US3441648A - Compositions and methods for lowering blood pressure with 1,4-dihydropyridines - Google Patents
Compositions and methods for lowering blood pressure with 1,4-dihydropyridines Download PDFInfo
- Publication number
- US3441648A US3441648A US614393A US3441648DA US3441648A US 3441648 A US3441648 A US 3441648A US 614393 A US614393 A US 614393A US 3441648D A US3441648D A US 3441648DA US 3441648 A US3441648 A US 3441648A
- Authority
- US
- United States
- Prior art keywords
- dihydro
- dicarbethoxy
- compositions
- dihydropyridines
- pyridine
- 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
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
-
- 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
-
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- This invention relates to new hypotensive compositions containing 1,4-dihydropyridines and to methods of lowering blood pressure by administering these compositions.
- this invention relates to 1,4-dihydro-4-(2-trifluoromethylphenyl)pyridines which are new compounds having hypotensive activity.
- 1,4-dihydropyridine compounds of the hypotensive compositions of this invention are known to the art, for example, as reported in Beilstein, Handbuch der Organischen Chemie, 27: 327, III, 389; 22: 172; 27: I, 383 and Hinkel et al., J. Chem. Soc., 750 (1929), and 1835 (1931).
- the present invention resides in the finding of hypotensive activity using a series of 4-aryl, 4- aralkyl, 4-aralkenyl or 4-heteroaryl-1,4-dihydropyridines and in certain new 1,4 dihydro 4 (Z-trifiuoromethylphenyl)pyridine compounds which have hypotensive activity.
- the nature of the 4-substituent on the 1,4-dihydropyridines is apparently not critical as compounds having a variety of 4-substituents chosen from aryl, aralkyl, aralkenyl or heteroaryl groups have hypotensive activity.
- 4-substituents chosen from aryl, aralkyl, aralkenyl or heteroaryl groups have hypotensive activity.
- compounds having substituents on the ortho positions of the aryl nuclei have particularly advantageous therapeutic properties as will be noted hereinafter.
- hypotensive compositions of this invention in dosage unit form, contain an effective but nontoxic amount of a 1,4-dihydropyridine of the formula:
- R is lower alkyl having 1-6 carbon atoms
- R is COOR' or COR"
- R is phenyl, halophenyl, dihalophenyl, lower alkylphenyl, di-lower alkylphenyl, tri-lower alkylphenyl, lower alkoxyphenyl, di-lower alkoxyphenyl, tri-lower alkoxyphenyl, trifluoromethylphenyl, benzyl, styryl, furyl, thienyl, pyridyl, or pyrrolyl, said lower alkyl and lower alkoxy groups having 1-4 carbon atoms;
- R is hydrogen or lower alkyl having l-6 carbon atoms and R and R are lower alkyl having l-6 carbon atoms.
- Preferred hypotensive compositions of this invention which have advantageous oral activity contain, as the active ingredient, a 1,4-dihydropyridine of Formula I in which R, is methyl; R is carbomethoxy or carbethoxy; R is chlorophenyl, preferably o-chlorophenyl, tolyl, preferably o-tolyl, trimethylphenyl, preferably 2,4,6-trimethylphenyl, trifluoromethylphenyl, preferably 0 trifiuoromethylphenyl, furyl, preferably 2-furyl, pyridyl, preferably 2- or 3-pyridyl, or pyrrolyl, preferably 2-pyrrolyl; and R is hydrogen.
- R is methyl
- R is carbomethoxy or carbethoxy
- R is chlorophenyl, preferably o-chlorophenyl, tolyl, preferably o-tolyl, trimethylphenyl, preferably 2,4,6-trimethylphenyl, triflu
- composition of this invention consists of, in a dosage unit, a pharmaceutical carrier and 3,5 dicarbethoxy 1,4-dihydro-2,6-dimethyl-4-(2-trifluoromethylphenyl) pyridine.
- compositions of this invention contain a 1,4-dihydropyridine of Formula I in an amount of from about 5 mg. to about 500 mg., preferably from about 25 mg. to about 250 mg., per dosage unit.
- the amount of the active ingredient in the claimed dosage unit compositions will be from about 0.1 mg./kg. to about 10 mg./kg., preferably from about 0.5 mg./kg, to about 5 rug/kg.
- the active ingredients in dosage unit form will be combined with a pharmaceutical carrier.
- the pharmaceutical carrier may be, for example, either a solid or a liquid.
- solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
- liquid carriers are peanut oil, olive oil or sesame oil.
- the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
- a wide vriety of pharmaceutical forms can be employed.
- a solid carrier used, the preparation can be tabletted, placed in a hard gelatin capsule or in the form of a troche or lozenge.
- the amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm.
- a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a liquid suspension, or a sterile suspension or solution for parenteral use.
- a method of lowering blood pressure in accordance with this invention comprises administering internally to animals an effective but nontoxic amount of a 1,4-dihydropyridine of Formula I
- the active ingredient will pref erably be administered in dosage unit form as described above.
- the route of administration will be orally and/or parenterally.
- the active ingredient will be administered in a total daily dosage of from about 5 mg. to about 2000 mg., preferably from about 50 mg. to about 1000 mg.
- hypotensive activity is produced.
- the dosage units or dosage ranges presented herein are designed for a hypertensive subject of about 50 kg.
- hypotensive activity of the 1,4-dihydropyridines of Formula I is demonstrated by standard procedures, that is, by intravenous administration to anesthetized dogs or cats and, for compounds which are orally active, in particular the active ingredients of the preferred hypotensive compositions indicated hereabove, by oral administration to neurogenic, hypertensive dogs or to normotensive dogs.
- a preferred compound of Formula II is the compound in which R is methyl and R is ethyl, i.e. 3,5-dicarbethoxy 1,4 dihydro 2,6 dimethyl-4-(Z-trifluoromethylphenyhpyridine, which has particularly advantageous activity, that is, potent hypotensive activity of relatively long duration on oral administration.
- 1,4-dihydropyridines of Formula I in which R; is hydrogen are prepared by methods generally known to the art such as the following:
- R R and R are as defined above.
- one molar equivalent of an aldehyde is reacted with two molar equivalents of the keto compound and an excess of ammonia.
- the reaction is preferably carried out in a solvent, such as a lower alkanol or dioxane, at elevated temperature, conveniently at reflux temperature, for about 1 to 4 hours.
- one molar equivalent of an aldehyde is reacted with two molar equivalents of the unsaturated amino compound.
- the reaction is carried out in a solvent, such as a lower alkanol or dioxane, at elevated temperature, conveniently at reflux temperature.
- compounds of Formula I are prepared by reacting one molar equivalent of an aldehyde with one molar equivalent of the keto compound used in procedure I and one molar equilavent of the unsaturated amino compound used in procedure H. The reaction is carried out at elevated temperature.
- R to R are as defined above and X is an anion.
- the oxidation of the dihydropyridine is carried out with an oxidizing agent such as a nitrous oxide, nitrous acid, hydroxylamine, hydrogen peroxide, oxygen, etc.
- an oxidizing agent such as a nitrous oxide, nitrous acid, hydroxylamine, hydrogen peroxide, oxygen, etc.
- the resulting pyridine compound is quaternized by using any suitable alkyl ester such as methyl iodide, ethyl sulfate, butyl methane sulfonate and the like.
- the resulting quaternary salt is reduced by catalytic hydrogenation or by using a chemical reducing agent such as sulfur dioxide or sodium hydrosulfite to give principally the 1,4-dihydropyridine or sodium borohydride to give principally the 1,2-dihydropyridine.
- Example 2 Twelve grams of the diethylacetal of m-trifluoromethylbenzaldehyde is mixed and refluxed with 50 m1. of 6 N hydrochloric acid for three hours under nitrogen. The mixture is then cooled and the oil and aqueous layers are separated. The aqueous layer is washed with methylene chloride. The, oil layer and extract are combined and treated with 12.6 g. of ethyl acetoacetate followed by 25 ml. of ethanol and 45.0' ml. of concentrated ammonium hydroxide. The resulting mixture is heated at reflux for one hour, allowed to stand overnight at room temperature, then refluxed for two hours, cooled and poured into 500 ml. of ice water. Filtering and recrystallizing from isopropyl ether gives 3,5-dicarbethoxy-1,4-dihydro-2,6-dimethyl-4- 3-trifluoromethylphenyl pyridine.
- Example 3 A mixture of 20 g. of p-trifiuoromethylbenzaldehyde oxime and ml. of 20% sulfuric acid is heated for two hours on a steam bath. Extracting with ether, then removing the ether from the extract in vacuo gives p-trifluoromethylbenzaldehyde.
- Example 5 A mixture of 100 g. of t-butyl acetoacetate, 33.6 g. of benzaldehyde and 40 ml. of ammonium hydroxide is heated at reflux for 45 minutes, 20 ml. of ammonium hydroxide is added and the resulting mixture is refluxed for 30 minutes. The mixture is concentrated and methanol is added. The solution is cooled; the precipitate is filtered off and recrystallized from cyclohexane to give 3,5-di-tbutoxycarbonyl 1,4 dihydro 2,6-dimethyl-4-phenylpyridine.
- Example 7 Sodium nitrite (20 g.) is added portionwise with stirring to a mixture of 22 g. of 3,5-dicarbethoxy-1,4-dihydro- 2,6-dimethyl-4-(2 trifluoromethylphenyl)pyridine (prepared as in Example 1) in 250 ml. of acetic acid. The resulting mixture is heated until the evolution of nitrogen oxide fumes ceases, then is poured into 1.5 l. of water.
- Example 8 Ingredients: Amounts, mg.
- a tablet prepared as described above is administered several times daily to a hypertensive subject.
- Example 9 A tablet is made as described in Example 8 using, as the active ingredient, 3,5-dicarbethoxy-4-(2-chlorophenyl)- 1,4-dihydro-2,6-dimethylpyridine.
- Example 10 Ingredients: Amounts, mg. 3,5-dicarbethoxy 1,4 dihydro-2,6-dimethyl-4- (2-pyrrolyl)pyridine 150 Lactose 75 The ingredients are mixed, screened and filled into a hard gelatin capsule.
- a capsule, prepared as described above, is administered three times per day to a hypertensive subject.
- Example 11 Ingredients: Amounts, mg. 3,5-dicarbethoxy 1,4 dihydro-2,6-dimethyl-4- (3-pyridyl)pyridine 100 Lactose 150 The ingredients are screened, mixed and filled into a hard gelatin capsule.
- Example 12 Ingredients: Amounts, mg. 3,5-dicarbethoxy 1,4 dihydro-2,6-dimethyl-4- (4-pyridyl)pyridine 75 Lactose Magnesium stearate 5 The ingredients are mixed, screened and filled into a hard gelatin capsule.
- Example 13 Ingredients: Amounts, mg. 3,5-dicarbethoxy-4-(2-furyl) 1,4 dihydro-2,6-
- dimethylpyridine 50 Lactose The ingredients are screened, mixed and filled into a hard gelatin capsule.
- the ingredients are sterilized, mixed to form a solution and filled into a sterile ampule.
- Example 16 Ingredients:
- Example 17 Ingredients:
- a pharmaceutical dosage unit in the form of a tablet, capsule, troche, lozenge, liquid parenteral suspension or parenteral solution for internal administration to produce hypotensive activity comprising a pharmaceutical carrier and from about 5 mg. to about 500 mg. of a dihydropyridine of the formula:
- R is lower alkyl having 1-6 carbon atoms
- R is 000K or CO
- R is phenyl, halophenyl, dihalophenyl, lower alkylphenyl, di-lower alkylphenyl, tri-lower alkylphenyl, lower alkoxyphenyl, di-lower alkoxyphenyl, tri-lower alkoxyphenyl, trifluoromethylphenyl, benzyl, styryl, furyl, thienyl, pyridyl or pyrrolyl, said lower alkyl and lower alkoxy groups having 1-4 carbon atoms;
- R is hydrogen or lower alkyl having 1-6 carbon atoms
- R and R" are lower alkyl having l-6 carbon atoms.
- the pharmaceutical dosage unit of claim 1 in a solid form for oral administration in the form of a tablet, capsule, troche or lozenge to produce hypotensive activity comprising a pharmaceutical carrier and from about 5 mg. to about 500 mg. of a dihydropyridine of the formula:
- R is carbomethoxy or carbethoxy and R is chlorophenyl, tolyl, trimethylphenyl, trifluoromethylphenyl, furyl, pyridyl or pyrrolyl in a daily dosage of from about 5 mg. to about 2000 mg. 10. The method of claim 9 in which the 1,4-dihydropyridine is administered orally.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US61439367A | 1967-02-07 | 1967-02-07 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3441648A true US3441648A (en) | 1969-04-29 |
Family
ID=24461057
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US614393A Expired - Lifetime US3441648A (en) | 1967-02-07 | 1967-02-07 | Compositions and methods for lowering blood pressure with 1,4-dihydropyridines |
Country Status (13)
Country | Link |
---|---|
US (1) | US3441648A (ko) |
BE (1) | BE710391A (ko) |
CH (1) | CH498113A (ko) |
DE (1) | DE1695826C3 (ko) |
DK (1) | DK131819C (ko) |
ES (1) | ES350204A1 (ko) |
FI (1) | FI49299C (ko) |
FR (2) | FR1574702A (ko) |
GB (1) | GB1167447A (ko) |
IE (1) | IE31932B1 (ko) |
IL (1) | IL29354A (ko) |
NL (1) | NL156135B (ko) |
SE (1) | SE337024B (ko) |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3696112A (en) * | 1969-12-17 | 1972-10-03 | Bayer Ag | Sulphur-containing 1,4-dihydropyridine derivatives |
FR2169113A1 (ko) * | 1972-01-22 | 1973-09-07 | Yamanouchi Pharma Co Ltd | |
US3764683A (en) * | 1969-12-17 | 1973-10-09 | Bayer Ag | Composition and method for effecting coronary dilation using cyanophenyl-1,4-dihydropyridine derivatives |
US3862161A (en) * | 1970-01-24 | 1975-01-21 | Bayer Ag | 4-pyridyl substituted 1,4-dihydropyridines |
US3922278A (en) * | 1972-06-12 | 1975-11-25 | Sterling Drug Inc | 4-(3-Nitrophenyl)-3,5-pyridinedicarboxylic acid |
US3959292A (en) * | 1972-08-12 | 1976-05-25 | Bayer Aktiengesellschaft | 2-Amino-4,5-dihydropyridine derivatives |
US3971790A (en) * | 1972-03-06 | 1976-07-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
US3971791A (en) * | 1972-03-06 | 1976-07-27 | Bayer Aktiengesellschaft | 2-Amino-1,4-dihydropyridine derivatives |
US4048171A (en) * | 1970-02-05 | 1977-09-13 | Bayer Aktiengesellschaft | 1,4-Dihydropyridines |
US4136187A (en) * | 1972-08-12 | 1979-01-23 | Bayer Aktiengesellschaft | Antihypertensive 2-amino-4,5-dihydropyridine derivatives |
US4264611A (en) * | 1978-06-30 | 1981-04-28 | Aktiebolaget Hassle | 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same |
US4285955A (en) * | 1978-10-31 | 1981-08-25 | Bayer Aktiengesellschaft | 1,4-Dihydropyridinecarboxylic acids |
US4321384A (en) * | 1981-02-27 | 1982-03-23 | American Home Products Corporation | Antihypertensive agents |
US4365063A (en) * | 1981-08-31 | 1982-12-21 | American Home Products Corporation | Antihypertensive agents |
US4652573A (en) * | 1985-03-14 | 1987-03-24 | Nelson Research & Development Co. | Calcium antagonist N-hetero ester 1,4-dihydropyridines |
US4677101A (en) * | 1983-09-26 | 1987-06-30 | Merck & Co., Inc. | Substituted dihydroazepines useful as calcium channel blockers |
US4722931A (en) * | 1984-03-27 | 1988-02-02 | Laboratorios Delagrange | Calcium antagonist |
US4849436A (en) * | 1986-03-11 | 1989-07-18 | Nelson Research & Development Co. | 1,4-dihydropyridines |
US4952592A (en) * | 1987-08-03 | 1990-08-28 | Instituto De Investigacion Y Desarrollo Quimicobiologico S.A. | 1,4-dihydro 2,6-dimethyl 4-(2,3-methylenedioxyphenyl) 3-alkoxy carbonyl 5-[2-(substituted amino)ethoxy]carbonyl pyridine |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1923990C3 (de) * | 1969-05-10 | 1978-11-23 | Bayer Ag | Verfahren zur Herstellung von N-substituierten M-Dihydropyridin-S.S-dicarbonsäureestern |
SU706410A1 (ru) * | 1978-01-11 | 1979-12-30 | Ордена Трудового Красного Знамени Институт Органического Синтеза Ан Латвийской Сср | 2,6-Диметил-3,5-дикарбметокси-4(0-дифторметоксифенил)-1,4-дигидропиридин,обладающий выраженной гипотензивной активностью и оказывающий действие на функции вегетативной нервной системы |
US4435574A (en) * | 1981-07-20 | 1984-03-06 | Kastron Valeria V | 2,6-Dimethyl-3,5-dicarbomethoxy-4-(ortho-di-fluoromethylthiophenyl)-1,4-dihydropyridine |
US4771057A (en) * | 1986-02-03 | 1988-09-13 | University Of Alberta | Reduced pyridyl derivatives with cardiovascular regulating properties |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3221017A (en) * | 1964-04-07 | 1965-11-30 | Aldrich Chem Co Inc | Aralkoxyamides of 4-phenyl-1,2,5,6-tetrahydropyridino alkanoic acids and intermediates thereof |
US3325505A (en) * | 1965-02-24 | 1967-06-13 | Smith Kline French Lab | 4-cycloalkyl(or cycloalkenyl)-dihydropyridines |
-
1967
- 1967-02-07 US US614393A patent/US3441648A/en not_active Expired - Lifetime
-
1968
- 1968-01-17 DK DK16968*#A patent/DK131819C/da active
- 1968-01-21 IL IL29354A patent/IL29354A/en unknown
- 1968-01-25 GB GB4049/68A patent/GB1167447A/en not_active Expired
- 1968-01-31 IE IE121/68A patent/IE31932B1/xx unknown
- 1968-01-31 FI FI680251A patent/FI49299C/fi active
- 1968-02-01 DE DE1695826A patent/DE1695826C3/de not_active Expired
- 1968-02-02 SE SE01402/68A patent/SE337024B/xx unknown
- 1968-02-05 FR FR1574702D patent/FR1574702A/fr not_active Expired
- 1968-02-05 FR FR138648A patent/FR7046M/fr not_active Expired
- 1968-02-06 CH CH169368A patent/CH498113A/de not_active IP Right Cessation
- 1968-02-06 ES ES350204A patent/ES350204A1/es not_active Expired
- 1968-02-06 BE BE710391D patent/BE710391A/xx not_active IP Right Cessation
- 1968-02-07 NL NL6801710.A patent/NL156135B/xx not_active IP Right Cessation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3221017A (en) * | 1964-04-07 | 1965-11-30 | Aldrich Chem Co Inc | Aralkoxyamides of 4-phenyl-1,2,5,6-tetrahydropyridino alkanoic acids and intermediates thereof |
US3325505A (en) * | 1965-02-24 | 1967-06-13 | Smith Kline French Lab | 4-cycloalkyl(or cycloalkenyl)-dihydropyridines |
Cited By (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3764683A (en) * | 1969-12-17 | 1973-10-09 | Bayer Ag | Composition and method for effecting coronary dilation using cyanophenyl-1,4-dihydropyridine derivatives |
US3696112A (en) * | 1969-12-17 | 1972-10-03 | Bayer Ag | Sulphur-containing 1,4-dihydropyridine derivatives |
US3862161A (en) * | 1970-01-24 | 1975-01-21 | Bayer Ag | 4-pyridyl substituted 1,4-dihydropyridines |
US4048171A (en) * | 1970-02-05 | 1977-09-13 | Bayer Aktiengesellschaft | 1,4-Dihydropyridines |
FR2169113A1 (ko) * | 1972-01-22 | 1973-09-07 | Yamanouchi Pharma Co Ltd | |
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 |
US3922278A (en) * | 1972-06-12 | 1975-11-25 | Sterling Drug Inc | 4-(3-Nitrophenyl)-3,5-pyridinedicarboxylic acid |
US3959292A (en) * | 1972-08-12 | 1976-05-25 | Bayer Aktiengesellschaft | 2-Amino-4,5-dihydropyridine derivatives |
US4136187A (en) * | 1972-08-12 | 1979-01-23 | Bayer Aktiengesellschaft | Antihypertensive 2-amino-4,5-dihydropyridine derivatives |
US4264611A (en) * | 1978-06-30 | 1981-04-28 | Aktiebolaget Hassle | 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same |
US4285955A (en) * | 1978-10-31 | 1981-08-25 | Bayer Aktiengesellschaft | 1,4-Dihydropyridinecarboxylic acids |
US4321384A (en) * | 1981-02-27 | 1982-03-23 | American Home Products Corporation | Antihypertensive agents |
US4365063A (en) * | 1981-08-31 | 1982-12-21 | American Home Products Corporation | Antihypertensive agents |
US4677101A (en) * | 1983-09-26 | 1987-06-30 | Merck & Co., Inc. | Substituted dihydroazepines useful as calcium channel blockers |
US4722931A (en) * | 1984-03-27 | 1988-02-02 | Laboratorios Delagrange | Calcium antagonist |
US4652573A (en) * | 1985-03-14 | 1987-03-24 | Nelson Research & Development Co. | Calcium antagonist N-hetero ester 1,4-dihydropyridines |
US4849436A (en) * | 1986-03-11 | 1989-07-18 | Nelson Research & Development Co. | 1,4-dihydropyridines |
US4952592A (en) * | 1987-08-03 | 1990-08-28 | Instituto De Investigacion Y Desarrollo Quimicobiologico S.A. | 1,4-dihydro 2,6-dimethyl 4-(2,3-methylenedioxyphenyl) 3-alkoxy carbonyl 5-[2-(substituted amino)ethoxy]carbonyl pyridine |
Also Published As
Publication number | Publication date |
---|---|
DE1695826C3 (de) | 1978-03-23 |
ES350204A1 (es) | 1969-04-16 |
GB1167447A (en) | 1969-10-15 |
DE1695826B2 (de) | 1977-07-14 |
DK131819C (da) | 1976-02-09 |
FI49299B (ko) | 1975-01-31 |
NL6801710A (ko) | 1968-08-08 |
NL156135B (nl) | 1978-03-15 |
BE710391A (ko) | 1968-08-06 |
DE1695826A1 (de) | 1971-05-13 |
FR1574702A (ko) | 1969-07-18 |
DK131819B (da) | 1975-09-08 |
IL29354A (en) | 1971-11-29 |
IE31932L (en) | 1968-08-07 |
FR7046M (ko) | 1969-06-16 |
IE31932B1 (en) | 1973-02-21 |
CH498113A (de) | 1970-10-31 |
FI49299C (fi) | 1975-05-12 |
SE337024B (ko) | 1971-07-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3441648A (en) | Compositions and methods for lowering blood pressure with 1,4-dihydropyridines | |
US3905970A (en) | 1,4-Dihydropyridine carboxylic acid esters | |
US4656181A (en) | Esters of 1,4-dihydropyridines, processes for the preparation of the new esters, and medicaments containing the same | |
Meguro et al. | New 1, 4-dihydropyridine derivatives with potent and long-lasting hypotensive effect | |
US3511847A (en) | 2,6-di-lower alkyl - 1,4-dihydro - 4-(2-trifluoromethylphenyl) - 3,5 - pyridinedicarboxylic acid esters | |
US3574843A (en) | 1,4-dihydropyridine derivatives for the treatment of angina pectoris | |
US3775422A (en) | Unsymmetrical 1,4-dihydro-4-aryl-nicotinate esters | |
US4188395A (en) | 1,4-Dihydropyridine derivatives substituted in the 2 position, and their use as medicaments | |
IE56057B1 (en) | Dihydropyridine derivatives,their production and use | |
JPS63290874A (ja) | 1,4−ジヒドロピリジンカルボン酸化合物の製造方法 | |
JPH05271078A (ja) | ジヒドロピリジン類 | |
US3996234A (en) | 1,4-Dihydropyridine carboxylic acid esters | |
US4853393A (en) | 3,5-Diacyl-4-aryl-1,4 dihydropyridine derivatives, their uses and compositions | |
US3455945A (en) | 4-(carboxy (and carbo-lower alkoxy)phenyl)-1,4-dihydropyridines | |
JPH05506216A (ja) | 医薬としてのピリジン | |
US4497821A (en) | Medicaments having antihypoxic and ischaemia-protective activity | |
US4652573A (en) | Calcium antagonist N-hetero ester 1,4-dihydropyridines | |
JPS63170359A (ja) | 抗高血圧性の還元されたピリジル誘導体類 | |
DE3109794A1 (de) | "bluthochdruck senkende amine" | |
US3956341A (en) | 1,3,5-Tricarbo-1,4-dihydropyridines | |
IE54879B1 (en) | Pyridinecarboxylic esters, processes for their preparation and their use as medicaments | |
US4021434A (en) | Sodium β-[2,6-dimethyl-3,5-bis(ethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydropyridine-1-yl]ethyl sulfate | |
EP0107619A1 (en) | Dihydropyrazolo(3,4-b)pyridine derivatives and production thereof | |
SU1007556A3 (ru) | Способ получени 1,4-дигидропиридинов | |
US3860601A (en) | 2,6-diamino-1,4-dihydropyridine derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SMITHKLINE BECKMAN CORPORATION, PENNSYLVANIA Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 Owner name: SMITHKLINE BECKMAN CORPORATION Free format text: CHANGE OF NAME;ASSIGNOR:SMITHKLINE CORPORATION;REEL/FRAME:004080/0769 Effective date: 19820304 |