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
  • C07D209/10—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 derivatives, processes for their preparation, and pharmaceutical compositions containing them.
• Any alkyl, alkoxy or alkylthio radical in any of the above significances has preferably two carbon atoms, and signifies especially methyl, methoxy or methylthio.
• Halogen means fluorine, chlorine, bromine or iodine, especially chlorine.
• A is 1,4-cyclohexylidene
• this may be cis or trans-1,4-cyclohexylidene.
• A is optionally substituted trimethylene, this is preferably either unsubstituted or mono-substituted, conveniently at the middle carbon atom.
• R, 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 mono-substituted 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 heteroatom, e.g. thienyl, furyl, pyrrolyl, pyridyl or pyrazinyl. Conveniently the heterocycle is bound to X by a ring carbon atom adjacent to a heteroatom.
• 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, R3 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 0°C to 25°C.
• 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°C to 25°C.
• 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°C to 150°C.
• 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-1,5-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, 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 Ila wherein A' is 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, and/or R 2 is hydrogen may be converted into a corresponding compound wherein R, and R 2 are both alkyl, or R, 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 or 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" together with R, and the nitrogen atom to which R, 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 10 to 2000 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from 2,5 to 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
• 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 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; (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 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, is hydrogen or (C 1-5 ) alkyl, or A together with R i and the nitrogen atom to which R, 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 5 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)

Applications Claiming Priority (4)

Publications (2)

Family

ID=25691930

Family Applications (1)

Country Status (14)

Families Citing this family (8)

• 1978
  • 1978-06-12 PH PH21359A patent/PH14993A/en unknown
  • 1978-06-29 DE DE7878100274T patent/DE2861502D1/de not_active Expired
  • 1978-06-29 EP EP78100274A patent/EP0000355B1/en not_active Expired
  • 1978-07-03 IT IT7850140A patent/IT7850140A0/it unknown
  • 1978-07-03 FI FI782138A patent/FI782138A/fi not_active Application Discontinuation
  • 1978-07-03 DK DK783009A patent/DK300978A/da not_active Application Discontinuation
  • 1978-07-10 NZ NZ187813A patent/NZ187813A/xx unknown
  • 1978-07-10 PT PT68270A patent/PT68270A/pt unknown
  • 1978-07-10 ES ES471593A patent/ES471593A1/es not_active Expired
  • 1978-07-10 IE IE1382/78A patent/IE47209B1/en unknown
  • 1978-07-10 IL IL55116A patent/IL55116A/xx unknown
  • 1978-07-11 AU AU37939/78A patent/AU521641B2/en not_active Expired
  • 1978-07-11 JP JP8363778A patent/JPS5436259A/ja active Pending
  • 1978-07-11 CA CA307,174A patent/CA1114381A/en not_active Expired

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