US 5,322,843 AGrant
Benzoxazolinonyl and Benzothiazolinonyl Ethyl Morpholinoacetamides
Issue Date:1994-06-21
•8 Claims
Abstract
Compounds of general formula (I): ##STR1## wherein R, X, A, B and p are defined in the description. Medicinal products useful for treating sleep disorders comprising the same.
Metadata
Assignee
- Adir et Compagnie
Inventors
- Said Yous
- Isabelle Lesieur
- Patrick Depreux
- Daniel H. Caignard
- Beatrice Guardiola
- Gerard Adam
- Pierre Renard
Application Information
Application Number:US 0547204
Filing Date:1993-04-28
Priority Date:1991-03-25
Art Unit:122
Classifications
IPC:
C07D27768
Field of Search:
514544233.8135;139
Patent Drawings
This patent does not have any drawings.
Description
The present invention relates to new heterocycle-substituted alkylamides, to a process for preparing them and to pharmaceutical compositions containing them.
Very few heterocycle-substituted alkylamides containing a benzoxazolinone, benzothiazolinone or benzoxazinone unit have been described. Moreover, some benzoxazolinone- or benzothiazolinone-substituted 2-haloacetamides, described as herbicides, are known (U.S. Pat. No. 4,311,858, U.S. Pat. No. 4,258,196).
The Applicant has now discovered new heterocycle-substituted ethylamides which possess the property of binding with very high affinity to melatonin receptors. This feature makes the compounds of the invention advantageous in disorders of the central nervous system--in particular as anxiolytics and antipsychotics--and of the cerebral circulation and as analgesics. The compounds of the invention are also capable of being used as ovulation regulators, as well as in the treatment of some cancers on account of their immunostimulatory properties.
More especially, the invention relates to the compounds of general formula (I): ##STR2## in which: A represents an oxygen or sulfur atom,
X represents a CH.sub.2 group or a single bond,
R represents: either a hydrogen atom or a lower alkyl group, and in this case p=1 and B represents an arrangement --CH.sub.2 --CH.sub.2 --NR.sub.1 --CO--R.sub.2 where
R.sub.1 represents a hydrogen atom or a linear or branched lower alkyl group, and
R.sub.2 represents:
a hydrogen atom,
a cycloalkyl or linear or branched lower alkyl group, optionally substituted with a halogen atom,
a cycloalkyl group substituted with a linear or branched lower alkyl group,
an aryl or heteroaryl or aryl(lower alkyl) or substituted aryl or substituted heteroaryl or substituted arylalkyl group, on the understanding that heteroaryl group is understood to mean pyridyl, or indolyl,
a group of formula: ##STR3## G representing a linear or branched lower alkyl group, R.sub.3 and R.sub.4, which may be identical or different, each represent a lower alkyl group or a hydrogen atom or a phenyl or phenyl(lower alkyl) group, or R.sub.3 and R.sub.4, with the nitrogen atom to which they are attached, form a mono- or bicyclic, aromatic or non-aromatic heterocyclic system optionally comprising another hetero atom chosen from nitrogen, oxygen or sulphur and optionally substituted with one or more lower alkyl or oxo, aryl or aryl(lower alkyl), or substituted aryl or substituted aryl(lower alkyl) groups, on the understanding that, in the definitions of R.sub.2, R.sub.3 and R.sub.4, the term substituted qualifying aryl and arylalkyl and heteroaryl groups means that these groups are substituted with one or more radicals chosen from lower alkyl, lower alkoxy, trifluoromethyl or halogen atom,
or alternatively R.sub.1, with R.sub.2 and the group N--CO, forms a heterocyclic system of formula: ##STR4## with J being a linear or branched alkyl radical comprising from 2 to 8 carbon atoms, or an arrangement (CH.sub.2).sub.2 --NR.sub.1 --CO--R.sub.2 with R.sub.1 and R.sub.2 having the same definition as above, and in this case p equals 0 or 1 and B represents a lower alkoxy group,
where appropriate their isomers, epimers and diastereoisomers as well as, where appropriate, their addition salts with a pharmaceutically acceptable acid or base, on the understanding that lower alkyl and lower alkoxy mean groups comprising from 1 to 6 carbon atoms and that cycloalkyl means groups comprising from 3 to 8 carbon atoms.
Among pharmaceutically acceptable acids which can, where appropriate, be added to the compounds of formula (I) to obtain a salt, hydrochloric, sulfuric, tartaric, maleic, fumaric, oxalic, methanesulfonic and camphoric acids, and the like, may be mentioned without implied limitation.
Among pharmaceutically acceptable bases which can, where appropriate, be added to the compounds of formula (I) to obtain a salt, sodium, potassium, calcium or aluminum hydroxides, alkali metal or alkaline earth metal carbonates or organic bases such as triethylamine, benzylamine, diethylamine, tert-butylamine, dicyclohexylamine, arginine, and the like, may be mentioned without implied limitation.
The subject of the present invention is also the process for preparing the compounds of formula (I), wherein:
when B is other than an arrangement --CH.sub.2 --CH.sub.2 NR.sub.1 COR.sub.2, a compound of formula (II): ##STR5## in which A, B, p and X have the same definition as in the formula (I) except for the case where B represents an arrangement --CH.sub.2 --CH.sub.2 --NR.sub.1 COR.sub.2, is used as starting material, which compound is treated with an alkali metal agent to obtain a compound of formula (III): ##STR6## which is treated:
either with a compound of formula (IV/A):
where Hal and Halo, which may be identical or different, represent a halogen atom, to obtain a compound of formula (V/A): ##STR7## in which A, X, B, p and Halo have the same meaning as above, which is treated with an amine of formula HNR.sub.1 where R.sub.1 has the same definition as in the formula (I), to obtain a compound of formula (VI): ##STR8## in which A, B, p, R.sub.1 and X have the same definition as above,
or with a compound of formula (IV/B):
in which Hal has the same meaning as above, to obtain a compound of formula (V/B): ##STR9## in which X, A, B and p have the same meaning as above, which compound of formula (V/B) is subjected to a reducing agent and then, when R.sub.1 represents a lower alkyl group in the compound of formula (I) which it is desired to obtain, to an alkylating agent, to obtain a compound of formula (VI) as defined above, which compound of formula (VI) is treated:
either with a compound of formula (VII): ##STR10## in which E denotes a leaving group chosen from hydroxyl, lower alkoxy or halogen, G, R.sub.3 and R.sub.4 having the same meaning as in the formula (I), optionally in the presence of an alkaline agent, to yield a compound of formula (I/A), a special case of the compounds of formula (I): ##STR11## in which A, B, X, R.sub.1, R.sub.3, R.sub.4, G and p have the same definition as above,
R.sub.2 here denoting a group: ##STR12## on condition that B does not represent a group:
which is purified, if so desired, by conventional techniques such as chromatography or crystallization and which is purified, if so desired, with a pharmaceutically acceptable acid,
or with an acid chloride of formula (IX):
or with the corresponding acid anhydride,
R'.sub.2 here denoting:
a cycloalkyl or linear or branched lower alkyl group optionally substituted with a halogen atom, or a cycloalkyl group substituted with a linear or branched lower alkyl group,
an aryl or heteroaryl or aryl(lower alkyl) group optionally substituted with one or more halogen atoms or groups chosen from lower alkyl, lower alkoxy or trifluoromethyl, the term heteroaryl having the same meaning as above,
to yield a compound of formula (I/B): ##STR13## a special case of the compounds of formula (I) in which m, X, A, B, p, R.sub.1 and R'.sub.2 have the same definition as above, it not being possible for B to represent an arrangement --CH.sub.2 --CH.sub.2 --NR.sub.1 COR.sub.2, which is purified, if necessary, by conventional techniques such as chromatography and/or crystallization, which compound of formula (I/B), in the case where R'.sub.2 represents a linear or branched lower alkyl group substituted with a halogen atom, may be subjected, if so desired, to the action of an amine of formula (X): ##STR14## in which R.sub.3 and R.sub.4 have the same definition as above, in excess or in the presence of a tertiary amine or an alkali metal salt, to yield a compound of formula (I/A) as defined above, which, if so desired, is purified by a conventional technique such as chromatography and/or crystallization, and/or salified with a pharmaceutically acceptable acid, which compound of formula (I/B), when R'.sub.2 represents a linear or branched alkyl substituent comprising at least two carbon atoms and substituted with a halogen atom, and when R.sub.1 simultaneously represents a hydrogen atom, may be subjected, if so desired, to the action of a strong base and preferably an alkali metal alcoholate to yield a compound of formula (I/C): ##STR15## in which B, p, X and Z have the same meaning as above, on the understanding that B cannot represent a group --CH.sub.2 --CH.sub.2 NRCOR.sub.2 and J represent a linear or branched alkyl group comprising from 2 to 8 carbon atoms, a special case of the compounds of formula (I) for which R.sub.1 and R.sub.2 with NCO form a monocyclic system substituted with an oxo group and optionally substituted with one or more lower alkyl groups, which is purified, if so desired, by a technique chosen from crystallization or chromatography,
when B represents an arrangement --CH.sub.2 --CH.sub.2 NR.sub.1 COR.sub.2 and p resents 1, a compound of formula (VIII): ##STR16## in which R.sub.1, R, X and A have the same definition as in the formula (I), these compounds being described in Patent Application FR 90/11,866 (corresponding to U.S. Ser. No. 07/765,959, filed Sep. 26, 1991, now U.S. Pat. No. 5,196,434, issued Mar. 23, 1993), and in U.S. Pat. Nos. 4,554,284 and 4,558,060, is used as starting material, which compound is treated:
either with a compound of formula (VII): ##STR17## in which E denotes a leaving group chosen from hydroxyl, lower alkoxy or halogen, G, R.sub.3 and R.sub.4 having the same meaning as in the formula (I), optionally in the presence of an alkaline agent, to yield a compound of formula (I/D), a special case of the compounds of formula (I): ##STR18## in which X and A, R.sub.1, R.sub.3, R.sub.4 and G have the same definition as above and R represents a hydrogen atom or a lower alkyl group,
R.sub.2 here denoting a group: ##STR19## which is purified, if so desired, by conventional techniques such as chromatography and/or crystallization and which is salified, if so desired, with a pharmaceutically acceptable acid or, when R represents a hydrogen atom, with a pharmaceutically acceptable base,
or with an acid chloride of formula (IX):
or with the corresponding acid anhydride,
R'.sub.2 here denoting:
a cycloalkyl or linear or branched lower alkyl group optionally substituted with a halogen atom, or a cycloalkyl group substituted with a linear or branched lower alkyl group,
an aryl or heteroaryl or aryl(lower alkyl) group optionally substituted with one or more halogen atoms or groups chosen from lower alkyl, lower alkoxy or trifluoromethyl, the term heteroaryl having the same meaning as above,
to yield a compound of formula (I/E): ##STR20## a special case of the compounds of formula (I) in which R.sub.1, X, A and R'.sub.2 have the same definition as above and R represents a lower alkyl group or a hydrogen atom, which is purified, if necessary, by conventional techniques such as chromatography and/or crystallization and which is salified, if so desired, with a pharmaceutically acceptable base when R represents a hydrogen atom, which compound of formula (I/E), in the case where R'.sub.2 represents a linear or branched lower alkyl group substituted with a halogen atom, may be subjected, if so desired, to the action of an amine of formula (X): ##STR21## in which R.sub.3 and R.sub.4 have the same definition as above, in excess or in the presence of a tertiary amine or an alkali metal salt, to yield a compound of formula (I/D) as defined above, which, if so desired, is purified by a conventional technique such as chromatography and/or crystallization, and/or salified with a pharmaceutically acceptable acid, which compound of formula (I/E), when R'.sub.2 represents a linear or branched alkyl substituent comprising at lest two carbon atoms and substituted with a halogen atom, and when R.sub.1 simultaneously represents a hydrogen atom, may be subjected, if so desired, to the action of a strong base and preferably an alkali metal alcoholate to yield a compound of formula (I/F): ##STR22## in which R represents a hydrogen atom or a lower alkyl group, X and A have the same meaning as above and J represents a linear or branched alkyl group comprising from 2 to 8 carbon atoms, a special case of the compounds of formula (I) for which R.sub.1 and R.sub.2 with NCO form a monocyclic system substituted with an oxo group and optionally substituted with one or more lower alkyl groups, which is purified, if so desired, by a technique chosen from crystallization or chromatography and which is salified, if so desired, when R represents a hydrogen atom, with a pharmaceutically acceptable base.
The products of formula (VI) are new and form part of the invention on the same basis as the products of formula (I), for which they constitute synthesis intermediates, except for the compounds for which:
X represents a single bond,
A represents a sulfur atom and p represents 0.
The products of formulae (V/A) and (V/B) for which p is other than 0 are also new, and also form part of the invention on the same basis as the products of formula (I), for which they constitute synthesis intermediates.
Another special case relates to the compounds of formula (I/K): ##STR23## which is obtained in a single step by catalytic reduction of the compounds of formula (V/K) in an acetic anhydride medium: ##STR24## followed, if necessary, by purification and, when R.sub.1 represents a lower alkyl group, by treatment with an alkylating agent.
The compounds of formula (I) possess advantageous pharmacological properties.
A pharmacological study of the compounds of the invention showed, in effect, that they are of low toxicity and endowed with appreciable affinity for melatonin receptors, and that, in addition, they substantially increase melatonin synthesis by the pineal gland. Furthermore, they possess considerable activity in relation to the central nervous system and, in particular, sedative, anxiolytic, antipsychotic and analgesic properties as well as effects on the microcirculation have been noted, these enabling it to be established that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depression, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite regulation, insomnia, psychotic disorders, epilepsy, Parkinson's disease, senile dementia, the various disorders linked to normal or pathological aging, migraine, memory loss, Alzheimer's disease and also disorders of the cerebral circulation.
In another sphere of activity, it is apparent that the products of the invention possess ovulation-inhibiting properties, and immunomodulatory properties and that they are hence capable of being used in the treatment of certain cancers, and that, when administered externally, they are useful in the treatment of psoriasis, acne and seborrhea, protect the skin and promote hair growth. They can also have a veterinary application owing to their effect on the coat.
The subject of the present invention is also pharmaceutical compositions containing the products of formula (I) or, where appropriate, one of their addition salts with a pharmaceutically acceptable acid, alone or in combination with one or more pharmaceutically acceptable, non-toxic, inert excipients or vehicles.
Among the pharmaceutical compositions according to the invention, there may be mentioned, more especially, those which are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration, and in particular simple or sugar-coated tablets, sublingual tablets, sachets, packets, hard gelatin capsules, sublingual preparations, troches, suppositories, creams, ointments, skin gels, ampuls for oral use or injection, and the like.
The dosage varies according to the patient's age and weight, the administration route and the nature of the therapeutic indication or of any associated treatments, and ranges between 0.1 mg and 1 gram per 24 hours.
The examples which follow illustrate the invention but in no way limit it.
EXAMPLE 1
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]acetamide
STAGE A
(6-methoxy-3-benzoxazolinonyl)acetonitrile
0.1 gram-atom of sodium is added in small pieces with magnetic stirring into a 250-cm.sup.3 round-bottomed flask containing 100 cm.sup.3 of absolute ethanol.
The mixture is left stirring until the sodium has dissolved completely. 0.1 mol of 6-methoxybenzoxazolinone is added, stirring is continued for 30 minutes and the mixture is then taken to dryness.
The sodium derivative obtained is solubilized in 80 cm.sup.3 of anhydrous dimethylformamide. With magnetic stirring, 0.12 mol of chloroacetonitrile is added via a dropping funnel. The reaction mixture is heated to 80.degree. C. for 1 hour 30 minutes. It is allowed to cool and then poured into 400 cm.sup.3 of ice-cold water.
The precipitate formed is drained, washed until the washing liquors are neutral, dried and recrystallized.
Recrystallization solvent: 95.degree. strength alcohol
Yield: 95%
Melting point: 142.degree.-143.degree. C.
Infrared spectrometry: (3060-2940) cm.sup.-1, .nu. C--H 1770 cm.sup.-1, .nu. CO(O--CO--N) 1630 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.85 ppm, (s, 3H), OCH.sub.3 4.75 ppm, (s, 2H), CH.sub.2 --CN 6.80 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6 7.05 ppm, (d, 1H), H.sub.7
STAGE B
2-(6-methoxy-3-benzoxazolinonyl)ethylamine Hydrochloride
In a round-bottomed flask, 0.03 mol of (6-methoxy-3-benzoxazolinonyl)acetonitrile is dissolved with magnetic stirring in 50 cm.sup.3 of tetrahydrofuran at room temperature.
0.05 mol of methylborane sulfide is added slowly under a nitrogen atmosphere using a dropping funnel. The mixture is heated to reflux for 30 minutes. It is cooled in an ice bath, and 30 cm.sup.3 of 6N hydrochloric acid solution are then added very slowly. The mixture is heated to reflux for 30 minutes.
It is allowed to cool, and the precipitate formed is drained, washed with 30 cm.sup.3 of acetone, dried and recrystallized in a suitable solvent.
Recrystallization solvent: 95.degree. strength alcohol
Yield: 83%
Melting point: >260.degree. C.
Infrared spectrometry: (3120-2500) cm.sup.-1, .nu. NH.sub.2 salt 1770 cm.sup.-1, .nu. CO(O--CO--N) (1635-1620) cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.25 ppm, (t, 2H), CH.sub.2 --NH.sub.2 3.75 ppm, (s, 3H), OCH.sub.3 4.15 ppm, (t, 2H), .dbd.N--CH.sub.2 6.82 ppm, (dd, 1H), H.sub.5 7.00 ppm, (d, 1H), H.sub.7 7.40 ppm, (d, 1H), H.sub.4 8.40 ppm, (signal, 2H), NH.sub.2 disappears in D.sub.2 O
STAGE C
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]acetamide
0.02 mol of 3-(2-aminoethyl)-6-methoxybenzoxazolinone hydrochloride is dissolved in a water/chloroform mixture. 0.02 mol of potassium carbonate is added and the mixture is left stirring for 1 hour.
It is cooled in an ice bath, and 0.022 mol of acetyl chloride is then added slowly. The mixture is kept stirring for 1/2 hour. The chloroform phase is taken to dryness, and the residue is then recrystallized in a suitable solvent.
Recrystallization solvent: Absolute alcohol
Yield: 86%
Melting point: 162.degree.-164.degree. C.
Infrared spectrometry: 3320 cm.sup.-1, .nu. N--H (3060-2840) cm.sup.-1, .nu. C--H 1765 cm.sup.-1, .nu. CO(O--CO--N) 1640 cm.sup.-1, .nu. CO (amide) 1620 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.94 ppm, (s, 3H), COCH.sub.3 3.60 ppm, (multiplet, 2H), CH.sub.2 --CH.sub.2 --NH 3.80 ppm, (s, 3H), OCH.sub.3 3.95 ppm, (t, 2H), N--CH.sub.2 6.20 ppm, (signal, 1H), NH 6.65 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7 6.96 ppm, (d, 1H), H.sub.4
EXAMPLE 2
N-[2-(5-methoxy-3-benzoxazolinonyl)ethyl]acetamide
Using the procedure described in Example 1, but replacing 6-methoxybenzoxazolinone in stage A by 5-methoxybenzoxazolinone, the following are obtained:
STAGE A
(5-methoxy-3-benzoxazolinonyl)acetonitrile
Melting point: 148.degree.-149.degree. C.
Yield: 93%
Infrared spectrometry: (3060-2900) cm.sup.-1, .nu. C--H 1790 cm.sup.-1, .nu. CO(O--CO--N) 1620 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.86 ppm, (s, 3H), OCH.sub.3 4.75 ppm, (s, 2H), CH.sub.2 --CN 6.70 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6 7.20 ppm, (d, 1H), H.sub.7
STAGE B
2-(5-methoxy-3-benzoxazolinonyl)ethylamine Hydrochloride
Recrystallization solvent: 95.degree. strength alcohol
Yield: 81%
Melting point: >260.degree. C.
Infrared spectrometry: (3120-2500), .nu. NH.sub.2 salt 1765 cm.sup.-1, .nu. CO(O--CO--N) 1620 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.25 ppm, (t, 2H), .dbd.CH.sub.2 --CH.sub.2 --NH.sub.2 3.75 ppm, (s, 3H), OCH.sub.3 4.16 ppm, (t, 2H), --CH.sub.2 --CH.sub.2 6.70 ppm, (dd, 1H), H.sub.6 (7-7.40) ppm, (unresolved peaks, 2H), H.sub.4, H.sub.7 9.50 ppm (signal, 2H) NH.sub.2 disappears in D.sub.2 O
STAGE C
N-[2-(5-methoxy-3-benzoxazolinonyl)ethyl]acetamide
Recrystallization solvent: Toluene
Yield: 87%
Melting point: 118.degree.-120.degree. C.
Infrared spectrometry: 3300 cm.sup.-1, .nu. N--H (amide) (3060-2840) cm.sup.-1, .nu. C--H 1765 cm.sup.-1, .nu. CO(O--CO--N) 1655 cm.sup.-1, .nu. CO (amide) 1630 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.93 ppm, (s, 3H), COCH.sub.3 3.58 ppm, (multiplet, 2H), CH.sub.2 --NH 3.80 ppm, (s, 3H), OCH.sub.3 3.94 ppm, (t, 2H), CH.sub.2 N.dbd. 6.25 ppm, (signal, 1H), NH 6.64 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6 7.10 ppm, (d, 1H), H.sub.7
EXAMPLE 3
N-[2-(5-methoxy-3-benzoxazolinonyl)ethyl]isobutyramide
Using the procedure described in Example 2, stage C, but replacing acetyl chloride by isobutyryl chloride, the product of the title is obtained.
Recrystallization solvent: Toluene/Hexane
Yield: 82%
Melting point: 130.degree.-131.degree. C.
Infrared spectrometry: 300 cm.sup.-1, .nu. N--H (3080-2840) cm.sup.-1, .nu. C--H 1760 cm.sup.-1, .nu. CO(O--CO--N) 1640 cm.sup.-1, .nu. CO (amide) 1625 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.10 ppm, (d, 6H), CH(CH.sub.3).sub.2 2.25 ppm, (multiplet, 1H), CH 3.75 ppm, (s, 3H), OCH.sub.3 6.20 ppm, (signal, 1H), NH 6.60 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6 7.10 ppm, (d, 1H), H.sub.7
EXAMPLE 4
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]isobutyramide
Using the procedure described in Example 2, stage C, but replacing acetyl chloride by isobutyryl chloride, the product of the title is obtained.
Recrystallization solvent: Toluene
Melting point: 161.degree.-162.degree. C.
Yield: 86%
Infrared spectrometry: 3300 cm.sup.-1, .nu. N--H (3080-2840) cm.sup.-1, .nu. C--H 1760 cm.sup.-1, .nu. CO(O--CO--N) 1640 cm.sup.-1, .nu. CO (amide) 1625 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.10 ppm, (d, 6H), CH(CH.sub.3).sub.2 2.25 ppm, (multiplet, 1H), CH 3.60 ppm, (multiplet, 2H), CH.sub.2 --NH 3.75 ppm, (s, 3H), OCH.sub.3 3.95 ppm, (t, 2H), CH.sub.2 --N.dbd. 6.15 ppm, (signal, 1H), NH 6.65 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7 6.95 ppm, (d, 1H), H.sub.4
EXAMPLE 5
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]phenylacetamide
Using the procedure described in Example 2, but replacing acetyl chloride by phenacetyl chloride, the product of the title is obtained.
Infrared spectrometry: 3300 cm.sup.-1, .nu. N--H 1760 cm.sup.-1, .nu. CO(O--CO--N)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.75 ppm, singlet, 3H, OCH.sub.3
EXAMPLE 6
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-(2-oxo-1pyrrolidinyl)acetamide ##STR25##
A mixture of 0.02 mol of 3-(2-aminoethyl)-6-methoxybenzoxazolinone and 0.022 mol of methyl (2-oxo-1-pyrrolidinyl)acetate is heated with magnetic stirring to a temperature of 80.degree. C. for 3 hours. The medium is taken up with slightly acid water and the precipitate is drained.
Infrared spectrometry: 3300 cm.sup.-1, .nu. N--H 1760 cm.sup.-1, .nu. CO(O--CO--N)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.75 ppm, singlet, 3H, OCH.sub.3
EXAMPLE 7
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-4-chlorobutyramide
Using the procedure described in Example 2, but replacing acetyl chloride by 4-chlorobutyryl chloride, the product of the title is obtained.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO(O--CO--N)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.80 ppm, singlet, 3H, OCH.sub.3
EXAMPLE 8
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-pyrrolidinone
0.01 gram-atom of sodium is dissolved in 50 cm.sup.3 of ethanol. N-[2-(6-Methoxy-3-benzoxazolinonyl)ethyl]-4-chlorobutyramide, obtained in the preceding example, is added with magnetic stirring. The mixture is kept stirring for 20 minutes. It is taken to dryness. The residue is solubilized in 40 cm.sup.3 of anhydrous dimethylformamide. The mixture is heated to boiling for 7 hours. It is evaporated under vacuum and the residue is taken up with ether. The mixture is filtered and taken to dryness. The product is recrystallized.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO(O--CO--N)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.80 ppm, singlet, 3H, OCH.sub.3
EXAMPLE 9
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-bromoacetamide
The same procedure as in Example 7, replacing 4-chlorobutyryl chloride by bromoacetyl chloride.
EXAMPLE 10
N-[2-(6-methoxy-3benzoxazolinonyl)ethyl]-2-morpholinoacetamide
0.01 mol of morpholine is dissolved with magnetic stirring in 50 cm.sup.3 of acetone. 0.012 mol of triethylamine and 0.01 mol of N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-bromoacetamide are added. The mixture is brought to reflux for one hour with magnetic stirring. The precipitate formed is drained and the filtrate is evaporated. The residue is taken up with alkaline water. The precipitate is drained, washed, dried and recrystallized.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO(O--CO--N)
EXAMPLE 11
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)met hyl]-1-piperazinyl}acetamide
Using the procedure described in the preceding example, but replacing morpholine by 1-[(2,3,4-trimethoxyphenyl)methyl]piperazine, the product of the title is obtained.
EXAMPLE 12
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-N-methylacetamide
By replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine in Example 1 by N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-N-methylamine, the product of the title is obtained.
EXAMPLE 13
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]benzamide
By replacing acetyl chloride in Example 1, stage C, by benzoyl chloride, the product of the title is obtained.
Infrared spectrometry:
1760 cm.sup.-1, .nu. CO
EXAMPLE 14
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-para-toluenecarboxamide
By replacing acetyl chloride in Example 1, stage C, by para-toluoyl chloride, the product of the title is obtained.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO
EXAMPLE 15
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-4-fluorobenzamide
By replacing acetyl chloride in Example 1, stage C, by para-fluorobenzoyl chloride, the product of the title is obtained.
Infrared spectrometry: 1765 cm.sup.-1, .nu. CO
EXAMPLE 16
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
By replacing acetyl chloride in Example 1, stage C, by 3-(trifluoromethyl)benzoyl chloride, the product of the title is obtained.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO
EXAMPLE 17
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-3,5-dichlorobenzamide
By replacing acetyl chloride in Example 1, stage C, by 3,5-dichlorobenzoyl chloride, the product of the title is obtained.
EXAMPLE 18
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]isonicotinamide
By replacing acetyl chloride in Example 1, stage C, by isonicotinoyl chloride, the product of the title is obtained.
EXAMPLE 19
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-indolecarboxamide
By replacing acetyl chloride in Example 1, stage C, by 2-indolecarbonyl chloride, the product of the title is obtained.
Infrared spectrometry: 3400 cm.sup.-1, .nu. NH (indole) 1760 cm.sup.-1, .nu. CO
EXAMPLE 20
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-(benzylamino)acetamide
Using the procedure described in Example 10, and replacing morpholine by benzylamine, the product of the title is obtained.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO
EXAMPLE 21
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
Using the procedure described in Example 10, but replacing morpholine by N,N-diethylamine, the product of the title is obtained.
Infrared spectrometry: 1765 cm.sup.-1, .nu. CO (OCON)
EXAMPLE 22
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-aminoacetamide Hydrochloride
0.012 mol of hexamethylenetetramine is dissolved with magnetic stirring in 15 cm.sup.3 of chloroform, and 0.01 mol of N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-bromoacetamide, obtained in Example 9, dissolved in 20 cm.sup.3 of chloroform, is introduced. The mixture is brought to reflux for 100 hours. The product is drained and dried. The precipitate is introduced into a ground-necked flask. 150 cm.sup.3 of alcohol and 30 cm.sup.3 of concentrated hydrochloric acid are added.
The mixture is brought to reflux for 2 hours. The solvent is evaporated off. The product is recrystallized in 90.degree. strength alcohol.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO (OCON)
EXAMPLE 23
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazin yl]acetamide
Using the procedure described in Example 10, but replacing morpholine by 1-(4-fluorophenyl)piperazine, the product of the title is obtained.
EXAMPLE 24
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]- 1-piperazinyl}acetamide
Using the procedure described in Example 10, but replacing morpholine by 1-[3-(trifluoromethyl)phenyl]piperazine, the product of the title is obtained.
EXAMPLE 25
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]cyclohexanecarboxamide
(R.sub.2 =cyclohexyl)
Using the procedure described in Example 1, but replacing acetyl chloride by cyclohexanecarbonyl chloride, the product of the title is obtained.
EXAMPLE 26
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]formamide
0.01 mol of 2-(6-methoxy-3-benzoxazolinonyl)ethylamine and 0.02 mol of formic acid are placed in a porcelain crucible. The mixture is heated to 120.degree. C. until a dry residue is obtained. The product is recrystallized.
EXAMPLE 27
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]cyclopropanecarboxamide
Using the procedure described in Example 1, but replacing acetyl chloride by cyclopropanecarbonyl chloride, the product of the title is obtained.
EXAMPLE 28
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]pentanamide
Using the procedure described in Example 1, but replacing acetyl chloride by valeroyl chloride, the product of the title is obtained.
EXAMPLE 29
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]cyclobutanecarboxamide
Using the procedure described in Example 1, but replacing acetyl chloride by cyclobutanecarbonyl chloride, the product of the title is obtained.
Using the procedure described in the preceding examples, the following are likewise obtained:
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-4-bromobutyramide
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-5-bromopentanamide
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-3-bromopropionamide
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-3-morpholinopropionamide
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-4-morpholinobutyramide
N-[2-(6-methoxy-3-benzoxazolinony)ethyl]-4-{4-[(2,3,4-trimethoxyphenyl)meth yl]-1-piperazinyl}-butyramide
N-[2-(6 -methoxy-3-benzoxazolinonyl)ethyl]-3-{4-[(2,3,4-trimethoxyphenyl)methyl]-1 -piperazinyl}-propionate
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-piperidone
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-bromopropionamide
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)met hyl]-1-piperazinyl}-propionate
By replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine in Examples 5 to 9 by 2-(5-methoxy-3-benzoxazolinonyl)ethylamine, the products of the preceding examples methoxylated, respectively, at position 5 of the benzoxazolinone are obtained instead of the compounds methoxylated at position 6.
EXAMPLE 30
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]acetamide
STAGE A
(6-methoxy-3-benzothiazolinonyl)acetonitrile
The procedure used is that described in Example 1, stage A, replacing 6-methoxybenzoxazolinone by 6-methoxybenzothiazolinone.
Recrystallization solvent: 95.degree. strength alcohol
Yield: 93%
Melting point: 168.degree.-169.degree. C.
Infrared spectrometry: (3080-2940) cm.sup.-1, .nu. C--H 1680 cm.sup.-1, .nu. CO(S--CO--N) 1630-1580) cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.85 ppm, (s, 3H), OCH.sub.3 4.75 ppm, (s, 2H), CH.sub.2 --CN 6.75 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.5 7.30 ppm, (d, 1H), H.sub.7
STAGE B
2-(6-methoxy-3-benzothiazolinonyl)ethylamine Hydrochloride
The procedure used is that described in Example 1, stage B, replacing (6-methoxy-3-benzoxazolinonyl)acetonitrile by (6-methoxy-3-benzothiazolinonyl)acetonitrile obtained in stage A.
Recrystallization solvent: 95.degree. strength alcohol/water (5:1)
Yield: 83%
Melting point: >260.degree. C.
Infrared spectrometry: (3120-2500) cm.sup.-1, .nu. NH.sub.2 salt 1640 cm.sup.-1, .nu. CO(S--CO--N) 1600 cm.sup.-1, .nu. C.dbd.C (aromatic)
STAGE C
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]acetamide
The procedure used is that described in Example 1, stage C, replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride by 2-(6-methoxy-3-benzothiazolinonyl)ethylamine hydrochloride obtained in stage B.
Recrystallization solvent: Toluene
Yield: 80%
Melting point: 152.degree.-154.degree. C.
Elemental analysis:
Infrared spectrometry: 3240 cm.sup.-1, .nu. N--H (3060-2840) cm.sup.-1, .nu. C--H 1675 cm.sup.-1, .nu. CO(S--CO--N) 1650 cm.sup.-1, .nu. CO (amide) 1580 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.94 ppm, (s, 3H), COCH.sub.3 3.80 ppm, (s, 3H), OCH.sub.3 6.10 ppm, (signal, 1H), NH 6.80 ppm, (dd, 1H), H.sub.5 7.00 ppm, (d, 1H), H.sub.7 7.20 ppm, (d, 1H), H.sub.4
EXAMPLE 31
N-[2-(5-methoxy-3-benzothiazolinonyl)ethyl]acetamide
STAGE A
(5-methoxy-3-benzothiazolinonyl)acetonitrile
The procedure used is that described in Example 1, stage A, replacing 6-methoxybenzoxazolinone by 5-methoxybenzothiazolinone.
Recrystallization solvent: 95.degree. strength alcohol
Yield: 93%
Melting point: 154.degree.-156.degree. C.
Infrared spectrometry: (3080-2940) cm.sup.-1, .nu. C--H 1680 cm.sup.-1, .nu. CO(S--CO--N) (1630-1580) cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.85 ppm, (s, 3H), OCH.sub.3 4.75 ppm, (s, 2H), CH.sub.2 --CN 6.75 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6 7.30 ppm, (d, 1H), H.sub.7
STAGE B
2-(5-methoxy-3-benzothiazolinonyl)ethylamine Hydrochloride
The procedure used is that described in Example 1, stage B, replacing (6-methoxy-3-benzoxazolinonyl)acetonitrile by (5-methoxy-3-benzothiazolinonyl)acetonitrile obtained in stage A.
Recrystallization solvent: 95.degree. strength alcohol
Yield: 86%
Melting point: >260.degree. C.
Infrared spectrometry: (3100-2500) cm.sup.-1, .nu. NH.sub.2 salt 1640 cm.sup.-1, .nu. CO(S--CO--N) 1590 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 3.75 ppm, (s, 3H), OCH.sub.3 6.80 ppm, (dd, 1H), H.sub.6 7.25 ppm, (d, 1H), H.sub.4 7.50 ppm, (d, 1H), H.sub.7 8.50 ppm, (signal, 2H), NH.sub.2 disappears in D.sub.2 O
STAGE C
N-[2-(5-methoxy-3-benzothiazolinonyl)ethyl]acetamide
The procedure used is that described in Example 1, stage B, replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride by 2-(5-methoxy-3-benzothiazolinonyl)ethylamine hydrochloride obtained in stage B.
Recrystallization solvent: Toluene
Yield: 86%
Melting point: 120.degree.-122.degree. C.
Infrared spectrometry: 3280 cm.sup.-1, .nu. N--H amide (3080-2840) cm.sup.-1, .nu. C--H 1675 cm.sup.-1, .nu. CO(S--CO--N) 1650 cm.sup.-1, .nu. CO (amide) 1610 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.93 pm, (s, 3H), COCH.sub.3 3.55 ppm, (multiplet, 2H), CH.sub.2 --CH.sub.2 --NHCOCH.sub.3 3.80 ppm, (s, 3H), OCH.sub.3 4.15 ppm, (t, 2H), CH.sub.2 --CH.sub.2 --NHCOCH.sub.3 6.10 ppm, (signal, 1H), NH 6.75 ppm, (dd, 1H), H.sub.6 6.90 ppm, (d, 1H), H.sub.4 7.30 ppm, (d, 1H), H.sub.7
EXAMPLE 32
N-[2-(5-methoxy-3-benzothiazolinonyl)ethyl]isobutyramide
The procedure used is that described in Example 31, replacing acetyl chloride in stage C by isobutyryl chloride.
Recrystallization solvent: Toluene/cyclohexane
Yield: 87%
Melting point: 158.degree.-159.degree. C.
Infrared spectrometry: 3280 cm.sup.-1, .nu. N--H (3080-2840) cm.sup.-1, .nu. C--H 1675 cm.sup.-1, .nu. CO(S--CO--N) 1640 cm.sup.-1, .nu. CO (amide) 1600 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.10 ppm, (s, 6H), CH(CH.sub.3).sub.2 2.25 ppm, (multiplet, 1H), CH 3.58 ppm, (multiplet, 2H), CH.sub.2 NHCO 3.85 ppm, (s, 3H), OCH.sub.3 4.10 ppm, (t, 2H), CH.sub.2 CH.sub.2 NHCO 6.15 ppm, (signal, 1H), NH 6.70 ppm, (dd, 1H), H.sub.6 6.80 ppm, (d, 1H), H.sub.4 7.26 ppm, (d, 1H), H.sub.7
EXAMPLE 33
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]isobutyramide
The procedure used is that described in Example 31, replacing acetyl chloride in stage C by isobutyryl chloride.
Recrystallization solvent: Toluene/cyclohexane
Yield: 85%
Melting point: 136.degree.-138.degree. C.
Infrared spectrometry: 3300 cm.sup.-1, .nu. N--H (3080-2840) cm.sup.-1, .nu. C--H 1680 cm.sup.-1, .nu. CO(S--CO--N) 1640 cm.sup.-1, .nu. CO (amide) 1600 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.10 ppm, (d, 6H), CH(CH.sub.3).sub.2 2.25 ppm, (multiplet, 1H), CH 3.80 ppm, (s, 3H), OCH.sub.3 6.10 ppm, (signal, 1H), NH 6.85 ppm, (dd, 1H), H.sub.5 7.00 ppm, (d, 1H), H.sub.7 7.20 ppm, (d, 1H), H.sub.4
EXAMPLES 34 TO 58
Using the procedure described in Examples 5 to 29, but replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride in stage C by 2-(6-methoxy-3-benzothiazolinonyl)ethylamine hydrochloride, the following are obtained, respectively:
EXAMPLE 34
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]phenylacetamide
EXAMPLE 35
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
EXAMPLE 36
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)-4-chloro butyramide
EXAMPLE 37
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-pyrrolidinone
EXAMPLE 38
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-bromoacetamide
EXAMPLE 39
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-morpholinoacetamide
EXAMPLE 40
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)m ethyl]-1-piperazinyl)acetamide
EXAMPLE 41
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-N-methylacetamide
EXAMPLE 42
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]benzamide
EXAMPLE 43
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-para-toluenecarboxamide
EXAMPLE 44
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-4-fluorobenzamide
EXAMPLE 45
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-3-(trifluoro)benzamide
EXAMPLE 46
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-3,5-dichlorobenzamide
EXAMPLE 47
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]isonicotinamide
EXAMPLE 48
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-indolecarboxamide
EXAMPLE 49
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-(benzylamino)acetamide
EXAMPLE 50
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
EXAMPLE 51
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-aminoacetamide
EXAMPLE 52
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperaz inyl]acetamide
EXAMPLE 53
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl ]-1-piperazinyl}acetamide
EXAMPLE 54
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]cyclohexanecarboxamide
EXAMPLE 55
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]formamide
EXAMPLE 56
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]cyclopropanecarboxamide
EXAMPLE 57
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]valeramide
EXAMPLE 58
N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]cyclobutanecarboxamide
By replacing 2-(6-methoxy-3-benzothiazolinonyl)ethylamine in Examples 34 to 58 by 2-(5-methoxy-3-benzothiazolinonyl)ethylamine, the products of the preceding examples methoxylated, respectively, at position 5 are obtained instead of the compounds methoxylated at position 6.
EXAMPLE 59
N-[2-(6-methoxy-4-benzoxazinonyl)ethyl]acetamide
By replacing 6-methoxybenzoxazolinone in Example 1, stage A, by 6-methoxybenzoxazinone, the following are obtained, respectively:
STAGE A
2-(6-methoxy-4-benzoxazinonyl)acetonitrile
STAGE B
2-(6-methoxy-4-benzoxazinonyl)ethylamine Hydrochloride
STAGE C
N-[3-(6-methoxy-3-benzoxazinonyl)ethyl]acetamide
EXAMPLE 60
N-[2-(7-methoxy-4-benzoxazinonyl)ethyl]acetamide
Using the procedure described in Example 1, but replacing 6-methoxybenzoxazolinone by 7-methoxybenzoxazinone, the following are obtained, respectively:
2-(7-methoxy-4-benzoxazinonyl)acetonitrile
2-(7-methoxy-4-benzoxazinonyl)ethylamine Hydrochloride
N-[2-(7-methoxy-4-benzoxazinonyl)ethyl]acetamide
EXAMPLE 61
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]acetamide
0.02 mol of 2-(3-methyl-6-benzoxazolinonyl)ethylamine hydrochloride described in Patent Application EP 0,110,781, is dissolved in a water/chloroform mixture. 0.02 mol of potassium carbonate is added and the mixture is left stirring for one hour.
It is cooled in an ice bath and 0.022 mol of acetyl chloride is then added. The mixture is kept stirring for 30 minutes. The chloroform phase is washed with water, dried over calcium chloride and taken to dryness. The residue is recrystallized in toluene.
Yield: 76%
Melting point: 150.degree. C.
Infrared spectrometry: 2260 cm.sup.-1, .nu. N--H (3080-2880) cm.sup.-1, .nu. C--H 1775 cm.sup.-1, .nu. CO(O--CO--N) 1640 cm.sup.-1, .nu. CO (amide) 1615 cm.sup.-1, .nu.C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.96 ppm, (s, 3H), COCH.sub.3 2.84 ppm, (t, 2H), CH.sub.2 CH.sub.2 NH 3.43 ppm, (s, 3H), NCH.sub.3 3.50 ppm, (multiplet, 2H), CH.sub.2 --CH.sub.2 NH 5.60 ppm, (signal, 1H), NH 6.80 ppm, (d, 1H), H.sub.4 7.00 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7
EXAMPLE 62
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]acetamide
By replacing 2-(3-methyl-6-benzoxazolinonyl)ethylamine hydrochloride in Example 61 by 2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride, described in French Patent Application 90/11,866, the product of the title is obtained.
Yield: 79%
Melting point: 134.degree.-136.degree. C.
Infrared spectrometry: 3280 cm.sup.-1, .nu. N--H (3080-2860) cm.sup.-1, .nu. C--H 1670 cm.sup.-1, .nu. CO(S--CO--N) 1630 cm.sup.-1, .nu. CO (amide) 1600 cm.sup.-1, .nu. C.dbd.C (aromatic)
Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3): 1.96 ppm, (s, 3H), COCH.sub.3 2.85 ppm, (t, 2H), CH.sub.2 CH.sub.2 NHCOCH.sub.3 3.50 ppm, (unresolved peaks, 5H), CH.sub.2 NHCOCH.sub.3 and NCH.sub.3 5.50 ppm, (signal, 1H), NH 6.95 ppm, (d, 1H), H.sub.4 7.20 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7
EXAMPLE 63
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]isobutyramide
Using the procedure described in Example 61, but replacing acetyl chloride by isobutyryl chloride, the product of the title is obtained.
Infrared spectrometry: 1760 cm.sup.-1, .nu. CO (OCON) 1640 cm.sup.-1, .nu. CO (amide)
EXAMPLE 64
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]phenylacetamide
Using the procedure described in Example 61, but replacing acetyl chloride by phenacetyl chloride, the product of the title is obtained.
EXAMPLE 65
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide ##STR26##
The procedure used is that described in Example 6, replacing 3-(2-aminoethyl)-6-methoxybenzoxazolinone by 2-(3-methyl-6-benzoxazolinonyl)ethylamine; the product of the title is obtained.
EXAMPLES 66 TO 88
Using the procedure described in Examples 7 to 29, but replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride by 2-(3-methyl-6-benzoxazolinonyl)ethylamine hydrochloride, the following are obtained:
EXAMPLE 66
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-4-chlorobutyramide
EXAMPLE 67
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-pyrrolidinone
EXAMPLE 68
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-bromoacetamide
EXAMPLE 69
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-morpholinoacetamide
EXAMPLE 70
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)meth yl]-1-piperazinyl}acetamide
EXAMPLE 71
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-N-methylacetamide
EXAMPLE 72
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]benzamide
EXAMPLE 73
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-para-toluenecarboxamide
EXAMPLE 74
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-4-fluorobenzamide
EXAMPLE 75
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
EXAMPLE 76
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-3,5-dichlorobenzamide
EXAMPLE 77
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]isonicotinamide
EXAMPLE 78
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-indolecarboxamide
EXAMPLE 79
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-(benzylamino)acetamide
EXAMPLE 80
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
EXAMPLE 81
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-aminoacetamide
EXAMPLE 82
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperaziny l]acetamide
EXAMPLE 83
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1 -piperazinyl}acetamide
EXAMPLE 84
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]cyclohexanecarboxamide
EXAMPLE 85
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]formamide
EXAMPLE-86
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]cyclopropanecarboxamide
EXAMPLE 87
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]valeramide
EXAMPLE 88
N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]cyclobutanecarboxamide
EXAMPLES 89 TO 113
Using the procedure described in Examples 5 to 20, but replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride by 2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride, the following are obtained:
EXAMPLE 89
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]phenylacetamide
EXAMPLE 90
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
EXAMPLE 91
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-4-chlorobutyramide
EXAMPLE 92
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-pyrrolidinone
EXAMPLE 93
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-bromoacetamide
EXAMPLE 94
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-morpholinoacetamide
EXAMPLE 95
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)me thyl]-1-piperazinyl}acetamide
EXAMPLE 96
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-N-methylacetamide
EXAMPLE 97
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]benzamide
EXAMPLE 98
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-para-toluenecarboxamide
EXAMPLE 99
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-4-fluorobenzamide
EXAMPLE 100
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
EXAMPLE 101
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-3,5-dichlorobenzamide
EXAMPLE 102
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]isonicotinamide
EXAMPLE 103
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-indolecarboxamide
EXAMPLE 104
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-(benzylamino)acetamide
EXAMPLE 105
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
EXAMPLE 106
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-aminoacetamide
EXAMPLE 107
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazi nyl]acetamide
EXAMPLE 108
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl] -1-piperazinyl}acetamide
EXAMPLE 109
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]cyclohexanecarboxamide
EXAMPLE 110
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]formamide
EXAMPLE 111
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]cyclopropanecarboxamide
EXAMPLE 112
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]valeramide
EXAMPLE 113
N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]cyclobutanecarboxamide
By replacing 2-(3-methyl-6-benzothiazolinonyl)ethylamine in Examples 89 to 113 by 2-(3-methyl-7-benzothiazolinonyl)ethylamine, obtained in Patent Application EP 174,811, products are obtained which are isomeric with those above, the side chain being at position 7 instead of at position 6:
EXAMPLE 114
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]phenylacetamide
EXAMPLE 115
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
EXAMPLE 116
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-4-chlorobutyramide
EXAMPLE 117
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-pyrrolidinone
EXAMPLE 118
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-bromoacetamide
EXAMPLE 119
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-morpholinoacetamide
EXAMPLE 120
N-[2- (3- methyl-7-benzothiazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl]-1 -piperazinyl}-acetamide
EXAMPLE 121
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-N-methylacetamide
EXAMPLE 122
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]benzamide
EXAMPLE 123
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-para-toluenecarboxamide
EXAMPLE 124
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-4-fluorobenzamide
EXAMPLE 125
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
EXAMPLE 126
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-3,5-dichlorobenzamide
EXAMPLE 127
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]isonicotinamide
EXAMPLE 128
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-indolecarboxamide
EXAMPLE 129
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-(benzylamino)acetamide
EXAMPLE 130
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
EXAMPLE 131
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-aminoacetamide
EXAMPLE 132
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazi nyl]acetamide
EXAMPLE 133
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl] -1-piperazinyl}acetamide
EXAMPLE 134
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]cyclohexanecarboxamide
EXAMPLE 135
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]formamide
EXAMPLE 136
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]cyclopropanecarboxamide
EXAMPLE 137
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]valeramide
EXAMPLE 138
N-[2-(3-methyl-7-benzothiazolinonyl)ethyl]cyclobutanecarboxamide
EXAMPLES 139 TO 162
Using the procedure described in Examples 5 to 26, but replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride in stage C by 2-(4-methyl-7-benzoxazinonyl)ethylamine hydrochloride, the following are obtained, respectively:
EXAMPLE 139
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]phenylacetamide
EXAMPLE 140
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
EXAMPLE 141
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-4-chlorobutyramide
EXAMPLE 142
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-pyrrolidinone
EXAMPLE 143
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-bromoacetamide
EXAMPLE 144
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-morpholinoacetamide
EXAMPLE 145
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl ]-1-piperazinyl}acetamide
EXAMPLE 146
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-N-methylacetamide
EXAMPLE 147
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]benzamide
EXAMPLE 148
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-para-toluenecarboxamide
EXAMPLE 149
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-4-fluorobenzamide
EXAMPLE 150
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-3-(trifluoromethyl)benzamide
EXAMPLE 151
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-3,5-dichlorobenzamide
EXAMPLE 152
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]isonicotinamide
EXAMPLE 153
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-indolecarboxamide
EXAMPLE 154
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-(benzylamino)acetamide
EXAMPLE 155
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
EXAMPLE 156
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-aminoacetamide
EXAMPLE 157
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl) acetamide
EXAMPLE 158
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1-p iperazinyl}acetamide
EXAMPLE 159
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]cyclohexanecarboxamide
EXAMPLE 160
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]formamide
EXAMPLE 161
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]cyclopropanecarboxamide
EXAMPLE 162
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]valeramide
EXAMPLE 163
N-[2-(4-methyl-7-benzoxazinonyl)ethyl]cyclobutanecarboxamide
Using the procedure described in Examples 5 to 29, but replacing 2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride in stage C by 2-(4-methyl-6-benzoxazinonyl)ethylamine hydrochloride, described in Patent Application FR 90/11,866 the following are obtained:
EXAMPLE 164
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]phenylacetamide
EXAMPLE 165
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-(2-oxo-1-pyrolidinyl)acetamide
EXAMPLE 166
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-4-chlorobutyramide
EXAMPLE 167
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-pyrrolidinone
EXAMPLE 168
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-bromoacetamide
EXAMPLE 169
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-morpholinoacetamide
EXAMPLE 170
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl ]-1-piperazinyl}acetamide
EXAMPLE 171
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-N-methylacetamide
EXAMPLE 172
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]benzamide
EXAMPLE 173
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-para-toluenecarboxamide
EXAMPLE 174
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-4-fluorobenzamide
EXAMPLE 175
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-3-(trifluoromethyl)benzamide
EXAMPLE 176
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-3,5-dichlorobenzamide
EXAMPLE 177
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]isonicotinamide
EXAMPLE 178
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-indolecarboxamide
EXAMPLE 179
N-[2-(4-methyl-6-benzoxazolinonyl)ethyl]-2-(benzylamino)acetamide
EXAMPLE 180
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
EXAMPLE 181
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-aminoacetamide
EXAMPLE 182
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl] acetamide
EXAMPLE 183
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1-p iperazinyl}acetamide
EXAMPLE 184
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]cyclohexanecarboxamide
EXAMPLE 185
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]formamide
EXAMPLE 186
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]cyclopropanecarboxamide
EXAMPLE 187
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]valeramide
EXAMPLE 188
N-[2-(4-methyl-6-benzoxazinonyl)ethyl]cyclobutanecarboxamide
EXAMPLE 189
N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-methylcyclopropanecarboxamide
R.sub.2 =2-methylcyclopropyl
Using the procedure described in Example 1, but replacing acetyl chloride in stage C by 2-methylcyclopropanecarbonyl chloride, the product of the title is obtained.
EXAMPLE 190
N-[2-(5-methoxy-3-benzoxazolinonyl)ethyl]-2-methylcyclopropanecarboxamide
Using the procedure described in Example 189, but replacing 6-methoxybenzoxazolinone in stage A by 5-methoxybenzoxazolinone, the product of the title is obtained.
EXAMPLE 191
N-[2-(5-methoxy-3-benzoxazolinonyl)ethyl]cyclopropanecarboxamide
Using the procedure described in Example 1, but replacing 6-methoxybenzoxazolinone in stage A by 5-methoxybenzoxazolinone, and acetyl chloride by cyclopropanecarbonyl chloride, the product of the title is obtained.
Recrystallization: toluene
Melting point: 150.degree.-151.degree. C.
EXAMPLE 192
N-[2-(5-methoxy-3-benzothiazolinonyl)ethyl]cyclopropanecarboxamide
Using the procedure described in Example 1, but replacing 6-methoxybenzoxazolinone in stage A by 5-methoxybenzothiazolinone, and acetyl chloride by cyclopropanecarbonyl chloride, the product of the title is obtained.
Recrystallization: toluene
Melting point: 135.degree.-136.degree. C.
Using the procedure described in Examples 1 and 4 to 29, but replacing 6-methoxybenzoxazolinone by benzoxazolinone itself, the following are obtained:
N-[2-(3-benzoxazolinonyl)ethyl]acetamide
N-[2-(3-benzoxazolinonyl)ethyl]isobutyramide
N-[2-(3-benzoxazolinonyl)ethyl]phenylacetamide
N-[2-(3-benzoxazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
N-[2-(3-benzoxazolinonyl)ethyl]-4-chlorobutyramide
N-[2-(3-benzoxazolinonyl)ethyl]-2-pyrrolidinone
N-[2-(3-benzoxazolinonyl)ethyl]-2-bromoacetamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-morpholinoacetamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl]-1-pip erazinyl}acetamide
N-[2-(3-benzoxazolinonyl)ethyl]-N-methylacetamide
N-[2-(3-benzoxazolinonyl)ethyl]benzamide
N-[2-(3-benzoxazolinonyl)ethyl]-para-toluenecarboxamide
N-[2-(3-benzoxazolinonyl)ethyl]-4-fluorobenzamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl]acetami de
N-[2-(3-benzoxazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
N-[2-(3-benzoxazolinonyl)ethyl]-3,5-dichlorobenzamide
N-[2-(3-benzoxazolinonyl)ethyl]isonicotinamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-indolecarboxamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-(benzylamino)acetamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-aminoacetamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1-piperazi nyl}acetamide
N-[2-(3-benzoxazolinonyl)ethyl]cyclohexanecarboxamide
N-[2-(3-benzoxazolinonyl)ethyl]formamide
N-[2-(3-benzoxazolinonyl)ethyl]cyclopropanecarboxamide
N-[2-(3-benzoxazolinonyl)ethyl]valeramide
N-[2-(3-benzoxazolinonyl)ethyl]cyclobutanecarboxamide
Using the procedure described in Examples 1 and 4 to 29, but replacing 6-methoxybenzoxazolinone by benzothiazolinone, the following are obtained:
N-[2-(3-benzothiazolinonyl)ethyl]acetamide
N-[2-(3-benzothiazolinonyl)ethyl]isobutyramide
N-[2-(3-benzothiazolinonyl)ethyl]phenylacetamide
N-[2-(3-benzothiazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
N-[2-(3-benzothiazolinonyl)ethyl]-4-chlorobutyramide
N-[2-(3-benzothiazolinonyl)ethyl]-2-pyrrolidinone
N-[2-(3-benzothiazolinonyl)ethyl]-2-bromoacetamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-morpholinoacetamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl]-1-p iperazinyl}acetamide
N-[2-(3-benzothiazolinonyl)ethyl]-N-methylacetamide
N-[2-(3-benzothiazolinonyl)ethyl]benzamide
N-[2-(3-benzothiazolinonyl)ethyl]-para-toluenecarboxamide
N-[2-(3-benzothiazolinonyl)ethyl]-4-fluorobenzamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl]aceta mide
N-[2-(3-benzothiazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
N-[2-(3-benzothiazolinonyl)ethyl]-3,5-dichlorobenzamide
N-[2-(3-benzothiazolinonyl)ethyl]isonicotinamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-indolecarboxamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-(benzylamino)acetamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-aminoacetamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1-pipera zinyl}acetamide
N-[2-(3-benzothiazolinonyl)ethyl]cyclohexanecarboxamide
N-[2-(3-benzothiazolinonyl)ethyl]formamide
N-[2-(3-benzothiazolinonyl)ethyl]cyclopropanecarboxamide
N-[2-(3-benzothiazolinonyl)ethyl]valeramide
N-[2-(3-benzothiazolinonyl)ethyl]cyclobutanecarboxamide
Using the procedure described in Examples 61 to 88, but replacing 3-methylbenzoxazolinone by benzoxazolinone itself, the following are obtained:
N-[2-(6-benzoxazolinonyl)ethyl]acetamide
N-[2-(6-benzoxazolinonyl)ethyl]isobutyramide
N-[2-(6-benzoxazolinonyl)ethyl]phenylacetamide
N-2-(6-benzoxazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
N-[2-(6-benzoxazolinonyl)ethyl]-4-chlorobutyramide
N-[2-(6-benzoxazolinonyl)ethyl]-2-pyrrolidinone
N-[2-(6-benzoxazolinonyl)ethyl]-2-bromoacetamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-morpholinoacetamide
N-[2-(3-benzoxazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl]-1-pip erazinyl}acetamide
N-[2-(6-benzoxazolinonyl)ethyl]N-methylacetamide
N-[2-(6-benzoxazolinonyl)ethyl]benzamide
N-[2-(6-benzoxazolinonyl)ethyl]-para-toluenecarboxamide
N-[2-(6-benzoxazolinonyl)ethyl]-4-fluorobenzamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl]acetami de
N-[2-(6-benzoxazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
N-[2-(6-benzoxazolinonyl)ethyl]-3,5-dichlorobenzamide
N-[2-(6-benzoxazolinonyl)ethyl]isonicotinamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-indolecarboxamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-(benzylamino)acetamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-aminoacetamide
N-[2-(6-benzoxazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1-piperazi nyl}acetamide
N-[2-(6-benzoxazolinonyl)ethyl]cyclohexanecarboxamide
N-[2-(6-benzoxazolinonyl)ethyl]formamide
N-[2-(6-benzoxazolinonyl)ethyl]cyclopropanecarboxamide
N-[2-(6-benzoxazolinonyl)ethyl]valeramide
N-[2-(6-benzoxazolinonyl)ethyl]cyclobutanecarboxamide
Using the procedure described in Examples 61 to 88, but replacing 3-methylbenzoxazolinone by benzothiazolinone itself, the following are obtained:
N-[2-(6-benzothiazolinonyl)ethyl]acetamide
N-[2-(6-benzothiazolinonyl)ethyl]isobutyramide
N-[2-(6-benzothiazolinonyl)ethyl]phenylacetamide
N-[2-(6-benzothiazolinonyl)ethyl]-(2-oxo-1-pyrrolidinyl)acetamide
N-[2-(6-benzothiazolinonyl)ethyl]-4-chlorobutyramide
N-[2-{6-benzothiazolinonyl)ethyl]-2-pyrrolidinone
N-[2-(6-benzothiazolinonyl)ethyl]-2-bromoacetamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-morpholinoacetamide
N-[2-(3-benzothiazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl]-1-p iperazinyl}acetamide
N-[2-(6-benzothiazolinonyl)ethyl]-N-methylacetamide
N-[2-(6-benzothiazolinonyl)ethyl]benzamide
N-[2-(6-benzothiazolinonyl)ethyl]-para-toluenecarboxamide
N-[2-(6-benzothiazolinonyl)ethyl]-4-fluorobenzamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl]aceta mide
N-[2-(6-benzothiazolinonyl)ethyl]-3-(trifluoromethyl)benzamide
N-[2-(6-benzothiazolinonyl)ethyl]-3,5-dichlorobenzamide
N-[2-(6-benzothiazolinonyl)ethyl]isonicotinamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-indolecarboxamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-(benzylamino)acetamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-(N',N'-diethylamino)acetamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-aminoacetamide
N-[2-(6-benzothiazolinonyl)ethyl]-2-{4-[3-trifluoromethyl)phenyl]-1-piperaz inyl}acetamide
N-[2-(6-benzothiazolinonyl)ethyl]cyclohexanecarboxamide
N-[2-(6-benzothiazolinonyl)ethyl]formamide
N-[2-(6-benzothiazolinonyl)ethyl]cyclopropanecarboxamide
N-[2-(6-benzothiazolinonyl)ethyl]valeramide
N-[2-(6-benzothiazolinonyl)ethyl]cyclobutanecarboxamide
PHARMACOLOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION
EXAMPLE A
Study of Acute Toxicity
Acute toxicity was assessed after oral administration to batches of 8 mice (26.+-.2 grams). The animals were observed at regular intervals during the first day and daily during the two weeks following treatment. The LD.sub.50 causing the death of 50% of the animals was evaluated.
The LD.sub.50 of the products tested is greater than 1000 mg.multidot.kg.sup.-1 for most of the compounds studied, which indicates the low toxicity of the compounds of the invention.
EXAMPLE B
Activity Measurement
The animals are placed in plexiglass boxes equipped with photoelectric cells placed in a darkened environment. Six animals are tested simultaneously, and the number of interruptions of the photoelectric beams by each animal is recorded by computer during one hour.
The test compounds are administered intraperitoneally immediately before placing the animals in the apparatus.
The products of the invention decrease the animals' activity
EXAMPLE C
Four Plates Test
The products of the invention are administered via the esophagus to batches of ten mice. One batch receives acacia syrup.
30 minutes after administration of the test products, the animals are placed in compartments the floor of which comprises four metal plates. Every time the animal passes from one plate to another, it receives a mild electric shock (0.35 mA). The number of transfers from one plate to another is recorded during one minute. After administration, the compounds of the invention significantly increase the number of transfers from one plate to another, demonstrating the anxiolytic activity of the compounds of the invention.
EXAMPLE D
Activity of the Products of the Invention in Relation to Ischemic Microcirculation
The experimental study was carried out on the cremaster muscles of male rats (Sprague-Dawley) after ligation of the common iliac artery.
The muscles were placed in a transparent chamber perfused with a bicarbonate buffer solution equilibrated with a 5:95% CO.sub.2 /N.sub.2 gaseous mixture. The velocity of the red cells and the diameter of the first or second order arterioles irrigating the cremaster were measured, and the arteriolar blood flow was calculated. Identical data were obtained for four types of venules.
The same type of measurement was made simultaneosuly:
on the normally perfused cremaster,
on the ligated cremaster, that is to say the ischemic cremaster, 2, 7, 14 and 21 days after ligation.
Two group of animals were studied:
an untreated control group,
a group treated orally with a product of the invention at the rate of 0.1 mg.multidot.kg.sup.-1 per day.
No difference was noted in the velocity of the red cells or in the diameter of the vessels in the normally irrigated cremaster muscles in the treated animals in comparison to the controls.
In contrast, in the ischemic cremaster muscle, the mean diameter of the arterioles was improved in the treated animals in comparison to the controls. The velocity of the red cells was normalized by treatment for 21 days.
In fact, in the treated animals, the velocity of the red cells and the blood flow measured 7 days after ligation show no significant difference from the values obtained in the non-ischemic cremaster. These results are obtained without modification of arterial blood pressure.
These results indicate that long-term treatment with a compound of the invention improves the microcirculation and irrigation with blood of ischemic areas.
EXAMPLE E
Stimulation of the Immune Response
Batches of six mice were administered sheep red cells. These batches of mice were then treated subcutaneously with the compounds of the invention for six days, and a control group was treated with a placebo. The mice were then left undisturbed for four weeks and thereafter received a booster injection of sheep red cells without receiving further administrations of a product of the invention. The immune response was evaluated 3 days after the booster injection. It statistically increased in the group treated with the compounds of the invention.
EXAMPLE F
Inhibition of Ovulation
Adult female rats with regular four-day cycles were used.
Daily vaginal smears were prepared, and rats were selected after showing at least two consecutive four-day cycles.
Each cycle consists of two days of diestrus, one day of proestrus and one day of estrus.
In the afternoon of the day of proestrus, luteinizing hormone is released into the blood by the pituitary. This hormone induces ovulation, which results in the presence of ova in the oviduct on the day of estrus.
The compounds of the invention are on set orally at midday on the day of estrus. The treated and control rats are sacrificed on the day of estrus. The oviducts are examined. A significant percentage decrease in the number of ova is noted in the oviducts of treated rats.
EXAMPLE G
Demonstration of Analgesic Activity
The activity against pain was investigated in mice (23-25 g) according to a protocol derived from the technique described by SIEGMUND (SIEGMUND E. A., R. A. CADMUS & GOLU, J. Pharm. Exp. Ther. 119, 1874, 1954). Mice, randomized in batches of 12 animals, received the treatment orally (excipient in the case of controls) 1 hour before intraperitoneal injection of a 0.02% aqueous-alcoholic solution of phenyl-p-benzoquinone (Sigma). The writhing movements are counted between the 5th and 10th minute after injection.
It was apparent that some compounds of the invention possess analgesic activity.
EXAMPLE H
Potentiation of Barbiturate-Induced Sleep
Mice (22-25 g) are injected intraperitoneally with pentobarbital at 50 mg.multidot.kg.sup.-1. The time of onset and the duration of sleep are measured. The animals are taken to be asleep when they lose the righting reflex. The test compounds are administered intraperitoneally 30 minutes before the barbiturate injection. The products of the invention increase the duration of pentobarbital-induced sleep.
EXAMPLE I
Test of Binding to Melatonin Receptors
Binding of the compounds of the invention to melatonin receptors was carried out according to conventional techniques. It is apparent that the compounds of the invention bind beneficially to melatonin receptors.
EXAMPLE J
Study of Hypoglycemic Activity
Male KK mice were placed in cages at the age of eight weeks. They are used for the experiment when their weight is greater than 40 grams at the age of 4-5 months.
The compound of the invention is suspended in acacia syrup. Each compound tested is administered orally 18 hours before blood sampling.
Blood is collected by sampling from the caudal vein in a hematocrit tube, and then centrifuged. The plasma is collected and the blood sugar level assayed.
It is apparent that some compounds of the invention significantly decrease the blood sugar level.
EXAMPLE K
Study of the Influence of the Products of the Invention on Melatonin Synthesis
The products of the invention are administered intraperitoneally to rats (Sprague-Dawley) at doses 1, 5 and 25 mg.multidot.kg.sup.-1. Three hours after administration, the animals are sacrificed and melatonin assayed radioimmunologically. The measurement is validated by performing parallel controls. A considerable increase is observed in the plasma melatonin level after administration of the products of the invention.
EXAMPLE L
Pharmaceutical Composition: Tablets
Tablets containing 30 mg of N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]acetamide
Claims
We claim:
1. A compound selected from those of formula (I): ##STR27## in which A represents oxygen or sulfur, X represents a single bond, R represents: hydrogen or lower alkyl and in this case p=1 and B represents --CH.sub.2 --CH.sub.2 --NR.sub.1 --CO--R.sub.2 where R.sub.1 represents hydrogen or linear or branched lower alkyl, and R.sub.2 represents: a group of the formula: ##STR28## G representing linear or branched lower alkyl, R.sub.3 and R.sub.4, together with the nitrogen atom to which they are attached, from a morpholino group optionally substituted with one or more lower alkyl, or oxo, phenyl phenyl(lower alkyl), or substituted phenyl or substituted phenyl(lower alkyl) in the definitions of R.sub.3 and R.sub.4, the term substituted qualifying phenyl and phenyl(lower-alkyl) meaning that these groups are substituted with one or more radicals chosen from lower alkyl, lower alkoxy, trifluoromethyl and halogen or R represents (CH.sub.2).sub.2 --NR.sub.1 --CO--R.sub.2 with R.sub.1 and R.sub.2 having the same definition given above, and in which case p equals 0 or 1 and B represents lower alkoxy and its isomers, epimers and diastereoisomers as well as, its addition salts with a pharmaceutically-acceptable acid or base, lower alkyl and lower alkoxy having 1 to 6 carbon atoms, and inclusive.
2. A compound as claimed in claim 1 in which R represents (CH.sub.2).sub.2 --NR.sub.1 --CO--R.sub.2, B represents methoxy, and p represents 1, its isomers as well as, were appropriate, its addition salts with a pharmaceutically-acceptable acid.
3. A compound as claimed in claim 1 which is N-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-morpholinoacetamide.
4. A compound as claimed in claim 1 which is N-[2-(6-methoxy-3-benzothiazolinonyl)ethyl]-2-morpholinoacetamide.
5. A compound as claimed in claim 1 which is N-[2-(3-methyl-6-benzothiazolinonyl)ethyl]-2-morpholinoacetamide.
6. A compound as claimed in claim 1 which is N-[2-(3-methyl-6-benzoxazolinonyl)ethyl]-2-morpholinoacetamide.
7. A pharmaceutical composition containing as active principle a compound as claimed in claim 1, in combination with a pharmaceutically-acceptable excipient or vehicle.
8. A method for treating a living animal afflicted with a sleep disorder comprising the step of administering to the said living animal an amount of a compound of claim 1 which is effective for alleviation o the said condition.
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