IE55337B1 - Dihydropyridyl cyclic imidate esters - Google Patents

Description

5 3 3 7 This invention relates to dibydrogycidyl cyclic imidate esters processes Bar preparing them, pharmaceutical oppositions containing than, and their use.

The heterocyclic carbon cxarpcunds of the present invention 5 are cyclic imidate esters linked directly to the 5- position of substituted 1,4-dihydrcpyridine moieties and these ocnpounds possess bio-affecting properties.

A substantial body of prior art has evolved over the last H (1) decade involving compounds of 4-aryl-1,4-dihydropyridine series which io have calcium antagonist properties and are useful in the treatment of cardiovascular diseases. These calcium blocking effects appear to mediate vasodilation which makes these compounds useful in treating angina and hypertension. These structures are typified by nifedipine (Formula 1); 15 chemically, 4-(2'-nitrophenyl)-2,6-dimethyl-3,5-dicarbomethoxy-l,4-dihydropyridine. Nifedipine and some related 4-aryl-l,4-dihydropyridines are the subject of U.S. Patent No. 3,485,847 issued December 23, 1969. Numerous subsequent patents have been granted covering 1,4-dihydro-20 pyridines in which other substituent groups have been employed in the various ring positions of the dihydropyridine moiety. The structure of these later patented compounds which relate to the present invention can be represented by Formula 2.

H - 2 - (2) Bossert, et al, U.S. 3,488,359 patented Jan. 6, 1970 and 3,574,843 patented Apr. 13, 1971 disclose compounds where the variation 2 4 involves R and R being alkoxyalkyl groups.

Murakami, et al_, Ger. Offen. 2,407,115 disclose compounds ο 5 where R is a disubstituted ami noalkyl group.

Kojima, et al_, U.S. 4,220,649 patented September 2, 1980 2 disclose compounds in which R is a pyrrolidine ring.

Loev, et al_, U.S. 3,511,847 patented May 12, 1970 list 3 compounds having extensive variation in the nature of R . Also, the 2 4 10 carboxyl groups which bond to R and R are replaced by carbonyl groups in the disclosure but these compounds are not claimed nor is any preparative method given for their synthesis.

Teulon, et al, U.S. 4,096,270 patented June 20, 1978 disclose 3 dihydropyridines where R is a substituted pyridine moiety.

In summary, these and other earlier patented dihydropyridine compounds which relate to the instant invention can be represented by 12 4 5 Formula 2. In general, R , R , R , and R are alkyl groups or alkyl groups bearing miscellaneous substituents, e.g. amine, ether, mercapto 3 groups, etc. The nature of R varies extensively but useful cardio-20 vascular properties seem maximized when this group is an electron withdrawing aryl or heterocyclic moiety.

Meyers and Gabel reported in Heterocycles, Vol. 11, pages 133-138 (1978) a new synthesis of 1,4-dihydropyridines. This synthesis utilizes oxazolines as activating groups to facilitate organo metallic 25 addition to the pyridine ring to yield 1,4-dihydropyridines (Formula 3).

No utility was given for these compounds and they were usually converted to pyridines under mild oxidative conditions.

The present invention provides the compounds of Formula I and the acid addition salts of these substances. In the foregoing structural formula, the symbols R, R1, R2, R3, R4, R5, m, and n have the following meanings. R and are independently selected from hydrogen, C1-4 alkyl or alkoxy-C.^ alkyl groups; R2 is alkyl, phenyl, to or thienyl; R is cycloalkyl of 5 to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, hetaryl which is furanyl, indolyl, pyridyl, or thienyl, or aryl, which is phenyl, naphthyl, or substituted phenyl with the substituents selected frcm acetylamino, C^-Cj alkyl, C-j-C^ alkoxy, cyano, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethylsulfonyl, and methylsulfonyl; is alkyl or C^_4 alkoxy-C^_^ alkyl, amino-C^^alkyl, halo-C^_^alkyl, 5 or ci-C^_^alkylamino-C^_^alkyl; R is alkyl or phenyl·;', m is 0 or 1; and n is 0, 1, or 2.

The compounds of the present invention can exist as optical isomers and both the racemates of these isomers and the individual racemic modifications themselves are within the scope of the present invention. The racemates can be separated into their individual isomers through well known techniques such as the separation of diastereomeric salts formed with optically active acids, followed by conversion back to the optically active bases.

For potential medical use, the pharmaceutically acceptable acid addition salts are preferred. The pharmaceutically acceptable acid addition salts are those salts in which the anion does not contribute significantly to the toxicity or pharmacological activity of the salt, and as such, they are the pharmacological equivalents of the bases having the foregoing structural formulae. The acid addition salts are obtained either by reaction of an organic base of structure I with an acid, preferably by contact in solution, or by any of the standard methods detailed in the literature and available to any practitioner skilled in the art.

The compounds of this invention were shown to be calcium ion channel blockers on the basis of in vitro pharmacologic testing. Currently, some calcium channel blocking agents are being extensively evaluated in patients with coronary heart disease due to the beneficial cardiovascular effects mediated by these agents.

Biological testing of the subject compounds of Formula I using an in vitro smooth muscle tissue preparation demonstrates that these compounds possess specific blocking action on calcium ion channels. This in vitro calcium ion channel blocker test consists of suspending 5 guinea pig ileal longitudinal smooth muscle strips in baths containing Tyrodes solution maintained at 37°C aerated with 95¾ - 5¾ CC^. The tissues are equilibrated for 60 minutes prior to the start of all experiments. A single response to carbachol is obtained and used in all experiments as a control maximum. In between successive doses, 10 the tissues are re-equilibrated and washed with Tyrodes solution every 15 minutes. To study the effect of the compounds, the tissues are exposed to the antagonist for 10 minutes prior to the additon of carbachol. For all experiments, only one antagonist at any one concentration is tested in any tissue. Results are expressed as 15 molar concentrations of antagonists which inhibit the muscle response by 50¾.

Since calcium antagonism generally inhibits excitation-contraction coupling in vascular smooth muscle, agents of this type usually evoke vasodilation. Testing of selected compounds, for example, 20 ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridtaeoarboxylate and ethyl 5-(4,5- dihydro-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylafce; of the present invention in the ganglion- blocked, angiotensin II-supported rat model (Deitchman, et al_., J_.

Pharmacol. Methods, 3^, 311-321 (1980)) demonstrated vasodilation with its concomitant lowering of blood pressure.

Additionally, these selected compounds of the present invention have been examined in vitro and in vivo in laboratory tests developed to predict a drug's potential to protect cardiac tissue from injury 30 due to ischemia. These tests utilize the known relationship between - 6 - progressive depletion of high energy phosphate and the onset of lethal cell injury in ischemic myocardium. Results of these screening tests demonstrate that these selected compounds possess anti-ischemia action.

Pharmaceutical compositions of this invention, in dosage unit form, contain an effective but non-toxic amount of a compound of Formula I and a suitable pharmaceutical carrier. The amount of the Formula I compound in the composition would range from 5 mg to 500 mg. One skilled in the art will recognize that in determining the amounts of the active ingredient in such dosage unit compositions, the activity of the chemical ingredient as well as the size of the host animal must be considered.

Generally, the active ingredients in dosage unit form will be combined with a pharmaceutical carrier. This pharmaceutical carrier may be either a solid or a liquid. Examples of solid carriers would be lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar, pectin, or acacia. Examples of liquid carriers would be peanut oil, olive oil or sesame oil. Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. In examples using a solid carrier, the preparation may be tableted, placed in hard gelatin capsules, or put in the form of a lozenge.

The amount of solid carrier will vary widely but generally would be 25 mg to 1 g. When a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a liquid suspension, or a sterile suspension or solution for parenteral use.

A method of treating via^ vasodilatation cardiovascular disorders such as angina or hypertension - 7 - comprises administering internally to manuals an effective but non-toxic amount of a compound of Formula I. The active ingredient will preferably be administered in dosage unit form as described above. The route of administration will be oral and/or parenteral.

The compounds of thepresent invention are prepared by application of known processes to the appropriate starting materials. Specifically, the present invention utilizes a process for preparation of the compounds of Formula I according to the following reaction scheme.

(I) The process for preparing compounds of formulae XI and III are the subject of Patent Specification No. c- Hf - , divided out of the present Application, and U.K. Divisional Patent Application No. 86/17591. - 8 - 1 2 3 4 5 In the foregoing scheme, R, R , R , R , R , R , m, and n are as defined in Formula I. The preferred method for making compounds of Formula I consists of refluxing the intermediate adducts II and III in ethanol solution for 18 to 24 hours. Removal of the solvent gives a material which, if ft is a solid, is purified by recrystallization and, if it is an oil, is converted to an acid addition salt and then purified. This facile reaction takes place in ordinary laboratory or plant equipment under convenient operating conditions. Preparation of compounds of Formula I according to the process of the invention generally comprises heating II and III neat or in the presence of a wide variety of reaction inert organic solvents. Suitable solvents include but are not limited to benzene, toluene, tetrahydrofuran, dibutylether, butanol, hexanol, methanol, dimethoxyethane, ethyleneglycol, etc. Suitable reaction temperatures are from 60° to 150°C. No catalyst or condensation agent is required.

The intermediate cyclic imidate ester enamines (II) are conveniently prepared by reacting an appropriately substituted metalated methyl heterocycle (IV) with an appropriate nitrile followed by quenching the reaction with ammonium chloride solution.

The intermediate acetylcinnamate compounds of structure III are prepared utilizing known Knoevenagel condensation reaction conditions. In general, appropriately substituted aldehydes and acetoacetates were condensed to give III.

The compounds which constitute this invention and their methods of preparation will appear more fully from a consideration of - 9 - the following examples and appended claims which are given for the purpose of illustration only and are not to be construed as limiting the invention in sphere or scope. In examples which follow, used to illustrate the foregoing processes, temperatures are expressed in 5 degrees centrigrade and melting points are uncorrected. The proton nuclear magnetic resonance (NMR) spectral characteristics refer to chemical shifts (5) expressed as parts per million (ppm) versus tetramethylsilane (TMS) as internal reference standard. The relative area reported for the various shifts in the proton NMR soectral data 10 corresponds to the number of hydrogen atoms of a particular functional type in the molecule. The nature of the shifts as to multiplicity is reported as broad singlet (bs), singlet (s), multiplet (m), or doublet (d). Abbreviations employed are DMSO-dg (deuterodimethylsulfoxide), CDClj (deuterochloroform), and are otherwise conventional. The infrared 15 (IR) spectral descriptions include only absorption wave numbers (cm'1) having functional group identification value. The IR determinations were employed using potassium bromide (KBr) as diluent.

The elemental analyses are reported as percent by weight.

SYNTHESIS OF INTERMEDIATES 20 A. Intermediates of Formula II EXAMPLE 1 2-Amino-l-(4,5-dihydro-2-oxazolyl)-l-butene A solution of 2-methyl-2-oxazoline (8.5 g; 0.10 mole) in 100 mL dry tetrahydrofuran (THF) was added via_ syringe to a stirred 25 suspension of freshly prepared lithium diisopropylamide in 50 mL THF.

The suspension was kept stirred under a nitrogen atmosphere at -78°C for an additional hour after the addition was completed. At this - 10 - point propionitrile (10 mL; 0.14 mole) was added to the stirred suspension which was then allowed to warm to room temperature with continued stirring. The reaction was then quenched with 25 mL saturated NH^Cl solution. The organic layer was separated and washed with water. The water wash was back extracted with ether and the organic portions combined and washed with brine. The organic solution was dried over KgCOj, filtered, and concentrated to 13 g of yellow liquid. Distillation (90-95°C at 1 mm Hg) yielded 6.5 g clear liquid as product (70¾ yield).

EXAMPLE 2 2-Amino-l-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-l-propene A solution of 4,5-dihydro-2,4,4-trimethyl-2-oxazoline (25 g; 0.22 mole) and tetramethylethylenediamine (25.5 g; 0.22 mole) was added to a stirred mixture of lithium diisopropyl amide (freshly prepared from 0.23 mole di isopropyl amine and 0.23 mole of ii-butyl lithium in 100 mL dry THF) kept under a nitrogen atmosphere at -78°C. The resultant whitish suspension was stirred at -78°C for an additional 2.5 hr. A solution of acetonitrile (15 g; 0.35 mole) in 50 mL THF was added to the stirred reaction mixture which was then allowed to warm to room temperature. The reaction was then quenched with saturated ammonium chloride solution and water added in a quantity sufficient to dissolve all solids in the mixture. A 100 mL portion of ether was added and the resulting layers separated. The organic layer was washed with brine and dried (KgCOj), filtered, and concentrated in vacuo to yield 24.9 g yellow liquid. Distillation afforded a 10* yield of product enamino oxazoline, b.p. 102-105°C at 4 mm Hg. - 11 - EXAMPLE 3 2-Ami no-1-(5,6-di hydro-4,4,6-trimethy1-4H-1,3-oxazin-2-yl)-l-butene_ To a solution of 11.0 mmoles of lithium diisopropylamide (11.1 g di isopropyl amine; 50 mL of 2.4M £-butyl lithium in ji-hexane) in 100 mL THF, kept at 78°C under a nitrogen atmosphere, was added a solution of 5,6-dihydro-4,4,6-trimethyl-4H-l,3-oxazine (14.1 g; 0.10 mole) in 100 mL THF. The reaction mixture was then allowed to stir at -78° for 2 additional hours at which time a solution of propionitrile (8.3 g; 0.15 mole) in 50 mL THF was added. The reaction mixture was allowed to warm to room temperature and was quenched with 75 mL saturated NH^Cl solution. A 100 mL portion of ether was added, the organic layer was separated, washed with brine, and dried (K2C03).

After the K2C03 was removed by filtration, the filtrate was concentrated in vacuo to give 21.2 g of a yellow liquid which was distilled to yield 15.5 g (79% yield) of product as a pale yellow oil, b.p. 140°C at 4 mm Hg.

EXAMPLE 4 2-Ami no-1-(4,5-dihydro-4-methoxymethyl-4-methyl-2-oxazolyl)-1-butene ' A solution of 4,5-dihydro-2,4-dimethy1-4-hydroxymethyl-oxazole [10.0 g; 0.78 mole. For synthesis of this hydroxyoxazoline, cf: H. Witte and W. Seeliger, Angew. Chem., Int. fd., Vol 11, 287 (1972); J. Nys and J. Libeer, Bull. Soc. Chim. Beiges., Vol. 65, 377 (1956)] in 100 mL THF was added dropwise to a stirred suspension of sodium hydride (3.6 g of a 57% suspension in mineral oil) in 40 mL dry THF under a nitrogen atmosphere at room temperature. The resulting suspension was stirred for 3 hr under the nitrogen atmosphere - 12 - and then a solution of methyl iodide (12.1 g; 0.08 mole) in 25 mL THF was added and the mixture allowed to continue stirring overnight.

A 100 mL portion of ether was added following which the layers were separated and the organic layer was washed twice with water and then with brine. The organic layer was dried (KgCOj), filtered, and concentrated in vacuo to 8.4 g yellow residual liquor which on distillation afforded 4.4 g (39¾ yield) of clear liquid product, b.p. 90°C at 10 mm Hg.

To a stirred, chilled (-78°C) mixture of lithium diisopropyl-amide (27 mmoles, prepared from 2.7 g of the amine, 11.3 mL of 2.4M £-butyllithium in n-hexane) in 10 mL THF was added a solution of the oxazoline intermediate (3.6 g; 25 m) prepared above. The resulting yellow mixture was stirred at -78° for 1.5 hr at which time propionitrile (2.8 g; 0.05 mole) in 10 mL THF was added. This mixture was allowed to warm to room temperature and was then quenched with a saturated NfyjCl solution. The reaction mixture was then worked up as in the above examples and distillation yielded 1.2 g (25¾ yield) of the product enamino oxazoline, b.p. 120° at 1 mm Hg.

Some additional examples of intermediates of Formula II which can be prepared using the procedure followed in the foregoing examples are given in Table 1.

Table 1 Additional Formula II Intermediates (IV) (II) Ex. R R1 R2 m R5 n bp (9C/0.1 mm) mp°C 5 Me Me Et 0 - 1 70-72 - 6 Me H Et 0 - i· - - 7 H H Et 0 - 2 - - 8 H H Et 1 Et 1 - - 9 Me0CH2 Me Me 0 - 2 - - 10 H Me Ph 0 - 1 - - 11 Me Me CHMe2 0 - 1 80 58-61 12 Me Me CMe3 0 - 1 132-133 13 Me Me Ph 0 - 1 - 74-75 14 Me Me 2-thienyl 0 - 1 107 69-70 15 H H Et 1 Ph 1 175(at 2.5nm) - B. Intermediates of Formula III EXAMPLE 16 Ethyl g-Acetyl-3-nitrocinnamate A reaction mixture containing in-nitrobenzaldehyde (151 g; 1.0 mole), ethyl acetoacetate (130 g; 1.0 mole), piperidine (4 mL) 20 and glacial acetic acid (12 mL) in 200 mL benzene was refluxed for 2.5 hr while removing water (19 mL) by means of a Dean Stark trap.

The dark brown reaction solution was allowed to cool to room temperature and was then water washed several times and concentrated in vacuo to give a dark yellow solid. This solid was recrystallized from ethanol to yield 182 g (69¾ yield) of yellow solid, m.p. 103-5 106°C. Literature m.p.: S. Ruhemann, J_. Chem. Soc., Vol 83, 717 (1903) -m.p. 110°C.

Additional examples of intermediates of Formula III which were prepared using the procedure given in Example 11 are listed in Table 2.

Table 2 Additional Formula III Intermediates R 3 0 r3-cho + ch3cch2co2r4 r4o2c· ψ (HI) Ex. R3 R4 n b-P· (°C/0.1mm) m.p.(°C) 17 m-nitrophenyl i_-propyT - - 18 m-nitrophenyl butyl - - 19 m-nitrophenyl methoxyethyl - - 20 m-nitrophenyl dimethyl ami noethyl - - 21 £-nitrophenyl ethyl - 59.5-61.5 22 cyclohexyl ethyl 160-170 - 23 1-naphthyl ethyl 120-130 - 24 3-indolyl ethyl - 121-122.5 25 2-furanyl ethyl 118-120 - 26 2-thienyl ethyl 110-120 - - 15 - Table 2 - Continued Ex. R3 R4 n b*P· rC/O.lmm) m.o.(°C) 27 3-pyridyl ethyl 145-165 - 5 28 2-bicycloheptenyl ethyl 134-140 - 29 phenyl ethyl 97 - 30 m-cyanophenyl ethyl 130-160 - 31 o_-chlorophenyl ethyl - - 10 32 m~hydroxy-£- nitro-phenyl ethyl - - 33 o-fluorophenyl ethyl 130 - 34 m-chlorophenyl ethyl 120-123 - 35 m-trif1uororaethyl-phenyl ethyl 100-110 - 15 36 £-hydroxy-m-ni trophenyl ethyl - - 37 £-methoxyphenyl ethyl - - 38 m-methylphenyl ethyl 140 - 39 £-hydroxy-m-methoxy- ethyl - 110-112 20 40 £-acetomi dophenyl ethyl - - 41 m-methylsulfonyl- ethyl - - 42 m-tri f1uoromethyl-sulfonylphenyl ethyl - - 25 43 £-chloro-m-nitro- phenyl ethyl - - 44 £-nitrophenyl methyl - - 45 m-nitrophenyl methyl - 145-146 46 nr-ni trophenyl £-propyl - - 47 m-nitrophenyl 2-chloroethyl - 68-76 - 16 - SYNTHESIS OF PRODUCTS EXAMPLE 48 Ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl 1,4-dihydro-2-methyl-4-(3-nitrophenyl )-3- pyrid toecarboxylate A reaction mixture consisting of ethyl α-acetyl-3-nitro-cinnamate (Example 15; 13.2 g, 50.0 imole), 2-amino-l-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-l-butene (Example 5; 8.4 g, 50.0 nmoles) and 75 mL ethanol was refluxed for 19 hrs. The mixture was concentrated in vacuo to 21.0 g of a yellow solid which was recrystallized from aqueous ethanol to give 17.4 g (84% yield) yellow crystals, m.p. 162-163°C.

Anal. Calcd. for C22H27N3°5: C* 63,91; H> 6,59; N* 10·17· Found: C, 63.90; H, 6.58; N, 10.13.

This and the other dihydro oxalyl dihydropyridine bases of the instant invention are readily convertable to their hydrochloride salts by treating an isopropyl alcohol solution of the base with aqueous HC1 followed by conventional work up and purification.

Conversion of the above base to its monohydrochloride salt gave a yellow solid, m.p. 234-235°.

Anal. Calcd. for C22H27N3°5-HC1: C, 58.73; H, 6.27; N, 9.34. Found: C, 58.76; H, 6.43; N, 9.36.

NMR (DMSO-dg): 1.21 (6,t [7.0 Hz]); 1.24 (3,s); 1.51 (3,s); 2.39 (3,s); 2.86 (2,m); 4.08 (2,q [7.0 Hz]); 4.58 (2,s); 5.32 (1,s); 7.59 (1 ,t [8.1 Hz]); 7.97 (2,m); 8.28 (l,m); 10.64 (l,bs); 12.60 (l,bs).

IR (KBr): 1065, 1125, 1230, 1270, 1350, 1440, 1490, 1530, 1585, 1605, 1700, and 2980 cm"1. - 17 - EXAMPLE 49 Ethyl 5-(4,5-dihydro-2-oxazo1yl)-6-ethyl-l,4-di hydro-2-roethyl-4-(3-ni tropheny1)-3-pyri di neearboxy1ate A mixture of 2-amino-l-(4,5-dihydro-2-oxazolyl)-l-butene (Example 1; 5.0 g, 35.7 mmole) and ethyl o-acetyl-3-nitrocinnamate (Example 15; 9.4 g, 35.7 mmole) in 75 mL ethanol was refluxed 23 hrs. Concentration of the reaction mixture in vacuo gave 16.5 g of yellow solid. Recrystallization from ethanol afforded 11.3 (82¾ yield) yellow solid, m.p. 149-150°C.

Anal. Calcd. for C20H23N305: C, 62.33; H, 6.02; N, 10.91, Found: C, 62.23; H, 5.96; N, 10.75.

Conversion of the above base to the hydrochloride salt was accomplished by treating an isopropanol solution of the base with IDS aqueous HC1. The reaction solution was filtered, concentrated in vacuo to a yellow solid and recrystallized from methanol to yield yellow solid, m.p. 206-207°C.

NMR (CFjCOOH): 1.42 (6,t [7.4 Hz]); 2.49 (3,s); 3.01 (2,q [7.4 Hz]); 4.11 (2,t [9.0 Hz]); 4.39 (2,q [7.4 Hz]); 5.17 (2,t [9.0 Hz]); 5.20 (l,s); 7.75 (2,m); 8.12 (l,bs); 8.21 (l.m); 8.36 (l,m); 8.71 (l,bs).

IR (KBr): 1070, 1130, 1230, 1260, 1285, 1350, 1435, 1490, 1530, 1590, 1610, 1700, and 2980 cm'1.

EXAMPLE 50 Ethyl 5-[4,5-dihydro-4-(methoxymethyl)-4-methyl-2-oxazolyl]-6-ethyl-l,4-dihydro-2-methyl-4- (3-nitropheny!)-3-pyridinecarboxy1ate Monohydrochloride A mixture of 2-amino-l-(4,5-dihydro-4-methoxymethyl-4-methyl-2-oxazolyl)-l-butene (Example 4; 0.9 g, 4.6 mmoles) and ethyl a-acetyl-3-nitrocinnamate (Example 15; 1.2 g, 4.0 mmoles) in 10 mL ethanol was refluxed for 23 hrs. The reaction mixture was - 18 - concentrated in vacuo to a yellow oil which represented the crude product. This crude base was converted to the hydrochloride salt (isopropyl alcohol and 10¾ aqueous HC1) which upon recrystallization from ethanol yielded 0.25 g (11.3¾ yield) yellow solid, m.p. 257-258°C (dec).

Anal. Calcd. for C23H2gN306-HCl: C, 57.56; H, 6.31; N, 8.76. Found: C, 57.34; H, 6.25; N, 8.46.

NMR (DMS0-d6): 1.22 (6,m); 1.44 (3,s); 2.37 (3,s); 2.78 (2,m); 2.92 (3,s); 3.27 (2,m); 4.10 (2,q [7.4 Hz]); 4.48 (l.d [8.2 Hz]); 4.70 (l.d [8.2 Hz]); 5.31 (l,s); 7.75 (2,m); 8.10 (l.m); 8.28 (l,m); 10.52 (1,bs).

IR (KBr): 1068, 1125, 1225, 1280, 1350, 1440, 1450, 1470, 1495, 1532, 1595, 1620, 1642, and 2980 cm-1.

EXAMPLE 51 Ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl) -l,4-dihydro-2,6-dimethyl-4-(3-nitro phenyl)-3-pyridinecarboxylate Monohydrochloride A mixture of 2-amino-l-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1-propene (Example 2; 2.9 g, 18.8 mmoles) and ethyl a-acetyl-3-nitrocinnamate (Example 15; 4.9 g, 18.8 mmoles) in 20 mL ethanol was refluxed for 18 hrs. The reaction mixture was concentrated in vacuo to an orange oil representing the crude product. This crude base was converted to the hydrochloride salt (isopropanol and 10¾ aqueous HC1) to yield 4.25 g (52¾ yield) of yellow crystalline product, m.p. 236°C (dec) after recrystallization from aqueous ethanol.

Anal. Calcd. for C21H25N305'HC1: C, 57.87; H, 6.02; N, 9.65. Found: C, 57.71; H, 6.23; N, 9.62. - 19 - NMR (DMSO-dg): 1.19 (3,t [6.6 Hz]); 1.24 (3,s); 1.47 (3,s); 2.36 (3,s); 2.44 (3,s); 4.09 (2,q [6.6 Hz]); 4.53 (2,s); 5.20 (1,s); 7.76 (2,m); 8.09 (1,m); 8.25 (1,m); 10.50 (1,bs).

IR (KBr); 1025, 1125, 1240, 1260, 1350, 1445, 1485, 1530, 5 1590, 1605, 1700, and 2980 cm'1.

EXAMPLE 52 Ethyl 5-(5,6-dihydro-4,4,6-trimethyl-4(H)-1,3- oxazm-2-yl )-6- ethyl-1,4-di hydro- 2-methyi -4-(3-nitrophenyl)-3-pyridinecarboxy1ate Monohydrochloride 10 A mixture of 2-amino-1-(5,6-dihydro-4,4,6-trimethyl-4H- 1,3-oxazin-2-y1)-1-butene (Example 3; 4.90 g, 25.0 nmole) and ethyl e-acetyl-3-nitrocinnamate (Example 15; 6.-58 g, 25.0 mmole) in 75 mL ethanol was refluxed for 20 hr. Concentration in vacuo yielded a yellow solid which was recrystallized from ethanol to afford 8.9 g 15 (81¾ yield) of yellow solid, m.p. 159-163°C.

The yellow solid base product prepared above was converted to the hydrochloride salt in the same manner as for the previous examples to yield a yellow solid monohydrochloride salt, m.p. 259-260°C (dec).

Anal. Calcd. for ^^NjOg-HCl: C, 60.31; H, 6.75; 20 N, 8.80. Found: C, 60.49; H, 6.78; N, 8.59.

NMR (DMS0-d6): 1.19 (9,m); 1.40 (6,s); 1.90 (2,m); 2.36 (3,s); 2.60 (2,m); 4.06 (2,q [7.0 Hz]); 4.83 (1,m); 4.92 (1,s); 7.68 (2,m); 8.09 (2,m); 9.80 (l,bs).

IR (KBr): 1070, 1105, 1125, 1220, 1265, 1350, 1485, 1530, 25 1605, 1620, 1695, and 2975 cm'1.

Additional examples of products of the instant invention are given in Table 3. These additional products were synthesized using the procedures described in Examples 43-52.

Table 3 Additional Formula 1 Products Ex. R R1 R2 R3 R4 m n 53 H H Et 3-N02Ph Me 0 - 1 5 54 He Me Et 2-furanyl Et 0 - 1 55 Me Me Et 4-N02Ph Et 0 - 1 56 Me Me Et Ph Et 0 - 1 57 Me Me Et 2-FPh Et 0 - 1 58 Me Me i_-Pr 3-N02Ph Et 0 - 1 10 59 Me Me t-Bu 3-N02Ph Et 0 - 1 60 Me Me Ph 3-N02Ph Et 0 - 1 61 Me Me 2-thienyl 3-N02Ph Et 0 - 1 62 Me Me Et 2-Cl-5-N02Ph Et 0 - 1 63 Me Me Et 3-ClPh Et 0 - 1 15 64 Me Me Et 3-CF3Ph Et 0 - 1 65 Me Me Et 2-thienyl Et 0 - 1 66 Me Me Et 4-0H-3-Me0Ph Et 0 - 1 67 Me Me Et 3-MePh Et 0 - 1 68 Me Me Et 1-naphthyl Et 0 - 1 20 69 Me Me Et 3-pyridyl Et 0 - 1 70 Me Me Et 2-ClPh Et 0 - 1 - 21 - Table 3 - Continued Ex. R_ R1 R2 R3 R^_ m_ 71 Me Me Et 3-CNPh Et 0 72 Me Me Et 2-Me0Ph Et 0 5 73 Me Me Et 2-bicycloheptenyl Et 0 74 Me Me Et cyclohexyl Et 0 75 Me Me Et 4-AcNHPh Et 0 76 Me Me Et 3-0H-4-N02Ph Et 0 77 Me H Me 4-isobutyl phenyl Et 1 10 78 H CH20Me Et 4-propoxyphenyl Et 0 79 Me Me Et 3-ethylphenyl MeOCH2CH2 0 80 Me Me Et 3-CH3S02Ph Me2NCH2CH2 0 81 Me CH20Me Et 3-CF3S02Ph Et 0 82 Me CH2QMe Et 4-CF3S02Ph MeOCH2CH2 0 15 83 Me Me Et 3-indolyl m r* o 84 Me Me Et 4-0H-3-N02Ph Et 0 85 H H Et 3-N02Ph v-Pr 0 86 H H Et 3-N02Ph MeOCH2CH2 0 87 H H Et 3-N02Ph cich2ch2 0 20 88 H H Et 3-N02Ph Et 1 89 H H Et 3-N02Ph h2nch2ch2 0 - 22 - The physical properties, where available, of the products of the examples listed in Table 3 are given in Table 4.

Table 4 Physical Properties - Formula I Products Anal.

Ex. Name m.p.(°C) Calcd. Found 53 Methyl 5-(4,5-dihydro-Z-oxazolyl)- 201-202 c, 55.96 55.99 6-ethyl-1,4-di hydro-2-methyl-4- H, 5.44 5.60 (3-nitrophenyl)-3-pyridine-carboxylate monohydrochloride N, 10.31 10.03 54 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 138.5-140 c, 67.02 66.88 2-oxazolyl)-6-ethyl-4-(2-furanyl)- H, 7.31 7.36 1,4-di hydro-2-methyl-3-pyri di ne-carboxylate N, 7.82 7.97 55 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 246-248 c, 58.73 58.36 2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(4-nitrophenyl)-3- H, 6.28 6.63 N, 9.34 9.40 pyridinecarboxylate monohydrochloride 56 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 147-149 c, 71.71 71.69 2-oxazolyl)-6-ethyl-l,4-dihydro-2- H, 7.66 7.66 methyl-4-phenyl-3-pyridinecarboxyl ate N, 7.60 7.48 57 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 175-177 c, 62.48 62.41 2-oxazolyl)-6-ethyl-4-(2-fluoro- H, 6.68 6.70 phenyl )-1,4-dihydro-2-methyl-3-pyri di necarboxylate monohydrochlori de N, 6.63 6.51 58 Ethyl 5-(4,5-di hydro-4,4-dimethyl- 216-217 c, 59.55 59.45 2-oxazolyl)-1,4-dihydro-2-methyl- H, 6.52 6.72 6-(1-methyl ethyl)-4-(3-ni trophenyl)- N, 9.06 9.41 3-pyridinecarboxylate monohydrochlori de 59 Ethyl 5-(4,5-di hydro-4,4-di methyl- 155-157 c, 65.29 64.90 2-oxazolyl)-6-(1,1-dimethylethyl)- H, 7.08 7.17 1,4-di hydro-2-methyl-4-(3-ni tro-pyridinecarboxylate N,. 9.52 9.17 60 Ethyl 5-(4,5-dihydro-4,4-dimethy1- 112-113 c, 67.67 67.73 2-oxazolyl)-1,4-dihydro-2-methyl- H, 5.90 5.86 4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate N, 9.11 9.04 Table 4 - Continued Ex. Anal. Name m.p.(°C) Calcd. Found 61 Ethyl 5-(4,5-di hydro-4,4-di methyl- 143-145 c, 57.20 57.17 5 2-oxazoly1)-1,4-dihydro-2-methyl- H, 5.21 5.31 4-(3-ni tropheny1)-6-(2-th i enyl)-3-pyri di necarboxylate monohydrochlori de N, 8.34 8.06 62 Ethyl 4-(2-chloro-5-nitrophenyl)- 220-224 c, 54.56 54.59 5-(4,5-di hydro-4,4-di methyl-2- H, 5.62 5.70 10 oxazolyl)-6-ethyl-l,4-dihydro-2- N, 8.68 8.58 methyl-3-pyri di necarboxylate monohydrochloride 63 Ethyl 4-(3-chlorophenyl)-5-(4,5- 170-172.5 C, 65.58 65.62 di hydro-4,4-dimethyl-2-oxazoly1)- H, 6.75 6.73 15 6-ethyl-l,4-dihydro-2-methyl-3- N, 6.95 6,84 pyri di necarboxylate Cl, 8.80 8.83 64 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 78-81 C, 63.30 62.95 2-oxazolyl)-6-ethyl-1,4-dihydro-2- H, 6.24 6.29 methyl-4-[3-(tri f1ueromethyl)phenyl]- N, 6.42 6.12 20 65 3-pyri di necarboxylate Ethyl 5-(4,5-di hydro-4,4-di methyl- 155-158 C, 64.14 63.92 2-oxazolyl)-6-ethyl-l,4-dihydro-2- H, 7.00 7.06 methyl-4-(2-thieny1) -3-pyridine-carboxyl ate N, 7.48 7.17 25 66 Ethyl 5-(4,5-di hydro-4,4-dimethyl- 182-185 C, 66.65 66.28 2-oxazolyl)-6-ethyl-1,4-dihydro- H, 7.30 7.32 4-(4-hydroxy-3-methoxypheny1)-2-methyl-3-pyri di necarboxylate N, 6.76 6.54 67 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 162-163 C, 72.23 72.01 30 2-oxazolyl)-6-ethyl-1,4-dihydro-2- H, 7.91 7.97 methyl-4-(3-methyl phenyl )-3-pyri di necarboxylate N, 7.33 7.25 68 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 236-238 C, 68.63 68.79 2-oxazolyl)-6-ethyl-1,4-dihydro-2- H, 6.87 6.65 35 methyl-4-(l-naphthalenyl)-3- N, 6.16 ' 5.87 pyridinecarboxylate monohydrochloride 69 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 161.5-163.5 C, 67.94 67.70 2-oxazolyl)-6-ethyl-l,4-dihydro- H, 7.39 7.48 2-methyl-4-(3-pyridinyl)-3- N, 11.32 11.22 40 pyri di necarboxylate H20, 0.49 0.5 70 Ethyl 4-(2-chlorophenyl)-5-(4,5- 179-182 C, 60.15 59.78 di hydro-4,4-dimethyl-2-oxazolyl)- H, 6.43 6.18 6-ethyl-l,4-dihydro-2-methyl-3- N, 6.38 6.40 pyridi necarboxylate monohydrochlori de Cl, 16.14 16.13 - 24 - Table 4 - Continued m.p.(°C) Anal. Ex. Name Calcd. Found 71 Ethyl 4-(3-cyanophenyl)-5-(4,5- 179-181 c, 70.21 70.15 di hydro-4,4-dimethyl-2-oxazolyl)- H, 6.92 6.92 6-ethyl-1,4-di hydro-2-methyl-3-pyri d i necarboxy1 a te N, 10.68 10.54 72 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 230 c, 63.52 63.22 2-oxazolyl)-6-ethyl-1,4-dihydro-4- H, 7.19 7.20 (2-methoxyphenyl)-2-methyl-3- N, 6.45 6.24 pyridinecarboxy!ate monohydrochloride 73 Ethyl 4- (bi cycl0(2.2.1Jhept-5-en- 165-166.5 c, 71.84 72.22 2-yl)-5-(4,5-dihydro-4,4-dimethyl- H, 8.39 8.34 2-oxazolyl)-6-ethyl-l,4-dihydro-2-methy1-3-pyri d i necarboxy!ate N, 7.29 7.33 74 Ethyl 4-cyclohexy1-5-(4,5-di hydro- 205-208 c, 64.30 64.14 4,4-dimethyl-2-oxazolyl)-6-ethyl- H, 8.59 8.56 1,4-di hydro-2-methyl-3-pyri di necarboxy late monohydrochloride N, 6.82 ' 6.42 75 Ethyl 4-[4-(acetylamino)phenyl]- 240.5-241 c, 60.62 60.51 5-(4,5-dihydro-4,4-dimethyl-2- H, 7.10 7.17 oxazolyl)-6-ethyl-l,4-dihydro-2- N, 8.84 8.51 methyl-3-pyri di necarboxylate H-0, , 2.84 2.70 monohydrochloride 75 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 145.5-146 c, 61.53 61.69 2-oxazoly1)-6-ethyl-1,4-di hydro-4- H, 6.34 6.35 (3-hydroxy-4-nitrophenyl)-2-methyl-3-pyri di necarboxylate N, 9.79 9.78 83 Ethyl 5-(4,5-di hydro-4,4-dimethy1- 124.5-125 c, 68.32 68.67 2-oxazolyl)-6-ethyl-l,4-dihydro- H, 7.57 7.45 4-(lH-i ndol-3-yl)-2-methyl-3- N, 9.56 9.62 pyri (Tinecarboxy late ethanol ate M, 2.05 1.97 hemihydrate 84 Ethyl 5-(4,5-dihydro-4,4-dimethyl- 134.5-135 c, 56.72 56.62 2-oxazolyl)-6-ethyl-l,4-dihydro-4-(4-hydroxy-3-nitrophenyl)-2- H, 6.06 6.08 N, 9.02 8.82 methyl-3-pyri di necarboxylate monohydrochloride 85 1-Methylethyl 5-(4,5-dihydro-2- 160-161 c, 63.17 63.15 oxazolyl)-6-ethyl-1,4-di hydro- H, 6.31 6.38 2-methyl-4-(3-nitrophenyl)-3- N, 10.52 10.27 pyridinecarboxylate - 25 - Table 4 - Continued Name m.p. (°C) Anal. Ex. Calcd. Found 86 5 2-methoxyethyl 5-(4,5-dihydro-2- 190-191 oxazolyl)-6-ethyl-l,4-dihydro-2- methyl-4-(3-ni trophenyl)-3- pyri di necarboxylate monohydrochlori de C, 55.82 H, 5.80 N, 9.30 55.65 5.77 9.30 o 00 00 Ethyl 5-(4,5-dihydro-5-phenyl-2- 193-195 oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-4-(3-ni trophenyl)-3- C, 62.72 H, 5.67 N, 8.44 62.59 5.65 8.33 pyridinecarboxylate monohydrochloride.

Claims (43)

1. A compound having the formula or an acid addition salt thereof wherein 5 R and R1 are independently selected from hydrogen, alkyl or C1-4 alkoxy“C1_4 alkyl groups; r2 is c^_4 alkyl, phenyl or thienyl; R3 is cycloalkyl of 5 to 7 carbon atoms, bicycloalkenyl of 7 to 9 carbon atoms, or 10 hetaryl or aryl (as hereinbefore defined); R4 is Οχ_4 alkyl, C·^ alkoxy-c1_4 alkyl, amino-C1_4 alkyl, halo-C1_4 alkyl, or di-C1_4 alkylamino-C1_4 alkyl; R5 is Cj__4 alkyl or phenyl; 15. is 0 or 1; and n is 0, 1, or 2. 2

2. A compound according to claim 1, wherein R is ci_4 alkyl, R3 is 3-nitrophenyl, m is 0, and n is 1. -27- Ethyl 5-(4,5-dihyd.ro-4,4- 3 . dimethyl-2-oxazolyl)-6-ethy1-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3 pyri di necarboxylate.

3. 4. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-ethy1-4-(2-furany1)-l,4-dihydro-2-methyl-3-pyridinecarboxylate.

4. 5. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-4-(4-nitrophenyl)-3-pyridinecarboxylate.

5. 6. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-4-phenyl-3-pyri di necarboxylate.

6. 7. Ethyl 5-(4,5-dihyaro-4,4- dimethyl-2-oxazolyl)-6-ethyl-4-(2-fluorophenyl)-l,4-dihydro-2-methyl 3-pyridinecarboxylate.

7. 8. Ethyl 5-(4,5-dihydro-4,4- d i methyl-2-oxazolyl)-1,4-di hydro-2-methyl-6-(l-methylethyl)-4-(3-nitrophenyl)-3-pyridinecarboxylate.

8. 9. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-(1,1-dimethylethyl)-1,4-dihydro-2-methy1)-4-(3-ni trophenyl)-3-pyri di necarboxylate.

9. 10. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate. Ethyl 5-(4,5-dihydro-4,4- 11 . dimethyl-2-oxazolyl)-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-6-(2-thienyl)-3-pyridinecarboxylate.

10. 12. Ethyl 5-(4,5-dihydro-5-phenyl 5 2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3- pyridinecarboxylate.

11. 13. Ethyl 4-(2-chloro-5-nitrophenyl)- 5-(4,5-dihydro-4,4-dimethy1-2-oxazo1y1)-6-ethyl-l,4-dihydro-2-methyl-3-pyri d i necarboxylate.

12. 14. Ethyl 4-(3-chlorophenyl)-5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-3-pyri di necarboxylate.

13. 15. Ethyl 5--(4,5-dihydro-4,4-dimethy1-2-oxazo1yl)-6-ethy1-1,4-dihydro-2-methyl-4-[3-(trifl uoro- 15 methyl)phenyl]-3-pyri di necarboxylate.

14. 16. Ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazo1yl)-6-ethy1-l,4-dihydro-2-methy1-4-(2-thienyl )-3-pyri di necarboxylate.

15. 17. Ethyl 5-(4,5-dihydro-4,4- 20 dimethyl-2-oxazolyl)-6-ethy1-l,4-dihydro-4-(4-hydroxy-3-methoxyphenyl)- 2- methyl-3-pyri di necarboxylate.

16. 18. Ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethy1-l,4-dihydro-2-methyl-4-(3-methyl phenyl )- 3- pyridinecarboxylate. - 29 - Ethyl 5-(4,5-dihydro-4,4- 19 . dimethyl-2-oxazolyl)-6-ethy1-l,4-dihydro-2-methyl-4-(l-naphthalenyl) 3-pyri di necarboxylate.

17. 20. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-ethyl-1,4-di hydro-2-methyl-4-(3-pyridi nyl)-3-pyri di necarboxylate.

18. 21. Ethyl 4-(2-chlorophenyl)-5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-3-pyri di necarboxyl ate.

19. 22. Ethyl 4-(3-cyanophenyl)-5~ (4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dibydro-2-methy1-3-pyridinecarboxylate.

20. 23. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-4-(2-methoxyphenyl}-2-methyl-3-pyridinecarboxylate.

21. 24. Ethyl 4-(bicyclo[2.2.1]hept-5- en-2-yl)-5-(4,5-dihydro-4,4-diinethyl-2-oxazolyl)-6-ethyl-lJ4-dihydro-2-methyl-3-pyridinecarboxylate.

22. 25. Ethyl 4-cyclohexyl-5-(4,5- dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl-3-pyridi necarboxylate.

23. 26. Ethyl 4-[4-(acetylamino)phenyl] 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methyl- 3-pyridinecarboxylate. Ethyl 5-(4, 5-dihydro-4,4- 27 . dimethy1-2-oxazo1yl)-6-ethy1-1,4-dihydro-4-(3-hydroxy-4-nitropheny!)-2-methyl-3-pyridinecarboxylate.

24. 28. Ethyl 5-(4,5-dihydro-4,4- 5 ^ιπκ1Ιψ1-2-οχ3Ζθ^1)-6-6ί1ν1-1,4^ι·ϊ^Γθ-4-(1Η^ι^ο1-3^1)-2-πιβ^1- 3- pyri di necarboxylate.

25. 29. Ethyl 5-(4,5-dihydro-4,4- dimethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-4-(4-hydroxy-3-nitrophenyl)-2-methy1-3-pyri di necarboxylate.

26. 30. Methyl 5-(4,5-dihydro-2- oxazolyl)-6-ethy1-1,4-dihydro-2-methy1-4-(3-nitrophenyl)-3-pyridine-carboxylate.

27. 31. Ethyl 5-(4,5-dihydro-2-oxazolyl)- 6-ethy1-l,4-dihydro-2-methy1-4-(3-nitrophenyl)-3-pyridinecarboxy1ate. 15 -32. Ethyl 5-[4,5-dihydro-4- {methoxymethyl)-4-methy1-2-oxazo1y1]-6-ethy1-1,4-dihydro-2-methyl- 4- (3-ni tropheny1)-3-pyri di necarboxylate.

28. 33. Ethyl 5-(4,5-dihydro~4,4- dimethyl-2-oxazolyl)-1,4-dihydro-2,6-dimethy1-4-(3-nitropheny!)-3-20 pyridinecarboxylate.

29. 34. Ethyl 5-(5,6-dihydro-4,4,E-trimethy1-4H-l,3-oxazin-2-y1 )-6-ethyl-l,4-dihydro-2-iiBthyl-4-(2-nitro-pheny1)-3-pyri di necarboxy1 ate. - 31 - 35. l-Methylethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate. 36. 2-Methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6- 5 ethyl-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridine-carboxylate.

30. 37. A pharmaceutical composition for the treatment of cardiovascular disease comprising from 5 to 500 mg of a compound of Formula I or a pharmaceutically acceptable 10 non-toxic salt thereof in combination with a pharmaceutically acceptable, non-toxic inert carrier.

31. 38. A composition according to claim 37, wherein the cardiovascular disease is angina or hypertension.

32. 39· A process for the manufacture of a compound of 15 formula I as defined in claim 1, which comprises heating a compound of formula II ,5 R' (ID 32 wherein, R, Rj, R2, R®, m and n are as defined in claim 1, with a compound of formula III (III) wnerein R^ and R1* are as defined ih claim 1, in the absence or presence 5 :of an inert organic solvent,to give a oonpound of formula I, and/or optionally convertinga catpound of formula I to an acid addition salt thereof, 40 .A process according to claim 39, wherein compounds of the formula I according to claim 1 , are manufactured, 10 wherein R is c1-4 alkyl, R is 3-nitrophenyl, m is o, and n is 1. 41 .A process according to claim 39, wherein ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-6-ethy1-1,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate; ethyl 5-(4, 5-dihydro- 4.4- dimethyl-2-oxazolyl)-6-ethyl-4-(2-furanyl)-l ,4-dihydro-2-iiiethyl-3-15 pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)- 6-ethyl-l,4-dihydro-2-methyl-4-(3-nitrophenyl)-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-5-ethyl-l,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethy 1-2-oxazolyl )-6-ethyl-4-(2-f luoropheny 1)-1,4-d'ihydro-2-methyl-20 3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)- 1.4- dihydro-2-methyl-5-(1-methylethyl)-4-(3-nitrophenyl)-3-pyridine-carboxylate; ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-6- - 33 - (1,1-dimethylethy1)-1,4-dihydro-2-metny1)-4-(3-nitrophenyl)-3-pyri-dinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-1,4-d i hydro-2-methy 1-4- (3-nitrophenyl )-6-phenyl-3-pyn'dinecarboxy late; ethyl 5-(4,5-aihydro-4,4-dimethyl-2-oxazoly1)-1,4-dihydro-2-methyl-4-5 (3-nitrophenyl)-6-{2-thienyl)-3-pyridinecarboxylate; ethyl 5-(4,5- dihydro-5-phenyl-2-oxazolyl)-6-ethy1-1,4-dihydro-2-methy1-4-(3-nitro-phenyl)-3-pyridinecarboxy1ate monohydrochloride; ethyl 4-(2-chloro-5-nitropheny1)-5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-6-ethy1-1,4-d i hydro-2-methy1-3-pyr i dinecarboxylate; ethy1 4-(3-ch1orophenyl)-5-10 (4,5-dihydro-4,4-dimethyl-2-0xazolyl)-6-ethyl-l,4-dihydro-2-methyl- 3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethy1-1,4-dihydro-2-methyl-4-[3-triflurormethyl)phenyl]-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethy 1-1,4-dihydro-2-methy1-4-(2-thienyl)-3-pyridinecarboxylate; 15 ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-4- (4-hydroxy-3-methoxyphenyl)-2-methy1-3-pyridinecarboxylate; ethyl 5- (4,5-dihydro-4,4-dimethyl-2-Oxazolyl)-6-ethy1-l,4-dihydro-2-methyl-4-(3-methylphenyl)-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-5-ethy1-1,4-dinydro-2-methy1-4-(1-naphthaleny1)- 20 3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)- 6- ethy1-1,4-dihydro-2-methy1-4-(3-pyridinyl)-3-pyridinecarboxy!ate; ethyl 4-(2-chlorophenyl)-5-(4,5 -^ihydro-i,4-6imethyl-2-oxazolyl)-6-ethyl-1,4-dihydro-2-methy1-3-pyridinecarboxy!ate; ethyl 4-(3-cyanophenyl)-5- (4,5-dihydro-4,4-dimethy1-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methy1-3-25 pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6- ethy 1-1,4-dihydro-4-(2-methoxybhenyl)-2-methyl-3-pyridinecarboxylate; - 34 - ethyl 4-(bicyclo(2.2.l]hept-5-en-2-yl)-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methy 1-3-pyridirtecarboxylate; ethyl 4-cyclonexy1-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethy1-1,4-d ihydro-2-metny 1-3-pyr i d i necarboxy1 ate; ethyl 4-(4-( acetyl ami no) phenyl]-5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethyl-l,4-dihydro-2-methy1-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl )-6-ethy 1-1,4-di hydro-4- (3-hydroxy-4-ni tropheny l)-2-methy 1-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-6-ethy 1-1,4-dihydro-4-(lH-indol-3-yl)-2-methyl-3-pyridinecarboxylate; ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-6-ethyl-l,4-dihydro- 4- (4-hydroxy-3-nitrophenyl)-2-methyl-3-pyridinecarboxylate; methyl 5- (4,5-dihydro-2-oxazolyl)-6-ethy1-l,4-dihydro-2-methyl-4-(3-nitro-phenyl)-3-pyridinecarboxylate monohydrochloride; ethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethy1-l,4-dihydro-2-methy1-4-(3-nitropheny!)- 3- pyridinecarboxylate; ethyl 5-[4,5-dihydro-4-(methoxymethyl)-4-methy1-2-oxazolyl]-5-ethy1-1,4-dihydro-2-methy1-4-(3-nitropheny1)-3-pyridinecarboxylate monohydrochloride; ethyl 5-(4,5-dihydro-4,4-dimethy1-2-oxazolyl)-1,4-dihydro-2,6-dimethy 1-4-(3-nitropheny1)-3-pyridinecarboxylate monohydrochloride; ethyl 5-(5,6-dihydro-4,4,6-trimethyl-4H-l ,3-oxazin-2-yl )-6-ethyl-l ,4-dihydro-2-rrethyl-4- (3-nitro -phenyl)-3-pyridinecarboxylate; 1-methylethyl 5-(4,5-dihydro-2-Oxazolyl)-6-ethy1-1,4-dihydro-2-methy1-4-(3-nitropheny1)-3-pyridine-carooxylate; 2-methoxyethyl 5-(4,5-dihydro-2-oxazolyl)-6-ethy1-1, 4- dihydro-2-methy1-4-(3-nitrophenyl)-3-pyridinecarboxylate monohydrochloride; are manufactured.

33. 42. A process for making a compound as defined in claim 1, substantially as hereinbefore specifically described in the exanples 48-52 and 53-89.

34. 43. A compound of formula I given and defined in claim 1 or an acid addition salt thereof when produced by a process as claimed in any one of claims 39 to 42. - 35 -

35. 44. A pharmaceutical compound as defined in claim 1 for use in a method of treatment by therapy of the hunan or animal body.

36. 45. A compound according to claim 1 for use as a vasodilator.

37. 46. A compound according to claim 1 for use as a non-toxic antihypertensive agent.

38. 47. A compound according to claim 1 for use as an antiischemia agent.

39. 48. A compound according to claim 1, substantially as hereinbefore specifically described in the examples for the use hereinbefore specifically described.

40. 49. A compound as described in claim 1,substantially as hereinbefore specifically described in each of the Examples 48-52 and 53-89.

41. 50. A pharmaceutical composition according to claim 37, substantially as hereinbefore specifically described.

42. 51. The use of a substance according to claim 1 for the manufacture of a medicament which is an anti-hypertensive agent.

43. 52- The use of a substance according to claim 1 for the manufacture of a medicament which is an anti-ischemia agent. F. R. KELLY & CO., AGENTS FOR THE APPLICANTS.