DK164668B - Analogy process for preparing 1,4-dihydropyrid-5- yl(cyclic imidate) esters - Google Patents

Description

in

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The present invention relates to an analogue and process for the preparation of novel 1,4-dihydropyrid-5-yl (cycle in skimidate) esters, which compounds have biological properties.

A considerable amount of prior art has emerged over the last decade with regard to compounds of the 4-aryl-1,4-dihydropyridine series, which 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 the treatment of angina and hypertension. These structures are typified by nifedipine (Formula 1): (8i H3CO2Cvy ^ J \ / CO2CH3

15 I

H3C "^ \ n CH3 f

H

(1) chemically designated 4- (2'-nitrophenyl) -2,6-dimethyl-3,5-dicarbo-methoxy-1,4-dihydropyridine. Nifedipine and some related 4-aryl-1,4-dihydropyridines are disclosed in U.S. Patent No. 3,485,847, issued December 23, 1969. Numerous subsequent patents have been issued for 1,4-dihydropyridines wherein other substituent groups are have been used in the various ring positions of the dihydro-pyridine moiety. The structure of these later patented compounds which are of interest to the present invention can be shown by Formula 2.

30 R3 r4 ° 2O / ^ \ CO2r2

T T

35 r5 ^ n r1 t

H

(2) 2

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Bossert, et al., U.S. Patent No. 3,488,359, issued 6.

January 1970, and No. 3,574,843, issued April 13, 1971, disclose 24 compounds wherein the change implies that R and R are alkoxyalkyl groups.

Murakami, et al., DE-OS No. 2,407,115 discloses compounds 2 wherein R is a di-substituted aminoalkyl group.

Kojima, et al., U.S. Patent No. 4,220,649, issued 2.

September 2, 1980, discloses compounds wherein R is a pyrrolidine ring.

10 Loev, et al., U.S. Patent No. 3,511,847, issued May 12, 1970, lists compounds with wide variations in the nature of R.

2 4

Further, the carboxyl groups bonded to R and R are replaced by carbonyl groups in the specification, but no claims are made on these compounds, nor is a process for synthesizing them.

Teulon, et al., U.S. Patent No. 4,096,270, issued 20.

June 3, 1978, discloses dihydropyridines wherein R is a substituted pyridine moiety.

In summary, these and other previously patented dihydropyridine compounds of interest to the present invention may be represented by Formula 2. In general, R, R, R and R are alkyl groups or alkyl groups bearing various substituents. , eg. amino, ether, mercapto groups, etc. The nature of R varies considerably, but useful cardiovascular properties appear to be maximized when this group is an electron-attracting aryl moiety or heterocyclic moiety.

Meyers and Gabriel reported in Heterocycles, vol 11, pp.

133-138 (1978) a new synthesis of 1,4-dihydropyridines. This synthesis uses oxazolines as activating groups to facilitate 30 organometallic addition to the pyridine ring to form 1,4-dihydropyridines (Formula 3).

I mg * I

II J or> <Γ / -

”--- cKJ

H

(3) 3

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

The present invention provides compounds of formula (I)

R4o O

V r3 R5 \ - / O-tCHl * ίο Hn _K Γ "f-Λ, Λι

H r2 R R

(I) 15 and acid addition salts of these compounds. In the above formula, R 1, R 2, R 2, R 3, R 4, R 5, m and n have the following meanings. R and R 1 are independently selected from hydrogen, C 1-4 alkyl and C 1-4 alkoxy-C 1-4 alkyl groups, wherein alkoxyalkyl refers to a C 1 to alkylene chain 20 and a C 1 to alkyl group linked to an oxygen atom; R 2 is C 1-4 alkyl, phenyl or thienyl; R 3 is cyclic oalkyl having 5 to 7 carbon atoms, bicycloalkenyl having 7 to 9 carbon atoms, furanyl, indolyl, pyridyl, thienyl, phenyl, naphthyl or substituted phenyl with the substituents comprising acetamino, C halogen, hydroxyl, nitro and trifluoromethyl; R 4 is C 1-4 alkyl or C 1-4 alkoxy-C 1-4 alkyl as defined above; R 1 is C 1-6 alkyl or phenyl; m is 0 or 1; and n is 0 or 1.

The present compounds may exist as optical isomers, and both the racemates of these isomers as well as the individual racemic modifications fall within the scope of the invention. The racemates can be cleaved into their individual isomers by well-known techniques, such as 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 significantly contribute to the toxicity or pharmacological activity of the salt.

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and as such are the pharmacological equivalents to the bases of the above formula. The acid addition salts are obtained either by reacting an organic base of formula (I) with an acid, preferably by contact in solution, or by any of the standard methods detailed in the literature available to any skilled person.

The compounds of this invention were shown to be calcium ion channel blocking on the basis of in vitro pharmacological testing. Currently, some calcium channel blockers are being investigated extensively in patients 10 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 giat muscle tissue preparation shows that these compounds have specific blocking effect on calcium ion channels. This in vitro test for calcium ion channel blockage consists in suspending longitudinal guinea pig ileum muscle strips in baths containing Tyrode's solution which is maintained at 37 ° C and vented with 95% 0, - 5% COg. The tissues are equilibrated for 60 min. before the start of all trials. A single response to carbachol is obtained and used in all 20 trials as a control maximum. Between successive doses, the tissues are re-equilibrated and washed with Tyrode's solution every 15 min.

To study the effect of the compounds, the tissues are exposed to the antagonist for 10 min. before the addition of carbachol. For all experiments, only one antagonist is tested for any concentration and in any tissue.

The results shown in Table V are expressed as molar concentrations of antagonists that inhibit the muscle response by 50%.

Since calcium antagonism generally inhibits excitation-contraction coupling in vascular smooth muscle, agents of this type usually induce vasodilation. Testing selected compounds, e.g. ethyl 5- (4,5-dihydro-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate of the invention at that time , angiotensin (II) supported rat model (Deitchman, et al., J. Pharmacol.

35 Methods, 3, 311-321 (1980)) showed vasodilation with its accompanying lowering of blood pressure.

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Furthermore, these selected compounds of the present invention have been studied in vitro and in vivo in laboratory experiments designed to predict the potential of a drug to protect cardiac tissue from damage due to ischemia. These experiments utilize the known relationship between progressive depletion of high-energy phosphate and the onset of lethal cell damage in ischemic myocardium. Results from these screening trials show that these selected compounds possess anti-ischemic activity.

Unit dosage form pharmaceutical compositions contain an effective but non-toxic amount of a compound of formula (I) and a suitable pharmaceutical carrier. The amount of the compound of formula (I) in the composition will vary from ca. 5 mg to approx. 500 mg.

Those skilled in the art will appreciate that in determining the amounts of the active ingredient in such unit dose preparations, both the activity of the chemical component and the size of the host animal must be taken into account.

Generally, the active ingredients in unit dosage form will be combined with a pharmaceutical carrier. This pharmaceutical carrier may be either a solid or a liquid. Examples of solid carriers may be lactose, magnesium stearate, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Examples of liquid carriers may be peanut oil, olive oil or sesame oil.

Similarly, the carrier or diluent may contain a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be used.

As examples of the use of a solid carrier, the composition may be tableted, placed in hard gelatin capsules or in the form of a lozenge.

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

For the treatment via vasodilatation of cardiovascular irregularities, such as angina or hypertension, an effective non-toxic amount of a compound of formula (I) is administered internally to humans or mammals. The active ingredient is preferably administered in unit dosage form, as described above. Admin- 6

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the ring pathway may be oral and / or parenteral.

The present compounds are prepared using known methods on the appropriate starting materials. Specifically, the present invention employs a process for preparing the compounds of formula (I) according to the following reaction scheme.

R lithium- R3 ^ 0 [CH diisopropyl- 0- [CH] m 0- [CH] m 10 CH3- <tCH2] n -Ϊ52-, LiCH-y [CH] I [CH2] n »n * ΓΑ * R H2N / R2 CIV) (II) R3

in r4 ° 2V

r3-cho + CH3'cCH2CO2R4- *

on H jrS

3 (III) R5 25 4 f / ° '[^

J I R

H

(I) 1 2 3 4 5 1 The above scheme has R, R, R, R, R, R, m and n having the same meanings as in formula (I). The preferred process for preparing the compounds of formula (I) consists in refluxing the adduct intermediates (II) and (III) in ethanol in so-called solution for 18 to 24 hours. Removal of the solvent gives a material which, if it is a solid, is purified by recrystallization and, if it is an oil, is converted to an acid addition salt and then 7

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cleaned. This light reaction takes place in usual laboratory or plant equipment under appropriate operating conditions. Preparation of compounds of formula (I) according to the process of the invention generally comprises heating (II) and (III) pure or in the presence of a variety of organic solvent inert for the reaction. Suitable solvents include, but are not limited to, benzene, toluene, tetrahydrofuran, di-butyl ether, butanol, hexanol, methanol, dimethoxyethane, ethylene glycol, etc. Suitable reaction temperatures are from 60 ° to 150 ° C.

No catalyst or condensing agent is required.

The process according to the invention is illustrated in more detail in the following examples. Temperatures are expressed in ° C and the melting points are uncorrected. The values of the nuclear magnetic resonance spectra (NHR) refer to chemical shift values (δ) expressed as 15 parts per minute. million (ppm) relative to tetramethylsilane (TMS) as internal reference standard. The relative area reported for the different shift values in the NMR spectral data corresponds to the number of hydrogen atoms for a particular functional type in the molecule. The nature of changing in terms of multiplicity is given as 20 broad singlet (bs), singlet (s), multiplet (m) or doublet (d).

Abbreviations used are DMSO-dg (deuterodimethylsul foxide), CDCl3 (deuterochloroform), and are otherwise conventional. The infrared spectral descriptors (IR) only include wave absorption numbers (cnf *) with identification value for a functional group. The IR determinations were made using potassium bromide (KBr) as diluent. The elemental analyzes are given as% by weight.

SYNTHESIS OF INTERMEDIATES

A. Intermediates of Formula (II) 30

Example 1 2-Amino-1- (4,5-dihydro-2-oxazolyl) -1-butene

A solution of 2-methyl-2-oxazoline (8.5 g, 0.10 mol) in 100 ml of dry tetrahydrofuran (THF) was added via syringe to a stirred suspension of freshly prepared 1 lithium diisopropyl amide in 50 ml of THF. The suspension was kept stirred under a nitrogen atmosphere at -78 ° C for an additional hour after the addition was complete. At this point, propionitrile (10 mL, 0.14 mol) was added to the stirred suspension

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sion, which was then allowed to warm to room temperature with continued stirring. The reaction mixture was then cooled with 25 ml of saturated NH 2 Cl solution. The organic layer was separated and washed with water. The aqueous wash liquid was extracted with ether, 5 and the organic portions were combined and washed with brine. The organic solution was dried over KgCO3, filtered and concentrated to 13 g of yellow liquid. Distillation (90-95 ° C at 1 mm Hg) gave 6.5 g of clear liquid as product (70% yield).

Example 2 2-Amino-1- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1-propene

A solution of 4,5-dihydro-2,4,4-trimethyl-2-oxazoline (25 g, 0.22 mol) and tetramethylethylenediamine (25.5 g, 0.22 mol) was added to a stirred mixture of lithium diisopropyl amide (freshly prepared from 0.23 mole of diisopropylamine and 0.23 mole of n-butyllithium in 100 ml of dry THF), which was kept under a nitrogen atmosphere at -78 ° C. The resulting whitish suspension was stirred at -78 ° C for an additional 2.5 hours. A solution of acetonitrile (15 g, 0.35 mol) in 50 mL of THF was added to the stirred reaction mixture, which was then allowed to warm to room temperature. The reaction mixture was cooled with saturated ammonium chloride solution and water was added in a sufficient quantity 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 (KgCO 3), filtered and concentrated in vacuo to give 24.9 g of yellow liquid.

Distillation yielded a 10% product yield of enamino-oxazoline, b.p.

102-105 ° C at 4 mm Hg.

Example 3 2-Amino-1- (5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl) -1-butene To a solution of 11.0 mmol lithium diisopropyl amide (11.1 g of diisopropylamine, 50 ml of 2.4 M n-butyllithium in n-hexane) in 100 ml of THF, kept at -78 ° C under a nitrogen atmosphere, was added a solution of 5,6-dihydro-4.4 , 6-trimethyl-4H-1,3-oxazine (14.1 g, 0.10 mol) in 100 ml of THF. The reaction mixture was then stirred at -78 ° for a further 2 hours, at which time a solution of propionitrile (8.3 g, 0.15 mol) in 50 ml of THF was added. The reaction mixture was allowed to warm to room temperature and cooled to 9

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75 ml of saturated NH4 Cl solution. A 100 ml portion of ether was added, the organic layer was separated, washed with brine and dried (1 CO 2).

After removal of KgCO 3 by filtration, the filtrate was concentrated in vacuo to give 21.2 g of a yellow liquid distilled to give a product yield of 15.5 g (79% yield) as a pale yellow oil, b.p.

140 ° C at 4 mm Hg.

Example 4 2-Amino-1- (4,5-dihydro-4-methoxymethyl-4-methyl-2-oxazolyl) -1-butene A solution of 4,5-dihydro-2,4-dimethyl-4-hydroxymethyl - -oxazole [10.0 g, 0.78 mol. For the synthesis of this hydroxyoxazoline, cf. H. Witte and W. Seeliger, Angew. Chem. Int. Ed., Vol. 11, 287 (1972); J. Nys and J. Libeer, Bull. Soc. Chim. Belges., Vol. 65, 377 (1956)] in 100 ml of THF was added dropwise to a stirred suspension of sodium hydride (3.6 g of a 57% suspension in mineral oil) in 40 ml of dry THF under a nitrogen atmosphere at room temperature. The resulting suspension was stirred for 3 hours under a nitrogen atmosphere, then a solution of methyl iodide (12.1 g, 0.08 mol) in 25 ml of THF was added and the mixture was allowed to stir overnight. A 100 ml portion of ether was added, then the layers were separated and the organic layer was washed twice with water and then with brine.

The organic layer was dried (K 2 CO 2), filtered and concentrated in vacuo to 8.4 g of yellow residual liquid to give, by distillation, 4.4 g (39% yield) of clear liquid product, b.p. 90C at 10 mm Hg.

To a stirred, cooled (~ 78 ° C) mixture of 1 lithium diisopropyl amide (27 mmol), prepared from 2.7 g of the amine, 11.3 ml of 2.4 M n-butyllithium in n-hexane) To 10 ml of THF was added a solution of the above-prepared oxazoline mixture (3.6 g, 25 mm). The resulting yellow mixture was stirred at -78 ° for 1.5 hours, at which time propionitrile (2.8 g, 0.05 mol) in 10 ml of THF was added.

This mixture was allowed to warm to room temperature and then cooled with a saturated NH4 Cl solution. The reaction mixture was then worked up as in the previous examples and distillation gave 1.2 g (25% yield) of the product enamino-oxazoline, 35 kp. 120 ° at 1 mm Hg.

Some additional examples of intermediates of formula (II) which can be prepared using the process set forth in the preceding examples are given in Table I.

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Table I

Additional intermediates of formula (II) 5 R5? 5

LiCH2 - / [CH2] n + R2CN -> I t®2] n x -7 <, 'P'T ^ 10 E E η2Λ2 (IV) (II)

Ex. R R1 R2 m R5 n kp. (° C / 0.1 mm) snip. ° C

15 5 Me He It 0 - 1 70-72 6 Me H It 0 - 1 7 Η H It 0 - 2 8 Η Η It 1 It 1 9 MeOCH2 Me Me 0 - 2 20 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- 0 - 1 107 69-70 25 thienyl 15 Η H Et 1 Ph 1 175 (at 2.5 mm) - B. Intermediates of Formula (III) Example 16

Ethyl E-acetyl-3-nitrocinnamate

A reaction mixture containing m-nitrobenzaldehyde (151 g, 1.0 mol), ethyl acetoacetate (130 g, 1.0 mol), piperidine (4 ml) and glacial acetic acid (12 ml) in benzene (200 ml) for reflux for 2.5 hours under 35 removal of water (19 ml) using a Dean Stark trap. The dark brown reaction solution was allowed to cool to room temperature and then washed with water several times and concentrated in vacuo to give a dark yellow solid. This solid

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N was recrystallized from ethanol to give 182 g (69% yield) of yellow solid, m.p. 103-106 ° C. Literature snip .: S. Ruhemann, J.

Chem. Soc., Vol. 83, 717 (1903) - m.p. 110 ° C.

Further examples of intermediates of formula (III) prepared using the procedure given in Example 16 are given in Table II.

Table II

Additional intermediates of formula (III) R3 o

r3-cho + CH3CCH2C02R4 -> T

15 J

(III)

Kp. Mp.

Ex. R3 R4 (° C / 0.1 mm) (° C) 20 - - - - - 17 m-nitrophenyl i-propyl 18 m-nitrophenyl butyl 19 m-nitrophenyl methoxyethyl 20 m-nitrophenyl dimethyl aminoethyl 21 p nitrophenyl ethyl 59.5-61.5 22 cyclohexyl ethyl 160-170 23 1-naphthyl ethyl 120-130 24 3-indolyl ethyl 121-122.5 30 2-furanyl ethyl 118-120 26 2-thienyl ethyl 110 -120 27 3-pyridyl ethyl 145-165 28 2-bicycloheptenyl ethyl 134-140 29 phenyl ethyl 97 35 30 m-cyanophenyl ethyl 130-160 31 o-chlorophenyl ethyl 32 m-hydroxy-p-ethyl nitro-phenyl 12

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Kp. Mp.

Ex. R3 R4 (° C / 0.1 mm) (° C) 33 o-fluorophenyl ethyl 130 5 34 m-chlorophenyl ethyl 120-123 35 m-trifluoromethylethyl 100-110 phenyl 36 p-hydroxy-m-ethyl nitro phenyl 10 37 o-methoxyphenyl ethyl 38 m-methylphenyl ethyl 140 39 p-hydroxy-m-ethyl - 110-112 methoxyphenyl 40 p-acetamidoethyl phenyl 41 m-methylsulfonylethyl phenyl 42 m-trifluoromethylethyl sulfonylphenyl 20 43 o-chloro-m-nitroethyl phenyl 44 o-nitrophenyl methyl 45 m-nitrophenyl methyl - 145-146 46 m-nitrophenyl n-propyl 47 47 m-nitrophenyl 2-chloroethyl - 68-76 SYNTHESIS OF PRODUCTS Example 48

Ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-30-methyl-4- (3-nitrophenyl) 3-pyridine carboxylate

A reaction mixture consisting of ethyl α-acetyl-3-nitrocinnamate (Example 15; 13.2 g, 50.0 mmol), 2-amino-1- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) 1-Butene (Example 5; 8.4 g, 50.0 mmol) and 75 mL of ethanol refluxed for 19 hours. The mixture was concentrated in vacuo to 21.0 g of 35 yellow solid which was recrystallized from aqueous ethanol to give 17.4 g (84% yield) of yellow crystals, m.p. 162-163 ° C.

Analysis calculated for C 22 H 27 N 3 ° 5: 63> 91 »6.59; N, 10.17.

Found: C, 63.90; H, 6.58; N, 10.13.

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This and the other disclosed dihydro-oxalyl-dihydropyridine bases can be readily converted to their hydrochloride salts by treating an isopropyl alcohol solution of the base with aqueous HCl, followed by conventional work-up and purification. Conversion of the above base to its monohydrochloride salt gave a yellow solid, m.p. 234-235 °.

Analysis calculated for C 22 H 27 Cl 3: VHCl H, 6.27; N, 9.34. Found: C, 58.76; H, 6.43; N, 9.36.

NMR (DMSO-d 6): 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 (l, t [8.1 Hz]); 7.97 (2, m); 8.28 (1, m); 10.64 (1, bs); 12.60 (1, bs).

IR (KBr); 1065, 1125, 1230, 1270, 1350, 1440, 1490, 1530, 1585, 1605, 1700 and 2980 cm "1.

Example 49

Ethyl 5- (4,5-dih.ydro-2-oxazoly1) -6-ethyl-l, 4-dihydro-2-methyl-4- (3 - nitrophenyl) -3-pyridinecarboxylate

A mixture of 2-amino-1- (4,5-dihydro-2-oxazolyl) -1-butene (Example 1; 5.0 g, 35.7 mmol) and ethyl α-acetyl-3-nitrocinnamate 20 ( Example 15; 9.4 g, 35.7 mmol) in 75 ml of ethanol for reflux for 23 hours. Concentration of the reaction mixture in vacuo gave 16.6 g of yellow solid. Recrystallization from ethanol gave 11.3 g (82% yield) of yellow solid, m.p. 149-150 ° C.

Analysis calculated for C20 H23 N3 ° 5: 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 10% aqueous HCl. The reaction solution was filtered, concentrated in vacuo to a yellow solid and recrystallized from methanol to give a yellow solid, m.p. 206-207 ° C.

NMR (CF 3 COOH); 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 (s, t [9.0 Hz]); 5.20 (1, s); 7.75 (2, m); 8.12 (1, bs); 8.21 (1, m); 8.36 (1, m); 8.71 (1, bs).

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

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Example 50

Ethyl-5- [4,5-dihydro-4- (methoxymethyl) -4-roethyl-2-oxazolyl] -6-ethyl-1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3- A mixture of 2-amino-1- (4,5-dihydro-4-methoxymethyl-4- -methyl-2-oxazolyl) -1-butene (Example 4; 0.9 g, 4) (6 mmol) and ethyl α-acetyl-3-nitrocinnamate (Example 15; 1.2 g, 4.0 mmol) in 10 ml of ethanol were refluxed for 23 hours. The reaction mixture was concentrated in vacuo to a yellow oil representing the crude product.

This crude base was converted to the hydrochloride salt (isopropyl alcohol and 10% aqueous HCl) which, after recrystallization from ethanol, gave 0.25 g (11.3% yield) of yellow solid, m.p. 257-258 ° C (decomp.).

Analysis calculated for C CggHggNN₂Og.HCl: C, 57.56; H, 6.31; N, 8.76. Found: C, 57.34; H, 6.25; N, 8.46.

NMR (DMSO-d 6): 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 (1, d [8.2 Hz]); 4.70 (1, d [8.2 Hz); 5.31 (1, s), 7.75 (2, m), 8.10 (1, n), 8.28 (1, m); 10.52 (1, bs).

IR (KBr): 1068, 1125, 1225, 1280, 1350, 1440, 1450, 1470, 20 1495, 1532, 1595, 1620, 1642 and 2980 cm -1.

Example 51

Ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3-pyridinecarboxy1 monohydrochloride 25 A mixture of 2-amino-1- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1-propene (Example 2; 2.9 g, 18.8 mmol) and ethyl α-acetyl-3-nitrocinnamate (Example 15; 4.9 g, 18.8 mmol) in 20 mL of ethanol reflux for 18 hours. 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 10% aqueous HCl) to give 4.25 g (52% yield) of yellow crystalline product, m.p. 236 ° C (decomp.) After recrystallization from aqueous ethanol.

Analysis calculated for i g gNNOO.HCl: 57.87; H, 6.02; N, 9.65. Found: C, 57.71; H, 6.23; N, 9.62.

NMR (DMSO-d 6): 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, 15

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1590, 1605, 1700 and 2980 cm -1.

Example 52

Ethyl 5- (5,6-dihydro-4,4,6-trimethyl-4 (H) -1,3-oxazin-2-yl) -6-ethyl-1,4-dihydro-2-methyl 4- (3-nitrophenyl) -3-pyridinecarboxylate, monohydrochloride

A mixture of 2-amino-1- (5,6-dihydro-4,4,6-trimethyl-4H-1,3-oxazin-2-yl) -1-butene (Example 3; 4.90 g, 25.0 mmol) and ethyl α-acetyl-3-nitrocinnamate (Example 15; 6.58 g, 25.0 mmol) in 75 ml of ethanol were refluxed for 20 hours. Concentration in vacuo afforded a 10 yellow solid which was recrystallized from ethanol to give 8.9 g (81% yield) of a 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 in the previous examples to give a yellow solid monohydrochloride salt, m.p. 259-260 ° C (decomp.).

Calcd. For C H HH f fHCl: C, 60.31; H, 6.75; N, 8.80. Found: C, 60.49; H, 6.78; N, 8.59.

NMR (DMSO-d 6): 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 (1, bs).

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

Further examples of the compounds of the invention are given in Table III. These additional products were synthesized using the procedures described in Examples 48-52.

Table III

Additional products of formula (I) 30 R3 R5 H3cA + AN7 Rl

h2A2 R

- * i 16

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Ex. R R1 R2 R3 R4 m R5 n 53 Η H Et 3-N02Ph Me 0-1 54 Me Me Et 2-Furanyl Et 0-1 5 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 59 Me Me t-Bu 3-N02Ph Et 0-1 10 60 Me Me Ph 3-N02Ph Et 0-1 61 Me Me 2-Thienyl 3-N0 £ Ph Et 0-1 62 Me Me Et 2-Cl-5-NO2Ph Et 0-1 63 Me Me Et 3-ClPh Et 0-1 64 Me Me Et 3-CF3Ph Et 0 -1 15 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 69 Me Me Et 3-Pyridyl Et 0-1 20 70 Me Me Et 2-ClPh Et 0-1 71 Me Me Et 3-CNPh Et 0-1 72 Me Me Et 2-MeOPh Et 0-1 73 Me Et 2-bicyclohep- Et 0-1 tenyl 25 74 Me Me Et cyclohexyl Et 0-1 75 Me Me Et 4-AcNHPh Et 0-1 76 Me Me Et 3-0H-4-NO2Ph Et 0-1 77 Me H Me 4-isobutylphenyl Et 1 Ph 1 78 H CH 2 Ome Et 4-propoxyphenyl Et 0-1 30 79 Me Me Et 3-Ethylphenyl MeOCH2CH2 0 - 1 80 Me Me Et 3-CH3 SO2Ph Me2NCH2CH2 0 - 1 81 Me CH20Me Et 3-CF3SO2Ph Et 0-1 82 Me CH 2 Me Et 4-CF 3 SO 2 Ph MeOCH 2 CH 2 0 - 1 83 Me Me Et 3-indolyl Et 0-1 35 84 Me Me Et 4-0H-3-NO2Ph Et 0-1

DK 164668B

17

Ex. R R1 R2 R3 R4 m R5 n 85 Η H Et 3-NO2Ph i-Pr 0-1 86 Η H Et 3-NO2Ph MeOCH2CH2 0 - 1 5 87 Η H Et 3-NO0Ph C1CH2CH2 0 - 1 88 Η H Et 3- N02Ph Et 1 Ph 0 89 Η H Et 3-N02Ph H2NCH2CH2 0 - 1

The physical properties of the products according to the examples set out in Table III 10 are available to an extent in Table IV.

Table IV

Physical Properties - Compounds of Formula (I) Analysis

Ex. Name Mp. (° C) Calculated Found 53 methyl-5- (4,5-dihydro-2-oxazo-201-202 C, 55.96 55.99 yl) -6-ethyl-1,4-dihydro-2-methyl H, 5.44 5.60 Thyl-4- (3-nitrophenyl) -3-pyridine, 10.31 10.03 din-carboxylate, monohydrochloride 54 Ethyl 5- (4,5-dihydro-4, 4-di-138.5-140 C, 67.02 66.68 methyl-2-oxazolyl) -6-ethyl-4- (2- H, 7.31 7.36-furanyl) -1,4-methyl dihydro-2-methyl-N, 7.82 7.97 -3-pyridine carboxylate Ethyl 5- (4,5-dihydro-4,4-di-246-248 ° C, 58.73 58.36 methyl 2-oxazolyl) -6-ethyl-1,4-H, 6.28 6.63 -dihydro-2-methyl-4- (4-nitro-N, 9,34 9.40 phenyl) -3- pyridinecarboxylate, monohydrochloride 56 Ethyl 5- (4,5-dihydro-4,4-di-147-149 ° C, 71.71 71.69 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7.66 7.66-dihydro-2-methyl-4-phenyl-3- N, 7.60 7.48 pyridinecarboxylate 57 Ethyl 5- (4,5-dihydro-4,4-di - 175-177 ° C , 62.48, 62.41 (2-methyl-2-oxazolyl) -6-ethyl-4- H, 6.68 6.70 - (2-fluorophenyl) -1,4-dihydro-2- N, 6, 63 6.51 methyl 3-pyridinecarboxylate, monohydrochloride 45 58 Ethyl -5- (4,5-di hydro-4,4-di-216-217 ° C, 59.55 59.45 methyl-2-oxaz olyl) -1,4-dihydro-H, 6.52 6.72 2-methyl-6- (1-methylethyl) -4- N, 9.06 9.41 - (3-nitrophenyl) -3-pyridinecarbyl oxylate, monohydrochl ori d

DK 164668B

18

Analysis

Ex. Name Mp. (° C) Calculated Found 59 Ethyl 5- (4,5-dihydro-4,4-di-155-157 C, 65.29 64.90 methyl-2-oxazolyl) -6- (1,1- di-H, 7.08 7.17 methylethyl) -1,4-dihydro-2- N, 9.52 9.17 methyl-4- (3-nitropyridinecarboxylate) Ethyl 5- (4,5- dihydro-4,4-di-112-113 C, 67.67 67.73 methyl-2-oxazolyl) -1,4-dihydro-H, 5.90 5.86 -2-methyl-4- (3- nitrophenyl) -6- N, 9,11 9,04 -phenyl-3-pyridinecarboxylate 61 Ethyl 5- (4,5-dihydro-4,4-di-143-145 C, 57.20 57.17 methyl 2-oxazolyl) -1,4-dihydro-H, 5.21 5.31 -2-methyl-4- (3-nitrophenyl) -6- N, 8.34 8.06 - (2-thienyl) -3-Pyridinecarboxylate, monohydrochloride 62 Ethyl 4- (2-chloro-5-nitrophenyl) - 220-224 ° C, 54.56 54.59 -5- (4,5-dihydro-4,4-dimethyl-2 - H, 5.62 5.70 -oxazolyl) -6-ethyl-1,4-dihydro-N, 8.68 8.58 -2-methyl-3-pyridinecarboxylate, monohydrochloride 63 Ethyl 4- (3- chlorophenyl) -5- (4.5-170-172.5 C, 65.58 65.62-dihydro-4,4-dimethyl-2-oxazolo-H, 6.75 6.73yl) -6-ethyl -1,4-dihydro-2-meth-N, 6.95 6.84 ethyl 3-pyridinecarboxylate Cl, 8.80 8.83 64 Ethyl 5- (4,5-dihydro-4,4-di - 78 -81 C, 63.30 62.95 methyl-2-oxazolyl) -6-ethyl-1,4-H, 6.24 6.29 dihydro-2-methyl-4- [3- (trifluoro-N, 6 , 42 6,12 (methyl) phenyl] -3-pyridinecarboxylate 65 Ethyl 5- (4,5-dihydro-4,4-di-155-158 ° C, 64.14 63.92 methyl-2-oxazolyl ) -6-ethyl-1,4-H, 7,00 7,06 40-dihydro-2-methyl-4- (2-thienyl-H, 7,48 7,17 -3-pyridinecarboxylate 66 Ethyl-5 (4,5-di hydro-4,4-di-182-185 ° C, 66.65 66.28 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7.30 7.32 dihydro-4- (4-hydroxy-3-meth-N, 6.76, 6.54 oxyphenyl) -2-methyl-3-pyridinecarboxyl at 67 Ethyl 5- (4,5-dihydro-4,4-di 162-163 ° C, 72.23, 72.01 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7.91 7.97-dihydro-2-methyl-4- (3-methyl-N , 7.33 7.25 phenyl-3-pyridinecarboxylate 55 19

DK 164668 B

Analysis

Ex. Name Mp. (° C) Calculated Found 68 Ethyl 5- (4,5-dihydro-4,4-di-236-238 ° C, 68.63 68.79 methyl-2-oxazolyl) -6-ethyl-1,4 - H, 6.87 6.65-dihydro-2-methyl-4- (1-naphtha-N, 6.16 5.87 lenyl) -3-pyridinecarboxylate, monohydrochloride 69 Ethyl 5- (4, 5-dihydro-4,4-di-161.5-163.5 C, 67.94 67.70 methyl-2-oxazolyl) -6-ethyl -1,4- H, 7,39 7,48-dihydro -2-methyl-4- (3-pyridin-N, 11,32 11,22 nyl) -3-pyridinecarboxylate H 2 O, 0.49 0.5 70 Ethyl 4- (2-chlorophenyl) -5- (4.5 179-182 C, 60.15 59.78-dihydro-4,4-dimethyl-2-oxazo-H, 6,43 6,18-yl) -6-ethyl-1,4-dihydro-2-methyl N, 6.38 6.40 Thyl-3-pyridinecarboxylate, mono-Cl, 16.14 16.13 hydrochloride 71 Ethyl 4- (3-cyanophenyl) -5- (4,5- 179-181 C, 70 (21, 70,15-dihydro-4,4-dimethyl-2-oxazo-H, 6,92 6,92 yl) -6-ethyl-1,4-dihydro-2-meth-N, 10,68 10,54 thyl -3-Pyridinecarboxylate 72 Ethyl 5- (4,5-dihydro-4,4-di-230 C, 63.52 63.22 methyl-2-oxazolyl) -6-ethyl-1,4-H, 7 , 19 7,20-dihydro-4- (2-methoxyphenyl) - N, 6.45 6.24 -2-methyl-3-pyridinecarboxylate, monohydrochloride 73 Ethyl 4- (bicyclic) lo [2,2] hept-5-ene-165-166.5 C, 71.84 72.22 -2-yl) -5- (4,5-di hydro-4,4-di-H, 8 , 39 8.34 methyl-2-oxazolyl) -6-ethyl-1,4-N, 7.29 7.33-dihydro-2-methyl-3-pyridinecarboxyl at 74 Ethyl-4-cyclohexyl-5 (4,5-di-205-208 C, 64,30 64,14 hydro-4,4-dimethyl-2-oxazolyl) - H, 8.59 8.56 40 -6-ethyl-1,4-dihydro -2-methyl - N, 6.82 6.42 -3-pyridinecarboxylate, monohydrochloride 75 Ethyl 5- [4- (acetylamino) phe-240.5-241 C, 60.62 60.51 Nyl] -5 - (4,5-dihydro-4,4-di-H, 7,10 7,17 methyl-2-oxazolyl) -6-ethyl-1,4-N, 8,84,5,5-dihydro-2 methyl 3-pyridine-FLO, 2.84 2.70 carboxyl, monohydrochloride 50 76 Ethyl 5- (4,5-dihydro-4,4-di-145.5-146 ° C, 61.53 61.69 methyl-2-oxazolyl) -6-ethyl-1,4-H, 6.34 6.35 dihydro-4- (3-hydroxy-4-nitro-N, 9.79 9.78 phenyl) -2-methyl -3-pyridinecarboxylate 55

DK 164668 B

Analysis

Ex. Name Mp. (° C) Calculated Found 83 Ethyl 5- (4,5-dihydro-4,4-di-124.5-125 ° C, 68.32 68.67 methyl-2-oxazolyl) -6-ethyl-1 , 4- H, 7.57 7.45-dihydro-4- (1H-indol-3-yl) -2- N, 9,56 9,62-methyl-3-pyridinecarboxylate H 2 O, 2.05 1.97 ethanol, hemi hydrate 84 Ethyl 5- (4,5-dihydro-4,4-di-134.5-135 ° C, 56.72 56.62 methyl-2-oxazolyl) -6-ethyl -1,4- H, 6,06 6,08-dihydro-4- (4-hydroxy-3-nitro-N, 9,02 8,82 phenyl) -2-methyl-3-pyridinecarboxylate, monohydrochloride 85 1-methylethyl-5- (4,5-dihydro-160-161 C, 63.17 63.15 -2-oxazolyl) -6-ethyl-1,4-di-H, 6.31 6.38 hydro-2-methyl-4- (3-nitrophen-N, 10.52 10.27 nyl 3-pyridinecarboxylate 86 2-methoxyethyl-5- (4,5-dihydro-190-191 C, 55.82 55 , 65 -2-oxazolyl) -6-ethyl-1,4-di-H, 5.80 5.77 hydro-2-methyl-4- (3-nitrophen-N, 9.30 9.30 nyl) -3-pyridinecarboxylate, monohydrochloride 88 Ethyl 5- (4,5-dihydro-5-phenyl-193-195 ° C, 62.72 62.59 -2-oxazolyl) -6-ethyl-1,4 -di-H, 5.67 5.65 hydro-2-methyl-4- (3-nitrophen-N, 8,44 8,33 nyl) -3-pyridinecarboxylate, monohydrochloride

The data in the table shows that the compounds of formula I have specific blocking effect on calcium ion channels.

TABLE V

Fascie and tonic contractions of longitudinal needle muscle strip are of guinea pig 40 Ex. IC5Q (nm) No. fascic tonic 48 20 5 49 10 30 45 52 400 800 53 20 100 54 60 200

Claims (3)

21 DK 164668 B 1. Analogous Process for Preparation of 1,4-Dihydropyrid-5-yl (Cyclic Imidate) Esters of General Formula (I) • \ 2 '/ K 10. RR or acid addition salts thereof, wherein R and R * are independently selected from hydrogen, C 1-4 alkyl and C 1-4 alkoxy-C 14 alkyl, R 9 is C 1-4 alkyl, phenyl or thienyl, 15. is cyclic or 5 to 7 cycloalkyl. carbon atoms, bicycloalkenyl having 7 to 9 carbon atoms, furanyl, indolyl, pyridyl, thienyl, phenyl, naphthyl or substituted phenyl, wherein the substituents include acetamino, C 1-4 alkyl, C 1-4 alkoxy, cyano, halogen, hydroxyl, nitro and trifluoromethyl, R 1 is C 14 alkyl or C 1-4 alkoxy-C 1-4 alkyl, R 5 is C 1-4 alkyl or phenyl, m is 0 or 1, and n is 0 or 1, characterized by heating a compound of the general formula (II) R5 inHCHJa [CH0] _ (ΤΠ fVy h2n / r2125 wherein R, R, R, R, m and n have the above meanings, with a compound of the general formula (III) 22 DK 164668 BA r3 RVJY (III) h3ctN 3 4 5 wherein R and R have the above meanings, in the absence or presence of an inert organic solvent, to form a compound of formula (I) and then, if desired, convert a compound of formula ( I) to an acid addition salt thereof o Method according to claim 1, characterized in that R is 3 C is -alkyl, R is 3-nitrophenyl, m is 0 and n is 1. Process according to claim 1, characterized in that ethyl-5- (4,5-di-hydro-4,4-di-methyl-2-oxazolyl) -6-ethyl-1 is prepared from the corresponding starting materials. , 4-di hydro-2-methyl 1-4 - (3-nitro-phenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl -4- (2-furanyl) -1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl -5- (4,5-dihydro-4,4-dimethyl-2-carboxylic acid) oxazolyl) -6-ethyl -1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6- ethyl 4- (2-fluorophenyl) -1,4-dihydro-2-methyl-3-pyridine carboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1, 4-dihydro-2- methyl-6- (methyl ethyl) -4- (3-nitrophenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) ) -6- (1,1-dimethyl ethyl) -1,4-dihydro-2-methyl) -4- (3-nitrophenyl) -3-pyridinecarboxylate, 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-dimethyl-2-oxazolyl) 1,4-dihydro-2-methyl-4- (3-nitrophenyl) -6- (2-thienyl) -3-pyridine carboxylate, ethyl-4 - (2-chloro-5-nitrophenyl) -5- (4,5-di hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4- (3-chlorophenyl) -5- (4,5-di hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl -5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- [3-trifluoromethyl) phenyl] -3 pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (2-thienyl) -3-pyridinecarboxylate , ethyl 5- (4,5-di hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-4- (4-hydroxy-3-methoxyphenyl) -2-methyl 3-Pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (3-methylphenyl) -3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-4- (1-naphthyl) -3 pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2- oxazolyl) -6-ethyl-1,4-di hydro-2-methyl-4- (3- pyridinyl} -3-pyridinecarboxylate, ethyl 4- (2-chlorophenyl) -5- (4.5 -hydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4- (3-cyanophenyl) -5- (4,5-dihydro) -4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2- oxazolyl) -6-ethyl-1,4-dihydro-4- (2-methoxyphenyl) -2-methyl-3-pyridinecarboxylate, ethyl 4- (bicyclo- [2,2,1] hept-5-ene-2 -yl) -5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4-cyclohexyl-5 (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 4- [4-10 (acetylamino) phenyl ] -5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4 4-Dimethyl-2-oxazolyl) -6-ethyl-1,4-dihydro-4- (3-hydroxy-4-nitrophenyl) -2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro -4,4-dimethyl-2-oxazolyl) -6-ethyl-1,4-d ihydro-4- (1H-indol-3-yl) -2-methyl-3-pyridinecarboxylate, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -6-ethyl -1,4-di-hydro-4- (4-hydroxy-3-nitrophenyl) -2-methyl-3-pyridinecarboxylate, methyl 5- (4,5-dihydro-2-oxazolyl) -6-ethyl-1 4-dihydro-2-methyl-4- (3-nitro-phenyl) -3-pyridinecarboxylate, monohydrochloride, ethyl 5- (4,5-dihydro-2-oxazolyl) -6-ethyl-1,4-dihydro 2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, ethyl 5- [4,5-dihydro-4- (methoxymethyl) -4-methyl-2-oxazolyl] -6-ethyl 1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, monohydrochloride, ethyl 5- (4,5-dihydro-4,4-dimethyl-2-oxazolyl) -1,4- di hydro-2,6-dimethyl-4- (3-nitrophenyl) -3-pyridinecarboxylate monohydrochloride, ethyl 5- (5,6-dihydro-4,4,6-trimethyl-4H-1,3- oxazin-2-yl) -6-ethyl-1,4-dihydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, 1-methylethyl-5- (4,5-dihydro- 2-oxazolyl) -6-ethyl-1,4-di hydro-2-methyl-4- (3-nitrophenyl) -3-pyridinecarboxylate, 2-methoxyethyl-5- (4,5-dihydro-2-oxazolyl) ) -6-ethyl-l, 4-dihydro-2-methyl -4- (3-nitrophenyl) -3-pyridinecarboxylate, monohydrochloride. 30