EP0000151A1 - 1-Substituted aminoindolines, process for their production and pharmaceutical compositions containing them - Google Patents

1-Substituted aminoindolines, process for their production and pharmaceutical compositions containing them 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
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Prior art keywords
hydrogen
compound
formula
carbon atoms
alkyl
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EP78100166A
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German (de)
French (fr)
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EP0000151B1 (en
Inventor
Gerhard Dr. Bormann
Richard Dr. Berthold
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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
    • C07D209/08—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.

Abstract

The compounds of formula I,
Figure imga0001
wherein R, to Rs and n have various significances, are useful as vasoconstricting agents.

Description

  • The present invention relates to 1-aminoindoline derivatives.
  • In accordance with the invention there are provided compounds of formula I,
    Figure imgb0001
    wherein
    • one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms,
    • R3 is hydrogen or alkyl of 1 to 4 carbon atoms, in the 2- or 3-position,
    • R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to'4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, and n is 2, 3 or 4.
  • Alkyl, alkoxy and alkylthio preferably contain 1 or 2, especially 1 carbon atom. Halogen is preferably chlorine.
  • R1, R21 R3 and R5 are preferably hydrogen. R4 is preferably hydrogen, alkyl or halogen, especially hydrogen.
  • R3 is preferably in the 3 position of the indoline nucleus. R4 is preferably in the 4, 5 or 6, especially in the 4 or 5, preferably in the 4-position.
    n is preferably 2.
  • In accordance with the invention, a compound of formula I may be obtained by a process comprising cyclizing a compound of formula II,
    Figure imgb0002
    wherein R1 to R5 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 -NHRa, wherein R is alkyl of 1 to 4 carbon atoms, especially methyl, or Ra 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 R1 or R2. 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,
    Figure imgb0003
    wherein R3 to R5 and X are as defined above and the group -S-Y is a leaving group, with a compound of formula IV,
    Figure imgb0004
    wherein R1, R2 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.
  • When in the compounds of formula III Y is alkyl of 1 to 4 carbon atoms and X is a group -NH-R , the reaction conditions for producing compounds of formula I directly from corresponding compounds of formula III.are analogous to known reaction conditions for the production of a l-(indolin-l-yl)-guanidine derivative from a l-(indolin-1-yl)-2-(lower)alkylisothiourea.
  • Insofar as the production of the starting materials is not described, these are known or may be produced and purified in accordance with known processes, or in a manner analogous to the processes described above or analogous to known processes.
  • In the following non-limitative Examples all temperatures are indicated in degrees Centigrade and are uncorrected.
    • Example 1: 1-(Imidazolidin-2-ylidenamino;indoline
  • To 10 g 1-(indolin-1-yl)-2-methylisothiourea hydrochloride dissolved in 40 ml ethanol are added 8 mi ethylene diamine and the reaction mixture is boiled for 6 hours with stirring. The mixture is then evaporated to dryness and the residue is extracted from a 1 M solution of sodium hydroxide with methylene chloride. The organic phase is then dried over magnesium sulphate and evaporated. The title compound is obtained (M.P. of the hydrogen maleate 171-172° - from ethanol/ether).
  • 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 following compounds of formula I are obtained in a manner analogous to Example 1, using the corresponding starting materials of formula III, wherein Y is methyl and X is -NH2 or -NH-CH3, and of formula IV:
    Figure imgb0005
  • The compounds of formula I exhibit pharmacological activity. In particular, the compounds possess vasoconstricting
    activity, as indicated by standard tests. For example, 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 µg/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.
  • For this use 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.

Claims (10)

1. A process for the production of a compound of Formula I,
Figure imgb0006
wherein
one of R1 and R2 is hydrogen and the other is hydrogen or alkyl of 1 to 4 carbon atoms,
R3 is hydrogen or alkyl of 1 to 4 carbon atoms, in the 2- or 3-position,
R4 and R5 independently are hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halogen of atomic number of from 9 to 35, and
n is 2, 3 or 4,

which comprises cyclizing a compound of formula II,
Figure imgb0007
wherein R1 to R5 and n are as defined above and X is a leaving group.
2. A compound of formula I, as defined in claim 1.
3. The compound of claim 2, wherein R1 to R5 are hydrogen and n is 2.
4. A compound of claim 2, wherein R1, R2 and R5 are hydrogen and n is 2.
5. The compound of claim 4, wherein R3 is hydrogen and R4 is 5-chloro, or R3 is 2-methyl and R4 is hydrogen.
6. The compound of claim 4, wherein R3 is 3-methyl and R4 is hydrogen, or R3 is hydrogen and R4 is 4-methyl.
7. The compound of claim 4, wherein R3 is hydrogen and R4 is 4-methoxy, or R3 is hydrogen and R4 is 7-methyl.
8. A compound according to any one of claims 2 to 7, in free form.
9. A compound according to any one of claims 2 to 7, in acid addition salt form.
10. A pharmaceutical composition comprising a compound according to any one of claims 2 to 7 in free form or in pharmaceutically acceptable acid additicn salt form, in association with a pharmaceutical carrier or diluent.
EP78100166A 1977-06-28 1978-06-15 1-substituted aminoindolines, process for their production and pharmaceutical compositions containing them Expired EP0000151B1 (en)

Applications Claiming Priority (2)

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CH7915/77 1977-06-28
CH791577 1977-06-28

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

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

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 (en) * 1978-12-13 1979-11-28 Sandoz Ag DERIVATIVES OF 1-AMINOINDOLIN THEIR PREPARATION AND APPLICATION AS MEDICINAL PRODUCTS
DE3133302A1 (en) * 1981-08-22 1983-03-03 Beiersdorf Ag, 2000 Hamburg ISOINDOLIN-2-YL-AMINO-IMIDAZOLINE AND ISOINDOLIN-2-YL-GUANIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
DE3343801A1 (en) * 1983-12-03 1985-06-13 Dr. Karl Thomae Gmbh, 7950 Biberach NEW INDOLDER DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH529702A (en) * 1970-07-06 1972-10-31 Sandoz Ag Optically active benz(c,d)indole derivs - with vasoconstrictive and cns - smoothing activity
FR2230363A1 (en) * 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 (en) * 1970-07-06 1972-10-31 Sandoz Ag Optically active benz(c,d)indole derivs - with vasoconstrictive and cns - smoothing activity
FR2230363A1 (en) * 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

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

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