CA1179343A - Benzoxazolinones, substituted in the 6-position by an amino-alcohol chain or amino-ketone chain, their preparation and their use in pharmaceutical preparations - Google Patents
Benzoxazolinones, substituted in the 6-position by an amino-alcohol chain or amino-ketone chain, their preparation and their use in pharmaceutical preparationsInfo
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- CA1179343A CA1179343A CA000386770A CA386770A CA1179343A CA 1179343 A CA1179343 A CA 1179343A CA 000386770 A CA000386770 A CA 000386770A CA 386770 A CA386770 A CA 386770A CA 1179343 A CA1179343 A CA 1179343A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
The invention is dealing with compounds of the formula:
The invention is dealing with compounds of the formula:
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 ~
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 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-
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 ~
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 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
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.
'~ ' ' ~: . ~ .- . . . .
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
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.
'~ ' ' ~: . ~ .- . . . .
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.
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-
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 ~ 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-(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:
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 ~ _
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 ~ 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-(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:
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 _ ~ _ _ _ _ _ .
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 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
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 _ ~ _ _ _ _ _ .
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 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
Claims (21)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a compound of the formula I
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
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 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 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.
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
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 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 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 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 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 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
II
in which Hal represents bromine, R1 represents hydrogen or methyl, and R2 repre-sents hydrogen or methyl, is used.
II
in which Hal represents bromine, R1 represents hydrogen or methyl, and R2 repre-sents hydrogen or methyl, is used.
10. A process according to claim 5, 6 or 7 in which a 6-haloacetyl benzoxazolinone derivative of the formula II
II
in which Hal represents bromine, R1 represents hydrogen or methyl, and R2 represents hydrogen or methyl, is used.
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.
(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.
(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.
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 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
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 whenever prepared or produced by the process of claim 1 or by an obvious chemical equivalent thereof.
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 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 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 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 (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:
(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.
(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.
(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 in which R1a represents hydrogen or methyl, R2a represents hydrogen or methyl, 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.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8020861A FR2491066A1 (en) | 1980-09-29 | 1980-09-29 | BENZOXAZOLINONES SUBSTITUTED IN 6 BY AN AMINOALCOHOL OR AMINOCETONE CHAIN, THEIR PREPARATION AND THEIR THERAPEUTIC USE |
| FR80.20861 | 1980-09-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1179343A true CA1179343A (en) | 1984-12-11 |
Family
ID=9246379
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000386770A Expired CA1179343A (en) | 1980-09-29 | 1981-09-28 | Benzoxazolinones, substituted in the 6-position by an amino-alcohol chain or amino-ketone chain, their preparation and their use in pharmaceutical preparations |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0049203A1 (en) |
| JP (1) | JPS57501427A (en) |
| CA (1) | CA1179343A (en) |
| DK (1) | DK49682A (en) |
| FR (1) | FR2491066A1 (en) |
| GR (1) | GR82309B (en) |
| HU (1) | HU185975B (en) |
| PT (1) | PT73740B (en) |
| WO (1) | WO1982001186A1 (en) |
| ZA (1) | ZA816555B (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3278014D1 (en) * | 1982-10-01 | 1988-02-25 | Merck & Co Inc | Aralkylaminoethanol heterocyclic compounds |
| FR2536749A1 (en) * | 1982-11-25 | 1984-06-01 | Cerm Cent Europ Rech Mauvernay | SUBSTITUTED (AMINO-2 ETHYL) -6 BENZOXAZOLINONES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATIONS |
| GB8325370D0 (en) * | 1983-09-22 | 1983-10-26 | Fujisawa Pharmaceutical Co | Benzoxazoline and benzothiazoline derivatives |
| FR2637286A1 (en) * | 1988-10-04 | 1990-04-06 | Adir | NOVEL BENZOXAZOLINON DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US5182278A (en) * | 1989-02-28 | 1993-01-26 | Adir Et Compagnie | Analgesic benzoxazolinones having at the 6-position a 1-hydroxy-3-morpholinopropyl side chain |
| FR2643634A1 (en) * | 1989-02-28 | 1990-08-31 | Adir | NOVEL BENZOXAZOLINONIC DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME |
| IL93473A0 (en) * | 1989-02-28 | 1990-11-29 | Pfizer | Antiinflammatory benzoxazolones |
| FR2645149A1 (en) * | 1989-03-30 | 1990-10-05 | Adir | |
| FR2646350B1 (en) * | 1989-04-28 | 1991-06-28 | Adir | NOVEL BENZOTHIAZOLINON DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| US5166353A (en) * | 1989-04-28 | 1992-11-24 | Adir Et Compagnie | Benzothiazolinone compounds |
| FR2663634B1 (en) * | 1990-06-22 | 1992-09-04 | Adir | NOVEL ACYL BENZOXAZOLINONES, PROCESS FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
| ATE194982T1 (en) * | 1992-04-24 | 2000-08-15 | Takeda Chemical Industries Ltd | BENZOXAZEPINE DERIVATIVES AS CHOLINESTERASE INHIBITORS |
| AU2006326850A1 (en) * | 2005-12-21 | 2007-06-28 | Cortical Pty Ltd | MIF inhibitors |
| DE102007047737A1 (en) | 2007-10-05 | 2009-04-30 | Merck Patent Gmbh | Piperidine and piperazine derivatives |
| CN101759665B (en) * | 2008-12-23 | 2012-03-28 | 江苏恩华药业股份有限公司 | Substituent phenylpiperazine aryl alkanol derivant and application thereof in preparing analgesics |
| DE102009049211A1 (en) | 2009-10-13 | 2011-04-28 | Merck Patent Gmbh | sulfoxides |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2244507A1 (en) * | 1973-06-26 | 1975-04-18 | Inst Nat Sante Rech Med | Chalcones and analogues - analgesics having low toxicity |
| CA1041523A (en) * | 1974-06-19 | 1978-10-31 | Queen's University | Preparation of 1-oxapenicillins and novel intermediates therefor |
-
1980
- 1980-09-29 FR FR8020861A patent/FR2491066A1/en active Granted
-
1981
- 1981-09-21 WO PCT/EP1981/000149 patent/WO1982001186A1/en active Application Filing
- 1981-09-21 HU HU813255A patent/HU185975B/en unknown
- 1981-09-21 JP JP56503061A patent/JPS57501427A/ja active Pending
- 1981-09-21 ZA ZA816555A patent/ZA816555B/en unknown
- 1981-09-28 CA CA000386770A patent/CA1179343A/en not_active Expired
- 1981-09-28 GR GR66134A patent/GR82309B/el unknown
- 1981-09-28 PT PT73740A patent/PT73740B/en unknown
- 1981-09-28 EP EP81401497A patent/EP0049203A1/en not_active Withdrawn
-
1982
- 1982-02-05 DK DK49682A patent/DK49682A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| GR82309B (en) | 1984-12-13 |
| PT73740B (en) | 1982-12-30 |
| FR2491066A1 (en) | 1982-04-02 |
| ZA816555B (en) | 1982-09-29 |
| EP0049203A1 (en) | 1982-04-07 |
| PT73740A (en) | 1981-10-01 |
| DK49682A (en) | 1982-04-15 |
| HU185975B (en) | 1985-04-28 |
| FR2491066B1 (en) | 1983-06-17 |
| WO1982001186A1 (en) | 1982-04-15 |
| JPS57501427A (en) | 1982-08-12 |
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