SUBSTITUTED AND BRIDGED PYRIDINES USEFUL AS PHARMACEUTICAL AGENTS

Abstract: There are disclosed novel substituted and bridged pyridines having the formula wherein: R is hydrogen; C₁-C₈ straight chain or branched alkyl; benzyl; R¹ and R⁴ are, e.g., hydrogen or hydrocarbon having up to 8 carbon atoms; R² and R³ are, e.g., hydrocarbon having up to 8 carbon atoms; C₃-C₈ cycloalkyl; C₂-C₈ alkyl interrupted by 1 to 2 oxygen atoms or substituted with NR⁵R⁶ wherein R⁵ and R⁶ can independently by hydrogen, C₁-C₈ alkyl, aralkyl wherein the alkyl groups has up to 8 carbon atoms end the aryl has 6 carbon atoms, or R⁵ and R⁶ together with the N atom can be joined to form a 5- or 6-membered ring wherein the 6-membered ring can contain an O or N hetereoatom and the N heteroatom can be substituted with C₁-C₆ alkyl; X, W, Z and U can independently by, e.g., hydrogen; phenyl; halo or NO₂; provided that two of X, W, Z and U are hydrogen; or, X and W, W and Z, or Z and U, together with the phenyl ring form naphthyl or benzooxadiazole rings; Y is O; S; SO; n is 0 or 1; and, the pharmaceutically acceptable acid addition salts thereof. Those compounds are useful as calcium entry blockers.

Description: BACKGROUND OF THE INVENTION Substituted dihydropyridines are known to be useful for reducing blood pressure, effecting dilation of the coronary vessels, and preventing vasospasms. Typical of such substituted dihydropyridines are those disclosed in U.S. Patents 3,923,818; 3,905,970; 4,044,141; 4,237,137; and, 4,285,955. The substituted dihydropyridines disclosed in these patents do not include bridged ring structures. Weller et al . [ J. Org. Chem , 48 , 3061-67 (1983)] disclose fused ring and bridged ring structures (e.g., spiro piperidines, spiro pyridines) but indicate that in such structures no exceptionally active analgesics have been found. Furthermore, the bridge portion in these structures is from the ortho position of the benzene ring to the para position of the piperidine or pyridine rings. 4-Phenyl-1,4-dihydropyridines without bridged ring structures are known from EP-A-0088274 and Pharmazic heute 104(3), 139-146 (1983). 3-Phenyl-1,2,5,6-tetrahydropyridines, 3-Phenyl-1,2,3,4-tetrahydropyridines and 3- or 4-Phenylpiperidines-all containing a bridge between the phenyl group and the tetrahydropyridine group or the piperidine group - are known from U.S. Patents 4,132,710 and 4,305,938. SUMMARY OF THE INVENTION This invention relates to novel substituted and bridged pyridines and related compounds which are useful as calcium channel blockers and to methods for preparing such compounds. The compounds of this invention can be represented by the general formula: wherein: R is hydrogen; C₁-C₈ straight chain or branched alkyl; benzyl; R¹ and R⁴ are independently hydrogen; straight chain or branched, saturated hydrocarbon having up to 8 carbon atoms; hydroxy-C₁-C₈-alkyl; CO₂-loweralkyl of C₁-C₈ C₃-C₈ cycloalkyl; R² and R³ are independently straight chain or branched, saturated or unsaturated hydrocarbon having up to 8 carbon atoms; C₃-C₈ cycloalkyl; C₂-C₈ alkyl interrupted by 1 to 2 oxygen atoms or substituted with NR⁵R⁶ wherein R⁵ and R⁶ can independently be hydrogen, C₁-C₈ alkyl, or aralkyl wherein the alkyl group has up to 8 carbon atoms and the aryl has 6 carbon atoms, or R⁵ and R⁶ together with the N atom can be joined to form a 5- or 6-membered ring wherein the 6-membered ring can contain an O, S, or N heteroatom and the N heteroatom can be substituted with C₁-C₆alkyl; X, W, Z and U can independently be hydrogen; phenyl and substituted phenyl wherein the substituents can be 1-2 halo (Cl, Br, F) atoms; halo; NO₂; trifluoromethyl; C₁-C₈alkoxy; C₁-C₈ linear or branched alkyl, linear or branched alkenyl or alkynyl having up to 8 carbon atoms; C₁-C₈ thioalkyl wherein the S atom can be substituted with 1-2 O atoms; cyano; NH₂; wherein R⁷ is C 1-8 alkoxy or C₁-C₈ alkyl; provided that two of X, W, Z and U are hydrogen; or X and W, W and Z, or Z and U, together with the phenyl ring, form naphthyl or benzooxadiazole rings; Y is O; S; SO; n is 0 or 1; and, the pharmaceutically acceptable acid addition salts thereof; with the proviso that X cannot be C₁-C₈ alkoxy or C₂-C₈ alkenyl. Preferred are compounds of Formula 1 wherein: R is hydrogen; R¹ and R⁴ are independently C 1-8 alkyl; R² and R³ are independently C 1-8 alkyl which can be substituted with NR⁵R⁶ wherein R⁵ and R⁶ are as defined above; X is hydrogen or halo; U and W can each be NO₂; CF₃; or halo; Z is hydrogen; Y is O or S; and, n is 0 or 1. Most preferred are those compounds of Formula 1 wherein: R is hydrogen; R¹ and R⁴ are methyl; R² and R³ are C 1-4 alkyl; X is hydrogen or halo; U and W can each be NO₂, CF₃ or halo; Z is hydrogen; Y is O or S; and, n is 0 or 1. The invention further relates to compounds having the formula: wherein R-R⁴, X, W, Z and U are as defined above and, R¹¹ is C₁-C₈ loweralkyl. The compounds of the invention can be prepared by the methods set forth hereinbelow. In these methods, unless otherwise indicated, the starting materials employed are commercially available or known in the literature, R-R⁴, W, X, Y, Z, U, and n are as defined above, and all temperatures are in degrees Celsius. METHOD A Step 1 : As shown in Reaction Scheme I, either dihydropyridine (R⁸=C₁-C₈ alkyl, benzyl, paramethoxy benzyl; X, W, Z and U are not alkoxy, Y is O, and n is ⊘) or W and X, W and Z, or Z and U with the phenyl form napthyl [both of which compounds can be prepared as described in U.S. Patent 3,959,296] is treated with about 1-5 mole equivalent (meq) (preferably 1 meq) of a boron halide or boron halide complex such as boron tribromide, (BBr₃), boron trichloride, (BCl₃), boron tribromide/dimethylsulfide (BBr₃/DMS), dimethylboron bromide or pyridine/hydrochloride or aluminum chloride (AlCl₃) (preferably BBr₃) neat or in a suitable solvent such as methylene chloride (CH₂Cl₂), chloroform (CHCl₃), benzene (preferably (CH₂Cl₂)) at a temperature of about -78° to the reflux temperature of the solvent (preferably 25°C to reflux) under an inert atmosphere (Ar or N₂) for a period of about 1-25 hours (preferably 1 hour). The intermediate lactone compound (Reaction Scheme II, Method D) is isolated and treated as described below in Step 2. Step 2 : The reaction mixture, maintained under the inert atmosphere, is then treated with about 2-5 meq (preferably 5 meq) potassium carbonate, potassium hydride, lithium hydride, or sodium hydride (preferably potassium carbonate) and 2-25 meq of R²OH, preferably about 10 meq, neat or in a suitable solvent such as dimethylformamide (DMF), dimethoxyethane (DME) or tetrahydrofuran (THF) at about 25°-125°C (preferably about 25°C) for about 1-48 hours to afford a compound of Formula 1. Method B Step 1 : In this method (R⁸=CH₂-C₆H₅, Y=O, n=0, 1), compound (Reaction Scheme I) is treated with hydrogen under pressure (1 atm. or 2-3 atm.) in the presence of about 10%-100% weight equivalents of a catalyst such as 5% Pd/C, 10% Pd/C or PtO₂ in a suitable solvent such as ethanol (EtOH), ethyl acetate, methanol (CH₃OH), isopropanol, petroleum ether, preferably EtOH, at 10°-40°C (preferably 25°C) for about 25-36 hours to obtain compound Step 2: Compound is first treated as described above in Method B, Step 1, to obtain an intermediate phenol dihydropyridine which is then treated with about 0.1-0.3 meq (preferably 0.1 meq) of an acid (toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, methanesulfonic acid, sulfuric acid; preferably, camphorsulfonic acid) in a solvent such as CH₂Cl₂, CHCl₃, dichloroethane, THF, DME, or mixtures thereof (preferably methylene chloride) at about 25 to 50°C for about 2-24 hours to obtain compound Method C Dihydropyridine (R⁸=CH₂-C₆H₅ or Y=O or S, n=0 or 1) (Reaction Scheme I) is treated under an inert atmosphere (Ar or N₂) with about 5-50 meq (preferably 10 meq) trifluoroacetic acid neat or in the presence of a solvent (anisole, CH₂Cl₂, CHCl₃, dichloroethane) at 25°-100°C (preferably 25°C) for about 10-60 minutes to obtain the Formula 1 compound. Method D In this method (Reaction Scheme II R⁸=C₁-C₈alkyl, benzyl, paramethoxybenzyl; Y=O; n=O; and, X, W, Z and U are not alkoxy), dihydropyridine or naphthyldihydropyridine is treated under an inert atmosphere (Ar or N₂) with about 1 meq BBr₃ or BCl₃ in an organic solvent (CH₂Cl₂, dichloromethane, CHCl₃, benzene; preferably CH₂Cl₂) at a temperature of about -78° to 40°C for about 3 hours to obtain oxo-carbonyl bridged dihydropyridine intermediate This intermediate is then isolated and treated as described above in Method A, Step 2, to obtain the phenol dihydropyridine intermediate (Method B, Step 2) which is treated as described above in Method B, Step 2, to afford compound Method E Step 1 : As shown in Reaction Scheme III, substituted benzoic acid is treated under an inert atmosphere (Ar, N₂) with about 1 meq of a borane complex such as borane/THF, borane/DMS, borane/piperidine (preferably borane/THF) in a polar aprotic solvent (THF, CH₂Cl₂, toluene; preferably THF) at about 0°-85° (preferably 25°C) for 2 hours to obtain the alcohol intermediate Step 2 : Intermediate is then treated with about 1.2 meq of a thioalkanoate compound, preferably potassium thioacetat e or sodium thioacetate (R⁶=C₁-C₈ alkyl; C₆ or C₁₀ aryl) using DMF as the solvent under the same conditions as in Step 1 to yield the methylthioacetate intermediate Step 3 : Thioacetate intermediate is then reacted with about 2 meq (preferably 1.5 meq) MnO₂, pyridinium chlorochromate (PCC), Collins reagent, dimethylsulfoxide (DMSO), oxalylchloride/triethylamine (TEA) (preferably MnO₂) in an organic solvent (CH₂Cl₂, dichloroethane, benzene, hexane; preferably CH₂Cl₂) at about -75° to 110°C (preferably 25°C) for about 48 hours to obtain aldehyde intermediate Step 4 : Aldehyde intermediate is reacted under an inert atmosphere (Ar, N₂) with about 1 meq each of acetoacetate and aminocrotonate in a polar solvent (isopropanol, EtOH, CH₃OH, toluene, DME, THF; preferably isopropanol) at 60°-130°C, preferably the reflux temperature of the solvent to afford dihydropyridine intermediate Step 5 : Upon treatment with a base (K₂CO₃, KOH, Na₂CO₃, NaOH; preferably K₂CO₃) in a lower alkanol solvent (methanol, ethanol; preferably methanol) under an inert atmosphere (Ar, N₂) at a temperature of about 25°-110°C (preferably 25°C) for 2 hours, intermediate is converted to the methyl-sulfur bridged compound of the invention. Further treatment of compound with a suitable oxidizing agent such as metachloroperoxybenzoic acid, osmium tetroxide, sodium periodate, hydrogen peroxide, or t-butyl hydroperoxide affords the sulfoxide compound of the invention. Method F As shown in Reaction Scheme IV, substituted halobenzonitrile is treated with the sulfhydryl compound, HSR¹⁰ (1-5 meq) in a solvent (dimethylformamide (DMF), CH₃OH, EtOH, isopropanol or N-methyl-2-pyrrolidinone) in the presence of an alkali (lithium hydride, sodium hydride, potassium hydride, potassium carbonate, sodium methoxide, sodium ethoxide, potassium hydroxide) at about 0°-100°C (preferably 0°-25°C) for about 5 hours to obtain substituted thiobenzonitrile intermediate Treatment of intermediate with diisobutylaluminum hydride (DIBAL) (1-2 meq) under an inert atmosphere (Ar, N₂) in an organic solvent (CH₂Cl₂, THF, hexane, toluene, dichloroethane) at about -78°C to the reflux temperature of the solvent (preferably -78° to 25°C) for about 3 hours followed by treatment with an aqueous acid (HCl, H₂SO₄, acetic acid) affords aldehyde intermediate Intermediate is then reacted with 1 meq each of an acetoacetate and an aminocrotonate in the same solvent at a temperature of about 25°-130°C for about 12 hours to obtain dihydropyridine intermediate which can then be reacted with trifluoroacetic acid and anisole (each at 5-50 meq; preferably 5 meq) either neat or in an organic solvent (CH₂Cl₂, dichloroethane, or CHCl₃), under an inert atmosphere (Ar, N₂) at about 0°-100°C (preferably 0°-25°C) for about 15 minutes to directly yield the sulfur bridged compound of the invention. Alternatively, dihydropyridine intermediate is oxidized as described in Method E, Step 5, to obtain sulfonyl dihydropyridine intermediate which is then treated with an alkanoic acid anhydride such as acetic anhydride (10-100 meq, preferably 5-50 meq) under an inert atmosphere (Ar, N₂) at about 80°-130°C (preferably 90°C) for about 1 hour to obtain dihydropyridine intermediate Upon treatment with an alkali (potassium carbonate, sodium hydride, lithium hydride, potassium hydride, potassium hydroxide, sodium hydroxide) under an inert atmosphere (Ar, N₂) in a lower alkanol organic solvent (ethanol, methanol) at about 25°-100°C (preferably 25°C) for about 5 hours, intermediate affords compound Compounds of Formula 1 can exist in different isomeric forms such as, for example, threo, erythro, diastereomeric, enantiomeric, and all such forms are included within the scope of this invention. This invention relates further to pharmaceutical compositions consisting essentially of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of the invention. As indicated above, the compounds of this invention are useful as calcium entry blockers, and thus have broad pharmacological utility in that they exhibit (i) pronounced and long-lasting vasodilating effect accompanied by an energy-sparing effect on cardiac metabolism; (ii) antiarrythmic and antianginal action on cardiac muscle; (iii) vascular spasmolytic action; (iv) antihypertensive action; (v) spasmolytic action on the smooth muscle of the gastrointestinal and urogenital tracts and the cerebrovascular and respiratory system; (vi) are useful cholesterolemic and lipademic agents and for treating cerebral and peripheral circulatory disorders; (vii) protect ischemic myocardium; (viii) inhibit irritable bowel syndrome and esophagus spasm; and, (ix) inhibit migraine. Some of these compounds may also be useful cardiotonic agents. The compounds of the present invention were found to inhibit vascular calcium contraction, reduce cardiac contractile force, inhibit tracheal calcium contraction, inhibit calcium uptake in pituitary cells, and displace tritiated nitrendepine from membranes. The compounds of the present invention can be administered in any suitable form; e.g. orally, sublingually, transdermally, or parenterally; i.e. intravenously, or interperitoneally. Thus, the compounds can be offered in a form (a) for oral administration e.q. as tablets in combination with other compounding ingredients customarily used such as talc, vegetable oils, polyols, benzyl alcohols, gums, gelatin, starches and other carriers; dissolved or dispersed or emulsified in a suitable liquid carrier; in capsules or encapsulated in a suitable encapsulating material; or (b) for sublingual administration; e.g., nitroglycerine tablets, or lactose tablets for rapid dissolution or high molecular weight methylcellulose tablets, or carboxymethylcellulose tablets for slower, time-releasing delivery; or, (c) for parenteral administration e.g. dissolved or dispersed in a suitable liquid carrier or emulsified. The ratio of active compound to compounding ingredients i.e. carrier, or diluent will vary as the dosage form requires. Whatever form is used, the amount of compound of the present invention administered should be sufficient to achieve the pharmaceutical and/or therapeutic effect desired or required in the patient. Generally, doses of the compounds of the invention of from about 30 to about 3000 mg per day may be used, preferably about 100 to about 1000 mg per day. Dosages may be single or multiple depending on the daily total required and the unit dosage administered. Of course, the dose will vary depending upon the nature and severity of disease, weight of the patient, and other factors which a person skilled in the art will recognize. It is often advantageous to administer compounds of this invention in combination with angiotensin converting enzyme inhibitors and/or antihypertensives and/or diuretics and/or β-blocking agents, and/or cardiotonic agents. For example, the compounds of this invention can be given in combination with such compounds as enalapril, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, timolol, or digitalis, as well as admixtures and combinations thereof. Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly. Naturally, these dose ranges can be adjusted on a unit basis as necessary to permit divided daily dosages and, as noted above, can be varied depending on the nature and severity of the disease, weight of patient, special diets and other factors. DETAILED DESCRIPTION OF THE INVENTION The following Examples are provided to further illustrate the best mode currently known for obtaining the compounds of the invention, but are not to be construed as being limitative of the invention. Unless otherwise indicated, all temperatures are in °C. EXAMPLE 1 Diethyl 3,6-dihydro-2,4-dimethyl-8-nitro-2,6-methano-2H-1,3-benzoxazocine-5,11-dicarboxylate (18&19) Step 1: Ethyl 3,10-B-dihydro-2,4-dimethyl-9-nitro-5-oxo-5H-(1)-benzopyrano-(3,4-c)pyridine-1-carboxylate A stirred solution of 404 mg (1 mm) of diethyl 2,6-dimethyl-4-(2-methoxy-5-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in 20 mL of dry CH₂Cl₂ cooled to -78°C under an Ar atmosphere was treated dropwise with 1.25 mL of 1.0 M BBr₃ in CH₂Cl₂. The cooling bath was removed and the mixture was allowed to reach 25°C. After 20 minutes at 25°C, the reaction was quenched with saturated aqueous NaHCO₃ and extracted with CH₂Cl₂. The combined organic phases were washed with 5% aqueous NaHCO₃, and brine, dried (anhydrous MgSO₄), filtered, concentrated and recrystallized (5% EtOH in CH₂Cl₂) to afford 320 mg (93%) of ethyl 3,10B-dihydro-2,4-dimethyl-9-nitro-5-oxo-5H-(1)-benzopyrano(3,4-c)pyridine-1-carboxylate 'H NMR (360 MHz, DMSO), δ=1.11 (t, J-7.5 Hz, 3H, CH₂C H ₃); =2.05, 2.31 (s, 3H each, CH₃); 4.04, 4.21 (dq, J=10.5 and 7.5Hz, 1H each, OCH₂); 4.88 (s, 1H, ArC H ); 7.34 (d, J=9.0Hz, 1H, Ar H ); 7.51 (dd, J-3,10 Hz, 1H, Ar H ); 8.15 (dd, J=3.0, 9.0Hz, 1H, Ar H ); 9.19 (bs, 1H, N- H ). Step 2 : A solution of 360 mg (1.05 mm) of pyridine in 30 ml of absolute ethanol under Ar atmosphere was stirred with 1.20 g of powdered anhydrous K₂CO₃ at 25°C for 12 hr. This was neutralized with 30 ml of saturated aqueous NH₄Cl and extracted with CH₂Cl₂ (200 ml). The organic portion was washed with pH 7 phosphate buffer (20 mL) and brine, dried (anhydrous Na₂SO₄), filtered and concentrated to give 420 mg of crude phenol Step 3 : The crude phenol was dissolved in anhydrous CH₂Cl₂ and stirred under Ar with 15 mg of dl-camphorsulfonic acid for 3 hours at 25°C. The mixture was then neutralized by washing with pH 7 phosphate buffer and brine, dried (anhydrous MgSO₄), filtered, concentrated to give 400 mg of crude mixture of 2 cyclized products. This was then flash chromatographed (silica gel, 75% ether in hexane) to separate the fast diastereomer (100 mg) and the slower diastereomer. This slower product was further purified by preparative thick layer chromatography (PTLC) (silica gel, 2.5% acetone in CH₂Cl₂) and the product crystallized from ether/hexane; yield, 100 mg of 'H NMR (360 MHz, CDCL₃) δ=1.25, 1.42 (t, J=7.5 Hz, 3H each, CH₂C H ₃); δ=1.94 (s, 3H, OCC H ₃); δ=2.24 (s, 3H, C H ₃); 2.94 (dd, J=2.8, 0.8Hz, 1H, C H CO₂); 4.08-4.36 (bm, 4H, OC H ₂); 4.67 (d, J=2.8Hz, 1H, Ar-C H ); 5.05 (1H, N-H)); 6.86 (d, J=9.0 Hz, 1H, ArH); 7.98 (dd, J-3.0, 9.0 Hz, 1H, Ar-H); 8.32 (d, J=3.0Hz, 1H, ArH) m.p. 159-160°C. 'H NMR (360 MHz, CDCl₃) δ=1.15, 1.43 (t, J=7.5Hz, 3H each, CH₂C H ₃), 1.89 (s, 3H, CH₃C-O), 2.25 (s, 3H, C H ₃); 2.91 (d, J=2.4 Hz, 1H, C H CO₂), 4.09 (dq, J=1.0, 7.5 Hz, 2H, OC H ₂CH₃); 4.18, 4.34 (dq, J=10.5, 7.5 Hz, 1H each, OC H ₂CH₃); 4.53 (d, J=2.4Hz, 1H, ArC H ); 4.95 (bs, 1H, N H ); 6.87 (d, J=9.0Hz, 1H, Ar H ); 7.98 (dd, J=3.0, 9.0Hz, 1H, Ar H ); 8.31 (d, J-3.0Hz, 1H, Ar H ). m.p. 157-8°C. 'H NMR (360 MHz, CDCl₃) δ=1.21 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.42 (s, 6H, CH₃); 4.15 (m, OC H ₂); 5.07 (s, 1H, ArC H ); 5.97 (bs, 1H, N H ); 6.87 (d, J=9.0Hz, 1H, Ar H ); 7.89 (d, J=3.0Hz, 1H, ArH); 7.98 (dd, J=3.0, 9.0 Hz, 1H, ArH); 9.92 (s, 1H, O H ). EXAMPLE 2 Diethyl 4,5-dihydro-3,5-dimethyl-1,5-methano-1H-naphth(1,2-G)(1,3)oxazocine-2,13-dicarboxylate (21&22) A solution of 2.25 g (5.5 mm) of diethyl 1,4-dihydro-4-(2-methoxy-1-naphthalenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate in 12.0 mL of dry 1,2-dichloroethane was stirred under Ar at 25°C and treated with 2.40 g (7.68 mm) of BBr₃.CH₃SCH₃ complex. After stirring at 25°C for 20 hours, 10.0 g of anhydrous powdered K₂CO₃ and 100 mL of absolute ethanol were added. Stirring was continued for 60 hours at 25°. The reaction was quenched with saturated aqueous NH₄Cl and extracted with 500 ml of CH₂Cl₂. The organic layer was washed with pH 7 phosphate buffer and brine, dried (anhydrous Na₂SO₄), filtered, evaporated and flash chromatographed (silica gel, 2% acetone in CH₂Cl₂). The separated diastereomers, and were crystallized from ether/hexane; yield: fast 500 mg; slow 100 mg. Fast : 'H NMR (360 MHz, CDCl₃) δ=1.29, 1.38 (t, J=7.0Hz, 3H each, C H ₃CH₂); 1.96 (s, 3H, C H ₃-C-O); 2.18 (s, 3H, C H ₃); 3.06 (dd, J=H₂O, 1.0Hz, 1H, H CCO₂); 4.07-4.33 (m, 4H, CC H ₂CH₃), 4.97 (bs, 1H, N H ); 5.28 (d, J=4.0Hz, 1H, ArC H ); 7.02 (d, J=9.0Hz, 1H, Ar- H ); 7.33 (dt, J=1.0, 7.5 Hz, 1H, Ar H ); 7.48 (dt, J=1.0, 7.5 Hz, 1H, Ar H ); 7.61 (d, J=9.0 Hz, 1H, Ar H ); 7.75 (bd, J=7.5 Hz, 1H, Ar H ); 8.55 (d, J=9.0 Hz, 1H, Ar H ). m.p. 180-190°C. Slow : 'H NMR (300 MHz, CDCl₃) δ=1.00, 1.39 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.94 (s, 3H, OCC H ₃); 2.36 (s, 3H, C H ₃); 2.87 (d, J=3.0 Hz, 1H, H CCO₂); 4.00 (q, J=7.5 Hz, 2H, OC H ₂CH₃); 4.22, 4.32 (dq, J=10.0 Hz, 7.5 Hz, 1H each, OC H ₂CH₃); 4.91 (bs, 1H, N H ); 5.23 (d, J=3.0 Hz, 1H, ArC H ); 7.02 (d, J-7.0 Hz, 1H, Ar H ); 7.31 (bt, J=7.5 Hz, 1H, Ar H ); 7.46 (bt, J=7.5 Hz, 1H, Ar H ); 7.59 (d, J=9.0 Hz, 1H, Ar H ); 7.7 (bd, J=8.0 Hz, 1H, ArH); 8.55 (d, J=9.0 Hz, 1H, Ar H ); m.p 185-92°C. EXAMPLE 3 Diethyl 3,6-dihydro-2,4-dimethyl-2,6-methano-2H-1,3-benzoxazocine-5,11-dicarboxylate (26&27) Step 1: Ethyl 3,10B-dihydro-2,4-dimethyl-5-oxo-5H-(1)benzopyrano(3,4-c)pyridine-1-carboxylate (24) 36 mL of BBr₃ in CH₂Cl₂ (1.0 M, 36 mm) was added dropwise to a cold (-78°C) stirred solution of diethyl-1,4-dihydro-4-(2-methoxyphenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate, (10.77 g, 30 mm) in 60 ml of dry CH₂Cl₂ under an Ar atmosphere. After stirring an additional 15 minutes at -78°C, the reaction mixture was allowed to reach 25°C and stirred 1 hour. This was quenched with saturated aqueous NH₄Cl and extracted with CHCl₃. The organic portion was washed with pH 7 phosphate buffer and brine, dried (anhydrous MgSO₄), filtered and evaporated to give a solid which was washed with ether and dried 12 hours/40°C/ P₂O₅/1 mm; yield 9.00 g of yellow solid (99%). This was used without further purification in Step 2. Analytical sample was obtained by recrystallization from CH₂Cl₂. 'H NMR (360 MHz, CDCl₃) δ=1.95 (t, J=7.5 Hz, 3H, CH₂C H ₃); 2.12, 2.34 (s, 3H each, C H ₃); 4.19 (m, 2H, OC H ₂); 4.91 (s, 1H, ArC H ); 5.47 (bs, 1H, N- H ); 6.87 (d, J=7.5 Hz, 1H, ArH); 7.07 (t, J=7.5 Hz, 1H, ArH); 7.09 (d, J=7.5 Hz, 1H, Ar H ); 7.20 (t, J=7.5 Hz, 1H, ArH). Ir (KBr) =1690, 1615 cm⁻¹. m.p. 238-240°C. Step 2 : Lactone (9.00 g) in 150 mL of absolute ethanol was vigorously stirred under Ar with 30 g of powdered anhydrous K₂CO₃ for 48 hours. This was treated with saturated aqueous NH₄Cl and extracted with CH₂Cl₂. The organic portion was washed with pH 7 phosphate buffer and brine, dried (anhydrous MgSO₄), filtered, evaporated and flash chromatographed (silica gel, 60% ether in hexane) to afford and Fast : 'H NMR (360 MHz, CDCl₃) δ=1.23, 1.34 (t, J=7.5Hz, 3H each, CH₂C H ₃); 1.89 (s, 3H, OCCH₃); 2.20 (s, 3H, C H ₃); 2.95 (dd, J=3.0, 1.0 Hz, 1H, C H CO₂); 4.04-4.26 (m, 4H, C H ₂CH₃); 4.61 (d, J=3.0Hz, 1H, ArC H ); 4.97 (bs, 1H, N- H ); 6.79 (d, J=7.5Hz, 1H, Ar);; 6.84 (dt, J=1.0, 7.5Hz, 1H, Ar H ); 7.07 (dt, J=1.0, 7.5 Hz, 1H, Ar H ); 7.36 (dd, J=1.6, 7.5 Hz, 1H, ArH). m.p. 159-60°C. Slow : 'H NMR (360 MHz, CDCl₃) δ=1.11, 1.37 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.87 (s, 3H, OCC H ₃); 2.18 (s, 3H, C H ₃); 2.79 (d, J=3.0 Hz, 1H, H CCO₂); 4.06 (q, J=7.5 Hz, 2H, OC H ₂); 4.18, 4.25 (dq, J=10.5, 7.5 Hz, 1H each, OC H ₃), 4.50 (d, J=3.0Hz, 1H, ArC H ); 4.84 (bs, 1H, N H ); 6.79 (d, J=8.0Hz, 1H, ArH); 6.84 (dt, J=1.0, 8.0 Hz, 1H, ArH); 7.06 (dt, J-10, 8.0 Hz, H, ArH); 7.34 (dd, J=1.0, 8.0 Hz, 1H, Ar H ). m.p. 100-102°C. 'H NMR (360 MHz, CDCl₃) δ=1.19 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.36 (s, 6H, C H ₃); 4.12 (bm, 4H, OC H ₂); 5.09 (s, 1H, ArC H ); 5.78 (bs, 1H, N H ); 6.79 (t, J=7.5 Hz, 1H, Ar H ); 6.88 (d, J=7.5 Hz, 1H, Ar H ); 7.04 (d, J=7.5 Hz, 1H, Ar H ); 7.06 (t, J=8.0 Hz, 1H, Ar H ); 8.72 (s, 1H, O- H ). m.p. 165-9°C. EXAMPLE 4 Diethyl 8,10-dichloro-3,6-dihydro-2,4-dimethyl-2,6-methano-2H-1,3-benzoxazocine-5,11-dicarboxylate (31&32) The same procedure was used as in Example 1 to obtain compounds 31 and 32 . Lactone : 'H NMR (360 MHz, CDCl₃) δ=1.20 (t, J=7.5 Hz, 3H, CH₂C H ₃); 2.14, 2.37 (s, 3H each, C H ₃); 4.13, 4.27 (dq, J=7.5, 10.0 Hz, 1H each, OC H ₂); 4.88 (s, 1H, ArC H ); 5.83 (bs, 1H, N- N ); 6.72, 7.27 (m, 1H each, Ar H ). IR (KBr) =1680 cm⁻¹ Phenol : 'H NMR (360 MHz, CDCl₃) δ=1.21 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.38 (s, 6H, C H ₃); 4.14 (m, 4H, OC H ₂); 5.08 (s, 1H, ArC H ); 5.81 (bs, 1H, N- H ); 6.85 (d, J=3.0 Hz, 1H, Ar- H ); 7.16 (d, J=3.0 Hz, 1H, Ar H ); 9.31 (s, 1H, O H ). m.p. 178-9°C. Fast :'H NMR (360 MHz, CDCl₃/DMSO (3/1)) δ=1.23, 1.34 (t, J=7.5 Hz, 3H each, CH=C H ₃); 1.94 (s, 3H, OCC H ₃); 2.21 (s, 3H, C H ₃); 2.91 (dd, J=3.0, 0.8 Hz, 1H, H CCO₂); 4.04-4.28 (m, 4H, OCH₂); 4.55 (d, J=3.0 Hz, 1H, ArC H ); 7.03 (bs, 1H, N- H ); 7.09 (d, J=3.0 Hz, 1H, Ar H ); 7.25 (d, J=3.0 Hz, 1H, Ar H ). m.p. 190-2°C. Slow : 'H NMR (360 MHz, CDCl₃ δ=1.15, 1.37 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.91 (s, 3H, OCC H ₃); 2.21 (s, 3H, C H ₃); 2.83 (d, J=3.0, 1H, H CCO₂); 4.09 (q, J=7.5 Hz, 2H, OC H ₂); 4.17, 4.28 (dq, J-7.5, 11.0 Hz, 1H each, OC H ₂); 4.46 (d, J=3.0 Hz, 1H, ArC H ); 4.96 (bs, 1H, N H ); 7.13 (d, J=3.0 Hz, 1H, Ar H ); 7.26 (d, J=3.0 Hz, 1H, Ar H ). m.p. 199-203°C. EXAMPLE 5 Diethyl 3,6-dihydro-2,4-dimethyl-2,6-methano-2H-1,3-benzothiazocine-5,11-dicarboxylate (36&37) Step 1: Diethyl 1,4-dihydro-2,6-dimethyl-4-[2-(methylsulfinyl)-phenyl]-3,5-pyridinedicarboxylate (34) A solution of 1.092 g (2.91 mm) of diethyl-2,6-dimethyl-4-(2-methylthiophenyl)-1,4-dihydropyridine-3,5-dicarboxylate in 35 mL of dry CH₂Cl₂ was stirred at -78°C under Ar and treated with 650 mg (3.20 mm) of m -chloroperbenzoic acid. After 1 hour the reaction was diluted with CH₂Cl₂ (150 mL) and washed with 10% aqueous sodium thiosulfate, H₂O, and brine, dried (anhydrous MgSO₄), filtered and concentrated to give 1.10 g of crude sulfoxide (100%) used without purification for the following step. Analytical sample was obtained by crystallization from MeOH, m.p. 232-3°C. Diethyl-1,4-dihydro-2,6-dimethyl-4-(2-(methylsulfinyl)phenyl)-3,5-pyridinedicarboxylate 'H NMR (360 MHz, CDCl₃) δ=1.20, 1.22 (t, J=7.5 Hz, 3H, CH₂C H ₃); 2.30, 2.32 (s, 3H each, C H ₃); 2.82 (s, 3H, S(O)C H ₃); 4.00-4.24 (m, 4H, C H ₂CH₃); 5.45 (s, 1H, ArC H ); 5.91 (bs, 1Hz, N H ); 7.38 (m, 3H, Ar H ); 8.00 (m, 1H, Ar H ). m.p. 232-3°C. Step 2: Diethyl-4-[2-[[(acetyloxy)methyl]thio]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (35) A suspension of 3.31 g (8.46 mm) of sulfoxide and NaOAc (anhydrous, 1.10 g) in 9.1 mL of acetic-anhydride was stirred at reflux for 40 minutes. The acetic anhydride was removed at reduced pressure, and the residue diluted with 250 mL of CH₂Cl₂ and 50 mL of H₂O. The organic portion was washed with 10% aqueous HCl, 5% aqueous NaHCO₃, and brine, dried (anhydrous MgSO₄), filtered, evaporated, and flash chromatographed (silica gel, 30% EtOAc in hexane) to give acetate (1.60 g, 44%). An analytical sample was obtained by recrystallization from ether/hexane. 35 'H NMR (360 MHz, CDCl₃) δ=1.19 (t, J=7.0 Hz, 6H, CH₂C H ₃); 2.14 (s, 3H, C H ₃C(O)); 2.28 (s, 6H, C H ₃); 3.99-4.14 (m, 4H, OC H ₂); 5.40 (s, 2H, C(O)C H ₂S); 5.42 (s, 1H, ArC H ); 5.56 (bs, 1H, N H ); 7.13 (dq, J=2.0, 7.5 Hz, 1H, Ar H ); 7.14 (dq, J=2.0, 7.5 Hz, 1H, ArH); 7.37 (dd, J=7.5, 2.0 Hz, 1H, Ar H ); 7.49 (dd, J=7.5, 2.0 Hz, 1H, Ar H ). m.p. 117-118°C. Step 3: Diethyl-3,6-dihydro-2,4-dimethyl-2,6-methano-2H-1,3-benzothiazocine-5,11-dicarboxylate (36&37) An absolute ethanol (30 mL) solution of 1.00 g (2.31 mm) of was degassed with Ar and treated with anhydrous K₂CO₃ (2.20 g). After 3 hours of stirring under Ar, saturated aqueous NH₄Cl was added and the mixture extracted with CH₂Cl₂. The organic portions were washed with H₂O and brine, dried (anhydrous MgSO₄), filtered and concentrated. Flash chromatography (silica gel, 2.5% acetone in CH₂Cl₂) separated the two diastereomers which crystallized from ether/hexane. 36 (isomer A) Fast : 'H NMR (360 MHz, CDCl₃) δ=1.03 (t, J=7.0 Hz, 3H, CH₂C H ₃); 1.33 (t, J=7.0 Hz, 3H, CH₂C H ₃); 1.96 (s, 3H, SCC H ₃); 2.23 (s, 3H, C H ₃); 2.96 (d, J=4.5 Hz, 1H, H CCO₂); 3.90-4.25 9m, 4H, OCH₂); 4.64 (bs, 1H, N- H ); 4.67 (d, J=4.9 Hz, 1H, ArC H ); 6.92-7.05 (m, 3H, Ar H ); 7.44 (dd, J=7.5, 1.0 Hz, 1H, Ar H ). 37 (isomer B) Slow : 'H NMR (360 MHz, CDCl₃) δ=1.26, 1.32 (t, J=7.5 Hz, 3H each, OCH₂C H ₃); 1.90 (s, 3H, SCC H ₃); 2.24 (s, 3H, C H ₃); 3.02 (dd, J=1.5, 1.7 Hz; H CCO₂); 4.18-4.24 (m, 4H, OC H ₂); 4.55 (bs, 1H, ArC H ); 4.75 (bs, 1H, N- H ); 7.01 (m, 3H, ArH); 7.50 (d, J=8.0 Hz, 1H, ArH). m.p. 147-148.5°C. EXAMPLE 6 Diethyl 1,3,4,7-tetrahydro-3,5-dimethyl-3,7-methano-2,4-benzothiazonine-6,12-dicarboxylate (42&43) Step 1: Diethyl 4-[2-[(acetyl)thio]phenyl]-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxyate (41) A solution of 2.00 g (9.30 mm) of o -(a-bromomethyl)benzoic acid (Shawnee Chem.Co.) in 10 mL of dry THF was stirred under Ar at 0°C while 14.6 mL (14.6 mm) of 1.0M BH₃.THF was added dropwise. This mixture was stirred for 1.5 hours at 0°C, warmed to 25°C, and stirred an additional 0.5 hour. Water was added at 0°C to quench the reaction followed by saturated aqueous sodium potassium tartrate. After extraction with ethyl acetate, the organic portion was washed with H₂O and brine, dried (anhydrous MgSO₄), filtered and concentrated. The crude product was treated directly with anhydrous DMF (8 mL) and stirred while 1.42 g of potassium thioacetate was added. After 10 minutes at 25°C, H₂O was added and the mixture was extracted with ethyl acetate. The organic portion was dried (anhydrous MgSO₄), filtered, and evaporated to give crude alcohol (2.00 g). The crude alcohol was dissolved in 100 mL of CH₂Cl₂ and stirred with 6.00 g of activated MnO₂ for 5 days. Filtration through Celite® and evaporation afforded 1.40 g of aldehyde Aldehyde 'H NMR (90 MHz, CDCl₃) δ=2.25 (s, 3H, C H ₃ C(O)); 4.45 (s, 2H, C H ₂S); 7.00-7.90 (m, 4H, Ar H ); 10.15 (s, 1H, C H O). Alcohol Crude : 'H NMR (90 MHz, CDCl₃) δ=2.25 (s, 3H, C H ₃ C(O)); 4.15 (s, 2H, SC H ₂); 4.70 (s, 2H, C H ₂O); 5.4 (s, 1H, O H ); 7.0-9.2 (m, 4H, Ar H ). 1.40 Gram of aldehyde was refluxed in isopropyl alcohol (10 mL) with 930 mg of ethyl aminocrotonate and 930 mg of ethyl acetoacetate under Ar for 24 hours. This was concentrated and flash chromatographed (silica gel, 2.5% acetone in CH₂Cl₂) to give: 500 mg 'H NMR (90 MHz, CDCl₃), δ=1.20 (t, J=7.5 Hz, 6H, C H ₂CH₃), 2.30 (s, 6H, C H ₃CN); 2.39 (s, 3H, C H ₃ C(O)); 4.15 (q, J=7.5 Hz, 4H, OC H z); 4.55 (s, 2H, SC H ₂); 5.30 (s, 1H, ArC H ); 5.60 (bs, 1H, N H ; 7.00-7.40 (m, 4H, ArH). Step 2: Diethyl 1,3,4,7-tetrahydro-3,5-dimethyl-3,7-methano-2,4-benzothiazonine-6,12-dicarboxylate (42&43) A mixture of 5.20 g of dihyropyridine 15.0 g of anhydrous potassium carbonate, and 150 mL of degassed absolute ethanol was vigorously stirred under an Ar atmosphere for 12 hours. Saturated aqueous NH₄Cl was added, and the whole was extracted with ethylacetate. The organic portion was washed with H₂O, and brine, dried (anhydrous MgSO₄), filtered, and flash chromatographed (silica gel, 2% acetone in CH₂Cl₂) to afford and 'H NMR (360 MHz, CDCl₃) δ= 1.12, 1.27 (t, J=7.0 Hz, 3H each, CH₂- CH ₃); 1.57 (S, 3H, S-C-C H ); 2.45 (s, 3H, C H ₃); 3.33 (d, J=15.0 Hz, 1H, S-C H aHb); 3.47 (bs, 1H, H CO₂); 3.94 (m, 2H, OC H ₂); 4.17 (m, 2H, OCH₂); 4.24 (bs, 1H, ArC H ); 4.62 (bs, 1H, N H ); 4.73 (d, J=15.0 Hz, 1H, S-CHa H b); 6.95 (dd, J=1.0, 7.0 Hz, 1H, Ar H ); 7.08 (dt, J=1.0, 7.0 Hz, 1H, Ar H ); 7.16 (dt, J=1.0, 7.0 Hz, 1H, Ar H ); 7.33 (dd, J=1.0, 7.0 Hz, 1H, Ar H ). 43 'H NMR (360 MHz, CDCl₃) δ=1.14, 1.17 (t, J=7.0 Hz, 3H each, CH₂C H ₃); 1.69 (S, 3H, SCC H ₃); 2.42 (S, 3H, C H ₃); 3.18 (d, J=6.0 Hz, 1H, H CO₂); 3.27 (d, J=15.0 Hz, 1H, SC H aHb); 3.99 (M, 2H, C H ₂CH₃); 4.47 (bs, 1H, N- H ); 4.56 d, J=15.0 Hz, 1H, SCHa H b); 4.65 (d, 5=6.0 Hz, 1H, ArC H ); 6.94 (dd, J=1.0, 7.0 Hz, 1H, Ar H ); 7.04 (dt, J=1,0, 7.0 Hz, 1H, Ar H ); 7.08 (dt, J=1,0, 7.0 Hz, 1H, Ar H ); 7.27 (dd, J=1.0, 7.0 Hz, 1H, Ar H ). EXAMPLE 7 Diethyl 1,3,4,7-tetrahydro-3,5-dimethyl-8-(trifluoromethyl)-3,7-methano-2,4-benzothiazocine-6,12-dicarboxylate (47&48) STEP 1 : A cold (-78°C) anhydrous methylene chloride (90 mL) solution of nitrile (28.0 g, 86.6 mm) was stirred while 87 mL of 1.0 M diisobutylaluminum hydride in Hexane (87 mm) was added dropwise over 15 minutes. This was stirred an additional 1.0 h at -78°C then allowed to reach 25°C. The mixture was recooled to -78°C and treated with 20 mL of methanol and 50 mL of saturated sodium potassium tartrate. After warming to 25°C, ethyl acetate was added and the mixture was stirred while 2.4 N HCl was added to acidify the aqueous layer. After stirring for 1 hour at room temperature, the organic portion was separated and the aqueous portion was extracted with ethyl acetate. The combined organic portions were washed with H₂O, and brine, dried (anhydrous MgSO₄), filtered and concentrated. The oil crystalized from ether/hexane (1/1) to afford 26.0 grams of a white solid (92%). a-(4methoxy-a-toluenylthio)-5-(trifluoromethyl)benzaldehyde: 1H NMR (90 MHz, CDCl₃) δ=3.75 (S, 3H, OC H ₃); 4.12 (S, 2H, SC H ₂), 6.7-8.0 (multiplets, 7H, Ar H ); 10.15 (S, 1H, C H O). STEP 2 : 23.1 g (70.8 mm) of aldehyde 9.20 g of methyl acetoacetate and 9.20 g of ethylaminocrotonate were refluxed in 30 mL of isopropylalcohol for 20 hours. After cooling to 25°C and evaporation of the solvents, a white solid precipitated from ether. This was washed with ether/hexane (1:1) to give 23.0 grams of diethyl-1,4-dihydro-4-(2-(4-methoxy-a-toluenylthio)5-(trifluoromethyl)phenyl)-2,6-dimethlyl-3,5-pyridine dicarboxylate 'H NMR (90 MHz, CDCl₃) δ 1.15 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.18 (S, 6H, pyr.-C H ₃); 3.70 (S, 3H, OC H ₃); 3.95 (q, J=7.5 Hz, 4H, OC H ₂); 4.05 (S, 2H, SC H ₂); 5.35 (S, 1H, Aryl. C H ); 5.73 (bs, 1H, N-H); 6.70-7.50 (m, 7H, Ar-H). STEP 3 : A solution of 2.20 grams of was dissolved in 10 mL of anisole and degassed with Ar for 15 minutes. This was stirred while 10 mL of trifluoroacetic acid was added dropwise over 2 minutes at 25°C. After 15 minutes, the reaction was complete and the mixture diluted with CH₂Cl₂ and washed with H₂O, and saturated aqueous NaHCO₃, dried (anhydrous MgSO₄), filtered and concentrated. The two diastereomers formed were separated by flash chromatography (silica gel, CH₂Cl₂, then 2.5% acetone in CH₂Cl₂). After concentration of appropriate fractions the pure diastereomers were crystallized from ether/hexane to afford the and isomers. Yield: 500 mgs of the fast diastereomer 350 mgs of the slow diastereomer and 1.00 gr of a mixture of and 'H NMR (CDCl₃), 360 mHz) δ=1.01 and 1.35 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.97 (S, 3H, S-C-C H ₃); 2.25 (S, 3H, CC H ₃); 3.00 (d, J=4.5 Hz, 1H, H CCOz); 3.92-4.27 (m, 4H, OC H ₂); 4.68 (d, J=4.5 Hz, 1H, ArC H ); 4.72 (bs, 1H, N- H ); 7.13 (d, J=7.5 Hz, 1H, ArH); 7.24 (dd, J=7.5 Hz, 1.5H, 1H, ArH); 7.69 (d, J=1.5 Hz, 1H, ArH). 48 1H NMR (CDCl₃, 360 MHz) δ=1.27 and 1.34 (t, J=6.0 Hz, 3H each, CH₂C H ₃); 1.93 (S, 3H, SCC H ₃); 2.27 (S, 3H, C H ₃); 2.97 (dd, J=3.0, 1.5 Hz, 1H, H CCO₂); 4.07-4.27 (m, 4H, OC H ₂); 4.58 (bs, 1H, ArC H ); 4.83 (bs, 1H, N H ); 7.13 (d, J=7.5 Hz, 1H, ArH; 7.27 (dd, J=7.5, 1.5 Hz, 1H, ArH); 7.76 (d, =1.5 Hz, 1H, ArH). EXAMPLE 8 Diethyl 1,3,4,7-tetrahydro-3,5-dimethyl-8-nitro-3,7-methano-2,4-benzothiazocine-6,12-dicarboxylate (53&54) STEP 1 : A solution of 0.84 g of p -methoxy-a-toluenethiol (5.45 mm) in 15 mL of degassed methanol cooled to 0°C was stirred while 393 mg of sodium methoxide was added. After stirring for 10 minutes, 1.03 g (5.64 mm) of 2-chloro-5-nitrobenzonitrile was added in one portion and this was allowed to stir for 1 hour at 0°C, then 2 hours at 25°C. This mixture was then diluted with H₂O (60 mL) and stirred 5 minutes. The solid precipitate that formed was collected by filtration and washed with H₂O. This was dried at 80°C (1 mm - 1.33 mbar) for 12 hours from which was removed by sublimation. The remaining yellow solid, 2-(4-methoxy-a-toluenethio)-5-nitro-benzo-nitrile (1.40 g, 77% yield) was used without further purification for the next step. 50 1H NMR (90 MHz, CDCl₃) δ=3.80 (S, 3H, OC H ₃); 4.30 (S, 2H, SC H ₂); 6.80-7.60 (m, 5H, ArH); 8.30 (dd, J=3.0, 9.0 Hz, 1H, ArH); 8.45 (d, J=3.0 Hz, 1H, ArH). STEP 2 : Nitrile was reduced in the same manner as compound (Example 7) to give aldehyde as a yellow solid in 65% yield. 2-(4-methoxy-a-toluenethio)-5-nitrobenzaldehyde: 'H NMR (90 MHz, CDCl₃) δ=3.80 (S, 3H, OC H ₃); 4.30 (S, 2H, SC H ₂); 6.90 (d, J=8.0 Hz, 2H, Ar H ); 7.39 (d, J=8.0 Hz, 2H, Ar H ); 7.58 (d, J=9.0 Hz, 1H, Ar H ); 8.32 (dd, J=9.0, 3.0 Hz, 1H, Ar H ); 8.68 (d, J=3.0 Hz, 1H, ArH); 10.38 (S, 1H, C H O). STEP 3 : Aldehyde was condensed in a similar manner to compound (Example 7) to provide dihydropyridine after crystalization from ether/hexane/CH₂Cl₂ in 50% yield. diethyl 1,4-dihydro-4-(2-(4-methoxy-a-toluenylthio)-5-nitrophenyl)-2,b-dimethyl-3,5-pyridinedicarboxylate: 'H NMR (70 MHz, CDCl₃): δ=1.10 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.22 (S, 6H, C H ₃); 6.77 (S, 3H, CC H ₃); 4.03 (q, J=7.5 Hz, 4H, OC H ₂); 4.14 (S, 2H, SC H ₂); 5.40 (S, 1H, ArC H ); 5.68 (bs, 1H, N H ); 7.79 (d, J=8.0 Hz, 2H, Ar H ); 7.23 (m, 3H, Ar H ); 7.81 (dd, J=3.0, 9.0 Hz, 1H, Ar H ); 8.08 (d, J=3.0 Hz, 1H, ArH). STEP 4 : 5.4 grams of dihydropyridine was treated similarly to dihydropyridine (Example 7) to provide two diastereomeric benzothiazocines and which were separated by flash chromatography (silica gel, 2.5% acetone in methylene chloride) to give, after crystalization, the isomers and 'H NMR (360 MHz, CDCl₃) δ=1.07 and 1.41 (t, J=7.5 Hz) 3H each, CH₂C H ₃); 1.98 (S, 3H, SCC H ₃); 2.26 (S, 3H, C H ₃); 3.05 (d, J=4.5 Hz, 1H, HCCO₂); 3.90-4.30 (m, 4H, OC H ₂); 4.73 (d, J=4.5 Hz, 1H, ArC H ); 4.77 (bs, 1H, N H ); 7.16 (d, J=9.0 Hz, 1H, ArH); 7.88 (dd, J=3.0, 9.0 Hz) 1H, ArH); 8.33 (d, J=3.0 Hz, 1H, Ar H ). 'H NMR (360 MHz, CDCl₃) δ=1.28, 1.39 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.96 (S, 3H, SCC H ₃); 2.28 (S, 3H, C H ₃); 2.96 (dd, J=2.0, 1.5 Hz, 1H, H CCO₂); 4.09-4.28 (m, 4H, OC H ₂); 4.64 (bs, 1H, ArC H ); 4.87 (bs, 1H, N H ); 7.15 (d, J=9.0 Hz, 1H, Ar H ); 7.90 (dd, J=3.0, 9.0 Hz, 1H, Ar H ); 8.38 (d, J=3.0 Hz, 1H, Ar H ). EXAMPLE 9 Dimethyl 8-(2,4-difluorophenyl)-3,6-dihydro-2,4-dimethyl-2,6-methano-2H-1,3-benzoxazocine-5,11-dicarboxylate (61&62) STEP 1 : A solution of 2', 4'-difluoro-4-hydroxy (1,1'-biphenyl)-3-carboxylic acid (1.00 g, 4.00 mm) in 8 mL of dimethylformamide was stirred at 25°C and treated with 5.52 g (40.00 mm) of powdered potassium carbonate and 1.2 mL of benzyl bromide (10.0 mm). After 24 hours, the mixture was diluted with H₂O and extracted with ethyl acetate. The organic portion was washed with H₂O and brine, dried (anhydrous MgSO₄), filtered and evaporated to yield, after crystallization from ether/hexane, 1.50 g of as a white solid (81%). 56 benzyl 2',4'-difluoro-4-benzyloxy(1,1'-biphenyl) -3-carboxylate. 'H NMR (90 MHz, CDCl₃) δ=5.20 (S, 2H, OC H ₂); 5.40 (S, 2H, O C H ₂); 6.8-7.2 (m, 15 H, Ar H ); 7.97 (m, 1H, ArH). STEP 2 : (7.25 g, 16.86 mm) was dissolved in 125 mL of anhydrous tetrahydrofuran and diethyl ether (1/3), stirred at 0°C under Ar, and treated with lithium aluminum hydride (641 mg, 16.86 mm). After 1 hour the reaction was quenched with 10% aqueous tetrahydrofuran and then dried (anhydrous MgSO₄), filtered and concentrated to give 5.25 g (92%) of a white solid after recrystallization from ether/hexane. 57 2-benzyloxy-5-(2,4-difluorophenyl)benzylalcohol: 'H NMR (90 MHz, CDC ) δ=2.27 (t, J=6.0 Hz, 1H, 0 H ); 4.82 (d, J=6.0 Hz, 2H, C H ₂OH); 5.18 (S, 2H, C H ₂); 6.70-6.90 (m, 3H, ArH); 7.40 (M, 8H, ArH). STEP 3 : A methylene chloride (200 mL) solution of alcohol 57 (5.25 g) was stirred with 15.0 g of activated MnO₂ for 60 hours at 25°C. After filtration and concentration aldehyde was obtained (3.20 g, 61%) as a white solid. 2',4'-difluoro-4-benzyloxy(1,1'-biphenyl)-3-carboxaldehyde. 'H NMR (90 MHz CDCl₃) δ=5.25 (S, 2H, OCH₂); 6.75-7.75 (m, 10H, Ar H ); 8.00 (d, J=3 Hz, 1H, Ar H ); 10.60 (S, 1H, C H O). m.p. 124.0-125.5°C. STEP 4 : 3.00 g of was condensed under similar conditions as aldehyde to give 3.00 g of dihydropyridine after recrystallization from ether/hexane. diethyl 1,4-dihydro-4-(2-benzyloxy-5-(2,4-difluorophenyl)phenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate: 'H NMR (90 MHz, CDCl₃) δ=1.10 (t, J=7.0 Hz, 6H, CH₂C H ₃); 2.05 (S, 6H, C H ₃); 4.03 (q, J=7.0 Hz, 4H, OC H ₂CH₃); 4.80 (bs, 1H, N H ); 5.00 (S, 2H, OC H ₂Ar); 5.25 (S, 1H, ArC H ); 6.90-7.50 (m, 11H, Ar H ). STEP 5 : An absolute ethanol solution of dihydropyridine 59 (2.66 g in 100 mL) was charged with 210 mg of 5% Pd on carbon and shaken under 1 Atm of H₂ for 4 days. This was filtered and concentrated to give the phenol (2.40 g). diethyl 1,4-dihydro-4-(5-(2,4-difluorophenyl)-2-hydroxyphenyl)-2,6-dimethyl-3,5-pyridine dicarboxylate: 1H NMR (90 MHz, CDCl₃) δ=1.20 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.35 (S, 6H, C H ₃); 4.10 (q, 5=7.5 Hz, 4H, OC H ₂); 5.15 (S, 1H, ArC H ); 6.10 (bs, 1H, NH); 6.70-7.45 (m, 6H, ArH); 9.05 (bs, 1H, O H ). STEP 6 : Phenol was treated in a similar manner to compound (Example 1) to give, after flash chromatography (silica gel, 2.5% acetone in methylenechloride) and concentration of appropriate fractions, the two title diastereomeric benzoxazocines 61 and 62 as white solids (from ether/hexane). 61 'H NMR (360 MHz, CDCl₂) δ=1.13, 1.33 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.88 (S, 3H, OCC H ₃); 2.21 (S, 3H, C H ₃); 2.83 (d, J=3 Hz, H CCO₂); 4.09 (q, J=7.5 Hz, 2H, OC H ₂); 4.10-4.30 (m, 2H, OC H ₂); 4.54 (d, J=3.0 Hz, 1H, ArC H ); 4.89 (bs, 1H, N H ); 6.87 (m, 3H, Ar H ); 7.22 (dt, J=8.0 Hz, 2.0 Hz, 1H, ArH); 7.36 (dt, J=7.0, 8.0 Hz, 1N, Ar H ); 7.53 (bs, 1H, Ar H ). 62 'H NMR (360 MHz, CDCl₃) δ=1.25, 1.32 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.93 (S, 3H, OCC H ₃); 2.24 (S, 3H, C H ₃); 3.00 (dd, J=3.0, 1.5 Hz, 1H, HCCO₂, collapses to doublet J=3.0 Hz upon irradiation at 4.97 ppm); 4.05-4.26 (m, 4H, OC H ₂); 4.64 (d, J=3.0 Hz, 1H, ArC H ); 4.97 (bs, 1H, N H ); 6.89 (m, 3H, ArH); 7.22 (dt, 5=8.0 Hz, 1.5 Hz, 1H, Ar H ); 7.35 (dt, J=7.0, 9.0 Hz, 1H, Ar H ); 7.53 (t, J=1.5 Hz, 1H, Ar H ). EXAMPLE 10 Diethyl 3,6-dihydro-2,4-dimethyl-10-nitro-2,6-methano-2H-1,3-benzothiazocine-5,11-dicarboxylate (68&69) STEP 1 : An anhydrous dimethylformamide (DMF) solution of p -methoxy-a-toluenethiol (1.86 mL in 15 mL of DMF) was cooled to 0°C under Ar and 106 mg (13.37 mm) of lithium hydride was added. This stirred suspension was warmed to 25°C for 20 minutes and then methyl 2-chloro-3-nitrobenzoate 63 was added in one portion. An exothermic reaction took place and was cooled to 0°C. The mixture was rewarmed to 25°C and stirred for 10 minutes, diluted with H₂O, and extracted with ethyl acetate. The organic portion was washed with H₂O and brine, dried (anhydrous MgSO₄), filtered, concentrated and flash chromatographed (silica gel, 50% ether in hexane). After concentration of appropriate fractions, 2.80 g (75%) of 64 as a yellow oil was obtained. 64 Methyl 2-( p -methoxy-a-toluenylthio)-3-nitrobenzoate: 1H NMR (90 MHz, CDCl₃) δ=3.73, 3.90 (S, 3H each) OC H ₃); 4.08 (S, 2H, SC H ₂); 6.7-7.8 (m, 7H, Ar H ). STEP 2 : The methyl benzoate 64 was treated similarly to compound (Example 7) with diisobutyl aluminum hydride at -78°C. The crude product 65 was isolated as a yellow oil in 96% yield. 2-( p -methoxy-a-toluenethio)-3-nitrobenzyl alcohol: 'H NMR (90 MHz, CDCl₃) δ=2.20 (bt, J=5.0 Hz, 1H, O H ); 3.74 (S, 3H, OC H ₃); 3.95 (S, 2H, SC H ₂); 4.63 (bd, J=5.0 Hz, 2H, OC H ₂); 6.68-7.70 (m, 7H, ArH). STEP 3 : Treatment of alcohol under conditions similar to alcohol (Example 9) gave an 80% yield of as a yellow solid from ether/hexane. 1-(p-methoxy-a-toluenethio)-2-nitrobenzaldehyde: 'H NMR (90 MHz, CDCl₃) δ=3.80 (S, 3H, OC H ₃); 4.00 (S, 2H, SC H ₂); 6.70-7.10 (m, 4H, Ar H ); 7.50-8.10 (m, 3H, Ar H ); 10.20 (s, 1H, C H O). m.p. 95.0-97.5°C. STEP 4 : Dihydropyridine 67 was obtained from aldehyde by the same conditions as used for dihydropyridine (Example 9). 67 crystallized from ether/hexane as a yellow solid. Diethyl 1,4-dihydro-4-(2-(((4-methoxyphenyl) methyl)thio)-3-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate: 'H NMR (360 MHz, CDCl₃) δ=1.17 (t, J=7.5 Hz, 6H, CH₂C H ₃); 2.27 (S, 6H, C H ₃); 3.80 (S, 3H, OC H ₃); 4.07 (S, 2H, SC H ₂); 4.08 (m, 4H, OC H ₂); 5.59 (bs, 1H, NH); 5.81 (S, 1H, ArC H ); 6.84 (d, J=8.0 Hz, 2H, ArH); 7.33 (d, J=8.0 Hz, 2H, ArH); 7.34 (m, zH, ArH); 7.62 (dd, J=7.5, 1.5 Hz, 1H, Ar H ). STEP 5 : Dihydro pyridine 67 was reacted under conditions similar to dihydropyridine 52 (Example 8) to give the two benzothiazocine diastereomers and 69 which were separated by flash chromatography (silica gel, 2.5% acetone in methylene chloride) and crystalized from ether/hexane. 68 'H NMR (360 MHz, CDCl₃) δ=1.05, 1.31 (t, J=7.5 Hz, 3H each, CH₂C H ₃); 1.96 (S, 3H, SCC H ₃); 2.24 (S, 3H, C H ₃); 3.01 (d, J=4.0 Hz, 1H, H CCO₂); 4.01 (q, J=7.5 Hz, 2H, OC H ₂); 4.07-4.25 (m, 2H, OC H ₂); 4.77 (d, J=4.0 Hz, 1H, ArC H ); 4.80 (6S, 1H, N H ); 7.11 (t, J=7.5 Hz, 1H, ArH); 7.76 (dd, J=7.5 Hz, 1.5 Hz, 1H, ArH); 8.07 (dd, J=7.5, 1.5 Hz, 1H, Ar H ). 69 'H NMR (360 MHz, CDCl₃) δ=1.27, 1.30 (t, J-7.5Hz, 3H each, CH₂ CH ₃); 1.95 (s, 3H, SCC H ₃); 2.26 (s, 3H, C H ₃); 2.92 (t, J-1.5Hz, 1H, H CCO₂); 4.05-4.25 (m, 4H, OC H ₂); 4.68 (bs, 1H, ArC H ); 4.68 (bs, 1H, N H ); 7.14 (t, J=9.0Hz, 1H, ArH); 7.82 (d, J=9.0Hz, 1H, ArH); 8.07 (d, J=9.0Hz, 1H, ArH). EXAMPLE 11 Diethyl 3,6-dihydro-2,4-dimethyl-10-nitro-2,6-methano-2H-1,3-benzoxazocine-5,11-dicarboxylate (74&75) Step 1 : A mixture of (16.7 g, 0.1 mole), pulverized potassium carbonate (13.8 g, 0.1 mole), and benzyl bromide (48 ml, 0.4 mole) in DMF (100 ml) was stirred overnight at room temperature. H₂O was added and the separated solid was filtered off and washed with H₂O, then with ether and dried to yield 16.2 g (63%) of Compound was condensed under similar conditions to give the dihydropyridine 'H NMR (90 MHz, CDCl₃): δ 5.2 (s, 2H, -O CH ₂); 7.4 (s, 5H, C ₆ H ₅); 7.4 (m, 1H, Ar H ); 8.0-8.2 (m, 2H, Ar H ), 10.25 (s, 1H, - CH O). 'H NMR (360 MHz, CDCl₃): δ 1.13 (t, J-7.5Hz, 6H, -CH₂ CH ₃); 2.17 (s, 6H, - CH ₃); 3.95-4.08 (m, 4H, - CH ₂CH₃); 4.97 (s, 2H, - CH ₂); 5.2 (bs, 1H, - NH ); 5.35 (s, 1H, Ar CH ); 7.08 (t, J=7.5Hz, 1H, Ar H ); 7.3-7.4 (m, 3H, Ar H ); 7.52 (bd, 2H, Ar H ); 7.58 (dd, J=1.5, 7.5Hz, 1H, Ar H ); 7.69 (dd, J=1.5, 7.5Hz, 1H, Ar H ). M.p. 147-149°C. Step 2 : Anisole (5 ml) was degassed and then (2 g) was added. The reaction mixture was protected from light and stirred under nitrogen and trifluoroacetic acid (5 ml) was added. The resulting yellow solution was stirred at room temperature for 15 minutes, a saturated solution of NaHCO₃ (5 ml) was added, and the mixture extracted with CH₂Cl₂. The extract was dried (Na₂SO₄), filtered and concentrated in vacuo to yield an oil which was a mixture of Flash chromatography (silica gel, 1:1 ether-hexane) separated from the mixture of A solution of in CHCl₃ containing a catalytic amount of dl-10-camphorsulfonic acid was stirred at room temperature for 15 minutes and then concentrated in vacuo . The residue, which contained a mixture of was chromatographed, and the recovered was again reacted. This procedure provided a sufficient quantity of and to be obtained for separation and purification. The mixture of was flash chromatographed (silica gel, 1:1 ether-hexane) to yield as a yellow solid (from ether) and as a yellow solid (from ether). An analytical sample of was obtained from ether. 'H NMR (360 MHz, CDCl₃): δ 1.19 (t, J=7.5Hz, 6H, -CH₂ CH ₃); 2.32 (s, 6H, - CH ₃); 4.0-4.15 (m, 4H, - CH ₂CH₃); 5.35 (s, 1H, Ar CH ); 5.67 (bs, 1H, -N H ); 6.85 (t, J=7.5Hz, 1H, Ar H ); 7.6 (dd, J=1.5, 9Hz, 1H, Ar H ); 7.95 (dd, J=1.5, 9Hz, 1H, Ar H ). m.p. 150-151°C. (Fast isomer) 'H NMR (360 MHz, CDCl₃) : δ 1.25, 1.35 (t, J=7.5Hz, 3H each, -CH₂ CH ₃); 1.98 (s, 3H, -OCC H ₃); 2.23 (s, 3H, - CH ₃); 2.97 (dd, J=3.0, 1.5Hz, 1H, CH CO₂); 4.07-4.26 (m, 4H, - CH ₂CH₃); 4.7 (d, J=3.0Hz, 1H, Ar CH ); 5.13 (bs, 1H, -N H ); 6.9 (t, J=7.5Hz, 1H, Ar H ); 7.6 (dd, J=1.5, 7.5Hz, 1H, Ar H ); 7.66 (dd, J=1.5, 7.5Hz, 1H, Ar H ). m.p. 130-139°C. (Slow isomer) 'H NMR (360 MHz, CDCl₃): δ 1.11, 1.35 (t, J=7.5Hz, 3H each, -CH₂ CH ₃); 1.9 (s, 3H, OC CH ₃); 2.21 (s, 3H, - CH ₃); 2.87 (d, J=3.0Hz, 1H, CHCO₂); 4.05-4.28 (m, 4H, - CH ₂CH₃); 4.55 (d, J=3.0Hz, 1H, Ar CH ); 5.04 (bs, 1H, -N H ); 6.9 (t, J=7.5Hz, 1H, Ar H ); 7.58 (dd, J=1.5, 7.5Hz, 1H, Ar H ); 7.66 (dd, J=1.5, 7.5Hz, 1H, Ar H ). m.p. 168-169°C. EXAMPLE 12 Diethyl 3,6-dihydro-2,4-dimethyl-9-nitro-2,6-methano-2H-1,3-benzoxazocine-5,11-dicarboxylate (77&78) Phenol was prepared in a similar fashion to phenol (Example 1). 'H NMR (90 MHz, CDCl₃): δ 1.2 (t, J=7.5Hz, 6H, -CH₂ CH ₃); 2.35 (s, 6H, - CH ₃); 4.1 (q, J=7.5Hz, 4H, - CH ₂CH₃); 5.1 (s, 1H, Ar CH ); 6.2 (bs, 1H, NH ); 7.1-7.7 (m, 3H, Ar H ); 9.4 (bs, 1H, - OH ). Benzoxazocines 77 and 78 were prepared simarlarly to and (Example 1). 77 Fast isomer 'H NMR (360 MHz, CDCl₃): δ 1.25, 1.35 (t, J=7.5Hz, 3H each, -CH₂ CH ₃); 1.93 (s, 3H, OC CH ₃); 2.22 (s, 3H, - CH ₃); 2.95 (dd, J=1.5, 3.0Hz, 1H, CH CO₂); 4.07-4.26 (m, 4H, - CH ₂CH₃); 4.7 (d, J=3.0Hz, 1H, Ar CH ); 5.05 (bs, 1H, - NH ), 7.5 (d, J=9.0Hz, 1H, Ar H ); 7.65 (d, J=3.0Hz, 1H, Ar H ), 7.7 (dd, J=3.0, 9.0Hz, 1H, Ar H ). m.p. 144-147°C. Slow isomer 'H NMR (360 MHz, CDCl₃): δ 1.15, 1.35 (t, J=7.5Hz, 3H each, -CH₂ CH ₃); 1.87 (s, 3H, OC CH ₃); 2.2 (s, 3H, CH ₃); 2.87 (d, J=2Hz, 1H, CH CO₂); 3.85-4.1 (m, 4H, - CH ₂CH₃); 4.37 (d, J=2Hz, 1H, Ar CH ); 4.75 (bs, 1H, NH ); 7.5 (d, J=8Hz, 1H, Ar H ); 7.65 (d, J=2Hz, 1H, Ar H ); 7.73 (dd, J=2.0, 8.0Hz, 1H, Ar H ). m.p. broad, clear melt at 115°C. EXAMPLE 13 0.526 Grams of dihydropyridine in 3 mL of anhydrous tetrahydrofuran can be treated with 150 mg of lithium aluminum hydride at 0°C. This can then be warmed to 25°C and the amine isolated in the usual manner to give 300 mg of EXAMPLE 14 0.500 Grams of amine can be treated using the general procedure with nitrous acid to generate the diazonium salt and this salt can be used for further transformation. EXAMPLE 15 0.40 Grams of diazonium salt can be treated with 0.33 g of tetrafluoroboric acid diethyl ether complex and the precipitate collected and heated to give, after the usual isolation, fluorodihydropyridine 82 (0.15 g). EXAMPLE 16 0.30 Grams of diazonium salt can be treated with 0.50 g of copper (I) cyanide to give, after the usual workup, nitrile (0.20 g). EXAMPLE 17 0.30 Grams of diazonium salt can be treated with sodium methylmercaptide (.2 g) which, when treated under usual conditions, will yield the methylthio dihydropyridine (0.10 g). EXAMPLE 18 1.00 Gram of compound (Example 1) can be treated with 5% Pd on charcoal under an atmosphere of hydrogen in ethanol to produce dihydropyridine (0.90 g) which can be isolated in the usual manner. EXAMPLE 19 Dihydropyridine (0.50 g) can be diazotized in a manner similar to (Example 1) to give the diazonium species which can then be treated with sodium n -butylmercaptide to give dihydropyridine EXAMPLE 20 Dihydropyridine can be oxidized with metachloroperbenzoic acid in CH₂Cl₂ to give mixtures of sulfoxide and sulfone Compounds and can then be separated from each other by chromatography on silica gel. The known iodide (10.0 g) can be treated with 10 g of potassium cyanide in 100 mL of DMF followed by 0.87 g of 18-crown-6 for 20 hours and extracted into ether. After usual isolation procedures, the nitrile can be isolated (6.0 g). Nitrile (6.0 g) can be treated with 9.40 g of zinc dust and 12.6 mL of ethyl bromo acetate in 130 mL of tetrahydrofuran for one hour at reflux to give, after usual workup, amino-crotonate (8.00 g). Compound (8.0 g) can be refluxed with 4.40 g of in isopropyl alcohol for 12 hours to give dihydropyridine (3.80 g). Dihydropyridine (3.0 g) can be treated with 10 mL of 1.0 molar ( n Bu)₄NF in tetrahydrofuran at 25°C for 1.5 hours to give, after isolation, diol EXAMPLE 22 Aldehyde (3.0 g), 3.0 g of ethyl acetate, and 10 mL of 40% methylamine in H₂O can be refluxed in 10 mL of isopropanol for 12 hours. After usual isolation procedure, dihydropyridine can be obtained (1.50 g). EXAMPLE 23 Following the procedure of Example 22, benzyl amine can be used to obtain N-benzyldihydropyridine EXAMPLE 24 Dihydropyridine can be prepared from the acetoacetate using conditions outlined in the literature ( Chem. Pharm. Bull. 27 (6) 1426-1440 (1979)). EXAMPLE 25 Dihydropyridine can be used to prepare both dl pairs of diastereomers by treatment with trifluoroacetic acid in anisole. Following the methods shown and described in the Reaction Schemes and using the procedures set forth in the Examples, additional compounds of Formula 1 can be prepared as set forth in Table I below: TABLE I Additional Compounds of Formula 1

Claims: A compound having the formula wherein: R is hydrogen; C₁-C₈ straight chain or branched alkyl; benzyl; R¹ and R⁴ are independently hydrogen; straight chain or branched, saturated hydrocarbon having up to 8 carbon atoms; hydroxy-C₁-C₈-alkyl; C₃-C₈ cycloalkyl; CO₂-loweralkyl of C₁-C₈ R² and R³ are independently straight chain or branched, saturated or unsaturated hydrocarbon having up to 8 carbon atoms; C₃-C₈ cycloalkyl; C₂-C₈ alkyl interrupted by 1 to 2 oxygen atoms or substituted with NR⁵R⁶ wherein R⁵ and R⁶ can independently be hydrogen, C₁-C₈ alkyl, aralkyl wherein the alkyl group has up to 8 carbon atoms and the aryl has 6 carbon atoms, or R⁵ and R⁶ together with the N atom can be joined to form a 5- or 6-membered ring wherein the 6-membered ring can contain an O or N heteroatom and the N heteroatom can be substituted with C₁-C₆ alkyl;; X, W, Z and U can independently be: hydrogen; phenyl and substituted phenyl wherein the substituents can be 1-2 halo atoms; halo; NO₂; trifluoromethyl; C₁-C₈ alkoxy; C₁-C₈ linear or branched alkyl, linear or branched alkenyl or alkynyl having up to 8 carbon atoms; C₁-C₈ thioalkyl wherein the S atom can be substituted with 1-2 O atoms; cyano; NH₂; wherein R⁷ is C₁-C₈ alkoxy or C₁-C₈ alkyl; provided that two of X, W, Z and U are hydrogen; or, X and W, W and Z, or Z and U, together with the phenyl ring form naphthyl or benzooxadiazole rings; Y is O; S; SO; n is 0 or 1; and, the pharmaceutically acceptable acid addition salts thereof; with the proviso that X cannot be C₁-C₈ alkoxy or C₂-C₈ alkenyl. The compound of claim 1 wherein: R is hydrogen; R¹ and R⁴ are independently C₁₋₈ alkyl; R² and R³ are independently C₁₋₈ alkyl which can be substituted with NR⁵R⁶ wherein R⁵ and R⁶ are as defined in Claim 1; X is hydrogen or halo; U and W can each be NO₂; CF₃; or halo; Z is hydrogen; Y is O; S; and, n is 0 or 1. The compound of claim 1 wherein: R is hydrogen; R¹ and R⁴ are methyl R² and R³ are C₁-C₄ alkyl; X is hydrogen or halo; U and W can each be NO₂; CF₃; or halo; Z is hydrogen; Y is S; and, n is 0 or 1. A compound having the formula: wherein R-R⁴, X, W, Z and U are as defined in Claim 1; and, R¹¹ is C₁-C₈ loweralkyl. A pharmaceutical composition useful for providing a cardiotonic effect, a vasodilating effect, an antiarrhythmic action on cardiac muscle, vascular spasmolytic action, antihypertensive effect, spasmolytic action on the smooth muscle of the gastrointestinal and urogenital tracts and the respiratory system, cerebral and peripheral circulation and protecting ischemic myocardium which composition consists essentially of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of Claim 1. The composition of Claim 5 wherein said pharmaceutical composition includes an additional pharmaceutical agent selected from the group, an angiotensin converting enzyme inhibitor, an anti-hypertensive, a diuretic, a β-blocker, and a cardiotonic agent as well as admixtures and combinations thereof. The composition of Claim 6 wherein said additional pharmaceutical agent is selected from the group: enalapril, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, timolol, and digitalis.

Inventors: CLAREMON, DAVID A.
Applicants: MERCK & CO. INC.
Application year: 1985
Main classification: C07D495
IPC codes: C07D211, C07D495, C07C45, A61P9, C07D335, C07D493, A61K31, C07D491, C07F7