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EP0000355B1 - Dérivés de l'indole, procédé pour leur préparation et compositions pharmaceutiques les contenant. - Google Patents

Dérivés de l'indole, procédé pour leur préparation et compositions pharmaceutiques les contenant. Download PDF

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Publication number
EP0000355B1
EP0000355B1 EP78100274A EP78100274A EP0000355B1 EP 0000355 B1 EP0000355 B1 EP 0000355B1 EP 78100274 A EP78100274 A EP 78100274A EP 78100274 A EP78100274 A EP 78100274A EP 0000355 B1 EP0000355 B1 EP 0000355B1
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EP
European Patent Office
Prior art keywords
alkyl
hydrogen
compound
formula
alkoxy
Prior art date
Legal status (The legal status 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 status listed.)
Expired
Application number
EP78100274A
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German (de)
English (en)
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EP0000355A1 (fr
Inventor
Paul Dr. Stadler
Franz Dr. Troxler
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Sandoz AG
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Sandoz AG
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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.

Landscapes

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

Claims (15)

1. Un composé de formule 1
Figure imgb0027
dans laquelle
n signifie 2 ou 3;
soit A signifie un groupe triméthylène éventuellement substitué par de l'alkyle contenant de 1 à 4 atomes de carbone, ou un groupe 1,4-cyclohexylidène et R1 signifie l'hydrogène ou un groupe alkyle contenant de 1 à 5 atomes de carbone,
soit A, avec R1 et l'atome d'azote auquel R1 est rattaché, forment ensemble un radical 4-pipéridyle,
R2 signifie l'hydrogène ou un groupe alkyle contenant de 1 à 5 atomes de carbone,
R3 signifie un groupe alkyl contenant de 1 à 4 atomes de carbone; cycloalkyle contenant de 3 à 6 atomes de carbone; amino; alkylamino contenant de 1 à 4 atomes de carbone; dialkylamino dont les restes alkyle contiennent de 1 à 4 atomes de carbone; phénylamino dans lequel le cycle phénylique est non substitué ou mono-, di- ou trisubstitué indépendamment par des radicaux halogène, alkyl contenant de 1 à 4 atomes de carbone, alcoxy contenant de 1 à 4 atomes de carbone, alcoxy contenant de 1 à 4 atomes de carbone ou dialkylamino dont les restes alkyl continennent de 1 à 4 atomes de carbone; phényle ou benzyle dans lesquels les cycles phényliques sont non substitués ou mono-, di- ou trisubstitués indépendamment par des radicaux halogène, hydroxy, alkyl contenant de 1 à 4 atomes de carbone ou dialkylamino dont les restes alkyle contiennent de 1 à 4 atomes de carbone; 2-, 3- ou 4-pyridylméthyle; ou un hétérocycle aromatique à 5 ou 6 chaînons contenant un hétéroatome choisi parmi l'azote, l'oxygène ou le soufre et éventuellement un ou deux hétéroatomes d'azote supplémentaires,
R4 signifie l'hydrogène, le chlore, le brome ou un group alkyle contenant de 1 à 4 atomes de carbone,
R5 signifie l'hydrogène, un groupe alkyle contenant de 1 à 4 atomes de carbone, alcoxy contenant de 1 à 4 atomes de carbone ou alkylthio contenant de 1 à 4 atomes de carbone, et
X signifie -CO- ou -CS-.
2. Un composé selon la revendication 1, dans lequel X signifie -CO-.
3. Un compose' selon la revendication 1 ou 2, dans lequel A signifie un groupe triméthylène éventuellement substitué par de l'alkyle contenant de 1 à 4 atomes de carbone, ou un groupe 1,4-cyclohexylidène.
4. Un composé selon la revendication 1, 2 ou 3, dans lequel A signifie un groupe triméthylène éventuellement substitué par de l'alkyle contenant de 1 à 4 atomes de carbone.
5. Un composé selon la revendication 3 ou 4, dans lequel R, et R2 signifient un groupe alkyle.
6. Un composé selon la revendication 1, dans lequel
n signifie 3,
A signifie un groupe triméthylène,
R, signifie l'hydrogène ou un groupe alkyle contenant de 1 à 5 atomes de carbone,
R2 signifie l'hydrogène ou un groupe alkyle contenant de 1 à 5 atomes de carbone,
R3 signifie un groupe phényle ou benzyle non substitués ou mono-, di ou trisubstitués indépendamment par des radicaux halogène, hydroxy, alkyle contenant de 1 à 4 atomes de carbone, alcoxy contenant de 1 à 4 atomes de carbone ou dialkylamino dont les restes alkyle contiennent de 1 à 4 atomes de carbone; cycloalkyle contenant de 3 à 6 atomes de carbone; ou un hétérocycle aromatique à 5 ou 6 chaînons contenant un hétéroatome choisi parmi l'azote, l'oxygène ou le soufre,
R4 signifie l'hydrogène, le chlore, le brome ou un groupe alkyle contenant de 1 à 4 atomes de carbone,
Rs signifie l'hydrogène, un groupe alkyle contenant de 1 à 4 atomes de carbone, alcoxy contenant de 1 à 4 atomes de carbone ou alkylthio contenant de 1 à 4 atomes de carbone, et
X signifie -CO-.
7. Un composé selon la revendication 1, dans lequel
n signifie 2,
soit A signifie un groupe triméthylène et R1 signifie l'hydrogène ou un groupe alkyle contenant de 1 à 5 atomes de carbone,
soit A avec R1 et l'atome d'azote auquel R1 est rattaché, forment ensemble un radical 4-pipéridyle,
R2 signifie l'hydrogène ou un groupe alkyle contenant de 1 à 5 atomes de carbone.
R3 signifie un group alkyle contenant de 1 à 4 atomes de carbone; phényle non substitué ou mono-, di- ou trisubstitué indépendamment par des radicaux halogène, alkyle contenant de 1 à 4 atomes de carbone ou alcoxy contenant de 1 à 4 atomes de carbone; cycloalkyle contenant de 3 à 6 atomes de carbone; ou un hétérocycle aromatique à 5 ou 6 chaînons contenant un hétéroatome choisi parmi l'azote, l'oxygène ou le soufre,
R4 signifie l'hydrogène, le chlore, le brome ou un groupe alkyle contenant de 1 à 4 atomes de carbone,
R5 signifie l'hydrogène, un groupe alkyle contenant de 1 à 4 atomes de carbone ou alcoxy contenant de 1 à 4 atomes de carbone, et
X signifie -CO- ou -CS-.
8. Un composé selon l'une quelconque des revendications précédentes, dans lequel R4 et R5 signifient l'hydrogène.
9. Un composé selon l'une quelconque des revendications précédentes, dans lequel R3 signifie un groupe phényle non substitué.
10. Un composé selon la revendication 1, qui est le N-benzoyl-N'-[3-(3-indolyl)propyl]-N'-- méthyl-1,3-diaminopropane.
11. Un composé selon la revendication 1, qui est le N-méthyl-N-benzoyl-N'-méthyl-N'-[2-(3- indolyl)éthyl]-2-méthyl-1,3-diaminopropane.
12. Un composé selon l'une quelconque des revendications 1 à 11, sous forme de sel d'addition d'acides.
13. Un composé tel que revendiqué à l'une quelconque des revendications 1 à 12, pour l'utilisation comme antihypertenseur.
14. Une composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 11, sous forme de base libre ou sous forme d'un sel d'addition d'acides acceptable du point de vue pharmaceutique, en association avec un véhicule ou diluant pharmaceutique.
15. Un procédé de préparation d'un composé de formule I tel que défini à la revendication 1, comprenant
a) l'acylation d'un composé de formule Il
Figure imgb0028
dans laquelle n, A et R, à R5 sont tels que définis à la revendication 1, ou
b) la condensation d'un composé de formule III
Figure imgb0029
dans laquelle n, R4 et R5 sont tels que définis à la revendication 1, et Y signifie un groupe susceptible d'être éliminé,

avec un composé de formule IV
Figure imgb0030
dans laquelle A, R1 à R3 et X sont tels que définis à la revendication 1.
EP78100274A 1977-07-12 1978-06-29 Dérivés de l'indole, procédé pour leur préparation et compositions pharmaceutiques les contenant. Expired EP0000355B1 (fr)

Applications Claiming Priority (4)

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

Publications (2)

Publication Number Publication Date
EP0000355A1 EP0000355A1 (fr) 1979-01-24
EP0000355B1 true EP0000355B1 (fr) 1982-01-06

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EP78100274A Expired EP0000355B1 (fr) 1977-07-12 1978-06-29 Dérivés de l'indole, procédé pour leur préparation et compositions pharmaceutiques les contenant.

Country Status (14)

Country Link
EP (1) EP0000355B1 (fr)
JP (1) JPS5436259A (fr)
AU (1) AU521641B2 (fr)
CA (1) CA1114381A (fr)
DE (1) DE2861502D1 (fr)
DK (1) DK300978A (fr)
ES (1) ES471593A1 (fr)
FI (1) FI782138A7 (fr)
IE (1) IE47209B1 (fr)
IL (1) IL55116A (fr)
IT (1) IT7850140A0 (fr)
NZ (1) NZ187813A (fr)
PH (1) PH14993A (fr)
PT (1) PT68270A (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2960547D1 (en) * 1978-02-24 1981-11-05 Pfizer Ltd 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
JPH0283380A (ja) * 1988-09-21 1990-03-23 Kotobuki Seiyaku Kk 新規ジアミン誘導体、抗不整脈剤及びその製法
FR2642422A1 (fr) * 1988-12-22 1990-08-03 Roussel Uclaf Nouvelles polyamines acylees, leur procede de preparation et leur application comme fongicides
KR100238346B1 (ko) * 1993-04-07 2000-03-02 오쓰까 아끼히꼬 피페리딘 유도체를 유효성분으로 하는 말초혈관확장제
MY142362A (en) 2004-01-29 2010-11-30 Otsuka Pharma Co Ltd Pharmaceutical composition for promoting angiogenesis
EP3852215A1 (fr) * 2020-01-15 2021-07-21 Solaredge Technologies Ltd. Système photovoltaïque comprenant plusierus étages de puissance
CN116478134B (zh) * 2022-01-17 2025-07-25 上海医药工业研究院有限公司 Ssri/5-ht1a双靶点抗抑郁甲酰哌啶类化合物及其制备方法和应用
CN115433164B (zh) * 2022-09-14 2023-12-12 南京师范大学 烟酰胺衍生物及其制备方法和在抗衰老延长寿命中的应用

Also Published As

Publication number Publication date
FI782138A7 (fi) 1979-01-13
IE47209B1 (en) 1984-01-11
PT68270A (en) 1978-08-01
JPS5436259A (en) 1979-03-16
NZ187813A (en) 1981-03-16
IL55116A (en) 1982-02-28
IT7850140A0 (it) 1978-07-03
AU521641B2 (en) 1982-04-22
EP0000355A1 (fr) 1979-01-24
CA1114381A (fr) 1981-12-15
DE2861502D1 (en) 1982-02-25
IL55116A0 (en) 1978-09-29
DK300978A (da) 1979-01-13
PH14993A (en) 1982-03-22
IE781382L (en) 1979-01-12
AU3793978A (en) 1980-01-17
ES471593A1 (es) 1979-10-01

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