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US5650447A
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Nitric oxide-releasing polymers to treat restenosis and related disorders
Assignee: Comedicus Inc
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Filing: 1994-03-17
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Granted: 1997-07-22
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Expires: 2014-03-17
Abstract
Abstract Methods of amelioration, treatment and prevention for restenosis and related disorders are provided. Methods involve the administration of nitric oxide by a nitric oxide delivery means comprising a restenosis-ameliorating or therapeutically/prophylactically effective amount of either a polymer to which is bound a nitric oxide-releasing N 2 O 2 - functional group a compound comprising a nitric oxide-releasing N 2 O 2 - functional group. Also provided are nitric oxide delivery means comprising such nitric oxide-releasing polymers or compounds for use in such methods. Preferably, the delivery means is coated with a nitric oxide-releasing polymer, which may be biodegradable, and enables the controllable and predictable release of NO to a given site in such a manner that effective ameliorating, prophylactic or therapeutic dosing is realized.
Inventors
- 👤 Larry K. Keefer
- 👤 Thomas C. Hutsell
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-29 07:10
CPC Classifications
A; A61; A61K; A61K31/00; A61K31/655; A61K31/74; A61K31/785; A61K47/00; A61K47/50; A61K47/51; A61K47/56; A61K47/58; A61K47/59; A61K47/60; A61K47/62; A61K47/64; A61P; A61P9/00; A61P9/08; C; C08; C08F; C08F8/00; C08F8/30; C08F8/32
Claims Analysis
Total Claims: 46
Claim 1
Independent Claim
99 words
A method for the prophylaxis of restenosis and related disorders in a mammal, which method comprises the administration of nitric oxide by a nitric oxide delivery means, said delivery means comprising a prophylactically effective amount of a nitric oxide-releasing agent, said agent selected from the group consisting of a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and a polymer matrix into which has been incorporated a nitric oxide-releasing N 2 O 2 - functional group, said agent being capable of locally releasing nitric oxide to a site at risk for restenosis in said mammal.
Claim 2
Independent Claim
99 words
A method for the prophylaxis of restenosis and related disorders in a mammal, which method comprises the administration of nitric oxide by a nitric oxide delivery means, said delivery means comprising a prophylactically effective amount of a nitric oxide-releasing agent, said agent selected from the group consisting of a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and a polymer matrix into which has been incorporated a nitric oxide-releasing N 2 O 2 - functional group, said agent being capable of locally releasing nitric oxide to a site at risk for restenosis in said mammal.
Claim 3
Dependent Claim
40 words
The method of claim 1 wherein M +x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound.
Claim 4
Dependent Claim
30 words
The method of claim 2 wherein J is a moiety which is linked to the nitrogen of the remainder of the compound through an atom other than a carbon atom.
Claim 5
Dependent Claim
22 words
The method of claim 2 wherein the nitric oxide releasing compound is a compound other than a salt of alanosine or dopastin.
Claim 6
Dependent Claim
100 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR10## wherein b and d are the same or different and are zero or one, R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are hydrogen, a C 3-8 cycloalkyl, a C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.
Claim 7
Dependent Claim
91 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR11## wherein B is ##STR12## R 6 and R 7 are the same or different and are hydrogen, a C 3-8 cycloalkyl, a C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl,or 2,2,2-trichloro-t-butoxycarbonyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety ##STR13## then f is an integer from 2 to 12.
Claim 8
Dependent Claim
13 words
The method of claim 6 wherein B is the substituted piperazine moiety. ##STR14##
Claim 9
Dependent Claim
75 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR15## wherein R 8 is hydrogen, a C 3-8 cycloalkyl, a C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R 9 is hydrogen or a C 1 -C 12 straight or branched chain alkyl, and g is an integer from 2 to 6.
Claim 10
Dependent Claim
64 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR16## wherein R 1 and R 2 are independently selected from the group consisting of a C 1-12 straight or branched chain alkyl and benzyl, M +x is a pharmaceutically acceptable cation, and x is the valence of the cation.
Claim 11
Dependent Claim
48 words
The method of claim 9 wherein R 1 and R 2 are selected so that R 1 and R 2 are unbranched on the alpha carbon atom or R 1 and R 2 , together with the nitrogen atom to which they are bonded, form a heterocyclic group.
Claim 12
Dependent Claim
21 words
The method of claim 10 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.
Claim 13
Dependent Claim
167 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: K[(M).sub.x.sup.x' (L).sub.y (R.sup.1 R.sup.2 N--N.sub.2 O.sub.2).sub.z ](VI) wherein M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R 1 R 2 N--N 2 O 2 ) and is bound to at least one metal, R 1 and R 2 are each organic moieties and are the same or different, x is an integer from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer from 1 to 6, y is an integer from 1 to 18, with the proviso that when y is at least 2, the ligands L are the same or different, z is an integer from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary.
Claim 14
Dependent Claim
36 words
The method of claim 12 wherein when M is copper, x is one L is methanol, and y is one, then at least one of R 1 or R 2 is a moiety other than ethyl.
Claim 15
Dependent Claim
138 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: [R--N(H)N(NO)O-].sub.y X (VII) wherein R is a C 2-8 lower alkyl, phenyl, benzyl, or a C 3-8 cycloalkyl, any of which R groups can be substituted by one to three substituents, which are the same or different and are selected from the group consisting of halo, hydroxy, a C 1-8 alkoxy, --NH 2 , --C(O)NH 2 , --CH(O), --C(O)OH, and --NO 2 , X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of a C 1-8 lower alkyl, --C(O) CH 3 , and --C(O)NH 2 , and y is an integer from 1 to 3, consistent with the valence of X.
Claim 16
Dependent Claim
216 words
The method of claim 1 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR17## wherein R 1 and R 2 are independently chosen from a C 1-12 straight chain alkyl, a C 1-12 alkoxy or acyloxy substituted straight chain alkyl, a C 2-12 hydroxy or halo substituted straight chain alkyl, a C 3-12 branched chain alkyl, a C 3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, a C 3-12 straight or branched chain olefinic unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R 3 is a group selected from a C 1-12 straight chain and a C 3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, a C 2-12 straight chain or a C 3-12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, a C 1-12 unsubstituted or substituted acyl, sulfonyl, and carboxamido; or R 3 is a group of the formula --(CH 2 ) n --ON═N(O)NR 1 R 2 , wherein n is an integer of 2-8, and R 1 and R 2 are as defined above.
Claim 17
Dependent Claim
29 words
The method of claim 15 wherein R 1 , R 2 and R 3 contain a moiety other than a halo or a hydroxy substituent α to a heteroatom.
Claim 18
Dependent Claim
21 words
The method of claim 15 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino, and morpholino.
Claim 19
Dependent Claim
28 words
The method of claim 1 wherein said polymer is selected from the group consisting of polyolefins, polyethylenimine and derivatives thereof, polyethers, polyesters, polyamides, polyurethanes, colestipol and derivatives thereof.
Claim 20
Dependent Claim
10 words
The method of claim 1 wherein said polymer is biodegradable.
Claim 21
Independent Claim
329 words
A method for the treatment of restenosis in a mammal, which method comprises the administration of nitric oxide by a nitric oxide delivery means, said delivery means comprising an effective treatment amount of a nitric oxide-releasing agent, said agent selected from the group consisting of (i) a compound comprising a nitric oxide-releasing N 2 O 2 - functional group wherein said compounds is of the formula I, II, III, IV, V, VI, VII or VIII, or (ii) a polymer in admixture with a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and having the formula I, II, III, IV, V, VI, VII or VIII, or (iii) a polymer comprising a polymeric backbone, wherein said polymeric backbone is selected from the group consisting of a polyolefin, a polyether, a polyester, a polyamide, polyethyleneimine, a polyurethane, colestipol, a peptide, a starburst dendrimer, a protein, and at least one nitric oxide-releasing functional group selected from the group consisting of X.brket open-st.B(O)NO] or [N(O)NO.brket close-st.X wherein X is an organic moiety covalently bonded to said group, and wherein said group is covalently bonded is said polymer through said organic moiety X, wherein in the compound of said formula I, J is an inorganic moiety or an organic moiety selected from the group consisting of C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenylcarbonyl, substituted benzylcarbonyl, substituted phenylcarbonyl, C 1 -C 12 acyl, and ##STR18## wherein R is C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl or substituted phenyl, and said substituted benzyl and substituted phenyl is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono C 1 -C 4 alkylamino, di C 1 -C 4 alkyl-amino, phenyl and phenoxy, said agent being capable of locally releasing nitric oxide to a site affected by restenosis in said mammal.
Claim 22
Independent Claim
329 words
A method for the treatment of restenosis in a mammal, which method comprises the administration of nitric oxide by a nitric oxide delivery means, said delivery means comprising an effective treatment amount of a nitric oxide-releasing agent, said agent selected from the group consisting of (i) a compound comprising a nitric oxide-releasing N 2 O 2 - functional group wherein said compounds is of the formula I, II, III, IV, V, VI, VII or VIII, or (ii) a polymer in admixture with a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and having the formula I, II, III, IV, V, VI, VII or VIII, or (iii) a polymer comprising a polymeric backbone, wherein said polymeric backbone is selected from the group consisting of a polyolefin, a polyether, a polyester, a polyamide, polyethyleneimine, a polyurethane, colestipol, a peptide, a starburst dendrimer, a protein, and at least one nitric oxide-releasing functional group selected from the group consisting of X.brket open-st.B(O)NO] or [N(O)NO.brket close-st.X wherein X is an organic moiety covalently bonded to said group, and wherein said group is covalently bonded is said polymer through said organic moiety X, wherein in the compound of said formula I, J is an inorganic moiety or an organic moiety selected from the group consisting of C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenylcarbonyl, substituted benzylcarbonyl, substituted phenylcarbonyl, C 1 -C 12 acyl, and ##STR18## wherein R is C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl or substituted phenyl, and said substituted benzyl and substituted phenyl is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono C 1 -C 4 alkylamino, di C 1 -C 4 alkyl-amino, phenyl and phenoxy, said agent being capable of locally releasing nitric oxide to a site affected by restenosis in said mammal.
Claim 23
Dependent Claim
67 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR19## wherein J is an organic or inorganic moiety, M +x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound.
Claim 24
Dependent Claim
30 words
The method of claim 21 wherein J is a moiety which is linked to the nitrogen of the remainder of the compound through an atom other than a carbon atom.
Claim 25
Dependent Claim
19 words
The method of claim 21 wherein the compound is a compound other than a salt of alanosine or dopastin.
Claim 26
Dependent Claim
100 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR20## wherein b and d are the same or different and are zero or one, R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are hydrogen, a C 3-8 cycloalkyl, a C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.
Claim 27
Dependent Claim
72 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR21## wherein B is ##STR22## R 6 and R 7 are the same or different and are hydrogen, a C 3-8 cycloalkyl, a C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, and f is an integer from 0 to 12.
Claim 28
Dependent Claim
13 words
The method of claim 25 wherein B is the substituted piperazine moiety. ##STR23##
Claim 29
Dependent Claim
76 words
The method of claim 20 wherein said nitric oxide- releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR24## wherein R 8 is hydrogen, a C 3-8 cycloalkyl, a C 1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, R 9 is hydrogen or a C 1 -C 12 straight or branched chain alkyl, and g is an integer from 2 to 6.
Claim 30
Dependent Claim
63 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR25## wherein R 1 and R 2 are independently selected from the group consisting of a C 1-12 straight or branched chain alkyl and benzyl, M +x is pharmaceutically acceptable cation, and x is the valence of the cation.
Claim 31
Dependent Claim
48 words
The method of claim 28 wherein R 1 and R 2 are selected so that R 1 and R 2 are unbranched on the alpha carbon atom or R 1 and R 2 , together with the nitrogen atom to which they are bonded, form a heterocyclic group.
Claim 32
Dependent Claim
21 words
The method of claim 29 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.
Claim 33
Dependent Claim
167 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: K[(M).sub.x.sup.x' (L).sub.y (R.sup.1 R.sup.2 N--N.sub.2 O.sub.2).sub.z ](VI) wherein M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R 1 R 2 N--N 2 O 2 ) and is bound to at least one metal, R 1 and R 2 are each organic moieties and are the same or different, x is an integer from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer from 1 to 6, y is an integer from 1 to 18, with the proviso that when y is at least 2, the ligands L are the same or different, z is an integer from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary.
Claim 34
Dependent Claim
34 words
The method of claim 31 wherein when M is copper, x is one, L is methanol, and y is one, then at least one R 1 or R 2 is moiety other than ethyl.
Claim 35
Dependent Claim
136 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: [R--N(H)N(NO)O--].sub.y X (VII) wherein R is a C 2-8 lower alkyl, phenyl, benzyl, or a C 3-8 cycloalkyl, any of which R groups can be substituted by one to three substituents, which are the same or different and are selected from the group consisting of halo, hydroxy, C 1-8 alkoxy, --NH 2 , --C(O)NH 2 , --CH(O), --C(O)OH, and --NO 2 , X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of a C 1-8 lower alkyl, --C(O)CH 3 , and --C(O)NH 2 , and y is an integer from 1 to 3, consistent with the valence of X.
Claim 36
Dependent Claim
216 words
The method of claim 20 wherein said nitric oxide-releasing N 2 O 2 - functional group is contained in a compound of the formula: ##STR26## wherein R 1 and R 2 are independently chosen from a C 1-12 straight chain alkyl, a C 1-12 alkoxy or acyloxy substituted straight chain alkyl, a C 2-12 hydroxy or halo substituted straight chain alkyl, a C 3-12 branched chain alkyl, a C 3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, a C 3-12 straight or branched chain olefinic unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R 1 and R 2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R 3 is a group selected from a C 1-12 straight chain and a C 3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, a C 2-12 straight chain or a C 3-12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, a C 1-12 unsubstituted or substituted acyl, sulfonyl, and carboxamido; or R 3 is a group of the formula --(CH 2 ) n --ON═N(O)NR 1 R 2 , wherein n is an integer of 2-8, and R 1 and R 2 are as defined above.
Claim 37
Dependent Claim
29 words
The method of claim 34 wherein R 1 , R 2 and R 3 contain a moiety other than a halo or a hydroxy substituent α to a heteroatom.
Claim 38
Dependent Claim
21 words
The method of claim 34 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.
Claim 39
Dependent Claim
28 words
The method of claim 20 wherein said polymer is selected from the group consisting of polyolefins, polyethylenimine and derivatives thereof, polyethers, polyesters, polyamides, polyurethanes, colestipol and derivatives thereof.
Claim 40
Dependent Claim
10 words
The method of claim 20 wherein said polymer is biodegradable.
Claim 41
Independent Claim
318 words
A method for the prophylaxis of restenosis in a mammal, which method comprises the administration of a prophylactically effective amount of a nitric oxide-releasing agent, said agent selected from the group consisting of (i) a compound comprising a nitric oxide-releasing N 2 O 2 - functional group wherein said compound is of the formula I, II, III, IV, V, VI, VII or VIII, or (ii) a polymer in admixture with a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and having the formula I, II, III, IV, V, VI, VII or VIII, or (iii) a polymer comprising a polymeric backbone, wherein said polymeric backbone is selected from the group consisting of a polyolefin, a polyether, a polyester, a polyamide, polyethyleneimine, a polyurethane, colestipol, a peptide, a starburst dendrimer, a protein, and at least one nitric oxide-releasing functional group selected from the group consisting of X.brket open-st.N(O)NO] or [N(O)NO.brket close-st.X wherein X is an organic moiety covalently bonded to said group, and wherein said group is covalently bonded in said polymer through said organic moiety X, wherein in the compound of said formula I, J is an inorganic moiety or an organic moiety selected from the group consisting of C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenycarbonyl, substituted benzylcarbonyl, substituted phenylcarbonyl, C 1 -C 12 acyl, and ##STR27## wherein R is C 1 --C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl or substituted phenyl, and said substituted benzyl and substituted phenyl is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono C 1 -C 4 alkylamino, di C 1 -C 4 alkyl-amino, phenyl and phenoxy, said agent being capable of locally releasing nitric oxide to a site at risk for restenosis in said mammal.
Claim 42
Independent Claim
318 words
A method for the prophylaxis of restenosis in a mammal, which method comprises the administration of a prophylactically effective amount of a nitric oxide-releasing agent, said agent selected from the group consisting of (i) a compound comprising a nitric oxide-releasing N 2 O 2 - functional group wherein said compound is of the formula I, II, III, IV, V, VI, VII or VIII, or (ii) a polymer in admixture with a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and having the formula I, II, III, IV, V, VI, VII or VIII, or (iii) a polymer comprising a polymeric backbone, wherein said polymeric backbone is selected from the group consisting of a polyolefin, a polyether, a polyester, a polyamide, polyethyleneimine, a polyurethane, colestipol, a peptide, a starburst dendrimer, a protein, and at least one nitric oxide-releasing functional group selected from the group consisting of X.brket open-st.N(O)NO] or [N(O)NO.brket close-st.X wherein X is an organic moiety covalently bonded to said group, and wherein said group is covalently bonded in said polymer through said organic moiety X, wherein in the compound of said formula I, J is an inorganic moiety or an organic moiety selected from the group consisting of C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenycarbonyl, substituted benzylcarbonyl, substituted phenylcarbonyl, C 1 -C 12 acyl, and ##STR27## wherein R is C 1 --C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl or substituted phenyl, and said substituted benzyl and substituted phenyl is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono C 1 -C 4 alkylamino, di C 1 -C 4 alkyl-amino, phenyl and phenoxy, said agent being capable of locally releasing nitric oxide to a site at risk for restenosis in said mammal.
Claim 43
Independent Claim
317 words
A method for the therapeutic treatment of restenosis in a mammal, which method comprises the administration of a therapeutically effective amount of a nitric oxide-releasing agent, said agent selected from the group consisting of (i) a compound comprising a nitric oxide-releasing N 2 O 2 - functional group wherein said compound is of the formula I II, III, IV, V, VI, VII or VIII, or (ii) a polymer in admixture with a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and having the formula I, II, III, IV, V, VI, VII or VIII, or (iii) a polymer comprising a polymeric backbone, wherein said polymeric backbone is selected from the group consisting of a polyolefin, a polyether, a polyester, polyamide, polyethyleneimine, a polyurethane, colestipol, a peptide, a starburst dendrimer, a protein, and at least one nitric oxide-releasing functional group selected from the group consisting of X.brket open-st.N(O)NO] or [N(O)NO.brket close-st.X wherein X is an organic moiety covalently bonded to said group, and wherein said group is covalently bonded in said polymer through said organic moiety X, wherein in the compound of said formula I, J is an inorganic moiety or an organic moiety selected from the group consisting of C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenylcarbonyl, substituted benzylcarbonyl, substituted phenylcarbonyl, C 1 -C 12 acyl, and ##STR28## wherein R is C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl or substituted phenyl, and said substituted benzyl and substituted phenyl is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono C 1 -C 4 alkylamino, di C 1 -C 4 alkyl-amino, phenyl and phenoxy, said agent being capable of locally releasing nitric oxide to a site affected by restenosis in said mammal.
Claim 44
Independent Claim
317 words
A method for the therapeutic treatment of restenosis in a mammal, which method comprises the administration of a therapeutically effective amount of a nitric oxide-releasing agent, said agent selected from the group consisting of (i) a compound comprising a nitric oxide-releasing N 2 O 2 - functional group wherein said compound is of the formula I II, III, IV, V, VI, VII or VIII, or (ii) a polymer in admixture with a compound comprising a nitric oxide-releasing N 2 O 2 - functional group and having the formula I, II, III, IV, V, VI, VII or VIII, or (iii) a polymer comprising a polymeric backbone, wherein said polymeric backbone is selected from the group consisting of a polyolefin, a polyether, a polyester, polyamide, polyethyleneimine, a polyurethane, colestipol, a peptide, a starburst dendrimer, a protein, and at least one nitric oxide-releasing functional group selected from the group consisting of X.brket open-st.N(O)NO] or [N(O)NO.brket close-st.X wherein X is an organic moiety covalently bonded to said group, and wherein said group is covalently bonded in said polymer through said organic moiety X, wherein in the compound of said formula I, J is an inorganic moiety or an organic moiety selected from the group consisting of C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenylcarbonyl, substituted benzylcarbonyl, substituted phenylcarbonyl, C 1 -C 12 acyl, and ##STR28## wherein R is C 1 -C 12 aliphatic, C 3 -C 8 cycloalkyl, benzyl, phenyl, substituted benzyl or substituted phenyl, and said substituted benzyl and substituted phenyl is substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, amino, mono C 1 -C 4 alkylamino, di C 1 -C 4 alkyl-amino, phenyl and phenoxy, said agent being capable of locally releasing nitric oxide to a site affected by restenosis in said mammal.
Claim 45
Dependent Claim
37 words
The method of claim 18 wherein said polyolefin is selected from the group consisting of polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene , difluoride, and polyvinylchloride; said polyether is polyethyleneglycol; said polyester is poly(lactide/glycolide); and said polyamide is nylon.
Claim 46
Dependent Claim
36 words
The method of claim 37 wherein said polyolefin is selected from the group consisting of polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, and polyvinylchloride; said polyether is polyethyleneglycol; said polyester is poly(lactide/glycolide); and said polyamide is nylon.
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