CA2248800A1 - Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders - Google Patents

Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders

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CA2248800A1
CA2248800A1 CA002248800A CA2248800A CA2248800A1 CA 2248800 A1 CA2248800 A1 CA 2248800A1 CA 002248800 A CA002248800 A CA 002248800A CA 2248800 A CA2248800 A CA 2248800A CA 2248800 A1 CA2248800 A1 CA 2248800A1
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hydrogen
defined above
group
compounds
independently selected
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CA2248800C (en
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David S. Garvey
L. Gordon Letts
H. Burt Renfroe
Stewart K. Richardson
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Nitromed Inc
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Nitromed, Inc.
David S. Garvey
L. Gordon Letts
H. Burt Renfroe
Stewart K. Richardson
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C313/08—Sulfenic acids; Derivatives thereof
    • C07C313/18—Sulfenamides
    • C07C313/36—Sulfenamides having nitrogen atoms of sulfenamide groups further bound to other hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals
    • C07J71/0031—Oxygen-containing hetero ring cyclic ketals at positions 16, 17

Abstract

Disclosed are (i) compounds of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO2 group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, .beta.-agonists, anticholinergics, mast cell stabilizers and PDE
inhibitors, which can optionally be substituted with at least one NO or NO2 moiety or a group which stimulates endogenous production of NO or EDRF in vivo, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO) or that stimulates endogenous production of NO or EDRF in vivo; and (iii) uses for them in preventing and/or treating respiratory disorders.

Claims (16)

1. A compound comprising a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a phosphodiesterase inhibitor to which is directly or indirectly linked at least one NO or NO2 group or a group which stimulates endogenous production of NO or EDRF synthesis in vivo.
2. A compounds of claim 1 selected from the group consisting of:
(i) compounds having the structure:

wherein A is selected from -CH=CH- or -CH2-CH2-;
R1 is selected from (1) -C(O)CH2-B-D wherein B is oxygen or sulfur; D is selected from (i) -NO; (ii) -NO2; (iii) -C(R d)-O-C(O)-Y-[C(R e)(R f)]p-T-Q in which R d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl, Y is oxygen, sulfur, or NR i in which R i is hydrogen, lower alkyl, lower haloalkyl, or heteroaryl, R e and R f are at each occurance independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, carboxy, carboxamido, or taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6, T is a covalent bond, oxygen, sulfur or nitrogen and Q is selected from -NO or -NO2; (iv) -C(O)-T1-[C(R e)(R f)]p-T2-Q wherein T1 and T2 are independently selected from T and R e, R f, p, Q, and T are as defined above; (v) -C(O)-T[C(R y)(R z)]p wherein R y and R z are independently selected from -T1-[C(R e)(R f)]p-G-[C(R e)(R f)]p-T2-Q wherein G is (i) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T, or (iv) Y, and wherein R d, R e, R f, p, Q, T, and Y are as defined above;
(2) -C(O)-C(O)-O-R i wherein R i is as defined above;
(3) -C(O)-B-R i wherein B and R i are as defined above;
(4) -C(O)-CH2-B-C(O)-R i wherein B and R i are as defined above;
(5) -C(O)-CH2-X wherein X is halogen;
(6) -S-R i wherein R i is as defined above;
(7) -C(O)CH2-B-M wherein M is selected from -C(O)T-[C(R e)(R f)]p-G-[C(R e)(R f)]p-N[N-(O-)N=O]-R i or -C(R d)-O-C(O)T-[C(R e)(R f)]p-G-[C(R e)(R f)]p-N[N-(O-)N=O]- R i wherein Re, Rf, Ri, p, G and T are as defined above;
R2 and R3 are independently selected from hydrogen, hydroxyl, lower alkyl, -O(O)C-R i, or -S-R i wherein R i is as defined above or R2 and R3 when taken together are wherein R1 i and R2 i are independently selected from R i wherein R i is as defined above;
R4 and R5 are independently selected from hydrogen or halogen;
R6 is selected from hydrogen, D, or M wherein D and M are as defined above with the provision that R6 must be D or M if the selection for R1 does not include D or M;
(ii) compounds having the structure:

wherein, E is nitrogen or C-R7 wherein R7 is hydrogen, halogen, -CH2O-R j, or -O-R j wherein R j is hydrogen, D or M wherein D and M are defined as above;
R8 and R9 are independently selected from amino, hydrogen, -CH2O-R j, or -O-R k wherein R k is -C(O)- R d or R j and R d and R j are as defined above;
S is (1) -CH2-N(Z)-R10 wherein Z is hydrogen, -[N(O-)N=O], or M wherein M is as defined above and R10 is selected from (i) lower alkyl (ii) -(CH2)p-O-(CH2)a-C6H5 wherein a is an integer from 1 to 4 and p is as defined above (iii) wherein Z is as defined above; and R11 is selected from hydrogen, D, or M with the provision that R11 must be D
or M if neither R8 or R9 include D or M and Z is hydrogen;
(iii) compounds having the structure:

wherein, K is a a monovalent anion selected from halide, nitrate, or nitrite;
R12 and R13 are hydrogen or, when taken together are oxygen;
R14 is lower alkyl or haloalkyl;
R15 is selected from:

wherein R v is selected from D or M and D and M are as defined above;
(iv) compounds having the structure:

wherein R14 is as defined above;
R16 is selected from hydrogen, -C(R d)-O-C(O)-Y-[C(R e)(R f)]p-T-Q, -C(O)-T1-[C(R e)(R f)]p-T2-Q, or M; and wherein R d, R e, R f,, M, p, T, T1, T2, Q, and Y are defined as above; and R17 and R18 are independently selected from a lone pair of electrons, -C(R d)-O-C(O)-Y-[C(R e)(R f)]p-T-Q, or M wherein R d, R e, R f,, M, p, T, Q, and Y are defined as above with the provision that R17 and/or R18 must be -C(R d)-O-C(O)- Y-[C(R e)(R f)]p-T-Q or M when R16 is hydrogen;
(v) compounds having the structure:

wherein R19 is selected from -[C(R e)(R f)]p-G-[C(R e)(R f)]p-T-Q or -S(O2)-[C(R e)(R f)]p-G-[C(R e)(R f)]p-N[N-(O-)N=O]- R j wherein R e, R f, R i, p, G, Q and T are as defined above; and wherein R14, R17, and R18 are as defined above;

(vi) compounds having the structure:

wherein, F is selected from oxygen or NR i wherein R i is as defined above;
R20 and R21 are independently selected from (1) -Y-[C(R e)(R f)]p-H-[C(R e)(R f)]p- T-Q; wherein H is (i) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T;
(iv) -C(Y-C(O)-R m)- wherein R m is heteroaryl or heterocyclic ring; and wherin Y, R d, R e, R f, p, Q and T are as defined above; (2) T-[C(R e)(R f)]p-H-[C(R e)(R f)]p-N[N-(O-)N=O]- R i wherin R d, R e, R f, R i, p, H and T are as defined above; (3) in which W is a heterocyclic ring or NR s R's wherein R s and R's are independently selected from lower alkyl, aryl or alkenyl; (4) sodium or (5) hydrogen;
R22 is hydrogen, M, or D with the provision that R22 must be M or D when R20 and R21 are selected as sodium or hydrogen;

(vii) compounds having the structure:

wherein, R23 is alkoxy, cycloalkoxy, or halogen;
R24 is hydrogen, alkoxy, or haloalkoxy; and R25 is selected from:

wherein X is halogen and R26 is selected from D or M and wherein R16, R18, and R19 are defined as above.
3. A composition comprising (i) a therapeutically effective amount of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor and (ii) a compound that donates, transfers or releases nitric oxide or stimulates endogenous production of NO or EDRF in vivo.
4. The composition of claim 3 wherein (i) the steroid is selected from the group consisting of beclomethasone, fluticasone, flunisolide, triamcinolone, butixocort, dexamethasone, fluocortin, budesonide, tixocortol, tipredane and mometasone;
(ii) the .beta.-agonist is selected from the group consisting of salmeterol, albuterol, metaproternol, terbutaline, pirbuterol, rimiterol, clenbuterol, bitolterol and reproterol;
(iii) the anticholinergic is selected form the group consisting of ipratrupium, flutropium, tiotropium and rispenzepine;
(iv) the mast cell stabilizer is selected from the group consisting of cromolyn and nedocromil; and (v) the PDE inhibitor is selected from the group consisting of tolafentrine, piclamilast, rolipram, filaminast, denbufylline, and zardaverine.
5. The composition of claim 3 wherein the compound that donates, transfers or releases nitric oxide is a S-nitrosothiol.
6. The composition of claim 5 wherein the S-nitrosothiol is selected from the group consisting of those having the structures:
(i) CH3[C(R e)(R f)]x SNO;

(ii) HS[C(R e)(R f)]x SNO;
(iii) ONS[C(R e)(R f)x B; and (iv) H2N-(CO2H)-(CH2)x-C(O)NH-C(CH2SNO)-C(O)NH-CH2-CO2H
wherein x equals 2 to 20; R e and R f are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, hereroaryl, arylalkyl, alkylamino, dialkylamino or taken together are carbonyl, cycloalkyl or bridged cycloalkyl; and B is selectedfrom the group consisting of fluoro, alkoxy, cyano, carboxamido, cycloalkyl, arylkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl.
7. The composition of claim 3 wherein the compound that donates, transfers or releases nitric oxide is selected from the group consisting of:
(i) compounds that include at least one ON-O-, ON-N- or ON-C- group;
(ii) a 2-hydroxy-2-nitrosohydrazine which has an R61R62-N(O-M+)-NO group wherein R61 and R62 include polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, hydrocarbons where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon or anaromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds;
(iii) a thionitrate which has the structure R70-S-NO2 wherein R10 includes polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, anda hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon or an aromatic hydrocarbon; and (iv) a nitrate which has the structure R70-O-NO2 wherein R70 is as defined above.
8. The composition of claim 3 wherein the compound that stimulates the endogenous production of NO or EDRF in vivo is selected from the group consisting of L-arginine, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein and endothelein.
9. A composition comprising (i) a compound selected from the group consisting of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer and a PDE inhibitor to which is directly or indirectly linked at least one nitro or nitroso group or a group which stimulates endogenous synthesis of NO or EDRF in vivo and (ii) a compound that donates, transfers or releases nitric oxide or elevatesendogenous synthesis levels of nitric oxide.
10. The composition of claim 9 wherein the steroid, .beta.-agonist, anticholinergic, mast cell stabilizer or PDE inhibitor is a compound which has been linked through a site selected from the group consisting of oxygen, sulfur, carbon and nitrogen.
11. The composition of claim 9 wherein compound (i) is selected from the group consisting of:

(i) compounds having the structure:

wherein A is selected from -CH=CH- or-CH2-CH2-;
R1 is selected from (1) -C(O)CH2-B-D wherein B is oxygen or sulfur; D is selected from (i) -NO; (ii) -NO2; (iii) -C(R d)-O-C(O)-Y-[C(R e)(R f)]p-T-Q in which R d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl, Y is oxygen, sulfur, or NR i in which R i is hydrogen, lower alkyl, lower haloalkyl, or heteroaryl, R e and R f are at each occurance independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, carboxy, carboxamido, or taken together are carbonyl, cycloalkyl or bridged cycloalkyl, pis an integer from 1 to 6, T is a covalent bond, oxygen, sulfur or nitrogen and Q is selected from -NO or -NO2; (iv) -C(O)-T1-[C(R e)(R f)]p-T2-Q wherein T1 and T2 are independently selected from T and R e, R f, p, Q, and T are as defined above;
(v) -C(O)-T[C(R y)(R z)]p wherein R y and R z are independently selected from -T1-[C(R e)(R f)]p-G-[C(R e)(R f)]p-T2-Q wherein G is (i) a covalent bond; (ii) -T-C(O)-;
(iii) -C(O)-T, or (iv) Y, and wherein R d, R e, R f, p, Q, T, and Y are as defined above;
(2) -C(O)-C(O)-O-R i wherein R i is as defined above;
(3) -C(O)-B-R i wherein B and R i are as defined above;
(4) -C(O)-CH2-B-C(O)-R i wherein B and R i are as defined above;
(5) -C(O)-CH2-X wherein X is halogen;
(6) -S-R i wherein R i is as defined above;
(7) -C(O)CH2-B-M wherein M is selected from -C(O)T-[C(R e)(R f)]p-G-[C(R e)(R f)]p-N[N-(O-)N=O]- R i or -C(R d)-O-C(O)T-[C(R e)(R f)]p-G-[C(R e)(R f)]p-N[N-(O-)N=O]-R i wherein R e, R f, R i, p, G and T are as defined above;
R2 and R3 are independently selected from hydrogen, hydroxyl, lower alkyl, -O(O)C-R i, or -S-R i wherein R i is as defined above or R2 and R3 when taken together are wherein R1; and R2; are independently selected from R i wherein R i is as defined above;
R4 and R5 are independently selected from hydrogen or halogen;
R6 is selected from hydrogen, D, or M wherein D and M are as defined above with the provision that R6 must be D or M if the selection for R1 does not include D or M;
(ii) compounds having the structure:

wherein, E is nitrogen or C-R7 wherein R7 is hydrogen, halogen, -CH2O-R j, or -O-R j wherein R j is hydrogen, D or M wherein D and M are defined as above;
R8 and R9 are independently selected from amino, hydrogen, -CH2O-R j, or -O-R k, wherein R k is -C(O)- R d or R j and R d and R j are as defined above;
S is (1) -CH2-N(Z)-R10 wherein Z is hydrogen, -[N(O-)N=O], or M wherein M is as defined above and R10 is selected from (i) lower alkyl (ii) -(CH2)p-O-(CH2)a-C6H5 wherein a is an integer from 1 to 4 and p is as defined above;

wherein Z is as defined above; and R11 is selected from hydrogen, D, or M with the provision that R11 must be D
or M if neither R8 or R9 include D or M and Z is hydrogen;
(iii) compounds having the structure:

wherein, K is a a monovalent anion selected from halide, nitrate, or nitrite;
R12 and R13 are hydrogen or, when taken together are oxygen;
R14 is lower alkyl or haloalkyl;
R15 is selected from:

wherein R v is selected from D or M and D and M are as defined above;
(iv) compounds having the structure:

wherein R14 is as defined above;
R16 is selected from hydrogen, -C(R d)-O-C(O)-Y-[C(R e)(R f)]p-T-Q, -C(O)-T1-[C(R e)(R f)]p- T2-Q, or M; and wherein R d, R e, R f,, M, p, T, T1, T2, Q, and Y are defined as above; and R17 and R18 are independently selected from a lone pair of electrons, -C(R d)-O- C(O)-Y-[C(R e)(R f)]p-T-Q, or M wherein R d, R e, R f,, M, p, T, Q, and Y are defined as above with the provision that R17 and/or R18 must be -C(R d)-O-C(O)-Y-[C(R e)(R f)]p-T-Q or M when R16 is hydrogen;
(v) compounds having the structure:

wherein R19 is selected from -[C(R e)(R f)]p-G-[C(R e)(R f)]p-T-Q or -S(O2)-[C(R e)(R f)]p-G-[C(R e)(R f)]p-N[N-(O-)N=O]- R i wherein R e, R f, R i, p, G, Q and T are as defined above; and wherein R14, R17, and R18 are as defined above;

(vi) compounds having the structure:

wherein, F is selected from oxygen or NR i wherein R i is as defined above;
R20 and R21 are independently selected from (1) -Y-[C(R e)(R f)]p-H-[C(R e)(R f)]p- T-Q; wherein H is (i) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T;
(iv) -C(Y-C(O)-R m)- wherein R m is heteroaryl or heterocyclic ring; and wherin Y, R d, R e, R f, p, Q and T are as defined above; (2) T-[C(R e)(R f)]p-H-[C(R e)(R f)]p-N[N-(O-)N=O]- R i wherin R d, R e, R f, R i, p, H and T are as defined above; (3) in which W is a heterocyclic ring or NR s R's wherein R s and R's are independently selected from lower alkyl, aryl or alkenyl; (4) sodium or (5) hydrogen;
R22 is hydrogen, M, or D with the provision that R22 must be M or D when R20 and R21 are selected as sodium or hydrogen;

(vii) compounds having the structure:

wherein, R23 is alkoxy, cycloalkoxy, or halogen;
R24 is hydrogen, alkoxy, or haloalkoxy; and R25 is selected from:

wherein X is halogen and R26 is selected from D or M and wherein R16, R18, and R19 are defined as above.
12. The composition of claim 9 wherein (i) the steroid is selected from the group consisting of beclomethasone, fluticasone, flunisoloide, triamicnolone, butixocort, dexamethasone, fluocortin,budesonide, tixocortol, tipredane and mometasone;
(ii) the .beta.-agonist is selected from the group consisting of salmeterol, albuterol, metaproternol, terbutaline, pirbuterol, clenbuterol, bitolterol and reproterol;
(iii) the anticholinergic is selected form the group consisting of ipratropium, flutropium, tiotropium and rispenzepine;
(iv) the mast cell stabilizer is selected from the group consisting of cromolyn and nedocromyl; and (v) the PDE inhibitor is selected from the group consisting of filaminast, denbufyllene, piclamilast, zardaverine and rolipram.
13. The composition of claim 9 wherein the compound that donates, transfers or releases nitric oxide is a S-nitrosothiol.
14. The composition of claim 13 wherein the S-nitrosothiol is selected from the group consisting of those having the structures:

(i) CH3[C(R e)(R f)]x SNO;
(ii) HS[C(R e)(R f)]x SNO;
(iii) ONS[C(R e)(R f)]x B; and (iv) H2N-(CO2H)-(CH2)x-C(O)NH-C(CH2SNO)-C(O)NH-CH2-CO2H
wherein x equals 2 to 20; R e and R f are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, hereroaryl, arylalkyl, alkylamino, dialkylamino or taken together are carbonyl, cycloalkyl or bridged cycloalkyl; and B is selectedfrom the group consisting of fluoro, alkoxy, cyano, carboxamido, cycloalkyl, arylkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl,N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl.
15. The composition of claim 13 wherein the compound that donates, transfers or releases nitric oxide is selected from the group consisting of:
(i) compounds that include at least one ON-O-, ON-N- or ON-C- group;
(ii) a N-oxo-N-nitrosoamine which has an R61R62-N(O-M+)-NO group wherein R61 and R62 include polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, hydrocarbons where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon or anaromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds; and (iii) a thionitrate which has the structure R70-S-NO2 wherein R70 includes polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, anda hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon or an aromatic hydrocarbon; and (iv) a nitrate which has the structure R70-O-NO2 wherein R70 is as defined above.
16. The composition of claim 9 wherein the compound that stimulates the endogenous production of NO or EDRF in vivo is selected from the group consisting of L-arginine, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, and endothelein.
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