NITROSATED AND NITROSYLATED alpha -ADRENERGIC RECEPTOR ANTAGONIST COMPOUNDS, COMPOSITIONS AND THEIR USES

Abstract: Disclosed are nitrosated and nitrosylated alpha -adrenergic receptor antagonists, compositions of an alpha -adrenergic receptor antagonist ( alpha -antagonist), which can optionally be substituted with at least one NO or NO2 moiety, 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.); and uses for each of them in treating human impotence or erectile dysfunction.

Description: NITROSATED AND NITROSYLATED α-ADRENERGIC RECEPTOR ANTAGONIST COMPOUNDS, COMPOSITIONS AND THEIR USES This application is a continuation-in-part of U.S. patent application serial no. 08/595.732 filed February 2. 1996 (copending). This invention generally relates to α-adrenergic receptor antagonists, compositions containing them and their use in treating human male impotence. Erectile dysfunction or impotence is a widespread disorder that is thought to affect about ten to fifeteen percent of adult men. Some pharmacological methods of treatment are available. Such methods, however, have not proven to be highly satisfactory or without potentially severe side-effects. Papaverine is now widely used to treat impotence, although papaverine is ineffective in overcoming impotence due. at least in part, to severe atherosclerosis. Papaverine is effective in cases where the dysfunction is psychogenic or neurogenic and severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific antagonist and hypotensive, into a corpus cavernosum has been found to cause an erection sufficient for vaginal penetration however, these treatments are not without the serious and often painful side effect of priapisim. Also, in cases where severe atherosclerosis is not a cause of the dysfunction, intracavernosal injection of phentolamine, an α-adrenergic antagonist, is used. As an alternative or. in some cases. an adjunct to α-adrenergic blockade, prostaglandin El (PGEl ) has been administered via intracavernosal injection. A major side effect frequently associated with intracorprally delivered PGEl is penile pain and burning. Thus, there is a need for treatments of human male impotence without the undesirable side effects of those agents currently used. Nitric oxide (NO) and NO donors have been recognized as mediators of nonvascular smooth muscle relaxation. This effect includes the dilation of the corpus cavemosum smooth muscle, an event involved in the penile erection process. However, the effects of such compounds together with α-adrenergic receptor antagonists or the modifications of α-adrenergic receptor antagonists to be directly or indirect!} linked with a nitric oxide adduct have not been investigated. In the process of arriving at the present invention it was recognized that the risk of toxicities and adverse effects that are associated with high doses of α-adrenergic receptor antagonists can be avoided by the use of such α-adrenergic receptor antagonists when nitrosated or nitrosylated or when administered in conjunction with compounds that donate, release or transfer nitric oxide. Such toxicities and adverse effects include postural hypotension, reflex tachycardia and other arrythmias, syncope and. with respect to the ergot alkaloids, nausea and vomiting and, upon prolonged or excessive administration, vascular insufficiency and gangrene of the extremities. The α-adrenergic receptor antagonists and compounds that donate, release or transfer nitric oxide work together to permit the same efficacy with lower doses of the α-adrenergic receptor antagonists. Accordingly, in one aspect the invention provides novel nitrosated and nitrosylated α-adrenergic receptor antagonists (NO„-α-antagonists) wherein n is 1 or 2. The α-adrenergic antagonist can be nitrosylated or nitrosated through sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and nitrogen. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. In another aspect the invention provides a composition comprising a therapeutically effective amount of an α-adrenergic receptor antagonist (α-antagonist). which can optionally be substituted with at least one NO or NO : moiety, 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*), preferably in a one to ten fold molar excess. The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier. The α-adrenergic receptor antagonist used in the composition can be those described above and others which are known and can alternatively be such α-antagonists which have been nitrosated or nitrosylated in accordance with the invention. In another aspect, the invention provides a method for treating male impotence in humans which comprises administering to an individual in need thereof a therapeutically effective amount of a nitrosated or nitrosylated α-antagonist. In another aspect, the invention provides a method for treating male impotence in humans which comprises administering to an individual in need thereof a composition comprising a therapeutically effective amount of an α-antagonist which can optionally be substituted with at least one NO or NO, moiety, 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»). The α-antagonist or α-antagonist directly or indirectly linked to at least one NO or NO, group, and nitric oxide donor can be administered separately or as components of the same composition. Figure 1 shows the percent peak erectile response in vivo compared to that produced by 150 μl of papaverine/phent amine/PGEl (pap/phent/PGEl ) (30 mg/ml: 1 mg/ml: 10 μg/ml) in the anesthetized rabbit following the intracavernosal injection of 150 μl of yohimbine (150 μg. 500 μg). Example 1 (500 μg). and a combination of yohimbine (150 μg) and Example 1 (500 μg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various drugs given. Figure 2 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of yohimbine (150 μg, 500 μg). Example 1 (500 μg), and a combination of yohimbine (150 μg) and Example 1 (500 μg). The ordinate indicates the various drugs given and the abscissa is the duration in minutes. Figure 3 shows the percent peak erectile response in vivo compared to that produced by 150 μl of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 μg/ml) in the anesthetized rabbit following the intracavernosal injection of yohimbine (150 μg. 500 μg and 1 mg) and Example 2 (500 μg, 1 mg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various doses of yohimbine and Example 2 given. Figure 4 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of yohimbine (150 μg, 500 μg and 1 mg) and Example 2 (500 μg and 1 mg). The ordinate indicates the various doses of yohimbine and Example 2 given and the abscissa is the duration in minutes. Figure 5 compares the effects of intracavernosal injections of Example 2 (500 μg) and the standard mixture of pap/phent/PGEl on systemic blood pressure in the anesthetized rabbit. Figure 6 shows the percent peak erectile response in vivo compared to that produced by 150 μl of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 μg/ml) in the anesthetized rabbit following the intracavernosal injection of moxisylyte ( 1 mg) and Example 6 (1 mg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the dose of moxisylyte and Example 6 given. Figure 7 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of moxisylyte ( 1 mg) and Example 6 ( 1 mg). The ordinate indicates the dose of moxisylyte and Example 6 the abscissa is the duration in minutes. The term "lower alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl. n-butyl. t-butyl. neopentyl and the like. The term "alkoxy" as used herein refers to R 50 O- wherein R 50 is lower alkyl as defined above. Representative examples of alkoxy groups include methoxy. ethoxy. t-butoxy and the like. The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to. methoxymethyl. methoxyethvl. isopropoxvmethvl and the like. The term "hydroxy" as used herein refers to -OH. The term "hydroxyalkyl" as used herein refers to a hydroxy group as previously defined appended to a alkyl group as previously defined. The term "alkenyl" as used herein refers to a branched or straight chain C,-C 10 hydrocarbon which also comprises one or more carbon-carbon double bonds. The term "amino" as used herein refers to -NH,. The term "carboxy" as used herein refers to -C(O)O-. The term "nitrate" as used herein refers to -O-NO,. The term "amido" as used herein refers to -C(O)NH-. The term "alkylamino" as used herein refers to R,,NH- wherein R n is a lower alkyl group, for example, methylamino. ethylamino. butylamino, and the like. The term "alkylamido" as used herein refers to -C(O)NR, r wherein R n is defined as above. The term "dialkylamino" as used herein refers to R,,R π N- wherein R,, and R are independently selected from lower alkyl. for example dimethylamino, diethylamino. methyl propylamino and the like. The term "nitro" as used herein refers to the group -NO, and "nitrosated" refers to compounds that have been substituted therewith. The term "nitroso" as used herein refers to the group -NO and "nitrosylated" refers to compounds that have been substituted therewith. The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to. phenyl. naphthyl. tetrahydronaphthyl, indanyl, indenyl. and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one. two or three substituents independently selected from loweralkyl. haloalkyl. alkoxy. amino. alkylamino. dialkylamino. hydroxy, halo, and nitro. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl. The term "arylalkyl" as used herein refers to a lower alkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl. hydroxybenzyl. fluorobenzyl. fluorophenylethyl and the like. The term "cycloalkyl" as used herein refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl. cyclobutyl. cyclopentyl. cyclohexyl and the like. The term " halogen" or "halo" as used herein refers to I, Br, Cl, or F. The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent. for example, chloromethyl, fluoroethyl or trifluoromethyl and the like. The term "heteroaryl" as used herein refers to a mono- or bi- cyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroaryl groups (including bicyclic heteroaryl groups) can be unsubstituted or substituted with one. two or three substituents independently selected from lower alkyl. haloalkyl. alkoxy. amino. alkylamino, dialkylamino, hydroxy, halo and nitro. Examples of heteroaryl groups include but are not limited to pyridine. pyrazine. pyrimidine. pyridazine. pyrazole. triazole. thiazole, isothiazole. benzothiazole. benzoxazole. thiadiazole. oxazole. pyrrole, imidazole and isoxazole. The term "heterocyclic ring" refers to any 3-. 4-. 5-, 6-. or 7-membered nonaromatic ring containing at least one nitrogen atom, oxygen atom, or sulfur atom. The term "arylheterocyclic ring" as used herein refers to a bi- or tricyclic ring comprised of an aryl ring as previously defined appended via two adjacent carbons of the aryl group to a heterocyclic ring as previously defined. The term "heterocyclic compounds" herein refers to mono and polycyclic compounds containing at least one heteroaryl or heterocyclic ring. Compounds of the invention which have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers. mixtures of enantiomers. mixtures of diastereomers. racemic mixtures of enantiomers. diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof. The α-adrenergic receptor antagonists that are nitrosated or nitrosylated in accordance with the invention and/or are included in the compositions of the invention can be any of those known to the art. including those exemplified below. Structurally, the α- antagonists can generally be categorized as haloalkylamines, imidazolines. quinozolines. indole derivatives, phenoxypropanolamines, alcohols, alkaloids, amines, piperizines and piperidines. The first group of α-antagonists are the haloalkylamines that block a,- and a,- adrenergic receptors irreversibly. Included in this group are. for example, phenoxybenzamine and dibenamine. Phenoxybenzamine is used in the treatment of pheochromocytomas. tumors of the adrenal medulla and sympathetic neurons that secrete catecholamines into the circulation. It controls episodes of severe hypertension and minimizes other adverse effects of catecholamines such as contraction of plasma volume and injury ofthe myocardium. Another group of such α-antagonists are the imidazolines. These include phentolamine and tolazoline. Phentolamine has similar affinity for a, and a, receptors. Phentolamine is used in short-term control of hypertension in patients with pheochromocytoma and direct, intracavemous injection of phentolamine (usualh in combination with papaverine) has been proposed as a treatment for male sexual dysfunction. Tolazoline is used in the treatment of persistent pulmonary hypertension in neonates. Others include idazoxan, deriglidole, RX 821002. BRL 44408 and BRL 44409 (see Eur. J. Pharm., 7r5c?:381, 1989) Another group of α-antagonist compounds that are contemplated are the quinazolines. These include, for example, prazosine. a very potent and selective a,- adrenergic antagonist, terazosin. doxazosin. alfuzosin, bunazosin. ketanserin. trimazosin and abanoquil. This group of compounds is principally used in the treatment of primary systemic hypertension and also in the treatment of congestive heart failure. Another class of such α-adrenergic blocking agents are indole derivatives. These include, for example, carvedilol and BAM 1303. Another class of such α-adrenergic blocking agents are alcohols. These include, for example, labetelol and ifenprodil. Another class of such α-adrenergic blocking agents are alkaloids. These include, for example, "ergotoxine." which is a mixture of three alkaloids, i.e.. ergocomine, ergocristine and ergocryptine. Both natural and dihydrogenated peptide alkaloids produce α-adrenergic blockade. The principal uses are to stimulate contraction of the uterus post- partum and to relieve the pain of migraine headaches. Another indole alkaloid is yohimbine. This compound is a competitive antagonist that is selective for a,- adrenergic receptors. In humans, it has been observed to increase blood pressure and heart rate and has been used in the treatment of male sexual dysfunction. Other alkaloid α-blockers include rauwolscine, corynathine, raubascine, tetrahydroalstonine. apoyohimbine. akuammigine. β-yohimbine. yohimbol. pseudoyohimbine and epi-3α- yohimbine. Another class of such α-adrenergic blocking agents are amines. These include, for example, tamsulosin. benoxathian. atipamezole, BE 2254, WB 4101 and HU-723. Another class of such α-adrenergic blocking agents are piperizines. These include, for example, naftopil and saterinone. Another class of such α-adrenergic blocking agents are piperidines. These include, for example, haloperidol. Each of the above contemplated α-antagonists is described more fully in the literature, such as in Goodman and Gilman. The Pharmacological Basis of Therapeutics (8th Edition). McGraw-Hill, 1993, Pgs. 638-381. One embodiment of this aspect includes substituted compounds of the formula: wherein. R a is selected from hydrogen or alkoxy; R h is selected from wherein a is an integer of 2 or 3; R c is selected from heteroaryl. heterocyclic ring, lower alkyl. hydroxyalkyl. and arylheterocyclic ring; D is selected from (i) -NO; (ii) -NO,; (iii) -C(R d )-O-C(O)-Y-Z-[C(R e )(R f )] μ -T-Q in which R d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl. Y is oxygen, sulfur, or NR, in which R, is hydrogen, lower alkyl, R e and R i are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl. heteroaryl. arylalkyl, amino. alkylamino. amido. alkylamido, dialkylamino. carboxy, 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. Z is selected from a covalent bond, alkyl, cycloalkyl. aryl. heteroaryl. arylalkyl or arylheterocyclic ring, and Q is selected from -NO or -NO,; (iv) - C(O)-T'-Z-[C(R e )(R f )] p - T 2 -Q wherein T 1 and T are independently selected from T and R e . R f . p. Q. Z. and T are as defined above; (v) -C(0)-T[C(R (R ? )] p wherein R, and R z are independently selected from -T'-[C(R e )(R f )] p -G-[C(R e )(R f )] p -T -Q wherein G is (/) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T. or (iv) Y. and wherein R d , R e . ^. p. Q. T. and Y are as defined above; Another embodiment of this aspect is substituted compounds ofthe formula: wherein, R u , is selected from: wherein D, is selected from hydrogen or D wherein D is as defined above and with the proviso that D, must be selected from D if there is no other D in the molecule. Another embodiment of this aspect includes substituted compounds ofthe formula: III. I I wherein R h is selected from hydrogen. -C(O)-OR d or -C(O)-X wherein X is ( 1 ) -Y-[C(R e )(R f )] p -G,-[C(R e )(R f )] p -T-Q; wherein G, is (i) a covalent bond: (ii) -T-C(O)-: (iii) -C(O)-T; (iv) -C(Y-C(O)-R m )- wherein R ^ is heteroaryl or heterocyclic ring: and in which Y , R d . R e . R f , p, Q and T are as defined above; or (2) in which W is a heterocyclic ring or NR,R', wherein R, and R', are independently selected from lower alkyl, aryl or alkenyl; and wherein R } is selected from -D. hydrogen, or - (O)CR d wherein D and R d are as defined above. Another embodiment of this aspect includes substituted compounds ofthe formula: IV. wherein, A, is oxygen or methylene and X and R ( are as defined above. Another embodiment of this aspect includes substituted compounds of the formula: V. wherein, R and R ' k are independently selected from hydrogen or lower alkyl; and wherein R, is selected from: wherein b is an integer of 0 or 1 : D and D, are as defined above; and R„ is selected from: wherein A, is oxygen or sulfur. Another embodiment of this aspect includes substituted compounds of the formula: VI. wherein R„ is selected from: and R p is selected from: aand R k . D. and D, are as defined above. Another embodiment of this aspect includes substituted compounds of the formula: VII. wherein R d . T and D are defined as above. Another embodiment of this aspect includes substituted compounds of the formula: VIII. wherein a, R,, R',, R c , R f . and D are defined as above. The present invention also relates to processes for preparing the compounds of formula (I), (II), (III). (IV). (V). (VI). (VII). or (VIII) and to the intermediates useful in such processes. Some of the nitrosated and nitrosylated α-antagonists of the present invention may be synthesized as shown in reaction Schemes I through XXI presented below, in which R a . R b , R c . R d . R e , R f , R g . R h . R ± , R ' ,. R .. R k . R,. R^. R__. R o . R p . A,. A 2 . a. n. W and X are as defined above or as depicted in the reaction schemes for formulas I. II. III. IV . V. VII. or VIII. P 1 is an oxygen protecting group and P 2 is a sulfur protecting group. The reactions are performed in solvents appropriate to the reagents and materials employed are suitable for the transformations being effected. It is understood by those skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some ofthe reaction conditions required in some ofthe methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to skilled practitioners in the art. The use of sulfur and oxygen protecting groups is well known in the art for protecting thiol and alcohol groups against undesirable reactions during a synthetic procedure and many such protecting groups are known, cf.. T.H. Greene and P.G.M. Wuts. Protective Groups in Organic Synthesis. John Wiley & Sons. New York (1991 ). The chemical reactions described above are generally disclosed in terms of their broadest application to the preparation ofthe compounds of this invention. Occasionally, the reactions may not be applicable as described to each compound included within the disclosed scope. The compounds for which this occurs will be readily recognized by those skilled in the art. In all such cases, either the reactions can be successfully performed by conventional modifications known to those skilled in the art. e.g.. by appropriate protection of interfering groups, by changing to alternative conventional reagents, by routine modification of reaction conditions, and the like, or other reactions disclosed herein or otherwise conventional, will be applicable to the preparation of the corresponding compounds of this invention. In all preparative methods, all starting materials are known or readily preparable from known starting materials. Nitroso compounds of formula (I ) wherein R a . R b . R e . R f . and p are as defined above and an O-nitrosylated amide is representative of the D group as defined above may be prepared according to Scheme I. The amine group ofthe quinazoline of the formula 1 is converted to the amide ofthe formula 2 wherein p. R e and R f are as defined above by reaction with an appropriate protected alcohol containing activated acylating agent wherein P' is as defined above. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected alcohol-containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula IA. Scheme I Nitroso compounds of formula (I) wherein R a . R h . R e . R i . and p are defined as above and an S-nitrosylated amide is representative of the D group as defined above may be prepared according to Scheme II. The amine group ofthe quinazoline ofthe formula 1 is converted to the amide ofthe formula 3 wherein p. R e and R f are defined as above b\ reaction with an appropriate protected thiol-containing activated acylating agent wherein P " is as defined above. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate. as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate. or as a thioether such as a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert- butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride, THF, DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula IB. Alternatively, treatment of compound 3 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound ofthe formula IB. Nitro compounds of formula (I) wherein R a . R b , R e , R f , and p are defined as above and an O-nitrosated amide is representative ofthe D group as defined above may be prepared according to Scheme III. The amine group ofthe quinazoline of the formula 1 is converted to the amide ofthe formula IC wherein p, R e and R f are defined as above by reaction with an appropriate nitrate containing activated acylating agent. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of the formula IC. Nitroso compounds of formula (II) wherein R e , R f , R p , and p are defined as above and an O-nitrosylated acyl imidazoline is representative of the D group as defined above may be prepared according to Scheme IV. The imidazoline group ofthe formula 4 is converted to the acyl imidazoline ofthe formula 5 wherein p, R c and R f are defined as above by reaction with an appropriate protected alcohol containing activated acylating agent wherein P 1 is as defined above. Preferred methods for the formation of acyl imidazolines are reacting the imidazoline with the preformed acid chloride or symmetrical anhydride ofthe protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert- butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane. THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula HA. Scheme IV 11 A Nitroso compounds of formula (II) wherein R e , R f . R p . and p are defined as above and an S-nitrosylated acyl imidazoline is representative of the D group as defined above may be prepared according to Scheme V. The imidazoline group of the formula 4 is converted to the acyl imidazoline ofthe formula 6 wherein p. R e and R f are defined as above by reaction with an appropriate protected thiol containing activated acylating agent wherein P 2 is as defined above. Preferred methods for the formation of acyl imidazolines are reacting the imidazoline with the preformed acid chloride or symmetrical anhydride ofthe protected thiol containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate. or as a thioether such as a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride. THF. DMF or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIB. Alternatively, treatment of compound 6 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound of the formula IIB. " Scheme V IIB Nitro compounds of formula (II) wherein R e , R f , R„, and p are defined as above and an O-nitrosated acyl imidazoline is representative of the D group as defined above may be prepared according to Scheme VI. The imidazoline group of the formula 4 is converted to the acyl imidazoline of the formula IIC wherein p. R e and R f are defined as above by reaction with an appropriate nitrate containing activated acylating agent. Preferred methods for the formation of acyl imidazolines are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound ofthe formula IC. Scheme VI IIC Nitroso compounds of formula (III) wherein R e . R f . R h . R.. and p are defined as above and an O-nitrosylated ester is representative of the D group as defined above may be prepared according to Scheme VII. The alcohol group of formula 7 is converted to the ester of formula 8 wherein p. R c and R f are defined as above by reaction with an appropriate protected alcohol containing activated acylating agent wherein P' is as defined above. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride ofthe protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane. THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula IIIA. Scheme VII Nitroso compounds of formula (III) wherein R e . R f . R,,. R_. and p are defined as above and an S-nitrosylated ester is representative ofthe D group as defined above may be prepared according to Scheme VIII. The alcohol group of the formula 7 is converted to the ester of the formula 9 wherein p. R e and R f are defined as above by reaction with an appropriate protected thiol containing activated acylating agent wherein P is as defined above. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride ofthe protected thiol containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate. as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate. or as a thioether such as a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection ofthe thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride. THF, DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula IIIB. Alternatively, treatment of compound 9 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound ofthe formula IIIB. Scheme VIII Nitro compounds of formula (III) wherein R e . R f , R h , R j , and p are defined as above and an O-nitrosated ester is representative ofthe D group as defined above may be prepared according to Scheme IX. The alcohol group ofthe formula 7 is converted to the ester of the formula IIIC wherein p, R e and R f are defined as above by reaction with an appropriate nitrate containing activated acylating agent. Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford a compound of the formula IIIC Nitroso compounds of formula (IV) wherein A,. R e . R f . R n . R r and p are defined as above and an O-nitrosylated ester is representative ofthe X group as defined above may be prepared according to Scheme X. An acid of the formula 10 is converted into the ester ofthe formula 11 wherein p, R e , and R f are defined as above by reaction with an appropriate monoprotected diol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloro formate such as isobutylchloroformate in the presence of a non nucleophilic base such as triethylamine in an anhydrous inert solvent such as dichloromethane. diethylether, or THF. The mixed anhydride is then reacted with the monoprotected alcohol preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine. Alternatively, the acid 10 may be first converted to the acid chloride be treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the monoprotected alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamino- pyridine and a tertiary amine base such as triethyl amine to afford the ester 11. Alternatively, the acid 10 and monoprotected diol may be coupled to afford 11 by treatment with a dehydration agent such as dicyclohexylcarbodiimide. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert- butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. or nitrosium tetrafluoro borate in a suitable anhydrous solvent such as dichloromethane. THF, DMF. or acetonitrile affords the compound ofthe formula IVA. Scheme X IVA Nitroso compounds of formula (IV) wherein A,, R e . R f . R h , R j . and p are defined as above and an S-nitrosylated ester is representative ofthe X group as defined above may be prepared according to Scheme XI. An acid of the formula 10 is converted into the ester of the formula 12 wherein p. R e . and R f are defined as above and a S-nitrosylated ester is representative ofthe X group as defined above by reaction with an appropriate protected thiol containing alcohol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloroformate such as isobutylchloroformate in the presence of a non nucleophilic base such as triethylamine in an anhydrous inert solvent such as diethylether or THF. The mixed anhydride is then reacted with the thiol containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine. Alternatively, the acid 10 may be first converted to the acid chloride be treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the monoprotected thiol preferably in the presence of a condensation catalyst such as 4-dimethylaminopyridine and a tertiary amine base such as triethyl amine to afford the ester 12. Alternatively, the acid and thiol containing alcohol may be coupled to afford 12 by treatment with a dehydration agent such as dicyclohexylcarbodiimide. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate. as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate. or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether. or a S-triphenylmethyl thioether. Deprotection ofthe thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thiolesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride. THF. DMF or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IVB. Alternatively, treatment of compound 12 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound ofthe formula IVB. Scheme XI IVB Nitro compounds of formula (IV) wherein A,, R e , R f , R h , R } , and p are defined as above and an O-nitrosated ester is representative ofthe X group as defined above may be prepared according to Scheme XII. An acid ofthe formula 10 is converted into the ester of the formula IVC wherein p. R t . and R f are defined as above by reaction with an appropriate nitrate containing alcohol. Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloroformate such as isobutylchloroformate in the presence of a non nucleophilic base such as triethylamine in an anhydrous inert solvent such as dichloromethane, diethylether, or THF. The mixed anhydride is then reacted with the nitrate containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamino-pyridine. Alternatively, the acid 10 may be first converted to the acid chloride be treatment with oxalyl chloride in the presence of a catalytic amount of DMF. The acid chloride is then reacted with the nitrate containing alcohol preferably in the presence of a condensation catalyst such as 4- dimethylaminopyridine and a tertiary amine base such as triethyl amine to afford the a compound ofthe formula IVC. Alternatively, the acid 10 and nitrate containing alcohol may be coupled to afford a compound ofthe formula IVC by treatment with a dehydration agent such as dicyclohexylcarbodiimide. Scheme XII Nitroso compounds of formula (V) wherein R e , R f . R . R,, R„. and p are defined as above and an O-nitrosylated N-acyloxyalkyl amine is representative ofthe D group as defined above may be prepared according to Scheme XIII. The amine group ofthe compound of the formula 13 is converted to the N-acyloxyalkyl amine ofthe formula 14 wherein p, R e . and R f . are defined as above by reaction with an appropriate protected alcohol containing chloromethyl acyl derivative wherein P' is as defined above. Preferred methods for the formation of N-acyloxyalkyl amines are reacting the amine with the preformed chloromethyl acyloxyalkyl derivative ofthe protected alcohol. Preferred protecting groups for the alcohol moiety are silyl ethers such as a triethylsilyl or a tert- butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. or nitrosium tetrafluoro borate in a suitable anhydrous solvent such as dichloromethane. THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula VA. Scheme XIII / VA Nitroso compounds of formula (V) wherein R e . R f , R k . R,. R„. and p are defined as above and an S-nitrosylated N-acyloxyalkyl amine is representative ofthe D group as defined above may be prepared according to Scheme XIV. The amine group ofthe compound ofthe formula 13 is converted to the N-acyloxyalkyl amine of the formula 15 wherein p, R e . and R f . are defined as above by reaction with an appropriate protected thiol containing chloromethyl acyl derivative wherein P 2 is as defined above. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate. as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate. or as a thioether such as a tetrahydropyranyl thioether. Deprotection ofthe thiol moiety (triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate or silver nitrate are used to remove a tetrahydropyranyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert- butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride. THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula VB. Scheme XIV VB Nitro compounds of formula (V) wherein R e , R f , R k . R„ R^. and p are defined as above and an O-nitrosated N-acyloxyalkyl amine is representative ofthe D group as defined above may be prepared according to Scheme XV. The amine group ofthe compound of the formula 13 is converted to the N-acyloxyalkyl amine of the formula VC wherein p. R e , and R f are defined as above by reaction with an appropriate nitrate containing chloromethyl acyl derivative. Preferred methods for the formation of N- acyloxyalkyl amines are reacting the amine with the preformed chloromethyl acyloxyalkyl derivative ofthe nitrate containing derivative to afford the compound ofthe formula VC. Scheme XV 13 VC Nitroso compounds of formula (VII) wherein R d . R e . R f . T. and p are defined as above and an O-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme XVI. The amine group of the dihydropyridine of the formula 14 is converted to the amide ofthe formula 15 wherein p. R e and R f are defined as above by reaction with an appropriate protected alcohol containing activated acylating agent wherein P 1 is as defined above. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride ofthe protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane. THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VII A. Scheme XVI Nitroso compounds of formula (VII) wherein R d . R f . R f . T. and p are defined as above and an S-nitrosylated amide is representative ofthe D group as defined above may be prepared according to Scheme XVII. The amine group of the dihydropyridine of the formula 14 is converted to the amide ofthe formula 16 wherein p. R e and R f are defined as above by reaction with an appropriate protected thiol containing activated acylating agent wherein P 2 is as defined above. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate. as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite. a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methvene chloride. THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIIB. Alternatively, treatment of compound 16 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound ofthe formula VIIB. Scheme XVII Nitro compounds of formula (VII) wherein R d . R c . R f . T. and p are defined as above and an O-nitrosated amide is representative of the D group as defined above may be prepared according to Scheme XVIII. The amine group ofthe dihydropyridine of the formula 14 is converted to the amide ofthe formula VIIC wherein p. R and R f are defined as above by reaction with an appropriate nitrate containing activated acylating agent. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of the formula VIIC. Scheme XVIII Nitroso compounds of formula (VIII) wherein R e . R f , R,. R " ,. a and p are defined s above and an O-nitrosylated ester is representative of the D group as defined above may be prepared according to Scheme XIX. The hydroxyl group ofthe phenol ofthe formula 17 is converted to the ester of the formula 18 wherein a. p. R e and R f are defined as above by reaction with an appropriate protected alcohol containing activated acylating agent wherein P' is as defined above. Preferred methods for the formation of esters are reacting the hydroxyl with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection ofthe hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as dichloromethane, THF, DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound ofthe formula VIIIA. Scheme XIX Nitroso compounds of formula (VIII) wherein R e , R f . R,, R',. a. and p are defined as above and an S-nitrosylated ester is representative ofthe D group as defined above may be prepared according to Scheme XX. The hydroxyl group of the phenol of the formula 17 is converted to the ester of the formula 19 wherein a. p. R e and R f are defined as above by reaction with an appropriate protected thiol containing activated acylating agent wherein P 2 is as defined above. Preferred methods for the formation of esters are reacting the hydroxyl with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate. as a disulfide. as a thiocarbamate such as N- methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether. Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N- methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride. THF. DMF. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula VIIIB. Alternatively, treatment of compound 17 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound of the formula VIIIB. Scheme XX Nitro compounds of formula (VIII) wherein R e . R f , R,, R " „ a. and p are defined as above and an O-nitrosated ester is representative ofthe D group as defined above may be prepared according to Scheme XXI. The hydroxyl group ofthe phenol of the formula 15 is converted to the ester of the formula VIIIC wherein a. p. R e and R f are defined as above by reaction with an appropriate nitrate containing activated acylating agent. Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound ofthe formula VIIIC. Scheme XXI VIIIC As noted above, another aspect the invention provides a composition comprising a therapeutically effective amount of an α-adrenergic receptor antagonist (α-antagonist). which can optionally be substituted with at least one NO or NO, moiety, 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 » ). Another embodiment of this aspect is one where the α-blocker is not substituted with at least one NO or NO, moiety. Additional α-blockers that are suitable for this embodiment include amines, such as tedisamil. mirtazipine, setiptiline. reboxitine and delequamine: amides, such as indoramin and SB 216469; piperizines. such as SL 89.0591. ARC 239. urapidil, 5-methylurapidil and monatepil. Indoramin is a selective, competitive a, -antagonist that has been used for the treatment of hypertension. Urapidil is also known to be a selective a,-adrenergic antagonist that has a hypotensive effect in humans. The compounds that donate, transfer or release nitric oxide can be any of those known to the art. including those mentioned and/or exemplified below. Nitrogen monoxide can exist in three forms: NO " (nitroxyl), NO* (nitric oxide) and NO " (nitrosonium). NO* is a highly reactive short-lived species that is potentially toxic to cells. This is critical, because the pharmacological efficacy of NO depends upon the form in which it is delivered. In contrast to NO*, nitrosonium and nitroxyl do not react with O-, or 0 species, and are also resistant to decomposition in the presence of redox metals. Consequently, administration of NO equivalents does not result in the generation of toxic by-products or the elimination ofthe active NO moiety. Compounds contemplated for use in the invention are nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, in vivo. As used here, the term "nitric oxide" encompasses uncharged nitric oxide (NO») and charged nitric oxide species, particularly including nitrosonium ion (NO " ) and nitroxyl ion (NO ). The reactive form of nitric oxide can be provided by gaseous nitric oxide. The nitric oxide releasing, delivering or transferring compounds, having the structure F-NO wherein F is a nitric oxide releasing, delivering or transferring moiety, include any and all such compounds which provide nitric oxide to its intended site of action in a form active for their intended purpose. As used here, the term "NO adducts" encompasses any of such nitric oxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols. S-nitrothiols, O-nitrosoalcohols. O-nitroalcohols, sydnonimines. 2-hydroxy-2- nitrosohydrazines (NONOates). (E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides, nitrosoamines. as well a subtstates for the endogenous enzymes which synthesize nitric oxide. It is contemplated that any or all of these "NO adducts" can be mono- or poly-nitrosylated or nitrosated at a variety of naturally susceptible or artificially provided binding sites for nitric oxide or derivatives which donate or release NO. One group of such NO adducts is the S-nitrosothiols. which are compounds that include at least one -S-NO group. Such compounds include S-nitroso-polypeptides (the term "polypeptide" includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof): S-nitrosylated sugars. S-nitrosylated-modified and unmodified oligonucleotides (preferably of at least 5. and more particularly 5-200. nucleotides); and an S-nitrosylated hydrocarbons where the hydrocarbon can be a branched or unbranched. and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; S- nitrosylated hydrocarbons having one or more substituent groups in addition to the S- nitroso group; and heterocyclic compounds. S-nitrosothiols and the methods for preparing them are described in U.S. Patent No. 5.380.758: Oae et ai. Org. Prep. Proc. Int..15(3): 165- 198 (1983); Loscalzo et al., J. Pharmacol. Exp. Ther.. 249(3):726729 ( 1989) and Kowaluk et al., J. Pharmacol. Exp. Ther., 256: 1256- 1264 (1990), all of which are incoφorated in their entirety by reference. One particularly preferred embodiment of this aspect relates to S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof. For example, such compounds include the following: S-nitroso-N- acetylcysteine. S-nitroso-captopril. S-nitroso-homocysteine. S-nitroso-cysteine and S- nitroso-glutathione. Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur group on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins. such as lipoproteins. heme proteins such as hemoglobin and serum albumin; and biologically protective proteins. such as the immunoglobulins and the cytokines. Such nitrosylated proteins are described in PCT Publ. Applic. No. WO 93/09806, published May 27. 1993. Examples include polynitrosylated albumin where multiple thiol or other nucleophilic centers in the protein are modified. Further examples of suitable S-nitrosothiols include those having the structures: (i)CH,[C(R e )(R f )] x SNO wherein x equals 2 to 20 and R e and R f are as defined above; (ii)HS[C((R c )(R f )] x SNO wherein x equals 2 to 20: and R e and R f are as defined above; (iii)ONS[C(R e )(R f )] x B; and (iv)H 2 N-(CO-H)-(CH,) -C(O)NH-C(CH j SNO)-C(O)NH-CH--CO,H wherein x equals 2 to 20: R,. and R f are as defined above; and B is selected from the group consisting of fluoro. C,-C„ alkoxy. cyano. carboxamido, cycloalkyl, arylakoxy, alkylsulfinyl. arylthio. alkylamino. dialkylamino, hydroxy, carbamoyi, N-alkylcarbamoyl, N,N-dialkylcarbamoyl. amino. hydroxyl, carboxyl, hydrogen, nitro and aryl. Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaNO, under acidic conditions (pH is about 2.5) to yield the S-nitroso derivative. Acids which may be used for this puφose include aqueous sulfuric. acetic and hydrochloric acids. Alternatively, the precursor thiol may be nitrosylated by treatment with an alkyl nitrite such as tert-butyl nitrite. Another group of such NO adducts are those wherein the compounds donate, transfer or release nitric oxide and are selected from the group consisting of compounds that include at least one ON-N- or ON-C- group. The compound that includes at least one ON-N- or ON-C- group is preferably selected from the group consisting of ON-N- or ON-C-polypeptides (the term "polypeptide" includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof): ON-N- or ON-C-amino acids(including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-N- or ON-C-sugars; ON-N- or ON-C-modified and unmodified oligonucleotides (preferably of at least 5. and more particularly 5-200. nucleotides). ON- 0-. ON-N- or ON-C-hydrocarbons which can be branched or unbranched. saturated or unsaturated aliphatic hydrocarbons or aromatic hydrocarbons; ON-N- or ON-C- hydrocarbons having one or more substituent groups in addition to the ON-N- or ON-C- group; and ON-N- or ON-C-heterocyclic compounds. Another group of such NO adducts is the nitrites which have an -O-NO group wherein the organic template to which the nitrite group is appended is a protein, polypeptide. amino acid, carbohydrate, branched or unbranched and saturated or unsaturated alkyl. aryl or a heterocyclic compound. A preferred example is the nitrosylated form of isosorbide. Compounds in this group form S-nitrosothiol intermediates in vivo in the recipient human or other animal to be treated and can therefore include any structurally analogous precursor R-O-NO ofthe S-nitrosothiols described above. Another group of such adducts are nitrates which donate, transfer or release nitric oxide and are selected from the group consisting of compounds that include at least one at least one O N-0-. O,N-N-. O-.N-S- or O-.N-C- group. Preferred among these are those selected from the group consisting of O,N-0-. O 2 N-N-. O 2 N-S- or O 2 N-C- polypeptides; 0 2 N-0-. O-N-N-. O-N-S- or O 2 N-C-amino acids; O 2 N-0-. 0 2 N-N- O 2 N- S- or O 2 N-C- sugars; 0 2 N-0-. 0,N-N-. O 2 N-S- or O 2 N-C-modified and unmodified oligonucleotides; 0 2 N-O-. O 2 N-N-, 0 : N-S- or O ^ N-C- hydrocarbons which can be branched or unbranched. saturated or unsaturated aliphatic hydrocarbons or aromatic hydrocarbons: O 2 N-O-. O 2 N-N-. O 2 N-S- or O,N-C- hydrocarbons having one or more substituent groups in addition to the O 2 N-O-. O 2 N-N-, O 2 N-S- or O 2 N-C-group: and 0,N-0-. O-N- N-. O 2 N-S- or O N-C-heterocyclic compounds. Preferred examples are isosorbide dinitrate and isosorbide mononitrate. Another group of such NO adducts is the nitroso-metal compounds which have the structure (R\-A-M-(NO\. R includes polypeptides (the term "polypeptide" includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof): amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars; modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200. nucleotides): and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon: hydrocarbons having one or more substituent groups in addition to the A-nitroso group: and heterocyclic compounds. A is S. O. or N. n and x are each integers independentl y selected from 1. 2 and 3. and M is a metal, preferably a transition metal. Preferred metals include iron, copper, manganese, cobalt, selenium and luthidium. Also contemplated are N-nitrosylated metal centers such as nitroprusside. Another group of such adducts are N-oxo-N-nitrosoamines which donate, transfer or release nitric oxide and have a R,R 2 -N(O-M ' )-NO group wherein R, and R 2 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 an aromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds. M * is a metal cation, such as, for example, a Group I metal cation. Another group of such adducts are thionitrates which donate, transfer or release nitric o ixxiiddee aanndd hhaavvee tthe structure R ιn -S-N0 wherein R l0 is as described above for the N- oxo-N-nitrosoamines. Agents which stimulate endogenous NO synthesis such as L-arginine. the substrate for nitric oxide synthase. are also suitable for use in accordance with the invention. When administered in vivo, the nitric oxide may be administered in combination with pharmaceutical carriers and in dosages described herein. In another aspect the invention provides a method of treating male impotence in an individual in need thereof by administering to the individual a therapeutically effective amount of a composition comprising a nitrosated or nitrosylated α-antagonist ofthe invention in a pharmaceutically acceptable carrier. In another aspect the invention provides a method of treating male impotence in an individual in need thereof which comprises treating an individual for male impotence by administering to the individual a therapeutically effective amount of a composition comprising an α-adrenergic receptor antagonist (α-antagonist). which can optionally be substituted with at least one NO or N0 2 moiety, and a compound that donates, transfers or releases nitric oxide in a pharmaceutically acceptable carrier. Total daily dose administered to a host in single or divided doses may be in amounts, for example, from about 1 to about 100 mg/kg body weight daily and more usually about 3 to 30 mg/kg. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. The dosage regimen for treating a disease condition with the compounds and/or compositions of this invention is selected in accordance with a variety of factors, including the type. age. weight, sex. diet and medical condition ofthe patient, the severity ofthe disease, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound employed, whether a drug delivery system is utilized and whether the compound is administered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore may deviate from the preferred dosage regimen set forth above. The compounds ofthe present invention may be administered orally, parenteral 1> or topically in dosage unit formulations containing conventional nontoxic pharmaceutical ly acceptable carriers, adjuvants, and vehicles as desired. Topical administration ma> also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1. 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water. Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed an a solvent or suspending medium. For this puφose any bland fixed oil may be employed including synthetic mono- or diglycerides. in addition, fatty acids such as oleic acid find use in the preparation of injectables. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g.. lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art. such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds which are known to be effective against the specific disease state that one is targeting for treatment. The compositions ofthe invention can be administered as a mixture of an α- antagonist and a nitric oxide donor, they can also be used in combination with one or more compounds which are known to be effective against the specific disease state that one is targeting for treatment. The invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions ofthe invention. Associated with such containers) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. Example 1 N-(N-L-g-glutamvI- S-Nitroso-L-cvsteinyl)glvcine N-(N-L-g-glutamyl-L-cysteinyl)glycine (100 g. 0.325 mol) was dissolved in deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperature and then the reaction mixture was cooled to 0°C. With rapid stirring, a solution of sodium nitrite (24.4 g. 0.35 mol) in water (40 ml) was added. Stirring with cooling of the reaction mixture was continued for approximately 1 hour after which time the pink precipitate which formed was collected by vacuum filtration. The filter cake was resuspended in chilled 40% acetone-water (600 ml) and collected by vacuum filtration. The filter cake was washed with acetone (2 X 200 ml) and ether (100 ml) and then dried under high vacuum at room temperature in the dark to afford the title compound as a pink powder. Η NMR (D,O) : 1.98 (m. 2H). 2.32 (t. 2H). 3.67 (t, IH), 3.82 (s 2H). 3.86 (dd. I H). 3.98 (dd. IH). 4.53 (m. I H). Example 2 2-Acyl-17α(3-methyl-3-nitrosothiolbutoxy)vohimban-16α- carboxylic acid methyl ester hydrochloride salt 2a. 3-Methyl-3(2-tetrahvdropyranyl)thiobutyric acid 3-Methyl-3-thiobutyric acid (4.2 g. 31 mmol), dihydropyran (2.8 ml. 31 mmol). and 200 μl of 4 N HCl/Et,O were allowed to stand at room temperature overnight. The volatiles were evaporated in vacuo (2 mm Hg) yielding 6.6 g (30 mmol) of material which was used without further purification. Η-NMR (CDC 1 ,): 4.92 (d. J = 8.1 Hz, I H). 4.09 (d. J = 10.5 Hz. IH). 3.49-3.56 (mult. IH), 2.73 (dd, J = 1.2 and 13.7 Hz, IH). 2.64 (d. J = 13.8 Hz. IH). 1.84-1.89 (mult 2H). 1.55-1.69 (mult. 4H). 1.51(s. 3H). 1.42 (s. 3H). 2b. 3.3'-Dimethyl-3.3'(2-ditetrahvdropyranyl)thiobutyric acid anhydride The product of Example 2a (1.1 g. 5 mmol) and triethylamine (710 μl. 5 mmol) was dissolved in ethyl acetate (50 ml) and cooled to 0° C. Triphosgene (250 mg, 0.85 mmol) was added all in one portion and the reaction was stirred at 0° C for 15 minutes then warmed to room temperature with continued stirring for 30 minutes. The precipitate which formed was removed by filtration and the filtrate was concentrated by rotary evaporation to afford 1.0 g (5 mmol) of the title compound. Η-NMR (CDC1 J: 5.03-5.06 (mult. 2H). 4.04-4.08 (mult. 2H). 3.46-3.51 (mult, 2H). 2.89 (d. J = 15.7 Hz. 2H). 2.77 (d. J = 15.6 Hz. 2H), 1.79-1.88 (mult. 4H). 1 .51 -1.67 (mult. 8H). 1.54 (s. 6H). 1.49 (s. 6H). 2c. 17a (3-methv -3-tetrahvdropyranylthiolbutoxy)vohimban-16α- carboxylic acid methyl ester To a solution of yohimbine (1.6 g. 4.5 mmol) in pyridine (6 ml) was added the product of Example 2b (2.5 g. 6 mmol) and 4-dimethyIaminopyridine (730 mg, 6 mmol). The reaction mixture was stirred at room temperature for 6 days. Acetonitrile (50 ml) was added to the reaction and then all of the volatile components were evaporated in vacuo. The residue was dissolved in ethyl acetate (100 ml) and washed with a 10 % solution of aqueous sodium carbonate. The aqueous wash was then back extracted once with ethyl acetate. The combined organic extracts were washed with H,0, brine, and then dried over anhydrous sodium sulfate. Treatment ofthe solution with activated charcoal followed by filtration and concentration ofthe filtrate in vacuo gave 2.8 g of a dark syrup. Chromatography on silica gel eluting with 1 : 1 hexane/ethyl acetate containing 1 % by volume triethylamine afforded 670 mg (20%) of the title compound. Η-NMR (CDCl,): 7.76 (s, IH), 7.46 (d. J = 7.2 Hz, IH), 7.29 (dd, J = 1.0 and 7.0 Hz. IH), 7.12 (ddd; J = 1.3. 7.1. and 7.1 Hz; IH). 7.07 (ddd; J = 1.1. 7.2. and 7.2 Hz; IH). 5.46 (d. J = 2.6 Hz, IH). 5.07-5.1 1 (mult, IH). 4.06-4.1 1 (mult, IH). 3.69 (s, 3H). 3.47-3.55 (mult, IH). 3.39 (d. J = 10.4 Hz. I H). 3.02-3.12 (mult. 2H), 2.97 (dd. J = 4.5 and 12.2 Hz. IH), 2.80 (d. J = 14.3 Hz. IH). 2.71 (mult. IH). 2.69 (d, J = 13.2 Hz. IH). 2.61 -2.65 (mult. IH). 2.39 (dd. J = 2.6 and 11.6 Hz. IH). 2.23-2.33 (mult. 2H), 1.71-2.07 (mult. 5H), 1.58-1.69 (mult. 8H). 1.51 (s. 3H). 1.49 (s. 3H). Anal Calcd for (C 3I H«N-05S- 1/2 H,0): C. 66.05; H. 7.69; N. 4.97: S. 5.69. Found C. 65.74: H, 7.33; N. 4.88; S, 5.57. 2d. 2-Acyl- 17a(3 -methyl-3 -thiolbutoxy)vohimban-16α-carboxylic acid methyl ester The product of Example 2c (620 mg, 1.1 mmol) was refluxed in a mixture of acetic acid (5 ml) and acetyl chloride (5 ml) for 4 hours. The solvent was evaporated in vacuo (2 mm Hg). The residue was partitioned between 5% aqueous ammonium hydroxide and ethyl acetate. The aqueous wash was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with 1 : 1 hexane/ethyl acetate containing 1% by volume triethylamine to afford 210 mg (34 %) of 2-acyl-17α.(3-methyl-3-thioacetylbutoxy)yohimban-16 α- carboxylic acid methyl ester. This diacetate (180 mg. 0.32 mmol) was dissolved in acetic acid (4 ml) to which was added mercuric trifluoroacetate ( 190 mg. 0.45 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The volatiles were evaporated in vacuo leaving a gum which was triturated with IN HCl (6 ml) to afford a yellow powder. The powder was partitioned between ethyl acetate and 10% aqueous ammonium hydroxide. The organic phase was filtered through Celite to remove the gray solid which was present and then the filtrate was washed with brine and then dried over anhydrous sodium sulfate. Evaporation of the volatiles in vacuo afforded a solid which was chromatographed on silica gel eluting with a gradient of with 1 :1 hexane/ethyl acetate containing 1% by volume triethylamine to ethyl acetate containing I % by volume triethylamine to yield 60 mg (37 %) ofthe title compound as a white powder. Η-NMR (CDC1 ,): 7.81 (d. J = 7.0 Hz. IH). 7.41 (d. J = 6.8 Hz. IH). 7.23-7.29 (mult. 2H). 5.46 (s. I H). 4.17 (d. J - 9.9 Hz. IH). 3.64 (s. 3H). 3.1 1 -3.15 (mult. I H). 3.00 (dd. J = 3.5 and 12.4 Hz. I H). 2.64-2.84 (mult. 10H). 2.31 (dd. J = 2.6 and 1 1.7 Hz. IH), 2.24 (d. J = 12.7 Hz. IH). 2.04-2.0 8 (mult. 2H). 1.41-1.62 (mult, 1 1 H). π C-NMR (CDC1 ,): 171.6. 170.7. 169.5. 13 7.3. 136.4. 129.6. 124.1. 122.9. 1 18.3. 1 17.2. 1 14.6. 70.0. 61.0. 59.8. 51.9. 51.8. 50.9. 47.7. 45.6. 37.8. 37.6. 36.22. 36.2. 33.2. 29.9. 27.1. 23.8. 22.3. 2e. 2-Acyl-17a(3-methyl-3-nitrosothiolbutoxy)vohimban-16α-carboxylic acid methyl ester hvdrochloride salt To a slurry of the compound of Example 2d (40 mg. 0.078 mmol) in 1 : 1 methanol/ IN HCl (4 ML) with dimethylformamide (400 μl) was added a solution of sodium nitrite (1 1 mg. 0. 16 mmol) in H 2 0 (200 μl). The white powder turned green as the slurry was stirred at room temperature for 25 minutes. At this juncture dimethylformamide (600 μl) and additional aqueous sodium nitrite (1 1 mg in 200 μl of H 2 0) was added and stirring at room temperature was continued for an additional 15 minutes. The reaction mixture was partitioned between CHC1 , and H 2 O adding 10% aqueous ammonium hydroxide to the aqueous phase until basic to pH paper. The aqueous layer was extracted with CHO , and the combined organic extracts were washed with brine and then dried over anhydrous sodium sulfate. The volatiles were evaporated in vacuo and the residue was dissolved in ether. The product was precipitated with ethereal HC 1 to afford 19 mg of the title compound as a green solid. Η-NMR (CDC 1 ,): 7.81 (dd. J = 1.7 and 6.8 Hz. IH). 7.42 (d. J = 6.8 Hz. IH). 7.23-7.29 (mult. 2H). 5.43 (d. J = 2.6 Hz. IH). 4.15 (d. J = 9.8 Hz. IH). 3.63 (s. 3H). 3.36 (d. J = 15.1 Hz. I H). 3.30 (d. J = 15.1 Hz. IH). 3.12 (dd. J = 4.9 and 1 1.0 Hz, IH). 3.00 (dd. J = 3.7 and 12.3 Hz. IH). 2.72 (s. 3H). 2.63 -2.82 (mult. 3H). 2.31 (dd, J = 2.6 and 11.7 Hz. IH). 2.03 (s. 3H). 2.00 (s. 3H). 1.0-2.0 (mult, 9H). Example 3 2-{f β-(4-(3-S-Nitroso-3-methyl-butyric acid)phenyl) ethyljaminomethyll-1 - tetralone ester hydrochloride 3a. 2-{[β-(4-Hvdroxyphenyl) ethyl] t-butoxycarbonylaminomethvU-1 -tetralone 2-{fβ-4-Hydroxyphenyl) ethyl] aminomethyl}-l -tetralone (3.39 g. 1 1.5 mmol) was dissolved in dichloromethane (50 mL) and di-tert-butyldi carbonate (2.50 g. 1 1.5 mmol) was added. The reaction mixture was stirred for 100 minutes at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica-gel. eluting with hexane/ethyl acetate (3:1) to give 2.32 g (51 %) of the title compound . Η NMR (CDC1,, 300 MHz) 1.44 (s, 9 H), 1.61-1.89 (m, 1 H). 2.15-2.29 (m. 1 H). 2.50-2.85 (m. 4 H), 2.90-3.08 (m. 2 H). 3.29-3.45 (m, 3 H), 3.49-3.64 (m. 1 H). 6.76 (d, 2 H). 7.04 (d. 2 H). 7.19-7.32 (m. 2 H). 7.39-7.50 (m, 1 H). 8.01 (d. 1 H). 3b. 2-{fβ-(4-(3-Tetrahvdropyranylthio-3-methvI-butyric acid)phenyl) ethyllaminomethyl } - 1 -tetralone ester The product of Example 3a (0.300 g. 0.76 mmol) was dissolved in pyridine (0.5 mL) and a solution of the product of Example 2b (0.397 g. 0.95 mmol) in pyridine (0.5 mL) was added. The resulting solution was stirred for 18 hours at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica- gel, eluting with hexane/ethyl acetate (4: 1 ) to give 0.332 g (73 %) of the title compound. Η NMR (CDC1 300 MHz) _1.44 (s. 9 H). 1.56 (d. 6 H). 1.52-1.78 m, 6 H). 1.66-1.97 (m, 1 H). 2.16-2.31 (m. 1 H). 2.73- 3.06 (dd. overlapping with multiplet. 7H). 3.33-3.67 ( , 5 H). 4.05-4.17 (m. 1 H). 5.09-5.17 (m. 1 H). 7.01 (d, 2 H), 7.13-7.36 (m. 4 H), 7.47 (t. 1 H). 8.01 (d. 1 H). 3c. 2-f |O-(4-(3-Mercapto-3-methyl-butyric acid)phenyl) ethyl]-t-buvoxycarbonyl- aminometh yl } - 1 -tetralone ester The product of Example 3b (0.192 g. 0.32 mmol) was dissolved in methanol (2 mL) and a solution of silver nitrate (0.1 17g. 0.69 mmol) in water (0.4 mL) was added. The resulting mixture was stirred for 1 hour at room temperature. The solvent was evaporated, the residue was suspended in acetone/water (1 : 10) and IN HCl ( 1 mL) was added. After stirring for 18 hours at room temperature, the precipitate was filtered and filtrate was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.085 g (51 %) of the title compound . Η NMR (CDC1,, 300 MHz) J .44 (s. 9 H). 1.58 (d. 6 H). 1.73-1.96 (m. 1 H). 2.17-2.31 (m. 1 H). 2.38 (s. 1 H). 2.64-2.93 (m. 5 H). 2.94-3.07 (m. 2 H). 3.45 (t. 3 H). 3.58-3.67 (m. 1 H). 7.02 (d, 2 H), 7.15-7.36 (m. 4 H). 7.47 (t. 1 H). 8.01 (d. 1 H). 3d. 2- f [β-(4-(3-Mercapto-3-methyl-butyric acid)phenyl) ethyljaminomethyl } - 1 - tetralone ester The product of Example 3c (0.149 g. 0.29 mmol) was dissolved in dichloromethane (3 mL) and trifluoroacetic acid (3 mL) was added. The resulting solution was stirred for 15 minutes at room temperature. The solvent was evaporated, and the residue was dissolved in dichloromethane (10 mL). Water (5 mL) was added and pH was made basic with saturated sodium bicarbonate solution. Organic layer was separated and aqueous fraction was extracted with dichloromethane. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.098 g (82 %) of the title compound. Η NMR (CDC1„ 300 MHz) 159 (s, 6 H), 1.84-2.03 (m. 1 H). 2.15-2.26 (m. 1 H). 2.39 (s. 1 H), 2.82- 3.16 (m, 1 1 H), 7.06 (d, 2 H). 7.18-7.35 (m. 4 H). 7.49 (t. 1 H). 8.00 (1 H). 3e. 2- [ β-(4-(3-S-Nitroso-3-methyl-butyric acid)phenyl ) ethyllaminomethyl } - 1 - tetralone ester hydrochloride The product of Example 3d (0.081 g. 0.20 mmol) was dissolved in methanol (4 mL) and I N HCl was added. A solution of sodium nitrite (0.045 g, 0.65 mmol) in water (0.25 mL) was added. After stirring for 15 minutes at room temperature an additional sodium nitrite (0.045 g. 0.65 mmol) in water (0.25 mL) was added. The reaction mixture was stirred for 15 more minutes, and was then extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated to give 0.072 g (81 %) of the title compound as a green solid. Η NMR (CDC1,. 300 MHz) 5: 1.72-1.93 (m. 1 H). 2.09 (s. 6 H). 2.18-2.30 (m. 1 H). 2.84-3.1 1 (m, 1 H), 3.14-3.33 (m. 6 H). 3.36-3.57 (m. 4 H). 7.03 (d. 2 H). 7.18-7.42 (m. 4 H). 5.53 (t. 1 H). 7.94 (d. 1 H). Example 4 4-(2-methoxyphenyl)-α-[(l-naphthalenyloxy)methyll-l-piperazineethvoxy-[3-S- nitroso-3-methyl-buryric acid] ester 4a. 3-Methyl-3-(2.4.6-trimethoxyphenylmethylthio)butyric acid To a solution of 3-mercapto-3-methyibutyric acid (B.J. Sweetman et al. ./. Med Chem., 14. 868 (1971)) (4.6 g. 34 mmol) in methylene chloride (250 mL) under nitrogen and cooled over ice/salt to 5°C (internal temperature) was added trifluoroacetic acid (82 g. 0.72 mol). No significant temperature rise was noted during the addition. To this was then added dropwise a solution of 2.4,6-trimethoxybenzyl alcohol (M.C. Munson et al.. J. Org. Chem.. 57, 3013 (1992)) (6.45 g, 32 mmol) in methylene chloride (150 mL) such that the reaction temperature does not rise above 5°C. After the addition was complete, the mixture was stirred for an additional 5 minutes at 5°C and the volatiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried over anhydrous sodium sulfate, filtered and the volatile material evaporated in vacuo. The residue was treated with activated charcoal and recrystalised from diethyl ether/hexane. The product was isolated as an white solid in 70% yield (7 g) mp 103-105 ϋ C. Η NMR (CDCl_,) δ: 6.12 (s. 2H), 3.80-3.85 (m. 1 1 H). 2.74 (s. 2H). 1.47 (s. 6H). π C NMR (CDC1,) 173.9. 160.6. 158.6. 105.6, 90.5. 55.7. 55.3. 45.9. 43.6. 28.4. 21.0. 4b. 4-(2-methoxyphenyl)-α-[( l -naphthalenyloxy)methyll-l -piperazineethyoxy- 3- (2.4.6-trimethvoxybenzylthio)-3-methyl-butyric acid] ester Under a nitrogen atmosphere, 4-(2-methoxyphenyl)-α-[(l - naphthalenyloxy)methyl]-l -piperazineethanol (0.130 g, 0.35 mmol) was dissolved in anhydrous dimethylformamide (2 mL) and 4-dimethylaminopyridine (0.017 g. 0.14 mmol) was added, followed by the product of Example 4a (0.21 1 g. 0.69 mmol) and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.132 g, 0.69 mmol). The resulting mixture was stirred 2 hours at room temperature and then 24 hours at 50°C. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with hexane/ ethyl acetate (3:1 ) to (2:1 ) to give the title compound (0.133 g, 56 % yield). 'HNMR (CDC1,. 300 MHz) δ: 1.49-1.53 (d, 6 H, j = 2.42 Hz). 2.70- 2.84 (m. 8H). 2.98-3.09 (m. 4 H). 3.75-3.85 (m. 1 1 H). 3.86 (s. 3 H). 4.31-4.36 (m. 2 H ). 5.43- 5.52 (m. 1 H), 6.08 (s. 2 H). 6.81 -6 86 (m. 2 H). 6.90-6.93 (m. 2 H). 6.97- 7.01 (m. I H). 7.33-7.7- (m. 4 H). 7.77-7.82 (m. 1 H). 8.23-8.27 (m. 1 H). 4c. 4- ( 2-methoxy p henyl ) -α-[ ( l -naphthalenyloxy ) methyl]-l - p iperazineethvox\ - 3- mercapto-3-methyl-butyric acid] ester The product of Example 4b (0.128 g, 0.186 mmol) was dissolved in methylene chloride (0.50mL). and then anisole (0.13 mL. 1.20 mmol), phenol (0.013 g.0.14 mmol). water (0.13 mL). and trifluoroacetic acid (0.80 mL. 10.4 mmol) were added. After 1 hour of stirring at room temperature, toluene (2 mL) was added and volatiles were evaporated. The residue was purified by flash chromatography on silica gel eluting with hexane/ ethyl acetate (2: 1 ) to give the title compound (0.055 g. 60 % yield) as a solid. Η NMR (CDC1,. 300 MHz) 1.49-1.53 (d. 6 H. J =2.42 Hz). 2.59 (s. 1 H). 2.69-2.86 (m. 8 H). 3.01 -3.09 (m. 4 H). 3.86 (s. 3 H). 4.26-4.39 (m. 2 H). 5.53-5.63 (m. 1 H). 6.81 -6.88 (d. 2 H. J =7.5 Hz). 6.90-6 95 (m, 2 H). 6.98-7.04 (m, 1 H), 7.34-7.40 (t. 1 H. J=7.5Hz). 7.43- 7.78 (m, 3 H), 7.79-7.82 (m. 1 H), 8.23-8.26 (m. 1 H). 4d. 4-(2-methoxyphenvπ-α-[(l-naphthalenyloxy)methyl1-l-piperazineethvoxy-r3-S- nitroso-3-methyl-butyric acid] ester The product of Example 4c (0.048 g, 0.097 mmol) was dissolved in methanol (5mL) and IN solution of hydrochloric acid (1.5 mL) was added. The resulting mixture was cooled to 0°C and a solution of sodium nitrite 0.040 g. 0.058 mmol) in water (0.5mL) was added. After 1 hour stirring at 0°C the reaction mixture was extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give the title compound (0.045 g. 82 % yield) as a green solid. 'HNMR(CDC1,. 300 MHz) 5: 2.00 (s, 6 H), 3.38-3.50 (m. 13 H), 3.88 (s, 3 H). 4.31-4.40 (m, 2 H). 5.91 (s. 1 H). 6.79-6.95 (m, 5 H), 7.33-7.70 (m, 4 H), 7.79- 7.82 (m, 1 H), 8.09-8.12 (m. 1 H). Example 5 2-14-(2-furovnpiperazin-l-vU-(4-(3-S-nitroso-3-methyl-butyric acid)l-6. 7- dimethvoxyquinazoline amide 5a. 2-I4-(2-Furoyl Ipiperazin- 1 -vn-r4-(3-(2.4.6-trimethvoxybenzylthio ι-3-methyl- butyric acid)]-6. 7-dimethvoxyquinazoline amide Under a nitrogen atmosphere 2-f4-(2-furoyl)piperazin- ! -yl]-amino-6. 7- dimethyoxyquinazoline (0.200 g. 0.52 mmol) was dissolved in anhydrous dimethylformamide (5 L) and 4-dimethyiaminopyridine (0.025 g. 0.21 mmol) was added, followed by the product of Example 4a (0.319 g. 1.04 mmol) and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (0.199 g, 1.04 mmol). The resulting mixture was stirred at 50°C for 48 hours. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with hexane/ethyl acetate (3:1 ) to (1 :5) to give 0.072 g (20 % yield) of the title compound as a white solid. Η NMR (CDC1„ 300 MHz) δ: 1.52 (s, 6 H). 2.88 (s. 1 H), 2.90 (s. 2 H), 2.96 (s. 1 H). 3.56 (s.6H). 3.72 (s. 3 H). 3.90-4.01 (m. 16 H), 6.48-6.52 (dd, 1 H. J = 1.69 and 3.32 Hz). 6.94 (s. 1 H), 7.01-7.05 (d. 1 H, J - 3.45 Hz). 7 19 (s. 1 H), 7.50-7.53 (m. 1 H). 5b. 2-f4-(2-Furoyl)piperazin-l-yl]- 4-(3-mecapto-3-methyl-butyric acid)]-6. 7- dimethvoxyquinazoline amide The product of Example 5a (0.160 g. 0.24 mmol) was dissolved in methylene chloride (0.67 mL). and then anisole (0.16 mL. 1.47 mmol). phenol (0.007 g. 0.047 mmol). water (0.16 mL). and trifluoroacetic acid (0.67 mL, 8.63 mmol) were added. After 45 minutes of stirring at room temperature toluene (5 mL) was added and volatiles were evaporated. The residue was purified by flash chromatography on silica gel eluting with methylene chloride/ methanol (30:1 ) to (15:1 ) to give the title compound (0.043 g. 36 % yield) as a solid. Η NMR (CDC1 300 MHz) δ: 1..58 (s. 6 H), 2.45 (s. 1 H). 3.00 (s.2H), 3.87-3.94 (d. 6 H. J = 6.28 Hz), 3.92-4.06 (m. 8 H). 6.53-6.57 (dd. 1 H. J=1.68 and 3.41 Hz). 6.98 (s. 1 H). 7.15-7.18 (d, 1 H. J = 3.48 Hz). 7.49 (s. 1 H), 7.54-7.59 (m. 1 H). 5c. 2-f4-(2-Furoyl)piperazin-l-yl]-r4-(3-S-nitroso-3-methyl-butyric acid)]-6. 7- dimethvoxyquinazoline amide The product of Example 5b (0.036 g, 0.080 mmol) was dissolved in methanol and IN solution of hydrochloric acid (1 mL) was added. The resulting mixture was cooled to 0°C and a solution of sodium nitrite (0.067 g, 0.97 mmol) in water (0.5 mL) was added. After 40 min. stirring at 0°C the reaction mixture was extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give the title compound (0.023 g. 55 % yield) as a green solid. 'HNMR(CDC1 300 MHz) δ: 2.12 (s. 6 H), 3.49 (s. 2 H). 3.85-3.99 (m. 14 H). 6.51 -6.55 (dd. IH, J = 1.74 and 3.45 Hz). 6.79-6.98 (m. 2 H). 7.06-7.09 (d. 1 H. J = 3.23 Hz). 7.54- 7.58 (m. 1 H). Example 6 4-f2-(Dimethylamino)ethoxyl-2-methyl-5-(l-methylethyl)phenol-(3-S-nitroso-3- methyl-butyric acid) ester 6a. 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(l-methylethyl)phenol 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(l-methylethyl)phenol acetate ester (1.00 g. 3.20 mmol) was dissolved in methanol (10 mL) and sodium hydroxide (0.317 g. 7.92 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes, diluted with ethyl ether (10 mL) and washed with sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate. filtered and concentrated in vacuo to give the title compound (0.71 g. 93 % yield) as a white solid. Η NMR (CDC1,. 300 MHz) δ: 1.10-1.13 (d. 6 H. J = 6.9 Hz). 2.19 (s, 3 H), 2.41 (s. 6 H). 2.80-2.85 (t. 2 H. J = 5.9 Hz). 3.19-3.26 (m. 1 H). 4.02-4.07 (t. 2 H. J=5.9Hz). 6.57- 6.59 (d. 2 H. J = 3.72 Hz). 6b. 4-[2-(Dimethylamino)ethoxyl-2-methyl-5-(l-methylethvπphenol- 3-(2.4.6- trimethvoxybenzylthioi] -3-methyl-butyric acid) ester Under a nitrogen atmosphere, the product of Example 6a (0.270 g. 1.14 mmol) was dissolved in anhydrous dimethylformamide (2 mL) and 4-dimethylaminopyridine (0.028g. 0.23 mmol) was added, followed by the product of Example 4a (0.418 g, 1.36 mmol) and l-ethyl-3-(3-dimethylaminopropy )carbodiimide (0.260 g, 1.36 mmol). The resulting mixture was stirred at 55°C for 24 hours. The solvent was evaporated in vacuo and the residue was purified by flash chromatography on silica gel. eluting with methylene chloride/ methanol (20:1 ) to give 0.232 g (39 % yield) of the title compound. 'H NMR (CDC1,. 300 MHz) δ: 1.14-1.18 (d. 6 H, J = 6.9 Hz), 1.59 (s, 6 H). 2.15 (s, 3 H), 2.35 (s. 6 H). 2.72-2.77 (t. 2 H. J = 5.9 Hz), 2.93-2.96 (m, 2 H). 3.23-3.28 (m. 1 H), 3.74- 4.02 (m, 1 1 H), 4.03-4.07 (t. 2 H. J = 5.9 Hz). 6.1 1 (s, 2H). 6.67 (s. I H). 6.81 (s, 1 H). 6c. 4-[2-(Dimethylamino)ethoxyl-2-methyl-5-( l -methylethyl)phenol-(3-mercapto-3- methyl-butyric acid) ester The product of Example 6b (0.220 g. 0.42 mmol) was dissolved in methylene chloride (0.30mL) and anisole (0.22 mL. 2.02 mmol), phenol (0.022 g. 0.23 mmol). water (0.22 mL) and trifluoroacetic acid (1.0 mL. 13.0 mmol) were added. After 1 hour of stirring at room temperature, toluene (5 mL) was added and volatiles were evaporated. The residue was purified by flash chromatography on silica gel. eluting with methylene chloride/ methanol (20:1 ) to give the title compound (0.095 g. 64 % yield). Η NMR (CDC1-. 300 MHz) δ: 1.14-1.16 (d. 6 H, J = 6.9 Hz). 1.58 (s. 6 H). 2.14 (s. 3 H). 2.40 (s. 1 H). 2.87-2.94 (m. 8 H). 3.14-3.20 (m. 1 H), 3.50-3.53 (m. 2 H). 4.31 -4.34 (m. 2H). 6.67 (s. I H), 6.84 (s. 1 H). 6d. 4-f2-(Dimethylamino)ethoxy]-2-methyl-5-(l-methylethvπphenol-( ' 3-S-nitroso-3- methyl-butyric acid) ester The product of Example 6c (0.035 g, 0.10 mmol) was dissolved in methanol (5mL) and IN solution of hydrochloric acid (1 mL) was added. The resulting mixture was cooled to 0°C and a solution of sodium nitrite (0.014 g, 0.20 mmol) in water (0.7 mL) was added. After 20 minutes stirring at 0°C, an additional sodium nitrite (0.032 g. 0.46mmol) in water (0.7 mL) was added and the resulting mixture was stirred for 30 minutes. The reaction mixture was extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to afford the product (0.028 g, 67% yield) as a green solid. 'HNMR (CDC1„ 300MHz) δ: 1.13-1.17 (d. 6 H. J = 6.9 Hz). 2.08-2.1 1 (m. 9 H). 2.95 (s. 6 H). 3.13-3.20 (m, 1 H). 3.45-3.51 (m. 4 H). 4.43-4.46 (m. 2 H). 6.23 (s. 1 H). 6.70 (s. 1 H), 6.76 (s. 1 H). Example 7 3-f[4.5-Dihvdro-l-(3-S-nitroso-3-methyl butyloxy)-imidazol-2-yl)methyl)(4- methylphenyl)amino)phenol-(3-S-nitroso-3-methyl-butyric acid) ester 7a.3-Mercapto-3-methyl butyl acetate 3-Mercapto-3-methyl butanol (Sweetman et al. J. Med Chem. 14. 868 (1 71 ) (5 g, 42 mmol) and pyridine (3.6 mL. 43 mmol) were dissolved in methylene chloride (50 mL) and cooled to -78°C. Acetyl chloride (3.1 mL. 43 mmol) was added dropwise. The solution was kept cold for 30 min then allowed to warm to room temperature. Stirring was continued for 1.5 hr. The reaction mixture was diluted with methylene chloride, washed with 1 N HCl and brine, and dried over sodium sulfate. Evaporation ofthe solvent gave 6.6 g of the title compound which was used without further purification. Η- NMR (CDC1 δ: 4.25 (t. J = 7.1 Hz. 2H), 2.21 (s, I H), 2.03 (s. 3H). 1.92 (t. J = 7.2 Hz, 2H). 1.41 (s, 3H). 7b. 3-Tetrahvdropyranylthio -3-methyl butyl acetate The product of Example 7a (6.6 g. 41 mmol). dihydropyran (4 mL. 44 mmol). and 4 N HCl/Et 2 O ( 1 mL) were allowed to stand at room temperature for 24 hours. The volatiles were evaporated in vacuo to leave the title compound as a viscous oil which was used without further purification. Η-NMR (CDCl,) δ: 4.97 (dd. J = 3.4 and 6.6 Hz. I H). 4.24 (t. J = 7.1 Hz, 2H). 4.04-4.09 (mult. IH). 3.46-3.52 (mult, IH). 2.03 (s. 3H). 1.93 (t. J = 7.5 Hz. 2H). 1.42-1.88 (mult. 6H). 1.37 (s. 3H). 1.36 (s. 3H). 7c. 3-Tetrahvdropyranylthio-3-methyl butanol The product of Example 7b (800 mg. 3.3 mmol) and sodium bicarbonate ( 1.4 g. 16 mmol) were dissolved in methanol (10 mL) and stirred at room temperature for 18 hours. The reaction mixture was diluted with ether (30 mL) to precipitate the salts and filtered through Celite. Evaportation ofthe solvent and chromatography on silica gel eluting with 3: 1 hexane/ethyl acetate gave 340 mg (51%) of the title compound. Η- NMR (CDCl j ) δ: 4.92 (dd. J = 3.1 and 7.6 Hz, IH), 4.05 (ddd; J = 4.0. 4.0. and 1 1.6 Hz. I H), 3.81 (ddd; J = 6.3. 6.3. and 12.6 Hz. I H). 3.78 (ddd; J = 6.3. 6.3. and 12.6 Hz. IH). 3.49 (ddd; J = 3.8. 7.7. and 1 1.8 Hz. IH). 1.79-1.89 (mult. 4H). 1.60-1.67 (mult. 4H), 1.56 (s. 3H). 1.55 (s. 3H). Anal calcd for C l0 H 20 O,S: C; 58.78, H; 9.87. S; 15.69. Found C: 58.42. H: 9.73. S: 15.58. 7d. 3-f [4.5-Dihvdro- 1 -(3-tetrahvdropyranylthio-3-methyl butyloxy)-imidazol-2- yl)methyl](4-methylphenyl)amino]phenol-(3- tetrahvdropyranylthio-3-methyl- butyric acid) ester The product of Example 7c (700 mg. 3.5 mmol) was dissolved in tetrahydrofuran (5 mL) and cooled to -78°C. To this solution was added 2.5 M BuLi (1.38 mL. 3.5 mmol), and the reaction mixture was stirred at -78°C for 20 minutes. A solution of 1.93 M phosgene in toluene (3.6 mL. 7.0 mmol) was cooled to -78°C and the cold solution of lithium alkokide was rapidly cannulated into the phosgene solution. The reaction mixture was stirred at -78°C for 30 minutes and then warmed to room temperature and stirred for 2 hours. The solution was filtered through a cotton plug and concentrated to give the chloroformate as a syrup. A slurry of 3-[[4.5-dihydro-l H- imidazol-2-yl)methyl](4- methylphenyl)amino]phenol hydrochloride (500 mg, 1.6 mmol) and triethylamine (650 μL, 4.7 mmol) in methylene chloride (10 mL) was cooled to to -78°C. The chloroformate was dissolved in methylene chloride (4 mL) and this solution was added to the slu . The resulting reaction mixture was stirred at -78°C for 30 minutes and was then warmed to room temperature and stirred for 20 hours. The reaction mixture was diluted with methylene chloride and then washed successively with 0.1 N HCl. saturated aqueous sodium bicarbonate, and brine; followed by drying over sodium sulfate. Evaporation of the solvent and chromatography on silica gel eluting with 2: 1 hexane/ethyl acetate gave 540 mg (46 %) of the title compound. Η-NMR (CDCI,) δ: 7.18 (d. J = 8.6 Hz. 2H). 7.13 (d. J = 8.0 Hz, 2H), 7.12 (t, J = 8.2 Hz, IH), 6.57-6.62 (mult, 2H). 6.51 (t. J = 2.2 Hz. IH). 4.94-4.99 (mult, 2H), 4.89 (s, 2H), 4.38 (t. J = 7.3 Hz, 2H), 4.32 (t. J = 7.1 Hz. 2H). 4.03-4.08 (mult. 2H). 3.79 (s. 4H). 3.46-3.52 (mult. 2H). 2.32 (s. 3H). 1.51 -2.05 (mult. 16H). 7e. 3-rr4.5-Dihvdro-l-(3-thiol-3-methyl butyloxy)-imidazol-2-yl)methvn(4- methylphenyl)amino]phenol-f3-thiol-3-methyl-butyric acid) ester The product of Example 7d (400 mg, 0.54 mmol). ercaptoethanol (760 μL. 10 mmol). and 4 N HCl in ether (250 μL, 1 mmol) were kept at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate, water, and brine, and then dried over sodium sulfate. Hydrochloric acid was added and the solvent was evaporated to leave a syrup. The syrup was triturated with ethanol and ether. Decantation ofthe solvents and subjecting the residue to high vacuum overnight afforded 130 mg of solid. The solid was chromatographed on silica gel eluting with 3:1 hexane/ethyl acetate to give 30 mg (10 %) of the title compound. Η-NMR (CDC1,) δ: 7.18 (d. J = 8.6 Hz. 2H). 7.14 (d. J = 7.9 Hz, 2H). 7.13 (t. J = 8.2 Hz. IH). 6.61 (dd. J = 2.4 and 8.3 Hz. IH). 6.59 (dd. J = 2.1 and 7.9 Hz. I H). 6.52 (t. J = 2.2 Hz. I H). 4.90 (s. 2H). 4.41 (t. J = 7.3 Hz. 2H). 4.35 (t. J - 7.0 Hz. 2H). 3.80 (s. 4H). 2.33 (s. 3H). 2.02 (t, J = 7.1 Hz, 2H), 1.97 (t, J = 7.1 Hz. 2H). 1.76 (s, I H). 1.75 (s. IH). 1.43 (s. 12H). 7f. 3-ri4.5-Dihvdro-l -(3-S-nitroso-3-methvI butyloxy)-imidazoI-2-yl)methyl](4- methylphenyl)amino]phenol-(3-S-nitroso-3-methyl-butyric acid) ester The product of Example 7e (18 mg. 0.033 mmol) was dissolved in dimethylforamide (200 μL) and 4 N HCl in ether (25 μL, 0.1 mmol) was added. The reaction mixture was cooled to 0°C and tert-butyl nitrite (12 μL, 0.12 mmol) was added and then the reaction mixture was stirred at for 0°C for 20 minutes. The solvent was evaporated in vacuo and the solid residue obtained was azetroped with chloroform to afford the title compound as a foam. Η-NMR (DMSO-d 6 ) δ: 7.09 (d. J = 8.0 Hz. I H). 6.89 (d. J = 8.2 Hz, I H), 6.61-6.72 (mult. 6H). 5.10 (br s. 2H). 4.44 (t. J = 6.7 Hz. 2H). 4.38 (t. J = 6.7 Hz. 2H). 4.00-4.10 (mult. 2H). 3.89-4.00 (mult. 2H). 2.65 (t. J = 6.5 Hz. 2H). 2.62 (t. J = 6.6 Hz, 2H). 2.30 (s. 3H), 1.92 (s, 6H). 1.89 (s. 6H). Example 8 4-[2- ( Dimethylamino ) ethoxy)-2-methyl-5-(l-methylethyl)phenol-(4-O-nitro-3- butyric acid) ester 8a. 4-r2-(Dimethylamino)ethoxy]-2-methyl-5-(l -methylethyl)phenol-(4-bromo- butyric acid) ester 4-Bromobutyric acid (1 g. 6 mmol) and triethylamine (836ml. 6 mmol) was dissolved in ethyl acetate (40 ml) and cooled to 0 °C. Triphosgene (309 mg. 1 .04 mmol ) was added all in one portion and the reaction was stirred at 0 °C for 15 minutes then warmed to room temperature with continued stirring forl hour. The precipitate which formed was removed by filtration and the filtrate was concentrated by rotary evaporation to afford a light beige oil which was used without further purification. The product of Example 6a (395 mg. 1.78 mmol) was dissolved in dry acetonitrile (10 ml) and added to the preformed symmetrical anhydride. Scandium trifiate (20 mg. 0.04 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours after which time additional triethylamine (203 mg. 2 mmol) was added and stirring was continued for an additional 4 hours. The reaction was concentrated in vacuo and the residue partioned between ethyl acetate and phosphate buffer (pH 7.1 ). The organic phase was dried over sodium sulfate and the solvent evaportated in vacuo to afford a brown oil. The oil was chromatographed on silica gel eluting with 9: 1 methylene chloride/methanol to give 152 mg (22 %) ofthe title compound as a light beige oil. Η-NMR (CDCl,) δ: 6.84 (s. IH), 6.69 (s. 1 H). 4.35 (dd. J = 4.7 Hz and 4.7 Hz. 2H). 3.55 (t, J = 6.4 Hz. 2H). 3.41 (dd. J = 4.7 Hz and 4.7 Hz. 2H). 3.18 (m. 1 H). 2.90 (s. 6H). 2.79 (t, J = 7.2 Hz. 2H). 2.30 (m. 2H). 2.13 (s. 3H). 1.18 (d. J = 6.9 Hz. 6H). 8b. 4-[2-(Dimethylamino)ethoxy1-2-methyl-5-( 1 -methylethyl )phenol-(4-iodo- butyric acid) ester The product of Example 8a (150 mg. 0.39 mmol). sodium iodide (1 16 mg. 0.77 mmol ) and acetone (15 ml) were stirred at 50 °C for 3 hours. The solvent was evaporated in vacuo and the residue pardoned between methylene chloride and and phosphate buffer (pH 7.1 ). The organic phase was dried over sodium sulfate and the solvent evaporated in vacuo to afford 131 mg ofthe crude title compound which was imidiately carried on to the next step. Η-NMR (CDC1 3 ) δ: 6.82 (s, IH), 6.69 (s. IH), 4.23 (dd. J = 5.4 Hz and 5.4 Hz. 2H), 3.32 (t, J = 6.6 Hz. 2H), 3.23 (m, IH), 3.04 (dd. J = 5.4 Hz and 5.4 Hz. 2H). 2.72 (t. J = 7.2 Hz. 2H), 2.56 (s, 6H). 2.28 (m. 2H). 2.12 (s, 3H). 1.18 (d. J = 6.9 Hz. 6H). 8b. 4-r2-(Dimethylamino)ethoxy]-2-methyl-5-(l -methylethyl)phenol-(O-nitro- butyric acid) ester The product of Example 8b (130 mg, 0.30 mmol) was dissolved in acetonitrile (5 ml) and silver nitrate (102 mg. 0.60 mmol) was added and the reaction mixture was left over night at tomm temperature. The reaction mixture was filtered through a PTFE membrane and the solvent evaporated in vacuo. The residue was chromatographed on silica gel eluting with 9: 1 methylene chloride/methanol to give 19 mg (17 %) of the title compound as an oil which was solubilized in a small volume of ethyl acetate and precipitated by the addition of ether, mp: 105-107 °C MS: (DCI/NH,): m/z = 369 (M+H) " Η-NMR (CDC1 δ: 6.84 (s. IH), 6.71 (s. IH), 4.49 (t, J = 6.2 Hz. 2H). 4.36 (dd. J = 4.5 Hz and 4.5 Hz. 2H). 3.56 (dd, J = 4.5 Hz and 4.5 Hz. 2H). 3.19 (m. IH). 2.99 (s. 6H). 2.72 (t. J = 7.2 Hz. 2H). 2.19 (m, 1 H). 2.1 1 (s. 3H). 1.17 (d. J = 6.6 Hz. 6H). Example 9 In Vivo Comparative Erectile Responses Male New Zealand white rabbits weighing 2.5 kg were used as the animal model. Animals were first relaxed with an i.m. injection of 25 mg/kg ketamine prior to anesthesia with a bolus i.v. injection of 10 mg/kg Profol and maintained with i.v. infusion at 0.5 mg/kg/min. Ventilation of the animals was performed with 1 % halothane plus 0.8 L/min 0 2 and 1 L/min N 2 0. A 22 gauge angiocatheter was placed in the femoral artery for measurement of systemic blood pressure. A dorsal incision was made in the penis and the coφora cavernosa exposed and cannulated with a 21 gauge butterfly needle to measure intracavernosal pressure. Drugs at various concentrations were delivered intracavernosal ly at a volume of 150 μl through a 25 gauge needle. A 150 μl solution of a mixture of papaverine (30 mg/kg), phentolamine (1 mg/kg) and prostaglandin El (10 μg/ml) (pap/phent/PGEl ) was injected in the coφora as a standard solution for comparison with the response of yohimbine, the compound of Example 1. the compound of Example 2. and the combination of yohimbine and the compound of Example 1. This pap/phent PGEl mixture is considered to cause a maximal erection-inducing effect. As shown in Figure 1. yohimbine dose dependently induced erectile response in the anesthetized rabbit. A 500 μg dose of the compound of Example 1 was able to induce near maximal response relative to the standard dose of pap/phent/PGE 1. A combination of the submaximal dose of yohimbine (150 μg) and the compound of Example 1 (500 μg) also induced maximum erectile response. Yohimbine at both the submaximal and maximal efficacy doses produced very short duration of action (Figure 2). The compound of Example 1 produced a much longer duration of action. The duration of action is potentiated by a combination of the compound of Example 1 and yohimbine which is longer than the sum ofthe duration of each ofthese compounds alone (Figure 2). Figure 3 shows that the compound of Example 2 at the 500 μg dose is equipotent to the standard dose of pap/phent/PGE 1. A higher dose ofthe compound of Example 2 ( 1 mg) is at least equal to or more efficacious that the standard dose ofthe pap/phent/PGEl mixture. Figure 4 shows that the compound of Example 2 has the advantage of producing longer duration of action compared to yohimbine. Figure 5 demonstrates that a dose (500 μg) of the compound of Example 2 effective in the erectile response did not produce any effect on systemic blood pressure upon intracavernosal injection. However, a standard dose ofthe mixture of pap/phent/PGEl produced a significant decrease in systemic blood pressure upon intracavernosal injection, suggesting that the compound of Example 2 lacks this side effect. Figure 1 shows the percent peak erectile response in vivo compared to that produced by 150 μl of pap/phent PGEl (30 mg/ml: 1 mg/ml: 10 μg/ml) in the anesthetized rabbit following the intracavernosal injection of 150 μl of yohimbine (150 μg. 500 μg). the compound of Example 1 (500 μg). and a combination of yohimbine (150 μg) and the compound of Example 1 (500 μg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various drugs given. Figure 2 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of yohimbine ( 150 μg. 500 μg). the compound of Example 1 (500 μg). and a combination of yohimbine (150 μg) and the compound of Example 1 (500 μg). The ordinate indicates the various drugs given and the abscissa is the duration in minutes. Figure 3 shows the percent peak erectile response in vivo compared to that produced by 150 μl of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 μg/ml) in the anesthetized rabbit following the intracavernosal injection of 150 gl of yohimbine (150 μg, 500 μg and 1 mg) and the compound of Example 2 (500 μg. 1 mg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various doses of yohimbine and Example 2 given. Figure 4 shows the duration ofthe erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of yohimbine (150 μg. 500 μg and 1 mg) and the compound of Example 2 (500 μg and 1 mg). The ordinate indicates the various doses of yohimbine and the compound of Example 2 given and the abscissa is the duration in minutes. Figure 5 compares the effects of intracavernosal injections ofthe compound of Example 2 (500 μg) and the standard mixture of pap/phent/PGEl on systemic blood pressure in the anesthetized rabbit. Figure 6 shows the percent peak erectile response in vivo compared to that produced by 150 μl of pap/phent/PGE l (30 mg/ml: 1 mg/ml: 10 μg/ml) in the anesthetized rabbit following the intracavernosal injection of moxisylyte (1 mg) and the compound of Example 6 ( 1 mg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the dose of moxisylyte and the compound of Example 6 given. Figure 7 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of moxisylyte ( 1 mg) and the compound of Example 6 (1 mg). The ordinate indicates the dose of moxisylyte and the compound of Example 6 the abscissa is the duration in minutes.

Claims: What Is Claimed Is: 1. Nitrosated and nitrosylated α-adrenergic receptor antagonists. 2. The nitrosated and nitrosylated α-adrenergic receptor antagonists of claim selected from the group consisting of: (i) compounds having the structure: rT D I. wherein, R a is selected from hydrogen or alkoxy: R b is selected from wherein a is an integer of 2 or 3: R c is selected from heteroaryl. heterocyclic ring, lower alkyl. hydroxyalkyl. and arylheterocyclic ring; D is selected from (i) -NO; (ii) -NO,; (iii) -C(R d )-O-C(O)-Y-Z-[C(R c )(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, in which R, is hydrogen, lower alkyl. R c and R f are independently selected from hydrogen, lower alkyl. cycloalkyl, aryl, heteroaryl, arylalkyl. amino. alkylamino. amido, alkylamido, dialkylamino. carboxy. 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. Z is selected from a covalent bond, alkyl. cycloalkyl. aryl. heteroaryl. arylalkyl or arylheterocyclic ring, and Q is selected from -NO or -N0 2 : (iv) - C(O)-T'-Z-[C(R.)(R f )] p - T 2 -Q wherein T 1 and T 2 are independently selected from T and R e . R f . p. Q. Z. and T are as defined above; (v) -C(O)-T[C(R )(R 7 )] p wherein ^ and R. are independently selected from -T'-fC(R c )(R f )] p -G-[C(R e )(R f )] p -T 2 -Q wherein G is (/) a covalent bond; (//) -T-C(O)-; ( ) -C(0)-T. or (iv) Y. and wherein R d . R c . R f . p. Q. T. and Y are as defined above: (ii) compounds having the structure: II. wherein, R p is selected from: wherein D, is selected from hydrogen or D wherein D is as defined above and with the proviso that D, must be selected from D if there is no other D in the molecule: (iii) compounds having the structure: III. wherein R h is selected from hydrogen. -C(O)-OR d or -C(O)-X wherein X is ( 1 ) -Y-[C(R e )(R f )] p -G,-[C(R e )(R f )] p -T-Q; wherein G, 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 in which Y , R d , R e . R f . p, Q and T are as defined above; or (2) in which W is a heterocyclic ring or NR,R', wherein R, and R' t are independently selected from lower alkyl. aryl or alkenyl; and wherein Rj is selected from -D or -(0)CR d wherein D and R d are as defined above; (iv) compounds having the structure: wherein. A, is oxygen or methylene and X and R j are as defined above; v) compounds having the structure: V. wherein R and R ' k are independently selected from hydrogen or lower alkyl; and R, is selected from: wherein b is an integer of 0 or 1: D, is as defined above: and R„ is selected from: OCH, wherein A, is oxygen or sulfur: (vi) compounds having the structure: VI. wherein R n is selected from: and R p is selected from: \ and R, . D and D, are as defined above; (vii) compounds having the structure: VII. wherein R d . T and D are defined as above; and (viii) compounds having the structure: VIII. wherein a. R,. R',. R e . R,. and D are defined as above. 3. A composition comprising (i) a therapeutically effective amount of an α- adrenergic receptor antagonist and (ii) a compound that donates, transfers or releases nitric oxide or elevates endogenous synthesis levels of nitric oxide. 4. The composition of claim 3 wherein the α-adrenergic receptor antagonist is selected from the group consisting of haloalkylamines, imidazolines. quinazoiines. indole derivatives, phenoxypropanolamines. alcohols, alkaloids, amines, piperazines and piperidines. 5. The composition of claim 4 wherein the haloalkylamine is selected from the group consisting of phenoxybenzamine and dibenamine; the imidazoline is selected from the group consisting of phentolamine, tolazoline. idazoxan. deriglidole. RX 821002. BRL 44408 and BRL 44409: the quinazoline is selected from the group consisting of prazosine. terazosin. doxazosin. alfuzosin. bunazosin. ketanserin. trimazosin and abanoquil: the indole derivative is selected from the group consisting of carvedilol and BAM 1303: the alcohol is selected from the group consisting of labetalol and ifenprodil: the alkaloid is selected from the group consisting of ergotoxine. ergocornine. ergocristine. ergocryptine. rauwolscine. corynathine. raubascine. tetrahydroalstonine. apoyohimbine. akuammigine, β-yohimbine. yohimbol, pseudoyohimbine and epi-3α-yohimbine: the amine is selected from the group consisting of tamsulosin. benoxathian. atipamezole. tedisamil. mirtizipine. setiptiline. reboxitine. delequamine. chlorpromazine, phenothiazine. BE 2254. WB 4101 and HU-723: the piperizine is selected from the group consisting of naftopil and saterinone; and the piperidine is haloperidol. 6. The composition of claim 3 wherein the α-adrenergic receptor antagonist is selected from the group consisting of amines, amides and piperizines. 7. The composition of claim 6 wherein the amine is selected from the group consisting of tedisamil. BE 2254. HU-723. WB 4101. benoxathian, atipamezole. mirtazipine. setiptiline. reboxitine and delequamine; the amide is selected from the group consisting of indoramin and SB 216469; and the piperizine is selected from the group consisting of SL 89.0591. ARC 239. urapidil. 5-methylurapidil and monatepil. 8. The composition of claim 3 wherein the compound that donates, transfers or releases nitric oxide is a S-nitrosothiol. 9. The composition of claim 8 wherein the S-nitrosothiol is selected from the group consisting of those having the structures: (i) CH,[C(R e )(R f )] v SNO; (ii) HS[C(R e )(R f )] SNO; (iii) ONS[C(R e )(R f )] N B; and (iv) H 2 N-(C0 2 H)-(CH 2 ) x -C(O)NH-C(CH 2 SNO)-C(O)NH-CH : -CO H 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 selected from the group consisting of fluoro, alkoxy. cyano. carboxamido, cycloalkyl. arylkoxy. alkylsulfinyl. arylthio. alkylamino. dialkylamino, hydroxy, carbamoyi. N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino. hydroxyl, carboxyl. hydrogen, nitro and aryl. 10. 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 N-oxo-N-nitrosoamine which has an R,R 2 -N(O-M T )-NO group wherein R, and R 2 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 an aromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds; (iii) a thionitrate which has the structure R l0 -S-NO 2 wherein R 10 includes polypeptides, amino acids, sugars, modified and unmodified oligonucleotides, and a 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 R 10 -O-NO 2 wherein R l0 is as defined above. 1 1. A composition comprising (i) an α-adrenergic receptor antagonist to which is directly or indirectly linked at least one nitro or nitroso group and (ii) a compound that donates, transfers or releases nitric oxide or elevates endogenous synthesis levels of nitric oxide. 12. The composition of claim 1 1 wherein the α-adrenergic receptor antagonist is a compound which has been nitrosated or nitrosylated through a site selected from the group consisting of oxygen, sulfur, carbon and nitrogen. 13. The composition of claim 1 1 wherein the nitrosated or nitrosylated α- adrenergic receptor antagonist is selected from the group consisting of: (i) compounds having the structure: wherein, R a is selected from hydrogen or alkoxy; R„ is selected from wherein a is an integer of 2 or 3; R c is selected from heteroaryl. heterocyclic ring, lower alkyl. hydroxyalkyl. and arylheterocyclic ring; D is selected from (i) -NO: (ii) -NO,: (iii) -C(R d )-0-C(0)-Y-Z-[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, in which R, is hydrogen, lower alkyl. R e and R f are independent!} selected from hydrogen, lower alkyl. cycloalkyl. aryl. heteroaryl. arylalkyl. amino. alkylamino. amido. alkylamido. dialkylamino. carboxy. 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, Z is selected from a covalent bond, alkyl. cycloalkyl. aryl. heteroaryl. arylalkyl or arylheterocyclic ring, and Q is selected from -NO or -N0 ; (iv) - C(O)-T'-Z-[C(R e )(R f )] p - T"-Q wherein T 1 and T 2 are independently selected from T and R e , R f , p, Q. Z, and T are as defined above; (v) -C(O)-T[C(R )(R,)] p wherein i and R, are independently selected from -T'-[C(R.)(R f )] p -G-[C(R e )(R f )] p -T 2 -Q wherein G is (/) a covalent bond; ( /) -T-C(O)-; (iii) -C(O)-T. or (iv) Y, and wherein R d . R c . R f . p, Q. T. and Y are as defined above; (ii) compounds having the structure: II. wherein. R„ is selected from: wherein D, is selected from hydrogen or D wherein D is as defined above and with the proviso that D, must be selected from D if there is no other D in the molecule: (iii) compounds having the structure: III. wherein R h is selected from hydrogen. -C(0)-OR d or -C(O)-X wherein X is (1 ) -Y-[C(R e )(R f )] p -G i -[C(R c )(R f )] p -T-Q: wherein G f is (i) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T; (iv) -C(Y-C(O)-R - wherein R m is heteroaryl or heterocyclic ring: and in which Y . R d , R e . R f , p, Q and T are as defined above; or (2) in which W is a heterocyclic ring or NR,R', wherein R, and R', are independently selected from lower alkyl. aryl or alkenyl; and wherein Rj is selected from -D or -(0)CR d wherein D and R d are as defined above: (iv) compounds having the structure: IV. wherein. A, is oxygen or methylene and X and R j are as defined above; (v) compounds having the structure: V. wherein R k and R are independently selected from hydrogen or lower alkyl; and R, is selected from: wherein b is an integer of 0 or 1 : D, is as defined above; and R^ is selected from: OCH, wherein A, is oxygen or sulfur; (vi) compounds having the structure: VI. wherein R n is selected from: and R p is selected from: and R . D and D, are as defined above: (vii) compounds having the structure: VII. wherein R,, T and D are defined as above: and (viii) compounds having the structure: VIII. wherein a. R,. R',, R e . R f . and D are defined as above. 14. The composition of claim 1 1 wherein the α-adrenergic receptor antagonist is selected from the group consisting of haloalkylamines. imidazolines. quinazoiines, indole derivatives, phenoxypropanolamines, alcohols, alkaloids, amines, piperazines and piperidines. 15. The composition of claim 14 wherein the haloalkylamine is selected from the group consisting of phenoxybenzamine and dibenamine: the imidazoline is selected from the group consisting of phentolamine. tolazoline, idazoxan. deriglidole. RX 821002, BRL 44408 and BRL 44409; the quinazoline is selected from the group consisting of prazosine, terazosin. doxazosin, alfuzosin. bunazosin. ketanserin. trimazosin and abanoquil; the indole derivative is selected from the group consisting of carvedilol and BAM 1303; the alcohol is selected from the group consisting of labetalol and ifenprodil; the alkaloid is selected from the group consisting of ergotoxine. ergocornine. ergocristine. ergocryptine. rauwolscine. corynathine. raubascine. tetrahydroalstonine. apoyohimbine. akuammigine. β-yohimbine. yohimbol, pseudoyohimbine and epi-3α- yohimbine: the amine is selected from the group consisting of tamsulosin. beoxathian. atipamezole. chlorpromazine, phenothiazine. BE 2254, WB 4101 and HU-723; the piperizine is selected from the group consisting of naftopil and saterinone: and the piperidine is haloperidol. 16. The composition of claim 1 1 wherein the compound that donates, transfers or releases nitric oxide is a S-nitrosothiol. 17. The composition of claim 16 wherein the S-nitrosothiol is selected from the group consisting of those having the structures: (i) CH,[C(R e )(R f )] λ SNO ; (ii) HS[C(R e )(R f )] SNO: (iii) ONS[C(R e )(R f )] B: and (iv) H 2 N-(CO,H)-(CH,) -C(0)NH-C(CH,SNO)-C(O)NH-CH 2 -CO,H wherein x equals 2 to 20; R e and R f are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl. hereroarvl. arylalkyl. alkylamino, dialkylamino or taken together are carbonyl, cycloalkyl or bridged cycloalkyl; and B is selected from the group consisting of fluoro, . cyano. carboxamido, cycloalkyl, arylkoxy. alkylsulfinyl, arylthio. alkylamino. dialkylamino. hydroxy. carbamoyi. N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino. hydroxyl, carboxyl, hydrogen, nitro and aryl. 18. The composition of claim 16 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 R,R,-N(O-M NO group wherein R, and R, 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 an aromatic hydrocarbon, hydrocarbons having one or more substituent groups and heterocyclic compounds: and (iii) a thionitrate which has the structure R ]0 -S-NO 2 wherein R 10 includes polypeptides. amino acids, sugars, modified and unmodified oligonucleotides. and a 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 R IO -O-NO, wherein R l0 is as defined above. 19. 2-acyl- 17α (3-methyl-3-nitrosothiolbutoxy) yohimban- 16α- carboxylic acid C,-C 4 alkyl ester and acid addition salts thereof. 20. 4-[2-(dimethylamino)ethoxy]-2-methyl-5-( 1 -methylethyl)phenol- (3-S-nitroso-3-methyl-butyric acid) ester and acid addition salts thereof. 21. A method of treating human impotence in an individual in need thereof which comprises treating an individual for human impotence by administering to the individual a therapeutically effective amount of a composition comprising a nitrosated or nitrosylated α-antagonist of the invention in a pharmaceutically acceptable carrier. 22. A method of treating human impotence in an individual in need thereof which comprises treating an individual for human impotence by administering to the individual a therapeutically effective amount of a composition comprising an α- adrenergic receptor antagonist, which can optionally be substituted with at least one NO or NO, moiety, and a compound that donates, transfers or releases nitric oxide in a pharmaceutically acceptable carrier.

Inventors: GARVEY DAVID S, SAENZ DE TEJADA INIGO, SCHROEDER JOSEPH D, GARVEY, DAVID, S., SAENZ DE TEJADA, INIGO, SCHROEDER, JOSEPH, D.
Applicants: GARVEY DAVID S, NITROMED INC, SAENZ DE TEJADA INIGO, SCHROEDER JOSEPH D, GARVEY, DAVID, S., NITROMED, INC., SAENZ DE TEJADA, INIGO, SCHROEDER, JOSEPH, D.
Application year: 1997
Main classification: A01N43
IPC codes: A61K31, A61K38, A61P15, C07C217, C07C311, C07C381, C07D211, C07D233, C07D239, C07D295, C07D401, C07D405, C07D459, C07D487