) is not present and instead the phenyl group substituted with R4 and R5 is directly bonded to C4 of the pyridazinone ring;
Y is CH2CONH;
and
R1 is CH3;
or
(m) X is NH;
Y is CH2CONH;
R1 is CH3;
and
C5 is additionally substituted with COCH3;
wherein R2, R3, R4 and R5 are independently hydrogen, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfide, cyano, nitro, or R2 and R3 and/or R4 and R5 is a bridged di-alkoxy group;
and
wherein said compound is administered for a time and under conditions sufficient for said compound to induce cardiomyocyte FPR1 activation.

75 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/548,555Filed 4 Feb 2016
Priority: AU 20159003364 Feb 2015
Published: US 2018/0092917 A15 Apr 2018
Granted: 25 Jun 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

A61K 31/501
Pyridazines; Hydrogenated pyridazines: not condensed and containing further heterocyclic rings
A61K 31/50
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyridazines; Hydrogenated…
A61P 9/10
Drugs for disorders of the cardiovascular system: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary…
A61K
Medicines and medical preparations