[go: up one dir, main page]

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 PDF

Info

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
Application number
US614393A
Inventor
Bernard Loev
Ralph E Tedeschi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SmithKline Corp filed Critical SmithKline Corp
Application granted granted Critical
Publication of US3441648A publication Critical patent/US3441648A/en
Assigned to SMITHKLINE BECKMAN CORPORATION reassignment SMITHKLINE BECKMAN CORPORATION CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). EFFECTIVE DATE: 03/04/82 Assignors: SMITHKLINE CORPORATION
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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)
  • Plural Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)

Description

United States Patent 3,441,648 COMPOSITIONS AND METHODS FOR LOWER- ING BLOOD PRESSURE WITH 1,4-DIHYDRO- PYRIDINES Bernard Loev, Broomall, Pa., and Ralph E. Tedeschi, Cherry Hill, N.J., assignors to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Feb. 7, 1967, Ser. No. 614,393 Int. Cl. A61k 27/00; C07d 29/40 US. Cl. 424-263 Claims ABSTRACT OF THE DISCLOSURE This invention relates to new hypotensive compositions containing 1,4-dihydropyridines and to methods of lowering blood pressure by administering these compositions. In addition, this invention relates to 1,4-dihydro-4-(2-trifluoromethylphenyl)pyridines which are new compounds having hypotensive activity.
Some of the 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. In the 4-aryl series, compounds having substituents on the ortho positions of the aryl nuclei have particularly advantageous therapeutic properties as will be noted hereinafter.
The hypotensive compositions of this invention, in dosage unit form, contain an effective but nontoxic amount of a 1,4-dihydropyridine of the formula:
FORMULA I R; \N R in in which:
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.
A particularly advantageous 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.
The 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.
One skilled in the art will recognize that in determining the amounts of the active ingredient in the claimed dosage unit compositions, the activity of the chemical ingredient as well as the size of the host animal must be considered. On a mg./kg. basis the amount of the active ingredient in the claimed 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.
Generally, 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. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liquid carriers are peanut oil, olive oil or sesame oil. Similarly, 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. Thus, if a solid carrier is 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. If 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. Advantageously, 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. When the administration is carried out as described above, hypotensive activity is produced.
The dosage units or dosage ranges presented herein are designed for a hypertensive subject of about 50 kg.
The 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.
The following results were obtained by administering intravenously the following 1,4-dihydropyridines to dogs 3 anesthetized with pentobarbital pressure response:
and recording the blood Administering the following 1,4-dihydropyridines orally to neurogenic, hypertensive dogs produced significant lowering of blood pressure at the doses indicated:
Compound (Dose: 10 mg./kg.)
(Dose: 5, l and 20 mgJkg.)
Dose: 2.5 b.i.d., mg./kg.)
(Dose: 20 and 30 mg/kg.)
R3 fl (Dose: 5 and ing/kg) 4 The new 1,4-dihydro-4-(Z-trifiuoromethylphenyl)-pyridines which are also objects of this invention are represented by the following formula:
FORMULA II R O O C I l O O O R R1\N R1 in which R and R are lower al-kyl having 1-6 carbon atoms.
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:
i R R RQCHO R.- -0H.R. NH. I
x R1 H The terms R R and R are as defined above.
According to procedure I, 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.
According to procedure II, one molar equivalent of an aldehyde is reacted with two molar equivalents of the unsaturated amino compound. Preferably, the reaction is carried out in a solvent, such as a lower alkanol or dioxane, at elevated temperature, conveniently at reflux temperature.
Also, 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.
Compounds of Formula 1 in which R, is lower alkyl are prepared from the compounds in which R; is hydrogen by the following procedure:
The terms R to R are as defined above and X is an anion.
In the above reaction, the oxidation of the dihydropyridine is carried out with 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.
Although the Z-trifluoromethylphenyl-dihydropyridines of this invention and the dihydropyridines which are the active ingredients of the compositions are drawn as having the 1,4-dihydropyridine structure, the positions of the double bonds are not known with certainty in all instances and thus it is understood that some of these compounds may have the following 1,2-dihydro structures, re-
spectively:
| RO o ofic o 0 R R1 III/ t 11 and Example 1 Twelve grams of the diethylacetal of o-trifluoromethylbenzaladehyde is mixed and refluxed with 50 ml. of 6 N hydrochloric acid for three hours under nitrogen. The mixture is cooled and the oil and aqueous layers are separated. The aqueous layer is washed with about 25 ml. of methylene chloride. To the combined oil and extract is added 12.6 g. of ethyl acetoacetate followed by 25 ml. of ethanol and 5.0 ml. of concentrated ammonium hydroxide. The resulting mixture is refluxed for 19 hours, then is chilled and poured onto about 500 ml. of ice water. Filtering and recrystallizing from isopropyl ether 6 gives 3,5-dicarbethoxy 1,4-dihydro-2,6-dimethyl-4-(2-trifiuoromethylphenyl) pyridine.
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.
To 18.4 g. of p-trifluoromethylbenzaldehyde in ml. of ethanol is added 27.6 g. of ethyl acetoacetate and 10 ml. of ammonium hydroxide. The resulting mixture is heated at reflux for five hours, then is poured into water. Methylene chloride is added. The organic layer is dried and concentrated. The resulting oil is dissolved in isopropyl ether. The resulting solution is cooled and filtered. The solid material is sublimed in vacuo to give 3,5-dicarbethoxy 1,4- dihydro-2,6 dimethyl 4(4-trifluoromethylphenyl) pyridine Example 4 A mixture of 17.5 g. of 2,6-dichlorobenzaldehyde, 26 g. of ethyl acetoacetate, 60 ml. of ethanol and 10 ml. of concentrated ammonium hydroxide is heated at reflux for 14 hours, then is poured into water. The gum which forms is filtered OE and heated with petroleum ether. The petroleum ether layer is decanted and the resulting oil is crystallized from methylcy-clohexane to give 3,5-dicarbethoxy-4- (2,4-dichlorophenyl)-1,4-dihydro 2,6-dimethylpyridine.
Example 5 Example 6 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.
7 The oil which separates is extracted with ether. The extract is rinsed with dilute base and then with water, then dried and concentrated to give 3,5-dicarbethoxy-2,6-dimethyl-4- (2-trifluoromethylphenyl) pyridine.
A mixture of 10.0 g. of the above prepared pyridine and 7.6 g. of dimethyl sulfate is heated on a steam bath for 15 hours. The mixture is cooled, stirred with ether and filtered to give the corresponding N-met-hyl pyridinium sulfate.
Five grams of the above prepared quaternary salt in a concentrated aqueous solution is added to a solution of 12 g. of sodium hydrosulfite and 15 g. of sodium carbonate in 100 ml. of Water. The mixture is stirred under nitrogen for two hours. The mixture is extracted with ether, washed with water, dried and concentrated. The residue is recrystallized from methanol to give 3,5-dicarbethoxy-1,4- dihydro-1,2,6-trimethyl-4- (2 trifluoromethylphenyl) pyridine. Alternatively, dissolving 5 g. of the quaternary salt in 50 ml. of 40% ethanol, adding 5 g. of sodium carbonate and 1 g. of sodium borohydride gives a mixture containing 3,5-dicarbethoxy-1,4-dihydro-1,2,6-trimethyl-4-(2-trifluoromethylphenyl)pyridine and, principally, the cor responding 1,2-dihydro compound.
Similarly, using in place of dimethyl sulfate, 6.5 g. of ethyl bromide, 7.4 g. of n-propyl bromide or 8.2 g. of nbutyl bromide in the above procedure using sodium hydrosulfite to reduce the quaternary salt the following products, respectively, are obtained:
3,5-dicarbethoxy-l-ethyl-1,4-dihydro-2,6 dimethyl-4-(2- trifluoromethylphenyl) pyridine, 3,5-dicarbethoxy-l,4-dihydro-2,6-dimethyl 1-(n-propy1)- 4-(2-tri-fluoromethylphenyl) pyridine and 1-(n-butyl)-3,5-dicarbethoxy-l,4-dihydro-2,6 dimethyl-4- (Z-trifluoromethylphenyl pyridine.
Example 8 Ingredients: Amounts, mg.
3,5-dicarbethoxy 1,4 dihydro-2,6-dimethyl-4- (Z-trifiuoromethylphenyl)pyridine 100 Sucrose 25 Starch 15 Talc 5 Stearic acid 3 The active ingredient is mixed with the sucrose and the resulting mixture is granulated with gelatin solution. The wet granules are screened, dried and then mixed with the starch, talc and stearic acid, screen and compressed into a tablet.
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:
3,5-dicarbethoxy 1,4 dihydro 2,6 dimethyl-4- styrylpyridine mg 20 N,N-dimethylacetamide (50% aqueous solution) The ingredients are sterilized, mixed to form a solution and filled into a sterile ampule.
Example 17 Ingredients:
4 benzyl 3,5 dicarbethoxy 1,4 dihydro-2,6-
dimethylpyridine mg 25 N,N-dimethylacetamide (50% aqueous solution) The ingredients are sterilized, mixed to form a solution and filled into a sterile ampule.
What is claimed is:
1. 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:
in which:
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;
and
R and R" are lower alkyl having l-6 carbon atoms.
2. The pharamceutical dosage unit of claim 1 in which R is methyl, R is COOCH CH R is Z-trifluoromethyl and R is hydrogen.
3. The pharmaceutical dosage unit of claim 1 in which R is methyl, R is COOCH CH R is 2-chlorophenyl and R is hydrogen.
4. 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, I R2 CHr- III CH3 H R1 I R; CHaiN CH3 1':
in which:
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.
References Cited UNITED STATES PATENTS 3,221,017 11/1965 Biel 167-65 X 3,325,505 6/1967 Loev 167-65 X ALBERT T. MEYERS, Primary Examiner.
S. FRIEDMAN, Assistant Examiner.
US. Cl. X.R. 260295.5
US614393A 1967-02-07 1967-02-07 Compositions and methods for lowering blood pressure with 1,4-dihydropyridines Expired - Lifetime US3441648A (en)

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 (en)
BE (1) BE710391A (en)
CH (1) CH498113A (en)
DE (1) DE1695826C3 (en)
DK (1) DK131819C (en)
ES (1) ES350204A1 (en)
FI (1) FI49299C (en)
FR (2) FR7046M (en)
GB (1) GB1167447A (en)
IE (1) IE31932B1 (en)
IL (1) IL29354A (en)
NL (1) NL156135B (en)
SE (1) SE337024B (en)

Cited By (19)

* Cited by examiner, † Cited by third party
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 (en) * 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
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
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1923990C3 (en) * 1969-05-10 1978-11-23 Bayer Ag Process for the preparation of N-substituted M-dihydropyridine-S.S-dicarboxylic acid esters
SU706410A1 (en) * 1978-01-11 1979-12-30 Ордена Трудового Красного Знамени Институт Органического Синтеза Ан Латвийской Сср 2,6-dimethyl-3,5-dicarbomethoxy-4-(o-difluoromethoxyphenyl)-1,4-dihydropyridine possessing expressed hypotensive activity and exhibiting action on vegetative nervous system functions
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)

* Cited by examiner, † Cited by third party
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 (en) * 1972-01-22 1973-09-07 Yamanouchi Pharma Co Ltd
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
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
DK131819C (en) 1976-02-09
FI49299C (en) 1975-05-12
DK131819B (en) 1975-09-08
ES350204A1 (en) 1969-04-16
DE1695826A1 (en) 1971-05-13
CH498113A (en) 1970-10-31
IE31932B1 (en) 1973-02-21
IL29354A (en) 1971-11-29
GB1167447A (en) 1969-10-15
SE337024B (en) 1971-07-26
BE710391A (en) 1968-08-06
NL6801710A (en) 1968-08-08
FR7046M (en) 1969-06-16
NL156135B (en) 1978-03-15
DE1695826B2 (en) 1977-07-14
FI49299B (en) 1975-01-31
FR1574702A (en) 1969-07-18
DE1695826C3 (en) 1978-03-23
IE31932L (en) 1968-08-07

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 (en) Manufacture of 1,4-dihydropyridinecarboxylic acid compound
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
US4497821A (en) Medicaments having antihypoxic and ischaemia-protective activity
US4705794A (en) Ischaemia or hypoxia controlling compositions containing pyridinecarboxylic acid esters
US4652573A (en) Calcium antagonist N-hetero ester 1,4-dihydropyridines
JPS63170359A (en) Antihypertensive reduced pyridyl derivatives
DE3109794A1 (en) "HIGH PRESSURE REDUCING AMINES"
US3956341A (en) 1,3,5-Tricarbo-1,4-dihydropyridines
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 (en) Method of producing 1,4-dehydropyridines
US3860601A (en) 2,6-diamino-1,4-dihydropyridine derivatives
US4004014A (en) 2-Amino-6-dialkylaminodihydropyridines, their production, pharmaceutical compositions and methods of use thereof
US3535330A (en) 2,6-diphenyl - 4 - (p-(dilower-alkyl amino lower - alkoxy)phenyl)pyridines and derivatives thereof

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