WO2000012075A1 - Nitrosated and nitrosylated alpha-adrenergic receptor antagonists, compositions and methods of use - Google Patents

Nitrosated and nitrosylated alpha-adrenergic receptor antagonists, compositions and methods of use Download PDF

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Publication number
WO2000012075A1
WO2000012075A1 PCT/US1999/020023 US9920023W WO0012075A1 WO 2000012075 A1 WO2000012075 A1 WO 2000012075A1 US 9920023 W US9920023 W US 9920023W WO 0012075 A1 WO0012075 A1 WO 0012075A1
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compound
composition
patient
nitric oxide
group
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PCT/US1999/020023
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English (en)
French (fr)
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David S. Garvey
Joseph D. Schroeder
Inigo Saenz De Tejada
Ricky D. Gaston
Tatiana E. Shelekhin
Tiansheng Wang
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Nitromed, Inc.
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Priority to CA002339145A priority Critical patent/CA2339145A1/en
Priority to JP2000567193A priority patent/JP2002523449A/ja
Priority to EP99944040A priority patent/EP1109542A4/en
Priority to AU57016/99A priority patent/AU770414B2/en
Publication of WO2000012075A1 publication Critical patent/WO2000012075A1/en
Priority to AU2004201585A priority patent/AU2004201585B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D459/00—Heterocyclic compounds containing benz [g] indolo [2, 3-a] quinolizine ring systems, e.g. yohimbine; 16, 18-lactones thereof, e.g. reserpic acid lactone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention describes novel nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists, and novel compositions comprising at least one nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and /or at least one vasoactive agent.
  • the present invention also provides novel compositions comprising at least one ⁇ -adrenergic receptor antagonist, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and /or at least one vasoactive agent.
  • the present invention also provides methods for treating or preventing sexual dysfunctions in males and females, for enhancing sexual responses in males and females, and for treating or preventing benign prostatic hyperplasia, hypertension, congestive heart failure, variant (Printzmetal) angina, glaucoma, neurodegenerative disorders, vasospastic diseases, cognitive disorders, urge incontinence, and overactive bladder, and methods for reversing the state of anesthesia.
  • benign prostatic hyperplasia hypertension
  • congestive heart failure variant (Printzmetal) angina
  • glaucoma neurodegenerative disorders
  • vasospastic diseases vasospastic diseases
  • cognitive disorders urge incontinence
  • overactive bladder and methods for reversing the state of anesthesia.
  • Adequate sexual function is a complex interaction of hormonal events and psychosocial relationships. There are four stages to sexual response as described in the International Journal of Gynecolog & Obstetrics, 51(3):265-277 (1995). The first stage of sexual response is desire. The second stage of sexual response is arousal. Both physical and emotional stimulation may lead to breast and genital vasodilation and clitoral engorgement (vasocongestion). In the female, dilation and engorgement of the blood vessels in the labia and tissue surrounding the vagina produce the "orgasmic platform," an area at the distal third of the vagina where blood becomes sequestered.
  • the erectile response in both males and females is the result of engorgement of the erectile tissues of the genitalia with blood which is caused by the relaxation of smooth muscles in the arteries serving the genitalia.
  • sexual dysfunction can include, for example, sexual pain disorders, sexual desire disorders, sexual arousal dysfunction, orgasmic dysfunction, dyspareunia, and vaginismus.
  • sexual dysfunction can be caused, for example, by pregnancy, menopause, cancer, pelvic surgery, chronic medical illness or medications.
  • Papaverine now widely used to treat impotence is generally effective in cases where the dysfunction is psychogenic or neurogenic and where severe atherosclerosis is not involved. Injection of papaverine, a smooth muscle relaxant, or phenoxybenzamine, a non-specific antagonist and hypotensive, into 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 priapism.
  • PGE j prostaglandin Ej
  • ⁇ -adrenergic receptor antagonists for the treatment and prevention of benign prostatic hyperplasia, hypertension, congestive heart failure, variant (Printzmetal) angina, glaucoma, neurodegenerative disorders, vasospastic diseases, cognitive disorders, urge incontinence, and overactive bladder, and for reversing the state of anesthesia has been described.
  • U.S. Patent No. 5,498,623 describes the treatment of cognitive disorders such as endogenous depression, age dependent memory impairment, and Alzheimer's disease
  • U.S. Patent No. 5,281,607 describes the treatment of numerous neurodegenerative diseases, such as infantile spinal muscular atrophy, juvenile spinal muscular atrophy, hypokinetic movement disorder, Down's Syndrome in middle age, and senile dementia of Lewy body type
  • Sereis et al., Neurourol. Urodyn., 31-36 (1998) describes the treatment of urge incontinence in women
  • Wein, Urology, 43-47, describes the treatment of overactive bladder
  • U.S. Patent No. 5,635,204 discloses reversing the state of anesthesia.
  • Nitric oxide has been shown to mediate a number of actions, including the bactericidal and tumoricidal actions of macrophages and blood vessel relaxation of endothelial cells. NO and NO donors have also been implicated as mediators of nonvascular smooth muscle relaxation. As described herein, this effect includes the dilation of the corpus cavernous smooth muscle, an event involved in the sexual response process in both males and females.
  • modified ⁇ -adrenergic receptor antagonists which are directly or indirectly linked with a nitric oxide adduct, and which are optionally used in conjunction with NO donors, have not been previously investigated.
  • ⁇ -adrenergic receptor antagonists nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists or by the use of at least one ⁇ -adrenergic receptor antagonist in combination with at least one nitric oxide donor.
  • toxicities and adverse effects include postural hypotension, reflex tachycardia and other arrhythmias, syncope and, with respect to the ergot alkaloids, nausea and vomiting and, upon prolonged or excessive administration, vascular insufficiency and gangrene of the extremities.
  • the smooth muscle relaxant properties of the ⁇ -adrenergic receptor antagonists and of compounds that donate, release or transfer nitrogen monoxide or elevate levels of endogenous nitric oxide or endothelium- derived relaxing factor (EDRF) or are substrates for nitric oxide synthase work together to permit the same efficacy with lower doses of the ⁇ -adrenergic receptor antagonists or work synergistically to produce an effect that is greater than the additive effects of the ⁇ -adrenergic receptor antagonist and the compound that donates, releases or transfers nitrogen monoxide or elevate levels of endogenous nitric oxide or EDRF or is a substrate for nitric oxide synthase.
  • One aspect of the present invention provides novel nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists.
  • the ⁇ -adrenergic receptor antagonists can be nitrosated and /or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and /or nitrogen.
  • the present invention also provides compositions comprising a therapeutically effective amount of such compounds in a pharmaceutically acceptable carrier.
  • compositions comprising a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, that is optionally substituted with at least one NO and/or N0 2 group (i.e., nitrosylated and/or nitrosated), and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO * ), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the present invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • compositions comprising a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, that is optionally substituted with at least one NO and/or N0 2 group (i.e., nitrosylated and/or nitrosated), at least one vasoactive drug, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO + ) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO * ), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the invention also provides for such compositions in a pharmaceutically acceptable carrier.
  • Yet another aspect of the present invention provides methods for treating and/or preventing sexual dysfunctions and/or enhancing sexual responses in patients, including males and females, by administering to a patient in need thereof a therapeutically effective amount of at least one nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist and, optionally, at least one 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 /or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • nitrosonium NO +
  • NO- nitroxyl
  • NO* neutral species
  • the methods can further comprise administering a therapeutically effective amount of at least one vasoactive agent.
  • the methods for treating and /or preventing sexual dysfunctions and /or enhancing sexual responses in patients can comprise administering a therapeutically effective amount of at least one nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist, at least one vasoactive agent, and, optionally, at least one 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 /or stimulates endogenous production of nitric oxide or
  • EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists, nitric oxide donors, and /or vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • the present invention also provides methods for treating and /or preventing sexual dysfunctions and /or enhancing sexual responses in patients, including males and females, by administering to a patient in need thereof a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist and at least one 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 /or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the methods can further comprise administering a therapeutically effective amount of at least one vasoactive agent.
  • the methods for treating and/or preventing sexual dysfunctions and/or enhancing sexual responses in patients can comprise administering a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, at least one vasoactive agent, and, optionally, at least one 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 /or stimulates endogenous production of nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase.
  • the ⁇ -adrenergic receptor antagonists, the nitric oxide donors, and the vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • the present invention also provides methods using the compounds and compositions described herein to prevent or treat benign prostatic hyperplasia, hypertension, congestive heart failure, variant (Printzmetal) angina, glaucoma, neurodegenerative disorders, vasospastic diseases, cognitive disorders, urge incontinence, or overactive bladder, or to reverse the state of anesthesia by administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds and /or compositions described herein.
  • the ⁇ -adrenergic receptor antagonists that are optionally nitrosated and /or nitrosylated, nitric oxide donors and vasoactive agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • Fig. 1 shows the percent peak erectile response in vivo compared to that produced by 150 ⁇ l of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 ⁇ g/ml) in the anesthetized rabbit following the intracavernosal injection of 150 ⁇ l of yohimbine (150 ⁇ g, 500 ⁇ g), Example 1 (500 ⁇ g), and a combination of yohimbine (150 ⁇ g) and Example 1 (500 ⁇ g).
  • the ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various drugs given.
  • Fig. 1 shows the percent peak erectile response in vivo compared to that produced by 150 ⁇ l of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 ⁇ g/ml) in the anesthetized rabbit following the intracavernosal injection of 150 ⁇ l of
  • Example 3 shows the percent peak erectile response in vivo compared to that produced by 150 ⁇ l of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 ⁇ g/ml) in the anesthetized rabbit following the intracavernosal injection of 150 ⁇ l of yohimbine (150 ⁇ g, 500 ⁇ g and 1 mg) and Example 2 (500 ⁇ g, 1 mg).
  • the ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the various doses of yohimbine and Example 2 given.
  • Fig. 4 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of yohimbine (150 ⁇ g, 500 ⁇ g and 1 mg) and Example 2 (500 ⁇ g and 1 mg). The ordinate indicates the various doses of yohimbine and Example 2 given and the abscissa is the duration in minutes.
  • Fig. 5A shows the effects of intracavernosal injections of Example 2 (500 ⁇ g) on systemic blood pressure in the anesthetized rabbit.
  • Fig. 5B shows the effects of intracavernosal injections of the standard mixture of pap/phent/PGEl on systemic blood pressure in the anesthetized rabbit.
  • Fig. 6 shows the percent peak erectile response in vivo compared to that produced by 150 ⁇ l of pap/phent/PGEl (30 mg/ml: 1 mg/ml: 10 ⁇ g/ml) in the anesthetized rabbit following the intracavernosal injection of moxisylyte (1 mg) and Example 6 (1 mg).
  • the ordinate is the percent response of intracavernosal pressure relative to that produced by pap/phent/PGEl and the abscissa indicates the dose of moxisylyte and Example 6 given.
  • Fig. 7 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of moxisylyte (1 and 2 mg) and Example 6 (1 and 2 mg).
  • the ordinate indicates the dose of moxisylyte and Example 6, and the abscissa is the duration in minutes.
  • Fig. 8 shows the percent peak erectile response in vivo, expressed as intercavernosal pressure (ICP) as a percent of the mean arterial blood pressure (%MABP) in the anesthetized rabbit following the intracavernosal injection of various doses of Example 9 (0.2 mg, 0.4 mg, 0.8 mg and 1.6 mg).
  • ICP intercavernosal pressure
  • %MABP mean arterial blood pressure
  • the ordinate is the percent response of intracavernosal pressure and the abscissa indicates the various doses of Example 9 given.
  • Fig. 9 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of Example 9 (0.2 mg, 0.4 mg, 0.8 mg and 1.6 mg). The ordinate is the duration in minutes and the abscissa indicates the various doses of Example 9 (0.2 mg, 0.4 mg, 0.8 mg and 1.6 mg).
  • Fig. 10 shows the percent peak erectile response in vivo, expressed as intercavernosal pressure (ICP) as a percent of the mean arterial blood pressure (%MABP) in the anesthetized rabbit following the intracavernosal injection of Example 10 (0.64 mg, 1.07 mg, 2.13 mg and 4.26 mg).
  • ICP intercavernosal pressure
  • %MABP mean arterial blood pressure
  • Fig. 11 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of Example 10 (0.64 mg, 1.07 mg, 2.13 mg and 4.26 mg). The ordinate is the duration in minutes and the abscissa indicates the doses of Example 10 given.
  • ⁇ -adrenergic receptor antagonists refers to any compound that reversibly or irreversibly blocks the activation of any ⁇ -adrenergic receptor.
  • Patient refers to animals, preferably mammals, more preferably humans.
  • Transurethral or “intraurethral” refers to delivery of a drug into the urethra, such that the drug contacts and passes through the wall of the urethra and enters into the blood stream.
  • Transdermal refers to the delivery of a drug by passage through the skin and into the blood stream.
  • Transmucosal refers to delivery of a drug by passage of the drug through the mucosal tissue and into the blood stream.
  • Pulmeation enhancement or “permeation enhancement” refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active agent such that the rate at which the drug permeates through the skin or mucosal tissue is increased.
  • Carriers or “vehicles” refers to carrier materials suitable for drug administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
  • Nitric oxide adduct or “NO adduct” refers to compounds and functional groups which, under physiological conditions, can donate, release and /or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO + , NO " , NO * ), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide releasing or “nitric oxide donating” refers to methods of donating, releasing and /or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO + , NO-, NO*), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide donor or “NO donor” refers to compounds that donate, release and/or directly or indirectly transfer a nitric oxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo.
  • NO donor also includes compounds that are substrates for nitric oxide synthase.
  • Alkyl refers to a lower alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein.
  • Lower alkyl refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms).
  • Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
  • Haloalkyl refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein.
  • exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2-bromobutyl, l-bromo-2- chloro-pentyl, and the like.
  • alkenyl refers to a branched or straight chain C 2 -C 10 hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon double bonds.
  • alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-l-yl, 3- methylbuten-1-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the like.
  • Alkynyl refers to an unsaturated acyclic C 2 -C 10 hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon triple bonds.
  • exemplary alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-l-yl, hexyl- 1-yl, hexyl-2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-l-yl, and the like.
  • Bridged cycloalkyl refers to two or more cycloalkyl groups, heterocyclic groups, or a combination thereof fused via adjacent or non-adjacent atoms.
  • Bridged cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alky lcarboxy lie acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.
  • Exemplary bridged cycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl, 2,6- dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl and the like.
  • Cycloalkyl refers to an alicyclic group comprising from about 3 to about 7 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino. alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Heterocyclic ring or group refers to a saturated or unsaturated cyclic hydrocarbon group having about 2 to about 10 carbon atoms (preferably about 4 to about 6 carbon atoms) where 1 to about 3 carbon atoms are replaced by one or more nitrogen, oxygen and /or sulfur atoms.
  • the heterocyclic ring or group can be fused to an aromatic hydrocarbon group.
  • Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino.
  • alkylarylamino hydroxy, oxo, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, aryl, amidyl, ester, carboxamido, alkylcarboxamido, arylcarboxamido, and nitro.
  • heterocyclic groups include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, 2-imidazonlinyl, imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morph
  • Heterocyclic compounds refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
  • Aryl refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings.
  • exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.
  • Aryl groups (including bicylic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino.
  • alkylarylamino hydroxy, alkylcarboxylic acid, alkylcarboxylic ester, aryl, amidyl, ester, carboxamido, alkylcarboxamido and nitro.
  • exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, and the like.
  • Alkylaryl refers to an alkyl group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary alkylaryl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.
  • Arylalkyl refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkylalkyl refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Heterocyclicalkyl refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Arylheterocyclic ring refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein.
  • exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the like.
  • Alkoxy refers to R 50 O-, wherein R 50 is an alkyl group, as defined herein.
  • exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, and the like.
  • Arylalkoxy or alkoxyaryl refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.
  • Alkoxyalkyl refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein.
  • exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
  • Alkoxyhaloalkyl refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein.
  • exemplary alkoxyhaloalkyl groups include 4 methoxy-2-chlorobutyl and the like.
  • Cycloalkoxy refers to R 54 O-, wherein R ⁇ is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Haloalkoxy refers to a haloalkyl group, as defined herein, to which is appended an alkoxy group, as defined herein.
  • exemplary haloalkyl groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.
  • Hydroxyalkyl refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
  • Amino refers to -NH 2 .
  • Nirate refers to -0-N0 2 .
  • Nirite refers to -O-NO.
  • Thionitrate refers to -S-N0 2 .
  • Thionitrite and nitrosothiol refer to -S-NO.
  • Niro refers to the group -N0 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • Niroso refers to the group -NO and “nitrosylated” refers to compounds that have been substituted therewith.
  • Nirile and cyano refer to -CN.
  • Halogen or “halo” refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F).
  • Alkylamino refers to R 50 NH-, wherein R 50 is an alkyl group, as defined herein.
  • exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
  • Arylamino refers to R SJ NH-, wherein R 55 is an aryl group, as defined herein.
  • Dialkylamino refers to R 52 R 53 N ⁇ , wherein R ⁇ and Rg 3 are each independently an alkyl group, as defined herein.
  • Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
  • Diarylamino refers to R ⁇ R ⁇ N-, wherein R ⁇ and Rgg are each independently an aryl group, as defined herein.
  • Alkylarylamino refers to R 52 R 55 N-, wherein R ⁇ is an alkyl group, as defined herein and R 55 is an aryl group, as defined herein.
  • Aminoalkyl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein.
  • Aminoaryl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an aryl group, as defined herein.
  • Alkylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonic acid refers to an sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
  • Sulfonic ester refers to -S(0) 2 OR 58 , wherein R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • Sulfonamido refers to -S(0) 2 -N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, and R 51 and Rg 7 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylsulfonamido refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonamido refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.
  • Alkylthio refers to R 50 S-, wherein R 50 is an alkyl group, as defined herein.
  • Arylthio refers to R 55 S-, wherein R ⁇ is an aryl group, as defined herein.
  • Alkylsulfinyl refers to R 50 -S(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyl refers to R 50 -S(O) 2 -, wherein R 50 is an alkyl group, as defined herein.
  • Arylsulfinyl refers to R 55 -S(0)-, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyl refers to R 55 -S(0) 2 -, wherein R 55 is an aryl group, as defined herein.
  • “Amidyl” refers to R 51 C(0)N(R 57 )- wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
  • “Ester” refers to Rs ⁇ C(0)0- wherein R ⁇ is a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
  • Carbamoyl refers to -0-C(0)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, and R 51 and R 57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Carboxyl refers to -C0 2 H.
  • Carbonyl refers to -C(O)-.
  • Metal refers to -C(S)-.
  • Carboxylic ester refers to -C(0)OR 58 , wherein R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • Alkylcarboxylic acid and “alkylcarboxyl” refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Alkylcarboxylic ester refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Arylcarboxylic acid refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Arylcarboxylic ester refers to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Carboxamido refers to -C(0)N(R 51 )(R 57 ), wherein R 51 and R j7 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, and R 51 and Rs 7 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylcarboxamido refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Arylcarboxamido refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
  • “Urea” refers to -N(R 58 )-C(0)N(R 51 )(R 57 ) wherein R 51 , R 57 , and R 58 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, and R 51 and R ⁇ when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Phosphoryl refers to -P(R 70 )(R 71 )(R 72 ), wherein R 70 is a lone pair of electrons, sulfur or oxygen, and R 7] and R ⁇ are each independently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy or an aryl, as defined herein.
  • “Silyl” refers to -Si(R 73 )(R 74 ), wherein R 73 and R 74 are each independently a covalent bond, a lower alkyl, an alkoxy, an aryl or an arylalkoxy, as defined herein.
  • the term "sexual dysfunction” generally includes any sexual dysfunction in a patient, including an animal, preferably a mammal, more preferably a human. The patient can be male or female. Sexual dysfunctions can include, for example, sexual desire disorders, sexual arousal disorders, orgasmic disorders and sexual pain disorders.
  • Female sexual dysfunction refers to any female sexual dysfunction including, for example, sexual desire disorders, sexual arousal dysfunctions, orgasmic dysfunctions, sexual pain disorders, dyspareunia, and vaginismus.
  • the female can be pre-menopausal or menopausal.
  • Male sexual dysfunction refers to any male sexual dysfunctions including, for example, male erectile dysfunction and impotence.
  • the present invention is directed to the treatment and /or prevention of sexual dysfunctions in patients, including males and females, by administering the compounds and compositions described herein.
  • the present invention is also directed to enhancing sexual responses in patients, including males and females, by administering the compounds and /or compositions described herein.
  • the novel compounds and novel compositions of the present invention are described in more detail herein.
  • the ⁇ -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 in the art, including those exemplified below.
  • the ⁇ -antagonists can generally be categorized as haloalkylamines, imidazolines, quinozolines, indole derivatives, phenoxypropanolamines, alcohols, alkaloids, amines, piperizines, piperidines and amides.
  • the first group of ⁇ -adrenergic receptor antagonists are the haloalkylamines that irreversibly block - and ⁇ 2 -adrenergic receptors. Included in this group are, for example, phenoxybenzamine and dibenamine. Phenoxybenzamine is used in the treatment of pheochromocytomas, tumors of the adrenal medulla and sympathetic neurons that secrete catecholamines into the circulation. It controls episodes of severe hypertension and minimizes other adverse effects of catecholamines such as contraction of plasma volume and injury of the myocardium.
  • Another group of ⁇ -adrenergic receptor antagonists are the imidazolines.
  • Phentolamine has similar affinity for ⁇ ⁇ and ⁇ 2 receptors. Phentolamine is used in short-term control of hypertension in patients with pheochromocytoma and direct, intracavernous injection of phentolamine (usually 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.
  • Other imidazolines include, for example, idazoxan, deriglidole, RX 821002, BRL 44408 and BRL 44409 (see, Young et al, Eur. J.
  • ⁇ -adrenergic receptor antagonists that are contemplated are the quinazolines. These include, for example, prazosine, a very potent and selective ⁇ j -adrenergic antagonist, terazosin, doxazosin, alfuzosin, bunazosin, ketanserin, trimazosin and abanoquil. This group of compounds is principally used in the treatment of primary systemic hypertension and also in the treatment of congestive heart failure.
  • ⁇ -adrenergic receptor antagonists are indoles and indole derivatives. These include, for example, carvedilol and BAM 1303.
  • ⁇ -adrenergic receptor antagonists are alcohols. These include, for example, labetelol and ifenprodil.
  • alkaloids include, for example, "ergotoxine” which is a mixture of three alkaloids: ergocornine, ergocristine and ergocryptine. Both natural and dihydrogenated peptide alkaloids produce ⁇ -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 ⁇ 2 -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.
  • alkaloid ⁇ -adrenergic receptor antagonists include rauwolscine, corynathine, raubascine, tetrahydroalstonine, apoyohimbine, akuammigine, ⁇ -yohimbine, yohimbol, pseudoyohimbine, epi-3 ⁇ -yohimbine, 10-hydroxy- yohimbine and 11-hydroxy-yohimbine.
  • the indole alkaloids are typically obtained from plant extracts or tree barks.
  • Another class of ⁇ -adrenergic receptor antagonists are amines.
  • tamsulosin include, for example, tamsulosin, benoxathian, atipamezole, BE 2254, WB 4101, HU-723, tedisamil, mirtazipine, setiptiline, reboxitine and delequamine.
  • ⁇ -adrenergic receptor antagonists are piperizines, which include, for example, naftopil, saterinone, SL 89.0591, ARC 239, urapidil, 5-methylurapidil and monatepi.
  • Urapidil is a selective ⁇ j-adrenergic antagonist that has a hypotensive effect in humans.
  • ⁇ -adrenergic receptor antagonists are piperidines. These include, for example, haloperidol.
  • ⁇ -adrenergic receptor antagonists are amides, such as indoramin and SB 216469.
  • Indoramin is a selective, competitive ⁇ ⁇ -antagonist that has been used for the treatment of hypertension.
  • ⁇ -adrenergic receptor antagonists include moxisylyte, trazodone, dapiprozole, efaroxan, Recordati 15/2739, SNAP 1069, SNAP 5089, SNAP 5272, RS 17053, SL 89.0591, KMD 3213, spiperone, AH 11110A, chloroethylclonidine, BMY 7378 and niguldipine.
  • Sources of information for these compounds include Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Ed.), McGraw-Hill, Inc. (1995), The Physician's Desk Reference (49th Ed.), Medical Economics (1995), Drug Facts and Comparisons (1993 Ed), Facts and Comparisons (1993), and The Merck Index (12th Ed.), Merck & Co., Inc. (1996), the disclosures of each of which are incorporated herein by reference in their entirety.
  • the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (I):
  • R a is a hydrogen or an alkoxy
  • R h is:
  • a is an integer of 2 or 3;
  • R c is a heterocyclic group, a lower alkyl group, a hydroxy alkyl group, or an arylheterocyclic ring;
  • Y is oxygen, S(0) 0 , lower alkyl or NR, o is an integer from 0 to 2;
  • R is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, -CH 2 -C(T-Q)(R (R f ), or -(N 2 0 2 " ) # M + , wherein M + in an organic or inorganic cation;
  • R e and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an al
  • T is independently a covalent bond, oxygen, S(O) 0 or NR : ,; Z is a covalent bond, an alkyl, an aryl, an alkylaryl, an arylalkyl, a heteroalkyl,
  • Q is -NO or -N0 2 ;
  • G is a covalent bond, -T-C(O)-, -C(0)-T- or T; q' is an integer from 0 to 5; P is a carbonyl, a phosphoryl or a silyl;
  • 1 and t are each independently an integer from 1 to 3; r, s, c, d, g, i and j are each independently an integer from 0 to 3; w, x, y and z are each independently an integer from 0 to 10; B at each occurrence is independently an alkyl, an aryl, or [C(R e )(R f )] p ;
  • E at each occurrence is independently -T-, an alkyl, an aryl, or -(CH 2 CH 2 0)q;
  • K at each occurrence is independently -C(O)-, -C(S)-, -T-, a heterocyclic ring, an aryl, an alkenyl, an alkynyl, an arylheterocyclic ring, or -(CH 2 CH 2 0) q ;
  • q is an integer of from 1 to 5;
  • V is oxygen, S(O) 0 , or NR ; ;
  • F' at each occurrence is independently B or carbonyl; n is an integer from 2 to 5; with the proviso that when R > is -CH 2 -C(T-Q)(R e )(R f ) or -(N 2 0 2 M + , or R e or R f are T-Q or [C(R e )(R f )] k -T-Q then the "-T-Q" subgroup designated in D can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl.
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (II):
  • R ⁇ is:
  • D ! is a hydrogen or D, where D is as defined herein, with the proviso that D, must be D if there is no other D in the compound.
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (III):
  • R h is a hydrogen, -C(0)-OR k or -C(0)-X; R k is hydrogen or lower alkyl; X is:
  • G j is a covalent bond, -T-C(O)-, -C(0)-T-, or -C(Y-C(0)-R m )-;
  • R m is a heterocyclic ring
  • W is a heterocyclic ring or NR q R' q wherein R q and R' q are each independently a lower alkyl, an aryl or an alkenyl, and R j is hydrogen, -D or -(0)CR d ; and wherein Y, R e , R f , p, Q, D, T and R d are as defined herein.
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (IV):
  • Aj is oxygen or methylene
  • X and R j are as defined herein.
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (V):
  • R is:
  • b is an integer of 0 or 1;
  • a 2 is oxygen or sulfur
  • R' k is independently selected from R k and R k , D and D ⁇ are as defined herein; with the proviso that D 2 must be D if there is no other D in the compound.
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (VI):
  • R is:
  • R k , O x and D are as defined herein, with the proviso that Dj must be D if there is no other D in the compound.
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (VII):
  • Another embodiment of the present invention describes nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of Formula (VIII):
  • R t and R tribe are each independently a hydrogen, a lower alkyl, a cycloalkyl, an aryl, or when taken together are a heterocyclic ring; and R k , R' k , and D are as defined herein.
  • Another aspect of the present invention provides processes for making the novel compounds of the invention and to the intermediates useful in such processes.
  • the compounds of the present invention of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII) can be synthesized by one skilled in the art following the methods and examples described herein.
  • nitrosated and nitrosylated ⁇ -antagonists of the present invention can be synthesized as shown in reaction Schemes I through XXIV presented below, wherein R a , R b , R c , R d , R e , R f , R g , R h , R,, R'êt R,, R k , R' k , R hinder F ,, R protagonist, R 0 , R p , R t , R,,, A réelle A 2 , a, n, W and X are as defined herein or as depicted in the reaction schemes for Formulas I, II, III, IV, V, VI, VII and VIII.
  • P 1 is an oxygen protecting group and P 2 is a sulfur protecting group.
  • the reactions are performed in solvents appropriate to the reagents and materials used are suitable for the transformations being effected. It is understood by one skilled in the art of organic synthesis that the functionality present in the compound must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions. Substituents on the starting materials may be incompatible with some of the reaction conditions required in some of the methods described, but alternative methods and substituents compatible with the reaction conditions will be readily apparent to one skilled in the art.
  • sulfur and oxygen protecting groups are 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, such as those described by T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York (1991), the disclosure of which is incorporated by reference herein in its entirety.
  • Nitroso compounds of Formula (I), wherein R a , R b , R e , R f , and p are as defined herein, and an O-nitrosylated amide is representative of the D group, as defined herein, may be prepared according to Scheme I.
  • the amine group of the quinazoline of the structure 1 is converted to the amide of the structure 2, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 1 is as defined herein.
  • Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected alcohol-containing acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • 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 structure IA.
  • Nitroso compounds of Formula (I), wherein R a , R b , R,,, R f , and p are as defined herein, and an S-nitrosylated amide is representative of the D group, as defined herein, may be prepared according to Scheme II.
  • the amine group of the quinazoline of the structure 1 is converted to the amide of the structure 3, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected thiol-containing activated acylating agent, wherein P 2 is as defined herein.
  • Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenyl-phosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while an aqueous base is typically utilized to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with 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
  • Nitro compounds of Formula (I), wherein R,, R b , Rg R f , and p are defined as Herein, and an O-nitrosated amide is representative of the D group, as defined herein, may be prepared according to Scheme III.
  • the amine group of the quinazoline of the structure 1 is converted to the amide of the structure IC, wherein p, R e and R f are as defined herein, by reaction with an appropriate nitrate containing activated acylating agent.
  • Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of structure IC.
  • Nitroso compounds of Formula (II), wherein R e R f , R g , and p are as defined herein, and an O-nitrosylated acyl imidazoline is representative of the D group, as defined herein, may be prepared according to Scheme IV.
  • the imidazoline group of the structure 4 is converted to the acyl imidazoline of the structure 5, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 1 is as defined herein.
  • Preferred methods for the formation of acyl imidazolines are reacting the imidazoline with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • 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 structure IIA.
  • Nitroso compounds of Formula (II), wherein R e R f , R g , and p are as defined herein, and an S-nitrosylated acyl imidazoline is representative of the D group, as defined herein, may be prepared according to Scheme V.
  • the imidazoline group of the structure 4 is converted to the acyl imidazoline of the structure 6, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 2 is as defined herein.
  • Preferred methods for the formation of acyl imidazolines are reacting the imidazoline with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thio-carbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydro-pyranyl thioether or a S-triphenylmethyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thio-carbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydro-pyranyl thioether or a S-triphenylmethyl thioether.
  • 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 used 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 tetrahydro-pyranyl thioether or a S-triphenylmethyl thioether group) followed by reaction with 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 m
  • Nitro compounds of Formula (II), wherein R,,, R f , R g , and p are as defined herein, and an O-nitrosated acyl imidazoline is representative of the D group, as defined herein, may be prepared according to Scheme VI.
  • the imidazoline group of the structure 4 is converted to the acyl imidazoline of the structure IIC, wherein p, R e and R f are as defined herein, by reaction with an appropriate nitrate containing activated acylating agent.
  • Preferred methods for the formation of acyl imidazolines are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of structure IC.
  • Nitroso compounds of Formula (III), wherein R e , R f , R h , R,, and p are as defined herein, and an O-nitrosylated ester is representative of the D group, as defined herein, may be prepared according to Scheme VII.
  • the alcohol group of structure 7 is converted to the ester of structure 8, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 1 is as defined herein.
  • Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • 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 structure IIIA.
  • Nitroso compounds of Formula (III), wherein Rg, R f , R h , R j , and p are as defined herein, and an S-nitrosylated ester is representative of the D group, as defined herein, may be prepared according to Scheme VIII.
  • the alcohol group of the structure 7 is converted to the ester of the structure 9, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected thiol containing activated acylating agent, wherein P 2 is as defined herein.
  • Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenyl-phosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while an aqueous base is typically used 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 m
  • Nitro compounds of Formula (III), wherein R e , R f , R h , R j , and p are as defined herein, and an O-nitrosated ester is representative of the D group, as defined herein, may be prepared according to Scheme IX.
  • the alcohol group of the structure 7 is converted to the ester of the structure IIIC, wherein p, R e and R f are as defined herein, by reaction with an appropriate nitrate containing activated acylating agent.
  • Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford a compound of structure HIC.
  • Nitroso compounds of Formula (IV), wherein A R e , R f , R h , R,, and p are as defined herein, and an O-nitrosylated ester is representative of the X group as defined herein may be prepared according to Scheme X.
  • An acid of the structure 10 is converted into the ester of the structure 11, wherein p, R e , and R f are as defined herein, by reaction with an appropriate monoprotected diol.
  • Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloroformate such as isobutylchloroformate in the presence of a non nucleophilic base such as triethylamine in an anhydrous inert solvent such as dichloromethane, diethylether, or THF.
  • a chloroformate such as isobutylchloroformate
  • a non nucleophilic base such as triethylamine
  • 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-dimethylamino pyridine.
  • the acid 10 may be first converted to the acid chloride by 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.
  • a condensation catalyst such as 4-dimethylamino- pyridine
  • a tertiary amine base such as triethyl amine
  • the acid 10 and monoprotected diol may be coupled to afford 11 by treatment with a dehydration agent such as dicyclohexylcarbodiimide.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • Nitroso compounds of Formula (IV), wherein A Rg, R f , R h , R j and p are as defined herein, and an S-nitrosylated ester is representative of the X group, as defined herein, may be prepared according to Scheme XL An acid of the structure 10 is converted into the ester of the structure 12, wherein p, R e , and R f are as defined herein, and a S-nitrosylated ester is representative of the X group, as defined herein, by reaction with an appropriate protected thiol containing alcohol.
  • Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloroformate such as isobutylchloroformate in the presence of a non nucleophilic base such as triethylamine in an anhydrous inert solvent such as diethylether or THF.
  • a chloroformate such as isobutylchloroformate
  • a non nucleophilic base such as triethylamine
  • an anhydrous inert solvent such as diethylether or THF.
  • the mixed anhydride is then reacted with the thiol containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethyl- aminopyridine.
  • 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.
  • a condensation catalyst such as 4-dimethylaminopyridine
  • a tertiary amine base such as triethyl amine
  • the acid and thiol containing alcohol may be coupled to afford 12 by treatment with a dehydration agent such as dicyclohexylcarbodiimide.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a S-triphenylmethyl thioether.
  • a thioester such as a thioacetate or thiobenzoate
  • a disulfide as a thiocarbamate such as N-methoxymethyl thiocarbamate
  • a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether, or a S-triphenylmethyl thioether.
  • 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 used to hydrolyze thiolesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate, silver nitrate, or strong acids such as trifluoroacetic or hydrochloric acid and heat are used to remove a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S- triphenylmethyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene
  • Nitro compounds of Formula (IV), wherein A P ⁇ , R f , R h , R, and p are as defined herein, and an O-nitrosated ester is representative of the X group as defined herein, may be prepared according to Scheme XII.
  • An acid of the structure 10 is converted into the ester of the structure IVC, wherein p, Rg, and R f are as defined herein, by reaction with an appropriate nitrate containing alcohol.
  • Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 10 with a chloroformate such as isobutylchloroformate in the presence of a non nucleophilic base such as triethylamine in an anhydrous inert solvent such as dichloromethane, diethylether, or THF.
  • a chloroformate such as isobutylchloroformate
  • a non nucleophilic base such as triethylamine
  • an anhydrous inert solvent such as dichloromethane, diethylether, or THF.
  • the mixed anhydride is then reacted with the nitrate containing alcohol preferably in the presence of a condensation catalyst such as 4-dimethylamino-pyridine.
  • the acid 10 may be first converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF.
  • the acid chloride is then reacted with the nitrate containing alcohol preferably in the presence of a condensation catalyst such as 4- dimethylaminopyridine and a tertiary amine base such as triethyl amine to afford the a compound of structure IVC.
  • a condensation catalyst such as 4- dimethylaminopyridine
  • a tertiary amine base such as triethyl amine
  • the acid 10 and nitrate containing alcohol may be coupled to afford a compound of structure IVC by treatment with a dehydration agent such as dicyclohexylcarbodiimide.
  • Nitroso compounds of Formula (V), wherein R e R f , R k , R' k , R ⁇ , and p are as defined herein, and an O-nitrosylated N-acyloxyalkyl amine is representative of the D group, as defined herein, may be prepared according to Scheme XIII.
  • the amine group of the compound of structure 13 is converted to the N-acyloxyalkyl amine of the structure 14, wherein p, R e and R f , are as defined herein, by reaction with an appropriate protected alcohol containing chloromethyl acyl derivative wherein P 1 is as defined herein.
  • N-acyloxyalkyl amines are reacting the amine with the preformed chloromethyl acyloxyalkyl derivative of the protected alcohol.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a triethylsilyl or a tert-butyldimethylsilyl ether.
  • Nitroso compounds of Formula (V), wherein R e , R f , R k , R' , R,, R,, and p are as defined herein, and an S-nitrosylated N-acyloxyalkyl amine is representative of the D group as defined herein may be prepared according to Scheme XIV.
  • the amine group of the compound of structure 13 is converted to the N-acyloxyalkyl amine of the structure 15, wherein p, R e and R f , are as defined herein, by reaction with an appropriate protected thiol containing chloromethyl acyl derivative wherein P 2 is as defined herein.
  • 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- methoxy -methyl thiocarbamate, or as a thioether such as a tetrahydropyranyl thioether.
  • thiol moiety triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while an aqueous base is typically used to hydrolyze thioesters and N-methoxymethyl thiocarbamates and mercuric trifluoroacetate or silver nitrate are used to remove a tetrahydropyranyl thioether group) followed by reaction with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile with or without an amine base such as pyridine or triethylamine affords the compound of structure VB.
  • a suitable nitrosylating agent such as thionyl chlor
  • Nitro compounds of Formula (V), wherein R e R f , R k , R' k , R,, R ⁇ , and p are as defined herein, and an O-nitrosated N-acyloxyalkyl amine is representative of the D group as defined herein may be prepared according to Scheme XV.
  • the amine group of the compound of structure 13 is converted to the N-acyloxyalkyl amine of the structure VC, wherein p, R e and R f are as defined herein, by reaction with an appropriate nitrate containing chloromethyl acyl derivative.
  • Preferred methods for the formation of N-acyloxyalkyl amines are reacting the amine with the preformed chloromethyl acyloxyalkyl derivative of the nitrate containing derivative to afford the compound of structure VC.
  • Nitroso compounds of Formula (VI), wherein R ⁇ , R f , R k , R 0 , R p , a and p are as defined herein, and an O-nitrosylated ester is representative of the D group, as defined herein, may be prepared according to Scheme XVI.
  • the hydroxyl group of the phenol of the structure 16 is converted to the ester of the structure 17, wherein a, p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 1 is as defined herein.
  • Preferred methods for the formation of esters are reacting the hydroxyl with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • Deprotection of the hydroxyl moiety fluoride ion is the preferred method for removing silyl ether protecting groups
  • 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 structure VIA.
  • Nitroso compounds of Formula (VI), wherein R e , R f , R k , R 0 , R p a and p are as defined herein, and an S-nitrosylated ester is representative of the D group, as defined herein may be prepared according to Scheme XVII.
  • the hydroxyl group of the phenol of the structure 16 is converted to the ester of the structure 18, wherein a, p, R g and R f are as defined herein, by reaction with an appropriate protected thiol containing activated acylating agent, wherein P 2 is as defined herein.
  • Preferred methods for the formation of esters are reacting the hydroxyl with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N- methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenyl-phosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically used 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 with 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 m
  • Nitro compounds of Formula (VI), wherein Rg, R f , R k , R lake, R p a and p are as defined herein, an O-nitrosated ester is representative of the D group, as defined herein may be prepared according to Scheme XVIII.
  • the hydroxyl group of the phenol of the structure 16 is converted to the ester of the structure VIC, wherein a, p, R e and R f are as defined herein, by reaction with an appropriate nitrate containing activated acylating agent.
  • Preferred methods for the formation of esters are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of structure VIC.
  • Nitroso compounds of Formula (VII), wherein R d R e , R f , T, and p are as defined herein, and an O-nitrosylated amide is representative of the D group, as defined herein may be prepared according to Scheme XIX.
  • the amine group of the dihydropyridine of the structure 19 is converted to the amide of the structure 20, wherein p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 1 is as defined herein.
  • Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • 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 structure VII A.
  • Nitroso compounds of Formula (VII) wherein Rj, R ⁇ R f , T, and p are as defined herein, and an S-nitrosylated amide is representative of the D group, as defined herein may be prepared according to Scheme XX.
  • the amine group of the dihydropyridine of the structure 19 is converted to the amide of the structure 21, wherein p, R e , and R f are as defined herein, by reaction with an appropriate protected thiol containing activated acylating agent, wherein P 2 is defined above.
  • Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N-methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • 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 used 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 with a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite such as tert-butyl nitrite, or nitrosium tetrafluoroborate in a suitable anhydrous solvent such as methylene
  • Nitro compounds of Formula (VII), wherein R d , R ⁇ , R f , T, and p are as defined herein, and an O-nitrosated amide is representative of the D group, as defined herein, may be prepared according to Scheme XXI.
  • the amine group of the dihydropyridine of the structure 19 is converted to the amide of the structure VIIC , wherein p, R e and R f are as defined herein, by reaction with an appropriate nitrate containing activated acylating agent.
  • Preferred methods for the formation of amides are reacting the amine with the preformed acid chloride or symmetrical anhydride of the nitrate containing acid to afford the compound of structure VIIC.
  • Nitroso compounds of Formula (VIII), wherein R e , R f , R k , R' k , R i , R ⁇ , a and p are as defined herein, and an O-nitrosylated ester is representative of the D group, as defined herein, may be prepared according to Scheme XXII.
  • the hydroxyl group of the phenol of the structure 22 is converted to the ester of the structure 23, wherein a, p, R e and R f are as defined herein, by reaction with an appropriate protected alcohol containing activated acylating agent, wherein P 1 is as defined herein.
  • esters are reacting the hydroxyl with the preformed acid chloride or symmetrical anhydride of the protected alcohol containing acid.
  • Preferred protecting groups for the alcohol moiety are silyl ethers such as a trimethylsilyl or a tert-butyldimethylsilyl ether.
  • Deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • 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 structure VIIIA.
  • Nitroso compounds of Formula (VIII), wherein R e , R f , R k , R' k , R t , R ⁇ a and p are as defined herein, and an S-nitrosylated ester is representative of the D group, as defined herein, may be prepared according to Scheme XXIII.
  • the hydroxyl group of the phenol of the structure 22 is converted to the ester of the structure 24, wherein a, p, R e and R f are as defined herein, by reaction with an appropriate protected thiol containing activated acylating agent, wherein P 2 is as defined herein.
  • Preferred methods for the formation of esters are reacting the hydroxyl with the preformed acid chloride or symmetrical anhydride of the protected thiol containing acid.
  • Preferred protecting groups for the thiol moiety are as a thioester such as a thioacetate or thiobenzoate, as a disulfide, as a thiocarbamate such as N- methoxymethyl thiocarbamate, or as a thioether such as a paramethoxybenzyl thioether, a tetrahydropyranyl thioether or a S-triphenylmethyl thioether.
  • thiol moiety (zinc in dilute aqueous acid, triphenyl-phosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base is typically used 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 with 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 m
  • the compounds of the present invention include ⁇ -adrenergic receptor antagonists, including those described herein, which have been nitrosated and /or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and/or nitrogen.
  • the nitrosated and/or nitrosylated ⁇ -adrenergic receptor antagonists of the present invention donate, transfer or release a biologically active form of nitrogen monoxide (nitric oxide).
  • 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.
  • NO nitric oxide radical
  • NO + nitrosonium
  • functionalities capable of transferring and /or releasing NO + and NO- are also resistant to decomposition in the presence of many redox metals. Consequently, administration of charged NO equivalents (positive and /or negative) does not result in the generation of toxic by-products or the elimination of the active NO moiety.
  • Compounds contemplated for use in the present invention are, optionally, used in combination with 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.
  • nitric oxide encompasses uncharged nitric oxide (NO ⁇ ) and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO + ) and nitroxyl ion (NO-).
  • the reactive form of nitric oxide can be provided by gaseous nitric oxide.
  • the nitric oxide releasing, delivering or transferring compounds have 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 its intended purpose.
  • NO adducts encompasses any nitric oxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, organic nitrites, organic nitrates, S-nitrothiols, sydnonimines, 2-hydroxy-2- nitrosohydrazines (NONOates), (E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides, nitrosoamines, furoxanes as well as substrates for the endogenous enzymes which synthesize nitric oxide.
  • the "NO adducts" can be mono- nitrosylated, poly-nitrosylated, mono-nitrosated and /or poly-nitrosated at a variety of naturally susceptible or artificially provided binding sites for nitric oxide.
  • S-nitrosothiols are compounds that include at least one -S-NO group.
  • S-nitroso-polypeptides include proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S- nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.
  • S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • Such compounds include, for example, S-nitroso-N- acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso- homocysteine, S-nitroso-cysteine and S-nitroso-glutathione.
  • Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins and cytokines.
  • TPA tissue-type plasminogen activator
  • cathepsin B transport proteins, such as lipoproteins; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as immunoglobulins and cytokines.
  • nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers in the protein are modified.
  • S-nitrosothiols include: (i) HS[C(R e )(R f )] m SNO;
  • R e and R f are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, am alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylsulf
  • Rj can be a substituent on any disubstituted nitrogen contained within the radical wherein R, is as defined herein.
  • Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaN0 2 under acidic conditions (pH is about 2.5) which yields the S-nitroso derivative. Acids which can be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids.
  • the thiol precursor can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate in an inert solvent.
  • NO adducts for use in the present invention, where the NO adduct is a compound that donates, transfers or releases nitric oxide, include compounds comprising at least one ON-O-, ON-N- or ON-C- group.
  • the compounds that include at least one ON-O-, ON-N- or ON-C- group are preferably ON-O-, ON-N- or ON-C-polypeptides (the term "polypeptide" includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ON-O-, ON-N- or ON-C-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-O-, ON-N- or ON-C -sugars; ON-O-, ON-N- or ON-C- modified or unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); ON-O-, ON-
  • NO adducts for use in the present invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or O z N-C- group.
  • Preferred among these compounds are 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); 0 2 N-0-, O z N-N-, 0 2 N-S- or 0 2 N-C- amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C-sugars; 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N
  • Preferred examples of compounds comprising at least one 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and propatylnitrate.
  • R 1 R 2 -N(0-M + )- NO N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R 1 R 2 -N(0-M + )- NO, where R 1 and R 2 are each independently a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and where M + is an organic or inorganic cation, such as, for example, an alkyl substituted ammonium cation or a Group I metal cation.
  • R 1 -(S)-N0 2 Another group of NO adducts are thionitrates that donate, transfer or release nitric oxide and are represented by the formula: R 1 -(S)-N0 2 , where R 1 is a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group.
  • R 1 is a polypeptide or hydrocarbon with a pair or pairs of thiols that are sufficiently structurally proximate, i.e., vicinal, that the pair of thiols will be reduced to a disulfide.
  • Such compounds include, for example, L-arginine, L-homoarginine, and N-hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L- arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L- arginine and /or physiologically acceptable salts thereof, including, for example, citrulline, ornithine or glutamine, inhibitors of the enzyme arginase (e.g., N- hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid
  • EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).
  • the present invention is also based on the discovery that the administration of a therapeutically effective amount of the compounds and compositions described herein is effective for treating or preventing sexual dysfunctions or enhancing sexual responses in patients, including males and females.
  • the patient can be administered a therapeutically effective amount of at least one nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist of the present invention.
  • the patient can be administered a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, optionally substituted with at least one NO and /or N0 2 group, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase.
  • the patient can be administered a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, optionally substituted with at least one NO and /or N0 2 group, and at least one vasoactive agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase.
  • the compounds can be administered separately or in the form of a composition.
  • vasoactive agent is any therapeutic agent capable of relaxing vascular smooth muscle.
  • Suitable vasoactive agents include, but are not limited to, potassium channel activators (such as, for example, nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam and the like); calcium blockers (such as, for example, nifedipine, verastrial, diltiazem, gallopamil, niludipine, nimodipins, nicardipine, and the like); ⁇ -blockers (such as, for example, butixamine, dichloroisoproterenol, propanolol, alprenolol, bunolol, nadolol, oxprenolol, perbutolol, pinodolol, sotalol, timolol, metoprolol, atenolol, acebutolol
  • Another embodiment of the present invention provides methods to prevent or treat benign prostatic hyperplasia, hypertension, congestive heart failure, variant (Printzmetal) angina, glaucoma, neurodegenerative disorders, vasospastic diseases, cognitive disorders, urge incontinence, and overactive bladder, and for reversing the state of anesthesia by administering to a patient in need thereof a therapeutically effective amount of the compounds and /or compositions described herein.
  • the patient can be administered a therapeutically effective amount of at least one nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist of the present invention.
  • the patient can be administered a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, optionally substituted with at least one NO and/or N0 2 group, and at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide or is a substrate for nitric oxide synthase.
  • the patient can be administered a therapeutically effective amount of at least one ⁇ -adrenergic receptor antagonist, optionally substituted with at least one NO and /or N0 2 group, and at least one vasoactive agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide, or elevates levels of endogenous EDRF or nitric oxide, or is a substrate for nitric oxide synthase.
  • the compounds and compositions of the present invention can also be administered in combination with other medications used for the treatment of these disorders.
  • the compounds and compositions of the present invention can be administered in combination with pharmaceutically acceptable carriers and in dosages described herein.
  • the compounds and compositions of the present invention are administered as a mixture of at least one nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist or at least one ⁇ -adrenergic receptor antagonist and at least one nitric oxide donor, they can also be used in combination with one or more additional compounds which are known to be effective against the specific disease state targeted for treatment (e.g., vasoactive agents).
  • nitric oxide donors and /or vasoactive agents can be administered simultaneously with, subsequently to, or prior to administration of the ⁇ -adrenergic receptor antagonists, including those that are substituted with one or more NO and /or N0 2 groups, and /or other additional compounds.
  • the compounds and compositions of the present invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection into the corpus cavernosum tissue, by transurethral drug delivery, transdermally, vaginally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired.
  • Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Transdermal drug administration which is known to one skilled in the art, involves the delivery of pharmaceutical agents via percutaneous passage of the drug into the systemic circulation of the patient.
  • Topical administration can also involve transdermal patches or iontophoresis devices.
  • Other components can be incorporated into the transdermal patches as well.
  • compositions and /or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.
  • Solid dosage forms for oral administration can include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels.
  • the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the present invention and vegetable oil.
  • Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin. Tablets and pills can be prepared with enteric coatings.
  • a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin.
  • Tablets and pills can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Dosage forms for topical administration of the compounds and compositions of the present invention can include creams, sprays, lotions, gels, ointments, coatings for condoms and the like. Administration of the cream or gel can be accompanied by use of an applicator or by transurethral drug delivery using a syringe with or without a needle or penile or vaginal insert or device, and is within the skill of the art.
  • a lubricant and/or a local anesthetic for desensitization can also be included in the formulation or provided for use as needed.
  • Lubricants include, for example, K-Y jelly (available from Johnson & Johnson) or a lidocaine jelly, such as Xylocaine 2% jelly (available from Astra Pharmaceutical Products).
  • Local anesthetics include, for example, novocaine, procaine, tetracaine, benzocaine and the like.
  • compositions of the present invention will typically be administered in a pharmaceutical composition containing one or more selected carriers or excipients.
  • suitable carriers include, for example, water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars, and the like.
  • compositions can also include one or more permeation enhancers including, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10MSO), polyethylene glycol monolaurate (PEGML), glyceral monolaurate, lecithin, 1- substituted azacycloheptan-2-ones, particularly l-N-dodecylcyclazacylcoheptan-2- ones (available under the trademark AzoneTM from Nelson Research & Development Co., Irvine, CA), alcohols and the like.
  • permeation enhancers including, for example, dimethylsulfoxide (DMSO), dimethyl formamide (DMF), N,N-dimethylacetamide (DMA), decylmethylsulfoxide (C10MSO), polyethylene glycol monolaurate (PEGML), glyceral monolaurate, lecithin, 1- substituted azacycl
  • Suppositories for vaginal or rectal administration of the compounds and compositions of the invention can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at rectal temperature, such that they will melt in the rectum and release the drug.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and /or suspending agents.
  • the sterile injectable preparation can 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.
  • the acceptable vehicles and solvents that can
  • the compounds and compositions of the present invention can be formulated as pharmaceutically acceptable neutral or acid salts, including, for example, those formed with free amino groups such as those derived from hydrochloric, hydrobromic, hydroiodide, phosphoric, sulfuric, acetic, citric, benzoic, fumaric, glutamic, lactic, malic, maleic, succinic, tartaric, p-toluenesulfonic, methanesulfonic acids, gluconic acid, and the like, and those formed with free carboxyl groups, such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • free amino groups such as those derived from hydrochloric, hydrobromic, hydroiodide, phosphoric, sulfuric, acetic, citric, benzoic, fumaric, glutamic, lactic, mal
  • “Therapeutically effective amount” refers to the amount of the ⁇ -adrenergic receptor antagonist, nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonist, nitric oxide donor and /or vasoactive agent that is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of each of the compounds and compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the composition, and which can be adjusted by one of ordinary skill in the art will vary, depending on the age, health, physical condition, sex, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction or disease.
  • ⁇ -adrenergic receptor antagonist including nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists
  • vasoactive agent which will be effective in the prevention or treatment of a particular dysfunction or disease will depend on the nature of the dysfunction or disease, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician's Desk Reference, supra; Medical Economics Company, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993.
  • the precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the dysfunction or disorder, and should be decided by the physician and the patient's circumstances.
  • the usual doses of ⁇ -adrenergic receptor antagonists are about 1 mg to about 100 mg per day, preferably about 0.5 mg to about 10 mg per day.
  • the oral dose of ⁇ -adrenergic receptor antagonists are about 1 mg to about 100 mg per day preferably about 5 mg to about 80 mg per day.
  • the doses of nitric oxide donors in the pharmaceutical composition can be in amounts of about 0.001 mg to about 20 g, although the actual amount administered will be dependent on the specific nitric oxide donor.
  • the dose when L-arginine is the nitric oxide donor, the dose is about 2 g/day to about 6 g/day, preferably about 3 g/day, administered orally at least one hour prior to sexual activity or sexual intercourse.
  • Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician's Desk Reference, supra.
  • the nitrosated and /or nitrosylated ⁇ -adrenergic receptor antagonists of the invention are used at dose ranges and over a course of dose regimen and are administered in the same or substantially equivalent vehicles /carrier by the same or substantially equivalent as their non-nitrosated/ nitrosylated counterparts.
  • the nitrosated and /or nitrosylated compounds of the invention can also be used in lower doses and in less extensive regimens of treatment.
  • the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the dosage regimen for treating a 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 of the dysfunction, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination.
  • the dosage regimen actually used can vary widely and therefore may deviate from the preferred dosage regimen set forth herein.
  • Particularly preferred methods of administration of the contemplated ⁇ -adrenergic receptor antagonist compositions for the treatment of male sexual dysfunction are by oral administration, by transdermal application, by injection into the corpus cavernosum, by transurethral administration or by the use of suppositories.
  • the preferred methods of administration for female sexual dysfunction are by oral administration, topical application, transdermal application or by the use of suppositories.
  • the present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and /or compositions of the present invention, including, one or more ⁇ -adrenergic receptor antagonists, optionally substituted with one or more NO and /or N0 2 groups, one or more of the NO donors, and one or more vasoactive agents.
  • kits can also include, for example, other compounds and/or compositions (e.g., permeation enhancers, lubricants, and the like), a device(s) for administering the compounds and /or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
  • other compounds and/or compositions e.g., permeation enhancers, lubricants, and the like
  • a device(s) for administering the compounds and /or compositions e.g., permeation enhancers, lubricants, and the like
  • written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflects approval by the agency of manufacture, use or sale for human administration.
  • Example 1 4-(N- ⁇ (lR)-l-[N-(carboxymethyl)carbamoyl1-2- (nitrosothio)ethyl ⁇ carbamoyl) (2S)-2-aminobutanoic acid
  • N-(N-L-y-glutamyl-L-cysteinyl)glycine (100 g, 0.325 mol) was dissolved in deoxygenated water (200 ml) and 2N HCl (162 ml) at room temperature and then the reaction mixture was cooled to 0 °C. With rapid stirring, a solution of sodium nitrite (24.4 g, 0.35 mol) in water (40 ml) was added. Stirring with cooling of the reaction mixture was continued for approximately 1 hour after which time the pink precipitate which formed was collected by vacuum filtration. The filter cake was resuspended in chilled 40% acetone-water (600 ml) and collected by vacuum filtration.
  • Example 2a The product of Example 2a (1.1 g, 5 mmol) and triethylamine (710 ⁇ l, 5 mmol) was dissolved in ethyl acetate (50 ml) and cooled to 0 °C. Triphosgene (250 mg, 0.85 mmol) was added all in one portion and the reaction was stirred at 0 °C for 15 minutes then warmed to room temperature with continued stirring for 30 minutes. The precipitate which formed was removed by filtration and the filtrate was concentrated by rotary evaporation to afford 1.0 g (5 mmol) of the title compound.
  • Example 3a The product of Example 3a (0.300 g, 0.76 mmol) was dissolved in pyridine (0.5 mL) and a solution of the product of Example 2b (0.397 g, 0.95 mmol) in pyridine (0.5 mL) was added. The resulting solution was stirred for 18 hours at room temperature. The solvent was evaporated, and the residue was purified by flash chromatography on silica-gel, eluting with hexane/ethyl acetate (4:1) to give 0.332 g (73%) of the title compound.
  • Example 3b 4-(2- ⁇ (Tert-butoxy)-N-[(l-oxo(2-2,3,4-trihydronaphthyl))methyl] carbonylamino ⁇ ethyl)phenyl 3-methyl-3-sulfanylbutanoate
  • methanol 2 mL
  • a solution of silver nitrate (0.117 g, 0.69 mmol) in water (0.4 mL) was added.
  • the resulting mixture was stirred for 1 hour at room temperature.
  • the solvent was evaporated, the residue was suspended in acetone/water (1:10) and IN HCl (1 mL) was added.
  • Example 3c 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.
  • Example 3e 4-(2- ⁇ [(l-Oxo-2-2,3,4-trihydronaphthyl)methyl]amino ⁇ ethyl)phenyl 3-methyl- 3-(nitrosothio)butanoate hydrochloride
  • the product of Example 3d (0.081 g, 0.20 mmol) was dissolved in methanol (4 mL) and IN HCl was added. A solution of sodium nitrite (0.045 g, 0.65 mmol) in water (0.25 mL) was added. After stirring for 15 minutes at room temperature an additional sodium nitrite (0.045 g, 0.65 mmol) in water (0.25 mL) was added.
  • Example 4 2-[4-(2-Methoxyphenyl)piperazinyn-l-(naphthyloxymethyl)ethyl 3- methyl-3-(nitrosothio)butanoate hdrochloride 4a. 3-Methyl-3-(2,4,6-trimethoxvphenylthio)butanoic acid
  • Example 4c The product of Example 4c (0.048 g, 0.097 mmol) was dissolved in methanol (5 mL) 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 (0.5 mL) was added. After 1 hour stirring at 0 °C the reaction mixture was extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give the title compound (0.045 g, 82% yield) as a green solid.
  • Example 5c N- ⁇ 2-[4-(2-furylcarbonyl)piperazinyl]-6,7-dimethoxyquinazolin-4-yl ⁇ -3- methyl-3-(nitrosothio)butanamide
  • the product of Example 5b (0.036 g, 0.080 mmol) was dissolved in methanol and IN solution of hydrochloric acid (1 mL) was added. The resulting mixture was cooled to 0°C and a solution of sodium nitrite (0.067 g, 0.97 mmol) in water (0.5 mL) was added. After 40 minutes stirring at 0 °C the reaction mixture was extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate.
  • Example 6 4-f2-(Dimethylamino)ethoxy1-2-methyl-5-(methylethyl)phenyl 3- methyl-3-(nitrosothio)butanoate hydrochloride 6a .
  • Example 6a Under a nitrogen atmosphere, the product of Example 6a (0.270 g, 1.14 mmol) was dissolved in anhydrous dimethylformamide (2 mL) and 4-dimethylamino- pyridine (0.028 g, 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.
  • Example 6c 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 3-methyl-3- sulfanylbutanoate
  • methylene chloride 0.30mL
  • anisole 0.22 mL, 2.02 mmol
  • phenol 0.22 g, 0.23 mmol
  • water 0.22 mL
  • trifluoroacetic acid 1.0 mL, 13.0 mmol
  • Example 6c The product of Example 6c (0.035 g, 0.10 mmol) was dissolved in methanol (5 mL) and IN solution of hydrochloric acid (1 mL) was added. The resulting mixture was cooled to 0 °C and a solution of sodium nitrite (0.014 g. 0.20 mmol) in water (0.7 mL) was added. After 20 minutes stirring at 0°C, an additional sodium nitrite (0.032 g, 0.46 mmol) in water (0.7 mL) was added and the resulting mixture was stirred for 30 minutes. The reaction mixture was extracted with methylene chloride, washed with brine and dried over anhydrous sodium sulfate.
  • Example 7a The product of Example 7a (6.6 g, 41 mmol), dihydropyran (4 mL, 44 mmol), and 4 N HCl/Et 2 0 (1 mL) were allowed to stand at room temperature for 24 hours. The volatiles were evaporated in vacuo to leave the title compound as a viscous oil which was used without further purification.
  • Example 7b 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. Evaporation of the solvent and chromatography on silica gel eluting with 3:1 hexane/ethyl acetate gave 340 mg (51%) of the title compound.
  • reaction mixture was diluted with methylene chloride and then washed successively with 0.1 N HCl, saturated aqueous sodium bicarbonate, and brine; followed by drying over sodium sulfate. Evaporation of the solvent and chromatography on silica gel eluting with 2:1 hexane/ethyl acetate gave 540 mg (46%) of the title compound.
  • Example 7e The product of Example 7e (18 mg, 0.033 mmol) was dissolved in dimethylforamide (200 ⁇ L) and 4 N HCl in ether (25 ⁇ L, 0.1 mmol) was added. The reaction mixture was cooled to 0°C and tert-butyl nitrite (12 ⁇ L, 0.12 mmol) was added and then the reaction mixture was stirred at for 0°C for 20 minutes. The solvent was evaporated in vacuo and the solid residue obtained was azetroped with chloroform to afford the title compound as a foam.
  • Example 6a The product of Example 6a was dissolved in anhydrous chloroform (32 mL) and glutaric anhydride (0.886 g, 7.77 mmol) was added, followed by DMAP (0.190 g, 1.56 mmol) and triethylamine (0.820 mL, 5,84 mmol). The resulting mixture was stirred at 55 °C for 42 hours. The mixture was cooled down to room temperature and poured into dichloromethane /water mixture. The organic fraction was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give (1.42 g, 94% yield) of the title compound as a clear oil.
  • Example 8a Under a nitrogen atmosphere, the product of Example 8a (1.4 g, 3.62 mmol) was dissolved in anhydrous chloroform (20 mL) and l-(aminomethyl)cyclohexane-l- thiol (0.71 g, 4.8 mmol) was added, followed by DMAP (0.195 g, 1.6 mmol). A solution of ED AC (0.764 g, 4.00 mmol) in chloroform (10 mL) was added dropwise and the resulting mixture was stirred at 55 °C for 40 hours.
  • Example 8b The product of Example 8b (0.285 g, 0.60 mmol) was dissolved in dichloromethane (9 mL) and 2.9 N HCl in ether (0.06 mL) was added. The resulting mixture was cooled to 0°C and tert-butyl nitrite (0.300 mL, 2.53 mmol) was added, followed by 2.9 NHC1 in ether (0.05 mL). The reaction mixture was stirred on ice for 45 minutes (0.13 mL, 1.20 mmol), phenol (0.013 g, 0.14 mmol), water (0.13 mL), and trifluoroacetic acid (0.80 mL, 10.4 mmol) were added.
  • Example 9 4-F2-(Dimethylamino)ethoxy1-2-methyl-5-(methylethyl)phenyl2-( ⁇ N- f2-methyl-2-(nitrosothio)propyncarbamoyl ⁇ methoxy)acetate> fumaric acid salt.
  • 9a 2- ⁇ [N-(2-methyl-2-sulfanylpropyl)carbamoyl]methoxy ⁇ acetic acid.
  • Example 9a The product of Example 9a (5.76 g, 26.03 mmol) was dissolved in methylene chloride (100 mL) and t-butyl nitrite (3.2 mL, 27.37 mmol) was added. After stirring for 30 minutes at room temperature, the reaction mixture was concentrated in vacuo and the residue was solidified upon cooling.
  • Example 6a Under a nitrogen the product of Example 6a (4.52 g, 19.1 mmol) was dissolved in anhydrous methylene chloride (60 mL) and 4-dimethylaminopyridine (0.932 g, 7.64 mmol) was added. The resulting solution was cooled to 0 °C and the product of Example 9b (4.77 g, 19.1 mmol) was added, followed by a solution of 1,3- dicyclohexylcarbodiimide (3.93 g, 19.1 mmol) in methylene chloride (30 mL). The resulting mixture was stirred at 0 °C for 1 hour and then at room temperature for 4 hours.
  • Example 9c 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 2-( ⁇ N-[2- methyl-2-(nitrosothio)propyl]carbamoyl ⁇ methoxy)acetate, fumaric acid salt.
  • the product of Example 9c (0.259 g, 0.55 mmol) was dissolved in methanol (3 mL) and fumaric acid (0.064 g, 0.55 mmol) was added.
  • reaction mixture was stirred at 0 °C for further 15 minutes and then at room temperature for 30 minutes.
  • the excess L1ALH4 was destroyed by the addition of ethyl acetate.
  • the reaction mixture was then poured over ice cold water, acidified with 1 N HCl and extracted with dichloromethane (2 x 200 mL).
  • Example 10a To a solution of the product of Example 10a (3.12 g, 10 mmol) and HCl/isopropanol (5.3 M, 0.2 mL) in 100 mL dichloromethane at 0 °C was added tert- butylnitrite (11 mmol, 1.260 g, 1.45 mL). The ice bath was removed, and the solution was stirred for an additional 1.5 hours at room temperature. The reaction mixture was washed with water, and dried over magnesium sulfate. After rotary evaporation, the crude material was purified via column chromatography (5% methanol /chloroform) to yield a green oil.
  • Example 6a To a solution of the product of Example 6a (1.117 g, 4.71 mmol) and the product of Example 10b (1.93 g, 5.65 mmol) in anhydrous dichloromethane (100 mL) were added l-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (ED AC) (1.083 g, 5.65 mmol) and dimethylaminopyridine (DMAP) (0.23 g, 1.88 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight.
  • ED AC l-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride
  • DMAP dimethylaminopyridine
  • Example 11 4-f2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 2- ⁇ 2- r2-(nitrosothio)adamantan y ⁇ ethypoxycarbonyl) methoxy] cetate, succinic acid salt.
  • Example 11a Under a nitrogen atmosphere the product of Example 11a (7.15 g, 31.9 mmol) was dissolved in anhydrous chloroform (30 mL) and the product of Example 6a (7.56 g, 31.9 mmol) was added, followed by 4-dimethylaminopyridine (3.89 g, 31.9 mmol).
  • a solution of ED AC (6.09 g, 31.9 mmol) in chloroform (15 mL) was added dropwise and the resulting mixture was stirred at room temperature for 22 hours. Volatiles were evaporated and the residue was purified by flash chromatography on silica gel, eluting with methylene chloride /methanol (20:1) to give 2.9 g of the title compound as a colorless oil.
  • Example lib Under the nitrogen atmosphere the product of Example lib (2.9 g, 6.55 mmol) was dissolved in methanol (60 mL) and palladium on activated carbon (0.20 g) was added. The nitrogen atmosphere line was exchanged with 1 atmosphere hydrogen and the resulting mixture was stirred at room temperature for 2 hours 30 minutes. The reaction mixture was filtered through celite and volatiles were evaporated to give 2.25 g (97%) of the title compound as a white solid.
  • Example lie (0.800 g, 2.27 mmol) was dissolved in anhydrous chloroform (20 mL) and the product of Example 10c (0.614 g, 2.54 mmol) was added, followed by 4-dimethylaminopyridine (0.124 g, 1.04 mmol).
  • Example 6a To a solution of the product of Example 6a (2.37 g, 10 mmol) and the product of Example 12c (2.22 g, 10 mmol) in anhydrous dichloromethane (125 mL) were added l-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride (ED AC) (3.82 g, 20 mmol) and dimethylaminopyridine (DMAP) (2.44 g, 20 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature overnight.
  • ED AC l-ethyl-3-(3-dimethylaminopropyl)carbamide hydrochloride
  • DMAP dimethylaminopyridine
  • the reaction mixture was then cooled to 0 °C temperature and a solution of the product of Example 12a (1.205 g, 5 mmol) in anhydrous dichloromethane (25 mL) was added dropwise at 0 °C.
  • the reaction mixture was stirred at 0 °C for 30 minutes and then slowly allowed to warm to room temperature and further stirred at room temperature for 5 hours.
  • the solvent was evaporated at reduced pressure and residue was extracted with ethyl acetate and water.
  • Example 12f 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 2-[2- (nitrosothio)adamantan-2-yl]ethyl pentane-l,5-dioate, citrate salt
  • acetone 5 mL
  • butylated hydroxytoluene (BHT) 5 mg
  • solution was cooled to 0 °C.
  • Solution of citric acid 154 mg, 0.8 mmol
  • methanol was added dropwise at 0 °C temperature under nitrogen atmosphere and stirred at 0 °C for 10 minutes.
  • Example 13 4-f2-(Dimethylamino)ethoxy1-2-methyl-5-(methylethyl)phenyl 4- ⁇ N- f2-me yl-2-(nitrosothio)propyl arbamoyl ⁇ butanoate, citrate salt 13a. 4-[N-(2-Methyl-2-sulfanylpropyl)carbamoyl]butanoic acid
  • Example 14 4-r2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 4- ⁇ N- methyl-N-f2-methyl-2-(nitrosothio)propyl]carbamoyl)butanoate, fumaric acid salt 14a. 4-[N-Methyl-N-(2-methyl-2-sulfanylpropyl)carbamoyl]butanoic acid To a suspension of l-N-methylmino-2-methylpropane-2-thiol hydrochloride
  • Example 15 4-f2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 5- ⁇ 4- [2-methyl-2-(nitrosothio)propynpiperazinyl ⁇ -5-oxopentanoate, hydrochloride salt.
  • Example 15b Under a nitrogen atmosphere the product of Example 15b (0.486 g, 1.69 mmol) was dissolved in anhydrous chloroform (12 mL) the product of Example 6a (0.400 g, 1.69 mmol) was added, followed by 4-dimethylaminopyridine (0.206 g, 1.69 mmol). A solution of 1,3-dicyclohexylcarbodiimide (0.348 g, 1.69 mmol) in chloroform (5 mL) was added dropwise and the resulting mixture was stirred at room temperature for 24 hours. The precipitate was removed by filtration and the filtrate was concentrated in vacuo.
  • Example 15c The product of Example 15c (0.760 g, 1.40 mmol) was dissolved in methylene chloride (14 mL) and 4N HCl in ether (0.500 mL) was added. The resulting mixture was cooled to 0 °C and tert-butyl nitrite (0.270 mL, 2.80 mmol) was added. The reaction mixture was stirred on ice for 10 minutes and volatiles were evaporated. The residue was purified by flash chromatography on silica gel, eluting with methylene chloride /methanol (30:1) to give 0.380 g (45%) of the title compound.
  • Example 15d 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 5- ⁇ 4-[2-methyl- 2-(nitrosothio)propyl]piperazinyl ⁇ -5-oxopentanoate, hydrochloride salt.
  • the product of Example 15d (0.380 g, 0.62 mmol) was dissolved in methylene chloride (3 mL) and 4N HCl in ether (1 mL) was added. The solvent was evaporated to afford 0.415 g of the title compound as a green solid, mp 30-42 °C.
  • Example 16 4-[2-(Dimethylamino)ethoxyl-2-methyl-5-(methylethyl)phenyl 2-(2- ⁇ N-f2-methyl-2-(nitrosothio)propyl]carbamoyl ⁇ phenyl) benzoate 16a. 2- ⁇ 2-[N-(2-methyl-2-sulfanylpropyl)carbamoyl]phenyl ⁇ benzoic acid
  • Example 16a To a solution ofthe product of Example 16a (1.23g, 3.73 mmol) in methylene chloride (25 mL) at room temperature was added t-butyl nitrite (0.46 mL, 3.93 mmol). After 30 minutes, the reaction was concentrated and the residue was triturated with hexane to afford the title compound as a green solid (1.32 g, 98.6%).
  • Example 17 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl l-f3- methyl-3-(nitrosothio)butanovnpiperidine-4-carboxylate, succinic acid salt 17a.
  • Ethyl isonipecotate (1.99 g, 12.7 mmol) was dissolved in anhydrous chloroform (30 mL) the product of Example 4a (4.0 g, 12.7 mmol) was added, followed by 4-dimethylaminopyridine (1.55 g, 12.7 mmol).
  • a solution of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.42 g, 12.7 mmol) in chloroform (10 mL) was added dropwise and the resulting mixture was stirred at room temperature for 22 hours.
  • Example 17b l-[3-Methyl-3-(2,4,6-trimethoxyphenylthio)butanoyl]piperidine-4-carboxylic acid.
  • the product of Example 17a (2.44 g, 5.39 mmol) was dissolved in ethanol (25 mL) and a solution of sodium hydroxide (1.94 g, 48.5 mmol) in water (12 mL) was added. The reaction mixture was stirred at reflux temperature for 20 minutes and volatiles were evaporated. The residue was cooled to 0 °C and 2N HCl (25 mL) was added to produce a white precipitate. The reaction mixture was concentrated in vacuo, and the precipitate was separated by filtration.
  • Example 17c The product of Example 17c (1.95 g, 3.03 mmol) was dissolved in methylene chloride (21 mL) and anisole (1.5 mL), phenol (1.5 g), water (1.5 mL) and trifluoroacetic acid (9 mL) were added. After 1 hour 20 minutes of stirring at room temperature, toluene (25 mL) was added and volatiles were evaporated. The residue was purified by flash chromatography on silica gel, eluting with hexane/ethyl acetate (9:1) to (1:1), and then with methylene chloride/methanol (20:1) to give 1.1 g (79%) of the title compound.
  • Example 17e The product of Example 17e (0.628 g, 1.27 mmol) was dissolved in methanol (3 mL) and succinic acid (0.150 g, 1.27 mmol) was added. The solvent was evaporated and the residue was recrystallized from the mixture of acetone (3 mL) and ethyl ether (1 mL) to afford 0.340 g of the title compound as a green crystalline solid, mp 84-85 °C.
  • Example 18 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 2,2- bisf(nitrooxy)methyll-3-(nitrooxy)propyl pentane-l,5-dioate 18a.
  • Example 18a The product of Example 18a (332 mg, 0.89 mmol) was dissolved in 4 mL of dry methylene chloride. Fuming nitric acid (335 mg, 5.32 mmol, 6 eq, 0.24 mL of the 90% nitric acid) and acetic anhydride (1.20 mL) were premixed (exothermic) and then the pale yellow solution was added dropwise to the methylene chloride solution at ambient temperature. The reaction mixture was stirred at ambient temperature for 30 minutes at which point TLC (7:3 EtOAc /hexanes) indicated that the reaction had gone to completion.
  • Example 18b 400 mg, 0.79 mmol was dissolved in 5 mL of THF. Tetrabutyl-n-butylammonium fluoride (1.2 eq, 0.94 mmol, 0.94 mL of the IM solution in THF) was added at ambient temperature to the trinitrate solution producing a dark brown solution. The reaction mixture was stirred at ambient temperature for 1.5 hours at which point TLC (1:9 EtOAc/hexanes) indicated that the reaction had gone to completion. The reaction mixture was worked-up by passing the solution through a short pad of silica gel, eluting with 1:1 EtOAc /hexanes. Concentration of the solvent in vacuo afforded a pale yellow oil.
  • Example 12d 4-[2-(Dimethylamino)ethoxy]-2-methyl-5-(methylethyl)phenyl 2,2- bis[(nitrooxy)methyl]-3-(nitrooxy)propyl pentane-l,5-dioate
  • the product of Example 12d (739 mg, 2.10 mmol) and the product of Example 18c (627 mg, 2.31 mmol, 1.1 eq) are dissolved in 10 mL of dry methylene chloride under Ar in an oven-dried round-bottomed flask at ambient temperature. A small crystal of DMAP was added at ambient temperature followed immediately by the addition of EDAC (463 mg, 2.42 mmol, 1.15 eq).
  • reaction mixture was stirred at ambient temperature for 18 h at which time TLC (3:7 EtOAc/Hexanes) indicated reaction to be complete.
  • TLC 3:7 EtOAc/Hexanes
  • the reaction was worked-up by dilution with methylene chloride and washing 2x10 mL of water and then 1 x lOmL of brine.
  • the organic layer was dried over sodium sulfate, the solvent evaporated in vacuo and then preadsorbed onto 2 g of silica gel.
  • Example 19 In Vivo Comparative Erectile Responses - I Male New Zealand white rabbits weighing 2.5 kg were used as the animal model. Animals were first relaxed with an i.m. injection of 25 mg/kg ketamine prior to anesthesia with a bolus i.v. injection of 10 mg/kg Profol and maintained with i.v. infusion at 0.5 mg/kg /minutes. Ventilation of the animals was performed with 1% halothane plus 0.8 L/min 0 2 and 1 L/min N 2 0. A 22 gauge angiocatheter was placed in the femoral artery for measurement of systemic blood pressure. A dorsal incision was made in the penis and the corpora cavernosum exposed and cannulated with a 21 gauge butterfly needle to measure intracavernosal pressure.
  • Drugs at various concentrations were delivered intracavernosally at a volume of 150 ⁇ l through a 25 gauge needle.
  • pap/phent/PGEl was injected in the corpora as a standard solution for comparison with the response of yohimbine, Example 1, Example 2, and the combination of yohimbine and Example 1.
  • This pap/phent/PGEl mixture is considered to cause a maximal erection-inducing effect.
  • a 500 ⁇ g dose of Example 1 was able to induce near maximal response relative to the standard dose of pap/phent/PGEl.
  • a combination of the submaximal dose of yohimbine (150 ⁇ g) and Example 1 (500 ⁇ g) also induced maximum erectile response.
  • Yohimbine at both the submaximal and maximal efficacy doses produced very short duration of action (Fig. 2).
  • Example 1 produced a much longer duration of action.
  • the duration of action is potentiated by a combination of Example 1 and yohimbine which is longer than the sum of the duration of each of these compounds alone (Fig. 2).
  • Fig. 3 shows that the compound of Example 2 at the 500 ⁇ g dose is equipotent to the standard dose of pap/phent/PGEl.
  • a higher dose of the compound of Example 2 (1 mg) is at least equal to or more efficacious than the standard dose of the pap/phent/PGEl mixture.
  • Fig. 4 shows that the compound of Example 2 has the advantage of producing longer duration of action compared to yohimbine.
  • FIG. 5A demonstrates that a dose (500 ⁇ g) of the compound of Example 2 effective in the erectile response did not produce any effect on systemic blood pressure upon intracavernosal injection.
  • Fig. 5B demonstrates that a standard dose of the mixture of pap/phent/PGEl produced a significant decrease in systemic blood pressure upon intracavernosal injection, suggesting that the compound of Example 2 lacks this side effect.
  • Fig. 6 shows that intracavernosal administration of 1 mg of Example 6 is more efficacious than 1 mg moxisylyte in inducing the erectile response in vivo in the anesthetized rabbit.
  • Fig. 7 shows that a 1 mg dose of Example 6 produces a longer duration of erectile response compared to 1 mg moxisylyte. Also, Fig. 7 shows that 2 mg of Example 6 produces a much longer duration of action compared to 2 mg moxisylyte.
  • Example 20 In vivo Comparative Erectile Responses - II White New Zealand male rabbits (2.6 -3.0 kg) were anesthetized with pentobarbital sodium (30 mg/kg).
  • the femoral artery was exposed and indwelled with PE 50 tubing connected to a transducer for recording systemic arterial blood pressure.
  • the ventral aspect of the penis was then exposed via surgical cut and intracavernosal blood pressure was measured using a 23 gauge needle inserted to the corpus cavemosum.
  • the contralateral corpus cavemosum was implanted with a 23 gauge needle for the administration of drugs.
  • ICP intracavernosal blood pressure
  • MABP mean arterial blood pressure
  • Drugs at various concentrations were prepared as aqueous solution (injection volume of 200 ⁇ L). Following drug injection the tubing was flushed with 100 ⁇ L distilled water. All drug treatments were administered after stable intracavernosal and systemic blood pressures were established. If an increase in intracavernosal blood pressure (ICP) was observed, the effect was monitored throughout its entire duration. Animals that did not exhibit an increase in ICP received an injection of a combination of phentolamine (0.2 mg) and papaverine (6.0 mg) to confirm the accuracy of needle implantation and to evaluate the erectile responsiveness of the animal. Animals that did not respond to this combination were disregarded from the analysis.
  • Fig. 9 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of various doses of Example 9 (0.2 mg,
  • Fig. 10 shows the peak erectile response in vivo in the anesthetized rabbit following the intracavernosal administration of various doses of Example 10 (0.64 mg, 1.07 mg, 2.13 mg and 4.26 mg).
  • Fig. 11 shows the duration of the erectile response in vivo in the anesthetized rabbit upon intracavernosal administration of various doses of Example 10 (0.64 mg,
  • Fig. 10 and Fig. 11 show that 1.07 mg of Example 10 produces a moderate and short-lasting increase of ICP. At 2.13 mg and 4.26 mg of Example 10 a robust effect on both the magnitude and duration of increase in intracavernosal pressure was observed. At 4.26 mg, the duration of the erectile response exceeded 120 minutes.
  • Fig. 8 to Fig. 11 show that the doses of Example 9 needed to produce a robust increase of ICP is lower than the doses of Example 10. At the doses of Example 9, the duration of the erectile was somewhat shorter than that of Example 10.
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JP2006524197A (ja) * 2003-04-24 2006-10-26 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング トリアザ−およびテトラアザ−アントラセンジオン誘導体、それらの製造法ならびに医薬としてのそれらの使用
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CA2339145A1 (en) 2000-03-09
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EP1109542A1 (en) 2001-06-27
AU5701699A (en) 2000-03-21
US6294517B1 (en) 2001-09-25
US6417162B1 (en) 2002-07-09
EP1109542A4 (en) 2008-03-26
US6514934B1 (en) 2003-02-04
AU770414B2 (en) 2004-02-19

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