CA2266908A1 - O2-arylated or o2-glycosylated 1-substituted diazen-1-ium-1,2-diolates and o2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates - Google Patents

O2-arylated or o2-glycosylated 1-substituted diazen-1-ium-1,2-diolates and o2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates

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CA2266908A1
CA2266908A1 CA002266908A CA2266908A CA2266908A1 CA 2266908 A1 CA2266908 A1 CA 2266908A1 CA 002266908 A CA002266908 A CA 002266908A CA 2266908 A CA2266908 A CA 2266908A CA 2266908 A1 CA2266908 A1 CA 2266908A1
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diazeniumdiolate
group
chain alkyl
substituted
formula
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CA2266908C (en
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Joseph E. Saavedra
Larry K. Keefer
Aloka Srinivasan
Christian Bogdan
William G. Rice
Xinhua Ji
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US Department of Health and Human Services
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Diazeniumdiolates, wherein the N1 position is substituted by an inorganic or organic moiety and the O2-oxygen is bound to a substituted or unsubstituted aromatic group, are provided. Also provided are O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates (O2-glycosylated diazeniumdiolates) and O2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates (1-[(2-carboxylato)pyrrolidin-1-yl]diazeniumdiolates). The O2-aryl diazeniumdiolates are stable with respect to the hydrolytic generation of nitric oxide in neutral to acidic solutions and generate nitric oxide in basic or nucleophilic environments or microenvironments. Also provided are compositions, including pharmaceutical compositions, comprising such compounds and methods of using such compounds.

Claims (84)

1. An O 2-aryl substituted diazeniumdiolate having the formula wherein X is selected from the group consisting of an amino, a polyamino, a C1-C24 aliphatic, a C3-C30 aryl, and C3-C30 nonaromatic cyclic, an oxime, a polycyclic, and an aromatic polycyclic, and Q is an aryl group selected from the group consisting of an acridine, an anthracene, a benzene, a benzofuran, a benzothiophene, a benzoxazole, a benzopyrazole, a benzothiazole, a carbazole, a chlorophyll, a cinnoline, a furan, an imidazole, an indole, an isobenzofuran, an isoindole, an isoxazole, an isothiazole, an isoquinoline, a naphthalene, an oxazole, a phenanthrene, a phenanthridine, a phenothiazine, a phenoxazine, a phthalimide, a phthalazine, a phthalocyanine, a porphin, a pteridine, a purine, a pyrazine, a pyrazole, a pyridazine, a pyridine. a pyrimidine, a pyrrocoline, a pyrrole, a quinolizinium ion, a quinoline, a quinoxaline, a quinazoline, a sydnone, a tetrazole, a thiazole, a thiophene, a thyroxine, a triazine, and a triazole, wherein an atom of the ring of said aryl group is bonded to the O2-oxygen, with the proviso that, when Q is an imidazole, X is not an imidazole.
2. The diazeniumdiolate of claim 1, wherein the Q moiety is that of a vitamin.
3. The diazeniumdiolate of claim 1, wherein the Q moiety is that of a hormone.
4. The diazeniumdiolate of claim 1, wherein Q is a pyrimidine, which, optionally, is part of a nucleic acid.
5. The diazeniumdiolate of claim 4, wherein Q is a ribosylpyrimidine.
6. The diazeniumdiolate of claim 1, wherein Q is a purine, which, optionally, ispart of a nucleic acid.
7. The compound of claim 6, wherein Q is a ribosylpurine.
8. The diazeniumdiolate of any of claims 1-7, wherein X is linked to the N 1 nitrogen through an atom other than a carbon atom.
9. The diazeniumdiolate of any of claims 1-8, wherein X is substituted with one or more moieties selected from the group consisting of -[N(NO)O-], a halo, a hydroxy, an alkylthio, an alkoxy, an aryloxy, an amino, a cyano, a sulfonato, a mercapto, a nitro, a C1-C12 aliphatic, a C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, a C2-C12 olefinic, a benzyl, a phenyl, a benzylcarbonyl, a phenylcarbonyl, a saccharide, phosphono, phosphato, and phosphato in which one or more oxygen atoms are independently replaced with S or NR1, wherein R1 is a C1-C8 aliphatic, a C3-C8 cycloalkyl or a C3-C8 aryl group.
10. The diazeniumdiolateof any of claims 1-9, wherein Q is substituted with one or more moieties selected from the group consisting of X[N(O)NO]-, wherein X is as defined in claim 1, halo, hydroxy, alkylthio, arylthio, alkoxy, aryloxy, amino, mono- ordi-substituted amino, ammonio, substituted ammonio, nitroso, cyano, sulfonato, mercapto, nitro, oxo, C1-C24 aliphatic, C2-C12 olefinic, C3-C24 cycloalkyl, C2-C24 heterocycloalkyl, benzyl, phenyl, substituted benzyl, substituted phenyl, benzylcarbonyl, phenylcarbonyl, saccharides, substituted benzylcarbonyl, substituted phenylcarbonyl, phosphono, phosphato, and phosphato in which one or more oxygen atoms are independently replaced with S or R1, wherein R1 is a C1-C10 aliphatic, a C3-C10 cycloalkyl or a C1-C10 aryl group.
11. The diazeniumdiolateof claim 1, having the formula wherein b and d can be the same or different and may be zero or one, R1, R2, R3, R4, and R5 are the same or different and are selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl,or 2,2,2-trihalo-t-butoxycarbonyl, and i, j, and k are the same or different and are integers from 2 to 12.
12. The diazeniumdiolateof claim 1, having the formula wherein D is or and wherein R10 and R11 are the same or different and are selected from the group consisting of hydrogen, C3-8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, and 2,2,2-trichloro-t-butoxycarbonyl, and f is an integer from 0 to 12.
13. The diazeniumdiolate of claim 1, having the formula:

wherein R6 and R7 can be the same or different and are H, a C1-C12 straight chain alkyl, a C1-C12, alkoxy or acyloxy substituted straight chain alkyl, a C2-C12 hydroxy or halo substituted straight chain alkyl, a C3-C12 branched chain alkyl, a C3-C12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, a C2-C12 straight chain olefinic, or a C3-C12 branched chain olefinic, wherein R6 and R7 are optionally substituted with hydroxy, alkoxy, acyloxy, halo or benzyl; or R6 and R7 together with the nitrogen atom to which they are bonded form a heterocyclic ring selected from the group consisting of:

, , and wherein A is N, O, or S, w is 1 to 12, y is 1 or 2, z is 1 to 5, R8 is hydrogen, a C1-C8 straight chain alkyl, a C3-C8 branched chain alkyl, a C3-C8 cycloalkyl, a C3-C30 aryl, and R9 is hydrogen, a C1-C6 straight chain alkyl or a C3-C6 branched chain alkyl.
14. The diazeniumdiolate of claim 13, wherein R6 is hydrogen.
15. The diazeniumdiolate of claim 13, wherein R6 and R7 are ethyl and Q is selected from the group consisting of:

, , , , and .
16. The diazeniumdiolate of any of claims 1-15, wherein X is bound to a polymer.
17. The diazeniumdiolate of claim 16, wherein said polymer is selected from the group consisting of a polyolefin, a polyurethane, a peptide, a protein, a polyethyleneimine,a starburst dendrimer, a polyamide, a polyether, a polyester, a nucleic acid, and a polysaccharide.
18. The diazeniumdiolate of claim 17, wherein said polyolefin is selected from the group consisting of a polystyrene, a polyethylene, a polytetrafluoroethylene, a polyvinylchloride, and a polyvinylidenedi fluoride.
19. The diazeniumdiolate of claim 17, wherein said polyamide is nylon.
20. The diazeniumdiolate of any of claims 1 and 8-19, wherein said atom of said aryl ring bonded to said O2-oxygen is carbon or nitrogen.
21. An O2-aryl substituted diazeniumdiolate having the formula wherein X is an inorganic moiety and Q is an aryl group selected from the group consisting of an acridine, an anthracene, a benzene, a benzofuran, a benzothiophene, a benzoxazole, a benzopyrazole, a benzothiazole, a carbazole, a chlorophyll, a cinnoline, a furan, an imidazole, an indole, an isobenzofuran, an isoindole, an isoxazole, an isothiazole, an isoquinoline, a naphthalene, an oxazole, a phenanthrene, a phenanthridine, a phenothiazine, a phenoxazine, a phthalimide, a phthalazine, a phthalocyanine, a porphin, a pteridine, a purine, a pyrazine, a pyrazole, a pyridazine, a pyridine, a pyrimidine, a pyrrocoline, a pyrrole, a quinolizinium ion, a quinoline, a quinoxaline, a quinazoline, a sydnone, a tetrazole, a thiazole, a thiophene, a thyroxine, a triazine, and a triazole; wherein an atom of the ring of said aryl group is bonded to the O2-oxygen.
22. The diazeniumdiolate of claim 21, wherein X is -O- or -O3S-.
23. A composition comprising a diazeniumdiolate of any of claims 1-22 and a carrier.
24. The composition of claim 23, wherein said atom of said aryl ring bonded to said O2-oxygen is carbon or nitrogen.
25. A pharmaceutical composition comprising an O2-aryl substituted diazeniumdiolate of formula , wherein X and Q are imidazoles, and a pharmaceutically acceptable carrier.
26. Use of a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, in preparation of a medicament for treating or preventing a biological disorder in an animal, wherein said biological disorder is treatable or preventable with nitric oxide.
27. Use of a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, in preparation of a medicament for treating an animal infected with an infectious agent comprising a zinc finger protein that can be inactivated by a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles.
28. The use of claim 27, wherein said zinc finger protein comprises a C-X2-C-X4-H-X4-C domain.
29. Use of a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, in preparation of a medicament for treating an animal for cancer, wherein said cancer involves a protein that can be inactivated by a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles.
30. A method of treating a plant, a plant cell or a tissue culture thereof, which is infected with an infectious agent comprising a protein that can be inactivated by a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, which method comprises contacting said plant, plant cell or tissue culture thereof with an amount of a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, sufficient to inactivate the protein in said infectious agent so as to treat the infection in said plant, plant cell or tissue culture thereof.
31. The method of claim 30, wherein said infectious agent is a virus.
32. The method of claim 31, wherein said virus is selected from the group consisting of tobacco streak virus and alfalfa mosaic virus.
33. Use of a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, in preparation of a medicament for modulating steroid hormone activity in a mammal, which is in need of modulation of steroid hormone activity and which comprises a steroid hormone receptor protein that comprises a zinc finger that can be inactivated by a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles.
34. A method of reducing on an inanimate object the presence of an infectious agent comprising a zinc finger protein that can be inactivated by a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, which method comprises contacting said inanimate object with an amount of a diazeniumdiolate of any of claims 1-22 or a diazeniumdiolate of formula , wherein X and Q are imidazoles, sufficient to inactivate the zinc finger protein so as to reduce the presence of the infectious agent on said inanimate object.
35. The method of claim 34, wherein said infectious agent is selected from the group consisting of a virus, a bacterium, and a parasite.
36. An O2-glycosylated 1-substituted diazen-1-ium-1,2-diolate of Formula Ia:

, in which X is selected from the group consisting of an amino, a polyamino, a C1-C24 aliphatic, a C6-C30 aryl and a C6-C30 non-aromatic cyclic, and R is a saccharide, which is attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose ring or a furanose ring, with the proviso that, when X is a saccharide, it is not attached to N1 of the diazeniumdiolate by the 2 position of a pyranose or a furanose ring.
37. The diazeniumdiolate of claim 36, wherein said saccharide is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, and a polysaccharide.
38. The diazeniumdiolate of claim 37, wherein said disaccharide is sucrose or maltose.
39. The diazeniumdiolate of claim 37, wherein the monosaccharide is mannose, fucose or glucose.
40. The diazeniumdiolate of claim 36, wherein said saccharide is a recognition sequence for receptor-mediated cellular phenomena.
41. The diazeniumdiolate of claim 36, wherein X is an amino group that is linkedto the nitrogen of the diazeniumdiolate through a nitrogen atom.
42. The diazeniumdiolate of any of claims 36-41, wherein said X is substituted with a moiety selected from the group consisting of -[N(NO)O-], a halo, a hydroxy, an alkylthio, an alkoxy, an aryloxy, an amino, a cyano, a sulfonato, a mercapto, a nitro, a C1-C12 aliphatic, a C3-C8 cycloalkyl, a C3-C8 heterocycloalkyl, a C3-C12 olefinic, a benzyl, a phenyl, a benzylcarbonyl, a phenylcarbonyl, a saccharide, phosphono, phosphato, and phosphato in which one or more oxygen atoms is independently replaced with S or NR1, wherein R1 is a C1-C8 aliphatic, a C3-C8 cycloalkyl, benzyl, phenyl, or R18C=N(OH) in which R18 is a C1-C10 aliphatic.
43. The diazeniumdiolate of any of claims 36-42, having the formula wherein b and d can be the same or different and may be zero or one, R1, R2, R3, R4, and R5 are the same or different and are selected from the group consisting of hydrogen, C3-C8 cycloalkyl, C1-12 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl,or 2,2,2-tri-halo-t-butoxycarbonyl, and i, j, and k are the same or different and are integers from 2 to 12.
44. The diazeniumdiolate of any of claims 36-43, wherein X is R19R20N-and R19 and R20 are the same or different and are hydrogen, a C1-12 straight chain alkyl, a C3,12 branched chain alkyl, or a C3-12 straight or C3,12 branched chain olefinic, wherein R19 and R20 are optionally substituted with an alkoxy, an acyloxy, an acylthio, a hydroxy, a halo or a benzyl group, or R19 and R20, together with the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of:

, , and wherein A is N, O, or S, w is 1-12, y is 1 or 2, z is 1-5, R8 is hydrogen, a C1-8 straight chain alkyl, a C3-8 branched chain alkyl, a C3-8 cycloalkyl, an aryl, or carboxylato, and R9 is hydrogen, a C1-6 straight chain alkyl or a C3-6 branched chain alkyl.
45. The diazeniumdiolate of claim 44, wherein R19R20N- is N(CH2CH2NH2)2 and the saccharide is fucose or mannose.
46. The diazeniumdiolate of claim 36, wherein said saccharide is a pentose or a hexose. either one of which is phosphorylated, 3,5-cyclophosphorylated, or polyphosphorylated, ribose, deoxyribose, lactose, galactose, fructose, glucosamine, glucose, mannose, fucose, galactosamine, and glucuronic acid.
47. The diazeniumdiolate of claim 46, wherein said glucosamine has the structure:

wherein R12 and R13 can be the same or different and are a hydrogen, a C1-6 alkyl, an acyl, a phosphate, a sulfate, a peptide or a protein.
48. The diazeniumdiolate of claim 46, wherein said glucuronic acid has the structure:

wherein RlJ is XIR'5R'5, wherein X' is N, O or S and, when X' is N, R~5 and Rl6 are independently hydrogen or a C, 24 alkyl, C3 ,~ cycloalkyl, C, ,4 olefinic, a C3-C30 aryl or a heterocyclic group selected from the group consisting of:

, and wherein A is N, O, or S, w is I -12, y is I or 2, z is 1-5, R8 is hydrogen, a C, 8 straight chain alkyl, a C3.8 branched chain alkyl, a C3 8 cycloalkyl, an aryl or carboxylato, and R9 is hydrogen, a C, 6 straight chain alkyl or a C3 6 branched chain alkyl, and when X' is O or S, there is no Rl6 group.
49. The di~eniumdiolate of claim 4~, wherein said aryl is selected from the group consisting of an acridine, an anthracene, a benzene, a benzofuran, a benzothiophene, a benzox~ole, a benzopyr~ole, a benzothiazole, a carbazole, a chlorophyll, a cinnoline, a ~uran, an imidazole, an indole, an isobenzofuran, an isoindole, an isox~ole, an isothiazole, an isoquinoline, a n~phth~lene, an oxazole, a ph~n~nthrene, a ph~n~nthridine~ a phenothi~7ine, a phenoxazine, a phth~limide, a phth~l~7ine, a phthalocyanine, a porphin, a pteridine, a purine, a pyr~ine, a pyrazole, a pyridazine, a pyridine, a pyrimidine, a pyrrocoline, a pyrrole, a quinolizinium ion, a quinoline, a quinoxaline, a quinazoline, a sydnone, a tetrazole, a thi~ole, a thiophene, a thyroxine, a triazine, and a tri~ole.
50. An 02-glycosylated l-substituted di~en-1-ium-1,2-diolate of Formula Ia:

in which X is an inorganic moiety and R is a saccharide, which is attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose ring or a furanose ring.
51. The diazeniumdiolate of claim 50, in which X is -O3S ~ or O ~.
52. An O2-glycosylated 1-substituted diazen-1-ium-1,2-diolate of formula , wherein D is or and wherein R21 is a saccharide, which is attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose ring or a furanose ring, f is an integer from 0 to 12. and R10 and R11, which can be the same or different, can be hydrogen, a C3-C8 cycloalkyl, a C1-C12 straight-or a C3-C12 branched-chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl or 2,2,2-trihalo-t-butoxycarbonyl.
53. An O2-substituted 1 -[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate derivative of formula II:

wherein R is a C1-12 straight chain alkyl, a C3.12 branched chain alkyl, a C2.12 straight chain or a C3-12 branched chain olefinic, a C1-12 acyl, sulfonyl, carboxamido, a glycosyl group, a C1-C30 aryl group or a group of the formula -(CH2)n-ON=N(O)NR28R29, wherein n is an integer of 2-8, and R28 and R29 are independently a C1-12 straight chain alkyl, a C3-12 branched chain alkyl, or a C2-12 straight chain or a C3-12 branched chain olefinic, or R28 and R29, together with the nitrogen atom to which they are bonded, form a heterocyclic group selected from the group consisting of a pyrrolidino, a piperidino, a piperazino and a morpholino group; and R22 is hydrogen, hydroxyl, OM, wherein M is a cation, a halo, X1R23R24, wherein X1 is O, N
or S, and R23 and R24 are independently a C1-24 alkyl, a C3-24 cycloalkyl, a C2-24 olefinic, a C3-C30 aryl, or a heterocyclic group, and, when X1 is O or S, there is no R24.
54. The diazeniumdiolate of claim 53, wherein said moiety R is substituted with moieties selected from the group consisting of hydroxy, halo, acyloxy, alkoxy, acylthio and benzyl.
55. The diazeniumdiolate of claim 53, wherein, when X1 is nitrogen, R23 and R24,together with the nitrogen to which they are bonded, form a heterocyclic ring selected from the group consisting of:

, , , and , in which A is O, N or S, w is 1-12, y is 1 or 2, z is 1-5, R8, R9, R25, and R26 are hydrogen, a C1-8 straight chain alkyl, a C3-8 branched chain alkyl, a C3-8 cycloalkyl, or a C3-C30 aryl.
56. The diazeniumdiolate of any of claims 53-55, wherein said aryl is selected from the group consisting of an acridine, an anthracene, a benzene, a benzofuran, a benzothiophene, a benzoxazole, a benzopyrazole, a benzothiazole, a carbazole, a chlorophyll, a cinnoline, a furan, an imidazole, an indole, an isobenzofuran, an isoindole, an isoxazole, an isothiazole, an isoquinoline, a naphthalene, an oxazole, a phenanthrene, a phenanthridine, a phenothiazine, a phenoxazine, a phthalimide, a phthalazine, a phthalocyanine, a porphin, a pteridine, a purine, a pyrazine, a pyrazole, a pyridazine, a pyridine, a pyrimidine, a pyrrocoline, a pyrrole, a quinolizinium ion, a quinoline, a quinoxaline, a quinazoline, a sydnone, a tetrazole, a thiazole, a thiophene, a thyroxine, a triazine, or a triazole.
57. The diazeniumdiolate of claim 55 or 56, wherein, when X1 is nitrogen and R23 and R24, together with the nitrogen to which they are bonded, form the heterocyclic ring , R25 is hydrogen, a C1-C8 straight chain alkyl, a C3-C8 branched chain alkyl, a C3-C8 cycloalkyl or a C3-C30 aryl, R26 is hydrogen, a C1-C8 alkyl, a C3-C30 aryl, or C(O) - YR27, wherein Y is sulfur, oxygen or nitrogen and R27 is CH2OCH3, vinyl, a C1-C9 straight chain alkyl a C3-C6 branched chain alkyl, a C3-C8 cycloalkyl, polyethylene glycol, a polysaccharide, a peptide or a protein.
58. A composition comprising a diazeniumdiolate of any of claims 36-57 and a carrier.
59. A pharmaceutical composition comprising a diazeniumdilate of Formula Ia:

, in which X and R are saccharides, which are attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose ring or a furanose ring.
60. Use of a diazeniumdiolate of any of claims 36-57 or a diazeniumdiolate of formula , in which X and R are saccharides, which are attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose ring or a furanose ring, in preparation of a medicament for treating or preventing a biological disorder in an animal, wherein said biological disorder is treatable or preventable with nitric oxide.
61. The use of claim 60, wherein said biological disorder is selected from the group consisting of infection, inflammation, metastasis, fillminant liver failure, malaria, a respiratory disorder, impotence, a cardiovascular disorder and a hematologic disorder.
62. A method of inactivating or inhibiting a protein, which method comprises contacting said protein with an amount of a diazeniumdiolate of any of claims 36-57 or a diazeniumdiolate of formula , in which X and R are saccharides, which are attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose ring or a furanose ring, sufficient to inactivate or inhibit said protein.
63. The method of claim 62, wherein said virus is selected from the group consisting of tobacco streak virus (TSV) and alfalfa mosaic virus (AIMV).
64. A method of modulating steroid hormone activity in a mammal, which is in need of modulation of steroid hormone activity and which comprises a steroid hormone receptor protein, which comprises a zinc finger and which can be inactivated by a compound of any of claims 1-31, which method comprises administering to said mammal an amount of a compound of any of claims 1-31 sufficient to inactivate the steroid hormone receptor protein so as to modulate steroid hormone activity in said mammal.
65. A method of reducing on an inanimate object the presence of an infectious agent comprising a zinc finger protein that can be inactivated by a compound of any of claims 1-31, which method comprises contacting said inanimate object with an amount of a compound of any of claims 1-31 sufficient to inactivate the zinc finger protein so as to reduce the presence of the infectious agent on said inanimate object.
66. The method of claim 65, wherein said infectious agent is selected from the group consisting of a virus, a bacterium, and a parasite.
67. An O2-glycosylated 1-substituted diazen-1-ium-1,2-diolate of Formula I:

, in which R is a saccharide, which is attached to the O2 of the diazeniumdiolate by the 2 position of a pyranose or furanose ring.
68. The compound of claim 67, wherein said saccharide is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, and a polysaccharide.
69. The compound of claim 68, wherein said disaccharide is sucrose or maltose.
70. The compound of claim 68, wherein the monosaccharide is mannose, fucose or glucose.
71. The compound of claim 68, wherein said saccharide is a recognition sequence for receptor-mediated cellular phenomena.
72. The compound of claim 67, wherein said moiety X
contains atoms other than carbon and hydrogen, and is linked to the nitrogen of the diazeniumdiolate through an atom other than carbon.
73. The compound of claim 67, wherein said moiety X
is an amine, and is linked to the nitrogen of the diazeniumdiolate through a nitrogen atom.
74. An O2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate of formula II:

wherein R is any covalently bound organic or inorganic group other than hydrogen and R22 is hydrogen, hydroxyl, OM, wherein M is a cation, halo, X1R23R24, wherein X1 is O, N or S, and R23 and R24 are independently a C1-24 alkyl, a C3-24 cycloalkyl, a C2-24 olefinic, an aryl, or a heterocyclic group, and when X1 is O or S, there is no R24.
75. The compound of claim 74, wherein, X1 is nitrogen and R23 and R24, together with the nitrogen to which they are bonded, form a heterocyclic ring selected from the group consisting of:

, , , and , in which A is O, N or S, w is 1-12, y is 1 or 2, z is 1-5, R8, R9, R25, and R26 are hydrogen, a C1-8 straight chain alkyl, a C3-8 branched chain alkyl, a C3-8 cycloalkyl, or an aryl.
76. The compound of claim 74, wherein said moiety R
is a C1-12 straight chain alkyl, a C3-12 branched chain alkyl, a C2-12 straight chain or a C3-12 branched chain olefinic, a C1-12 acyl, sulfonyl, carboxamido, a glycosyl group, an aryl group or a group of the formula -(CH2) n-ON=N (O) NR28R29, wherein n is an integer of 2-8, and R28 and R29 are independently a C1-12 straight chain alkyl, a C3-12 branched chain alkyl, or a C2-12 straight chain or a C3-12 branched chain olefinic, or R28 and R29, together with the nitrogen atom to which they are bonded, form a heterocyclic group selected from the group consisting of a pyrrolidino, a piperidino, a piperazino and a morpholino group.
77. The compound of claim 76, wherein said moiety R
is substituted.
78. A composition comprising a compound of any of claims 67-77.
79. A method of treating or preventing a biological disorder in an animal, wherein said disorder is treatable or preventable with nitric oxide, which method comprises administering to the animal an amount of a compound of any of claims 67-77 sufficient to treat or prevent the biological disorder.
80. The method of claim 79, wherein said biological disorder is selected from the group consisting of infection, inflammation, metastasis, fulminant liver failure, malaria, a respiratory disorder, impotence, a cardiovascular disorder and a hematologic disorder.
81. The method of claim 80, wherein said infection is due to an agent selected from the group consisting of a virus, a bacterium and a parasite.
82. The method of claim 81, wherein said parasite is Leishmania.
83. The method of claim 82, wherein said compound is a compound of any claims 67-73.
84. A method of inactivating or inhibiting a zinc finger protein, which method comprises contacting said zinc finger protein with an amount of a compound of any of claims 1-31 sufficient to inactivate or inhibit said zinc finger protein.
CA2266908A 1996-09-27 1997-09-26 O2-arylated or o2-glycosylated 1-substituted diazen-1-ium-1,2-diolates and o2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates Expired - Lifetime CA2266908C (en)

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