EP0000151A1 - 1-Substituierte Aminoindoline, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen - Google Patents

1-Substituierte Aminoindoline, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen Download PDF

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Publication number
EP0000151A1
EP0000151A1 EP78100166A EP78100166A EP0000151A1 EP 0000151 A1 EP0000151 A1 EP 0000151A1 EP 78100166 A EP78100166 A EP 78100166A EP 78100166 A EP78100166 A EP 78100166A EP 0000151 A1 EP0000151 A1 EP 0000151A1
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.)
Granted
Application number
EP78100166A
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English (en)
French (fr)
Other versions
EP0000151B1 (de
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
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sandoz AG filed Critical Sandoz AG
Publication of EP0000151A1 publication Critical patent/EP0000151A1/de
Application granted granted Critical
Publication of EP0000151B1 publication Critical patent/EP0000151B1/de
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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-aminoindoline derivatives.
  • Alkyl, alkoxy and alkylthio preferably contain 1 or 2, especially 1 carbon atom.
  • Halogen is preferably chlorine.
  • R 1 , R 21 R 3 and R 5 are preferably hydrogen.
  • R 4 is preferably hydrogen, alkyl or halogen, especially hydrogen.
  • R 3 is preferably in the 3 position of the indoline nucleus.
  • R 4 is preferably in the 4, 5 or 6, especially in the 4 or 5, preferably in the 4-position.
  • n is preferably 2.
  • a compound of formula I may be obtained by a process comprising cyclizing a compound of formula II, wherein R 1 to R 5 and n are as defined above and X is a leaving group.
  • 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 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 intauto- meric form, i.e. with the double bond adjacent to one of the other two nitrogen atoms of the guanidine moiety, insofar this nitrogen atom is not substituted by an alkyl group R 1 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 R5 and X are as defined above and the group -S-Y is a leaving group, with a compound of formula IV, wherein R 1 , 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 of formula II.
  • the starting material is obtained as follows.
  • 1-Aminoindoline is reacted with benzoyl isothiocyanate in boiling tetrahydrofurane and, after saponification of the product over 15 minutes with diluted sodium hydroxide under reflux, l-(indolin-l-yl)thiourea (M.P. 225-227° - from methanol) is obtained.
  • This product is converted into 1-(indolin-1-yl)-2-methyl- isothiourea hydroiodide by heating up for 1 hour with methyl iodide in methanol.
  • the free base is obtained by addition of aqueous sodium hydroxide and is further reacted with a 2N methanolic solution of hydrochloric acid to give l-(indolin-l-yl)-2-methylisothiourea hydrochloride (M.P. 227-229° - from methanol/ether).
  • 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 pg/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 from 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

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Peptides Or Proteins (AREA)
  • Indole Compounds (AREA)
EP78100166A 1977-06-28 1978-06-15 1-Substituierte Aminoindoline, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen Expired EP0000151B1 (de)

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 true EP0000151A1 (de) 1979-01-10
EP0000151B1 EP0000151B1 (de) 1981-05-20

Family

ID=4332315

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100166A Expired EP0000151B1 (de) 1977-06-28 1978-06-15 1-Substituierte Aminoindoline, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende pharmazeutische Zusammensetzungen

Country Status (13)

Country Link
EP (1) EP0000151B1 (de)
JP (1) JPS5412373A (de)
AU (1) AU3746878A (de)
CA (1) CA1094553A (de)
DE (1) DE2860709D1 (de)
DK (1) DK275278A (de)
ES (1) ES471125A1 (de)
FI (1) FI781947A (de)
IL (1) IL55005A (de)
IT (1) IT7850073A0 (de)
NZ (1) NZ187675A (de)
PT (1) PT68217A (de)
ZA (1) ZA783708B (de)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022216993A2 (en) 2021-04-08 2022-10-13 Marengo Therapeutics, Inc. Multifuntional molecules binding to tcr and uses thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT7950924A0 (it) * 1978-12-13 1979-11-28 Sandoz Ag Derivati dell'1-amminoindolina loro preparazione e loro applicazione come medicamenti
DE3133302A1 (de) * 1981-08-22 1983-03-03 Beiersdorf Ag, 2000 Hamburg Isoindolin-2-yl-amino-imidazoline und isoindolin-2-yl-guanidine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel
DE3343801A1 (de) * 1983-12-03 1985-06-13 Dr. Karl Thomae Gmbh, 7950 Biberach Neue indolderivate, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung

Citations (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
FR2230363A1 (de) * 1973-05-25 1974-12-20 Lepetit Spa

Patent Citations (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
FR2230363A1 (de) * 1973-05-25 1974-12-20 Lepetit Spa

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022216993A2 (en) 2021-04-08 2022-10-13 Marengo Therapeutics, Inc. Multifuntional molecules binding to tcr and uses thereof

Also Published As

Publication number Publication date
AU3746878A (en) 1980-01-03
ES471125A1 (es) 1979-09-16
FI781947A (fi) 1978-12-29
NZ187675A (en) 1981-02-11
IL55005A0 (en) 1978-08-31
IT7850073A0 (it) 1978-06-28
EP0000151B1 (de) 1981-05-20
DK275278A (da) 1978-12-29
IL55005A (en) 1981-12-31
DE2860709D1 (en) 1981-08-27
PT68217A (fr) 1978-07-01
CA1094553A (en) 1981-01-27
JPS5412373A (en) 1979-01-30
ZA783708B (en) 1980-02-27

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