WO2005016885A2

WO2005016885A2 - COMPOUNDS WITH COMBINED CALCIUM CHANNEL BLOCKER AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITIES FOR TREATMENT OF HEART DISEASE

Info

Publication number: WO2005016885A2
Application number: PCT/US2004/026326
Authority: WO
Inventors: Gregory S. Hamilton
Original assignee: Artesian Therapeutics, Inc.
Priority date: 2003-08-14
Filing date: 2004-08-16
Publication date: 2005-02-24
Also published as: WO2005016885A3

Abstract

The present invention provides compounds possessing inhibitory activity against β-adrenergic receptors and L-type calcium channels. The present invention further provides pharmaceutical compositions comprising such compounds, methods of preparing such compounds, and methods of using such compounds for regulating calcium homeostasis, for treating a disease, disorder or condition in which disregulation of calcium homeostasis is implicated, and for treating hypertension, cardiovascular disease, congestive heart failure, myocardial ischemia, cardiomyopathies, stroke or epilepsy.

Description

COMPOUNDS WITH COMBINED CALCIUM CHANNEL BLOCKER AND β-ADRENERGIC ANTAGONIST OR PARTIAL AGONIST ACTIVITIES FOR TREATMENT OF HEART DISEASE

Hypertensive vascular disease is one of the most significant public health problems in developed countries. Elevated arterial pressure leads to lethal complications if not properly treated. During the development of hypertension, alterations in cardiac and vascular smooth muscle functions occur. These alterations in muscle functions are major contributing factors to the development of hypertension. Muscle functions are controlled by intracellular ions, especially calcium. Studies show that in spontaneously hypertensive rats, there is an alteration of calcium homeostasis, including impaired sarcoplasmic reticulum calcium re-uptake (Aoki et al., Jap. Heart. J, 15:475, 1974; Aoki et al., Jap. Circ. J, 38:1115, 1974; Moore et al., Biochim. Biophys. Ada, 413:432, 1975) and decreased vascular smooth muscle relaxation (Cohen et al., J Pharmacol. Exp. Ther., 196:396, 1976). These studies suggest that abnormalities of calcium handling in myocytes, including abnormal Ca⁺² flux through the cell membrane and Ca⁺² uptake and release by the sarcoplasmic reticulum, play a role in the development and continuance of hypertension. Disregulation of calcium homeostasis has also been implicated in other disease states, including chronic heart failure, stroke, epilepsy, ophthalmic disorders and migraine. Calcium channel blockers, such as nifedipine, are peripheral vasodilators that act by affecting transmembrane calcium flux through L-type calcium channels. By antagonizing Ca⁺² ion function, they reduce contraction of myocardial and vascular fibers and induce relaxation. The combined effects of these actions result in a Blowering of elevated blood pressure. While they are of interest in the treatment of hypertension, vasodilators possess certain side effects, such as reflex cardiac stimulation, that limit the fall in blood pressure by causing vasoconstriction, tachycardia and increased cardiac output (Baldwin et al., J Med. Chem., 24:628, 1981). Agents that antagonize β-adrenergic receptors can inhibit the tachycardia caused by vasodilators. A study shows that while nifedipine alone increases heart rate and plasma rennin levels of hypertensive patients, these effects are blocked by coadministration of a β-adrenergic receptor blocker, propanolol, with nifedipine (Aoki et al., Am. Heart , 96:218, 1978). The study concludes that the antihypertensive effect of nifedipine is enhanced and prolonged by coadministration of the β- adrenergic receptor blocker, and that co-therapy with a calcium channel blocker and a β-adrenergic receptor blocker results in satisfactory management of hypertension with minimal adverse drug reactions. There is, thus, a need for pharmacological agents that are capable of blocking both β-adrenergic receptors and L-type calcium channels, as improved therapies for the management of hypertension.

SUMMARY OF THE INVENTION

DETAILED DESCRIPTION

DEFINITIONS "Alkyl" refers to a saturated straight or branched chain hydrocarbon radical. Examples include without limitation methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. "Alkylene" refers to a divalent alkyl radical. "Alkylthio" refers to a sulfur substituted alkyl radical. "Alkenyl" 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 alkenyl 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 alkenyl 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 alkenyl 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 fluoro, 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 isomorpbic 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. "Substituted phenyl" refers to a phenyl that is substituted with one or more substituent(s). Examples of such substituent(s) include without limitation Cι-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Cι-C₆ alkoxy, C₂-C₆ alkenoxy, phenoxy, benzyloxy, hydroxy, carboxy, hydroperoxy, carbamido, carbamoyl, carbamyl, carbonyl, carbozoyl, amino, hydroxyamino, formamido, formyl, guanyl, cyano, cyanoamino, isocyano, isocyanato, diazo, azido, hydrazino, triazano, nitrilo, nitro, nitroso, isonitroso, nitrosamino, imino, nitrosimino, oxo, Cι-C₆ alkylthio, sulfamino, sulfamoyl, sulfeno, sulfhydryl, sulfinyl, sulfo, sulfonyl, thiocarboxy, thiocyano, isothiocyano, thioformamido, halo, haloalkyl, chlorosyl, chloryl, perchloryl, trifluoromethyl, iodosyl, iodyl, phosphino, phosphinyl, phospho, phosphono, arsino, selanyl, disilanyl, siloxy, silyl, silylene and carbocyclic and heterocyclic moieties. "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, safflower 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 hydrosolubihty), 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. "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: m is O or 1; n is 0 or 1 ; R¹ and ⁴ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C4 alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or

wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² and R³ are independently -COOR⁷, -CONR⁵R⁶, nitro, cyano or trifluoromethyl; R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, CrC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁷ is -Cs alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C₄ alkoxy or -NR⁵R^δ; L is Cι-C₁₂ alkylene, C₂-Cι₂ alkenylene or C₂-C₁₂ alkynylene, wherein one or more -CH - group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to -(L)_m, one to three substituent(s) independently selected from Ci-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C alkylthio, C1-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifiuoro ethyl, pentafluoroethyl, trifiuoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹, and -COOR⁷, wherein one or more -CH - group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to -(L)_m and -β, one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); β is -CH(OH)CH₂NR⁸R⁹ or -OCH₂CH(OH)CH₂NR⁸R⁹; and R⁸ and R⁹ are independently hydrogen, -Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C -C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when R¹ and R⁴ are each -Cs alkyl, Ar¹ is phenyl or substituted phenyl, β is -OCH₂CH(OH)CH₂NR⁸R⁹ and R² is -COOR⁷, then R³ is -CONR⁵R⁶, nitro, cyano or trifluoromethyl; and further provided that when m is 1, L is -OCH₂-, R¹ and R⁴ are each Cι-C₈ alkyl, Ar¹ is phenyl or substituted phenyl, β is -CH(OH)CH₂NR⁸R⁹ and R² is - COOR⁷, then R³ is -CONR⁵R⁶, nitro, cyano or trifluoromethyl. In one embodiment, Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar^J Ar⁴ Ar^b Ar

U = -CH₂CH₂-, -CH=CH=, W = -0-, -S-, -NH- U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -O- or a bond Ar' Ar⁸ Ar⁹

Examples of a compound of Formula I include without limitation:

Methyl 4-{2-chloro-4-[3-(4-{2-hydroxy-3-[(methylethyl)amino]propoxy}- phenoxy)propoxy]phenyl}-5-cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (1)

Methyl 4-(2-chloro-4-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenyl)-5-cyano- 2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (2)

This invention further provides a compound of Formula II

II

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is 0 or 1 ; n is 0 or 1; R¹ and R⁴ are independently hydrogen, Cj.-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₄ alkylthio, C₁-C alkoxy, halo, nitro, cyano, trifluoromethyl or

wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R³ is -COOR⁷, -CONR⁵R⁶, nitro, cyano or trifluoromethyl; R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or - NR⁵R⁶-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁷ is - alkyl, C₂-C₈ alkenyl or C -C₈ alkynyl, wherem the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C₄ alkoxy or -NR R ; L is Cι-C₁₂ alkylene, C -C₁₂ alkenylene or C₂-Cι₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to -(L)_m and -β, one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C -C₈ cycloalkenyl, C C alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with - O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); β is -CH(OH)CH₂NR⁸R⁹ or -OCH₂CH(OH)CH₂NR⁸R⁹; and R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when m is 1, n is 1, R¹ is Cι-C₈ alkyl, R⁴ is Cι-C₈ alkyl, cyano or trifluoromethyl, Ar¹ is phenyl, substituted phenyl or benzoxadiazolyl, and L comprises a -COOCH₂- moiety bonded directly to the dihydropyridine ring, then R³ is -CONR⁵R⁶, nitro, cyano or trifluoromethyl. In one embodiment, Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar³ Ar⁴ Ar⁵ Ar

U = -CH₂CH₂-, -CH=CH=, w= -o-, -S-, -NH- U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -O- or a bond Ar' Ar^b Ar⁹

Examples of a compound of Formula II include without limitation:

4-(2-chlorophenyl)-5-cyano-2,6-dimethyl(3-l,4-dihydropyridine)]-N-[3-(4-{2- hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl]carboxamide (3)

3-(4-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl 4-(2- chlorophenyl)-5-cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate (4)

-(2-Chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid 3-{3- [4-(2-hydroxy-3-isopropylamino-propoxy)-9H-carbazol-l-yloxyl]-propyl} ester 5- methyl ester (13)

4-(2-Chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid 3-{3- [4-(3-tert-butylamino-2-hydroxy-propoxy)-9H-carbazol-l-yloxyl]-propyl} ester 5- methyl ester (14)

-(2-Chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[3-(4- {2-hydroxy-3-[2-(2-methoxy-phenoxy)-ethylamino]-propoxy}-9H-carbazol-l- yloxyl)-propyl] ester 5-methyl ester (15)

This invention further provides a compound of Formula III

III

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is 0 or 1; n is 0 or 1; R⁴ is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₄ alkylthio, C - C alkoxy, halo, nitro, cyano, trifluoromethyl or -NR R , wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S— , -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² and R³ are independently -COOR⁷, -CONR⁵R⁶, nitro, cyano or trifluoromethyl; R and R are independently a lone pair of electrons, hydrogen, - alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or - NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R is Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with C C₄ alkoxy or -NR⁵R⁶; L is 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, SO₂ and/or NR⁵, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoro ethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R₈, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to (L)_ra and β, one to three substituent(s) independently selected from -Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C1-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more one or more -CH - group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); β is -CH(OH)CH₂NR⁸R⁹ or -OCH₂CH(OH)CH₂NR⁸R⁹; and R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s);; provided that when m is 1, R⁴ is Cι-C₈ alkyl, cyano or trifluoromethyl, Ar¹ is phenyl or substituted phenyl, and R² is -COOR⁷, then R³ is nitro, cyano or trifluoromethyl. In one embodiment, Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar³ Ar⁴ Ar° Ar^b

U = -CH₂CH₂-, -CH=CH=, W = -0-, -S-, -NH- U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -O- or a bond Ar⁷ Ar⁸ Ar⁹

Examples of a compound of Formula III include without limitation:

Methyl 4-(2-chlorophenyl)-5-cyano-2- {[3-(4- {2-hydroxy-3- [(methylethyl)amino]propoxy}phenoxy)propoxy]methyl} -6-methyl- 1 ,4- dihydropyridine-3-carboxylate (5)

Methyl 4-(2-chlorophenyl)-5-cyano-2- {[3-(2- {2-hydroxy-3-

[(methylethyl)amino]propoxy}phenoxy)propoxy]methyl} -6-methyl- 1 ,4- dihydropyridine-3-carboxylate (6)

Methyl 4-(2-chloroρhenyl)-2-({2-[2-(3-cyano-4-{2-hydroxy-3-

[(methylethyl)amino]propoxy}phenoxy)acetylamino]ethoxy}methyl)-5- (methoxycarbonyl)-6-methyl-l,4-dihydropyridine-3-carboxylate (7)

This invention further provides a compound of Formula IV

IV

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: n is 0 or 1 ; R¹ and R are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C alkylthio, C₁-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR R , wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, CrC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² and R³ are independently -COOR⁷, nitro, cyano or trifluoromethyl; R⁷ is C C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C₄ alkoxy or -NR R ; L is Ci-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-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to L, one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, Cτ-C alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R and R are independently hydrogen, -Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when n is 1, then at least one of R² and R³ is trifluoromethyl, nitro or cyano; and further provided that when n is 0 and Ar¹ is substituted with nitro, then L is not -OCH₂CH₂-. In one embodiment, Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar³ Ar⁴ Ar^& Ar^b

-CH₂CH2-, -CH— CH— , W = -0-, -S-, -NH- U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -O- or a bond Ar' Ar^b Ar⁹

Examples of a compound of Formula TV include without limitation:

Methyl 4-(2-chloro-4-{[N-(2-{[3-(2-cyano-phenoxy)-2-hydroxypropyl]amino}-2- methylpropyl)carbamoyl]methoxy}phenyl)-5-cyano-2,6-dimethyl-l,4- dihydropyridine-3-carboxylate (8)

Methyl 4- {2-chloro-4-[(N- {2-[(2-hydroxy-2-phenylethyl)amino]-2- methylpiOpyl}carbamoyl)methoxy]phenyl}-5-(methoxy-carbonyl)-2,6-dimethyl-l,4- dihydropyridine-3-carboxylate (9)

This invention further provides a compound of Formula V

V

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherem: n is 0 or 1; R¹ and R⁴ are independently hydrogen, Cι_.-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, C₁-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR⁵R⁶, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and or hydroxyl(s); R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² is -COOR⁷, nitro, cyano or trifluoromethyl; R⁷ is Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C₄ alkoxy or -NR⁵R⁶; L is 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-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C -C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₄ alkylthio, C C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Ci- C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Cι-C₄ alkylthio, C1-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR R , -NR COR , -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- grouρ(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁸ and R⁹ are independently hydrogen, Ci -C₈ alkyl, C₂-C₈ alkenyl, C -C₈ alkynyl, C -C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when n is 0 and Ar¹ is phenyl substituted with nitro, or when n is 1, then L does not comprise a -COOCH₂- moiety bonded directly to the dihydropyridine ring. In one embodiment, Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar^J Ar⁴ Ar° Ar^b

-CH₂CH2", -CH— CH⁼, W = -0-, -S-, -NH- U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -O- or a bond Ar' Ar^B Ar⁹

Examples of a compound of Formula V include without limitation:

Methyl 4-(2-chlorophenyl)-5-pSf-(2-{[3-(2-cyano-phenoxy)-2-hydroxyρropyl]amino}- 2-methyl-propyl)carbamoyl] -2,6-dimethyl- 1 ,4-dihydropyridine- 3-carboxylate (10)

Methyl 4-(2-chlorophenyl)-5-(N-{2-[(2-hydroxy-2-phenylethyl)amino]-2- methylpropyl} carbamoyl)-dimethyl- 1 ,4-dihydropyridine-3-carboxylate (11)

5-{2-[3-9H-Carbazol-4-yloxy-2-hydroxy-propylamino]-2-methyl-propylcarbamoyl}- 4-(2-chloro-phenyl)-2,6-dimethyl- 1 ,4-dihydro-pyridine-3-carboxylic acid methyl ester (16) This invention further provides a compound of Formula VI

VI

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: n is 0 or 1 ; R⁴ is hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, Ci- C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR⁵R⁶, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R and R are independently -COOR , nitro, cyano or trifluoromethyl; R is CrC₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C alkoxy or -NR⁵R⁶; L is Cι_.-C₁₂ alkylene, C₂-Cι₂ alkenylene or C₂-Cι₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from C C₈ allcyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, C₁-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Ci- C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or - NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when n is 1 and R is methyl, then at least one of R and R is cyano, nitro or trifluoromethyl. In one embodiment, Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar³ Ar⁴ Ar° Ar^b

U = -CH₂CH₂-, -CH=CH=,

, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond -O- or a bond Ar⁷ Ar⁸ Ar⁹

Examples of a compound of Formula VI include without limitation:

4-(2-Chlorophenyl)-5-cyano-2-({2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]-2- methylpropylamino}methyl)-6-methyl-l,4-dihydropyridine-3-carboxylic acid methyl ester (12)

The definition of any variable substituent at a particular location in a molecule is independent of its definitions elsewhere in that molecule. Substituents and substitution patterns on the inventive compounds can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein. Since the inventive compounds may possess one or more asymmetric carbon center(s), they maybe 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 The present invention further provides a method for regulating calcium homeostasis, comprising administering an effective amount of a compound of the present invention to an animal in need of such regulation. The present invention further provides a method for treating a disease, disorder or condition in which disregulation of calcium homeostasis is implicated. The present invention further provides a method for treating cardiovascular disease, stroke or epilepsy, comprising administering an effective amount of a compound of the present invention to an animal in need of such treatment. In one embodiment of the inventive method, the cardiovascular disease is hypertension, heart failure, myocardial ischemia, cardiomyopathies, SA/AV node disturbance, arrhythmia, hypertrophic subaortic stenosis or angina. In another embodiment of the inventive method, the heart failure is chronic heart failure or congestive heart failure. The present invention further provides a method for inl ibiting a β-adrenergic receptor and/or PDE, including PDE-3, comprising administering an effective amount of a compound of the present invention to an animal in need of such treatment. The compound of the present invention may be administered by any means known to an ordinarily skilled artisan. For example, the compound of the present invention 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, mtrathecal, intraventricular, intrastemal, 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 compound of the present invention 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 compound of the present invention are useful for the inventive methods, with preferred levels being about 0.1 mg/kg/d to about 1,000 mg/kg/d, and more preferred levels being 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 admimstration. 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 inventive compound 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 this invention. The inventive compound 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 the present 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 microemulsions; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, 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) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.

EXAMPLES

Synthesis of Compounds

Example 1: Methyl 4-{2-chloro-4-[3-(4-{2-hydiOxy-3-[(methylethyl)amino] propoxy}phenoxy)propoxy]phenyl}-5-cyano-2,6-dimethyl-l,4-dihydropyridine-3- carboxylate is synthesized according to Scheme I.

SCHEME I OHn

NHiPr

3-Chloro-4-( ,3-dioxolan-2-vI)phenol. A mixture of 2-chloro-5- hydroxybenzaldehyde (10 g, 63.87 mmol), 2-methoxy-l,3-dioxolane (8.31 g, 79.84 mmol), ethylene glycol (10 ml), and p-TSOH (p-toluene sulfonic acid; 0.5 g, 2.62 mmol) is heated to 100 C for 2 hours. Upon cooling, the mixture is diluted with EtOAc (ethyl acetate; 100 ml) and washed with H O (3 x 50 ml) and saturated brine (3 x 50 ml). The organic phase is dried over Na₂SO and evaporated to dryness to give 14.15 g of the product.

2-Chloro-l- 3-dioxolan-2-yl -4-{3-r4-(phenylmethoxy)phenoxylpropoxy}benzene. A mixture of 3-chloro-4-(l,3-dioxolan-2-yl)phenol (10 g; 49.8 mmol), 3-[4- (phenyhnethoxy)phenoxy] propan-1-ol (14.16 g; 54.8 mmol), diethylazododicarboxylate (9.57 g; 55 mmol; as a 40% wt. solution in toluene), and triphenylphosphine (14.42 g; 55 mmol) in 200 ml of toluene is stirred for 4 hours at room temperature. Workup and purification of the crude product on a silica gel column, eluting with 20% EtOAc in hexane, delivers 14.55 g (33 mmol; 60%) of the product as a waxy solid.

4-[3-(3-Chloro-4- 3-dioxolan-2-yl phenoxy)propoxy]phenol. 2-Chloro-l-(l,3- dioxolan-2-yl)-4-{3-[4-(phenylmethoxy)phenoxy]propoxy}benzene (843mg, 1.91 mmol) in 10 ml of anhydrous EtOH (ethanol) is hydrogenated at 60 p.s.i /H₂ in the presence of 10% Pd/C (100 mg) overnight. The catalyst is removed by filtration and the filtrate is evaporated to dryness to deliver the debenzylated product as an oil (613 mg; 1.75 mmol).

2-Chιoro-l-α -dioxolan-2-viy4-{3-[4-foxiran-2- ylmethoxy)phenoxy|propoxy}benzene. _The compound is prepared from 4-[3-(3- chloro-4-(l,3-dioxolan-2-yl)phenoxy) propoxyjphenol and (2S)-(+)-glycidyl 3- nitrobenzenesulfonate according to a method described in Sharpless et al., J. Org. Chem., 54:1295-1304, 1989. l-(4-[3-(3-Chloro-4-( 3-dioxolan-2-yl phenoxy propoxy]phenoxyl-3-[(methylethyl) amino]propan-2-ol. A solution of 2-chloro-l-(l,3-dioxolan-2-yl)-4-{3-[4-(oxiran-2- ylmefhoxy)phenoxy]propoxy}benzene (700 mg; 1.72 mmol) and isopropylamine (122 mg; 2.06 mmol) in 10 ml of EtOH is heated to reflux under N₂ for 24 hours. The solvent is removed in vacuo and the residue is purified on a silica gel column, eluting with 95:5 CHCl₃:MeOH (chloroform:methanol) to deliver 641 mg (1.38 mmol; 80%) of the amine product.

2-ChloiO-4- 3- 4-(2-hvdroxy-3-f(methylethyl)amino]propoxy>phenoxy propoxy] benzaldehyde. A stirred solution of l-{4-[3-(3-chloro-4-(l,3-dioxolan-2-yl)phenoxy) propoxy]phenoxy}-3-[(methylefhyl) amino]propan-2-ol (635 mg; 1.36 mmol) in a mixture of 1:1 dioxane/2N HCI (15 ml) is heated at 40 - 50 C for 5 hours. After removal of dioxane in vacuo, the residue is extracted with EtOAc. The EtOAc layer is washed with saturated NaHCO₃ and brine, dried over Na₂SO , and evaporated in vacuo to dryness. The resulting residue is purified by flash silica gel chromatography, eluting with 95:5 CHCl₃:MeOH to obtain 400 mg (0.95 mmol; 70%) of the aldehyde product as a thick oil that solidifies on standing.

Methyl 4- {2-chloro-4-[3-(4- {2-hvdroxy-3-r(methylethyl amino] propoxyjphenoxy) propoxy1phenyl|-5-cvano-2,6-dimethyl- 4-dihydropyridine-3-carboxylate (Example 1). A mixture of 2-chloro-4-[3-(4-{2-hydroxy-3-

[(methylethyl)amino]propoxy}phenoxy)-propoxy]benzaldehyde (300 mg; 0.71 mmol), 3-aminocrotononitrile (60 mg; 0.71 mmol), and methyl acetoacetate (82.5 mg; 0.71 mmol) in EtOH (25 ml) is heated to reflux for 24 hours. EtOH is removed under reduced pressure and the residue is purified on a silica gel column, eluting with 95:5 CHCl₃:MeOH to furnish the compound of Example 1 as a solid.

Example 2: Methyl 4-(4-{(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2- chloro- phenyl)-5-cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate is synthesized according to Scheme II.

SCHEME II

iPrNH2

4-[((2S)oxiran-2-yl methoxy]-2-chlorobenzaldehyde. The compound is prepared from 2-chloro-4-hydroxybenzaldehyde and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate according to a method described in Sharpless et al., supra. 4-((2S -2-hydroxy-3- (methylethyl amino1propoxyl-2-chlorobenzaldehyde. A solution of 4-[((2S)oxiran-2-yl)methoxy]-2-chlorobenzaldehyde (500 mg; 2.35 mmol) and isopropylamine (245 mg; 4.12 mmol) in 10 ml of EtOH is heated to reflux under N₂ for 24 hours. The solvent is removed in vacuo and the residue is purified on a silica gel column, eluting with 95:5 CHCl₃:MeOH to deliver 510 mg (1.88 mmol; 80%) of the amine product.

Methyl 4-(4- {(2Sy2-hvdroxy-3-[(methylethyl amino]propoxyl -2-chloro-phenylV5- cyano-2,6~dimethyl-l ,4-dihydropyridine-3-carboxylate (Example 2). A mixture of 4- {(2S)-2-hydroxy-3-[(methylethyl)amino]propoxy}-2-chlorobenzaldehyde (176 mg; 0.65), 3-aminocrotononitrile (60 mg; 0.71 mmol), and MeOAc (methyl acetoacetate, 82.5 mg; 0.71 mmol) in EtOH (15 ml) is heated to reflux for 24 hours. EtOH is removed under reduced pressure and the residue is purified on a silica gel column, eluting with 95:5 CHCl₃:MeOH to furnish the compound of Example 2 as a solid.

Example 3: [4-(2-Chlorophenyl)-5-cyano-2,6-dimethyl(3-l,4-dihydropyridyl)]-N-[3- (4-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl]carboxamide is synthesized according to Scheme III.

SCHEME III

4-(2-chlorophenyl)-5-cvano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylic acid. The compound is synthesized from 2-chlorobenzaldehyde, 3-aminocrotononitrile, and 2- cyanoethyl 3-oxobutanoate according to a method described in Sircar et al., J. Med. Chem., 34:2248-2260, 1991.

2-{3-r4-(phenylmethoxy phenoxy1propyl|isoindoline-l,3-dione. Sodium hydride (60% dispersion in oil; 27 mmol) is added to a stirred solution of 4-benzyloxyρhenol (5 g; 25 mmol) in THF (tetrahydrofuran). After gas evolution ceases, 2-(3- bromopropyl)isoindoline-l,3-dione (7.37 g; 27.5 mmol) is added as a THF solution, and the resulting mixture is stirred overnight at room temperature under N₂. The reaction is quenched by the addition of MeOH followed by dilute aqueous acid, and the product is extracted into EtOAc. The organic phase is dried, concentrated, and purified on a silica gel column to obtain the product as a thick oil. 3-[4-(phenylmethoxy)phenoxy]propylamine. A solution of 2-{3-[4-(phenylmethoxy) phenoxy]propyl}isoindoline-l,3-dione (3.0 g; 7.74 mmol) in THF is treated with 10 equivalents of hydrazine hydrate and heated to reflux for 3 hours. After cooling, the solution is made acidic (pH 1-2) and partitioned between EtOAc and H₂O. The aqueous phase is made basic (pH 10) and extracted with EtOAc, and the organic phase is dried and concentrated to deliver the crude product as an oil, which is used without further purification.

[4-(2-chlorophenyl -5-cyano-2,6-dimethyl(3- 4-dihvdropyridyl 1-N- (3-|^~4 (phenyl- methoxy phenoxy]propyl>carboxamide. 4-(2-Chlorophenyl)-5-cyano-2,6-dimethyl- l,4-dihydropyridine-3-carboxylic acid (563 mg; 1.95 mmol), EDC (l-ethyl-3-(3- dimethylaminopropyl)carbodiimide, 375 mg, 1.96 mmol) and HO At (l-hydroxy-7- azabenzotriazole, 106 mg, 0.781 mmol) are mixed as solids. DMF (dimethylformamide; 25 ml) is added and the mixture is sonicated for 5 minutes at room temperature to obtain a homogeneous, light yellow solution. 3-[4- (Phenylmethoxy)-phenoxy]propylamine (499 mg; 1.94 mmol) is added and the reaction mixture is stirred at ambient temperature overnight before being poured onto water (200 ml). The mixture is left to stand at ambient temperature for 1 hour and the precipitate which forms is filtered off, washed with water, and dried with suction to give the dihydropyridine product as a yellowish solid, which is used without further purification. r4-(2-chlorophenyl -5-cvano-2,6-dimethyl(3- 4-dihvdropyridyl)l-N- 3-(4- hvdroxyphenoxy)prop yl] carboxamide. The dihydropyridine from the previous step (600 mg; 1.14 mmol) is dissolved in EtOAc, treated with a catalytic amount of 10% Pd/C, and hydrogenated at atmospheric pressure overnight. The reaction mixture is filtered through Celite to remove the catalyst, and concentrated to deliver the debenzylated product as a solid.

[4-(2-chlorophenyl -5-cyano-2,6-dimethyl(3-l,4-dihydropyridyl)l-N-[3-(4-{2- hydroxy-3-[(methylethyl amino]propoxy}phenoxy^)propyllcarboxamide (Example 3). The phenol from the previous step is successively reacted with (2S)-(+)-glycidyl 3- nitrobenzenesulfonate and isopropylamine to deliver the compound of Example 3.

Example 4: 3-(4-{2-Hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl 4-(2- chlorophenyl)-5-cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate is synthesized according to Schemes III and IV.

SCHEME IV

3-[4-(phenylmethoxy)phenoxy|propan-l-ol. A mixture of 4-(phenylmethoxy)phenol (5.01 g; 25 mmol), 3-perhydro-2H-pyran-2-yloxypropan-l-ol (4.40 g; 27.5 mmol), diethylazododicarboxylate (4.82 g; 27.5 mmol; as a 40%> wt. solution in toluene), and triphenylphosphine (7.21 g; 27.5 mmol) in 100 ml of toluene is stirred for 4 hours at room temperature. The crude material obtained from workup is dissolved in CH₂C1₂ (methylene chloride), treated with p-TSOH (0.2 equivalent), and stirred at 50°C for 2 hours. Workup and purification of the crude product on a silica gel column, eluting with 20% EtOAc in hexane, delivers 3.23 g (12.5 mmol; 50%> for two steps) of the product as a waxy solid.

3- 4-(phenylmethoxy phenoxy]propyl 4-(2-chlorophenyl -5-cyano-2,6-dimethyl- 4- dihydro pyridine- 3-carboxylate. The alcohol from the previous step is reacted with 4-(2-chlorophenyl)-5-cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylic acid according to Scheme III (EDC/HOAt).

3-(4-(2-Hvdroxy-3- (methylethyl)aminolpropoxylphenoxy propyl 4-(2- chlorophenylV 5-cvano-2.6-dimethyl- 1.4-dihvdropyridine-3-carboxylate (Example 4). The compound is prepared from the product of the previous step by debenzylation of the protected phenol followed by successive reaction with (2S)-(+)-glycidyl 3- nitrobenzenesulfonate and isopropylamine.

Example 5: Methyl 4-(2-chlorophenyl)-5-cyano-2-{[3-(2-{2-hydroxy-3- [(methylethyl)amino]propoxy}phenoxy)propoxy]methyl} -6-methyl- 1 ,4- dihydropyridine-3-carboxylate is synthesized according to Scheme V.

SCHEME V

iPrNH2

1 -(Phenylmethoxy)-2- f3-( 1 , 1 ,2,2-tetramethyl- 1 -silapropoxy propoxylbenzene. (3- Bromopropoxyl)-tert-butyldimethylsilane (2.18 g, 2.0 ml, 8.61 mmol) is added to a solution of 2-(benzyloxy)phenol (2.15 g, 1.88 ml, 10.76 mmol) and potassium carbonate (1.48 g, 10.76 mmol) in acetone (20 ml). The resulting mixture is refluxed for 5 hours and then cooled to room temperature. The solvents are removed and the residue is dissolved in EtOAc (150 ml) and water (30 ml). The organic layers are dried over Na₂SO₄ and filtered, and the filtrate is concentrated to give a syrup, which is purified by column chromatography with hexane-5%> EtOAc/hexane to give the product (2.90 g, 90%).

3-r2-(Phenylmethoxy)phenoxy]propan-l-ol. A solution of 1.0 M tetrabutylammonium fluoride (10.09 ml) in THF is added drop-wise to a solution of the silyl ether from the previous step (1.88 g, 5.05 mmol) at 0°C, and the mixture is stirred at room temperature for 1 hour. 15 ml of aqueous saturated NH₄C1 is added to the mixture, the solvents are removed in vacuo, and the residue is partitioned between EtOAc (60 ml) and water (40 ml). The organic layer is dried over Na₂SO₄, filtered, and concentrated to yield the crude product as a light-brown oil (1.20 g, 90%). Methyl 3-[2-(phenylmethoxy)phenoxy]propyl propane-l,3-dioate. A solution of the alcohol of the previous step (1.30 g, 5.0 mmol) in THF (10 ml) is added drop-wise to a stirred suspension of 60% NaH (520 mg, 13.0 mmol) in THF (20 ml). The resulting mixture is treated with a solution of methyl chloroacetoacetate (758 mg, 0.58 ml, 5.0 mmol) in THF (10 ml), and stirred at room temperature overnight. The solvents are removed to give a residue, which is treated with 10% HO Ac and extracted with EtOAc (45 ml x 2). The combined extracts are washed with brine, dried over Na₂SO₄, and filtered. The filtrate is concentrated to give a syrup, which is purified by column chromatography with 30% EtOAc/hexane to afford the product as a yellow oil (1.34 g, 74%).

Methyl 4-(2-chlorophenviy5-cyano-6-methyl-2-({3-[2-(phenylmethoxy^phenoxy] propoxy} methyl)- 1 ,4-dihvdropyridine-3-carboxylate. A solution of 2-chlorobenz- aldehyde (343 mg, 0.27 ml, 2.44 mmol), 3-aminocrotononitrile (2.44 mmol), and the keto ester prepared above (1.18 g, 3.17 mmol) in EtOH (20 ml) is refluxed overnight and cooled to room temperature. The solvents are removed by evaporation to give a residue, which is purified by column chromatography to afford a yellow solid. Methyl 4-(2-chlorophenyl -5-cyano-2-{r3-(2-hvdroxyphenoxy piOpoxylmethyl}-6- methyl- 1 ,4-dihydropyridine-3 -carboxylate. The dihydropyridine from the previous step (950 mg, 1.6 mmol) is hydrogenated in MeOH (20 ml) over 5% Pd/CaCO₃ for 4 hours. The mixture is filtered through a pad of Celite and the filtrate is concentrated to give a residue, which is purified by column chromatography with hexane-30% EtOAc/hexane to afford the product as a light-yellow oil (330 mg, 41%>). Methyl 4-(2-chlorophenyl -5-cyano-6-methyl-2-({3-[2-(oxiran-2-ylmethoxy^ phenoxy]propoxy>methyl)-l,4-dihvdropyridine-3-carboxylate. To a solution of the phenol prepared above (2.70 mmol) and (2S)-(+)-glycidyl 3-nitrobenzenesulfonate (1.78 ml, 22.7 mmol) in dioxane (2.5 ml) is added a solution of NaOH/H₂O (108 mg/ 4 ml). The resulting mixture is stirred at room temperature under a slow stream of N₂ for 2 days. The reaction is diluted with EtOAc and the organic layer is separated, washed with water, dried over Na₂SO₄, and filtered. The filtrate is concentrated to give a residue, which is purified by column chromatography with 30% EtOAc/hexane to afford the product (1.0 g, 66%).

Methyl 4-(2-chlorophenvD-5-cyano-2- {[3-(2- j2-hydroxy-3-[(methylethyl amino] propoxy}phenoxy)propoxy]methyl|-6-methyl- 4-dihydropyridine-3-carboxylate (Example 6). Isopropylamine (204 mg, 0.29 ml, 1.38 mmol) and the epoxide from the previous step (1.38 mmol) are dissolved in MeOH and the mixture is stirred at room temperature for 3 days under N₂. The reaction mixture is concentrated to give a residue, which is purified by column chromatography with hexane-50% EtOAc/hexane to afford the compound of Example 5 as a yellow semi-solid.

Example 6: Methyl 4-(2-chlorophenyl)-5-cyano-2-{[3-(4-{2-hydroxy-3- [(methylethyl)amino]propoxy}phenoxy)propoxy]methyl} -6-methyl- 1 ,4- dihydropyridine-3-carboxylate is synthesized according to a method similar to Scheme V. Example 7: 2-({2-[2-(4-{(2S)-2-Hydroxy-3-[(methylethyl)amino]propoxy}phenoxy) acetylamino]ethoxy}methyl)-4-(2-chlorophenyl)-5-cyano-6-methyl-l,4- dihydropyridine-3-carboxylate is synthesized according to Scheme VI.

SCHEME VI

O CI l. K₂CO₂, EtO^' Bn

5% Pd/C, EtOAc

iPrNH2

Ethyl 4-[2-(l,3-dioxoisoindolin-2-yl)ethoxy1-3-oxobutanoate. A solution of 2-(2- hydroxyethyl)isoindoline~l,3-dione (10 g; 52.31 mmol) in DMF (150 ml) is cooled to 0°C and treated with 1.1 equivalents of a 60%) dispersion of sodium hydride in mineral oil. After gas evolution has ceased, ethyl 4-chloro-3-oxobutanoate (7.75 g; 47.08 mmol) in 20 ml of DMF is added drop-wise, and the resulting solution is stirred overnight at room temperature. The pH of the mixture is then adjusted to 6-7 by the addition of 1 N HCI, and the product is partitioned between H₂O and EtOAc. The aqueous phase is extracted again with EtOAc, and the combined organic phases are washed with water and brine, dried over magnesium sulfate, and concentrated to a crude residue, which is purified on a silica gel column, eluting with 25% EtOAc in hexane to obtain 7.52 g (23.54 mmol; 50%) of the product as an oil. Ethyl 2- {[2-(l .3-dioxoisoindolin-2-yl ethoxy]methyl> -4-(2-chlorophenyl -5-cvano-6- methyl- 1 ,4-dihydropyridine-3-carboxylate. A mixture of 2-chlorobenzaldehyde (2.64 g; 18.79 mmol), 3-aminocrotononitrile (1.54 g; 18.79 mmol), and ethyl 4-[2-(l,3- dioxoisoindolin-2-yl)ethoxy]-3-oxobutanoate (6 g; 18.79 mmol) in MeOH is heated to reflux for 6 days. After cooling, the solvent is removed under reduced pressure and the crude product is purified on a silica gel column to obtain the product in 70%> yield as a light yellow solid.

Ethyl 2-[^"(2-aminoethoxy)methyl]-4-(2-chlorophenyl -5-cyano-6-methyl-l,4-dihydro- pyridine-3-carboxylate. A solution of ethyl 2-{[2-(l,3-dioxoisoindolin-2-yl) ethoxy] methyl}-4-(2-chlorophenyl)-5-cyano-6-methyl-l,4-dihydropyridine-3-carboxylate (3.0 g; 5.93 mmol) in THF is treated with 10 equivalents of hydrazine hydrate and heated to reflux for 3 hours. After cooling, the solution is made acidic (pH 1-2) and partitioned between EtOAc and H₂O. The aqueous phase is made basic (pH 10) and extracted with EtOAc, and the organic phase is dried and concentrated to deliver the crude product as an oil, which is used without further purification (1.67g; 4.45 mmol; 75%).

Ethyl 2-[4-(phenylmethoxy)phenoxy| acetate. A mixture of 12.3 g (61.43 mmol) of 4- (phenylmethoxy) phenol, 8.28 g (67.57 mmol) of ethyl chloro acetate, and 9.33 g of potassium carbonate in 150 ml of acetone is heated to reflux for 6 hours. The mixture is cooled to room temperature and filtered to remove insoluble material. The filtrate is concentrated in vacuo and the residue is purified on a silica gel column (20% ether in hexane) to give 12.32 g (43 mmol; 70%) of the product as an oil. 2- |^"4-(Phenylmethoxy phenoxyl acetic acid. 50 ml of a 50% v/v aqueous EtOH solution containing 5 g of ethyl 2-[4-(phenylmethoxy)phenoxy]acetate and 2.5 g of NaOH are stirred together for 40 minutes at 80 C and then cooled. The solution is acidified with HCI and the precipitated crystals are recrystallized from aqueous EtOH to provide 3.35 g of 2-[4-(phenylmethoxy)phenoxy]acetic acid. Ethyl 4-(2-chlorophenyl -5-cvano-6-methyl-2-r(2- (2-|^"4-(phenylmethoxy) phenoxy] acetylamino|ethoxy^methyl]-l,4-dihydropyridine-3-carboxylate. 2- [4- (Phenylmethoxy)-phenoxy] acetic acid (1.55g, 6.00 mmol), EDC (1.15 g, 6.00 mmol) and HO At (318 mg, 2.34 mmol) are mixed as solids. DMF (50 ml) is added and the mixture is sonicated for 5 minutes at room temperature to obtain a homogeneous, light yellow solution. The dihydropyridine from the previous step (2.25 g, 5.98 mmol) is added and the reaction mixture is stirred at ambient temperature overnight before being poured onto water (200 ml). The mixture is left to stand at ambient temperature for 1 hour and the precipitate which forms is filtered off, washed with water and dried with suction to give the pure amide as a light yellow powder (2.10g; 57% yield). Ethyl 4-(2-chlorophenyl -5-cyano-2-({2-[2-(4-hvdroxyphenoxy acetylaminolethoxy> methyl)-6-methyl-l,4-dihydropyridine-3-carboxylate. The benzyl protected compound from the previous step (1.23 g, 2.0 mmol) is hydrogenated in MeOH (25 ml) over 5% Pd/CaCO₃ for 4 hours. The mixture is filtered with a pad of Celite and the filtrate is concentrated to give a residue, which is purified by column chromatography with hexane-30% EtOAc/hexane to afford the product as a light- yellow oil (558 mg; 1.06 mmol; 53%).

Ethyl 2-({2- 2-(4-{(2Sy2-hydroxy-3-[(methylethyl)amino]propoxy>phenoxy acetylamino1ethoxylmethyl)-4-(2-chlorophenyl -5-cvano-6-methyl-l,4- dihvdropyridine-3-carboxylate (Example 7). The phenol obtained in the previous step is successively reacted with (2S)-(+)-glycidyl 3-nitrobenzenesulfonate and isopropylamine to obtain the compound of Example 7. Example 8: Methyl 4-(4-{[N-(2-{[(2S)-3-(2-cyanophenoxy)-2- hydroxypropyl] amino } -2-methylpropyl)carbamoyl]methoxy} -2-chlorophenyl)-5 - cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate is synthesized according to Scheme VII.

SCHEME VII

Ethyl 2-(3-chloro-4-( 3-dioxolaι 2-yl ρhenoxy)acetate. A mixture of 7.90 g (39.98 mmol) of 3-chloro-4-(l,3-dioxolan-2-yl)phenol, 5.90 g of ethyl chloroacetate (48.14 mmol), and 5.6 g of potassium carbonate (40.52 mmol) in 35 ml of acetone is heated to reflux for 6 hours. The mixture is cooled to room temperature and filtered to remove insoluble material. The filtrate is concentrated in vacuo and the residue is purified on a silica gel column, eluting with 95%> hexane/EtOAc to give 8.94 g (31.18 mmol; 78%>) of the product as an oil.

2-(3-Chloro-4-(l ,3-dioxolan-2-yl phenoxy acetic acid. The ester from the previous step (6.91 g; 24.1 mmol) is added to a solution of sodium hydroxide (7.50 g) in 150 ml of 50%) EtOH/water. After heating to 80°C for 1 hour, the mixture is cooled and treated with concentrated HCI until the pH is adjusted to 1. The white crystals which form are collected via filtration, washed with cold hexane, and dried in vacuo to obtain 5.86 g (22.65 mmol; 94%) of the carboxylic acid product. N-(2-Amino-2-methylpropyl -2-(3-chloro-4-( 3-dioxolan-2-yl phenoxy acetamide. The carboxylic acid from the previous step (913 mg, 3.53 mmol), EDC (800 mg, 4.12 mmol) and HOAT (550 mg, 4.04 mmol) are mixed as solids. DMF (20 ml) is added and the mixture is sonicated for 5 minutes at room temperature to obtain a homogeneous, light yellow solution. 2,3-Diamino-2-methylpropane (360 mg, 4.08 mmol) is added as a solution in DMF (10 ml). The reaction mixture is stirred at room temperature overnight, poured into water (200 ml), made alkaline (pH 11) with aqueous 2N NaOH solution, and extracted into EtOAc (3 x 200 ml). The combined organic layers are washed with water (100 ml), dried over MgSO , and evaporated to dryness to provide the crude product, which is purified on a silica gel column, eluting with 95:5 CH₂Cl :MeOH to deliver the amine product in 45% yield. N-(2-{ (2S -3-(2-cvanophenoxy)-2-hydroxypropyl]amino>-2-methylpropyl -2-(3- chloro-4-( 3-dioxolan-2-yl phenoxy)acetamide. A solution of (2S)-3-(2- cyanophenoxy)-l,2-epoxypropane (223 mg; 1.28 mmol), prepared according to a method described in Sharpless et al., supra, and N-(2-amino-2-methylpropyl)-2-(3- chloro-4-(l,3-dioxolan-2-yl)phenoxy)acetamide (559 mg, 1.70 mmol) in 7 ml of MeOH is refluxed under N₂ for 15 hours. After concentrating in vacuo, the residue is chromato graphed on a silica gel column, eluting with 95:5 CHCl₃:MeOH to give 420 mg (65%) of the adduct as an amorphous white solid.

N-(2-{ (2Sy3-(2-Cvanophenoxy -2-hvdroxypropyl]amino|-2-methylpropyl -2-(3- chloro-4-formylphenoxy acetamide. A stirred solution of the above acetal (756 mg, 1.5 mmol) in a mixture of 1 : 1 dioxane/2N HCI (100 ml) is heated at 40 - 50°C for 5 hours. Dioxane is removed and the residue is extracted with EtOAc. The EtOAc layer is washed with saturated NaHCO₃ and brine, dried over Na₂SO₄, and evaporated in vacuo to dryness. The resulting residue is purified by flash silica gel chromatography, eluting with 95:5 CHCl₃:MeOH to deliver 497 mg (1.08 mmol; 72%) of the aldehyde product as an oil which crystallizes upon standing. Methyl 4-(4- { N-(2- ( [Y2SV 3 -(2-cvanophenoxy -2-hvdroxyprop yl] aminol -2-methyl- propyl)carbamoyl1methoxy>-2-chlorophenyl -5-cyano-2,6-dimethyl- 4- dihvdropyridine-3-carboxylate (Example 8). A mixture of methyl 3-oxobutanoate, 3- aminocrotononitrile, and the aldehyde prepared above is heated to reflux in EtOH for 4 days. Workup and purification delivers the compound of Example 8 in 45% yield.

Example 9; Methyl 4- {2-chloro-4-[(N- {2-[(2-hydroxy-2-phenylethyl)amino]-2- methylpropyl} carbamoyl)methoxy]phenyl} -5-(methoxycarbonyl)-2,6-dimethyl- 1 ,4- dihydropyridine-3-carboxylate is prepared according to Scheme VII, using styrene oxide in the epoxide ring-opening step, and methyl (2E)-3-aminobut-2-enoate instead of 3-aminocrotonate in the final (Hantzsch reaction) step.

Example 10: Methyl 4-(2-chlorophenyl)-5-[N-(2-{[3-(2-cyanophenoxy)-2- hydroxypropyl] amino} -2-methylpropyl)carbamoyl] -2,6-dimethyl- 1 ,4- dihydropyridine-3-carboxylate is prepared according to Scheme VIII.

SCHEME VIII

10 4-(2-Chlorophenyiy5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3- carboxylic acid. The compound is prepared according to the method described in Sircar et al., supra.

Methyl 5- N-(2-amino-2-methylpropyl)carbamoyl]-4-(2-chlorophenyl^')-2,6-dimethyl- 1 ,4-dihydrop yridine-3 -carboxylate. The compound is prepared from 4-(2- chlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylic acid and 2,3-diamino-2-methylpropane using the coupling procedure of Scheme VII. Methyl 4-(2-chlorophenyl)-5- N-(2-{[3-(2-cyanophenoxy -2-hvdroxypropyllaminol- 2-methylpropyl)carbamoyll-2 6-dimethyl-L4-dihvdropyridine-3-carboxylate (Example 10). Methyl 5-[N-(2-ammo-2-methylpropyl)-carbamoyl]-4-(2- chlorophenyl)-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate is reacted with 2- (oxiran-2-ylmethyl)benzene-carbonitrile to obtain the compound of Example 10.

Example 11: Methyl 4-(2-chloroρhenyl)-5-(N-{2-[(2-hydroxy-2- phenylethyl)amino]-2-methylpropyl} carbamoyl)-2,6-dimethyl- 1 ,4-dihydropyridine- 3-carboxylate is synthesized from methyl 5-[N-(2-amino-2-methylpropyl)carbamoyl]- 4-(2-chlorophenyl)-2,6-dimethyl-l ,4-dihydropyridine-3-carboxylate and styrene oxide, according to a method similar to Scheme VIII.

Example 12: Methyl 2-{[(2-{[(2S)-3-(2-cyanophenoxy)-2-hydroxypropyl]amino}-2- methylpropyl)amino]methyl} -4-(2-chlorophenyl)-5-cyano-6-methyl- 1 ,4- dihydropyridine-3-carboxylate is synthesized according to Scheme IX.

SCHEME IX

Methyl 2-(bromomethyl -4-(2-chlorophenyl -5-cyano-6-methyl- 1 ,4-dihvdropyridine- 3-carboxylate. The compound is prepared from methyl 4-(2-chlorophenyl)-5-cyano- 2,6-dimethyl-l,4-dihydropyridine-3-carboxylate and pyridiniυm tribromide, in 75% yield, by a method described in Sircar et al., supra.

Methyl 2-[((2-r(tert-butoxy)carbonylamino]-2-methylpropyllamino)methyl]-4-(2- chlorophenyl -5-cyano-6-methyl-1.4-dihydropyridine-3-carboxylate. A mixture of N- (2-amino-tert-butyl)(tert-butoxy)carboxamide (2.07 g; 11 mmol) and the bromide from the previous step (2 g; 5.24 mmol) in 50 ml of DMF is s irred at 50°C for 3 hours and then poured into 100 ml of water. The aqueous phase is extracted with 2 x 100 ml of CH₂C1₂. The organic layers are washed several times with water and brine, concentrated, and purified on a silica gel column, eluting with 95:5 CH₂Cl₂:MeOH to obtain the product as a thick oil which crystallizes upon standing (1.74 g; 68 >): Methyl 2-{[(2-amino-2-methylpropyl)amino]methyll-4-(2-chlorophenylV5-cvano-6- methyl-l,4-dihvdropyridine-3-carboxylate. A solution of the Boc-protected amine from the previous step (1.57 g; 3.21 mmol) in 25 ml of CH₂C1₂ is cooled to 0 C and treated with 4 ml (4 mmol) of a 1.0 M solution of trifluoroacetic acid in CH₂C1₂. 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 CH₂C1₂. The organic extracts are dried, concentrated, and purified on a silica gel column, eluting with 95:5 CH₂Cl₂:MeOH to obtain the amine product as a darkish oil (1.04 g; 83%). Methyl 2-{[(2-{[^"(2S)-3-(2-cyanophenoxy)-2-hydroxypropyl]amino}-2-methylpropyl amino]methyl|-4-(2-chlorophenyl)-5-cyano-6-methyl-l,4-dihydropyridine-3- carboxylate (Example 12). The amine from the previous step is reacted with 2- (oxiran-2-ylmethyl)-benzenecarbonitrile to afford the compound of Example 12 in 60% yield.

Example 13: 4-(2-Chloro-phenyl)-2,6-dimethyl-l ,4-dihydro-pyridine-3,5- dicarboxylic acid 3- {3-[4-(2-hydroxy-3-isopropylamino-propoxy)-9H-carbazol-l- yloxyl] -propyl} ester 5-methyl ester is synthesized according to Scheme X.

SCHEME X

Examples of R-NH₂ include H,N"

and

Example 14: 4-(2-Chloro-phenyl)-2,6-dimethyl-l ,4-dihydro-pyridine-3,5- dicarboxylic acid 3-{3-[4-(3-tert-butylamino-2-hydroxy-propoxy)-9H-carbazol-l- yloxyl] -propyl} ester 5-methyl ester is synthesized according to Scheme X. Example 15: 4-(2-Chloro-phenyl)-2,6-dimethyl-l ,4-dihydro-pyridine-3,5- dicarboxylic acid 3-[3-(4- {2-hydroxy-3-[2-(2-methoxy-phenoxy)-ethylamino]- propoxy}-9H-carbazol-l-yloxyl)-propyl] ester 5-methyl ester is synthesized according to Scheme X.

Example 16: 5-{2-[3-9H-Carbazol-4-yloxy-2-hydroxy-propylamino]-2-methyl- propylcarbamoyl}-4-(2-chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3- carboxylic acid methyl ester is synthesized according to Scheme XL

SCHEME XI

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 lαiown 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 17: 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 [³H]nitrendipine (80 Ci/mmol) and increasing concentrations of test compounds in 50 mM Tris-HCI (2-amino-2-(hydroxymethyl)- 1,3-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-HCI buffer, pH 7.4, and transfeπed 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.

β-Adrenergic Receptor Binding and Blocking Activity β-Adrenergic receptor binding and blocking activity is evaluated by one or more of the methods described below.

Example 18: Radioligand for measuring β,-receptor affinity β,-Adrenergic receptor binding is measured in human recombinant beta-1 receptors expressed in CHO-REX16 cells, using [¹²⁵I] (-) iodocyanopindolol (2000 Ci/mmol) as the radioligand, as described in Kalaria et al., J. Neurochem., 53:1772- 81, 1998, and Minneman et al, Mol. Pharmacol., 16:34-46, 1979. Example 19: Radioligand for measuring β,-receptor affinity β₂-Adrenergic receptor binding is measured in human recombinant beta-2 receptors expressed in CHO-WT21 cells, using [¹²⁵I] (-) iodocyanopindolol (2000 Ci/mmol) as the radioligand, as described in Kalaria et al. (1998) and Minneman et al. (1979), supra.

Example 20: Determination of β?-adrenergic blocking activity in the guinea pig Tracheal chains are prepared as described by Castillo et al., J Pharm. Exp. Ther., 90:104, 1947, suspended in tissue baths maintained at 37°C containing Tyrodes solution gassed with 95%> O₂-5%> CO₂, and attached to an isometric force- displacement transducer. After an equilibration period of 2 hours, the preparations are induced to contract with carbachol (3 x 10^"7 M), and relaxation is induced with cumulative dose response curves for isoproterenol first in the absence of and then in the presence of the test compound. A contact time of 10 minutes is allowed for all test compounds. Affinity constants are determined by comparing the shift in the dose- response curve for each test compound with that of isoproterenol (EC₅₀ = 2.3 x 0.2 x 10^"8 M). 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

WHAT IS CLAIMED IS:

1. A compound of Formula I

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is 0 or 1 ; n is 0 or 1 ; R¹ and R⁴ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR R , wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² and R³ are independently -COOR⁷, -CONR⁵R⁶, nitro, cyano or trifluoromethyl; R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, -Cs alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁷ is -Ce alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with -C alkoxy or -NR⁵R⁶; L is Cι-C₁₂ alkylene, C₂-C₁ alkenylene or C₂-Cι₂ alkynylene, wherem one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to -(L)_m, one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoro ethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹, and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to -(L)_m and -β, one to three substituent(s) independently selected from -Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); β is -CH(OH)CH₂NR⁸R⁹ or -OCH₂CH(OH)CH₂NR⁸R⁹; and R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when R¹ and R⁴ are each Cι-C₈ alkyl, Ar¹ is phenyl or substituted phenyl, β is -OCH₂CH(OH)CH₂NR⁸R⁹ and R² is -COOR⁷, then R³ is -CONR⁵R⁶, nitro, cyano or trifluoromethyl; and further provided that when m is 1, L is -OCH₂-, R¹ and R⁴ are each Ci-Cg alkyl, Ar¹ is phenyl or substituted phenyl, β is -CH(OH)CH₂NR⁸R⁹ and R² is - COOR⁷, then R³ is -CONR⁵R⁶, nitro, cyano or trifluoromethyl.

2. The compound of claim 1, wherein Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

U = -CH₂CH₂-, -CH=CH=, W = -0-, -S-, -NH- u < ⁼ -CH₂CH 2-, -Ch l=CH=, -0-, -S-, -NH-, or a bond -0- -, -s-, -NH-, or a bond z = - -0- or a I bond Ar' Ar^B Ar⁹

3. The compound of claim 1, which is selected from: methyl 4- {2-chloro-4-[3-(4- {2-hydroxy-3-[(methylethyl)amino]propoxy} - phenoxy)propoxy]phenyl} -5-cyano-2,6-dimethyl- 1 ,4-dihydropyridine-3-carboxylate; and methyl 4-(2-chloro-4-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenyl)-5- cyano-2,6-dimethyl-l,4-dihydropyridine-3-carboxylate.

4. A compound of Formula II

II

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is 0 or 1; n is 0 or 1; R¹ and R⁴ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C alkylthio, C₁-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR >5'R_π 6⁰ wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R³ is -COOR⁷, -CONR⁵R⁶, nitro, cyano or trifluoromethyl; R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or - NR⁵R⁶-; and the allcyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁷ is Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C₄ alkoxy or -NR⁵R⁶; L is CrC₁₂ 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-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, C₁-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to -(L)_m and -β, one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, Cι-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with - O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); β is -CH(OH)CH₂NR⁸R⁹ or -OCH₂CH(OH)CH₂NR⁸R⁹; and R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when m is 1, n is 1, R¹ is Cι-C₈ alkyl, R is Cι-C₈ alkyl, cyano or trifluoromethyl, Ar¹ is phenyl, substituted phenyl or benzoxadiazolyl, and L comprises a -COOCH₂- moiety bonded directly to the dihydropyridine ring, then R³ is -CONR⁵R⁶, nitro, cyano or trifluoromethyl.

5. The compound of claim 4, wherein Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar , Ar⁵, Ar , Ar⁷, Ar⁸ or Ar⁹

Ar³ Ar⁴ Ar^b Ar^b

-CH₂CH₂-, -CH— CH⁼, W = -0-, -S-. -NH- U * ⁼ -CH₂CH; _r, -CH =CH=, -0-, -S-, -NH-, or a bond -0- -, -s-, -NH-, ( DΓ a bond Z = = -0- or a I bond Ar' Ar⁸ Ar⁹

6. The compound of claim 4, which is selected from: 4-(2-chlorophenyl)-5-cyano-2,6-dimethyl(3-l,4-dihydropyridine)]-N-[3-(4-{2- hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl]carboxamide; 3-(4-{2-hydroxy-3-[(methylethyl)amino]propoxy}phenoxy)propyl 4-(2- cb.lorophenyl)-5 -cyano-2,6-dimethyl- 1 ,4-dihydropyridine-3 -carboxylate; 4-(2-Chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid 3-{3-[4-(2-hydroxy-3-isopropylamino-propoxy)-9H-carbazol-l-yloxyl]-propyl} ester 5-methyl ester; 4-(2-Chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid 3-{3-[4-(3-tert-butylamino-2-hydroxy-propoxy)-9H-carbazol-l-yloxyl]-propyl} ester 5-methyl ester; and 4-(2-Chloro-phenyl)-2,6-dimethyl-l,4-dihydro-pyridine-3,5-dicarboxylic acid 3-[3-(4-{2-hydroxy-3-[2-(2-methoxy-phenoxy)-ethylamino]-propoxy}-9H-carbazol- l-yloxyl)-propyl] ester 5-methyl ester.

7. A compound of Formula III

III

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: m is 0 or 1; n is 0 or 1 ; R⁴ is hydrogen, Cτ-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C alkylthio, C_\- C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR⁵R⁶, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S~, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² and R³ are independently -COOR⁷, -CONR⁵R⁶, nitro, cyano or trifluoromethyl; R⁵ and R⁶ are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or - NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁷ is -Cs alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C₄ alkoxy or -NR⁵R⁶; L is 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, SO₂ and/or NR⁵, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkylthio, Cι-C alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R₈, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO - and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to (L)_m and β, one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C₁-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO - and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); β is -CH(OH)CH₂NR⁸R⁹ or -OCH₂CH(OH)CH₂NR⁸R⁹; and o n R and R are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s);; provided that when m is 1, R⁴ is Cι-C₈ alkyl, cyano or trifluoromethyl, Ar¹ is phenyl or substituted phenyl, and R² is -COOR⁷, then R³ is nitro, cyano or trifluoromethyl.

8. The compound of claim 7, wherein Ar and Ar are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar³ Ar⁴ Ar³ Ar

U = -CH₂CH₂-, -CH=CH=,

U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -0- or a bond Ar' Ar^β Ar⁹

9. The compound of claim 7, which is selected from: methyl 4-(2-chlorophenyl)-5-cyano-2- {[3-(4- {2-hydroxy-3-

[(methylethyl)amino]propoxy}phenoxy)propoxy]methyl} -6-methyl- 1 ,4- dihydrop yridine-3 -carboxylate; methyl 4-(2-chlorophenyl)-5-cyano-2- {[3-(2- {2-hydroxy-3- [(methylethyl)amino]propoxy}phenoxy)propoxy]methyl} -6-methyl- 1 ,4- dihydropyridine-3-carboxylate; and methyl 4-(2-chlorophenyl)-2-({2-[2-(3-cyano-4- {2-hydroxy-3- [(methylethyl)amino]propoxy}phenoxy)acetylamino]ethoxy}methyl)-5- (methoxycarbonyl)-6-methyl- 1 ,4-dihydropyridine-3-carboxylate.

10. A compound of Foπnula IV

IV

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: n is 0 or 1; R¹ and R⁴ are independently hydrogen, Cι-C₈ allcyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C₄ alkyltliio, CrC₄ alkoxy, halo, nitro, cyano,

wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁵ and R⁶ are independently a lone pair of electrons, Jiydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R² and R³ are independently -COOR⁷, nitro, cyano or trifluoromethyl; R⁷ is Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with Cι-C alkoxy or -NR⁵R⁶; L is 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-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with, in addition to L, one to tliree substituent(s) independently selected from -Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, Cι-C alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the allcyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C -C₈ cycloalkenyl, C₁-C₄ alkylthio, -C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the allcyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when n is 1, then at least one of R² and R³ is trifluoromethyl, nitro or cyano; and further provided that when n is 0 and Ar¹ is substituted with nitro, then L is not -OCH₂CH₂-.

1 9

11. The compound of claim 10, wherein Ar and Ar are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

U = -CH₂CH₂-, -CH=CH=, W = -0-, -S-, -NH- U ' - -CH₂CH; ,-, -CH^: =CH=, -0-, -S-, -NH-, or a bond -0- -, -S-, -NH-, or a bond z-- = -0- or a I Dond Ar' Ar⁸ Ar⁹

12. The compound of claim 10, which is selected from: methyl 4-(2-chloro-4- {[N-(2- {[3-(2-cyano-phenoxy)-2- hydroxypropyl]amino}-2-methylpropyl)carbamoyl]methoxy}phenyl)-5-cyano-2,6- dimethyl-1 ,4-dihydropyridine-3-carboxylate; and methyl 4- {2-chloro-4-[(N- {2-[(2-hydroxy-2-phenylethyl)amino]-2- methylpropyl}carbamoyl)methoxy]phenyl}-5-(methoxy-carbonyl)-2,6-dimethyl-l,4- dihydropyridine-3-carboxylate.

13. A compound of Formula V

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: n is O or 1; R¹ and R⁴ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₁-C₄ alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR⁵R⁶, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R and R are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxy l(s); R² is -COOR⁷, nitro, cyano or trifluoromethyl; R⁷ is Cι-C₈ alkyl, C -C₈ alkenyl or C₂-C₈ alkynyl, wherein the allcyl, alkenyl or alkynyl is optionally substituted with C₁-C₄ alkoxy or -NR⁵R⁶; L is 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 - and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C1-C4 alkylthio, Cι-C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the allcyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO - and or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Ci- C₈ alkyl, C₂-C₈ alkenyl, C -C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl, C1.-C₄ alkylthio, C₁-C4 alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- grouρ(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the allcyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁸ and R⁹ are independently hydrogen, Ci-Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH - group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when n is 0 and Ar¹ is phenyl substituted with nitro, or when n is 1, then L does not comprise a -COOCH₂- moiety bonded directly to the dihydropyridine ring.

14. The compound of claim 13, wherein Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

U = -CH₂CH₂-, -CH=CH=, W = -0-, -S-, -NH- U = -CH₂CH₂-, -CH=CH=, -0-, -S-, -NH-, or a bond -0-, -S-, -NH-, or a bond Z = -O- or a bond Ar' Ar" Ar⁹

15. The compound of claim 13 , which is selected from methyl 4-(2-chlorophenyl)-5-[N-(2- {[3-(2-cyano-phenoxy)-2- hydroxypropyl]amino}-2-methyl-propyl)carbamoyl]-2,6-dimethyl-l,4- dihydropyridine-3-carboxylate; methyl 4-(2-chlorophenyl)-5-(N-{2-[(2-hydroxy-2-phenylethyl)amino]-2- methylpropyl} carbamoyl)-dimethyl- 1 ,4-dihydropyridine-3-carboxylate; and 5-{2-[3-9H-Carbazol-4-yloxy-2-hydroxy-propylamino]-2-methyl- propylcarbamoyl}-4-(2-chloro-phenyl)-2,6-dimethyl-l,4-dihydiO-pyridine-3- carboxylic acid methyl ester.

16. A compound of Formula VI

VI

or a pharmaceutically acceptable equivalent, an isomer or a mixture of isomers thereof, wherein: n is 0 or 1; R⁴ is hydrogen, Cι-C₈ alkyl, C -C₈ alkenyl, C₂-C₈ alkynyl, -C₄ alkylthio, C_\- C₄ alkoxy, halo, nitro, cyano, trifluoromethyl or -NR⁵R⁶, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R and R are independently a lone pair of electrons, hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with phenyl or substituted phenyl; one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-; and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); 9 ^ 7 R and R are independently -COOR , nitro, cyano or trifluoromethyl; R⁷ is Cι-C₈ alkyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl, wherein the alkyl, alkenyl or alkynyl is optionally substituted with CrC₄ alkoxy or -NR⁵R⁶; L is CrC₁₂ alkylene, C₂-C₁₂ alkenylene or C₂-Cι₂ alkynylene, wherein one or more -CH₂- group(s) of the alkylene, alkenylene or alkynylene is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkylene, alkenylene or alkynylene is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar¹ is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to three substituent(s) independently selected from Cι-C₈ alkyl, C -C₈ alkenyl, C₂-C₃ alkynyl, Cι-C₄ alkylthio, C1-C4 alkoxy, halo, nitro, cyano, trifluoromethyl, trifluoroethyl, pentafluoroethyl, trifluoromethoxy, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸, -NR⁵CONR⁸R⁹ and -COOR⁷, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); Ar² is an aryl or heteroaryl radical, which aryl or heteroaryl radical is optionally substituted with one to tliree substituent(s) independently selected from Ci-Cs alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkenyl,

C₄ alkylthio, C C₄ alkoxy, halo, nitro, cyano, trifluoromethyl, -NR⁵R⁶, -NR⁵COR⁸, -NR⁵SO₂R⁸ and -NR⁵CONR⁸R⁹, wherein one or more -CH₂- grouρ(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or -NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); R⁸ and R⁹ are independently hydrogen, Cι-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, C₃-C₈ cycloalkyl or C₃-C₈ cycloalkenyl, wherein one or more -CH₂- group(s) of the alkyl, alkenyl or alkynyl is/are optionally replaced with -O-, -S-, -SO₂- and/or - NR⁵-, and the alkyl, alkenyl or alkynyl is optionally substituted with one or more carbonyl oxygen(s) and/or hydroxyl(s); provided that when n is 1 and R⁴ is methyl, then at least one of R² and R³ is cyano, nitro or trifluoromethyl.

17. The compound of claim 16, wherein Ar¹ and Ar² are independently phenyl, naphthyl, pyridyl, isoxazolyl, pyridyl, quinolyl, isoquinolyl, Ar³, Ar⁴, Ar⁵, Ar⁶, Ar⁷, Ar⁸ or Ar⁹

Ar^J Ar⁴ Ar^s Ar^b

18. The compound of claim 16, which is 4-(2-chlorophenyl)-5-cyano-2-({2-[3-(2- cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino}methyl)-6-methyl-l,4- dihydropyridine-3 -carboxylic acid methyl ester.

19. A pharmaceutical composition comprising:

(i) an effective amount of any compound of claims 1-18; and (ii) a pharmaceutically acceptable carrier.

20. The pharmaceutical composition of claim 19, 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.

21. The phannaceutical composition of claim 19, wherein the pharmaceutically acceptable carrier is selected from fillers , diluents, excipients, and solvent encapsulating materials.

22. The pharmaceutical composition of claim 19, wherein the pharmaceutically acceptable carrier is active.

23. The pharmaceutical composition of claim 19, 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) pyro gen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; and (21) polyesters,' polycarbonates and polyanhydrides.

24. The pharmaceutical composition of claim 19, 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, com oil, soybean oil, propylene glycol, glycerin, sorbitol, mannitol, polyethylene glycol, ethyl oleate, ethyl laurate, magnesium hydroxide solutions, and aluminum hydroxide solutions.

25. The pharmaceutical composition of claim 19, wherein the pharmaceutically acceptable carrier is liquid.

26. The pharmaceutical composition of claim 19, wherein the pharmaceutically acceptable carrier is solid.

27. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition has a form selected from solids and liquids.

28. The pharmaceutical composition of claim 19, wherem 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 foπnulations, creams, ointments, controlled-release patches, controlled-release topical sprays; pessaries, and foams.

29. The pharmaceutical composition of claim 19, 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.

30. 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 1-18.

31. 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 1-18.

32. The method of claim 31 , wherein the cardiovascular disease is selected from heart failure, hypertension, SA/AV node disturbance, arrythmia, hypertrophic subaortic stenosis, and angina.

33. The method of claim 32, wherein the heart failure is chronic heart failure or congestive heart failure.

34. 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 1-18.

35. The method of claim 33, wherein both β-adrenergic receptors and PDE are inhibited.

36. The method of claim 33, wherein PDE3 is inhibited.

37. The method of claim 33, wherein the compound is administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir.

38. The method of claim 33, wherein the compound is administered by subcutaneous, intravenous, intramuscular, intraperitoneal, mtrathecal, intraventricular, intrastemal, intracranial, or intraosseous injection.

39. The method of claim 33, wherein the compound is administered by an infusion technique.

40. The method of claim 33, further comprising administering one or more additional agent(s) for simultaneous, separate, or sequential use.

41. The method of claim 40, wherein the one or more additional agent(s) is/are selected from therapeutic agents.

42. A method of claim 41 , 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.

43. The method of any one of claims 30-42, wherein the mammal is a human.