PROCEDURE FOR the PRODUCTION OF NEW ONE 2-AMINO-1,4-DIHYDROPYRIDINEN

- dihydropyridinen with a Carbonylfunktion, which is usable as drugs, in particular as Antihypertensiva and Coronarmittel. It is already become known that the conversion of Benzylidenacetessigsaumathylester with Aminocrotons supplies with to iureestem 1,6-Dihydropyridine. (Knoevenagel, Ber. 31, P. 748). It was found that one the new 2-Amino-1, 4-dihydropyridine of the general formula (1) in which g 1 for a geradkettigen or branched or cyclischen alkyl residue or for a Phenylrest, that 1 to 3 equal if necessary or different substituents from the group alkyl, Alkoxy, halogen, Nitro, tri fluorine methyl, Cyano and SOn alkyl (n = 0 to 2) or flr R contains a PyridyI, Thenyloder Furylrest, which is replaced with alkyl or Alkoxy if necessary, flr hydrogen or a geradkettigen or branched Alk3rlrest, R-S for a geradkettigen or branched, gesichtigten or insatiated or cyclischen hydrocarbon remainder, or for a Pbenykest, that if necessary I to 3 adjusts or different 8ubstituenten g [uppe alkyl, Alkoxy, halogen, Nttro, Cyano, tri fluorine methyl, Carbalkoxy or SOn - alkyl (n = 0 to 2) or for substituiertcn Naphthyl, Chinolyl, Pyridyl, Pyrimidyl, Thenyl, Furyloder Pyrrylrest contains if necessary stands, and R4 for one by alkyl, Alkoxy, halogen for a geradkettigen or branched Alkoxyoder Alkenoxyrest, which is interrupted if necessary by 1 to 2 oxygen atoms in the chain, or an amino group stands, receives, if one A, ß - ungest ttigte Ketorm of the general formula 2 g 1 R - C-- C=CH-RS o (IL) in which RI, RZ and R-S the meaning indicated above have, with Amidinen of the general formula H2N C -- CH2COR4 HN (in) in which R the meaning indicated above has, in presence of inert organic solvents at temperatures between 20 und200°C converts. The new 2-Amino-1, 4-dihydropyridine of the general formula (I) exhibit long lasting coronarerweiternds and antihypertensive characteristics. It is expressed surprisingly to be called that in accordance with effindungsgemä the EN Umsstzung the new 2-Amino-1, 4-dihydropyridinc of of the general formula (I) in so good yields and so high purity, there one develops after dern state of the art an addition of the Amidinfunktion to cq the B-unges ittigte Kctoslxuktur to the Dihydropyrimidinderivaten (IV) had had to expect: ! [...] Uùr', t za o < i - [...] u o R2 2 H R3 NH R,/NZ \ cù H 4 COR 2 (check valve) (see E.F.Silversmith, J. Org.Chem. 27, 8,4090). A substantial advantage erfindungsgemtt of the EN of procedure is in that it supplies high yields and products of large purity and spends and to high economy with is accomplished as single-step process with small technical kaIm. If 2, - more tureisopropylester than basic materials, is used Chlorbenzylidenaceton and Amidinoessigs can be shown the reactions blauf by the following formula pattern: 'C, /COOCH (CH3) 2 /H COC H [...] > /1/../ (C, j, o NH2 Bc HN \ NH c/HN in the Formei R2 I I0 RICOC=CHRS (II) RI stands for the 1 or 2 for an alkyl residue with 1 to 4 carbon atoms or for a Phenylrest, preferably equal or different substituents to the group the alkyl, Alkoxy with ever 1 to 4 carbon atoms, halogen, in particular fluorine, chlorine and bromine, Nitro, tri fluorine methyl, Cyanound then alkyl (n= 0 or 2) whereby the Alkylgmppe 1 to 4 carbon atoms carry it can or for a Pyri yl, Thenyloder Fnrylrest, RZ vorzngsweise for hydrogen or an alkyl residue with 1 to 4 carbon atoms and R s preferably for a geradkettigen, branched or or different substituents from the group of AlkT1, Alkoxy, halogen, Nitro, Cyano, tri fluorine methyl, Carbalkoxy equal to cyclischen, satisfied or unges tttigtenKohlenwasserstoffrest with up to 6 C-flavours or far a Phenylrest, the 1 or 2, whereby the Alkoxy, Alkylund Carbalkoxygmppen 1 to 4 carbon atoms contains or for a THEN - alkyl residue (n = 0 or 2) with 1 to 4 carbon atoms in the alkyl group or for a n Naphthyl, Ctänolyl, Pyridyl, Furyloder Thenylrest. The usable according to invention C B-insatiated Ketone already are well-known or can after be26 knew methods to be manufactured (Org.Reactions XV, P. 204 fr). As examples are mentioned: A, B-insatiated Ketone: Benzylidenaeeton Benzylidena eetophenon (Chalkon) 2 t - Chlorbenzylidena concrete _ 3 t - Chlorbenzylidena concrete 4w - C hlorbenzylide well ceton 21,4w - Dinhlorbenzylidenaceton 2w, 6t-DichlorbenzyHdenaceton 2t - Methoxybenzylidenaceton 21 -, 3 w. or 41 - Methylbenzylidenaceton 21 -, 3 t - or 41 - Nitro6enzylide well eeton I0 8 t - Nitro4t - chlorbenzylidena ceton 21 - Methylmer approx. ptobenzylidenaceton 21, 3toder 41-Trifluormethylbenzylidenaceton 21, 31oder 41-Cyanbenzy! idenaeeton 3 t - C work äthoxybenzylldenaceton 1Phenylpenten (1) - on-3 1Pheny! - 2methylbuten (1) - on-3 i (A-Pyridyl) - buten (1) - on-3 1 - (B-PyädyI) - buten (1) - on-3 1 - (A-Pyridyl) - buten (1) - on-3 1 - (21 - Buryl) - buten (1) - on-3 1 - (1 - (21-Thenyl) - buten (1) - on-3 1 - (aoder B-Naphthyl) - buten (1) - on-3 1 - (2 ' - or 4, - Chtnolyl) - buten (1) - on-3 1 - (31-Nitrophenyl) - 2-isopropylbuten (1) - on-3 1Phenyl4, 4-dimethylbuten (1) - on-3 2, 3oder 4-Chlorbenzylidenacetophenon 2, 3oder 4-Nitrobenzylidenacetophenon 2, 3oder 4-Trffluormethylbenzylidenacetophenon Benzyliden4t - fluoracetophenon 3-Brombenzylidena cetophenon 3-Chlorbenzyllden41 - chlora cetophenon Benzyliden-2t - nitroacetophenon 4Nitrobenzyliden41-bromacetophenon 2-Nitrobenzyliden41 - nitroacetophenon 2-Nitrobenzyliden-2' - nitroacetophenon 4-Nitrobenzyliden-31 - nitroa cetophenon 3, 4, 5-Tr [methoxybenzylidenacetophe* on 2Methy hnercaptobenzylldena cetophenon 4Methylmereaptobenzylidena cetophenon 2-ChlorbenzylfdeIl41-trifluormethylacetophenon 3-Ch! orbenzyliden4t - methylmercaptoacetophenon 1 - (A-Pyridyl) - 3-phenyl-propen (1) - on-3 1-Pheny! - 3 - (“- pyridyl) - propen (1) - on-3 1 - (S-Pyridyl) - 3-phenylpropen (1) - on-3 1Phenyl-3 (2t-thenyl) - propen (1} - on-3 1Phenyl-3 (21-furyl) - propen (1) - on-8 i, 3-Diphenyl2-methyl-propen (1) - on-3 I, 3-Diphenyl-2-isopropyl-propen (1) - on-3 IMethyl3-phenylpropen (I) - on3 1-Cyclohexy! - 3phenylpropen (1) - on-3 1Isopr opyl3 phenylpropen (i) - on-3 i (AS-Cyclohexenyl) - 3-phenylpropen” (1) - on3. b) In the formula (III) R4 preferably far efnenAlkoxyoder Alkenoxyrest with up to 6 Kohlemtoffatomen, that stands for f an amino group by 1 oxygen atom in the chain if necessary is interrupted or. Usable the according to invention Amidine already is well-known or can according to well-known methods be manufactured (S.M.Mc Elvain, B.E. Tate, J.A.C.S. 3, S.2760). As examples are mentioned: Amines: Amidinoessigsäuremethylester, Amidinoessigsaumtithylester, Amidinoessigs RH-n-propylester, Amidinoessigs ureisopropylester, Amidinoessigsäum-8-methoxy thylester, Aminoessigsäure (aoder/3) thoxyethylester, Amidinoessigstturepropargylester, Amidinoaeetamid. The Amidine can be used either in free form or in form of their salts (e.g. hydraulic halides). From the salts they become with basic means (e.g. AlkaHalkoholaten) set free. As Verdtlnnungsmittel all inert organic solvents are applicable. Hiezu preferably belong alcohols such as methanol, ethanol, Propanol; Ether such as Dioxan, diethylether or glacial acetic acid, akridin, Dlmethylformamid, Dimethylsulfoxyd or Acetonitri!. The reaction temperatures can within a larger range varied whose. Generally O one works between 20 and 200 C, preferably at boiling temperature of the solvent. The conversion can be durchgeftlhrt with Norrnaldruck, in addition, with increased pressure. Generally one works at Normaldtuck. With the Durchfährung of the erfindungsgemäflen procedure the materials taken part in the reaction are used in each case into molecular quantities. The new connections are as medicine center! usable substances. They have a broad and versatile pharmakologisches action spectrum. In detail the following main effects can be proven " 1. the connections to cause with parenteral, oral and perlingualer gift a clear and long lasting Erweiternng of the Coronargefaße in the animal experiment. This effect on the coronary container is strengthened by a equivalent riitritähnlichen heart-exculpatory effect. They affect and/or change the Herstoffwechsel in the sense of an energy saving. 2. The connections lower the blood pressure of normotonen and hypertonic animals and can thus as antihypertensive means be used. 8. The excitation barness of the Keizbildungsund Erregungsleltungssystems within the heart is lowered, so that a Antifklimmerwirkung provable in therapeutic doses resulüert. 4. The tonus of the smooth Muskulator of the containers is strongly decreased under the effect of the connections. This gefaßspasmolytische effect can take place in the entire overall system or more or less isolates itself in umsehriebenen discharge areas (like e.g. central nervous system) to manifest. The connections have strongly muscular spasmolyüsche effects, which become clear to the smooth Muskulator of the stomach, the intestine tract, the Urogenitaltraktes and the Respirationssystems. 6. The connections affect the Cholesterinbzw. Lipidspiegel of the blood. The new active substances can be übergeftlhrt in well-known way into the usual formulations, like tablets, caps, dragees, pills, granulates, aero brine, syrups, emulsions, suspensions and solutions, using inertly, not more toxic, phamaazeutisch suitable carrier materials or solvents. Hiebei soi1 the therapeutically effective connection in each case in a concentration of approximately 0, 5 to 90 Gew. - °] o of the total mixture its to reach i.e. in quantities, which are sufficient, in order angegebenenDosiemngsspielraum. The formulations are for example manufactured, by drawing the active substances with solvents and/or carrier materials, if necessary using emulsifying means and/or dispersing agents, whereby e.g. in the case of the use of water as diluents organic solvents can be used if necessary as auxiliary solvents. As auxiliary materials are exemplarily aufgeftthrt: Water, not-toxic organic solvents, like paraffins (z, B. Erdölfraktionen), vegetable oils (e.g. peanut /Sesamöl), alcohols (e.g. ethyl alcohol, Glycerin), glycols (e.g. prop.) rlenglykol, PL glycol), firm of carrier materials, like e.g. natttrliche Gesteinsmehie (e.g. kaolin aluminas, talcum powder, chalk), synthetic powdered minerals (e.g. hochdisperse silicic acid, silicates), sugars (e.g. raw, milk grape sugar) emulsifying means, like nichtionogene and anionische emulsifying agents (e.g. Polyoxy of thylen fat ure ester, Polyoxyäthylen Fettalkohol ether, Alkylsulfonate), dispersion center! (e.g. lignin, Sulfitablaugen, methyl cellulose, strong one and Polyvinylpyrrolidon) and lubricants (e.g. magnesium stearate, talcum powder, stearic acid, sodium sulfate and Natriumlaurylsulfat). The application takes place in {Iblicher way, preferably orally or parenterally, in particular perlingual or intravenously. In case of oral application tablets can contain additives naturally except the TrägerB0 mentioned materials also such as sodium CIT act, calcium carbonate and Dikalziumphosphat as well as different aggregates like strong ones, preferably potato strength, C-elatine u.dgl. Further lubricants can be along-used such as Magnes£umstearat, Natriumlaurylsulfat and talcum powder for the Tablettieren. In case of aqueous suspension and/or Elixieren, which are meant for oral applications, the active substances can be shifted except with the auxiliary materials with different Geschmacksaufbessemngen or coloring materials, specified above, • 55. For the case of parenteral application solutions of the active substances can be used using suitable liquid Trägermateñalien. Generally has it see proven as favourable to preferably give with intravenous Applikaüon quantities from approximately 0.1 to mg/kg 0, 5 to t0 mg/kg body weight/day for the achievement of effective results and with oral application amount to the dosage about 1 to 100 mg/kg, veszugsweise 5 to 50 mg/kg body weight/day. -6 NR, öz'/u± nevertheless it can be if necessary necessary to deviate from the quantities mentioned and zw. as a function of the body weight of the experimental animal and/or the kind of the application way, in addition, due to the animal species and their individual behavior opposite the medicine and/or the kind its Pormulierung and the time and/or interval, to which the administration takes place. So it can be sufficient in some cases to get along with less than the aforementioned Mfndestmenge be exceeded resisting in other cases the upper border mentioned must, in case of A pplikation larger Mengenkannes be recommendable to distribute these in several single gifts over the day. F the App] ikation in the Humanmedizin is intended the same Dosierungsspiekaum. Lüebei also the above Ausf is valid in a general manner [lhrungen. The Coronarwirkung of the connections is exemplary into Tabe! le I shown " table I: Manufacture example clearly recognizable rise of the No. of oxygen tttigung in the Coronaränus example 9 with 0,2 mg/kg i.v. The Coronarwirkung anaesthetized on, herzkatheterisiertenBastardhunden determined by measurement of the Sauerstoffsattigungsanstiegs in the coronary sine. Lutdmekwirkung some connections according to invention is to be taken out of the table [...]. The indicated dose in the 2.Spalte refers to a blood pressure lowering with the Hochdruekratte of at least 15 mm Hg. Table [...]: Manufacture example No. Toxlzlt tt mouse mg/kg by OS Blutdtucksenkung high pressure rat mg/kg by OS 3 starting from 31, i0 starting from I0, 0 Hetstellungsheispiele: Example 1: O COOCz H [...] II/\ NH H z by 2sttlndiges cooking a solution of 14, 6 g Benzylidenaceton and 13.0 g Amidinoessigs u eäthy! - estet in 150 ml ithano! became the 2-Amino-6-methyl-4-pheny! -! , 4-dihydropyridin-3-carbonsäuteßthylester of the F p. 150 °C (ethanol) receive. Yield 7,3% D. Th. Example 2: After 2sttlndigem heating a solution up of 20, 8 g Benzylidenacetophenon and 13.0 g Amidinoessigs more ureäthylester in 250 ml ethanol became the 2-Amino-4, 6-diphenyl-1,4-dihydropyridin-8-earbonstturettthylester of the Pp. 159°C (ethanol) receive. Yield 69% d.Th. Example 8: ÖOCz Hs f i [/NI \ H sports club H NH2 after 2sttlndigem cooking a solution of 18, I g 21-Chlorbenzylidenaceton and 13, 0 g Amidinoessigsaureäthylester in 150 ml ethanol became the 2-Amino-6-methyl-4 (21-ehlorphenyl) - l, 4-dihydropyridin-8-carI0 bonsäure more tthylester by the Fp. 171°C (ethanol) receive. Yield 62% D. Th. Example 4: HS i --> , /I// ' rear OOC2 Hs FF FF HsC H --NH2 by 2sttlndiges heating a solution up of 17, 5 g 41-Methoxybenzylidenaceton and IS, 0 g to [more dinoessigsäureßthylester in 150 ml ethanol became the 2-Amino-6-methyl-4 (41-methoxyphenyl) - l, 4-dihydropyridin -3-carbonsäure; more tthylester in front Fp. 160 to 161°C receives (ethanol). Yield 52% d.Th. Example 5: c1 cooc//zHs I I N \ H3C H N after 3stündigemErhitzen of a solution of 18, 1 g 3t-Chlorbenzylidenaceton and 13.0 g Amidinoessigs ure more tthylester in 150 ml ethanol became the 2-Amino-6-methyl-4. (SW-chlorphenyl) - l, 4.dihydropyridin-3-carbons ure more tthylester of the MP. 140°C (isopropanol) receive. Yield 56% D. Th. Example 6: CI of /I//HiOOC2Hs l/NJ \ after 4sdlndigem heating a solution up of 24,3 g 3-Chlorl nzylidenacetophenon and 13.0 g Amidinoessigs ure in 250 ml ethanol the 2-Amino-6-phenyl-4 became more thylester. (SW-chlorphenyl) - l, 4.dihydropyridini0 -3-carbonsäureäthylester of the Fp. 161°C (isopropanol) receive, yield 73% d.Th. Example 7: NO COOCHs I J N \/H NH after 2sttlndigem cooking a solution of 25, 8 g 8-Nitrobenzylidenacetophenon and 18.0 g Amidinoessigstture more tthylester in 250 ml ethanol became the 2-Amino6-phenyl4 (8 wrdtrophenyl) - l, 4-dihydropyridin -8-carbonsäuret more thylester by the Fp. 171 bis172°C (ethanol) receive. Exploit 71%d.Th. Example 8: I--CHs H C00C2 H {{I HsC-- H --NHz after 2sttlndigem heating up a solution of 16, 0 g 2T-Methylbenzylidenaeeton and 13, 0 g Amidinoessigs ure more thylester in 150 ml ethanol became the 2-Amino-6-methyl-4 (21-methylphenyl) - 1, 4-dihydropyridin-3 - earbons ture more thylester of the Fp. 1590C (isopropanol) receive. Exploit 61%d.Th. Example 9: c1 IS c°°c2H IL f/HN --NH after hour cooking of a solution of 24, 3 g 2 - Chlorbenzylidenacetophenon and 23.0 g Amidinoessigs in 250 rrfi Äthsnol the 2Amino6 phenyl4 (21 - chlorine phenyl) became more äureäthylester - 1, 4-dihydropyridin -3carbomäureäthylester of the Fp. 196°C (alcohol) receive. Yield 68% D. Th. Example 10: I Jc1 HsC' H NHz after hour heating of a solution up of 18,1 g 21-Chlorbenzylidenaceton and 14, 4 g Amidinoessigs ureisopr0pylester in 200 ml isopropanol became the 2-Amine-6-methy! - 4 - (21-chlorphenyl) - 1, 4dihydropyridin3 earbons t of the Fpo16 tureisopropyleste! °C (isopropanol) receive. Yield 51 o D. Th. 1, - I0Nr.327901 PATENT of REQUIREMENTS " procedures for the production of new 2-Amino-l, 4-dihydropyridinen of the general formula to hands R-S 4 t IL (i) in which RÆ for a geradkettigen ode branched or to cyclischen Alkylxest or f k a Phenylrest, the ge0 gebenenfalls 1 to 3 equal or versclKedene Substttuenten from the group of Alky! , Alkoxy, ha! ogen, Nitro, Trifluo methy! , Cyano and SO - Alky! (n = 0 to 2) contains or ftkeinen l ridy! -, Thenyl or Furyltest, those if necessary by A1 qk'y! or Alkoxy are substituted, RZ fü hydrogen or a geradkettfgen or branched Alky! xest, R-S for a geradkettigen or a branched, a satisfied or a ungesattelten odet cyelischen hydrocarbon remainder, or for a Phenylrest, that 1 to 3 equal or different substituents from the group to Alky if necessary! , Alkoxy, ha! ogen, Nitro, Cyano, Trifluotmethy! , Carbalkoxy or 80 - - alkyl (n = 0 to 2) contains or for one if necessary by Alky! , Alkoxy, ha! ogen substituiertenn Naphthyl, Chinolyl, Pyridyl, Pytimidyl, Theny! -, Puryloder Pynyltest stand, and for R4 ftlr a geradkettigen or branched Alkoxyoder Alkenoxyrest, gegebenenfa! LS by I bis2! 5 oxygen atoms into de Kette is interrupted, or an amino group stands, thereby characterized, Daßwang ungesättigteKetonederallgemeinenFormel for R2 I g 1 -- C -- C. - - CH-- R-S [...] O (I.t) in which RZ, RZ and R s the meaning indicated above have, with Amidinen of a! lgemeinen form! , (III) in which R4 the meaning indicated above has, in presence of inert organic solvents at temperatures between 20 und200°C converts. 2. Procedure according to requirement I, thereby marked that one eimetzt a connection of the general formula (IL), in R for an alkyl residue by 1 to 4 C-atoms or for a Phenylrest, the 1 or 2 equal or different substituents from the group to Alky! , ALkoxy with ever 1 to 4 C-flavours, halogen, imbesondere fluorine, chlorine or bromine, Nile o, tri fluorine methyl, Cyano or SOn alkyl (n = 0 or 2), how a11T1 uppe i as far as 4 C-atoms carry can, or fllr I ridyl, Thenyl or Fury1 stands, for RZ ftir hydrogen or an alkyl residue also! to 4 C-flavours and R-S stands for the I or 2 for a Koklenwasserstoffrest with up to 6 C-atoms or for a Phenylrest, equal or different substituents from the group alkyl, Alkoxy, halogen, Nitro, Cyano, Tdfluormethyl, Carhalkoxy, how A! koxy, Alkylund Carbalkoxygruppen i to 4 Kohl confining off atoms contained can or for an SOn alkyl residue (n = 0 or 2) with I to 4 C-flavours in A! - stands kylgmppe or fflr a NaphthylD Chinolyl, Pyridyl, Purylode Thenylrest. 8. Procedure according to requirement i ode 2, by it characterized that one uses a connection of the general formula (LII), Indian R4 fiir a Alkoxyoder Alkenoxytest by up to 6 C-flavours, which is interrupted by 1 oxygen atom in the chain if necessary, or fttr the Arninogruppe stands. 4. Procedure according to requirement I, thereby characterized that one converts 2t-Chlorbenzylldenaceton with Amidinoessigsäureäthylester.