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US3775422A - Unsymmetrical 1,4-dihydro-4-aryl-nicotinate esters - Google Patents

Unsymmetrical 1,4-dihydro-4-aryl-nicotinate esters Download PDF

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US3775422A
US3775422A US00107849A US3775422DA US3775422A US 3775422 A US3775422 A US 3775422A US 00107849 A US00107849 A US 00107849A US 3775422D A US3775422D A US 3775422DA US 3775422 A US3775422 A US 3775422A
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carbon atoms
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branched chain
moieties
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F Bossert
W Vater
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • R is hydrogen, straight, branched or cyclic lower alkyl
  • R is straight or branched chain alkyl of 1 to 4 carbon atoms
  • R is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain dialkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 6 carbon atoms, straight or branched chain alkinyl of 2 to 6vcarbon atoms, cyclic alkyl of 3 to 6 carbon atoms, cyclic alkenyl of 3 to 6 carbon atoms, straight or branched chain alkyl or alkenyl of 2 to 6 carbon atoms interrupted by 1 or 2 oxygen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms substituted by hydroxyl, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted by hydroxyl;
  • R is aryl, unsubstituted or substituted by 1 to 3 members selected from the group consisting of 1 to 3 nitro moieties, 1 or 2 cyano moieties, 1 to 3 halogen atoms, 1 or 2 hydroxyl moieties, 1 or 2 acyloxy moieties of 1 or 2 carbon atoms in the acyl portion, 1 to 3 alkoxy moieties of 1 to 4 carbon atoms, a dioxymethylene moiety of the formula:
  • alkylmercapto moiety of 1 to 4 carbon atoms in the alkyl portion trifluoromethyl, carboxyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxy portion and an alkylsulphonyl moiety of 1 to 4 carbon atoms in the alkyl portion; benzyl; styryl; pyridyl; pyrimidyl; furyl;
  • pyrrolyl pyridyl, pyrrolyl, thienyl or furyl substituted by alkyl of 1 or 2 carbon atoms
  • pyrimidyl substituted by at least one member selected from the group consisting of alkyl of 1 or 2 carbon atoms, 1 or 2 methoxy moieties and 1 or 2 ethoxy moieties;
  • R is straight or branched chain alkyl of 1 to 4 carbon atoms.
  • R200 C CO-Rt wherein R is hydrogen, straight, branched or cyclic lower alkyl
  • R is straight or branched chain alkyl of 1 to 4 carbon atoms
  • R i straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain dialkyl of l to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, straight or branched chain alkinyl of 2 to 6 carbon atoms, cyclic alkyl of 3 to 6 carbon atoms, cyclic alkenyl of 3 to 6 carbon atoms, straight or branched chain alkyl or alkenyl of 2 to 6 carbon atoms interrupted by 1 or 2 oxygen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms substituted by hydroxyl, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted by hydroxyl;
  • R is aryl, unsubstituted or substituted by l to 3 members selected from the group consisting of 1 to 3 nitro moieties, 1 or 2 cyano moieties, l to 3 halogen atoms, 1 or 2 hydroxyl moieties, 1 or 2 acyloxy moieties of 1 or 2 carbon atoms in the acyl portion, 1 to 3 alkoxy moieties of 1 to 4 carbon atoms, a dioxymethylene moiety of the formula:
  • alkylmercapto moiety of 1 to 4 carbon atoms in the alkyl portion trifluoromethyl, carboxyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxy portion and an alkylsulphonyl moiety of 1to 4 carbon atoms in the alkyl portion; benzyl, styryl; pyridyl; pyrimidyl; furyl; thienyl; pyrrolyl; pyridyl, pyrrolyl, thienl or furyl substituted by alkyl of l or 2 carbon atoms; or pyrimidyl substituted by at least one member selected from the group consisting of alkyl of 1 or 2 carbon atoms, 1 or 2 methoxy moieties and 1 or 2 ethoxy moieties; and
  • R is straight or branched chain alkyl of l to 4 carbon atoms
  • the compounds of the present invention may be produced by reacting a xylidene derivative of the formula:
  • R and R are as above defined, and ammonia or an amine of the formula HzN-R wherein R is as above defined, or a salt thereof, or
  • an elevated temperature preferably from about 70 C. to about 120 C. in the presence of at least one organic solvent, such as an alcohol, glacial acetic acid, pyridine, dioxane, dimethylformamide, dimethylsulphoxide or a halogenated hydrocarbon.
  • organic solvent such as an alcohol, glacial acetic acid, pyridine, dioxane, dimethylformamide, dimethylsulphoxide or a halogenated hydrocarbon.
  • the xylidene derivatives of the Formula 2 above are produced by condensing an aldehyde with an 0:,[3-dik6't0116.
  • the compounds of the present invention may also be produced by reacting a xylidene derivative of the formula:
  • RLC CHCRI NH-R (8) wherein R and R are as above defined under the re action conditions above set forth.
  • xylidene derivatives of Formula 6 above can be produced by condensing an aldehyde with an acyl-fatty acid ester.
  • R in Formula 1 above is other than hydrogen
  • the compounds of the present invention may be produced according to a process carried out in the presence of pyridine, which process is set forth in co-pending application Le A 12 217-A U.S. Ser. No. 35,574, filed May 7, 1970.
  • Suitable reactants for use in the process of the present invention and for the production of the compounds of the present invention include as illustrative examples the following:
  • Aldehydes Benzaldehyde, 2-, 3-, or 4 hydroxy- 'benzaldehyde, 2,4- or 2,6 dihydroxybenzaldehyde, 2-, 3-, or 4 methoxybenzaldehyde, 2 isopropoxybenzaldehyde, 3 butoxybeu zaldehyde, 3,4,5 trimeth- 4 oxybenzaldehyde, 2-, 3-, or 4 chloro or bromo or fluorobenzaldehyde, 2,4 or 2,6 dichlorobenzaldehyde, 2-methylbenzaldehyde, 2,4-dimethylbenzaldehyde, 3,5-dlisopropyl 4 hydroxybenzaldehyde, 2-, 3- or 4-nitrobenzaldehyde, 2,4- or 2,6-dinitrobenzaldehyde, 2-nitro-6- bromobenzaldehyde, 2-nitro-3-methoxy-6-chlorobenzaldehyde, 2-nitro-3-hydroxy-4-chlor
  • Acyl-fatty acid esters Formylacetic acid ethyl ester, formylacetic acid butyl ester, acetoacetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid propyl ester, acetoacetic acid isopropyl ester, acetoacetic acid- (on or 3-) hydroxyethyl ester, acetoacetic acid (aor 8-) methoxyethyl ester, acetoacetic acid (01- or ,8)-ethoxyethyl ester, acetoacetic acid(aor 13-) propoxyethyl ester, acetoacetic acid furfuryl ester, acetoacetic acid tetrahydrofurfuryl ester, acetoacetic acid allyl ester, acetoacetic acid propargyl ester, acetoacetic acid cyclohexyl ester, propionylacetic acid ethy
  • Amines Methylamine, ethylamine, propylarnine, isopropylamine, butylamine, allylamine, propargylamine, 1- hydroxyethylamine-2, l,3-dihydroxyisopropylamine, cyclohexylamine, benzylamine, 4-chlorobenzylamine, 3,4- dimethoxybenzylamine and phenethylamine.
  • R is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl or phenethyl, R is straight or branched chain alkyl 1 to 4 carbon atoms, R is monoor dialkyl of 1 to 6 carbon atoms, alkinyl of 2 to 6 carbon atoms, cyclic alkyl of 3 to 6 carbon atoms, alkyl of 2 to 6 carbon atoms interrupted by oxygen, or cyclic alkyl of 3 to 6 carbon atoms wherein the ring contains oxygen as a heteroatom, R is benzyl; phenyl unsubstituted or substituted by 1 or 2 nitro moieties, cyano moieties, halogen atoms especially fluorine, chlorine or bromine, alkoxy moieties of 1 to 3 carbon atoms or trifiuoromethyl; pyridyl, pyrrolyl, furyl or thienyl unsubstituted or substituted by alkyl of
  • the 1,4-dihydropyridines of the present invention have a broad range of utility as indicated above and the following effects have been exhibited in animal experiments:
  • the compounds produce a distinct and long-lasting dilation of the coronary vessels on parenteral, oral and perlingual administration. This action on the coronary vessels is intensified by a simultaneous, nitrite-like, effect of reducing the load on the heart.
  • the tonus of the smooth muscles of the vessels is greatly reduced under the action of the compounds.
  • This vascular-spasmolytic action can occur in the total vascular system or can manifest itself to a more or less isolated extent in circumscribed vascular regions (such as for example the central-nervous system).
  • the compounds reduce the blood pressure of normal tonic and hypertonic animals and can thus be used as anti-hypertensive agents.
  • the compounds have strong muscular-spasmolytic actions, which manifest themselves on the smooth muscle of the gastro-intestinal tract, the urogenital tract, and the respiratory system.
  • compositions are produced which comprise a compound of the present invention or more than one compound of the present invention in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.
  • the present invention further includes a medicament in unit dosage form which comprises a compound of the present invention or more than one compound of the present invention per se or in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier.
  • the medicament may include a protective envelope containing the active compound or compounds, and if present, the pharmaceutically acceptable non-toxic inert diluent or carrier.
  • medicament in unit dosage form means a medicament as defined above in the form of discrete portions each containing a unit dosage, or a multiple or sub-multiple of a unit dose of the active compound or compounds, for example two, three or four unit doses or a half, a third or a fourth of a unit dose.
  • Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such a wrapped powders, cachets, sachets or capsules; in ampoules, either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.
  • the 1,4-dihydropyridines of the Formula 1 can be administered orally or parenterally.
  • the compounds of Formula 1 can be administered as such or as pharmaceutical compositions as described above.
  • suitable forms of application in combination with various inert carriers are: tablets, capsules, dragees, ampoules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like.
  • Such carriers comprise solid diluents or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like. Tablets and the like intended or oral application may, of course, be provided with sweetening additives and similar substances.
  • the therapeutically active compound should be present at a concentration of about 0.5 to 90 percent by weight of the total mixture, in quantities which are sufiicient to achieve the range of dosage, mentioned above.
  • the tablets or capsules may also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other additives, such as starch, preferably potato starch, and the like, and binding agents, such as polyvinylpyrrolidone, gelatin and the like.
  • additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other additives, such as starch, preferably potato starch, and the like, and binding agents, such as polyvinylpyrrolidone, gelatin and the like.
  • Lubricants such as magnesium stearate, sodium lauryl sulphate and talc may also be added for the production of tablets.
  • the active substance may be used with various flavouring agents, coloring substances, emulsifiers and/or together with diluents, such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations of this type.
  • solutions of the active substances in sesame or peanut oil or in aqueous propylene glycol or N,N-dimethyl formamide can be used, as can sterile aqueous solutions in the case of the water-soluble compounds.
  • Aqueous solutions of this type should be buffered in the usual way, when required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose.
  • These aqueous solutions are particularly suitable for intravenous and intraperitoneal injections.
  • Sterile aqueous media of this type may be prepared in a manner per se known.
  • compositions in orally administrable form are the preferred embodiment of the pharmaceutical compositions.
  • Table sets forth a range of viable dosages for compounds representative of those of the present invention:
  • the compound of Example 1 has exhibited good activity when administered orally at a dosage range of from 1 to about 50 mg./kg.
  • EXAMPLE 1 4- (2-pyridyl -2, 6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester After stirring a solution of 21.4 g. of pyridin-2-aldehyde and 20 g. of acetylacetone in 250 ccs. of benzene, with the addition of 2 ccs. of piperidine for approx. 12 hours at room temperature, the water is separated off, the solution is dried and the solvent is distilled off in vacuo.
  • EXAMPLE 3 4 phenyl 2,6 dimethyl-3-aceto-1,4-dihydropyridine-5- carboxylic acid ethyl ester (identical to Example 1(b) 0.1 mol of benzalacetic acid ethyl ester (obtained from 10.6 g. of benzaldehyde and 13 g. of acetoacetic acid ethyl ester in benzene with the addition of piperidine) is heated for 3-4 hours with g. of Z-aminopenten-(2)-one-(4) to 90-100, after cooling the solid reaction product is taken up in a little ether, and after filtering off and recrystallizing, yellow crystals of melting point 167 C. (alcohol) are obtained.
  • EXAMPLE 4 (2' methylphenyl) 2,6 dimethyl 3 aceto-1,4- dihydropyridine-S-carboxylic acid ethyl ester (melting point 155 (C.) was prepared by a method analogous to that described in Example 3 from 2-methyl-benzal-acetylacetone and fl-aminocrotonic acid ethylester.
  • EXAMPLE 5 4-(4'-pyrimidyl -2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester 1 cc. of piperidine is added to a solution of 10 g. of pyrimidine-4aldehyde and 10 g. of acetylacetone in 150 ccs. of benzene, the mixture is stirred for 48 hours at room temperature, the Water is then separated 01f, the solution is dried and evaporated, and the residue (pyrimid- 4-al-acetylacetone) is heated with 13 g. of B-aminocrotonic acid ethyl ester for 5 hours on a water-bath.
  • R is straight chain alkyl of 1 to 4 carbon atoms.
  • R is hydrogen or methyl
  • R is methyl
  • R is methyl, ethyl, diethyl, B-methoxyethyl, propargyl or furfuryl
  • R is phenyl, nitrophenyl, cyanophenyl, fluorophenyl, trifluoromethylphenyl, benzyl, or nitrochlorophenyl
  • R is methyl.
  • R is monoalkyl of l to 6 Colunm 6, line 69 should read as follows:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

1,4-DIHYDROPYRIDINES OF THE FORMULA:

1-R,2-R4,3-(R4-CO-),4-R3,5-(R2-OOC-),6-R1-),4-DIHYDRO-


WHEREIN

ARE USEFUL FOR THEIR CORONARY DILATING EFFECT, THEIR NITRITELIKE EFFECT ON THE HEART, THEIR ANTI-FIBRILATION EFFECT, THEIR VASCULAR-SPASMOLYTIC EFFECT AND MUSCULAR-SPASMOLYTIC EFFECT, AND AS ANTI-HYPERTENSIVES.

AN ALKYLMERCAPTO MOIETY OF 1 TO 4 CARBON ATOMS IN THE ALKYL PORTION, TRIFLUOROMETHYL, CARBOXYL, CARBALKOXY OF 1 TO 4 CARBON ATOMS IN THE ALKOXY PORTION AND AN ALKYLSULPHONYL MOIETY OF 1 TO 4 CARBON ATOMS IN THE ALKYL PORTION; BENZYL; STYRYL; PYRIDYL; PYRIMIDYL; FURYL; THIENYL; PYRROLYL; PYRIDYL, PYRROLYL, THIENYL OR FURYL SUBSTITUTED BY ALKYL OF 1 OR 2 CARBON ATOMS; OR PYRIMIDYL SUBSTITUTED BY AT LEAST ONE MEMBER SELECTED FROM THE GROUP CONSISTING OF ALKYL OF 1 OR 2 CARBON ATOMS, 1 OR 2 METHOXY MOIETIES AND 1 OR 2 ETHOXY MOITIES; AND R4 IS STRAIGHT OR BRANCHED CHAIN ALKYL OF 1 TO 4 CARBON ATOMS.

(3,4-(-O-CH2-O-)PHENYL)-

R IS HYDROGEN, STRAIGHT, BRANCHED OR CYCLIC LOWER ALKYL, LOWER ALKENYL, OR LOWER ALKINYL, UNSUBSTITUTED OR SUBSTITUTED BY HYDROXYL OR ALKOXY OF 1 TO 3 CARBON ATOMS; OR BENZYL, OR PHENETHYL, UNSUBSTITUTED OR SUBSTITUTED IN THE ARYL PORTION BY 1 TO 7 MEMBERS SELECTED FROM THE GROUP CONSISTING OF 1 TO 3 ALKOXY MOIETIES OF 1 TO 3 CARBON ATOMS, 1 OR 2 ALKYL MOIETIES OF 1 TO 3 CARBON ATOMS, AND 1 OR 2 HALOGEN ATOMS; R1 IS STRAIGHT OR BRANCHED CHAIN ALKYL OF 1 TO 4 CARBON ATOMS; R2 IS STRAIGHT OR BRANCHED CHAIN ALKYL OF 1 TO 6 CARBON ATOMS, STRAIGHT OR BRANCHED CHAIN DIALKYL OF 1 TO 6 ATOMS, STRAIGHT OR BRANCHED CHAIN DIALKYL OF 1 TO 6 CARBON ATOMS, STRAIGHT OR BRANCHED CHAIN ALKENYL OF 2 6 CARBON ATOMS, STRAIGHT OR BRANCHED CHAIN ALKINYL OF 2 TO 6 CARBON ATOMS, CYCLIC ALKYL OF 3 TO 6 CARBON ATOMS, CYCLIC ALKENYL OF 3 TO 6 CARBON ATOMS, STRAIGHT OR BRANCHED CHAIN ALKYL OR ALKENYL OF 2 TO 6 CARBON ATOMS INTERRUPTED BY 1 OR 2 OXYGEN ATOMS, STRAIGHT OR BRANCHED CHAIN ALKYL OF 1 TO 6 CARBON ATOMS SUBSTITUTED BY HYDROXYL, OR STRAIGHT OR BRANCHED CHAIN ALKENYL OF 2 TO 6 CARBON ATOMS SUBSTITUTED BY HYDROXYL; R3 IS ARYL, UNSUBSTITUTED OR SUBSTITUTED BY 1 TO 3 MEMBERS SELECTED FROM THE GROUP CONSISTING OF 1 TO 3 NITRO MOIETIES, 1 TO 2 CYANO MOIETIES, 1 TO 3 HALOGEN ATOMS, 1 OR 2 HYDROXYL MOIETIES, 1 OR 2 ACYLOXY MOIETIES OF 1 OR 2 CARBON ATOMS IN THE ACYL PORTION, 1 TO 3 ALKOXY MOIETIES OF U TO 4 CARBON ATOMS, A DIOXYMETHYLENE MOIETY OF THE FORMULA:
PYRIDINE

Description

United States Flt-cot Olhce 3,775,422 UNSYMME'I'RICAL 1,4-DIHYDRO-4-ARYL- NICOTINATE ESTERS Friedrich Bossert, Wuppertal-Elberfeld, and Wulf Vater, Opladen, Germany, assignors to Farbenfabriken Bayer Akfiengesellschaft, Leverkusen, Germany No Drawing. Filed Jan. 19, 1971, Ser. No. 107,849 Claims priority, application Germany, Jan. 24, 1970, P 20 03 146.3
Int. Cl. C07d 31/36, 31/46 US. Cl. 260-2943 19 Claims ABSTRACT OF THE DISCLOSURE 1,4-dihydropyridines of the formula:
wherein R is hydrogen, straight, branched or cyclic lower alkyl,
lower alkenyl, or lower alkinyl, unsubstituted or substituted by hydroxyl or alkoxy of 1 to 3 carbon atoms; or benzyl, or phenethyl, unsubstituted or substituted in the aryl portion by 1 to 7 members selected from the group consisting of 1 to 3 alkoxy moieties of 1 to 3 carbon atoms, 1 or 2 alkyl moieties of 1 to 3 carbon atoms, and 1 or 2 halogen atoms;
R is straight or branched chain alkyl of 1 to 4 carbon atoms;
R is straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain dialkyl of 1 to 6 carbon atoms, straight or branched chain alkenyl of 2 6 carbon atoms, straight or branched chain alkinyl of 2 to 6vcarbon atoms, cyclic alkyl of 3 to 6 carbon atoms, cyclic alkenyl of 3 to 6 carbon atoms, straight or branched chain alkyl or alkenyl of 2 to 6 carbon atoms interrupted by 1 or 2 oxygen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms substituted by hydroxyl, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted by hydroxyl;
R is aryl, unsubstituted or substituted by 1 to 3 members selected from the group consisting of 1 to 3 nitro moieties, 1 or 2 cyano moieties, 1 to 3 halogen atoms, 1 or 2 hydroxyl moieties, 1 or 2 acyloxy moieties of 1 or 2 carbon atoms in the acyl portion, 1 to 3 alkoxy moieties of 1 to 4 carbon atoms, a dioxymethylene moiety of the formula:
an alkylmercapto moiety of 1 to 4 carbon atoms in the alkyl portion, trifluoromethyl, carboxyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxy portion and an alkylsulphonyl moiety of 1 to 4 carbon atoms in the alkyl portion; benzyl; styryl; pyridyl; pyrimidyl; furyl;
th'ienyl; pyrrolyl; pyridyl, pyrrolyl, thienyl or furyl substituted by alkyl of 1 or 2 carbon atoms; or pyrimidyl substituted by at least one member selected from the group consisting of alkyl of 1 or 2 carbon atoms, 1 or 2 methoxy moieties and 1 or 2 ethoxy moieties; and
R is straight or branched chain alkyl of 1 to 4 carbon atoms.
are useful for their coronary dilating effect, their nitritelike efifect on the heart, their anti-fibrillation effect, their Patented Nov. 27, 1973 vascular-spasmolytic efi'ect and muscular-'spasmolytic effect, and as anti-hypertensives.
R200 C CO-Rt wherein R is hydrogen, straight, branched or cyclic lower alkyl,
lower alkenyl, or lower alkinyl, unsubstituted or substituted by hydroxyl or alkoxy of l to 3 carbon atoms; or benzyl, or phenethyl, unsubstituted or substituted in the aryl portion by 1 to 7 members selected from the group consisting of 1 to 3 alkoxy moieties of l to 3 carbon atoms, 1 or 2 alkyl moieties of 1 to 3 carbon atoms, and l or 2 halogen atoms;
R, is straight or branched chain alkyl of 1 to 4 carbon atoms;
R i straight or branched chain alkyl of 1 to 6 carbon atoms, straight or branched chain dialkyl of l to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbon atoms, straight or branched chain alkinyl of 2 to 6 carbon atoms, cyclic alkyl of 3 to 6 carbon atoms, cyclic alkenyl of 3 to 6 carbon atoms, straight or branched chain alkyl or alkenyl of 2 to 6 carbon atoms interrupted by 1 or 2 oxygen atoms, straight or branched chain alkyl of 1 to 6 carbon atoms substituted by hydroxyl, or straight or branched chain alkenyl of 2 to 6 carbon atoms substituted by hydroxyl;
R is aryl, unsubstituted or substituted by l to 3 members selected from the group consisting of 1 to 3 nitro moieties, 1 or 2 cyano moieties, l to 3 halogen atoms, 1 or 2 hydroxyl moieties, 1 or 2 acyloxy moieties of 1 or 2 carbon atoms in the acyl portion, 1 to 3 alkoxy moieties of 1 to 4 carbon atoms, a dioxymethylene moiety of the formula:
an alkylmercapto moiety of 1 to 4 carbon atoms in the alkyl portion, trifluoromethyl, carboxyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxy portion and an alkylsulphonyl moiety of 1to 4 carbon atoms in the alkyl portion; benzyl, styryl; pyridyl; pyrimidyl; furyl; thienyl; pyrrolyl; pyridyl, pyrrolyl, thienl or furyl substituted by alkyl of l or 2 carbon atoms; or pyrimidyl substituted by at least one member selected from the group consisting of alkyl of 1 or 2 carbon atoms, 1 or 2 methoxy moieties and 1 or 2 ethoxy moieties; and
R is straight or branched chain alkyl of l to 4 carbon atoms These compounds are useful as coronary dilators, for their nitrite-like efiect on the heart, as anti-fibrillation agents, for their vascular-spasmolytic and muscular-spasmolytic effect, and as anti-hypertensives.
The compounds of the present invention may be produced by reacting a xylidene derivative of the formula:
CO-Ri wherein R and R are as above defined,
either (a) with a p-keto compound of the formula:
R;C-CHi-C o R:
wherein R and R are as above defined, and ammonia or an amine of the formula HzN-R wherein R is as above defined, or a salt thereof, or
(b) with an enamine of the formula:
Rio=oH--co0Ra NH-R wherein R, R and R are as above defined,
at an elevated temperature preferably from about 70 C. to about 120 C. in the presence of at least one organic solvent, such as an alcohol, glacial acetic acid, pyridine, dioxane, dimethylformamide, dimethylsulphoxide or a halogenated hydrocarbon. When an organic solvent is used, it is preferred to carry out the reaction at approximately the boiling point of the solvent or of the solvent mixture.
The xylidene derivatives of the Formula 2 above are produced by condensing an aldehyde with an 0:,[3-dik6't0116.
The compounds of the present invention may also be produced by reacting a xylidene derivative of the formula:
o o R, (6) wherein R R and R are as above defined, either (a) with a fi-keto compound of the formula:
R4-C-CH -C-R (7) with ammonia or an amine of the formula:
H N--R (4) wherein R is as above defined, or a salt thereof;
or (b) with an enamine of the formula:
RLC=CHCRI NH-R (8) wherein R and R are as above defined under the re action conditions above set forth.
These xylidene derivatives of Formula 6 above can be produced by condensing an aldehyde with an acyl-fatty acid ester.
When R in Formula 1 above is other than hydrogen, the compounds of the present invention may be produced according to a process carried out in the presence of pyridine, which process is set forth in co-pending application Le A 12 217-A U.S. Ser. No. 35,574, filed May 7, 1970.
An alternate procedure for producing compounds of the present invention is described in Helv. chim. Acta 41 (1958) 2066 wherein when the compounds of Formula 1 have R as hydrogen, 1,4-dihydropyridines are oxidized with suitable oxidizing agents, the resulting pyridine derivatives are quaternized with alkyl esters, and these esters are reduced to the corresponding 1,4-dihydropyridines with suitable reducing agents.
Suitable reactants for use in the process of the present invention and for the production of the compounds of the present invention include as illustrative examples the following:
Aldehydes: Benzaldehyde, 2-, 3-, or 4 hydroxy- 'benzaldehyde, 2,4- or 2,6 dihydroxybenzaldehyde, 2-, 3-, or 4 methoxybenzaldehyde, 2 isopropoxybenzaldehyde, 3 butoxybeu zaldehyde, 3,4,5 trimeth- 4 oxybenzaldehyde, 2-, 3-, or 4 chloro or bromo or fluorobenzaldehyde, 2,4 or 2,6 dichlorobenzaldehyde, 2-methylbenzaldehyde, 2,4-dimethylbenzaldehyde, 3,5-dlisopropyl 4 hydroxybenzaldehyde, 2-, 3- or 4-nitrobenzaldehyde, 2,4- or 2,6-dinitrobenzaldehyde, 2-nitro-6- bromobenzaldehyde, 2-nitro-3-methoxy-6-chlorobenzaldehyde, 2-nitro-3-hydroxy-4-chlorobenzaldehyde, 3-nitro-4- hydroxybenzaldehyde, 2-nitro-S-hydroxybenzaldehyde, 2- nitro-4-chlorobenzaldehyde, 2 nitro-4-methoxybenzaldehyde, 2-nitro-5-methoxybenzaldehyde, 2-, 3- or 4-trifluoromethylbenzaldehyde, 2-, 3- or 4-cyanobenzaldehyde, 2- nitro 4 cyanobenzaldehyde, 3-chloro-4-cyanobenzaldehyde, benzaldehyde 2 (3 or 4 sulphonic acid, 5-nitrobenzaldehyde-2-sulphonic acid, benzaldehyde-2-(3- or 4*) carboxylic acid, benzaldehyde-Z-carboxylic acid ethyl ester, benzaldehyde 3 carboxylic acid isopropyl ester, benzaldehyde 4 carboxylic acid butyl ester, 2- nitrobenzaldehyde 4 carboxylic acid, 3-nitrobenzaldehyde-4-carboxylic acid ethyl ester, cinnamaldehyde, hydrocinnamaldehyde, 2-, 3- or 4-methylmercaptobenzaldehyde, 2-methylmercapto-5-nitrobenzaldehyde, 2-butylmercaptobenzaldehyde, 2-, 3- or 4-methylsulphinylbenzaldehyde, 2-, 3- or 4-methylsulphonylbenzaldehyde, cinnamaldehyde, dihydrocinnamaldehyde, formylcyclohexane, 1- formyl-cyclohexene-3, l-formyl-cyclohexine-1,3, l-formylcyclopentene-3, 11,13- or 'y-pyridinaldehyde, 6 methylpyridine-Z-aldehyde, pyrimidine 5 aldehyde, 4,6-dimethoxy-pyrimidine-5-a1dehyde, furan-Z-aldehyde, thiophen- 2-aldehyde and pyrrol-Z-aldehyde.
Acyl-fatty acid esters: Formylacetic acid ethyl ester, formylacetic acid butyl ester, acetoacetic acid methyl ester, acetoacetic acid ethyl ester, acetoacetic acid propyl ester, acetoacetic acid isopropyl ester, acetoacetic acid- (on or 3-) hydroxyethyl ester, acetoacetic acid (aor 8-) methoxyethyl ester, acetoacetic acid (01- or ,8)-ethoxyethyl ester, acetoacetic acid(aor 13-) propoxyethyl ester, acetoacetic acid furfuryl ester, acetoacetic acid tetrahydrofurfuryl ester, acetoacetic acid allyl ester, acetoacetic acid propargyl ester, acetoacetic acid cyclohexyl ester, propionylacetic acid ethyl ester, butyrylacetic acid ethyl and ester and isobutyrylacetic acid ethyl ester.
Diones: Pentanedione-(2,4), heptanedione-(3,5), nonanedioue-(4,6) and 2,6-dirnethyl-heptanedione-(3,5).
Amines: Methylamine, ethylamine, propylarnine, isopropylamine, butylamine, allylamine, propargylamine, 1- hydroxyethylamine-2, l,3-dihydroxyisopropylamine, cyclohexylamine, benzylamine, 4-chlorobenzylamine, 3,4- dimethoxybenzylamine and phenethylamine.
According to a preferred embodiment of the present invention R is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl or phenethyl, R is straight or branched chain alkyl 1 to 4 carbon atoms, R is monoor dialkyl of 1 to 6 carbon atoms, alkinyl of 2 to 6 carbon atoms, cyclic alkyl of 3 to 6 carbon atoms, alkyl of 2 to 6 carbon atoms interrupted by oxygen, or cyclic alkyl of 3 to 6 carbon atoms wherein the ring contains oxygen as a heteroatom, R is benzyl; phenyl unsubstituted or substituted by 1 or 2 nitro moieties, cyano moieties, halogen atoms especially fluorine, chlorine or bromine, alkoxy moieties of 1 to 3 carbon atoms or trifiuoromethyl; pyridyl, pyrrolyl, furyl or thienyl unsubstituted or substituted by alkyl of 1 or 2 carbon atoms; or pyrimidyl unsubstituted or substituted by alkyl of l or 2 carbon atoms, 1 or 2 methoxy moieties, or 1 or 2 ethoxy moieties; and R is alkyl of 1 to 4 carbon atoms.
The 1,4-dihydropyridines of the present invention have a broad range of utility as indicated above and the following effects have been exhibited in animal experiments:
l) The compounds produce a distinct and long-lasting dilation of the coronary vessels on parenteral, oral and perlingual administration. This action on the coronary vessels is intensified by a simultaneous, nitrite-like, effect of reducing the load on the heart.
They influence or modify the heart metabolism in the sense of a saving of energy.
(2) The excitability of the stimulus-forming and stimulus-conducting system within the heart is lowered, so that an anti-fibrillation action, demonstrable in the therapeutic doses, results.
(3) The tonus of the smooth muscles of the vessels is greatly reduced under the action of the compounds. This vascular-spasmolytic action can occur in the total vascular system or can manifest itself to a more or less isolated extent in circumscribed vascular regions (such as for example the central-nervous system).
(4) The compounds reduce the blood pressure of normal tonic and hypertonic animals and can thus be used as anti-hypertensive agents.
(5) The compounds have strong muscular-spasmolytic actions, which manifest themselves on the smooth muscle of the gastro-intestinal tract, the urogenital tract, and the respiratory system.
According to the present invention, pharmaceutical compositions are produced which comprise a compound of the present invention or more than one compound of the present invention in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier. The present invention further includes a medicament in unit dosage form which comprises a compound of the present invention or more than one compound of the present invention per se or in combination with a pharmaceutically acceptable non-toxic inert diluent or carrier. The medicament may include a protective envelope containing the active compound or compounds, and if present, the pharmaceutically acceptable non-toxic inert diluent or carrier.
The term medicament in unit dosage form as used above means a medicament as defined above in the form of discrete portions each containing a unit dosage, or a multiple or sub-multiple of a unit dose of the active compound or compounds, for example two, three or four unit doses or a half, a third or a fourth of a unit dose. Such portions may, for example, be in monolithic coherent form, such as tablets, suppositories, pills or dragees; in wrapped or concealed form, such a wrapped powders, cachets, sachets or capsules; in ampoules, either free or as a sterile solution suitable for parenteral injection; or in any other form known to the art.
The 1,4-dihydropyridines of the Formula 1 can be administered orally or parenterally.
In general, it has proved advantageous to administer amounts of about 0.01 mg. to about 100 mg., preferably about 0.1 to 50 mg. per kg. body weight per day, in order to achieve satisfactory results. Nevertheless, it may sometimes be necessary to deviate from the above ranges, depending on the body weight of the treated person or the method of application. In some cases it may be suflicient to use less than the minimum amount stated above, whereas in other cases the aforesaid upper limit will have to be exceeded. If larger amounts are applied, it may be advisable to distribute these in several individual doses over the day.
The compounds of Formula 1 can be administered as such or as pharmaceutical compositions as described above. Suitable forms of application in combination with various inert carriers are: tablets, capsules, dragees, ampoules, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such carriers comprise solid diluents or fillers, a sterile aqueous medium as well as various non-toxic organic solvents and the like. Tablets and the like intended or oral application may, of course, be provided with sweetening additives and similar substances. In the aforesaid case the therapeutically active compound should be present at a concentration of about 0.5 to 90 percent by weight of the total mixture, in quantities which are sufiicient to achieve the range of dosage, mentioned above.
In the case of oral administration, the tablets or capsules may also contain additives, such as sodium citrate, calcium carbonate and dicalcium phosphate together with various other additives, such as starch, preferably potato starch, and the like, and binding agents, such as polyvinylpyrrolidone, gelatin and the like. Lubricants, such as magnesium stearate, sodium lauryl sulphate and talc may also be added for the production of tablets. In the case of aqueous suspensions and/ or elixirs which are intended for oral application, the active substance may be used with various flavouring agents, coloring substances, emulsifiers and/or together with diluents, such as water, ethanol, propylene glycol, glycerol and similar compounds or combinations of this type.
In the case of parenteral administration, solutions of the active substances in sesame or peanut oil or in aqueous propylene glycol or N,N-dimethyl formamide can be used, as can sterile aqueous solutions in the case of the water-soluble compounds. Aqueous solutions of this type should be buffered in the usual way, when required, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose. These aqueous solutions are particularly suitable for intravenous and intraperitoneal injections. Sterile aqueous media of this type may be prepared in a manner per se known.
The 1,4-dihydropyridines of the present invention are particularly useful because they are suitable for oral administration. Therefore, pharmaceutical compositions in orally administrable form are the preferred embodiment of the pharmaceutical compositions. The following table sets forth a range of viable dosages for compounds representative of those of the present invention:
LIST OF DOSAGE RATES Dosage rate in mg./kg.,
Compound: i.v. application Example 1 0.3-0.5 Compound (a) 0.5-2.0 Compound (b) 0.1-0.5 Compound (c) 0.03-O.1 Example 5 0.5-1.0 Compound (a) 3.0-5.0 Example 6 1.0-3.0
The compound of Example 1 has exhibited good activity when administered orally at a dosage range of from 1 to about 50 mg./kg.
The following non-limitative examples more particularly illustrate the present invention.
EXAMPLE 1 4- (2-pyridyl -2, 6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester After stirring a solution of 21.4 g. of pyridin-2-aldehyde and 20 g. of acetylacetone in 250 ccs. of benzene, with the addition of 2 ccs. of piperidine for approx. 12 hours at room temperature, the water is separated off, the solution is dried and the solvent is distilled off in vacuo.
The residue, pyrid-(2)-al acetylacetone, is heated for 5 hours on a water bath with 26 g. of B-aminocrotonic acid ethyl ester, and the reaction product (named above) is treated with ether, cooled, filtered off and re-crystallized from 250 ccs. of alcohol.
20 g. of yellow crystals of melting point C.
The following compounds were prepared in an analogous manner from the reactants specified:
(a) 4- (3-pyridyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester of melting point 188 C. from pyridal-(3)-acetylacetone and B-aminocrotonic acid ethylester.
(b) 4 phenyl-2,6-dimethyl-3-aceto-1,4-dihydropyridine- S-carboxylic acid diethyl ester, melting point 167 C., from benzalacetylacetone and ,B-aminocrotonic acid ethylester.
(c) 4 (2-nitrophenyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester of melting point 174-176 C., from Z-nitrobenzal-acetylacetone and ,8- aminocrotonic acid ethylester.
7 EXAMPLE 2 The following compounds were produced by a procedure analogous to that described in Example 1 from the reactants specified:
(a) 4 (2'-cyanophenyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester, melting point 184 C., from 2 cyanobenzal-acetylacetone and f3- aminocrotonic acid ethylester.
(b) 4 (3' nitrophenyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester, melting point 200 C., from 3-nitrobenzal-acetylacetone and paminocrotonic acid methylester.
(c) 4 (2 fluorophenyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester, melting ester, melting point 177 C., from 2-fluorbenzal acetylacetone and paminocrotonic acid methylester.
(d) 4 (2' trifluoromethylphenyl)-2,6-dimethyl-3-aceto- 1,4 dihydropyridine-S-carboxylic acid ethyl ester, melting point 141 to 143 C., from Z-trifiuormethylbenzalacetylacetone and fl-aminocrotonic acid ethylester.
(e) 4 (3 trifiuoromethylphenyl)-2,6-dimethyl-3-acet0- 1,4dihydropyridine-S-carboxylic acid methyl ester, melting point 170 C., from 3-trifiuormethylbenzalacetylacetone and B-aminocrotonic acid methylester.
(f) 4 (3 nitro-4'-chlorophenyl)-2,6-dimethyl-3-aceto- 1,4-dihydropyridine-5-carboxylic acid methyl ester, melting point 177 C., from 3-nitro-4-chlorbenzalacetylacetone and B-aminocrotonic acid methyl ester.
(g) 4 phenyl 2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid B-methoxyethyl ester (oil) from benzal-acetylacetone, acetoacetic acid ,3- methoxyethyl ester and ammonia.
(h) 4 phenyl-2,6-dimethyl-3-aceto-1,4-dihydropyridine- S-carboxylic acid furfuryl ester (oil) from benzal-acetylacetone, acetoacetic acid furfuryl ester and ammonia.
(i) 4 phenyl-2,6-dimethyl-3-aceto-1,4-dihydropyridine-5- carboxylic acid propargyl ester, melting point 199 C., from benzal-acetylacetone, acetoacetic acid propargyl ester and ammonia.
EXAMPLE 3 4 phenyl 2,6 dimethyl-3-aceto-1,4-dihydropyridine-5- carboxylic acid ethyl ester (identical to Example 1(b) 0.1 mol of benzalacetic acid ethyl ester (obtained from 10.6 g. of benzaldehyde and 13 g. of acetoacetic acid ethyl ester in benzene with the addition of piperidine) is heated for 3-4 hours with g. of Z-aminopenten-(2)-one-(4) to 90-100, after cooling the solid reaction product is taken up in a little ether, and after filtering off and recrystallizing, yellow crystals of melting point 167 C. (alcohol) are obtained.
EXAMPLE 4 4 (2' methylphenyl) 2,6 dimethyl 3 aceto-1,4- dihydropyridine-S-carboxylic acid ethyl ester (melting point 155 (C.) was prepared by a method analogous to that described in Example 3 from 2-methyl-benzal-acetylacetone and fl-aminocrotonic acid ethylester.
EXAMPLE 5 4-(4'-pyrimidyl -2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester 1 cc. of piperidine is added to a solution of 10 g. of pyrimidine-4aldehyde and 10 g. of acetylacetone in 150 ccs. of benzene, the mixture is stirred for 48 hours at room temperature, the Water is then separated 01f, the solution is dried and evaporated, and the residue (pyrimid- 4-al-acetylacetone) is heated with 13 g. of B-aminocrotonic acid ethyl ester for 5 hours on a water-bath.
After addition of some ether, 13 g. of yellow crystals of melting p int 183-185 C. (alc h l) are obtained.
8 The 4 (4,6'-dimethoxy-5-pyrimidyl)-2,6-dimetl1yl-3- aceto-l,4-dihydropyridine-S-carboxylic acid ethyl ester, melting point 236239 C., is obtained in the same manner, from 4,6-dimethoxypyrimid-S-aI-acetylacetone and B- aminocrotonic-acid ethyl ester.
EXAMPLE 6 N-methyl-4-phenyl-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester 0.1 mol of benzalacetylacetone (prepared analogously to pyrid-(2)-al acetylacetone in Example (1) is heated with 12 ccs. of acetoacetic acid methyl ester and 8 g. of methylamine hydrochloride in 25 ccs. of pyridine to for 1 hour, the mixture is poured into ice water, and after filtering OE and recrystallizing from 500 ccs. of methanol, yellow crystals of melting point 187 C. are obtained.
EXAMPLE 7 The following compounds were produced by a procedure analogous to that described in Example 6 from the reactants specified:
(a) N methyl 4 (3 nitro 4 chlorophenyl) 2,6-
dimethyl-3-aceto-l,4-dihydropyridine-S-carboxylic acid methyl ester, melting point 118 C., from 3-nitro-4- chlorobenzal-acetylacetone, acetoacetic acid methyl ester and methyl-aminc-hydrochloride.
(b) N methyl (3' nitro 4 chlorophenyl) 2,6 dimethyl-3-aceto-1,4-dihydropyridine-5 carboxylic acid propargyl ester, melting point C., from 3-nitro-4- chlorobenzal-acetylacetone, acetone, acetoacetic acid propargyl ester and methylamino-hydrochloride.
(c) N methyl 4 (3' nitrophenyl) 2,6 dimethyl- 3-aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester, melting point 147 C., from 3-nitrobenzal-acetylacetone, acetoacetic acid methyl ester and methylaminohydrochloride.
What is claimed is: 1. A 1,4-dihydropyridine of the formula:
0 6 CHz and R is straight chain alkyl of 1 to 4 carbon atoms. 2.A compound according to claim 1 wherein R is hydrogen or methyl, R is methyl, R is methyl, ethyl, diethyl, B-methoxyethyl, propargyl or furfuryl, R is phenyl, nitrophenyl, cyanophenyl, fluorophenyl, trifluoromethylphenyl, benzyl, or nitrochlorophenyl, and R is methyl.
3. The compound according to claim 1 which is 4-phenyl-2,6-dimethyl 3 aceto 1,4 dihydropyridine-S-carboxylic acid diethyl ester.
4. The compound according to claim 1 which is 4-(2'- nitrophenyl) 2,6 dimethyl-3-aceto-1,4-dihydropyridine- S-carboxylic acid ethyl ester.
5. The compound according to claim 1 which is 4-(2'- cyanophenyl) 2,6-dimethyl-3-aceto-l,4-dihydropyridine- S-carboxylic acid ethyl ester.
6. The compound according to claim 1 which is 4-(3'- nitrophenyl) 2,6 dimethyl-3-aceto-1,4-dihydropyridine- S-carboxylic acid methyl ester.
7. The compound according to claim 1 which is 4-(2- fluorophenyl) 2,6-dimethyl-3-aceto-1,4-dihydropyridine- S-carboxylic acid methyl ester.
8. The compound according to claim 1 which is 4-(2- trifluoromethylphenyl) 2,6 dimethyl-3-aceto-1,4-dihydropyridine-$-carboxylic 'acid methyl ester.
9. The compound according to claim 1 which is 4-(3'- trifluoromethylphenyl) 2,6 dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester.
10. The compound according to claim 1 which is 4-(3- nitro-4'-chlorophenyl) 2,6 dimethyl 3 aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester.
11. The compound according to claim 1 which is 4 phenyl 2,6 dimethyl-3-aceto-1,4-dihydropyridine-S- carboxylic acid B-methoxyethyl ester.
12. The compound according to claim 1 which is 4 phenyl 2,6 dimethyl-3-aceto-1,4-dihydropyridine-5- carboxylic acid furfuryl ester.
13. The compound according to claim 1 which is 4 phenyl 2,6 dimethy1-3-aceto-1,4-dihydropyridine-5- carboxylic acid propargyl ester.
14. The compound according to claim 1 which is 4-phenyl 2,6 dimethyl 3 aceto-1,4-dihydropyridine-5- carboxylic acid ethyl ester.
15. The compound according to claim 1 which is 4 (2 methylphenyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid ethyl ester.
16. The compound according to claim 1 which is N methyl 4 phenyl-2,6-dimethyl-3-aceto-1,4-dihydropyridine-S-carboxylic acid methyl ester.
17. The compound according to claim 1 which is N-methyl 4 (3 -nitro-4-chlorophenyl)-2,6-dimethyl-3- aceto-l,4-dihydropyridine-S-carboxylic acid methyl ester.
18. The compound according to claim 1 which is N methyl (3' nitro-4'-chlorophenyl)-2,6-dimethyl-3- aceto 1,4 dihydropyridine-S-carboxylic acid propargyl ester.
19. The compound according to claim 1 which is N methyl 4 (3' nitrophenyl)-2,6-dimethyl-3-aceto- 1,4-dihydropyridine-S-carboxylic acid methyl ester.
US. Cl. X.R.
260-2955 R, 295.5 B, 294.8 D, 240 D, 256.4 R; 424- 251 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION patent No. 3,775,422 Dated November 27, 1973 Inve Friedrich Bossert et a1.
It is certified that error appears in the above-identified patent Q and that said Letters Patent are hereby corrected as shown below:
Column 1, line 36 should read as follows:
-- atoms,
. line 37 should read as follows:
"straight or branched chain alkenyl of 2 to Column 2, line 32 should read as follows:
- atoms,
" line 33 should read as follows:
0 straight or branched chain alkenyl of 2 Column 4, line 52 should read as follows:
- l to 4 carbon atoms, R is monoalkyl of l to 6 Colunm 6, line 69 should read as follows:
-- S-carboxylic acid ethyl ester, melting point 167C.
IN THE CLAIMS Column 8, line 68, claim 1 should read as follows R is methyl, ethyl, B-methoxyethyl, pro parg'yl or- Column 8, line 75, claim 3, should read as follows ylic acid ethyl ester. H
Signzd and Scaled this Fifth Day of October 1976 [SEAL] Attest:
- RUTH C. MASON C. MARSHALL DANN Arresting Officer Commissioner oj'Parenrs and Trademarks
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US20090214675A1 (en) * 2005-07-22 2009-08-27 Bayer Healthcare Ag 4-Chromenonyl-1,4-dihydropyridinecarbonitriles and the use thereof
US20100022484A1 (en) * 2005-07-22 2010-01-28 Alexander Kuhl 4-Chromenonyl-1,4-dihydropyridines and their use
US7989633B2 (en) 2005-07-22 2011-08-02 Bayer Schering Pharma Aktiengesellschaft 4-Chromenonyl-1,4-dihydropyridines and their use
US8058447B2 (en) 2005-07-22 2011-11-15 Bayer Pharma Aktiengesellschaft 4-Chromenonyl-1,4-dihydropyridinecarbonitriles and the use thereof
US9828344B2 (en) 2012-06-01 2017-11-28 LEIBNIZ-INSTITUT FÜR ALTERSFORSCHUNG FRITZ-LIPMANN-INSTITUT e.V. (FLI) Inhibitors of the notch signaling pathway and secretion for use in medicine

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BE761929A (en) 1971-07-22
CA945167A (en) 1974-04-09
CS163748B2 (en) 1975-11-07
FR2081452A1 (en) 1971-12-03
IE34890B1 (en) 1975-09-17
CH586200A5 (en) 1977-03-31
ES387562A1 (en) 1974-01-01
SU379091A3 (en) 1973-04-18
GB1317425A (en) 1973-05-16
DE2003146A1 (en) 1971-07-29
AT306720B (en) 1973-04-25
ZA7152B (en) 1971-10-27
CS163747B2 (en) 1975-11-07
AT304552B (en) 1973-01-10
NL7100816A (en) 1971-07-27
IE34890L (en) 1971-07-24
FR2081452B1 (en) 1974-08-23
IL35924A0 (en) 1971-02-25
HU162199B (en) 1973-01-29
IL35924A (en) 1974-09-10
SU383290A3 (en) 1973-05-25

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