CA2088209A1

CA2088209A1 - 4-cinnolinyl- and 4-naphthyridinyl-dihydropyridines, processes for their preparation and their use in medicaments

Info

Publication number: CA2088209A1
Application number: CA002088209A
Authority: CA
Inventors: Alexander Straub; Jurgen Stoltefuss; Siegfried Goldmann; Rainer Gross; Martin Bechem; Siegbert Hebisch; Joachim Hutter; Howard-Paul Rounding
Original assignee: Bayer AG
Current assignee: Bayer AG
Priority date: 1992-01-30
Filing date: 1993-01-27
Publication date: 1993-07-31
Also published as: EP0555657A1; US5364855A; NZ245781A; KR930016414A; CN1074906A; JPH05286968A; AU664406B2; ZA93639B; HU9300247D0; AU3205893A; HUT65938A; IL104525A0; DE4202526A1; US5410055A; MX9300268A; CZ372192A3; PL297561A1

Abstract

New 4-cinnoliny1- and 4-naphthyridiny1-dihydropridines, processes for their preparation and their use in medicaments Abstract The invention relates to new 4-cinnolinyl- and 4-naph-thyridinyl-dihydropyridines of the general formula I

(I), in which R1 to R5 have the meaning given in the descrip-tion, to processes for their preparation and to their use in medicaments, in particular in compositions having positively inotropic action.

Le A 28 864

Description

2~8~20~

The in~T~ntion relates to new 4-cinnolinyl- an~ 4-naph-thyridinyl-dihydropyridines, to processes for their preparation and to their use in medicaments, in parti-cular in compositions having positively inotropic action=

S It is already known that 1,4-dihydropyridines have vasodilatinq properties and can be used as coronary agents and antihypertensives [cf. Brit. Patent 1,173,062 and 1,358,951; German Offenlegungsschrifts 2,629,892 and 2,7S2,820]. It is additionally known that 1,4-dihydro-pyridines cause an inhibition of the contractility ofsmooth and cardiac muscles and can be employed for the treatment of coronary and vascular diseases [cf. Flecken-stein, Ann. Rev. Pharmacol. Toxicol., 17, 149 - 166 (lg77)].

It is additionally known that 3-nitro-dihydropyridines in general, in addition to a positively inotropic cardiac action, can show khe disadvantage of an undesired con-stricting action on the coronary vessels [cf. Schramm et al., Nature 303, 535-537 (1983) and German Offen legun~sschrift 3,447,159].

With knowledge of the prior art, it was not foreseeable that the compounds according to the invention would have a contractility-enhancing, positively inotropic action on the heart muscle with substantially neutral or dilating vascular behaviour.

Le A 28 864 - 1 -2~8~
~he invention relates to 4-cinnolinyl- and 4-naphthyrid-inyl-dihydropyridines of the general formula ( R ~ CO2R4 ~ ~ (I), in which Rl and Rs are identical or different and represent S straight-chain or branched alkyl having up to 8 carbon atoms, R2 represents straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, which is optionally substituted by straisht-chain or branched alkoxy having up to 4 carbon atoms, represents nitro or cyano, or Rl and R2 together form a lactone ring of the formula 0 ~

Le A 28 864 - 2 -'2~8209 R3 represents a heterocyclic radical of the formula ~' ~ ~ , or in which R5 denotes hydrogen, halogen or straight-chain or S branched alkyl or alkoxy each having up to 8 carbon atoms, R7 denotes aryl having 6 to lO carbon atoms, which is optionally substituted up to 2 times by identical or different substituents from the group consisting of halogen, nitro, cyano, tri~luoromethyl, trifluoromethoxy, trifluoro-methylthio, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 8 carbon atoms and carboxyl, or denotes pyridyl or thienyl, R~ represents hydrogen, or represents straight-chain or branched alkyl, alk-enyl, alkadienyl or alkinyl each having up to 10 carbon atoms, each of which is optionally substitu-ted up to 2 times by identical or different substit-uents from th~ group consisting of trifluoromethyl, halogen, hydroxyl, carboxyl, cyano, nitro and Le A 28 864 - 3 -2~ 2~
phenoxy or by s~raight~chain ox branched alkylthio/
alkoxy, alkoxycarbonyl, acyl or acyloxy each having up to 8 carbon a~oms or by phenoxy or phenyl, where the latter can for their part be substituted up to 2 times by identical or different halogen substitu-ents or by straight-chain or branched alkyl or alkoxy each havlng up to 6 carbon atoms and their physiologically acceptable salts.

Physiologically acceptable salts can be salts of the compounds according to the in~ention with inorga~ic or organic acids. Preferred salts are those with inorganic acids such as, for example, hydrochloric acid, hydro-bromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acidr toluenesulphonic acid or naphtha~
lenedisulphonic acid.

The compounds according to the invention exist in stereo-isomeric forms, which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invsntion relates both to the antipodes and to the racemic forms as well as the diastereomer mixtures. Like the diastexeomers, the racemic fQrmS can also be separated in a known manner into the stereoisomerically uniform constituents (cf.

Le A 28 864 - 4 -2 ~ ~
E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 196_).

Preferred compounds of the general formula (I) are those in which Rl and Rs are identical or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, R2 represents straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, which is optionally substituted by straight-chain or branched alkoxy having up to 3 carbon atoms, represents nitro or cyano, o~

R' and ~2 toge~her form a lactone ring of the formula o 0 ~

R3 represents a hetsrocyclic radical of the formula Le A 28 864 - 5 -2~

or 6 in which R5 denotes hydrogen, fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 2 carbon atoms, R7 denotes phenyl which is optionally substituted by fluorine, chlorine, nitro, cyano or tri-fluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atom~, R~ represents hydrogen, or represents straight--chain or branched alkyl or alk-enyl each having up to 8 carbon atoms, each of which is optionally substituted by trifluoromethyl, lS fluorine, chlorine, hydroxyl, carbo~yl, cyano or nitro or by straight-chain or branched alkylthio, alkoxy, alkoxycarbonyl, acyl or acyloxy each having up to 6 carbon atoms or by phenoxy or phenyl, and their physiologically acceptable salts.

Particularly preferred compounds of the general formula Le A 28 864 - 6 -~8~2~'~
(I~ are those in which R- and Rs are identical or different and represent straight-chain or branched alkyl having up to 4 carbon a~oms, R2 represents straight-chain or branched alkoxycarhonyl having up to 3 carbon atoms, or methoxyethoxy-carbonyl, or represents nitro or cyano, or Rl and R2 together form a lactone ring of the fonmula o O\~

R3 represents a heterocyclic radical of the form~lla N ~
~ ~5~Ror ~ R7 Le A 28 864 - 7 -'~0~82~
in which R6 denotes hydrogen, chlorine or methyl, R denotes phenyl which is optionally substituted by fluorine, chlorine, nitro or trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 4 car~on atoms, R~ represents hydrogen, or represents straight-chain or branched alkyl havin~
up to 6 carbon atoms, which is optionally substitu-ted by trifluoromethyl, hydroxyl, carboxyl or cyano or by straight-chain or branched alko~ycarbonyl, ~lkoxy or acyloxy each having up to 4 carbon atoms and their physiologically acceptable salts.

Additionally, a process for the preparation of the compounds of the general formula (I) according to the invention has been found, characterised in that in the case in which Rl and R2 have the abovementioned meaning, but do not together form a lactone ring, [A] aldehydes of the general formula (II) R3-CHo (II) in which Le A 28 864 - 8 -8 c~ ~ ~
R3 has the abovementioned meaning, are first reacted wi~h acetoacetic esters of the general formula (III) Rs-co-cH2-co2-R4 ( in which R' and Rs have the abovementioned meaning, if appropriate with isolation of the corresponding ylidene compounds of ~he general formula (IV) R3- C~ = C- CO~-~
I (I~), Co-R5 in which R3, R~ and Rs have the abovementioned meaning, and are subsequently reacted either with compounds of the general formula (V) Rl~CO-CH2-R2 (V) in which Le A 28 864 - 9 -~8~09 R` and R? have the abovementioned meaning, în the presence of ammoniA or ammonium salts, or directly with amino derivatives of the general formula (VI) Rl--C=~CH R2 ¦ (VI), ~2 in which R1 and R2 have the abovementioned meaning, if appropriate in the presence of inert organic solvents, or [B] the aldehydes of the general formula (II) are first reacted with the compounds of the general formula (V), if appropriate with isolation of the ylidene compounds of the general formula (VII) R3- CH = ~- R2 I (VII), CO-R

in which Le A 28 864 - 10 -R-, R- and R3 ha~e the abovementioned meaning, and are reacted in a ne~t step with the abovementioned compounds of the general ormula ~III) in inert solvents, in the presence of ammonia or ammonium salts or directly with enaminocarboxylic acid derivatives of the general formula (VIII) R5 - ~ CH - CO2- R4 I (~III), ~TH2 in which R~ and Rs have the abovementioned meaning, or in the case in which R1 and R2 together form a lactone ring, [C] firstly according to the methods mentioned in and [TB], compounds of the general formula (Ia) R~OOC ~ CO2R4 Il ~ (Ia), R9~2C R5 Le A 28 B64 - 11 -~a~a~

in which R3, R4 and R5 have the abovementioned me~ning, R8 represents a C; C~-alkyl radical and R9 represents a leaving group such as, for example, chlorine or acetoxy, are prepared and an acid- or base-catalysed ring closure is added according to known methods, or in the case in which R4 does not denote hydrogen, ~D] compound~ of the general formula (I) in which Rl, R2, R3, R4 and Rs have the abovementioned meaning and Rq represents hydrogen, are reacted with the approp-riate alcohols, if appropriate via a reactive acid derivative, the corresponding enantiomers of the esters being obtained by use of the enantiomerically pure G arbo~ylic acids (R4=H).

The process according ~o the invention can be illustrated by way of example by the following reaction scheme:
[~3 ~ N ~ 02N ,~ CO2CH~

C~O C6H5 H3C ~ O O ~ CH3 Le A 28 864 - 12 -208~209 ,~, N ,~, ~ C6H5 2~ CO2CH3 H3C ~ ~ CH3 'A!

~N
6Hs + O.~N ~

N ~

~ C6H5 2~ CO2CH3 H3C ~ I~T CH3 Le A 28 864 - 13 -2 ~ 9 ~` ~ `~` N ~ :~
~ ,~ ~
O,N ~ F
HJC ~0 2~ ~
I ',C ~0 ~ o ~ C02C~H~
~CO2C2Hs H N~CH
O CH~ I
NH~OOC-CH3 ~ 7 N~N;l ~F
02N ~,~ coOC2Hs H

~C~

N~ F H- N~ F
H6C200C~CoOCH3 11~ O~COOCH3 Cl-H2C N CH3 N CH3 H H

Le A 28 864 - 14 -~8~g Suitable solvents for processes [A], [s] and [C] are all the inert organic solvents. These preferably include alcohols such as methanol, ethanol, n- or iso-propanol, ethers such as diethyl ether, tetrahydrofuran, dioxane or glycol monomethyl or dimethyl ether, glacial acetic acid, pyridine, dimethylformamide, dimethyl sulphoxide, aceto-nitrile or hexamethylphosphoramide or toluene.

Suitable solvents for process [D] are the abovementioned solvents with the exception of the alcohols.

The reaction temperature for processes [A], [B], [C] and [D] can be varied within a relatively wide range. In general, the reaction is carried out in a range from 10C
to 200C, preferably from 20C to 150C.

~he processes can be carried out at normal pressure, elevated press~re or reduced p~essure (for example from O.5 to 5 bar), pre~erably at normal pressure.

When carrying out the process according to the invention, any ~esired ratio of the su~stances involved in the reaction can be used. In general, however, molar amounts of the reactants are used.

To activate the carboxylic acid, suitable reagents are the customary reagen~s such as inorganic halides, for example thionyl chloride, phosphorus trichloride or phosphorus pentachloride, or carbonyldiimidazole, carbo-diimides such as cyclohexylcarbodiimide or l-cyclohexyl-Le A 28 864 - 15 -3 [2-~N-me~hylmorpholino)ethyl]-carbodiimide p-toluene-sulphonate or N-hydroxyphthalimide or N-hydroxy-benzo-triazole.

Enantlomerically pure forms are obtained, ~or example, by separating diastereomer mixtures of the compounds of the general formula (I), in which R4 represents an optical ester radical, by a customary method, subsequently preparing the enantiomerically pure carboxylic acids and then optionally converting into the enantiomerically pure dihydropyridines by esterification with appropriate alcohols.

Suitable chiral ester radicals are all the esters of enantiomerically pure alcohols such as, for example, 2-butanol, l-phenylethanol, lactic acid, lactic acid esters, mandelic acid, mandelic acid esters, 2-amino-alcohol~, sugar de~ivatives and many other enantiomeri~
cally pure alcohols.

The diastereomers ar~ in general separated either by fractional crvstallisation, by column chromatography or by Craig partition. Which is the optimum process must be decided from case to case, sometime~ it is also expedient to use combinations of the individual processes. Separa-tion by crystallisation or Craig partition or a combina-tion of both processes is particularly suitable.

The enantiomerically pure dihydropyridines are preferably esterified in ethers such as diethyl ether or tetrahydro-Le A 28 864 - 16 -2 ~
furan, dimethylformantide, methylene chloride, chloroform, acetonitrlle ox toluene.

The aldehydes of the general formula ~II) are also new and can be prepared by cyclising, in the case in which R3 represents the radical of the formula ~ R~

a) substituted pyridines of the general formula (IX) ~>< CH(OR8)2 H3C ~ .~'H-D (IX), R6 ~ 1!

in which R5 has the abovementioned meaning, preferably chlorine, R7 has the abovemen~ioned meaning, D represents a protective group such as, for example, Le A 28 864 - 17 -~:~g~
tert-butylcarbonyl and R8 represents stxaight-chain or branched alkyl having up to 4 carbon atoms, first with protonic acids, preferably hydrochloric acid, and subsequent hydrogenation, to give the compounds of the general formula (X) ~ R

in which R6 and R~ have the abovementioned meaning, in lnert solvents and in a last step oxidising the methyl group in an organic solvent or naphthalene, preferably naphthalene, and in the cas~ in which R3 represents the radical of the formula Le A 28 864 ~ 18 -2~ 2~

`N

b) cyclising compounds of the general formula (XI) ~lH2 R7 (X~, in which R6, R7 and R8 have the abovementioned meaning, after hydrolysis, via the diazotised step (NH2 - N2+ ), to give compounds of the general formula (XII) H

R6 ~ (XII), ~7 c~3 o Le A 28 864 - '9 -2~8~2~
in which R~ and R have the abovementioned meaning, converting in a second step with PC15/POC13 to compounds of the general ~ormula (XIII) ~ T
R6 - ~ R7 (XIII), H3C Cl in which R6 and R7 have the abovementioned meaning, hydrogenat.ing and subsequently oxidisin~ the methyl group in inert solvents.

The processes according to the invention can be illustra ted by way of example by the following reaction scheme:

a) MsC20 ~C2Hs `r ~13C ~ CI N ~ N~
~G~N --~ C~~
IYM-OC C(CH3)~

Le A 28 864 - 20 -'~8~2~

~ ~ S~2 1 ~ ~
~ naphthalene b) b) ~" !IH2 I~CI ~ N2 ~ Cl N~NO~ ~ CO--CH~3 CH, OC~13 ~ ~_ ~3C

N POCI3 ~ ~N ~2 ~; 3 PC15 ~ Cl W

~N ~N~N
~3 so C~3 naphthalene c~o Le A 28 864 - 21 -2 0 ~3 Suitable solvents in this connection are all the inert organic solvents which do not change under the reaction conditions. These preferably include alcohols such as methanol, ethanol, propanol or isopropanol, or ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or diethylene glycol dimethyl ether or amides such as hexamethylphosphoramide or dimethylform-amide, or acetic acid as well as methylene chloride, carbon tetrachloride or toluene. It i5 also possible to use mixtures of th~ solvents mentioned.

The compounds of the general formulae (X) and (XII) are in general oxidised using oxidising agents such as, for example, chrom~l chloride, ceric ammonium nitrate, silver( II ) oxide, selenium dioxide or a chromium(VI~
oxide in conjunction with acetic anhydride. Selenium dioxide is preferred.

The oxida~ion can be carried out at normal pressur~ or elevated or reduced pressure (for example from 0.5 to 5 bar), preferably at normal pressure.

Suitable bases for the individual process steps are those mentioned above, preferably sodium hydroxide and sodium hydrogencarbonate.

The compounds of the general formulae (X), (XII) and (XIII) are new and can be prepared by the abovementioned process.

Le A 28 864 - 22 -~8~

The compounds of the general formula (IX) are new and can be ~repared by, for example, by first reducing the known compound 2-chloro-3,4-dimethyl-5-nitropyridine [cf.
Y. ~orisawa et al., J. Med. Chem. 21, 194 (1978)] to give S the corresponding 5-amino group by customary methods, for example by hydrogenation ~ith H2JPd/C in dioxane, subse-quently blocking the amino group by reaction with pival-oyl chloride, intermediately deprotonating with n-butyl-lithium in tetrahydrofuran and in a last step reaoting with 2,2-dialkoxyacetophenones.

The compounds of the general formula (XI) are known or can be prepared by customary methods.

The acetoacetic esters of the formula (III) are known or can be prepared by customary methods [cf. D. Borrmann, "Umsetzung von Diketonen mit Alkoholen, Phenolen und Mercaptanen" ~Reaction of Diketones ~ith Alcohols, Phenols and Mercaptans), in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry), Vol.
VIII/4, 230 et seq. (1968)].

The ylidene compounds (IV) and (VII) are new, but can be prepared by customary me~hods [cf. H. Dornow and W. Sassenberg, I,iebigs Ann. Chem. 602~ 14 (1957)].

The aminocrotonic acid derivatives of the formulae (VI) and (VIII) are known or can be pr~pared by known methods [S.A. GlicXman, A.C. Cope, J. Am. Chem. Soc. 67, 1017 (19~6)].

Le A 28 864 - 23 -~88209 The c~mpounds of the general formula (v) are also known [cf. N. Levy, C.~. Scaife, J. Chem. Soc. (London) 1946, 110Q, C.D. Hurd, M.E. Nilson, J. Org. Chem. 20, 927 (1955~j.

The above preparation processes are only given ~or clarification. The preparation of the compounds of the formulae (I) and (II) is not restricted to these pro-cesses, but any modification of these processes can be used in the same way for the preparation of the compounds according to the invention.

The compounds according to the invention show an unfore-seeable, useful spectrum of pharmacological action. They effect the contractility of the heart and the tone of the smooth muscl-lature. They can therefore be employed in medicamen~s for effecting pathologically modified blood p_essure, as coronary therapeutics and for the treatment of cardiac insufficiency. Moreover, they can be used for the treatment of cardiac arrhythmias, for decreasing the blood sugar, for the detumescence of mucous membranes and for affecting the salt and liquid balance.

The cardiac and vascular actions were found in isolated perfused guinea-pig hear~s. For this purpose, the hearts of guinea-pigs of weight 250 to 350 g are used. The animals are killed by a blow to the head, the thorax is opened/ and a metal cannula is tied into the exposed aorta. The heart is separated from the thorax with the lungs and connected to the perfusion apparatus via an Le A 28 864 - 24 -~88~2~

aor~a cannula while perfusing continuously. The lungs are separated at the lung roo~. The perfusion medium used is a Krebs-Henseleit solu~ion (1) ~118.5 mmol/l of NaCl, 4.75 mmol/l of KCl, 1.19 mmolJl of KH2PO~, 1.19 mmol/l of ~.gSO , 25 ~ol/l of NaHCO3, 0.013 mmol/l of Na2EDTA), whose CaCl2 content is 1.2 mmol/l. 10 mmol/l of glucose is added as the energy-producing substrate. Before perfusion, the solution is filtered free of particles.
The solution is aerated with 95~ O2, 5% CO2 to maintain pH
7.4. The hearts are perfused at a constant flow rate ~10 ml/min) at 32C by means of a peristaltic pump.

To measure cardiac function, a liquid-filled latex balloon which is connected to a pressure transducer via a liquid column is introduced through the left auricle into the left ventricle, and the isovolumetric contrac-tions are recorded on a rapid recorder (Opie, L., J.
Physiol. 18~ (1965), 529-541). The perfusion pressure is recorded by means of a pressure transducer which Ls connected to the perfusion system upstream of the heart.
Vnder these conditions~ a fall in the perfusion pressure indicates coronary dilatation, an increase or decrease in the left ~entricular contraction amplitude indicates a fall or a rise in cardiac contractility. The compounds according to the in~ention are perfused into the per-fusion system at suitable dilutions shortly upstream of the isolated heart.

Le A 28 864 - 25 -~8~09 Suhstance effects on the contraction amplitude of iso lated guinea-pig heart auricles at an active substance concentration of 10-4 g/l.

Ex. No. ~ change in the ventricular pressure amplitude 8 ~10 +35 23 +28 _ .

The new active subst~nces can be converted in a known manner into the customary formulations, such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
In this case, the therapeutically active compound should in each case be present in a concentration of about 0.5 to 9Q~ by weight of the total mixture, i.e. in amounts which are sufficient in order ~o achieve the dosage range indicated.

?0 The formulations are prepared, for example, by extending the active substances with solvents and/or excipients, if appropriate using emulsifiers and/or dispersants, where, for example, in the case of the use of water as a dilu-ent, organic solvents can optionally he used as auxiliary solvents.

Administration is carried out in a customary manner, Le A 28 864 - 26 -preferably orally or parenterall~ ~! 8i8 2a0rgicular perlin-yually or intravenously.

In general, it has proved advantageous on intravenous administration to administ~r amounts of about 0.001 to 1 mg/kg, preferably about 0.01 to 0.5 mg/kg of body weight, to achieve effective results, and on oral admini-stration the dosage is about 0.01 to 20 mg/kg, preferably 0.1 to 10 mg/~g of body weight.

In spite of this, it may be necessary to deviate from the amounts mentioned, in particular depending on the body weight or the type of administration route, on individual behaviour towards the medicament, the manner of its formulation and the time or interval at which administra-~ion takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned minimum amount, while in other cases the upper limit mentioned must be exceeded. In the case of the administration of relatively large amounts, it may be ad~isable to divide these into several individual doses over the course of ~he day.
The invention also extends to a commercial package containing, as active pharmaceutical ingredient, a compound of the invention, together with instructions for its use for affect-ing pathologically modified blood pressure for the treatment of cardiac insufficiency and cardiac arrhythmias, for decreasing the blood suyar, Eor detumescing of mucous membranes, for aEfectiny the salt and liquid balance and as a coronary therapeutic.

Le A 28 864 - 27 -2088~
Startinq C~ ds ~xample I

3-[2-chloro-3-methyl-5-pivaloylamino-4-pyridyl]
diethoxy-2-hydroxy~2-phenylpropan~

~1 NH~ C~CH~)3 144.3 g (0.6 mol) of 2-chloro-3,4-dimethyl-5-pivaloyl-aminopyridine are dissolved in 2.9 1 of abs. THF and the solution is treated under argon at -78C with 127 ml of a 10.4 N solution of n-BuLi in n-hexane (1.32 mmol). The mixture is stirred at O~C for 3 h, 129.8 ml ~Q.6 mol) of 2 t 2-diethoxyacetophenone are slo~ly added at -78C and the mixture is stirred at room temperature overnight. It is then added to water and extracted 3 times with ethyl acetate, dried and concentrated on a rotary evaporator.
The purity is sufficient for further reaction. Af~er chromatographyl 180.5 g (67%) of the title compound are obtained.
M.p.: 133~C

Le A 28 864 - 28 -2 ~ ~
E~ample II

6-Chloro-5~me~hyl-3-phenyl-1,7-n~phthyridine I ~ q cl~
c~3 180.5 g (0.4 mol) of finely divided compound from Example S I are intensively stirred under reflux for 5 h in 2.6 l of 2N HCl using a mechanical stirrer~ The mixture is then neutralised with NaHCO3 and extracted several times with ethyl acetate, and the extracts are dri.ed. 37.6 g of the title compound are obtained by crystallisation. Chromato-graphy of the mother liquor (silica gel, toluene -toluene/ethyl acetate 2:1) yields a further 23.1~ y of the title compound .
Total yield: 60%
M.p.: 136 C

Le A 28 86~ - 29 -2~8~2~9 Example III

5-Methyl-3-phenyl-1,7-naphthyridine N~N
~3 33.7 g (132 mmol) of the compound from Example II are dissolved in 60Q ml of ethanol, the solution is treated with 293 ml of lN NaOH and 10 g of 5% Pd/C and the mixture is immediately hydrogenated in ~he Parr apparatus at 3 bar for 30 min. It is filtered through kieselguhr and the ethanol content is evaporated in vacuo. The product precipitated in this way is filtered off with suction, washed with plenty of water and then with ether and dried.
Yield: 23.6 g (81.2~) .p.: 135-138C

Le A 28 864 - 30 -o ~
E.Yam~1e IV

3-Phenyl-1,7-n~phthyridine-5-carboxaldehyd~

c~o ~

36.2 g ~164 mmol) of the compound from Example IlI are well stirred with 27.4 y of selenium dioxide in 130 g of naphthalene at 180C. After 5 h, a further 3.65 g of SeO2 are added and ~he mixture is stirred for a further 3 h at 200C. It is allowed to cool and is dissolved in CH2C1z and the solution is concentrated on a rotary evapora~or after addition of 200 g of silica gel. The residue is applied to a large silica gel column and chromatographed (toluene - ethyl acetate).
Yield: 18 g (47~) M.p.: 148 C

Le A 28 864 - 31 -Example V 2~382~9 ~ Amino-3-~ethyl-2-phenyl)-1-methoxy-2-phenylethene N~12 ~3C OCH3 ~

A mixture of 282.3 g (1.21 mol) of 2-iodo-3-methyl-aniline, 420 ml of butyronitrile, 147.7 g (1.1 mol) of styryl methyl ether, 170 ml of triethylamine and 2 . 5 g (11 mmol) of Pd(II) acetate is heated at reflux for 8 h.
The solution is partly concentrated on a rotary evapora-tor, mixed with water and extracted 3 times with ethyl acetate. The residue obtained after evaporation of the organic phase is then chromatographed on silica gel.
Yield: 158.8 g (60.3~) MS (EI): 239 (18%~ 135 (28%), 91 (22~), 75 (100%) Le A 28 864 - 32 -Example VI

4-Hydroxy-5-methyl-3-phenylcinnoline ~N~

~,~ O ~

60 . 5 g ( 253 m~r.ol ) of the compound from Example V are well stirred for 2 h in 1.1 1 of 2N HCl and the mixture is ~oiled under ref lux . The solid precipitated in the couxse of this is processed without isolation by cooling ~he solution to 0C and slowly adding a solution of 17 . 4 g (252 mmol) of sodium nitrite in 114 ml of water with vigorous stirring. The mixture is then slowly allowed ~o come to room temperature and is stirred for a further 3 days. The solid is filtered off with suction and washed with ether.
Yield: 27.3 g ~46g) M.p.: 215-217C

Le A 28 864 - 33 -~820~
Exam~le VII

4-Chloro-5-methyl-3-phenylcinnoline ~ N~!~l ~3 H3G Cl 27.3 g (0.116 mol) of the compound from Example VI arP
boiled under reflux with 18.3 g of PCls and 200 ml of POCl3 for 18 h. The mixture is added to ice with good stirring and extracted with methylene chloride, and the organic phase is washed with saturated Na~CO3 solution, dried and evaporated in vacuo. 12 g (41~ crude yield) of a solid are obtained, which after chromatography has a m.p. of 1289C.

Example VIII

5-Methyl-3-phenylcinnoline ~ N~
~, 12 g (47.2 mmol) of the compound from Example VII are Le A 28 864 - 34 -82~
hydrogenated for several hours at 3 bar in the Parr apparatus in 400 ml of dioxane and 75 ml of lN NaOH in the preRence of 1.5 g of Pd-C (5~ strength) with TLC
checking. Solid is then filtered off with suction through ~ieselguhr and the filtrate is concentrated on a ro~ary e~aporator. After chromatography on silica gel ttoluene - toluene/ethyl acetate 1:1), 1.8 g (17~) of the pure title compound are obtainedO
Y..p.: 101 C

Example IX

3-~henyl-5-cinnolinecarboxaldehyde ~N~

C~O ~

1.65 g (7.5 mmol) of the compound from Example VIII are stirred for 6 h at 200C with 1.85 g of selenium dioxide in 17 g of naphthalene. After chromatography on silica gel, 0.75 g (43%) of the title compound is obtained. In some batches, it is necessary to stop the reaction before complete conversion of the starting material, since by-products increasingly occur.
M.p.: 156-157 C

Le A 28 864 - 35 -2~8~0~
Pre~aration Examples Example 1 Isopropyl 5-cyano~ dihydro-2, 6-dimethyl~4-( 3-phenyl-cinnolin-5-yl)pyridine 3 carboxylate ,~N,~
O ~
CN ~J

H3C N ~ CH3 ~50 mg (3.2 mmol) of 3-phenyl-5-cinnolinecarboxaldehyde, 263 mg ~3.2 mmol) of 3-aminocrotononitrile and 457 mg (3.2 ~mol) of isopropyl acetoacetate are boiled under reflux for ~.5 days in 25 ml of ethanol. The mixture is concentrated and separated on a silica gel column using toluene/ethyl acetate mixtures. The desired fractions are collected and concentrated. The evaporation residue obtained is crystallised using ether and filtered off with suction. 320 m~ of crystals of melting point 200-202C are obtained.

Le A 28 864 - 36 -~8~09 Example 2 Isopropyl 5-cyano-1,4 dihydro-2,6-dimethyl-4-(3 phenyl-1,7-naphthyridin-5-yl)pyridine-3-carboxylate ~o~

2 g (8.54 mmol) of 3-phenyl-1,7 naphthyridine-5-carbox-aldehyde, 701 mg (8.54 mmol) of 3-aminocrotononitrile and 1.22 g (8.54 mmol) of isopropyl acetoacetate are boiled under reflux for 3 days in 25 ml of ethanol. The mixture is concentrated and separated on a silica gel column usinq toluene/ethyl acetate mixtures. The desired rrac-tions are collected and concentrated. The evaporation residue obtained is c~ystallised using ether and filtered off with suction. 573 mg of crystals of meltin~ point 192C are obtained.

lS The compounds shown in Table l are prepared in analogy to the procedure of Example 1:

Le A 28 864 - 37 ~

~0~8209 ~able 1 N ,~

R2 `1~

~x.No. Rl R2 R4 M p C/R /
enantiomer 3 -CH3 ~CN -CH ( CH3 ) 2 2 0 2 4 -CH3 -CN -c2~s 190 ~ -CE~(C~)2 150 6 -CH3 -No2 -c2~3s 218 8 -~3 -CN n-C3H7 19 0 9 -CH3 -CN -CH ( CH3 ~ 2 226-227 /enantiomer 1 o -CH3 -CN -C~ ( CH3 ) 2 226-227 /en~ntiomer 2 Le A 28 84 - 38 -~8~
Compounds sho~ in Table 2 are prepared in analogy to the procedure of Example 2 c IY

o h~ ~

Z~ X ~ V

P~ ~ o r O Z;

.. c~ v c~ u P: I I i I

..
Q~ O
~ Z
,Q
~i X --I ~ ~ ~r Ln ~D

Le A 28 864 39 -2U~20~

a~

o o ~ o o + + -- _ V~
o o U ~

~, . .
r ~~ U 'ur ,~ U ", ,....... ...
a~ O O Z Z :~ Z ~ Z
~ o~o ~ 1 >
o .
c :~ X 3: ~ O X
.
._~ o o x ~00 Le A 28 864 - 40 -

Claims

1. Dihydropyridines of the general formula (I) (I), in which R1 and R5 are identical or different and represent straight-chain or branched alkyl having up to 8 carbon atoms, R2 represents straight-chain or branched alkoxy-carbonyl having up to 6 carbon atoms, which is optionally substituted by straight-chain or branched alkoxy having up to 4 carbon atoms, represents nitro or cyano, or R1 and R2 together form a lactone ring of the formula Le A 28 864 - 41 -R3 represents a heterocyclic radical of the formula or in which R6 denotes hydrogen, halogen or straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, R7 denotes aryl having 6 to 10 carbon atoms, which is optionally substituted up to 2 times by identical or different substitu-ent from the group consisting of halogen, nitro, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 8 carbon atoms and carboxyl, or denotes pyridyl or thienyl, R4 represents hydrogen, or represents straight-chain or branched alkyl, alkenyl, alkadienyl or alkinyl each having up to 10 carbon atoms, each of which is optionally Le A 28 864 - 42 -substituted up to 2 times by identical or different substituents from the group consist-ing of trifluoromethyl, halogen, hydroxyl, carboxyl, cyano, nitro and phenoxy or by straight-chain or branched alkylthio, alkoxy, alkoxycarbonyl, acyl or acyloxy each having up to 8 carbon atoms or by phenoxy or phenyl, where the latter can for their part be substi-tuted up to 2 times by identical or different halogen substituent 8 or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms and their physiologically acceptable salts.

2. Compounds of the general formula (I) according to Claim 1, in which R1 and R5 are identical or different and represent straight-chain or branched alkyl having up to 6 carbon atoms, R2 represents straight-chain or branched alkoxy-carbonyl having up to 4 carbon atoms, which is optionally substituted by straight-chain or branched alkoxy having up to 3 carbon atoms, represents nitro or cyano, or Le A 28 864 - 43 -R1 and R2 together form a lactone ring of the formula R3 represents a heterocyclic radical of the formula or in which R6 denotes hydrogen, fluorine, chlorine or straight-chain or branched alkyl or alkoxy each having up to 2 carbon atoms, R7 denotes phenyl which is optionally substituted by fluorine, chlorine, nitro, cyano or trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms, R4 represents hydrogen, or represents straight-chain or branched alkyl or Le A 28 864 - 44 -alkenyl each having up to 8 carbon atoms, each of which is optionally substituted by trifluoromethyl, fluorine, chlorine, hydroxyl, carboxyl, cyano or nitro or by straight-chain or branched alkylthio, alkoxy, alkoxycarbonyl, acyl or acyloxy each having up to 6 carbon atoms or by phenoxy or phenyl.

3. Compounds of the general formula (I) according to Claim 1, in which R1 and R5 are identical or different and represent straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents straight-chain or branched alkoxy-carbonyl having up to 3 carbon atoms, or methoxyethoxycarbonyl, or represents nitro or cyano, or R1 and R2 together form a lactone ring of the formula R3 represents a heterocyclic radical of the formula Le A 28 864 - 45 - or in which R6 denotes hydrogen, chlorine or methyl, R7 denotes phenyl which is optionally substituted by fluorine, chlorine, nitro or trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms, R4 represents hydrogen, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by trifluoromethyl, hydroxyl, carboxyl or cyano or by straight-chain or branched alkoxycarbonyl, alkoxy or acyloxy each having up to 4 carbon atoms.

4. The compound isopropyl 5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-phenyl-cinnolin-5-yl)pyridine-3-carboxylate of the formula .

5. The compound ethyl 1,4-dihydro-2,6-dimethyl-5-nitro-4-(3-phenyl-cinnolin-5-yl)pyridine-3-carboxylate of the formula .

6. The compound isopropyl 5-cyano-1,4-dihydro-2,6-dimethyl-4-(3-phenyl-1,7-naph-thyridin-5-yl)pyridine-3-carboxylate of the formula .

7. The compound isopropyl 1,4-dihydro-2,6-dimethyl-5-nitro-4-(3-phenyl-1,7-naphthyridin-5-yl)pyridine-4-carboxylate of the formula

8. The compound 3-isopropyl-5-methoxyethyl-1,4-dihydro-2,6-dimethyl-4-(3-phenyl-1,7-naphthyridin-5-yl)pyridine-3,5-dicarboxylate of the formula .

9. A process for preparing a dihydropyridine of the general formula (I) as defined in claim 1, or a physiologically acceptable salt thereof, which process comprises [A](i) to prepare a compound of the general formula (I) in which R3, R4 and R5 are as defined in claim 1 and R1 and R2 do not form a lactone ring but are otherwise as defined in claim 1, reacting an ylidene compound of the general formula (IV) (IV) in which R3, R4 and R5 are as defined in claim 1, with a compound of the general formula (V) R1-CO-CH2-R2 (V) in which R1 and R2 are as defined above in the presence of ammonia or an ammonium salt;
[A](ii) to prepare a compound of the general formula (I) in which R3, R4 and R5 are as defined in claim 1 and R1 and R2 do not form a lactone ring but are otherwise as defined in claim 1, reacting an ylidene compound of the general formula (IV) above with an amino compound of the general formula (VI) (VI) in which R1 and R2 are as defined above;
[B](i) to prepare a compound of the general formula (I) in which R3, R4 and R5 are as defined in claim 1 and R1 and R2 do not form a lactone ring but are otherwise as defined in claim 1, reacting an ylidene compound of the general formula (VII) (VII) in which R1 and R2 are as defined above and R3 is as defined in claim 1, with an acetoacetic ester of the general formula (III) R5-CO-CH2-CO2-R4 (III) in which R4 and R5 are as defined in claim 1, in the presence of ammonia or an ammonium salt;
[B](ii) to prepare a compound of the general formula (I) in which R3, R4 and R5 are as defined in claim 1 and R1 and R2 do not form a lactone ring but are otherwise as defined in claim 1, reacting an ylidene compound of the general formula (VII) above with an enaminocarboxylic acid of the general formula (VIII) (VIII) in which R4 and R5 are as defined in claim 1;
[C] to prepare a compound of the general formula (I) in which R1 and R2 together form a lactone ring, subjecting a compound of the general formula (Ia) (Ia) in which R3, R4 and R5 are as defined in claim 1, R8 represents a C1-C6-alkyl radical and R9 represents a leaving group, to an acid-catalysed or base-catalysed ring closure; or [D] to prepare a compound of the general formula (I) in which R1, R2, R3 and R5 are as aefined in claim 1 and R4 is other than hydrogen but is otherwise as defined in claim 1, reacting a compound of the general formula (I) in which R1, R2, R3 and R5 are as defined in claim 1 and R4 is hydrogen with an alcohol of the general formula in which R4 is as defined in claim 1; and if required, converting an obtained compound of formula (I) into a physiologically acceptable salt thereof.

10. A process according to claim 9 [A] in which the ylidene compound of the general formula (IV) is prepared in situ by reacting an aldehyde of the general formula (II) R3-CHO (II) in which R3 is as defined in claim 9, with an acetoacetic acid or ester of the general formula (III) in which R4 and R5 are as defined in claim 9.

11. A process according to claim 9 [B] in which the ylidene compound of the general formula (VII) is prepared in situ by reacting an aldehyde of the general formula (II) R3-CHO (II) in which R3 is as defined in claim 9, with a compound of the general formula (V) as defined in claim 9.

12. A composition for affecting pathologically modified blood pressure, for the treatment of cardiac insufficiency and cardiac arrhythmias, for decreasing the blood sugar, for the detumescence of mucous membranes, for affecting the salt and liquid balance and as a coronary therapeutic comprising an amount effective therefor of a compound according to any one of claims 1 to 8, or a physilogically acceptable salt thereof, and a pharmacologically acceptable diluent.

13. A process for preparing a composition for affecting pathologically modified blood pressure, for the treatment of cardiac insufficiency and cardiac arrhythmias, for decreasing blood sugar, for detumescence of mucous membranes, for affecting the salt and liquid balance and as a coronary therapeutic which process comprises admixing a compound of the general formula (I) according to any one of claims 1 to 8, or a physiologically acceptable salt thereof, with a pharmacologically acceptable diluent.

14. Use of a compound of the general formula (I) according to any one of claims 1 to 8, or a physiologically acceptable salt thereof, for affecting pathologically modified blood pressure, for the treatment of cardiac insufficiency and cardiac arrhythmias, for decreasing blood sugar, for detumescence of mucous membranes, for affecting the salt and liquid balance and as a coronary therapeutic.

15. A commercial package containing, as active pharma-ceutical ingredient, a compound of the general formula (I) according to any one of claims 1 to 8, or a physiologically acceptable salt thereof, together with instructions for its use for affecting pathologically modified blood pressure, for the treatment of cardiac insufficiency and cardiac arrhythmias, for decreasing blood sugar, for detumescence of mucous membranes, for affecting the salt and liquid balance and as a coronary therapeutic.

16. Aldehydes of the general formula (II) R3-CHO (II) in which R3 has the meaning given in claim 1.

17. The compound 3-phenyl-1,7-naphthyridine-5-carbaldehyde of the formula .

18. The compound 3-phenyl-5-cinnoline-carboxaldehyde of the formula .

19. A process for preparing an aldehyde of the general formula (II) according to claim 16, which process comprises subjecting a compound of the general formula in which R3 is as defined in claim 16, to oxidation to convert the methyl group to an aldehyde group.

20. A process according to claim 19, wherein the oxidation is carried out by means of selenium oxide in naphthalene.

21. Compounds of the general formula (IX) (IX) in which R6 and R7 have the meaning given in claim 1, D
represents a protective group and R8 represents lower alkyl.

22. A process for preparing a compound of the general formula (IX) as defined in claim 21, which process comprises deprotonating a compound of the general formula in whish R6 and D are as defined in claim 21, and reacting the deprotonated compound with a 2,2-dialkoxyketo compound of the general formula in which R7 and R8 are as defined in claim 21.

23. The method of affecting pathologically modified blood pressure, for the treatment of cardiac insufficiency and cardiac arrhythmias, of decreasing the blood sugar, of detumescing of mucous membranes of affecting the salt and liquid balance and of treating coronary diseases in a patient in need thereof which comprises administering to such patient an amount effective therefor of a compound or a physiologically acceptable salt thereof according to any one of claims 1 to 8.