DERIVES DE L'INDOLINE SUBSTITUEE EN 1 PAR UN GROUPEMENT AMINO, SERVANT COMME AGENTS VASOCONSTRICTEURS

1-AMINO SUBSTITUTED INDOLINE DERIVATIVES AS VASOCONSTRICTING AGENTS

Abrégé anglais

Abtract
The compounds of formula I,
<IMG> I
wherein R1 to R5 and n have various significances,
are usefula as vasoconstricting agents.

Revendications

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Canada
The embodiments of the invention in which an
exclusive property or priviledge is claimed are defined
as follows:
1. A process for the production of a compound of
Formula I,
<IMG> 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,
or a pharmaceutically acceptable acid addition salt
thereof,
which comprises cyclizing a compound of formula II,

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Canada
<IMG> II
wherein R1 to R5 and n are as deined above and
X is a leaving group,
and where necessary or desired, converting the resulting compound of
formula I into a pharmaceutically acceptable acid addition
salt thereof.
2. A compound of formula I as defined in claim 1 or a
pharmaceutically acceptable acid addition salt thereof, whenever
produced by a process according to claim 1, or an obvious
chemical equivalent thereof.
3. A process according to claim 1 for the production
of 1-(Imidazolidin-2-ylidenamino)indoline, which comprises
cyclizing a compound of formula II, wherein R1 to R5 are
hydrogen, n is 2 and X is a leaving group.
4. A process accordlng to claim 1 for the production
of 1-(Imidazolidin-2-ylidenamino)indoline, which comprises
cyclizing 1-(indolin-1-yl)-2-methylisothiourea hydrochloride
by heating it in a mixture of ethanol and ethylene
diamine.
5. 1-(Imidazolidin-2-ylidenamino)indoline whenever
produced by a process according to claims 3 or 4, or by
an obvious chemical equivalent thereof.

Description

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l-AMINO SUBSTITUTED INDOLINE
DERIVATIVES AS VASOCONSTRICTING AGENTS
The present invention relates to 1-aminoindoline
derivati~es.
In accordance with the invention there are provided
compounds of formula I,
R4
~ ~ R
R5 1 l2
~C~ ~ (CH )
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 l 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 l to 4 carbon
atoms, alkylthio of l to 4 carbon atoms or
halogen of atomic number of from 9 to 35, and
j~

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n is 2,3 or 4, and pharmaceutically acceptable
acid addition salts thereof.
Alkyl, alkoxy and aLkyl ~ o preferably contain 1 or 2, carbon atoms,
and especially l carbon atom.~lalogen is preferably chlorine.
Rl,R2,R3 and R5 are preferably hydrogen. R4 is prefer-
ably 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,
4 ~
~ N ~ 12 II
R5 N~ / NH
\N ~ 2 n
5 wherein Rl to R5 and n are as defined above and
X is a leaving group.
Where necessary or desired the resulting compound of
formula I may be converted into a pharmaceutically
acceptable acid addition salt thereof.
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
Ra is alkyl of 1 to 4 carbon atoms~ especially

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methyl, or R is hydrogen. The reaction is preferably
e~fected 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 convenient-
ly 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 150C and is preferably at least 50C, 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 Rl 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,

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R--~ 3
`~`C I I I
\S--Y
wherein R3 to R5 and X are as defined abo~e and the group
-S-Y is a leaving group, with a compound of formula IV,
Rl-NH-(CH2)n N~ 2 IV
wherein Rl, 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 ldentical 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 com-
pounds 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 analoqous
to known reaction conditions for the production of a
l-(indolin-l-yl)-guanidine derivative from a l-~indolin-
l-yl)-2-(lower)alkylisothiourea.

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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 kno~n processes.
In the following non-limitative Examples all temperatures
are indicated in degrees Centigrade and are uncorrected.
Exam~le 1: 1-(Imidazolidin-2-ylidenamino)indoline
To 10 g 1-(indolin-1-yl)-2-methyliscthiourea hydrochloride
dissolved in 40 ml ethanol are added 8 ml ethylene diamine
and the reaction mixture is boiled for 6 hours ~ith
stirring. The mixture is then evaporated to dryness and
the residue is extracted from a 1 N solution of sodium
hydroxide with methylene chlorid-e. The organic phase is
then dried over magnesium sulphate and evaporated. The
title compound is obtained (M.P. o~ the hydrogen maleate
171-172 - from ethanol/ether).
The starting material is obtained as follows:
l-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 l-(indolin-l-yl)-2-meth~l-
isothiourea hydroiodide by heating up for 1 hour withmethyl iodide in methanol. The free base is obtained by

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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 hydro-
chloride (M.P. 227-229 - from methanol/ether).
The following compounds of formula I are obtained in a
manner analogous to ~xample 1, using the corresponding
starting materials of formula III, wherein Y is methyl
and X is -NH2 or -NH-CH3, and of formula IV:
Ex.No. Rl R2 R3 4 R5 n ¦ M.P.
, . .. _. . ___ .. . . _
2 H H H 5-Cl H 2b 182-184
3 H H 2-Me H H 2hcl 226-228
4 ~ H 3-Me H ~ 2b 173-174
H H H 4-Me H 2b 148-149
6 H H H 4-OMe H 2hma 160-162
7 H- H H 7-Me H 2hcl 194-196
b = in free form
hcl = hydrochloride
hma = hydrogen maleate
~ - .. . . .
The compounds of formula I exhibit pharmacological0 activity. In particular, the compounds possess vasoconstricting
activity, as indicated by standard tests. For
example, this activity may be observed ln vlvo in rats
treated in accordance with the principles of J.S.
Gillespie and T.C. Muir, Br.J. Pharmac.Chemother. ~1967)

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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.
For this use an indicated daily dose is from about
0.0025 to about 1 mg, conveniently administered in
- divided doses 2 to ~ times a day in unit dosage from
containing from about O.OOP5to about 0.5 mg, or in
sustained release form.
The activit~ 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 acceptabie
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.