Combination therapy

Abstract

The present invention relates to a method for treating, preventing, or reducing a disease or disorder, e.g., hypertension, in a subject in need thereof. In embodiments, the method comprises co-administering to the subject an effective amount of a cytochrome P4503A4 (CYP3A4) inhibitor, an effective amount of a nitric oxide (NO) potentiator, and an effective amount of a phosphodiesterase-5 (PDE5) inhibitor. In some embodiments, the CYP3A4 inhibitor and the NO potentiator are the same compound.

Description

[0001] COMBINATION THERAPY

[0002] RELATED APPLICATION

[0003] This application claims the benefit of U. S. Provisional Application No. 63 / 720,592, filed on November 14, 2024. The entire teachings of the above application are incorporated herein by reference.

[0004] BACKGROUND OF THE INVENTION

[0005] The physiological and clinical effects of inhibitors of cyclic guanosine 3', 5'-monophosphate specific phosphodiesterase (cGMP-specific PDE) suggest that such inhibitors have utility in a variety of disease states in which modulation of smooth muscle, renal, hemostatic, inflammatory, and / or endocrine function is desired. Type 5 cGMP-specific phosphodiesterase (PDE5) is the major cGMP hydrolyzing enzyme in vascular smooth muscle. Thus, an inhibitor of PDE5 may be indicated in the restoration or maintenance of endothelial and cardiovascular health and treatment of cardiovascular disorders, including but not limited to hypertension, cerebrovascular disorders, and disorders of the urogenital system, particularly erectile disfunction.

[0006] Although pharmaceutical drugs that provide selective inhibition of PDE5 are currently available, for example, vardenafil (marketed under the trade name Levitra®) is a potent and selective inhibitor of PDE5 and is currently indicated for the treatment of erectile dysfunction. There is a present need to improve the pharmacokinetic properties of PDE5 inhibitors.

[0007] SUMMARY OF THE INVENTION

[0008] The present invention relates to the use of therapeutic agents that inhibit cytochrome P4503A4 (CYP3A4) to improve the pharmacokinetic (PK) properties of PDE5 inhibitors. Without wishing to be bound to any particular theory, it is believed that by inhibiting CYP3 A4, the PK properties of PDE5 inhibitors is improved as a result of reducing the metabolism of the PDE5 inhibitor in the intestine, thereby increasing the overall bioavailability of the PDE5 inhibitor.

[0009] In particular, the present invention relates to a method for treating, preventing, or reducing hypertension in a subject in need thereof, the method comprising co-administering to the subject an effective amount of a cytochrome P4503A4 (CYP3A4) inhibitor and an effective amount of a phosphodiesterase-5 (PDE5) inhibitor.

[0010] BRIEF DESCRIPTION OF THE DRAWINGS

[0011] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.

[0012] Fig. 1 shows the tissue distribution of [14C]-labeled compound of Embodiment XX in the tissues of male rats.

[0013] Fig. 2 depicts the extended release formulation comprising 20 mg of the compound of Embodiment XX provided plasma levels above the minimum effective concentration but below the concentrations where adverse events occur.

[0014] Fig. 3A and Fig. 3B depicts PK data comparing pre-administration and simultaneous administration of a CYP3A4 inhibitor (amlodipine) with a PDE5 inhibitor (Embodiment XX) in rats.

[0015] Fig. 4 depicts the effect of amlodipine in combination with a PDE5 inhibitor (Embodiment XIX) on blood pressure.

[0016] Fig. 5 is an experimental PXRD diffractogram for a crystalline form of Compound I (Form A).

[0017] DETAILED DESCRIPTION

[0018] The invention provides a method for treating, preventing, or reducing a disease or disorder in a subject in need thereof. The disease or disorder includes any chronic disease and / or cardiovascular condition related to or caused by high blood pressure.

[0019] The methods of the present invention can be employed for the maintenance and / or the restoration of endothelial and cardiovascular health. The methods of the present invention can be employed for the treatment of conditions where the inhibition of phosphodiesterases, particularly PDE5, would be beneficial. For example, the methods of the invention may be used for the treatment of cardiovascular disorders, cerebrovascular disorders, and disorders of the urogenital system. Cardiovascular disorders include, but are not limited to, hypertension, isolated systolic hypertension (ISH). pulmonary hypertension, acute heart failure, chronic heart failure, ischemic heart disease (including, but not limited to chronic angina), peripheral arterial disease, pre-eclampsia, Raynaud's Disease, endothelial dysfunction / pre-hypertension, chronic obstructive pulmonary disease (COPD). Meniere's disease, or neuropathic pain in diabetes. Disorders of the urogenital system include, but are not limited to, benign prostatic hypertrophy, erectile dysfunction, and female sexual dysfunction. Preferably the cardiovascular disorder is hypertension. Preferably, the disorder of the urogenital system is erectile dysfunction.

[0020] In particular, the present invention relates to a method for treating, preventing, or reducing hypertension in a subject in need thereof, the method comprising co-administering to the subject an effective amount of a cytochrome P4503A4 (CYP3A4) inhibitor, an effective amount of a nitric oxide (NO) potentiator, and an effective amount of a phosphodiesterase-5 (PDE5) inhibitor.

[0021] In embodiments, the present invention also relates to a method of treating, preventing, or reducing diseases and / or conditions caused by or associated with hypertension in a subject in need thereof, the method comprising co-administering to the subject an effective amount of a cytochrome P450 3A4 (CYP3A4) inhibitor, an effective amount of a nitric oxide (NO) potentiator, and an effective amount of a phosphodiesterase-5 (PDE5) inhibitor. Such diseases and / or conditions caused by or associated with hypertension include, but are not limited to, primary' hypertension, secondary' hypertension, resistant hypertension, pregnancy-related hypertensive disorder, pulmonary hypertension, renal hypertension, angina, and coronary heart disease.

[0022] In embodiments of any of the methods described herein, the CYP3A4 inhibitor and the NO potentiator is the same agent. In such embodiments of any of the methods described herein, an effective amount of an agent that is a dual cytochrome P4503A4 (CYP3A4) inhibitor and an NO potentiator and an effective amount of a phosphodiesterase-5 (PDE5) inhibitor co-administered to the subject in need thereof.

[0023] Without wishing to be bound to any particular theory, it is believed that the inhibition of CYP3A4 and the release of NO in combination with the inhibition of cGMP degradation by a PDE5 inhibitor, provides an improved effect in vasodilation and a decrease in blood pressure as compared to these activities alone or any two of these activities in combination.

[0024] The term “pharmaceutically effective amount”, “therapeutically effective amount”, and “effective amount” are used interchangeably and generally refers to an amount sufficient to affect a desired biological effect, such as a beneficial result, in at least a sub-population of cells in an animal at a reasonable benefit / risk ratio applicable to any medical treatment, e.g. reasonable side effects applicable to any medical treatment. Thus, an effective amount will depend upon the context in which it is being administered. An effective amount may be administered in one or more prophylactic or therapeutic administrations.

[0025] Co- Administration

[0026] The term “co-administration” generally refers to the administration of at least two different substances, for example, a PDE5 inhibitor and a CYP3A4 inhibitor, sufficiently close in time to provide the desired response. Co-administration includes sequential, simultaneous or separate administration of the active compound in a way that the therapeutical effects of the first administered one is not entirely disappeared when the subsequent is administered.

[0027] The term “in combination with” generally means in the course of treating the same disease in the same patient and includes administering two or more agents in any order, including co-administration, as well as temporally spaced order from a few seconds up to several days apart. Such combination treatment may also include more than a single administration of one or more of the agents. The administration of the two or more agents may be by the same or different routes.

[0028] In embodiments, the CYP3 A4 inhibitor, and optionally the NO potentiator, is administered to the subject at the same time as the PDE5 inhibitor. In some embodiments, a single agent is both a CYP3A4 inhibitor and a NO potentiator.

[0029] In embodiments, the CYP3 A4 inhibitor, and optionally the NO potentiator, is administered to the subject prior to the PDE5 inhibitor e.g., 1 minute to about 60 minutes, 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks prior to the administration of the PDE5 inhibitor. In embodiments, the CYP3A4 inhibitor, and optionally the NO potentiator, is administered to the subject about 1 minute to about 60 minutes prior to the PDE5 inhibitor. In some embodiments, a single agent is both a CYP3A4 inhibitor and a NO potentiator.

[0030] In embodiments, the CYP3A4 inhibitor, and optionally the NO potentiator, is administered to the subject after the PDE5 inhibitor e.g., 1 minute to about 60 minutes. 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the PDE5 inhibitor. In some embodiments, a single agent is both a CYP3A4 inhibitor and a NO potentiator.

[0031] In some embodiments, the PDE5 inhibitor and the CYP3A4 inhibitor, and optionally the NO potentiator, are administered concurrently but on different schedules. In some embodiments, a single agent is both a CYP3A4 inhibitor and a NO potentiator. Cytochrome P4503A4 (CYP3A4)

[0032] Cytochrome P450 3A4 (CYP3A4), encoded by CYP3A4 gene, is a member of the cytochrome P450 family of oxidizing enzymes. CYP3A4 is an enzyme found mainly in the liver and in the intestine. CYP3A4 oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body.

[0033] CYP3A4 inhibitors can bind either to the active site, to the allosteric site, or both of the CYP3A4 enzyme to inhibit CYP3A4 activity.

[0034] CYP4503A4 inhibition means that one drug (CYP3A4 inhibitor) decreases the activity of the CYP3A4 enzyme and consequently increases the blood concentration of another drug (e.g. the PDE5 inhibitor), the substrate of the CYP3A4 enzyme. A substance is an "inhibitor” of CYP3A4 activity when the specific activity of the CYP3A4 enzyme is decreased by the presence of the substance, without reference to the precise mechanism of such decrease. For example, a substance can be an inhibitor of CYP3A4 enzyme activity by competitive, non-competitive, allosteric or other ty pe of enzyme inhibition, by decreasing expression of the enzyme, or other direct or indirect mechanisms. Co-administration of a PDE5 inhibitor with a CYP3A4 inhibitor may decrease the rate of metabolism of that PDE5 inhibitor through the metabolic pathway listed. By way of example, strong inhibitors of CYP3A4 include clarithromycin, indinavir, nefazodone, saquinavir, suboxone, telithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, and goldenseal. Intermediate strength inhibitors of CYP3A4 include aprepitant. erythromycin, fluconazole, grapefruit, verapamil, and diltiazem. Weak inhibitors of CYP3A4 include cimetidine. Other possible inhibitors include amiodarone, boceprevir, chloramphenicol, ciprofloxacin, delaviridine, diethyl-dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, starfruit, telaprevir, and voriconazole.

[0035] In embodiments, the CYP3A4 inhibitor is an antihypertensive drug. Without wishing to be bound to any particular theory, it is believed that by co-administering an antihypertensive drug that also inhibits CYP3A4 with a PDE5 has multiple beneficial effects. For example, when treating hypertension, two drugs are being administered that have pharmacological effects on hypertension while, at the same time, the PK properties of PDE5 inhibitors can be improved as a result of reducing the metabolism of the PDE5 inhibitor in the intestine through CYP3A4 inhibition, thereby increasing the overall bioavailability of the PDE5 inhibitor.

[0036] In embodiments, the antihypertensive drug is selected from the group consisting of a beta blocker, a calcium (Ca) channel blocker, a potassium (K+)-sparing diuretic, and a loop diuretic. Non-limiting examples of antihypertensive drugs that inhibit CYP3A4 activity are shown in Table 1.

[0037] Table 1

[0038] Class Drugs

[0039] Beta blockers Bisoprolol

[0040] Carvedilol

[0041] Ca channel blockers Amlodipine

[0042] Ddtlazem

[0043] Felodipine

[0044] isradipine

[0045] : Nifedipine

[0046] i Nimodipine

[0047] N;so!rflpine

[0048] : Nitrendipine

[0049] . Verapamil

[0050] fe sparing diuretics Eplerenone

[0051] Spironolactone

[0052]

[0053] Loop diuretics Indapamide

[0054] Preferably, the antihypertensive drug is a calcium (Ca) channel blocker. Ca channel blockers have been shown to have significant anti-CYP3A4 activities (see e.g., Ma et al., Drug Met. Disp. (2000) and Racha et al., Drug Metab. Pharmacokin. (2003)). Preferably, the calcium (Ca) channel blocker is selected from the group consisting of amlodipine, diltiazem. felodipine, isradipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and varapamil.

[0055] In some embodiments, the CYP3A4 inhibitor is an antihypertensive drug that also is an NO potentiator. In embodiments, the antihypertensive drug that also is an NO potentiator is a calcium (Ca) channel blocker selected from amlodipine, nifedipine, and nimodipine.

[0056] Preferably, the calcium (Ca) channel blocker is amlodipine. Preferably, the calcium (Ca) channel blocker is nifedipine. Preferably, the calcium (Ca) channel blocker is nimodipine.

[0057] NO Potentiator

[0058] Nitrogen monoxide can exist as various redox species with distinctive properties and reactivities. These species include: NO+(nitrosonium), NO* (nitric oxide), and NO (nitroxyl anion). Of these species, nitric oxide (commonly referred to as NO) has been implicated in a wide range of biological functions. For example, NO is associated with the maintenance of vascular homeostasis (e.g., vascular endothelial cells may produce NO that regulates vasomotor tone, inhibits vascular smooth muscle cell proliferation, and inhibits platelet adhesion to the vascularure). In addition, studies have shown that endothelial cells in the inner intimal layer of an artery produce NO in response to shear stress or other vasodilatory stimuli. Additionally, endothelial NO may cause vascular smooth muscle to relax and allow dilation to occur.

[0059] The NO potentiator includes any nitric oxide donor, precursors or generating agent that results in the production or release of NO under physiological conditions.

[0060] Examples of NO potentiators include, but are not limited to, nitric oxide donors such as sodium nitroprusside (SNP), S-nitroso-L-glutathione (GSNO), GSNO monoethyl ester, S-nitroso-N-acetylpenicillamine (SNAP), gly co-SNAP, L-arginine, N, N'-dinitroso-N, N'-dimethylphenylenediamine (BNN3), N. N'-dinitrosophenylenediamine-N. N'-diacetic acid (BNN5), BNN5-Na, BNN5 methyl ester, 2-hydroxybenzoic acid 3 -nitrooxy methylphenyl ester (B- NOD), dephostatin, 3,4-dephostatin, diethylamine NONOate, diethylamine NONOate / AM, SiS1- dinitrosodithiol, S-nitrosocaptopril, NG-hydroxy-L-arginine monoacetate salt, Angeli's salt, 1- hydroxy-2-oxo-3-(3-aminopropyl)-3-isopropyl-l-tnazene (NOC-5), l-hydroxy-2-oxo-3-(N-3-methyl- aminopropyl)-3-methyl-l -triazene (NOC-7), 6-(2-hydroxy-l-methyl-2-nitrisohydrazino)-N-methyl-l- hyxanamine (NOC-9), 1 -hydroxy -2-oxo-3-(N-ethyl-2-aminoethyl)-3-ethyl-l -triazene (NOC-12), 2,2'-(hydroxynitrosohydrazono)bis-ethanamine (NOC-18), (±)-(E)-Methyl-2-[ (E)-hydroxyimino|-5-nitro-6- methoxy-3-hexeneamide (NOR-l), (±)-(E)-4-ethyl-2-[(E)-hydroxyiminol-5-nitro-3-hexenamide (NOR-3), (±) -N-[(E)-4-ethyl-2-[(Z)-hydroxyimino]-5-nitro-3-hexene-l -yl]-3-pyridine carboxamide (NOR-4), 4-phenyl-3-furoxancarbonitrile, PROLI / NO (L-proline in methanolic sodium methoxide), 3- morphorlinosydnonimine (SIN-1), S-nitroso-N-valerylpenicillamine (SNVP), spermine NONOate, ethyl nitrite and streptozotocin.

[0061] In general, nitric oxide donors, including S-nitroso, O-nitroso, C-nitroso andN-nitroso compounds and nitro derivatives thereof and metal NO complexes, but not excluding other NO generating compounds, useful for the purposes of the present invention may be found in " Methods in Nitric Oxide Research," edited by Feelisch, M., and Stamler, J. S., John Wiley & Sons, New York, 1996, pages 71-115, the disclosure of which is incorporated herein by reference. A range of additional nitric oxide donors are known to those skilled in the art and the present invention is not limited by the identity of the particular donor(s) used. Indeed the selection of the appropriate donor for a particular application of the invention may be made on a case-by-case basis. In embodiments, the NO potentiator may comprise one or more nitric Q oxide donors. Said one or more nitric oxide donors may be selected from sodium nitroprusside. S- nitroso-L-glutathione, S-nitroso-N-acetylpenicillamine or a combination thereof. In one embodiment the nitric oxide donor is sodium nitroprusside.

[0062] In embodiments, the NO potentiator is a nitric oxide (NO) supplement. NO supplements do not have nitric oxide; rather, NO supplements typically contain substances, such as amino acids (e.g., L-arginine and L-citrulline) and nitrates that the body can convert into nitric oxide.

[0063] In some embodiments, the NO potentiator is a nitric oxide-containing compounds that spontaneously release NO under physiological conditions are described in WO 1995 / 012394, which is incorporated herein by reference.

[0064] PDE5 Inhibitors

[0065] PDE5 inhibitors are known in the art and any can be used in the practice of the invention, including deuterated analogs thereof. Examples of PDE5 inhibitors include, but are not limited to, sildenafil (Compound 1), vardenafil (Compound 2), tadalafil (Compound 3), EMD 360527, DA 8159, or analogs thereof, or any other compound that inhibits cGMP hydrolysis by phosphodiesterase-5 (PDE5).

[0066] Compound 1

[0067]

[0068] Compound 2

[0069] Compound 3

[0070]

[0071] PDE inhibitors useful in the practice of the invention, as well as methods of making, include those disclosed in U. S. Pat. No. 8,853,394. In Embodiment I, such compounds have formula A:

[0072]

[0073] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl; R2is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkydthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0074] R3is selected from the group consisting of the group consisting of C1-C4 alkyl, lower alkenyl and lower alkynyl, wherein the C1-C4 alky 1, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C=(O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0075] A is N or C-H;

[0076] B is N, C-H, C-(SO2-R4), or C-CO-R4;

[0077] D is N, C-H, C-(SO2-R4) or C-CO-R4;

[0078] E is N or C-H;

[0079] wherein only one of A, B or E is N, and one of B or D is C-(SO2-R4) or C-CO-R4; R4is a group having the formula:

[0080] -NH-R41,

[0081] -N(R42)(R43),

[0082]

[0083] or

[0084] -N(R46)2;

[0085] R41is selected from the group consisting of straight-chain C3-C6 alkyl, branched-chain C3-C6 alkyl, C2-C3alkyl-OH, -(CH2N(H)(R51) and -(CH2)a-N(R52)(R53);

[0086] R51is selected from the group consisting of the group consisting of C4-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

[0087] R52and R53are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, ary l, and a heterocyclic group, a is 1 to 6;

[0088] R42is selected from the group consisting of straight-chain alkyl, branched-chain alkyl, and C2-C6 alkyl-O-alkyl-;

[0089] R43is selected from the group consisting of C4-C6 alkyl, C2-C6 alkyl-NH-alkyl, C2-C6 alkyl-O-alkyl, alkyl-CO2H, C2-C6 alkyl-CH(O-alkyl)(O-alkyl), C2-C6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, -(CH2)a-N(H)(R51), and -(CH2)a-N(R52)(R53);

[0090] R44is selected from the group consisting of -(CH2)q-N(R12)(R13), -(CH2)r-N(R11)-(CH2)sC(O)R14, -(CH2)q-C(O)R14, -(CH2)r-C(O)-(CH2)sOR11, -(CH2)r-C(O)-(CH2)sN(R12)(R13), and -(CH2)rO-(CH2)s-C(O)R14,

[0091] each R11is independently selected from the group consisting of H, C3-C6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0092] each R12and R13are independently selected from the group consisting of H, C2-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12and R13may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl. aralkyl, aryl, and a heterocyclic group;

[0093] each R14is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0094] q is 1 to 6;

[0095] r is 0 to 6;

[0096] s is 0 to 6;

[0097] R45is selected from the group consisting of -(CH2)V-N(R25)(R26),

[0098] -(CH2)V-N(R21)-(CH2)„-C(O)R24, -(CH2)V-C(O)R24, -(CH2)Z-C(O)-(CH2)WOR21, -(CH2)rC(O)(CH2)w-N(R22)(R23), and -(CH2)V-O-(CH2)W-C(O)R24;

[0099] each R21is independently selected from the group consisting of H, C5-C6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0100] each R22and R23are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22and R23may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0101] each R24is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl. alkenyl, alkynyl. cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group:

[0102] R25and R26taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0103] t is 0 to 6;

[0104] v is 1 to 6;

[0105] w is 0 to 6;

[0106] x is 1 or 2;

[0107] y is 1 or 2; and

[0108] R46are independently C2-C6 alkyl-O-C2-C6 alkyl.

[0109] In Embodiment II, the compound of Embodiment I has the formula A1:

[0110] (A1)

[0111]

[0112] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl;

[0113] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group; R3is selected from the group consisting of C1-C4 alkyl, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0114] R4is a group having the formula:

[0115] -NH-R41,

[0116] -N(R42)(R43),

[0117]

[0118] or

[0119] -N(R46)2;

[0120] R41is selected from the group consisting of straight-chain C3-C6 alkyl, branched-chain C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)a-N(H)(R51) and -(CH2)a-N(R52)(R53);

[0121] R31is selected from the group consisting of C4-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

[0122] R52and R53are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alky 1. cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0123] a is 1 to 6;

[0124] R42is selected from the group consisting of straight-chain alkyl, branched-chain alkyl, and C2-C6alkyl-O-alkyl-;

[0125] R43is selected from the group consisting of C4-C6 alkyl, C2-C6 alkyl-NH-alkyl, C2-C6 alkyl-O-alkyl, alkyl-CO2H, C2-C6 alkyl-CH(O-alkyl)(O-alkyl), C2-C6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, -(CH2)a-N(H)(R51), and -(CH2)«-N(R52)(R53);

[0126] R44is selected from the group consisting of the group consisting of

[0127] -(CH2)q-N(R12)(R13), -(CH2)r-N(R11)-(CH2)sC(O)R14, -(CH2)q-C(O)R14, -(CH2)r-C(O)-(CH2)sOR11, -(CH2)r-C(O)-(CH2)sN(R12)(R13), and -(CH2)r-O-(CH2)sC(O)R14; each R11is independently selected from the group consisting of H, C3-C6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0128] each R12and R13are independently selected from the group consisting of H, C2-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12and R13may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0129] each R14is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0130] q is 1 to 6;

[0131] r is 0 to 6;

[0132] s is 0 to 6;

[0133] R45is selected from the group consisting of -(CH2)V-N(R25)(R26),

[0134] -(CH2)v-N(R21)-(CH2)u-C(O)R24, -(CH2)v-C(O)R24, -(CH2)z-C(O)-(CH2)wOR21, -(CH2)rC(O)(CH2)w-N(R22)(R23), and -(CH2)V-O-(CH2)W-C(O)R24;

[0135] each R21is independently selected from the group consisting of H, C5-C6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0136] each R22and R23are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22and R23may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0137] each R24is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0138] R25and R26taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0139] t is 0 to 6;

[0140] v is 1 to 6;

[0141] w is 0 to 6;

[0142] x is 1 or 2;

[0143] y is 1 or 2; and

[0144] R46are both selected from the group consisting of C2-C6 alkyl-O-C2-C6 alkyl.

[0145] In Embodiment III, the compound of Embodiment II has the formula A2:

[0146]

[0147] or a pharmaceutically acceptable salt or stereoisomer thereof, wherein

[0148] R4is a group having the formula:

[0149] -NH-R41,

[0150] -N(R42)(R43),

[0151]

[0152] or

[0153] -N(R46)2;

[0154] R41is selected from the group consisting of straight-chain C3-C6 alkyl, branched-chain C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)a-N(H)(R51) and -(CH2)a-N(R52)(R53);

[0155] R31is selected from the group consisting of C4-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

[0156] R52and R53are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group,

[0157] a is 1 to 6;

[0158] R42is selected from the group consisting of straight-chain alky l, branched-chain alkyl, and C2-C6 alkyl-O-alkyl-;

[0159] R43is selected from the group consisting of C4-C6 alkyl, C2-C6 alkyl-NH-alkyl, C2-C6 alkyl-O-alkyl, alkyl-CO2H, C2-C6 alkyl-CH(O-alkyl)(O-alkyl), C2-C6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, -(CH2)«-N(H)(R51), and -(CH2)„-N(R52)(R53);

[0160] R44is selected from the group consisting of the group consisting of

[0161] -(CH2)q-N(R12)(R13), -(CH2)r-N(R11)-(CH2)sC(O)R14, -(CH2)q-C(O)R14, -(CH2)r-C(O)-(CH2)sOR11, -(CH2)r-C(O)-(CH2)sN(R12)(R13), and -(CH2)rO-(CH2)s-C(O)R14, each R11is independently selected from the group consisting of H, C5-C6alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0162] each R12and R13are independently selected from the group consisting of H, C2-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12and R13may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0163] each R14is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl. alkenyl, alkynyl. cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0164] q is 1 to 6;

[0165] r is 0 to 6;

[0166] s is 0 to 6;

[0167] R45is selected from the group consisting of the group consisting of

[0168] -(CH2)v-N(R25)(R26), -(CH2)v-N(R21)-(CH2)w-C(O)R24, -(CH2)v-C(O)R24, -(CH2)zC(O)-(CH2)wOR21, -(CH2)v-C(O)(CH2)w-N(R22)(R23), and -(CH2)v-O-(CH2)w-C(O)R24; each R21is independently selected from the group consisting of H, C5-C6 alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0169] each R22and R23are independently selected from the group consisting of H, alkyd, cycloalkyl, cycloalkeny 1, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22and R23may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0170] each R24is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0171] R25and R26taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0172] t is 0 to 6;

[0173] v is 1 to 6;

[0174] w is 0 to 6;

[0175] x is 1 or 2;

[0176] y is 1 or 2; and

[0177] R46are independently C2-C6 alkyl-O-C2-C6 alkyl.

[0178] In Embodiment IV, the compound of Embodiment I has the formula Bi:

[0179] (B1)

[0180]

[0181] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl;

[0182] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0183] R3is selected from the group consisting of C1-C4 alkyl, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0184] R41is selected from the group consisting of straight-chain C3-C6 alkyl, branched-chain C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)a-N(H)(R51) and -(CH2)«-N(R52)(R53);

[0185] R51is selected from the group consisting of C4-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

[0186] R52and R53are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, and

[0187] a is 1 to 6.

[0188] In Embodiment V, the compound of Embodiment IV has the formula B2;

[0189]

[0190] wherein,

[0191] R41is selected from the group consisting of straight-chain C3-C6 alkyl, branched-chain C3-C6 alkyl, C2-C3alkyl-OH, -(CH2)a-N(H)(R51) and -(CH2)a-N(R52)(R53); R51is selected from the group consisting of C4-C6 alky l, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group;

[0192] R52and R53are taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which is substituted at a ring carbon with one or two oxo groups and which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group, and

[0193] a is 1 to 6.

[0194] In Embodiment VI, the compound of Embodiment I has a structure selected from the group consisting of:

[0195]

[0196] and

[0197]

[0198] In embodiment VII, the compound of Embodiment I has the formula Ci:

[0199]

[0200] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl;

[0201] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0202] R3is selected from the group consisting of C1-C4 alkyl, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0203] R42is selected from the group consisting of straight-chain alkyd, branched-chain alkyl, and C2-C6 alkyl-O-alky 1-; and R43is selected from the group consisting of C4-C6 alky l. C2-C6 alkyl-NH-alkyl, C2-C6 alkyl-O-alkyl, alkyl-CO2H, C2-C6 alkyl-CH(O-alkyl)(O-alkyl), C2-C6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, -(CH2)a-N(H)(R51), and -(CH2)a-N(R52)(R53).

[0204] In Embodiment VIII, the compound of Embodiment VII has the formula C2:

[0205]

[0206] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R42is selected from the group consisting of straight-chain alkyl, branched-chain alkyl, and C2-C6 alkyl-O-alkyl-; and

[0207] R43is selected from the group consisting of C4-C6 alkyl, C2-C6 alkyl-NH-alkyl, C2-C6 alkyl-O-alkyl, alkyl-CO2H, C2-C6 alkyl-CH(O-alkyl)(O-alkyl), C2-C6 alkyl-CH(O-alkyl)-alkyl-O-alkyl, -(CH2)a-N(H)(R51), and -(CH2)a-N(R52)(R53).

[0208] In Embodiment IX, the compound of Embodiment I is selected from the group consisting of:

[0209]

[0210]

[0211]

[0212] 23

[0213]

[0214] In Embodiment X, the compound of Embodiment I has the formula Di:

[0215]

[0216] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl;

[0217] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0218] R3is selected from the group consisting of C1-C4 alky l, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy. CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, ary l, or a heterocyclic group;

[0219] R44is selected from the group consisting of -(CH2)q-N(R12)(R13),

[0220] -(CH2)r-N(R11)-(CH2)sC(O)R14, -(CH2)9-C(O)R14. -(CH2)rC(O)-(CH2)sOR11,

[0221] -(CH2)r-C(O)-(CH2)sN(R12)(R13), and -(CH2)rO-(CH2)s-C(O)R14,

[0222] each R11is independently selected from the group consisting of H, C5-C6alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkeny l, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0223] each R12and R13are independently selected from the group consisting of H, C2-C6 alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12and R13may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group:

[0224] each R14is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0225] q is 1 to 6;

[0226] r is 0 to 6;

[0227] s is 0 to 6; and

[0228] x is 1 or 2.

[0229] In Embodiment XI, the compound of Embodiment X has the formula D2:

[0230]

[0231] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl:

[0232] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0233] R3is selected from the group consisting of C1-C4 alky l, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy. CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, ary l, or a heterocyclic group; R44is selected from the group consisting of -(CH2)q-N(R12)(R13), -(CH2)r-N(R11)-(CH2)sC(O)R14, -(CH2)q-C(O)R14, -(CH2)rC(O)-(CH2)sOR11,

[0234] -(CH2)r-C(O)-(CH2)sN(R12)(R13), and -(CH2)rO-(CH2)s-C(O)R14,

[0235] each R11is independently selected from the group consisting of H, C3-C6alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cy cloalkyl, cy cloalkenyl, aralkyl, aryl and a heterocyclic group;

[0236] each R12and R13are independently selected from the group consisting of H, C2-C6alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12and R13may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0237] each R14is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl. alkenyl, alkynyl. cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0238] q is 1 to 6;

[0239] r is 0 to 6; and

[0240] s is 0 to 6.

[0241] In Embodiment XII, the compound of Embodiment XI has the formula Ds:

[0242]

[0243] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R44is selected from the group consisting of -(CH2)q-N(R12)(R13), -(CH2)r-N(R11)-(CH2). C(O)R14, -(CH2)7-C(O)R14. -(CH2),-C(O)-(CH2)4OR11.

[0244] -(CH2),-C(O)-(CH2N(R12)(R13), and -(CH2)rO-(CH2).s-C(O)R14,

[0245] each R11is independently selected from the group consisting of H, C3-C6alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cy cloalkyl, cy cloalkenyl, aralkyl, aryl and a heterocyclic group;

[0246] each R12and R13are independently selected from the group consisting of H, C2-C6alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R12and R13may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0247] each R14is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl-O-alkyl, -alkyl-O-aryl. alkenyl, alkynyl. cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0248] q is 1 to 6;

[0249] r is 0 to 6; and

[0250] s is 0 to 6.

[0251] In Embodiment XIII. the compound of Embodiment XII has a structure:

[0252]

[0253] In Embodiment XIV. the compound of Embodiment I has the formula Ei:

[0254]

[0255] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl;

[0256] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocyclic group;

[0257] R3is selected from the group consisting of C1-C4 alky l, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy. CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, ary l, or a heterocyclic group;

[0258] R45is selected from the group consisting of -(CH2)v-N(R25)(R26),

[0259] -(CH2)v-N(R21)-(CH2)w-C(O)R24, -(CH2)v-C(O)R24, -(CH2)t-C(O)-(CH2)wOR21,

[0260] -(CH2)v-C(O)(CH2)w-N(R22)(R23), and -(CH2)v-O-(CH2)w-C(O)R24;

[0261] each R21is independently selected from the group consisting of H, C5-C6alkyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0262] each R22and R23are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22and R23may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0263] each R24is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl -O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0264] R25and R26taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alky l, cycloalkyl, alkenyl, alkynyl, aralkyl, ary l, and a heterocyclic group;

[0265] t is 0 to 6;

[0266] v is 1 to 6; and

[0267] w is 0 to 6.

[0268] In Embodiment XV, the compound of Embodiment XIV has the formula E2:

[0269] (E2)

[0270]

[0271] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R45is selected from the group consisting of -(CH2)v-N(R25)(R26),

[0272] -(CH2)v-N(R21)-(CH2)w-C(O)R24, -(CH2)v-C(O)R24, -(CH2)t-C(O)-(CH2)wOR21, -(CH2)v-C(O)(CH2)w-N(R22)(R23), and -(CH2)v-O-(CH2)w-C(O)R24;

[0273] each R21is independently the group consisting of H. Cs-Ce alkyl, alkyl-O-alkyl, alkyl-O-aryl. alkenyl, alkynyl. cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group; each R22and R23are independently selected from the group consisting of H, alkyl, cycloalkyl, cycloalkenyl, alkyl-O-alkyl, alkyl-O-aryl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic group; or R22and R23may be taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic group;

[0274] each R24is independently selected from the group consisting of H, alkyl, -OH, -O-alkyl, -O-aryl, -O-aralkyl, -alkyl -O-alkyl, -alkyl-O-aryl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl and a heterocyclic group;

[0275] R25and R26taken together with the nitrogen to which they are attached to form a 5- to 7-membered ring which may optionally contain a further heteroatom and may be optionally substituted with up to three substituents selected from the group consisting of halo, CN, NO2, oxo, alky l, cycloalkyl, alkenyl, alkynyl, aralkyl, ary l, and a heterocyclic group;

[0276] t is 0 to 6;

[0277] v is 1 to 6; and

[0278] w is 0 to 6.

[0279] In Embodiment XVI, the compound of Embodiment I has a structure selected from the group consisting of:

[0280]

[0281]

[0282]

[0283]

[0284] In Embodiment XVII, the compound of Embodiment I has the formula:

[0285]

[0286] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R1is lower alkyl;

[0287] R2is selected from the group consisting of lower alkyl, and lower alkenyl and lower alkynyl, wherein the lower alky l, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-C(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkenyl, alkynyl, aralkyl, aryl, or a heterocy clic group;

[0288] R3is selected from the group consisting of C1-C4 alkyl, lower alkenyl and lower alkynyl, wherein the C1-C4 alkyl, lower alkenyl, and lower alkynyl may be optionally substituted with one or more halogen, lower alkoxy, hydroxy, CN, NO2, amino, acylamino, amido, alkylthio, and -X-(=O)-R or -C(=O)X-R, wherein X is a bond or oxygen or sulfur and R is H, alkyl, alkynyl, aralkyl, aryl, or a heterocyclic group; and

[0289] R46are both selected from the group consisting of C2-C6 alkyl-O-C2-C6 alkyl. In Embodiment XVIII, the compound of Embodiment XVII has the formula:

[0290]

[0291] or a pharmaceutically acceptable salt, stereoisomer, or hydrate thereof, wherein R46are independently C2-C6 alkyl-O-C2-C6 alkyl.

[0292] In Embodiment XIX, Embodiment I has the structure:

[0293]

[0294] The PDE inhibitor of Embodiment XIX (also referred to herein as ‘“RTN-001”) is preferred as it distributes preferentially to vascular tissue and provides a significant antihypertensive response as a single agent in a hypertension therapy resistant population. Fig. 1 shows the tissue distribution of [14C]-labeled compound of Embodiment XIX in the tissues of male rats. The x-axis represents AUC ng*h / g compound of Embodiment XIX equivalents. Following administration of [14C]-labeled compound of Embodiment XIX, the amount of radioactivity was found not to be uniform among tissues and organs at peak plasma concentration (0.5-2 h). Significantly more [14C] was found in the aorta and heart than in the blood or plasma, and very little [14C] was found in the eye or brain. These data show that the PDE5 inhibitor of Embodiment XIX distributes preferentially to vascular tissue. In contrast, for sildenafil, at peak concentration in male rats, the drug preferably distributed to the lungs: lungs > pituitary gland > salivary gland > pineal gland, cardiac (NDA 20-895, Pharmacology Reviews, page 122). For vardenafil hydrochloride (LEVITRA), at 2 hours post dose, iv and 2, 4, and 8 hours po in rats, the drug preferentially distributed to bile ducts and small intestine (extra high) > harderian gland, kidney, liver, spleen, pharyngeal and large intestinal mucosa (high) > adrenal, aorta, bone marrow, brown adipose, choroid plexus, pituitary, lung, lymph nodes, pancreas, prostate, salivary glands, skeletal muscle, thymus (medium) > blood, cartilage, meninges, lens, skin, spinal nerves, testes, white adipose (low) > brain, spinal cord (PH-28719). ND A 021400; Pharmacology Reviews Part 2, page 3. PDE inhibitors useful in the practice of the invention, as well as method of making, also include those disclosed in U. S. Pat. Nos. 8.299.083.

[0295] In Embodiment XX, PDE5 inhibitors are represented by the structure (Formula I): Formula I

[0296]

[0297] in which R1is H, C1-C3 alkyl, C3-C5 cycloalkyl or C1-C3 perfluoroalkyl; R2is H, Ci-Ce alkyl optionally substituted by OH, C1-C3 alkoxy or C3-C6 cycloalkyl, or C1-C3 perfluoroalkyl; R3is C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C6 cycloalkyl, C1-C6 perfluoroalkyl or (C3-C6 cycloalkyl) Ci-Ce alkyl; R4taken together with the nitrogen atom to which it is attached completes a 4-N-(R6)-piperazinyl group; R5is H, C1-C4 alkyl, C1-C3 alkoxy, NR7R8, or CON R7R8; R6is H, C1-C6 alkyl, (C1-C3 alkoxy) C2-C6 alkyl, hydroxy C2-C6 alkyl, (R7R8N) C2-C6 alkyl, (R7R8NCO) C1-C6 alkyl, CON R7R8, CSN R7R8or C(NH)N R7R8; R7and R8are each independently H, C1-C4 alkyl, (C1-C3 alkoxy) C2-C4 alkyl or hydroxy C2-C4 alkyl; and pharmaceutically acceptable salts thereof.

[0298] In Embodiment XXI, useful PDE5 inhibitors are disclosed in U. S. Pat. No. 6,362,178 are represented by the structure (Formula II):

[0299]

[0300] in which

[0301] R1represents hydrogen or straight-chain or branched al kyl having up to 4 carbon atoms,

[0302] R2represents straight-chain alkyl having up to 4 carbon atoms,

[0303] R3and R4are identical or different and each represents hydrogen or represents straight-chain or branched alkenyl or alkoxy having in each case up to 8 carbon atoms, or represents a straight-chain or branched alkyl chain having up to 10 carbon atoms which is optionally interrupted by an oxygen atom and which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of trifluoromethyl. trifluoromethoxy, hydroxyl, halogen, carboxyl, benzyloxy carbonyl, straight-chain or branched alkoxy carbonyl having up to 6 carbon atoms and / or by radicals of the formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', -S(O)b-R9, -P(O)(OR10)(ORn),

[0304]

[0305] in which

[0306] a and b are identical or different and each represents a number 0 or 1,

[0307] A represents a radical CO or SO2,

[0308] R7, R7', R8and R8'are identical or different and each represents hydrogen, or represents cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms, a 5- to 6-membered unsaturated, partially unsaturated or saturated, optionally benzo-fused heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, carboxyl, halogen, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms or by a group of the formula -(SO2)c-NR12R13, in which

[0309] c represents a number 0 or 1,

[0310] R12and R13are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 5 carbon atoms, or

[0311] R7, R7', R8and R8'each represent straight-chain or branched alkoxy having up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 8 carbon atoms which is optionally mono- or poly substituted by identical or different substituents selected from the group consisting of hydroxyl, halogen, aryl having 6 to 10 carbon atoms, straight- chain or branched alkoxy or alkoxy carbonyl having in each case up to 6 carbon atoms or by a group of the formula -(CO)d-NR14R15.

[0312] in which R14and R15are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and

[0313] d represents a number 0 or 1, or

[0314] R7and R8and / or R7'and R8'together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O or a radical of the formula -NR16, in which

[0315] R16represents hydrogen, aryl having 6 to 10 carbon atoms, benzy l, a 5- to 7-membered aromatic or saturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O which is optionally substituted by methyl, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl,

[0316] R9represents aryl having 6 to 10 carbon atoms, or represents straight-chain or branched alkyl having up to 4 carbon atoms,

[0317] R10and R11are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and / or the alkyl chain listed above under R3 / R4is optionally substituted by cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or by a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O or a radical of the formula -NR17, in which

[0318] R17represents hydrogen, hydroxyl, formyl, tri fluoromethyl, straight-chain or branched acyl or alkoxy having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl and straight-chain or branched alkoxy having up to 6 carbon atoms, and where aryl and the heterocycle are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of nitro, halogen, -SO3H, straight-chain or branched alkyd or alkoxy having in each case up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy and / or by a radical of the formula -SO2-NR18R19, in which

[0319] R18and R19are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, and / or

[0320] R3or R4represents a group of the formula -NR20R21, in which R20and R21have the meanings of R18and R19given above and are identical to or different from them, and / or R3or R4represents adamantyl, or represents radicals of the formulae

[0321]

[0322] or represents cycloalkyl having 3 to 8 carbon atoms, aryl having 6 to 10 carbon atoms or represents a 5- to 7-membered partially unsaturated, saturated or unsaturated, optionally benzo-fused heterocycle which may contain up to 4 heteroatoms from the group consisting of S, N and O, or a radical of the formula -NR22, in which

[0323] R22has the meaning of R16given above and is identical to or different from it, or represents carboxyl, formyl or straight-chain or branched acyl having up to 5 carbon atoms, and where cycloalkyl, aryl and / or the heterocycle are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of halogen, triazolyl, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched acyl or

[0324] alkoxy carbonyl having in each case up to 6 carbon atoms, nitro and / or by groups of the formulae -SO3H, -OR23, (SO2)cNR24R25, -P(O)(OR26)(OR27), in which e represents a number 0 or 1,

[0325] R23represents a radical of the formula

[0326]

[0327] or represents cycloalkyl having 3 to 7 carbon atoms, or represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms which is optionally substituted by cycloalkyl having 3 to 7 carbon atoms, benzyloxy. tetrahydropyranyl, tetrahydrofuranyl, straight-chain or branched alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, carboxyl, benzyloxy carbonyl or phenyl which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of straight-chain or branched alkoxy having up to 4 carbon atoms, hydroxyl and halogen, and / or alkyl which is optionally substituted by radicals of the formulae -CO-NR28R29or -CO-R30, in which

[0328] R28and R29are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, or

[0329] R28and R29together with the nitrogen atom form a 5- to 7-membered saturated heterocycle which may optionally contain a further heteroatom from the group consisting of S and O, and

[0330] R30represents phenyl or adamantyl,

[0331] R24and R25have the meanings of R18and R19given above and are identical to or different from them,

[0332] R26and R27have the meanings of R10and R11given above and are identical to or different from them and / or cycloalkyl, aryl and / or the heterocycle are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl, carboxyl, by a 5- to 7-membered heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, or by groups of the formula -SO2-R31, P(O)(OR32)(OR33) or -NR34R35, in which

[0333] R31represents hydrogen or has the meaning of R9given above and is identical to or different from it,

[0334] R32and R33have the meanings of R10and R11given above and are identical to or different from them,

[0335] R34and R35are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms which is optionally substituted by hydroxyl or by straight-chain or branched alkoxy having up to 4 carbon atoms, or

[0336] R34and R35together with the nitrogen atom form a 5- to 6-membered saturated heterocycle which may contain a further heteroatom from the group consisting of S and O, or a radical of the formula -NR36, in which

[0337] R36represents hydrogen, hydroxyl, straight-chain or branched alkoxy carbonyl having up to 7 carbon atoms or straight-chain or branched alkyl having up to 5 carbon atoms which is optionally substituted by hydroxyl, or

[0338] R3and R4together with the nitrogen atom form a 5- to 7-membered unsaturated or saturated or partially unsaturated, optionally benzo-fused heterocycle which may optionally contain up to 3 heteroatoms from the group consisting of S, N and O, or a radical of the formula -NR37, in which R37represents hydrogen, hydroxyl, formyl, trifluoromethyl, straight-chain or branched acyl, alkoxy or alkoxy carbonyl having in each case up to 4 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxy carbonyl having in each case up to 6 carbon atoms, or by groups of the formula -(D)f-NR38R39, -CO-(CH2)g-O-CO-R40, -CO-(CH2)h-OR41or -P(O)(OR42)(OR43), in which

[0339] g and h are identical or different and each represents a number 1, 2, 3 or 4, and f represents a number 0 or 1,

[0340] D represents a group of the formula -CO or -SO2,

[0341] R38and R39are identical or different and each has the meaning of R7and R8given above,

[0342] R40represents straight-chain or branched alkyl having up to 6 carbon atoms, R41represents straight-chain or branched alkyl having up to 6 carbon atoms, R42and R43are identical or different and each represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or

[0343] R37represents a radical of the formula -(CO)i-E, in which i represents a number 0 or 1,

[0344] E represents cycloalkyl having 3 to 7 carbon atoms or benzyl, represents aryl having 6 to 10 carbon atoms or a 5- to 6-membered aromatic heterocycle having up to 4 heteroatoms from the group consisting of S, N and O, where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different constituents selected from the group consisting of nitro, halogen, -SO3H, straight-chain or branched alkoxy having up to 6 carbon atoms, hydroxyl, trifluoromethyl, trifluoromethoxy, or by a radical of the formula -SO2-NR44R45, in which

[0345] R44and R45have the meaning of R18and R19given above and are identical to or different from them, or

[0346] E represents radicals of the formulae N N— -CH3, or

[0347] N

[0348]

[0349] and the heterocycle listed under R3and R4, which is formed together with the nitrogen atom, is optionally mono- or polysubstituted, if appropriate also geminally, by identical or different substituents selected from the group consisting of hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxy carbonyl having in each case up to 6 carbon atoms, nitro and groups of the formulae -P(O)(OR46)(OR47),

[0350]

[0351] =NR48, or -C(O)jNR49R50, in which

[0352] R46and R47have the meanings of R10and R11given above and are identical to or different from them,

[0353] R48represents hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms, j represents a number 0 or 1, and

[0354] R49and R50are identical or different and have the meanings of R14and R15given above, and / or the heterocycle listed under R3and R4, which is formed together with the nitrogen atom, is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of hydroxyl, halogen, carboxyl, cycloalkyl or cycloalkyloxy having in each case 3 to 8 carbon atoms, straight-chain or branched alkoxy or alkoxy carbonyl having in each case up to 6 carbon atoms, or by a radical of the formula -SO3H, -NR51R52or P(O)OR53OR54, in which

[0355] R51and R52are identical or different and each represents hydrogen, phenyl, carboxyl, benzyl or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,

[0356] R53and R54are identical or different and have the meanings of R10and R11given above, and / or the alkyl is optionally substituted by aryl having 6 to 10 carbon atoms which for its part may be mono- or polysubstituted by identical or different substituents selected from the group consisting of halogen, hydroxyl, straight-chain or branched alkoxy having up to 6 carbon atoms, or by a group of the formula -NR51R52, in which

[0357] R51and R52have the meanings of R51and R52given above and are identical to or different from them, and / or the heterocycle listed under R3and R4, which is formed together with the nitrogen atom, is optionally substituted by aryl having 6 to 10 carbon atoms or by a 5- to 7-membered saturated, partially unsaturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of S, N and O, optionally also attached via a nitrogen function, where the ring systems for their part may be substituted by hydroxyl or by straightchain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, or

[0358] R3and R4together with the nitrogen atom form radicals of the formulae

[0359]

[0360] R5and R6are identical or different and each represents hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or represents straight-chain or branched alkoxy having up to 6 carbon atoms, and their salts, hydrates, N-oxides and structural isomers.

[0361] In Embodiment XXII, other suitable compounds include those of the following Formula III:

[0362]

[0363] wherein in Formula III, R° represents hy drogen, halogen, or Ci-6 alky l;

[0364] R1represents hydrogen, Ci-6 alkyl. C2-6 alkenyl, C2-6 alkynyl, haloCi-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkylCi-3 alkyl, arylCi-3 alkyl, or heteroarylCi-3 alkyl; R2represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring;

[0365]

[0366] attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur, and nitrogen; and

[0367] R3represents hydrogen or C1-3 alkyl, or R1and R3together represent a 3- or 4-membered alkyl or alkenyl chain; and pharmaceutically and salts and solvates (e.g., hydrates) thereof.

[0368] In Embodiment XXIII, the PDE5 inhibitors include those of the following Formula

[0369]

[0370] wherein in Formula IV, R° represents hydrogen, halogen, or C1-6 alkyl;

[0371] R1represents hydrogen, C1-6 alkyl, haloCi-6 alkyl, C3-8 cycloalkylCi-3 alkyl, arylCi-3 alkyl, or heteroarylCi-3 alkyl; and R2represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan, and pyridine, or an optionally substituted bicyclic ring

[0372]

[0373] attached to the rest of the molecule via one of the benzene ring carbon atoms, and wherein the fused ring A is a 5- or 6-membered ring which can be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or tw o heteroatoms selected from oxygen, sulphur, and nitrogen; and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof.

[0374] In Embodiment XXIV, the PDE5 inhibitors include compounds of the following Formula V:

[0375]

[0376] wherein in Formula V: R° represents hydrogen, halogen, or Ci-6 alkyl; R1represents hydrogen or Ci-6 alkyl: R2represents the bicyclic ring

[0377]

[0378] which can be optionally substituted by one or more groups selected from halogen and Ci-3 alkyl; and

[0379] R3represents hydrogen or C1-3 alkyl; and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof.

[0380] In Embodiment XXV, the compound of Embodiment XXIV with respect to R1. the term ’‘aryl” as part of an arylCi-s alkyl group means phenyl or phenyl substituted by one or more (e.g., 1, 2, or 3) substituents selected from halogen, Ci-6 alkyl, Ci-6 alkoxy, and methylenedioxy. The term “heteroary l” as part of a heteroarylCi-3 alkyl group means thienyl, furyl, or pyridyl, each optionally substituted by one or more (e.g.. 1, 2, or 3) substituents selected from halogen, Ci-6 alkyl, and Ci-6 alkoxy. The term “C3-8 cycloalkyl” as a group or part of a C3-8 cycloalkylCi-3 alky l group means a monocyclic ring comprising three to eight carbon atoms. Examples of suitable cycloalkyl rings include the C3-6 cycloalkyl rings cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0381] In formula IV above, with respect to R2, optional benzene ring substituents are selected from one or more (e.g., 1, 2, or 3) atoms or groups comprising halogen, hydroxy, Ci-6 alkyl, C1-6 alkoxy, CO2 Rb, haloCi-6 alkyl, haloCi-6 alkoxy, cyano, nitro, and NRaRb, where Raand Rbare each hydrogen or C1-6 alky l, or Raalso can represent C2-7 alkanoyl or C1-6 alkylsulphonyl. Optional substituents for the remaining ring systems are selected from one or more (e.g., 1. 2, or 3) atoms or groups comprising halogen, Ci-6 alkyl, Ci-6 alkoxy, and arylCi-3 alkyl as defined above. The bicyclic ring

[0382]

[0383] can, for example, represent naphthalene, a heterocycle such as benzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline, indole, benzothiophene, benzofuran, or

[0384] (CH2)n

[0385]

[0386] wherein n is an integer 1 or 2 and X and Y each can represent CH2, O, S, or NH.

[0387] The term "alkyl" refers to the radical of saturated aliphatic groups, including straightchain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups each having up to 20 carbon atoms. In preferred embodiments, a straight chain or branched chain alkyl has 10 or fewer carbon atoms in its backbone (e.g., C1-C10 for straight chain, C3-C10 for branched chain), and more preferably 6 or fewer. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

[0388] Unless the number of carbons is otherwise specified, ‘lower alkyl” as used herein means an alkyd group, as defined above, but having from one to six carbons, and more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0389] The term “aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0390] The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0391] The term “aryl” as used herein includes 5- and 6-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "‘aryl heterocycles” or ‘“heteroaromatics.” The aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alky l, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydry l, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CFs, -CN, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cy clic rings can be cycloalkyls, cycloalkenyls, aryls and / or heterocyclic groups.

[0392] The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 5- or 6-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be polycycles. Heterocyclic groups include, for example, thiophene, thianthrene. furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole. isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.

[0393] The terms “polycyclyl” or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, aryls and / or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms are termed “bridged” rings. Each of the rings of the polycyclic group can be substituted with such substituents as described above, for example, halogen, alky l, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate. phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like. As used herein, the term “nitro” means -NO2; the term “halogen” designates -F, -Cl, -Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO-.

[0394] The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety' that can be represented by the general formulae -NRR' or -NRR'R”+, wherein R, R' and R" each independently represent a group permitted by the rules of valence, preferably H. alkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic groups.

[0395] The term “acylamino” is art-recognized and refers to a moiety that can be represented by the general formula -NR-C(=O)-R', wherein R and R' are as defined above.

[0396] The term “amido” is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula -C(=O)-NRR'. wherein R and R' are as defined above. Preferred embodiments of the amide will not include imides which may be unstable.

[0397] The term “alkylthio” refers to an alkyl group, as defined above, having a sulfur radical attached thereto. In some embodiments, the “alkylthio” moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R'8, wherein m and R's are defined above.

[0398] Representative alkylthio groups include methylthio, ethyl thio, and the like.

[0399] The term “carbonyl” is art recognized and includes such moieties as can be represented by the general formulae -X-C(=O)-R or -C(=O)-X-R, wherein X is a bond or represents an oxygen or a sulfur, and R and R' are as defined above.

[0400] The terms “alkoxy!” or “alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.

[0401] The term “sulfonate” is art recognized and includes a moiety that can be represented by the general formula -SO2-OR41, in which R41 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0402] The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference. The term “sulfate” is art recognized and includes a moiety that can be represented by the general formula -O-SO2-OR41, in which R41 is as defined above.

[0403] The term “sulfonylamino” is art recognized and includes a moiety that can be represented by the general formula -NR-SO2-R.

[0404] The term “sulfamoyl” is art-recognized and includes a moiety that can be represented by the general formula -SO2-NR2.

[0405] The term “sulfonyl”, as used herein, refers to a moiety that can be represented by the general formula -SO2-R44, in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.

[0406] The term “sulfoxido” as used herein, refers to a moiety that can be represented by the general formula -S(=O)-R44, in which R44 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl.

[0407] A “selenoalkyl” refers to an alkyl group having a substituted seleno group attached thereto. Exemplary “selenoethers” which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and -Se-(CH2)m-R7, m and R7 being defined above.

[0408] Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, aminoalkenyls, aminoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

[0409] As used herein, the definition of each expression, e.g. alkyl, m, n. R, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.

[0410] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.

[0411] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0412] Other PDE5 inhibitors may be found in U. S. Pat. Nos. 6,916,927, 6,911,542, 6,903,099, 6,878,711, 6,872,721, 6,858,620, 6,825,197, 6,774,128, 6,723,719, 6,699,870, 6,670,366, 5,859,006 and 5,250,534. Other PDE5 inhibitors useful in the methods of the invention are descnbed in WO 03 / 063875; WO 03 / 1012761 WO 2004 / 037183, and WO 98 / 38168. All of the patents and patent applications cited herein are incorporated herein by reference in their entirety.

[0413] Sildenafil is commercially available in three dosages of 25, 50, or 100 mg. Vardenafil is commercially available in three dosages of 5 mg, 10 mg, and 20 mg. Tadalafil is commercially available in three dosages of 5, 10, or 20 mg.

[0414] Other exemplary PDE5 inhibitors include UK-343,664 (Walker et al., Xenobiotica, 31: 651-664), UK-427,387, UK-357903 [l-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4, 3-d]pyrimidin-5-yl]-2-(2-methoxy ethoxy )-5-pyridylsulphonyl}pip- erazine] (Gardiner et al. J Pharmacol Exp Ther. 2005; 312: 265-271), UK-371800 (Pfizer), UK-313794 (Pfizer) and UK-343664 (Abel et al., Xenobiotica. 2001 31:665-76); TA-1790 from Tanabe Seiyaku; CP-248, CP-461 and exisulind (Deguchi et al., Molecular Cancer Therapeutics 803-809, 2002). which are available from Osi Pharmaceuticals; pyrazolinone; EMD82639 (4-(4-[2-ethyl-phenylamino)-methylene]-3-methyl-5-oxo-4,5-di-hyd- ro-pyrazol-l-yl)-benzoic acid (Senzaki et al., FASEB Journal. 2001; 15:1718-1726); [7-(3-Chloro-4-methoxy-benzylamino)-l-methyl-3-propyl-lH-pyrazolo[4,3-d]p- yrimidin-5-ylmethoxyl]-acetic acid (EMD360527), 4-[4-(3-Chloro-4-methoxy-benzylamino)-benzo[4,5]thieno[2,3-d]-pyrimidin-2- -yl] -cyclohexanecarboxylic acid, ethanolamin salt (EMD221829) and 5-[4-(3-Chloro-4-methoxy-benzylamino)-5, 6,7,8-tetrahydro-benzo[4,5]thieno- [2,3-d]pyrimidin-2-yl]-pentanoic acid (EMD171827), which are commercially available from Merck KgaA (Damistadt, DE) and are described, for example, in Scutt et al. (BMC Pharmacol. 2004; 4: 10); 3-(l-Methyl-7-oxo-3-propyl-6,7-dihydro-lH-pyrazolo-[4,3-d]pyrimidin-5-yl)-N-[2-(l-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide (DA-8259); E-4021 (Dukarm et al., Am. J. Respir. Crit. Care Med., 1999, 160:858-865); pentoxifylline and FR22934 (Fujisawa). Pharmaceutical Compositions

[0415] In another aspect, provided are pharmaceutically acceptable compositions which comprise atherapeutically-effective amount of one or more of the PDE5 inhibitors, formulated together with one or more pharmaceutically acceptable carriers (additives) and / or diluents. As described in detail below, the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

[0416] The pharmaceutical formulations may be immediate release or sustained release formulations. Methods for preparing immediate release and sustained release formulations are well known to those of skill in the art.

[0417] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals with toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0418] The phrase “pharmaceutically-acceptable carrier” as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e.g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in cartying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[0419] As set out above, certain compounds may contain a basic functional group, such as amino or alkydamino, and are, thus, capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable acids. The term “pharmaceutically-acceptable salts” in this respect, refers to the relatively non-toxic, inorganic and organic acid addition salts of the PDE5 inhibitors. These salts can be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting a purified compound of the PDE5 inhibitor in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed during subsequent purification. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0420] The pharmaceutically acceptable salts of the subject compounds include the conventional nontoxic salts or quaternary ammonium salts of the compounds, e.g., from non-toxic organic or inorganic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloride, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isothionic, and the like.

[0421] In other cases, the PDE5 inhibitors may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically-acceptable bases. The term “pharmaceutically-acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of PDE5 inhibitors. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically -acceptable metal cation, with ammonia, or with a pharmaceutically-acceptable organic primary, secondary or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like.

[0422] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. (See, for example, Berge et al., supra).

[0423] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0424] Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA). butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

[0425] Formulations of the PDE5 inhibitors include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety -nine percent of active ingredient, from about 5 percent to about 70 percent, or from about 10 percent to about 30 percent.

[0426] In certain embodiments, a formulation comprising a PDE5 inhibitor also comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a PDE5 inhibitor. In certain embodiments, an aforementioned formulation renders orally bioavailable a PDE5 inhibitor. Methods of preparing these formulations or compositions include the step of bringing into association a PDE5 inhibitor with the carrier and. optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a PDE5 inhibitor with liquid carriers, or finely divided solid carriers, or both, and then, if necessary', shaping the product.

[0427] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a PDE5 inhibitor as an active ingredient. A PDE5 inhibitor may also be administered as a bolus, electuary or paste.

[0428] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; (7) wetting agents, such as, for example, cety l alcohol, glycerol monostearate, and non-ionic surfactants; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof; (10) coloring agents; and (11) controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0429] A tablet may be made by compression or molding, optionally with one or more accessory’ ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0430] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceuticalformulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be formulated for rapid release, e.g., freeze-dried. They may be sterilized by. for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated foam, if appropriate, with one or more of the above-described excipients.

[0431] Liquid dosage forms for oral administration of the PDE5 inhibitors include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0432] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Formulations of the pharmaceutical compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

[0433] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0434] Dosage forms for the topical or transdermal administration of a PDE5 inhibitor include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0435] The ointments, pastes, creams and gels may contain, in addition to PDE5 inhibitor, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0436] Powders and sprays can contain, in addition to a PDE5 inhibitor, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0437] Transdermal patches have the added advantage of providing controlled deliver}’ of a PDE5 inhibitor to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0438] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated.

[0439] Pharmaceutical compositions suitable for parenteral administration comprise one or more PDE5 inhibitors in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0440] Examples of suitable aqueous and nonaqueous carriers which may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0441] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

[0442] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon cry stal size and crystalline form. Alternatively, delayed absorption of a parenterally -administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

[0443] Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-poly glycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by¬ entrapping the drug in liposomes or microemulsions which are compatible with body tissue.

[0444] When the PDE5 inhibitors are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example. 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier. The preparations may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.

[0445] The phrases “parenteral administration” and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0446] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.

[0447] These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally and topically, as by powders, ointments or drops, including buccally and sublingually.

[0448] Regardless of the route of administration selected, the PDE5 inhibitors, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions, are formulated into pharmaceutically-acceptable dosage forms by conventional methods know n to those of skill in the art.

[0449] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0450] The selected dosage level will depend upon a variety of factors including the activity of the particular compound employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

[0451] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0452] In general, a suitable daily dose of the PDE5 inhibitor will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, and subcutaneous doses of the compounds, when used for the indicated effects, will range from about 0.1 to about 300 mg. In other embodiments, the doses will be 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, 225, 250, 275 or 300 mg depending on the abi 1 i ty of the particular PDE5 inhibitor to partition to the vasculature.

[0453] If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.

[0454] In certain embodiments, a controlled release formulation comprises a biocompatible polymer selected from the group consisting of polyamides, polycarbonates, polyalkylenes, polymers of acrylic and methacrylic esters, polyvinyl polymers, poly glycolides, polysiloxanes, polyurethanes and co-polymers thereof, celluloses, polypropylene, polyethylenes, polystyrene, polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho)esters, poly(butic acid), poly(valeric acid), poly(lactide-co-caprolactone). polysaccharides, proteins, polyhyaluronic acids, poly cyanoacrylates, and blends, mixtures, or copolymers thereof.

[0455] The release characteristics of a formulation depend on the encapsulating material, the concentration of encapsulated drug, and the presence of release modifiers. For example, release can be manipulated to be pH dependent, for example, using a pH sensitive coating that releases only at a low pH, as in the stomach, or a higher pH, as in the intestine. An enteric coating can be used to prevent release from occurring until after passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach, followed by later release in the intestine. Release can also be manipulated by inclusion of salts or pore forming agents, which can increase water uptake or release of drug by diffusion from the capsule. Excipients which modify the solubility of the drug can also be used to control the release rate. Agents which enhance degradation of the matrix or release from the matrix can also be incorporated. They can be added to the drug, added as a separate phase (i.e., as particulates), or can be codissolved in the polymer phase depending on the compound. In all cases the amount should be between 0.1 and th i rty percent (w / w polymer). Types of degradation enhancers include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid, and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate, and zinc hydroxide, and organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine, and triethanolamine and surfactants such as Tween® and Pluronic®. Pore forming agents which add microstructure to the matrices (i.e., water soluble compounds such as inorganic salts and sugars) are added as particulates. The range should be between one and thirty’ percent (w / w polymer).

[0456] Uptake can also be manipulated by altering residence time of the particles in the gut. This can be achieved, for example, by coating the particle with, or selecting as the encapsulating material, a mucosal adhesive polymer. Examples include most polymers with free carboxyl groups, such as chitosan, celluloses, and especially polyacrylates (as used herein, polyacrylates refers to polymers including acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates).

[0457] In one embodiment, the pharmaceutical composition is an immediate release composition. In another embodiment, the immediate release composition comprises the PDE5 inhibitor, microcrystalline cellulose, crospovidone, colloidal silicon dioxide, and magnesium stearate. In another embodiment, the pharmaceutical composition comprises 5 mg of the compound of Embodiment XIX as shown in Table 1.

[0458] Table 1

[0459] Component Function Grade Amount (%) Embodiment XIX PDE5 inhibitor N / A 4.2 Microcrystalline Binder USP / NF Ph Eur 91.8

[0460] cellulose JP

[0461] Crospovidone Binder USP / NF 3.0

[0462] Colloidal silicon Filler Ph Eur 0.2

[0463] dioxide

[0464]

[0465] Magnesium stearate Lubricant USP / NF Ph Eur 0.8

[0466] JP

[0467] Total 100.0

[0468]

[0469] In another embodiment, the pharmaceutical composition is an immediate release composition. In another embodiment, the immediate release composition comprises the PDE5 inhibitor, hypromellose, anhydrous lactose, and microcrystalline cellulose. In another embodiment, the pharmaceutical composition comprises 10 or 20 mg of the compound of Embodiment XIX as shown in Table 2.

[0470] Table 2

[0471] Component Low dose, immediate release High dose, immediate release (quantity per tablet, mg) (quantity per tablet, mg) Embodiment XIX 10.0 20.0

[0472] Hypromellose 11.6 11.6

[0473] Lactose anhydrous 58.0 48.0

[0474] Microcrystalline 46.3 46.3

[0475] cellulose

[0476]

[0477] In another embodiment, the pharmaceutical composition is an extended release composition. As shown in Fig. 2, an extended release formulation comprising 20 mg of the compound of Embodiment XIX provided plasma levels above the minimum effective concentration but below the concentrations where adverse events occur. In one embodiment, the extended release composition comprises the PDE5 inhibitor, higher amounts of hypromellose, anhydrous lactose, and microcrystalline cellulose. In another embodiment, the pharmaceutical composition comprises 10 or 20 mg of the compound of Embodiment XIX as shown in Table 3.

[0478] Table 3

[0479] Component Low dose, extended release High dose, extended release (quantity per tablet, mg) (quantity per tablet, mg) Embodiment XIX 10.0 20.0

[0480] Hypromellose 23.2 23.2

[0481] Lactose anhydrous 56.4 46.4

[0482]

[0483] Microcrystalline 36.3 36.3

[0484] cellulose

[0485]

[0486] Kits

[0487] Also provided are kits comprising a container comprising a PDE5 inhibitor and instructions for administering the PDE inhibitor together with a CYP3A4 inhibitor. Such kits may comprise a box with appropriate labeling and containers such as bottles, vials, tubes and the like. Appropriate labeling includes directions for administering a PDE5 inhibitor to treat hypertension. In one embodiment, the PDE5 is packaged in a unit dose form.

[0488] In one embodiment, the CYP3A4 inhibitor is an antihypertension drug. In another embodiment, the antihypertension drug is a calcium channel blocker. In another embodiment, the instructions comprise treating a patient with hypertension. In another embodiment, the PDE5 inhibitor is present in the kit at a dose of 0.1 to 300 mg. In another embodiment, the PDE5 inhibitor is present in the kit at a dose of 10, 20, 30, 40, 50, 60. 70, 80, 90, 100, 125. 150, 175, 200, 225, 250, 275 or 300 mg. In another embodiment, the PDE5 inhibitor is formulated as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical composition is an immediate release composition. In another embodiment, the pharmaceutical composition is a sustained release composition. In another embodiment, the sustained release pharmaceutical composition releases the PDE5 inhibitor over a period of 4-24 hours. In another embodiment, the sustained release pharmaceutical composition releases the PDE5 inhibitor over a period of 4-8, 4-12, 8-12 or 12-24 hours.

[0489] Crystalline Form of Embodiment XIX

[0490] In any of the methods, compositions, and / or kits described herein, the PDE5 inhibitor can be a solid, crystalline form of Embodiment XIX. The solid state of a compound can be important when the compound is used for pharmaceutical purposes. The physical properties of a compound can change from one solid form to another, which can affect the suitability of the form for pharmaceutical use. For example, a particular crystalline solid compound can overcome the disadvantage of other solid forms of the compound such as, e.g., physical instability and / or reduced purity.

[0491] As with all pharmaceutical compounds and compositions, the chemical and physical properties of the crystalline form of Embodiment XIX utilized can be important in commercial development and manufacturing. These properties include, but are not limited to: (1) packing properties such as molar volume, density and hygroscopicity, (2) thermodynamic properties such as melting temperature, vapor pressure and solubility, (3) kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture, and under storage conditions), (4) surface properties such as surface area, wettability, interfacial tension and shape, (5) mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend; and (6) filtration properties. These properties can affect, for example, processing and storage of pharmaceutical compositions comprising Embodiment XIX.

[0492] The crystalline form provided herein can be characterized by, for example, powder X-ray diffraction (PXRD). The crystalline form described herein is identifiable on the basis of characteristic peaks in a powder X-ray diffraction analysis. Powder X-ray diffraction (PXRD) is a scientific technique using X-ray, neutron, or electron diffraction on powder, microcrystalline, or other solid materials for structural characterization of solid materials. Powder x-ray diffraction (PXRD) diffractograms can be obtained using any method and equipment known in the art, for example, a PANalytical X'Pert PRO MPD diffractometer using an incident beam of Cu radiation produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror can be used to focus Cu Kα x-rays through the specimen and onto the detector.

[0493] PXRD diffractograms of Embodiment XIX provided herein is obtained by a method utilizing Cu Kα / radiation. The crystalline form of Embodiment XIX is not limited to those made in accordance with the methods described herein.

[0494] In one embodiment, the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 14.0190, 20.0045, and 24.8947.

[0495] In another embodiment, the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 13.4699, 13.8105, 15.4971, and 15.6786.

[0496] In another embodiment, the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 13.4699, 13.8105, 14.0190, 15.4971, 15.6786, 20.0045, and 24.8947.

[0497] In another embodiment, the cry stal 1 ine form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 13.2893, 13.4699, 13.8105, 14.0190. 15.4971. 15.6786, 20.0045, 23.1513, 24.0973, 24.8947, and 34.0159. In another embodiment, the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 13.2893, 13.4699, 13.8105, 14.0190, 15.4971, 15.6786, 16.7928, 17.5616, 19.3294, 20.0045, 20.7937, 23.1513, 24.0973, 24.8947, 27.1547, and 34.0159.

[0498] In another embodiment, the crystalline form of Embodiment XIX has a PXRD diffractogram substantially as depicted in FIG. 5. In one embodiment, the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) as shown in FIG. 5.

[0499] In one embodiment, the cry stal 1 ine form of Embodiment XIX is characterized by any two, three, four, five, six, seven, or eight peaks as shown in Table 1. In another embodiment, the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) as shown in Table 4.

[0500] Table 4

[0501] Angle

[0502] Peak Number

[0503] (degrees 20)

[0504] 1 8.3647

[0505] 2 10.2792

[0506] 3 11.7626

[0507] 4 13.2893

[0508] 5 13.4699

[0509] 6 13.8105

[0510] 7 14.0190

[0511] 8 15.4971

[0512] 9 15.6786

[0513] 10 16.1763

[0514] 11 16.7928

[0515] 12 17.5616

[0516] 13 18.3924

[0517] 14 18.5060

[0518] 15 19.3294

[0519] 16 20.0045

[0520] 17 20.7937

[0521] 18 21.8819

[0522]

[0523] 19 22.2703

[0524] 20 23.1513

[0525] 21 24.0973

[0526] 22 24.8947

[0527] 23 26.9752

[0528] 24 27.1547

[0529] 25 29.6558

[0530] 26 34.0159

[0531]

[0532] Examples

[0533] PK study in rats

[0534] Four rat PK studies, Sprague-Dawley (7-9 weeks, 270-320 g, male) were purchased from JH Laboratory Animal Co. They were fasted overnight before dosing. Test articles were prepared as 0.4% aqueous suspension of methylcellulose (MC, 400 cps) at the indicated doses and administered as oral gavage at 5 mL / kg. Amlodipine was either dosed 30 min before dosing of RTN-001 (PK1 and PK3) or simultaneously with RTN-001 using a MC suspension containing both amlodipine and RTN-001 (PK2 and PK4). At each time point (0.25, 0.5, 0.75, 1, 2. 4, 6, 8 h post dosing), the animals were restrained manually. Approx.

[0535] 150 µL of blood samples were taken from the animals via jugular vein injection for serial bleeding into K2EDTA tubes. Blood samples were placed on ice and centrifuged to obtain plasma samples (2000 g, 5 min under 4°C) within 15 minutes. For bioanalysis, working solution of standards were prepared in 80:20 (v:v. Acetonitrile: water). An aliquot of 10 µL working solution was mixed with 190 pL blank plasma to get standards. For LC / MS, an aliquot of 10 µL sample was added with 300 pL IS (Osalmid,40 ng / mL) in Acetonitrile to 96well plate. The mixture was mixed for 5 min, and centrifuged at 5800 rpm for 10 min. 90 pL supernatant was transferred to a new plate. An 0.5 µL aliquot of the mixture was injected to LC-MS / MS for quantitation. Representative PK curves of co- administration of a CYP3 A4 inhibitor (amlodipine) with a PDE5 inhibitor (Embodiment XIX) and PDE5 inhibitor (Embodiment XIX) alone in rats are shown in Fig. 3. Amlodipine in combination with a PDE5 inhibitor (Embodiment XIX) in a patient with hypertension

[0536] The effect of amlodipine in combination with a PDE5 inhibitor (Embodiment XIX) was evaluated in a patient with hypertension receiving ongoing antihypertensive medication. The patient received 10 mg of amlodipine + Embodiment XIX for 14 days and amlodipine + placebo in a 14-day repeat dosing period.

[0537] The patient took part in three in-house study periods. In the first in-house study period, the patient received one dose of single blind placebo on Day 0 followed by the first of 14 daily doses of investigational product (active or placebo) on Day 1. The patient remained in the clinic for the first 7 days of dosing, having vital signs measurements (supine blood pressure and heart rate) recorded every morning (approx. 0800 - 0900 h) and evening (approx. 2000 - 2100 h; not in the evening on Day 7) that were not study days (0, 1, 14, 15 and 28). The patient left the clinic 4hr after dosing on Day 7 and self-administered the investigational product for days 8 - 13. The patient underwent monitoring of vital signs and blood sampling for PK trough blood concentration and safety assessments pre-dose on the morning of Day 7. The patient was re-admitted to the clinical unit on the evening of Day 13.

[0538] In the second in-house study period, the patient received the final dose of the first investigational product on Day 14 (end of Period 1) followed by the first dose of the second investigational product on Day 15 (start of Period 2). The patient remained in the clinic for the first 7 days of dosing of Period 2, having vital signs measurements (supine blood pressure and heart rate) recorded every morning (approx. 0800 - 0900 h) and evening (approx. 2000 -2100 h; not in the evening on Day 21). The patient left the clinic 4hr after dosing on Day 21 and self-administered the investigational product for days 22 - 27. The patient was readmitted to the clinical unit on the evening of Day 27.

[0539] In the third in-house study period, the patient received the final dose of the second investigational product on Day 28 and was discharged from the clinic on completion of all study procedures on the morning of Day 29.

[0540] The patient was monitored for adverse events and fitted with an ambulatory BP monitoring device to measure peripheral systolic blood pressure (SBP). diastolic blood pressure (DBP) and heart rate twice every hour during the day (0700 - 0000 h) and once every hour during the night (0000 - 0700 h). The patient completed a follow-up assessment approximately 5 - 7 days following the final dose. The results are shown in Fig. 4. Crystalline form of Embodiment XIX

[0541] The crystalline form of Embodiment XIX was made as described below. The resulting material was then analyzed using the analytical techniques described herein, that is, powder X-ray diffraction.

[0542] The crystalline form of Embodiment XIX was obtained according to the following method: A solution of Embodiment XIX (1 equiv.) in ethanol (6 volumes) is heated to reflux (75-80 °C) and stirred for 10-15 minutes. Heptane (32 volumes) is slowly added to the solution over 15-30 minutes at 65-80 °C. The solution is slowly cooled to 25-30 °C over 1-2 hours and stirred at this temperature for 1-1.5 hours to induce crystallization. The product is filtered from solution and washed with heptane (6 volumes). The product is then dried to constant weight under vacuum at 60-70 °C. for 10-14 hours.

[0543] X-ray powder diffraction pattern is obtained on a PANalytical instrument (Model -Empyrean) operating with Cu Kα / β radiation at 45 kV and 40 mA using a PIXcellPD-Medipix3 scanning line detector. The powder diffraction pattern of the sample is obtained from 2 to 50 °20 at a rate of 1°2θ / 48 seconds. Raw data files are collected and processed using HighScore software.

[0544] The relative intensity of each diffractogram peak in Table 4 as well as FIG. 5 may change or shift under certain conditions, although the crystalline form is the same. One of ordinary skill in the art should be able to readily determine whether a given crystalline form is the same crystalline form as described in FIG. 5 or Table 4.

[0545] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed:

1. A method for treating, preventing, or reducing hypertension in a subject in need thereof, the method comprising co- administering to the subject an effective amount of a cytochrome P4503A4 (CYP3A4) inhibitor, an effective amount of a nitric oxide (NO) potentiator, and an effective amount of a phosphodiesterase-5 (PDE5) inhibitor.

2. The method according to claim 1, wherein the CYP3A4 inhibitor is administered to the subject at the same time as the PDE5 inhibitor; wherein the CYP3A4 inhibitor is administered to the subject prior to the PDE5 inhibitor; or wherein the CYP3A4 inhibitor is administered to the subject after the PDE5 inhibitor.

3. The method according to claim 2, wherein the CYP3A4 inhibitor is administered to the subject prior to the PDE5 inhibitor.

4. The method according to claim 3, wherein the CYP3A4 inhibitor is administered to the subject about 1 minute to about 60 minutes prior to the PDE5 inhibitor.

5. The method according to any one of claims 1 to 4. wherein the CYP3A4 inhibitor is an antihypertensive drug.

6. The method according to claim 5, wherein the antihypertensive drug is selected from the group consisting of a beta blocker, a calcium (Ca) channel blocker, a potassium (K+)-sparing diuretic, and a loop diuretic.

7. The method according to claim 6, wherein the antihypertensive drug is the CYP3A4 inhibitor and the NO potentiator.

8. The method according to claim 6 or 7, wherein the antihypertensive drug is a calcium (Ca) channel blocker.

9. The method according to claim 8, wherein the calcium (Ca) channel blocker is selected from the group consisting of amlodipine, diltiazem, felodipine, isradipine. nifedipine, nimodipine, nisoldipine, nitrendipine, and varapamil.

10. The method according to claim 9, wherein the calcium (Ca) channel blocker is selected from the group consisting of amlodipine, nifedipine, and nimodipine.

11. The method according to claim 10, wherein the calcium (Ca) channel blocker is selected from the group consisting of amlodipine.

12. The method according to any one of claims 1 to 11, wherein the PDE5 inhibitor is sildenafil, vardenafil, tadalafil, avanafil, microdenafil, udenafil, or lodenafil carbonate.

13. The method according to any one of claims 1 to 11, wherein the PDE5 inhibitor has the structure:

14. The method according to any one of claims 1 to 11, wherein the PDE5 inhibitor has the structure:

15. The method according to claim 13, wherein the PDE5 inhibitor is in a crystalline form, wherein the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 14.0190, 20.0045, and 24.8947.

16. The method according to claim 15, wherein the cry stalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 13.4699, 13.8105, 15.4971, and 15.6786.

17. The method according to claim 15 or 16, wherein the cry stalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626. 13.4699, 13.8105, 14.0190, 15.4971, 15.6786. 20.0045. and 24.8947.

18. The method according to any one of claims 15-17, wherein the cry stalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 13.2893, 13.4699, 13.8105, 14.0190, 15.4971, 15.6786, 20.0045, 23.1513, 24.0973, 24.8947, and 34.0159.

19. The method according to any one of claims 15-18, wherein the crystalline form of Embodiment XIX is characterized by a PXRD diffractogram having peaks expressed in degrees 2-theta at angles (± 0.2 degrees) of 11.7626, 13.2893, 13.4699, 13.8105, 14.0190, 15.4971, 15.6786, 16.7928, 17.5616, 19.3294, 20.0045, 20.7937, 23.1513, 24.0973, 24.8947, 27.1547, and 34.0159.

20. The method according to claim 13, wherein the PDE5 inhibitor is in a crystalline form, wherein the crystalline form of Embodiment XIX is characterized by the PXRD diffractogram as substantially depicted in FIG. 5.

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