US3862161A - 4-pyridyl substituted 1,4-dihydropyridines - Google Patents
4-pyridyl substituted 1,4-dihydropyridines Download PDFInfo
- Publication number
- US3862161A US3862161A US344344A US34434473A US3862161A US 3862161 A US3862161 A US 3862161A US 344344 A US344344 A US 344344A US 34434473 A US34434473 A US 34434473A US 3862161 A US3862161 A US 3862161A
- Authority
- US
- United States
- Prior art keywords
- carbon atoms
- ester
- dimethyl
- aceto
- dihydropyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
1,4-Dihydropyridines substituted at position 4 by pyridyl or alkyl substituted pyridyl. The said products exhibit a nitritelike effect on the heart and have utility as coronary dilators, anti-fibrillators, vascular-spasmolytics, muscular-spasmolytics and anti-hypertensives.
Description
United States Patent Bossert et al.
[ Jan. 21, 1975 4-PYRIDYL SUBSTITUTED 1,4-DIHYDROPYRIDINES Inventors: Friedrich Bossert,
Wuppertal-Elberfeld; Wulf Vater, Opladen, both of Germany Bayer Aktiengesellschaft, Leverkusen, Germany Filed: Mar. 23, 1973 Appl. No.: 344,344
Related U.S. Application Data Division of Ser. No. 107,849, Jan. 19, 1971, Pat. No. 3,775,422.
Assignee:
Foreign Application Priority Data Jan. 24, 1970 Germany 2003146 US. Cl ..260/295.5 R, 260/2564 R, 260/2564 C, 260/240 D, 260/294.8 D, 260/2948 G. 260/2949, 260/2955 B,
Primary Examiner-Alan L. Rotman [57] ABSTRACT 1,4-Dihydropyridines substituted at position 4 by pyridyl or alkyl substituted pyridyl. The said products exhibit a nitrite'like effect on the heart and have utility as coronary dilators, antifibrillators, vascularspasmolytics, muscular-spasmolytics and antihypertensives.
4 Claims, N0 Drawings 4-PYRIDYL SUBSTITUTED 1,4-DIHYDROPYRIDINES This is a division of application Ser. No. 107,849, filed Jan. 19, 1971, now US. Pat. No. 3,775,422 dated Nov. 27, 1973.
The present invention is concerned with 1,4- dihydropyridines, processes for their production, pharmaceutical compositions embodying said 1,4- dihydropyridines as the active ingredient and methods of administration which utilize the administration of said 1,4-dihydropyridines orally or parenterally.
More particularly, the present invention relates to 1,4-dihydropyridines of the formula:
Ra H
R200 C] V-CO-Jh R 1 wherein R is hydrogen, straight, branched or cyclic lower alkyl, lower alkenyl, or lower alkinyl, unsubstituted or substituted by hydroxyl or alkoxy of one to three carbon atoms; or benzyl, or phenethyl, unsubstituted or substituted in the aryl portion by one to seven members selected from the group consisting of one to three alkoxy moieties of one to three carbon atoms, one or two alkyl moieties of one to three carbon atoms, and one or two halogen atoms;
R, is straight or branched chain alkyl of one to four carbon atoms;
R is straight or branched chain alkyl of one to six carbon atoms, straight or branched chain dialkyl of one to six carbon atoms, straight or branched chain alkenyl of two to six carbon atoms, straight or branched chain alkinyl of two to six carbon atoms, cyclic alkyl of three to six carbon atoms, cyclic alkenyl of three to six carbon atoms, straight or branched chain alkyl or alkenyl of two to six carbon atoms interrupted by one or two oxygen atoms, straight or branched chain alkyl of one to six carbon atoms substituted by hydroxyl, or straight or branched chain alkenyl of two to six carbon atom substituted by hydroxyl;
R is aryl, unsubstituted or substituted by one to three members selected from the group consisting of one to three nitro moieties, one or two cyano moieties, one to three halogen atoms, one or two hydroxyl moieties, one or two acyloxy moieties of one or two carbon atoms in the acyl portion, one to three alkoxy moieties of one to four carbon atoms, a dioxymethylene moiety of the formula:
an alkylmercapto moiety of one to four carbon atoms in the alkyl portion, trifluoromethyl, carboxyl, carbalkoxy of one to four carbon atoms in the alkoxy portion and an alkylsulphonyl moiety of one to four carbon atoms in the alkyl portion; benzyl, styryl; pyridyl; pyrimidyl; furyl; thienyl; pyrrolyl; pyridyl, pyrrolyl, thienyl or furyl substituted by alkyl of one or two carbon atoms; or pyrimidyl substituted by at least one member selected from the group consisting of alkyl of one or two carbon atoms, one or two methoxy moieties and one or two ethoxy moieties; and
R is straight or branched chain alkyl of one to four carbon atoms.
These compounds are useful as coronary dilators, for their nitrite-like effect on the heart, as anti-fibrillation agents, for their vascular-spasmolytic and muscularspasmolytic effect, and as anti-hypertensives.
The compounds of the present invention may be produced by reacting a xylidene derivative of the formula:
O 0-lt. 3) wherein R and R are as above defined,
either a. with a B-keto compound of the formula:
wherein R, and R are as above defined,
with ammonia or an amine of the formula:
H N R wherein R is as above defined, or a salt thereof, or
b. with an anamine of the formula:
.lt -(J=C11COOR:
1lIn1t 5) wherein R, R and R are as above defined, at an elevated temperature preferably from about C. to about 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 a,B-diketone.
The compounds of the present invention may also be produced by reacting a xylidene derivative of the formula:
wherein R R and R are as above defined, either a. with a B-keto compound of the formula:
R4" |-|7-CH2 [fR4 and 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:
R4-C:CH(|-|JR4 N1I-R 0 (s) wherein R and R, are as above defined under the reaction conditions above set forth. These Xylidene derivatives of the 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 copending application Le A, US. Ser. No. 35,574, filed May 7, 1970, now abandoned.
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 l have R as hydrogen, l,4dihydropyridines are oxidized with suitable oxidizing agents, the resulting pyridine derivatives are quaternized with alkyl esters, and these esters are reduced to the corresponding l,4-dihydropyridines with suitable reducing agents.
Suitable reactants for use in the processes 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-hydroxybenzaldehyde, 2,4- or 2,o-dihydroxybenzaldehyde, 2-, 3- or 4- methoxybenzaldehyde, 2-isopropoxybenzaldehyde, 3- butoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 2-, 3- or 4-chloro or bromo or fluorobenzaldehyde, 2,4-or 2,6-dichlorobenzaldehyde, 2- methylbenzaldehyde, 2,4-dimethylbenzaldehyde,, 3,5- diisopropyl-4-hydroxybenzaldehyde, 2-, 3- or 4- nitrobenzaldehyde, 2,4- or 2,6-dinitrobenzaldehyde, 2-nitro-6bromobenzaldehyde, 2-nitro-3- methoxy-6-chlorobenzaldehyde, 2-nitro-3-hydroxy-4- chlorobenzaldehyde, 3-nitro-4-hydroxybenzaldehyde, 2-nitro-5-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-cyanobenzaldhyde, 3-chloro-4-cyanobenzaldehyde, benzaldehyde-2-(3- or 4-)-sulphonic acid, 5-nitrobenzaldehyde-Z-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-S-nitrobenzaldehyde, 2-butylmercaptobenzaldehyde, 2-, 3- or 4-methylsulphinylbenzaldehyde, 2 3- or 4-methylsulphonylbenzaldehyde, cinnamaldehyde, dihydrocinnamaldehyde, formylcyclohexane, l-formyl-cyclohexene-3, l-formylcyclohexinel ,3, l-formylcyclopentene-3, a,B-or
'y-pyridinaldehyde, 6-methylpyridine-2-aldehyde, pyrimidine-S-aldehyde, 4,6-dimethoxy-pyrimidine-5- aldehyde, furan-2-aldehyde, thiophen-Z-aldehyde and pyrrol-2-aldehyde.
Acyl-Fatty Acid Esters:
Formylaeetic 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-(aor 5-) hydroxyethyl ester, acetoacetic acid (01- or B-)methoxyethyl ester, acetoacetic acid (a or B)-ethoxyethyl ester, acetoacetic acid(aor ,8-) 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 ester and isobutyrylaeetic acid ethyl ester. Diones:
Pentanedion-(2,4), heptanedione-(3.5). nonancdione-(4,6) and 2,6-dimethyl-heptanedione-(3.5l. Amines:
Methylamine, ethylamine, propylamine, isopropylamine, butylamine, allylamine, proparglyamine. l-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 one to six carbon atoms, benzyl or phenethyl, R, is straight or branched chain alkyl of one to four carbon atoms, R is monoor dialkyl of one to six carbon atoms, alkinyl of two to six carbon atoms, cyclic alkyl of three to six carbon atoms, alkyl of two to six carbon atoms interrupted by oxygen, or cyclic alkyl of three to six carbon atoms wherein the ring contains oxygen as a heteroatom, R is benzyl; phenyl unsubstituted or substituted by one or two nitro moieties, cyano moieties, halogen atoms especially fluorine, chlorine or bromine, alkoxy moieties of one to three carbon atoms or trifluoromethyl pyridyl, pyrrolyl, furyl or thienyl unsubstituted or substituted by alkyl of one or two carbon atomos; or pyrimidyl unsubstituted or substituted by alkyl of one or two carbon atoms, one or two methoxy moieties, or one or two ethoxy moieties; and R is alkyl of one to four carbon atoms.
The 1,4-dihydropyridines of the present invention have a broad range of utility as indicatd above and the following effects have been exhibited in animal experiments:
1. The compounds produce a distinct and longlasting 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 therapeutic doses, results.
3. The tonus of the smooth muscles of the vessels is greatly reduced under the action of the compounds. This vascularspasmolytic 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 gastrointestinal 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 ofdiscrete portions each containing a unit dosage, or a multiple or sub-multiple ofa 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 as 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 and 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 sufficient to use less than the minimum amount stated above, whereas in other cases the aforesaid upper limit will have to be exceeded. 1f 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 per cent by weight of the total mixture, in quantities which are sufficient 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 polyvinyl-pyrrolidone, 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 compounrs. Aqueous solutions of this type should be buffered in the usual way, when re quired, and the liquid diluent should previously be rendered isotonic by the addition of the necessary amount of salt or glucose. These aqueous solutions are particu larly suitable for intravenous and intraperieoncal injections. Sterile aqueous media of this type may be prepared ln 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 composi' tions 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 Compound Dosage rate in mg/kg 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 0.1 Example 5 0.5 1.0 Compound :1) 3.0 5.0
Example 6 1.0 3.0
EXAMPLE 1 4-( 2'-Pyridyl )-2,6-dimethyl-3-acetol ,4-dihydropyridine-S-carboxylic acid ethyl ester After stirring a solution of 21.4 g of pyridine-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 waterbath with 26 g of B-aminocrotonic acid ethyl ester, and the reaction product (named above) is treated with ether, cooled, filtered off and recrystallized 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 '-pyriclyl)-2,6-dimethyl-3-aceto-l ,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-
dihydropyridiner5-carboxylic acid diethyl ester, melting point 167 C, from benzal acetylacetone and B-aminocrotonic acid ethylester.
c. 4-(2'-nitrophenyl)-2,6-dimethyl-3-aceto-1,4-
dihydropyridine-5carboxylic acid ethyl ester of melting point 174 176 C, from 2-nitrobenzalacetylacetone and B-aminocrotonic acid ethylester.
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 B-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-nitrobenzalacetylacetone and B-aminocrotonic acid methylester.
0. 4-(2'-fluorophenyl)-2,6-dimethyl-3-aceto-1,4-
dihydropyridine-5carboxylic acid methyl ester, melting point 177 C, from 2-1'luorbcnzal acetylacetone and B-aminocrotonic acid methylester.
4-(2' -trifluoromethylphenyl)-2,6-dimcthyl-3- aceto-l,4-dihydropyridine-S-carboxylic acid ethyl ester, melting point 141 to 143 C, from 2- trifluormethylbenzal-acetylacetone and B-aminocrotonic acid ethylester.
e. 4-(3-trifluoromethylphenyl)-2,6-dimethyl-3- aceto-l ,4-dihydropyridine-5-carboxylic acid methyl ester, melting point 170 C, from 3- trifluormethylbenzal-acetylaeetone and B-aminocrotonic acid methylester. 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- chlorbenzal-acetylaceton 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 B-methoxyethyl ester and ammonia.
4-phenyl-2,6-dimethyl-3-aceto-1,4- dihydropyridine-S-carboxylic acid furfuryl ester (oil) from benzal-acetylacetone, Acetacetoacetic acid furfuryl ester and ammonia.
i. 4-phenyl-2,6-dimethyl-3-aceto-1,4-
dihydropyridine-S-carboxylic acid propargyl ester, melting point 199 C, from benzal-acetylacetone acetoacetic acid propargyl ester and ammonia.
EXAMPLE 3 4-Pheny1-2,6-dimethyl-3-aceto-1,4-dihydropyridine-5- carboxylic acid ethyl ester (identical to Example lb) 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 2-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 Z-methyl-bcnzalacetylacetonc and fl-aminocrotonic acid ethyl ester.
EXAMPLE 5 4-(4-Pyrimi)-2.6-dimethyl-3-aceto-l .4-dihydro pyridine-5carboxylic acid ethyl ester.
1 cc. of piperidine is added to a solution of 10 g of pyrimidine-4-aldehyde 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 oft", 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 point 183 185 C (alcohol) are obtained.
The 4-(4,6-dimethoxy-5'-pyrimidyl)-2,6-dimethyl- 3-aceto1,4-dihydropyridine-5-earboxylic acid ethyl ester, melting point 236 239 C, is obtained in the same manner, from 4,6-dimethoxypyrimidin-4- aldehyde and 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 off 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- 1 ,4-dihydropyridine-5carboxylic acid methyl ester, melting point 118 C, from 3- nitro-4-chlorobenzal-acetylacetone, acetoacetic acid methyl ester methyl-amino-hydrochloride.
b. N-methyl-(3-nitro-4-chlorophenyl)-2,6-dimethyl-3-aceto-l,4-dihydropyridine-5-carb0xylic acid propargyl ester, melting point C, from 3-nitro- 4-chlorobenzal-acetylaceton, acetone, acetoacetic acid propargyl ester and methylaminohydrochloride.
c. N-methyl-4-(3-nitrophenyl)-2,6-dimethyl-3- aceto-l ,4-dihydropyridine-5-carboxylic acid methyl ester, melting point 147 C, from 3-nitrobenzal-acetylacetone, acetoacetic acid methyl ester and methylamino-hydrochloride.
What is claimed is:
l. A 1,4-dihydropyridine of the formula:
I ll
wherein 9 10 R is hydrogen, alkyl of one to six carbon atoms, ben- 2. A compound according to claim 1 wherein R is hyzyl or phenethyl, drogen or methyl, R is methyl, R is methyl, ethyl, di- R iS straight or branched chain Of one to four ethyl fi methoxyethyl propargyl or fu furyl R3 is pyri.
Carbon atoms dyl and R is methyl.
R is monoor dialkyl of one to six carbon atoms, 5 propargyl, cyclic alkyl of three to six carbon atoms,
1 t b t t t d 2 2 m fi i Car on a Oms m errup e by Oxy dme-S-carboxylrc acid ethyl ester.
R is id l Or id Substituted by an alkyl of one 4. The compound according to claim 1 which is 4- or t carbon atoms, 10 (3'-pyridyl)-2,6-dimethyl-3-aceto-l,4-dihydropyri- R is straight or branched chain alkyl of one to four ine- -carb0xylic acid ethyl ester.
carbon atoms.
3. The compound according to claim 1 which is 4- (2'-pyridyl)-2,6-dimethyl-3-aceto-l ,4-dihydropyri- UNITED STATES PATENT @FHQE @ERTWICATE GE RREGlFlN 0 Patent No 3,862,161 Dated January Zl l975 lnventofls) Friedrich Bossert at alm It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: 9
Colurm l, line 35 should read as follows:
carbon aroms,
line 36 should read as follows:
. a... straight or branched chain w Column line 21 should read as follows:
chain alkyl of one to four carbon atoms R is Q line 22 should read as follows:
M alkyl of one to six carbon atoms olkinyl of two to six O Colurm 6, line 63 should read as follows:
==- dihydropyridine==5-carboxylio acid ethyl ester, M
l0, claimZ, line 2 should read as follows:
---=drogen or methyl, R is methyl R is methyl, ethyl,-= line 3 should read as follows:
0 M fi methoxyethyl, propargyl or forforyl, R is pyri M 9 KSEAM Arrest:
v RUTH 6. Mom o Maosmm MNN fl g ffi fommsommr of Parents and Trademarks
Claims (3)
- 2. A compound according to claim 1 wherein R is hydrogen or methyl, R1 is methyl, R2 is methyl, ethyl, diethyl, Beta -methoxyethyl, propargyl or furfuryl, R3 is pyridyl and R4 is methyl.
- 3. The compound according to claim 1 which is 4-(2''-pyridyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-5-carboxylic acid ethyl ester.
- 4. The compound according to claim 1 which is 4-(3''-pyridyl)-2,6-dimethyl-3-aceto-1,4-dihydropyridine-5-carboxylic acid ethyl ester.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US344344A US3862161A (en) | 1970-01-24 | 1973-03-23 | 4-pyridyl substituted 1,4-dihydropyridines |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19702003146 DE2003146A1 (en) | 1970-01-24 | 1970-01-24 | New 1,4-dihydropyridine derivatives |
| US344344A US3862161A (en) | 1970-01-24 | 1973-03-23 | 4-pyridyl substituted 1,4-dihydropyridines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3862161A true US3862161A (en) | 1975-01-21 |
Family
ID=25758531
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US344344A Expired - Lifetime US3862161A (en) | 1970-01-24 | 1973-03-23 | 4-pyridyl substituted 1,4-dihydropyridines |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3862161A (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3943140A (en) * | 1972-09-30 | 1976-03-09 | Bayer Aktiengesellschaft | 2,3,5,6-Tetracarboxy-1,4-dihydropyridine derivatives |
| US3946027A (en) * | 1972-09-30 | 1976-03-23 | Bayer Aktiengesellschaft | 3,5,6-Tricarboxy-4-pyridyl-1,4-dihydropyridine derivatives |
| US3946026A (en) * | 1972-03-06 | 1976-03-23 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| US3946028A (en) * | 1972-09-30 | 1976-03-23 | Bayer Aktiengesellschaft | 2,3,5,6-Tetracarboxy-4-pyridyl-1,4-dihydropyridine derivatives |
| US3951991A (en) * | 1972-08-31 | 1976-04-20 | Bayer Aktiengesellschaft | 4-Aryl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid ester |
| US3951992A (en) * | 1972-08-31 | 1976-04-20 | Bayer Aktiengesellschaft | 4-Thenyl-or furyl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid ester |
| US3959296A (en) * | 1972-06-10 | 1976-05-25 | Bayer Aktiengesellschaft | 1,4-Dihydropyridines |
| US3971791A (en) * | 1972-03-06 | 1976-07-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| US3971790A (en) * | 1972-03-06 | 1976-07-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| US3987176A (en) * | 1972-08-31 | 1976-10-19 | Bayer Aktiengesellschaft | Composition and use of 3,4-dihydropyridones as vasodilators and antihypertensive agents |
| US4001259A (en) * | 1974-02-09 | 1977-01-04 | Bayer Aktiengesellschaft | 3,6-diamino-3,4-dihydro-2-pyridones |
| US4362735A (en) * | 1981-08-31 | 1982-12-07 | Sterling Drug Inc. | 3-[(3-Oxo-1-butenyl)amino]-5-(pyridinyl)-2(1H)-pyridinones and their cardiotonic use |
| US4412986A (en) * | 1977-06-07 | 1983-11-01 | Yamanouchi Pharmaceutical Co. Ltd. | Nifedipine-containing solid preparation composition |
| US4497808A (en) * | 1981-12-30 | 1985-02-05 | Ciba-Geigy Corporation | N-Oxide compounds useful in the treatment of cardiovascular ailments |
| US4877797A (en) * | 1986-06-13 | 1989-10-31 | Nisshin Flour Milling Co., Ltd. | 1,4-Dihydropyridine derivatives and pharmaceutical compositions containing same |
| US20070113654A1 (en) * | 2005-11-23 | 2007-05-24 | Carim Hatim M | Weighted bioacoustic sensor and method of using same |
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3441648A (en) * | 1967-02-07 | 1969-04-29 | Smithkline Corp | Compositions and methods for lowering blood pressure with 1,4-dihydropyridines |
| US3455945A (en) * | 1967-06-07 | 1969-07-15 | Smithkline Corp | 4-(carboxy (and carbo-lower alkoxy)phenyl)-1,4-dihydropyridines |
-
1973
- 1973-03-23 US US344344A patent/US3862161A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3441648A (en) * | 1967-02-07 | 1969-04-29 | Smithkline Corp | Compositions and methods for lowering blood pressure with 1,4-dihydropyridines |
| US3455945A (en) * | 1967-06-07 | 1969-07-15 | Smithkline Corp | 4-(carboxy (and carbo-lower alkoxy)phenyl)-1,4-dihydropyridines |
Cited By (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3946026A (en) * | 1972-03-06 | 1976-03-23 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| US3971791A (en) * | 1972-03-06 | 1976-07-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| US3971790A (en) * | 1972-03-06 | 1976-07-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
| US3959296A (en) * | 1972-06-10 | 1976-05-25 | Bayer Aktiengesellschaft | 1,4-Dihydropyridines |
| US3951991A (en) * | 1972-08-31 | 1976-04-20 | Bayer Aktiengesellschaft | 4-Aryl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid ester |
| US3951992A (en) * | 1972-08-31 | 1976-04-20 | Bayer Aktiengesellschaft | 4-Thenyl-or furyl-6-amino-3,4-dihydropyrid-2-one-3,5-dicarboxylic acid ester |
| US3987176A (en) * | 1972-08-31 | 1976-10-19 | Bayer Aktiengesellschaft | Composition and use of 3,4-dihydropyridones as vasodilators and antihypertensive agents |
| US3943140A (en) * | 1972-09-30 | 1976-03-09 | Bayer Aktiengesellschaft | 2,3,5,6-Tetracarboxy-1,4-dihydropyridine derivatives |
| US3946027A (en) * | 1972-09-30 | 1976-03-23 | Bayer Aktiengesellschaft | 3,5,6-Tricarboxy-4-pyridyl-1,4-dihydropyridine derivatives |
| US3946028A (en) * | 1972-09-30 | 1976-03-23 | Bayer Aktiengesellschaft | 2,3,5,6-Tetracarboxy-4-pyridyl-1,4-dihydropyridine derivatives |
| US4001259A (en) * | 1974-02-09 | 1977-01-04 | Bayer Aktiengesellschaft | 3,6-diamino-3,4-dihydro-2-pyridones |
| US4412986A (en) * | 1977-06-07 | 1983-11-01 | Yamanouchi Pharmaceutical Co. Ltd. | Nifedipine-containing solid preparation composition |
| US4362735A (en) * | 1981-08-31 | 1982-12-07 | Sterling Drug Inc. | 3-[(3-Oxo-1-butenyl)amino]-5-(pyridinyl)-2(1H)-pyridinones and their cardiotonic use |
| US4497808A (en) * | 1981-12-30 | 1985-02-05 | Ciba-Geigy Corporation | N-Oxide compounds useful in the treatment of cardiovascular ailments |
| US4877797A (en) * | 1986-06-13 | 1989-10-31 | Nisshin Flour Milling Co., Ltd. | 1,4-Dihydropyridine derivatives and pharmaceutical compositions containing same |
| 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 |
| US20070113654A1 (en) * | 2005-11-23 | 2007-05-24 | Carim Hatim M | Weighted bioacoustic sensor and method of using same |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3775422A (en) | Unsymmetrical 1,4-dihydro-4-aryl-nicotinate esters | |
| US3862161A (en) | 4-pyridyl substituted 1,4-dihydropyridines | |
| US4048171A (en) | 1,4-Dihydropyridines | |
| US3905970A (en) | 1,4-Dihydropyridine carboxylic acid esters | |
| US3488359A (en) | 1,4-dihydropyridine derivatives | |
| US4248873A (en) | Nitro-substituted 1,4-dihydropyridines, processes for _their production and their medicinal use | |
| US4188395A (en) | 1,4-Dihydropyridine derivatives substituted in the 2 position, and their use as medicaments | |
| US3773956A (en) | Azido-aryl 1,4-dihydropyridines in effecting coronary dilation | |
| US4177278A (en) | 2-Alkyleneaminodihydropyridines compounds, their production and their medicinal use | |
| US4735956A (en) | Certain 1,4-dihydro-2,6-di-lower hydrocarbyl-4-heterocyclic-3,5-pyridine dicarboxylates which are useful as calcium channel blockers | |
| PL92084B1 (en) | ||
| US3777030A (en) | Sulphur-containing 1,4-dihydropyri-dine derivatives for coronary ves-sel dilation | |
| US3764683A (en) | Composition and method for effecting coronary dilation using cyanophenyl-1,4-dihydropyridine derivatives | |
| PL83824B1 (en) | ||
| US4853395A (en) | Certain 3-carboxylate or 3-carbamyl-5-acyl-2-(1H)-pyridinones having cardiotonic properties | |
| US3511847A (en) | 2,6-di-lower alkyl - 1,4-dihydro - 4-(2-trifluoromethylphenyl) - 3,5 - pyridinedicarboxylic acid esters | |
| US4146627A (en) | Aminoalkylideamino-1,4-dihydropyridines and their use as medicaments | |
| US3855231A (en) | 2,6-diamino-1,4-dihydropyridine derivatives | |
| US4237137A (en) | Sila-substituted 1,4-dihydropyridine derivatives and their medicinal use | |
| US3966948A (en) | Spasmolytic, vaso-dilating and anti-hypertensive compositions and methods | |
| EP0002231A1 (en) | 1-N-aryl-1,4-dihydropyridines, process for their preparation and their pharmaceutical application | |
| JPH036151B2 (en) | ||
| US4021434A (en) | Sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-1-yl]ethyl sulfate | |
| US4162321A (en) | Sulphur-containing amino-dihydropyridines, and their use as medicants | |
| US4004014A (en) | 2-Amino-6-dialkylaminodihydropyridines, their production, pharmaceutical compositions and methods of use thereof |