(12) United States Patent (10) Patent No.: US 6,331,543 B1 Garvey Et Al

USOO6331543B1 (12) United States Patent (10) Patent No.: US 6,331,543 B1 Garvey et al. (45) Date of Patent: Dec. 18, 2001

(54) NITROSATED AND NITROSYLATED WO95/26725 10/1995 (WO). PHOSPHODIESTERASE INHIBITORS, WO 96/25184 8/1996 (WO). COMPOSITIONS AND METHODS OF USE 9703675 2/1997 (WO). 9703985 2/1997 (WO). WO 97/34871 9/1997 (WO). (75) Inventors: David S. Garvey, Dover, MA (US); WO 97/39760 10/1997 (WO). Inigo Saenz de Tejada, Madrid (ES); 9743287 11/1997 (WO). Richard A. Earl, Westford; Subhash P. 98.17668 4/1998 (WO). Khanapure, Clinton, both of MA (US) 98.19672 5/1998 (WO). 9849166 11/1998 (WO). (73) Assignee: NitroMed, Inc., Bedford, MA (US) 9852569 11/1998 (WO). 992 1558 5/1999 (WO). (*) Notice: Subject to any disclaimer, the term of this 992 1562 5/1999 (WO). patent is extended or adjusted under 35 9922731 5/1999 (WO). U.S.C. 154(b) by 0 days. 9930697 6/1999 (WO). OTHER PUBLICATIONS (21) Appl. No.: 09/387,727 International Preliminary Examination Report for PCT/ (22) Filed: Sep. 1, 1999 US99/20024 dated Dec. 19, 2000. Patnaik et al, Indian Journal of Pharmacology, 11 Related U.S. Application Data (2):139–142 (1979). (63) Continuation-in-part of application No. 09/145,142, filed on Agarwal et al, Indian Journal of Chemistry, 29B:80-84 Sep. 1, 1998, now Pat. No. 5,958,926, which is a continu (1990). ation-in-part of application No. 08/740,764, filed on Nov. 1, 1996, now Pat. No. 5,874,437, and a continuation-in-part of (List continued on next page.) application No. PCT/US97/19870, filed on Oct. 31, 1997. Primary Examiner Richard L. Raymond (51) Int. Cl." ...... A61K 31/4985; CO7D 471/14 (74) Attorney, Agent, or Firm-Hale and Dorr LLP (52) U.S. Cl...... 514/250; 514/246; 514/259; (57) ABSTRACT 514/267; 514/292; 514/307; 514/404; 514/619; 514/655; 514/676; 514/716; 514/728; 544/237; The present invention describes novel nitrosated and/or 544/251; 544/293; 544/343; 54.6/111; 546/149; nitrosylated phosphodiesterase inhibitors, and novel com 548/367.7; 568/306; 568/584; 568/588; positions containing at least one nitrosated and/or nitrosy 568/716; 568/744; 564/163; 564/384 lated phosphodiesterase inhibitor, and, optionally, one or (58) Field of Search ...... 544/343,237, more compounds that donate, transfer or release nitric oxide, 544/251, 293; 514/250, 246, 259, 267, elevate endogenous levels of endothelium-derived relaxing 292, 307, 404, 619, 655, 676, 716, 728; factor, Stimulate endogenous Synthesis of nitric oxide or is a Substrate for nitric oxide Synthase and/or one or more 546/111, 149; 548/367.7; 564/163, 384; vasoactive agents. The present invention also provides novel 568/306, 584, 588, 716, 744 compositions containing at least one phosphodiesterase (56) References Cited inhibitor, and one or more compounds that donate, transfer or release nitric oxide, elevate endogenous levels of U.S. PATENT DOCUMENTS endothelium-derived relaxing factor, Stimulate endogenous 4,308,278 12/1981 Schneider et al...... 424/273 Synthesis of nitric oxide or is a Substrate for nitric oxide 4,963,541 10/1990 Brooks et al...... 514/183 Synthase and/or one or more vasoactive agents. The present 5,171,217 12/1992 March et al...... 604/53 invention also provides methods for treating or preventing 5,190,967 3/1993 Riley ...... 514/411 Sexual dysfunctions in males and females, for enhancing 5,196.426 3/1993 Saccomano et al. . ... 514/258 Sexual responses in males and females, and for treating or 5,223,504 6/1993 Noverola et al...... 514/263 preventing diseases induced by the increased metabolism of 5,254,575 10/1993 Picket al...... 514/365 cyclic guanosine 3',5'-monophosphate (cGMP), Such as 5,340,827 8/1994 Beeley et al...... 514/352 hypertension, pulmonary hypertension, congestive heart 5,380,758 1/1995 Stamler et al. ... 514/562 failure, renal failure, myocardial infraction, Stable, unstable 5,426,107 6/1995 Bell et al...... 514/234.2 and variant (Prinzmetal) angina, atherosclerosis, cardiac (List continued on next page.) edema, renal insufficiency, nephrotic edema, hepatic edema, Stroke, asthma, bronchitis, chronic obstructive pulmonary FOREIGN PATENT DOCUMENTS disease (COPD), cystic fibrosis, de mentia, 0 252 721 1/1988 (EP). immunodeficiency, premature labor, dysmenorrhoea, benign O352 960 1/1990 (EP). prostatic hyperplasis (BPH), bladder outlet obstruction, O 442 204 8/1991 (EP). incontinence, conditions of reduced blood vessel patency, O 463 756 1/1992 (EP). e.g., postpercutaneous transluminal coronary angioplasty O 506 194 9/1992 (EP). (post-PTCA), peripheral vascular disease, allergic rhinitis, 2547501 12/1984 (FR). glucoma, and diseases characterized by disorders of gut WO 93/07149 4/1993 (WO). WO 93/12068 6/1993 (WO). motility, e.g., irritable bowel syndrome (IBS). 9501338 1/1995 (WO). WO95/09636 4/1995 (WO). 94 Claims, 60 Drawing Sheets US 6,331,543 B1 Page 2

U.S. PATENT DOCUMENTS Patnaik et al., Chemical Abstracts, vol. 92:69309, 1980.* 5,438,060 8/1995 Miyazaki et al...... 514/258 Chemical Abstracts, vol. 120, No. 1, Abstract No. 5451d 5,439,938 8/1995 Snyder et al. . ... 514/565 (1994). 5,491,147 2/1996 Boyd et al...... 514/247 Martel et al, Drugs of the Future, 22(2):138-143 (1997). 5,492.911 2/1996 Stief ...... 514/252 Boolell et al, British Journal of Urology, 78(2):257-261 5,543,430 8/1996 Kaesemeyer ...... 514/565 (1996). 5,545,647 8/1996 Tanaka et al...... 514/343 5,565,466 10/1996 Gioco et al...... 514/280 Chemical Abstracts, vol. 116, No. 1, Abstract No. 4477 (Jan. 5,583,101 12/1996 Stamler et al...... 514/2 6, 1992). 5,614,627 3/1997 Takase et al...... 544/293 Chemical Abstracts, vol. 125, No. 15, Abstract No. 191382 5,618,814 4/1997 Heckel et al...... 514/234.2 (Oct. 7, 1996). 5,645,839 7/1997 Chobanian et al...... 424/400 Chemical Abstracts, vol. 123, No. 1, Abstract No. 574 (Jul. 5,646,181 7/1997 Fung et al...... 514/506 5,698,589 12/1997 Allen ...... 514/509 3, 1995). 5,716,993 2/1998 OZaki et al. ... 514/619 Chemical Abstracts, vol. 120, No. 25, Abstract No. 315630 5,731,339 3/1998 Lowrey ...... 514/400 (Jun. 20, 1994). 5,767,160 6/1998 Kaesemeyer ...... 514/565 Chemical Abstracts, vol. 121, No. 7, Abstract No. 73410 5,824,669 10/1998 Garvey et al...... 514/174 (Aug. 15, 1994). 5,849,741 12/1998 Watanabe et all ... 514/248 5,859,006 1/1999 Daugan ...... 514/249 Boolell et al., International Journal of Impotence Research, 5,869,516 2/1999 Arlt et al...... 514/.404 8:47–52 (1996). 5,877,216 3/1999 Place et al...... 514/573 Krane et al, New England Journal of Medicine, 5,932,538 8/1999 Garvey et al...... 514/2 321(24): 1648–1659 (1989). 5,958,926 9/1999 Garvey et al. . ... 514/253 Trigo-Rocha et al, Neurourol. Urodyn., 13(1):71-80 (1994). 5,973,011 10/1999 Noack et al...... 514/742 5,981.527 * 11/1999 Daugan et al. ... 514/250 Sparwasser et al., J. Urol., 152:6, Pt. 1, pp. 2159-21.63 6,007,824 12/1999 Duckett et al...... 424/195.1 (1994). 6,037,346 3/2000 Doherty, Jr. et al. ... 514/258 Terrett et al, Bioorg. Med. Chem. Lett., 6(15): 1819-1824 6,143,746 11/2000 Daugan et al...... 514/249 (1996). Park et al, Biochem. BiophyS. Res. Commun., OTHER PUBLICATIONS 249(3):612-617 (1998). Saxena et al, QSAR Strategies Des. Bioact. Compd., Proc. Mathers et al., European Urology, 35(suppl 2):67 (abstract Eur. Symp. Quant. Struct. Act. Relat., 5th (1985), Meeting 266) (1999). Date 1984, pp. 361-365. Zorgniotti et al, Int. J. Impotence Res., 6:33-36 (1994). Agarwal et al., Chemical Abstracts, vol. 112:235217, 1990.* Saxena et al., Chemical Abstracts, vol. 104:6224.5, 1984.* * cited by examiner U.S. Patent Dec. 18, 2001 Sheet 1 of 60 US 6,331,543 B1

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O F Sildenafi Sildenafi SNO-Glu -- SNO-Glu US 6,331.543 B1 1 2 NITROSATED AND NITROSYLATED produce an erection. The third Stage of Sexual response is PHOSPHODIESTERASE INHIBITORS, orgasm, while the fourth Stage is resolution. Interruption or COMPOSITIONS AND METHODS OF USE absence of any of the Stages of the Sexual response cycle can result in sexual dysfunction. One study found that 35% of RELATED APPLICATIONS males and 42% of females reported some form of sexual dysfunction. Read et al., J. Public Health Med., 19(4) This is a continuation-in-part of U.S. application Ser. No. :387-391 (1997). 09/145,142, filed Sep. 1, 1998, now U.S. Pat. No. 5,958,926, While there are obvious differences in the sexual response which is a continuation-in-part of U.S. application Ser. No. between males and females, one common aspect of the 08/740,764, filed Nov. 1, 1996, now U.S. Pat. No. 5,874, Sexual response is the erectile response. The erectile 437; and is a continuation-in-part of PCT/US97/19870, filed response in both males and females is the result of engorge Oct. 31, 1997. ment of the erectile tissues of the genitalia with blood which is caused by the relaxation of Smooth muscles in the arteries FIELD OF THE INVENTION Serving the genitalia. The present invention describes novel nitrosated and/or 15 In both pre-menopausal and menopausal females, Sexual nitrosylated phosphodiesterase inhibitors, and novel com dysfunction can include, for example, Sexual pain disorders, Sexual desire disorders, Sexual arousal dysfunction, orgas positions comprising at least one nitrosated and/or nitrosy mic dysfunction, dySpareunia, and vaginismus. Sexual dyS lated phosphodiesterase inhibitor, and, optionally, at least function can be caused, for example, by pregnancy, one compound that donates, transferS or releases nitric menopause, cancer, pelvic Surgery, chronic medical illness oxide, elevates endogenous levels of endothelium-derived or medications. relaxing factor, Stimulates endogenous Synthesis of nitric In males, Some pharmacological methods of treating oxide or is a Substrate for nitric oxide Synthase, and/or at Sexual dysfunctions are available, however, Such methods least one vasoactive agent. The present invention also pro have not proven to be highly Satisfactory or without poten vides novel compositions comprising at least one phoS tially severe side-effects. Papaverine now widely used to phodiesterase inhibitor, and at least one compound that 25 treat impotence, is generally effective in cases where the donates, transferS or releases nitric oxide, elevates endog dysfunction is psychogenic or neurogenic and where Severe enous levels of endothelium-derived relaxing factor, Stimu atherOSclerosis is not involved. Injection of papaverine, a lates endogenous Synthesis of nitric oxide or is a Substrate Smooth muscle relaxant, or phenoxybenzamine, a non for nitric oxide Synthase, and/or at least one vasoactive Specificantagonist and hypotensive, into corpus cavernoSum agent. The present invention also provides methods for has been found to cause an erection Sufficient for vaginal treating or preventing Sexual dysfunctions in males and penetration, however, these treatments are not without the females, for enhancing Sexual responses in males and Serious and often painful side effect of priapism. Also, in females, and for treating or preventing diseases induced by cases where Severe atherosclerosis is not a cause of the the increased metabolism of cyclic guanosine 3',5'- dysfunction, intracavernoSal injection of phentolamine, an monophosphate (cGMP), Such as hypertension, pulmonary 35 C.-adrenergic antagonist, is used. AS an alternative or, in hypertension, congestive heart failure, renal failure, myo Some cases, as an adjunct to C.-adrenergic blockade, pros taglandin E. (PGE) has been administered via intracaver cardial infraction, stable, unstable and variant (Prinzmetal) noSal injection. A major Side effect frequently associated angina, atherosclerosis, cardiac edema, renal insufficiency, with intracorparally delivered PGE is penile pain and nephrotic edema, hepatic edema, Stroke, asthma, bronchitis, burning. chronic obstructive pulmonary disease (COPD), cystic 40 The use of phosphodiesterase inhibitors for the treatment fibrosis, dementia, immunodeficiency, premature labor, and prevention of diseases induced by the increased metabo dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder lism of cyclic guanosine 3',5'-mono-phosphate (cGMP), outlet obstruction, incontinence, conditions of reduced Such as hypertension, pulmonary hypertension, congestive blood vessel patency, e.g., postpercutaneous transluminal heart failure, renal failure, myocardial infraction, Stable, coronary angioplasty (post-PTCA), peripheral vascular 45 unstable and variant (Prinzmetal) angina, atherosclerosis, disease, allergic rhinitis, and glucoma, and diseases charac cardiac edema, renal insufficiency, nephrotic edema, hepatic terized by disorders of gut motility, such as irritable bowel edema, Stroke, asthma, bronchitis, chronic obstructive pull syndrome (IBS). monary disease (COPD), cystic fibrosis, dementia, BACKGROUND OF THE INVENTION immunodeficiency, premature labor, dysmenorrhoea, benign 50 prostatic hyperplasis (BPH), bladder outlet obstruction, Adequate Sexual function is a complex interaction of incontinence, conditions of reduced blood vessel patency, hormonal events and psychoSocial relationships. There are e.g., postpercutaneous transluminal coronary angioplasty four Stages to Sexual response as described in the Interna (post-PTCA), peripheral vascular disease, allergic rhinitis, tional Journal of Gynecology & Obstetrics, 51(3):265-277 and glucoma, and diseases characterized by disorders of gut (1995). The first stage of sexual response is desire. The 55 motility, such as irritable bowel syndrome (IBS) have been Second Stage of Sexual response is arousal. Both physical previously described in, for example, U.S. Pat. Nos. 5,849, and emotional Stimulation may lead to breast and genital 741 and 5,869,486, WO 98/49166 and WO 97/03985, the vasodilation and clitoral engorgement (vasocongestion). In disclosures of each of which are incorporated herein by the female, dilation and engorgement of the blood vessels in reference in their entirety. the labia and tissue Surrounding the vagina produce the 60 There is a need in the art for new and improved treatments “orgasmic platform, an area at the distal third of the vagina of Sexual dysfunctions and other diseases. The present where blood becomes Sequestered. Localized perivaginal invention is directed to these, as well as other, important Swelling and vaginal lubrication make up the changes in this ends. Stage of Sexual response. Subsequently, ballooning of the proximal portion of the vagina and elevation of the uterus 65 SUMMARY OF THE INVENTION occurs. In the male, Vasodilation of the cavernoSal arteries Nitric oxide (NO) has been shown to mediate a number of and closure of the venous channels that drain the penis actions including the bactericidal and tumoricidal actions of US 6,331.543 B1 3 4 macrophages and blood vessel relaxation of endothelial thereof a therapeutically effective amount of at least one cells. NO and NO donors have also been implicated as nitrosated and/or nitrosylated phosphodiesterase inhibitor mediators of nonvascular Smooth muscle relaxation. AS and, optionally, at least one compound that donates, transfers described herein, this effect includes the dilation of the or releases nitric oxide as a charged species, i.e., nitroSonium corpus cavernoSum Smooth muscle, an event involved in the (NO") or nitroxyl (NO-), or as the neutral species, nitric Sexual response proceSS in both males and females. oxide (NO), and/or stimulates endogenous production of However, the effects of modified phosphodiesterase nitric oxide or EDRF in vivo and/or is a Substrate for nitric inhibitors, which are directly or indirectly linked with a oxide Synthase. The methods can further comprise admin nitric oxide adduct, have not been previously investigated. istering a therapeutically effective amount of at least one In arriving at the present invention it was recognized that vasoactive agent. Alternatively, the methods for treating the risk of toxicities and adverse effects that are associated and/or preventing Sexual dysfunctions and/or enhancing with high doses of phosphodiesterase inhibitors can be Sexual responses in patients, including males and females, avoided by the use of nitrosated and/or nitrosylated phos can comprise administering a therapeutically effective phodiesterase inhibitors or by the use of at least one phoS amount of at least one nitroSated and/or nitrosylated phos phodiesterase inhibitor in combination with at least one 15 phodiesterase inhibitor, at least one vasoactive agent, and, nitric oxide donor. Such toxicities and adverse effects optionally, at least one compound that donates, transferS or include hypotension, Syncope, as well as priapism. The releases nitric oxide as a charged Species, i.e., nitroSonium Smooth muscle relaxant properties of phosphodiesterase (NO") or nitroxyl (NO-), or as the neutral species, nitric inhibitors and of compounds that donate, release or transfer oxide (NO), and/or stimulates endogenous production of nitrogen monoxide or elevate levels of endogenous nitric oxide or EDRF in vivo and/or is a Substrate for nitric endothelium-derived relaxing factor (EDRF) or are sub oxide Synthase. The nitrosated and/or nitrosylated phos Strates for nitric oxide Synthase work together to permit the phodiesterase inhibitors, nitric oxide donors, and/or vasoac Same efficacy with lower doses of the phosphodiesterase tive agents can be administered Separately or as components inhibitors or work Synergistically to produce an effect that is of the same composition in one or more pharmaceutically greater than the additive effects of the phosphodiesterase 25 acceptable carriers. inhibitor and the compound that donates, releases or trans The present invention also provides methods for treating fers nitrogen monoxide or elevates levels of endogenous and/or preventing Sexual dysfunctions and/or enhancing nitric oxide or EDRF or is a Substrates for nitric oxide Sexual responses in patients, including males and females, Synthase. by administering to a patient in need thereof a therapeuti One aspect of the present invention provides novel nit cally effective amount of at least one phosphodiesterase rosated and/or nitrosylated phosphodiesterase inhibitors. inhibitor and at least one compound that donates, transfers The phosphodiesterase inhibitors can be nitroSated and/or or releases nitric oxide as a charged species, i.e., nitroSonium nitrosylated through one or more sites Such as oxygen (NO") or nitroxyl (NO-), or as the neutral species, nitric (hydroxyl condensation), Sulfur (Sulfhydryl condensation), oxide (NO), and/or stimulates endogenous production of 35 nitric oxide or EDRF in vivo and/or is a Substrate for nitric carbon and/or nitrogen. The present invention also provides oxide Synthase. The methods can further comprise admin compositions comprising a therapeutically effective amount istering a therapeutically effective amount of at least one of Such compounds in a pharmaceutically acceptable carrier. vasoactive agent. Alternatively, the methods for treating Another aspect of the present invention provides compo and/or preventing Sexual dysfunctions and/or enhancing Sitions comprising a therapeutically effective amount of at 40 Sexual responses in patients, including males and females, least one phosphodiesterase inhibitor (PDE inhibitor), that is can comprise administering a therapeutically effective optionally substituted with at least one NO and/or NO amount of at least one phosphodiesterase inhibitor, at least group (i.e., nitrosylated and/or nitrosated), and at least one one vasoactive agent, and, optionally, at least one compound compound that donates, transferS or releases nitrogen mon that donates, transferS or releases nitric oxide as a charged oxide as a charged species, i.e., nitroSonium (NO") or 45 species, i.e., nitrosonium (NO") or nitroxyl (NO-), or as the nitroxyl (NO-), or as the neutral species, nitric oxide (NO), neutral species, nitric oxide (NO), and/or Stimulates endog and/or Stimulates endogenous production of nitric oxide or enous production of nitric oxide or EDRF in vivo and/or is EDRF in vivo and/or is a substrate for nitric oxide synthase. a Substrate for nitric oxide Synthase. The phosphodiesterase The present invention also provides for Such compositions in inhibitors, the nitric oxide donors, and the vasoactive agents a pharmaceutically acceptable carrier. 50 can be administered Separately or as components of the same Yet another aspect of the present invention provides composition in one or more pharmaceutically acceptable compositions comprising a therapeutically effective amount carriers. of at least one phosphodiesterase inhibitor, that is optionally The present invention also provides methods using the substituted with at least one NO and/or NO group (i.e., compounds and compositions described herein to prevent or nitrosylated and/or nitrosated), at least one vasoactive drug, 55 treat diseases induced by the increased metabolism of cyclic and, optionally, at least one compound that donates, transfers guanosine 3',5'-monophosphate (cGMP), Such as or releases nitrogen monoxide as a charged Species, i.e., hypertension, pulmonary hypertension, congestive heart nitrosonium (NO") or nitroxyl (NO-), or as the neutral failure, myocardial infraction, Stable, unstable and variant Species, nitric oxide (NO), and/or Stimulates endogenous (Prinzmetal) angina, atherosclerosis, cardiac edema, renal production of nitric oxide or EDRF in vivo and/or is a 60 insufficiency, nephrotic edema, hepatic edema, Stroke, Substrate for nitric oxide Synthase. The invention also pro asthma, bronchitis, chronic obstructive pulmonary disease vides for Such compositions in a pharmaceutically accept (COPD), dementia, immunodeficiency, premature labor, able carrier. dysmenorrhoea, benign prostatic hyperplasis (BPH), bladder Yet another aspect of the present invention provides outlet obstruction, incontinence, conditions of reduced methods for treating and/or preventing Sexual dysfunctions 65 blood vessel patency, e.g., postpercutaneous transluminal and/or enhancing Sexual responses in patients, including coronary angioplasty (post-PTCA), peripheral vascular males and females, by administering to a patient in need disease, allergic rhinitis, cystic fibrosis, and glucoma, and US 6,331.543 B1 S 6 diseases characterized by disorders of gut motility, e.g., FIG. 25 shows a synthetic scheme for the preparation of irritable bowel syndrome (IBS) by administering to a patient nitrite containing benzo c1.6 naphthyridine derivatives. in need thereof a therapeutically effective amount of at least FIG. 26 shows a synthetic scheme for the preparation of one of the compounds and/or compositions described herein. nitroSothiol containing benzoc1,6 naphthyridine deriva In these methods, the phosphodiesterase inhibitors that are tives. optionally nitrosated and/or nitrosylated, nitric oxide donors FIG. 27 shows a synthetic scheme for the preparation of and vasoactive agents can be administered Separately or as components of the same composition in one or more phar nitrate containing benzoc1,6 naphthyridine derivatives. FIG. 28 shows a synthetic scheme for the preparation of maceutically acceptable carriers. nitrite containing 2,6-dihydroxyalkylamino-4,8- These and other aspects of the present invention are dipiperidino pyrimido 5,4-d pyrimidine derivatives. described in detail herein. FIG. 29 shows a synthetic scheme for the preparation of BRIEF DESCRIPTION OF THE DRAWINGS nitroSothiol containing 2,6-dihydroxyalkylamino-4,8- dipiperidino pyrimido 5,4-d pyrimidine derivatives. FIG. 1 shows a synthetic scheme for the preparation of 15 FIG. 30 shows a synthetic scheme for the preparation of nitrite containing Substituted benzene derivatives. nitrate containing 2,6-dihydroxyalkylamino-4,8- FIG. 2 shows a synthetic scheme for the preparation of dipiperidino pyrimido 5,4-d pyrimidine derivatives. nitroSothiol containing Substituted benzene derivatives. FIG. 31 shows a synthetic scheme for the preparation of FIG. 3 shows a synthetic scheme for the preparation of nitrite containing 1-((3,4-dihydroxyphenyl)methyl)-6,7- nitrate containing Substituted benzene derivatives. isoquinoline derivatives. FIG. 4 shows a synthetic scheme for the preparation of FIG. 32 shows a synthetic scheme for the preparation of nitrite containing imidazo2,1-biquinazoline derivatives. nitroSothiol containing 1-((3,4-dihydroxyphenyl)methyl)-6, FIG. 5 shows a synthetic scheme for the preparation of 7-isoquinoline derivatives. nitroSothiol containing imidazo2,1-biquinazoline deriva FIG. 33 shows a synthetic scheme for the preparation of tives. 25 nitrate containing 1-((3,4-dihydroxyphenyl)methyl)-6,7- FIG. 6 shows a synthetic scheme for the preparation of isoquinoline derivatives. nitrate containing imidazo 2,1-biquinazoline derivatives. FIG. 34 shows a synthetic scheme for the preparation of FIG. 7 shows a synthetic scheme for the preparation of nitrite containing Substituted quinazoline derivatives. nitrite containing purine-6-one derivatives. FIG. 35 shows a synthetic scheme for the preparation of FIG. 8 shows a synthetic scheme for the preparation of nitroSothiol containing Substituted quinazoline derivatives. nitroSothiol containing purine-6-one derivatives. FIG. 36 shows a synthetic scheme for the preparation of FIG. 9 shows a synthetic scheme for the preparation of nitrate containing Substituted quinazoline derivatives. nitrate containing purine-6-one derivatives. FIG. 37 shows a synthetic scheme for the preparation of FIG. 10 shows a synthetic scheme for the preparation of 35 nitrate containing Substituted phenol derivatives. nitrite containing pyrimidin-4-one derivatives. FIG. 38 shows a synthetic scheme for the preparation of FIG. 11 shows a synthetic scheme for the preparation of nitroSothiol containing Substituted phenol derivatives. nitroSothiol containing pyrimidin-4-one derivatives. FIG. 39 shows a synthetic scheme for the preparation of FIG. 12 shows a synthetic scheme for the preparation of 40 nitrate containing Substituted phenol derivatives. nitrate containing pyrimidin-4-one derivatives. FIG. 40 shows a synthetic scheme for the preparation of FIG. 13 shows a synthetic scheme for the preparation of nitrate containing Substituted 5, 11, 11a, 4-a- nitrite containing 2-pyridone derivatives. tetrahydropiperazinot1,2-bbeta-carboline-1 4-dione FIG. 14 shows a synthetic scheme for the preparation of derivatives. nitroSothiol containing 2-pyridone derivatives. 45 FIG. 41 shows a synthetic scheme for the preparation of nitro Sothiol containing Substituted 5,11,11a, 4a FIG. 15 shows a synthetic scheme for the preparation of tetrahydropiperazino1,2-bbeta-carboline-1,4-dione deriva nitrate containing 2-pyridone derivatives. tives. FIG. 16 shows a synthetic scheme for the preparation of FIG. 42 shows a synthetic scheme for the preparation of nitrite containing purine-2,6-dione derivatives. 50 nitrate containing Substituted 5, 11, 11a, 4-a- FIG. 17 shows a synthetic scheme for the preparation of tetrahydropiperazino1,2-bbeta-carboline-1,4-dione deriva nitroSothiol containing purine-2,6-dione derivatives. tives. FIG. 18 shows a synthetic scheme for the preparation of FIG. 43 shows a synthetic scheme for the preparation of nitrate containing purine-2,6-dione derivatives. nitrite containing Substituted 2-acyl-1,2,3,4-tetrahydrobeta FIG. 19 shows a synthetic scheme for the preparation of 55 carboline derivatives. nitrite containing quinoline derivatives. FIG. 44 shows a synthetic scheme for the preparation of FIG. 20 shows a synthetic scheme for the preparation of nitroSothiol containing Substituted 2-acyl -1,2,3,4- nitroSothiol containing quinoline derivatives. tetrahydrobeta-carboline derivatives. FIG. 21 shows a synthetic scheme for the preparation of FIG. 45 shows a synthetic scheme for the preparation of nitrate containing quinoline derivatives. 60 nitrate containing Substituted 2-acyl-1,2,3,4-tetrahydrobeta FIG. 22 shows a synthetic scheme for the preparation of carboline derivatives. nitrite containing Substituted pyridine derivatives. FIG. 46 shows a synthetic scheme for the preparation of FIG. 23 shows a synthetic scheme for the preparation of nitrite containing Substituted 2-pyrazolin-5-one derivatives. nitroSothiol containing Substituted pyridine derivatives. 65 FIG. 47 shows a synthetic scheme for the preparation of FIG. 24 shows a synthetic scheme for the preparation of nitroSothiol containing Substituted 2-pyrazolin-5-one nitrate containing Substituted pyridine derivatives. derivatives. US 6,331.543 B1 7 8 FIG. 48 shows a synthetic scheme for the preparation of “Transmucosal” refers to delivery of a drug by passage of nitrate containing Substituted 2-pyrazolin-5-one derivatives. the drug through the mucosal tissue and into the blood FIG. 49 shows a synthetic scheme for the preparation of Stream. nitrite containing Substituted phthalazine derivatives. “Penetration enhancement' or “permeation enhance FIG. 50 shows a synthetic scheme for the preparation of 5 ment” refers to an increase in the permeability of the skin or nitroSothiol containing Substituted phthalazine derivatives. mucosal tissue to a Selected pharmacologically active agent Such that the rate at which the drug permeates through the FIG. 51 shows a synthetic scheme for the preparation of skin or mucosal tissue is increased. nitrate containing Substituted phthalazine derivatives. “Carriers' or "vehicles' refers to carrier materials Suitable FIG. 52 shows a synthetic scheme for the preparation of for drug administration and include any Such material nitrite containing Substituted 2-aminobenzamide deriva known in the art Such as, for example, any liquid, gel, tives. Solvent, liquid diluent, Solubilizer, or the like, which is FIG. 53 shows a synthetic scheme for the preparation of non-toxic and which does not interact with any components nitroSothiol containing Substituted 2-aminobenzamide of the composition in a deleterious manner. derivatives. 15 "Nitric oxide adduct' or “NO adduct” refers to com FIG. 54 shows a synthetic scheme for the preparation of pounds and functional groups which, under physiological nitrate containing Substituted 2-aminobenzamide deriva conditions, can donate, release and/or directly or indirectly tives. transfer any of the three redox forms of nitrogen monoxide FIG. 55 shows a synthetic scheme for the preparation of (NO", NO, NO), such that the biological activity of the nitrite containing Substituted imidazoquinazoline deriva nitrogen monoxide species is expressed at the intended site tives. of action. FIG. 56 shows a synthetic scheme for the preparation of “Nitric oxide releasing” or “nitric oxide donating” refers nitroSothiol containing Substituted imidazoquinazoline to methods of donating, releasing and/or directly or indi rectly transferring any of the three redox forms of nitrogen derivatives. 25 FIG. 57 shows a synthetic scheme for the preparation of monoxide (NO", NO-, NO), such that the biological activ nitrate containing Substituted imidazoquinazoline deriva ity of the nitrogen monoxide Species is expressed at the tives. intended Site of action. “Nitric oxide donor” or “NO donor” refers to compounds FIG. 58 shows the comparative in vivo relaxation effects that donate, release and/or directly or indirectly transfer a of dipyridamole and the compound of Example 1 in nitric oxide Species, and/or Stimulate the endogenous pro phenylephrine-induced contacted human corpus caverno duction of nitric oxide or endothelium-derived relaxing Sum tissue. factor (EDRF) in vivo and/or elevate endogenous levels of FIG. 59 shows the percent peak erectile response in vivo, nitric oxide or EDRF in vivo. “NO donor” also includes expressed as intercavernosal pressure (ICP) as a percent of compounds that are Substrates for nitric oxide Synthase. the mean arterial blood pressure (%MABP) in the anesthe 35 “Alkyl” refers to a lower alkyl group, a haloalkyl group, tized rabbit following the administration of (i) sildenafil an alkenyl group, an alkynyl group, a bridged cycloalkyl alone (ii) the combination of silde nafil and S-nitrosoglutathione (SNO-Glu) (iii) S-nitrosoglutathione group, a cycloalkyl group or a heterocyclic ring, as defined (SNO-Glu) alone. The ordinate is the percent response of herein. 40 “Lower alkyl” refers to branched or straight chain acyclic intracavernosal pressure and the abscissa indicates the com alkyl group comprising one to about ten carbon atoms pounds administered. (preferably one to about eight carbon atoms, more preferably FIG. 60 shows the duration of the erectile response in vivo one to about six carbon atoms). Exemplary lower alkyl in the anesthetized rabbit following the administration of (i) groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sildenafil alone (ii) the combination of sildenafil and 45 isobutyl, Sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, S-nitrosoglutathione (SNO-Glu) (iii) S-nitrosoglutathione hexyl, octyl, and the like. (SNO-Glu) alone. The ordinate is the duration in minutes “Haloalkyl” refers to a lower alkyl group, an alkenyl and the abscissa indicates the compounds administered. group, an alkynyl group, a bridged cycloalkyl group, a DETAILED DESCRIPTION OF THE cycloalkyl group or a heterocyclic ring, as defined herein, to INVENTION 50 which is appended one or more halogens, as defined herein. Exemplary haloalkyl groups include trifluoromethyl, The following definitions may be used throughout the chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl, and Specification. the like. “Phosphodiesterase inhibitor” or “PDE inhibitor” refers “Alkenyl refers to a branched or Straight chain C-Co to any compound that inhibits the enzyme phosphodi 55 hydrocarbon (preferably a C-C hydrocarbon, more pref esterase. The term refers to Selective or non-Selective inhibi erably a C-C hydrocarbon) which can comprise one or tors of cyclic guanosine 3',5'-monophosphate phosphodi more carbon-carbon double bonds. Exemplary alkenyl esterases (cGMP-PDE) and cyclic adenosine 3',5'- groups include propylenyl, buten-1-yl, isobutenyl, penten monophosphate phosphodiesterases (cAMP-PDE). 1-yl, 2.2-methylbuten-1-yl, 3-methylbuten-1-yl, hexan-1-yl, “Patient” refers to animals, preferably mammals, more 60 hepten-1-yl, octen-1-yl, and the like. preferably humans. “Alkynyl refers to an unsaturated acyclic C-C hydro “Transurethral” or “intraurethral” refers to delivery of a carbon (preferably a C-C hydrocarbon, more preferably a drug into the urethra, Such that the drug contacts and passes C-C hydrocarbon) which can comprise one or more through the wall of the urethra and enters into the blood carbon-carbon triple bonds. Exemplary alkynyl groups Stream. 65 include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1- “Transdermal” refers to the delivery of a drug by passage yl, pentyl-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyl-2-yl, through the skin and into the blood Stream. hexyl-3-yl, 3,3-dimethyl-butyn-1-yl, and the like. US 6,331.543 B1 10 “Bridged cycloalkyl” refers to two or more cycloalkyl “Cycloalkylalkyl” refers to a cycloalkyl radical, as groups, heterocyclic groups, or a combination thereof fused defined herein, attached to an alkyl radical, as defined via adjacent or non-adjacent atoms. Bridged cycloalkyl herein. groups can be unsubstituted or Substituted with one, two or “Heterocyclicalkyl” refers to a heterocyclic ring radical, three Substituents independently Selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, as defined herein, attached to an alkyl radical, as defined alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic herein. ester, carboxamido, alkylcarboxamido, OXO and nitro. Exem "Arylheterocyclic ring” refers to a bi- or tricyclic ring plary bridged cycloalkyl groups include adamantyl, comprised of an aryl ring, as defined herein, appended via decahydronapthyl, quinuclidyl, 2,6-dioxabicyclo3.3.0 two adjacent carbon atoms of the aryl ring to a heterocyclic octane, 7-Oxabycyclo2.2.1]heptyl and the like. 1O ring, as defined herein. Exemplary arylheterocyclic rings “Cycloalkyl” refers to an alicyclic group comprising from include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the about 3 to about 7 carbon atoms. Cycloalkyl groups can be like. unsubstituted or Substituted with one, two or three Substitu "Alkoxy' refers to RsoO-, wherein Rso is an alkyl ents independently Selected from alkyl, alkoxy, amino, group, as defined herein. Exemplary alkoxy groups include alkylamino, dialkylamino, arylamino, diarylamino. 15 methoxy, ethoxy, t-butoxy, cyclopentyloxy, and the like. alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, "Arylalkoxy or alkoxyaryl” refers to an alkoxy group, as alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, defined herein, to which is appended an aryl group, as alkylcarboxamido, OXO and nitro. Exemplary cycloalkyl defined herein. Exemplary arylalkoxy groups include groups include cyclopropyl, cyclobutyl, cyclopentyl, benzyloxy, phenylethoxy, chlorophenylethoxy, and the like. cyclohexyl, and the like. "Alkoxyalkyl refers to an alkoxy group, as defined “Heterocyclic ring or group' refers to a Saturated or herein, appended to an alkyl group, as defined herein. unsaturated cyclic hydrocarbon group having about 2 to Exemplary alkoxyalkyl groups include methoxymethyl, about 10 carbon atoms (preferably about 4 to about 6 carbon methoxyethyl, isopropoxymethyl, and the like. atoms) where 1 to about 3 carbon atoms are replaced by one or more nitrogen, oxygen and/or Sulfur atoms. The hetero 25 "Alkoxyhaloalkyl refers to an alkoxy group, as defined cyclic ring or group can be fused to an aromatic hydrocarbon herein, appended to a haloalkyl group, as defined herein. group. Heterocyclic groups can be unsubstituted or Substi Exemplary alkoxyhaloalkyl groups include 4 methoxy-2- tuted with one, two or three Substituents independently chlorobutyl and the like. Selected from alkyl, alkoxy, amino, alkylamino, “Cycloalkoxy' refers to RO-, wherein Rs is a dialkylamino, arylamino, diarylamino. alkylarylamino, cycloalkyl group or a bridged cycloalkyl group, as defined hydroxy, OXO, halo, carboxyl, alkylcarboxylic acid, alkyl he rein. Exemplary cycloalkoxy groups include carboxylic ester, aryl, amidyl, ester, carboxamido, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the alkylcarboxamido, arylcarboxamido, and nitro. Exemplary like. heterocyclic groups include pyrrolyl, pyridinyl, pyrazolyl, "Haloalkoxy' refers to a haloalkyl group, as defined triazolyl, pyrimidinyl, pyridaZinyl, oxazolyl, thiazolyl, 35 herein, to which is appended an alkoxy group, as defined imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, he rein. Exemplary haloalkyl groups include 1,1,1- tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, trichloroethoxy, 2-bromobutoxy, and the like. oxazolindinyl 1,3-dioxolanyl, 2-imida Zonlinyl, “Hydroxy” refers to -OH. imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4- 40 “OXO refers to =O. thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4- “Hydroxyalkyl” refers to a hydroxy group, as defined dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, herein, appended to an alkyl group, as defined herein. pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, “Amino” refers to -NH. benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the 45 “Nitrate” refers to -O-NO. like. “Nitrite refers to -O-NO. “Heterocyclic compounds' refer to mono- and polycyclic “Thionitrate” refers to -S-NO. compounds comprising at least one aryl or heterocyclic ring. “Thionitrite and “nitroSothiol refer to -S-NO. "Aryl refers to a monocyclic, bicyclic, carbocyclic or “Nitro” refers to the group -NO and “nitrosated” refers heterocyclic ring System comprising one or two aromatic 50 rings. Exemplary aryl groups include phenyl, pyridyl, to compounds that have been substituted therewith. napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, “Nitroso’ refers to the group -NO and “nitrosylated” indenyl, indoyl, and the like. Aryl groups (including bicylic refers to compounds that have been substituted therewith. aryl groups) can be unsubstituted or Substituted with one, “Nitrile” and “cyano” refer to -CN. two or three Substituents independently Selected from alkyl, 55 “Halogen” or “halo" refers to iodine (I), bromine (Br), alkoxy, amino, alkylamino, dialkylamino, arylamino, diary chlorine (Cl), and/or fluorine (F). lamino. alkylarylamino, hydroxy, alkylcarboxylic acid, “Alkylamino” refers to RsNH-, wherein Rio is an alkyl alkylcarboxylic ester, aryl, amidyl, ester, carboxamido, alky group, as defined herein. Exemplary alkylamino groups lcarboxamido and nitro. Exemplary Substituted aryl groups include methylamino, ethylamino, butylamino, include tetrafluorophenyl, pentafluorophenyl, and the like. 60 cyclohexylamino, and the like. “Alkylaryl” refers to an alkyl group, as defined herein, to “Arylamino” refers to RsNH-, wherein Rss is an aryl which is appended an aryl group, as defined herein. Exem group, as defined herein. plary alkylaryl groups include benzyl, phenylethyl, “Dialkylamino” refers to RsRN-, wherein Rs and hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the Rs are each independently an alkyl group, as defined like. 65 he rein. Exemplary dialkylamino groups include “Arylalkyl” refers to an aryl radical, as defined herein, dimethylamino, diethylamino, methyl propargylamino, and attached to an alkyl radical, as defined herein. the like. US 6,331.543 B1 11 12 “Diarylamino” refers to Rss RoN-, wherein Rss and Rio alkyl group, an aryl group, an alkylaryl group or an aryl are each independently an aryl group, as defined herein. heterocyclic ring, as defined herein, and Rs and Rs, when “Alkylarylamino” refers to Rs2RsN-, wherein Rs is an taken together are a heterocyclic ring, a cycloalkyl group or alkyl group, as defined herein and Rss is an aryl group, as a bridged cycloalkyl group, as defined herein. defined herein. “Carboxyl” refers to -COH. “Aminoalkyl refers to an amino group, an alkylamino “Carbonyl” refers to -C(O)-. group, a dialkylamino group, an arylamino group, a diary “Methanthial” refers to -C(S)-. lamino group, an alkylarylamino group or a heterocyclic “Carboxylic ester” refers to -C(O)ORss, wherein Rss is ring, as defined herein, to which is appended an alkyl group, an alkyl group, an aryl group, an alkylaryl group or an aryl as defined herein. heterocyclic ring, as defined herein. “Aminoaryl refers to an amino group, an alkylamino “Alkylcarboxylic acid” and “alkylcarboxyl refer to an group, a dialkylamino group, an arylamino group, a diary alkyl group, as defined herein, appended to a carboxyl group, as defined herein. lamino group, an alkylarylamino group or a heterocyclic 15 ring, as defined herein, to which is appended an aryl group, “Alkylcarboxylic ester” refers to an alkyl group, as as defined herein. defined herein, appended to a carboxylic ester group, as defined herein. “Sulfinyl" refers to -S(O)-. "Arylcarboxylic acid” refers to an aryl group, as defined “Sulfonyl” refers to -S(O)-. herein, appended to a carboxyl group, as defined herein. “Sulfonic acid” refers to -S(O).OH "Arylcarboxylic ester” refers to an aryl group, as defined “Alkylsulfonic acid' refers to a Sulfonic acid group, as herein, appended to a carboxylic ester group, as defined defined herein, appended to an alkyl group, as defined herein. herein. “Carboxamido” refers to -C(O)N(Rs)(Rs.), wherein "Arylsulfonic acid” refers to an Sulfonic acid group, as 25 Rs and Rs 7 are each independently a hydrogen atom, an defined herein, appended to an aryl group, as defined herein alkyl group, an aryl group, an alkylaryl group or an aryl “Sulfonic ester” refers to-S(O)ORss, wherein Rss is an heterocyclic ring, as defined herein, and Rs and Rs7 when alkyl group, an aryl group, an alkylaryl group or an aryl taken together are a heterocyclic ring, a cycloalkyl group or heterocyclic ring, as defined herein. a bridged cycloalkyl group, as defined herein. “Sulfonamido” refers to -S(O)-N(Rs.)(Rs), wherein “Alkylcarboxamido” refers to an alkyl group, as defined Rs and Rs7 are each independently a hydrogen atom, an herein, appended to a carboxamido group, as defined herein. alkyl group, an aryl group, an alkylaryl group, or an aryl "Arylcarboxamido” refers to an aryl group, as defined heterocyclic ring, as defined herein, and Rs and Rs, when 35 herein, appended to a carboxamido group, as defined herein. taken together are a heterocyclic ring, a cycloalkyl group or “Urea” refers to -N(Rs.)-C(O)N(Rs)(Rs.) wherein a bridged cycloalkyl group, as defined herein. Rs, R57, and Rss are each independently a hydrogen atom, “Alkylsulfonamido” refers to a Sulfonamido group, as an alkyl group, an aryl group, an alkylaryl group, or an defined herein, appended to an alkyl group, as defined arylheterocyclic ring, as defined herein, and Rs and Rs.7 herein. 40 when taken together are a heterocyclic ring, a cycloalkyl "Arylsulfonamido” refers to a Sulfonamido group, as group or a bridged cycloalkyl group, as defined herein. defined herein, appended to an aryl group, as defined herein. “Phosphoryl” refers to -P(R)(R)(R), wherein Rio “Alkylthio” refers to RS-, wherein Rio is an alkyl is a lone pair of electrons, Sulfur or oxygen, and R7 and R7 group, as defined herein. 45 are each independently a covalent bond, a hydrogen, a lower "Arylthio’ refers to RssS-, wherein Rss is an aryl group, alkyl, an alkoxy, an alkylamino, a hydroxy or an aryl, as as defined herein. defined herein. “Alkylsulfinyl” refers to Rso S(O)-, wherein Rso is an “Silyl refers to -Si(R7)(R-7), wherein R7 and R7 are alkyl group, as defined herein. each independently a covalent bond, a lower alkyl, an 50 alkoxy, an aryl or an arylalkoxy, as defined herein. “Alkylsulfonyl” refers to Rs S(O), wherein R is The term “Sexual dysfunction' generally includes any an alkyl group, as defined herein. Sexual dysfunction in a patient, including an animal, pref “Arylsulfinyl” refers to Rss-S(O), wherein Rss is an aryl group, as defined herein. erably a mammal, more preferably a human. The patient can 55 be male or female. Sexual dysfunctions can include, for “Arylsulfonyl” refers to Rss-S(O), wherein Rss is an example, Sexual desire disorders, Sexual arousal disorders, aryl group, as defined herein. orgasmic disorders and Sexual pain disorders. Female Sexual “Amidyl” refers to RC(O)N(R)- wherein Rs and dysfunction refers to any female Sexual dysfunction Rs7 are each independently a hydrogen atom, an alkyl group, including, for example, Sexual desire disorders, Sexual an aryl group, an alkylaryl group, or an arylheterocyclic 60 arousal dysfunctions, orgasmic dysfunctions, Sexual pain ring, as defined herein. disorders, dySpareunia, and vaginismus. The female can be “Ester” refers to RC(O)O- wherein Rs is a hydrogen pre-menopausal or menopausal. Male Sexual dysfunction atom, an alkyl group, an aryl group, an alkylaryl group, or refers to any male Sexual dysfunctions including, for an arylheterocyclic ring, as defined herein. 65 example, male erectile dysfunction and impotence. “Carbamoyl” refers to -O-C(O)N(Rs)(Rs.), wherein The present invention is directed to the treatment and/or Rs and Rs7 are each independently a hydrogen atom, an prevention of Sexual dysfunctions in patients, including US 6,331.543 B1 13 14 males and females, by administering the compounds and wherein, compositions described herein. The present invention is also R to improving and/or Nin Sexual responses in R is an alkoxy, a cycloalkoxy, a halogen, or 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.

1O Phosphodiesterase inhibitors that may be used in the present invention include, for example, filaminast, piclamilast, rolipram, Org 20241, MCI-154, roflumilast, toborinone, posicar, lixazinone, Zaprinast, Sildenafil, pyra- Ris a hydrogen, an alkoxy, or a haloalkoxy; and R is: Zolopyrimidinones (such as those disclosed in WO 15 98/49166), motapiZone, pimobendan, Zardaverine, (i) SiguaZodan, CI 930, EMD 53998, imazodan, saterinone, loprinone hydrochloride, 3-pyridinecarbonitrile derivatives, denbufyllene, albifylline, torb afylline, doxofylline, 2O R4 theophylline, pentoxofylline, nanterinone, ciloStaZol, ciloStamide, MS 857, piroXimone, milrinone, amrinone, tolafentrine, dipyridamole, papaverine, E4021, thienopyri- (ii) midine derivatives (such as those disclosed in WO 25 98/17668), triflusal, ICOS-351, tetrahydropiperazino1,2-b R-N 2 beta-carboline-1,4-dione derivatives (such as those dis closed in U.S. Pat. No. 5,859,006, WO 97/03985 and WO O 97/03675), carboline derivatives, (such as those disclosed in 30 (iii) WO 97/43287), 2-pyrazolin-5-one derivatives (such as those re disclosed in U.S. Pat. No. 5,869,516), fused pyridazine derivatives (such as those disclosed in U.S. Pat. No. 5,849, S Na ?y 741), quinazoline derivatives (such as those disclosed in 35 U.S. Pat. No. 5,614.627), anthranilic acid derivatives (such D1 as those disclosed in U.S. Pat. No. 5,714.993), imidazo- (iv) quinazoline derivatives (such as those disclosed in WO o 96/26940), and the like. Also included are those phosphodi- 40 D-O M / esterase inhibitors disclosed in WO 99/21562 and WO 99/30697. The disclosures of each of which are incorporated (v) herein by reference in their entirety. Rs X

Sources of information for the above, and other, phos- 45 S phodiesterase inhibitors include Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Ed.), McGraw- X R4 Hill, Inc. (1995), The Physician's Desk Reference (49th (vi) Ed.), Medical Economics (1995), Drug Facts and Compari- sala X - R4 sons (1993 Ed), Facts and Comparisons (1993), and The Merck Index (12th Ed.), Merck & Co., Inc. (1996), the N 2 disclosures of each of which are incorporated herein by N reference in their entirety. 55 X (vii) In one embodiment, the present invention describes nit rosated and/or nitrosylated PDE inhibitors of Formula (I): r 60 US 6,331.543 B1 15 16 -continued an ester, a carboxylic ester, an alkylcarboxylic ester, an (viii) arylcarboxylic ester, a haloalkoxy, a Sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, -T-Q , or C(R)(R)) T-Q, or R, and R taken together are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; D N k is an integer from 1 to 3, n o1 S p is an integer from 1 to 10; T is independently a covalent bond, oxygen, S(O) or N NR; YD, Z is a covalent bond, an alkyl, an aryl, an arylalkyl, an (ix) alkylaryl, a heteroalkyl, or (C(R)(R)); O Q is -NO or -NO; G is a covalent bond, - T -C(O)-, -C(O)-T or T, b is an integer from 0 to 5; 15 P is a carbonyl, a phosphoryl or a Sillyl, r 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 s! 0 to 3; S N W, X, y and Z are each independently an integer from 0 to / 10; R4 O P is a covalent bond or P; (x) B at each occurrence is independently an alkyl group, an R12 V aryl group, or C(R)(R)); N E at each occurrence is independently -T-, an alkyl 25 group, an aryl group, or -(CH2CH2O): o={ q is an integer of from 1 to 5; N L at each occurrence is independently -C(O)-, / -C(S)--T-, a heterocyclic ring, an aryl group, an R11 alkenyl group, an alkynyl group, an arylheterocyclic ring, or -(CH2CH2O): wherein, W is oxygen, S(O), or NR; D is F" at each occurrence is independently Selected from B or (i) -NO, carbonyl, (ii) -NO, n is an integer from 2 to 5; 35 with the proviso that when R is -CH-C(T-Q)(R) O (R) or -(N2O) M", or R or Rare T-Q or C(R)(R)) T-Q, then the "-T-Q" subgroup desig nated in D can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl. 40 In cases where multiple designations of variables which reside in Sequence are chosen as a “covalent bond' or the (vii) -P-F"-L-E-IC(R)(R)).-E.) integer chosen is 0, the intent is to denote a single covalent (R)-L-C(R)(R)-L-E-L-CR (R)-T bond connecting one radical to another. For example, Eo or wherein, C(R)(R)) would denote a covalent bond, while E. R is a hydrogen, a lower alkyl, a cycloalkyl, an aryl or 45 denotes (E-E) and IC(R)(R)-C(R)(R)), denotes an arylalkyl, -C(R)(R)-C(R)(R)-. Y is oxygen, S(O), lower alkyl or NR; R is: o is an integer from 0 to 2, 5 (i) hydrogen; R is a hydrogen, an alkyl, an aryl, an alkylcarboxylic (ii) -CH(Rd)-O-C(O)-Y-Z-(C(R)(R)) T acid, an aryl carboxylic acid, an alkylcarboxylic ester, an 50 O arylcarboxylic e Ster, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an (iii) -C(O)-T-(C(R)(R))-T-Q; alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a (iv) -C(O)-Z-(G-(C(R)(R)) T-Q), or Sulfonamido, a carboxamido, a carboxylic ester, -CH2 (v) -W-L-E-C(R)(R)).-E.-C(R) (R)- C(T-Q)(R)(R), or -(NO-)-M", wherein M" in an L-C(R)(R))-L-E-L-C(R)(R)-T-Q organic or inorganic cation; 55 wherein rS,c,d.g.,i,j.o.p.W.X.y.z, R. R. R. E. L., G, T, Q, W, R, and Rare each independently a hydrogen, an alkyl, a Y, and Z areas defined herein; cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an Rs is a lone pair of electrons or -CH(R)-O-C(O)- alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a Y-Z-(C(R)(R)) T-Q; cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a R and R2 are independently Selected from hydrogen or haloalkoxy, an amino, an alkylamino, a dialkylamino, an 60 R; wherein R. R. R., R p, T, Q, Y, and Z are as defined arylamino, a diarylamino, an alkylarylamino, an herein; alkoxyhaloalkyl, a haloalkoxy, a Sulfonic acid, an alkylsul X is a halogen, and D is D or hydrogen, wherein D is as fonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, defined herein; and with the proviso that if the structure does an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, not contain D, then at least one of the variables R., Rs, R an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl 65 or R1 must contain the element “- T -Q'; carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a Another embodiment of the present invention provides carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, compounds of Formula (II): US 6,331.543 B1 18 -continued II O (ii)

n A\S $s O O a. wherein, R is R or a lower alkyl, R is as defined herein; with the proviso that R cannot be Rss is a lower alkyl or C(R)(R)-T-Q; and hydrogen; 1. p, R. R. R.R.T and Q are as defined herein; with the Rs is a hydrogen, a lower alkyl group or a haloalkyl proviso that at least one of the variables R1,R2, Razor Rs grOup, must contain the element “T-Q'. Ro is a hydrogen or a halogen; and Another embodiment of the present invention provides compounds of Formula (IV): Ro is: 2O (i) hydrogen, IV R4 (ii) s N ro1'sN 25 O

O wherein, (iii) G is -CH2- or Sulfur, R8 R and Rs are each as defined herein; and 35 N R is: ^-> (i) O

40 wherein Rs is as defined herein. Another embodiment of the present invention provides compounds of Formula (III): 45 III in (ii)

N1 /1Y. 50 N

O Y.22

wherein, 55 E is nitrogen or -CH-, G is nitrogen or -C(R)-; R is: (iii) (i) 60 ON1)-ct,

SX 65 s s US 6,331.543 B1 19 20 -continued -continued (iv) (iii) R6 V N

O co-( )-(N (v) (iv)

NN 21N-N

(vi) 15

21 C^ OCH wherein R is as defined herein; with the proviso that at least 2 one of the variables R., or R must contain the element (vii) “T O”. 25 Another embodiment of the present invention provides R6 CH compounds of Formula (VI): N N1 VI R ls O R R CN N N1 15 wherein, SillN O Re and Rare independently Selected from R, wherein 35 R 16 Riis as defined herein; with the proviso that at least one of the variables R,R or R, must contain the element “T-Q”. wherein, Another embodiment of the present invention provides Rs is a hydrogen, a lower alkyl, R., or -(CH2)4-C compounds of Formula (V): (CH)-O-D; wherein R is as defined herein; 40 R is a lower alkyl, and R7 is a hydrogen, a lower alkyl, CH-C(O)-CH2-; CH-O-CH, or D with the proviso that either Risor R, must contain D, wherein D and D are as defined herein. Another embodiment of the present invention provides 45 compounds of Formula (VII):

VII R8 i wherein, 50 N O R is as defined herein; and R is: 21 R18 (i) 55 wherein, R and Rs are as defined herein; and Rs is: 60 (ii) (i) CH

e N S. HC US 6,331.543 B1 21 22 -continued -continued (ii) (v) R8

O Ni CH

O NC N O (ii) R 1O (vi) in O N CH

crx 15 S and wherein Rs is as defined herein; with the proviso that R. cannot be hydrogen.

Another embodiment of the present invention provides and wherein R, R, and R2 are as defined herein; with the compounds of Formula (VIII): proviso that at least one of the variables R, R or R2 must contain the element “T-Q'. VIII 25 R19 / \ Another embodiment of the present invention provides compounds of Formula (IX):

wherein, Ro is: (i) 35

(ii) 45 wherein,

R20 is: 50 (i) (ii) (iii) O HC

/ R12 (v) go or (iii) -D; CH R11 M N wherein R is as defined herein; with the proviso that when Rao is not D, then R cannot be hydrogen. 65 Another embodiment of the present invention provides compounds of Formula (X): US 6,331.543 B1 23 24 -continued X (ii)

(iii) D1 1O O L-E D D1

15 R is hydrogen or K-G-D; wherein, K is: wherein, a is an integer from 2 to 3 and D and D are as defined (i) herein. 2O Another embodiment of the present invention provides compounds of Formula (XI): a V

XI O o1 D2 25 (ii) OYD, 3O -- cur O D1 NN Gs is (CH), (CH), oxygen, Sulfur or nitrogen; V is carbon or nitrogen; P.S., 2 35 A, A and A comprise the other Subunits of a 5- or 6-membered monocyclic aromatic ring and each is indepen dently (i) C-R wherein R at each occurrence is inde wherein, pendently D, a hydrogen, a halogen, an alkoxy, a nitrile, an D is hydrogen, a lower alkyl or D, wherein D is as alkyl, an arylalkyl, an alkylaryl, a carboxamido, a carboxyl, defined herein; with the proviso that at least one D must be 40 a haloalkyl, an alkoxyalkyl, an alkoxyaryl or a nitro, (ii) D. Sulfur, (iii) oxygen; and (iv) B=B, wherein B and B, are Another embodiment of the present invention provides each independently nitrogen or C-R wherein at each occurrence R is as defined herein; and wherein R, R-7, compounds of Formula (XII): R2s, Rao, and Rao are independently a hydrogen, a halogen, a hydroxy, a haloalkyl, an alkoxy, an alkoxyalkyl, an XII 45 R8 (CH2)p alkoxyaryl, an alkoxyhaloalkyl, a nitrile, a nitro, an alkyl, an N n alkylaryl, an arylalkyl, a hydroxy alkyl, a carboxamido, or a carboxyl, and A1 n wherein d, g, p, E, L, G, T, Y and D are as defined herein; / N with the proviso that at least one of the variables A, A, A, A. 2 50 J or R must contain the element “- T -Q' or “D’. As N R24 Another embodiment of the present invention provides compounds of Formula (XIII): wherein, XIII Rsis as defined herein; 55 J is:

(i) R26 O-R 60 R27 wherein, R is an alkyl, a halogen, a haloalkyl, or a haloalkoxy; R30 R28 R is Dor-C(O)-Rs, and D, D and Rs are as defined 65 herein. R29 Another embodiment of the present invention provides compounds of Formula (XIV): US 6,331.543 B1 25 26

XIV XV

1O wherein, wherein, A is CH, a carbonyl or a methanethial; R2s at each occurrence is a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an G is oxygen or Sulfur, 15 R is hydrogen, lower alkyl, alkenyl, alkynyl or alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an L-E-IC(R)(R)).E-IC(R)(R)-L-IC(R) arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, (R)-L-E-L-C(R)(R)-T-Q; an amino an alkoxy, an aryl, an arylalkyl, a carboxamido, a Rs and R are independently a hydrogen, a lower alkyl, alkyl carboxamido, an aryl carboxamido, a carboxyl, a an arylalkyl, an alkylary 1, a cycloalkylalkyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxy heterocyclicalkyl, T-Q or C(R)(R)) T-Q; lic ester, a carboxamido, an alkylcarboxamido, an Ras and Rs taken together are a carbonyl group, a arylcarboxamido, a haloalkoxy, a Sulfonamido, a urea, a methanethial group, a heterocyclic group or a cycloalkyl nitro, or L-E-ICOR)(R)).-E.-C(R)(R)-L- grOup, 25 IC(R)(R)-L-E-LC(R)(R)-T-Q; and Rs and Rss taken together are C(R)(R)), or -C(R) wherein c, d, g, i, j, k, r, S, W, X, y, Z, G, D, E, L, T, Q, R, (R)-C(R)=C(R)-C(R)(R)), wherein u is an integer Re, Rs7 and Rs are as defined herein; with the proviso that of 3 or 4, V is an integer of 1 or 2 and R. and R, at each D must be D if R or Rs do not-contain the element occurrence is independently a hydrogen, an alkyl, T-Q or “T O”. IC(R)(R)) T-Q; Another embodiment of the present invention provides Rs is a hydrogen, a halogen or a lower alkyl, and compounds of the Formula (XVI): R-7 is: XVI (i) 35 R26 R27

40 R30 R28 R29 (ii) wherein, 45 Rao is a hydrogen, a lower alkyl, a haloalkyl, a halogen, an alkoxy, an alkenyl, an alkynyl, a carbamoyl, a Sulfona G3 mido or L-E.-C(R)(R))-E-COR)(R)l-L- yw C(R)(R)-L-E-L-C(R)(R)-T-Q; and T O wherein c, d, g, i, j, k, r, , W, X, y, z, E, L, T, Q, R, and R. (iii) 50 are as defined herein; R is a lower alkyl, a hydroxyalkyl, an alkylcarboxylic acid, an alkylcarboxylic ester an alkylcarboxamido or e L-E-IC(R)(R))-E-IC(R)(R)-L-IC(R) T 55 (R)-L-E-L-C(R)(R)-T-Q; and S. wherein c, d, g, i, j, k, r, S, W, X, y, Z, E, L, T, Q, R, and R. R38 are as defined herein; R is: 60 wherein, (i) c, d, g, i, j, k, r, S, W, X, y, Z, D1, E, L, G, T, Q, Re, Re, R2, R27, R2s, Rao, Rao and Ras are as defined herein; with the proviso that D must be D if R, Ras R or R-7 do not - (R) contain the element “T-Q'. 65 Another embodiment of the present invention provides compounds of Formula (XV): US 6,331.543 B1 27 28 -continued wherein, (ii) R is: N (i) - (R) 5 21

(iii) 1O (CH2) Yo N --(R) (ii) 21 15 wherein, O 2O R at each occurrence is independently an amino, a (iii) cyano, a halogen, a nitro group, a carboxyl, a carbamoyl, a Sulfonic acid, a Sulfonic ester, a Sulfonamido, a heterocyclic ring, a carboxamido, a carboxylic ester, an ester, an amidyl, 1á.N 2 27 a phosphoryl or L-E.-C(R)(R)).-E.-C(R) 25 N (R)-L-C(R)(R)-L-E-L-C(R)(R)) —T-Q; and c, d, g, i, j, k, r, S, W, X, y, z, E, L T, Q, R., and R are Wherein d, g, p, D, E, L, Gs, GA, T, Rs, R26, R27, R2s, Ro, as defined herein; with the proviso that at least one of Rio, and Rao are as defined herein. R, or R must contain the element “T-Q'. 3O Another embodiment of the present invention provides compounds of the Formula (XIX): Another embodiment of the present invention provides compounds of the Formula (XVII): XIX 35 R8 R XVII R8 (CH2) H CO T-(C(R)(R))(UK)(K)) NV 46 N1 N N NN 21 R47 G={ 22 21 NN 40 MN N R - R8 N 2 N wherein, R24 Rae and R7 are independently Selected from lower alkyl, 45 hydroxyalkyl or D, or R and R, taken together are a heterocyclic ring, wherein G, T, Rs, and k are defined herein; with the proviso that at least one of the variables R. wherein Rs, R, R2, p and Jare as defined herein; with the or R, must be D or when the variables taken together are proviso that at least one R or J must contain the element a heterocyclic ring, the ring must contain NR, wherein R must contain the element “T-Q'. Compounds of the present invention that have one or more asymmetric carbon atoms may exist as the optically Another embodiment of the present invention provides pure enantiomers, pure diastereomers, mixtures of compounds of the Formula (XVIII): enantiomers, mixtures of diastereomers, racemic mixtures of 55 enantiomers, diastereomeric racemates or mixtures of dias tereomeric racemates. The present invention includes within XVIII its Scope all Such isomers and mixtures thereof. R26 G4 Another aspect of the present invention provides pro R2. 1 (CH2)p2p ceSSes for making the novel compounds of the invention and to the intermediates useful in Such processes. The com R44 60 pounds of the present invention may be Synthesized follow R8 ing the reaction schemes shown in FIGS. 1-57,in which R, R38 -R R2, R3, R1, Rs, R6, R7, Rs. Ro, Rio, R11, R12, R13, R1, R1s. R29 Ld R16, R17, R1s. Rio, R2o. R21, R22, R23, R24, R2s, R26, R27, SE-D R31, R32, R34, R3s, R36, R37, R3s, Rao, Rao, 65 R44, R4s, R46, R47, R, R al, P, A, A1, A2, A3, s D, D2, , G, G, G, G, J, K, T and X are as defined herein or as epicted in the reaction Schemes for formulas US 6,331.543 B1 29 30 I-XIX; P' is an oxygen protecting group and P is a sulfur disulfide groups while aqueous base is typically used to protecting group. The reactions are performed in Solvents hydrolyze thioesters and N-methoxymethyl thiocarbamates appropriate to the reagents, and materials used are Suitable and mercuric trifluoroacetate, Silver nitrate, or Strong acids, for the transformations being effected. One skilled in the art Such as trifluoroacetic or hydrochloric acid, and heat are of organic Synthesis will understand that the functionality used to remove a paramethoxy-benzyl thioether, a tetrahy present in the molecule must be consistent with the chemical dropyranylthioether, or a 2,4,6-trimethoxybenzyl thioether transformation proposed. This will, on occasion, necessitate group) followed by reaction a Suitable nitrosylating agent, judgment by the routine as to the order of Synthetic Steps, Such as thionyl chloride nitrite, thionyl dinitrite, a lower protecting groups required, and deprotection conditions. alkyl nitrite, Such as tert-butyl nitrite, or nitroSonium Substituents on the Starting materials may be incompatible tetrafluoroborate, in a Suitable anhydrous Solvent, Such as with Some of the reaction conditions required in Some of the methylene chloride, THF, DMF, or acetonitrile, with or methods described, but alternative methods and Substituents without an amine base, Such as pyridine or triethylamine, compatible with the reaction conditions will be readily affords the compound of structure IB. Alternatively, treat apparent to the Skilled practitioner in the art. The use of ment of the deprotected thiol derived from compound 3 with Sulfur and oxygen protecting groups is well known in the art 15 a Stoichiometric quantity of Sodium nitrite in an acidic for protecting thiol and alcohol groups against undesirable aqueous or alcoholic Solution affords the compound of reactions during a Synthetic procedure and many Such pro Structure IB. tecting groups are known, as described, for example, by T. Nitro compounds of structure (I), wherein R, R2, R. R. H. Greene and P. G. M. Wuts, Protective Groups in Organic and p are as defined herein, and a nitrate containing imide is Synthesis, John Wiley & Sons, New York (1991), the dis representative of the R group, as defined herein, may be closure of which is incorporated by reference herein in its prepared as shown in FIG. 3. The amide group of Structure entirety. 1 is converted to the imide of Structure 4, wherein p, R and Nitroso compounds of structure (I), wherein R, R2, R, Rare as defined herein, and X is a halogen, by reaction with Re, and p are as defined herein, and a nitrite containing imide an appropriate halide containing activated acylating agent. is representative of the R group, as defined herein, may be 25 Preferred methods for the formation of imides are reacting prepared as shown in FIG. 1. The amide group of Structure the amide with the preformed acid chloride of the halide 1 is converted to the imide of Structure 2, wherein p, R and containing acid in the presence of pyridine at low tempera R are as defined herein, by reaction with an appropriate ture or condensing the amide and halide containing Sym protected alcohol containing activated acylating agent, metrical anhydride in the presence of a catalyst, Such as wherein P' is as defined herein. Preferred methods for the Sulfuric acid. Preferred halides are bromide and iodide. formation of imides are reacting the amide with the pre Reaction of the imide of structure 4 with a suitable nitrating formed acid chloride of the protected alcohol containing agent, Such as Silver nitrate, in an inert Solvent, Such as acid in the presence of pyridine at low temperature or acetonitrile, affords the compound of Structure IC. condensing the amide and protected alcohol containing Nitroso compounds of structure (II), wherein Rs, Ro, Ro, Symmetrical anhydride in the presence of a catalyst, Such as 35 R. R. and p are as defined herein, and a nitrite containing Sulfuric acid. Preferred protecting groups for the alcohol amide is representative of the R group, as defined herein, moiety are silyl ethers, Such as a trimethylsilyl ether, a may be prepared as shown in FIG. 4. The imidazo2,1-b tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl quinazoline of Structure 5 is converted to the acylimidazo ether. Deprotection of the hydroxyl moiety (fluoride ion is 2,1-blouinazoline of structure 6, wherein p, R, and R are the preferred method for removing Sillyl ether protecting 40 as defined herein, by reaction with an appropriate protected groups) followed by reaction with a Suitable nitrosylating alcohol containing activated acylating agent, wherein P' is agent, Such as thionyl chloride nitrite, thionyl dinitrite, or as defined herein. Preferred methods for the formation of nitroSonium tetrafluoroborate, in a Suitable anhydrous acylimidazo2,1-biquinazolines are reacting the imidazo2, Solvent, such as dichloro-methane, THF, DMF, or 1-biquinazoline with the preformed acid chloride or Sym acetonitrile, with or without an amine base, Such as pyridine 45 metrical anhydride of the protected alcohol containing acid or triethylamine affords the compound of structure IA. or condensing the imidazo2,1-biquinazoline and protected Nitroso compounds of structure (I), wherein R, R2, R, alcohol containing acid in the presence of a dehydrating Re, and p are as defined herein, and a nitroSothiol containing agent, such as dicyclohexylcarbodiimide (DCC) or 1-ethyl-3 imide is representative of the R group, as defined herein, (3-dimethylaminopropyl) carbodiimide hydrochloride may be prepared as shown in FIG. 2. The amide group of 50 (EDAC.HCl) with or without a catalyst such as structure 1 is converted to the imide of structure 3, wherein 4-dimethylamino - pyridine (DMAP) O p, R, and R are as defined herein, by reaction with an 1-hydroxybenzotriazole (HOBt). Preferred protecting appropriate protected thiol containing activated acylating groups for the alcohol moiety are silyl ethers, Such as a agent, wherein P' is as defined herein. Preferred methods for trimethylsilyl or tertbutyldimethylsilyl ether. Deprotection the formation of imides are reacting the amide with the 55 of the hydroxyl moiety (fluoride ion is the preferred method preformed acid chloride of the protected thiol containing for removing silyl ether protecting groups) followed by acid in the presence of pyridine at low temperature or reaction a Suitable nitrosylating agent, Such as thionyl chlo condensing the amide and protected thiol containing Sym ride nitrite, thionyl dinitrite, or nitro Sonium metrical anhydride in the presence of a catalyst, Such as tetrafluoroborate, in a Suitable anhydrous Solvent, Such as Sulfuric acid. Preferred protecting groups for the thiol moi 60 dichloromethane, THF, DMF, or acetonitrile, with or without ety are as a thioester, Such as a thioacetate or thiobenzoate, an amine base, Such as pyridine or triethylamine, affords the as a disulfide, as a thiocarbamate, Such as N-methoxymethyl compound of Structure IIA. thiocarbamate, or as a thioether, Such as a paramethoxyben Nitroso compounds of structure (II), wherein Rs, Ro, Ro, Zyl thioether, a tetrahydropyranyl thioether or a 2,4,6- R., Re, and p are as defined herein, and a nitroSothiol trimethoxybenzylthioether. Deprotection of the thiol moiety 65 containing amide is representative of the R group, as (Zinc in dilute aqueous acid, triphenylphosphine in water defined herein, may be prepared as shown in FIG. 5. The and Sodium borohydride are preferred methods for reducing imidazo2,1-biquinazoline of structure 5 is converted to the US 6,331.543 B1 31 32 acylimidazo2,1-biquinazoline of Structure 7, wherein p, R. tert-butyldimethylsilyl ether or a tert-butyldiphenylsilyl and Rare as defined herein, by reaction with an appropriate ether. Deprotection of the hydroxyl moiety (fluoride ion is protected thiol containing activated acylating agent, wherein the preferred method for removing silyl ether protecting P is as defined herein. Preferred methods for the formation groups) followed by reaction a Suitable nitrosylating agent, of acylated imidazo2,1-bduinazolines are reacting the Such as thionyl chloride nitrite, thionyl dinitrite, or nitroSo imidazo2,1-b-quinazoline with the preformed acid chlo nium tetrafluoroborate, in a Suitable anhydrous Solvent, Such ride or Symmetrical anhydride of the protected thiol con as dichloromethane, THF, DMF, or acetonitrile, with or taining acid or condensing the imidazo2,1-b-quinazoline without an amine base, Such as pyridine or triethylamine, and protected thiol containing acid in the presence of a affords the compound of structure IIIA. dehydrating agent, such as DCC or EDAC.HCl with or Nitroso compounds of structure (III), wherein E, G, R, without a catalyst, such as DMAP or HOBt. Preferred R22, R., Re, and p are as defined herein, and an nitroSothiol protecting groups for the thiol moiety are a thioester, Such as containing amide is representative of the R group, as a thioacetate or thiobenzoate, a disulfide, a thiocarbamate, defined herein, may be prepared as shown in FIG. 8. The Such as N-methoxymethyi thiocarbamate, or a thioether, purine-6-one group of Structure 9 is converted to the acy Such as a paramethoxybenzyl thioether, a tetrahydropyranyl 15 lated purine-6-one of structure 11, wherein p, R and Rare thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotec as defined herein, by reaction with an appropriate protected tion of the thiol moiety (Zinc in dilute aqueous acid, triph thiol containing activated acylating agent, wherein P is as enyiphosphine in water and Sodium borohydride are pre defined herein. Preferred methods for the formation of ferred methods for reducing disulfide groups while aqueous acylated purine-6-ones are reacting the purine-6-one with base is typically used to hydrolyze thioesters and the preformed acid chloride or symmetrical anhydride of the N-methoxymethyl thiocarb amates and mercuric protected alcohol containing acid. Preferred protecting trifluoroacetate, Silver nitrate, or Strong acids, Such as trif groups for the thiol moiety are a thioester, Such as a luoroacetic or hydrochloric acid, and heat are used to thioacetate, or thiobenzoate, a disulfide, a thiocarbamate, remove a paramethoxybenzyl thioether, a tetrahydropyranyl Such as N-methoxymethyl thiocarbamate, or a thioether, thioether, or a 2,4,6-trimethoxybenzyl thioether group) fol 25 Such as a paramethoxybenzyl thioether, a tetrahydropyranyl lowed by reaction with a Suitable nitrosylating agent, Such as thioether or a 2,4,6-trimethoxybenzyl thioether. Deprotec thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, tion of the thiol moiety (Zinc in dilute aqueous acid, triph Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate, in enylphosphine in water and Sodium borohydride are pre a Suitable anhydrous Solvent, Such as methylene chloride, ferred methods for reducing disulfide groups while aqueous THF, DMF, or acetonitrile, with or without an amine base, base is typically used to hydrolyze thioesters and Such as pyridine or triethylamine, affords the compound of N-methoxymethyl thiocarb amates and mercuric structure IIB. Alternatively, treatment of the deprotected trifluoroacetate, Silver nitrate, or Strong acids, Such as trif thiol derived from compound 7 with a stoichiometric quan luoroacetic or hydrochloric acid, and heat are used to tity of Sodium nitrite in an acidic aqueous or alcoholic remove a paramethoxy-benzyl thioether, a tetrahydropyra solution affords the compound of structure IIB. 35 nyl thioether, or a 2,4,6-trimethoxybenzyl thioether group) Nitro compounds of structure (II), wherein Rs, Ro, Ro, followed by reaction a Suitable nitrosylating agent, Such as R., Re, and p are as defined herein, and a nitrate containing thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, amide is representative of the R group, as defined herein, Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate, in may be prepared as shown in FIG. 6. The imidazo2,1-b a Suitable anhydrous Solvent, Such as methylene chloride, quinazoline of Structure 5 is converted to the acylimidazo 40 THF, DMF, or acetonitrile, with or without an amine base, 2,1-blouinazoline of structure 8, wherein p, R, and Rare Such as pyridine or triethylamine, affords the compound of as defined herein, and X is halogen, by reaction with an structure IIIB. Alternatively, treatment of the deprotected appropriate halide containing activated acylating agent. Pre thiol derived from compound 11 with a stoichiometric ferred methods for the formation of the acylimidazo-2,1- quantity of Sodium nitrite in an acidic aqueous or alcoholic bquinazolines are reacting the imidazo2,1-biquinazoline 45 solution affords the compound of structure IIIB. with the preformed acid chloride or symmetrical anhydride Nitro compounds of structure (III), wherein E, G, R, of the halide containing acid or condensing the alcohol and R2, R., Re, and p are as defined herein, and a nitrate halide containing acid in the presence of a dehydrating containing amide is representative of the R group, as agent, such as DCC or EDAC.HCl, with or without a defined herein, may be prepared as shown in FIG. 9. The catalyst, such as DMAP or HOBt. Preferred halides are 50 purine-6-one of Structure 9 is converted to the acylated bromide and iodide. Reaction of the acylimidazo2,1-b purine-6-one of structure 12, wherein p, R, and R are as quinazoline of Structure 8 with a Suitable nitrating agent, defined herein and X is halogen. Preferred methods for the Such as Silver nitrate, in an inert Solvent, Such as acetonitrile, formation of acylated purine-6-ones are reacting the purine affords the compound of structure IIC. 6-one with the preformed acid chloride or symmetrical Nitroso compounds of structure (III), wherein E, G, R, 55 anhydride of the halide containing acid. Preferred halides are R22, R., Re, and p are as defined herein, and a nitrite bromide and iodide. Reaction of the of the acylated purine containing amide is representative of the R group, as 6-one of Structure 12 with a Suitable nitrating agent, Such as defined herein, may be prepared as shown in FIG. 7. The Silver nitrate, in an inert Solvent, Such as acetonitrile, affords purine-6-one group of Structure 9 is converted to the acy the compound of structure IIIC. lated purine-6-one of structure 10, wherein p, R and Rare 60 Nitroso compounds of Structure (IV), wherein G, R. R., as defined herein, by reaction with an appropriate protected R. R. and p are as defined herein, and a nitrite containing alcohol containing activated acylating agent, wherein P' is acyl hydrazide is representative of the R group, as defined as defined herein. Preferred methods for the formation of herein, may be prepared as shown in FIG. 10. The 3 acylated purine-6-ones are reacting the purine-6-one with (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine of structure 13 the preformed acid chloride or symmetrical anhydride of the 65 is converted to the 3 (2-acyl)-pyridaZinone or 2-acyl-1,2,3, protected alcohol containing acid. Preferred protecting 4-thiadiazine of structure 14, wherein p, R, and R are as groups for the alcohol moiety are silyl ethers, Such as a defined herein, by reaction with an appropriate protected US 6,331.543 B1 33 34 alcohol containing activated acylating agent, wherein P' is thiadiazines are reacting the 3 (2-H)-pyridaZinone or 2H-1, as defined herein. Preferred methods for the formation of 3 2,3,4-thiadiazine with the preformed acid chloride or sym (2-acyl)-pyridazinone or 2-acyl-1,2,3,4-thiadiazine are metrical anhydride of the halide containing acid or reacting the 3 (2H)-pyridaZinone or 2H-1,2,3,4-thiadiazine condensing the 3 (2-H)-pyridaZinone or 2H-1,2,3,4- with the preformed acid chloride or symmetrical anhydride thiadiazine and halide containing acid in the presence of a of the protected alcohol containing acid or condensing the 3 dehydrating agent such as DCC or EDAC.HCl with a (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine and protected catalyst such as DMAP or HOBt. Preferred halides are alcohol containing acid in the presence of a dehydrating bromide and iodide. Reaction of the 3 (2-acyl)-pyridazinone agent, such as DCC or EDAC.HCl with a catalyst, such as or 2-acyl-1,2,3,4-thiadiazine of structure 16 with a suitable DMAP or HOBt. Preferred protecting groups for the alcohol nitrating agent Such as Silver nitrate in an inert Solvent Such moiety are silyl ethers, Such as a tert-butyldimethylsilyl as acetonitrile affords the compound of structure IVC. ether or a tert-butyldiphenylsilyl ether. Deprotection of the Nitroso compounds of structure (V), wherein R. R. R. hydroxyl moiety (fluoride ion is the preferred method for and p are as defined herein, and an nitrite containing imide removing silyl ether protecting groups) followed by reaction is representative of the R group, as defined herein, may be a Suitable nitrosylating agent, Such as thionyl chloride 15 prepared as outlined in FIG. 13. The amide group of nitrite, thionyl dinitrite, or nitroSonium tetrafluoroborate, in structure 17 is converted to the imide of structure 18, a suitable anhydrous solvent, such as dichloromethane, THF, wherein p, R., and Rare as defined herein, by reaction with DMF, or acetonitrile, with or without an amine base, Such as an appropriate protected alcohol containing activated acy pyridine or triethylamine, affords the compound of Structure lating agent, wherein P' is as defined herein. Preferred IVA methods for the formation of imides are reacting the amide Nitroso compounds of Structure (IV), wherein G, Rs. with the preformed acid chloride of the protected alcohol Rs, R., Re, and p are as defined herein, and a nitroSothiol containing acid in the presence of pyridine at low tempera containing acyl hydrazide is representative of the R group, ture or condensing the amide and protected alcohol contain as defined herein, may be prepared as shown in FIG. 11. The ing Symmetrical anhydride in the presence of a catalyst Such 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine of structure 25 as Sulfuric acid. Preferred protecting groups for the alcohol 13 is converted to the 3 (2-acyl)-pyridazinone or 2-acyl-1, moiety are silyl ethers such as a tert-butyldimethylsilyl ether 2,3,4-thiadiazine of structure 15, wherein p, R, and Rare as or a tert-butyldiphenylsilyl ether. Deprotection of the defined herein, by reaction with an appropriate protected hydroxyl moiety (fluoride ion is the preferred method for thiol containing activated acylating agent, wherein P is as removing silyl ether protecting groups) followed by reaction defined herein. Preferred methods for the formation of 3 a Suitable nitrosylating agent Such as thionyl chloride nitrite, (2-acyl)-pyridazinones or 2-acyl-1,2,3,4-thiadiazines are thionyl dinitrite, or nitroSonium tetrafluoroborate in a Suit reacting the 3 (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine able anhydrous solvent such as dichloromethane, THF, with the preformed acid chloride or symmetrical anhydride DMF, or acetonitrile with or without an amine base Such as of the protected thiol containing acid or condensing the 3 pyridine or triethylamine affords the compound of Structure (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine and protected 35 VA. thiol containing acid in the presence of a dehydrating agent, Nitroso compounds of structure (V), wherein R. R. R. such as DCC or EDAC.HCl with a catalyst, such as DMAP and p are as defined herein, and a nitroSothiol containing or HOBt. Preferred protecting groups for the thiol moiety are imide is representative of the R group, as defined herein, a thioester, Such as thioacetate, or thiobenzoate, a disulfide, may be prepared as outlined in FIG. 14. The amide group of or a thioether, Such as paramethoxybenzyl thioether, tetrahy 40 structure 17 is converted to the imide of structure 19, dropyranyl thioether or 2,4,6-trimethoxybenzyl thioether. wherein p, R, and Rare as defined herein, by reaction with Deprotection of the thiol moiety (Zinc in dilute aqueous acid, an appropriate protected thiol containing activated acylating triphenylphosphine in water and Sodium borohydride are agent, wherein P is as defined herein. Preferred methods for preferred methods for reducing disulfide groups while mer the formation of imides are reacting the amide with the curic trifluoroacetate, Silver nitrate, or Strong acids, Such as 45 preformed acid chloride of the protected thiol containing trifluoroacetic or hydrochloric acid, and heat are used to acid in the presence of pyridine at low temperature or remove a paramethoxybenzyl thioether, a tetrahydropyranyl condensing the amide and protected thiol containing Sym thioether, or a 2,4,6-trimethoxybenzyl thioether group) fol metrical anhydride in the presence of a catalyst Such as lowed by reaction a Suitable nitrosylating agent, Such as Sulfuric acid. Preferred protecting groups for the thiol moi thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, 50 ety are as a thioester Such as a thioacetate or thiobenzoate, Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate, in as a disulfide, as a thiocarbamate Such as N-methoxymethyl a Suitable anhydrous Solvent, Such as methylene chloride, thiocarbamate, or as a thioether Such as a paramethoxyben THF, DMF, or acetonitrile, with or without an amine base, Zyl thioether, a tetrahydropyranyl thioether or a 2,4,6- Such as pyridine or triethylamine, affords the compound of trimethoxybenzylthioether. Deprotection of the thiol moiety structure IVB. Alternatively, treatment of the deprotected 55 (Zinc in dilute aqueous acid, triphenylphosphine in water thiol derived from compound 15 with a stoichiometric and Sodium borohydride are preferred methods for reducing quantity of Sodium nitrite in an acidic aqueous or alcoholic disulfide groups while aqueous base is typically used to solution affords the compound of structure IVB. hydrolyze thioesters and N-methoxymethyl thiocarbamates Nitro compounds of structure (IV), wherein G, Rs, R, and mercuric trifluoroacetate, Silver nitrate, or Strong acids R., Re, and pare as defined herein, and an nitrate containing 60 Such as trifluoroacetic or hydrochloric acid and heat are used acyl hydrazide is representative of the R group, as defined to remove a paramethoxybenzyl thioether, a tetrahydropy herein, may be prepared as outlined in FIG. 12. The 3 ranylthioether, or a 2,4,6-trimethoxybenzyl thioether group) (2-H)-pyridazinone or 2H-1,2,3,4-thiadiazine of structure 13 followed by reaction a Suitable nitrosylating agent Such as is converted to the 3 (2-acyl)-pyridaZinone or 2-acyl-1,2,3, thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite 4-thiadiazine of structure 16, wherein p, R, and R are as 65 Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate in defined herein, and X is halogen. Preferred methods for the a Suitable anhydrous Solvent Such as methylene chloride, formation of 3 (2-acyl)-pyridazinones or 2-acyl-1,2,3,4- THF, DMF, or acetonitrile with or without an amine base US 6,331.543 B1 35 36 Such as pyridine or triethylamine affords the compound of benzyl thioether, a tetrahydropyranyl thioether or a 2,4,6- structure VB. Alternatively, treatment of the deprotected trimethoxybenzylthioether. Deprotection of the thiol moiety thiol derived from compound 19 with a stoichiometric (Zinc in dilute aqueous acid, triphenylphosphine in water quantity of Sodium nitrite in an acidic aqueous or alcoholic and Sodium borohydride are preferred methods for reducing solution affords the compound of structure VB. disulfide groups while aqueous base is typically utilized to Nitro compounds of structure (V), wherein R. R. R. hydrolyze thioesters and N-methoxymethyl thiocarbamates and p are as defined herein, and a nitrate containing imide is and mercuric trifluoroacetate, Silver nitrate, or Strong acids representative of the R group, as defined herein, may be Such as trifluoroacetic or hydrochloric acid and heat are used prepared as outlined in FIG. 15. The amide group of the to remove a paramethoxybenzyl thioether, a tetrahydropy formula 17 is converted to the imide of the formula 20, ranylthioether, or a 2,4,6-trimethoxybenzyl thioether group) wherein p, R, and R are as defined herein, and X is a followed by reaction a Suitable nitrosylating agent Such as halogen by reaction with an appropriate halide containing thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite activated acylating agent. Preferred methods for the forma Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate in tion of imides are reacting the amide with the preformed acid a Suitable anhydrous Solvent Such as methylene chloride, chloride of the halide containing acid in the presence of 15 THF, DMF, or acetonitrile with or without an amine base pyridine at low temperature or condensing the amide and Such as pyridine or triethylamine affords the compound of halide containing Symmetrical anhydride in the presence of structure VIB. Alternatively, treatment of the deprotected a catalyst Such as Sulfuric acid. Preferred halides are bro thiol derived from compound 23 with a stoichiometric mide and iodide. Reaction of the imide of the formula 20 quantity of Sodium nitrite in an acidic aqueous or alcoholic with a Suitable nitrating agent Such as Silver nitrate in an solution affords the compound of structure VIB. inert Solvent Such as acetonitrile affords the compound of Nitro compounds of structure (VI), wherein Ris, R., R., Structure VC. Re, and p are as defined herein, and an nitrate containing Nitroso compounds of structure (VI), wherein R, R, acylated 1H-purine-2,6-dione is representative of the R, R, R and p are as defined herein, and a nitrite containing group, as defined herein, may be prepared as outlined in acyl imidazolide is representative of the R7 group, as 25 FIG. 18. The 1H-purine-2,6-dione of the formula 21 is defined herein, may be prepared as outlined in FIG. 16. The converted to the acylated derivative of the formula 24, 1H-purine-2,6-dione of structure 21 is converted to the wherein p, R, and R are as defined herein, and X is a acylated derivative of the formula 22, wherein p, R, and R. halogen, by reaction with an appropriate halide containing are as defined herein, by reaction with an appropriate activated acylating agent. Preferred methods for the forma protected alcohol containing activated acylating agent, tion of acylated 1H-purine-2,6-diones are reacting the wherein P' is as defined herein. Preferred methods for the 1H-purine-2,6-dione with the preformed acid chloride or formation of acylated 1H-purine-2,6-diones are reacting the Symmetrical anhydride of the halide containing acid or 1H-purine-2,6-dione with the preformed acid chloride or condensing the 1H-purine-2,6-dione and halide containing Symmetrical anhydride of the protected alcohol containing acid in the presence of a dehydrating agent Such as DCC or acid or condensing the 1H-purine-2,6-dione and protected 35 EDAC.HCl with a catalyst such as DMAP or HOBt. Pre alcohol containing acid in the presence of a dehydrating ferred halides are bromide and iodide. Reaction of the agent such as DCC or EDAC.HCl with a catalyst such as acylated 1H-purine-2,6-dione of the formula 24 with a DMAP or HOBt. Preferred protecting groups for the alcohol Suitable nitrating agent Such as Silver nitrate in an inert moiety are silyl ethers such as a tert-butyldimethylsilyl ether Solvent Such as acetonitrile affords the compound of Struc or a tert-butyldimethyl-silyl ether. Deprotection of the 40 ture VIC. hydroxyl moiety (fluoride ion is the preferred method for Nitroso compounds of Structure (VII), wherein Rs, Ris, removing silyl ether protecting groups) followed by reaction R. R. and p are as defined herein, and a nitrite containing a Suitable nitrosylating agent Such as thionyl chloride nitrite, imide is representative of the R group, as defined herein, thionyl dinitrite, or nitroSonium tetrafluoroborate in a Suit may be prepared as outlined in FIG. 19. The amide nitrogen able anhydrous solvent such as dichloromethane, THF, 45 of structure 25 is converted to the imide of structure 26, DMF, or acetonitrile with or without an amine base Such as wherein p, R, and Rare as defined herein, by reaction with pyridine or triethylamine affords the compound of Structure an appropriate protected alcohol containing activated acy VIA lating agent, wherein P' is as defined herein. Preferred Nitroso compounds of structure (VI), wherein R, R, methods for the formation of imides are reacting the amide R., Re, and p are as defined herein, and a nitroSothiol 50 with the preformed acid chloride of the protected alcohol containing acyl imidazolide is representative of the R7 containing acid in the presence of pyridine at low tempera group, as defined herein, may be prepared as outlined in ture or condensing the amide and protected alcohol contain FIG. 17. The 1H-purine-2,6-dione of structure 21 is con ing Symmetrical anhydride in the presence of a catalyst Such verted to the acylated derivative of the formula 23, wherein as Sulfuric acid. Preferred protecting groups for the alcohol p, R, and R are as defined herein, by reaction with an 55 moiety are silyl ethers such as a tert-butyldimethylsilyl ether appropriate protected thiol containing activated acylating or a tertbutyldiphenylsilyl ether. Deprotection of the agent, wherein P is as defined herein. Preferred methods for hydroxyl moiety (fluoride ion is the preferred method for the formation of acylated 1H-purine-2,6-diones are reacting removing silyl ether protecting groups) followed by reaction the 1H-purine-2,6-dione with the preformed acid chloride or a Suitable nitrosylating agent Such as thionyl chloride nitrite, Symmetrical anhydride of the protected thiol containing acid 60 thionyl dinitrite, or nitroSonium tetrafluoroborate in a Suit or condensing the 1H-purine-2,6-dione and protected thiol able anhydrous solvent such as dichloromethane, THF, containing acid in the presence of a dehydrating agent Such DMF, or acetonitrile with or without an amine base Such as as DCC or EDAC.HCl with a catalyst such as DMAP or pyridine or triethylamine affords the compound of Structure HOBt. Preferred protecting groups for the thiol moiety are VIIA. as a thioester Such as a thioacetate or thiobenzoate, as a 65 Nitroso compounds of Structure (VII), wherein Rs, Ris, disulfide, as a thiocarbamate Such as N-methoxymethyl R., Re, and p are as defined herein, and a nitroSothiol thiocarbamate, or as a thioether Such as a paramethoxy containing imide is representative of the R group, as US 6,331.543 B1 37 38 defined herein, may be prepared as outlined in FIG. 20. The or a tert-butyldiphenylsilyl ether. Deprotection of the amide nitrogen of Structure 25 is converted to the imide of hydroxyl moiety (fluoride ion is the preferred method for structure 27, wherein p, R, and Rare as defined herein, by removing silyl ether protecting groups) followed by reaction reaction with an appropriate protected thiol containing acti a Suitable nitrosylating agent Such as thionyl chloride nitrite, vated acylating agent, wherein P is as defined herein. thionyl dinitrite, or nitroSonium tetrafluoroborate in a Suit Preferred methods for the formation of imides are reacting able anhydrous solvent such as dichloromethane, THF, the amide with the preformed acid chloride of the protected DMF, or acetonitrile, with or without an amine base, Such as thiol containing acid in the presence of pyridine at low pyridine or triethylamine, affords the compound of Structure temperature or condensing the amide and protected thiol VIIIA containing Symmetrical anhydride in the presence of a Nitroso compounds of structure (VIII), wherein R. R. catalyst Such as Sulfuric acid. Preferred protecting groups for and p are as defined herein, and a nitroSothiol containing the thiol moiety are as a thioester Such as a thioacetate or imide is representative of the Rio group, as defined herein, thiobenzoate, as a disulfide, as a thiocarbamate Such as may be prepared as outlined in FIG. 23. The amide nitrogen N-methoxymethylthiocarbamate, or as a thioether Such as a of structure 29 is converted to the imide of structure 31, paramethoxybenzyl thioether, a tetrahydropyranylthioether 15 wherein p, R, and Rare as defined herein, by reaction with or a 2,4,6-trimethoxybenzyl thioether. Deprotection of the an appropriate protected thiol containing activated acylating thiol moiety (Zinc in dilute aqueous acid, triphenylphosphine agent, wherein P is as defined herein. Preferred methods for in water and sodium borohydride are preferred methods for the formation of imides are reacting the amide with the reducing disulfide groups while aqueous base is typically preformed acid chloride of the protected thiol containing used to hydrolyze thioesters and N-methoxymethyl thiocar acid in the presence of pyridine at low temperature or bamates and mercuric trifluoroacetate, Silver nitrate, or condensing the amide and protected alcohol containing Strong acids Such as trifluoroacetic or hydrochloric acid and Symmetrical anhydride in the presence of a catalyst Such as heat are used to remove a paramethoxybenzyl thioether, a Sulfuric acid. Preferred protecting groups for the thiol moi tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl ety are as a thioester Such as a thioacetate or thiobenzoate, thioether group) followed by reaction a Suitable nitrosylating 25 as a disulfide, as a thiocarbamate Such as N-methoxymethyl agent Such as thionyl chloride nitrite, thionyl dinitrite, a thiocarbamate, or as a thioether Such as a paramethoxyben lower alkyl nitrite Such as tert-butyl nitrite, or nitroSonium Zyl thioether, a tetrahydropyranyl thioether or a 2,4,6- tetrafluoroborate in a Suitable anhydrous Solvent Such as trimethoxybenzylthioether. Deprotection of the thiol moiety methylene chloride, THF, DMF, or acetonitrile with or (Zinc in dilute aqueous acid, triphenylphosphine in water without an amine base Such as pyridine or triethylamine and Sodium borohydride are preferred methods for reducing affords the compound of structure VIIB. Alternatively, treat disulfide groups while aqueous base is typically utilized to ment of the deprotected thiol derived from compound 27 hydrolyze thioesters and N-methoxymethyl thiocarbamates with a Stoichiometric quantity of Sodium nitrite in an acidic and mercuric trifluoroacetate, Silver nitrate, or Strong acids aqueous or alcoholic Solution affords the compound of Such as trifluoroacetic or hydrochloric acid and heat are used Structure VIIB. 35 to remove a paramethoxybenzyl thioether, a tetrahydropy Nitro compounds of structure (VII), wherein Rs, Ris, R, ranylthioether, or a 2,4,6-trimethoxybenzyl thioether group) Re, and p are as defined herein, and a nitrate containing imide followed by reaction a Suitable nitrosylating agent Such as is representative of the R group, as defined herein, may be thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite prepared as outlined in FIG. 21. The amide group of the Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate in formula 25 is converted to the imide of the formula 28, 40 a Suitable anhydrous Solvent Such as methylene chloride, wherein p, R, and R are as defined herein, and X is a THF, DMF, or acetonitrile with or without an amine base halogen, by reaction with an appropriate halide containing Such as pyridine or triethylamine affords the compound of activated acylating agent. Preferred methods for the forma structure VIIB. Alternatively, treatment of the deprotected tion of imides are reacting the amide with the preformed acid thiol derived from compound 31 with a stoichiometric chloride of the halide containing acid in the presence of 45 quantity of Sodium nitrite in an acidic aqueous or alcoholic pyridine at low temperature or condensing the amide and solution affords the compound of structure VIIIB. halide containing Symmetrical anhydride in the presence of Nitro compounds of structure (VIII), wherein R. R. and a catalyst Such as Sulfuric acid. Preferred halides are bro p are as defined herein, and a nitrate containing imide is mide and iodide. Reaction of the imide of the formula 28 representative of the Rio group, as defined herein, may be with a Suitable nitrating agent Such as Silver nitrate in an 50 prepared as outlined in FIG. 24. The amide group of the inert Solvent Such as acetonitrile affords the compound of formula 29 is converted to the imide of the formula 32, Structure VIIC. wherein p, R, and R are as defined herein, and X is a Nitroso compounds of structure (VIII), wherein R. R. and halogen, by reaction with an appropriate halide containing p are as defined herein, and a nitrite containing imide is activated acylating agent. Preferred methods for the forma representative of the Rio group, as defined herein, may be 55 tion of imides are reacting the amide with the preformed acid prepared as outlined in FIG. 22. The amide nitrogen of chloride of the halide containing acid in the presence of structure 29 is converted to the imide of structure 30, pyridine at low temperature or condensing the amide and wherein p, R, and Rare as defined herein, by reaction with halide containing Symmetrical anhydride in the presence of an appropriate protected alcohol containing activated acy a catalyst Such as Sulfuric acid. Preferred halides are bro lating agent, wherein P' is as defined herein. Preferred 60 mide and iodide. Reaction of the imide of the formula 32 methods for the formation of imides are reacting the amide with a Suitable nitrating agent Such as Silver nitrate in an with the preformed acid chloride of the protected alcohol inert Solvent Such as acetonitrile affords the compound of containing acid in the presence of pyridine at low tempera Structure VIIIC. ture or condensing the amide and protected alcohol contain Nitroso compounds of structure (IX), wherein Rao, R., R. ing Symmetrical anhydride in the presence of a catalyst, Such 65 and p are as defined herein, and an nitrite containing as Sulfuric acid. Preferred protecting groups for the alcohol acylated amide or Sulfonamide is representative of the R moiety are silyl ethers such as a tert-butyldimethylsilyl ether group, as defined herein, may be prepared as outlined in US 6,331.543 B1 39 40 FIG. 25. The amide or sulfonamide nitrogen of structure 33 and Rare as defined herein, and X is a halogen, by reaction is converted to the N-acylated derivative of structure 34, with an appropriate halide containing activated acylating wherein p, R, and Rare as defined herein, by reaction with agent. Preferred methods for the formation of acylated an appropriate protected alcohol containing activated acy amides or Sulfonamides are reacting the amide or Sulfona lating agent, wherein P' is as defined herein. Preferred mide with the preformed acid chloride of the halide con methods for the formation of acylated amides or Sulfona taining acid in the presence of pyridine at low temperature mides are reacting the amide or Sulfonamide with the or condensing the amide or Sulfonamide and halide contain preformed acid chloride of the protected alcohol containing ing Symmetrical anhydride in the presence of a catalyst Such acid in the presence of pyridine at low temperature or as Sulfuric acid. Preferred halides are bromide and iodide. condensing the amide or Sulfonamide and protected alcohol Reaction of the imide or Sulfonamide of the formula 36 with containing Symmetrical anhydride in the presence of a a Suitable nitrating agent Such as Silver nitrate in an inert catalyst Such as Sulfuric acid. Preferred protecting groups for Solvent Such as acetonitrile affords the compound of Struc the alcohol moiety are silyl etherS Such as a tert ture IXC. butyldimethylsilyl ether or a tertbutyldiphenylsilyl ether. Nitroso compounds of structure (X), wherein D, R, Re, Deprotection of the hydroxyl moiety (fluoride ion is the 15 and p are as defined herein, and a nitrite containing ester is preferred method for removing silyl ether protecting groups) representative of the D group, as defined herein, may be followed by reaction a Suitable nitrosylating agent Such as prepared according to FIG. 28. The alcohol group of Struc thionyl chloride nitrite, thionyl dinitrite, or nitrosonium ture 37 is converted to the ester of structure 38, wherein p, tetrafluoroborate in a Suitable anhydrous Solvent Such as R. and R are as defined herein, by reaction with an appro dichloromethane, THF, DMF, or acetonitrile with or without priate protected alcohol containing activated acylating an amine base Such as pyridine or triethylamine affords the agent, wherein P' is as defined herein. Preferred methods for compound of Structure IXA. the formation of esters are reacting the alcohol with the Nitroso compounds of structure (IX), wherein Rao, R., R. preformed acid chloride or Symmetrical anhydride of the and p are as defined herein, and an nitroSothiol containing protected alcohol containing acid or condensing the alcohol acylated amide or Sulfonamide is representative of the R 25 and protected alcohol containing acid with a dehydrating group, as defined herein, may be prepared as outlined in agent such as DCC or EDAC.HCl in the presence of a FIG. 26. The amide or sulfonamide nitrogen of structure 33 catalyst Such as DMAP or HOBt. Preferred protecting is converted to the N-acylated derivative of structure 35, groups for the alcohol moiety are silyl etherS Such as a wherein p, R, and Rare as defined herein, by reaction with trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotec an appropriate protected thiol containing activated acylating tion of the hydroxyl moiety (fluoride ion is the preferred agent, wherein P is as defined herein. Preferred methods for method for removing silyl ether protecting groups) followed the formation of acylated amides or Sulfonamides are react by reaction a Suitable nitrosylating agent Such as thionyl ing the amide or Sulfonamide with the preformed acid chloride nitrite, thionyl dinitrite, or nitroSonium tetrafluo chloride of the protected thiol containing acid in the pres roborate in a Suitable anhydrous Solvent Such as ence of pyridine at low temperature or condensing the amide 35 dichloromethane, THF, DMF, or acetonitrile with or without or Sulfonamide and protected thiol containing Symmetrical an amine base Such as pyridine or triethylamine affords the anhydride in the presence of a catalyst Such as Sulfuric acid. compound of Structure XA. Preferred protecting groups for the thiol moiety are as a Nitroso compounds of structure (X), wherein D, R, Re, thioester Such as a thioacetate or thiobenzoate, as a disulfide, and p are as defined herein, and a nitroSothiol containing as a thiocarb amate Such as N-methoxy methyl 40 ester is representative of the D group, as defined herein, may thiocarbamate, or as a thioether Such as a paramethoxy be prepared as shown in FIG. 29. The alcohol group of benzyl thioether, a tetrahydropyranyl thioether or a 2,4,6- structure 37 is converted to the ester of structure 39, wherein trimethoxybenzylthioether. Deprotection of the thiol moiety p, R, and R are as defined herein, by reaction with an (Zinc in dilute aqueous acid, triphenylphosphine in water appropriate protected thiol containing activated acylating and Sodium borohydride are preferred methods for reducing 45 agent, wherein P' is as defined herein. Preferred methods for disulfide groups while aqueous base is typically utilized to the formation of esters are reacting the alcohol with the hydrolyze thioesters and N-methoxymethyl thiocarbamates preformed acid chloride or Symmetrical anhydride of the and mercuric trifluoroacetate, Silver nitrate, or Strong acids protected thiol containing acid or condensing the alcohol Such as trifluoroacetic or hydrochloric acid and heat are used and protected thiol containing acid with a dehydrating agent to remove a paramethoxybenzyl thioether, a tetrahydropy 50 such as DCC or EDAC.HCl in the presence of a catalyst ranylthioether, or a 2,4,6-trimethoxybenzyl thioether group) such as DMAP or HOBt. Preferred protecting groups for the followed by reaction a Suitable nitrosylating agent Such as thiol moiety are as a thioester Such as a thioacetate or thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite thiobenzoate, as a disulfide, as a thiocarbamate Such as Such as tert-butyl nitrite, or nitroSonium tetrafluoroborate in N-methoxymethylthiocarbamate, or as a thioether Such as a a Suitable anhydrous Solvent Such as methylene chloride, 55 paramethoxybenzyl thioether, a tetrahydropyranylthioether THF, DMF, or acetonitrile with or without an amine base or a S-triphenylmethyl thioether. Deprotection of the thiol Such as pyridine or triethylamine affords the compound of moiety (Zinc in dilute aqueous acid, triphenyl-phosphine in structure IXB. Alternatively, treatment of the deprotected water and sodium borohydride are preferred methods for thiol derived from compound 35 with a stoichiometric reducing disulfide groups while aqueous base is typically quantity of Sodium nitrite in an acidic aqueous or alcoholic 60 utilized to hydrolyze thioesters and N-methoxymethylthio solution affords the compound of structure IXB. carbamates and mercuric trifluoroacetate, Silver nitrate, or Nitro compounds of structure (IX), wherein Rao, R. R. Strong acids Such as trifluoroacetic or hydrochloric acid and and pare as defined herein, and a nitrate containing acylated heat are used to remove a paramethoxybenzyl thioether, a amide or Sulfonamide is representative of the R group, as tetrahydropyranylthioether or a S-triphenylmethylthioether defined herein, may be prepared as outlined in FIG. 27. The 65 group) followed by reaction a Suitable nitrosylating agent amide or sulfonamide group of the formula 33 is converted Such as thionyl chloride nitrite, thionyl dinitrite, a lower to the N-acylated derivative of the formula 36, wherein p, R. alkyl nitrite Such as tert-butyl nitrite, or nitrosium tetrafluo US 6,331.543 B1 41 42 roborate in a Suitable anhydrous Solvent Such as methylene thiol moiety (Zinc in dilute aqueous acid, triphenyl chloride, THF, DMF, or acetonitrile with or without an phosphine in water and Sodium borohydride are preferred amine base Such as pyridine or triethylamine affords the methods for reducing disulfide groups while aqueous base is compound of structure XB. Alternatively, treatment of the typically utilized to hydrolyze thioesters and deprotected thiol derived from compound 39 with a sto N-methoxymethyl thiocarb amates and mercuric ichiometric quantity of Sodium nitrite in aqueous or alco trifluoroacetate, Silver nitrate, or Strong acids, Such as trif holic acid affords the compound of structure XB. luoroacetic or hydrochloric acid, and heat are used to Nitro compounds of structure (X), wherein D, R, Re, and remove a paramethoxybenzyl thioether, a tetrahydropyranyl p are as defined herein, and a nitrate containing ester is thioether or a S-triphenylmethyl thioether group) followed representative of the D group, as defined herein, may be by reaction a Suitable nitrosylating agent, Such as thionyl prepared according to FIG. 30. The alcohol group of the chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, Such formula 37 is converted to the ester of the formula 40, as tert-butyl nitrite, or nitrosium tetrafluoroborate, in a wherein p, R, and R are as defined herein, and X is a Suitable anhydrous Solvent, Such as methylene chloride, halogen, by reaction with an appropriate halide containing THF, DMF, or acetonitrile, with or without an amine base, activated acylating agent. Preferred methods for the forma 15 Such as pyridine or triethylamine, affords the compound of tion of esters are reacting the alcohol with the preformed structure XIB. Alternatively, treatment of the deprotected acid chloride or Symmetrical anhydride of the halide con thiol derived from compound 43 with a stoichiometric taining acid or condensing the alcohol and halide containing quantity of Sodium nitrite in aqueous or alcoholic acid acid with a dehydrating agent such as DCC or EDAC.HCl affords the compound of structure XIB. in the presence of a catalyst such as DMAP or HOBt. Nitro compounds of structure (XI), wherein D, R, Re, Preferred halides are bromide and iodide. Reaction of the and p are as defined herein, and a nitrate containing ester is ester of the formula 40 with a Suitable nitrating agent Such representative of the D group, as defined herein, may be as Silver nitrate in an inert Solvent Such as acetonitrile affords prepared according to FIG. 33. The alcohol group of the the compound of structure XC. formula 41 is converted to the ester of the formula 44, Nitroso compounds of structure (XI), wherein D, R, R, 25 wherein p, R, and R are as defined herein, and X is a and p are as defined herein, and a nitrite containing ester is halogen, by reaction with an appropriate halide containing representative of the D group, as defined herein, may be activated acylating agent. Preferred methods for the forma prepared according to FIG. 31. The alcohol group of Struc tion of esters are reacting the alcohol with the preformed ture 41 is converted to the ester of Structure 42, wherein p, acid chloride or Symmetrical anhydride of the halide con R, and R are as defined herein, by reaction with an taining acid or condensing the alcohol and halide containing appropriate protected alcohol containing activated acylating acid with a dehydrating agent, such as DCC or EDAC.HCl, agent, wherein P' is as defined herein. Preferred methods for in the presence of a catalyst, such as DMAP or HOBt. the formation of esters are reacting the alcohol with the Preferred halides are bromide and iodide. Reaction of the preformed acid chloride or Symmetrical anhydride of the ester of the formula 44 with a Suitable nitrating agent, Such protected alcohol containing acid or condensing the alcohol 35 as Silver nitrate, in an inert Solvent, Such as acetonitrile, and protected alcohol containing acid with a dehydrating affords the compound of structure XIC. agent, such as DCC or EDAC.HCI, in the presence of a Nitroso compounds of structure (XII), wherein R, R A, catalyst, such as DMAP or HOBt. Preferred protecting A, A, J., V and p are as defined herein, and a nitrite groups for the alcohol moiety are silyl ethers, Such as a containing thioester is representative of the R group, as trimethylsilyl or a tert-butyldimethylsilyl ether. Deprotec 40 defined herein, may be prepared according to FIG. 34. The tion of the hydroxyl moiety (fluoride ion is the preferred carboxylic acid group of Structure 45 is converted to the method for removing silyl ether protecting groups) followed thioester of structure 46, wherein p, R, and Rare as defined by reaction a Suitable nitrosylating agent, Such as thionyl herein, by reaction with an appropriate protected alcohol chloride nitrite, thionyl dinitrite, or nitroSonium containing thiol agent, wherein p' is as defined herein. tetrafluoroborate, in a Suitable anhydrous Solvent, Such as 45 Preferred methods for the formation of thioesters are react dichloromethane, THF, DMF, or acetonitrile, with or without ing the thiol with the preformed acid chloride or symmetri an amine base, Such as pyridine or triethylamine, affords the cal anhydride of the carboxylic acid or condensing the thiol compound of Structure XIA. and carboxylic acid with a dehydrating agent, Such as DCC Nitroso compounds of structure (XI), wherein D. R. R. or EDAC.HCl, in the presence of a catalyst, such as DMAP and p are as defined herein, and a nitroSothiol containing 50 or HOBt. Preferred protecting groups for the alcohol moiety ester is representative of the D group, as defined herein, may are silyl ethers, Such as a trimethylsilyl or a tert be prepared according to FIG. 32. The alcohol group of butyldimethylsilyl ether. Deprotection of the hydroxyl moi structure 41 is converted to the ester of structure 43, wherein ety (fluoride ion is the preferred method for removing silyl p, R, and R are as defined herein, by reaction with an ether protecting groups) followed by reaction a Suitable appropriate protected thiol containing activated acylating 55 nitrosylating agent, Such as thionyl chloride nitrite, thionyl agent, wherein P' is as defined herein. Preferred methods for dinitrite, or nitroSonium tetrafluoroborate, in a Suitable anhy the formation of esters are reacting the alcohol with the drous solvent, Such as dichloromethane, THF, DMF, or preformed acid chloride or Symmetrical anhydride of the acetonitrile, with or without an amine base, Such as pyridine protected thiol containing acid or condensing the alcohol or triethylamine, affords the compound of structure XIIA. and protected thiol containing acid with a dehydrating agent, 60 Nitroso compounds of structure (XII), wherein R, R A, such as DCC or EDAC.HCl, in the presence of a catalyst, A, A, J, V and p are as defined herein, and a nitroSothiol such as DMAP or HOBt. Preferred protecting groups for the containing thioester is representative of the R group, as thiol moiety are as a thioester, Such as a thioacetate or defined herein, may be prepared according to FIG. 35. The thiobenzoate, as a disulfide, as a thiocarbamate, Such as carboxylic acid group of Structure 45 is converted to the N-methoxymethyl thiocarbamate, or as a thioether, Such as 65 thioester of structure 47, wherein p, R, and Rare as defined a paramethoxybenzyl thioether, a tetrahydropyranyl thioet herein, by reaction with an appropriate mono protected her or a S-triphenylmethyl thioether. Deprotection of the dithiol. Preferred methods for the formation of thioesters are US 6,331.543 B1 43 44 reacting the free thiol with the preformed acid chloride or wherein p, R and R are as defined herein, by reaction with Symmetrical anhydride of the carboxylic acid or condensing a monoprotected diol, wherein P' is as defined herein. the free thiol and carboxylic acid with a dehydrating agent, Preferred methods for the formation of esters are reacting such as DCC or EDAC.HCl, in the presence of a catalyst, the alcohol with the preformed acid chloride or symmetrical such as DMAP or HOBt. Preferred protecting groups for the anhydride of the carboxylic acid or condensing the alcohol thiol moiety are as a thioester, Such as a thioacetate or and carboxylic acid with a dehydrating agent, Such as DCC thiobenzoate, as a disulfide, as a thiocarbamate, Such as or EDAC.HCl, in the presence of a catalyst, such as DMAP N-methoxymethyl thiocarbamate, or as a thioether, Such as or HOBt. Preferred protecting groups for the alcohol moiety a paramethoxybenzyl thioether, a tetrahydropyranyl thioet are silyl ethers, Such as a trimethylsilyl or a tert her or a S-triphenylmethyl thioether. Deprotection of the butyldimethylsilyl ether. Deprotection of the hydroxyl moi thiol moiety (Zinc in dilute aqueous acid, triphenyl ety (fluoride ion is the preferred method for removing silyl phosphine in water and Sodium borohydride are preferred ether protecting groups) followed by reaction a Suitable methods for reducing disulfide groups while aqueous base is nitrosylating agent, Such as thionyl chloride nitrite, thionyl typically utilized to hydrolyze thioesters and dinitrite, or nitroSonium tetrafluoroborate, in a Suitable anhy N-methoxymethyl thiocarb amates and mercuric 15 drous solvent, Such as dichloromethane, THF, DMF, or trifluoroacetate, Silver nitrate, or Strong acids, Such as trif acetonitrile, with or without an amine base, Such as pyridine luoroacetic or hydrochloric acid, and heat are used to or triethylamine, affords the compound of structure XIIIA. remove a paramethoxybenzyl thioether, a tetrahydropyranyl Nitroso compounds of structure (XIII), wherein R. R. thioether or a S-triphenylmethyl thioether group). Reaction R, R2, and p are as defined herein, and a nitroSothiol of the free thiol with a Suitable nitrosylating agent, Such as containing ester is representative of the D group, as defined thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, herein, may be prepared according to FIG. 38. The carboxy Such as tert-butyl nitrite, or nitrosium tetrafluoroborate, in a lic acid group of Structure 49 is converted to the ester of Suitable anhydrous Solvent, Such as methylene chloride, structure 51, wherein p, R and R are as defined herein, by THF, DMF, or acetonitrile, with or without an amine base, reaction with an appropriate protected thiol containing alco Such as pyridine or triethylamine, affords the compound of 25 hol. Preferred methods for the formation of esters are structure XIIB. Alternatively, treatment of the deprotected reacting the alcohol with the preformed acid chloride or thiol derived from compound 47 with a stoichiometric Symmetrical anhydride of the carboxylic acid or condensing quantity of Sodium nitrite in aqueous or alcoholic acid the primary thiol and carboxylic acid with a dehydrating affords the compound of structure XIIB. agent, such as DCC or EDAC.HCl, in the presence of a Nitro compounds of structure (XII), wherein R. R. A. catalyst, such as DMAP or HOBt. Preferred protecting A, A, J, V and p are as defined herein, and a nitrate groups for the thiol moiety are as a thioester, Such as a containing thioester is representative of the R group, as thioacetate or thiobenzoate, as a disulfide, as a defined herein, may be prepared according to FIG. 36. The thiocarbamate, Such as N-methoxymethyl thiocarbamate, or carboxylic acid group of the formula 45 is converted to the as a thioether, Such as a paramethoxybenzyl thioether, a thioester of structure 46, wherein p, R, and Rare as defined 35 tetrahydropyranyl thioether or a S-triphenylmethyl thioet herein, by reaction with an appropriate protected alcohol her. Deprotection of the thiol moiety (Zinc in dilute aqueous containing thiol agent, wherein P' is as defined herein. acid, triphenyl-phosphine in water and Sodium borohydride Preferred methods for the formation of thioesters are react are preferred methods for reducing disulfide groups while ing the thiol with the preformed acid chloride or symmetri aqueous base is typically utilized to hydrolyze thioesters and cal anhydride of the carboxylic acid or condensing the thiol 40 N-methoxymethyl thiocarb amates and mercuric and carboxylic acid with a dehydrating agent, Such as DCC trifluoroacetate, Silver nitrate, or Strong acids, Such as trif or EDAC.HCl, in the presence of a catalyst, such as DMAP luoroacetic or hydrochloric acid, and heat are used to or HOBt. Preferred protecting groups for the alcohol moiety remove a paramethoxybenzyl thioether, a tetrahydropyranyl are silyl ether, Such as trimethylsilyl or a tert thioether or a S-triphenylmethyl thioether group) Reaction butyldimethylsilyl ether. Deprotection of the hydroxyl moi 45 of the free thiol with a Suitable nitrosylating agent, Such as ety (fluoride ion is the preferred method for removing silyl thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, ether protecting groups) followed by reaction of the alcohol Such as tert-butyl nitrite, or nitrosium tetrafluoroborate, in a with a Suitable nitrating agent, Such as nitric acid and acetic Suitable anhydrous Solvent, Such as methylene chloride, anhydride in ethyl acetate/acetic acid affords the compound THF, DMF, or acetonitrile, with or without an amine base, of structure XIIC. Alternatively, the carboxylic acid group of 50 Such as pyridine or triethylamine, affords the compound of structure 45 is converted to the thioester of structure 48, structure XIIIB. Alternatively, treatment of the deprotected wherein p, R and Rare as defined herein, and X is halogen, thiol derived from compound 51 with a stoichiometric by reaction with an appropriate halide containing thiol. quantity of Sodium nitrite in aqueous or alcoholic acid Preferred methods for the formation of thioesters are react affords the compound of structure XIIIB. ing the thiol with the preformed acid chloride or symmetri 55 Nitro compounds of structure (XIII), wherein R. R. Rai, cal anhydride of the carboxylic acid or condensing the thiol R and pare as defined herein, and a nitrate containing ester and carboxylic acid with a dehydrating agent, Such as DCC is representative of the D group, as defined herein, may be or EDAC.HCl, in the presence of a catalyst, such as DMAP prepared according to FIG. 39. The carboxylic acid group of or HOBt. Preferred halides are bromide and iodide. Reaction the formula 49 is converted to the ester of structure 50, of the ester of Structure 48 with a Suitable nitrating agent, 60 wherein p, R, and Rare as defined herein, by reaction with Such as Silver nitrate in an inert Solvent, Such as acetonitrile, an appropriate mono-protected diol, wherein p' is as defined affords the compound of structure XIIC. herein. Preferred methods for the formation of esters are Nitroso compounds of structure (XIII), wherein R. R. reacting the alcohol with the preformed acid chloride or R, R2, and pare as defined herein, and a nitrite containing Symmetrical anhydride of the carboxylic acid or condensing ester is representative of the D group, as defined herein, may 65 the alcohol and carboxylic acid with a dehydrating agent, be prepared according to FIG. 37. The carboxylic acid group such as DCC or EDAC.HCl, in the presence of a catalyst, of structure 49 is converted to the ester of structure 50, such as DMAP or HOBt. Preferred protecting groups for the US 6,331.543 B1 45 46 alcohol moiety are silyl ether, Such as trimethylsilyl or a oxygen is representative of G, as defined herein, and a tert-butyldimethylsilyl ether. Deprotection of the hydroxyl nitroSothiol containing Substituent is representative of the moiety (fluoride ion is the preferred method for removing R group, as defined herein, may be prepared according to silyl ether protecting groups) followed by reaction of the FIG. 41. Hydrolysis of the ester of the compound of struc alcohol with a Suitable nitrating agent, Such as nitric acid and ture 54 affords the carboxylic acid which is reacted with a acetic anhydride in ethyl acetate/acetic acid affords the Sulfanyl protected primary amino containing thiol, wherein compound of structure XIIIC. Alternatively, the carboxylic P’ is as defined herein, to afford the compound of structure acid group of Structure 49 is converted to the ester of 56. Preferred methods for the formation of amides are structure 52, wherein p, R, and Rare as defined herein, and reacting the amine with the preformed acid chloride or X is halogen, by reaction with an appropriate halide con Symmetrical anhydride of the carboxylic acid or condensing taining alcohol. Preferred methods for the formation of the amine and carboxylic acid with a dehydrating agent, esters are reacting the alcohol with the preformed acid such as DCC or EDAC.HCl, in the presence of a catalyst, chloride or Symmetrical anhydride of the halide containing such as DMAP or HOBt. Preferred protecting groups for the acid or condensing the alcohol and halide containing alcohol thiol moiety are as a thioester Such as a thioacetate or with a dehydrating agent, such as DCC or EDAC.HCl in the 15 thiobenzoate, as a disulfide, as a thiocarbamate Such as presence of a catalyst, such as DMAP or HOBt. Preferred N-methoxymethylthiocarbamate, or as a thioether Such as a halides are bromide and iodide. Reaction of the ester of paramethoxy-benzyl thioether, a tetrahydropyranylthioether Structure 52 with a Suitable nitrating agent, Such as Silver or a 2,4,6-trimethoxybenzyl thioether. A preferred method nitrate in an inert Solvent, Such as acetonitrile, affords the for facilitating the cyclization to the afford the 3,6,17-triaza compound of structure XIIIC. 1-methyltetracyclo8.7.0.0<3,8>.0<11,16>heptadeca-11 Nitroso compounds of structure (XIV), wherein R. R. (16), 12,14-triene-4,7-dione is to heat the C-halo diamide Ras, Rao, R-7, Ras, D and pare as defined herein, a carbonyl intermediate wherein X is preferably chlorine or bromine in group is representative of the Agroup, as defined herein, and an inert Solvent Such as methanol. Deprotection of the a nitrite containing Substituent is representative of the R Sulfanyl moiety (Zinc in dilute aqueous acid, triphenylphos group, as defined herein, may be prepared according to FIG. 25 phine in water and Sodium borohydride are preferred meth 40. The methyl 9a-methyl-1,2,3,4,4a,9a-hexahydrobeta ods for reducing disulfide groups while aqueous base is carboline-3-carboxylate of structure 53 is converted to the typically utilized to hydrolyze thioesters and acylated derivative of the formula 54, wherein p, Ras and N-methoxymethyl thiocarb amates and mercuric Rae are as defined herein, oxygen is representative of G, as trifluoroacetate, Silver nitrate, or Strong acids Such as trif defined herein, by reaction with an appropriate C-halo luoroacetic or hydrochloric acid and heat are used to remove containing activated acylating agent, wherein X is prefer a paramethoxybenzyl thioether, a tetrahydropyranyl ably chlorine or bromine. Preferred methods for the forma thioether, or a 2,4,6-trimethoxybenzyl thioether group) fol tion of N-acylated 1,2,3,4,4a,9a-hexahydrobeta-carboline-3- lowed by reaction with a Stoichometric quantity of a Suitable carboxylate esters are reacting the 1,2,3,4,4a,9a nitrosylating agent Such as thionyl chloride nitrite, thionyl hexahydrobeta-carboline-3-carboxylate ester with the 35 dinitrite, a lower alkyl nitrite Such as tert-butyl nitrite, or preformed acid chloride or Symmetrical anhydride of the nitroSonium tetrafluoroborate in a Suitable anhydrous Sol C-halo containing acid or condensing the 5 1,2,3,4,4a,9a vent such as methylene chloride, THF, DMF, or acetonitrile hexahydrobeta-carboline-3-carboxylate ester and C-halo with or without an amine base Such as pyridine or triethy containing acid in the presence of a dehydrating agent Such lamine affords the compound of structure XIVB. as DCC or EDAC.HCl with a catalyst such as DMAP or 40 Alternatively, treatment of the deprotected thiol derived HOBt. Hydrolysis of the ester affords the carboxylic acid from compound 55 with a Stoichiometric quantity of Sodium followed by Subsequent reaction with a hydroxy protected nitrite in an acidic aqueous or alcoholic Solution affords the primary amino containing alcohol, wherein P' is as defined compound of structure XIVB. herein, affords the compound of structure 55. Preferred Nitro compounds of structure (XIV), wherein R, Re, Ras, methods for the formation of amides are reacting the amine 45 Rs6, R-7, Ras, D and p are as defined herein, a carbonyl with the preformed acid chloride or symmetrical anhydride group is representative of the A group, as defined herein, of the carboxylic acid or condensing the amine and carboxy oxygen is representative of G, as defined herein, and a lic acid with a dehydrating agent, Such as DCC or nitrate containing Substituent is representative of the R EDAC.HCl, in the presence of a catalyst, such as DMAP or group, as defined herein, may be prepared according to FIG. HOBt. Preferred protecting groups for the alcohol moiety 50 42. Deprotection of the hydroxyl moiety of the compound of are silyl ethers, Such as a trimethylsilyl or a tert structure 54 (fluoride ion is the preferred method for remov butylidimethylsilyl ether. A preferred method for facilitating ing silyl ether protecting groups) followed by activation and the cyclization to the afford the 3,6,17-triaza-1- nucleophilic displacement of the hydroxyl by a halogen methyltetracyclo8.7.0.0<3,8>.0<11,16>]heptadeca-11(16), affords the compound of structure 57, wherein X is prefer 12,14-triene-4,7-dione is to heat the C-halo diamide inter 55 ably a bromine or an iodine. Preferred methods for convert mediate in an inert Solvent Such as methanol. Deprotection ing a hydroxyl group to a halogen moiety are to first activate of the hydroxyl moiety (fluoride ion is the preferred method it as the meSylate or tosylate by reacting it with methansul for removing silyl ether protecting groups) followed by fonyl chloride or p-toluesulfonyl chloride in an inert solvent reaction with a Stoichometric quantity of a Suitable nitrosy such as methylene chloride or THF in the presence of a base lating agent, Such as thionyl chloride nitrite, thionyl dinitrite, 60 Such as triethylamine followed by nucleophilic displacement or nitroSonium tetrafluoroborate, in a Suitable anhydrous of the sulfonate moiety with iodide or bromide by reaction Solvent, such as dichloromethane, THF, DMF, or with Sodium iodide or Sodium bromide in refluxing acetone. acetonitrile, with or without an amine base, Such as pyridine Reaction of the compound of structure 57 with a suitable or triethylamine, affords the compound of structure XIVA. nitrating agent Such as Silver nitrate in an inert Solvent Such Nitroso compounds of structure (XIV), wherein R. R. 65 as acetonitrile affords the compound of structure XIVC. Ras, Rao, R-7, Ras, D and pare as defined herein, a carbonyl Nitroso compounds of structure (XV), wherein R. R. group is representative of the A group, as defined herein, R7, Ras, D and p are as defined herein, and a nitrite US 6,331.543 B1 47 48 containing ester Substituent is representative of the Ras verted to the N-acylated compound of the formula 61, group, as defined herein, may be prepared according to FIG. wherein X is as defined herein, and oxygen is representative 43. 1,2,3,4-Tetrahydrobeta-carboline of the formula 58 is of G, as defined herein, by reaction with a halogen con converted to the N-acylated compound of the formula 59, taining carboxylic ester Substituted cinnamic acid derivative. wherein P' is as defined herein, and oxygen is representative Preferred methods for the formation of amides are reacting of G, as defined herein, by reaction with a hydroxy pro the amine with the preformed acid chloride or Symmetrical tected carboxylic ester Substituted cinnamic acid derivative. anhydride of the halide containing acid or condensing the Preferred methods for the formation of amides are reacting amine and halide containing acid with a dehydrating agent, the amine with the preformed acid chloride or Symmetrical such as DCC or EDAC.HCl in the presence of a catalyst, anhydride of the carboxylic acid or condensing the amine Such as DMAP or HOBt. Preferred halides are bromide and and carboxylic acid with a dehydrating agent, Such as DCC iodide. Reaction of the amide of structure 61 with a Suitable or EDAC.HCl, in the presence of a catalyst, such as DMAP nitrating agent, Such as Silver nitrate in an inert Solvent, Such or HOBt. Preferred protecting groups for the alcohol moiety as acetonitrile, affords the compound of structure XVC. are silyl ethers, Such as a trimethylsilyl or a tert Nitroso compounds of structure (XVI), wherein R., R. butyldimethylsilyl ether. Deprotection of the hydroxyl moi 15 Rao, Rand p are as defined herein, and a nitrite containing ety (fluoride ion is the preferred method for removing silyl benzoic ester Substituent is representative of the R group, ether protecting groups) followed by reaction with a sto as defined herein, may be prepared according to FIG. 46. ichometric quantity of a Suitable nitrosylating agent, Such as 2-Pyrazolin-5-one of the formula 62 is converted to the ester thionyl chloride nitrite, thionyl dinitrite, or nitrosonium of the formula 63, wherein P' is as defined herein, by tetrafluoroborate, in a Suitable anhydrous Solvent, Such as reaction with a monoprotected diol. Preferred methods for dichloromethane, THF, DMF, or acetonitrile, with or without the formation of esters are reacting the alcohol with the an amine base, Such as pyridine or triethylamine, affords the preformed acid chloride or Symmetrical anhydride of the compound of structure XVA. carboxylic acid or condensing the alcohol and carboxylic Nitroso compounds of structure (XV), wherein R. R. acid with a dehydrating agent, such as DCC or EDAC.HCl, R7, Ras, D and p are as defined herein, and a nitroSothiol 25 in the presence of a catalyst, such as DMAP or HOBt. containing ester Substituent is representative of the Ras Preferred protecting groups for the alcohol moiety are silyl group, as defined herein, may be prepared according to FIG. ethers, such as a trimethylsilyl or a tert-butyldimethylsilyl 44. 1,2,3,4-Tetrahydrobeta-carboline of the formula 58 is ether. Deprotection of the hydroxyl moiety (fluoride ion is converted to the N-acylated compound of the formula 60, the preferred method for removing silyl ether protecting wherein P is as defined herein, and oxygen is representative groups) followed by reaction with a Stoichometric quantity of G, as defined herein, by reaction with a Sulfanyl pro of a Suitable nitrosylating agent, Such as thionyl chloride tected carboxylic ester Substituted cinnamic acid derivative. nitrite, thionyl dinitrite, or nitroSonium tetrafluoroborate, in Preferred methods for the formation of amides are reacting a Suitable anhydrous Solvent, Such as dichloromethane, THF, the amine with the preformed acid chloride or Symmetrical DMF, or acetonitrile, with or without an amine base, Such as anhydride of the carboxylic acid or condensing the amine 35 pyridine or triethylamine, affords the compound of Structure and carboxylic acid with a dehydrating agent, Such as DCC XVIA or EDAC.HCl, in the presence of a catalyst, such as DMAP Nitroso compounds of structure (XVI), wherein R. R. or HOBt. Preferred protecting groups for the thiol moiety are Rao, R. and p are as defined herein, and a nitroSothiol as a thioester Such as a thioacetate or thiobenzoate, as a containing benzoic ester Substituent is representative of the disulfide, as a thiocarbamate Such as N-methoxymethyl 40 R group, as defined herein, may be prepared according to thiocarbamate, or as a thioether Such as a paramethoxy FIG. 47.2-Pyrazolin-5-one of the formula 62 is converted to benzyl thioether, a tetrahydropyranyl thioether or a 2,4,6- the ester of the formula 64, wherein P’ is as defined herein, trimethoxybenzyl thioether. Deprotection of the sulfanyl by reaction with a sulfanyl protected alcohol. Preferred moiety (Zinc in dilute aqueous acid, triphenylphosphine in methods for the formation of esters are reacting the alcohol water and sodium borohydride are preferred methods for 45 with the preformed acid chloride or symmetrical anhydride reducing disulfide groups while aqueous base is typically of the carboxylic acid or condensing the alcohol and car utilized to hydrolyze thioesters and N-methoxymethyl thio boxylic acid with a dehydrating agent, Such as DCC or carbamates and mercuric trifluoroacetate, Silver nitrate, or EDAC.HCl, in the presence of a catalyst, such as DMAP or Strong acids Such as trifluoroacetic or hydrochloric acid and HOBt. Preferred protecting groups for the thiol moiety are heat are used to remove a paramethoxybenzyl thioether, a 50 as a thioester Such as a thioacetate or thiobenzoate, as a tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl disulfide, as a thiocarbamate Such as N-methoxymethyl thioether group) followed by reaction with a stoichometric thiocarbamate, or as a thioether Such as a paramethoxy quantity of a Suitable nitrosylating agent Such as thionyl benzyl thioether, a tetrahydropyranyl thioether or a 2,4,6- chloride nitrite, thionyl dinitrite, a lower alkyl nitrite Such as trimethoxybenzyl thioether. Deprotection of the sulfanyl tert-butyl nitrite, or nitroSonium tetrafluoroborate in a Suit 55 moiety (Zinc in dilute aqueous acid, triphenylphosphine in able anhydrous solvent such as methylene chloride, THF, water and sodium borohydride are preferred methods for DMF, or acetonitrile with or without an amine base Such as reducing disulfide groups while aqueous base is typically pyridine or triethylamine affords the compound of Structure utilized to hydrolyze thioesters and N-methoxymethylthio XVB. Alternatively, treatment of the deprotected thiol carbamates and mercuric trifluoroacetate, Silver nitrate, or derived from compound 60 with a stoichiometric quantity of 60 Strong acids Such as trifluoroacetic or hydrochloric acid and Sodium nitrite in an acidic aqueous or alcoholic Solution heat are used to remove a paramethoxybenzyl thioether, a affords the compound of structure XVB. tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl Nitro compounds of structure (XV), wherein R, Re, Rs7, thioether group) followed by reaction with a stoichometric Ras, D and p are as defined herein, and a nitrate containing quantity of a Suitable nitrosylating agent Such as thionyl ester Substituent is representative of the Ras group, as 65 chloride nitrite, thionyl dinitrite, a lower alkyl nitrite Such as defined herein, may be prepared according to FIG. 45. tert-butyl nitrite, or nitroSonium tetrafluoroborate in a Suit 1,2,3,4-Tetrahydrobeta-carboline of the formula 58 is con able anhydrous solvent such as methylene chloride, THF, US 6,331.543 B1 49 SO DMF, or acetonitrile with or without an amine base Such as carbamates and mercuric trifluoroacetate, Silver nitrate, or pyridine or triethylamine affords the compound of Structure Strong acids Such as trifluoroacetic or hydrochloric acid and XVIB. Alternatively, treatment of the deprotected thiol heat are used to remove a paramethoxybenzyl thioether, a derived from compound 64 with a Stoichiometric quantity of tetrahydropyranyl thioether, or a 2,4,6-trimethoxybenzyl Sodium nitrite in an acidic aqueous or alcoholic Solution thioether group) followed by reaction with a stoichometric affords the compound of structure XVIB. quantity of a Suitable nitrosylating agent Such as thionyl Nitro compounds of structure (XVI), wherein R, R Rao, chloride nitrite, thionyl dinitrite, a lower alkyl nitrite Such as Rand p are as defined herein, and a nitrate containing tert-butyl nitrite, or nitroSonium tetrafluoroborate in a Suit benzoic ester Substituent is representative of the R group, able anhydrous solvent such as methylene chloride, THF, as defined herein, may be prepared according to FIG. 48. DMF, or acetonitrile with or without an amine base Such as 2-Pyrazolin-5-one of the formula 62 is converted to the ester pyridine or triethylamine affords the compound of Structure of the formula 65, wherein X is as defined herein, by XVIIB. Alternatively, treatment of the deprotected thiol reaction with a halogen containing alcohol. Preferred meth derived from compound 68 with a stoichiometric quantity of ods for the formation of esters are reacting the alcohol with Sodium nitrite in an acidic aqueous or alcoholic Solution the preformed acid chloride or symmetrical anhydride of the 15 affords the compound of structure XVIIB. carboxylic acid or condensing the alcohol and carboxylic Nitro compounds of structure (XVII), wherein R, R Rs. acid with a dehydrating agent, such as DCC or EDAC.HCl, R J and p are as defined herein, and a nitrate containing in the presence of a catalyst, such as DMAP or HOBt. Substituent is representative of the R group, as defined Preferred halides are bromide and iodide. Reaction of the herein, may be prepared according to FIG. 51. Deprotection amide of Structure 64 with a Suitable nitrating agent, Such as of the hydroxyl moiety of the compound of structure 67 Silver nitrate in an inert Solvent, Such as acetonitrile, affords (fluoride ion is the preferred method for removing silyl ether the compound of structure XVIC. protecting groups) followed by activation and nucleophilic Nitroso compounds of structure (XVII), wherein R. R. displacement of the hydroxyl by a halogen affords the Rs, R., J and pare as defined herein, and a nitrite containing compound of structure 69, wherein X is preferably a bro amino containing Substituent is representative of the R2 25 mine or an iodine. Preferred methods for converting a group, as defined herein, may be prepared according to FIG. hydroxyl group to a halogen moiety are to first activate it as 49. Chlorophthalazine of the formula 66 is converted to the the meSylate or tosylate by reacting it with methanSulfonyl compound of Structure 67 by reaction with an amine con chloride or p-tolueSulfonyl chloride in an inert Solvent Such taining a protected hydroxyl group, wherein P' is as defined as methylene chloride or THF in the presence of a base such herein. Preferred conditions for the formation of the com as triethylamine followed by nucleophilic displacement of pound of Structure 67 are to heat the amine and the com the Sulfonate moiety with iodide or bromide by reaction with pound of structure 65 at 170° C. for several hours in a high Sodium iodide or Sodium bromide in refluxing acetone. boiling inert Solvent Such as 2-methylpyrrollidone in the Reaction of the compound of Structure 69 with a Suitable presence of an amine base Such as diisopropylethylamine. nitrating agent Such as Silver nitrate in an inert Solvent Such Preferred protecting groups for the alcohol moiety are silyl 35 as acetonitrile affords the compound of structure XVIIC. ethers, such as a trimethylsilyl or a tert-butyldimethylsilyl Nitroso compounds of structure (XVIII), wherein R. R. ether. Deprotection of the hydroxyl moiety (fluoride ion is Rs, R2, R27, R2s, Rao, R. and p are as defined herein, and the preferred method for removing Sillyl ether protecting a nitrite containing ester Substituted benzoate is representa groups) followed by reaction with a Stoichometric quantity tive of the D group, as defined herein, may be prepared of a Suitable nitrosylating agent, Such as thionyl chloride 40 according to FIG. 52. Anthranilic amide of the formula 70 is nitrite, thionyl dinitrite, or nitroSonium tetrafluoroborate, in converted to the N-acylated compound of the formula 71, a suitable anhydrous solvent, such as dichloromethane, THF, wherein P' is as defined herein, by reaction with a hydroxy DMF, or acetonitrile, with or without an amine base, Such as protected carboxylic ester Substituted benzoic acid deriva pyridine or triethylamine, affords the compound of Structure tive. Preferred methods for the formation of amides are XVIIA. 45 reacting the amine with the preformed acid chloride or Nitroso compounds of structure (XVII), wherein R., R. Symmetrical anhydride of the carboxylic acid or condensing Rs, R., J and p are as defined herein, and a nitroSothiol the amine and carboxylic acid with a dehydrating agent, containing amino containing Substituent is representative of such as DCC or EDAC.HCl, in the presence of a catalyst, the R group, as defined herein, may be prepared according such as DMAP or HOBt. Preferred protecting groups for the to FIG. 50. Chlorophthalazine of the formula 66 is converted 50 alcohol moiety are Silyl ethers, Such as a trimethylsilyl or a to the compound of Structure 68 by reaction with an amine tert-butyldimethylsilyl ether. Deprotection of the hydroxyl containing a protected thiol group, wherein P is as defined moiety (fluoride ion is the preferred method for removing herein. Preferred conditions for the formation of the com silyl ether protecting groups) followed by reaction with a pound of Structure 68 are to heat the amine and the com Stoichometric quantity of a Suitable nitrosylating agent, Such pound of structure 65 at 170° C. for several hours in a high 55 as thionyl chloride nitrite, thionyl dinitrite, or nitroSonium boiling inert Solvent Such as 2-methylpyrrollidone in the tetrafluoroborate, in a Suitable anhydrous Solvent, Such as presence of an amine base Such as diisopropylethylamine. dichloromethane, THF, DMF, or acetonitrile, with or without Preferred protecting groups for the thiol moiety are as a an amine base, Such as pyridine or triethylamine, affords the thioester Such as a thioacetate or thiobenzoate, as a disulfide, compound of structure XVIIIA. as a thiocarb amate Such as N-methoxy methyl 60 Nitroso compounds of structure (XVIII), wherein R. R. thiocarbamate, or as a thioether Such as a paramethoxy Rs, R, R27, Ras, Rao, R. and p are as defined herein, and benzyl thioether, a tetrahydropyranyl thioether or a 2,4,6- a nitroSothiol containing ester Substituted benzoate is rep trimethoxybenzyl thioether. Deprotection of the sulfanyl resentative of the D group, as defined herein, may be moiety (Zinc in dilute aqueous acid, triphenylphosphine in prepared according to FIG. 53. Anthranilic amide of the water and sodium borohydride are preferred methods for 65 formula 70 is converted to the N-acylated compound of reducing disulfide groups while aqueous base is typically structure 72, wherein P’ is as defined herein, by reaction utilized to hydrolyze thioesters and N-methoxymethyl thio with a sulfanyl protected carboxylic ester Substituted ben US 6,331.543 B1 S1 52 zoic acid derivative. Preferred methods for the formation of palladium on charcoal in an inert Solvent Such as ethanol at amides are reacting the amine with the preformed acid a temperature of 25 C. to 50° C. or iron, tin or zinc metal chloride or Symmetrical anhydride of the carboxylic acid or in aqueous or alcoholic acid. Preferred protecting groups for condensing the amine and carboxylic acid with a dehydrat the alcohol moieties are silyl ethers, Such as trimethylsilyl or ing agent, such as DCC or EDAC.HCl, in the presence of a tert-butyldimethylsilyl ethers. Deprotection of the hydroxyl catalyst, such as DMAP or HOBt. Preferred protecting moieties (fluoride ion is the preferred method for removing groups for the thiol moiety are as a thioester Such as a silyl ether protecting groups) followed by reaction with a thioacetate or thiobenzoate, as a disulfide, as a thiocarbam Stoichometric quantity of a Suitable nitrosylating agent, Such ate Such as N-methoxymethyl thiocarbamate, or as a thio as thionyl chloride nitrite, thionyl dinitrite, or nitroSonium ether Such as a paramethoxy-benzyl thioether, a tetrahydro tetrafluoroborate, in a Suitable anhydrous Solvent, Such as pyranyl thioether or a 2,4,6-trimethoxybenzyl thioether. dichloromethane, THF, DMF, or acetonitrile, with or without Deprotection of the Sulfanyl moiety (Zinc in dilute aqueous an amine base, Such as pyridine or triethylamine, affords the acid, triphenylphosphine in water and Sodium borohydride compound of structure XIXA. are preferred methods for reducing disulfide groups while Nitroso compounds of structure (XIX), wherein R., R. aqueous base is typically utilized to hydrolyze thioesters and 15 Rs, G., T and p are as defined herein, and nitroSothiol N-methoxymethyl thiocarb amates and mercuric containing Substituents are representative of the R and R, trifluoroacetate, Silver nitrate, or Strong acids Such as trif groups, as defined herein, may be prepared according to luoroacetic or hydrochloric acid and heat are used to remove FIG. 56. Chloroquinazoline of the formula 74 is converted a paramethoxybenzyl thioether, a tetrahydropy ranyl to the compound of structure 77 by reaction with a substi thioether, or a 2,4,6-trimethoxybenzyl thioether group) fol tuted benzyl amine containing protected thiol groups, lowed by reaction with a Stoichometric quantity of a Suitable wherein P’ is as defined herein. Preferred conditions for the nitrosylating agent Such as thionyl chloride nitrite, thionyl formation of the compound of structure 77 are to heat the dinitrite, a lower alkyl nitrite Such as tert-butyl nitrite, or amine and the compound of Structure 74 for Several hours in nitroSonium tetrafluoroborate in a Suitable anhydrous Sol an inert Solvent Such as isopropanol at reflux. Compound of vent such as methylene chloride, THF, DMF, or acetonitrile 25 the formula 77 is then converted into compound of the with or without an amine base Such as pyridine or triethy formula 78 by reduction of the nitro substituent followed by lamine affords the compound of structure XVIIIB. reaction with phosgene, thiophosgene or an equivalent in the Alternatively, treatment of the deprotected thiol derived presence of a base Such as pyridine or triethylamine. Pre from compound 72 with a Stoichiometric quantity of Sodium ferred methods for the reduction of nitro groups are to use nitrite in an acidic aqueous or alcoholic Solution affords the hydrogen (1-3 atmospheres) in the presence of a palladium compound of structure XVIIIB. catalyst Such as palladium on charcoal in an inert Solvent Nitro compounds of structure (XVIII), wherein R, Re, Rs. such as ethanol at a temperature of 25 C. to 50° C. or iron, R2, R27, R2s, Rao, R. and p are as defined herein, and a tin or Zinc metal in aqueous or alcoholic acid. Preferred nitrate containing ester Substituted benzoate is representa protecting groups for the thiol moiety are as a thioester Such tive of the D group, as defined herein, may be prepared 35 as a thioacetate or thiobenzoate, as a disulfide, as a thiocar according to FIG. 54. Anthranilic amide of the formula 70 is bamate Such as N-methoxymethyl thiocarbamate, or as a converted to the N-acylated compound of the formula 73, thioether Such as a paramethoxybenzyl thioether, a tetrahy wherein X is as defined herein, by reaction with a halogen dropyranylthioether or a 2,4,6-trimethoxybenzyl thioether. containing carboxylic ester Substituted benzoic acid deriva Deprotection of the Sulfanyl moiety (Zinc in dilute aqueous tive. Preferred methods for the formation of amides are 40 acid, triphenylphosphine in water and Sodium borohydride reacting the amine with the preformed acid chloride or are preferred methods for reducing disulfide groups while Symmetrical anhydride of the halide containing acid or aqueous base is typically utilized to hydrolyze thioesters and condensing the amine and halide containing acid derivative N-methoxymethyl thiocarb amates and mercuric with a dehydrating agent, such as DCC or EDAC.HCl in the trifluoroacetate, Silver nitrate, or Strong acids Such as trif presence of a catalyst, such as DMAP or HOBt. Preferred 45 luoroacetic or hydrochloric acid and heat are used to remove halides are bromide and iodide. Reaction of the amide of a paramethoxybenzyl thioether, a tetrahydropyranyl Structure 73 with a Suitable nitrating agent, Such as Silver thioether, or a 2,4,6-trimethoxybenzyl thioether group) fol nitrate in an inert Solvent, Such as acetonitrile, affords the lowed by reaction with a Stoichometric quantity of a Suitable compound of structure XVIIIC. nitrosylating agent Such as thionyl chloride nitrite, thionyl Nitroso compounds of structure (XIX), wherein R. R. 50 dinitrite, a lower alkyl nitrite Such as tert-butyl nitrite, or Rs, G., T and p are as defined herein, and nitrite containing nitroSonium tetrafluoroborate in a Suitable anhydrous Sol Substituents are representative of the Re and R7 groups, as vent such as methylene chloride, THF, DMF, or acetonitrile defined herein, may be prepared according to FIG. 55. with or without an amine base Such as pyridine or triethy Chloroquinazoline of the formula 74 is converted to the lamine affords the compound of structure XIXB. compound of structure 75 by reaction with an Substituted 55 Alternatively, treatment of the deprotected thiol derived benzyl amine containing protected hydroxyl groups, from compound 78 with a Stoichiometric quantity of Sodium wherein p' is as defined herein. Preferred conditions for the nitrite in an acidic aqueous or alcoholic Solution affords the formation of the compound of structure 75 are to heat the compound of structure XIXB. amine and the compound of Structure 74 at an elevated Nitro compounds of structure (XIX), wherein R, Re, Rs. temperature for Several hours in an inert Solvent Such as 60 G, T, k and p are as defined herein, and nitrate containing isopropanol at reflux. Compound of the formula 75 is then Substituents are representative of the R and R, groups, as converted into compound of the formula 76 by reduction of defined herein, may be prepared according to FIG. 57. the nitro Substituent followed by reaction with phosgene, Deprotection of the hydroxyl moiety of the compound of thiophosgene or an equivalent in the presence of a base Such structure 76 (fluoride ion is the preferred method for remov as pyridine or triethylamine. Preferred methods for the 65 ing silyl ether protecting groups) followed by activation and reduction of nitro groups are to use hydrogen (1-3 nucleophilic displacement of the hydroxyl by a halogen atmospheres) in the presence of a palladium catalyst Such as affords the compound of structure 79, wherein X is prefer US 6,331.543 B1 S3 S4 ably a bromine or an iodine. Preferred methods for convert and Synthetic amino acids and their Stereoisomers and ing a hydroxyl group to a halogen moiety are to first activate racemic mixtures and derivatives thereof); S-nitrosylated it as the meSylate or tosylate by reacting it with methanSul Sugars, S-nitrosylated, modified and unmodified, oligo fonyl chloride or p-toluesulfonyl chloride in an inert solvent nucleotides (preferably of at least 5, and more preferably such as methylene chloride or THF in the presence of a base 5-200 nucleotides); straight or branched, saturated or Such as triethylamine followed by nucleophilic displacement unsaturated, aliphatic or aromatic, Substituted or unsubsti of the Sulfonate moiety with iodide or bromide by reaction tuted S-nitrosylated hydrocarbons; and S-nitroso heterocy with Sodium iodide or Sodium bromide in refluxing acetone. clic compounds. S-nitroSothiols and methods for preparing Reaction of the compound of structure 79 with a suitable them are described in U.S. Pat. Nos. 5,380,758 and 5,703, nitrating agent Such as Silver nitrate in an inert Solvent Such 073; WO 97/27749; WO 98/19672; and Oae etal, Org. Prep. as acetonitrile affords the compound of structure XIXC. Proc. Int., 15(3):165–198 (1983), the disclosures of each of The compounds of the present invention include PDE which are incorporated by reference herein in their entirety. inhibitors, including those described herein, which have Another embodiment of the present invention is S-nitroso been nitrosated and/or nitrosylated through one or more Sites amino acids where the nitroSo group is linked to a Sulfur Such as oxygen (hydroxyl condensation), Sulfur (sulfhydryl 15 group of a Sulfur-containing amino acid or derivative condensation), carbon and/or nitrogen. The nitrosated and/or thereof. Such compounds include, for example, S-nitroSo nitrosylated PDE inhibitors of the present invention donate, N-acetylcysteine, S-nitroso-captopril, S-nitroso-N- transfer or release a biologically active form of nitrogen acetylpenicillamine, S-nitroSo-homocysteine, S-nitroSo monoxide (nitric oxide). cysteine and S-nitroSO-glutathione. Nitrogen monoxide can exist in three forms: NO Suitable S-nitrosylated proteins include thiol-containing (nitroxyl), NO (nitric oxide) and NO" (nitrosonium). NO proteins (where the NO group is attached to one or more is a highly reactive short-lived species that is potentially Sulfur groups on an amino acid or amino acid derivative toxic to cells. This is critical because the pharmacological thereof) from various functional classes including enzymes, efficacy of NO depends upon the form in which it is Such as tissue-type plasminogen activator (TPA) and cathe delivered. In contrast to the nitric oxide radical (NO), 25 psin B; transport proteins, Such as lipoproteins, heme nitrosonium (NO") does not react with O. or O- species, proteins, Such as hemoglobin and Serum albumin; and bio and functionalities capable of transferring and/or releasing logically protective proteins, Such as immunoglobulins and NO" and NO- are also resistant to decomposition in the cytokines. Such nitrosylated proteins are described in WO presence of many redox metals. Consequently, administra 93/09806, the disclosure of which is incorporated by refer tion of charged NO equivalents (positive and/or negative) ence herein in its entirety. Examples include polynitrosy does not result in the generation of toxic by-products or the lated albumin where one or more thiol or other nucleophilic elimination of the active NO moiety. centers in the protein are modified. Compounds contemplated for use in the present invention Other examples of suitable S-nitrosothiols include: (e.g., PDE inhibitors antagonists and/or nitrosated and/or (i) HSC(R)(R)), SNO; nitrosylated PDE inhibitors) are, optionally, used in combi 35 (ii) ONSIC(R)(R)).R.; and nation with nitric oxide and compounds that release nitric (iii) HN-CH(COH)–(CH)-C(O)NH-CH oxide or otherwise directly or indirectly deliver or transfer (CHSNO)-C(O)NH-CH-COH: nitric oxide to a Site of its activity, Such as on a cell wherein m is an integer of from 2 to 20; R and R are each membrane in vivo. independently a hydrogen, an alkyl, a cycloalkoxy, a The term "nitric oxide' encompasses uncharged nitric 40 halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an oxide (NO) and charged nitrogen monoxide species, pref arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a erably charged nitrogen monoxide species, Such as nitroSo heterocyclicalkyl, am alkoxy, a haloalkoxy, an amino, an nium ion (NO") and nitroxyl ion (NO-). The reactive form alkylamino, a dialkylamino, an arylamino, a diarylamino, an of nitric oxide can be provided by gaseous nitric oxide. The alkylarylamino an alkoxyhaloalkyl, a haloalkoxy, a Sulfonic nitric oxide releasing, delivering or transferring compounds, 45 acid, an alkylsulfonic acid, an arylsulfonic acid, an have the structure F-NO, wherein F is a nitric oxide arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, releasing, delivering or transferring moiety, include any and an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, all Such compounds which provide nitric oxide to its a carboxamido, a alkyl carboxamido, an aryl carboxamido, intended site of action in a form active for its intended an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, purpose. The term "NO adducts' encompasses any nitric 50 an arylcarboxylic acid, an ester, a carboxylic ester, an oxide releasing, delivering or transferring compounds, alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, including, for example, S-nitroSothiols, organic nitrites, a Sulfonamido, an alkylsulfonamido, an arylsulfonamido, a organic nitrates, S-nitrothiols, Sydnonimines, 2-hydroxy-2- urea, a nitro, or -T-Q; or R, and R taken together are a nitrosohydrazines (NONOates), (E)-alkyl-2-(E)- carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl hydroxyimino)-5-nitro-3-hexene amines or amides, 55 group or a bridged cycloalkyl group, Q is -NO or -NO; nitroSoamines, furoxanes as well as Substrates for the endog and T is independently a covalent bond, an oxygen, S(O) or enous enzymes which synthesize nitric oxide. The “NO NR, wherein o is an integer from 0 to 2, and R is a adducts' can be mono-nitrosylated, poly-nitrosylated, hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl mono-nitroSated and/or poly-nitrosated at a variety of natu carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic rally Susceptible or artificially provided binding Sites for 60 ester, an alkylcarboxamido, an arylcarboxamido, an nitric oxide. alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, One group of NO adducts is the S-nitrosothiols, which are an arylsulfonyl, a Sulfonamido, carboxamido, -CH2-C compounds that include at least one -S-NO group. These (T-Q)(R)(R), or -(N.O.-)M", wherein M" in an compounds include S-nitroso-polypeptides (the term organic or inorganic cation; with the proviso that when R is "polypeptide' includes proteins and polyamino acids that do 65 -CH-C(T-Q)(R)(R) or -(NO-)M"; then “-T- not possess an ascertained biological function, and deriva Q' can be a hydrogen, an alkyl group, an alkoxyalkyl group, tives thereof); S-nitrosylated amino acids (including natural an aminoalkyl group, a hydroxy group or an aryl group. US 6,331.543 B1 SS S6 In cases where R, and R are a heterocyclic ring or taken Another group of NO adducts are thionitrates that donate, together R, and R are a heterocyclic ring, then R, can be a transfer or release nitric oxide and are represented by the Substituent on any disubstituted nitrogen contained within formula: R'-(S)-NO, where R' is a polypeptide, an the radical wherein R is as defined herein. amino acid, a Sugar, a modified or unmodified Nitrosothiols can be prepared by various methods of oligonucleotide, a Straight or branched, Saturated or Synthesis. In general, the thiol precursor is prepared first, unsaturated, aliphatic or aromatic, Substituted or unsubsti then converted to the S-nitrosothiol derivative by nitrosation tuted hydrocarbon, or a heterocyclic group. Preferred are of the thiol group with NaNO under acidic conditions (pH those compounds where R is a polypeptide or hydrocarbon is about 2.5) which yields the S-nitroso derivative. Acids which can be used for this purpose include acqueous Sulfuric, with a pair or pairs of thiols that are Sufficiently structurally acetic and hydrochloric acids. The thiol precursor can also 1O proximate, i.e., vicinal, that the pair of thiols will be reduced be nitrosylated by reaction with an organic nitrite Such as to a disulfide. Compounds which form disulfide species tert-butyl nitrite, or a nitroSonium Salt Such as nitroSonium release nitroxyl ion (NO-) and uncharged nitric oxide tetraflurorborate in an inert Solvent. (NO). Compounds where the thiol groups are not suffi Another group of NO adducts for use in the present ciently close to form disulfide bridges generally provide invention, where the NO adduct is a compound that donates, 15 nitric oxide as the NO- form and not as the uncharged NO transferS or releases nitric oxide, include compounds com form. prising at least one ON-O-, ON-N- or ON-C The present invention is also directed to agents that group. The compounds that include at least one ON-O-, Stimulate endogenous NO or elevate levels of endogenous ON-N- or ON-C - group are preferably ON-O-, endothelium-derived relaxing factor (EDRF) in vivo or are ON-N- or ON-C-polypeptides (the term “polypeptide' Substrates for nitric oxide Synthase. Such compounds includes proteins and polyamino acids that do not possess an include, for example, L-arginine, L-homoarginine, and ascertained biological function, and derivatives thereof); N-hydroxy-L-arginine, including their nitrosated and ON-O-, ON-N- or ON-C-amino acids (including nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated natural and Synthetic amino acids and their Stereoisomers L-arginine, nitrosated N-hydroxy-L-arginine, nitroSylated and racemic mixtures); ON-O-, ON-N- or ON-C- 25 N-hydroxy-L-arginine, nitrosated L-homoarginine and Sugars; ON-O-, ON-N- or ON-C - modified or nitrosylated L-homoarginine), precursors of L-arginine and/ unmodified oligonucleotides (comprising at least 5 or physiologically acceptable Salts thereof, including, for nucleotides, preferably 5-200 nucleotides); ON-O-, example, citruline, ornithine or glutamine, inhibitors of the ON-N- or ON-C-straight or branched, Saturated or enzyme arginase (e.g., N-hydroxy-L-arginine and 20S)- unsaturated, aliphatic or aromatic, Substituted or unsubsti amino-6-boronohexanoic acid) and the Substrates for nitric tuted hydrocarbons; and ON-O-, ON-N- or ON-C- oxide Synthase, cytokines, adenosin, bradykinin, heterocyclic compounds. calreticulin, bisacodyl, and phenolphthalein. EDRF is a Another group of NO adducts for use in the present vascular relaxing factor Secreted by the endothelium, and invention include nitrates that donate, transfer or release has been identified as nitric oxide (NO) or a closely related nitric oxide, Such as compounds comprising at least one 35 derivative thereof (Palmer et al, Nature, 327:524–526 ON-O-, ON-N-, ON-S- or ON-C - group. (1987); Ignarro et al., Proc. Natl. Acad. Sci. U.S.A, Preferred among these compounds are ON-O-, ON 84:9265–9269 (1987)). N-, ON-S- or ON-C- polypeptides (the term The present invention is also based on the discovery that "polypeptide' includes proteins and also polyamino acids the administration of a therapeutically effective amount of that do not possess an ascertained biological function, and 40 the compounds and compositions described herein is effec derivatives thereof); ON-O-, ON-N-, ON-S- or tive for treating or preventing Sexual dysfunctions or ON-C- amino acids (including natural and Synthetic enhancing Sexual responses in patients, including males and amino acids and their Stereoisomers and racemic mixtures); females. For example, the patient can be administered a ON-O-, ON-N-, ON-S- or ON-C-Sugars; therapeutically effective amount of at least one nitrosated ON-O-, ON-N-, ON-S- or ON-C-modified 45 and/or nitrosylated PDE inhibitor of the present invention. and unmodified oligonucleotides (comprising at least 5 In another embodiment, the patient can be administered a nucleotides, preferably 5-200 nucleotides); ON-O-, therapeutically effective amount of at least one PDE ON-N-, ON-S- or ON-C-straight or branched, inhibitor, optionally substituted with at least one NO and/or Saturated or unsaturated, aliphatic or aromatic, Substituted or NO group, and at least one compound that donates, trans unsubstituted hydrocarbons; and ON-O-, ON-N-, 50 ferS or releases nitric oxide, or elevates levels of endogenous ON-S- or ON-C- heterocyclic compounds. Pre EDRF or nitric oxide, or is a Substrate for nitric oxide ferred examples of compounds comprising at least one Synthase. In yet another embodiment, the patient can be ON-O-, ON-N-, ON-S- or ON-C - group administered a therapeutically effective amount of at least include isosorbide dinitrate, isosorbide mononitrate, one PDE inhibitor, optionally substituted with at least one clonitrate, erythrityltetranitrate, mannitol heXanitrate, 55 NO and/or NO group, and at least one vasoactive agent, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and and, optionally, at least one compound that donates, transfers propatylnitrate. or releases nitric oxide, or elevates levels of endogenous Another group of NO adducts are N-oxo-N-nitroSoamines EDRF or nitric oxide, or is a Substrate for nitric oxide that donate, transfer or release nitric oxide and are repre Synthase. The compounds can be administered Separately or sented by the formula: RR-N(O-M")-NO, where R' 60 in the form of a composition. and R are each independently a polypeptide, an amino acid, A vasoactive agent is any therapeutic agent capable of a Sugar, a modified or unmodified oligonucleotide, a Straight relaxing vascular Smooth muscle. Suitable vasoactive agents or branched, Saturated or unsaturated, aliphatic or aromatic, include, but are not limited to, potassium channel activators Substituted or unsubstituted hydrocarbon, or a heterocyclic (Such as, for example, nicorandil, pinacidil, cromakalim, group, and where M is an organic or inorganic cation, Such 65 minoxidil, aprilkalim, loprazolam and the like), calcium as, for example, an alkyl Substituted ammonium cation or a blockers (such as, for example, nifedipine, Veraparmil, Group I metal cation. diltiazem, gallopamil, niludipine, nimodipins, nicardipine, US 6,331.543 B1 57 58 and the like); f-blockers (such as, for example, butixamine, When administered in Vivo, the compounds and compo dichloroisoproterenol, propanolol, alprenolol, bunolol, Sitions of the present invention can be administered in nadolol, Oxprenolol, perbutolol, pinodolol, Sotalol, timolol, combination with pharmaceutically acceptable carriers and metoprolol, atenolol, acebutolol, bevantolol, pafenolol, in dosages described herein. When the compounds and tolamodol, and the like), long and short acting C.-adrenergic compositions of the present invention are administered as a receptor antagonist (Such as, for example, mixture of at least one nitrosated and/or nitrosylated PDE phenoxybenzamide, dibenamine, doxazosin, teraZosin, inhibitor or at least one PDE inhibitor and at least one nitric phentolamine, tolazoline, proZosin, trimaZosin, yohimbine, oxide donor, they can also be used in combination with one moxisylyte and the like adenosine, ergot alkaloids (Such as, or more additional compounds which are known to be for example, ergotamine, ergotamine analogs, including, for effective against the Specific disease State targeted for treat example, acetergamine, braZergoline, bromerguride, ment (e.g., vasoactive agents). The nitric oxide donors cianergoline, delorgotrile, disulergine, ergonoVine maleate, and/or vasoactive agents can be administered Simulta ergotamine tartrate, etisulergine, lergotrile, lysergide, neously with, Subsequently to, or prior to administration of meSulergine, metergoline, metergotamine, nicergoline, the PDE inhibitors, including those that are substituted with pergolide, propisergide, proterguride, terguride); vasoactive 15 one or more NO and/or NO groups, and/or other additional intestinal peptides (Such as, for example, peptide histidine compounds. isoleucine, peptide histidine methionine, Substance P, calci The compounds and compositions of the present inven tonin gene-related peptide, neurokinin A, bradykinin, neu tion can be administered by any available and effective rokinin B, and the like), dopamine agonists (such as, for delivery System including, but not limited to, orally, bucally, example, apomorphine, bromocriptine, testosterone, parenterally, by inhalation Spray, by topical application, by cocaine, Strychnine, and the like), opioid antagonists (Such injection into the corpus cavernoSum tissue, by transurethral as, for example, naltrexone, and the like), prostaglandins drug delivery, transdermally, vaginally, or rectally (e.g., by (Such as, for example, alprostadil, prostaglandin E, pros the use of Suppositories) in dosage unit formulations con taglandin F, misoprostol, en prostil, arbaprostil, taining conventional nontoxic pharmaceutically acceptable unoprostone, trimoprostil, carboprost, limaprost, gemeprost, 25 carriers, adjuvants, and vehicles, as desired. Parenteral lantanoprost, ornoprostil, beraprost, Sulpostrone, rioprostil, includes Subcutaneous injections, in travenous, and the like), endothelin antagonists (such as, for example, intramuscular, intrasternal injection, or infusion techniques. boSentan, Sulfonamide endothelin antagonists, BQ-123, SQ Transdermal drug administration, which is known to one 28.608, and the like) and mixtures thereof. skilled in the art, involves the delivery of pharmaceutical Another embodiment of the present invention provides agents via percutaneous passage of the drug into the Sys methods to prevent or treat diseases induced by the temic circulation of the patient. Topical administration can increased metabolism of cyclic guanosine 3',5'- also involve transdermal patches or iontophoresis devices. monophosphate (cGMP), including, for example, Other components can be incorporated into the transdermal hypertension, pulmonary hypertension, congestive heart patches as well. For example, compositions and/or transder failure, renal failure, myocardial infraction, Stable, unstable 35 mal patches can be formulated with one or more preserva and variant (Prinzmetal) angina, atherosclerosis, cardiac tives or bacterioStatic agents including, but not limited to, edema, renal insufficiency, nephrotic edema, hepatic edema, methyl hydroxybenzoate, propyl hydroxybenzoate, Stroke, asthma, bronchitis, chronic obstructive pulmonary chlorocreSol, benzalkonium chloride, and the like. disease (COPD), cystic fibrosis, de mentia, Solid dosage forms for oral administration can include immunodeficiency, premature labor, dysmenorrhoea, benign 40 capsules, tablets, effervescent tablets, chewable tablets, pills, prostatic hyperplasis (BPH), bladder outlet obstruction, powders, Sachets, granules and gels. In Such Solid dosage incontinence, conditions of reduced blood vessel patency, forms, the active compounds can be admixed with at least e.g., postpercutaneous transluminal coronary angioplasty one inert diluent Such as Sucrose, lactose or Starch. Such (post-PTCA), peripheral vascular disease, allergic rhinitis, dosage forms can also comprise, as in normal practice, glucoma and diseases characterized by disorders of gut 45 additional Substances other than inert diluents, e.g., lubri motility, e.g., irritable bowel syndrome (IBS) by administer cating agents Such as magnesium Stearate. In the case of ing to a patient in need thereof a therapeutically effective capsules, tablets, effervescent tablets, and pills, the dosage amount of the compounds and/or compositions described forms can also comprise buffering agents. Soft gelatin herein. For example, the patient can be administered a capsules can be prepared to contain a mixture of the active therapeutically effective amount of at least one nitrosated 50 compounds or compositions of the present invention and and/or nitrosylated PDE inhibitor of the present invention. vegetable oil. Hard gelatin capsules can contain granules of In another embodiment, the patient can be administered a the active compound in combination with a Solid, pulveru therapeutically effective amount of at least one PDE lent carrier Such as lactose, Saccharose, Sorbitol, mannitol, inhibitor, optionally substituted with at least one NO and/or potato Starch, corn Starch, amylopectin, cellulose derivatives NO group, and at least one compound that donates, trans 55 of gelatin. Tablets and pills can be prepared with enteric ferS or releases nitric oxide, or elevates levels of endogenous coatings. EDRF or nitric oxide or is a Substrate for nitric oxide Liquid dosage forms for oral administration can include Synthase. In yet another embodiment, the patient can be pharmaceutically acceptable emulsions, Solutions, administered a therapeutically effective amount of at least Suspensions, Syrups, and elixirs containing inert diluents one PDE inhibitor, optionally substituted with at least one 60 commonly used in the art, Such as water. Such compositions NO and/or NO group, and at least one vasoactive agent, can also comprise adjuvants, Such as wetting agents, emul and, optionally, at least one compound that donates, transfers Sifying and Suspending agents, and Sweetening, flavoring, or releases nitric oxide, or elevates levels of endogenous and perfuming agents. EDRF or nitric oxide, or is a Substrate for nitric oxide Dosage forms for topical administration of the com Synthase. The compounds and compositions of the present 65 pounds and compositions of the present invention can invention can also be administered in combination with include creams, sprays, lotions, gels, ointments, coatings for other medications used for the treatment of these disorders. condoms and the like. Administration of the cream or gel can US 6,331.543 B1 59 60 be accompanied by use of an applicator or by transurethral SeX, weight, extent of the dysfunction of the recipient, drug delivery using a Syringe with or without a needle or frequency of treatment and the nature and Scope of the penile or vaginal insert or device, and is within the Skill of dysfunction. the art. Typically a lubricant and/or a local anesthetic for The amount of a given PDE inhibitor (including nitro deSensitization can also be included in the formulation or sated and/or nitrosylated PDE inhibitors) which will be provided for use as needed. Lubricants include, for example, effective in the prevention or treatment of a particular dysfunction or condition will depend on the nature of the K-Yjelly (available from Johnson & Johnson) or a lidocaine dysfunction or condition, and can be determined by Standard jelly, such as Xylocaine 2% jelly (available from Astra clinical techniques, including reference to Goodman and Pharmaceutical Products). Local anesthetics include, for Gilman, Supra; The Physician's Desk Reference, Supra; example, novocaine, procaine, tetracaine, benzocaine and Medical Economics Company, Inc., Oradell, N.J., 1995; and the like. DrugFacts and Comparisons, Inc., St. Louis, Mo., 1993. The The compounds and compositions of the present inven precise dose to be used in the formulation will also depend tion will typically be administered in a pharmaceutical on the route of administration, and the Seriousness of the composition containing one or more Selected carriers or dysfunction or disorder, and should be decided by the excipients. Examples of Suitable carriers include, for 15 physician and the patient's circumstances. example, water, Silicone, waxes, petroleum jelly, polyethyl The usual doses of PDE inhibitors (including nitrosated ene glycol, propylene glycol, liposomes, Sugars, and the and/or nitrosylated PDE inhibitors) are about 0.001 mg to like. The compositions can also include one or more per about 100 mg per day, preferably about 0.5 mg to about 50 meation enhancers including, for example, dimethylsulfox mg per day. The oral dose of PDE inhibitors (including ide (DMSO), dimethyl formamide (DMF), N,N- nitrosated and/or nitrosylated PDE inhibitors) are about 1 dimethylacetamide (DMA), decylmethylsulfoxide mg to about 200 mg per day preferably about 5 mg to about (C10MSO), polyethylene glycol monolaurate (PEGML), 100 mg per day. glyceral monolau rate, lecithin, 1 - Substituted The doses of nitric oxide donors in the pharmaceutical a Za cycloheptan-2- one S, particularly 1 - N composition can be in amounts of about 0.001 mg to about dodecylcyclazacylcoheptan-2-ones (available under the 25 20g and the actual amount administered will be dependent trademark AZone TM from Nelson Research & Development on the Specific nitric oxide donor. For example, when Co., Irvine, Calif.), alcohols and the like. L-arginine is the nitric oxide donor, the dose is about 2 g/day Suppositories for vaginal or rectal administration of the to about 6 g/day, preferably about 3 g/day, administered compounds and compositions of the invention can be pre orally at least one hour prior to Sexual activity or Sexual pared by mixing the compounds or compositions with a intercourse. Effective doses can be extrapolated from dose Suitable nonirritating excipient Such as cocoa butter and response curves derived from in vitro or animal model test polyethylene glycols which are Solid at room temperature Systems and are in the same ranges or less than as described but liquid at rectal temperature, Such that they will melt in for the commercially available compounds in the Physi the rectum and release the drug. cian's Desk Reference, Supra. Injectable preparations, for example, Sterile injectable 35 The nitrosated and/or nitrosylated PDE inhibitors of the aqueous or oleaginous Suspensions can be formulated invention are used at dose ranges and over a course of dose according to the known art using Suitable dispersing agents, regimen and are administered in the same or Substantially wetting agents and/or Suspending agents. The Sterile inject equivalent vehicles/carrier by the same or Substantially able preparation can also be a Sterile injectable Solution or equivalent as their non-nitrosated/nitrosylated counterparts. Suspension in a nontoxic parenterally acceptable diluent or 40 The nitrosated and/or nitrosylated compounds of the inven Solvent, for example, as a Solution in 1,3-butanediol. Among tion can also be used in lower doses and in leSS eXtensive the acceptable vehicles and Solvents that can be used are regimens of treatment. The amount of active ingredient that water, Ringer's Solution, and isotonic Sodium chloride Solu can be combined with the carrier materials to produce a tion. Sterile fixed oils are also conventionally used as a Single dosage form will vary depending upon the host Solvent or Suspending medium. 45 treated and the particular mode of administration. The compounds and compositions of the present inven The dosage regimen for treating a condition with the tion can be formulated as pharmaceutically acceptable neu compounds and/or compositions of this invention is Selected tral or acid Salt forms. Pharmaceutically acceptable Salts in accordance with a variety of factors, including the type, include, for example, those formed with free amino groups age, weight, Sex, diet and medical condition of the patient, such as those derived from hydrochloric, hydrobromic, 50 the Severity of the dysfunction, the route of administration, hydroiodide, phosphoric, Sulfuric, acetic, citric, benzoic, pharmacological considerations Such as the activity, efficacy, fumaric, glutamic, lactic, malic, maleic, Succinic, tartaric, pharmacokinetic and toxicology profiles of the particular p-tolueneSulfonic, methaneSulfonic acids, gluconic acid, and compound used, whether a drug delivery System is used, and the like, and those formed with free carboxyl groups, Such whether the compound is administered as part of a drug as those derived from Sodium, potassium, ammonium, 55 combination. Thus, the dosage regimen actually used can calcium, ferric hydroxides, isopropylamine, triethylamine, vary widely and therefore may deviate from the preferred 2-ethylamino ethanol, histidine, procaine, and the like. dosage regimen Set forth herein. “Therapeutically effective amount” refers to the amount Particularly preferred methods of administration of the of the PDE inhibitor, nitrosated and/or nitrosylated PDE contemplated PDE inhibitor compositions (including nitro inhibitor, nitric oxide donor and/or vasoactive agent that is 60 sated and/or nitrosylated PDE inhibitor compositions) for effective to achieve its intended purpose. While individual the treatment of male Sexual dysfunction are by oral patient needs may vary, determination of optimal ranges for administration, by transdermal application, by injection into effective amounts of each of the compounds and composi the corpus cavernoSum, by transurethral administration or tions is within the skill of the art. Generally, the dosage by the use of suppositories. The preferred methods of required to provide an effective amount of the composition, 65 administration for female Sexual dysfunction are by oral and which can be adjusted by one of ordinary skill in the art administration, topical application, transdermal application will vary, depending on the age, health, physical condition, or by the use of Suppositories. US 6,331.543 B1 61 62 The present invention also provides pharmaceutical kits 1c. 2,6-bis(diethyl-3-methyl-3-mercaptobutyric acid comprising one or more containers filled with one or more ester)amino)-4,8-dipiperidinopyrimido-5,4-d- of the ingredients of the pharmaceutical compounds and/or pyrimidine compositions of the present invention, including, one or more PDE inhibitors, optionally substituted with one or 5 The product of Example 1b (1.00 g, 0.63 mmol) was more NO and/or NO groups, one or more of the NO donors, dissolved in methylene chloride (5.5 ml) and anisole (4.0 ml, and one or more vasoactive agents. Such kits can also 36.9 mmol), phenol (0.400 g, 4.25 mmol), water (4.0 ml) include, for example, other compounds and/or compositions and trifluoracetic acid (16 ml, 208 mmol) were added. After (e.g., permeation enhancers, lubricants, and the like), a 1.5 hours of Stirring at room temperature, toluene (5 ml) was device(s) for administering the compounds and/or added and Volatiles were evaporated. The residue was puri compositions, and written instructions in a form prescribed fied by flash chromatography on Silica gel eluting with by a governmental agency regulating the manufacture, use hexane/ethyl acetate (5:1) to (3:1) to give the title compound or Sale of pharmaceuticals or biological products, which (0.360 g, 59% yield). H NMR (CDC1,300 MHz) 81.47 (s, instructions can also reflects approval by the agency of 24 H), 1.68–1.72 (m, 12 H), 2.29 (s, 4 H), 2.63 (s, 8 H), manufacture, use or Sale for human administration. 15 3.85–3.92 (m, 8 H), 3.97-4.03 (m 8H), 4.28–4.35 (m, 8 H). 1d. 2,6-bis(diethyl(3-methyl-3(nitrosothiol)butyric EXAMPLES acid ester)amino)-4,8-dipiperidinopyrimido-5,4-d- Example 1 pyrimidine 2,6-bis(diethyl(3-methyl-3-(nitrosothio)butyric acid The product of Example 1c (0.353 g, 0.36 mmol) was ester)amino)-4,8-dipiperidinopyrimido-5,4-d- dissolved in acetic acid (20 ml) and 1 N solution of hydro pyrimidine chloric acid (3.5 ml) was added, followed by 1 N sodium nitrite solution (2.2 ml). After 30 minutes stirring at room 1a. 3-Methyl-3(2,4,6-trimethoxyphenylmethylthio) temperature, the reaction mixture was lyophilized, the resi butyric acid 25 due was Suspended in methylene chloride and washed with To a solution of 3-mercapto-3-methylbutyric acid water, brine, and dried over anhydrous Sodium Sulfate. The (Sweetman et al., J. Med Chem., 14:868 (1971)) (4.6 g., 34 Solvent was evaporated in vacuo, and the residue was mmol) in methylene chloride (250 ml) under nitrogen and purified by flash chromatography on Silica gel eluting meth cooled over ice/salt to 5 C. (internal temperature) was ylene chloride/methanol (12:1) to give the title compound added trifluoroacetic acid (82 g, 0.72 mol). No significant (0.144 g., 37% yield). (CDC1,300 MHz) 81.52–1.73 (m, 12 temperature rise was noted during the addition. To this was H), 1.98 (s, 24H), 3.20–3.38 (m, 8 H), 3.39–3.92 (m, 12 H), then added dropwise a solution of 2,4,6-trimethoxybenzyl 3.94-4.35 (m, 12 H). alcohol (Munson et al., J. Org. Chem, 57:3013 (1992)) (6.45 g. 32 mmol) in methylene chloride (150 ml) such that the Example 2 reaction temperature does not rise above 5 C. After the 35 1-(4-(1,3-benzodioxol-5-methyl)amino)-6-chloro addition was complete, the mixture was stirred for an 2-quinazolinyl)-4 piperidine-carboxylic ethyl-(3- additional 5 minutes at 5 C. and the volatiles were removed methyl-3(nitrosothiol)butyramide) thioester in vacuo (toluene or ethyl acetate can be used to assist in the hydrochloride removal of volatile material). The residue was partitioned between diethyl ether and water and the organic phase dried 40 2a. 3-Methyl-3(thioacetyl)butyric acid over anhydrous sodium sulfate, filtered and the volatile material removed in vacuo. The residue was treated with To a solution of 3-mercapto-3-methylbutyric acid activated charcoal and recrystalized from diethyl ether/ (Sweetman et al., J. Med. Chem., 14:868 (1971)) (1.03 g, 7.7 hexane. The product was isolated as a white solid in 70% mmol) in pyridine (1.6 ml) was added acetic anhydride (1.57 yield (7 g); mp 103-105° C. "H NMR (CDC1) 86.12 (s, 2 45 g, 15.4 mmol) and the reaction mixture was stirred at room H), 3.80–3.85 (m, 11 H), 2.74 (s, 2 H), 1.47 (s, 6 H). 'C temperature over night. The reaction mixture was slowly NMR (CDC1) 8173.9, 160.6, 158.6, 105.6, 90.5, 55.7, 55.3, added to a 0° C. solution of 1 NHCl (20 ml) then water (10 45.9, 43.6, 28.4, 21.0. ml) was added and the reaction mixture was stirred at room temperature for 20 hours. The solution was extracted with 1b. 2,6-bis(diethyl-3-methyl-3(2,4,6- 50 diethyl ether and the organic phase was washed with brine trimethoxyphenylmethylthio)butyric acid ester) and then dried over anhydrous sodium sulfate. The solvent amino)-4,8-dipiperidinopyrimido-5,4-d-pyrimidine was evaporated in vacuo, and the residue was purified by Under a nitrogen atmosphere, dipyridamole (1.50g, 2.97 flash chromatography on Silica gel eluting with ethyl acetate/ mmol) was dissolved in anhydrous dimethylformamide (30 hexane (1:4) to give the title compound (0.791 g, 58% ml) and 4-dimethylaminopyridine (1.46g, 11.9 mmol) was 55 yield). (CDC1,300 MHz) 81.55 (s, 6 H), 2.25 (s.3 H), 2.99 added, followed by the product of Example 1a (3.64g, 11.9 (s, 2 H). mmol) and EDAC (2.28 g, 11.9 mmol). The resulting mixture was stirred 44 hours at 50° C. The solvent was 2b. Mercaptoethyl-3-methyl-3(thioacetyl) evaporated in vacuo, and residue was partitioned between butyramide methylene chloride and water, washed with brine and dried 60 The product of Example 2a (0.556 g., 3.1 mmol) was over anhydrous Sodium Sulfate. Volatiles were evaporated dissolved in methylene chloride (10 ml) containing a cata and the residue was purified by flash chromatography on lytic amount of dimethylforamide (10 ul). Oxalyl chloride Silica gel, eluting with hexane/ethyl acetate (2:1) to (1:1) to (0.556 g, 4.4 mmol) was added and the reaction mixture was give the title compound (1.02 g, 23% yield). H NMR Stirred at room temperature for 1 hour. The Volatile compo (CDC1, 300 MHz) 81.45 (s, 24 H), 1.58-1.69 (m, 12 H), 65 nents were then evaporated in vacuo and the residue azeo 2.70 (s, 8 H), 3.64-3.88 (m, 52 H), 4.02–406 (m, 8 H), troped with toluene (2x5 ml). The yellow oil remaining was 4.25–432 (m, 8 H), 6.10 (s, 8 H). added to a -78 C. solution of 2-aminoethanethiol hydro US 6,331.543 B1 63 64 chloride (0.341 g, 3.0 mmol), and triethylamine (0.303 g, 3.0 Volatiles were evaporated, the residue was diluted with water mmol) in dimethylformamide (6 ml). The reaction mixture (2 ml) and 1 NHCl was added until the pH of the reaction was stirred at -78 C. for 1 hour and then at room tempera mixture registered pH 7. The reaction mixture was then ture for 2 hours. The reaction was quenched with water (20 filtered and the precipitate was washed with water (2 ml). ml) and then extracted with ethyl acetate. The organic phase Ethanol was added to the precipitate and the Volatiles were was dried over anhydrous Sodium Sulfate and then concen evaporated to give 0.080 g (86% yield) of the title compound trated in vacuo to afford the title compound (0.349 g, 53% as a pale yellow solid. "H NMR (300 MHz, DMSO) yield) which was used without further purification. (CDC1, 81.36-1.45 (m, 2 H), 1.75–1.83 (m, 2 H), 2.92-3.02 (m, 3 300 MHz) 81.5 (s, 6 H), 2.3 (s, 3 H), 2.6 (dd, 2 H), 2.8 (s, H), 4.54–4.60 (m, 4H), 5.94 (s, 2 H), 6.83 (s, 2 H), 6.93 (s, 2 H), 2.9 (s, 1 H), 3.4 (dd, 2 H), 6.0 (brs, 1 H). 1H), 7.21–7.26 (d. 1 H), 7.44-7.49 (d. 1 H), 8.13 (s, 1 H), 8.51–8.53 (t, 1H). 2c. Mercaptoethyl-3-methyl-3(mercapto)butyramide 2g. 1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6- The product of Example 2b (0.314 g, 1.4 mmol) was chloro-2-quinazolinyl)-4-piperidine-carboxylic dissolved in methanol (10 ml) and solid sodium hydroxide ethyl-(3-methyl-3-(thioacetyl)butyramide) thioester (85 mg, 2.1 mmol) was added. After stirring 5 minutes, the 15 reaction mixture was diluted with ethyl acetate (50 ml) and Under a nitrogen atmosphere, the product of Example 2f washed with Saturated aqueous Sodium bicarbonate, fol (0.147 g., 0.31 mmol) and triethylamine (0.043 ml, 0.31 lowed by brine, and then dried over anhydrous sodium mmol) were combined in 3 ml of DMF and heated to 50° C. Sulfate. The Volatile components were evaporated in vacuo to dissolve all solid. A solution of Example 2c (0.067g, 0.38 leaving the title compound as a colorless oil (0.188 g, 75% mmol) in DMF (2 ml) was added, followed by EDAC (0.073 yield) which was used without further purification. (CDC1, g, 0.38 mmol) and DMAP (0.015 g, 0.12 mmol). The 300 MHz) 8:1.42 (s, 6 H), 1.55 (s, 1 H), 2.17 (s, 1 H), 2.41 resulting mixture was stirred at room temperature for 5 (s, 2 H), 2.61 (dd, J=12.5 Hz, k 6.2 Hz, 2 H), 3.39 (dd, J=12.5 hours and then at 50° C. overnight. The reaction mixture was HZ, 6.2 Hz, 2 H). diluted with water (20 ml) and extracted with dichlo 25 romethane. The combined organic phase was washed with 2d. 4-(1,3-benzodioxol-5-ylmethyl)amino)-2,6- brine and dried over anhydrous sodium sulfate. The volatiles dichloro quinazoline were evaporated and the residue was purified by flash A solution of 2,4,6-trichloroquinazoline (0.186 g., 0.80 chromatography on Silica gel eluting with hexane/ethyl mmol) in ethanol (20 ml) was heated to 55° C. and pipero acetate (1:2) to give 0.038 g (21% yield) of the title nylamine (0.145 g, 0.96 mmol) was added. The resulting compound. "H NMR (300 MHz, CDC1) 8:1.48 (s, 6 H), mixture was stirred at 55 C. over night. Volatiles were 1.64–1.75 (m, 2 H), 1.94-2.00 (m, 2 H), 2.04 (s, 1 H), 2.45 evaporated and the residue was partitioned between meth (s, 2 H), 2.70–2.77 (m, 1 H), 2.91-2.96 (t, 2 H), 3.01-3.08 ylene chloride and Saturated Solution of ammonium hydrox (t, 2 H), 3.42–3.48 (t, 2 H), 4.64–4.68 (d, 2 H), 4.87–4.94 (d. ide. The organic phase was dried over anhydrous Sodium 35 2 H), 5.64–5.68 (m, 1 H), 5.96 (s, 2 H), 6.17–6.20 (m, 1 H), sulfate and concentrated in vacuo to yield 0.268 g (96% 6.75-6.85 (m, 3 H), 7.38–7.45 (m, 3 H). yield) of the title compound as a white solid. "H NMR (300 2h. 1-(4-(1,3-benzodioxol-5-methyl)amino)-6- MHz, DMSO) 84.59–4.63 (d, 2 H), 5.98 (s, 2 H), 6.86 (s, 2 chloro-2-quinazolinyl)-4-piperidine-carboxylic H), 6.86 (s, 2 H), 6.96 (s, 1H), 7.62-7.66 (d. 1 H), 7.79–7.84 ethyl-(3-methyl-3(nitrosothiol)butyramide) thioester (d. 1 H), 8.46 (s, 1 H), 9.24-9.28 (t, 1H). 40 hydrochloride 2e. 1-(4-(1,3-benzodioxol-5-ylmethyl)amino)-6- The product of Example 2g (0.034g, 0.057 mmol) was chloro-2-quinazolinyl)-4-piperidine-carboxylic acid dissolved in methanol/dichloromethane (1 ml, 1:1) and 4N ethyl ester HCl in ether (0.100 ml) was added. Concentration in vacuo 45 afforded a white Solid. The white Solid was then dissolved in The product of Example 2d (0.164 g. 0.47 mmol) and a mixture of methylene chloride (3 ml) and methanol (1 ml), ethylisonipecotate (0.200 ml, 1.27 mmol) were combined in and the resulting solution was cooled to 0 C. Tert-butyl 5 g of phenol. The resulting mixture was heated at reflux nitrite (0.034 ml, 0.29 mmol) was added and the reaction temperature (240° C) for 5 hours. The mixture was allowed mixture was stirred at 0° C. for 30 minutes. The volatiles to cool down, dissolved in 20 ml chloroform and washed 50 were evaporated to give 0.037 g (98% yield) of the title with 1 N solution of sodium hydroxide (2x40 ml). The organic fraction was dried over anhydrous Sodium Sulfate compound as a green solid. "H NMR (300 MHz, CDC1) and concentrated in vacuo. The residue was purified by flash 8:1.61-1.76 (m, 4 H), 1.99 (s, 6 H), 2.66-2.85 (m, 1 H), chromatography on Silica gel, eluting with hexane/ethyl 2.90–3.04 (m, 2 H), 3.18–3.45 (m, 4 H), 3.48 (s, 2 H), acetate (9:1) to (5:1) to give 0.164 g (53% yield) of the title 4.59–4.86 (m, 4H), 5.87 (s, 2 H), 6.62–6.71 (d. 1 H), 6.74 compound as a solid. 'H NMR (300 MHz, CDC1) 55 (s, 1 H), 6.80–6.88 (d. 1 H), 6.90 (s, 1 H), 7.48-7.56 (m, 1 81.24-1.30 (t, 3 H), 1.70–1.79 (m, 2 H), 1.96–2.06 (m, 2 H), H), 7.65–7.76 (m, 1 H), 8.14-8.19 (d. 1 H), 8.43 (s, 1 H). 2.54–2.58 (m, 1 H), 3.01-3.10 (t, 2 H), 4.10-4.20 (q, 2 H), Example 3 4.66–4.70 (d, 2 H), 4.77–4.84 (d, 2 H), 5.59 (s, 1 H), 5.97 (s, 2 H), 6.77–6.89 (m, 3 H), 7.40–7.45 (m, 3 H). 60 In Vitro Comparative Relaxation Responses 2f. 1-(4-((1,3-benzodioxol-5-ylmethyl)amino)-6- Human corpus cavernoSum tissue biopsies were obtained chloro-2-quinazolinyl)-4-piperidine-carboxylic acid at the time of penile prosthesis implantation from impotent men. The tissue was maintained in a chilled Krebs The product of Example 2e (0.100 g, 0.21 mmol) was bicarbonate Solution prior to assay. The tissue was cut into dissolved in ethanol (1 ml) and water (0.5 ml) was added, 65 strips of 0.3x0.3x1 cm and Suspended in organ chambers for followed by sodium hydroxide (0.082 g, 2.05 mmol). The isometric tension measurement. Tissues were incrementally resulting mixture was heated at 100° C. for 20 minutes. The Stretched until optimal isometric tension for contraction was US 6,331.543 B1 65 66 obtained. Once this was achieved, the tissues were con Each of the publications, patents and patent applications tracted with phenylephrine (7x10.7 M) and once a stable described herein is hereby incorporated by reference herein contraction was achieved, the tissues were exposed to either in their entirety. dipyridamole or the compound of Example 1 (10 to Various modifications of the invention, in addition to 3x10 M) by cumulative additions to the chamber. At the those described herein, will be apparent to one skilled in the end of the experiment, papaverine (10" M) was added to art from the foregoing description. Such modifications are obtain maximal relaxation. FIG. 58 shows that the com also intended to fall within the Scope of the appended claims. pound of Example 1 at doses of 10 uM and 30 uM was more What is claimed is: efficacious in relaxing the phenylephrine-induced contrac 1. A compound of formula (XI), formula (XII), formula tion than was an equimolar dose of the phosphodiesterase (XIII), formula (XIV), formula (XV), formula (XVI), for inhibitor dipyridamole. Data were expressed as the percent mula (XVII), formula (XVIII), formula (XIX), or a phar loss in tone from the phenylephrine-induced contraction (0% maceutically acceptable Salt thereof: = phenylephrine contraction; -100% = tone after adminis tration of papaverine). wherein the compound of formula (XI) is: 15 Example 4 XI -'D In vivo Comparative Erectile Responses O White New Zealand male rabbits (2.6-3.0 kg) were YD, 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 O exposed via Surgical cut and intracavernoSal blood pressure D1 NN was measured using a 23-gauge needle inserted to the corpus 25 cavernosum. The contralateral corpus cavernoSum was P.S., 2 implanted with a 23-gauge needle for the administration of drugs. Following all Surgical procedures, rabbits were allowed to wherein rest for 10 minutes during which intracavernosal blood D is a hydrogen, a lower alkyl or D, pressure (ICP) and mean arterial blood pressure (MABP) D is: were continuously recorded. All drug treatments were administered after Stable intracavernoSal and Systemic blood (ii) -NO, preSSures were established. If an increase in intracavernoSal (iii) -CH(R)-O-C(O)-Y-Z-(C(R)(R))- blood pressure (ICP) was observed, the effect was monitored 35 T-Q, throughout its entire duration. Animals that did not exhibit (iv) -C(O)-Y-Z-(G-(C(R)(R)). T-Q); an increase in ICP received an injection of a combination of (v) -P-Z-(G-(C(R)(R)) T-Q); phentolamine (0.2 mg) and papaverine (6.0 mg) to confirm (vi) -P-B-W-B-L-E-(C(R)(R)),- the accuracy of needle implantation and to evaluate the E-(C(R)(R))-L-(C(R)(R)),-L-E- erectile responsiveness of the animal. Animals that did not 40 L-(C(R)(R)- -Q; O respond to this combination were disregarded from the (vii) -P-F-L-E-(C(R)(R))-E-(C(R) analysis. (R))-L-(C(R)(R)),-L-E-L-(C(R) Sildenafil hydrochloride was prepared as an aqueous (R)O-T-Q; R is a hydrogen, a lower alkyl, a cycloalkyl, an aryl or Solution (injection volume 1 ml) and administered intrave 45 nously into the ear vein. S-nitrosoglutathione (SNO-Glu) an arylalkyl, was prepared as an aqueous Solution (200 ug in 200 uD) and Y is oxygen, S(O), lower alkyl or NR; injection intracorporally. Following drug injection the tub o is an integer from 0 to 2, ing was flushed with 100 till distilled water. The following R is a hydrogen, an alkyl, an aryl, an alkylcarboxylic parameters were obtained from each experimental record 50 acid, an aryl carboxylic acid, an alkylcarboxylic ester, ing: (i) Maximum ICP (mm Hg), (ii) Duration (minutes), an arylcarboxylic ester, an alkylcarboxamido, an defined as the time in minutes, that the increase in ICP is arylcarboxamido, an alkylaryl, an alkylsulfinyl, an greater than the 50% difference between baseline and maxi alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a mum response. Data were analyzed using ANOVA Statistical Sulfonamido, a carboxamido, a carboxylic ester, analysis (p<0.05). 55 -CH2-C(T-Q)(R)(R), or -(N2O). M", FIG. 59 shows the peak erectile response in vivo in the wherein M" in an organic or inorganic cation; anesthetized rabbit following the administration of (i) R, and R are each independently a hydrogen, an alkyl, a sildenafil hydrochloride alone (ii) the combination of cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an sildenafil hydrochloride and SNO-Glu (iii) SNO-Glu alone. alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a FIG. 60 shows the duration of the erectile response in vivo 60 cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a in the anesthetized rabbit following the administration of (i) haloalkoxy, an amino, an alkylamino, a dialkylamino, sildenafil hydrochloride alone (ii) the combination of an arylamino, a diarylamino, an alkylarylamino, an sildenafil hydrochloride and SNO-Glu (iii) SNO-Glu alone. alkoxyhaloalkyl, a haloalkoxy, a Sulfonic acid, an The administration of the combination of Sildenafil and alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, SNO-Glu shows an unexpected and Superior duration that is 65 an alkylthio, an arylthio, a cyano, an aminoalkyl, an greater than the additive effect of sildenafil and SNO-Glu aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, individually. a carboxamido, a alkyl carboxamido, an aryl US 6,331.543 B1 67 68 carboxamido, an amidyl, a carboxyl, a carbamoyl, an J is: alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcar (i) boxylic ester, a haloalkoxy, a Sulfonamido, an R26 alkylsulfonamido, an arylsulfonamido, a urea, a nitro, R27 -T-Q, or (C(R)(R)). T-Q, or R. and R, taken together with the carbon atoms to which they are attached are a carbonyl, a methanthial, a heterocyclic R30 R28 ring, a cycloalkyl group or a bridged cycloalkyl group; k is an integer from 1 to 3, R29 (ii) p is an integer from 1 to 10; T is independently a covalent bond, oxygen, S(O) or G3 NR; 15 w Z is a covalent bond, an alkyl, an aryl, an arylalkyl, an y alkylaryl, a heteroalkyl, or (C(R)(R)); T O Q is -NO or -NO; (iii) G is a covalent bond, - T -C(O)-, -C(O) T or T, b is an integer from 0 to 5; L-E D P is a carbonyl, a phosphoryl or a Sillyl, 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 25 R is hydrogen or K-G-D; 0 to 3; K is: W, X, y and Z are each independently an integer from 0 to 10; (i) P is a covalent bond or P; B at each occurrence is independently an alkyl group, an aryl group, or (C(R)(R)); A, E at each occurrence is independently -T-, an alkyl group, an aryl group, or -(CH2CH2O): 35 q is an integer of from 1 to 5; L at each occurrence is independently -C(O)-, (ii) -C(S)--T-, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an arylheterocyclic ring, or -(CH2CH2O): 40 ---- W is oxygen, S(O), or NR; Fat each occurrence is independently Selected from B or carbonyl, G is (CH), (CH), oxygen, Sulfur or nitrogen; n is an integer from 2 to 5; 45 V is carbon or nitrogen; with the proviso that when R is -CH-C(T-Q)(R) A, A and A comprise the other Subunits of a 5- or (R) or -(N.O.)M", or R, or R are T-Q or (C(R) 6-membered monocyclic aromatic ring and each is (R)). T-Q, then the "-T-Q" subgroup designated independently (i) C-R wherein R at each occur in D can be a hydrogen, an alkyl, an alkoxy, an rence is independently D, a hydrogen, a halogen, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl; and 50 alkoxy, a nitrile, an alkyl, an arylalkyl, an alkylaryl, a with the proviso that at least one D must be D; carboxamido, a carboxyl, a haloalkyl, an alkoxyalkyl, wherein the compound of formula (XII) is: an alkoxyaryl or a nitro, (ii) Sulfur, (iii) oxygen; and (iv) B=B, wherein B and B, are each independently XII 55 nitrogen or C-R wherein R at each occurrence is as defined herein; and R2, R27, R-2s, Rao, and Rao are each independently a hydrogen, a halogen, a hydroxy, a haloalkyl, an alkoxy, 60 an alkoxyalkyl, an alkoxyaryl, an alkoxyhaloalkyl, a nitrile, a nitro, an alkyl, an alkylaryl, an arylalkyl, a hydroxy alkyl, a carboxamido, or a carboxyl, d, g, p, E., L., G, T, Y and D are as defined herein; wherein, 65 with the proviso that at least one of the variables A, A, Rs is a hydrogen, a lower alkyl group or a haloalkyl A, J or R2 must contain the element "-T-Q’ or grOup, “D’; US 6,331.543 B1 69 70 wherein the compound of formula (XIII) is: -continued (iii) XIII

R31 D 5 e T S. O-R R38 1O wherein, R is an alkyl, a halogen, a haloalkyl, or a haloalkoxy; D is Dor hydrogen; R is D, or -C(O)-Rs c, d, g, i, j, k, r, S, W, X, y, Z, E, L, G, T, Q, Re, R, R26, 32. s 89 R27, Ras, Rao, Rao and Rs are a defined herein; D is D or hydrogen; and D and Rs are as defined herein; 15 with the proviso that D must be D if R, Ras, R or R-7 wherein the compound of formula (XIV) is: do not contain the element “T-O'; wherein the compound of formula (XV) is: XIV R '6 A. R 2O XV N1 34 Re 2/ R35 N D R36 25 S N X 1. R37 G4 (R25)k G4 wherein wherein A is CH 2, a carbonylbonvl or a melnanenial;thanethial: 3O Ras at each occurrence is independently a hydrogen, an G is oxygen or Sulfur, alkyl, a cycloalkoxy, a halogen, a hydroxy, an R is hydrogen, lower alkyl, alkenyl, alkynyl or hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, L-E,-(C(R)(R))-E-(C(R)(R))-L-(C an alkylaryl, an arylalkoxy, an alkylthio, an arylthio, a (R)(R))-L-L-E-(C(R)(R))-T-Q; Ras is cyano, an aminoalkyl, an amino an alkoxy, an aryl, an and Rs are each independently a hydrogen, a lower arylalkyl, a carboxamido, a alkyl carboxamido, an aryl alkyl, an arylalkyl, an alkylaryl, a cycloalkylalkyl, a carboxamido, a carboxyl, a carbamoyl, alkylcar heterocyclicalkyl, T-Q or (C(R)(R)) T-Q; or boxylOXy IIc acid,d an arylcarDOXytylcarboxyl 11C acIC1,d a CarDOXyboxylic IIC esteSler, Ras and R taken together with the carbon to which an alkylcarboxylic ester, an arylcarboxylic ester, a h35 36 hed bonvl hanethial carbo X amido, an alkyl carbo X amido, an they are attached are a carbonyl group, a methanethlal 40 arylcarboxamido, a haloalkoxy, a Sulfonamido, a urea, group, a heterocyclic group or a cycloalkyl group; or a nitro, or L-E,-(C(R)(R))-E-(C(R)(R)- R and Ras taken together with the carbon to which L-(C(R)(R))-L-E-L-(C(R)(R))-T- they are attached are (C(R)(R)), or -C(R)(R)-C O; e Vyfy y i i g e Vyff - (R)=C(R)-(C(R)(R)), wherein u is an integer of c, d, g, i, j, k, r, S, W, X, y, Z, G, D, E, L, T, Q, Re, R, 3 or 4, V is an integer of 1 or 2 and R, and R, at each 45 R, and Rs are as defined herein; occurrence is independently a hydrogen, an alkyl, with the proviso that D must be D if R or Rs do not T-Q or (C(R)(R)) T-Q; contain the element “T-O'; R is a hydrogen, a halogen or a lower alkyl, wherein the compound of formula (XVI) is: Rs7 is: 50 XVI (i) R41 R26 Na R27 55 N o>1 R40 R121. N \ / R30 R28 R29 go wherein (ii) Rao is a hydrogen, a lower alkyl, a haloalkyl, a halogen, an alkoxy, an alkenyl, an alkynyl, a carbamoyl, a G3 Sulfonamido or L-E,-(C(R)(R))-E-(C(R) W (R))-L-(C(R)(R)),-L- E-L-(C(R) T or R, is a lower alkyl, a hydroxyalkyl, an alkylcarboxylic acid, an alkylcarboxylic ester an alkylcarboxamido or US 6,331.543 B1

wherein R is: (i) R26 5 (i) R27

N - (R) R30 R28 1O 2 R29 (ii) (ii)

N G3 - (RAs) or 2 15 y T O (iii) (iii) w(CH2)a "So N - (R) 2O 17s. 21 NeN

R at each occurrence is independently an amino, a 25 wherein d, 9, P, D, E, L, Gs, G4, T, Rs, R26, R27, Rs, R29, cyano, a halogen, a nitro group, a carboxyl, a and Rao are as defined herein; carbamoyl, a Sulfonic acid, a Sulfonic ester, a wherein the compound of formula (XIX) is: Sulfonamido, a heterocyclic ring, a carboxamido, a carboxylic ester, an ester, an amidyl, a phosphoryl or XIX L-E,-(C(R)(R))-E-(C(R)(R))-L-(C (R)(R))-L-E-L-(C(R)(R)-T-Q; and R8 N N ?tic c, d, g, i, j, k, r, S, W, X, y, z, E, L T, Q, R., and R are as H -T-CR (R)-X defined herein; N s S4 R47 with the proviso that at least one of Rio, R., or R must 35 G-( contain the element “T-O'; N 2 wherein the compound of formula (XVII) is: A

XVII R CH 40 wherein, 8- N - 2r. J Rae and R7 are each independently a lower alkyl, hydroxyalkyl or D, or R and R7 taken together with the nitrogen atom to which they are attached are a 21 n N heterocyclic ring, R - 45 G, T, Rs, and k are as defined herein; S 2 N with the proviso that at least one of the variables R or R7 must be D or when the variables taken together are R24 a heterocyclic ring, the ring must contain NR, wherein R must contain the element “T-Q”. 50 2. The compound of claim 1, wherein the compound is a wherein Rs, R, R p and J are as defined herein; nitrosated papaveroline, a nitrosylated papaveroline, a nit rosated and nitrosylated papaveroline, a a nitrosated E 4021, with the proviso that at least one R or J must contain the a nitroSated nitrosylated E 4021, a nitrosated and nitrosy element "-T-Q’ or lated E 4021, a nitrosated thienopyrimidine derivative, a wherein the compound of formula (XVIII) is: 55 nitrosylated thienopyrimidine derivative, a nitroSated and nitrosylated thienopyrimidine derivative, a nitrosated XVIII trifusal, a nitroSylated trifusal, a nitrosated and nitroSylated R26 G4 trifusal, a nitrosated ICOS-351, a nitrosylated ICOS-351, a R27 CH.) nitrosated and nitrosylated ICOS 351, a nitrosated N R44 60 tetrahydropipera Zino (1,2-b)beta-carboline-1,4-dione R8 derivative, a nitrosylated tetrahydropiperazino(1,2-b)beta carboline-1,4-dione derivative, a nitrosated and nitrosylated tetrahydropipera Zino (1,2-b)beta-carboline-1,4-dione R29 Ld derivative, a nitrosated carboline derivative, a nitroSylated YE-D 65 carboline derivative, a nitroSated and nitrosylated carboline derivative, a nitrosated 2-pyrazolin-5-one derivative, a nitrosylated 2-pyrazolin-5-one derivative, a nitroSated and US 6,331.543 B1 73 74 nitrosylated 2-pyrazolin-5-one derivative, a nitrosated fused edema, hepatic edema, Stroke, asthma, bronchitis, chronic pyridazine derivative, a nitrosylated fused pyridazine ob Structive pulmonary disease, de mentia, derivative, a nitrosated and nitrosylated fused pyridazine immunodeficiency, premature labor, dysmenorrhoea, benign derivative, a nitroSated quinazoline derivative, a nitroSylated prostatic hyperplasis, bladder outlet obstruction, quinazoline derivative, a nitrosated and nitrosylated incontinence, a condition of reduced blood vessel patency, quinazoline derivative, a nitrosated anthranilic acid postpercutaneous transluminal coronary angioplasty, periph derivative, a nitrosylated anthranilic acid derivative, a nit eral vascular disease, allergic rhinitis, cystic fibrosis, rosated and nitrosylated anthranitic acid derivative, a nitro glaucoma, or a disease characterized by a gut motility Sated imidazoquinazoline derivative, a nitrosylated imida disorder. Zoquinazoline derivative, or a nitrosated and nitroSylated 18. A composition comprising at least one compound of imidazoquinazoline derivative. claim 1 and at least one compound that donates, transfers, or 3. A composition comprising the compound of claim 1 releases nitric oxide, or induces the production of endog and a pharmaceutically acceptable carrier. enous nitric oxide or endothelium-derived relaxing factor or 4. A method for treating a Sexual dysfunction in a patient is a Substrate for nitric oxide Synthase. in need thereof comprising administering a therapeutically 15 19. The composition of claim 18, wherein the compound effective amount of the composition of claim 3. that donates, transfers, or releases nitric oxide, or induces the 5. The method of claim 4, wherein the patient is female. production of endogenous nitric oxide or endothelium 6. The method of claim 4, wherein the patient is male. derived relaxing factor or is a Substrate for nitric oxide 7. The method of claim 4, wherein the composition is Synthase is an S-nitroSothiol. administered orally, by intracavernoSal injection, by tran 20. The composition of claim 19, wherein the Surethral application, or by transdermal application. S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso 8. A method for treating or preventing a disease induced captopril, S-nitroso-N-acetylpenicillamine, S-nitroSo by the increased metabolism of cyclic guanosine 3',5'- homocysteine, S-nitroSo-cysteine or S-nitroSO-glutathione. monophosphate in a patient in need thereof comprising 21. The composition of claim 19, wherein the administering a therapeutically effective amount of the com 25 S-nitroSothiol is: position of claim 3. (i) HS(C(R)(R)),SNO; 9. The method of claim 8, wherein the disease induced by (ii) ONS(C(R)(R)), R.; or the increased metabolism of cyclic guanosine 3',5'- (iii) HN-CH(COH)–(CH),C(O)NH-CH monophosphate is hypertension, pulmonary hypertension, (CHSNO)-C(O)NH-CH-COH: congestive heart failure, renal failure, myocardial infarction, wherein m is an integer of from 2 to 20; R and R are Stable, unstable or variant (Prinzmetal) angina, each independently a hydrogen, an alkyl, a atherosclerosis, cardiac edema, renal insufficiency, nephrotic cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, edema, hepatic edema, Stroke, asthma, bronchitis, chronic an alkoxyalkyl, an arylheterocyclic ring, an obstructive pulmonary disease, cystic fibrosis, dementia, alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, am immunodeficiency, premature labor, dysmenorrhoea, benign 35 alkoxy, a haloalkoxy, an amino, an alkylamino, a prostatic hyperplasis, bladder outlet obstruction, dialkylamino, an arylamino, a diarylamino, an alky incontinence, a condition of reduced blood vessel patency, larylamino an alkoxyhaloalkyl, a haloalkoxy, a Sul postpercutaneous transluminal coronary angioplasty, periph fonic acid, an alkylsulfonic acid, an arylsulfonic eral vascular disease, allergic rhinitis, glaucoma, or a disease acid, an arylalkoxy, an alkylthio, an arylthio, a characterized by a gut motility disorder. 40 cyano, an aminoalkyl, an aminoaryl, an alkoxy, an 10. The composition of claim 3, further comprising at aryl, an arylalkyl, an alkylaryl, a carboxamido, a least one vasoactive agent. alkyl carboxamido, an aryl carboxamido, an amidyl, 11. The composition of claim 10, wherein the vasoactive a carboxyl, a carbamoyl, an alkylcarboxylic acid, an agent is a potassium channel activator, a calcium blocker, an arylcarboxylic acid, an ester, a carboxylic ester, an C.-blocker, a B-blocker, adenosine, an ergot alkaloid, a 45 alkylcarboxylic ester, an arylcarboxylic ester, a vasoactive intestinal peptide, a dopamine agonist, an opioid haloalkoxy, a Sulfonamido, an alkylsulfonamido, an antagonist, a prostaglandin, an endothelin antagonist or a arylsulfonamido, a urea, a nitro, or -T-Q; or R. mixture thereof. and R taken together with the carbon atoms to which 12. A method for treating a Sexual dysfunction in a patient they are attached are a carbonyl, a methanthial, a in need thereof comprising administering a therapeutically 50 heterocyclic ring, a cycloalkyl group or a bridged effective amount of the composition of claim 10. cycloalkyl group; Q is -NO or -NO; and T is 13. The method of claim 12, wherein the patient is female. independently a covalent bond, an oxygen, S(O) or 14. The method of claim 12, wherein the patient is male. N, wherein o is an integer from 0 to 2, and R is a 15. The method of claim 12, wherein the composition is hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, administered orally, by intracavernoSal injection, by tran 55 an aryl carboxylic acid, an alkylcarboxylic ester, an Surethral application or by transdermal application. arylcarboxylic ester, an alkylcarboxamido, an 16. A method for treating or preventing a disease induced arylcarboxamido, an alkylaryl, an alkylsulfinyl, an by the increased metabolism of cyclic guanosine 3',5'- alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a monophosphate in a patient in need thereof comprising sulfonamido, carboxamido, -CH-C(T-Q)(R) administering a therapeutically effective amount of the com 60 (R), or -(N.O.)M", wherein M' in an organic or position of claim 10. inorganic cation; with the proviso that when R is 17. The method of claim 16, wherein the disease induced -CH-C(T-Q)(R)(R) or -(N.O.)M"; then by the increased metabolism of cyclic guanosine 3',5'- "-T-Q' can be a hydrogen, an alkyl group, an monophosphate is hypertension, pulmonary hypertension, alkoxyalkyl group, an aminoalkyl group, a hydroxy congestive heart failure, renal failure, myocardial infarction, 65 group or an aryl group. Stable, unstable or variant (Prinzmetal) angina, 22. The composition of claim 18, wherein the compound atherosclerosis, cardiac edema, renal insufficiency, nephrotic that donates, transfers, or releases nitric oxide, or induces the US 6,331.543 B1 75 76 production of endogenous nitric oxide or endothelium 27. The method of claim 26, wherein the patient is female. derived relaxing factor or is a Substrate for nitric oxide 28. The method of claim 26, wherein the patient is male. Synthase is L-arginine, L-homoarginine, N-hydroxy-L- 29. The method of claim 26, wherein the composition is arginine, nitrosated L-arginine, nitrosylated L-arginine, nit administered orally, by intracavernoSal injection, by tran rosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L- Surethral application or by transdermal application. arginine, an inhibitor of the enzyme arginase, citrulline, 30. A method for treating or preventing a disease induced ornithine or glutamine. by the increased metabolism of cyclic guanosine 3',5'- 23. The composition of claim 18, wherein the compound monophosphate in a patient in need thereof comprising that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium administering a therapeutically effective amount of the com derived relaxing factor or is a Substrate for nitric oxide position of claim 18. Synthase is: 31. The method of claim 30, wherein the disease induced (i) a compound that comprises at least one ON-O-, by the increased metabolism of cyclic guanosine 3',5'- ON-N- or ON-C-group; monophosphate is hypertension, pulmonary hypertension, (ii) a compound that comprises at least one O-N-O-, congestive heart failure, renal failure, myocardial infarction, ON-N-, ON-S- or -ON-C-group; 15 Stable, unstable or variant (Prinzmetal) angina, (iii) a N-oxo-N-nitrosoamine having the formula: R'R- atherOSclerosis, cardiac edema, renal insufficiency, nephrotic N(O-M')-NO, wherein R and R are each inde edema, hepatic edema, Stroke, asthma, bronchitis, chronic pendently a polypeptide, an amino acid, a Sugar, an ob Structive pulmonary disease, de mentia, oligonucleotide, a Straight or branched, Saturated or immunodeficiency, premature labor, dysmenorrhoea, benign unsaturated, aliphatic or aromatic, Substituted or unsub prostatic hyperplasis, bladder outlet obstruction, Stituted hydrocarbon, or a heterocyclic group, and M" incontinence, a condition of reduced blood vessel patency, is an organic or inorganic cation; or postpercutaneous transluminal coronary angioplasty, periph (iv) a thionitrate having the formula: R'-(S)-NO, eral vascular disease, allergic rhinitis, glaucoma, cystic wherein R is a polypeptide, an amino acid, a Sugar, an fibrosis, or a disease characterized by a gut motility disorder. oligonucleotide, a Straight or branched, Saturated or 25 32. The composition of claim 18, further comprising at unsaturated, aliphatic or aromatic, Substituted or unsub least one vasoactive agent. Stituted hydrocarbon, or a heterocyclic group. 33. The composition of claim 32, wherein the vasoactive 24. The composition of claim 23, wherein the compound agent is a potassium channel activator, a calcium blocker, an comprising at least one ON-O-, ON-N- or ON-C- C.-blocker, a B-blocker, adenosine, an ergot alkaloid, a group is an ON-O-polypeptide, an ON-N-polypeptide, an vasoactive intestinal peptide, a dopamine agonist, an opioid ON-C-polypeptide, an ON-O-amino acid, an ON-N- antagonist, a prostaglandin, an endothelin antagonist or a amino acid, an ON-C-amino acid, an ON-O-Sugar, an mixture thereof. ON-N-sugar, an ON-C-sugar, an ON-O- 34. A method for treating a sexual dysfunction in a patient oligonucleotide, an ON-N-oligonucleotide, an ON-C- in need thereof comprising administering a therapeutically oligonucleotide, a Straight or branched, Saturated or 35 effective amount of the composition of claim 32. unsaturated, Substituted or unsubstituted, aliphatic or aro 35. The method of claim 34, wherein the patient is female. matic ON-O-hydrocarbon, a straight or branched, satu 36. The method of claim 34, wherein the patient is male. rated or unsaturated, Substituted or unsubstituted, aliphatic 37. The method of claim 34, wherein the composition is or aromatic ON-N-hydrocarbon, a straight or branched, administered orally, by intracavernoSal injection, by tran Saturated or unsaturated, Substituted or unsubstituted, ali 40 Surethral application or by transdermal application. phatic or aromatic ON-C-hydrocarbon, an ON-O- 38. A method of treating or preventing a disease induced heterocyclic compound, an ON-N-heterocyclic compound by the increased metabolism of cyclic guanosine 3',5'- or a ON-C-heterocyclic compound. monophosphate in a patient in need thereof comprising 25. The composition of claim 23, wherein compound administering a therapeutically effective amount of the com comprising at least one ON-O-, ON-N-, ON-S- 45 position of claim 32. or ON-C-group is an ON-O-polypeptide, an ON 39. The method of claim 38, wherein the disease induced N-polypeptide, an ON-S-polypeptide, an ON-C- by the increased metabolism of cyclic guanosine 3',5'- polypeptide, an ON-O-amino acid, ON-N-amino acid, monophosphate is hypertension, pulmonary hypertension, ON-S-amino acid, an ON-C-amino acid, an ON-O- congestive heart failure, renal failure, myocardial infarction, Sugar, an ON-N-Sugar, ON-S-Sugar, an ON-C-Sugar, 50 Stable, unstable or variant (Prinzmetal) angina, an ON-O-oligonucleotide, an ON-N-oligonucleotide, atherOSclerosis, cardiac edema, renal insufficiency, nephrotic an ON-S-oligonucleotide, an ON-C-oligonucleotide, a edema, hepatic edema, Stroke, asthma, bronchitis, chronic Straight or branched, Saturated or unsaturated, aliphatic or ob Structive pulmonary disease, de mentia, aromatic, substituted or unsubstituted ON-O- immunodeficiency, premature labor, dysmenorrhoea, benign hydrocarbon, a Straight or branched, Saturated or 55 prostatic hyperplasis, bladder outlet obstruction, unsaturated, aliphatic or aromatic, Substituted or unsubsti incontinence, a condition of reduced blood vessel patency, tuted ON-N-hydrocarbon, a straight or branched, satu postpercutaneous transluminal coronary angioplasty, periph rated or unsaturated, aliphatic or aromatic, Substituted or eral vascular disease, allergic rhinitis, cystic fibrosis, unsubstituted ON-S-hydrocarbon, a straight or branched, glaucoma, or a disease characterized by a gut motility Saturated or unsaturated, aliphatic or aromatic, Substituted or 60 disorder. unsubstituted ON-C-hydrocarbon, an ON-O- 40. A kit comprising the compound of claim 1. heterocyclic compound, an ON-N-heterocyclic 41. The kit of claim 40, further comprising (i) at least one compound, an ON-S-heterocyclic compound or an compound that donates, transferS or releases nitrogen ON-C-heterocyclic compound. monoxide, induces the production of endogenous 26. A method for treating a Sexual dysfunction in a patient 65 endothelium-derived relaxing factor, Stimulates endogenous in need thereof comprising administering a therapeutically Synthesis of nitrogen monoxide or is a Substrate for nitric effective amount of the composition of claim 18. oxide Synthase, (ii) at least one vasoactive agent or (iii) at