US3414578A - 1-(3', 4'-di-lower-alkylphenyl)-2-[phenylpyridyl-(2')-propylamino]-propanol-(1) and derivatives thereof - Google Patents

1-(3', 4'-di-lower-alkylphenyl)-2-[phenylpyridyl-(2')-propylamino]-propanol-(1) and derivatives thereof Download PDF

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Publication number
US3414578A
US3414578A US589816A US58981666A US3414578A US 3414578 A US3414578 A US 3414578A US 589816 A US589816 A US 589816A US 58981666 A US58981666 A US 58981666A US 3414578 A US3414578 A US 3414578A
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general formula
compounds
acid
group
phenyl
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Ehrhart Gustav
Lindner Ernst
Hartfelder Gunter
Ott Heinrich
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Hoechst AG
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Hoechst AG
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    • 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
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/62—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Definitions

  • the present invention relates to basically substituted phenyl-propane derivatives corresponding to the general Formula I R: OH R4 (a) reducing compounds of the general Formula II @ymamglaatg in which R represents hydrogen or the benzyl group and R -R have the meanings given above,
  • the reduction of the keto group can be carried out for instance by catalytic hydogenation with the aid of metals of the 8th group of the Periodic System, preferably by means of nickel catalysts, in the presence of appropriate solvents such, for instance, as aqueous alcohols, alcohols or water.
  • the compounds may likewise be reduced by means of nascent hydrogen, for instance, aluminium amalgam and alcohol, sodium amalgam, lithium-aluminium hydride, sodium boron hydride or likewise electrolytically.
  • the starting ketones of the general Formula II can be prepared, for instance, by reaction of l-phenyl-lpyridyl-(2)-propyl(3)-amine with halogenated ketones of the general formula This reaction is advantageously carried out in the presence of agents splitting off hydrogen halides.
  • the starting substances corresponding to the general Formula II may likewise be prepared by reacting l-phenyl-lpyridyl-(2)-3-halogen-propanes with the corresponding amino-ketones of the general formula 2 Nmawg
  • the products corresponding to the general Formula I can likewise be prepared by dealkylating in the usual manner according to the method described sub (b) corresponding compounds which as R contain an alkyl group, or by splitting off a benzyl group from compounds containing the latter as R
  • the dealkylation can be carried out, for instance, by heating the compounds with hydrogen bromide or with aluminium chloride or with pyridinehydro-chloride.
  • the benzyl radical is advantageously separated catalytically while using noble metal catalysts, such for instance as palladium black, or by boiling with hydrobromic acid.
  • the starting substances corresponding to the general Formula III used according to the operation method described sub (b) are prepared in an analogous manner to that applied for the compounds of the general Formula II.
  • 1-phenyl-1-pyridyl(2)-propyl(3)-amine can be reacted, for instance, with halogenated ethers corresponding to the formula R2 Hal(3H-CH or with oxo-compounds of the general formula benzyl R an eventually present CN-group being split off by a method known per se.
  • the N-benzyl group can be separated prior to or after the cleavage of ether, preferably by catalytic hydrogenation. If R likewise represents a benzyl group, the two 0- and N-benzyl groups can be separated off in one operation by catalytic hydrogenation.
  • the starting materials of the general Formula IV used for the operation method mentioned sub (0) can be prepared correspondingly as described for compounds II and III.
  • compounds of the general Formula IV in which Ac represents the acetyl, propionyl or benzoyl radical.
  • the hydrolysis is carried out in the usual manner in an aqueous-alkaline medium or with alcoholic or aqueousalcoholic solution. It can likewise be realized by means of dilute acids such as hydrochloric acid or sulfuric acid.
  • Another method of operation of the process according to (d) consists in hydrogenating the CC-double linkage in compounds of the Formula V.
  • the reduction is advantageously carried out by catalytic hydrogenation by using metals of the 8th group of the Periodic System, preferably with precious metals.
  • the solvents usually applied for the hydrogenation, for instance, alcohols, water or aqueous alcohols.
  • the starting compounds of the general Formula V are prepared, for instance, by condensation of compounds of the general Formula XII with amines of the general Formula XIII (XII) (XIII) and partial hydrogenation according to Bull. Soc. Chim. France, 1952, p. 1046.
  • a further advantageous possibility for preparing the desired compounds comprises (e) reacting amines of the general Formula VI with ethylene-oxides of the general Formula VII, the reaction advantageously being performed in the presence of a solvent such as, for example, ethanol, and at an elevated temperature.
  • ketones or aldehydes of said type the following compounds may be used:
  • the reduction favorably proceeds by catalytic hydrogenation of equimolar amounts of the two compounds in the presence of an inert solvent.
  • catalysts metals of the 8th group of the Periodic System are used, preferably precious metals.
  • the most suitable solvents are those generally used for hydrogenation, for instance, alcohols, aqueous alcohols or water.
  • Nickel catalysts may likewise be used. It is likewise possible first to condense the oxo compounds of the Formula VIII with the amines of the Formula VI and then to reduce the condensation product with nascent hydrogen, for instance with aluminium amalgam and alcohol, sodium amalgam, lithium-aluminium-hydride or so dium boron-hydride. The reduction may likewise be carried out electrolytically.
  • the condensation is characterized by the fact that preferably the keto-group adjacent to the methyl group or the aldehyde group reacts with the amine; the other OX0 group may be reduced simultaneously or subsequently to the hydroxyl group in the manner mentioned sub (a).
  • An appropriate amine which may be used as starting substance for the reaction according to (e), is for example 3-phenyl-3-pyridyl(2)-propyl-amine.
  • a further possibility of preparing the products according to the invention consists in condensing phenylpyridyl(2)-propionaldehyde of the Formula 1X with amino-alcohols r amino-ketones of the Formula X according to the method described sub (f).
  • the reaction of the aldehydes with the amino alcohols with simultaneous or subsequent reduction is, in principle, carried out according to the method described sub (e) for the prepara tion of the products of the invention, by starting from 1- phenyl-3-amino-propanes of the Formula VI and 0x0- compounds of the general Formula VHI.
  • amino alcohols of the Formula X may likewise be used in which the hydroxy group is protected by an alkyl, benzyl or acyl radical 'which may subsequently be separated according to (b) or (c).
  • the products of the invention can be converted into the corresponding salts by means ofinorganic or organic acids.
  • inorganic acids there may be used: hydrohalic acid such as hydrochloric acid and hydrobrornic acid, sulfur acid, phosphoric acid and amidosulfonic acid.
  • organic acids the following are mentioned, for example: acetic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, maleic acid, succinic acid, tartaric acid, benzoic acid, salicylic acid, citric acid, aceturic acid, hydroxy-ethane-sulfonic acid and ethylene-diamine-tetracetic acid.
  • the products of the invention are valuable medicaments having a very favorable action on cardiac and blood vascular circulation.
  • a single injection of 5 of l-(3,4'-dimethylphenyl)-2-(m-methoxy-diphenylpropylamino)-propanol-( 1) in the test on the isolated heart of guinea pigs according to Langendorff causes an increase of the perfusion of the coronary vessels within the same range as that caused by administering 57 of the known compounds 1-phenyl-2-[3',3'-diphenyl-propyl- (1')-amino] -propane.
  • the advantage of the new products consists, however, above all, in that in addition to their dilating action on the coronary vessels they show an excellent B-sympathicolytic action.
  • fi-sympathicolytically active substances inhibit the effect of adrenalin and isopropyl-noradrenalin which consists in increasing the heart rate and the contracting power of the heart.
  • Adrenalin and isopropylnoradrenalin likewise activate cardiac metabolism indirectly and by the above-mentioned actions also directly.
  • An activation of the sympathetic nervous system starting at an unsuitable moment for which the two substances constitute a particular example, may cause anoxemia of the heart, particularly if the coronary vessels show constrictions (due to calcareous degeneration).
  • a fl-sympathicolytic action protects the heart against a high increase in metabolism.
  • the products of the present invention show a favorable hypotensive effect.
  • the 1-(3',4'-dimethylphenyl)-2-[phenylpyridyl-(2")-propylamino]-propanol l) hydrochloride lowers the blood pressure considerably and for a prolonged period in rats suffering from renal high pressure.
  • the combination of the 3 effects mentioned above imparts to the products of the present invention special advantages in comparison with the compounds hitherto known.
  • the products of the present invention are especially suitable for the treatment of hypertonia, since in hypertonics the dilatory action on the coronary vessels is of advantage, the heart of said patients showing a considerably increased mass of muscles 'which must be nourished. Furthermore, the hypertonic tends to arteriosclerosis of the cardiac coronary vessels the consequences of which may be compensated by a dilatation of the small vessels free from calcification.
  • the benzene is distilled off under reduced pressure, the residue is dissolved in methanol and 1 gram of sodium-boronhydride is added in small portions, causing a vivid reaction.
  • the product is allowed to stand for about 15 minutes, acidified by means of dilute hydrochloric acid and the methanol is distilled off under reduced pressure.
  • the residue is shaken with dilute sodium hydroxide solution and ether.
  • the ether phase is separated, dried by means of potassium carbonate and the ether is distilled off.
  • the residue is dissolved in a small amount of methanol and hydrochloric acid is added. After elimination of the solvent by distillation the residue is recrystallized from a mixture of acetone and ether.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US589816A 1965-06-05 1966-10-27 1-(3', 4'-di-lower-alkylphenyl)-2-[phenylpyridyl-(2')-propylamino]-propanol-(1) and derivatives thereof Expired - Lifetime US3414578A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEF0046262 1965-06-05
DEF0047601 1965-11-05

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US3414578A true US3414578A (en) 1968-12-03

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US (1) US3414578A (forum.php)
AT (8) AT275500B (forum.php)
BE (1) BE682140A (forum.php)
BR (1) BR6680181D0 (forum.php)
CH (4) CH464960A (forum.php)
DE (2) DE1493715A1 (forum.php)
DK (1) DK118407B (forum.php)
ES (1) ES327479A1 (forum.php)
FI (1) FI45184C (forum.php)
GB (1) GB1124838A (forum.php)
IL (1) IL25875A (forum.php)
NL (1) NL6607736A (forum.php)
NO (1) NO117860B (forum.php)
SE (1) SE348457B (forum.php)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4275198A (en) * 1980-07-18 1981-06-23 Carter-Wallace Inc. Method for preparing basic dithienyl compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4275198A (en) * 1980-07-18 1981-06-23 Carter-Wallace Inc. Method for preparing basic dithienyl compounds

Also Published As

Publication number Publication date
AT272312B (de) 1969-07-10
DE1493715A1 (de) 1969-06-19
BR6680181D0 (pt) 1973-12-26
NO117860B (forum.php) 1969-10-06
FI45184C (fi) 1972-04-10
ES327479A1 (es) 1967-10-16
DK118407B (da) 1970-08-17
SE348457B (forum.php) 1972-09-04
BE682140A (forum.php) 1966-12-06
DE1545869A1 (de) 1969-12-04
AT272311B (de) 1969-07-10
CH464960A (de) 1968-11-15
AT275501B (de) 1969-10-27
AT275500B (de) 1969-10-27
FI45184B (forum.php) 1971-12-31
AT277980B (de) 1970-01-12
GB1124838A (en) 1968-08-21
NL6607736A (forum.php) 1966-12-06
CH465645A (de) 1968-11-30
AT272314B (de) 1969-07-10
CH464961A (de) 1968-11-15
AT272310B (de) 1969-07-10
IL25875A (en) 1970-04-20
AT272313B (de) 1969-07-10
CH464962A (de) 1968-11-15

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