CS277165B6

CS277165B6 - 1,4-dihydropyridine-3,5-dicarboxylic acid esters and their preparation

Info

Publication number: CS277165B6
Application number: CS91429A
Authority: CS
Inventors: Fridrich Rndr Csc Szemes; Alfonz Ing Csc Rybar; Ladislav Rndr Jezek; Jan Mudr Csc Drimal; Zdeno Rndr Csc Mahrla
Original assignee: Vyskumny Ustav Lieciv
Priority date: 1991-02-20
Filing date: 1991-02-20
Publication date: 1992-11-18
Also published as: CS42991A3

Abstract

Riešením sú nové estery kyseliny 1,4-dihydropyridín-3,5-dikarboxylovej s účinkami na kardiovaskulárny systém všeobecného vzorca I, v ktorom X představuje nitroskupinu v polohe 2' alebo 3' chlór a bróm skupinu v polohe 2' alebo 3* 1 a R1 představuje alkyl C-j· až C4 připadne rozvětvený alebo nenasýtený alkyl C3 alebo metoxyetylovú skupinu alebo je totožný s R2 a R2 představuje substiuovanú 1,3-dioxolánovú skupinu všeobecného vzorca II, v ktoré R3 a R4 představujú dva metyly alebo polymetylénovú skupinu (CH2)n, pričom n=4 až 7. Zosyntetizované zlúčeniny v in vivo testoch na zvieratách a v in vitro testoch vykazovali silný antihypertenzívny účinok a účinok na cerebrovaskulárny systém. Spůsob pripravy zlúčenín obecného vzorca I spočívá v tom, že sa nechá reagovat substituovaný benzaldehyd s este:·; i acetooctovej kyseliny a s esterom 3-aminokrotonovej kyseliny v prostředí inertného rozpúštadla pri 20 - 150 °C připadne za přítomnosti katalyzátorov. Lebo sa nechá reagovat substituovaný ester 2-(X-benzyliden) -3-ketokarboxylovej kyseliny s esterom 3-aminokrotonovej kyseliny za výše uvedených podmínok.The solution is new esters of 1,4-dihydropyridine-3,5-dicarboxylic acid with effects on the cardiovascular system of the general formula I, in which X represents a nitro group in position 2' or 3', chlorine and bromine groups in position 2' or 3* 1 and R1 represents an alkyl C-1 to C4, optionally branched or unsaturated alkyl C3 or a methoxyethyl group or is identical to R2 and R2 represents a substituted 1,3-dioxolane group of the general formula II, in which R3 and R4 represent two methyls or a polymethylene group (CH2)n, where n=4 to 7. The synthesized compounds in in vivo tests on animals and in in vitro tests showed a strong antihypertensive effect and an effect on the cerebrovascular system. The method for preparing compounds of the general formula I consists in reacting a substituted benzaldehyde with an ester:·; of acetoacetic acid and with 3-aminocrotonic acid ester in an inert solvent environment at 20 - 150 °C in the presence of catalysts. Because the substituted ester of 2-(X-benzylidene)-3-ketocarboxylic acid is allowed to react with the ester of 3-aminocrotonic acid under the above conditions.

Description

Vynález sa týká esterov kyselin 1,4-dihydropyridín-3,5-dikarboxylových a ich optických izomérov a diastereoizomérov s účinkami na kardiovaskulárny systém všeobecného vzorea IThe invention relates to esters of 1,4-dihydropyridine-3,5-dicarboxylic acids and their optical isomers and diastereoisomers with effects on the cardiovascular system of the general formula I

(I), v ktorom X představuje nitroskupinu v polohe 2', alebo chlór a bróm v polohe 2¹ alebo 3¹ a ·(I) in which X represents a nitro group in position 2 ', or chlorine and bromine in position 2 ¹ or 3 ¹ and ·

R¹ představuje alkyl C]_ až C₄, připadne rozvětvený alebo nenasý* V z 9 tený alkyl C₃ alebo metoxyetylovu skupinu, alebo je totožný s R aR ¹ represents C 1 to C ₄ alkyl, optionally branched or unsaturated C ₃ alkyl or methoxyethyl, or is identical to R a

R² představuje substituovaná 1,3-dioxolanovú skupinu všeobecného vzorea II ch₂- ch---CH₂ R ² represents a substituted 1,3-dioxolane group of general formula II ch ₂ - ch --- CH ₂

R³ R^u v ktorej R³, R⁴ predstavujú dva metyly alebo polymetylénovú skupinu (CH₂)_n, pričom n=4 až 7, alebo v ktorom X představuje nitroskupinu v polohe 3' a R^· představuje alkyl C₂ až C₄, připadne rozvětvený, alebo nenasýtený alkyl C₃, alebo metoxyetylovú skupinu alebo je totožný s R^4, aR ³ R ^u in which R ³ , R ⁴ represent two methyl or polymethylene group (CH ₂ ) _n , wherein n = 4 to 7, or in which X represents a nitro group in position 3 'and R 4 represents C ₂ to C alkyl ₄ , optionally branched or unsaturated C ₃ alkyl, or methoxyethyl or identical to R ^4, and

R² má vyššie uvedený význam, alebo v ktorom X představuje nitroskupinu v polohe 3' aR ² is as defined above, or in which X represents a nitro group in position 3 'and

R¹ představuje alkyl C-^ až C₄, připadne rozvětvený, alebo nenasýtený alkyl C₃, alebo metoxyetylovú skupinu aR ¹ represents C 1 to C ₄ alkyl, optionally branched or unsaturated C ₃ alkyl, or methoxyethyl and

OABOUT

R představuje substituovánu 1,3-dioxolanovu skupinu všeobecného vzorea II, v ktorej R³, R⁴ predstavujú heptametylénovú skupinu s n=7.R represents a substituted 1,3-dioxolane group of general formula II, in which R ³ , R ⁴ represent a heptamethylene group sn = 7.

Vynález sa týká aj spósobu přípravy zlúčenín vzorea I.The invention also relates to a process for the preparation of compounds of formula I.

Předmětné zlúčeniny majú dve centra chirality teda tvoria diastereoizoméry.The subject compounds have two centers of chirality and thus form diastereoisomers.

* Ί 2 3* Ί 2 3

Predmetne zlúčeniny všeobecného vzorca I, kde X, R , R , R a R⁴ majú vyššie uvedený význam, sa podía vynálezu vyrábajú cyklokondenzačnou reakciou substituovaného benzaldehydu vzorcaIn particular, the compounds of the formula I in which X, R, R, R and R ⁴ are as defined above are prepared according to the invention by a cyclocondensation reaction of a substituted benzaldehyde of the formula

IIIIII

(III), kde X má vyššie uvedený význam, s esterom kyseliny acetoctovej všeobecného vzorca IV(III), wherein X is as defined above, with an acetoacetic acid ester of formula IV

CH₃ - J - CH₂ - COO - R¹0 (IV), .CH ₃ - J - CH ₂ - COO - R ¹ 0 (IV),.

kde R ma vyssie uvedený význam a s esterom kyseliny 3-aminokrotonovej všeobecného vzorca V.wherein R is as defined above and with a 3-aminocrotonic acid ester of formula V.

CHo - C = CH - COO - R²í nh₂ (V), kde R² má vyššie uvedený význam, za přítomnosti inertného rozpúšťadla s výhodou nižších alifatických alkoholov s počtom uhlíkových atomov 1 až 4 pri 20 až 150 °C s výhodou pri teplote spatného toku rozpúšťadla. Na urýchlenie cyklokondenzačnej reakcie sa do reakčného prostredia přidává katalytické množstvo soli organických alebo anorganických kyselin a organických alebo anorganických zásad s výhodou chloridu vápenatého, pyridíniumchloridu alebo pyridíniumacetátu. Estery kyselin 1,4-dihydropyridín-3,5-dikarboxylových vzorca I sa podía vynálezu získavajú tiež cyklokondenzačnou reakciou esterov kyselin 2-(X-benzyliden)-3-ketokarboxylových všeobecného vzorca VIICH 2 - C = CH - COO - R ² nh ₂ (V), wherein R ² is as defined above, in the presence of an inert solvent, preferably lower aliphatic alcohols having 1 to 4 carbon atoms at 20 to 150 ° C, preferably at the temperature of the poor solvent flow. To accelerate the cyclocondensation reaction, a catalytic amount of a salt of organic or inorganic acids and organic or inorganic bases, preferably calcium chloride, pyridinium chloride or pyridinium acetate, is added to the reaction medium. According to the invention, the 1,4-dihydropyridine-3,5-dicarboxylic acid esters of the formula I are also obtained by a cyclocondensation reaction of 2- (X-benzylidene) -3-ketocarboxylic acid esters of the general formula VII.

(VII), kde R¹ má vyššie uvedený význam, s estermi kyseliny 3-aminokrotonovej všeobecného vzorca V, kde R ma vyššie uvedený význam, v inertnom organickom rozpúšťadle s výhodou alkoholov C]_ až C₄, etylacetátu, alkánov Cc až C₈ alebo cykloalkánov alebo v zmesi týchto inertných rozpúštadiel pri teplote 20 až 150 °C pri atmosferickom alebo pri zvýšenom tlaku. Cyklokondenzačná reakcia zlúčenín všeobecného vzorca V a VII sa výhodné uskutoční pri teplote spatného toku inertného organického rozpúšťadla alebo v zmesi týchto rozpúštadiel za súčasného azeotropného oddestilovávania reakčnej vody. Aj v tomto případe sme zistili, že přítomnost katalytických množstiev niektorých solí organických alebo anorganických kyselin a organických alebo anorganických zásad s výhodou chloridu vápenatého, pyridíniumchloridu a pyridíniumacetátu značné urýchluje reakciu.(VII), wherein R ¹ is as defined above, with 3-aminocrotonic acid esters of general formula V, wherein R is as defined above, in an inert organic solvent, preferably C 1 to C ₄ alcohols, ethyl acetate, C 1 to C _{8 alkanes} or cycloalkanes or in a mixture of these inert solvents at a temperature of 20 to 150 ° C at atmospheric or elevated pressure. The cyclocondensation reaction of the compounds of the formulas V and VII is preferably carried out at the reflux temperature of an inert organic solvent or in a mixture of these solvents, while azeotropically distilling off the water of reaction. In this case, too, we have found that the presence of catalytic amounts of certain salts of organic or inorganic acids and organic or inorganic bases, preferably of calcium chloride, pyridinium chloride and pyridinium acetate, considerably accelerates the reaction.

Estery kyseliny 3-aminokrotonovej všeobecného vzorca V sa podía vynálezu vyrobia pósobením amoniaku za katalýzy uhličitanu amonného, ktorý vzniká in situ z oxidu uhličitého a amoniaku na ester acetoctovej kyseliny všeobecného vzorca VI ch₃ C = CH₂ - COO - R² (VI) , kde R ma vyssie uvedený význam, v prostředí alkoholov Cj^ az C₄s výhodou v metanole pri -15 až +70 °C. Estery VI sa izolujú kryštalizáciou alebo vákuovou destiláciou. Tento sposob výroby poskytuje 3-aminokrotonany vzorca V vo vyššom výtažku a lepšej kvality ako známy postup (J. Robin a spol.: Francúzsky patent 2 577 552). Východzie látky, používané pri príprave předmětných zlúčenín, sú už známe alebo je možné ich připravit známými postupmi. Například esterov acetoctovej kyseliny vzorca IV a VI, kde R a R ma vyssie uvedený vyznám je mozne připravit z příslušných esterov kyseliny octovéj (J. Am. Chem. Soc. 56, 1766 (1934)) alebo výhodnejšie reakciou diketénu s příslušným alkoholem (Toshiro Izojima: Japonský patent 4873('52) (CA.48: 8818)). Esterov kyselin 2-(X-benzylidén)-3-ketokarboxylových všeobecného vzorca VII je možné připravit kondenzáciou acetoctanov všeobecného vzorca IV s aldehydem všeobecného vzorca III (Cope A. C.: J. Am. Chem. Soc. 67, 1017 (1945)).According to the invention, the 3-aminocrotonic acid esters of the formula V are prepared by the action of ammonia catalyzed by ammonium carbonate, which is formed in situ from carbon dioxide and ammonia, into the acetoacetic acid ester of the formula VI ch ₃ C = CH ₂ - COO - R ² (VI), wherein R is as defined above, in the environment of C 1 to C ₄ alcohols, preferably in methanol at -15 to + 70 ° C. Esters VI are isolated by crystallization or vacuum distillation. This production method provides 3-aminocrotonates of formula V in higher yield and better quality than the known process (J. Robin et al., French Patent 2,577,552). The starting materials used in the preparation of the subject compounds are already known or can be prepared by known methods. For example, acetoacetic acid esters of formula IV and VI, wherein R and R are as defined above, can be prepared from the corresponding acetic acid esters (J. Am. Chem. Soc. 56, 1766 (1934)) or more preferably by reacting diketene with the appropriate alcohol (Toshiro Izojima: Japanese Patent 4873 ('52) (CA.48: 8818)). 2- (X-Benzylidene) -3-ketocarboxylic acid esters of formula VII can be prepared by condensation of acetoacetates of formula IV with an aldehyde of formula III (Cope AC: J. Am. Chem. Soc. 67, 1017 (1945)).

V dalšom je predmet vynálezu popísáný v příkladech prevedenia bez toho, že by sa na tieto obmedzoval.In the following, the subject matter of the invention is described in the examples without being limited thereto.

Příklad 1Example 1

Etyl-,(l,4-dioxaspiro[4,5]dekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3 *-chlórfenyl)-3,5-pyridíndikarboxylovej a,(l,4-Dioxaspiro[4,5]dekan-2-yl)metylester kyseliny 3-aminokrotonovej1,4-Dihydro-2,6-dimethyl-4- (3 * -chlorophenyl) -3,5-pyridinedicarboxylic acid ethyl -, (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester and, 3-Aminocrotonic acid (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Do miešaného roztoku 76,9’g (l,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny acetoctovej v 80 ml metanolu sa přidá 0,5 g pevného oxidu uhličitého a po jeho rozpuštění 7,5 g plynného amoniaku. Zmes sa nechá reagovat pri 30 až 50 °C 2,5 hodiny, ochladí sa na 18 až 20 °C pričom začne kryštalizovat produkt.To a stirred solution of 76.9 g of (1,4-dioxaspiro [4.5] decan-2-yl) methyl acetoacetic acid ester in 80 ml of methanol was added 0.5 g of solid carbon dioxide and, after dissolving it, 7.5 g of gaseous carbon dioxide. ammonia. The mixture was allowed to react at 30-50 ° C for 2.5 hours, cooled to 18-20 ° C and the product began to crystallize.

Zmes sa uloží cez noc do mrazničky (-18 až -20 °C). Výtažok g, T. t. 58 až 60 °C b,Etyl-, (1,4-dioxaspiro[4,5]dekan-2-yl)metylester kyselinyThe mixture was stored in a freezer (-18 to -20 ° C) overnight. Yield g, T. t. 58-60 ° C b, Ethyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl acid ester

1,4-dihydro-2,6-dimetyl-4-(3'-chlórfenyl)-3,5-pyridíndikarboxylovej1,4-dihydro-2,6-dimethyl-4- (3'-chlorophenyl) -3,5-pyridinedicarboxylic

Zmes 7 g (l,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 6,8 g etylesteru kyseliny 3'-chlórbenzylidenacetoctovej v 20 ml metanolu sa zahrieva v uzavretom reaktore pri 90 až 92 °C 7 hodin. Produkt vykrystalizuje po přidaní 30 ml dietyléteru a 10 ml cyklohexánu a následným ochladením na -10 °C. Surový produkt sa prekryštalizuje zo zmesi 30 ml dietléteru, 10 ml octanu etylového a 30 ml cyklohexánu. Výtažok 4,2 g. T. t. 103 až 106 °C.A mixture of 7 g of 1,4-dioxaspiro [4.5] decan-2-yl) methyl ester of 3-aminocrotonic acid and 6.8 g of ethyl ester of 3'-chlorobenzylideneacetoacetic acid in 20 ml of methanol is heated in a closed reactor at 90-92 °. C 7 hours. The product crystallizes out after adding 30 ml of diethyl ether and 10 ml of cyclohexane and then cooling to -10 ° C. The crude product is recrystallized from a mixture of 30 ml of diethyl ether, 10 ml of ethyl acetate and 30 ml of cyclohexane. Yield 4.2 g. T. t. 103-106 ° C.

Pre C₂gH₃2^NO6^cl vypočítané, resp. nájdené: 63,73 resp. 63,95 % C, 6,58 resp. 6,73 % H a 2,86 resp. 2,86 % N.For C ₂ gH ₃ 2 ^N O6 ^c l calculated, resp. found: 63.73 resp. 63.95% C, 6.58 resp. 6.73% H and 2.86 resp. 2.86% N.

Příklad 2Example 2

Etyl-,(1,4-Dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3 *-chlórfenyl)-3,5-pyridíndikarboxylovej kyseliny a,(1,4-Dioxaspiro [4,4] nonan-2-yl)metylesteru kyseliny 3-aminokrotonovej1,4-Dihydro-2,6-dimethyl-4- (3 * -chloro-phenyl) -3,5-pyridinedicarboxylic acid ethyl, - (1,4-dioxo-spiro [4.4] nonan-2-yl) -methyl ester and 3-Aminocrotonic acid (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester

Do miešaného roztoku 72,7 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny acetoctovej v 80 ml metanolu sa přidá 0,5 g pevného oxidu uhličitého a po jeho rozpuštění 7,5 g amoniaku.To a stirred solution of 72.7 g of (1,4-dioxaspiro [4.4] nonan-2-yl) methyl acetoacetic acid ester in 80 ml of methanol was added 0.5 g of solid carbon dioxide and, after dissolving it, 7.5 g of ammonia.

Zmes sa nechá reagovat 2,5 hodiny pri 30 až 50 °C. V dalšom sa metanol odpaří za zníženého tlaku a odparok sa vákuovo predestiluje. Zachytává sa frakcia vrúca pri 142 až 145 °C a 53 Pa tlaku. Výtažok 68 g olej, produktu.The mixture was allowed to react at 30-50 ° C for 2.5 hours. Next, the methanol was evaporated under reduced pressure and the residue was distilled in vacuo. A fraction boiling at 142-145 ° C and 53 Pa pressure is collected. Yield 68 g of oil, product.

b,Etyl-,(l,4-dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-chlórfenyl)-3,5-pyridíndikarboxylovejb, 1,4-Dihydro-2,6-dimethyl-4- (3'-chlorophenyl) -3,5-pyridinedicarboxylic acid ethyl, (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester

Roztok 6,8 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 6,8 g etylesteru kyseliny 3'-chlórbenzylidenacetoctovej v 20 ml metanolu sa zahrieva v uzavretom reaktore pri 90 až 92 °C 8 hodin. Potom sa metanol odpaří za zníženého tlaku, odparok sa rozpustí v 30 ml dietyléteru přidá sa 10 ml cyklohexánu. Produkt krystalizuje pri -10 °C. Rekryštalizácia sa uskutoční z uvedenej zmesi. Výtažok 6,5 g. T. t. 79 až 83 °C.A solution of 6.8 g of (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester of 3-aminocrotonic acid and 6.8 g of ethyl ester of 3'-chlorobenzylideneacetoacetic acid in 20 ml of methanol is heated in a closed reactor at 90 to 92 ° C for 8 hours. The methanol is then evaporated off under reduced pressure, the residue is dissolved in 30 ml of diethyl ether and 10 ml of cyclohexane are added. The product crystallizes at -10 ° C. Recrystallization is performed from said mixture. Yield 6.5 g. T. t. 79-83 ° C.

Pre C₂5H₃qC1NO₆ vypočítané, resp. nájdené: 63,08 resp. 63,95 %For C ₂ 5H ₃ qClNO ₆ calculated, resp. found: 63.08 resp. 63,95%

Cl, 6,35 resp. 6,56 % H a 2,94 resp. 2,91 % N.Cl, 6.35 resp. 6.56% H and 2.94 resp. 2.91% N.

Příklad 3Example 3

Etyl-,(1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-brómfenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (2'-bromophenyl) -3,5-pyridinedicarboxylic acid ethyl, - (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Roztok 4,1 g (1,4-dioxaspiro[4,4]děkan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 4,45 g etylesteru kyseliny 2-brómbenzyliden5 acetoctovej v 20 ml etanolu za přítomnosti 0,04 ml ekvimolárnej zmesi kyseliny octovéj a pyridinu sa reflexuje 3 hodiny. Produkt krystalizuje pri ochadení na 0 až -4 °C. Rekryštalizuje sa z octanu etylového. Výťažok 3,6 g. T. t. 142 až 143 °C.A solution of 4.1 g of 3-aminocrotonic acid methyl ester (1,4-dioxaspiro [4.4] decan-2-yl) and 4.45 g of 2-bromobenzylidene-5-acetoacetic acid ethyl ester in 20 ml of ethanol in the presence of 0.04 ml of equimolar mixture. acetic acid and pyridine are refluxed for 3 hours. The product crystallizes on cooling to 0-4 ° C. Recrystallized from ethyl acetate. Yield 3.6 g. T. t. 142-143 ° C.

Pre C₂₆H₃₂BrNo₆ vypočítané, resp. nájdené 58,43 resp. 58,28 % C, 6,04 resp. 6,02 % H a 2,62 resp. 2,83 % N.For C ₂₆ H ₃₂ BrNo ₆ calculated, resp. found 58.43 resp. 58.28% C, 6.04 resp. 6.02% H and 2.62 resp. 2.83% N.

Příklad 4Example 4

Etyl-,(l,4-dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-brómfenyl)-3,5-pyridíndikarboxylovej ·1,4-Dihydro-2,6-dimethyl-4- (2'-bromophenyl) -3,5-pyridinedicarboxylic acid ethyl, (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester;

Roztok 4,3 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 4,5 g etylesteru kyseliny 2'-brómbenzylidenacetoctovej v 20 ml etanolu za přítomnosti 0,04 ml ekvimolárnej zmesi kyseliny octovéj a pyridinu sa refluxuje 3 hodiny. Etanol sa odpaří za zníženého tlaku a zvyšok sa kryštalizuje z 20 ml octanu etylového. Produkt sa rekryštalizuje z 15 ml octanu etylového. Výťažok 2 g. T.t. 130 až 132 °C.A solution of 4.3 g of (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester of 3-aminocrotonic acid and 4.5 g of ethyl ester of 2'-bromobenzylideneacetoacetic acid in 20 ml of ethanol in the presence of 0.04 ml of equimolar mixture acetic acid and pyridine are refluxed for 3 hours. The ethanol is evaporated off under reduced pressure and the residue is crystallized from 20 ml of ethyl acetate. The product is recrystallized from 15 ml of ethyl acetate. Yield 2 g. M.p. 130-132 ° C.

Pre C₂5H₃₀BrNO₆ vypočítané, resp. nájdené: 57,69 resp. 67,58 % C, 0,81 resp. 5,83 % H a 2,69 resp. 2,75 % N.For C ₂ 5H ₃₀ BrNO ₆ calculated, resp. found: 57.69 resp. 67.58% C, 0.81 resp. 5.83% H and 2.69 resp. 2.75% N.

Příklad 5Example 5

Metyl-,(2,2-dimetyl-l,3-dioxolan-4-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-nitrofenyl)-3,5-pyridíndikarboxylovej a,(2,2-Dimetýl-l,3-dioxolan-4-yl)metylester kyseliny 3-aminokrotonovej1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl - (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester a, 3-Aminocrotonic acid (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

Do miešaného roztoku 65 g (2,2-dimetyl-l,3-dioxolan-4-yl)metylesteru kyseliny acetoctovej v 80 ml metanolu sa přidá 0,5 g oxidu uhličitého a po jeho rozpuštění 11,6 g amoniaku. Zmes sa nechá reagovat pri 30 až 50 °C 2 hodiny, ochladí sa na 18 až 20 °C pričom začne kryštalizovať produkt. Pri 0 až -5 °C sa nechá stát 4 hodiny. Výťažok 55 g. T. t. 88 až 91 °C.To a stirred solution of 65 g of (2,2-dimethyl-1,3-dioxolan-4-yl) methyl acetoacetic acid ester in 80 ml of methanol was added 0.5 g of carbon dioxide and, after dissolving it, 11.6 g of ammonia. The mixture was allowed to react at 30-50 ° C for 2 hours, cooled to 18-20 ° C and the product began to crystallize. Allow to stand at 0 to -5 ° C for 4 hours. Yield 55 g. T. t. 88-91 ° C.

b,Metyl-,(2,2-dimetyl-l,3-dioxolan-4-yl)metylesteru kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-nitrofenyl)-3,5-pyridíndikarboxylovejb, 1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

Roztok 6,5 g (2,2,-dimetyl-l,3-dioxolan-4-yl)metylesteru kyseliny 3-aminokrotonovej a 7,5 g metylesteru kyseliny 2'-nitrobenzylidenacetoctovej sa zahrieva v uzavretom reaktore v 25 ml metanolu pri 90 až 92 °C 8 hodin. Produkt kryštalizuje pri 0 až -5 °C. Prekryštalizuje sa z 35 ml metanolu. Výťažok 7,7 g. T. t. 53 až 58 °C.A solution of 6.5 g of (2,2'-dimethyl-1,3-dioxolan-4-yl) methyl ester of 3-aminocrotonic acid and 7.5 g of methyl ester of 2'-nitrobenzylideneacetoacetic acid is heated in a closed reactor in 25 ml of methanol at 90 ml. to 92 ° C for 8 hours. The product crystallizes at 0 to -5 ° C. Recrystallize from 35 ml of methanol. Yield 7.7 g. T. t. 53-58 ° C.

Pre C₂₂H₂₆N₂O₈ vypočítané, resp. nájdené: 59,18 resp. 59,33 % C, 5,87 resp. 5,88 % H, 6,27 resp. 6,27 % N.For C ₂₂ H ₂₆ N ₂ O ₈ calculated, resp. found: 59.18 resp. 59.33% C, 5.87 resp. 5.88% H, 6.27 resp. 6.27% N.

Příklad 6Example 6

Etyl-,(2,2-dimetyl-l,3-dioxolan-4-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-chlórfenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-chlorophenyl) -3,5-pyridinedicarboxylic acid ethyl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

Roztok 4,5 g (2,2-dimetyl-l,3-dioxolan-4-yl)metylesteru kyselinyA solution of 4.5 g of (2,2-dimethyl-1,3-dioxolan-4-yl) methyl acid ester

3-aminokrotonovej, 5,5 g etylesteru kyseliny 3’-chlórbenzylidenacetoctovej a 0,005g pyridíniumchloridu v 15 ml etanolu sa refluxuje 2 hodiny. Krystalizuje sa 8 hodin pri 0 až -5 °C.3-Aminocrotonic acid, 5.5 g of ethyl 3'-chlorobenzylideneacetoacetate and 0.005 g of pyridinium chloride in 15 ml of ethanol are refluxed for 2 hours. Crystallize at 0-5 ° C for 8 hours.

Prekryštalizuje sa z 80%ného metanolu. Výťažok 4 g. T. t. 86 ažRecrystallize from 80% methanol. Yield 4 g. T. t. 86 to

87°C.87 ° C.

Pre C₂3H₂gClNOg vypočítané, resp. nájdené: 61,39 resp. 61,42 °C, 6,27 % H, 3,11 resp. 2,94 % N.For C ₂ 3H ₂ gClNOg calculated, resp. found: 61.39 resp. 61.42 ° C, 6.27% H, 3.11 resp. 2.94% N.

Příklad 7 ' 'Example 7 ''

Etyl-,(2,2-dimetyl-l,3-dioxolan-4-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-brómfenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (2'-bromophenyl) -3,5-pyridinedicarboxylic acid ethyl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

Roztok 4,5 g (2,2-dimetyl-l,3-dioxolan-4-yl)metylesteru kyseliny 3-aminokrotonovej a 6 g etylesteru kyseliny 2'-brómbenzylidenacetoctovej v 15 ml metanolu sa zahrieva v uzavretom reaktore pri 90 až 92 °C 8 hodin. Po ochladení na -5 °C krystalizuje produkt. Rekryštalizuje sa z 85%ného metanolu. Výťažok 5,2 g. T. t. 132 až 134 °C.A solution of 4.5 g of (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester of 3-aminocrotonic acid and 6 g of ethyl ester of 2'-bromobenzylideneacetoacetic acid in 15 ml of methanol is heated in a closed reactor at 90-92 °. C 8 hours. After cooling to -5 ° C, the product crystallizes. It is recrystallized from 85% methanol. Yield 5.2 g. T. t. 132-134 ° C.

Pre C₂₃H₂₈BrNO_g vypočítané, resp. nájdené: 55,87 resp. 55,84 % C, 5,71 resp. 5,70 % H a 2,83 resp. 2,74 % N.For C ₂₃ H ₂₈ BrNO _g calculated, resp. found: 55.87 resp. 55.84% C, 5.71 resp. 5.70% H and 2.83 resp. 2.74% N.

Příklad 8Example 8

Propargyl-,(1,4-dioxaspiro[4,5]dekan-2-yl)metylester kyselinyPropargyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl acid ester

1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic

Roztok 4,4 g (1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 4,4 g propargylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 15 ml etanolu sa refluxuje za přítomnosti 0,005 ml ekvimolárnej zmesi kyseliny octovéj a pyridinu 4 hodiny. Najprv sa za miešania kryštalizuje pri 18 až 20 °C a potom pri -5 °C. Rekryštalizuje sa z 80%ného etanolu. Výťažok 7 g. T. t. 124 až 126 °C.A solution of 4.4 g of 3-aminocrotonic acid (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester and 4.4 g of 3'-nitrobenzylideneacetoacetic acid propargyl ester in 15 ml of ethanol is refluxed in the presence of 0.005 ml of an equimolar mixture. acetic acid and pyridine for 4 hours. It is first crystallized with stirring at 18 to 20 ° C and then at -5 ° C. It is recrystallized from 80% ethanol. Yield 7 g. T. t. 124-126 ° C.

Pre C₂₇H₃₀N₂O₈ vypočítané, resp. nájdené: 63,51 resp. 63,46 % C, 5,92 resp. 5,90 % H a 5,49 resp. 5,44 % N.For C ₂₇ H ₃₀ N ₂ O ₈ calculated, resp. found: 63.51 resp. 63.46% C, 5.92 resp. 5.90% H and 5.49 resp. 5.44% N.

Příklad 9Example 9

Propargyl-,(1,4-dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovejPropargyl - (1,4-dioxaspiro [4.4] nonan-2-yl) methyl 1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid ester

Roztok 5,1 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 5,5 g propargylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 20 ml etanolu sa refluxuje za přítomnosti 0,005 ml ekvimolárnej zmesi pyridinu a kyseliny octovej 2 hodiny. Kryštalizuje sa najprv pri 18 až 20 °C potom pri -5 °C. Rekryštalizuje sa zo 75%ného metanolu. Výťažok 7,3 g. T. t. 124 až 128 °C.A solution of 5.1 g of 3-aminocrotonic acid (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester and 5.5 g of 3'-nitrobenzylideneacetoacetic acid propargyl ester in 20 ml of ethanol is refluxed in the presence of 0.005 ml of an equimolar mixture. pyridine and acetic acid for 2 hours. It crystallizes first at 18 to 20 ° C then at -5 ° C. It is recrystallized from 75% methanol. Yield 7.3 g. T. t. 124-128 ° C.

Pre C₂₆H₂₈N₂O_g vypočítané, resp. nájdené: 62,89 resp. 63,01 % C, 5,68 resp. 5,67 % H a 5,64 resp. 5,63 % N.For C ₂₆ H ₂₈ N ₂ O _g calculated, resp. found: 62.89 resp. 63.01% C, 5.68 resp. 5.67% H and 5.64 resp. 5.63% N.

Příklad 10Example 10

Propargyl-,(2,2-dimetyl-l,3-dioxolan-4-yl)metylester kyselinyPropargyl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl acid ester

1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridindikarboxylovej1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic

Roztok 4,5 g (2,2-dimetyl-l,3-dioxolan-4-yl)metylesteru kyseliny 3-aminokrotonovej a 5,5 g propargylesteru kyseliny 3'-nitrobenzyl idenacetoctovej v 15 ml metanolu sa zahrieva v 20 ml metanolu, pri 90 až 92 °C 8 hodin. Přidá sa 5 ml etanolu a 5 ml vody a odsaje sa s aktívnym uhlím. Produkt vykrystalizuje pri -5 °C. Rekryštalizuje sa z 23 ml 83%ného metanolu. Výťažok 6,6 g. T. t. 105 až 107 °C.A solution of 4.5 g of (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester of 3-aminocrotonic acid and 5.5 g of propargyl ester of 3'-nitrobenzylideneacetoacetic acid in 15 ml of methanol is heated in 20 ml of methanol. at 90-92 ° C for 8 hours. 5 ml of ethanol and 5 ml of water are added and filtered off with suction with activated charcoal. The product crystallizes at -5 ° C. It is recrystallized from 23 ml of 83% methanol. Yield 6.6 g. T. t. 105-107 ° C.

Pre ^2₄Η2βΝ₂Ο₈ vypočítané, resp. nájdené: 61,29 resp. 61,27 % C, 5,57 resp. 5,56 % H a 5,96 resp. 5,92 % N.For ^ 2 ₄ Η2βΝ ₂ Ο ₈ calculated, resp. found: 61.29 resp. 61.27% C, 5.57 resp. 5.56% H and 5.96 resp. 5.92% N.

Příklad 11Example 11

Di-(l,4-dioxaspiro[4,5]dekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridinedicarboxylic acid di- (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Roztok 5,1 g (l,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej, 5,6 g (l,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny acetoctovej a 3 g 2-nitrobenzaldehydu sa refluxuje v 20 ml metanolu za přítomnosti 0,1 g chloridu vápenatého 7 hodin. Produkt vykrystalizuje ochladením na -5 °C. Rekryštalizuje sa z 20 ml metanolu. Výťažok 5,1 g. T. t. 69 až 71 °C.A solution of 5.1 g of 3-aminocrotonic acid methyl ester (1,4-dioxaspiro [4.5] decan-2-yl), 5.6 g of (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester of acetoacetic acid and 3 g of 2-nitrobenzaldehyde are refluxed in 20 ml of methanol in the presence of 0.1 g of calcium chloride for 7 hours. The product crystallizes by cooling to -5 ° C. It is recrystallized from 20 ml of methanol. Yield 5.1 g. T. t. 69-71 ° C.

Pre C₃₃H₄₂N₂O₁₀ vypočítané, resp. nájdené: 63,23 resp. 63,31 % C, 6,76 resp. 6,81 % H a 4,47 resp. 4,44 % N.For C ₃₃ H ₄₂ N ₂ O ₁₀ calculated, resp. found: 63.23 resp. 63.31% C, 6.76 resp. 6.81% H and 4.47 resp. 4.44% N.

Příklad 12Example 12

Metyl-,(1,4-dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl - (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester

Roztok 9 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 8,4 g metylesteru kyseliny 2'-nitrobenzylidenacetoctovej v 25 ml metanolu sa zahrieva pri 92 až 95 °C 8 hodin. Kryštalizuje sa vychladením reakčnej zmesi na -5 °C. Produkt sa rekryštalizuje z 20 ml metanolu. Výťažok 9 g. T. t. 67 až 69 °C.A solution of 9 g of (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester of 3-aminocrotonic acid and 8.4 g of methyl ester of 2'-nitrobenzylideneacetoacetic acid in 25 ml of methanol is heated at 92-95 ° C for 8 hours. . It is crystallized by cooling the reaction mixture to -5 ° C. The product is recrystallized from 20 ml of methanol. Yield 9 g. T. t. 67-69 ° C.

Pre C₂₄H₂₈N₂O₈ vypočítané, resp. nájdené: 61,00 resp. 59,65 % C, 5,97 resp. 6,16 % H a 5,93 resp. 5,69 % N.For C ₂₄ H ₂₈ N ₂ O ₈ calculated, resp. found: 61.00 resp. 59.65% C, 5.97 resp. 6.16% H and 5.93 resp. 5.69% N.

Příklad 13Example 13

Metoxyetyl-,(1,4-dioxaspiro[4,5]dekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl} 3,5-pyridíndikarboxylove j1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl} -3,5-pyridinedicarboxylic acid methoxyethyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester.

Roztok 7 g (1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 6,1 g metoxyetylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 20 ml etanolu sa refluxuje za přítomnosti 0,01 g pyridíniumchloridu 2 hodiny. Produkt vykryštalizuje ochladením na -5 °C. Rekryštalizuje sa z etanolu. Výťažok 5,7 g. T. t.A solution of 7 g of 3-aminocrotonic acid (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester and 6.1 g of 3'-nitrobenzylideneacetoacetic acid methoxyethyl ester in 20 ml of ethanol is refluxed in the presence of 0.01 g of pyridinium chloride 2. hours. The product crystallizes by cooling to -5 ° C. It is recrystallized from ethanol. Yield 5.7 g. T. t.

130 až 132 °C.130-132 ° C.

Pre C₂₇H₃₄N₂O_g vypočítané resp. nájdené: 61,12 resp. 61,26 % C,For C ₂₇ H ₃₄ N ₂ O _g calculated resp. found: 61.12 resp. 61.26% C,

6,45 resp. 6,54 % H a 5,28 resp. 5,19 % N.6.45 resp. 6.54% H and 5.28 resp. 5.19% N.

Příklad 14Example 14

Metoxyetyl-,(1,4-dioxaspiro[4,4]nonan-2-yl)ester kyseliny 1,4-dihydro-2 ,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridindikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methoxyethyl (1,4-dioxaspiro [4.4] nonan-2-yl) ester

Roztok 13 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 3-aminokrotonovej a 14,7 g 2-metoxyetylesteru kyseliny 3'-nitrozylidenacetoctovej sa refluxuje v 35 ml etanolu 7 hodin. Produkt vykrystalizuje pri -5 °C. Rekryštalizuje sa zo zmesi etanolu a octanu etylového (4:1). Výtažok 12,5 g. T. t. 144 až 146 °C.A solution of 13 g of 3-aminocrotonic acid (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester and 14.7 g of 3'-nitrosylideneacetoacetic acid 2-methoxyethyl ester is refluxed in 35 ml of ethanol for 7 hours. The product crystallizes at -5 ° C. Recrystallize from a mixture of ethanol and ethyl acetate (4: 1). Yield 12.5 g. T. t. 144-146 ° C.

Pre C₂₆H₃₂N₂O_g vypočítané resp. nájdené: 60,45 resp. 60,38 % C, 6,24 resp. 6,28 % H a 5,42 resp. 5,37 % N.For C ₂₆ H ₃₂ N ₂ O _g calculated resp. found: 60.45 resp. 60.38% C, 6.24 resp. 6.28% H and 5.42 resp. 5.37% N.

Příklad 15Example 15

Metoxyetyl-,(1,4-dioxaspiro[4,7]dodekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridindikarboxylovej a,(1,4-dioxaspiro[4,7]dodekan-2-yl)metylester kyseliny 3-aminokrotonovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methoxyethyl, (1,4-dioxaspiro [4,7] dodecan-2-yl) methyl ester, and 3-Aminocrotonic acid (1,4-dioxaspiro [4.7] dodecan-2-yl) methyl ester

Do miešaného roztoku 49 g (1,4-dioxaspiro[4,7]dodekan-2-yl)metylesteru kyseliny acetoctovej v 50 ml metanolu sa přidá 0,5 g pevného oxidu uhličitého a po jeho rozpuštění sa do roztoku zavedie 7 g plynného amoniaku. Zmes sa nechá reagovat pri 35 až 50 °C 2 hodiny, ochladí sa na 0 až -5 °C pričom vykrystalizuje produkt. Před separáciou sa zmes ochladí na -13 až -15 °C a udržuje sa pri tejto teplote 2 hodiny. Produkt sa premyje rovnako vychladeným metanolom. Výtažok 36,7 g. T. t. 45 až 50 °C.To a stirred solution of 49 g of (1,4-dioxaspiro [4.7] dodecan-2-yl) methyl acetoacetic acid ester in 50 ml of methanol was added 0.5 g of solid carbon dioxide, and after dissolving it, 7 g of ammonia gas was introduced into the solution. . The mixture is allowed to react at 35 to 50 ° C for 2 hours, cooled to 0 to -5 ° C and the product crystallizes out. Prior to separation, the mixture was cooled to -13 to -15 ° C and maintained at this temperature for 2 hours. The product is washed with equally cooled methanol. Yield 36.7 g. T. t. 45-50 ° C.

b,Metoxyetyl-,(1,4-dioxaspiro[4,7]dodekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovejb, 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methoxyethyl, (1,4-dioxaspiro [4,7] dodecan-2-yl) methyl ester

Roztok 6 g (1,4-dioxaspiro[4,7]dodekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 5,66 g metoxyetylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 20 ml metanole sa zahrieva pri 90 až 92 °C v uzavretom reaktore 6 hodin. Potom sa metanol odpaří a zvyšok sa kryštalizuje v 18 ml n-butanolu. Produkt sa rekryštalizuje z etanolu. Výtažok 8 g. T. t. 126 až 129 °C.A solution of 6 g of 3-aminocrotonic acid (1,4-dioxaspiro [4,7] dodecan-2-yl) methyl ester and 5.66 g of 3'-nitrobenzylideneacetoacetic acid methoxyethyl ester in 20 ml of methanol is heated at 90-92 ° C in a closed reactor 6 hours. The methanol is then evaporated off and the residue is crystallized from 18 ml of n-butanol. The product is recrystallized from ethanol. Yield 8 g. T. t. 126-129 ° C.

Pre C₂₉H₃₈N₂O₉ vypočítané resp. nájdené: 62,35 resp. 62,75 % C, 6,83 resp. 6,99 % H a 5,02 resp. 5,00 % N.For C ₂₉ H ₃₈ N ₂ O ₉ calculated resp. found: 62.35 resp. 62.75% C, 6.83 resp. 6.99% H and 5.02 resp. 5.00% N.

Příklad 16Example 16

Metyl-,(1,4-dioxaspiro[4,7]dodekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl - (1,4-dioxaspiro [4,7] dodecan-2-yl) methyl ester

Roztok 4,24 g (1,4-dioxaspiro[4,7]dodekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a metylesteru kyseliny 3'-nitrobenzyliden acetoctovej v 20 ml metanolu sa zahrieva pri 90 až 92 °C 6 hodin.A solution of 4.24 g of (1,4-dioxaspiro [4.7] dodecan-2-yl) methyl ester of 3-aminocrotonic acid and methyl ester of 3'-nitrobenzylidene acetoacetic acid in 20 ml of methanol is heated at 90-92 ° C for 6 hours.

Roztok sa v dalšom odsaje sig živočišného uhlia a produkt vykryštalizuje pri 0 až -5 °C. Rekryštalizuje sa z etanolu. Výťažok 6,1 g. T. t. 143 až 146 °C.The solution is further filtered off with suction and the product crystallizes out at 0-5 [deg.] C. It is recrystallized from ethanol. Yield 6.1 g. T. t. 143-146 ° C.

Pre C2₇H₃₄N₂0g vypočítané resp. nájdené: 63,02 resp. 63,22 % C, 6,65 resp. 6,80 % H a 5,44 resp. 5,48 % N.For C2 ₇ H ₃₄ N ₂ 0g calculated resp. found: 63.02 resp. 63.22% C, 6.65 resp. 6.80% H and 5.44 resp. 5.48% N.

Příklad 17Example 17

Alyl-,(1,4-dioxaspiro[4,5]dekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid allyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Roztok 5,5 g (1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 5,5 g alylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 15 ml izopropanolu sa refluxuje za přítomnosti 0,05 g chloridu vápenatého 2 hodiny. Produkt vykryštalizuje sa po ochladení na 0 až -5 °C. Rekryštalizuje sa zo zmesi octanu etylového a cyklohexánu. Výťažok 4,5 g. T. t. 120 až 125 °C.A solution of 5.5 g of (1,4-dioxaspiro [4.5] decan-2-yl) methyl 3-aminocrotonic acid ester and 5.5 g of 3'-nitrobenzylideneacetoacetic acid allyl ester in 15 ml of isopropanol is refluxed in the presence of 0.05 g of calcium chloride 2 hours. The product crystallizes after cooling to 0-5 ° C. It is recrystallized from a mixture of ethyl acetate and cyclohexane. Yield 4.5 g. T. t. 120-125 ° C.

Pre C₂₇H₃₂N₂O₈ vypočítané resp. nájdené: 63,26 resp. 63,10 % C, 6,29 resp. 6,30 % H a 5,46 resp. 5,32 % N.For C ₂₇ H ₃₂ N ₂ O ₈ calculated resp. found: 63.26 resp. 63.10% C, 6.29 resp. 6.30% H and 5.46 resp. 5.32% N.

Příklad 18Example 18

Izopropyl-,(1,4-dioxaspiro[4,5]dekan-2-yl)metylester kyselinyIsopropyl - (1,4-dioxaspiro [4.5] decan-2-yl) methyl acid ester

1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxy lovej1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic

Roztok 5 g (l,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a.5,1 g izopropylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 15 ml etanolu sa refluxuje za přítomnosti 0,01 g pyridíniumchloridu 2 hodiny. Reakčná zmes sa v ďalšom přefiltruje s aktívnym uhlím, rozpúšťadlo sa odpaří a produkt kryštalizuje zo zmesi 15 ml dietyléteru a 15. ml petroléteru. Výťažok 5,2 g. T. t. 126 až 130 °C.A solution of 5 g of 1,4-dioxaspiro [4,5] decan-2-yl) methyl ester of 3-aminocrotonic acid and 5.1 g of isopropyl ester of 3'-nitrobenzylideneacetoacetic acid in 15 ml of ethanol is refluxed in the presence of 0.01 g of pyridinium chloride. 2 hours. The reaction mixture is further filtered with activated charcoal, the solvent is evaporated and the product is crystallized from a mixture of 15 ml of diethyl ether and 15 ml of petroleum ether. Yield 5.2 g. T. t. 126-130 ° C.

Pre C₂₇H₃₄N₂0₈ vypočítané resp. nájdené: 63,02 resp. 63,20 % C, 6,65 resp. 6,74 % H a 5,44 resp. 5,31 % N.For C ₂₇ H ₃₄ N ₂ 0 ₈ calculated resp. found: 63.02 resp. 63.20% C, 6.65 resp. 6.74% H and 5.44 resp. 5.31% N.

Příklad 19Example 19

Etyl-,(1,4-dioxaspiro[4,7]dodekan-2-yl)metylesteru kyselinyEthyl 1- (1,4-dioxaspiro [4.7] dodecan-2-yl) methyl ester

3-aminokrotonovej a 7,9 g etylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 25 ml metanolu sa zahrieva v uzavretom reaktore pri 90 až 95 °C 9 hodin. Produkt vykryštalizuje pri 0 až -5 °C. Rekryštalizuje sa z etanolu. Výťažok 10 g. T. t. 156 až 158 °C.Of 3-aminocrotonic acid and 7.9 g of ethyl 3'-nitrobenzylideneacetoacetate in 25 ml of methanol are heated in a closed reactor at 90-95 ° C for 9 hours. The product crystallizes at 0 to -5 ° C. It is recrystallized from ethanol. Yield 10 g. T. t. 156-158 ° C.

Pre C₂₈H₃₆N₂O₈ vypočítané, resp. nájdené: 63,61 resp. 63,47 % C, 6,86 resp. 7,00 % H a 5,30 resp. 5,26 % N.For C ₂₈ H ₃₆ N ₂ O ₈ calculated, resp. found: 63.61 resp. 63.47% C, 6.86 resp. 7.00% H and 5.30 resp. 5.26% N.

Příklad 20Example 20

Metyl-,(l,4-dioxaspiro[4,5]dekan-2-yl)metyIesteru kyseliny 1,4-dihydro-2,6-dimetyl-4-(2'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Roztok 5,4 g (1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 5 g metylesteru kyseliny 2'-nitrobenzylidenacetoctovej v 15 ml metanolu sa zahrieva pri 90 až 92 °C v uzaCS 277165 B6 vretom reaktore 8 hodin. Po ochladení na 0 až -5 °C vykrystalizuje produkt. Rekryštalizuje sa z 80%ného metanolu. Výťažok 3,7 g.A solution of 5.4 g of (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester of 3-aminocrotonic acid and 5 g of methyl ester of 2'-nitrobenzylideneacetoacetic acid in 15 ml of methanol is heated at 90-92 ° C in uzaCS. 277165 B6 reactor spindle 8 hours. After cooling to 0-5 ° C, the product crystallizes out. It is recrystallized from 80% methanol. Yield 3.7 g.

T. t. 115 až 121 °C.T. t. 115-121 ° C.

Pre ΰ25Η₃₀Ν₂Οθ vypočítané, resp. nájdené: 61,71 resp. 61,99 % C,For ΰ25Η ₃₀ Ν ₂ Οθ calculated, resp. found: 61.71 resp. 61.99% C,

6,42 resp. 6,31 % H a 5,76 resp. 5,74 % N.6.42 resp. 6.31% H and 5.76 resp. 5.74% N.

Příklad 21Example 21

Di-(1,4-dioxaspiro[4,5]děkan-2-yl)metylesteru kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid di- (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Roztok 5,1 g (1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej, 5,6 g (1,4-dioxaspiro[4,5]děkan-2-yl) metylesteru kyseliny acetoctovej a 3,1 g 3-nitrobenzaldehydu v 15 ml metanolu sa refluxuje za přítomnosti 0,1 g chloridu vápenatého 7 hodin. Produkt vykryštalizuje po ochladení na 0 až -5 °C. Rekryštalizuje sa z etanolu. Výťažok 5,1 g. T. t. 126 až 127 °C. Pre C₂₃H₄₂N₂O₁₀ vypočítané resp. nájdené: 63,24 resp. 63,32 % C, 6,76 resp. 6,76 % H a 4,47 resp. 4,39 % N.A solution of 5.1 g of 3-aminocrotonic acid methyl ester (1,4-dioxaspiro [4.5] decan-2-yl), 5.6 g of (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester of acetoacetic acid and 3.1 g of 3-nitrobenzaldehyde in 15 ml of methanol are refluxed in the presence of 0.1 g of calcium chloride for 7 hours. The product crystallizes after cooling to 0-5 ° C. It is recrystallized from ethanol. Yield 5.1 g. T. t. 126-127 ° C. For C ₂₃ H ₄₂ N ₂ O ₁₀ calculated resp. found: 63.24 resp. 63.32% C, 6.76 resp. 6.76% H and 4.47 resp. 4.39% N.

Příklad 22 .Example 22.

Izopropyl-,(1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid isopropyl - (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester

Roztok 9 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 7,2 g izopropylesteru kyseliny 3'-nitrobenzylidénacetoctovej v 30 ml etanolu sa refluxuje za přítomnosti 0,02 g pyridíniumchloridu 2 hodiny. Produkt vykryštalizuje pri 0 až -5 °C. Rekryštalizuje sa z metanolu. Výťažok 9,2 g. T. t. 119 až 120 °C.A solution of 9 g of 3-aminocrotonic acid (1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester and 7.2 g of 3'-nitrobenzylideneacetoacetic acid isopropyl ester in 30 ml of ethanol is refluxed in the presence of 0.02 g of pyridinium chloride 2. hours. The product crystallizes at 0 to -5 ° C. Recrystallize from methanol. Yield 9.2 g. T. t. 119-120 ° C.

Pre C₂₆H₃₂N₂O₈ vypočítané, resp. nájdené: 62,38 resp. 62,20 % C, 6,44 resp. 6,43 % H a 5,60 resp. 5,45 % N.For C ₂₆ H ₃₂ N ₂ O ₈ calculated, resp. found: 62.38 resp. 62.20% C, 6.44 resp. 6.43% H and 5.60 resp. 5.45% N.

Příklad 23Example 23

Etyl-,(1,4-dioxaspiro[4,5]děkan-2-yl)metylesteru kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid ethyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Roztok 12 g (1,4-dioxaspiro[4,5]dekan-2-yl)metylesteru kyseliny 3-aminokrotonovej a 12,5 g etylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 25 ml etanolu sa refluxuje za přítomnosti 0,005 g pyridíniumchloridu 2 hodiny. Produkt vykryštalizuje pri 0 až -5 °C. Rekryštalizuje sa z 80%ného metanolu. Výťažok 13 g. T. t. 109 až 111 °C.A solution of 12 g of 3-aminocrotonic acid (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester and 12.5 g of 3'-nitrobenzylideneacetoacetic acid ethyl ester in 25 ml of ethanol is refluxed in the presence of 0.005 g of pyridinium chloride for 2 hours. The product crystallizes at 0 to -5 ° C. It is recrystallized from 80% methanol. Yield 13 g. T. t. 109-111 ° C.

Pre C₂₆H₃₂N₂O₈ vypočítané resp. nájdené: 62,38 resp. 62,36 % C, 6,44 resp. 6,48 % H a 5,60 resp. 5,53 % N.For C ₂₆ H ₃₂ N ₂ O ₈ calculated resp. found: 62.38 resp. 62.36% C, 6.44 resp. 6.48% H and 5.60 resp. 5.53% N.

Příklad 24Example 24

Etyl-,(1,4-dioxaspiro[4,4,]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid ethyl - (1,4-dioxaspiro [4,4,] nonan-2-yl) methyl ester

Roztok 13 g (1,4-dioxaspiro[4,4]nonan-2-yl)metylesteru kyselinyA solution of 13 g of (1,4-dioxaspiro [4.4] nonan-2-yl) methyl acid ester

3-aminokrotonovej a 12,3 g etylesteru kyseliny 3'-nitrobenzylidenacetoctovej v 20 ml etanolu sa refluxuje 7 hodin. Produkt vykrystalizuje pri 0 až -5 °C. Rekryštalizuje sa z etanolu. Výťažok 14,5 g. T. t. 118 až 121 ’C.Of 3-aminocrotonic acid and 12.3 g of ethyl 3'-nitrobenzylideneacetoacetate in 20 ml of ethanol are refluxed for 7 hours. The product crystallizes at 0-5 ° C. It is recrystallized from ethanol. Yield 14.5 g. T. t. 118 to 121 ’C.

Pre υ₂₅Η₃₀Ν₂Ο₈ vypočítané resp. nájdené: 61,71 resp. 61,69 % C, 6,21 resp. 6,26 % H a 5,76 resp. 5,74 % N.For υ ₂₅ Η ₃₀ Ν ₂ Ο ₈ calculated resp. found: 61.71 resp. 61.69% C, 6.21 resp. 6.26% H and 5.76 resp. 5.74% N.

Farmakologické skúškyPharmacological tests

Tieto doposial nepopísané zlúčeniny vykázali v in vivo a v in vitro pokusoch nasledovné účinky: ’These hitherto undescribed compounds have shown the following effects in vivo and in vitro experiments:

Štúdie vazby na DPH receptoryVAT receptor binding studies

Nové zlúčeniny sa viažu na DPH receptory v tkanivách kostrového svalu, srdca a mozgu králíka. Štúdie boli realizované pomocou radioligandu ³Η PN200-110 (AMERSHAM). Hodnotila sa maximálna vazbová kapacita B_max a disociačná konstanta K_D. Příklady sú uvedené v tabulkách 1, 2 a 3.The new compounds bind to DPH receptors in rabbit skeletal muscle, heart and brain tissues. The studies were performed using radioligand ³ Η PN200-110 (AMERSHAM). The maximum binding capacity B _max and the dissociation constant K _D were evaluated. Examples are given in Tables 1, 2 and 3.

Výsledky ukazujú, že nové zlúčeniny sú schopné vazby na DHP receptory v tkanivách kostrového svalu, srdca a mozgu králíka.The results show that the new compounds are capable of binding to DHP receptors in rabbit skeletal muscle, heart and brain tissues.

Relaxačně účinky na izolovaných artériach psa kontrahovaných KCL.Relaxing effects on isolated arteries of a dog contracted by KCL.

Bazilárne a koronárne artérie boli izolované zo psov (bastardi oboch pohlaví, hmotnosti 7 až 10 kg) anestezováných pentobarbitalom (30 mg.kg^-1). Preparáty ciev vo forme prstencov boli umiestnená v Krebsovom roztoku zloženia v mmol.l^-1: NaCl 118; KCI 4,7; KH₂PO₄ 1,2; MgSO₄ 1,2; CaCl₂ 2,5; NaHCO₃ 25; glukóza 11. Roztok bol sýtený pneumoxidom (95 % 0₂ + 5 % C0₂) P^i teplote 37 °C. Změny sily izometrickej kontrakcie sa sledovali tenzometricky. Preparáty sa stabilizovali 2 hodiny pri predpátí 10 mN-bazilárna artéria a 60 mN koronárna artéria. Kontrakcia prstencov sa navodila přidáním 8.10^-2 mol.l^-1 KCI. Po dosiahnutí plato sa aplikovali látky v stúpajúcich koncentráciach 10^-12 až 10^-7 mol.l^-1 kumulatívnym sposobom. Použité rozpúšťadlo (najviac 0,96 % etanol) bolo bez účinku na cievny tonus.Basilar and coronary arteries were isolated from dogs (bastards of both sexes, weighing 7 to 10 kg) anesthetized with pentobarbital (30 mg.kg ^-1 ). The vascular preparations in the form of rings were placed in a Krebs solution of the composition in mmol.l ^-1 : NaCl 118; KCl 4.7; KH ₂ PO ₄ 1.2; MgSO ₄ 1.2; CaCl ₂ 2.5; NaHCO ₃ 25; glucose 11. The solution was saturated with pneumoxide (95% O ₂ + 5% CO ₂ ) at 37 ° C. Changes in the force of isometric contraction were monitored tensometrically. The preparations were stabilized for 2 hours at a bias of 10 mN-basilar artery and 60 mN coronary artery. The contraction of the rings was induced by the addition of 8.10 ^-2 mol.l ^-1 KCl. After reaching the plateau, the substances were applied in increasing concentrations of 10 ^-12 to 10 ^-7 mol.l ^{-1 in a} cumulative manner. The solvent used (maximum 0.96% ethanol) had no effect on vascular tone.

Účinnost látok sa vyjádřila hodnotou IC₅₀-koncentrácia látky vyvolávajúca 50% inhibíciu kontrakcie navodenej KČ1. Příklady sú uvedené v tabuíke 4.The potency of the substances was expressed as the IC ₅₀ value - the concentration of the substance causing 50% inhibition of the CK1-induced contraction. Examples are given in Table 4.

Výsledky ukazujú že nové zlúčeniny vyvolávajú silnú dilatáciu hladkých svalov izolovaných ciev psa (a.baziláris, a.coronária). Tento účinok je spósobený blokádou vstupu vápnika do buniek cez pomalé vápníkové kanály.The results show that the new compounds induce a strong dilatation of the smooth muscles of the isolated vessels of the dog (A. basilaris, A. coronary artery). This effect is due to the blockade of calcium entry into cells through slow calcium channels.

Antihypertenzívne účinkyAntihypertensive effects

Na bdělých spontánně hypertenzných potkanoch (SHR) bol sledovaný vplyv testovaných látok na systolický krvný tlak po p.o. podaní. Látky boli aplikované p.o. v dávkách 1,5 a 10 mg.kg po emulgacii v 5% roztoku arabskéj gumy. Hodnoty systolického tlaku boli sledované nekrvavou cestou (piezoelektrický snímač s registráciou na BP zapisovač fy UGO BASSILLE) na chvostovej artérii 1 až 4 hodiny po aplikácii testovaných látok. Před každým meraním boli zvieratá temperované 20 minút pri teplote 37 °C. Hodnotilo sa maximálně zníženie systolického krvného tlaku p (torr) dosiahnuté počas sledovaného časového intervalu. Kontrolně hodnoty tlaku sa nachádzali v rozpátí 200 až 240 torrov. Příklady sú uvedené v tabulke 5.In awake spontaneously hypertensive rats (SHR), the effect of test substances on systolic blood pressure after p.o. submission. The substances were applied p.o. in doses of 1.5 and 10 mg.kg after emulsification in 5% gum arabic solution. The systolic pressure values were monitored by a bloodless route (piezoelectric sensor with registration on a BP recorder by UGO BASSILLE) on the tail artery 1 to 4 hours after application of the test substances. Prior to each measurement, the animals were tempered at 37 ° C for 20 minutes. The maximum reduction in systolic blood pressure p (torr) achieved during the observed time interval was evaluated. Pressure control values ranged from 200 to 240 torr. Examples are given in Table 5.

Na bdělých psoch s renovaskulárnou hypertenziou (připravených podlá procedúry GOLDBLATTA (Goldbatt H.: J. Exp. Med., 65, 4, 671-675 (1973)) v modifikácií EBIHARA (Ebihara A., Grollmann A.: Am. J. Phiysiol., 214, 1, 1-5 (1968)) bol sledovaný antihypertenzívny účinok látok aplikovaných i v dávkách 0,01 až 1,0 mg .kg. Krvný tlak sa sledoval po chronickej katetrizacii a.carotis. Kontrolně hodnoty systolického resp. diastolického tlaku boli 175 ±6 torrov a 120 ±3 torry, srdcová frekvencia 146 ±0,6 c/min. Účinok látok sa vyjádřil hodnotou _5QED (koncentrácia látky, pri ktorej dochádza k poklesu krvného tlaku na 50 % hodnoty) resp. ako relativná účinnost oproti účinku nimodipínu. Příkladu sú uvedené v tabulke 6. ,In awake dogs with renovascular hypertension (prepared according to the GOLDBLATTA procedure (Goldbatt H .: J. Exp. Med., 65, 4, 671-675 (1973)) in EBIHARA modification (Ebihara A., Grollmann A .: Am. J. Phiysiol., 214, 1, 1-5 (1968)), the antihypertensive effect of substances administered at doses of 0.01 to 1.0 mg. Kg was monitored, and blood pressure was monitored after chronic catheterization of the carotid artery. 175 ± 6 torr and 120 ± 3 torr, heart rate 146 ± 0.6 c / min The effect of the substances was expressed as a _5Q ED (concentration of the substance at which the blood pressure drops to 50% of the value) or as a relative efficacy versus nimodipine, examples of which are given in Table 6.

Výsledky ukazujú, že nové zlúčeniny znižujú krvný tlak u hyperterzných zvierat, teda móžu nájsť v terapii uplatnenie ako antihypertenzíva.The results show that the new compounds lower blood pressure in hypertherapeutic animals, so they may find use in therapy as antihypertensives.

Účinok na kardiovaskulárny systém anestezovaných psovEffect on the cardiovascular system of anesthetized dogs

Na pertobarbitálom (30 μg.kg~¹) anestezovaných psoch, samcoch, hmotnosti 8 až 13 kg sa sledoval vplyv látok v dávke 3 mg.kg i.v. na krvný prietok vo vertebrálnej artérii (elektromagnetický pritokomer), krvný tlak v aorte a srdcovú frekvenciu. Sledované parametre boli merané a zaznamenávané na polygrafe HELLIGE. Příklady sú uvedené v tabulkách 7, 8 a 9. Výsledky ukazujú, že v pokusoch na anestezovaných psoch nové zlúčeniny v nízkých dávkách sposobujú výrazné zvýšenie prietoku v a.vertebralis bez výraznéjšieho vplyvu na krvný tlak. Tieto výsledky naznačujú možné použitie týchto látok na liečenie cerebrálnej cirkulácie.The effect of substances at a dose of 3 mg.kg iv on vertebral artery blood flow (electromagnetic flow meter), aortic blood pressure and heart rate was monitored in pertobarbital (30 μg.kg ~ ^{1) anesthetized dogs, males, weighing 8 to 13 kg.} The monitored parameters were measured and recorded on a HELLIGE polygraph. Examples are given in Tables 7, 8 and 9. The results show that in experiments on anesthetized dogs, the new compounds at low doses cause a significant increase in a.vertebral flow without a significant effect on blood pressure. These results suggest the possible use of these substances for the treatment of cerebral circulation.

Akútna toxicitaAcute toxicity

Akútna toxicita sa stanovila v opakovaných pokusoch na myšiach samcoch (SWIS., chov Dobrá Voda), hmotnosti 20 až 23 g. Látky boli aplikované i.v. po rozpuštění v 7%nom etanole lOtim skupinám zvierat (n=10). LD₅₀ bola identifikovaná metodou podlá Litchfielda a Wilcoxona J. Pharmacol. Ther., 96, 99-113 (1949). Příklady sú uvedené v tabulke 10.Acute toxicity was determined in repeated experiments on male mice (SWIS., Dobrá Voda), weighing 20 to 23 g. The substances were applied even after dissolution in 7% ethanol to 10 groups of animals (n = 10). LD ₅₀ was identified by the method of Litchfield and Wilcoxon J. Pharmacol. Ther., 96, 99-113 (1949). Examples are given in Table 10.

Výsledky ukazujú, že akútna toxicita nových zlúčenín je porovnatelná s akútnou toxicitou nimodipínu.The results show that the acute toxicity of the new compounds is comparable to the acute toxicity of nimodipine.

Tabulka 1Table 1

Maximálna vazbová kapacita (B__„) a disociačná konstanta (K_n) ILICLA.Maximum binding capacity (B__ „) and dissociation constant (K _n ) of ILICLA.

u testovaných látok na vzorkách kostrového svalu králíka.for test substances on rabbit skeletal muscle samples.

Zlúčenina Compound B_max(p mol/mg.prot.)B _max (p mol / mg.prot.) K_D(nmol/l)K _D (nmol / l) n n 6 8 21 Nimodipín Nisoldipín 6 8 21 Nimodipine Nisoldipine 0,81 + 0,16 0,86 + 0,16 0,30 + 0,06 0,67 + 0,08 0,33 + 0,07 0.81 ± 0.16 0.86 ± 0.16 0.30 ± 0.06 0.67 ± 0.08 0.33 ± 0.07 0,90 + 0,16 0,48 + 0,07 0,19 + 0,02 0,82 + 0,19 0,26 + 0,05 0.90 + 0.16 0.48 ± 0.07 0.19 ± 0.02 0.82 ± 0.19 0.26 ± 0.05 7 9 9 1,1 12 7 9 9 1.1 12

Číslo zlúčeniny je totožné s číslom příkladu v ktorom je popísaná jej příprava.The number of the compound is identical to the number of the example in which its preparation is described.

Tabulka 2Table 2

Maximálna vazbová kapacita (^B _max) ^a disociačná konstanta (¾) u testovaných látok na vzorkách mozgového tkaniva králíka.Maximum binding capacity ( ^B _max ) ^and dissociation constant (¾) for test substances on rabbit brain tissue samples.

Zlúčenina Compound B_max(p mol/mg.prot.)B _max (p mol / mg.prot.) K_D(nmol/l)K _D (nmol / l) n n 6 6 0,15 + 0,03 0.15 ± 0.03 1,08 + 0,12 1.08 ± 0.12 9 9 8 8 0,12 + 0,02 0.12 ± 0.02 1,01 + 0,19 1.01 ± 0.19 6 6 21 21 0,20 + 0,07 0.20 ± 0.07 1,12 + 0,37 1.12 ± 0.37 6 6 Nimodipín Nimodipine 0,13 + 0,02 0.13 ± 0.02 1,06 + 0,24 1.06 ± 0.24 5 5 Nisoldipín Nisoldipin 0,33 + 0,07 0.33 ± 0.07 4,58 + 0,64 4.58 ± 0.64 7 7

Tabulka 3Table 3

Maximálna vazbová kapacita (B___v) a disociačná konstanta (K_n) liid U u testovaných látok na vzorkách srdcového svalu králíka.Maximum binding capacity (B__ _v ) and dissociation constant (K _n ) of human U for test substances on rabbit heart muscle samples.

Zlúčenina Compound B_max(p mol/mg.prot.)B _max (p mol / mg.prot.) K_D(nmol/l)K _D (nmol / l) n n 6 6 0,69 + 0,10 0.69 ± 0.10 4,83 + 0,99 4.83 ± 0.99 4 4 8 8 0,05 + 0,01 0.05 + 0.01 0,37 + 0,09 0.37 ± 0.09 3 3 21 21 0,21 + 0,02 0.21 ± 0.02 0,84 + 0,26 0.84 ± 0.26 5 5 Nimodipín Nimodipine 0,28 + 0,08 0.28 ± 0.08 0,89 + 0,22 0.89 ± 0.22 5 5 Nisoldipín Nisoldipin 4,25 + 0,84 4.25 ± 0.84 9,05 + 0,75 9.05 ± 0.75 4 4

Relaxačně účinky testovaných látok na izolovanej bazilárnej a koronárnej artérii psa kontrahovanéj KC1 (n=5).Relaxing effects of test substances on isolated basilar and coronary artery of KC1-contracted dog (n = 5).

Tabulka 4Table 4

Zlúčenina Compound ICgQÍmol.l“¹)ICgQÍmol.l “ ¹ ) A. Bazilaris A. Bazilaris A. Coronaria A. Coronaria 13 13 1,18 . 10“⁹ 1.18. 10 “ ⁹ 1,17 - 10“⁸ 1.17 - 10 “ ⁸ 14 14 2,29 . 10“⁸ 2.29. 10 “ ⁸ 8,91 . 10“¹⁰ 8.91. 10 “ ¹⁰ 19 19 3,11 . 10“⁸ 3.11. 10 “ ⁸ 7,29 . 10“¹¹ 7.29. 10 “ ¹¹ 21 21 4,84 . 10“¹² 4.84. 10 “ ¹² 1,15 . 10“¹⁰ 1.15. 10 “ ¹⁰ 23 23 2,67 . 10⁹ 2.67. 10 ⁹ < 1 . 10“⁷ <1. 10 “ ⁷ 24 24 3,03. 10“⁸ 3.03. 10 “ ⁸ 6,02 . 10“⁹ 6.02. 10 “ ⁹ SR-1399 SR-1399 1,88 . 10“⁹ 1.88. 10 “ ⁹ 1,24 . 10“⁸ 1.24. 10 “ ⁸ Nimodipín Nimodipine 3,14 . 10“⁹ 3.14. 10 “ ⁹ 2,60 . 10“⁹ 2.60. 10 “ ⁹

Tabulka 5Table 5

Zníženie systolického krvného tlaku u SHR potkanov po p.o. aplikácii látok. V každéj dávkovéj skupině bolo 8 až 10 zvierat.Reduction of systolic blood pressure in SHR rats after p.o. application of substances. There were 8 to 10 animals in each dose group.

Zlúčenina ./ /dávka v //mg.kg“¹ Compound .//dose in //mg.kg “ ¹ Pokles systolického tlaku △ (torr) Systolic pressure drop △ (torr) 1 1 5 5 10 10 1 1 20,0 ± 9,6^a 20.0 ± 9.6 ^a 38,1 ± 16,9^a 38.1 ± 16.9 ^a 45,6 ± 15,2^a 45.6 ± 15.2 ^a 2 2 32,8 ± 11,5^a 32.8 ± 11.5 ^a 31,1 ± 18,2^a 31.1 ± 18.2 ^a 43,9 ± 13,9^a 43.9 ± 13.9 ^a 18 18 18,5 ± 13,1 18.5 ± 13.1 44,0 ± 20,5^a 44.0 ± 20.5 ^a 44,5 ± 26,7^a 44.5 ± 26.7 ^a 23 23 25,0 ± 17,3 25.0 ± 17.3 61,7 ± 18,4^a 61.7 ± 18.4 ^a 66,1 ± 27,2^a 66.1 ± 27.2 ^a Nisoldipín Nisoldipin 58,1 ± 29,5^a 58.1 ± 29.5 ^a 52,0 ± 17,2^a 52.0 ± 17.2 ^a 86,0 ± 16,5^a 86.0 ± 16.5 ^a

a p < 0,05and p <0.05

Tabulka 6Table 6

Relativná antihypertenzívna účinnost testovaných látok a vplyv na srdcovú frekvenciu voči Nimodipínu u psov s renovaskulárnou hypertenziou.Relative antihypertensive efficacy of test substances and effect on heart rate against Nimodipine in dogs with renovascular hypertension.

Zlúčinina Compound S[ED₅₀]S [ED ₅₀ ] Účinnost Efficiency D[ED₅₀]D [ED ₅₀ ] Účinnost Efficiency f[ED₅₀]f [ED ₅₀ ] Účinnost Efficiency n n 13 13 0,508 ±0,02 0.508 ± 0.02 1,17 1.17 0,250 ±0,02 0.250 ± 0.02 1,24 1.24 0,640 ±0,01 0.640 ± 0.01 1,52 1.52 4 4 14 14 0,561 ±0,02 0.561 ± 0.02 1,12 1.12 0,290 ±0,03 0.290 ± 0.03 1,47 1.47 0,600 ±0,03 0.600 ± 0.03 1,63 1.63 4 4 21 21 0,253 ±0,03 0.253 ± 0.03 2,54 2.54 0,210 ±0,02 0.210 ± 0.02 2,03 2.03 0,510 ±0,04 0.510 ± 0.04 1,92 1.92 4 4 23 23 0,317 ±0,02 0.317 ± 0.02 2,02 2.02 0,301 ±0,015 0.301 ± 0.015 2,14 2.14 • · · • · · • · · • · · 4 4 24 24 0,945 ±0,05 0.945 ± 0.05 0,68 0.68 0,295 ±0,02 0.295 ± 0.02 1,47 1.47 0,883 ±0,207 0.883 ± 0.207 1,12 1.12 4 4 SR-1399 SR-1399 0,266 ±0,05 0.266 ± 0.05 2,42 2.42 0,379 ±0,01 0.379 ± 0.01 1,13 1.13 0,467 ±0,01 0.467 ± 0.01 2,09 2.09 4 4 Nimodipín Nimodipine 0,465 ±0,03 0.465 ± 0.03 1 1 0,427 ±0,02 0.427 ± 0.02 1 1 0,979 ±0,05 0.979 ± 0.05 1 1 4 4

^ED50 “ ^v mmol.kg^-1 i-v. ^ED 50 “ ⁱⁿ mmol.kg ^-1 iv.

S - systolický tlakS - systolic pressure

D - diastolický tlak f - srdcová frekvenciaD - diastolic pressure f - heart rate

SR 1399 - je metyl [1,4-dioxaspiro[4,4]nonan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4-(3'-nitrofenyl)-3,5-pyridíndikarboxylovej (Fr. pat. 2577552)SR 1399 - 1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl [1,4-dioxaspiro [4.4] nonan-2-yl) methyl ester (Fr. Pat. 2577552)

CS. 277165 B6CS. 277165 B6

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Tabulka 8 — 1Table 8 - 1

Vplyv testovaných látok po i.v. po podaní v dávke 3 mg.kg na stredný krvný tlakThe effect of test substances after i.v. after administration at a dose of 3 mg.kg for mean blood pressure

Nisoldipí n Nisoldipí n 127,3 - 21,9 127.3 - 21.9 o 0 OJ + 1 to P about 0 OJ + 1 to P o o 0) + 1 to P about about 0) + 1 to P 115,6 - 30,0 115.6 - 30.0 117,3 - 31,5 117.3 - 31.5 120,3 Í 31,6 120.3 and 31.6 121,3 - 30,6 121.3 - 30.6 122,0 - 31,5 122.0 - 31.5 125,0 Í 33,4 125.0 and 33.4 to V 00 + 1 to <D OJ rH to V 00 + 1 to <D OJ rH 00 00 ti c ti c Nimodipín Nimodipine 135,5 Í 7,0 135.5 and 7.0 + b 113,0 - 10,4 + b 113.0 - 10.4 + b 118,5 - 9,3 + b 118.5 - 9.3 121,5 - 10,6^b 121.5 - 10.6 ^b 124,2 * 11,3^a 124.2 * 11.3 ^a O + 1 A O 2 ABOUT + 1 A ABOUT 2 133,2 í 9,3 133.2 and 9.3 138,7 Í 7,6 138.7 and 7.6 139,0 - 5,8 139.0 - 5.8 139,7 - 7,6 139.7 - 7.6 xr xr •H • H 14,6 14.6 OJ OJ . . .3. 14, 1 . . .3. 14, 1 ‘ετ ‘Ετ ti O m ti O m φ co Ή φ what Ή 14,8 14.8 17,0 17.0 15,8 15.8 ti OJ ti* you OJ ti * ,ý tlak (Torr) pressure (Torr) c c oj oj L30,3 - L30.3 - 121,3 - 121.3 - + 1 to m P + 1 to m P + 1 to A to + 1 to And that + 1 o A CO -d + 1 about A WHAT -d + 1 to co OJ + 1 to what OJ 131,3 131.3 - 9‘τετ - 9th 131,0 i 131.0 i 132,0 - 132.0 - 00 00 Φ Φ 2 2 21,4 21.4 Δ to CO Δ to WHAT Λ xí* P Λ xí * P % 2 % 2 17,5 17.5 19,7 19.7 19,0 19.0 18,4 18.4 O rd About rd krvi blood O ABOUT ω ω + 1 m + 1 m + 1 0) + 1 0) + 1 to + 1 to + 1 O + 1 ABOUT + 1 to + 1 to + 1 O + 1 ABOUT + 1 o + 1 about + 1 o + 1 about + 1 to + 1 to + 1 to + 1 to 00 00 S t redný S t red co P what P o P o P to P to P oí P oí P 0) P 0) P P P OJ P OJ P co m P co m P xr to xr to xř’ to xř ’it '□ '□ CO WHAT ti N ti N ti 7 ti 7 to to τΗ τΗ tH tH *χτ * χτ ti N ti N XI OJ XI OJ % % n n ω ω co what G G O ABOUT co what o' about' o about (D (D N N co what + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 m m p-4 p-4 st* st * OJ OJ OJ OJ to to to to o about o about ti⁴ ti ⁴ OJ OJ o about in OJ in OJ xr rH xr rH P P 2 2 OJ OJ OJ OJ co’ OJ co OJ OJ ó' on Ή ó 'on Ή 6' P 6 ' P o P about P o 00 P or 00 P N N in in ^ΛΡ ^{Λ Ρ} Λ OJ Λ OJ Ή Ή to to m m in in O ABOUT to to to to to to to to to to xr xr OJ OJ N N N N to to co what co what OJ OJ + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 co what 140,3 140.3 128,6 128.6 120,8 120.8 130,6 130.6 135,0 135.0 141,3 141.3 139, 0 139, 0 141,0 141.0 139,6 139.6 139,6 139.6 Čas(min.) Time (min.) Kontrola Control oj oj oo oo m m O vi O vi m m O OJ O OJ m OJ m OJ O 00 About 00 c c

p tip ti

P <y >υ o o.P <y> υ o o.

i cand c

m om o

AA

OABOUT

o.about.

I tiAnd you

♦ ♦ rých psov dogs c c 7,2 7.2 26,4 26.4 7 OJ 7 OJ 24, 5 24, 5 24,4 24.4 31,5 31.5 O OJ ABOUT OJ 29,5 29.5 S Φ (M WITH Φ (M 27,6 27.6 3 > 0 N Φ W Φ c <tí 5 3 3> 0 N Φ W Φ c <tí 5 3 <ú <ú Nisoldij Nisoldij - ε*^ετ -r - ε * ^ ετ -r + 1 O A £ + 1 ABOUT A £ 171,6 - 171.6 - + 1 Ό 00 N vl + 1 Ό 00 N vl - S't’ZT Τ’ - S't’ZT Τ ’ 178,3 - 178.3 - 176,3 - 176.3 - 176,0 - 176.0 - 176,0 - 176.0 - 174,0 - 174.0 - C C C C 31,2 31.2 37,2 37.2 36, 5^a 36, 5 ^a 37,9 37.9 37,4 37.4 35,7 35.7 36,4 36.4 31,9 31.9 31,0 31.0 0 r* 0 r * 0. 0. + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 XT XT Φ > ád Φ Í-. Φ> ád Φ Í-. Ή Ή Ό 0 £ Z Ό 0 £ FROM OJ ω v OJ ω v 179,7 179.7 166,2 166.2 S A a ΙΛ WITH A a ΙΛ 157,7 157.7 152,2 152.2 153,0 153.0 149,7 149.7 149,2 149.2 -1 ani v dávke 3 mg. kg na srdcovú j -1 nor at a dose of 3 mg. kg to cardiac j • / · “Iv ia ( r. mm. ) • / · “Iv ia (r. mm.) c Φ c Φ vH OJ vH OJ 145,6 í 10,7 145.6 and 10.7 03 O OJ + 1 o o 2 03 ABOUT OJ + 1 about about 2 176,0 -23,3 176.0 -23.3 «1 OJ Φ + 1 co A O rH «1 OJ Φ + 1 what A About rH aj 00 rH OJ + 1 O a ω aj 00 rH OJ + 1 ABOUT a ω aj Ή O N + 1 00 A 2 aj Ή O N + 1 00 A 2 Λ ω A ’Τ rH -Η Ο Γφ Λ ω A ’Τ rH -Η Ο .Φ + b 86,6 - 12,1 + b 86.6 - 12.1 188,6 - 14,2^a 188.6 - 14.2 ^a rH OJ + 1 Ό \0 Φ rH OJ + 1 Ό \ 0 Φ 00 00 Srdcová frekvence Heart rate >υ > υ oo Ή oo Ή 160,6 - 31,1 160.6 - 31.1 171,3 - 20,0 171.3 - 20.0 170,3 - 23,5 170.3 - 23.5 OJ rH OJ + 1 r. A 10 n OJ rH OJ + 1 r. A 10 n 175,6 í 20,5 175.6 and 20.5 176,6 - 18,1 176.6 - 18.1 173,6 - 20,7 173.6 - 20.7 172,6 - 21,0 172.6 - 21.0 173,6 - 21,5 173.6 - 21.5 172,0 -20,1 172.0 -20.1 00 00 o about 23,6 23.6 OJ ΛΙ OJ ΛΙ <n o v4 <n or v4 Λ O o Λ O about Π Ό O OJ Ό Ό ABOUT OJ Ό A O OJ Ό A O OJ η ο A V 0J the A V 0J al A o 0J al A o 0J N A o OJ N A o OJ OJ 2 OJ 2 Ό π Ό π i-4 4 Φ Φ + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 + 1 in in CL CL o about OJ OJ OJ OJ O ABOUT Ό Ό Ό Ό XT XT < po i. v. <po i. in. M M co m co m 179, 179, o 2 about 2 179, 179, 176, 176, 175, 175, 172, 172, 170, 170, 170, 170, 174, 174, O Λ ABOUT Λ s with a3 1Ω a3 1Ω <0 O <0 O aj σ> also σ> OJ OJ tn tn O ABOUT 00 00 0 4J xd 0 4J xd OJ OJ + 1 + 1 m + 1 m + 1 m + 1 m + 1 00 + 1 00 + 1 v + 1 in + 1 s + 1 with + 1 in + 1 in + 1 00* + 1 00 * + 1 + 1 + 1 in + 1 in + 1 00 00 £ 0 'X c £ 0 'X c 147,6 147.6 184,6 184.6 189,6 189.6 o o co about o co 00 A O co 00 A About what 183,6 183.6 177,0 177.0 170,6 170.6 168,0 168.0 164,0 164.0 o about > 0 -P « > 0 -P « c c aj aj Tabulka Table OJ -P £ OJ -P £ Čas (ml Time (ml 0 u -u c 0 iz 0 u -u c 0 iz OJ OJ 00 00 in in 10 10 15 15 20 20 25 25 30 30 c c

Q. I aj , η - počet zvieratQ. I aj, η - number of animals

Tabulka 10Table 10

Akútna toxicita textovaných látok po i.v. podaní u myší samcov (n=100).Acute toxicity of textured substances after i.v. administration in male mice (n = 100).

Zlúčenina Compound LD₅₀(mg.kg ¹)LD ₅₀ (mg.kg ¹ ) 1 1 0,52 0.52 5 5 1,26 1.26 7 7 1,88 1.88 8 8 0,78 0.78 9 9 0,86 0.86 10 10 0,83 0.83 12 12 1,06 1.06 13 13 0,99 0.99 14 14 2,76 2.76 15 15 1,65 1.65 19 19 4,07 4.07 20 20 1,07 1.07 21 21 1,41 1.41 22 22 0,85 0.85 23 23 3,64 3.64 24 24 1,23 1.23 SR 1399 SR 1399 0,93 0.93 SR 1308 SR 1308 1,60 1.60 Nimodipín Nimodipine 1,01 1.01

SR 1308 je metyl, (1,4-dioxaspiro[4,5]dekan-2-yl)metylester kyseliny 1,4-dihydro-2,6-dimetyl-4,(3'-nitrofenyl)-3,5-pyridíndikarboxylovej (Fr. pat. 2577552)SR 1308 is 1,4-dihydro-2,6-dimethyl-4, (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl, (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester. (Fr. Pat. 2577552)

SR 1399 pozři za tabulkou 6.SR 1399 see behind table 6.

Claims

CS 277165 Ββ 20 PATENT CLAIMS

1. Esters of 1,4-dihydropyridine-3,5-dicarboxylic acids and their apoptotic isomers and diastereoisomers with effects on the cardiovascular system of the general formula I

wherein X represents a nitro group at position 2 'or a chloro and bromo group at position 2' or 3 'and R 1 represents alkyl to C 4, optionally branched or unsaturated alkyl C 3 or methoxyethyl group, or R 2 and R 2 represent substituted 1, A 3-dioxolane group of the formula II CH 2 -CH 2 CH 2 x ° (II), wherein R 3, R 4 are two methyl or a polymethylene group (CH 9) "wherein n = 4 to 7 or wherein X is a nitro group in the 3 'position and R 1 represents a C 2 to C 4 alkyl, optionally a branched or unsaturated C 3 alkyl or a methoxyethyl group, or R 2 and R 2 are as defined above, or wherein X represents a 3' nitro group and R 1 represents an alkyl to C 4 group , optionally branched or unsaturated alkyl C3 or methoxyethyl group and R2 represents a substituted dioxolane group of formula II, wherein R3, R4 represent a heptamethylene group with n = 7.

Ethyl 1,4-dihydro-2,6-dimethyl-4- (3'-chlorophenyl) -3,5-dimethyl-4- (3'-chlorophenyl) methyl-1,4 (dioxaspiro [4,5] decan-2-yl) methyl ester pyridine dicarboxylic acid

Ethyl 1,4-dihydro-2,6-dimethyl-4- (3'-chlorophenyl) -3,5-dimethyl-4- (3'-chlorophenyl) methyl- (1,4-dioxaspiro [4,4] nonan-2-yl) methyl ester pyridine dicarboxylic acid

4. 1,4-Dihydro-2,6-dimethyl-4- (2'-bromophenyl) -3,5-pyridinedicarboxylic acid ethyl, 1,4-dioxaspiro [4,5] decan-2-yl) methyl ester

5. Ethyl 1,4-dihydro-2,6-dimethyl-4- (2'-bromophenyl) -3,5-dimethyl-4- (2'-bromophenyl) methyl- (1,4-dioxaspiro [4,4] nonan-2-yl) methyl ester pyridine dicarboxylic acid

6. Methyl 1,4-dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-dimethyl-1,3-dioxolan-4-yl methyl ester. pyridine dicarboxylic acid

7. 1,4-Dihydro-2,6-dimethyl-4- (3'-chlorophenyl) -3,5-pyridinedicarboxylic acid ethyl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester -ve j

8. 1,4-Dihydro-2,6-dimethyl-4- (2'-bromophenyl) -3,5-pyridinedicarboxylic acid ethyl, (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

9. 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid propargyl -, (1,4-dioxaspiro [4,5] decan-2-yl) methyl ester -xyl

10. 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid propargyl- (1,4-dioxaspiro [4,4] nonan-2-yl) methyl ester -xyl

11. 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid propargyl- (2,2-dimethyl-1,3-dioxolan-4-yl) methyl ester

12. 1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5- di- (1,4-dioxaspiro [4,5] decan-2-yl) methyl ester; pyridinedicarboxylic acid

Methyl 1,4- dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-dimethyl-4- (2'-nitrophenyl) methyl ester (1,4-dioxaspiro [4,4] nonan-2-yl) -3,5- pyridine dicarboxylic acid

14. 1,4-Dihydro-N-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methoxyethyl- (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester

Methoxyethyl, 1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-dimethyl-4- (1,4-dioxaspiro [4,4] nonan-2-yl) ester pyridinedicarboxylate;

16. Methoxyethyl 1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinediyl 1,4-dioxaspiro [4,7] dodecan-2-yl] methyl ester - CS 277165 B6 22 carboxylic acid

17. 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl, (1,4-dioxaspiro [4,7] dodecan-2-yl) methyl ester -xyl

18. 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5- diethyl-2,6-dimethyl-4- (3'-nitrophenyl) methyl allyl - (1,4-dioxaspiro [4,5] decan-2-yl) methyl ester pyridine dicarboxylic acid

1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid isopropyl- (1,4-dioxaspiro [4.5] decan-2-yl) methyl ester; -xyl

20. 1,4- Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid ethyl 1,4- (1,4-dioxaspiro [4,7] dodecan-2-yl) methyl ester

21. 1,4-Dihydro-2,6-dimethyl-4- (2'-nitrophenyl) -3,5-pyridinedicarboxylic acid methyl, (1,4-dioxaspiro [4,5] decan-2-yl) methyl ester

1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5- di-1,4-dioxaspiro [4,5] decan-2-yl) methyl ester; pyridinedicarboxylic acid

23.Isopropyl-1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-pyridinedicarboxylic acid 1,4-dioxaspiro [4,4] -nonan-2-yl) methyl ester

24. 1,4-Dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-dimethyl-4- (1,4-dioxaspiro [4,5] decan-2-yl) methyl ester pyridine dicarboxylic acid

25. Ethyl 1,4-dihydro-2,6-dimethyl-4- (3'-nitrophenyl) -3,5-dimethyl-4- (3'-nitrophenyl) methyl ester (1,4-dioxaspiro [4,4] nonan-2-yl) pyridine dicarboxylic acid

26. A process for the preparation of compounds of formula I according to claim 1, wherein the substituted benzaldehyde of formula III (III) wherein X is as defined above is reacted with an acetic acid ester of formula IV CH3 - C - CH2 - In which R 3 · is as defined above, and with a 3-aminocrotonic acid ester of formula V CH-> - C = CH - COO - R 2 '(V), I' NH 2 O in wherein R 6 is as defined above in a solvent-free medium, preferably in alcohols to C4 at 20 to 150 ° C, preferably at the low temperature of the solvent used, optionally in the presence of catalysts.

27. A process for the preparation of compounds of the formula I according to claim 1, characterized in that a substituted 2- (X-benzylidene) -3-ketocarboxylic acid ester of the general formula VII is reacted.

wherein X and R 1 are as defined above, with a 3-aminocrotonic acid ester of formula V wherein R 2 is as defined above, in an inert organic solvent preferably in C 1 to C 4 alcohols, ethyl acetate, alkanes or cycloalkanes C 5 to C 8 or in mixtures of these solvents at a temperature of 20 to 150 ° C under atmospheric or elevated pressure of up to 5 MPa, preferably at the low temperature of the solvent used, or a mixture of solvents used, while distilling off by the reaction of water.

28. A process according to claim 26 or 27 wherein the cyclo-condensation reaction is carried out in the presence of catalytic amounts of organic or inorganic acid salts of organic or inorganic bases, preferably organic or inorganic acid, preferably calcium chloride, pyridinium chloride or pyridinium acetate. End of document