WO2005035505A2 - Compounds with phosphodiesterase inhibiting and calcium channel blocking activities - Google Patents

Abstract

The present invention provides compounds that possess inhibitory activity against PDE-3 and L-type calcium channels. The present invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating cardiovascular disease, stroke, epilepsy, ophthalmic disorder or migraine.

Description

COMPOUNDS WITH PHOSPHODIESTERASE INHIBITING AND CALCIUM CHANNEL BLOCKING ACTIVITIES

This application claims the benefit of U.S. Provisional Patent Application No. 60/506,720, filed September 30, 2003, the entire contents of which are herein incorporated by reference. Congestive heart failure affects an estimated 4.8 million Americans with over 400,000 new cases diagnosed each year. Despite incremental advances in drug therapy, the prognosis for patients with advanced heart failure remains poor with annual mortality exceeding 40 percent. Although heart transplantation is an effective therapy for patients with advanced heart failure, less than 2,200 heart transplants are performed annually due to a limited supply of donor organs. Recent analyses indicate that further increases in the incidence and prevalence of advanced heart failure are likely, highlighting the pressing need for novel and effective therapeutic strategies. During heart failure, there is an alteration of calcium homeostasis, including impaired sarcoplasmic reticulum calcium re-uptake, increased basal (diastolic) calcium levels, decreased peak (systolic) calcium and reduced rate of calcium transients, resulting in a decreased force of contraction and a slowing of relaxation. The end results of these abnormalities in calcium homeostasis are depressed contractile function (decreased contractility and cardiac output), impaired ventricular relaxation, and myocyte loss via ischemia and/or apoptosis-related mechanisms. Disregulation of calcium homeostasis has also been implicated in a number of other disease states, including stroke, epilepsy, ophthalmic disorders, and migraine. Selective inhibitors of the type 3 phosphodiesterase (PDE-3) found in cardiac muscle, such as amrinone and milrinone, have been evaluated for the treatment of congestive heart failure. Such compounds produce positive inotropic effects (increased contractility of heart muscle) by enhancing cAMP levels, which results in the activation of protein kinase A (PKA). Phosphorylation of the PKA substrate protein phospholamban causes an increased uptake of intracellular calcium into the sarcoplasmic reticulum (SR), thereby affecting cardiac contractility, as well as increasing ventricular relaxation (lusitrophism). However, at high doses, PDE inhibitors may increase heart rate and cardiac output, and cause arrhythmia. These adverse effects of PDE inhibitors thus limit their utility in the treatment of heart failure. The failure of PDE inhibition alone to normalize calcium signaling is due to another effect of enhanced cAMP levels in cardiomyoctyes: PKA activates voltage- dependent L-type calcium channels in the myocyte membrane, allowing extracellular calcium to enter the cell. Selective inhibitors of L-type calcium channels, such as the clinically used agents amlodipine and diltiazem, decrease the influx of extracellular calcium into cardiomyocytes by blocking the voltage-dependent calcium channels, thereby decreasing heart rate and exerting anti-ischemic effects. A pharmacological agent which is capable of simultaneously inhibiting cardiac phosphodiesterase type-3 activity, resulting in increased ventricular relaxation and contractility, while preventing increased influx of extracellular calcium through voltage-dependent calcium channels, will have the effect of normalizing calcium homeostasis in failing heart, thereby producing therapeutic benefits without the adverse effects of PDE inhibition alone. Thus, there is a critical need for agents that are potent inhibitors of both PDE-3 and L-type calcium channels. Dihydropyridines such as amlodipine and nifedipine are one known chemical class of blockers of calcium currents through L-type calcium channels. Another structurally distinct class of calcium channel blockers are those comprising benzothiazepine and bezothiazine moieties, and related structures. Such calcium channel blockers may have enhanced selectivity for cardiac calcium channels over those in the vasculature. Accordingly, compounds containing such cardio-selective calcium channel blocking structural elements chemically linked to phosphodiesterase type-3 inhibitor moieties may have therapeutic benefit.

SUMMARY OF THE INVENTION

This invention provides compounds that possess inhibitory activity against PDE-3 and L-type calcium channels. This invention further provides pharmaceutical compositions comprising such compounds and methods of using such compounds for treating cardiovascular disease, stroke, epilepsy, ophthalmic disorder or migraine. DETAILED DESCRIPTION

DEFINITIONS "Alkyl" refers to a saturated straight or branched chain hydrocarbon radical. Examples include without limitation methyl, ethyl, propyl, iso-propyl, butyl, iso- butyl, tert-butyl, n-pentyl and n-hexyl. "Alkylene" refers to a divalent alkyl radical. "Alkylthio" refers to a sulfur substituted alkyl radical. "Alkenyi" refers to an unsaturated straight or branched chain hydrocarbon radical comprising at least one carbon to carbon double bond. Examples include without limitation ethenyl, propenyl, iso-propenyl, butenyl, iso-butenyl, tert-butenyl, n-pentenyl and n-hexenyl. "Alkenylene" refers to a divalent alkenyi radical. "Alkynyl" refers to an unsaturated straight or branched chain hydrocarbon radical comprising at least one carbon to carbon triple bond. Examples include without limitation ethynyl, propynyl, iso-propynyl, butynyl, iso-butynyl, tert-butynyl, pentynyl and hexynyl. "Alkynylene" refers to a divalent alkynyl radical. "Cycloalkyl" refers to a cyclic alkyl radical. Examples include without limitation cyclobutyl, cycopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Cycloalkenyl" refers to a cyclic alkenyi radical. Examples include without limitation cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. "Alkoxy" refers to an alkyl group bonded through an oxygen linkage. "Alkenoxy" refers to an alkenyi group bonded through an oxygen linkage. "Aryl" refers to a cyclic aromatic hydrocarbon moiety having one or more closed ring(s). Examples include without limitation phenyl, benzyl, naphthyl, anthracenyl, phenanthracenyl and biphenyl. "Heteroaryl" refers to a cyclic aromatic moiety having one or more closed rings with one or more heteroatom(s) (for example, sulfur, nitrogen or oxygen) in at least one ring. Examples include without limitation pyrryl, furanyl, thienyl, pyridinyl, oxazolyl, thiazolyl, benzofuranyl, benzothienyl, benzofuranyl and benzothienyl. "Halo" refers to a fiuoro, chloro, bromo or iodo radical. "Isosteres" refer to elements, functional groups, substituents, molecules or ions having different molecular formulae but exhibiting similar or identical physical properties. For example, tetrazole is an isostere of carboxylic acid because it mimics the properties of carboxylic acid even though they have different molecular formulae. Typically, two isosteric molecules have similar or identical volumes and shapes. Ideally, isosteric molecules should be isomorphic and able to co-crystallize. Other physical properties that isosteric molecules usually share include boiling point, density, viscosity and thermal conductivity. However, certain properties may be different: dipolar moments, polarity, polarization, size and shape since the external orbitals may be hybridized differently. The term "isosteres" encompasses "bioisosteres." "Bioisosteres" are isosteres that, in addition to their physical similarities, share some common biological properties. Typically, bioisosteres interact with the same recognition site or produce broadly similar biological effects. "Effective amount" refers to the amount required to produce a desired effect, for example, regulating calcium homeostasis, treating a disease, condition in which disregulation of calcium homeostasis is implicated, treating cardiovascular disease, stroke or epilepsy, or inhibiting a β-adrenergic receptor and/or PDE, including PDE-3. "Metabolite" refers to a substance produced by metabolism or by a metabolic process. "Pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ or portion of the body. Each carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation and suitable for use with the patient. Examples of materials that can serve as a pharmaceutically acceptable carrier include without limitation: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn 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, saffiower oil, sesame oil, olive oil, corn 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. "Pharmaceutically acceptable equivalent" includes, without limitation, pharmaceutically acceptable salts, hydrates, solvates, metabolites, prodrugs and isosteres. Many pharmaceutically acceptable equivalents are expected to have the same or similar in vitro or in vivo activity as the compounds of the invention. "Pharmaceutically acceptable salt" refers to an acid or base salt of the inventive compounds, which salt possesses the desired pharmacological activity and is neither biologically nor otherwise undesirable. The salt can be formed with acids that include without limitation acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride hydrobromide, hydroiodide, 2-hydroxyethane-sulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, thiocyanate, tosylate and undecanoate. Examples of a base salt include without limitation ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine and lysine. In some embodiments, the basic nitrogen-containing groups can be quarternized with agents including lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aralkyl halides such as phenethyl bromides. "Prodrug" refers to a derivative of the inventive compounds that undergoes biotransformation, such as metabolism, before exhibiting its pharmacological effect(s). The prodrug is formulated with the objective(s) of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). The prodrug can be readily prepared from the inventive compounds using conventional methods, such as that described in BURGER'S MEDICINAL CHEMISTRY AND DRUG CHEMISTRY, Fifth Ed., Vol. 1, pp. 172-178, 949-982 (1995). "Isomers" refer to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing with respect to the arrangement or configuration of the atoms. "Stereoisomers" refer to isomers that differ only in the arrangement of the atoms in space. "Diastereoisomers" refer to stereoisomers that are not mirror images of each other. Diastereoisomers occur in compounds having two or more asymmetric carbon atoms; thus, such compounds have 2ⁿ optical isomers, where n is the number of asymmetric carbon atoms. "Enantiomers" refers to stereoisomers that are non-superimposable mirror images of one another. "Enantiomer-enriched" refers to a mixture in which one enantiomer predominates. "Racemic" refers to a mixture containing equal parts of individual enantiomers. "Non-racemic" refers to a mixture containing unequal parts of individual enantiomers. "Animal" refers to a living organism having sensation and the power of voluntary movement, and which requires for its existence oxygen and organic food. Examples include, without limitation, members of the human, equine, porcine, bovine, murine, canine and feline species. In the case of a human, an "animal" may also be referred to as a "patient." "Mammal" refers to a warm-blooded vertebrate animal. "Calcium homeostasis" refers to the internal equilibrium of calcium in a cell. "Cardiovascular disease" refers to a disease of the heart, blood vessels or circulation. "Heart failure" refers to the pathophysiologic state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolizing tissues. "Congestive heart failure" refers to heart failure that results in the development of congestion and edema in the metabolizing tissues. "Hypertension" refers to elevation of systemic blood pressure. "SA/AN node disturbance" refers to an abnormal or irregular conduction and/or rhythm associated with the sinoatrial (SA) node and/or the atrioventricular (AN) node. "Arrhythmia" refers to abnormal heart rhythm. In arrhythmia, the heartbeats may be too slow, too fast, too irregular or too early. Examples of arrhythmia include, without limitation, bradycardia, fibrillation (atrial or ventricular) and premature contraction. "Hypertrophic subaortic stenosis" refers to enlargement of the heart muscle due to pressure overload in the left ventricle resulting from partial blockage of the aorta. "Angina" refers to chest pain associated with partial or complete occlusion of one or more coronary arteries in the heart. "Treating" refers to: (i) preventing a disease, disorder or condition from occurring in an animal that may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting a disease, disorder or condition, i.e., arresting its development; and/or (iii) relieving a disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. Unless the context clearly dictates otherwise, the definitions of singular terms may be extrapolated to apply to their plural counterparts as they appear in the application; likewise, the definitions of plural terms may be extrapolated to apply to their singular counterparts as they appear in the application.

COMPOUNDS

This invention provides a compound of formula I

I or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: X is CH₂ or S; R¹ is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl; R² is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Ci-Cg alkanoyl, C₃-C₈ cycloalkanoyl, or

—C-0-(C C₅ alkyl) 0 or -C-(CH₂)_m-0-(C C₃ alkyl) 0 n is 2, 3 or 4; m is 1 or 2; Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or Cι-C₄ alkoxy; each R³ is independently hydrogen, halo, trifluoromethyl, cyano, nitro, Ci-Cg alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR² or -OSO₂CF₃; L is a direct bond, Cι-C₁₂ alkylene, C₂-C₁₂ alkenylene or C₂-C₁₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y

B

u V

w

with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR'R¹, C₁-C₄ alkoxy, C₁-C₄ alkylthio, COOR¹, C1-C12 alkyl, C2-C12 alkenyi or C2-Ci2 alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s). In one embodiment of formula I, the compound has a structure according to formula I- A:

l-A

wherein Me is methyl, and Ar, R², R³, L and Z are as defined above. In one embodiment of formula I- A, Z is a moiety of formula A, J or O. In another embodiment of formula I, the compound has a structure according to formula I-B:

l-B

wherein Ar, R², R³, L and Z are as defined above. In one embodiment of formula I- A, Z is a moiety of formula A, J or O. Examples of a compound of formula I include without limitation:

(2S,3S)-5-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy]acetyl- amino}ethyl)methylamino]ethyl}-2-(4-methoxyphenyl)-4-oxo- 2H,3H-benzo[b] 1 ,4-thiazaperhydroepin-3-yl acetate

(2S,3S)-5-{2-[(2-{2-[4-(5-cyano-2-methyl-6-oxo(3-hydropyridyl))phenoxy]acetyl- amino}ethyl)methylamino]ethyl}-2-(4-methoxyphenyl)-4-oxo-2H,3H-benzo[b]l,4- thiazaperhydroepin-3-yl acetate

Compound 3 (4S,3R)-l-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy] acetyl- amino}ethyl)methylamino]ethyl}-4-(4-methoxyphenyl)-2-oxo- 3H,4H,5H-benzo[fJazaperhydroepin-3-yl acetate

(4S,3R)-l-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))ρhenoxy]acetyl amino } ethyl)methylamino] ethyl } -4-(4-methoxyphenyl)-2-oxo-3 H,4H,5H- benzo [f] azaperhydroepin-3 -y 1 acetate

This invention further provides a compound of formula II

II or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: X is CH₂ or S; R¹ is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl; R² is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, -Cs alkanoyl, C₃-C₈ cycloalkanoyl, or -C-0-(C C₅ alkyl) 0 or -C-(CH₂)_m-0-(C C₃ alkyl) 0 n is 2, 3 or 4; m is 1 or 2; Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or Cι-C₄ alkoxy; each R³ is independently hydrogen, halo, trifluoromethyl, cyano, nitro, Cι-C₈ alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR² or -OSO₂CF₃; R⁴ is C,-C₅ alkyl; L is a direct bond, Cι-C₁₂ alkylene, C₂-C₁₂ alkenylene or C2-C12 alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -0-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, N, W or Y, as described previously, with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR^!R\ Cι-C alkoxy, d-C alkylthio, COOR¹, C₁-C₁₂ alkyl, C2-C12 alkenyi or C2-C12 alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s). In one embodiment of formula II, the compound has a structure according to formula II-A

wherein Ar, R², L and Z are as defined above. In one embodiment of formula II-A, Z is a moiety of formula A, J or O. In another embodiment of formula II, the compound has a structure according to formula II-B

wherein Ar, R², L and Z are as defined above. In one embodiment of formula II-B, Z is a moiety of formula A, J or O. Examples of a compound of formula II include without limitation:

-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))phenoxy]acetylamino} ethyl)methylamino]ethyl}-7-(4-methoxyphenyl)-3-methyl-5-oxo-2-phenyl-6H,7H- l,4-thiazepin-6-yl acetate

-(4-methoxyphenyl)-3-methyl-4-{2-[methyl(2-{2-[4-(6-oxo(l,4,5-trihydropyridazin- 3-yl))phenoxy]acetylamino}ethyl)amino]ethyl}-2-(2-naphthyl)-5-oxo-6H,7H-l,4- thiazepin-6-yl acetate

4-{2-[(2-{2-[4-(5-cyano-2-methyl-6-oxo(3-hydropyridyl))phenoxy]acetylamino} ethyl)methylamino]ethyl}-7-(4-methoxyphenyl)-3-methyl-5-oxo-2-phenyl-6H,7H- l,4-thiazepin-6-yl acetate

Compond 8 7-(4-methoxyphenyl)-3-methyl-4-[2-(methyl{2-[2-(2-oxo(6-hydroquinolyloxy)) acetylamino]ethyl}amino)ethyl]-5-oxo-2-phenyl-6H,7H-l,4-thiazepin-6-yl acetate

This invention further provides a compound of formula III

III or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: R¹ is hydrogen, Cι-C₈ alkyl, C2-C₈ alkenyi, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl; Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or C₁-C₄ alkoxy; R⁶ is hydrogen, halo, trifluoromethyl, cyano or nitro; R⁷ is hydrogen, halo, trifluoromethyl, cyano, nitro, Cι-C₈ alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR², -OSO₂CF₃, wherein R² is as defined above; L is a direct bond, Cι-C₁₂ alkylene, C₂-C₁₂ alkenylene or C2-C₁₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, N, W or Y, as described previously, with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, ΝR' ¹, C₁-C₄ alkoxy, C₁-C₄ alkylthio, COOR¹, C1-C12 alkyl, C2-C₁₂ alkenyi or C₂-C1₂ alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -ΝR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s). In one embodiment of formula III, the compound has a structure according to in formula III-A

III-A wherein Ar, L and Z are as defined previously. In one embodiment of formula III-A, Z is a moiety of formula A, J or O. In another embodiment of formula III, the compound has a structure according to formula III-B

III-B wherein Ar, L and Z are as defined previously. In one embodiment of formula III-B, Z is a moiety of formula A, J or O. Examples of a compound of formula III include without limitation:

N-[2-({ [4-(2,4-dimethoxyphenyl)(4H-benzo[b]pyrrolo[l ,2-d] 1 ,4-thiazinyl)]methyl} methylamino)ethyl]-2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))phenoxy] acetamide

2-[4-(5-cyano-2-methyl-6-oxo(3-hydropyridyl))phenoxy]-N-[2-({[4-(4- methoxyphenyl) (4H-benzo[b]pyrrolo[l ,2-d] 1 ,4- thiaziny l)]methyl } methylamino)ethyl] acetamide

4-(4-methoxyphenyl)-l-[(methyl{2-[2-(2-oxo(6-hydroquinolyloxy)) acetylamino] ethyl } amino)methyl]benzo [e]pyrrolo [2, 1 -c] 1 ,4-thiazin-4-yl acetate

This invention further provides a compound of formula IV

IV or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or C1-C₄ alkoxy; R⁶ is hydrogen, halo, trifluoromethyl, cyano or nitro; R⁷ is hydrogen, halo, trifluoromethyl, cyano, nitro, Cι-C₈ alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR², -OSO₂CF₃, wherein R² is as defined above; L is a direct bond, Cι-Cn alkylene, C₂-C₁₂ alkenylene or C2- 2 alkynylene, wherein one or more -CH2- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y, as described previously, with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR¹^, C₁-C₄ alkoxy, Q-C₄ alkylthio, COOR¹, d-C.₂ alkyl, C2-Q2 alkenyi or C2-C12 alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s). In one embodiment of formula IV, the compound has a structure according to formula IV-A

IV-A wherein Ar, L and Z are as defined previously. In one embodiment of formula IV-A, Z is a moiety of formula A, J or 0. Examples of a compound of formula IV include without limitation:

2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))phenoxy]-N-(2-{[(l-oxo-4- phenyl(4H,3aH-benzo[e]pyrrolidino[2, 1 -c] 1 ,4-thiazaperhydroin-7-yl))methyl] amino}ethyl)acetamide This invention further provides a compound of formula V

V or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or Cι-C₄ alkoxy; R is hydrogen, halo, trifluoromethyl, cyano or nitro; R is hydrogen, halo, trifluoromethyl, cyano, nitro, Cτ-C₈ alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR², -OSO₂CF₃, wherein R² is as defined above; L is a direct bond, C1-C1₂ alkylene, C2- ₂ alkenylene or C₂-C1₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y, as described previously, with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR^¹, -C₄ alkoxy, -C alkylthio, COOR¹, C1- 2 alkyl, C₂- 2 alkenyi or C₂-C₁₂ alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s). In one embodiment of formula V, the compound has a structure according to formula V-A

V-A wherein Ar, L and Z are as defined previously. In one embodiment of formula V-A, Z is a moiety of formula A, J or O. Examples of a compound of formula V include without limitation:

2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))phenoxy]-N-[2-({[4-(4- chlorophenyl)-4-hydroxy- 1 -oxobenzo[b] 1 ,2,4-oxadiazolino [4,3 -d] 1 ,4- thiazaperhydroin-8-yl]methyl} amino)ethyl] acetamide

Every variable substituent is defined independently at each occurrence. Thus, the definition of a variable substituent in one part of a formula is independent of its definition(s) elsewhere in that formula and of its definition(s) in other formulas. Since the inventive compounds may possess one or more asymmetric carbon center(s), they may be capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures of optical isomers. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes. One such process entails formation of diastereoisomeric salts by treatment with an optically active acid or base, then separation of the mixture of diastereoisomers by crystallization, followed by liberation of the optically active bases from the salts. Examples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. A different process for separating optical isomers involves the use of a chiral chromatography column optimally chosen to maximize the separation of the enantiomers. Still another available process involves synthesis of covalent diastereoisomeric molecules, for example, esters, amides, acetals and ketals, by reacting the inventive compounds with an optically active acid in an activated form, an optically active diol or an optically active isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to deliver the enantiomerically pure compound. In some cases hydrolysis to the "parent" optically active drug is not necessary prior to dosing the patient, since the compound can behave as a prodrug. The optically active compounds of this invention likewise can be obtained by utilizing optically active starting materials. The compounds of this invention encompass individual optical isomers as well as racemic and non-racemic mixtures. In some non-racemic mixtures, the R configuration may be enriched while in other non-racemic mixtures, the S configuration may be enriched.

METHODS OF TREATMENT

This invention further provides a method for regulating calcium homeostasis, comprising administering an effective amount of an inventive compound to an animal in need of such regulation. This invention further provides a method for treating a disease, disorder or condition in which disregulation of calcium homeostasis is implicated, comprising administering an effective amount of an inventive compound to an animal in need of such treatment. This invention further provides a method for treating a cardiovascular disease, stroke, epilepsy, an ophthalmic disorder or migraine, comprising administering an effective amount of an inventive compound to an animal in need of such treatment. In one embodiment of the inventive method, the cardiovascular disease is heart failure, hypertension, SA/AV node disturbance, arrhythmia, hypertrophic subaortic stenosis or angina. In another embodiment, the heart failure is chronic heart failure or congestive heart failure. The inventive compound may be administered by any means known to an ordinarily skilled artisan. For example, the inventive compound may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, and intraosseous injection and infusion techniques. The exact administration protocol will vary depending upon various factors including the age, body weight, general health, sex and diet of the patient; the determination of specific administration procedures would be routine to an ordinarily skilled artisan. The inventive compound may be administered by a single dose, multiple discrete doses or continuous infusion. Pump means, particularly subcutaneous pump means, are useful for continuous infusion. Dose levels on the order of about 0.001 mg/kg/d to about 10,000 mg/kg/d of the inventive compound are useful. In one embodiment, the dose level is about 0.1 mg/kg/d to about 1,000 mg/kg/d. In another embodiment, the dose level is about 1 mg/kg/d to about 100 mg/kg/d. The specific dose level for any particular patient will vary depending upon various factors, including the activity and the possible toxicity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; the drug combination; the severity of the congestive heart failure; and the form of administration. Typically, in vitro dosage-effect results provide useful guidance on the proper doses for patient administration. Studies in animal models are also helpful. The considerations for determining the proper dose levels are well known in the art and within the skill of a physician. Any administration regimen well known to an ordinarily skilled artisan for regulating the timing and sequence of drug delivery can be used and repeated as necessary to effect treatment in the inventive method. The regimen may include pretreatment and/or co-administration with additional therapeutic agent(s). The compound of the present invention can be administered alone or in combination with one or more additional therapeutic agent(s) for simultaneous, separate, or sequential use. The additional agent(s) may be any therapeutic agent(s), including without limitation one or more compound(s) of the present invention. The compound of the present invention can be co-administered with one or more therapeutic agent(s) either (i) together in a single formulation, or (ii) separately in individual formulations designed for optimal release rates of their respective active agent.

PHARMACEUTICAL COMPOSITIONS

The present invention further provides a pharmaceutical composition comprising: (i) an effective amount of a compound of this invention; and (ii) a pharmaceutically acceptable carrier. The inventive pharmaceutical composition may comprise one or more additional pharmaceutically acceptable ingredient(s), including without limitation one or more wetting agent(s), buffering agent(s), suspending agent(s), lubricating agent(s), emulsifier(s), disintegrant(s), absorbent(s), preservative(s), surfactant(s), colorant(s), flavorant(s), sweetener(s) and additional therapeutic agent(s). The inventive pharmaceutical composition may be formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (for example, aqueous or non-aqueous solutions or suspensions), tablets (for example, those targeted for buccal, sublingual and systemic absorption), boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, emulsions and mlcroemulsions; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or sxxspension or a 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) sixblingually; (6) ocularly; (7) transdermally; or (8) nasally. EXAMPLES

Synthesis of Compounds Compounds of Formula I in which X is sulfur is prepared according to Scheme I. The starting benzothiazepin-4(5H)-ones are well known in the art and can be prepared by a variety of known methods. See, for example, Inoue et al. J. Med. Chem. 1991, 34, 675-687 and references cited therein; Morimoto et al. Heterocycles 1990, 30, 471-486 and references therein; Choudary et al. J Org. Chem. 2003, 68, 1736-1746 and references therein.

Examples 1 to 3: (2S,3S)-5-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy ] acetyl- amino } ethyl)methylamino] ethyl } -2-(4-methoxyphenyl)-4-oxo- 2H,3H-benzo[b]l,4-thiazaperhydroepin-3-yl acetate (Compound 1) is synthesized according to Scheme I.

SCHEME I

Compound 3

r2S.3SV5-[2-r(2- ert-butoxy carbonylamino1 ethvUmethylamino')ethyl]-2-(^'4- methoxyphenvD-4-oxo-2H,3H-benzo[b] 1 ,4-thiazaperhydroepin-3-yl acetate. (7ert- butoxy)-N-{2-[(2-chloroethyl)methylamino]ethyl}carboxamide (2.0 g; 8.4 mmol) is added to a mixture of (2S,3S)-2-(4-methoxyphenyl)-4-oxo-2H,3H,5H-benzo[b]l,4- thiazaperhydroepin-3-yl acetate (2.32 g; 6.7 mmol) and potassium carbonate (1.80 g; 13.0 mmol) in acetone (105 ml). The reaction mixture is then heated to reflux and stirred at this temperature under nitrogen for 7 h. After cooling to ambient temperature, the reaction mixture is filtered to remove insolubles. The filtrate is then concentrated under reduced pressure to give the product as highly viscous, light yellow oil.

(2S,3 S -5- {2-[f2-aminoethyl methylamino]ethyl| -2-(4-methoxyphenyl -4-oxo- 2H,3H-benzo b] 1.4-thiazaperhydroepin-3-yl acetate. A solution of the Boc-protected amine from the previous step (1.75 g; 3.22 mmol) in 25 ml of CH₂CI₂ is cooled to 0^°C and treated with 4 ml (4 mmol) of a 1.0 M solution of trifluoroacetic acid in CH₂CI₂. After stirring for 30 minutes at 0 C and 2 hours at room temperature, the mixture is made basic by the addition of 1 N NaOH and extracted into 2 x 50 ml of CH₂CI₂. The organic extracts are dried, concentrated, and purified on a silica gel column, eluting with 95:5

to obtain the amine product as a darkish oil. r2S,3S -5-{2-r -{2-r2-chloro-4-(6-oxor 4,5-trihvdropyridazin-3- yl) phenoxy]acetyl- amino>ethyl)methylamino]ethyl>-2-(^'4-methoxyphenylV4-oxo- 2H3H-benzorb11.4-thiazaperhydroepin-3-yl acetate (Compound 1 . 6-{4-[3- Carboxymethoxy]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone (1.38 g, 4.88 mmol), l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.935 g, 4.88 mmol) and 7-hydroxyazabenzotriazole (0.265 g, 1.95 mmol) are mixed as solids. N,N-dimethylformamide (70 mL) is then added and the mixture is sonicated at ambient temperature for 5 min. to give a homogeneous, light yellow solution. A solution of (2S,3 S)-5- {2-[(2-aminoethyl)methylamino]ethyl}-2-(4-methoxyphenyl)-4- oxo-2H,3H-benzo[b]l,4-thiazaperhydroepin-3-yl acetate. (2.16 g, 4.88 mmol) in N,N-dimethyl~ formamide (30 mL) is added and the reaction mixture is stirred at ambient temperature for 18 h. Ethyl acetate (100 mL) and water (120 mL) are then added and the mixture is extracted with ethyl acetate (3 x 100 mL). The combined organic layers are washed with aqueous sodium hydroxide solution (2 N, 100 mL) and brine (2 x 100 mL), dried (MgSO₄) and concentrated under reduced pressure to give yellow solid which is recrystallised from ethyl acetate / diethyl ether to obtain the title compound.

(2S,3 S)-5-{2-[(2-{2-[4-(5-Cyano-2-methyl-6-oxo(3-hydropyridyl))phenoxy]-acetyl- amino}ethyl)methylamino]ethyl}-2-(4-methoxyphenyl)-4-oxo-2H,3H-benzo[b]l,4- thiazaρerhydroeρin-3-yl acetate (Compound 2) and (4S,3R)-l-{2-[(2-{2-[2-Chloro-4- (6-ox:o(l,4,5-trihydropyridazin-3-yl))phenoxy]acetyl- amino}ethyl)methylamino]ethyl}-4-(4-methoxyphenyl)-2-oxo-3H,4H,5H- benzo[f]azaperhydroepin-3-yl acetate (Compound 3) are made in a manner similar to Scheme I, except that the amine in the final step is reacted with 2-[4-(5-cyano-2- methyl-6-oxo-3-hydropyridyl)phenoxy]-acetic acid and 2-(2-oxo-6- hydroquinolyloxy)acetic acid, respectively. The requisite pyridazinone, cyanopyridine, and carbostyril phosphodiesterase inhibitor moieties are prepared according to Schemes II-IN, respectively.

SCHEME II

Ethyl 2-chlorophenoxyacetate. To a stirred solution of 2-chlorophenol (20.0 g, 156 mmol) in acetone (300 mL) under nitrogen at ambient temperature are added potassium carbonate (23.7 g, 171 mmol) and ethyl bromoacetate (7, 26.0 g, 156 mmol). The reaction mixture is then heated to reflux and stirred at this temperature under nitrogen for 7 h. After cooling to ambient temperature, the reaction mixture is filtered to remove insolubles. The filtrate is then concentrated under reduced pressure to give the product as an oil.

4-T3 -Chloro-4-(ethoxycarbonylmethoxy phenyl1 -4-oxobutyric acid. To a stirred solution of ethyl 2-chlorophenoxyacetate (32.0 g, 149 mmol) in dichloromethane (75 mL) at ambient temperature under nitrogen is added succinic anhydride (22.4 g, 224 mmol). The reaction mixture is cooled in ice-water and to this is added portionwise aluminum trichloride (59.6 g, 447 mmol), whilst maintaining the temperature below 20°C. The reaction mixture is then allowed to stir at ambient temperature for 20 min. and is then heated to reflux for 3 h. The reaction mixture is allowed to cool to ambient temperature then poured into a mixture of ice, water (200 ml) and HC1 (IO N, 100 ml). The two phase system is separated and the aqueous layer is extracted with ethyl acetate (5 x 100 mL). All organic layers are then combined and washed with water (2 x 100 mL), dried (Νa₂SO₄), and concentrated under reduced pressure to give an orange oily solid. Hexane (300 mL) is added, and after standing at ambient temperature for 1 h, the precipitate is filtered off and recrystallised from ethyl acetate / hexane to give the dicarbonyl compound as a solid.

6-[3-Cl loro-4-(^'ethoxycarbonylmethoxy phenyl]-4,5-dihydro-3(2H^')-pyridazinone. To a stirred suspension of 4-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl]-4-oxobutyric acid (21 .5 g, 69.2 mmol) in ethanol (200 mL) at 0 °C is added a solution of hydrazine monohydrate (3.4 mL, 69.2 mmol) in ethanol (20 mL). The reaction mixture is then allowed to warm to ambient temperature and stirred at this temperature for 15 min. before heating to reflux for 3 h. Ethyl acetate (40 mL) is added to the hot solution and the mixiture is allowed to cool to ambient temperature. The precipitate which forms is filtered off and washed with water (2 x 100 mL) and cold ethanol (2 x 100 mL) then dried under high vacuum to give the ester as a light yellow powder. 6- (4-[3 -carboxymethoxy] -3 -chlorophenyl) -4,5-dihydro-3 (2H)-pyridazinone. To a stirred suspension of 6-[3-chloro-4-(ethoxycarbonylmethoxy)phenyl]-4,5-dihydro- 3(2H)-pyridazinone (17.6 g, 56.6 mmol) in ethanol (150 mL) at ambient temperature are added water (150 mL) and sodium hydroxide (9.10 g, 227 mmol). The reaction mixture is then heated to 80 °C and stirred at this temperature for 2.5 h. The solution is allowed to cool until precipitation occurred, then the suspension is acidified to pH 1-2 with HC1 (2 N, 100 mL) with stirring. After standing at ambient temperature for 1 h, the precipitate is filtered off and washed with water (2 x 100 mL) and ethanol (2 x 100 mL). The solid is dried under high vacuum at 45°C to give 6-{4-[3- carboxymethoxy]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone as a powder. SCHEME III

Ethyl 2-[4-f5-cvano-2-methyl-6-oxo-3-hydropyridyDphenoxy]acetate. A solution of 5-(4-hydroxyphenyl)-6-methyl-2-oxohydropyridine-3-carbonitrile (2.33 g; 10.30 mmol), prepared as described in U.S. Patent 4,465,686, in dimethylformamide (25 mL), is treated with sodium hydride (500mg; 20.6 mmol) at room temperature, and stirred for 1 hour. The reaction mixture is then treated with a solution of ethyl bromoacetate (2.06 g; 12.36 mmol) in 5 mL of DMF. The resulting mixture is heated to 80°C for 45 minutes, cooled, and partitioned between water and ethyl acetate. The layers are separated and the organic phase is washed repeatedly with brine and water, dried, and concentrated. The crude material is chromatographed on a silica gel column, eluting with 30% ethyl acetate in hexane, to deliver the ester. 2-r4-(5-cvano-2-methyl-6-oxo-3-hvdropyridyl phenoxy]acetic acid. To a stirred solution of ethyl 2-[4-(5-cyano-2-methyl-6-oxo-3-hydropyridyl)- phenoxy] acetate (10.9 g, 34.9 mmol) in 75 mL of a 1:1 mixture of ethanol water at ambient temperature is added lithium hydroxide (3.34 g; 139.6 mmol). The reaction mixture is then stirred at room temperature for 1 hour. The solution is acidified to pH 1-2 with HC1 (2 N, 100 mL) with stirring. After standing at ambient temperature for 1 h, the precipitate is filtered off and washed with water (2 x 100 mL) and ethanol (2 x 100 mL) and dried under high vacuum at 45°C to give 2-[4-(5-cyano-2-methyl-6-oxo-3- hydropyridyl)phenoxy] acetic acid as a powder.

SCHEME IV

Ethyl 2-f2-oxo-6-hvdroquinoryloxy)acetate. Ethyl bromoacetate (5.0 g; 30 mmol) is added dropwise to a solution of 6-hydroxyhydroquinolin-2-one (5.0 g; 31.02 mmol), prepared according to the method of J Med. Chem. 1986, 29, 2024-2028) and DBU in isopropanol (50 ml) with stirring under reflux. The mixture is refluxed overnight. The solvents are evaporated under vacuum and the residue is extracted with chloroform (140 mL). The extracts are washed successively with 0.5 N NaOH (40 mL), diluted HC1 (40 mL), and water (40 mL), dried over Na₂SO₄, and filtered. The filtrate is concentrated to give a residue, which is recrystallized from MeOH to afford the product as a solid.

2-(2-Oxo-6-hvdroquinoryloxy)acetic acid. A suspension of ethyl 2-(2-oxo-6- hydroquinolyloxy)acetate in 20% HC1 is stirred at 85-90 °C for 2 h and cooled down. The precipitated crystals are collected by filtration and washed with water and hexane to give the carboxylic acid as a solid. Example 4 Compounds of Formula I in which X is methylene, including (4S,3R)-l-{2- [(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))phenoxy]acetyl amino )-ethyl)methylamino]ethyl}-4-(4-methoxyphenyl)-2-oxo-3H,4H,5H- benzo f]azaperhydroepin-3-yl acetate (Compound 4), are prepared according to Scheme N. Intermediate compound, (4S,3R)-3-hydroxy-4-(4-methoxyphenyl)- lH,3H,4H,5H-benzo[f] azaperhydroepin- 2-one, can be synthesized according to the methods disclosed in Floyd et al., J Med. Chem. 1992, 35, 156-112, and converted to the final product according to the methods described in Scheme I.

SCHEME V

NaOMe, MeOH, reflux

Example 5 4-{2-[(2-{2-[2-Chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy] acetylamino} ethyl)methylamino]ethyl}-7-(4-methoxyphenyl)-3-methyl- 5-oxo-2-phenyl-6H,7H-l,4-thiazepin-6-yl acetate (Compound 5) is prepared according to Scheme VI starting from (4S,3R)-4-(4-methoxyphenyl)-7-methyl-2-oxo- 6-phenyl-lH,3H,4H,5H-azepin-3-yl acetate, which can be synthesized according to the methods disclosed in U.S. Patent No. 4,959,359.

SCHEME VI

Example 6 7-(4-methoxyρhenyl)-3-methyl-4-{2-[methyl(2-{2-[4-(6-oxo(l,4,5- trihydropyridazin-3 -yl))phenoxy] acetylamino } ethyl)amino] ethyl } -2-(2-naphthyl)-5- oxo-6H,7H-l ,4-thiazepin-6-yl acetate (Compound 6) is prepared in manner similar to Example 5, starting from (4S,3R)-4-(4-methoxyphenyl)-7-methyl-6-(2-naphthyl)-2- oxo-lH,3H,4H,5H-azepin-3-yl acetate, which can be synthesized according to the methods disclosed in U.S. Patent No. 4,652,561.

Examples 7 and 8 4-{2-[(2-{2-[4-(5-Cyano-2-methyl-6-oxo(3- hydropyridyl))phenoxy] acetylamino } ethy l)methylamino] ethyl } -7-(4- methoxyphenyl)-3 -methyl-5-oxo-2-phenyl-6H,7H- 1 ,4-thiazepin-6-yl acetate (Compound 7) and 7-(4-methoxyphenyl)-3-methyl-4-[2-(methyl{2-[2-(2-oxo(6- hydroquinolyloxy)) acetylamino]ethyl}amino)ethyl]-5-oxo-2-phenyl-6H,7H-l,4- thiazepin-6-yl acetate (Compound 8) are synthesized in a manner similar to Example 5, using the requisite carboxylic acids from Schemes III and IV.

Example 9 N-[2-({[4-(2,4-Dimethoxyphenyl)(4H-benzo[b]pyrrolo[l,2-d]l,4- thiazinyl)]methy 1 } methylamino)ethyι] -2- [2-chloro-4-(6-oxo( 1 ,4,5 -trihydropyridazin- 3-yl))phenoxy] acetamide (Compound 9) is prepared according to Scheme VII starting from 4-(2,4-dimethoxyphenyl)-4H-benzo[b]pyrrolo[l ,2-d] 1 ,4-thiazaper- hydroinecarbaldehyde, which can be synthesized according to the methods disclosed in Campiani et al, J Med. Chem. 1995, 38, 4393-4410.

SCHEME VII

Example 10 2-[4-(5-Cyano-2-methyl-6-oxo(3-hydropyridyl))ρhenoxy]-N-[2-({[4-(4- methoxyphenyl) (4H-benzo[b]pyrrolo[l,2-d]l,4- thiazinyl)]methyl}methylamino)ethyl]-acetamide (Compound 10) is synthesized a manner similar to Example 9, starting from 4-(4-methoxyphenyl)-4H- benzo [b]pyrrolo [ 1 ,2-d] 1 ,4-thiazaper-hydroinecarbaldehyde and 6- {4-[3 - carboxymethox:y]-3-chlorophenyl}-4,5-dihydro-3(2H)-pyridazinone.

Example 11 4-(4-Methoxyphenyl)-l-[(methyl{2-[2-(2-oxo(6-hydroquinolyloxy)) acetylamino] ethyl } amino)methyl]benzo [e]pyrrolo [2, 1 -c] 1 ,4-thiazin-4-yl acetate (Compound 11) is prepared according to Scheme VIII starting from 4-(4- methoxyphenyl)benzo[b]-pyrrolo[l,2-d]l,4-thiazaperhydroin-4-ol, which can be synthesized according to the methods disclosed in Campiani, supra. The Boc- protected intermediate can be converted to the final product by removal of the Boc group and coupling of the amine with the appropriate carboxylic acid, as described in previous schemes.

SCHEME VIII

Example 12 2- [2-Chloro-4-(6-oxo( 1,4,5 -trihydropyridazin-3 -yl))phenoxy] -N-(2- { [( 1 -oxo- 4-pheny 1(4H,3 aH-benzo [e]pyrrolidino [2, 1 -c] 1 ,4-thiazaperhydroin-7-yl))methyl] amino }ethyl)acetamide (Compound 12) is prepared according to Scheme IX, starting from 7-(l ,3 -dioxolan-2-yl)-4-phenyl-4H,3 aH-benzo [e]pyrrolidino [2, 1 -c] 1,4- thiazaperhydroin-1-one, which can be synthesized according to the methods described in Bioorg. Med. Chem. Lett. 1994, 4, 1235-1240 and J Het. Chem. 1990, 27, 1329. Following deprotection of the masked aldehyde, the aldehyde is converted to the final product by the same sequence of reactions described in Scheme VIII. SCHEME IX

Example 13 2-[2-Chloro-4-(6-oxo(l,4,5-trihydropyridazin-3-yl))phenoxy]-N-[2-({[4-(4- chlorophenyl)-4-hydroxy- 1 -oxobenzo [b] 1 ,2,4-oxadiazolino [4,3 -d] 1 ,4- thiazaperhydroin-8-yl]methyl} amino)ethyl]acetamide (Compound 13) is prepared according to Scheme X starting from 4-(4-chlorophenyl)-4-hydroxy-8- methylbenzo[b]l,2,4-oxadiazolino[4,3-d]l,4-thiazaperhydroin-l-one, which can be synthesized as described in J Med. Chem. 2002, 45, 3475. Following conversion of the aryl methyl group to a benzyl bromide, the bromide is reacted with the protected diamine of Scheme IX, and the product of this step is converted to the final product by the methods of Schemes VIII and IX. SCHEME X

L-type Ca+2 channel blocking activity Test compounds of the present invention are evaluated for their ability to inhibit calcium currents through voltage-sensitive calcium channels by any one of several methods known to those skilled in the art. For example, affinity for L-type calcium channels may be determined by measuring the potency of the test compounds to displace standard reference ligands from calcium channels in membrane preparations. Alternatively, ability to block voltage-dependent calcium entry into cells may be evaluated by measuring ⁴⁵Ca⁺² flux.

Example 14: Assay for measuring affinity of compounds for L-type calcium channels

[³H]nitrendipine, a selective blocker of L-type calcium channels, is used as a reference ligand for evaluating the ability of the test compounds to displace the reference ligand from rat cerebral cortex. Plasma membrane preparations from rat cerebral cortex are obtained as described by Schwartz et al., Br. J. Pharmacol, 84:511, 1985. Protein concentrations are determined by the method of Lowry et al., J Biol. Chem., 193:265, 1951. 1 ml of plasma membrane preparation (1 mg of protein) is incubated with 0.1 nM [ H]nιtrendipine (80 Ci/mmol) and increasing concentrations of test compounds in 50 mM Tris-HCl (2-amino-2-(hydroxymethyl)-l,3-propanediol, hydrochloride) buffer, pH 7.4 (total volume 2 ml). Incubation is carried out at 25°C for 90 minutes; bound and free ligands are separated by rapid filtration through Whatman GF/B filters. The filters are rapidly washed with 20 ml of 50 mM Tris-HCl buffer, pH 7.4, and transferred to counting vials containing 10 ml of scintillation cocktail. Radioactivity is measured in a Packard counter and non-specific binding is measured in the presence of 10^"5 M nitendipine. The IC50 of the test compounds, the concentration of the test compounds that inhibits the maximum specific binding of the ligand by 50%, is determined.

PDE-3 inhibitory activity

Example 15: Assay for measuring cAMP PDE-3 inhibitory activity Human platelet cyclic AMP phosphodiesterase is prepared according to the method of Alvarez et al., Mol. Pharmacol. 1986, 29, 554. The PDE incubation medium contains 10 mM Tris-HCl buffer, pH 7.7, 10 mM MgSO₄, and 1 μM [³H]AMP (0.2 μCi) in a total volume of 1.0 mL. Test compounds are dissolved in DMSO immediately prior to addition to the incubation medium, and the resulting mixture is allowed to stand for 10 minutes prior to the addition of enzyme. Following the addition of PDE, the contents are mixed and incubated for 10 minutes at 30°C. Three assays each are performed for each of five test compound concentrations, the mean of the determinations (n = 3) at each concentration is plotted, and IC₅₀ values are determined graphically.

Restoration of calcium homeostasis in heart tissue

Example 16: Assay for measuring contraction-relaxation in guinea pig papillary muscle Male guinea pigs (400-500 g) are killed by cervical dislocation and the hearts are quickly removed, immersed in ice-cold, and oxygenated in Kreb's solution containing 113.1 mM NaCl, 4.6 mM KC1, 2.45 mM CaCl₂, 1.2 mM MgCl₂, 22.0 mM NaH₂PO₄, and 10.0 mM glucose; pH 7.4 with 95% O₂ - 5% CO₂. The ventricles are opened and papillary muscles are removed with chordae tandineae and a base of surrounding tissue intact. The tendinous ends of the muscles are ligated with silk thread, and the muscles are mounted in vertical, double-jacketed organ baths containing 10 mL of oxygenated Kreb's solution kept at 37°C. The tendinous end is attached to a Grass isometric force transducer, while a metal hook is inserted into the base of the muscle. Following a 45-minute equilibration period under a 1 gram tension, control contractions are elicited by stimulating the muscle using stainless steel field electrodes at a frequency of 1.0 Hz, 2.0 ms duration. The amplitude of the stimulus is adjusted to be approximately 1.5 times the threshold amplitude sufficient to elicit a contraction of the tissues. Control contraction-relaxation cycles are recorded for 30 seconds continuously. Cumulative test drug concentrations are then injected directly into the bath while the tissue is being stimulated. Contraction-relaxation recordings are made continuously, for 30 seconds per test compound concentration. A series of washout contractions is recorded following a change of solution. Provided that the amplitude of contraction returns to that measured in control conditions, a single concentration of positive control is then tested on the tissue in the same manner as the test compound. Contraction amplitude as well as the time courses of contraction and relaxation are quantified. All recordings are normalized against control values; statistical analysis of the results is made using t-tests or ANOVAs. All publications, patents and patent applications identified above are herein incorporated by reference. The invention being thus described, it will be apparent to those skilled in the art that the same may be varied in many ways without departing from the spirit and scope of the invention. Such variations are included within the scope of the invention to be claimed.

Claims

I CLAIM:

1. A compound of formula I

I or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: X is CH₂ or S; R¹ is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl; R² is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C C₈ alkanoyl, C₃-C₈ cycloalkanoyl, or — C-0-(C C₅ alkyl) O or -C-(CH₂)_m-0-(C C₃ alkyl) O n is 2, 3 or 4; m is 1 or 2; Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or -C alkoxy; each R³ is independently hydrogen, halo, trifluoromethyl, cyano, nitro, - alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR² or -OSO₂CF₃; L is a direct bond, Cι-Cn alkylene, C₂-C₁ alkenylene or C₂-C₁₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y

B

K M

u V

w

with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR¹!*¹, -C alkoxy, Q-C₄ alkylthio, COOR¹, C1-C12 alkyl, C₂-C₁₂ alkenyi or C₂-C ₁₂ alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s).

2. The compound of claim 1, which has a structure according to formula I-A:

l-A

9 ^ wherein Ar, R , R , L and Z are as defined in claim 1.

3. The compound of claim 2, wherein Z is a moiety of formula A, J or O.

4. The compound of claim 1 , which has a structure according to formula I-B :

l-B

wherein Ar, R , R , L and Z are as defined in claim 1.

5. The compound of claim 4, wherein Z is a moiety of formula A, J or O.

6. The compound of claim 1 , which is selected from: (2S,3S)-5-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy]acetyl- amino}ethyl)methylamino]ethyl}-2-(4-methoxyphenyl)-4-oxo- 2H,3H-benzo[b]l ,4-thiazaperhydroepin-3-yl acetate; (2S,3S)-5-{2-[(2-{2-[4-(5-cyano-2-methyl-6-oxo(3- hydropyridyl))phenoxy]acetyl- amino}ethyl)methylamino]ethyl}-2-(4- methoxyphenyl)-4-oxo-2H₅3H-benzo[b]l,4-thiazaperhydroepin-3-yl acetate; (4S,3R)-l-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy]acetyl- amino}ethyl)methylamino]ethyl}-4-(4-methoxyphenyl)-2-oxo- 3H,4H,5H-benzo[f]azaperhydroepin-3-yl acetate; and (4S,3R)-l-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin-3- yl))phenoxy]acetyl amino} ethyl)methylamino]ethyl}-4-(4-methoxyphenyl)-2-oxo- 3H,4H,5H-benzo[f]azaperh.ydroepin-3-yl acetate.

7. A compound of formula II

II or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: X is CH₂ or S; R¹ is hydrogen, C C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl; R² is hydrogen, Cj-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C C₈ alkanoyl, C₃-C₈ cycloalkanoyl, or — C-C— (C C₅ alkyl) 0 or — C-(CH₂)_m-0-(C C₃ alkyl) O n is 2, 3 or 4; m is 1 or 2; Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or C₁-C₄ alkoxy; each R³ is independently hydrogen, halo, trifluoromethyl, cyano, nitro, -Cg alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR² or -OSO₂CF₃; R⁴ is d-Cs alkyl; L is a direct bond, C1-C12 alkylene, C₂-C₁₂ alkenylene or C₂-C₁₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y

B

u V

w with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR^¹, d-C₄ alkoxy, C₁-C₄ alkylthio, COOR¹, -Cn alkyl, C₂-C₁₂ alkenyi or C₂-C₁₂ alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and or hydroxyl(s).

8. The compound of claim 7, which has a structure according to formula II-A

wherein Ar, R², L and Z are as defined in claim 7.

9. The compound of claim 8, wherein Z is a moiety of formula A, J or O.

10. The compound of clai 1, which has a structure according to formula II-B

wherein Ar, R , L and Z are as defined in claim 7.

11. The compound of claim 10, wherein Z is a moiety of formula A, J or O.

12. The compound of claim 7, which is selected from: 4-{2-[(2-{2-[2-chloro-4-(6-oxo(l,4,5-trihydroρyridazin-3- yl))phenoxy] acetylamino} ethyl)methylamino]ethyl}-7-(4-methoxyphenyl)-3-methyl- 5-oxo-2-phenyl-6H,7H-l ,4-thiazepin-6-yl acetate; 7-(4-methoxyρhenyl)-3-methyl-4-{2-[methyl(2-{2-[4-(6-oxo(l,4,5- trihydropyridazin-3 -yl))phenoxy] acetylamino } ethyl)amino] ethyl } -2-(2-naphthyl)-5 - oxo-6H,7H-l ,4-thiazepin-6-yl acetate; 4-{2-[(2-{2-[4-(5-cyano-2-methyl-6-oxo(3- hydropyridyl))phenoxy]acetylamino} ethyl)methylamino]ethyl}-7-(4- methoxyphenyl)-3-methyl-5-oxo-2-phenyl-6H,7H-l,4-thiazepin-6-yl acetate; and 7-(4-methoxyphenyl)-3-methyl-4-[2-(methyl{2-[2-(2-oxo(6- hydroquinolyloxy)) acetylamino] ethyl} amino)ethyl]-5-oxo-2-phenyl-6H,7H- 1 ,4- thiazepin-6-yl acetate.

13. A compound of formula III

III or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: R¹ is hydrogen, Ci-C₈ alkyl, C₂-C₈ alkenyi, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl; Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or C₁-C₄ alkoxy; R⁶ is hydrogen, halo, trifl ioromethyl, cyano or nitro; R⁷ is hydrogen, halo, trifluoromethyl, cyano, nitro, -Cg alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR², -OSO₂CF₃, wherein R² is as defined above; L is a direct bond, C1- ₂ alkylene, C₂-C₁₂ alkenylene or C₂-C₁₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -0-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y

B

D

H

u V

w

with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR¹!*¹, C₁-C₄ alkoxy, d-C₄ alkylthio, COOR¹, C C₁₂ alkyl, C₂-C₁₂ alkenyi or C2-C12 alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s).

14. The compound of claim 13, which has a structure according to in formula III-

A

III-A wherein Ar, L and Z are as defined in claim 13.

15. The compound of claim 14, wherein Z is a moiety of formula A, J or O.

16. The compound of claim 13, which has a structure according to formula III-B

III-B wherein Ar, L and Z are as defined in claim 13.

17. The compound of claim 16, wherein Z is a moiety of formula A, J or O.

18. The compound of claim 13, which is selected from: N-[2-({ [4-(2,4-dimethoxyp enyl)(4H-benzo[b]pyrrolo[l ,2-d] 1 ,4- thiazinyl)]methyl} methylamino)ethyl]-2-[2-chloro-4-(6-oxo(l,4,5-trihydropyridazin- 3-yl))phenoxy] acetamide; 2-[4-(5-cyano-2-methyl-6-oxo(3-hydropyridyl))phenoxy]-N-[2-({[4-(4- methoxyphenyl) (4H-benzo[b]pyrrolo[l,2-d] 1,4- thiazinyl)]methyl}methylamino)ethyl]-acetamide; and 4-(4-methoxyphenyl)-l-[(methyl{2-[2-(2-oxo(6-hydroquinolyloxy)) acetylamino] ethyl}amino)methyl]benzo[e]pyrrolo[2, 1 -c] 1 ,4-thiazin-4-yl acetate.

19. A compound of formula IV

IV or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or C₁-C₄ alkoxy; R⁶ is hydrogen, halo, trifluoromethyl, cyano or nitro; R⁷ is hydrogen, halo, trifluoromethyl, cyano, nitro, Ci-Cs alkoxy carbonyl, -OR², -OCONHR¹, -OCF₂H, -SR², -OSO₂CF₃, wherein R² is as defined above; L is a direct bond, C₁-C₁₂ alkylene, C₂-C₁₂ alkenylene or C2-C₁₂ alkynylene, wherein one or more -CH₂- grouρ(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y,

B

H

M

u V

w

with Z connected to C through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR¹!*.¹, C1-C4 alkoxy, C1-C₄ alkylthio, COOR¹, C1-C12 alkyl, C₂-C₁₂ alkenyi or C₂-C ₂ alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR , and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s).

20. The compound of claim 19, which has a structure according to formula IV-A

IV-A wherein Ar, L and Z are as defined in claim 19.

21. The compound of claim 20, wherein Z is a moiety of formula A, J or O.

22. The compound of claim 19, which is 2-[2-chloro-4-(6-oxo(l,4,5- trihydropyridazin-3-yl))phenoxy]-N-(2- { [( 1 -oxo-4-phenyl(4H,3 aH- benzo [e]pyrrolidino [2, 1 -c] 1 ,4-thiazaperhydroin-7-yl))methyl] amino } ethyl)acetamide.

23. A compound of formula V

V or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: Ar is phenyl or heteroaryl optionally substituted in 1-3 position(s) with halo and/or C₁-C₄ alkoxy; R⁶ is hydrogen, halo, trifluoromethyl, cyano or nitro; R⁷ is hydrogen, halo, trifluoromethyl, cyano, nitro, Ci-Cg alkoxycarbonyl, -OR², -OCONHR¹, -OCF₂H, -SR², -OSO CF₃, wherein R² is as defined above; L is a direct bond, C1-C12 alkylene, C₂-Ci2 alkenylene or C₂-C₁₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR¹, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Z is a moiety of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W or Y

H

K L M

Q R s

u V

W

with Z connected to L through any one R; and each R is independently a direct bond, hydrogen, halo, nitro, cyano, trifluoromethyl, amino, NR¹^, C1-C4 alkoxy, Cj-C alkylthio, COOR¹, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyi or C₂-C₁₂ alkynyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyi or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR¹, and the alkyl, alkenyi or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s).

24. The compound of claim 23, which has a structure according to formula V-A

V-A wherein Ar, L and Z are as defined in claim 23.

25. The compound of claim 23, wherein Z is a moiety of formula A, J or O.

26. The compound of claim 24, which is 2-[2-chloro-4-(6-oxo(l ,4,5- trihydropyridazin-3-yl))phenoxy]-N-[2-({[4-(4-chlorophenyl)-4-hydroxy-l- oxobenzo [b] 1 ,2,4-oxadiazolino [4,3 -d] 1 ,4-thiazaperhydroin-8-yl]methyl} amino)ethyl]acetamide.

27. A pharmaceutical composition comprising:

(i) an effective amount of any compound of claims 1-26; and (ii) a pharmaceutically acceptable carrier.

28. The pharmaceutical composition of claim 27 , wherein the pharmaceutically- acceptable carrier is selected from wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, sweeteners and therapeutic agents other than those compounds of claim 1.

29. The pharmaceutical composition of claim 27, wherein the pharmaceutically- acceptable carrier is selected from fillers , diluents, excipients, and solvent encapsulating materials.

30. The pharmaceutical composition of claim 27, wherein the pharmaceutically- acceptable carrier is active.

31. The pharmaceutical composition of claim 27, wherein the pharmaceutically- acceptable carrier is selected from: (1) sugars; (2) starches; (3) cellulose band its derivatives; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients; (9) oils; (10) glycols; (11) polyols; (12) esters; (13) agar; (14) buffering agents; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; and (21) polyesters, polycarbonates and polyanhydrides.

32. The pharmaceutical composition of claim 27, wherein the pharmaceutically- acceptable carrier is selected from lactose, glucose, sucrose, corn starch, potato starch, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, cocoa butter, suppository waxes, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol, ethyl oleate, ethyl laurate, magnesium hydroxide solutions, and aluminum hydroxide solutions.

33. The pharmaceutical composition of claim 27, wherein the pharmaceutically- acceptable carrier is liquid.

34. The pharmaceutical composition of claim 27, wherein the pharmaceutically- acceptable carrier is solid.

35. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition has a form selected from solids and liquids.

36. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition has a form selected from drenches, tablets, boluses, powders, granules, pastes for application to the tongue, hard gelatin capsules, soft gelatin capsules, mouth sprays, emulsions, microemulsions, sterile solutions, sterile suspensions, sustained- release formulations, creams, ointments, controlled-release patches, controlled-release topical sprays; pessaries, and foams.

37. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition has a form selected from aqueous solutions, non-aqueous solutions, aqueous suspensions, non-aqueous suspensions, tablets for buccal adsorption, tablets for sublingual adsorption, and tablets for systemic absorption.

38. A method of regulating calcium homeostasis in a mammal in need thereof, comprising administering to the mammal an effective amount of any one compound of claims 1-26.

39. A method of treating cardiovascular disease, stroke, and/or epilepsy in a mammal in need thereof, comprising administering to the mammal an effective amount of any one compound of claims 1-26.

40. A method of claim 39, wherein the cardiovascular disease is selected from heart failure, hypertension, SA/AV node disturbance, arrythmia, hypertrophic subaortic stenosis, and angina.

41. The method of claim 40, wherein the heart failure is chronic heart failure or congestive heart failure.

42. A method of inhibiting β-adrenergic receptors and/or inhibiting phosphodiesterase PDE of a mammal in need thereof, comprising administering to the mammal an effective amount of any one compound of claims 1-26.

43. The method of claim 41 , wherein both β-adrenergic receptors and PDE are inhibited.

44. The method of claim 42, wherein PDE3 is inhibited.

45. The method of claim 42, wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

46. The method of claim 42, wherein the compound is administered by subcutaneous, intravenous, intramuscular, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, or intraosseous injection.

47. The method of claim 42, wherein the compound is administered by an infusion technique.

48. The method of claim 42, further comprising administering one or more additional agent(s) for simultaneous, separate, or sequential use. (

49. The method of claim 48, wherein the one or more additional agent(s) is/are selected from therapeutic agents.

50. A method of claim 49, wherein the one or more additional therapeutic agent(s) is/are administered (i) together in a single formulation with the compound of claims 1-26, or (ii) separately in individual formulations.

51. The method of any one of claims 38-50, wherein the mammal is a human.