EP0000355A1 - New indole derivatives, processes for their preparation, and pharmaceutical compositions containing them. - Google Patents

New indole derivatives, processes for their preparation, and pharmaceutical compositions containing them. Download PDF

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Publication number
EP0000355A1
EP0000355A1 EP78100274A EP78100274A EP0000355A1 EP 0000355 A1 EP0000355 A1 EP 0000355A1 EP 78100274 A EP78100274 A EP 78100274A EP 78100274 A EP78100274 A EP 78100274A EP 0000355 A1 EP0000355 A1 EP 0000355A1
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alkyl
hydrogen
compound
formula
alkoxy
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EP0000355B1 (en
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Paul Dr. Stadler
Franz Dr. Troxler
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Sandoz AG
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Sandoz AG
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    • 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
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • 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
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to new indole derivates, processes for their preparation, and pharmaceutical compositions containing them.
  • Any alkyl, alkoxy or alkylthio radical contains preferably two carbon atoms, especially one carbon atom.
  • Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
  • A is 1,4-cyclohexylidene
  • this may be cis or trans-l,4-cyclohexylidene.
  • A is optionally substituted trimethylene, this is preferably either unsubstituted or monosubstituted, conveniently at the middle carbon atom.
  • R 1 and R 2 are chosen from hydrogen or alkyl, these are preferably alkyl.
  • A is optionally substituted trimethylene or 1,4-cyclohexylidene.
  • A is optionally substituted trimethylene.
  • R 3 When R 3 is or contains a dialkylamino radical, the alkyl groups are preferably the same.
  • R 3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical. Conveniently these radicals are unsubstituted or monosubstituted preferably in the para position.
  • R 3 is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl. Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
  • R 3 is preferably unsubstituted phenyl.
  • R 4 and R 5 are conveniently hydrogen.
  • X is conveniently -CO-.
  • the present invention provides a process for the production of a compound of formula I as defined above, which comprises
  • Process a) may be effected in conventional manner for the production of amides or thio-amides from amines.
  • acylating agent a compound of formula V wherein X is as defined above, R 3 ' has the same signification as R 3 but is other than amino, alkylamino and optionally substituted phenylamino and Z is chlorine or bromine.
  • the reaction may be effected conveniently in a solvent such as pyridine and at temperatures from O to 25°.
  • R 3 is amino, alkylamino or optionally substituted phenylamino
  • a compound of formula VI wherein X is as defined above and R 6 is imino, alkylimino or optionally substituted phenylimino.
  • the reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25°.
  • a compound of formula VI wherein R 6 is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.
  • Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine.
  • Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy.
  • the reaction may be conveniently effected in acetone or dimethylformamide. Suitable reaction temperatures are from 20 to 150°.
  • the compounds of formula I may be isolated from the reaction mixture and purified in known manner.
  • the free base forms may be converted into acid addition salt forms in the usual manner and vice versa.
  • Suitable acids for salt formation are hydrochloric acid, oxalic acid, fumaric acid naphthalene-2-sulphonic acid and naphthalene-l,5-disulphonic acid.
  • the starting material of formula II may be produced from a compound of formula III and a compound of formula VII wherein A, R 1 and R 2 are as defined above, in analogous manner to process b).
  • the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the R 1 substituent.
  • the amine may be used in protected form of formula VIII wherein R 7 is a protecting group, such as benzyl or benzyloxy, which may be removed from the resulting product, e.g. by hydrogenolysis.
  • a starting material of formula IIa wherein A I is or and wherein R 8 is (C 1-4 )alkyl and n, R 2 , R 4 and R 5 are as defined above, may alternatively be produced by reducing a compound of formula IX wherein B is -CH(R 8 )-CH 2 - or -CH 2 -CH(R 8 )-and n, R 2 , R 4 , R 5 and R 8 are as defined above, e.g. by hydrogenation in the presence of Raney-nickel.
  • Any starting material of formula II wherein R 1 and/or R 2 is hydrogen may be converted into a corresponding compound wherein R 1 and R 2 are both alkyl, or R 1 is alkyl and R 2 is hydrogen under appropriate selective alkylation conditions.
  • the starting material of formula IV may be produced by acylating an amine of formula VII in analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.
  • a starting material of formula IVa wherein X, R 2 and R 3 are as defined above and A II together with R 1 and the nitrogen atom to which R 1 is bound, form a 4-piperidyl radical may alternatively be produced by acylating 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X wherein X and R 3 are as defined above, with a compound of formula XI wherein R 2 is as defined above, under simultaneous reduction, e.g. with hydrogen in presence of a catalyst.
  • the starting material may be obtained as follows :
  • the starting material may be obtained as follows:
  • the compounds of formula I exhibit pharmacological activity in animals.
  • the compounds exhibit anti-hypertensive activity, as indicated by standard tests, e.g. in the awake renal hypertonic Grollman rat upon administration of 1 to 50 mg/kg animal body weight of the compounds, and in the awake renal hypertonic Goldblatt dog upon administration of 1 to 10 mg/kg animal body weight of the compounds.
  • an indicated daily dose is from about lO to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about2,5 to about 1000 mg, or in sustained release form.
  • a particularly interesting compound is the
  • the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts exhibit the same order of activity as the free base forms.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent.
  • a suitable pharmaceutical form is a capsule.
  • A is trimethylene
  • R 1 is hydrogen or (C 1-5 )alkyl
  • R 2 is hydrogen or (C 1-5 )alkyl
  • R 3 is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C 1-4 )alkyl, (C 1-4 )alkoxy or di-(C 1-4 )alkylamino; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur
  • R 4 is hydrogen, chlorine, bromine or (C 1-4 )alkyl
  • R 5 is hydrogen, (C 1-4 )alkyl, (C 1-4 )alkoxy, or (C 1-4 )alkylthio
  • X is -CO-.
  • n 2
  • A is trimethylene and R 1 is hydrogen or (C 1-5 ) alkyl, or A together with R 1 and the nitrogen atom to which R 1 is bound form a 4-piperidyl radical
  • R 2 is hydrogen or (C 1-5 )alkyl
  • R 3 is (C 1-4 )alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C 1-4 )alkyl or (C 1-4 )alkoxy; (C 3-6 )cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur
  • R 4 is hydrogen, chlorine, bromine or (C 1-4 )alkyl
  • R S is hydrogen, (C 1-4 )alkyl or (C 1-4 )alkoxy
  • X is -CO- or -CS.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Indole compounds useful for the treatment of hypertension, of formula
Figure imga0001
wherein n is 2 or 3, A is 1,4-cyclohexylidene or trimethylene and R, is H or alkyl, or A together with NR, is 4-piperidyl, R2 is hydrogen or alkyl, R3 is alkyl, cycloalkyl, amino, alkylamino, dialkylamino, phenylamino, unsubstituted or substituted phenyl or benzyl, pyridylmethyl or an heterocycle, R4 is hydrogen, chlorine, bromine or alkyl, Rs is hydrogen, alkyl, alkoxy or alkylthio, and X is -CO- or -CS, a process for their production which comprises
  • a) acylating a compound of formula II
    Figure imga0002
    wherein n, A and R, to R5 are as defined above, or
  • b) condensing a compound of formula III
    Figure imga0003
    wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compound of formula IV
    Figure imga0004
    wherein A, R, to R3 and X are as defined above.

Description

  • The present invention relates to new indole derivates, processes for their preparation, and pharmaceutical compositions containing them.
  • In accordance with the inventionthere are provided new compounds of formula I
    Figure imgb0001
    wherein n is 2 or 3,
    • either A is trimethylene optionally substituted by (C1-4) alkyl or 1,4-cyclohexylidene and R1 is hydrogen or (C1-5) alkyl, or A together with R1 and the nitrogen atom to which R1 is bound, form a 4-piperidyl radical,
    • R2 is hydrogen or (C1-5) alkyl,
    • R 3 is (C1-4) alkyl; (C3-6)cycloalkyl; amino; (Cl-4)alkylamino; di(C1-4)alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1-4)alkyl, (C1-4)alkoxy or di(Cl-4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C1-4) alkyl, (C1-4)alkoxy or di-(C1-4)alkylamino; 2-,3- or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur and optionally additional one or two nitrogen atoms,
    • R4 is hydrogen, chlorine, bromine or (C1-4)alkyl,
    • R5 is hydrogen, (Cl-4)alkyl, (C1-4)alkoxy or (C1-4)alkylthio, and X is -CO- or -CS-.
  • Any alkyl, alkoxy or alkylthio radical contains preferably two carbon atoms, especially one carbon atom. Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
  • When A is 1,4-cyclohexylidene, this may be cis or trans-l,4-cyclohexylidene.
  • When A is optionally substituted trimethylene, this is preferably either unsubstituted or monosubstituted, conveniently at the middle carbon atom.
  • When R1 and R2 are chosen from hydrogen or alkyl, these are preferably alkyl.
  • Conveniently A is optionally substituted trimethylene or 1,4-cyclohexylidene. Preferably A is optionally substituted trimethylene.
  • When R3 is or contains a dialkylamino radical, the alkyl groups are preferably the same. When R3 is an optionally substituted phenyl or phenylamino radical, the substituents are conveniently identical. Conveniently these radicals are unsubstituted or monosubstituted preferably in the para position. When R3 is a heterocycle, conveniently this contains one heteroatom chosen from nitrogen, oxygen or sulphur and optionally a second nitrogen atom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl. Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
  • R3 is preferably unsubstituted phenyl.
  • R4 and R5 are conveniently hydrogen. X is conveniently -CO-.
  • The present invention provides a process for the production of a compound of formula I as defined above, which comprises
    • a) acylating a compound of formula II
      Figure imgb0002
      wherein n, A and R1 to R5 are as defined above, or
    • b) condensing a compound of formula III
      Figure imgb0003
      wherein n, R4 and R5 are as defined above, and Y is a leaving group, with a compound of formula IV
      Figure imgb0004
      wherein A, R1 to R3 and X are as defined above.
  • Process a) may be effected in conventional manner for the production of amides or thio-amides from amines. For example there may be used, as acylating agent, a compound of formula V
    Figure imgb0005
    wherein X is as defined above, R3' has the same signification as R3 but is other than amino, alkylamino and optionally substituted phenylamino and Z is chlorine or bromine. The reaction may be effected conveniently in a solvent such as pyridine and at temperatures from O to 25°. Alternatively when R3 is amino, alkylamino or optionally substituted phenylamino, there may be used a compound of formula VI
    Figure imgb0006
    wherein X is as defined above and R6 is imino, alkylimino or optionally substituted phenylimino. The reaction may be effected conveniently in a solvent such as dimethylformamide and at temperatures from 5 to 25°. A compound of formula VI wherein R6 is imino may be prepared in situ from potassium or sodium cyanate or thiocyanate, by treatment with acid , for example hydrochloric acid.
  • Process b) may be effected in conventional manner for a condensation reaction to produce a secondary or tertiary amine. Y is conveniently chlorine, bromine, iodine, tosyloxy or mesyloxy. The reaction may be conveniently effected in acetone or dimethylformamide. Suitable reaction temperatures are from 20 to 150°.
  • The compounds of formula I may be isolated from the reaction mixture and purified in known manner. The free base forms may be converted into acid addition salt forms in the usual manner and vice versa. Suitable acids for salt formation are hydrochloric acid, oxalic acid, fumaric acid naphthalene-2-sulphonic acid and naphthalene-l,5-disulphonic acid.
  • The starting material of formula II may be produced from a compound of formula III and a compound of formula VII
    Figure imgb0007
    wherein A, R1 and R2 are as defined above, in analogous manner to process b).
  • When the amine of formula VII is unsymmetrical, the conditions should be chosen to avoid the formation of the undesired corresponding compound produced by condensation at the nitrogen atom bearing the R1 substituent. For this purpose the amine may be used in protected form of formula VIII
    Figure imgb0008
    wherein R7 is a protecting group, such as benzyl or benzyloxy, which may be removed from the resulting product, e.g. by hydrogenolysis.
  • A starting material of formula IIa
    Figure imgb0009
    wherein AI is
    Figure imgb0010
    or
    Figure imgb0011
    and wherein R8 is (C1-4)alkyl and n, R2, R4 and R 5 are as defined above, may alternatively be produced by reducing a compound of formula IX
    Figure imgb0012
    wherein B is -CH(R8)-CH2- or -CH2-CH(R8)-and n, R2, R4, R5 and R8 are as defined above, e.g. by hydrogenation in the presence of Raney-nickel.
  • Any starting material of formula II wherein R1 and/or R2 is hydrogen may be converted into a corresponding compound wherein R1 and R2 are both alkyl, or R1 is alkyl and R2 is hydrogen under appropriate selective alkylation conditions.
  • The starting material of formula IV may be produced by acylating an amine of formula VII in analogous manner to process a). If desired, one nitrogen atom of an unsymmetrical amine may be protected to facilitate production of the desired product.
  • A starting material of formula IVa
    Figure imgb0013
    wherein X, R2 and R3 are as defined above and AII together with R1 and the nitrogen atom to which R1 is bound, form a 4-piperidyl radical, may alternatively be produced by acylating 4-piperidone with a compound of formula V or VI and condensing the resulting compound of formula X
    Figure imgb0014
    wherein X and R3 are as defined above, with a compound of formula XI
    Figure imgb0015
    wherein R2 is as defined above, under simultaneous reduction, e.g. with hydrogen in presence of a catalyst.
  • Insofar as the production of any starting material is not particularly described, these are known or may be produced in conventional manner or in a manner analogous to that described above.
  • In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
    • EXAMPLE 1 N-benzoyl-N'-[3-(3-indolyl) Propyl]-N'- methyl-1,3-diaminopropane
  • A solution of 10.1 g benzoyl chloride in 15 ml anhydrous methylene chloride is added dropwise with stirring for 25 minutes between 0 and 10° to a solution of 14.5 g N-[3-(3-indolyl)propyl]-N-methyl-l,3-diaminopropane in 150 ml anhydrous pyridine and the reddish clear solution is stirred for 2 hours at O°. The reaction mixture is divided between a 2N sodium carbonate solution and methylene chloride, and the organic phase is washed, dried and evaporated. Chromatographic purification of the resinous product on aluminium oxide using methylene chloride with 0.1 to 0.3% of methanol yields the title coumpound. The naphthalene-2-sulfonate-dihydrate, obtained by conventional methods, melts at 73-74° after crystallization from methanol/water/ethyl acetate (1:1:1).
  • The starting material may be obtained as follows :
    • a) A mixture of 57 g trifluoroacetic acid and 105 g trifluoroacetic anhydride in 400 ml anhydrous acetonitrile are added dropwise to a stirred suspension of 95.1 g 3-(3-indolyl)propionic acid in 500 ml anhydrous acetonitrile and maintained with stirring at -15° for 30 minutes. Under good cooling 500 ml anhydrous pyridine are added between -20 and -15° and quickly 238 ml of a 4.2 N solution of anhydrous methylamine in acetonitrile. The mixture is warmed with stirring at O° for 15 minutes and maintained to O° for 3 hours. 3-(3-indolyl)-N-methyl-propionamide (M.pt 97-98° after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
    • b) A solution of 60.6 g 3-(3-indolyl)-N-methyl-propiona- mide in 500 ml anhydrous tetrahydrofuran are added dropwise at 25° for 15 minutes under nitrogen atmosphere to a suspension of 34.2 g lithium aluminium hydride in 800 ml anhydrous tetrahydrofuran and maintained at 66° for 3 hours. N-methyl-3-(3-indolyl)-propylamine (M.pt 81-82° after crystallization from methylene chloride/ethyl acetate) is obtained after working up.
    • c) A mixture of 37.6 g N-methyl-3-(3-indolyl)-propylamine and 21,2 g acrylonitrile in 65 ml anhydrous 1,2-dimethoxyethane are warmed with stirring at 60° for 2 1/2 hours.N-(2-cyanoethyl)-N-methyl-3-(3-indolyl)propylamine (M.pt 48-49° after crystallization from isopropyl ether) is obtained after working up.
    • d) 36.2 g N-(2-cyanoethyl)-N-methyl-3-(3-indolyl)propyl amine are hydrogenated at normal pressure and at room temperature with 20 g Raney-nickel catalyst in 400 ml dioxan and 400 ml of a 10% ammonia solution. N-[3-(3-indolyl)propyl]-N-methyl-l,3-diaminopropane is obtained after working up. M.pt of the neutral fumarate:180-181° (with decomposition) after crystallization from ethanol.
  • From the appropriate compounds of formula II the following compounds of formula I wherein X is -CO- may be obtained in analogous manner to Example 1.
    Figure imgb0016
    Figure imgb0017
    Figure imgb0018
    Figure imgb0019
    • EXAMPLE 2: N-henlcarbamol-N'-[2-(3-indolyl)ethyl]-N'- methyl-1,3-diaminopropane
  • 3 ml phenyl isocyanate are added dropwise between 5 and 10° and with stirring to a solution of 5.8 g N-[2-(3- indolyl) ethyl]-N-methyl-1,3-diaminopropane in 25 ml anhydrous dimethylformamide. The solution is stirred for an hour between 10 and 15° and evaporated. The residue is dried in high vacuum and chromatographied on silicagel using methylene chloridewith 6 to 10% methanol,to yield the title compound (M.pt. of the hydrogen maleate 153-155° with decomposition after crystallization from alcohol/acetone).
  • The starting material may be obtained as follows:
    • a) Reaction of 3-[2-methylamino)ethyl]indole with acrylonitrile in dimethoxy-ethane yields the N-(2-cyanoethyl)-N-methyl-2-(3-indolyl)ethylamine which is worked up further directly.
    • b) Reduction of N-(2-cyanoethyl)-N-methyl-2-(3-indolyl)-ethylamine with Raney-Nickel catalyst yields the N-[2-(3-indolyl)ethyl]-N-methyl-1,3-diaminopropane (M.pt. of the fumarate 153-154°).
    EXAMPLE 3: N-Benzoyl-N'-[2-(3-indolyl)ethyl-13-diamino- propane
  • A solution of 8 g N-benzoyl-l,3-diaminopropane, 6,7 g 3-(2-bromoethyl)indole and 5 ml anhydrous triethylamine in 15 ml anhydrous dimethylformamide is maintained for 72 hours in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated. The residue is chromatographied on silicagel using as eluant methylene chloride+ 5% methanol + 0,3% ammonia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203-204° with decomposition after crystallization from ethanol).
  • The following compounds of formula
    Figure imgb0020
    may be obtained in analogous manner to Example 3 :
    Figure imgb0021
    • EXEMPLE 4:
  • From the appropriate 4-amino-piperidines and 2-(3-indolyl)ethyl bromide or 3-(3-indolyl)propyl bromide, the following compounds of formula
    Figure imgb0022
    may be obtained in analogous manner to Example 3:
    Figure imgb0023
  • The compounds of formula I exhibit pharmacological activity in animals. In particular, the compounds exhibit anti-hypertensive activity, as indicated by standard tests, e.g. in the awake renal hypertonic Grollman rat upon administration of 1 to 50 mg/kg animal body weight of the compounds, and in the awake renal hypertonic Goldblatt dog upon administration of 1 to 10 mg/kg animal body weight of the compounds.
  • The compounds are therefore indicated for use as anti-hypertensives. For this use an indicated daily dose is from about lO to about 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about2,5 to about 1000 mg, or in sustained release form.
  • A particularly interesting compound is the
    • Example 1 compound.
  • The compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form. Such salts exhibit the same order of activity as the free base forms.
  • The invention also provides a pharmaceutical composition comprising a compound of formula I, in free base or pharmaceutically acceptable acid addition salt form, in association with a pharmaceutical carrier or diluent. A suitable pharmaceutical form is a capsule.
  • In one group of compounds n is 3, A is trimethylene, R1 is hydrogen or (C1-5)alkyl, R2 is hydrogen or (C1-5)alkyl, R3 is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy or di-(C1-4)alkylamino; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (C1-4)alkyl, R5 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, or (C1-4)alkylthio, and X is -CO-.
  • In another group of compounds n is 2, either A is trimethylene and R1 is hydrogen or (C1-5) alkyl, or A together with R1 and the nitrogen atom to which R1 is bound form a 4-piperidyl radical, and R2 is hydrogen or (C1-5)alkyl, R3 is (C1-4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1-4)alkyl or (C1-4)alkoxy; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur, R4 is hydrogen, chlorine, bromine or (C1-4)alkyl, RS is hydrogen, (C1-4)alkyl or (C1-4)alkoxy, and X is -CO- or -CS.

Claims (9)

1) A compound of formula I
Figure imgb0024
wherein n is 2 or 3, either A is trimethylene optionally substituted by (C1-4)alkyl or 1, 4-cyclohexylidene and R1 is hydrogen or (C1-5) alkyl, or A together with R1 and the nitrogen atom to which R1 is bound, form a 4-piperidyl radical,
R2 is hydrogen or (C1-5)alkyl,
R3 is (C1-4) alkyl; (C3-6)cycloalkyl; amino; (C1-4)alkylamino; di(Cl-4)alkylamino; phenylamino wherein the phenyl ring is unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1-4)alkyl, (C1-4)alkoxy or di(Cl-4)alkylamino; phenyl or benzyl wherein the phenyl rings are unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy or di-(C1-4)alkylamino; 2-,3- or 4-pyridylmethyl;or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur and optionally additional one or two nitrogen atoms,
R4 is hydrogen, chlorine,bromine or (C1-4)alkyl,
R5 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy or (C1-4)alkylthio, and X is -CO- or -CS-.
2) A compound of claim 1 wherein n is 3,
A is trimethylene,
R1 is hydrogen or (C1-5) alkyl,
R2 is hydrogen or (C1-5)alkyl,
R3 is phenyl or benzyl unsubstituted or mono-, di- or trisubstituted independently by halogen, hydroxy, (C1-4)alkyl, (C1-4)alkoxy or di-(C1-4)alkylamino; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur,
R4 is hydrogen, chlorine, bromine or (C1-4)alkyl,
R5 is hydrogen, (C1-4)alkyl, (C1-4)alkoxy, or (C l-4) alkylthio, and X is -CO-.
3) A compound of claim 1 wherein n is 2 either A is trimethylene and R1 is hydrogen or (C1-5) alkyl,
or A together with R1 and the nitrogen atom to which R1 is bound form a 4-piperidyl radical,
R2 is hydrogen or (C1-5) alkyl,
R 3 is (C1-4)alkyl; phenyl unsubstituted or mono-, di- or trisubstituted independently by halogen, (C1-4)alkyl or (C1-4)alkoxy; (C3-6)cycloalkyl; or an aromatic 5- or 6-membered heterocycle containing one heteroatom chosen from nitrogen, oxygen or sulphur
R4 is hydrogen, chlorine, bromine or (C1-4)alkyl,
R5 is hydrogen, (C1-4)alkyl or (C1-4)alkoxy, and X is -CO- or -CS-.
4) A compound of claim 1 which is N-benzoyl-N'-[3-(3-indolyl)propyl]-N'-methyl-l,3-diaminopropane.
5) A compound of claim 1 which is N-methyl-N-benzoyl-N'-methyl-N'-[2-(3-indolyl)ethyl]-2-methyl-1,3-diaminopropane.
6) A compound of any one of claims 1 to 5 in free base form.
7) A compound of any one of claims 1 to 5 in acid addition salt form.
8) A process for the production of a compound of formula I as defined in claim 1, which comprises
a) acylating a compound of formula II
Figure imgb0025
wherein n, A and R1 to R5 are as defined in claim 1, or
b) condensing a compound of formula III
Figure imgb0026
wherein n, R4 and R5 are as defined in claim 1, and Y is a leaving group, with a compound of formula IV
Figure imgb0027
wherein A, R1 to R3 and X are as defined in claim 1.
9) A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 in free base form or in pharmaceutically acceptable acid addition salt form in association with a pharmaceutical carrier or diluent.
EP78100274A 1977-07-12 1978-06-29 New indole derivatives, processes for their preparation, and pharmaceutical compositions containing them. Expired EP0000355B1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CH858977 1977-07-12
CH8589/77 1977-07-12
CH300878 1978-03-20
CH3008/78 1978-03-20

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EP0000355A1 true EP0000355A1 (en) 1979-01-24
EP0000355B1 EP0000355B1 (en) 1982-01-06

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JP (1) JPS5436259A (en)
AU (1) AU521641B2 (en)
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DE (1) DE2861502D1 (en)
DK (1) DK300978A (en)
ES (1) ES471593A1 (en)
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IE (1) IE47209B1 (en)
IL (1) IL55116A (en)
IT (1) IT7850140A0 (en)
NZ (1) NZ187813A (en)
PH (1) PH14993A (en)
PT (1) PT68270A (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003901A2 (en) * 1978-02-24 1979-09-05 Pfizer Limited 3-(Imidazol-1-ylalkyl)indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them
US4634713A (en) * 1982-05-28 1987-01-06 Ciba-Geigy Corporation Antihypertensive 3-(ureidocyclohexyleneamino)propane-1,2-diol derivatives
GB2223012A (en) * 1988-09-21 1990-03-28 Kotobuki Seiyaku Co Ltd Thiophene derivatives
EP0376819A1 (en) * 1988-12-22 1990-07-04 Roussel-Uclaf Acrylated polyamines, process for their preparation and their use as fungicides
WO1994022826A1 (en) * 1993-04-07 1994-10-13 Otsuka Pharmaceutical Co., Ltd. Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients
US8445516B2 (en) 2004-01-29 2013-05-21 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical composition for promoting angiogenesis
EP3852215A1 (en) * 2020-01-15 2021-07-21 Solaredge Technologies Ltd. Photovoltaic system comprising a plurality of power stages

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115433164B (en) * 2022-09-14 2023-12-12 南京师范大学 Nicotinamide derivative, preparation method thereof and application thereof in resisting aging and prolonging life

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACT (1974) vol. 81, 105181k & Khim-Farm. Zk. 1974 8(6)-7-11. *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0003901A2 (en) * 1978-02-24 1979-09-05 Pfizer Limited 3-(Imidazol-1-ylalkyl)indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them
EP0003901A3 (en) * 1978-02-24 1979-09-19 Pfizer Limited 3-(imidazol-1-ylalkyl)indoles as selective inhibitors of thromboxane synthetase,pharmaceutical compositions thereof, and methods for preparing them
US4634713A (en) * 1982-05-28 1987-01-06 Ciba-Geigy Corporation Antihypertensive 3-(ureidocyclohexyleneamino)propane-1,2-diol derivatives
GB2223012B (en) * 1988-09-21 1992-04-29 Kotobuki Seiyaku Co Ltd Diamine derivatives,and method of manufacturing the same
GB2223012A (en) * 1988-09-21 1990-03-28 Kotobuki Seiyaku Co Ltd Thiophene derivatives
EP0376819A1 (en) * 1988-12-22 1990-07-04 Roussel-Uclaf Acrylated polyamines, process for their preparation and their use as fungicides
FR2642422A1 (en) * 1988-12-22 1990-08-03 Roussel Uclaf NOVEL ACYLATED POLYAMINES, PROCESS FOR PREPARING THEM AND THEIR APPLICATION AS FUNGICIDES
WO1994022826A1 (en) * 1993-04-07 1994-10-13 Otsuka Pharmaceutical Co., Ltd. Peripheral vasodilating agent containing n-acylated 4-amino piperidine derivatives as active ingredients
US5656642A (en) * 1993-04-07 1997-08-12 Otsuka Pharmaceutical Co., Ltd. Peripheral vasodilating agent containing piperidine derivative as active ingredient
US5760058A (en) * 1993-04-07 1998-06-02 Otsuka Pharmaceutical Co., Ltd. Peripheral vasodilating agent containing piperidine derivative as active ingredient
CN1052224C (en) * 1993-04-07 2000-05-10 大塚制药株式会社 Peripheral Vasodilating agent containing N-acylated 4-amino piperidine derivatives as active ingredients
US8445516B2 (en) 2004-01-29 2013-05-21 Otsuka Pharmaceutical Co., Ltd. Pharmaceutical composition for promoting angiogenesis
EP3852215A1 (en) * 2020-01-15 2021-07-21 Solaredge Technologies Ltd. Photovoltaic system comprising a plurality of power stages
US11764679B2 (en) 2020-01-15 2023-09-19 Solaredge Technologies Ltd. Power device

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CA1114381A (en) 1981-12-15
EP0000355B1 (en) 1982-01-06
NZ187813A (en) 1981-03-16
IE47209B1 (en) 1984-01-11
AU521641B2 (en) 1982-04-22
IL55116A0 (en) 1978-09-29
DE2861502D1 (en) 1982-02-25
ES471593A1 (en) 1979-10-01
FI782138A (en) 1979-01-13
IL55116A (en) 1982-02-28
IT7850140A0 (en) 1978-07-03
DK300978A (en) 1979-01-13
IE781382L (en) 1979-01-12
PH14993A (en) 1982-03-22
JPS5436259A (en) 1979-03-16
PT68270A (en) 1978-08-01

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