CH498113A - Hypotensive dihydropyridines - Google Patents

Hypotensive dihydropyridines

Info

Publication number
CH498113A
CH498113A CH169368A CH169368A CH498113A CH 498113 A CH498113 A CH 498113A CH 169368 A CH169368 A CH 169368A CH 169368 A CH169368 A CH 169368A CH 498113 A CH498113 A CH 498113A
Authority
CH
Switzerland
Prior art keywords
alkyl
general formula
dihydro
hypotensive
dihydropyridines
Prior art date
Application number
CH169368A
Other languages
German (de)
Inventor
Loev Bernard
Earl Tedeschi Ralph
Original Assignee
Smith Kline French Lab
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 Smith Kline French Lab filed Critical Smith Kline French Lab
Publication of CH498113A publication Critical patent/CH498113A/en

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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

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)

Abstract

(A) Pharmaceutical prepns. contng. as active ingredient a dihydropyridine deriv. (I) R' = 1-6C alkyl R2 = COOR', COR" R3 = Ph opt. substd. by mono/di-halo, mono/di/tri-1-4C alkyl/alkoxy, CF3; benzyl styryl, furyl, thienyl R4 = H, 1-6C alkyl R',R" = 1-6C alkyl (B) Cpds. of formula (II):- As hypotensive agents. Unit doses; 25-250 mg. for oral admin. at levels of 0.5-5 mg/kg.

Description

  

  
 



  Verfahren zur Herstellung von   1,4-Dihydro-4-(2-trifluormethylphenyl)-pyridinen   
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von neuen   1 ,4-Dihydro-4-(2-tnfluormethyl-    phenyl)-pyridinen der allgemeinen Formel I
EMI1.1     
 in der R, und R2 Alkylreste mit 1 bis 6 Kohlenstoffatomen bedeuten.



   Diese neuen Verbindungen sind Arzneimittel, und sie besitzen blutdrucksenkende Wirkung. Eine bevorzugte Verbindung der allgemeinen Formel   list    3,5-Dicarbäthoxy-   l,4-dihydro-2,6-dimethyl-4-(2-trifluormethyl-    phenyl)-pyridin, dass bei oraler Verabreichung eine besonders kräftige blutdrucksenkende Wirkung von ver   hältnismässig    langer Dauer zeigt.



   Die Erfindung betrifft ein Verfahren zur Herstellung der Verbindungen der allgemeinen Formel I, das dadurch gekennzeichnet ist, dass man etwa 1 Moläquivalent   o-    -Trifluormethylbenzaldehyd mit etwa 2 Moläquivalenten eines Acylessigsäureesters der allgemeinen Formel II
EMI1.2     
 in der R1 und   R.5    die obige Bedeutung haben, sowie Ammoniak im   Überschuss    bei erhöhter Temperatur kondensiert.



   Vorzugsweise wird das erfindungsgemässe Verfahren in einem Lösungsmittel, z.B. einem niederen aliphatischen Alkohol oder Dioxan, unter Rückflusskochen des Reaktionsgemisches durchgeführt. Die Reaktionszeit beträgt vorzugsweise 1 bis 4 Stunden.



   Das erfindungsgemässe Verfahren verläuft schematisch nach folgender Reaktionsgleichung
EMI1.3     

Obgleich die Formel der erfindungsgemässen 2-Trifluormethyl-phenyl-dihydropyridine so gezeichnet ist, als hätten sie die 1,4-Dihydropyridinstruktur, ist die Lage der Doppelbindungen nicht mit Sicherheit in jedem Fall bekannt. Einige dieser Verbindungen können die folgende 1,2-Dihydrostruktur haben:
EMI1.4     

Das Beispiel erläutert die Erfindung.

 

   Beispiel
12 g des Diäthylacetals von o-Trifluormethylbenzaldehyd werden mit 50 ml 6n Salzsäure unter Stickstoff versetzt und 3 Stunden unter Rückfluss gekocht. Das Reaktionsgemisch wird abgekühlt und die ölige von der wässrigen Schicht getrennt. Die wässrige Schicht wird mit etwa 25 ml Methylenchlorid gewaschen. Der Extrakt  wird mit dem öl vereinigt und dazu werden 12,6 g Acetessigsäureäthylester, dann 25 ml Äthanol und 5,0 ml konzentrierter wässriger Ammoniak gegeben. Die erhaltene Mischung wird 19 Stunden unter Rückfluss gekocht, dann abgekühlt und auf etwa 500 ml Eis-Wasser gegossen. Nach Filtrieren und Umkristallisieren aus Isopropyläther erhält man   3,5-Dicarbäthoxy-1,4-dihydro-2,6-di-    methyl-4-(2-trifluormethylphenyl)-pyridin vom Fp. 140142,50C. 



  
 



  Process for the preparation of 1,4-dihydro-4- (2-trifluoromethylphenyl) pyridines
The present invention relates to a process for the preparation of new 1,4-dihydro-4- (2-fluoromethyl-phenyl) -pyridines of the general formula I.
EMI1.1
 in which R, and R2 denote alkyl radicals having 1 to 6 carbon atoms.



   These new compounds are medicines and they have antihypertensive effects. A preferred compound of the general formula is 3,5-dicarbethoxy- 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethyl-phenyl) -pyridine that, when administered orally, has a particularly powerful antihypertensive effect that is relatively long Duration shows.



   The invention relates to a process for the preparation of the compounds of the general formula I, which is characterized in that about 1 molar equivalent of o- trifluoromethylbenzaldehyde is mixed with about 2 molar equivalents of an acyl acetic acid ester of the general formula II
EMI1.2
 in which R1 and R.5 have the above meaning, as well as excess ammonia condensed at elevated temperature.



   Preferably the process according to the invention is carried out in a solvent, e.g. a lower aliphatic alcohol or dioxane, carried out by refluxing the reaction mixture. The reaction time is preferably 1 to 4 hours.



   The process according to the invention runs schematically according to the following reaction equation
EMI1.3

Although the formula of the 2-trifluoromethyl-phenyl-dihydropyridines according to the invention is drawn as if they had the 1,4-dihydropyridine structure, the position of the double bonds is not known with certainty in every case. Some of these compounds can have the following 1,2-dihydro structure:
EMI1.4

The example illustrates the invention.

 

   example
12 g of the diethylacetal of o-trifluoromethylbenzaldehyde are mixed with 50 ml of 6N hydrochloric acid under nitrogen and refluxed for 3 hours. The reaction mixture is cooled and the oily layer is separated from the aqueous layer. The aqueous layer is washed with about 25 ml of methylene chloride. The extract is combined with the oil and 12.6 g of ethyl acetoacetate, then 25 ml of ethanol and 5.0 ml of concentrated aqueous ammonia are added. The mixture obtained is refluxed for 19 hours, then cooled and poured onto about 500 ml of ice-water. After filtration and recrystallization from isopropyl ether, 3,5-dicarbethoxy-1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) pyridine of melting point 140142.50C is obtained.

Claims (1)

PATENTANSPRUCH PATENT CLAIM Verfahren zur Herstellung von 1,4-Dihydro-4-(2-trifluormethylphenyl)-pyridinen der allgemeinen Formel I EMI2.1 in der R1 und R2 Alkylreste mit 1 bis 6 Kohlenstoffatomen bedeuten, dadurch gekennzeichnet, dass man etwa etwa 1 Moläquivalent o-Trifluormethylbenzaldehyd mit etwa 2 Moläquivalenten eines Acylessigsäureesters der allgemeinen Formel II EMI2.2 in der R1 und R2 die obige Bedeutung haben sowie Ammoniak im Überschuss bei erhöhter Temperatur konden-siert. Process for the preparation of 1,4-dihydro-4- (2-trifluoromethylphenyl) pyridines of the general formula I. EMI2.1 in which R1 and R2 denote alkyl radicals with 1 to 6 carbon atoms, characterized in that about 1 molar equivalent of o-trifluoromethylbenzaldehyde is mixed with about 2 molar equivalents of an acyl acetic acid ester of the general formula II EMI2.2 in which R1 and R2 have the above meaning and ammonia in excess condenses at elevated temperature. UNTERANSPRUCH Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man die Kondensationsreaktion in einem Lösungsmittel unter Rückfluss durchführt. SUBClaim Process according to patent claim, characterized in that the condensation reaction is carried out in a solvent under reflux.
CH169368A 1967-02-07 1968-02-06 Hypotensive dihydropyridines CH498113A (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
CH498113A true CH498113A (en) 1970-10-31

Family

ID=24461057

Family Applications (1)

Application Number Title Priority Date Filing Date
CH169368A CH498113A (en) 1967-02-07 1968-02-06 Hypotensive 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)

Families Citing this family (23)

* 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
DE1963186C3 (en) * 1969-12-17 1979-02-15 Bayer Ag, 5090 Leverkusen Sulfur-containing 1,4-dihydropyridine-33-dicarboxylic acid esters
DE1963188A1 (en) * 1969-12-17 1971-06-24 Bayer Ag New cyanophenyl-1,4-dihydropyridine derivatives
US3862161A (en) * 1970-01-24 1975-01-21 Bayer Ag 4-pyridyl substituted 1,4-dihydropyridines
DE2005116C3 (en) * 1970-02-05 1980-02-14 Bayer Ag, 5090 Leverkusen Symmetrical 1,4-dihydropyridine-3,5-dicarboxylic acid esters
GB1430961A (en) * 1972-01-22 1976-04-07 Yamanouchi Pharma Co Ltd 1-substituted-1,4-dihyddrypyridine 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
US3922278A (en) * 1972-06-12 1975-11-25 Sterling Drug Inc 4-(3-Nitrophenyl)-3,5-pyridinedicarboxylic acid
US4136187A (en) * 1972-08-12 1979-01-23 Bayer Aktiengesellschaft Antihypertensive 2-amino-4,5-dihydropyridine derivatives
DE2239815C2 (en) * 1972-08-12 1983-02-10 Bayer Ag, 5090 Leverkusen 2-Alkylamino-dihydropyridines, processes for their preparation and pharmaceuticals containing them
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
SE429652B (en) * 1978-06-30 1983-09-19 Haessle Ab 2,6-dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl 5-ethyl ester
US4285955A (en) * 1978-10-31 1981-08-25 Bayer Aktiengesellschaft 1,4-Dihydropyridinecarboxylic acids
US4365063A (en) * 1981-08-31 1982-12-21 American Home Products Corporation Antihypertensive agents
US4321384A (en) * 1981-02-27 1982-03-23 American Home Products Corporation Antihypertensive agents
US4435574A (en) * 1981-07-20 1984-03-06 Kastron Valeria V 2,6-Dimethyl-3,5-dicarbomethoxy-4-(ortho-di-fluoromethylthiophenyl)-1,4-dihydropyridine
US4677101A (en) * 1983-09-26 1987-06-30 Merck & Co., Inc. Substituted dihydroazepines useful as calcium channel blockers
IE57810B1 (en) * 1984-03-27 1993-04-21 Delagrange Lab 1,4-dihydropyridine derivatives,their preparation and their use
US4652573A (en) * 1985-03-14 1987-03-24 Nelson Research & Development Co. Calcium antagonist N-hetero ester 1,4-dihydropyridines
US4771057A (en) * 1986-02-03 1988-09-13 University Of Alberta Reduced pyridyl derivatives with cardiovascular regulating properties
US4849436A (en) * 1986-03-11 1989-07-18 Nelson Research & Development Co. 1,4-dihydropyridines
ATE61588T1 (en) * 1987-08-03 1991-03-15 Delagrange Lab 1,4-DIHYDROPYRIDINES, PROCESSES FOR THEIR PRODUCTION AND USE AS MEDICINAL PRODUCTS.

Family Cites Families (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

Also Published As

Publication number Publication date
SE337024B (en) 1971-07-26
DE1695826C3 (en) 1978-03-23
IE31932L (en) 1968-08-07
FR1574702A (en) 1969-07-18
DE1695826B2 (en) 1977-07-14
NL6801710A (en) 1968-08-08
DK131819C (en) 1976-02-09
FR7046M (en) 1969-06-16
FI49299C (en) 1975-05-12
IE31932B1 (en) 1973-02-21
FI49299B (en) 1975-01-31
DE1695826A1 (en) 1971-05-13
GB1167447A (en) 1969-10-15
ES350204A1 (en) 1969-04-16
US3441648A (en) 1969-04-29
DK131819B (en) 1975-09-08
BE710391A (en) 1968-08-06
NL156135B (en) 1978-03-15
IL29354A (en) 1971-11-29

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