The present invention relates to O2-aryl 1-substituted diazen-1-ium-1,2-diolates (O2-aryl diazeniumdiolates) O2-glycosylated 1-substituted diazeniumdiolates, and O2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazeniumdiolates, compositions comprising such diazeniumdiolates, methods of using such diazeniumdiolates, and methods of preparing O2-aryl diazeniumdiolates.
Nitric oxide (NO) has been implicated in a wide variety of bioregulatory processes, and compounds, which contain nitric oxide or are capable of releasing nitric oxide, have been identified as useful in regulating these processes. Many classes of nitric oxide-containing and/or -releasing adducts are known in the art, such as glyceryl trinitrate and nitroprusside (reviewed in U.S. Pat. No. 5,405,919 (Keefer et al.), including limitations of their use in biological applications). The limited utility of such compounds has, in part, given rise to the development of another class of nitric oxide-generating compounds, diazeniumdiolates, which are especially useful biologically.
Diazeniumdiolates include compounds containing an N2O2xe2x88x92 functional group and are structurally and functionally distinct from nitrosamines (see, e.g., Reilly, U.S. Pat. No. 3,153,094). The known diazeniumdiolates are disclosed in recently issued patents. U.S. Pat. Nos. 5,039,705 (Keefer et al.) and 5,208,233 (Keefer et al.) disclose secondary amine-nitric oxide adducts and salts thereof. U.S. Pat. Nos. 5,155,137 (Keefer et al.) and 5,250,550 (Keefer et al.) disclose complexes of nitric oxide and polyamines. U.S. Pat. No. 5,389,675 (Christodoulou et al.) discloses mixed ligand metal complexes of nitric oxide-nucleophile adducts and U.S. Pat. Nos. 5,525,357 (Keefer et al.) and 5,405,919 (Keefer et al.) disclose polymer-bound nitric oxide/nucleophile adduct compositions. U.S. Pat. Nos. 4,954,526 (Keefer et al.; the ""526 patent) and 5,212,204 (Keefer et al.) disclose the use of ionic diazeniumdiolates as cardiovascular agents. In addition, the ""526 patent discloses O2-substituted and metal-bound diazeniumdiolates. Keefer et al., U.S. Pat. No. 5,366,997 (""997), discloses diazeniumdiolates having the formula: 
in which the O2-oxygen of the N2O2xe2x88x92 group is bonded to the functional group R3. When the R3 group is cleaved from the O2-oxygen, NO can be released spontaneously.
Although Keefer et al. (""997) discloses that (i) R1 and R2, together with the nitrogen atom to which they are bonded, can form a pyrrolidinyl, piperazino or other heterocyclic group, (ii) R3 is a C1-12 straight-chain or C3-12 branched-chain alkyl, optionally olefinic and/or substituted with hydroxy, halo, acyloxy or alkoxy, a C1-12 unsubstituted/substituted acyl, sulfonyl, carboxamido, sulfinyl, sulfenyl, a carbonate derivative or a carbamate derivative, and (iii) the pyrrolidinyl group can have the structure: 
wherein w=4, and R4=hydrogen, a C1-8 straight or branched chain alkyl, a C3-6 cycloalkyl, or a substituted or an unsubstituted aryl, Keefer et al. (""997) does not disclose that R3 is an aryl or a substituted aryl or that the pyrrolidino group can be substituted with a substituted or unsubstituted carboxyl group (see, also, Example 1 of U.S. Pat. No. 5,632,981) at position 2. Similarly, Keefer et al. (""997) does not disclose O2-glycosylation of diazeniumdiolates.
Heretofore it was not known that O2-aryl substitutions of the diazeniumdiolates was possible. Further, chemical studies of previously disclosed diazeniumdiolates led to the conclusion that they are generally at least as stable at high pH as they are at low pH, and that, unlike certain other classes of xe2x80x9cnitrovasodilatorxe2x80x9d drugs, their rates of NO release are not affected by the presence of nucleophilic thiols.
Thus, there remains a need for such classes of diazeniumdiolates, which offer advantages over other currently available diazeniumdiolates. In this regard, the O2-aryl substituted diazeniumdiolates are advantageous in that they can release NO spontaneously under alkaline conditions or after nucleophilic attack. O2-Aryl substituted diazeniumdiolates also can release NO spontaneously after a combination of oxidative or electophilic activation and nucleophilic attack.
It is, therefore, a principal object of the present invention to provide a nitric oxide/nucleophile adduct in which the O2-oxygen of the N2O2xe2x88x92 group is derivatized with an aryl or substituted aryl group to protect the diazeniumdiolate against the spontaneous release of NO. It is another object of the invention to provide a novel class of diazeniumdiolates, which resists releasing nitric oxide in neutral or acidic solutions, but releases NO on nucleophilic attack or on increasing the pH. It is still another object of the present invention to provide 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. It is a further object of the present invention to provide compositions comprising such compounds, including compositions comprising a nitric oxide/nucleophile adduct comprising a novel targeting moiety. It is a related object to provide O2-aryl substituted diazeniumdiolates, which are amenable to biological tissue-targeting strategies, which offer greater flexibility and specificity for targeting NO release. It is a still further object of the present invention to provide methods of using such compounds. These and other objects of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
The present invention provides an O2-aryl substituted diazeniumdiolate (i.e., O2-aryl diazeniumdiolate) illustrated by the formula: 
wherein X is an inorganic or organic moiety and Q is an aryl moiety. In this novel class of compounds an atom of the aryl ring moiety Q is bonded to the O2-oxygen of the N2O2xe2x88x92 functional group. The diazeniumdiolates of Formula (I) are stable with respect to the hydrolytic generation of nitric oxide in neutral to acidic solutions. Surprisingly, these novel compounds, or the resultant product of these compounds after oxidative or electrophilic activation, have proven capable of generating nitric oxide in basic or nucleophilic environments, in which the aryl moiety is separated from the remainder of the diazeniumdiolate.
The present invention also provides 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, both of which can be represented by the formula: 
in which X and R are organic and/or inorganic moieties as defined herein, although for O2-glycosylated diazeniumdiolates, R must be a saccharide.
Further with respect to the O2-glycosylated 1-substituted diazen-1-ium-1,2-diolates, the moiety X can be any organic or inorganic group. Preferably, X contains atoms other than carbon and hydrogen, and is linked to the nitrogen of the diazeniumdiolate through an atom other than carbon. Most preferably, X is an amino group, and is linked to the nitrogen of the diazeniumdiolate through a nitrogen atom.
With respect to the O2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates, X of Formula Ia can be 
such that the [1-(2-carboxylato)pyrrolidin-1-yl]diazeniumdiolates can be structurally represented by the formula: 
wherein R22 is hydrogen, hydroxyl, OM, wherein M is a cation, halo, or X1R23R24, wherein X1 is oxygen, nitrogen or sulfur and R23 and R24 are independently a substituted or unsubstituted C1-24 alkyl, a substituted or unsubstituted C3-24 cycloalkyl, a substituted or unsubstituted C2-24 olefinic, a substituted or unsubstituted aryl (such as acridine, anthracene, benzene, benzofuran, benzothiophene, benzoxazole, benzopyrazole, benzothiazole, carbazole, chlorophyll, cinnoline, furan, imidazole, indole, isobenzofuran, isoindole, isoxazole, isothiazole, isoquinoline, naphthalene, oxazole, phenanthrene, phenanthridine, phenothiazine, phenoxazine, phthalimide, phthalazine, phthalocyanine, porphin, pteridine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrocoline, pyrrole, quinolizinium ion, quinoline, quinoxaline, quinazoline, sydnone, tetrazole, thiazole, thiophene, thyroxine, triazine, and triazole), or a heterocyclic group, such as glycosyl, and the like, and when X1 is O or S, there is no R24 group. Alternatively, when X1 is nitrogen, R23 and R24, together with X1, form a heterocyclic ring, such as a heterocyclic ring selected from the group consisting of: 
in which A is N, O, 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. The aforementioned R23 and R24 groups can be unsubstituted or substituted as appropriate. For example, the R23 and R24 groups can be substituted as appropriate with acyloxy, acylthio, hydroxyl, amino, carboxyl, mercapto, halo, amido, sulfonyl, sulfoxy, sulfenyl, phosphono, phosphate, and the like.
Further with respect to the O2-substituted 1-[(2-carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolates, the moiety R of Formula Ia can be any organic or inorganic moiety, which is covalently bound to the terminal oxygen of the diazeniumdiolate as shown but which is other than hydrogen and is a substituted or unsubstituted C1-12 straight chain or C3-12 branched chain alkyl, a substituted or unsubstituted C2-12 straight chain or C3-12 branched chain olefinic, a substituted or unsubstituted C1-12 acyl, sulfonyl, carboxamido, a glycosyl group, an aryl group, or a group of the formula xe2x80x94(CH2)nxe2x80x94ONxe2x95x90N (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, a C2-12 straight chain or C3-12 branched chain olefinic, or R28 and R29, together with the nitrogen atom to which they are bonded, form a heterocyclic group, preferably a pyrrolidino, piperidino, piperazino or morpholino group. The aforementioned R groups can be unsubstituted or substituted. Preferred substitutions include those made with hydroxy, halo, acyloxy, alkoxy, acylthio, or benzyl.
In another aspect, the present invention comprises a composition, including a pharmaceutical composition, comprising a present inventive diazeniumdiolate. The pharmaceutical composition preferably additionally comprises a pharmaceutically acceptable carrier.
In yet another aspect, the present invention provides methods of using a compound in accordance with the present invention.
In still another aspect, the present invention provides a method of making O2-aryl diazeniumdiolates.
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