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EP0000151B1 - Aminoindolines substituées en position 1, procédé de leur production et compositions thérapeutiques les contenant - Google Patents

Aminoindolines substituées en position 1, procédé de leur production et compositions thérapeutiques les contenant Download PDF

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Publication number
EP0000151B1
EP0000151B1 EP78100166A EP78100166A EP0000151B1 EP 0000151 B1 EP0000151 B1 EP 0000151B1 EP 78100166 A EP78100166 A EP 78100166A EP 78100166 A EP78100166 A EP 78100166A EP 0000151 B1 EP0000151 B1 EP 0000151B1
Authority
EP
European Patent Office
Prior art keywords
hydrogen
compound
formula
carbon atoms
alkyl
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
EP78100166A
Other languages
German (de)
English (en)
Other versions
EP0000151A1 (fr
Inventor
Gerhard Dr. Bormann
Richard Dr. Berthold
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sandoz AG
Original Assignee
Sandoz AG
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Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
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Publication of EP0000151B1 publication Critical patent/EP0000151B1/fr
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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
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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

Definitions

  • the present invention relates to 1-substituted aminoindoline derivatives.
  • Alkyl, alkoxy and alkylthio preferably contain 1 or 2, especially 1 carbon atom.
  • Halogen is preferably chlorine.
  • a compound of formula I may be obtained by a process comprising cyclizing a compound of formula II, wherein
  • the process according to the invention may be effected in a manner analogous to known methods for cyclizing analogous amino derivatives.
  • X is e. g. a group -NHR a , wherein R a is alkyl of 1 to 4 carbon atoms, especially methyl, or R a is hydrogen.
  • the reaction is preferably effected in an inert solvent such as methanol or ethanol, or, when the amine of formula IV (see below) is liquid at the reaction temperature, the reaction is conveniently effected in the absence of any additional solvent.
  • the reaction is preferably effected in the presence of a mineral acid such as hydrochloric or hydroiodic acid.
  • the reaction temperature may be from room temperature to about 150°C and is preferably at least 50° C, e. g. the boiling temperature of the reaction mixture.
  • the compounds of formula I may be isolated and purified in accordance with known methods.
  • the compounds of formula I may be present in free form, or in the form of acid addition salts.
  • Acid addition salt forms for example, the hydrochloride or hydrogen maleate, may be produced from the free form in known manner, and vice-versa.
  • the compounds of formula I may also be present in tautomeric form, i. e. with the double bond adjacent to one of the other two nitrogen atoms of the guanidine moiety, insofar as this nitrogen atom is not substituted by an alkyl group R i or R 2 . It is to be appreciated that such tautomeric forms also fall under the scope of formula I.
  • the production of the starting materials may be effected in known manner.
  • a compound of formula II may e. g. be produced by reacting a compound of formula III, wherein R 3 to R 5 and X are as defined above and the group -S-Y is a leaving group, with a compound of formula IV, wherein R i , R 2 and n are as defined above.
  • Y may e. g. be alkyl of 1 to 4 carbon atoms, preferably methyl.
  • the reaction conditions may be chosen such as to be identical with the conditions for cyclization according to the invention.
  • the compounds of formula III are then advantageously reacted with the compounds of formula IV to give directly the corresponding compounds of formula I, without intermediate isolation of the compounds offormula II.
  • the starting material is obtained as follows:
  • the compounds of formula I exhibit pharmacological activity.
  • the compounds possess vasoconstricting activity, as indicated by standard tests.
  • this activity may be observed in vivo in rats treated in accordance with the principles of J. S. Gillespie and T. C. Muir, Br. J. Pharmac. Chemother. (1967) 30, 78-87): a pressor effect is elicited following i. v. administration of from about 0.02 to about 50 ⁇ g/kg, particularly of from about 0.02 to about 0.5 ⁇ g/kg of the compounds.
  • the compounds are therefore indicated for use as vasoconstricting agents, e. g. for the prophylaxis and treatment of vascular headaches such as migraine, and of orthostatic disorders such as orthostatic hypotension and its symptoms, such as vertigo.
  • an indicated daily dose is from about 0.0025 to about 1 mg, conveniently administered in divided doses 2 to 4 times a day in unit dosage form containing from about 0.0005 to about 0.5 mg, or in sustained release form.
  • the activity of the compound of Example 1 is especially interesting.
  • the compounds of formula I may be administered in free form or in pharmaceutically acceptable acid addition salt form. Such forms exhibit the same order of activity as the free form.
  • the present invention also provides a pharmaceutical composition comprising a compound of formula I, in free form or in pharmaceutically acceptable salt form, in association with a pharmaceutical carrier or diluent. Such compositions may be in the form of, for example, a solution or a tablet.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (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)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Peptides Or Proteins (AREA)

Claims (11)

1. Un procédé de préparation d'un composé de formule I
Figure imgb0010
dans laquelle
l'un des symboles R1 et R2 est l'hydrogène et l'autre est l'hydrogène ou un groupe alkyle de 1 à 4 atomes de carbone,
R3 est l'hydrogène ou un groupe alkyle de 1 à 4 atomes de carbone, en position 2 ou 3,
R4 et R5 signifient indépendamment l'hydrogène, un groupe alkyle de 1 à 4 atomes de carbone, alcoxy de 1 à 4 atomes de carbone, alkylthio de 1 à 4 atomes de carbone ou un halogène d'un nombre atomique compris entre 9 et 35, et
n signifie 2, 3 ou 4,

ou une forme tautomère de ce composé, comprenant la cyclisation d'un composé de formule Il
Figure imgb0011
dans laquelle Ri à R5 et n sont tels que définis ci-dessus et X est un groupe susceptible d'être éliminé.
2. Un composé de formule I, tel que défini à la revendication 1, ou une forme tautomère de ce composé.
3. Un composé de la revendication 2, dans lequel Ri à R5 sont l'hydrogène et n est 2.
4. Un composé de la revendication 2, dans lequel Ri, R2 et R5 sont l'hydrogène et n est 2.
5. Un composé de la revendication 4, dans lequel R3 est l'hydrogène et R4 est un atome de chlore en position 5, ou R3 est un groupe méthyle en position 2 et R4 est l'hydrogéne.
6. Un composé de la revendication 4, dans lequel R3 est un groupe méthyle en position 3 et R4 est l'hydrogène, ou R3 est l'hydrogène et R4 est un groupe méthyle en position 4.
7. Un composé de la revendication 4, dans lequel R3 est l'hydrogène et R4 est un groupe méthoxy en position 4, ou R3 est l'hydrogène et R4 est un groupe méthyle en position 7.
8. Un composé selon l'une quelconque des revendications 2 à 7, sous forme libre.
9. Un composé selon l'une quelconque des revendications 2 à 7, sous forme de sel d'addition d'acide.
10. Une composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 2 à 7 sous forme libre ou sous forme d'un sel d'addition d'acide acceptable du point de vue pharmaceutique, en association avec un excipient ou diluant pharmaceutique.
11. Un composé de la revendication 2, pour l'utilisation dans une méthode de traitement thérapeutique du corps humain ou animal.
EP78100166A 1977-06-28 1978-06-15 Aminoindolines substituées en position 1, procédé de leur production et compositions thérapeutiques les contenant Expired EP0000151B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH791577 1977-06-28
CH7915/77 1977-06-28

Publications (2)

Publication Number Publication Date
EP0000151A1 EP0000151A1 (fr) 1979-01-10
EP0000151B1 true EP0000151B1 (fr) 1981-05-20

Family

ID=4332315

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100166A Expired EP0000151B1 (fr) 1977-06-28 1978-06-15 Aminoindolines substituées en position 1, procédé de leur production et compositions thérapeutiques les contenant

Country Status (13)

Country Link
EP (1) EP0000151B1 (fr)
JP (1) JPS5412373A (fr)
AU (1) AU3746878A (fr)
CA (1) CA1094553A (fr)
DE (1) DE2860709D1 (fr)
DK (1) DK275278A (fr)
ES (1) ES471125A1 (fr)
FI (1) FI781947A7 (fr)
IL (1) IL55005A (fr)
IT (1) IT7850073A0 (fr)
NZ (1) NZ187675A (fr)
PT (1) PT68217A (fr)
ZA (1) ZA783708B (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2444035A1 (fr) * 1978-12-13 1980-07-11 Sandoz Sa Nouvelles 1-amino-indolines, leur preparation et leur application comme medicaments
EP0072954A3 (en) * 1981-08-22 1983-09-28 Beiersdorf Aktiengesellschaft Isoindolin-2-yl-amino-imidazolines and isoindolin-2-yl guanidines, process for their preparation and their use as medicines
EP0146787A3 (en) * 1983-12-03 1985-11-21 Dr. Karl Thomae Gmbh Indole derivatives, medicaments containing these compounds, and process for their preparation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20240004462A (ko) 2021-04-08 2024-01-11 마렝고 테라퓨틱스, 인크. Tcr에 결합하는 다기능성 분자 및 이의 용도

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH529702A (de) * 1970-07-06 1972-10-31 Sandoz Ag Verfahren zur Herstellung neuer Benz(cd)indole
GB1408362A (en) * 1973-05-25 1975-10-01 Lepetit Spa 2-pyrrol-1-yl amino 4,5-dihydro-1-h-imidazole derivatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2444035A1 (fr) * 1978-12-13 1980-07-11 Sandoz Sa Nouvelles 1-amino-indolines, leur preparation et leur application comme medicaments
EP0072954A3 (en) * 1981-08-22 1983-09-28 Beiersdorf Aktiengesellschaft Isoindolin-2-yl-amino-imidazolines and isoindolin-2-yl guanidines, process for their preparation and their use as medicines
US4526897A (en) * 1981-08-22 1985-07-02 Beiersdorf Aktiengesellschaft Hypertensive isoindolin-2-yl-aminoimidazolines and isoindolin-2-yl-guanidines
EP0146787A3 (en) * 1983-12-03 1985-11-21 Dr. Karl Thomae Gmbh Indole derivatives, medicaments containing these compounds, and process for their preparation

Also Published As

Publication number Publication date
ZA783708B (en) 1980-02-27
DK275278A (da) 1978-12-29
IL55005A0 (en) 1978-08-31
IT7850073A0 (it) 1978-06-28
CA1094553A (fr) 1981-01-27
PT68217A (fr) 1978-07-01
JPS5412373A (en) 1979-01-30
DE2860709D1 (en) 1981-08-27
ES471125A1 (es) 1979-09-16
IL55005A (en) 1981-12-31
AU3746878A (en) 1980-01-03
NZ187675A (en) 1981-02-11
FI781947A7 (fi) 1978-12-29
EP0000151A1 (fr) 1979-01-10

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