Oxidant scavengers
AssigneesDuke University, University of Alabama at Birmingham Research Foundation, Aeolus Pharmaceuticals, Inc.
InventorsJames D. Crapo, Irwin Fridovich, Tim Oury, Brian J. Day, Rodney J. Folz, Bruce A. Freeman, Michael P. Trova, Ines Batinic-Haberle
Life of this patent
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Abstract
The present invention relates, in general, to a method of modulating physiological and pathological processes and, in particular, to a method of modulating intra- and extracellular levels of oxidants and thereby processes in which such oxidants are a participant. The invention also relates to compounds and compositions suitable for use in such methods.
Claims43
An oxidant scavenger comprising a nitrogen-containing macrocyclic moiety and a cell surface or extracellular matrix targeting moiety, or a pharmaceutically acceptable salt thereof.
An oxidant scavenger of the formula:
- 97
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is a bond
- 98
- 99
- wherein X is a halogen and Y is an alkyl group and wherein
- 100
- indicates bonding to R2 at any position and
- 101
- indicates bonding to R2 and the substituent at any position;
- and
- R2 is a bond, —(CY′2)n−, —(CY′2—CY═CY′)n−, —(CY′2—CY′2—CH═CH)n−, —(CY′═CY′)n−,
- 102
- wherein Y′ is hydrogen or an alkyl group and wherein n is 1 to 8;
- and
- R3 is —Y″, —OH, —NH2, —N+(Y″)3, —COOH, —COO−, —SO3H, —SO3, —C—PO3H2 or —C—PO3H−, wherein Y″ is an alkyl group,
- wherein, when R1 is
- 103
- and R2 is a bond, R3 is not Y″, and
- wherein, when R1 is
- 104
- and R2 is a bond, R3 is not —Y″, —N+(Y″)3, or COOH.
A method of treating a pathological condition of a patient resulting from degradation of NO. or a biologically active form thereof comprising administering to said patient an effective amount of a compound having the activity of a catalytic antioxidant under conditions such that said treatment is effected.
A method of treating a pathological condition of a patient resulting from peroxynitrite accumulation comprising administering to said patient an effective amount of a compound having the activity of a catalytic antioxidant under conditions such that said treatment is effected.
A method of treating an inflammatory condition in a patient in need of such treatment comprising administering to said patient an effective amount of a mimetic of SOD, EC-SOD, catalase or peroxidase under conditions such that said treatment is effected.
A method of treating a disorder resulting from aberrant smooth muscle function in a patient in need of such treatment comprising administering to said patient an effective amount of a mimetic of SOD, EC-SOD, catalase or peroxidase under conditions such that said treatment is effected.
A pharmaceutical composition comprising the scavenger according to claim 1, 4, 28 or 41 and a pharmaceutically acceptable carrier.
A kit comprising the scavenger according to claim 1, 4, 28 or 41 disposed within a container means.
An isolated EC-SOD gene having the sequence shown in FIG. 24, or portion thereof at least 18 nucleotides in length.
An oxidant scavenger of the formula:
- 123
- or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron, wherein:
- each R1′ is independently a bond,
- 124
- 125
- wherein Y″ is an alkyl group, and wherein
- 126
- indicates bonding to R2′ at any position and
- 127
- indicates bonding to R2′ and the R1′ phenyl substituent at any position;
- each R2′ is independently a bond, or —(CH2)n— wherein n is 1-4,
- each R3′ is independently —Y″, —Y′″, —H, —OH, —OY″, —NO2, —CN, —NH2, —COOH, —COY″, —COO−, or a heterocyclic group, wherein Y″ is as defined above and Y′″ is a primary, secondary, tertiary or quaternary amine,
- wherein when R1′ is
- 128
- R3′ is not COOH, COY″ or COO−,
- wherein when R1′ is
- 129
- or
- 130
- R3′ is not —NO2, and
- wherein —R1′—R2′—R3′, collectively, are not —H,
- 131
A method of protecting cells from oxidant-induced toxicity comprising contacting said cells with a non-toxic amount of a scavenger of the formula,
- 136
- or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron, wherein:
- each R1′ is independently a bond,
- 137
- 138
- wherein Y″ is an alkyl group, and wherein
- 139
- indicates bonding to R2′ at any position and
- 140
- indicates bonding to R2′ and the R1′ phenyl substituent at any position;
- each R2′ is independently a bond, or —(CH2)n— wherein n is 1-4,
- each R3′ is independently —Y″, —Y′″, —H, —OH, —OY″, —NO2, —CN, —NH2, —COOH, —COY″, —COO−, or a heterocyclic group, wherein Y″ is as defined above and Y′″ is a primary, secondary, tertiary or quaternary amine,
- wherein Y″ is as defined above,
- wherein when R1′ is
- 141
- R3′ is not COOH, COY″ or COO−,
- wherein when R1′ is
- 142
- or
- 143
- R3′ is not —NO2, and
- wherein —R1′—R2′—R3′, collectively are not —H,
- sufficient to effect said protection.
A method of inhibiting damage due to oxidation of a substance comprising contacting to said substance with a non-toxic amount of a scavenger of the formula,
- 144
- or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron, wherein:
- each R1′ is independently a bond,
- 145
- 146
- wherein Y″ is an alkyl group, and wherein
- 147
- indicates bonding to R2′ at any position and
- 148
- indicates bonding to R1′ and the R1′ phenyl substituent at any position;
- each R2′ is independently a bond, or —(CH2)n— wherein n is 1-4,
- each R3′ is independently —Y″, —Y′″, —H, —OH, —OY″, —NO2, —CN, —NH2, —COOH, —COY″, —COO−, or a heterocyclic group, wherein Y″ is as defined above and Y′″ is a primary, secondary, tertiary or quaternary amine,
- wherein when R1′ is
- 149
- R3′ is not COOH, COY″ or COO−,
- wherein when R1′ is
- 150
- or
- 151
- R3′ is not —NO2, and
- wherein R1′—R2′—R3′, collectively, are not —H, sufficient to effect said inhibition.
A method of inhibiting xanthine oxidase activity of a cell or tissue comprising contacting said cell or tissue with an amount of scavenger of the formula,
- 152
- or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron, wherein:
- each R1′ is independently a bond,
- 153
- 154
- wherein Y″ is a alkyl group, and wherein
- 155
- indicates bonding to R2′ at any position and
- 156
- indicates bonding to R2′ and the R1′ phenyl substituent at any position;
- each R2′ is independently a bond, or —(CH2)n— wherein n is 1-4,
- each R3′ is independently —Y″, —Y′″, —H, —OH, —OY″, —NO2, —CN, —NH2, —COOH, —COY″, —COO−, or a heterocyclic group, wherein Y″ is as defined above and Y′″is a primary, secondary, tertiary or quaternary amine,
- wherein when R1′ is
- 157
- R3′is not COOH, COY″ or COO−,
- wherein when R1′ is
- 158
- or
- 159
- R3′ is not —NO2, and
- wherein R1′—R2′—R3′, collectively, are not —H, sufficient to effect said inhibition.
A method of modulating NO. function as a neurotransmitter in a mammal comprising contacting said mammal with an amount of an oxidant scavenger of the formula,
- 160
- or a pharmaceutically acceptable salt thereof, wherein:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is a bond,
- 161
- 162
- wherein X is a halogen, and Y is an alkyl group and wherein
- 163
- indicates bonding to R2 at any position and
- 164
- indicates bonding to R2 and the substituent at any position;
- and
- R2 is a bond, —(CY′2)n−, —(CY′2—CY′═CY′)n−, —(CY′2—CY′2—CH═CH)n−, —(CY′═CY′)n−, or
- 165
- wherein Y′ is hydrogen or an alkyl group and wherein n is 1 to 8;
- and
- R3 is Y″, —OH, —NH2, —N+(Y″)3, —COOH, —COO−, —SO3H, —SO3−, —C—PO3H2 or —C—PO3H−, wherein Y″ is an alkyl group,
- optionally complexed with a metal selected from the group consisting of manganese, copper and iron, sufficient to effect said modulation.
A method of modulating NO. function as a neurotransmitter in a mammal comprising contacting said mammal with an amount of an oxidant scavenger of the formula,
- 166
- or a pharmaceutically acceptable salt thereof, or metal complex thereof wherein said metal is selected from the group consisting of manganese, copper and iron, wherein:
- each R1′ is independently a bond,
- 167
- 168
- wherein Y″ is an alkyl group, and wherein
- 169
- indicates bonding to R2′ at any position and
- 170
- indicates bonding to R2′ and the R1′ phenyl substituent at any position;
- each R2′ is independently a bond, or —(CH2)n— wherein n is 1-4,
- each R3′ is independently —Y″, —Y′″, —H, —OH, —OY″, —NO2, —CN, —NH2, —COOH, —COY″, —COO−, or a heterocyclic group, wherein Y″ is as defined above and Y′″ is a primary, secondary, tertiary or quaternary amine,
- wherein when R140 is
- 171
- R3′ is not COOH, COY″ or COO−,
- wherein when R1′ is
- 172
- or
- 173
- R3′ is not —NO2, and
- wherein —R1′—R2′—R3′, collectively, are not —H, sufficient to effect said modulation.
An oxidant scavenger of the formula:
- 174
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is a bond,
- 175
- 176
- wherein X is a halogen and Y is an alkyl group and wherein
- 177
- indicates bonding to R2 at any position and
- 178
- indicates bonding to R2 and the substituent at any position;
- and
- R2 is a bond, —(CY′2)n−, —(CY′2—CY′═CY′)n−, —(CY′3—CY′2—CH═CH)n−, —(CY′═CY′)n−, or
- 179
- wherein Y′ is hydrogen or an alkyl group and wherein n is 1 to 8;
- and
- R3 is —Y″, —CH, —NH2, —N+(Y″)3, —COOH, —COO−, —SO3H, —SO3−, —C—PO3H2 or —C—PO3H31, wherein Y″ is an alkyl group,
- wherein, when R1 is
- 180
- and R2 is a bond, R3 is not —CH3, and
- wherein, when R1 is
- 181
- and R2 is a bond, R3 is not —CH3, —N−(CH3)3, or COOH.
An oxidant scavenger of the formula:
- 182
- or a pharmaceutically acceptable salt thereof, wherein:
- each R1 is independently, a bond,
- 183
- 184
- wherein X is a halogen and Y is an alkyl group and wherein
- 185
- indicates bonding to R2 at any position and
- 186
- indicates bonding to R2 and the substituent at any position;
- and
- each R2 is independently, a bond, —(CY′2)n−, —(CY′2—CY′═CY′)n−,
- —(CY′2—CY′2—CH═CH)n−, —(CY′═CY′)n−, or
- 187
- wherein Y′ is hydrogen or an alkyl group and wherein n is 1 to 8;
- and
- each R3 is, independently —Y″, —OH, —NH2, —N+(Y″)3, —COOH, —COO−, —SO3H, —SO3−, —C—PO3H2 or —C—PO3H−, wherein Y″ is an alkyl group,
- each P is, independently, an electron withdrawing group or hydrogen wherein at least one P is not hydrogen, or
- 188
- or a pharmaceutically acceptable salt thereof, wherein
- each R1′ is independently a bond,
- 189
- 190
- wherein Y″ is an alkyl group, and wherein
- 191
- indicates bonding to R2′ at any position and
- 192
- indicates bonding to R2′ and the R1′ phenyl substituent at any position;
- each R2′ is independently a bond, or —(CH2)n— wherein n is 1-4,
- each R3′ is independently —Y″, —Y′″, —H, —OH, —OY″, —NO2, —CN, —NH2, —COOH, —COY″, —COO−, or a heterocyclic group, wherein Y″ is as defined above and Y′″ is a primary, secondary, tertiary or quaternary amine,
- each P is, independently, an electron withdrawing group or hydrogen wherein at least one P is not hydrogen;
- wherein said oxidant scavenger is a metal complex wherein said metal is selected from the group consisting of manganese, copper or iron,
- wherein when said metal is copper and all P's are Br, and when R1 is
- 193
- and R2 is a bond, R3 is not —CH3.
Dependencies are inferred from the claim text.