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1. (WO1995024908) USE OF NITRIC OXIDE-RELEASING POLYMERS TO TREAT RESTENOSIS AND RELATED DISORDERS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

WHAT IS CLAIMED IS:

1. 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 N202~ functional group and a polymer to which is bound a nitric oxide-releasing N202" functional group, said agent being capable of locally releasing nitric oxide to a site at risk for restenosis in said mammal.

2. The method of claim 1 wherein said nitric oxide-releasing N202~ functional group is contained in a
compound of the formula:


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.

3. 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.

4. The method of claim 2 wherein the nitric oxide-releasing compound is a compound other than a salt of alanosine or dopastin.

5. The method of claim 1 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:

R1-NH+-(CH2)χ-N-[(CH2)yN]d-[(CH2)z-N]b-R3
(ID

R, N202- Rr R„

wherein b and d are the same or different and are zero or one, R , R2, R3, R4, and R5 are the same or different and are hydrogen, a C3_8 cycloalkyl, a C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbony1, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.

6. The method of claim 1 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

(CH2)f-B (III)

wherein B is N—N202" ,

R6 and R7 are the same or different and are hydrogen, a C3_8 cycloalkyl, a C1-12 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

—N N-N202~

then f is an integer from 2 to 12.

7. The method of claim 6 wherein B is the
substituted piperazine moiety
/ \
—N N-N202" .

8. The method of claim 1 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

(CH2)g-NH2+-R8 (IV)


wherein R8 is hydrogen, a C3_8 cycloalkyl, a C^-^ straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a Cα-C12 straight or branched chain alkyl, and g is an integer from 2 to 6.

9. The method of claim 1 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:


wherein R and R2 are independently selected from the group consisting of a C1-C12 straight or branched chain alkyl and benzyl, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation.

10. The method of claim 9 wherein R-^ and R2 are selected so that R and R2 are unbranched on the alpha carbon atom or R2 and R2, together with the nitrogen atom to which they are bonded, form a heterocyclic group.

11. The method of claim 10 wherein the heterocyclic group is selected from the group consisting of
pyrrolidino, piperidino, piperazino and morpholino.

12. The method of claim 1 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:

K[(M)*'(L)y(R1R2N-N202)2] (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 (R1R2N-N202) and is bound to at least one metal, R1 and R2 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 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.

13. 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 R1 or R2 is a moiety other than ethyl.

14. The method of claim 1 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:
[R-N(H)N(N0)0-]yX (VII) wherein R is a C2_8 lower alkyl, phenyl, benzyl, or a C3_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 C1-8 alkoxy, -NH2, -C(0)NH2, -CH(O) , -C(0)OH, and -N02, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of a C1_8 lower alkyl, -C(0)CH3, and -C(0)NH2, and y is an integer from 1 to 3, consistent with the valence of X.

15. The method of claim 1 wherein said nitric oxide-releasing N02" functional group is contained in a compound of the formula:

R,R,N-N— > 0
II (VIII)
N-OR3

wherein R and R2 are independently chosen from a C1-12 straight chain alkyl, a C1-12 alkoxy or acyloxy
substituted straight chain alkyl, a C2_12 hydroxy or halo substituted straight chain alkyl, a C3_12 branched chain alkyl, a C3_12 hydroxy, halo, alkoxy, or acyloxy
substituted branched chain alkyl, a C3_12 straight or branched chain olefinic unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or Rχ and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from a C1-12 straight chain and a C3_12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, a C2_12 straight chain or a C3_12 branched chain olefinic which are unsubstituted or
substituted by halo, alkoxy, acyloxy or hydroxy, a C1-12 unsubstituted or substituted acyl, sulfonyl, and
carboxamido; or R3 is a group of the formula -(CH2)n-ON=N(0)NR1R2, wherein n is an integer of 2-8, and Rλ and R2 are as defined above.

16. The method of claim 15 wherein R , R2 and R3 contain a moiety other than a halo or a hydroxy
substituent α to a heteroatom.

17. The method of claim 15 wherein the heterocyclic group is selected from the group consisting of
pyrrolidino, piperidino, piperazino, and morpholino.

18. 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, and biopolymers.

19. The method of claim 1 wherein said polymer is biodegradable.

20. The method of claim 1 wherein said nitric oxide delivery means is selected from the group consisting of a vascular graft prosthetic implant, stent, heart valve, suture, drug pump, catheter, self-adhering means,
liposome, microparticle, microsphere, bead and disk.

21. 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 a compound comprising a nitric oxide-releasing N202" functional group and a polymer to which is bound a nitric oxide-releasing N202" functional group, said agent being capable of locally releasing nitric oxide to a site affected by restenosis in said mammal.

22. The method of claim 21 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:


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.

23. The method of claim 22 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.

24. The method of claim 22 wherein the compound is a compound other than a salt of alanosine or dopastin.

25. The method of claim 21 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

R1-NH+-(CH2)

wherein b and d are the same or different and may be zero or one, Rl t R2, R3, R , and R5 are the same or different and are hydrogen, a C3_8 cycloalkyl, a C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbony1, or 2,2,2-trichloro-t-butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12.

26. The method of claim 21 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:


wherein B is N-N202"

R6 and R7 are the same or different and are hydrogen, a c3-8 cycloalkyl, a C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl , t-butoxycarbony1, or 2,2, 2-trichloro-t-butoxycarbonyl , and f is an integer from 0 to 12.

27. The method of claim 26 wherein B is the
substituted piperazine moiety

-N N-N202"

28. The method of claim 21 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:

(CH2)g-NH2+-R8 (IV)


wherein R8 is hydrogen, a C3_8 cycloalkyl, a C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl , or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a C - C12 straight or branched chain alkyl, and g is an integer from 2 to 6.

29. The method of claim 21 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:


wherein R2 and R2 are independently selected from the group consisting of a C1-C12 straight or branched chain alkyl and benzyl, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation.

30, The method of claim 29 wherein R2 and R2 are selected so that Rλ and R2 are unbranched on the alpha carbon atom or Rχ and R2, together with the nitrogen atom to which they are bonded, form a heterocyclic group.

31. The method of claim 30 wherein the heterocyclic group is selected from the group consisting of
pyrrolidino, piperidino, piperazino and morpholino.

32. The method of claim 21 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

K[ (M)X'(L) (R1R2N-N202)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 (R1R2N-N202) and is bound to at least one metal, R1 and R2 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.

33. The method of claim 32 wherein when M is copper, x is one, L is methanol, and y is one, then at least one of R1 or R2 is a moiety other than ethyl.

34. The method of claim 21 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

[R-N(H)N(NO)0-]yX (VII)

wherein R is a C2_8 lower alkyl, phenyl, benzyl, or a C3_8 cycloalkyl, any of which R groups may 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-^ alkoxy, -NH2, -C(0)NH2, -CH(O) , -C(0)OH, and -N02 , X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of a C1-8 lower alkyl, -C(0)CH3, and -C(0)NH2, and y is an integer from 1 to 3, consistent with the valence of X.

35. The method of claim 21 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

RχR2N-N— > O
|| (VIII)
N-0R3

wherein x and R2 are independently chosen from a C1-12 straight chain alkyl, a C1_12 alkoxy or acyloxy
substituted straight chain alkyl, a C2_12 hydroxy or halo substituted straight chain alkyl, a C3_1 branched chain alkyl, a C3_12 hydroxy, halo, alkoxy, or acyloxy
substituted branched chain alkyl, a C3_1 straight or branched chain olefinic unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from a C1_12 straight chain and a C3_12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, a C2_12 straight chain or a C3_12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, a C1_12 unsubstituted or substituted acyl, sulfonyl, and
carboxamido; or R3 is a group of the formula
-(CH2)n-0N=N(0)NR1R2, wherein n is an integer of 2-8, and λ and R2 are as defined above.

36. The method of claim 35 wherein Rlf R2 and R3 contain a moiety other than a halo or a hydroxy
substituent α to a heteroatom.

37. The method of claim 35 wherein the heterocyclic group is selected from the group consisting of
pyrrolidino, piperidino, piperazino and morpholino.

38. The method of claim 21 wherein said polymer is selected from the group consisting of polyolefins, polyethylenimine and derivatives thereof, polyethers, polyesters, polyamides, polyurethanes, colestipol and derivatives thereof, and biopolymers.

39. The method of claim 21 wherein said polymer is biodegradable.

40. The method of claim 21 wherein said nitric oxide delivery means is selected from the group
consisting of a vascular graft prosthetic implant, stent, heart valve, suture, drug pump, catheter, self- adhering means, liposome, microparticle, microsphere, bead, and disk.

41. A nitric oxide delivery means for the treatment of restenosis comprising an effective amount of a polymer to which is bound a nitric oxide-releasing N202"
functional group, said delivery means being selected from the group consisting of a vascular implant, stent, heart valve, suture, drug pump, catheter, self-adhering means, liposome, microparticle, microsphere, bead and disk.

42. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:


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.

43. The nitric oxide delivery means of claim 42 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.

44. The nitric oxide delivery means of claim 42 wherein the compound is a compound other than a salt of alanosine or dopastin.

45. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:


wherein b and d are the same or different and are zero or one, Rl r R2, R3, R , and R5 are the same or different and are hydrogen, a C3_8 cycloalkyl, a C1-12 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.

46. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:

H
R6-Nl++-(CH2)f-B (III)
R7

wherein B is or — N—N202" ,

R6 and R7 are the same or different and are hydrogen, a C3_8 cycloalkyl, a C1-12 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.

47. The nitric oxide delivery means of claim 46 wherein B is the substituted piperazine moiety

— N-N202~ .

48. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:


wherein R8 is hydrogen, a C3_8 cycloalkyl, a C1_1 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri-chloro-t-butoxycarbonyl, R9 is hydrogen or a Cλ-C1 straight or branched chain alkyl, and g is an integer from 2 to 6.

49. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:


wherein R and R2 are independently selected from the group consisting of a straight or branched chain alkyl and benzyl, M+x is a pharmaceutically acceptable cation, and x is the valence of the cation.

50. The nitric oxide delivery means of claim 49 wherein R-L and R2 are selected so that R and R2 are unbranched on the alpha carbon atom or else R and R2, together with the nitrogen atom to which they are bonded, form a heterocyclic group.

51. The nitric oxide delivery means of claim 49 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.

52. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202~ functional group is contained in a compound of the formula:

K[(M)x'(L)y(R1R2N-N202)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 (R1R2N-N202) and is bound to at least one metal, R1 and R2 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.

53. The nitric oxide delivery means of claim 52 wherein when M is copper, x is one, L is methanol, and y is one, then at least one of R1 or R2 is a moiety other than ethyl.

54. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:
[R-N(H)N(NO)0-]yX (VII)

wherein R is a C2_8 lower alkyl, phenyl, benzyl, or a C3_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, C1_8 alkoxy, -NH2, -C(0)NH2, -CH(O) ,
-C(0)OH, and -N02, X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of a C1_8 lower alkyl, -C(0)CH3, and -C(0)NH2, and y is an integer from 1 to 3, consistent with the valence of X.

55. The nitric oxide delivery means of claim 41 wherein said nitric oxide-releasing N202" functional group is contained in a compound of the formula:


wherein R and R2 are independently chosen from a C1-12 straight chain alkyl, a C1-12 alkoxy or acyloxy
substituted straight chain alkyl, a C2_12 hydroxy or halo substituted straight chain alkyl, a C3_12 branched chain alkyl, a C3_12 hydroxy, halo, alkoxy, or acyloxy
substituted branched chain alkyl, a C3_12 straight or branched chain olefinic unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or R and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, and R3 is a group selected from a C^-^ straight chain and a C3_12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo, acyloxy or alkoxy, a C2_12 straight chain or a C3_12 branched chain olefinic which are unsubstituted or substituted by halo, alkoxy, acyloxy or hydroxy, a C1-12 unsubstituted or substituted acyl, sulfonyl, and
carboxamido; or R3 is a group of the formula
-(CH2)n-ON=N(0)NR1R2, wherein n is an integer of 2-8, and Rα and R2 are as defined above.

56. The nitric oxide delivery means of claim 55 wherein R , R2 and R3 contain a moiety other than a halo or a hydroxy substituent α to a heteroatom.

57. The nitric oxide delivery means of claim 55 wherein the heterocyclic group is selected from the group consisting of pyrrolidino, piperidino, piperazino and morpholino.

58. The method of claim 41 wherein said polymer is selected from the group consisting of polyolefins, polyethylenimine and derivatives thereof, polyethers, polyesters, polyamides, polyurethanes, colestipol and derivatives thereof, and biopolymers.

59. The nitric oxide delivery means of claim 41 wherein said polymer is biodegradable.

60. 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 a compound comprising a nitric oxide-releasing N202" functional group and a polymer to which is bound a nitric oxide-releasing N202" functional group, said agent being capable of locally releasing nitric oxide to a site at risk for restenosis in said mammal.

61. A method for the amelioration or therapeutic treatment of restenosis in a mammal, which method
comprises the administration of a restenosis-ameliorating or therapeutically effective treatment amount of a nitric oxide-releasing agent, said agent selected from the group consisting of a compound comprising a nitric oxide-releasing N202~ functional group and a polymer to which is bound a nitric oxide-releasing N202~ functional group, said agent being capable of releasing nitric oxide to a site affected by restenosis in said mammal.

62. 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) ; said polyamide is nylon; said biopolymer is selected from the group consisting of a peptide, a protein, an oligonucleotide, a nucleic acid, a starburst dendrimer, and an antibody.

63. The method of claim 38 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) ; said polyamide is nylon; said biopolymer is selected from the group consisting of a peptide, a protein, an oligonucleotide, a nucleic acid, a starburst dendrimer, and an antibody.

64. The nitric oxide delivery means of claim 41 wherein said delivery means is selected from the group consisting of a vascular graft prosthetic implant, stent, heart valve, suture, drug pump, catheter, self-adhering means, liposome, microparticle, microsphere, bead and disk.

65. The nitric oxide delivery means of claim 58 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) ; said polyamide is nylon; said biopolymer is selected from the group consisting of a peptide, a protein, an oligonucleotide, a nucleic acid, a starburst dendrimer, and an antibody.