CA2244879A1 - Compositions and kits comprising alpha-adrenergic receptor antagonists and nitric oxide donors and methods of use - Google Patents

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

W O 97/27749 PCTrUS97/01294 NITI~OSATED AND NITROSYLATED
a-ADRENERGIC REC~PTOR ~NTA.GONIST
COMPOUNDS, COMPOSITIONS AND THEIR U~ES

This application is a continuation-in-part of U.S. patent application serial no 08/~9~,732 filed February 2. 1996 (copending).

This invention generally relates to (x-adrenergic receptor antagonists~
compositions Cont~inins:l 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 potential1~ 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 phenoxyben7~n~ine, 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 phentolarnine~ an a-adrenergic antagonist, is used. As an altemative or, in sôme cases~
~ an adjunct to a-adrenergic blockade, pros~gl~nflin El (PGEI~ has been ~lmini.stered I

CA 02244879 l998-07-3l via intracavernosal injection. A major side effect frequently associated with intracorprally delivered PGE1 is penile pain and burning. Thus. there is a need for treatments of hurnan 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 dil-ation of the corpus cavernosum smooth muscle, an event involved in the penile erection process. However.
the effects of such compounds together with a-adrenergic receptor antagonists or the modifications of a-adrenergic receptor antagonists to be directly or indirectly linked with a nitric oxide adduct have not been invçstig~t~

In the process of arriving at the present invention it was recognized that the risL
of toxicities and adverse effects that are associated with high doses of a-adrenergic receptor antagonists can be avoided by the use of such a-adrenergic receptor antagonists when nitrosated or nitrosylated or when ~lministered in con~unction with compounds that donate~ release or transfer nitric oxide. Such toxicities and adverse effects include postural hypotension. reflex tachycardia and other a~vthmias, syncope and. with respect to the ergot alkaloids, nausea and vomiting and, upon prolonged or excessive zl~1mini~tration vascular insufficiency and gangrene of the extremities. The a--adrenergic receptor antagonists and compounds that donate, release or transfer nitric oxide work together to permit the same efficacy with lower doses of the a--adrenergic receptor antagonists.

Accordingly, in one aspect the invention provides novel nitrosated and nitrosvlated o~-adrenergic receptor antagonists (NO"-a--antagonists) wherein n is I or ~.
The a-adrenergic antagonist can be nitrosylated or nitrosated through sites such as oxygen (hvdroxyl condensation). sulfur (sulfllydryl con~len~1ion3, carbon and nitrogen.
The invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.

In another aspec~ the invention provides a composition comprising a therapeutically effective amount of an a-adrenergic receptor antagonist (a-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 ph~rm~e~ltically acceptable carrier. The a-adrenergic receptor antagonist used in the composition can be those described above and others which are known and can alternatively be such a-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 ~lmini~tering to an individual in need thereof a therapeuticallv effective amount of a nitrosated or nitrosylated a--antagonist.

In another aspect, the invention provides a method for treating male impotence in humans which comprises ~s~lmini~tering to an individual in need thereof a composition comprising a therapeutically effective amount of an a-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-3. The a~-antagonist or oc-antagonist directly or indirectly linked to at least one NO or NO2 group, and nitric oxide donor can be ~1mini~tered separately or as components of the same composition.

Figure 1 shows the percent peak erectile response in vivo compared to that produced by 150 ~1 of papaverine/phent amine/PGE1 (pap/phent/PGE1) (30 mg/ml: 1 mg/ml: 10 ~ug/ml) in the anesthetized rabbit following the intracavernosal injection of 150 ,ul of yohimbine (150 ~L~. 500 ~Lg3. Example I (500 ~ug). and a combination of vohimbine (150 ,ug) and Example 1 (500 ,ug). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGE1 and the abscissa indicates the various drugs given.

Figure 2 shows the duration of the erectile response in vivo in the anesthetizedrabbit upon intracavernosal ~lmin;~tration of yohimbine (150 ~Lg, 500 ,ug), Example I
(500 ~Lg), and a combination of yohimbine (150 ,ug) and Example I (500 ~ug). Theordinate indicates the various drugs given and the abscissa is the duration in minlltes W O 97/27749 PCTrUS97/01294 - Figure 3 shows the percent peak erecti}e response in vivo compared to that produced by 150 ~1 of pap/phent/PGE1 (30 mg/ml: I mg/ml: 10 llg/ml) in the anesthetized rabbit following the intracavernosal injection of yohimbine (150 ,ug. 500 ,ug and 1 mg) and Example 2 (500 ,llg, 1 mg). The ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGE1 and the abscissa indicates the various doses of yoh;mbine and Example 2 given.

Figure 4 shows the duration of the erectile response in vivo in the anesthetizedrabbit upon intracavernosal ~lmini~tration of yohimbine (l S0 ~lg~ 500 ~lg and 1 mg~ and Example 2 (500 ~lg and 1 mg). The ordinate indicates the various doses of yohimbine and Example ~ given and the abscissa is the duration in minutes.

Figure ~ compares the effects of intracavernosal injections of Example ' (500 ,ug) and the standard mixture of pap/phent/PGEI on systemic blood pressure in the anesthetized rabbit.

Figure 6 shows the percent peak erectile response in ViVO compared to that produced by 1~0 ~l of pap/phent/PGEl (30 mg/ml: I mg/ml: 10 ~lg/ml) in the anestheti~ed rabbit following the intracavernosal injection of moxisylyte (I 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 anesthetizedrabbit upon intracavernosal ~flmini~tration of moxisylyte (I mg) and Exarnple 6 (I mg).
The ordinate indicates the dose of moxisylyte and Example 6 the abscissa is the duration in minllt~s The term "lower alkyl" as used herein refers to branched or straight chain alkylgroups comprising one to ten carbon atoms including methyl. ethyl~ propyl, isopropyk n-butyl. t-butyl. neopentyl and the like.

The terrn "alkoxy" as used herein refers to RsoO- wherein R50 is lower alkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.

The terrn "alkoxyalkyl" as used herein refers to an alkoxy ~roup as previously ~ defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include~ but are not limited to. methoxymethyl. methoxyethyl. isopropoxymethyl and the like.

The terrn "hydroxy" as used herein refers to -OH.

The term "hydroxyalkyl" as used herein refers to a hydroxy ,~roup as previously defined appended to a alkyl group as previously defined.

The term "alkenyl" as used herein refers to a branched or straight chain C7-Clo hydrocarbon which also comprises one or more carbon-carbon double bonds.

The term "amino" as used herein refers to -NH7.

The term "carboxy" as used herein refers to -C(O)O-.

The term "nitrate" as used herein refers to -O-NO,.

The terrn "amido" as used herein refers to -C(O)NH-.

The term "alkylamino" as used herein refers to R"NH- wherein R" is a lower alkyl group~ for example. methylamino. ethylamino. butylamino. and the like.

The term "alkylamido" as used herein refers to -C(O)NR"- wherein R" is defined as above.

The term "dialkylamino" as used herein refers to Rl7R,3N- wherein Rl, and Rl3 are independently selected from lower alliyl~ for example dimethylamino, diethylamino~
methyl propylarnino and the like.

The terrn "nitro" as used herein refers to the group -NO. and "nitrosated" refers to .
s W O 97/2774~ PCT~US97/01294 compounds that have been substituted therewith.

The term "nikoso" as used herein refers to the group -NO and "nitrosvlated" 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 tetra~luorophenyl 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.
hydroxvbenzyl~ fluoroben_yl, fluorophenylethyl and the like.

The terrn "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"haloalkvl" as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent? for exarnple. chloromethyl, fluoroethyl or trifluoromethyl and the like.

The term "heteroaryl" as used herein refers to a mono- or bi- cyclic ring systemcont~ining one or two aromatic rings and Cont~ining at least one nikogen, 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, dialkylarnino, hydroxy, halo and nitro. Examples of heteroaryl ~roups include but are not limited to pyridine, pyrazine. pvrimidine. pyridazine. pvrazole. triazole. thiazole, isothiazole, benzothiazole.
benzoxazole. thi~ 701e ox~ole pyrrole. imidazole and isoxazole.

W O 97/27749 PCT~U~97/01294 The terrn "heterocyclic ring" refers to any 3-. 4-, 5-, 6-, or 7-membered nonaromatic ring contzlining 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 polycvclic compounds cont~ining 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 (x-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 a- anta~onists can generally be categorized as haloalkylamines, imidazolines, quinozolines. indole derivatives. phenoxypropanolamines~ alcohols. alkaloids. amines, piperizines and piperidines.

The first group of oc-antagonists are the haloalkylamines that block a,- and a,-adrenergic receptors irreversibl~. Included in this group are. for example.
phenoxyben7~mine and dibenamine. Phenoxyben7~mine 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 minimi7~s other adverse effects of catecholamines such as contraction of plasma volume and inJury of the myocardium.

Another group of such o~-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, intracavernous injection of phentolamine (usuallv 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 82100'~, BRL 44408 and BRL 44409 (see Eur. J. Pharm., 168:3 81, 1989) Another group of a-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 primar systemic hypertension and also in the treatment of congestive heart failure.

Another class of such oc-adrenergic blocking agents are indole derivatives. These include. for example, carvedilol and BAM 1303.

Another class of such a-adrenergic blocking agents are alcohols. These include~
for example. Iabetelol and ifenprodil.

Another class of such a-adrenergic blocking agents are alkaloids. These include,for example~ "ergotoxine." which is a mixture of three alkaloids, i.e.. ergocornine, ergocristine and ergocryptine. Both natural and dihydrogenated peptide alkaloidsproduce a-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 a-blockers include rauwolscine, coryn~thine, raubascine, tetrahydroalstonine~
apoyohimbine~ akuammi~ine. ~3-vohimbine, yohimbol, pseudoyohimbine and epi-3a-yohimbine.

Another class of such a-adrenergic blocking agents are amines. These include, for example. tamsulosin. benoxathian. atipamezole, BE ~'~54, WB 4101 and HU-723.Another class of such a-adrenergic blocking agents are piperizines. These W O 97/27749 PCT~US97/Q1294 include. for example~ naftopil and saterinone.

Another class of such a-adrenergic blocking agents are piperidines. These include~ for exarnple~ haloperidol.

Each of the above contemplated a-antagonists is descr;bed 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:

H3CO~ /N~ Rb H3CO/~\f :, N
~N~

I.

wherein~
Ra is selected from h~ drogen or alkoxy;
Rb is selected from N N ~ Rc (jj;) ~OCH3 O

CA 02244879 l998-07-3l W O 97/27749 PCT~US97/0129 wherein a is an integer of 2 or 3;
Rc is selected from heteroaryl, heterocyclic ring, lower alkyl, hydroxyalkvl~ and arylheterocyclic ring;
D is selected from (i) -NO; (ii) -NO2; (iii) -C(Rd)-O-C(O)-Y-Z-[C(Re)~R,)]p-T-Q in which Rd is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl. Y is oxygen, sulfilr, or NRt in which Rt is hydrogen. Iower alkyl, R~ and Rf are independently selected from hydrogen~ lower alkyl, cycloalkyl, aryl. heteroaryl, arylalkyl, amino, alkylamino, amido, aLkylarnido. dialkylamino. carboxy, or taken together are carbonvl~
cycloalkyl or bridged cycloalkyl, p is an integer from I to 6, T is a covalent bond~
oxygen, sulfur or nitrogen~ Z is selected from a covalent bond, alkyl, cycloalkyh ar~ l.
heteroaryh arylalkyl or arylheterocyclic ring. and Q is selected from -NO or -NO,; (iv) -C(O)-T'-Z-[C(Re)(R,)~p- T--Q wherein T' and T- are independently selected from T and R~ R,. p~ Q. Z, and T are as defined above; (v) -C(O)-T[C(R )(Rz)]p wherein R~ and Rz are independently selected from -T'-[C~Re)(Rf)]p-G-[C(R~)(Rf)]p-T'-Q wherein G is (i) a covalent bond; (ii~ -T-C(O)-; (iii) -C(O)-T, or (i-~) Y. and wherein Rd? Re~ Rf, p, Q, T~ and Y are as def1ned above;

Another embodiment of this aspect is substituted compounds of the formula:
N
Rg \N
I

II

W O 97/27749 PCTrUS97/01294 wherein, R~ is selected from:

~) H3C ~ (iv) CH3 N~ ~N

(i;) ~3~"~ (V)1~ ~N

(v~

(iii) ~ J\O_CH3 wherein D, is selected from hydro~en 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 of the formula:

III.

Il W O 97t27749 PCT~US97/01294 wherein Rh is selected from hydrogen, -C(O)-ORd or -C(O)-X wherein X is ( I ) -Y-rC(Re)(Rf)]p-Gj-rC(R~)(Rf)~p-T-Q; wherein Gj is (i) a covalent bond: (ii) -T-C(O)-~ (iii) -C(O)-T; (iv) -C(Y-C(O)-Rm)- wherein R" is heteroaryl or heterocvclic ring: and in which Y, Rd. Re~ Rf, p, Q and T are as defined above; or (2) O N
\\
N ~/ t- W

in which W is a heterocyclic ring or NRjR'j wherein Rj and R'j are independently selected from lower alkyl, aryl or alkenyl; and wherein Rj is selected from -D~ hydrogen, or -(O)CRd wherein D and Rd are as defined above.
Another embodiment of this aspect includes substituted compounds of the formula:
~A1 / ~\d Rj X ~O

IV.
wherein, Al is oxygen or methylene and X and Rj are as defined above.

W O 97/27749 PCTrUS97/01294 - Another embodiment of this aspect includes substituted compoùnds of the formula:
- D
Rn~/ N~ R
~ I I
Rk R'k V.
wherem, R,; and R ,; are independently selected from hydrogen or lower alkyl; and wherein R, is selected from:

(CH2)b ~ H3CO/W
f~ ~3 3 wherein b is an integer of 0 or 1: D and Dl are as defined above; and W O 97/27749 PCTrUS97/01294 - R,, is selected from:

O~ o (iii) ~~~

(ii) ~ (iv) J ,~

wherein A7 is oxy~en or sul~ur.
Another embodiment of this aspect includes substituted compounds of the forrnula:
o~D
Rk VI, wherein Ro is selected from:

~ ~ H

D1' '0 ~o~

W O 97/27749 PCT~US97/01294 and Rp is selected from:

~/ ~ J CH3 aand R~. D. and Dl are as defined above.

W O 97127749 PCTnJS97/01294 - Another embodiment of this aspect includes substituted compounds of the formula:
~~2 R~--T/D\~ T-~CH2):i--N

H3C \ N CH3 D

VII.
wherein Rd~ T and D are defined as above.

Another embodiment of this aspect includes substituted compounds of the forrnula:

r~/ D

Re\ (CH2)a~ OJ,~
I

Rf R'j VIII.

wherein a, R;, R'j, Re~ Rf~ and D are defined as above.

The present invention also relates to processes for preparing the compounds of formula (I), (II), (III)~ (IV). (V). (Vl), (VII). or (VIII) and to the intermediates useful in such processes.

Some of the nitrosated and nitrosylated oc-antagonists of the present invention W O 97J27749 PCT~US97/01294 may be synthesi7P-l as shown in reaction Schemes I through XXI presented below. in which Ra~ Rb, Rc~ Rd, Re~ Rf, Rg~ Rh. Ri, R i Rj- Rk. Rl, Rm~ Rn~ Ro~ Rp. Al. A2. a- n- W
and X are as defined above or as depicted in the reaction schemes for formulas I. I~. III.
IV . V, VII. or VIII. pl is an oxygen protecting group and p2iS a sulfur protectin group. The reactions are performed in solvents ~ opl,ate 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 con.ci~t~nt 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 of the reaction conditions required in some of the methods described. but alternative methods and substituents compatible with the reactionconditions will be readily ~p~ lt 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, c.fi. 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 theirbroadest application to the p~ ion of the 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 s-lrces~fully performed by conventional modifications known to those skilled in the art. e.g., by ~p~upliate protection of interfering groups. by ch~nging to alternative conventional reagents. by routine modification of reaction conditions. and the like~ or other reactions disclosed herein or otherwise conventional. ~ill 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 Ra~ Rb. Re~ Rp and p are as defined above and an O-nitrosylated arnide is representative of the D group as defined above may be prepared according to Scheme 1. The amine group of the quinazoline of the forrnula 1 is converted to the amide of the formula 2 wherein p, Rc and Rfare as defined above by W 097/27749 PCT~US97/01294 reaction with an appropriate protected alcohol cont~ining 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-cont~ining acid. PrefeITed protecting groups for the alcohol moietv 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 aspyridine or triethylamine affords the compound of the formula IA.

Scheme 1 H CO~'/~ H3CO~ Rb NH2 HN~ lRe ~C - (C)~o--P~
Ra ~ O ~f H3co~Jy~ R

H3CO \~--f HN\ lRe IA //C - ( 1)~~--NO
O Rf -W O 97/27749 PCTrUS97/01294 - Nitroso compounds of formula ~I) wherein Ra~ Rb~ Re~ 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 of the quinazoline of the formula 1 is converted to the arnide of the formula 3 wherein p, Re and Rf are defined as above b~
reaction with an ~ro~liate protected thiol-cont~ining activated acylating agent wherein P7 iS as defined above. Preferred methods for the formation of arnides are reacting the amine with the preforrned acid chloride or symmetrical anhydride of the protected thiol cont~in;n~ 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 reducin~ disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercurictrifluoroacetate. 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 IB. Alternatively,treatment of compound 3 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound of the formula IB.

W O 97/27749 PCTrUS97/01294 - Scheme II

H3C~~ H3C~~ " Rb NH2 HN\ I e ~C - ( I)P--S--p2 Ra ~ Rf H3CO~ ~ R

H3CO ~~ N
HN\ I e I B ~f - (Cl)p--S--NO

Nitro compounds of formula (I) wherein Ra~ Rb, Re~ 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 III. The amine group of the quinazoline of the formula 1 is converted to the amide of the formula IC wherein p, Re and Rf are defined as above by reaction with an a~pr~ iate 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 cont~inin~ acid to afford the compound of the formula IC.
Scheme III

H~CO~ b H CO~ ~ Rb NH2 HN\ I e IC /C--(C )p--O--NO2 ~ Rf CA 02244879 l998-07-3l Nitroso compounds of formula (II) wherein Re~ R~ and p are defined as above and an O-nitrosylated acyl imid~z01ine is representative of tne D ~roup as defined above ma~ be prepared according to Scheme IV. The imidazoline group of the formula 4 is converted to the acyl imidazoline of the formula S wherein p, R~ and Rf are defined as above by reaction with an appropriate protected alcohol Cont~inin~ activated acylating agent wherein pT iS as defined above. Preferred methods for the formation of acyl imidazolines are reacting the imidazoline with the preformed acid chloride or symmetrical anhydride of the protected alcohol cont~inin~ 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 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 of the formula IIA.

Scheme IV
N/~ N

/ R~ (C)p_o_p1 4 ~ 5 Rf \\
IRe Rg C - (C)p--O--NO

~ Rf IIA

Nitroso compounds of forrnula (Il) wherein R~, Rf, Rl!. and p are defined as above W O 97/27749 PCTnUS97/01294 and an S-nitrosylated acyl imida701ine is representative of the D group as defined above may be prepared according to Scheme V. The imidazoline group of the formula 4 isconverted to the acyl imidazoline of the formula 6 wherein p~ Re and R, are defined as above by reaction with an ~Lop1iate protected thiol cont~ining activated ac,vlating agent wherein P~ is as defined above. Preferred methods for the formation of acyl imidazolines are reacting the imidazoline with the preformed acid chloride or symmetrical anhydride of the protected thiol cont~ining 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 reducin~ disulfide groups while aqueous base is typicall~ 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 nitriee in aqueous acid affords the compound of the formula IIB.

2~

W O 97~27749 PCT~US97/01294 .
- Scheme V - ~

)\--N ~ R~/ C--(C)p_s_p2 4 ~ 6 Rf /~
\\
/ --N I e Rg C--(C)p--S NO

~ Rf IIB

Nitro compounds of formula ~II) wherein R~. Rf~ R,~7 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 Vl. The imidazoline group of the formula 4 is converted to the acyl imidazoline of the formula IIC wherein p, Re and Rf are defined as above by reaction with an appropriate nitrate conf~ining activated acylating agent.
Preferred methods for the formation of acyl imidazolines are reacting the amine with the preformed acid chloride or svmmetrical anhvdride of the nitrate cont~inin~ acid to afford the compound of the forrnula IC.

Scheme VI

)\~ \\
Rg H Rg C ~ ( I)p--O--NO2 ~ Rf W O 97/27749 PCTnJS97/01294 - Nitroso compounds of formula (III) wherein Re~ Rf. Rh. Rp 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 forrnula 7 is con~erted to the ester of formula 8 wherein p. Re and Rf are defined as above by reaction with anappropriate protected alcohol cont~ining activated acylating agent wherein P' is as defined above. Preferred methods for the formation of esters are reacting the alcohol with the preforrned acid chloride or symmetrical anhydride of the protected alcohol containin~
acid. Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl moietv (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, DM~. or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIIA.

Scheme VII

7 Rh OH

p1~ R

I I IA RhRc\ ~ C
,(C)p ~0 ONRf - Nitroso compounds of formula (III) wherein Re~ Rp Rh. Rj. and p are defined as above and an S-nitrosylated ester is representative of the D group as defined above may be prepared according to Scheme VI~I. The alcohol ~roup of the formula 7 is converted - to the ester of the formula 9 wherein p ~e and Rf are defined as above by reaction with an a~lopliate protected thiol conlz~;ning 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 symrnetrical anhydride of the protected thiol cont~3inin~ acid.
Plc;f~ d 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 aclueous base is typically utilized to hydrolvze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoro~cet~te 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 nikite such as tert-butyl nitrite. or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride?
TlHF? DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of the formula IIIB. Alternatively? treatment of compound 9 with a stoichiometric quantity of sodiurn nitrite in aqueous acid affords the compound of the formula IIIB

W O 97/27749 PCT~US97/01294 - Scheme VIII

7 Rh OH g ; ' S' R~
IIIB Re \ ,C~
(C~p o ON R~

Nitro compounds of formula (III) wherein Re Rf~ R,~, Rj, and p are defined as above and an O-nitrosated ester is representative of the D group as defined abo~ e may be prepared according to Scheme IX. The alcohol group of the formula 7 is converted to the ester of the formula IIIC wherein p, Re and Rf are defined as above by reaction with an ap~J,o,u.;ate nitrate cont~ining activated acylating agent. Preferred methods for the formation of esters are reacting the alcohol with the preforrned acid chloride or symmetrical anhydride of the nitrate containing acid to afford a compound of the forrnula IIIC.

WO 97/~7749 PCT/US97/01294 - Scheme I~ -~ ~r~
7 Rh OH Re\ C
~C)p O
02N Rf Nitroso compounds of forrnula ~IV) wherein A,. R~ . Rh, Rj~ and p are defined as above and an O-nitrosylated ester is representative of the X group as defined above may be prepared according to Scheme X. An acid of the formula 10 is converted into the ester of the formula 11 wherein p, Re~ and Rf are defined as above by reaction with an ~,rol~;ate monoprotected diol Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloroformate such as isobutylchlorofonnate 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 bytreatment with a dehydration agent such as dicyclohexylcarbo~iimicle 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 silvl 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 dichloromethane1 THF, DMF, or acetonitrile affords the compound of the formula IVA.

- Scheme X

O p1~ Rf ~

,(C)\ ~
ON Rf O
IVA

Nitroso compounds of formula (TV) wherein A,~ Re~ R", Rj. and p are defined as above and an S-nitrosylated ester is representative of the 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~. and R~ are defined as above and a S-nitrosylated ester is representative of the X group as defined above by reaction with an a~ iate protected thiol Cont~inin~ alcohol. Preferred methods for the ~JlepaldLion 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 cont~qinin~ alcohol preferably in the presence of a conflenc~tion catalyst such as 4-dimethylarninopyridine. 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 cont~inin~ alcohol may be coupled to afford 12 by treatment with a dehydration agent such as dicyclohexylcarbodiimide. Preferred protectino oroups 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 aparamethoxybenzyl thioether, a tetrahyd,~l,y,~lyl thioethert or a S-triphenvlmethvl 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 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 aparamethoxybenzyl thioether. a tetrahydropyranyl thioether or a S-triphenylmethvl 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 methvlene chloride.
THF~ DMF or acetonitrile with or vvithout 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 of the formula IVB.

W 097/27749 PCTrUS97/~1294 - Scheme XI

H C
Ro H ~/
~C)p --~
ON Rf o IVB

Nitro compounds of formula (IV~ wherein A" R~ R,l, Rj, and p are defined as above and an O-nitrosated ester is representative of the X group as defined above may be prepared according to Scheme XII. An acid of the formula 10 is converted into the ester of the formula IVC wherein P? Re~ and Rf are defined as above by reaction with an appropriate nitrate containing alcohol. Preferred methods for the preparation of esters are initially formin~ 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 anhvdrous inert solvent such as dichloromethane~ diethylether, or THF. The mixed anhydride is then reacted with the nitrate cont~inin~ alcohol preferably in the presence of a condensation catalyst such as 4-dimethvlamino-pyridine. Alternatively, the acid 10 mav 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-dimethvlaminopyridine and a tertiarv amine base such as triethyl arnine to afford the a compound of the formula IVC. Alternatively~ the acid 10 and nitrate containin~ alcohol may be coupled to afford a compound of the forrnula IVC by treatment with a W O 97/27749 PCTnUS97/01294 - dehydration a~ent such as dicyclohexylcarbodiimide.
Scheme XII

HO (~ ~
O o O

Nitroso compounds of formula (V) wherein Re~ ~, R~ R,, R". and p are defined as above and an O-nitrosylated N-acyloxyalkyl arnine is lc~les~ a~ive of the D group as defined above may be prepared according to Scheme XIII. The am;ne group of the compound of the formula 13 is converted to the N-acyloxyalkyl amine of the formula 14 wherein p, Re~ and E~ are defined as above by reaction with an appropriate protected alcohol cont~ininp chloromethyl acyl derivative wherein P' is as defined above.
Preferred methods for the formation of N-acyloxyalkyl amines are reacting the arnine with the preformed chloromethyl acvloxyalkyl derivative of the protected alcohol.
Preferred protecting groups for the alcohol moiety are silyl ethers such as a triethylsilyl or a tert- butyldimethylsilyl ether. Deprotection of the hydroxyl moiety (fluoride ion is the preferred method for removing silyl ether protecting groups) followed bv reaction a suitable nitrosylating a~ent 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 VA.

W O 97/27749 PCT~US97/01294 - Scheme XIII
Re R,~ N R, ~ ~ )P--O--p1 R! / R, ~ Rl / R, R, 13 Rk Rk 14 R" ~ ' C--(Cl~p--O--NO
R, f Rk Rk VA

Nitroso compounds of formula (V) wherein Re? R~, R~ R~, R". and p are defined asabove and an S-nitrosylated N-acyloxyalkyl amine is representative of the D group as defined above may be ~le~a,ed according to Scheme XIV. The amine group of the compound of the formula 13 is converted to the N-acyloxyalkyl amine of the formula 15 wherein p, Re~ and Rp are defined as above by reaction with an ~ru~liate protected thiol containing chloromethvl acyl derivative wherein P~ is as defined above. Preferred protecting croups for the thiol moietv are as a thioester such as a thioacetate or thiob~n7- ~tl~ as a disulfide. as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a tetrahydropyranyl thioether. Deprotection of the thiol moiety (triphenylphosphine in water and sodium borohydride are ~ rclled 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 tetrahydropyranvl 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 VB.

CA 02244879 l998-07-3l W O 97/27749 PCTrUS97/01294 - Scheme XIV

N R ~ ~C--(C)p--S--p2 Rl ~~ Rl ~ Rl ~~ Rl Rf 13 Rk Rk 15 ~,/
Re R ~ ~C - ( I)P- S - NO
R, Rf Rk Rk VB

Nitro compounds of formula (V) wherein Re~ Rf, R,;. R" Rn~ and p are defined as above and an O-nitrosated N-acyloxyalkyl amine is representative of the D group as defined above mav be prepared according to Scheme XV. The amine group of the compound of the formula 13 is converted to the N-acyloxyalkyl arnine of the forrnula VC
wherein p~ Re~ and Rf are defined as above by reaction with an ~plol-l;ate nitrate corlt~;ning chloromethyl acyl derivative. Preferred methods for the formation of N-acyloxyalkyl amines are reacting the amine with the preformed chloromethyl acyloxyalkyl derivative of the nitrate cont~ining derivative to afford the compound of the formula VC.

Scheme XV

Re ~? ? N/ o//

Nitroso compounds of formula (VII) wherein Rd~ Re~ T, and p are defilned as above and an O-nitrosylated amide is representative of the D group as defined above mav be prepared according to Scheme XVI. The amine group of the dihydropyridine of the fiormula 14 is converted to the amide of the forrnula 15 wherein p~ Re and Rf are defined as above by reaction with an a~lo~liate protected alcohol conts~tning activated acylating agent ~vherein 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 cont~ining 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 ~lefell~d method for removing silyl ether protectin~
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 aspyridine or triethylamine affords the compound of the formula VIIA.

CA 02244879 l998-07-3l W O g7/27749 PCTAUS97/01294 - Scheme XVI

Rd--T~ lv\QT (cHz)3-N3 H3C N \ CH 14 Rd T ~QT (;H2)3--N/ \/
R~ 15 ) 0~ (c)p_O

Rd - T 1~'1"T (;HZ)3-~ R7 ~~ NO

W O 97/27749 PCT~US97/01294 - Nitroso compounds of formula (VII) wherein Rd. Re~ R, T. and p are deflried as above and an S-nitrosylated amide is representative of the D group as defined above ma v be prepared according to Scheme XVII. The arnine group of the dihydropyridine of the formula ~4 is converted to the amide of the formula 16 wherein p. R, and Rf are defined as above by reaction with an appropriate protected thiol contS~ining activated acvlating agent wherein P' is as deflned above. Preferred methods for the forrnation of amides are reacting the arnine with the preformed acid chloride or symmetrical anhvdride of the protected thiol cont~ining acid. Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thioben70~te as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbarnate, 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 acid7 triphenylphosphine in water and sodium borohvdride are preferred methods for reducing disulfide groups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxvmethyl 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 all;yl nitrite such as tert-butyl nitrite. or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methyene chloride, THF, DMF, or acetonitrile with or ~ithout an amine base such as pvridine or triethylamine affords the compound of the forrnula VIIB. Alternatively. treatment of compound 16 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound of the forrnula V~

W O 97/27749 PCT~US97/01294 - Sc~eme X VII

~ J o ~

~3 O / S_ p2 Rd--T~ T (;H2)3_N/~3 W O 97/27749 PCT~US97/01294 - Nitro compounds of formula (VII) wherein Rd. R~? Rf~ T. and p are defined as above and an O-nitrosated amide is representative of the D ~roup as defined above may be prepared according to Scheme XVIII. The arnine group of the dihvdropyridine of the formula 14 is converted to the amide of the formula VIIC wherein p. Rc and E~f are defined as above by reaction with an ~p,~,pliate nitrate containing activated acylating agent. Preferred methods for the forrnation of amides are reactin~ the arnine with the preforrned acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of the formula VIIC.

Scheme XVIII

Rd--TJ~ T (cH2) H3C NCH3 14 \~

R~--T~ I ~ /~T (CH2)3_N //~3 }~3C N CH3 )/~~
Re VIIC \~/

~ R / ~ NO2 Nitroso compounds of formula (VIII) wherein Re? R~, R;. R ;. a and p are definedas above and an O-nitrosylated ester is representative of the D group as def ned above CA 02244879 l998-07-3l W O 97/27749 PCTrUS97/01294 may be prepared according to Scheme XIX. lIhe hydroxyl group of the~phenol of the forrnula 17 is converted to the ester of the formula 18 wherein a. P- ~e and R~ are defined as above by reaction with an a~ ;ate protected alcohol cont~ining activated acylating agent wherein pl is as defined above. Preferred methods for the formation of esters are reacting the hydroxyl with the preforrned acid chloride or symmetrical anhydride of the protected alcohol cont~inin~ acid. Preferred protecting ~roups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsil~l 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, DM~, or acetonitrile with or without an arnine base such as pyridine or triethylamine affords the compound of the formula VIIIA.

Scheme XIX

Ro~ ~CH2)a,,~ > Re~ ~CHz), ~ ~~ //
I, ~\
Rf 17 R'; . Rf 18 ~~\C//

Re~ ~CH2)a~O~G J R _(C)D

Rf R'; NO
VIIIA

Nitroso compounds offormula (VIII) wherein Re~ Rf~ Rj, R'j, a. and p are defined as above and an S-nitrosylated ester is representative of the D group as defined W O 97/27749 PCT~US97101294 above mav be prepared according to Scheme XX The hydroxyl ~roup of the phenol ofthe formula 17 is converted to the ester of the formula 19 wherein a. p. Re and ~ are defined as above by reaction with an apl)lopliate protected thiol 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 symmetricalanhydride of the protected thiol cont~inin~ 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 paramethoxyberl7yl thioether, a tetrahvdropyranyl 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 ~roups while aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate. silver nitrate, or stron~=
acids such as trifluoroacetic or hydrochloric acid and heat are used to remove aparamethoxvbenzvl 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 forrnula VIIIB Alternatively. treatment of compound 17 with a stoichiometric quantity of sodium nitrite in aqueous acid affords the compound of the formula VIIIB

~ W O 97127749 PCTAUS97/01294 - Scheme XX

R,,~ (CH~ R. N(CH2)a~o~l~0 Rf R j f 19 R; ~,/
~J \C//
Re~ (CH2~a~0 1~ R (C)p Rf R'; NO
VIIIB

Nitro compounds of formula (VIII) wherein Re~ Rf~ Ri, R'~, a, and p are defined as above and an O-nitrosated ester is representative of the D group as defined above may be prepared according to Scheme XXI. The hydroxyl group of the phenol of the formula 15 is converted to the ester of the formula VIIIC wherein a. p~ Re and Rf~ 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 anhvdride of the nitrate cont~ining acid to afford the compound of the forrnula VIIIC.

WO 97/27749 PCT~US97/01294 - Scheme XXI

R.~ ~CH~ \J ~ Re~ ~,CH2~

Rf 17 R'j Rf R'jNO2 VTIIC

As noted above. another aspect the invention provides a composition comprisin~ atherapeutically effective amount of an oc-adrenergic receptor antagonist (o~-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 (x-blocker is not substitutedwith at least one NO or NO~ moiety. Additional c~-blockers that are suitable for this embodiment include ~mine~ such as ter~i.c~mil mirtazipine, setiptiline~ reboxitine and delequarnine. amides~ such as indoramin and SB 216469; piperizines~ such as SL
89.0591~ ARC ~39~ urapidil, S-methylurapidil and monatepil. Indoramin is a selective.
competitive a,-antagonist that has been used for the treatment of hypertension. IJrapidil is also known to be a selective a,-adrenergic antagonist that has a hypotensive effect in hllm~n~.

The compounds that donate~ transfer or release nitric oxide can be any of those kno~n 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 pharrnacological 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 O,~ 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 elimin~tion of the active NO moiety.

4~

W O 97/27749 PCT~US97/0~29 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 terrn "nitric oxide" encompasses uncharged nitric oxide (NO-) and charged nitric oxide speciesparticularly including nitrosonium ion (NO-) and nitroxyl ion (NO-). The reactive forrn - 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 terrn "NO adducts" encompasses any of such nitric oxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols.
S-nitrothiols, O-nitrosoalcohols O-nitroalcohols, sydnonimin~s 2-hydroxy-?-nitrosohydrazines (NONOates), (E)-alkyl-2-t(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 o~ 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 racemicmixtures and derivatives thereofl: S-nitrosylated sugars~ S-nitrosylated-modified and unmodified oligonucleotides (preferablv 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 e~
al.. Org. Prep. Proc. Int.. 15(3): l 65- 198 (1983); Loscalzo et al., J. Pharmacol. Exp.
Ther., 249(3):726729 (1989) and Kowaluk et al., J. Pharmacol. Exp. Ther., 256: 1256-~ 1764 (1990), all of which are incorporated in their entirety by reference.

W O 97/27749 PCTrUS97/01294 - 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-cont~inin~ 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~roup 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 pl~minogen 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. Examplesinclude polvnitrosylated 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)CH3[C(Re)~Rf)], SNO
wherein x equals 2 to 20 and Re and Rf are as defined above;
(ii)HS[C((Rc)(Rf)3xSNo wherein x equals 2 to 20: and Re and Rf are as defined above;
(iii)ONSLC(Re)(Rf)]~B; and (iv)H,N-(CO~H)-(CH,)~-C(O)NH-C(CH~NO)-C(O)NH-CH~-CO~H

wherein x equals 2 to '~0: Re and R, are as defined above; and B is selected from the group consisting of fluoro, C,-C( alkoxy? cyano, carboxarnido, cycloalkyl, arylakoxy, alkylsulfinyl~ arylthio. alkylamino~ dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl. amino. hydroxyl, carboxyl, hydrogen, nitro and aryl.

Nitrosothiols can ~e 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 ~.5) to yield the S-nitroso derivati~ e. Acids which may be used for this purpose include aqueous sulfuric. acetic and hvdrochloric acids. Alternatively. the precursor thiol mav 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- ~roup. 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 arnino 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-~00, nucleotides). ON- O-, ON-N- or ON-C-hydrocarbons which can be branched or unbranched. saturated or unsaturated aliphatic hydrocarbons or aromatic hvdrocarbons:
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. arvl or a heterocyclic compound. A ~ f~ d example is the nitrosvlated forrn of isosorbide. Compounds in this group form S-nitrosothiol intermediates in vil o in the recipient human or other animal to be treated and can therefore include any structurally analogous precursor R-O-NO of the 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-O-, O.N-N-, O~N-S- or O,N-C- group. Preferred amon~ these are those selected from the group consisting of O.N-O-, O,N-N-, O,N-S- or 01N-C- polypeptides;
O,N-O-, O~N-N-, O.N-S- or O~N-C-amino acids; OlN-O-, O~N-N- O,N- S- or O~N-C-sugars; O~N-O-. O.N-N-, O~N-S- or O,N-C-modi~led and unmodified oligonucleotides;
O~N-O-~ OlN-Nr, O,N-S- or OlN-C- hydrocarbons which can be branched or unbranched. saturated or unsaturated aliphatic hydrocarbons or aromatic hydrocarbons:

W O 97/2774~ PCT~US97/01294 07N-0-, O.N-N-. 07N-S- or O.N-C- hydrocarbons having one or more substituent groups in addition to the O.N-0-~ O.N-N-, O.N-S- or 0,N-C-group. and O~N-0-. O.N-N-, 0,N-S- or O.N-C-heterocyclic compounds Preferred examples are isosorbide dinitrate and isosorbide mononitrate.

Another group of such N0 adducts is the nitroso-metal compounds which have the structure (R),-A-M-(N0)~. ~ includes polypeptides (the terrn "polypeptide" includes proteins and also polyarnino 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 5-2û0.
nucleotides)- and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon. or an aromatic hydrocarbon:
hvdrocarbons having one or more substituent groups in addition to the A-nitroso group:
and heterocyclic compounds. A is S. 0. or N. n and x are each inte~ers independently selected from 1. ~ and 3. and M is a metal, preferably a transition metal. Pre~erred metals include iron, copper, m~ng~nPse 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.-N(0-M )-N0 group wherein R, and R. include polypeptides. amino acids. sugars. modi~led 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 releasenitric oxide and have the structure Rlo-S-N0, wherein Rlo is as described above for the N-oxo-N-nitrosoamines .

Agents which stimulate endogenous N0 synthesis such as L-arginine. the substrate for nitric oxide synthase. are also suitable for use in accordance with the nventlon.

W O 97/27749 PCTAUS97/~1294 When ~dmin;stered in vivo. the nitric oxide may be ~rimini~tered 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 ~-lrn;ni~tering to the individual a therapeuticallv effective amount of a composition comprising a nitrosated or nitrosylated oc-antagonist of the invention in a pharmaceuticaily 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 a~lministering to the individual a therapeutically effective amount of a composition comprising an a-adrenergic receptor antagonist (o~-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.

Total daily dose ~-lmini~t~red to a host in single or divided doses may be in amounts, for example~ from about I to about 100 mg/lcg body weight daily and more usually about 3 to 30 mglkg. 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 dosaL~e forrn will ~ arv depending upon the host treated and the particular mode of ~lministration.

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 of the patient. the severity ofthe ~ e~e~ the route of ~lministration~ pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicolo~y profiles of the particular compound employed, whether a drug delivery s . stem is utilized and whether the compound is ~-lmini~tered as part of a drug combination. Thus, the dosage regimen actually employed may vary widely and therefore may deviate from the ~l~rel~ed dosage regimen set forth above.

W O 97/27749 PCT~US97/01294 The compounds of the present invention may be ~llministered orally. parenterally or topically in dosage unit formulations cont~inino conventional nontoxic pharrnaceutically acceptable carriers. adjuvants, and vehicles as desired. Topical allmini~tration may also involve the use of transdermal ~lministration 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 oleagrnous suspensions may be form~ ted 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 purpose any bland fixed oil may be emploved including synthetic mono- or diglycerides. in addition. fatty acids such as oleic acid fmd use in the preparation of injectables.

Solid dosa~e forms for oral a~lminictration 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 m~gnesium 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 ~1mini~tration 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, emulsif~ ing and suspending agents~ and sweetening. flavoring~ and perfuming agents.

While the compounds of the invention can be zltlmini~tered as the sole active phs~ ceutical 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 tar~~etin~ for treatment. The compositions of the invention can be ~lministered as a mixture of an a-antagonist and a nitric oxide donor, they can also be used in combination ~ ith one or more compounds which are known to be effective against the specific disease s~ate 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 pharm~e-ltical compositions of the invention. Associated with such container(s) can be a notice in the forrn prescribed by a governmental agency regulating the m~nllf~ture, use or sale of pharmaceuticals or biological products, which notice reflects approval bv the agency of m~nllf~cture~ use or sale for human ~flmini~tration.

W 097/27749 PCTrUS97/01294 - Exampie 1 N~ L-~-~lutamvl- S-Nitroso-~-cvsteinvl~lvcine N-(N-L-g-glutamyl-L-cysteinyl)glycine (100 g. 0.325 mol) was dissolved in deoxygenated water (200 ml) and 2N HCI (162 ml) at room temperature and then thereaction 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 (7 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. 'H NMR
(D,O): 1.98 (m, 2H)~ 2.37 (t. 2H)~ 3.67 (t~ lH), 3.82 (s 2H). 3.86 (dd. lH). 3.98 (dd. lH).
4.53 (m. IH).

Example 2 2-Acvl-17a(3-methvl-3-nitrosothiolbutoxv)vohimban-16a-carboxvlic acid methvl ester hvdrochloride salt 2a. 3 -Methvl -3 (2-tetrahvdropYranvl ~thiobutvric acid 3-Methyl-3-thiobutyric acid (4.2 g. 31 mmol), dihydropyran (7.8 ml. 31 mmol), and 700 1ll of 4 N HC I /Et,O were allowed to stand at room temperature overni~ht. The volatiles we~e evaporated in vacuo (2 mm Hg) yielding 6.6 g (30 mmol) of material which was used without further purification. 'H-NMR (CDC 13): 4.92 ~d. J = 8.1 Hz.
IH). 4.09 ~d. J = 10.5 Hz. lH)? 3.49-3.56 (mult. l~I), 7.73 (dd, J - 1.2 and 13.7 Hz, lH).
2.64 (d. J = 13.8 Hz. lH). 1.84-1.89 (mult 2H). 1.55-1.69 (mult, 4H), 1.51(s. 3H). 1.42 (s, 3H).

2b. 3.3'-Dimethvl-3.3'(7-ditetrahvdropvranyl)thiobutvric acid anhydride The product of Example 2a (1.1 g. 5 mmol) and triethylamine (710 ~11, 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 warrned 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) ofthe title compound. 'H-NMR (CDCl~):
5.03-5.06 (mult~ 2H). 4.04-4.08 (mult, 7H)~ 3.46-3.51 (mult, 2H)~ 2.89 (d, J = 15.7 Hz.

W O 97/27749 PCT~US97/01294 - 2H), '~.77 (d. J = 15.6 Hz 7H), 1.79 1.88 ~mult. 4H). 1.51-1.67 (mult. 8~I). 1.54 (s 6H).
1.49 (s~ 6H).

2c. 17a (3-methvl-3-tetrahydropvranylthiolbutoxv)vohimban-16a-carboxvlic 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-dimethylaminopyridine (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 H70, brine~ and then dried over anhydrous sodium sulfate. Treatment of the solution with activated charcoal followed by filtration and concentration of the filtrate in vacuo gave 2.8 g of a dark syrup.
Chromatography on silica gel eluting with 1 :1 hexane/ethyl acetate cont~ining 1%
by volume triethylamine afforded 670 mg (20%) of the title compound. 'H-NMR
(CDCl3): 7.76 (s, lH), 7.46 (d, J = 7.2 Hz, lH), 7.29 (dd, J = 1.0 and 7.0 Hz, lH), 7.17 (ddd; J = 1.3. 7.1~ and 7.1 Hz, lH), 7.07 (ddd; J = 1.1, 7.2, and 7.2 Hz, lH)~ 5.46 (d, J =
2.6 Hz~ lH), 5.07-5.11 (mult, lH). 4.06-4.11 (mult, lH), 3.69 (s, 3H), 3.47-3.55 (mult, lH)~ 3.39 (d, J = 10.4 Hz, 1~), 3.0'~-3.12 (mult, 2H), 2.97 (dd, J = 4.5 and 12.2 Hz, lH), 2.80 (d~ J - 14.3 Hz, lH), 't.71 (mult~ lH)~ 2.69 (d, J = 13.2 Hz, lH), 2.61-2.65 (mult, lH)~ '~.39 (dd. J = 2.6 and 11.6 H~ lH), 2.~3-2.33 (mult, 2H), 1.71-'7.07 (mult, 5H), 1.58-1.69 (mult, 8H~. 1.51 (s~ 3H). 1.49 (s~ 3H). Anal Calcd for (C3,H,7N705S-1/2 H70):
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. ~-Acvl- 17a~3 -methYI-3 -thiolbutoxy)yohimban-16a-carboxvlic acid methvl 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 ~acuo ('~ 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 sodiumsulfate. The solvent was evaporated in vaCuo and the residue was chromatographed on silica gel eluting with 1: I hexane/ethvl acetate Cont~ining 1% by volume triethylamine to sl afford ''10 mg (34 %~ of ~-acyl-17a.(3-nnethyl-3-thioacetylbutoxy)vohinnban-16 a-carboxylic acid methyl ester. This diacetate (180 mg~ 0.32 mmol~ was dissolved in acetic acid (~ ml) to which was added mercuric trifluoro~cet~te (190 mg. 0.45 mmol ) and the reaction mixture was stirred at room temperature for 2 hours. The volatiles wereevaporated i7Z l~acuo 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 arnmonium hydroxide. The organic phase was filtered through Celite to remove the ,~ray 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 chromatographedon silica gel ehlting with a gradient of with 1: 1 hexane/ethyl acetate containing I % bv volume triethylamine to ethyl acetate containing 1% by volume triethylamine to yield 60 mg (37 %) ofthe title compound as a white powder. 'H-NMR (CDCl ,~: 7.81 (d. J = 7.0 Hz~ lH)~ 7.41 (d. J = 6.8 Hz. lH), 7.23-7.29 (mult. 2H). 5.46 (s~ IH)? 4.17 (d. J = 9.9 Hz.
lH)~ 3.64 (s~ 3H),3.11-~.15 (mult. lH).3.00 (dd. J = 3.5 and 12.4 Hz. l~I). 2.64-2.84 (mult. lOH). 2.31 (dd, J = 2.6 and 11.7 Hz. lH)~ 2.~4 (d, J = 12.7 Hz. lH). 2.04-2.0 8 (mult. 2H). 1.41 - 1.62 (mult,1 l H). ' ~C-NMR (CDC 13): 171.6. 170.7, 169.5. 13 7.3.
136.4. 129.6, 1 ~4.1. 12'' .9. 118.3. 117.'' . 114.6, 70.0, 61.0, 59.8. ~ 1.9, 51.8, 5().9. 47.7.
45.6. 37.8. 37.6,36.~2. 36.2,33.~ 9.9, '77.1, 23.8. 22.3.

2e. 2-Acyl- 17a(3 -methvl-3-nitrosothiolbutoxY~yohimban- 16O~ -carboxYlic acid methvl ester hvdrochloride salt To a slurry of the compound of Example 2d (40 mg. 0.078 mmol) in 1: 1 methanol/lN HCI (4 ML) with dimethylformamide (400,ul) was added a solution of sodium nitrite (11 mg. 0. 16 mmol) in H,0 (~OO ,ul). The white powder turned green as the slurry was stirred at room temperature for 25 minutes. At this juncture dimethylformamide (600 ~Ll) and additional aqueous sodium nitrite (11 mg in 200 ,ul of H,0) was added and stirrin~ at room temperature was continued for an additional 15 minutes. The reaction mi~ture was partitioned between CHC 1 ~ and H,O adding 10%aqueous ammonium hydroxide to the aqueous phase until basic to pH paper. The aqueous layer was extracted with CHC1 ~ and the connbined organic extracts were washed with brine and then dried over anhydrous sodium sulfate. The ~ olatiles were evaporated in vacuo and the residue was dissolved in ether. The product ~as precipitated with =

W O 97/27749 PCTnUS97/01294 ethereal HC l to afford 19 m~ of the title compound as a green solid. 'H-NMR (CDC 1 ~):
7.81 (dd,3 = 1.7 and 6.8 Hz.1H)~ 7.42 (d. ~ = 6.8 Hz. IH), 7.23-7.?9 (mult~ 2H). 5.43 (d.
J = 2.6 Hz. lH)! 4.15 (d. J = 9.8 Hz. lH)~ 3.63 (s.3H).3.36 (d~ J = 15.1 Hz. IH).3.30 (d.
J = 1 j.1 H~ lH).3.12 (dd. J = 4.9 and 11.0 Hz. lH) 3.00 (dd, J = 3.7 and 12.3 Hz 1H).
'~.72 (s.3H). 2.63-2.8? (mult.3H)~ 2.31 (dd, J = ?.6 and 11.7 Hz. 1 H). '~.03 ~s. 3H). ~.00 (s.3H).1.0-2.0 (mult~ 9H).

2-{~M-(4-(3-S-Nitroso-3-methvl-butvric acid)phenvl) ethyllaminomethyl~-l -tctralone ester hvdrochloride 3a.2-{rl3-(4-Hvdroxvphenyl) ethyll t-butoxvcarbonvlaminomethvl~-l-tetralone ?-{IJ3-4-Hydroxyphenyl) ethyl] aminomethyl}-1-tetralone (3.39 g. 11.5 mmol) was dissolved in dichloromethane (50 mL) and di-tert-butyldicarbonate (2.50 g. 11.5 mmol) was added. The reaction mi~;ture was stirred for 100 minlltes 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 . 'H NMR (CDC13, 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-,.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. ~ H). 7.39-7.50 (m. l H)~ 8.01 (d. 1 H).

3b. 2-~rl3-(4-(3-Tetrahvdropvranvlthio-3-methvl-butvric acid)phenyl) ethvllaminometh~ 1-tetralone ester The product of Example 3a (0.300 ~. 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 resultin~ solution v~as 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/ethvl acetate (4: l ) to give 0.332 g (73 %) of the title compound.
'H NMR (CDC13. 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. I H). ~.73- 3 06 (dd. overlapping with multiplet, 7H), 3.33-3.67 (m, S H), 4.05-4.17 ~m. 1 H). 5.09-5.17 ~m. 1 E~). 7.01 (d, 2 H), 7.13-7.36 (m, 4 H), 7.47 (t. I H). 8.01 (d. l H).

3c. 2-~rl3-(4-(3-Mercapto-3-methvl-butvric acid)phenvl) ethyl~-t-buYoxvcarbonyl- aminometh~ - 1 -tetralone ester W 097127749 PCT~US97/01294 The product of Example 3b (0.192 8? 0.3~7 mmol) was dissolved in methanol (2 mL) and a solution of silver nitrate (0.117g~ 0.69 mmol) in water (0.4 mL) was added The resulting mixture was stirred for I hour at room temperature. The solvent was evaporated. the residue was suspended in acetone/water (1:10) and lN HCI (I 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 ~ (51 %) of the title compound . 'H NMR (CDC13, 300 MHz) _1.44 (s. 9 EI), 1.58 (d, 6 H)~ 1.73-1.96 (m? I H)~ ~.17-~.31 (m, I H)~ ~.38 (s. 1 H). 2.64-'7.93 (m. 5 H)~ 2.94-3.07 (m~ '~ H)~ 3.45 (t~ 3 H)~ 3.58-3.67 (m~ 1 ~), 7.02 (d, 2 H), 7.15-7.36 (m~ 4 H). 7.47 (t~ 1 H)~ 8.01 (d~ 1 H).

3d. ~-~rl3-(4-(3-Mercapto-3-methyl-butyric acid)phenvl) ethvl~aminomethvl}-l-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. 'H NMR (CDCl3, 300 MHz) 159 (s, 6 H),1.84-2.03 (m, 1 H)~ 2.15-2.26 (m, 1 H). '7.39 (s, 1 H), 2.82- 3.16 (m, 11 H), 7.06 (d, 2 H).
7.18-7.35 (m. 4 H), 7.49 (t. I H). 8.00 (I H).

3e. ~ 13-(4-(3-S-Nitroso-3-methvl-butYric acid)phen~ll') ethvl]aminomethYI}-1- tetralone ester hvdrochloride The product of Example 3d (0.081 g. 0.20 mmol) was dissolved in methanol (4 mL) and IN HCI was added. A solution of sodium nitrite (0.045 g, 0.65 mmol) in water (0.25 mL) was added. After stirring for 15 min1~tec 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 0.07~ g (81 %) of the title compound as a green solid. 'E~ NMR (CDC13? 30Q M~z) ~:1.72-1.93 (m. I H). 2.09 (s. 6 H). ''.18-2.30 (m. I H). 2.84-3.11 (m, 1 H), 3.14-3.33 (m.

-W O 97/27749 PCTrUS97/01294 - 6 H). 3.36-3.57 ~m~ 4 H). 7.03 (d. ? H). 7.18-7.42 (m. 4 H). 5.53 (t~ 1 H). 7.94 (d. I H).

- Example 4 ~ 4-(2-methoxyphenvl)-a--~(1-naphthalenyloxy)methvl~ piperazineethyox~-~3-S-nitroso-3-methyl-butvric acidl ester ~ 4a. ~-Methvl-3-(2.4A6-trimethoxYphenylmethylthio)but~ric acid To a solution of 3-mercapto-3-methylbutyric 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 (8~
g, 0.72 mol). No significant temperature rise was noted durin~ the addition. To this was then added dropwise a solution of 2 4.6-trimethoxybenzyl alcohol (M.C. Munson et al., J. Org Chem., ~7, 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 vo}atiles were evaporated in vacuo (toluene or ethyl acetate can be used to assist in the removal of volatile material). The residue was partitioned between diethvl 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 ~C. 'H NMR (CDCI,) ~: 6.1? (s. 2H), 3.80-3.85 (m. 11 H). ~.74 (s. 2H)~ 1.47 (s, 6H). 13C NMR (CDCI~) 173.9, 160.6. 158.6, 105.6, 90.5, 55.7, 55.3 45.9. 43.6, 28.4, 21Ø

4b. 4-(?-methoxyphenvl )-a-[( ~ -naphthalenvloxY)methyl3- 1 -piperazineethyoxv-~3-(2A4~6-trimethvoxvbenzvlthio)-3-methyl-butyric acidl ester Under a nitrogen atmosphere, 4-(2-methoxyphenyl )-a-[( 1-naphthalenyloxy)methyl]-1-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 (0.211 g. 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropvl )carbodiimide (0.132 g, 0.69 rnmol). 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 (CDCI~A 300 MHz) ~: 1.49-1.53 (d, 6 H, J = ~.4? Hz)~ 2.70- 2.84 ss W O 97/27749 PCT~US97/01294 (m. 8H). 2.98-3.09 (m~ 4 H), 3.75-3.85 (m. I ~ H), 3.86 ~s, 3 H). 4.31 -4.36 (m. 2 H j. 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. lH).
7.33-7.7- (m, 4 H). 7.77-7.82 (m, 1 H), 8.~3-8.27 (m. 1 H).

4c. 4-(2-methoxvphenyl)-a-~( l -naphthalenvloxv)methvl~ piperazineethvoxv -L3-mercapto-3-methyl-butvric 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 ~Ø14 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 hexanei ethyl acetate (':1) to ~ive the title compound (0.055 g~ 60 % yield) as a solid. 'H NMR
(CDCl3. 300 MHz) 1.49-1.53 (d. 6 H. J =2.4~ Hz). 2.59 (s~ I H). ~.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~ I II). 6.81-6.88 (d. 2 H, J =7.5 Hz)s 6.90-6 95 (m, 7 H), 6.98-7.04 (m, I H), 7.34-7.40 (t, I H. J=7.5Hz). 7.43-7.78 (m, 3 H), 7.79-7.82 (m. 1 H), 8.23-8.26 (m, I H).

4d. 4-(2-methoxvphenvl)-a-~(1 -naphthalenvloxy)methyl~- I -piperazineethyoxv-[3-S-nitroso-3-methvl-butyric acid~ ester The product of Exarnple 4c (0.048 g, 0.097 mmol) was dissolved in methanol (SmL) 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 I hour stirring at 0~C the reaction mixture was extracted with methylene chloride. ~-ashed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to ~ive the title compound (0.045 g. 82 % yield) as a green solid. 'HNM~(CDCI~. 300 MHz) ~: 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, I H), 8.09-8.12 (m. I H).

Example 5 2-14-(2-furoyl)piperazin-1-vl)-~4-(3-S-nitroso-3-methvl-butyric acid)l-6. 7-dimethvoxvquinazoline amide 5a.7-~4-(2-Furoyl )piperazin-l -vl]-~4-(3-(2.4.6-trimethYoxvbenzYlthio~-3-methvl-butvric acid)~-6. 7-dimethvoxYquinazoline arnide W O 97/27749 PCT~US97/01294 Under a nitro~en atmosphere 2-r4-('7-furoyl)piperazin-l-yl~-amino-6. 7-dimethyoxyquinazoline (0.200 g 0.52 mmol) was dissolved in anhvdrous dimethylformamide (S mL) and 4-dimethylaminopyridine (O.O''S g. 0.2 I mmol) was added. followed by the product of Example 4a (0.319 g. 1.04 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.199 g, 1.04 mmol). The resultinc mixture wasstirred at 50~C for 48 hours. The solvent was evaporated in vacuo and the residue was purified by flash chromato~raphy on silica gel eluting with hexane/ethyl acetate (3:1) to (l:S) to give 0.072 g (20 % yield) of the title compound as a white solid. 'H NMR
(CDCl3, 300 MHz) o: 1.52 (s, 6 H). 2.88 (s, I H), 2.90 (s. 2 H), ~.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 3.3'2 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).

Sb. 2-~4-('7-Furovl)piperazin-1-yl~-r4-(3-mecapto-3-methYl-butYric acid)l-6. 7-dimethvoxyquinazoline amide The product of Example Sa (0.160 g, 0.24 mmol) was dissolved in methylene chloride (0.67 mL). and then anisole (0.16 mL. 1.47 mmol)s 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 stirrin~ at room temperature toluene (S 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 (IS:I) to give the title compound (0.043 g. 36 %
yield) as a solid. 'H NMR (CDCIl. 300 MHz) â: 1..58 (s. 6 H), 2.45 (s, 1 H). 3.00 (s.2EI), 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~ I H), 7.15-7.18 (d. I H. J = 3.48 Hz), 7.49 (s. 1 H), 7.54-7.59 (m, I H).

5c. 2-[4-(~-Furovl)piperazin-l-vl]-r4-(3-S-nitroso-3-methYl-butvric acid)]-6. 7-dimethvoxvquinazoline amide The product of Example Sb (0.036 g, 0.080 mmol) was dissolved in methanol and lN 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 ~ive the title compound (0.023 g. 55 % yield) as a green solid.
'HNMR(CDCI~. 300 MHz~ o: ~.12 (s. 6 H), 3.49 (s. 2 H), 3.85-3.99 (m. 14 H), 6.51-6.55 (dd. lH. J = 1.7~ and 3.45 Hz). 6.79-6.98 (m, 2 H). 7.06-7.09 (d, 1 E~, J = 3.23 ~z). 7.54-W O 97127749 PCT~US97/01294 7.58 (m. 1 H).

- Example 6 4-~2-(Dimethvlamino)ethoxyl-2-methvl-5-(1-methvlethvltphenol-~3-S-nitroso-~-meth~l-butvric acid~ ester 6a. 4-r2-(Dimethylamino)ethoxyl-7-methyl-5-(l-methylethvllphenol 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(1-methylethvl)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 i~?
l~ac2~0 to give the title compound (0.71 g. 93 % yield) as a white solid. 'H NM~ (CDCI~
300 MHz) ~: 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. I H)~ 4.0~-4.07 (t. ~ H, J=5.9Hz). 6.57- 6.59 (d. '' H. J = 3.72 Hz).

6b. 4-~2-(Dimethylamino)ethoxy]-2-methvl-5-(l-methylethyl)phenol-r3-(7~4~6 trimethyoxybenzvlthio)~ -3-methvl-butvric acid) ester Under a nitrogen atmosphere, the product of Example 6a (0.270 ,~. 1.14 mmol) was dissolved in anhydrous dimethylforrnamide (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-dimethylaminopropyl)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 ~el. eluting withmethvlene chloride/ methanol (20:1) to give 0.732 g (39 % yield) of the title compound.
'H NMR (CDC13, 300 MHz) o: 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), 7.93-2.96 (m, 2 H), 3.23-3.28 (m, 1 H), 3.74-4.07 (m, l l H),4.03-4.07 (t. 2 H. J = 5.9 Hz). 6.11 (s. 2H). 6.67 (s~ IH), 6.81 (s, 1 H).

6c . 4-~7-(DimethYlamino )ethoxY]-7 -methvl-5-(1 -methvlethYI ~phenol -(3-mercapto-3-methvl-butYric acid~ ester The product of Example 6b (0.220 g. 0.42 mmol) was dissoJved in methylene chloride (0.30mL) and anisole (0.2~ mL, 2.02 mmol), phenol (0.022 g. 0.23 mmol). water (0.~7 mL) and trifluoroacetic acid (1.0 mL. 13.0 mmol) were added. After I hour of W O 97/27749 PCTrUS97/01294 .
stirring at room temperature. toluene (5 mL) was added and volatiles were evaporated.
The residue was purified by flash chromatography on silica ~el. eluting with methvlene chloride/ methanol (20:1) to ~ive the title compound (0.095 g. 64 % yield). 'H NMR
(CDCl3.300MHz)~: 1.14-1.16(d~6H,J=6.9Hz). 1.58(s,6H).2.14(s.3H).2.40(s. I
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, lH), 6.84 (S7 I H).

6d. 4-~2-(Dimethylamino)ethox~1-2-methyl-5-(1-methylethvl)phenol-(3-S-nitroso-3-methYI-butYric acid) ester The product of Example 6c ~0.035 g, 0.10 mmol) was dissolved in methanol (5mL) and lN solution of hydrochloric acid (I mL) was added. The resulting mixture was cooled to 0~C and a solution of sodium nitrite (0.014 g, 0.20 mrnol) in water (0.7 mL) was added. After 20 minllte~ stirring at 0~C, an additional sodium nitrite (0.032 ,~.
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 anh~drous sodium sulfate. The solvent was evaporated in vacuo to afford the product (0.028 g, 67% yield) as a green solid. 'HNMR (CDCI3, 300MHz) ~: 1.13-1.17 (d. 6 H. J = 6.9 Hz~ 2.0g-~.11 (m. 9 H)~ 2.95 (s~ 6 H), 3.13-3.20 (m, I H),3.45-3.51 (m. 4 H). 4.43-4.46 (m~ 2 H). 6.~3 (s. I H). 6.70 (s. I H), 6.76 (s, 1 H).

Example 7 3-[14.~-Dihvdro-1-(3-S-nitroso-3-meth~l butvloxy)-imidazol-2-vl)methyl](4-methylphenvl~aminoll~henol-(3-S-nitroso-3-methvl-butvric acid) ester 7a.3-Mercapto-3-meth~-l butyl acetate 3-Mercapto-3-methyl butanol (Sweetman et al. J: Med Chem. 14, 868 (1971) (5 g, 42 mmol) and pyridine (3.6 mL. ~3 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 I N HCI and brine. and dried over sodium sulfate. Evaporation of thesolvent gave 6.6 g of the title compound which was used without further purification. 'H-NMR (CDC13) â: 4.25 (t. J = 7.1 Hz. 'H), '7.21 (s, IH), 2.03 (s, 3H), 1.92 (t, J = 7.~ Hz, 2H). 1.41 (s, 3H).
-W O 97/27749 PCT~US97/01294 .
7b. 3-Tetrahvdropvranvlthio -3-methvl butvl acetate The product of Example 7a (6.6 g. 41 mrnol). dihvdropyran (4 mL. 44 mmol). and 4 N HCl/Et70 (1 mL) were allowed to stand at room temperature for '~4 hours. Thevolatiles were evaporated in vacuo to leave the title compound as a viscous oil which was used without further purification. 'H-NMR (CDC13) â: 4.97 (dd. J = 3.4 and 6.6 Hz. 1 H).
4.24 (t. J = 7.1 Hz 2H), 4.04-4.09 (mult, lH), 3.46-3.52 (mult, lH)~ 2.03 (s. 3H3. 1.93 (t.
J = 7.5 Hz. 2H), 1.42-1.88 (mult. 6H)~ 1.37 (s. 3H). 1.36 (s, 3H).

7c. 3-Tetrahydropvranvlthio-3-methvl 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 of the solvent and chromatography on silica ~el eluting with 3:1 hexane/ethyl acetate gave 340 mg (51%) of the title compound. 'H-NMR (CDCI3) o: 4.92 (dd, J = 3.1 and 7.6 Hz, IH), 4.05 (ddd; 3 = 4.0, 4Ø and 11.6 Hz.
lH), 3.81 (ddd; J = 6.3, 6.3. and 12.6 Hz lH)~ 3.78 ~ddd, J = 6.3~ 6.3, and 12.6 Hz~ IH), 3.49 (ddd, J = 3.8~ 7.7. and 11.8 Hz, lH). 1.79-1.89 (mult, 4H). 1.60-1.67 (mult, 4H), 1.56 (s. 3H), l.SS (s~ 3H). Anal calcd for CloH~oO~S C; 58.78, H; 9.87. S; 1~.69. Found C; 58.42, H; 9.73, S; 15.58.

7d. 3-rr4.5~Dihvdro-1 -(3-tetrahvdropvranvlthio-3-methYI butYloxY)-imidazol-2-vl)methvl](4-meth~ lphenvl)amino~phenol-(3- tetrahvdropvranYlthio-3-methYI-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 rapidlv 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 '~ 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-lH- imidazol-2-yl)methyl3(4-methylphenyl)amino]phenol hydrochloride (500 mg, 1.6 mmol) and triethylamine (650 ~lL, 4.7 mmol) in methylene chloride (10 mL) was cooled to to -78~C. The chloroformate W O 97/27749 PCT~US97101294 was dissolved in methylene chloride (4 mL~ and this solution was added to the slurry.
The resultin~ reaction mixture was stirred at -78~C for 30 minllte~ 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: I hexane/ethvl acetate ~ave 540 mg (46 %) of the title compound. 'H-NMR (CDCl3~ ~: 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.~1 (t. J = ~.~
Hz, lE~), 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 7H)~ 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-~4~5-Dihvdro-1-(3-thiol-3-methyl butvloxv~-imidazol-2-vl)methvll(4-methylphenvl)aminolphenol-(3-thiol-3-methvl-butvric acid) ester The product of Example 7d (400 mg~ 0.54 mmol). mercaptoethanol (760 ~lL 10 mmol). and 4 N EICl in ether (250 IlL, 1 mmol) were kept at room ~cmpcl~lL~Ire ~or '~4 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 of the solvents andsubjecting the residue to hi~h vacuum overnight afforded 130 mg of solid. The solid was chromato~raphed on silica gel eluting with 3:1 hexane/ethyl acetate to give 30 mg (10 %) ofthe title compound. 'H-NMR (CDC13) ~: 7.18 (d, J= 8.6 Hz. 2H). 7.14 (d. J = 7.9 Hz, 2H). 7.13 (t. J = 8.2 Hz. lH). 6.61 (dd, J = 2.4 and 8.3 Hz. IH). 6.59 (dd. J = '7.1 and 7.9 Hz lH). 6.52 (t. J = 2.2 Hz. lH). 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, lH), 1.75 (s, IH), 1.43 (s. 12H).

7f. 3-rr4.5-Dih~dro-1-(3-S-nitroso-3-methyl butYloxv)-imidazol-2-Yl)methY13(4- rnethylphenvl)aminolphenol-(3-S-nitroso-3-methyl-butyric acid) ester The product of Example 7e (18 mg. 0.033 n~nol) was dissolved in dimethylforamide (200 IlL) and 4 N HCI in ether (25 IlL, 0.1 mmol) was added. The reaction mixture was cooled to 0~C and tert-butyl nitrite (I 2 IlL, 0.12 mmol) was added and then the reaction mixture was stirred at for 0~C for 20 minutes. The solvent was W O 97/27749 PCT~US97/01294 evaporated in ltacuo and the solid residue obtained was azetroped with chlorofo~m to afford the title compound as a foam. 'H-NMR (DMSO-d6) o: 7.09 (d~ J = 8.0 Hz. lH).
6.89 (d~ J = 8.2 Hz, IH), 6.61-6.72 (mult, 6H). 5.10 (br s. 2H). 4.44 (t, 3 = 6.7 Hz. ''H)~
4.38 ~t. J = 6.7 Hz, 2H), 4.00-4.10 (mult, 2H). 3.89-4.00 (mult, '7H), 2.6~ (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 4-12-~Dimethvlamino)ethoxvl-2-methvl-5-(i-methvlethvl)phenol-(4-O-nitro-3-butvric acid) ester 8a. 4-~2-(Dimethylarnino)ethoxy~-2-methvl-5-(1 -methYlethvl)phenol-(4-bromo-butvric acid) ester 4-Bromobutyric acid (I g. 6 mmol) and triethylamine (836ml. 6 mmol? was dissolved in eth~l acetate (40 ml) and cooled to 0 ~C. Triphos~ene (309 m~. 1.0 ~ 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 li~ht 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 symrnetrical anhydride. Scandium triflate (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 bet~een 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 ~el elutin~ with 9: I methylene chloride/methanol to give 15'~
mg (~' 7 %) of the title compound as a light beige oil. 'H-NMR (CDCI33 o: 6.84 (s lH), 6.69 (s. lH). 4.35 ~dd~ J = 4.7 Hz and 4.7 Hz. 2H). 3.55 (t, 3 = 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 E~z. 6H).

8b. 4-~'~-¢Dimethvlamino)ethox~ -methvl-5-( l -methYlethYl )Phenol-(4-iodo-butvric acid) ester W O 97/27749 PCT~US97/01294 - The product of Example 8a (150 mg~ 0.39 mmol). sodium iodide (116 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 partioned 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 of the crude title compound which was imidiately carried on to the next step. 'H-NMR (CDC13) â: 6.82 (s, lH)~ 6.69 (s, lH), 4.~3 (dd, J = 5.4 Hz and 5.4 Hz. 2H), 3.32 (t, J = 6.6 Hz, 2H), 3.23 (m, lH), 3.04 (dd. J = 5.4 Hz and 5.4 Hz. 2H).
'7.72 (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-~2-(Dimethvlamino)ethoxy~-~-methyl-5-( 1 -methvlethYI )phenol-(O-nitro-butyric acid) ester The product of Example 8b (130 mg, 0.30 mrnol) 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 PTFl~:
membrane and the solvent evaporated in vacuo. The residue was chromatographed onsilica 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/NH3): m/z = 369 (M+H)- 'H-NMR (CDC13) ~: 6.84 (s. lH), 6.71 (s~ ), 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, '7H), 3.1~ (m, I H). 2.99 (s. 6H), 2.7. (t~ J = 7.2 Hz. 2H), ~.19 (m, lH), 2.11 (s, 3H). 1.17 (d~ J = 6.6 Hz, 6H).

Example 9 In Vivo Comparative Erectile Responses Male New 7:e~1~n~1 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/lcg Profol and maintained with i.v. infusion at 0.5 mg/kg/min. Ventilation of the ~nim~l.s was performed with 1% halothane plus 0.8 L/min 0~ and 1 L/min N~0. A 72 gauge angiocatheter was placed in the femoral artery for measurement of systemic blood pressure. A dorsal incision was made in the penis and the corpora cavernosa exposed and cann~ ted with a 21 gauge butterfly needle to measure intracavernosal pressure.

W O 97/27749 PCT~US97/01294 Drugs at various concentrations were delivered intracavernosall~ at a volume of 150 ~I through a 25 gauge needle. A l SO ~:LI solution of a mixture of papaverine (30 mg/kg), phentolamine (1 mg/kg) and prost~gl~nclin El (10 ~lg/ml) (pap/phent/PGEl ) was injected in the corpora 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/PGEI
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 ,ug dose of the compound of Example I was able to induce near maximal response relati~e to the standard dose of pap/phent/PGE 1 . A combination of the submaximal dose of ~ ohimbine ( 150 ~g) and the compound of Example 1 (SOO ,ug) 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 I produced a much longer duration of action. The duration ofaction is potentiated b~- a combination of the compound of Example I and yohimbine which is longer than the sum of the duration of each of these compounds alone (Figure '~).

Figure 3 shows that the compound of Example 2 at the 500 ~Lg dose is e~uipotent to the standard dose of pap/phent/PGE 1. A higher dose of the compound of Example 2 ( I
mg3 is at least equal to or more efficacious that the standard dose of the pap/phent/PGEI
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 ,ug) of the compound of Exarnple 2 effective in the erectile response did not produce any effect on s~stemic blood pressure upon intracavernosal injection. However.
a standard dose of the mixture of pap/phent/PGEI 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 ,ul of pap/phent/PGEI (30 mg/ml: 1 mg/ml: 10 !lg/ml) in the anesthetized rabbit followin the intracavernosal injection of 150 ~LI of yohimbine ( 150 llg~ 500 ~lg), the compound of Example 1 (500 llg). and a combination of vohimbine ( 150 ,ug) and the compound of Example 1 (500 ,ug). The ordinate is the percent response of W O 97127749 PCTrUS97/01294 intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various drugs given.

Figure '~ shows the duration of the erectile response in ~ o in the anesthetizedrabbit upon intracavernosal z~rlministration of yohimbine ( 150 ~g. 500 ,ug). the compound of Example I (500 ,ug), and a combination of yohimbine ~150 ,ug) and the compound of Example 1 (500 ~Lg). The ordinate indicates the various drugs given and the abscissa is the duration in minlltçs Figure 3 shows the percent peak erectile response in vivo compared to that produced by 150 ~1 of pap/phent/PGE1 (30 mg/ml: 1 mg/ml: 10 ~g/ml) in the anesthetized rabbit following the intracavemosal injection of 150 ,~1 of yohimbine (150 ~lg, 500 ~lg and I mg) and the compound of Example 2 (500 ,ug. 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 '~
given.

Figure 4 shows the duration of the erectile response in VilJO in the anesthetized rabbit upon intracavernosal ~-1mini~tration of yohimbine (1~0 ,ug, 500 ~Lg and I mg) and the compound of Example '7 (500 ,ug and I mg). The ordinate indicates the various doses of yohimbine and the compound of Example ~ given and the abscissa is the duration in minntes.

Figure S compares the effects of intracavernosal injections of the compound of Example ~ (~01) ,ug) and the standard mixture of pap/phent/PGEl on systemic blood pressure in the anesthetized rabbit.

Figure 6 shows the percent peal; erectile response in vivo compared to that produced by 150 ,ul of pap/phent/PGEI (30 mg/ml: I mg/ml: lO ~ug/ml) in the anesthetized rabbit followin~ the intracavernosal injection of moxisylyte (1 mg) and the compound of Example 6 ( I mg). The ordinate is the percent response of intracavernosa]
plCS~ulc relative to that produced by pap/phent/PGE1 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 W O 97/27749 PCT~US97/01294 rabbit upon intracavernosal ~11mini.ctration 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 minlltes.

Claims (22)

What Is Claimed Is:

1. Nitrosated and nitrosylated .alpha.-adrenergic receptor antagonists.

2. The nitrosated and nitrosylated .alpha.-adrenergic receptor antagonists of claim 1 selected from the group consisting of:

(i) compounds having the structure:

wherein, Ra is selected from hydrogen or alkoxy;
Rb is selected from wherein a is an integer of 2 or 3:

Rc is selected from heteroaryl. heterocyclic ring, lower alkyl, hydroxyalkyl, and arylheterocyclic ring;
D is selected from (i) -NO; (ii) -NO2; (iii) -C(Rd)-O-C(O)-Y-Z-[C(Re)(Rf)]p-T-Q in which Rd is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl. aryl or heteroaryl. Y is oxygen, sulfur, or NR~ in which R~ is hydrogen, lower alkyl, Re and Rf 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 -NO2; (iv) -C(O)-T1-Z-[C(Re)(Rf)]p-T2-Q wherein T1 and T2 are independently selected from T and Re. Rf, p. Q, Z. and T are as defined above; (v) -C(O)-T[C(Ry)(RZ)]p wherein R~ and Rz are independently selected from -T1-[C(Re)(Rf)p-G-[C(Re)(Rf]p-T2-Q wherein G is (i) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T. or (iv) Y- and wherein Rd. Re, Rf. p. Q. T. and Y are as defined above:
(ii) compounds having the structure:

wherein, Rg is selected from:

wherein D1 is selected from hydrogen or D wherein D is as defined above and with the proviso that D1 must be selected from D if there is no other D in the molecule;

(iii) compounds having the structure:

wherein Rh is selected from hydrogen, -C(O)-ORd or -C(O)-X wherein X is (1) -Y-[C(Re)(Rf)]p-Gi-[C(Re)(Rf)]p-T-Q; wherein Gi is (i) a covalent bond, (ii) -T-C(O)-; (iii) -C(O)-T; (iv) -C(Y-C(O)-Rm)- wherein Rm is heteroaryl or heterocyclic ring; and in which Y, Rd, Re, Rf, p, Q and T are as defined above, or (2) in which W is a heterocyclic ring or NRiR'i wherein Ri and R'i are independently selected from lower alkyl, aryl or alkenyl; and wherein Rj is selected from -D or -(O)CRd wherein D and Rd are as defined above;
(iv) compounds having the structure:

wherein, A1 is oxygen or methylene and X and Rj are as defined above;

(v) compounds having the structure:

wherein Rk and R'k are independently selected from hydrogen or lower alkyl;

and R1 is selected from:

wherein b is an integer of 0 or 1; D1 is as defined above; and Rn is selected from:

wherein A2 is oxygen or sulfur:

(vi) compounds having the structure:

wherein R0 is selected from:

and Rp is selected from:

and Rk, D and D1 are as defined above;

(vii) compounds having the structure:

wherein Rd. T and D are defined as above; and (viii) compounds having the structure:

wherein a. Ri. R'i, Re. Rf. and D are defined as above.

3. A composition comprising (i) a therapeutically effective amount of an .alpha.-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 .alpha.-adrenergic receptor antagonist is selected from the group consisting of haloalkylamines, imidazolines, quinazolines. indole derivatives, phenoxypropanolamines, alcohols, alkaloids. amines, piperazines andpiperidines.

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, ergocomine, ergocristine, ergocryptine, rauwolscine, corynathine, raubascine, tetrahydroalstonine, apovohimbine, akuammigine, .beta.-yohimbine, yohimbol, pseudoyohimbine and epi-3.alpha.-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-773; 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 .alpha.-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, atiparnezole, 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) CH3[Re)(Rf)]xSNO;
(ii) HS[C(Rc)(Rf)]xSNO;
(iii) ONS[C(Re)(Rf)]xB; and (iv) H2N-(CO2H)-(CH2)x-C(O)NH-C(CH2SNO)-C(O)NH-CH3-CO2H

wherein x equals 2 to 20; Re and Rf 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 groupconsisting of fluoro, alkoxy, cyano carboxamido, cycloalkyl, arylkoxy, alkylsulfinyl, arylthio. alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen. nitro and aryl.

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 R1R2-N(O-M~)-NO group wherein R1 and R2include 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 R10-S-NO2 wherein R10 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 hvdrocarbon; and (iv) a nitrate which has the structure R10-O-NO2 wherein R10 is as defined above.

11. A composition comprising (i) an .alpha.-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 11 wherein the .alpha.-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 11 wherein the nitrosated or nitrosylated .alpha.-adrenergic receptor antagonist is selected from the group consisting of:(i) compounds having the structure:

wherein, Ra is selected from hydrogen or alkoxy;
Rb is selected from wherein a is an integer of 2 or 3:
Rc is selected from heteroaryl, heterocyclic ring lower alkyl, hydroxyalkyl, and arylheterocyclic ring;

D is selected from (i) -NO; (ii) -NO2;(iii) -C(Rd)-O-C(O)-Y-Z-[C(Re)(Rf)]p T-Q in which Rd is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl, Y is oxygen, sulfur, or NRt in which Rt is hydrogen, lower alkyl, Re and Rf 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 -NO2; (iv) -C(O)-T1-Z-[C(Re)(Rf)]p- T2-Q wherein T1 and T2 are independently selected from T and Re, Rf, p, Q, Z, and T are as defined above; (v) -C(O)-T[C(Ry)(Rz)]p wherein Ry and Rz are independently selected from -T1-[C(Re)(Rf)]p-G-[C(Re)(Rf)p-T3-Q wherein G is (i) a covalent bond; (ii)-T-C(O)-; (iii) -C(O)-T, or (iv) Y, and wherein Rd, Re, Rf, p, Q, T, and Y are as defined above;
(ii) compounds having the structure:

wherein, Rg is selected from:

wherein D1 is selected from hydrogen or D wherein D is as defined above and with the proviso that D1 must be selected from D if there is no other D in the molecule;

(iii) compounds having the structure:

III.
wherein Rh is selected from hydrogen, -C(O)-ORd or -C(O)-X wherein X is (1) -Y-[C(Re)(Rf)]p-Gi-[C(Re)(Rf)p-T-Q; wherein Gi is (i) a covalent bond; (ii) -T-C(O)-; (iii) -C(O)-T; (iv) -C(Y-C(O)-Rm)- wherein Rm is heteroaryl or heterocyclic ring; and in which Y - Rd, Re, Rf, p, Q and T are as defined above; or (2) in which W is a heterocyclic ring or NRiR'i wherein Ri and R'i are independently selected from lower alkyl, aryl or alkenyl; and wherein Rj is selected from -D or -(O)CRd wherein D and Rd are as defined above;

(iv) compounds having the structure:

wherein.
A1 is oxygen or methylene and X and Rj are as defined above;

(v) compounds having the structure:

wherein Rk and R'k are independently selected from hydrogen or lower alkyl;

and R1 is selected from:

wherein b is an integer of 0 or 1; D1 is as defined above; and Rn is selected from:

wherein A2 is oxygen or sulfur;

(vi) compounds having the structure:

wherein Ro is selected from:

and Rp is selected from:

and Rk, D and Dl are as defined above;

(vii) compounds having the structure:

wherein Rd, T and D are defined as above; and (viii) compounds having the structure:

wherein a, Ri, R'i, Re, Rf, and D are defined as above.

14. The composition of claim 11 wherein the .alpha.-adrenergic receptor antagonist is selected from the group consisting of haloalkylamines, imidazolines, quinazolines, indole derivatives, phenoxypropanolamines, alcohols, alkaloids, arnines, piperazines and piperidines.

15. The composition of claim 14 wherein the haloalkylamine is selected from the group consisting of phenoxybenzamine and dibenamine: the imidazoline isselected 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 andifenprodil; the alkaloid is selected from the group consisting of ergotoxine, ergocornine, ergocristine, ergocryptine, rauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, akuammigine, .beta.-yohimbine, yohimbol, pseudoyohimbine and epi-3.alpha.-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 11 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) CH3[C(Re)(Rf)]xSNO;
(ii) HS[C(Re)(Rf)]xSNO;
(iii) ONS[C(Re)(Rf)]xB; and (iv) H2N-(CO2H)-(CH2)x-C(O)NH-C(CH2SNO)-C(O)NH-CH2-CO2H

wherein x equals 2 to 20; Re and Rf 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 groupconsisting of fluoro, alkoxy, cyano, carboxamido, cycloalkyl, arylkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl.

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 R1R2-N(O-M-)-NO group wherein R1 and R2 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 R10-S-NO2 wherein R10 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 R10-O-NO2 wherein R10 is as defined above.

19. 2-acyl-17.alpha. (3-methyl-3-nitrosothiolbutoxy) yohimban-16.alpha.-carboxylic acid C1-C4 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 .alpha.-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.alpha.-adrenergic receptor antagonist, which can optionally be substituted with at least one NO
or NO2 moiety, and a compound that donates, transfers or releases nitric oxide in a pharmaceutically acceptable carrier.