BENZOXAZOLINONES SUBSTITUEES EN 6 PAR UNE CHAINE AMINO-ALCOOL OU AMINO-CETONE; PREPARATION ET UTILISATION DANS DES PRODUITS PHARMACEUTIQUES

BENZOXAZOLINONES, SUBSTITUTED IN THE 6-POSITION BY AN AMINO-ALCOHOL CHAIN OR AMINO-KETONE CHAIN, THEIR PREPARATION AND THEIR USE IN PHARMACEUTICAL PREPARATIONS

Abrégé anglais

ABSTRACT
The invention is dealing with compounds of
the formula:
<IMG>
and pharmaceutically acceptable salts thereof,
in which R1 and R2 represent hydrogen or a lower
alkyl radical, A represents the amino radical, a
secondary or tertiary amino radical or a radical,
in which the nitrogen linkage atom is included in
a heterocyclic ring and B represents either the
carbonyl radical or the hydroxy-methylene radical,
having antihypertensive and analgesic properties.

Revendications

23804-173
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the
formula I
<IMG>
or a pharmaceutically acceptable salt thereof, in which R1 represents
hydrogen or a lower alkyl radical; R2 represents hydrogen or a
lower alkyl radical; A represents the amino radical, a secondary
or tertiary amino radical or a radical, in which the nitrogen
linkage atom is included in a 5 or 6-membered heterocyclic ring;
and B represents either the carbonyl radical or the hydroxy-
methylene radical which process comprises:
(A) condensing an amine of the formula AH in which A is as
defined above, with a 6-haloacetyl benzoxazolinone derivative of
the general formula II
<IMG> II
in which R1 and R2 are as defined above, and Hal stands for
halogen to obtain a compound of formula I in which B represents
the carbonyl radical, or
(B) reacting an amine of the formula
OA/8480-083
- 20 -

<IMG>
in which R3 represents hydrogen or a lower alkyl, with the 6-
haloacetyl benzoxazolinone derivative of the general formula II,
thereby otaining a compound of formula I in which B represents
the carbonyl radical and A represents a radical of the formula
<IMG>
- 21 -

and then removing the benzyl group of the resulting compound by catalytic hydro-
genation to obtain a compound of formula I in which B represents the carbonyl
radical and A represents -NHR3 in which R3 is as defined above, or
(C) reacting the 6-haloacetyl benzoxazolinone derivative of the general
formula II as defined above with hexamethylene tetramine, and then heating the
reaction mixture in an acidic medium to hydrolyse, thereby preparing a compound
of formula I in which B represents the carbonyl radical and A represents the
amino radical, and
(D) when required, N-alkylating or N-aralkylating the amino radical or a
secondary amino radical in a compound of formula I produced by process variant
(A), (B) or (C) thereby preparing a compound of formula I in which B represents
the carbonyl radical and A represents a secondary or tertiary amino radical,
and
(E) when required, reducing the keto carbonyl radical in the compound
produced by process variant (A), (B), (C) or (D) whereby preparing a compound
of formula I in which B represents the hydroxy-methylene radical, and
(F) when required, converting a compound of formula I produced by process
variant (A), (B), (C), (D) or (E) into a pharmaceutically acceptable salt
thereof.
2. A process according to claim 1, wherein process variant (A) is
carried out using an amine of formula AH in which A is an amino group, or
mono- or disubstituted amino group, the substituent being selected from the
group consisting of an alkyl radical containing 1 to 6 C atoms or a phenylalkyl
radical containing 1 to 6 C atoms in the alkyl moiety, the phenyl group in the
phenylalkyl radical being unsubstituted or substituted with one or more halogen,
lower alkoxy having 1 to 6 C atoms or CF3 radicals, or A is a 5- or 6-membered
heterocyclic ring which may contain a further oxygen or nitrogen ring atom and
may be substituted with (1-4 C) alkyl, phenyl or benzyl wherein the aromatic
- 22 -

group may be substituted by halogen, (1-4 C) alkoxy or trifluoromethyl.
3. A process according to claim 1, wherein process variant (D) is
carried out using a compound produced by the process according to claim 2.
4. A process according to claim 1 for the preparation of a compound of
formula I in which B, R1 and R2 are as defined in claim 1 and A is a mono-
lower alkyl amino group, wherein process variant (A) and where required (E) are
carried out using a starting material of formula AH wherein A is as defined
above; process variant (B) and where required (E) are carried out using a
starting material of formula
<IMG>
in which R3 is a 1-6 C alkyl; or process variant (D) is carried out by mono-
lower alkylating a compound of formula I in which A is the amino radical and
where required the mono-lower alkylated compound is reduced by process variant
(E).
5. A process according to claim 1 for the preparation of a compound of
formula I in which B, R1 and R2 are as defined in claim 1 and A is a di-lower
alkyl amino group, wherein process variant (A) and where required (E) are
carried out using a starting material of formula AH wherein A is as defined
above; or process variant (D) is carried out by mono- or di-loweralkylating
a compound of formula I in which A is the amino radical or mono-loweralkyl
amino radical and where required the di-loweralkylated compound is reduced by
process variant (E).
6. A process according to claim l for the preparation of a compound of
formula I in which B, R1 and R2 are as defined in claim 1 and A is benzylamino
or a N-benzyl N-lower alkyl amino group, wherein process variant (A) is carried
- 23 -

out using a starting material of formula AH wherein A is as defined above
whereby preparing a compound of formula I in which B is the carbonyl group and
A is as defined above and where required process variant (E) is carried out by
reducing the carbonyl group of the thus prepared compound with a complex metal
hydride whereby preparing a compound of formula I in which B is the hydroxy-
methylene radical and A is as defined above; process variant (D) is carried out
by N-lower alkylating a compound of formula I wherein A is the benzylamino
radical or by N-benzylating a compound of formula I wherein A is a mono-lower
alkyl amino radical.
7. A process according to claim 2 for the preparation of a compound of
formula I in which B, R1 and R2 are as defined in claim 1 and A is a heterocyclic
ring selected from the group consisting of piperidino, morpholino, 4-benzyl
piperidyl, 4-methyl piperazinyl, 4(2-lower alkoxy-2-phenylethyl) piperazinyl and
4-phenylpiperazinyl, in which the aromatic ring is unsubstituted or substituted
by halogen, a lower alkoxy radical or the trifluoromethyl radical, wherein an
amine of formula AH in which A is as defined above is used as the starting
material.
8. A process according to claim 1, wherein process variant (D) is
carried out using a compound produced by the process according to claim 7.
9. A process according to claim 1, 2 or 4 in which a 6-haloacetyl
benzoxazolinone derivative of the formula II
<IMG> II
in which Hal represents bromine, R1 represents hydrogen or methyl, and R2 repre-
sents hydrogen or methyl, is used.
- 24 -

10. A process according to claim 5, 6 or 7 in which a 6-
haloacetyl benzoxazolinone derivative of the formula II
<IMG> II
in which Hal represents bromine, R1 represents hydrogen or methyl,
and R2 represents hydrogen or methyl, is used.
11. A process for the preparation of 2-[4-(4-fluorophenyl)-
piperazinyl]-1-(3-methyl-2-benzoxazolinon-6-yl) propanone or a
pharmaceutically acceptable acid addition salt thereof, which
process comprises:
(a) reacting 2-bromo-1-(3-methyl-2-benzoxazolinon-6-
yl)propanone with 4-(4-fluoro) phenyl piperazine, and
(b) if desired, converting the product of step (a) into
a pharmaceutically acceptable acid addition salt thereof.
12. A process for the preparation of 2-isopropylamino-l-
(2-benzoxazolinon-6-yl) ethanol or a pharmaceutically acceptable
acid addition salt thereof, which process comprises:
(a) reacting 2-bromo-1-(2-benzoxazolinon-6-yl) ethanone
with isopropylamine whereby preparing 2-isopropylamino-l-(2-
benzoxazolinon-6-yl) ethanone, and
(b) reducing the keto carbonyl radical of the product
of step (a) with a complex metal hydride or by a catalyst
hydrogenation, and
(c) if desired, converting the reduction product in a
pharmaceutically acceptable acid addition salt thereof.
- 25 -

13. 2-Isopropylamino-1-(2-benzoxazolinon-6-yl) ethanol or a
pharmaceutically acceptable acid addition salt thereof whenever
prepared or produced by the process of claim 12 or by an obvious
chemical equivalent thereof.
14. A process according to claim 1 for the preparation of a
compound of formula I in which R1 and R2 each represent hydrogen,
B represents the hydroxymethylene radical and A is the isopropyl-
amino radical, wherein process variant combination (A) + (E) is
carried out using isopropylamine as the amine of formula AH and
the 6-haloacetyl benzoxazolinone derivative of formula II in
which R1 and R2 are hydrogen, and Hal is bromine; process variant
combination (B) + (E) is carried out using an amine of the formula
<IMG>
in which R3 is isopropyl and the 6-haloacetyl benzoxazolinone
derivative of formula II in which R1 and R2 are hydrogen and Hal
is bromine; or process variant combination (C) + (D) + (E) is
carried out using the 6-haloacetyl benzoxazolinone derivative of
formula II in which R1 and R2 are hydrogen and Hal is bromine in
process variant (C) and N-isopropylating in process variant (D).
15. A compound of the formula I
<IMG>
- 26 -

or a pharmaceutically acceptable salt thereof, in which R1
represents hydrogen or a lower alkyl radical; R2 represents
hydrogen or a lower alkyl radical; A represents the amino radical,
a secondary or tertiary amino radical or a radical, in which the
nitrogen linkage atom is included in a 5 or 6-membered hetero-
cyclic ring; and B represents either the carbonyl radical or the
hydroxy-methylene radical
- 27 -

whenever prepared or produced by the process of claim 1 or by an obvious
chemical equivalent thereof.
16. A process for the preparation of a compound of formula I-a
<IMG>
in which R1a represents hydrogen or methyl, R2a represents hydrogen or methyl,
Aa represents the amino radical, a mono- or di-lower alkylamino, a mono-lower
alkyl benzylamino, a (3,4-di-lower alkoxy)phenylethylamino or a heterocyclic
ring selected from the group consisting of morpholino, piperidino, 4-benzyl-
piperidinyl, 4-(2-lower alkoxy-2-phenylethyl)piperazinyl and 4-phenylpiperazinyl
in which the phenyl ring is substituted by halogen, a lower alkoxy or trifluoro-
methyl, or a pharmaceutically acceptable acid addition salt thereof, which
comprises
[I] preparing a compound of formula I-b
<IMG>
in which R1a, R2a and Aa are as defined above, by (A) condensing an amine
of the formula Aa-H in which Aa is as defined above with a 6-bromoacetyl
benzoxazolinone derivative of the formula II-a
- 28 -

<IMG> (II-a)
in which R1a and R2a are as defined above; or
(C) reacting the 6-bromoacetyl benzoxazolinone derivative of the formula
II-a as defined above with hexamethylene tetramine, and then heating the
reaction mixture in an acidic medium to hydrolyse, thereby preparing a compound
of formula I-b in which Aa represents the amino radical, and
[2] reducing the keto carbonyl radical in the compound of formula I-b
with a complex metal hydride or by a catalytic hydrogenation into the hydroxy
methylene radical.
17. A process according to claim 16, wherein a compound of the formula
I-b in which R2a is methyl is used in step [1] and the reduction is carried
out using an alkali metal borohydride in step [2], whereby preparing a compound
of formula I-a of a threo configuration in which R2a is methyl.
18. A process according to claim 16, wherein a compound of the formula
I-b in which R2a is methyl is used in step [1] and the reduction is carried
out by a catalytic hydrogenation in step [2], whereby preparing a compound
of formula I-a of an erythro configuration in which R2a is methyl.
19. A process for the preparation of erythro 2-[4-(2-methoxyphenyl)-
piperazinyl]-1-(3-methyl-2-benzoxazolinon-6-yl)propanol or a pharmaceutically
acceptable acid addition salt thereof, which process comprises:
- 29 -

(a) condensing 2-bromo-1-(3-methyl-2-benzoxazolinon-6-yl)propanone
with 4-(2-methoxyphenyl)piperazine to obtain 2-[4-(2-methoxyphenyl)piperazinyl]-
1-(3-methyl-2-benzoxazolinon-6-yl)propanone,
(b) catalytically hydrogenating the product of step (a) so as to reduce
the keto carbonyl radical to the hydroxy-methylene radical, thereby preparing
the title compound, and
(c) if desired, converting the product of step (b) into a pharmaceutically
acceptable acid addition salt thereof.
20. A process for the preparation of 2-[4-(3-trifluoromethylphenyl)-
piperazinyl]-1-(3-methyl-2-benzoxazolinon-6-yl)ethanol or a pharmaceutically
acceptable acid addition salt thereof, which process comprises:
(a) condensing 2-bromo-1-(3-methyl-2-benzoxazolinon-6-yl)ethanone with
4-(3-trifluoromethylphenyl)piperazine to obtain 2-[4-(3-trifluoromethylphenyl)-
piperazinyl]-1-(3-methyl-2-benzoxazolinon-6-yl)ethanone,
(b) reducing the keto carbonyl radical in the resulting product of
step (a) into the hydroxy-methylene radical thereby preparing the title com-
pound, and
(c) if desired, converting the product of step (b) into a pharmaceutically
acceptable acid addition salt thereof.
21. A compound of formula I-a
<IMG>
in which R1a represents hydrogen or methyl, R2a represents hydrogen or methyl,
- 30 -

Aa represents the amino radical, a mono- or di-loweralkylamino, a mono-loweralkyl
benzylamino, a (3,4-di-loweralkoxy)phenylethylamino or a heterocyclic ring
selected from the group consisting of morpholino, piperidino, 4-benzylpiper-
idinyl, 4-(2-loweralkoxy-2-phenylethyl)piperazinyl and 4-phenylpiperazinyl
in which the phenyl ring is substituted by halogen, a lower alkoxy or tri-
fluoromethyl or a pharmaceutically acceptable acid addition salt thereof,
whenever prepared or produced by the process of claim 16 or by an obvious
chemical equivalent thereof.
- 31 -

Description

7~3L~
NOVEL BENZOXAZOLINON~S, SUBSTITUTED IN THE
6-POSITIO~ BY AN AMINO-ALCOHOL CHAIN OR AMINO-KETONE
CHAIN, THEIR PREPARATION AND THEIR USE IN
YHARMACEUTICAL PREPARATIONS.
The present invention is dealinq with n~vel
benzoxazolinone derivatives, substituted in the
6-position by an amino-alcohol chain or amino-ketone
chain, as well as their pharmaceutically acceptable
salts.
More particularly the invention is dealing with
benzoxazolinone derivatives of the general formula:
A - CH - B ~ \
R 2 ~f
Rl :
and pharmaceuticalJ.y acceptable salts thereof,
in which
~1 represents hydrogen or a lower alkyl radical;
R2 represents hydrogen or a lower alkyl radical;
A represents the amino radical or a secondary or
tertiary amino radical, or
a radical, in which the nitrogen linkage atom is inc
luded in a 5 or.6-membered heterocyclic ring;
V~

B represents either -the carbonyl radical (-C-) or
O
the hydroxy-methylene radical -(CH~
OH
These compounds of formula I and pharmaceutically accept-
able sal-ts thereof are useful in pharmaceutical preparations,
especially because of their interesting antihypertensive
properties.
The invention also is dealing with a process for producing
the compounds o~ formula I or their pharmaceutically acceptable
salt, which process comprises:
(A) condensing an amine of the Eormula AH in which A is
as defined above, with a 6-haloacetyl benzoxazolinone deriva-tive
of the general formula II
Hal-CH C ~ O
R2 ~ ~ ~ II
Rl
in which Rl and R2 are as defined above, and Hal stands for
halogen -to obtain a compound of formula I in which B represents
-the carbonyl radical, or
(~) reacting an amine oE -the Eo:rmula
E-[N-CH2 ~
R3
in whlch R3 represents hyd.ro~en or a lower alkyl wi-th -the 6-
haloacetyl benzoxazolinone deriva-tive of the general Eormula II,

Ç_~
thereby obtaining a compound of formula I in which B represents
the carbonyl radical and A represents a radical of the formula
-N-CH2 -
and then removing the benzyl group of the resulting compound by
catalytic hydrogenation to obtain a compound of formula I in
which B represents the carbonyl radical and A represents -NHR3
in which R3 is as defined above, or
(C) reacting the 6-haloacetyl benzoxazolinone derivative
of the general formula II as defined above with hexamethylene
tetramine, and then heating the reaction rnixture in an acidic
medium to hydrolyse, thereby preparing a compound of formula I
in which B represents the carbonyl radical and A represents the
amino radical, and
(D) when required, N--alkylating or N-aralkylating the
amino radical or a secondary amino radical in a compound of
formula I produced ~y process variant (A), (B) or (C) thereby
preparing a compound of formula I in which B represents the
carbonyl radical and A represents a secondary or tertiary amino
radical, and
(E) when requlred, reducing the keto carbonyl radlcal
in -the compound procluced by process variarlt (A), (~), (C) or (D)
whereby prepcl:r:Lng a compouncl of formula I in which B :represen-ts
the hycl:roxy-methy].ene raclical, and
(E') when required, converting a compound of formula I
produced by process variant (A), (B), (C), (D) or (E.) into a
i -2a-

-
pharmaceutically acceptable salt thereof.
In formula I, the lower alkyl group as used in the
definition of Rl and R2 is preferably an alkyl group with 1 to 6
carbon atoms, and more particularly an alkyl group with l-4
carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl,
tert. butyl or isobutyl.
By the secondary or tertiary amino radical;as used in
the definition of A is to be understood an amino ra~1cal in which
one or both hydrogens have been replaced by lower alkyl (1-6 Cj
defined before or phenyl (1-6 C) alkyl, whereby the phenyl group
may be substituted by one or more halogen, lower alkoxy (l-6 C)
or CF3 radicals.
Examples of the secondary amino radical are: methyl
amino, ethyl amino, propyl amino, isopropyl amino, n.butyl amino,
isobutyl amino, tert.; butyl amino, benzyl amino, phenylethyl
amino, m.p. dimethoxyphenylethyl amino, p. methoxyphenylmethyl
amino and p. fluoro- or p. chlorophenylethyl amino.
Examples of the tertiary amino radical are: dimethyl
amino, diethyl amino, d1propyl amino, methylethyl amlno and
methylbenzyl amino.
By the radlcal in which the nitrogen linkage atom is
included in a 5 or 6 membered heterocyclic
-2b-
~: .

~L7~43
ring, is to be understood a five or six membered
nitrogen containing ring, that may contain a
further oxygen or nitrogen atom and may optionally
be substituted with alkyl (1~4 C), phenyl or benzyl,
S whereby the aromatic group may be substituted by
- halogen, alkoxy (1-4 C) or trifluoromethyl.
Examples o~ such radicals are:
; piperidina, morpholino, piperazino, 4-benzylpiperidyl,
4-methyl-piperazinyl, 4-phenyl-piperazinyl~ in
which the phenyl moiety may be substltuted by e.g.
o. methoxy, p. fluoro or mr CF3, and 4(2-alkoxy-
2-phenyl-ethyl)piperazinyl.
The compounds of formula I and their
pharmaceutically acceptable salts are prepared by
methods in actual use or described in the literature~
For example the compounds I may be prepared
by condensing an amine A-H and a 6-halo-acetyl-
benzoxazolinone III( preferably the bromo-acetyl
derivative), suitably substituted by Rl and R2, and
if necessary followed by reduction of the ketone
thus obtained into the corresponding alcohol using
con~entional reduction means.
This synthesis corresponds to the following
reaction scheme:
l
Hal-CH-C ~ C--O ~~ / =0
II Rl
Hal = halogen, preferably bromine.

The reaction takes plaee in a suitable organic solvent.
Preferably, acetone is used, but, as the ease may be, other
eustomary organic solvents, such as acetonitrile, benzene, dioxan,
chloroform, tetrahydrofuran or an aleohol may be used.
The two starting produets preferably react in sueh pro-
portions that there are at least two moleeules of the amine ~= AH]
for one molecule of halogenated derivative of formula II. The
reaction may also be performed using equimoleeular quantities but
adding in addition another basic compound, such as triethylamine
or potassium carbonate, to the reaetion medium.
Aeeording to variant (s) of the above process, compounds
of formula I, in which A represents a primary (A = MH2) or
secondary amino radical may also be prepared by reacting a
compound of formula II with an amine AH, in which A represents
the moiety:
-N-CH2 ' - ~3
in which R3 represen-ts hydrogen or alkyl (1-6 C), and treating
the N-benzyl derivative thus obtained wi~h hydrogen in the
presence of a suitable cata].yst, such as Pd/charcoal.
2t) Variant (C) oE the above process fo:r the preparation of
eompounds I, in whieh A represents an amino (-NH2) q.roup,
preferably consists o:E
a) re~aetlrl~ a compound oE Eormula :[I with the amine AH, in which
AH represents the compound hexamethylene te-t::ramine, in a
sui.table sol.vent,
b) refluxing the mixture and

3~3
c) heating the mixture in acidic medium in order to hydrolyse
the compound thus obtained.
The primary or secondary amines of formula I thus
obtained by any process variants mentioned above may be N-
alkylated or N-aralkylated in the usual manner, if desired.
The compounds I obtained by the above variants -thereof
may in addition~, and if necessary, be reduc~ed in order to obtain
the hydroxylated derivatlves according to formula I (s = -CH(O~
This reaction, reducing the carbonyl moiety into a
hydroxy methylene moiety, is effected in the usual manner~for
such reduction. For example the reduction may be carr1e~d~out by
catalytic hydrogenati~on, e.g. under hydrogen pressure at a
temperature of about 100C~and in the presence of 10~ Pd/charcoal,
or by using comple~x metalhydrides, such as lithium-aluminiumhydride
or, pre~erably, sodium borohydride, in a suitable liquid such
as methanol. ~
The compounds of formula I contain chiral carbon(s)
where B represents a hydroxy-methylene radlcal and/or R2 is
, ~
different from hydrogen. The optical isomers, which can be
obtained by usual resolution procedures, also belong to the
compounds of the invention.
When R2 is~different from hydrogen, the corresponding
alcohols of formula I have elther a threo- or an erythro-
arrangem~nt. The threo-1somers are the main product resulting
from the reduction of a compound ~ (in whlch B i5 a carbonyl group)
wlth borohydride and the erythro-lsomers are the maln product
resulting from a cata~ytic hydrogenation. Both isomers belong
to the compounds accordlng to the invention.
-5-
'~ ' '
~: . ~ .- . . . .

3~
In order to obtain the pharmaceutically
acceptable salts of the compounds of formula I,
the amines obtained are treated with pharmaceutically
acceptable acids, such as HCl, maleic acid, tartaric
acid, fumaric acid, citric acid, etc.
The pharmacological activity of the compounds
of the invention is shown in vitro by an
interference with the adrenergic receptors ~ 2
and a.
The following experiments have been carried
out in vitro:
- As to ~1 adrenergic receptors: the examination of
the antagonism of the positive inotropic e~fect of
isoprenaline on the ~1 receptors of the
electrically stimulated left guinea-pig auricle;
- As to ~2 adrenergic receptors: the investigation
of the antagonism of the bronchodilator effects
of isoprenaline on the P2 receptors of the
tracheal guinea-pig muscle;
- As to a adrenerglc receptors: the study of the
interference of the compounds of the invention
on the contraction of the isolated vas deferens
of the rat, caused by cumulative doses of nor-
adrenaline.
The results are expressed in TabIe I by the usual
parameters of molecular pharmacology in accordance
with the criteria used by Van Rossum, [Arch. Int.
Pharmacodyn. 143, 299/330, 1963].
Pharmacologlcal tests have ~urthex shown that the
compounds stuc3ied did possess a remarkably low
toxicity. The LD50 values in mice using oral
administration vary between 800 my/kg and
1200 mg/kg.

Table I
- Interference with the adrenergic receptors
No. .
1) 31 ~2
9 PA2 = 5,4 + 0,39
PD'2 = 3,8 partial agonist inac-tive
_, _ _
pA2 = 5,9 + 0~08
PD'2 =4,59 + 0,61 partial agonist P~2 ~ 5.3 ~ 0,12
_ _
13PA2 = 5,3 inactive t 10-4 M/l
_ _ _ _ I
16PA2 = 5,2 inactive PA2 = 4,73 + 0,52
18 PA2 =7,46 _ 0,17 PA2 = 6,11 + 0,10 P~2 = 6,03 + o,43
19PA2 =6,65 + o,ll PA2 = 5,83 + 0,40 lnactive
_ _ ~
22PA2 =5,55 + 0,50 partial agonist PA2 = 577 + 0,25
_ .
PA2 = 5,7 inactive + 310%
PD'2 = 4,2 at 10 4 M/l
_ _ I
PA2 = 6,14 + 0,31
27 PA2 =5,65 + 0,40 PA2 = 4,68 + 0,16 PD'2 = 4,73 + 0,38
. pA2 =5 , 21 + 0, 43
28 P 2 inactiveinactive
:_ _ _
pA2 = 5,53+0, 28 + 180%
29 PD'2= 4,50+0,21 partial agonist at 10 M/l
. 30 ~ o,So inactive lo~ 1
__ .
potentiation of the effects of noradrenaline.
) The compound~ imdicated by ~No~ are shown in table II
under the same number

~1 79~4;3
The results compiled in thic table show that
the compounds studied, on the whole, possess valuable
~1 blocking activity and that they can be
distinguished by their activity on the ~2 and a
receptors~ manifesting, on the one hand, their
more or less high cardio-selectivity and their
influence on the bronchial level and, on the other
hand, their vascular tropism~
Compound No. 18 is most valuable on account
of its hlgh ~1 blocking ac-tivity, combined with
a blocking activity and wea~ cardio-selectivity.
Compounds Nos. 27, 22 and 10 show largely
the same profile as compound NoO 18, although they
- exert a slightly lower ~1 blocking acti~ityl
These same activities appear again in compound
No. 16, but without much bronchodilator action.
Numerous other compounds (Nos. 9, 13, 25, 28 and 30)
possess great, even total, cardio-selectivity~
Compound No. 31, which has a slightly lower effect
on the adrenergic receptors as the other compounds
of the invention possesses in addition remarkable
analgesic properties shown by thermal stimulus
tests and chemical stimulus tests.
In the thermal stimulus test [according to
N.B. FDDY and D.J. LEIMBACH, Exp. Ther. 107, 385/393
(1953)], the FD50 (in mice) of -this compound is
4.4 mg/kg by oral administration.
Xn the chemical stimulus test [E. SIEGMUND,
R. G0 LU CADMUS, Proc. Soc. Exp. Biol. Med. 9S,
7~9/731 (1957)1, the ED50 (in mice) of this compound
is 9 mg~kg by oral administrakion.
Based upon the above mentloned results the
compounds of the invention can be used as anti-
hypertensive agents and in addition in case of
compound 31 for the treatment of pain syndromes.

~7~3~3
Combined with the usual pharmaceutical carriers
they may be administered enterally or parenterally
at a daily dose between 0,5 and 50 mg/kg body weight.
The preferred daily dosage for administration to
humans is between 100 and 1000 mg dependent upon
the mode of administrationO
Preferred compounds according to the invention
are the compounds of formula I, in which (whether
or not in combination):
Rl represents hydrogen or methyl,
R2 represents hydrogerl or methyl,
B represents the hydroxymethylene radical and
A represents a secondary or tertiary amino radical
and especially the alkylamino, dialkylamino and
benzylamino radical, or a radical in which the
amino linkage atom is included in a heterocyclic
ring.
More particularly that compound of formula I
is preferred in which Rl and R2 represent hydrogen,
B represents the hydroxymethylene radical and A is
an isopropylamino moiety. ~
,

~'7~3
Example 1
2-(N-methyl-N-benzv~lamino)-1-(3-methyl-2-benz-
oxazolinon-6-yl) propanone
1201 g ~0.10 M) o~ N-methylbenzylamine were
added to an acetone solution of 14.2 g tO.05 M) of
2-bromo-1-(3-methyl-2-benzoxazolinon-6 yl) propanone,
cooled to 0 C, and the reaction was allowed to
proceed, with stirrinq, the temperature being
maintained at 0 C ~or 1~ hours.
The precipitate was then filtered off, the
filtrate concentrated and the fresh precipitate
filtered; the two precipitate fractions were combined
and then treated with 250 cm3 of normal hydrochloric
acid. After filtration, the filtrate was rendered
alkaline with a 10% aqueous soda solution, the
precipitate filtered off, washed with water, dried
and recrystallised from ethanol at 95 C.
13 g Of compound as per heading were thus
obtained, having a melting point F = 154 C and
20 having theelemental analysis:
C% H% N%
calculated 70.35 6.21 8.63
found 70.32 6.23 8.64
Examele 2
2-methylamino-1-(3-methvl-2-benzoxa~olinon-6-yl)
propanone
3.24 g (0.01 M) of the compound, obtained in
Example 1, were dissolved ltl 100 cm3 of methanol,
containing 0.01 molecule of hydrochloric acid, then
100 rng of 10%-palladiurn on charcoal were added and
the mlxture was submitted to hydrogenation at
ordinary temperature and pressure up to absorption
of the theoretical volume of hydrogen. When the
reaction was finished, the mixture was filtered,

~75~3~3
the solvent evaporated in vacuo and the product
recrystallised from absolute alcohol.
1.8 g Of product as per heading were obtained,
having a melting point F = 240 C and this elementa
analysis:
C% H% N%
calculated51.52 5.76 10.01
found 51.52 5.49 10.05
Example 3
2-isopropylamino-1-(2-benzoxazolinon~6-yl)ethanone
Having dissolved 17.7 g (0.3 M) of isopropylamine
in 45 cm3 of methanol, 7.7 g (0.03 M) of 2-bromo-1-
(2-benzoxazolinon-6-yl)ethanone were added and the
reaction was allowed to proceed, with stirring, at
ambient temperature for 30 minutes. The precipitate
was then filtered off, washed, dried and then
dissolved in ethanol~ The product as per heading
was then obtained as crystals in the form of the
hydrochloride, by passing through a stream of dry
hydrogen chloride gas. 4 g Of product were thus
obtained, having a melting point F - 205 C, the
monohydrate of which having this element analysis:
C% H% N%
calculated 57.14 6.34 11.11
found 57~25 6.32 11.16
Example 4
2-~4-(2-methoxyphenyl)piperazinyll1-(3-methyl-2-
benzoxazollnon-6-yl)ethanone
Having dissolved 5.4 g ~0~02 M) of
2-bromo 1-~3-methyl-2-benzoxazolinon-1-yl)ethanone
in an adequate quantity of dioxan, a solution,
consistlng of 3~56 g ~0.02 M) of 2-methoxyphenyl
plperazine and 5 g ~0.05 M) of triethylamine in

~ ~'7.,~3~3
20 cm3 of dioxan was added drop by drop and with
stirring and the reaction was allowed to proceed
at ambient temperature for 24 hours. The precipitate
was then filtered off, the recovered solvent
evaporated, the second fraction of precipitate
combined with the first, treated with 50 cm3 of
10% soda, filtered and washed and then recrystallised
from acetone.
5.3 g Of product as per heading were then
obtained, having a melting polnt F = 186-187 C
and this element analysis:
C% H% N%
calculated 66.13 6.08 11.02
found 66.11 6011 10.99
Example 5
2-(4-benzyl-piperidinyl)l-(3-methyl-2-benzoxazolinon-
6-yl)ethanone
By proceeding as indicated in Example 4, but
replacing the amine indicated by 4-benzyl piperidine,
5.7 g of product as per heading are obtained, having
a melting point F = 168-169 C and this element
analysis:
C% H% N%
calculated 72.51 7.69 13.17
found 72.56 7.65 13.17
Example 6
2-amino-1-(2-benYoxazol~non-6-yl)ethanone
2.56 g (0.10 M) of 2-bromo-1(2-benY.oxa7olinoll-
6-yl)ethanone were introduced into a reactor
containing 1200 cm of absolute ethanol and 14.1 g
(0.10 M) o~ hexamethylene tetramine were added;
then the mixture was taken to reflux for 3 hours.
As soon as the reaction was finished, the

3~3
precipitate was filtered off and dried; then the
mixture was hydrolysed by heating under reflux
in the presence of 90 cm3 of concentrated hydro-
chloric acid and 170 cm3 of ethanol at 95 C.
After cooling, the precipitate was filtered off
and dried and then recrystallised from a solution
of hydrochloric acicl, (1 part concentrated
HCl - 1 part H20).
6.7 g of compound as per heading were thus
obtalned, having this element analysis:
C% H% N%
calculated 47.28 3.96 12.25
found 47.19 3.85 12.23
Example 7
2-isopropylamino~ 2-benzoxazolinon-6-yl)_ethanol
2.34 g (0.0 M) of the compound prepared in
accordance with Example 3 were dissolved in 100 cm3
of methanol; then 0.7 g (0.02 M) of sodium borohydride
was added with stirring and in small portions and
then the mixture was left, while being kep-t stirred,
for 4 hours at ambient temperature.
The mixture was then evaporated to dryness, the
residue taken up in absolute alcohol and a stream
of dry hydrochloric acid bubbled through and the
mass heated to boiling. After removing the sodium
chloride by filtration, the product was allowed to
recrystallise and 2 g of compound as per heading were
collected in the form of the hydrochloride, having a
~nelting point F = 220 C and this element analysis:
C% H% M%
calculated 52.84 6.28 10.27
found 52.81 6.33 10.35

14
~ xample 8
2-~4-(2-methoxy-phenyl) pipera~inylll-(3-methyl 2-
benzoxazolinon-6-yl) ethanol
Following the same procedure as that indicated
in Example 7, ~ut star-ting with the compound
obtained in Example 4, 3.3 g of product as per
heading are directly obtained in the form of the
base, having a melting point F = 126-127 C and
this element analysis:
C% H% N~
calculated 65.786.5710.96
found 65.54 6.58 10.95
~ le 9
2-(4-benzyl piperidinyl)-1-(3-methyl-2-benzoxazolinon-
6-yl) ethanol
By proceeding as indicated in Example 7, but
starting with the compound obtained in Example 5,
; 3.2 g of compound as per heading are directly
obtained in the form of the base, having a melting
point F = 156 C and this element analysis:
C% H% N~
calculated72.10 7.15 7.64
found 71.82 7.22 7.75
Example 10
; threo-2-[4-(3-trifluoromethyl phenyl?piperazinyl
L-~3-methyl-2-benzoxazolinon-6-yl) propanol
After preparing 2-L4-(3-trifluoromethyl phenyl)
piperazinyl~l-(3-methyl-2-benzoxazoLinon-6-yl) propanone
by an identical process to that described in
Example 4, 8.67 g of the said ketone were suspended
in methanol; then 1.4 9 o~ sodium borohydride were
added in small portions, with stirring. Stirring
was then allowed to continue for one hour at ambient

~t7~3~3
temperature. The precipitate of amino-alcohol
obtained was filtered off and it was recrys-tallised
from absolute alcohol, so as to produce 704 g of
compound as per heading, having a melting point
F = 192 C and this element analysis:
C~ H% N%
calculated 60.68 5.56 9.65
found 60.49 5.48 9.63
Example 1
erythro 2-[4-(2-methoxy-phenyl)-piperazinyl
(3-methyl-2-benzoxazolinon-6-yl) propanol
After preparing 2-[4-(2-methoxy-phenyl)-
piperazinyl]1-(3-methyl-2-benzoxazolinon-6-yl)
propanone by following the process of Example 4,
5 g of the said ketone were suspended in absolute
alcohol; then, after adding 0.5 g of 10%-palladised
charcoal, the mixture was submitted to a hydrogen
pressure of 80 bar, with stirring, the temperature
being gradually taken to 100 C. At the end of the
reaction, the catalyst was filtered off, the solvent
evaporated and the residue recrystallised from
absolute alcohol; 3.5 g of product as per heading
were obtained, having a melting point ~ 33 C
and this element analysis:
C% H% N%
calculated 66.486.85 10.57
found 66.64 6.93 10.33
Example 12
2-~-(3-trifluoromethyl)-phenyl-piperazinyl
(3-met~ 2-benzoxa~olinon-6-yl) ethanol
In a first step and following the same
procedure as that described in detail in Example ~,
2-~4-~3-trifluoromethyl)-phenyl-piperazinylll-

16
(3-methyl-2-benzoxazolinon-6-yl) ethanone was
prepared.
Then, in a second step, 4 g of the preceding
compound were reduced by means of sodium boro-
hydride by the process described in Example 7and 3.6 g of the compound as per heading were
obtained, having a melting point F = 139 C and
this ele~ent analysis:
C% H% N%
10calculated 59.85 5.26 9.97
found 59.79 5.49 9.93
ay the sa~e methods, the following compounds were
prepared:
15 TABLE II
A- CH - B -~^~
R
. _ _ _
: -ompound A B Rl R2Salt FC
~ . _ _
.~ 1 -NH-CH3 -ICO -CH3 H HCl 255
. .- . .
(Ex. 21 -NH-CH3 -Cj--CH3 -CH3 HCl ~240
_ _ .
3 < C H 3 --C-- --CH 3 --C H3 ~ ~ s ~ L__
4 L~ - . -C--CH 3 -C tl 3 j Ba se 1 6 8
S ¦ ~ _ -C-~1 -CH3 Base 194
,'.
;

~ 79~3
l7
Table I-I (continued)
___ _
compound¦ A B Rl 2 Salt FC
- CH3 -C- -CH3 -CH3 Base 154
(Ex. 1) -N ~ O
_ 2 ~ _
7 ~ ~ CF3 -IC- -CH3 -CH3 ~ase ll5
_ __
8 CH3 -C- H H HC1 205
~Ex. 3) -NH-CH \ O
~ _ _ _ _ __
9 OC~ -C- -CH3 H Base . 1~6
(Ex. 4) - ~ ~ O _
. -C- -CH3 -CH3 Base 193
O _ _. ¦
1l ~ -C- H -CH3 Base 775
12 ~ -C~- H H 207
13 r~ -C- -c~3 H Base 168
(~x. 5) -N ~ CH2 ~ _ _ _ _ _
. 14 - NH2 - ~ICo~ HH ` HCl>260
(Ex. 6) _ _ _ _
/ CH3 -CH- -CH3 H HCl 237
-NH-CH ~ OH
. ~ __
16 -NH2 -CH- H H HCl 230
_ . _ OH _ _
17 -NH-CH3 -CH- H H HCl 230
_~

Table II (continued)
~ .
cNmpound A B Rl R2 Salt FOC
.. . - __
18 CH3 CH- H H HCl 220
(Ex. 7) -NH-CH < OH
_ _ ~ 3 _ ~ _ _ _ _ _ .
19 CH3 CH- H H HC1 215
-NH-C- CH3 OH
CH3 _ _
~ F3 -CH- CH3 -CH3 Base 192
(Ex.10) ~ ~ . OH _ [Thréo~ _
21 ~-~ . ~ -CH- -CH3 -CH3 Base 232
OH _ [Thréo] _
22 >__~3 -CH--CH3 H Base 126
( E x . 8 ) _~ ~ OH .
_ _ ._ _ _
~- . 23 ~_~ -CH--CH3 -CH3 Base 217
__ OH . [Thréo]
_ .
~~~\ -CH- -CH3 H ~ase 155
(Ex. 9? - ~ -CH2 ~ OH _ .
26 ~ CP3 -CH- H -CH3 Base 187
-N ~ - ~ OH _ [Erythro~
27 ~-~ ~ -CH- -CH3 -CH3 Base 183
l ( Ex .ill) ~ ~ - ~ _ OH _ ~Erythro] _ _ .
: 28 . -CH- -CH3 -CH3 Base 157
_ ~ ~ _ _ OH ~ _ _ [Erythro¦
29 / -CH- -CH3 -CH3 Base 181 ¦
---N ~ CH? ~ ~ OH _ [Erythro~ _
_ . I
-CH- H H Base ?24
_ ~ ~ F bH .
_ _ . ~_ _~.----I
31 CP -CH- -CH H ~ase 139
r-~ r--~ 3 l 3
. OH _ _ .

3~3
19
Table II (continued)
_ _ _
cNomOpound A B R 1 R 2 S a 1 t F C
_ . _
3 2 OCH3 --CH-- H H HCl 23 3
--NH--CH 2--CH 2 ~)C~I 3 OH
_ _ _ .
3 3 J \ r~ --CH-- H H 2 HC 1 2 2 4
~ 2 1 ~> OH
__ _ _ _ _ - .
34/ \ ~--CH-- H H 2 HCl 230
--N N--CH2- CH ~0 OH
_ - _ _ _
35/ \/~\ --CH-- --CH3 H 2 HCI 230
./2 bc ~ OH . .
_ _ ~_
36~tl ~--CH ~) -CH- -CH3 H 223