[0001] The present invention relates to 1-aminoindoline derivatives.
[0002] In accordance with the invention there are provided compounds of formula I,

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.
[0003] Alkyl, alkoxy and alkylthio preferably contain 1 or 2, especially 1 carbon atom.
Halogen is preferably chlorine.
[0004] R
1, R
21 R
3 and R
5 are preferably hydrogen. R
4 is preferably hydrogen, alkyl or halogen, especially hydrogen.
[0005] 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.
[0006] In accordance with the invention, 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.
[0007] 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.
[0008] The compounds of formula I may be isolated and purified in accordance with known
methods.
[0009] 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.
[0010] 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.
[0011] The production of the starting materials may be effected in known manner.
[0012] 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.
[0013] 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.
[0014] 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.
[0015] 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.
[0016] In the following non-limitative Examples all temperatures are indicated in degrees
Centigrade and are uncorrected.
Example 1: 1-(Imidazolidin-2-ylidenamino;indoline
[0017] 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).
[0018] The starting material is obtained as follows.
[0019] 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).
[0020] 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 -NH
2 or -NH-CH
3, and of formula IV:

[0021] 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.
[0022] 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.
[0023] 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.
[0024] The activity of the compound of Example 1 is especially interesting.
[0025] 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.
1. A process for the production of a compound of Formula I,

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,

wherein R
1 to R
5 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.