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US 9,732,029 B2Granted
Nitroso compounds as nitroxyl donors and methods of use thereof
AssigneeCardioxyl Pharmaceuticals, Inc.
InventorsLisa Marie Frost, Stephen Martin Courtney, Frederick Arthur Brookfield, Vincent Jacob Kalish
Life of this patent
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Abstract
The invention relates to nitroso derivatives including carboxylic acid and phosphoric acid esters of hydroxy nitroso compounds that donate nitroxyl (HNO) under physiological conditions. The compounds and compositions of the invention are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure, ischemia/reperfusion injury and cancer.
Claims26
A compound having the formula II:
- or a pharmaceutically acceptable salt thereof
- wherein:
- X is O, NR4, CR5R6, S, S(O) or S(O)2;
- Y is CR5R6 or CR5R6—CR7R8;
- Z is CR5R6 or a bond, provided that when X is CR5R6, Z is CR5R6;
- R4 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted acyl, alkoxycarbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or sulfonyl;
- each R5, R6, R7, R8, R11a, R11b, R12a, and R12b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro, or is taken together with a geminal R group to form a carbonyl moiety, or is taken together with a vicinal R group to form a bond, or is taken together with another R group to form a ring;
- D is selected from:
- (i) the group consisting of C1-C8 alkyl-C(O)—, C1-C8 perhaloalkyl-C(O)—, C2-C10 alkenyl-C(O)—, C2-C10 alkynyl-C(O)—, C6-C14 aryl-C(O)—, C5-C6 heteroaryl-C(O)—, C5-C6 heterocyclyl-C(O)— and —P(O)(OC1-C8alkyl)2;
- and
- each alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halo, nitro, cyano, oxo, C6-C14 aryl, C1-C8 alkoxy, C1-C8 alkoxycarbonyl, acyl, acyloxy, acylamino, amino, hydroxyl, carboxyl, carboxyl-C1-C8 alkyl, thiol, thio-C1-C8 alkyl, C5-C6 heterocyclyl, and —OS(O)2—C1-C8 alkyl;
- and
- each aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halo, nitro, cyano, oxo, C6-C14 aryl, C1-C8 alkoxy, C1-C8 alkoxyl, acyl, acylamino, amino, hydroxyl, carboxyl, carboxyl-C1-C8 alkyl, thiol, thio-C1-C8 alkyl, C5-C6 heterocyclyl, and —OS(O)2—C1-C8 alkyl;
- and
- (ii) a moiety of the formula:
- provided that the compound is other than 1-nitrosocycloheptyl acetate, 1-nitrosocycloheptyl benzoate, 9-nitrosobicyclo[3.3.1]nonan-9-yl acetate or 8-methyl-3-nitroso-8-azabicyclo[3.2.1]octan-3-yl acetate;
- and
- (i) when the X—Y—Z ring is an unsubstituted 6-membered carbocyclic moiety, D is other than n-alkyl-C(O)—, ClCH2—C(O)—, CCl3—C(O)—, CF3—C(O)—, (CH3)3C—C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, unsubstituted aryl-C(O)—, mono-substituted aryl-C(O)— or an NSAID moiety;
- (ii) when the X—Y—Z ring is a substituted 6-membered carbocyclic moiety, the substituted 6-membered carbocyclic moiety is a monocyclic or bicyclic ring that is substituted with a moiety other than alkyl, nitroso, acyl, oxime, and substituted alkenyl;
- and
- (iii) when the X—Y—Z ring is an unsubstituted or substituted 6-membered heterocyclic moiety, the 6-membered heterocyclic moiety is a monocyclic or bicyclic ring other than acyloxy-substituted tetrahydropyan.
18 more elements
A compound having the formula III:
- or a pharmaceutically acceptable salt thereof, wherein:
- X is O, NR4, CR5R6, S, S(O) or S(O)2;
- R4 is H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C2-C8 alkynyl, substituted or unsubstituted acyl, alkoxycarbonyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, or sulfonyl;
- each R5, R6, R11a, R11b, R12a, R12b, R13a, R13b, R14a and R14b is independently H, substituted or unsubstituted C1-C8 alkyl, halo, hydroxyl, alkoxy, cyano or nitro, or is taken together with a geminal R group to form a carbonyl moiety, or is taken together with a vicinal R group to form a bond when X is CR5R6, or is taken together with another R group to form a ring;
- D is selected from the group consisting of C1-C8 alkyl-C(O)—, C1-C8perhaloalkyl-C(O)—, C2-C10 alkenyl-C(O)—, C2-C10 alkynyl-C(O)—, C6-C14 aryl-C(O)—, C5-C6 heteroaryl-C(O)—, C5-C6 heterocyclyl-C(O)— and —P(O)(OC1-C8alkyl)2;
- and
- each alkyl, alkenyl and alkynyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halo, nitro, cyano, oxo, C6-C14 aryl, C1-C8 alkoxy, C1-C8 alkoxycarbonyl, acyl, acyloxy, acylamino, amino, hydroxyl, carboxyl, carboxyl-C1-C8 alkyl, thiol, thio-C1-C8 alkyl, C5-C6 heterocyclyl, and —OS(O)2—C1-C8 alkyl;
- and
- each aryl, heteroaryl and heterocyclyl is unsubstituted or substituted with 1 to 5 substituents independently selected from halo, nitro, cyano, oxo, C6-C14 aryl, C1-C8 alkoxy, C1-C8 alkoxyl, acyl, acylamino, amino, hydroxyl, carboxyl, carboxyl-C1-C8 alkyl, thiol, thio-C1-C8 alkyl, C5-C6 heterocyclyl, and —OS(O)2—C1-C8 alkyl;
- provided that the compound is other than 9-nitrosobicyclo[3.3.1]nonan-9-yl acetate or 8-methyl-3-nitroso-8-azabicyclo[3.2.1]octan-3-yl acetate;
- and
- (i) when the X-ring is an unsubstituted 6-membered carbocyclic moiety, D is other than n-alkyl-C(O)—, ClCH2—C(O)—, CCl3—C(O)—, CF3—C(O)—, (CH3)3C—C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, unsubstituted aryl-C(O)—, mono-substituted aryl-C(O)— or an NSAID moiety;
- (ii) when the X-ring is a substituted 6-membered carbocyclic moiety, the substituted 6-membered carbocyclic moiety is a monocyclic or bicyclic ring that is substituted with a moiety other than alkyl, nitroso, acyl, oxime, and substituted alkenyl;
- and
- (iii) when the X-ring is an unsubstituted or substituted 6-membered heterocyclic moiety, the 6-membered heterocyclic moiety is a monocyclic or bicyclic ring other than dioxane or acyloxy-substituted tetrahydropyan.
12 more elements
A compound selected from:
- (S)-4-Nitrosotetrahydro-2H-pyran-4-yl 2-acetamido-3-phenylpropanoate (Compound 23);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2-benzamidoacetate (Compound 31);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2-acetamidopropanoate (Compound 32);
- 1-Methyl 4-(4-nitrosotetrahydro-2H-pyran-4-yl)N-[(benzyloxy)-carbonyl]aspartate (Compound 37);
- 1-tert-Butyl 4-(4-nitrosotetrahydro-2H-pyran-4-yl)N-(tert-butoxycarbonyl)aspartate (Compound 38);
- 2-(Methyl(2-(4-nitrosotetrahydro-2H-pyran-4-yloxy)-2-oxoethyl)amino)-propane-1,3-diyl diacetate (Compound 40);
- 2-(N-(2-(4-Nitrosotetrahydro-2H-pyran-4-yloxy)-2-oxoethyl)acetamido)propane-1,3-diyl diacetate (Compound 41);
- 4-Nitrosooxan-4-yl (2R)-2-{[tert-butoxy)carbonyl]amino}-propanoate (Compound 47);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2-(acetyloxy)benzoate (Compound 51);
- 4-nitrosooxan-4-yl 2-[(2R,3S,4R,5S)-3,4,5,6-tetrakis(acetyloxy)oxan-2-yl]acetate (Compound 55);
- 4-nitrosooxan-4-yl 2-amino-3-hydroxypropanoate (Compound 56);
- 4-nitrosooxan-4-yl (2E)-2,3,4,5,6-pentakis-(acetyloxy)hex-2-enoate (Compound 57);
- and
- pharmaceutically acceptable salts thereof.
11 more elements
A compound selected from:
- 1-Methyl-4-nitrosopiperidin-4-yl acetate (Compound 1);
- 1-Acetyl-4-nitrosopiperidin-4-yl acetate (Compound 3);
- 3-Nitro s otetrahydrothiophen-3-yl acetate (Compound 5);
- 1,2,2,6,6-Pentamethyl-4-nitrosopiperidin-4-yl acetate (Compound 7);
- 1-Nitrosocyclohexyl 2,4-dichlorobenzoate (Compound 9);
- 1-Nitrosocyclohexyl isobutyrate (Compound 10);
- 1-Methyl-4-nitrosopiperidin-4-yl 2,4-difluorobenzoate (Compound 12);
- 1-Nitrosocyclohexyl 2-chloro-2,2-difluoroacetate (Compound 13);
- 1-Nitrosocyclohexyl 4,4,4-trifluoro-3-methyl butanoate (Compound 14);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trifluoroacetate (Compound 15);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 3,3,3-trifluoropropanoate (Compound 16);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 4,4,4-trifluorobutanoate (Compound 17);
- 1-Nitrosocyclohexyl 2,2,3,3,3-pentafluoropropanoate (Compound 18);
- 1-Nitrosocyclohexyl 2-cyanoacetate (Compound 19);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2,2,2-trichloroacetate (Compound 20);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2,2,3,3,3-pentafluoropropanoate (Compound 21);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 2-chloro-2,2-difluoroacetate (Compound 22);
- 1-Methyl-4-nitrosopiperidin-4-yl pivalate (Compound 28);
- 1,2,2,6,6-Pentamethyl-4-nitrosopiperidin-4-yl pivalate (Compound 29);
- 8-Methyl-3-nitroso-8-azabicyclo[3.2.1]oct-3-yl acetate (Compound 39);
- 4-Nitrosotetrahydro-2H-pyran-4-yl 4-(acetyloxy)-3-[(acetyloxy)methyl]but-2-enoate (Compound 48);
- 1-Methyl-4-nitrosopiperidin-4-yl 4-(acetyloxy)-3-[(acetyloxy)methyl]butanoate (Compound 49);
- 1-Methyl-4-nitrosopiperidin-4-yl 3,5-difluorobenzoate (Compound 53);
- and pharmaceutically acceptable salts thereof.
21 more elements
Dependencies are inferred from the claim text.