Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/12—Radicals substituted by oxygen atoms

Definitions

• the compounds are useful in the treatment of angina pectoris and heart rhythm disorders.
• R is lower alkyl of one to six carbon atoms
• cycloalkyl of three or four carbon atoms or 3-phenylp py R is methyl, hydroxymethyl, methoxymethyl, alkoxycarbonyl wherein the alkoxy group is of one to four carbon atoms or carboxyl,
• the preferred compounds of formula I, wherein R, is lower alkyl are those wherein the alkyl radical is branched or compact, especially those which are branched on the a carbon atom, e.g. the isopropyl, sec.butyl, tert.butyl, or 3-pentyl radical.
• an indole derivative of formula I is obtained by a. reacting a compound of formula Ila,
• R is methyl, hydroxymethyl, methoxymethyl or alkoxycarbonyl wherein the alkoxy group is of one to four carbon atoms, or a compound of formula IIb,
• R is lower alkyl of one to six carbon atoms
• R is methyl, ethyl, propyl, isopropyl or cyclopropyl when R, is alkoxycarbonyl
• R and R are lower alkyl
• R is methyl or ethyl, and R and R are as defined above,
• R is hydrogen and R is phenethyl, 1 5 to obtain a compound of formula If,
• R and Alk are as defined above, or
• an inert organic solvent e.g. an aromatic hydrocarbon such as benzene or toluene, or in a wherein R," and R are as defined above, or cyclic ether such as dioxane, and has a duration of f. reducingacompound of formula Vlll, about 2 to 24 hours.
• the reaction temperature may range between 20 and 15C; the reaction is 0H preferably effected at the boiling temperature of the reaction mixture under reflux.
• Y preferably signifies CHQNRRI chlorine or bromine.
• the debenzylation of the compounds of formula 000R VH1 1V is conveniently effected by hydrogenation in H A. the presence of a catalyst, preferably a palladium catalyst, in an inert organic solvent, e.g. ethyl wherein R,"', R R and R are as defined above, in acetate, a cyclic or open chain ether such as the presence of a catalyst and a lower alkanol of the tetrahydrofuran, or a lower alkanol such as formula AlkOH, wherein Alk is as defined above, to
• Acid addition salts or salts of resulting free bases may be produced in conventional manner by reaction with an acid, and free bases may be liberated from salts by 35 treatment with a base.
• the production of the new compounds may, for example, be efiected as follows:
• reaction of a compound of formula ll with a compound of formula lll is preferably effected in methanol or ethanol. Hydrogenation if preferably effected at room temperature and normal pressure. After hydrogenation is complete, the catalyst is filtered off.
• the reduction of a compound of formula VI to a compound of formula Ic is likewise preferably effected in the presence of a palladium catalyst, conveniently at room temperature and normal pressure.
• a suitable metal catalyst preferably a palladium catalyst
• an inert organic solvent e.g.
• ethyl acetate or a lower alkanol such as methanol.
• an imine of formula IX is taken up in an inert organic solvent, e.g. a lower alkanol such as methanol, and solid sodium borohydride is added portionwise.
• an inert organic solvent e.g. a lower alkanol such as methanol
• Hydrolysis of a 2-alkoxycarbonyl compound of formula I to the corresponding 2-carboxyl compound of formula I may, for example, be effected with aqueous alcoholic solutions of an excess of an alkali metal or alkaline earth metal hydroxide, e.g. sodium, potassium or barium hydroxide.
• an alkali metal or alkaline earth metal hydroxide e.g. sodium, potassium or barium hydroxide.
• Lower alkanols such as methanol or ethanol are preferably used as alcohols.
• Hydrolysis may, for example, likewise be effected with an alkaline ion exchange resin.
• Reduction of a 2-alkoxycarbonyl compound of formula I to the corresponding Z-hydroxymethyl compound may, for example, be effected with a complex aluminum hydride such as lithium aluminum hydride or sodium dihydro-bis-(2-methoxyethoxy)aluminate, in an inert organic solvent,.e.g. a cyclic or open chain ether such as tetrahydrofuran, preferably at the boiling temperature of the reaction mixture, and has a duration of one-half to several hours.
• the reaction mixture may be worked up by adding, e.g. water or a lower alkanol, removing the resulting precipitate by filtration and separating the organic phase.
• the precipitate is subsequently washed out with an inert organic solvent, and the combined organic phases are dried, e.g. over sodium sulphate. Upon concentrating the organic phase by evaporation, the Z-hydroxymethyl compound of formula 1 is obtained as residue.
• the reduction may, for example, likewise be effected in accordance with the procedure of Bouveault-Blanc with sodium in alcohol.
• the reaction mixture obtained in accordance with the above embodiments of the process may, for example, be worked up by concentrating it by evaporation, shaking out the residue between an aqueous acid, e.g. l N tartaric acid or 1 N hydrochloric acid, and a inert organic solvent which is not miscible with the acid, such as ethyl acetate, making the acid aqueous phase neutral, e.g. with an aqueous sodium carbonate solution,taking up the liberated basic product in an inert organic solvent such as methylene chloride, separating and drying the organic phase and finally concentrating the same by evaporation, preferably at reduced pressure.
• an aqueous acid e.g. l N tartaric acid or 1 N hydrochloric acid
• a inert organic solvent which is not miscible with the acid
• ethyl acetate e.g. with an aqueous sodium carbonate solution
• an inert organic solvent such as methylene chloride
• a compound of formula II may, for example, be produced by reacting a compound of formula X,
• R is as defined above, with an epihalohydrin, preferably epichlorhydrin or epibromhydrin.
• the compound of formula X is preferably employed in the reaction inthe form of its ammonium or alkali metal salt, e. g. as sodium salt, with the epihalohydrin, conveniently in the absence of oxygen or alternatively in the presence of a base such as piperidine.
• This reaction may, for example, be effected as follows:
• One to three equivalents of a compound of formula XI are added to a solution or a suspension of a compound of formula X or its alkali metal or ammonium salt, e.g. the sodium salt of a compound of formula X.
• the reaction may, for example, be effected by stirring the mixture for an extended period, e.g. about 1 to 24 hours, while heating to 20 to l20C, preferably in the absence of oxygen.
• the compounds of formula Xla may be produced in accordance with known processes, e.g. by treatment of a compound of formula Xlb with an alkali.
• the compounds of formula Xlb may, for example, be obtained by reacting an amine of formula Xlll,
• reaction of a compound of formula Xll with a compound of formula X] may be effected in a manner analogous to that described for the production of compounds of formula IV.
• the compounds of formula Vll (including the compounds of formula Vlll) are likewise new.
• a compound Vll may be obtained in a manner analogous to the method for obtaining a compound of formula V, by aminomethylation of a compound of formula XlV,
• a compound of formula XIV, used as starting material for this reaction may be produced from a compound of formula Xll by reaction with an epihalohydrin (in a manner analogous to the production of a compound of formulas lla and llb) and treatment of the resulting reaction product with the corresponding amine (in a manner analogous to embodiment a) above).
• a compound [X may, for example, be produced by debenzylating a compound of formula XV,
• a compound of formula XV may be produced from a compound of formula X as described in process a).
• the compounds of formula X are new, and such compound may, for example, be produced by aminomethylation of a compound of formula XVll,
• Aminomethylation may be effected under the conditions of a Mannich reaction. Hydrogenation of a compound of formula XVlll may, for example, be effected as described in process b).
• a compound of formula Xll may, for example, be obtained by hydrogenolytic debenzylation of a compound of formula XVII.
• 4-Benzyloxy-Z-hydroxymethyl indole may be produced by reduction of 4-benzyloxyindole-2-carboxylic acid, e.g. with lithium aluminum hydride or sodium dihydro-bis-( 2-methoxyethoxy) aluminate, in an inert organic solvent such as dioxane or benzene.
• 4-Benzyloxy-2-methoxymethyl indole may, for example, be obtained by etherifying 4-benzyloxy-2- hydroxymethyl indole with diazomethane in the presence of boron trifluoride in an inert organic solvent, eg a cyclic or open chain ether such as diethyl ether.
• an inert organic solvent eg a cyclic or open chain ether such as diethyl ether.
• esters may be obtained by esterification of 4-benzyloxyindole-2-carboxylic acid, in accordance with conventional processes.
• the compounds of formula I and pharmaceutically acceptable acid addition salts thereof are useful because they possess pharmacological activity in animals. More particularly, the compounds are useful in the treatment of angina pectoris and heart rhythm disorders, including tachycardia, as indicated by their B-blocking activity (blocking effect on the vascular, adrenergic B-receptors). The activity is illustrated by an inhibition of the positive inotropic adrenalin effect on the spontaneously beating guinea pig atrium and also by an inhibition of the hypotension caused by isoproterenol l-( 3 ,4-dihydrxyphenyl )-2- isopropylamine-ethanol] in the narcotized cat.
• the dosage administered will naturally vary depending on the compound employed, the mode of administration and the treatment desired. However, in general, satisfactory results are obtained at doses between about 0.004 and 0.6 mg/kg animal body weight.
• the total daily dose is in the range of from about to about 100 milligrams of the compound.
• the daily dose may be given in divided doses two to three times a day, or in sustained release form.
• Dosage forms suitable for oral administration comprise from about L5 to about 50 milligrams of the compound admixed with a solid or liquid pharmaceutical carrier or diluent.
• the reaction mixture is stirred at room temperature for a further 24 hours, is extracted four times with methylene chloride, and the combined organic layers which have been dried over magnesium sulphate are concentrated by evaporation at reduced pressure.
• the resulting oily residue of 2,3-dimethyl-4- 2,3-epoxypropoxy)indole, without characterization, is heated to the boil for hours with 30 cc of isopropylamine in 70 cc of absolute dioxane.
• the reaction mixture is subsequently evaporated to dryness at reduced pressure, the residue is shaken out thrice between ethyl acetate and a l N tartaric acid solution, and 5 N sodium hydroxide solution is added to the combined tartaric acid phases until an alkaline reaction is obtained.
• 4-Benzyloxyindole-2-carboxylic acid dimethyl amide is reduced in boiling tetrahydrofuran with lithium aluminum hydride to 4-benzyloxy-Z-dimethylaminomethyl indole (M.P. ll6-l 18). Quaternization of this compound with methyl iodide and subsequent deamination with lithium aluminum hydride in boiling dioxane yields 4-benzyloxy-2-methyl indole (prisms from ether/petroleum ether with a MP.
• EXAMPLE 3 4-[ 2-l-lydroxy-3-( 3-pentylamino)propoxy1-3-methylindole-2-carboxylic acid ethyl ester [process a)]
• the title compound is obtained as a viscous oil in a manner analogous to that described in Example l or 2, from 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester, using 3-pentylamine in place of isopropylamine; the hydrogen maleate of the title compound crystallizes from ethanol/ether in cubes having a MP. of 153-l 55
• the 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester, used as starting material, is produced as follows:
• 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester is either produced directly with hydrogen in the presence of a palladium catalyst (5 percent Pd on charcoal), or the methiodide of the above Mannich base is reduced in ethanolic solution with sodium borohydride to give 4- benzyloxy-3-methylindole-2-carboxylic acid ethyl ester (M.P. l49150 from benzene in cubes), and this is subsequently debenzylated with hydrogen in the presence of a palladium catalyst (5 percent Pd on charcoal), to give 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester M.P. l60-l 62 from ethanol).
• the catalyst is filtered off, the filtrate is evaporated to dryness at reduced pressure and worked up as described in Example 1 to obtain the compound of the heading.
• l-( N-Benzylisopropylamino )-3-chloro-2-propanol may, for example, be produced as follows:
• EXAMPLE 6 4-[2-Hydroxy-3-( 3-pentylamino)propoxy]-3-methylindole-2-carboxylic acid ethyl ester [process g)]
• the title compound (M.P. 153-l 55) is produced in a manner analogous to the process described in Example 5, from 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester M.P. l60-162).
• EXAMPLE 7 4-( 2-Hydroxy-3-isopropylaminopropoxy-2-hydroxymethyl-3-methyl indole [process 0)] 55.5 g of 4-( 2-hydroxy-3-isopropylaminopropoxy)- 2-hydroxymethyl indole are heated to the boil for 8 hours with 38 g of benzyl bromide and 22.3g of triethylamine in 1.3 liters of tetrahydrofuran. The reaction mixture is evaporated to dryness and the residue is shaken out between methylene chloride and a l N tartaric acid solution.
• the pH of the combined tartaric acid phases is adjusted to 8 to 9 with a 10 percent soda solution, while cooling with ice, and are extracted 4 times with 200 cc amounts of methylene chloride. After drying the methylene chloride phases over magnesium sulphate, these are concentrated by evaporation at reduced pressure. The crude product is subsequently crystallized with ethanol and yields 4-(3- benzylisopropylamino-Z-hydroxypropoxy)-2-hydroxymethyl indole having a MP. of 133-l 36.
• the combined tartaric acid extracts are made alkaline with a 5 N sodium hydroxide solution, while cooling with ice, and are extracted with methylene chloride.
• the evaporation residue of the methylene chloride extracts is crystallized with ethanol/petroleum ether, whereby 3-dimethylaminomethyl-4-( 3- benzylisopropylamino-Z-hydroxypropoxy)-2-hydroxymethyl indole is obtained in the form of crystals having a MP. of l39-l40.
• the 2-hydroxymethyl-4-( 2-hydroxy-3- isopropylaminopropoxy)indole, used as starting material may, for example, be produced as described in Example 1, from 4-hydroxy- 2-hydroxymethy1 indole by reaction with epichlorhydrin and subsequent reaction of the reaction product with isopropylamine.
• 4-Hydroxy-2-hydroxymethyl indole (MP 1 12-1 14 from benzene/ethyl acetate) is obtained by debenzyla- EXAMPLE 8 4-( 3-Cyclopropylamino-2-hydroxypropoxy )-3- methylindole-2-carboxylic acid ethyl ester [process c)] 4-( 3-Benzylocyclopropylamino-2-hydroxypropoxy)- 3-dimethylaminomethylindole-Lcarboxylic acid ethyl ester is obtained in a manner analogous to that described in Example 7 by aminomethylation from 4- 3-benzylcylopropylamino-2-hydroxypropoxy)indole- 2-carboxylic acid ethyl ester (M.P.
• the compound is isolated by chromatography (silica gel with methylene chloride and 2 percent of methanol) and is taken up in 70 cc of ethanol without further purification and is shaken with hydrogen in the presence of 2 g of a palladium catalyst (5 percent Pd on charcoal) until the taking up of hydrogen is complete.
• the catalyst is filtered off, the filtrate is acidified with an excess of a 2 N solution of hydrochloric acid in ethanol and is concentrated by evaporation at reduced pressure until crystallization commences.
• the hydrochloride of the title compound crystallizes in fine needles having a M.P. of 228-231.
• 4-( 3-Benzylcyclopropylamino-2-hydroxypropoxy)indole-2-carboxylic acid ethyl ester (M.P. 125127 from benzene) is obtained in accordance with Example 3, by using 4-hydroxyindole-2-carboxylic acid ethyl ester in place of 4-hydroxy-3-methylindole-2-carboxylic acid ethyl ester and benzylcyclopropylamine in place of 3-pentylamine.
• 4-Hydroxyindole-2-carboxylic acid ethyl ester (M.P. l59l60) is obtained by catalytic debenzylation with palladium/hydrogen of 4-benzyloxyindole-2-carboxylic acid ethyl ester.
• EXAMPLE 9 4-( 2-Hydroxy-3-isopropylaminopropoxy)-3-methylindole-2-carboxylic acid methyl ester [process d)] 14.9 g of 4-( 3-benzylisopropylamino-2-hydroxypropoxy)-indole-2-carboxylic acid ethyl ester are dissolved in methanol, an excess of a 2 N solution of hydrochloric acid in methanol is added and the solution is concentrated by evaporation.
• Example 8 4-(3-Benzylisopropylamino-2-hydroxypropyl)indole12-carobxylic acid ethyl ester (M.P. l03-l05) is obtained as indicated in Example 8 for the production of 4-( 3-benzylcyclopropylamino-2-hydroxypropoxy)indole-2-carboxy1ic acid ethyl ester, except that benzylisopropylamine is used in place of benzylcyclopropylamine.
• EXAMPLE 10 4-(3-tert.butylamino-2-hydroxypropoxy)-3-methylin dole-2-carboxylic acid ethyl ester [process e)] 5.7 g of glacial acetic acid are added to a solution of 10.8 g of 4-( 3-tert.butylamino-2-hydroxypropoxy)indole-2-carboxy1ic acid ethyl ester in 500 cc of ethanol, while stirring and cooling with ice, 8.8 g of a 33 percent solution of dimethylamine in ethanol are then added and 4.0 g of a 36 percent aqueous solution of formaldehyde are finally added.
• reaction mixture is allowed to react at room temperature for 4 days, is then concentrated by evaporation at reduced pressure, and the basic components are isolated in the usual manner by extraction between ether/1 N tartaric acid. Chromatography on 50 parts of water-saturated silica gel with methylene chloride and 0.5 percent of methanol yields 4-(3tert.butylamino-Z-hydroxypropoxy)-3- dimethylaminomethylindole-2-carboxylic acid ethyl ester M.P. 139-l 40 from ethyl acetate.
• the ester used as starting material is obtained by reacting 4-hydroxyindole-2-carboxylic acid ethyl ester as indicated in Example 1 or 2with epichlorhydrin, reacting the reaction product with cyclopropylamine and aminomethylating the resulting 4-( 3- cyclopropylamino-2-hydroxypropoxy)indo1e-2-carboxylic acid ethyl ester M.P. l47).
• EXAMPLE 12 4-(2-l-lydroxy-3-isopropylaminopropoxy)-3-methylindole-2carboxylic acid (Hydrolysis of compound of Example 9) 4.6 g of 4-( 2-hydroxy-3-isopropylaminopropoxy)-3- methylindole-2-carboxylic acid methyl ester are heated to the boil while stirring for 2 hours with 4.55 g of crystalline barium hydroxide in 60 cc of methanol and 185 cc of water. l4.2 cc of 2 N sulphuric acid are subsequently added, the reaction mixture is filtered through talc until clear and is washed well with boiling water. After concentrating the filtrate, the title compound crystallizes in white crystals having a MP. of 27 l-273 (decomp.).
• the 4-hydroxy-2-hydroxymethyl-3-methyl indole, used as starting material, may, for example, be produced as follows:
• 4-Benzyloxy-2-hydroxymethyl indole is converted with formaldehyde, dimethylamine and glacial acetic acid in ethanolic solution into 4-benzyloxy-2-hydroxymethyl gramine (M.P. l27l29, crystallization from ethanol), and reduction is subsequently effected with hydrogen in the presence of a palladium catalyst percent Pd on charcoal), to give 4-hydroxy-2-hydroxymethyl-3-methyl indole.
• M.P. l35l36 from ethyl acetate.
• 4-Hydroxy-2-hydroxymethyl-3-methyl indole may likewise be obtained by converting 4-benzyloxyindole- 2-carboxylic acid ethyl ester in accordance with the above Mannich process into 4-benzyloxy-3- dimethylaminomethylindole-2-carboxylic acid ester (M.P. of the hydrochloride 205207, crystallization from ethanol), quaternizing the resulting ester with methyl iodide to the methiodide, reducing this with lithium aluminum hydride in tetrahydrofuran to 4- benzyloxy-2-hydroxymethyl-3-methyl indole (M.P. l29-l3l from methylene chloride), and finally debenzylating with hydrogen in the presence of a palladium catalyst 5 percent Pd on aluminum oxide).
• Example 14 The title compound which is identical with the compound produced in Example 14, is obtained in a manner analogous to that described in Example 14, except that 4-(2-hydroxy-3-isopropylaminopropoxy)-3- methylindole-2-carboxylic acid is used in place of 4-(2- hydroxy-3-isopropylaminopropoxy)-3-methylindole-2- carboxylic acid methyl ester.
• the 4-( 2-hydroxy-3-isopropylaminopropoxy)-3- methylindole-2-carboxylic acid, required as starting material, is, for example, produced as described in Example 12.

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Indole Compounds (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (5)

Publications (1)

Family

ID=27509196

Family Applications (1)

Country Status (8)

Cited By (8)

Families Citing this family (3)

Citations (1)

Family Cites Families (3)

• 0
  • BE BE754360D patent/BE754360A/xx unknown
• 1970
  • 1970-07-20 GB GB3509970A patent/GB1318050A/en not_active Expired
  • 1970-07-28 US US58985A patent/US3696120A/en not_active Expired - Lifetime
  • 1970-08-03 DE DE19702038482 patent/DE2038482A1/de not_active Ceased
  • 1970-08-03 PL PL1970142487A patent/PL81365B1/pl unknown
  • 1970-08-03 SE SE10622/70A patent/SE369522B/xx unknown
  • 1970-08-04 FR FR7028683A patent/FR2068461B1/fr not_active Expired
  • 1970-08-04 JP JP45068283A patent/JPS5022555B1/ja active Pending

Patent Citations (1)

Also Published As

Similar Documents