FR2514354A1 - NOVEL 5-AMINOISOXAZOLE DERIVATIVES AND METHODS OF THEIR PREPARATION - Google Patents

Abstract

THE PRESENT INVENTION CONCERNS NEW 5-AMINOISOXAZOLE DERIVATIVES. THESE COMPOUNDS ACCORDING TO THE INVENTION HAVE THE FOLLOWING GENERAL FORMULA: (CF DRAWING IN BOPI) IN WHICH R IS IN PARTICULAR A LOWER ALKYL GROUP, R IS IN PARTICULAR A HYDROGEN ATOM, R IS IN PARTICULAR A HYDROGEN ATOM, R AND R BEING EACH IN PARTICULAR A HYDROGEN ATOM, ONE OF THE SUBSTITUENTS A AND B IS IN PARTICULAR A CARBONYL GROUP AND THE OTHER A METHYLENE GROUP WHICH CAN BE SUBSTITUTED, AND D IS A -N - R GROUP (IN WHICH R IS ESPECIALLY A HYDROGENE ET R IS ESPECIALLY A C1-C6 ALKYL GROUP), AND THEIR NON-TOXIC SALTS. APPLICATION AS A MUSCLE RELAXATION AGENT.

Description

NEW XAZOLE 5-AMINOI DFRIVES AND PROCDES OF THEIR PREPARATION

  The present invention relates to new derivatives

  5 aminoisoxazole compounds useful as a relaxation agent

  muscles effective on the central nervous system and pos-

with high selectivity.

  Several physiological effects of aminoisoxazole drifts have been reported Zen'ichi et al.

  synthesizes 5- (2-diethylamino-1-actyl) amino-3,4-di-

  methylisoxazole, they studied its uterotonic effects and reported that it did not exhibit such effects.

  (see Yakugaku Zasshi, 81, 636 639 (1961) Torizo Taka-

  hashi et al have 2-dialkylamino derivatives

  ac 6 tylamino of 5-amino-3,4-dimethylisoxazole Yakugaku

  Zasshi, 82, 474,480 (1962) 1 and 2-dialkylamino derivatives.

  acetylamino of 5-amino-3-alkoxyethylisoxazole t Yakugaku

  Zasshi, 82, 481, 486 (1962) reported their activities.

  analgesics Shojiro et al synthesized the

  2-dialkylaminoacbtylamino rivets of 5-amino-3-methylisoxa

  zole lYakugaku Zasshi, 83, 198 200 (1963) 1 and reported their analgesic activities Andrè Luven Pons et al.

  synthesized the 2-dialkylaminoacetylamino derivatives of 5-

  amino-3-phenylisoxazole L French Patent No. 2,068,418

  Innotheraj and pointed out that they have

  ti-convulsive and anti-inflammatory J P Trivedi et al. synthesized the 2-dialkylaminoacetylamino derivatives of 5-amino-3,4-dimethylisoxazole Indian J Pharmaceutical Science 41 (1), 28 (1979) 1 and reported that they do not

  had no anti-inflammatory or anti-convulsive effect.

  The compounds of the present invention are the

  3-dialkylaminopropionylamino, 3-dialkylamino derivatives

  propylamino and 3-dialkylamino-3-oxo-1-propyl of 5-amino

  isoxazole having three, instead of two carbon atoms

  in the side chain unlike the 2-dial-derivatives

  kylaminoacetylamino of 5-aminoisoxazole reported in 1 '

  Prior Art Compared to the known 5-amino-drift

  isoxazole, the compounds of the present invention have stronger anticonvulsive effects on the central nervous system. Furthermore, the compounds of the present invention have only weak effects in the motor center,

  because they have a powerful effect of relaxing mus-

  keys of the central nervous system and that is why

  tends that their use as relaxation agents

  muscles of the central nervous system has a high selectivity.

  The present invention relates to the novel aminoisoxazole derivatives of general formula (I):

R 1 R 2 R 4

/ l -N A C B D (I) \ t / I t Ri R 5

R 3 K 5

  wherein R 1 is a lower alkyl group, a group

  phenyl which may be substituted by a lower alkyl group

  lower alkoxy or halogen, R 2 is a hydrogen atom, a halogen atom, an alkyl group

  or phenyl, R 3 is a hydrogen atom, a group

  eg C 1 -C 5 alkyl, phenyl group or benzyl group

  may be substituted by halogen or groups

  lower coxyls, R 4 and R 5 are each a hydrogen atom

  gene or a lower alkyl group, one of the substituents A or B is a carbonyl group and the other a methylene group which may be substituted by a lower alkyl group or A and B 3 are each a methylene group which may be substituted by a group lower alkyl, and D is a group -N / R 6 (wherein R 6 is a hydrogen atom or a 7-C 6 alkyl group and R 7 is a C 1 -C 6 alkyl group, a

  cycloalkyl group or a benzyl group), a morpho-

  lino, a hexamethyleneimino group, a heptamethyl group,

  leneimino, a pyrrolidino group that can be substituted

  by one or more lower alkyl groups, a group

  piperazino which may be substituted for a lower alkyl group

  lower, phenyl or halophenyl or a piperidine group

  dino which may be substituted by a phenyl group or a

benzyl group.

  As the lower alkyl group in R 1, R 2, R 4, R 5, A and B of the general formula cited above (I),

  may include methyl, ethyl, propyl or

  As halogen in R 1, R 2, R 3 and D, mention may be made of

  Chlorine, bromine, fluorine or iodine As the alkoxyl group in R 3, there may be mentioned the methyl group,

  Othoxyl, propoxyl or butoxyl As a cycloalkyl group

  kyle of R 7 in D, there may be mentioned the cyclopro-

  pyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohep-

tyl or cyclooctyl.

  As alkyl groups of R 6 and R 7 in D, those of C 1 -C 6 can be mentioned among them the groups

  In particular, the groups C 1 -C 4 alkyl are preferred.

  Ethyl and n-propyl are preferred.

  lidino substituted with one or more alkyl groups

  example, group 2.5-

  dimethylpyrrolidino. Among the compounds of the general formula (I) mentioned above, the compounds which are preferred from the point of view of pharmacological activity are those in which A is a carbonyl group, a methylene group or -CH, R 4 and

  R 5 being each a hydrogen atom or a gro U 3

  thyl and methylene or -H The most preferred compounds are those in H 3 where A is a carbonyl group, one of the substituents R 4 or R 5 is a hydrogen atom and the other a methyl group and X is a

methylene group.

  As compounds having a preferred combination of R 1, R 2, R 3 and D, there may be mentioned those compounds wherein R 1 is phenyl which may be substituted by lower alkyl or halo, R 2 is

The factor R 3 is u.

  hydrogen or lower alkyl, R 3 is hydrogen, C 1 -C 5 alkyl, phenyl

  or a benzyl group and D is a group having the formula

  the -NA 6 (wherein R 6 and R 7 are each a group

  R 7 alkyl C 1 -C 4), a pyrrolidino group which may be substituted by one or more lower alkyl groups, a 6-pipido ridino group or a heptamethyleneirrilno group,

  As compounds still having a predetermined composition,

  of the said groups, mention may be made of the compounds,

  in which R 1 is a phenyl group, a phenyl group

  nyl having a lower alkyl group or a halogen in o or m position, R 2 is a hydrogen atom, i 3 is a methyl group or a phenyl group, and D is a diethylamino, di-n-propylamino, pyrrolidino group, piperidino

or hexamethyleneimino.

  Typical examples of compounds having the

  General (I) of the present invention are as follows: Compound Compound No. 3 1,3-Piperidino-1-propionyl 3 amino-3-phenylisoxazole

  13-morpholino-1-propionyllamino-3-

ph & nyli soxazole '

  5 1,3-methylpiperazino-1-propionyl amine

3-phenylisoxazole

  4 5 3 3 4-phenylpiperazino-1-propionylamino

  3-phanylisoxazole, 5-methyl-3-pyrrolidino-1-propionylamino-3-phenylisoxazole

  6 5 1,3 (4-benzylpiperidino) -1-propionylamino

3-phdénylisoxazole

  7 5 1 3-piperazino-1-propionyllamino-3-phenyl-

isoxa zole

  8 5 1,3-diethylamino-1-propionyl) amino-3-

isoxazole

  9 5 l 3-di-n-p Dropylamino-1-propionyl jamiino 3-

phenvlisoxazole

  1-Piperidino-2-methylpropionylamino

3-phepnylisoxazole

  3-mnorpholino-2-methyl (1-propionyl) aminone

3-phenyli soxazole

  12 5-l 3- (4-methyl) -2-methyl Jthyl-1

  propionyl ainino 3-phenylisoxazole 13 5-1- (4-phe-n-pyridazino) -2-methyl-1-propionyl) arino-3-phenyl-soxazole

  14 5 1,3L 4- (2-chloropheryl) piperazinol-2-methyl

  1-propionylamino-3-phenylisoxazole

  1-pyrrolidino-2-methyl-1-propionylamino

3-phe 4 nyli soxa zole

  16 5 1 3 <4-pheenylpiperidino) -2-methyl-1-

  propionyl ar-ino-3-phenylisoxazole

  1517 -5 l 3-piperazino-2-methyl-1-propionyl 1 lamino-

3-phenylisoxazole

  18 5 1,3-dimethyl-2-amino-2-methyl-1-propionyl

amnino 3-phenyli soxazole

  19 5 1 3-Diethylamino-2-x-methyl-1-propionyl 1 -

amino 3-phenylisoxazole

  5 1,3-di-n-propylamino-2-methyl-1-propionyl

amnino 3-phenyl lisoxazole

  21 5 1,3-dimethylamino-2-methyl-1-propionyl -

amnino 3-niethylisoxazole

  22 5 1,3-Piperidino-1-propionylamino-3-methylmethyl

isoxazole

  23 5 I-3-piperidino-1-propionylamino-3-methylmethyl

4-pheénylisoxazole

  1-Dimethylamino-2-methyl-1-propionyl)

  amino-3-phenyl-4-isopropylisoxazole

2 5 1 4 3 5 4

  5-1,3-pyrrolidino-2-methyl-1-propionyllamino

3-phenyl-4-isopropylisoxazole

  5- (1,3-pyrrolidino) -2-methyl-1-propionylamino

3-phenyl-4-bromoisoxazole

  5-N-methyl-N- (3-trimethylamino-2-meth, 1-1-)

  propionyl) lamino-l-phé'nvlisoxazole

  5-NMR-N-methyl-N- (3-pyrrolidino-2-methyl-1-yl)

propionyl) lamino-3-phenylisoxazole

  5-N-methylyl-N- (3-diethyl-2-methyl-2-ethyl)

  propi-onyl) lamino-3-ph'énylisoxazole

  5-N-methyl-N- (3-di-n-propylamino-2-methyl)

  1-propionyl) lamino-3-phenylisoxazole.

  31 5-IN-methyl-N- (3-isopropylamino-2-methyl)

  1-proi Dionyl) lamino-3-phenylisoxazole

  2 (32 5-N-methyl-N- (3-tert-butylamino-2-methyl-2-yl)

  1-propionyl) lamino-3-phenylisoxazole

  5-NMR (2-methyl-1-propyl) -N- (3-pyrrolidino)

  2-methyl-1-propionyl) lamino-3-phé'nylisoxazole

  5-N- (2-methyl-1-propyl) -N '- (3-diethylamino)

  2-me 'thyl-1-propionyl) lamino-3-ph'énylisoxazole

  5-N- (2,2-dimethyl-1-propyl) -N- (3-pyrrolidino)

  2-methyl-1-propionyl) lamino-3-phenylisoxazole

  5-IN- (2,2-dimethyl-1-pror) yl) -N- (3-di-methyl)

  amino-2-rr-ethyl-1-propionyl) lamino-3-pliényl-

isoxazole

  5-N- (2,2-dimethyl-1-propyl) -I- (3-isouropyl)

  amino-2-methyl-1-propionyl) 1) amino-3-

Phenyli Soxa Zole

  38 1 N (2,2-dimethyl-1-propyl) -N (3-tert-)

  butylamninc-2-methyl-1-propionyl 1-amino-3-phenylisoxazole

  39 5 N -benzyl N (3-pyrrolidino-2-methyl-1)

  propionyl) Ianmino-3-phenylxazole

  1040 5-IN-benzyl-N 1- 3- (4- (2-chlorophenyl) piperazino)

  2-methyl-1-propionylamino-3-phenylisoxazole

  41 N -benzyl-N (3-dimethylamino-2-methyl-1-yl)

  propionyl) 3-amino-3-phenylisoxazole

  42 N -benzyl-N (3-diethylamino-2-methyl-1-yl)

  propionyl) Iainino-3-pheynylisoxazole

  1-N-benzyl-N- (3-di-n-propylamino-2-methyl)

  1-propioriyl) 3-aminophenylisoxazole

  44 5-IN (4-mnethoxybenzyl) -N (3 pyrrolidino-2-

  mnéthyl-1-propionyl) lIamnino-3-phenylisoxazole

  45 N- (3,4-dimethyloxybenzyl) -E (3-pyrrolidino)

  2-mnéthyl-1-propionyl)) arino-3-phenylisoxazole

  46 5-N (4-methoxybenzyl) -N, (3-diethylamino)

  2-methyl-1-p-ropionyl) amino-3-phenylisoxazole

  47 5-Len- <3,4 dime 6thoxybenzyl) -N- (3-diethlyl)

  amino-2-methyl-1-propionyl) amino-3-phenylisoxazole

  1-N-phenyl-N (3-pyrrolidino-2-ethylethyl) -1-

  propionyl) Jarnino-3-phenylisoxazole

  49 5-IN-Phenyl-N- (3-diethylamino-2-methyl-1-yl)

  propionyl) lamino-3-phenylisoxazole 5-N-phenyl-N- (3-diethylaminc-2-m)

Ethyl-1-

  propionyl) jamino-3-ter buvli-soxazole

  51 5-N-benzyl-N- (3-dimethylamino-2-methyl-1-yl)

  propionyl) 3-lamethyl-4-folded, nylisoxazole

  52 5-I-3-Piperidino-3-methyl-1-propionyllamino

3-phenylisoxazole

  53 5-1 3-Morpholino-3-methyl-1-propionyllamino

3-phenylisoxazole

  54 5-I 3- (4-methylpiperazino) -3-methyl-1-

propio nyllamino-3-phenylisoxazole

  5-I 3- (4-phe "nipiperazine) -3-methyl-1-

propionyllamino-3-phé'nylisoxazole

  56-5-1,3-pyrrolidino-3-methyl-1-propionyllamino

3-phenylisoxazole

  57 5-I-3-oxo-3-piperidino-1-methyl-1-propyll

amino-3-phénvlisoxazole

  58 5-I-3-oxo-3-morpholino-1-methyl-1-propyll

amino-3-phenylisoxazole

  59 5-I-3-oxo-3- (4-methylpiperazino) -1-methyl-ethyl

1-propyl) amino-3-phenylisoxazole

  5-I-3-oxo-3- (4-phenylpiperazino) -1-methyl-1-

propyl) amino-3-phenylisoxazole

  61 5-I-3-oxo-3-pyrrolidino-1-methyl-1-propyll

amino-3-phenylisoxazole

2 514354

  62 5 1 3-Oxo-3-piperidino-2-methyl-1-propyl

amnino 3-phe 5 yli soxa zole

  63 5 1,3-Oxo-3-pyrrolidino-2-methyl 11-propyl 11-

amnino-3-ph (nylisoxazole

  64 5-IN-methyl-N (3-oxo-3-pyrrolidino-1-methyl) -ethyl

  1-propylamino-3-ph-6-nylisoxazole

  5 l 3-piperidino-1-propylamino-3-ph 6 nyl-

isoxazole

  66 5 1 3-mnorpholino-1-propyl) amino-3-pheenyl

isoxazole

  1567 5 1-3 (4-methylpiperazino) -1-propyllamino

3-phéniylisoxazole

  68 5 1-3 (4-pheenylpiperazino) -1-propyl aryl

3-phenylisoxazo

  2069 5 1 3-pyrrolidino-1-propyllamiino-3-phenyl-

isoxazole

  5 1 (4-benzylpipe ridino) -1-propyllamino

3-phénxylisoxazole

  71 5 l 3-pipe 6 razino-1-propyllamino-3-phenyl

isoxazole

  72 5 1 3-Piperidino-3-methyl-1-propyl) amino-3-

ph (nylisoxazole

  73 5 1 3-Morpholino-3-methyl-1-propyllamino-3-

isoxazole

  74 5 l 3 (4-methylpiperazino) -3-methyl-1-

propyll amino-3-phenylisoxazole

14354

  5-l 13 (4-phenylpiperazinio) -3-methyli 1-1-

propylamino-3-phenylisoxazole

  76 5 1,3-pyrrolidino-3-methyl-1-propyl-3-aminio

  3-ph 6 nyli soxazole 77 5 l-ié, n iti 11 ppl m o 3-phernyli soxa zole

  78 5 1 3-Morpholinio-2-methyl-1-propyllamnino

3-ph Jnylisoxazole

  79 5-I 3 (4-methylpiperazino) -2-methyl-1-

propyll amino 3-phenylisoxazole

  -5-13 (4-phenylpiperazino) -2-methylth-1-

propyll amino-3-phenylisoxazole

  81 5 13-Pyrrolidino-2-methyl-1-propyllamino

3-phenylisoxazole

  82 5 1 3 (4-phenylpiperidino) -2-methy 11-1-

propyll anino-3-phenylisoxazole

  83 5-l 13-piperazirno-2-methyl-1-propyl) amino-3-

* pheny lisoxazole

  84 5 1 -Piperidino-1-methyl-1-propyllamino-3-

isoxazole

  5-I-13-morpholino-1-methyl-1-propyllamino-3-

phé'nylisoxazole

  13- (4-phenylpiperazino) -1-methyl-1-propyl)

amino 3-phenylisoxazole

  87 5-I-13-pyrrolidino-1-methyl-1-propyllamino-3-

phé'nvlisoxazole

2 5 1435 4

1.2

  88 5-N-benzyl-N- (3-piperidino-1-propyl) lamino

3-phenylisoxazole

  5-Benzyl-N- (3-morpholino-1-p-o-yl) lamino-

3-phenylisoxazole

  1-Benzyl-N-1,3 (4-ethylpiperazino) -1-

propyl) Jamino-3-phenylisoxazole

  91 5-N-benzyl-N-1 3- (4-phenylpiperazino) -1-

propylllaniino-3-phenylisoxazole

  92 5-N-benzyl-N- (3-pyrrolidino-1-propyl) -1-

amino-3 Dhe "nylisoxazole

  93 5-N-benzyl-N- (3- (4-benzylpiperidino) -1-

prop yl) Iamino-3-phenylisoxazole

  94 5-1N-benzyl-N- (3-piperidino-3-methyl-1-

propyl) 3-lamino-Dhenylisoxazole

  95 5-N-benzyl-N- (3-morpholino-3-methyl-1-

propyl) Iamino-3-phenylisoxazole

  96 5-N-benzyl-N-1 3- (4-methylpiperazino) -3-

  methyl-1-propyl) lamino-3-ph-énylisoxazole

  97 5-N-benzyl-N-1 3- (4-phenylpiperazino) 1-3-

  methyl-1-propyl) lamino-3-ph'énylisoxazole

  98 5-N-benzyl-N- (3-pyrrolidino-3-methyl-1-

propyl) lamino-3-phe "nylisoxazole

  99 5-N-benzyl-N- (3-piperidino-2-methyl-1-

propyl) lamino-3-ph-énylisoxazole

  5-lN benzyl-N- (3-morpholino-2-methyl-1-

propyl-) amino-3-phenylisoxazole

2 5 1435 4

1 3

  101 5-N-benzyl-N-13 (4-methylpipera 7-ino) -2-

  methyl-1-propyl) lamino-3-phënylisc> azole

  102 5-1N-benzyl-N-1 3- (4-phenylpiperazino) -2-

  1-methyl-propyl) -3-aminopropyl azole

  1- (3-pyrrolidino) -2-, ethyl-1-

propyl) jamino-3-phe "nylisoxazole

  104 5 1 N-benzyl-N l 3 (4-phenylpipe "ridino) -2-

  methyl-1-propyl) lamino-3-phenylisoxazole

  5-N-benzyl-N- (3-piperidino-1-methyl-1-yl)

propyl) Iamino-3-phenylisoxazole

  5-Ib-N-benzyl-N- (3-morpholino-1-methyl-1-yl)

propyl) lamino-3-phé'nylisoxazole

  107 5-N-benzyl-N- (3-pyrrolidino-1-methyl-1-yl)

propyl) lamino-3-ph'énylisoxazole

  5-NMR (4-methoxybenzyl) -N- (3-pyrrolidino) -3-

  Methyl-1-propyl) -amino-3-phenyl-isoxazole

  109 5-N- (4-Chlorobenzyl) -N- (3-pyrrolidino) 3-

  methyl-1-propyl) lamino-3-phenyl-e

  5-IN- (4-methox-ybenzyl) -N- (3-pyrrolidino)

  methyl-1-propyl "friend-no-3-ph'énylisoxazole

  5-N- (4-chlorobenzyl) -N- (1-pyrrolidino)

propyl) lamino-3-phenylisoxazole

  112 5-N-benzyl-N- (3-pyrrolidino-1-propyl) -lamino

3-phenyl-4-bromoisoxazole

  113 5-IN-methyl-N- (3-pyrrolidino-1-methyl-1-yl)

propyl) Iamino-3-phenylisoxazole

  114 5 N -benzyl-N- (3-dimethyl-2-methyl-1-yl) -ethyl

  propyl> 3-amnino-3-n-ethylisoxazole

  5-lH-3-pyrrolidino-2-methyl-1-propyl-onyl

amino-3 - ('4-chlorophenyl) isoxazole

  116 5-diethylamino-2-methyl-1-propylmethyl

  amnino-3 (4-chlorophenyl) isoxazole

  10117 5-IL-N-methyl-N, 3-diethylamino-2-methyl-1-yl

  propiornyl) Jamirio-3 (4-chlorophenyl) isoxazole

  118 5 1 3-Diethylamino-2-methyl-1-propionyl 1 -

amiino-3,4-diph nylisoxazole

  119 N-methyl-N-3-piperidino-2-methylyl-1-

  propionyl) amino-3-phenylisoxazole

  5-NM-methyl-N-3-hexamethyleneimino-2-methyl

  1-propionyl) -3-phenylisoxazole

  121 5-IN-methyl-N- (3-heptamethyl) -eneimino-2-

  Methyl-1-propionyl) lainino 3-phenylisoxazole

  122 5 LN-xnethyl-N <3 (2,5-dimethylpyrrolidino) -

  2-methyl-1-propionyl) jamiino-3-phenylisoxazole

  123 N-Methyl-N- (3- (N-methyl-N-benzyl) amino)

  2-mnethyl-1-propionyl) Jamnino-3-phenylisoxazole

  5-NM-thymethyl-N (3-N-propyl-N-ethyl) amino-2-

  1-methyl-1-propionylamino-3-phenylisoxazole

  5-Lt N-methyl-N-3-pip ridino-2-methyl-1

  propionyvl) Jamino-3 (2-ch 11 orphenyl) isoxazole

  126 5 N-Methyl-N '- (3-pyrrolidino-2-methyl-1-)

  propionyl amino-3 (2-chlorophenyl) isoxazole

2 5 1 43 5 4

1 5

  127 5-N-methyl-N- (3-methyl-2-methyl-1-methyl)

  propionyl) lamino-3- (2-chloropheenyl) isoxazole

  128 5-N-methyl-N- (3-piperidino-2-methyl-1-yl)

  propionyl) lar - ino - 3- (3-chloropheliv) isoxazole

  129 5-N-methyl-N- (3-diethylamino) -2-1-, ethrl-1

  propionyl) lamino-3 - ( '- chlorophenyl) isoxazole

  5-N-methyl-1- (3-diethylamino) -2-methyl-1-yl

  propionyl) lamino-3- (2-methylplien N, 1) isoxazole

  131 5-N-methyl-N- (3-diethylamino-2-methyl-1-yl)

  propionyl) lamino-3- (3-methylphenyl) isoxazole

  132 5-N-methyl-N- (3-diethylainino-2-methyl-1-yl)

  propionyl) lamino-3- (4-methylphenyl) isoxazole

  133 5-N-methyl-N- (3-piperidino-2-methyl-1-yl)

  propionyl) lamino-3- (4-methyl-L-oxyphenyl) isoxazole

  N-methyl-N- (3-diethylamino-2-methyl-1-

134 5

  propionyl) lamino-3- (4-methoxyphenyl) isoxazole

  5-N-methyl-N- (3-cycloheptylamino-2-methyl)

  1-propionyl) lamino-3-phenylisoxazole

  136 5-N-methyl-N (3-piperidino-2-methyl-1)

  propionyl) lam-ino-4-isopropyl-3-ph'ényl-

isoxazole

  137 5-N-methyl-N- (3-pyrrolidino-2-methyl-1-yl)

  propionyl) lamino-4-isopropyl-3-pliénylisoxazole

  138 5-IN-methyl-N- (3-diethylamino-2-methyl-1-yl)

  propionyl) lamino-4-isopropyl-3-p-pylyl

isaxazole

2 5 1 43 5 4

  139 5-1N-ethyl-N- (3-piperidino-2-methyl-1-

  propionyl) lamino-3-p 7 nenylisoxazole

  5-N-methyl-1-methyl-2-methyl-2-methyl-2-methyl

  proi Dionyl) laj-rno-3-phe / nylisoxazole

  141 5 1,1-Propyl-1 ', (3-piperidino-2-methyl-1)

propionyl) lamino-3-phénvlisoxazole

  5-1-N-propyl-N- (3-diethylaruno-2-methyl-1-yl)

propionyl) lamino-3-phe "nylisoxazole

  143 5-N-methyl-N- (3-pyrrolidino-3-methyl-1-yl)

propionyl) lamino-3-phenylisoxazole

  144 5-N-methyl-N- (3-diethylamino-3-methyl-1-yl)

  propionyl) lamino-3-ph% - = nvlisoxazole

  5-N-methyl-N- (3-pyrrolidino-1-propionyl) -

amino-3-phenylisoxazole

  146 5-lN-m -: - gthyl-N- (3-diethylamino-1-propionyl) l-

amino-3-phenylisoxazole

  147 (+) - 5-IN-methyl-N- (1-diethylamino-2-methyl)

  1-propionyl) lamino-3-phenylisoxazole

  148 (-) - 5-lN-methyl-N- (3-diethylamino-2-methyl-1-yl)

propionvl) lamino-3-phenylisoxazole

  149 (+) - 5-N- (3-pyrrolidino-2-methyl-1-propionyl) -1-

amino-'D-phenylisoxazole

  (-) - 5-N- (3-pyrrolidino-2-methyl-1-propionyl) -

amino-3-phenylisoxazole

  151 5 N-methyl-N (3-diethylamino-2-ethyl-1)

  Among these compounds, those which are used as muscle relaxation agents are the compounds Nos. 15, 25, 28, 29, 30, 34, 36, 39, 41, 42, 49, 87, 98,

  107, 119, 120, 122, 124, 125, 126, 127, 128, 129, 1350,

  131, 138, 140, 142, 147, 148, 149, 150 and 151. Particularly preferred compounds are No.

  28, 29, 30, 49, 119, 120, 126, 127, 129, 130, 147, 148

and 151.

  Methods for preparing compounds of the present invention represented by the general formula

  (I) mentioned above will be described below.

  The procedures for the preparation of the compounds of the

  invention can be roughly

the following four processes:

R R 2 R _ 2

1-NH + R COX -OR

R 3 R 3

(II) (III) (IV)

R R R

(IV) + H -D -2 /

NCOC B 'D

R 3 R 5

  (V) (la) wherein X is halogen, R is a group having the formula:

C = C-

H

  (wherein R 8 is a hydrogen atom or a group

  lower alkyl) or a group having the formula: R 8 R 4 X 9 y HRP 'is a methylene group which may be substituted by a lower alkyl group, and R 1, R 2, R 3, R 4, R 5 and D have the same meaning as above,

R 8 RH

(1 +

(II) + H C = C C O D H1-, f / 1

> / I

  (VI) wherein A 'is a methylene group which may be substituted by a lower alkyl group, and R 1, R 2, R 3, R 4, R 8 and D have the same meaning as above,

3 R R

(I Ia) or (Ib) R ducti -

  Reduction RR 13 R 4 AC-BR DR 5 wherein one of the substituents A and B is a m 4 tbylene group and the other is a methylene group which may be substituted by a lower alkyl group and R 1, R 2, R 3, R 4, R 5 and D have the same meaning as above, and 4.

R R 2 4

  N / NH "B, D + R'3 x R 5 (Ic ') 3 00 (VII)

R 1 R 2 R

R 1 \\ N A "C Pl D

R 3 R 5

  (Id) wherein X is halogen, R'3 is a C1-C5 alkyl group, or a benzyl group which may be substituted with 2. R 2 N A J 3 - R 4

C -CO D

  H (lb) 1 halogen or a lower alkoxyl group, and R 1, R 2,

  R 4, R 5, A ", F" and D have the same meaning as above.

  above. Process 1 mentioned above is suitable for the preparation of compounds having the general formula (I) mentioned above, wherein A is a carbonyl group. According to the process, an aminoisoxazole of general formula (II) is reacted. with an acid halide of general formula (III) (such as halogen, chlorine or bromine) in the presence of

  1-10 equivalents, preferably 2-5 equivalents of

  ethylamine or pyridine in a solvent such as a hydro-

  halogen carbide S, for example methylene chloride,

  chloroform or dichloroethane, an aromatic hydrocarbon

  such as benzene or toluene or a ketone,

  for example acetone or methyl ethyl ketone at a temperature of

  at -10 ° C to 100 ° C, preferably OCA to form a 5-acylamino derivative of general formula (IV) and then this compound (IV) is reacted with an amine of general formula (V) in the absence of any solvent or in a lower alcohol such as methanol, ethanol or propanol, a ketone such as acetone or

  methyl ethyl ketone or a lower alkyl ester of

  acetic acid such as methyl acetate or ethyl acetate between 0 C and 100 C, preferably between 20 and 80 C to form a compound of general formula (la)

of the present invention.

  Process 2 mentioned above is suitable for the preparation of compounds having the general formula (I) mentioned above, in which EB is a carbonyl group. According to this process, a compound of general formula (II) is reacted with an amide. of general formula (VI) in the presence

  base such as sodium amide or sodium hydride

  dium in a solvent such as a lower alcohol, for example

  methanol, ethanol or proparnol or tenzene, toluene or xylene from 0 OC to 150 OC, preferably

   At 100 ° C. to obtain a compound of general formula

  (Ib) of the present invention.

  Process 3 is suitable for the preparation of compounds having the general formula (I), cited above, wherein A and 2 are each a group other than

  According to this method 3, an amide of formula

  the general (Ia) or (Ib) obtained by the procedure 2 mentioned above is reduced with lithium aluminum hydride in ethyl ether, tetrahydrofuran, C dioxane or diglyme (dimethoxyethoxy ether) or with

  sodium dihydrobis (methoxyethoxy) aluminate in the

  Zene, toluene, ether, t & trahydrofuran or their mixture

  as a solvent to obtain a compound of general formula

  (Ic) of the present invention.

  Procedure 4 is suitable for the preparation of

  compounds of the general formula (I) above, in the

  which A and P are each a group other than a group

  carbonyl and R 3 is a group other than the hydrogen atom

  gene and the phenyl group According to method 4,

  react an amide of general formula (Ic ') with a hydro-

  halogenated carbide of general formula (VII) (as halogenated

  gene can be chlorine or bromine)

  a strong base such as sodium hydride or

  sodium amide in a solvent such as benzene, toluene

  ene or xylene of 0 C at 150 ° C, preferably from 1 ° C to 300 ° C to obtain a compound of general formula (Id)

of the present invention.

  These compounds obtained by the methods mentioned

  Above 1-4 can be converted to their addition salts with pharmacologically acceptable acids.

  such as their salts with mineral acids, for example

  hydrochloric acid, furic acid or acetic acid.

  phosphoric acid and organic acids, for example 1 '

  maleic acid, fumaric acid, malonic acid,

tartaric acid or citric acid.

  If the compound of the present invention has at least one asymmetric carbon in the molecule, the compound

  theoretically at least two optical isomers

  of the invention comprises such a racemic modification.

  The optical isomers can be separated from the racemic modification by a known method, in which, for example, their salt of an optically active acid is 6, then the two resulting diastereoisomeric salts are separated from one another.

  the other and the optical isomers are isolated from the di-

  The optical isomers can also be isolated by the following method: an acrylic acid ester derivative of the general formula:

4

H C = C COOR 9

  wherein one of the substituents R'4 and R'8 is a hydrogen atom

  gene and the other is a lower alkyl group and is a C 1 -C 4 lower alkyl group, is reacted with an amine of the general formula: wherein D has the same meaning as above,

  to form a propionic acid ester of general formula

rale: R '8 i

D CH CH COUR

  in which R, R 8, R 9 and D have the same significance

  as above and one of the carbons bearing the symbol

  bole is asymmetric, and then we react

  the resulting compound with 1α-methylbenzylamine in

* the presence of a Grignard reagent to obtain a diastereo-

  isomer of E-1-methylbenzyllopropionamide of formula

the general:

8 1-4

D CH CH CONHCH

s <j H 3

  in which R 4, Rè, D and t have the same meaning

  cation as above and the symbol * indicates the optical activity the resulting diastereoisomer is subjected to optical resolution in accordance with silica gel column chromatography and then reacted with the trifluoride / methanol complex (BF 3 F 2 CH 30 H) for

  obtain an optically acyl derivate and methyl propionate

tif of general formula: i R I 4

D CH CH COOCH 3

  (a.) (*) in which RI and RI have the same meaning as

4 8

  above and a symbol (-) indicates that one of them is optically active, without being racemized. Thereafter, the derivative is reacted with the -aminoisoxazole derivative of general formula (II) to obtain a compound. optically active agent of the general formula:

2 R R 58

y t CO CH CH D-

3 () ()

  wherein R 1, R 2, R, R, R, R, and Det (*) have the

  same meaning as above, according to the present

  vention. The pharmacological effects and acute toxicities of the typical compounds of the present invention

will be described now.

  3 o 1) Muscle relaxation effects:

  (A) To obtain an index of the effects of

  muscle laxation, a traction method reported by Saji et al. Yoshiaki Saji, Yuko Chiba, Yomei Take and Yuji Nagawa "Report of Takeda Laboratory" 30 (3), 406-426 (1971) was used to examine the relaxation effects of Concretely, ICR mice

  males (each group included 6 mice) were sus-

  hanged by their front legs on a 2 mm dia-

  horizontally stretched tensor and the muscle relaxation effects were determined from their tensile reactions on their hind legs (traction).

  Test sera were administered intraperitoneally.

  I Cases in which traction has disappeared or mice

  fell were considered as cases of

  laxation of muscles A quantity of a compound with the-

  which half of the mice used for the test presented

  the muscle relaxation effect was defined as

  50 (mg / kg) The results were illustrated in

Table 1.

  (B) For another index of muscle relaxation effects, a method by Fukuda et al. Hideomi Fukuda, Ito, Hashimoto, and Kudo Japanese Journal of Pharmacology 24, 810 (1974) was used to prepare anemic, deformed rigid samples. More specifically, a tracheal cannula was inserted into each Wistar mouse. mnle under anesthesia of ether The two common carotid arteries ligated and the basilar artery

  Was cauterized with bipolar coagula-

  circulating blood and preparing a rigid sample Rigidity is recorded as described below. A mouse is fixed on its back on a fixation support and its front legs can grip on one end of a celluloid plate.

  equipped with wires stretched on its two extremes Uin chan-

  the resistance observed, when the plate

  luloid is pushed upward by the rigidity of the patches

  your front is recorded as a voltage by a cir-

  It is bridged on a self-balancing recorder. A stiffness inhibition rate is determined according to the following formula: stiffness inhibition rate = abx 100 (%) b in which is a voltage recorded prior to the administration of a test compound and b represents

  a voltage recorded at the moment of the maximum reaction

  after intravenous dosing

  The amount (mg / kg) of each test compound with

  50% inhibition is reached, has been determined

born "X 50) -

  the results are shown in Table 1.

  Table I Relaxation effects of muscles Compound (A) Test of (B) Rigidity, decerebrate Toxicities Anemic fraction acute E mg / kg (ip) IYO 15 mg / kg <i Lv) LD 5 mg / kg <ip) 20 - 2.5 - 2.5 - 2.5 -

2.5 S

2.5 5

300

300 o

-300 I

"O O 1000

300

300 1000

300

-300 i -300

-300 I

300

300

300

100 <ivil 50 (iv) '

300

300

300

<- - - - - - 50

100

-1

-2 514354

-26

100

300

- - - -

100

2.5 24

300

300

300

1000 3000

300

300

300 1000

100

300

300 1000

300

1000 <

300

1000 <

300

300 1000

300

300

300 1000

looo <-10 O

2 5 1 43 5 4

  2) 5 2; 5 2 e 5 5 ld 25 -2) 5 l 25 -2) 5

2) 5 -5

2) 5 -5) 0

1) 25 -2) 5

2) 5 -5

2) 5 -5

2.) 5 -5, O

2) 1) O 2) 5 looo <

300

  (iv) 13 j 2 (iv) 19; 5 (iv) (iv) 8 (iv) 13 4 (iv) 50 (iv) 50 (iv) 16. i 3 (iv) 36 Y 5 (iv) 100 (iv) 100- (iv) 21> 9 (iv) 7 1 38 1 4 2 14 7 14 8

300

10 10

2514354-

  2 t 2) Anti-convulsive effects lYoshio et al. "Iyakuhin Kenkyoho" p 258 (published by Asakura Book Store) l: (C) Anti-convulsive effects due to pentetrazole (Pi TZ): 170 mg / kg of pentbtrazole were administered intraperitoneal routes to male ICR mice and effects of trials until seizures occur

  tonicity of hind legs caused by pent O tra

  For the tests, the compound was administered intraperitoneally 30 minutes later.

  pentbtrazole intrapharma-

  Tonic and ectatic tonic convulsions are observed When the convulsions disappeared, the compound was considered anti-convulsive The DE 50

  (mg / kg) was calculated 6th by the Van der Waer-

  den L Keijiro Takagi and Ozawa, "Yakubutsu-gaku Jikken (Pharmacological Experiments)", the third edition, published by Nanzan-do Book Storel The results are

illustrated in Table 2.

  (D) Effects on convulsions after

  maximum trochoc (MES): The electroshock (2000 V, 50 m A, 0 2 sec)

  is applied to the two eyeballs of each

  and the effects of the tests have been ex-

  ectatic tonic convulsions of the hind paws For the test, the compound

  tested was administered to mice intrapri-

  30 minutes later, an electroshock was

  and cases where rear-leg convulsions disappear, were evaluated as anti-convulsive. DF 50 (mg / kg) was calculated by

  Van der Waerden's method The results are pre-

shown in Table 2.

14354

  Table 2 Anti-convulsive effects Sifs Conps (C) PTZ (D) MES ag 1 50 mg / kg (ip) DE 0 mg / kg (ip) D 50 img / kg (ip) 28 '44 5 50

100

14 d O 28) i

17>) 7

173) 7>) 4, 3

14> O

16 J 6

8> j 1

100

50 50 50 50 i j

25143 4

123 50 -

  126 3 Y 6 25 (iv) 127 8> O 15) 8 (iv)

128 10 Y 3

129 6 7

12 5 -

i 13 4 (iv)

132 29 7

134 25

139 22 i 3

12 5

141 '4 25 50

142 25 56

147 57 3

  148 1 OY 7 36? (Iv) 149 2 5;, O 25 50 5 O 100 (iv) 12 y 25 50 50 100 (iv) 3) Acute toxicity:

  The LD 50 (mg / kg) of each test compound

  administered to mice intraperfitonally or intra-

  venous was determined. The results are pre-

  in Tables 1 and 2. 4) Central inhibition effects (E):

  For an index of inhibitory effects

  centralization, the inhibition effects of each

  test-pose on spontaneous movement were examined

  using male ICR mice using a

  rotary compound test developed by the applicant (Japanese Patent Publication No. 143252/1978) All test compounds were dissolved in isotonic sodium chloride solution and administered by

  Intraperitoneal route Immediately after administration

  the mouse was placed in a rotational cage and the number of rotations during lo min was counted. In the case of Baclofen, the number of rotations in 10

  min (20 minutes after administration) was counted

  Isotonic solution of sodium chloride

  was given to the control group Ul & and the number of rotations

  tions was counted in the same way as above.

  In the controlled group, the number of rotations in 10 min was 135 + 55 (average + normal deviation, 31 cases) The number of rotations less than 45 included the least average (standard deviation x 65) was regarded as effective for the control of spontaneous movement The DE 5 o was calculated by the Van der method

  Waerden The results of the typical examples are pre-

shown in Table 3.

  Table 3 Effects of Central Control and Selectivities of Composts E

Rigidity of cereals -

  anemic pitch 1.Faction channel, No. of Compound 6 of Compound 8, I-present invention __________

  adminis 15 29 Toluperi 1 Mephene Bacro-

  50 μg / kg g / g Mg / kg mg / kg IV.

I 'D.

J O 113

71, 5 i 2.5

9 39.7

> O

4,162.9

1 _ 3 O

54; O 2; 9 f O .; 9 1 '5, 1

3> 31

  J Effect -, () p T'z I D 17, 7 ____ 14 _4.0 31> 42> 089 O 14) 010 4

ti

  see 1 i (D) MY ID 25.0 5 4 25 0 2> 2 61> 51 0112 4 50 <> 1 Control 8 lej Number of days of mid-cycle 4 rotations ID 134 561 63.0 159 f 5.3 oro t _ _ _ _ _ __ _ _ _j Pl = E / A, E / B, E / C or E / D <4-n uy Effect of

rela xa -

  '(B) (A) Table 3 shows the results obtained by

  examination of the selectivities of compounds typical of the pre-

  invention as an index of the control effects

  tral, the control effects of spontaneous movement in a rotary cage were used. Referring to a method of NN Share et al N. N. Share and CS McFarlane, Neuropharmacology 14, 675 684 (1975), the DE 50 ratio in the muscle relaxation effect (A) or (B) or DE 50 the anticonvulsant effect (C) or (D) on DO (E) was also used as a selectivity index of a compound The higher the ratio, the more

  the selectivity is great The results are also pre-

shown in Table 3.

  The 5-aminoisoxazole derivatives of formula g $ -

  fer (II) used as a raw material for

  The first method consists of reacting a nitrile of general formula:

R 1 CN (VIII)

  in which R 1 is a C 1 -C 4 lower alkyl, a phenyl group or a substituted phenyl group, with a nitrile of the general formula:

R 2 CH 2 CN (IX)

  in which R 2 is a hydrogen atom or a C 1 -C 4 lower alkyl group, in the presence of a base, such as sodium hydride or sodium amide

  in an aprotic solvent such as benzene, the toluene

  ene, xylene, ethyl ether, tetrahydrofuran or hexane, preferably in benzene, toluene, ethyl ether or hexane at a temperature of from -10 ° C to 200 ° C, preferably OC 80 C according to a method of DN Ridge et al. J. Med Chem 22 (11)

  1385 (1979) 3 to obtain a 3-iminopropion derivative.

nitrile of general formula:

12

R 1 CHCH CN

  Wherein R 1 and R 2 have the same meaning as above Then the resulting derivative is reacted

  with hydroxylamine or its mineral salt in a soil

  such as water, a lower alcohol, for example methanol, ethanol or propanol or their mixture

  a temperature between 0 C, preferably

  this between 20 50 C to obtain a 5-amino derivative

  isoxazole of the general formula (I Ia): R 2

R 1 CN + R 2 -CH 2 CN R 1 C CH CN

i NH

R 2 R 1 __ R 2

R 1 C-CH-ON + H 2 N-OH NH 2

NH (I Ia)

  In the second method, a driv & 5-imino-

  propionitrile is hydrolysed with, for example, hydrochloric or uni nitrile acid of the general formula (IX) mentioned above is reacted with a carboxylic acid ester of general formula:

R 1 C OR '

  in which R 1 represents a lower alkyl group

  at C 1 -C 4, a phenyl group or a phenyl group

251435-4

  And R 'represents a C 1 -C 4 lower alkyl group, in the presence of a base such as sodium methoxide, sodium metal or sodium hydride

  to form a 6 acylac 6 tonitrile derivative of general formula -

rale: R 2 -12

R 1 COCHCN

  in which R 1 and R 2 have the same meaning as above, and then this derivative is reacted with

  hydroxylamine to form a 5-aminoisoxane derivative

zole of general formula (I Ia):

2 +

NH R 1 -COH-CN

  base R.1 CEH-C i 21 COHC 2 R 1 -COOR + R 2 -CH 2-CN bae

R R 1 R 2

R 1-COCH-CN + H 21 OH 2

  (Ia) In the third method, a methyl ketone derivative of the general formula is reacted:

3 U R 1 COCH 3

  wherein R 1 is a lower alkyl group in

  C 1 -C 4, a phenyl group, or a substituted phenyl group

  killed with pyrrolidine, morpholine or pip 6 ridin in

  presence of p-toluenesulphonic acid or tetra-

* titanium in benzene, toluene, xylene u titanium chloride in benzene, tolu Sne, xylene or

  a halogenated hydrocarbon such as methyl chloride

  ethene, chloroform or dichloroethane at a temperature between -20 ° C and 200 ° C, preferably between -10 ° C and 0 ° C (in the presence of titanium tetrachloride) or at the boiling point of the solvent (in the presence of p-acid). toluenesulfonic) according to a Tanaka method

  et al. Biol Chem 37 (10) 2365 (1973) 3 to ob-

  hold a hnamine of general formula:

R 1 CH 2

  Where R 1 has the same meaning as above and Y is CH 2-, -0 or a single bond

  the enamine is reacted with an isothiocyanate of

General mule:

R 3 NCS

  wherein R 3 has the same meaning as above, in an acetic acid ester according to a method of S. Humig et al. Chem. 95, 926 (1962) 1 to obtain a thioamide derivative of general formula:

HC C-NHR

R 35 -C S

  in which R 1, R 3 and Y have the same meaning

  than above and then we react the $ derivative

  sulting with hydroxylamine hydrochloride in

  this of a base such as sodium acetate, carbonate

  of sodium, sodium bicarbonate, pyridine or tri-

  ethylamine in a lower alcohol such as methanol or ethanol according to a method of Von G Griss (Liebig

  Ann Chem 738, 60 (1970) to obtain an aminoisox-

  substitute zole S in position 5 of general formula (I Ib):

R R 2

HC C-NHR + H 2 NOH Base N HR 3

R 10 C 3

  R -C t q IN In the fourth method, a ketone of general formula is reacted:

R 1 R 2

C ^

  in which R 1 represents a lower alkyl group

  at C 1 -C 4, a phenyl group or a substituted phenyl group

  killed and R 2 represents a lower alkyl group, a group

  phenyl or a substituted phenyl group, with a d 6-

  riveted with thiocyanate of general formula:

R 3 NCS

  in which R 3 has the same meaning as above,

  in the presence of a strong base such as hydride of

  dium, sodium amide or sodium metal in a solvent such as benzene, toluene or xylene from room temperature to 200 ° C., preferably at the boiling point of the solvent to form a thioamide derivative of general formula:

R 1 R 2

  oCNHR S in which R 1; R 2 and R 3 have the same meaning

  than above, and then the reactive derivative is reacted

  sulting with hydroxylamine hydrochloride in

  of a base such as sodium acetate, car-

  sodium bonate, sodium bicarbonate, pyridine or triethylamine in a lower alcohol such as methanol or ethanol to obtain a 5-substituted aminoisoxazole of general formula (Ic):

R 1 R 2

  No O -NHR (I Ic) in which R 1, R 2 and R have the same meanings 2 3

than above.

  In the fifth method, we react

  a 5-aminoisoxazole of the general formula (I Ia), in the

  which R 1 and R 2 have the same meaning as above with a carboxylic acid or an acyl chloride of the general formula:

R 3 "COX

in which R "'

  330 wherein R is H, or an alkyl group

  C 1 -C 4, or phenyl and X is OH (R "3 being H) or Cl, in the presence of a base such as triethylamine or pyridine in a solvent such as a halogenated hydrocarbon, for example methylene chloride or chloroform, benzene, toluene

  xylene to form a 5-acylaminoisoxane derivative

zole of general formula:

R 1 R 2

I -NHCOR "

  No 3 in which R 1, R and R "have the same meaning as above and then this derivative is reduced by the

  dihydrobis (methoxy-thoxy) sodium aluminate or hy-

  lithium-aluminum drure to obtain a derivative of

  substituted aminoisoxazole at the 5-position of general formula

rale (I Id):

R 1 R 2

  Wherein R 1, R 2, and R 3 have the same meaning

than above.

  The methods of preparing the compounds of the present invention will now be described

with reference to the examples.

EXAMPLE 1

  Synthesis of 5- (3-Moroholino-1-propionyl) amino-3-nhenyliso-

  xazole. (Compound N 2): (1) 3-phenyl-3-iminopropionitrile-1: 19.5 g of sodium amide in 90 ml of anhydrous ether are added to this solution and added dropwise

  To this suspension 25.78 g of benzonitrile and 20.53 g of acetonitrile

  nitrile in anhydrous ether.

  reflux for 15 hours, then cool the mixture

  lange reaction at 100 C and carefully added water

  while stirring to break down the excess sodium amide.

  Then 180 ml of ether and 150 ml of water are added to the mixture.

  The ether layer obtained is dried over sulfa

  anhydrous magnesium The desiccant is removed

  and the ether is distilled off to provide the

  crystals After recrystallization from benzene,

  23.69 g of 3-phenyl-3-iminopropionitrile (P 83

850 C).

  (2) 5-amino-3-phenylisoxazole: 72.09 g of the 3-phenyl-3-iminopropionitrile obtained as described in step (1) are dissolved in

  400 ml of ethanol is added 41.69 g of hydrochloride hydrochloride.

  xylamine to the solution keeping the temperature below 40 C A Drès 3 hours of agitation, one

  150 ml of water are added. The ethanol is removed under high pressure.

  The resulting crystals are filtered and dried at

   Under reduced pressure and provide 77.63 g of

  crude levels After recrystallization from benzene,

  70.10 g of 5-amino-3-phenylisoxazole are collected.

Yield: 77.6%, mp: 103105 C.

  (3) 5- (3-bromo-1-propionyl) amino-3-phenylisoxazole: 16.02 g of 5-amino-3-phenylisoxazole and 9.70 ml of pyridine are dissolved in 100 ml of chloroform. a solution of 20.6 g of 3-bromopropionyl chloride in 50 ml of chloroform with keeping the temperature below C followed by stirring for 2.5 hours.

  at room temperature Then the chloroform is chas-

  under reduced pressure and the residue thus obtained is

  80 ml of water and 700 ml of ethyl acetate.

  Separated ethyl acetate is blown with a solution

  saturated aqueous saline and is then dried over sodium sulphate

  anhydrous sium The drying agent is removed and the residue is evaporated under reduced pressure to provide 30.96 g of crude crystals. The crude crystals are recrystallized from 55 ml of benzene / ethyl acetate (3: 2) to obtain

  22.93 g (mp 147-150 ° C) of purified crystals.

(4 Y Compound N 2:

  29.5 g (0.1 mol) of 5- (3-bromo-1-propionyl) -

  amino-3-phenylisoxazole obtained in the preceding step (3) are suspended in 300 ml of benzene. 26.1 g (0.3 mole) of morpholine are added to the solution and the mixture is heated gently to reflux after 4 hours. Refluxing time, the reaction mixture is cooled. 100 ml of water are added and the resulting benzene layer is separated and washed three times with saturated aqueous saline solution. It is dried over sodium sulfate and concentrated under reduced pressure to obtain crude crystals. The crystals are dissolved in

  130 ml of benzene 180 ml of n-hexane are added to the solution.

  and allowed to stand in a refrigerator for 16 hours to form the crystals.

  crystals are filtered and dried under reduced pressure.

  Yield: 28.78 g (95.5%), mp: 117.5119C.

  The following compounds are synthesized as described in step (4) except that morpholine

  is replaced by a corresponding amine.

Compound N Yield P f.

1 75 76 77 o C

3 71 156.5 158.5

4 97 168 169.5

83.5 81 82

6 80.1 98 108

  8 69.9 167 168 (fumarate) 9 67.7 135 136 (fumarate)

EXAMPLE 2

  Synthesis of 5- (3-piperazino-1-pronionyl) amino-3-dienyliso-

xazole. (Combined N 7):

  2.58 g of piperhanol are dissolved in 90 ml of ethanol.

  anhydrous razine and 5.31 g of dihydrochloride monohydrate

  piperazine, then to this solution is added 5 r (3-bromine

  1-propionyl) amino-3-phenylisoxazole After heating the mixture at 600 ° C. for 10 hours with stirring, the ethanol is evaporated under reduced pressure.

  water and ethyl acetate to the residue and the

  The resulting compound is extracted from the aqueous layer with chloroform. The extract is

  dried over anhydrous sodium sulphate The desiccating agent

  This is removed and the chloroform is evaporated under pressure.

  The residue is purified by alumina column chromatography (eluted with benzene) to provide the

  desired compound Yield: 1.99 g, P f: 133 134 C.

EXAMPLE 3

  Synthesis of 5- (3-pyrrolidino-2-methyl-pro-pionyl) amino-3-

  phenylisoxazole (compound N 15): (1) 5- (2-methyl-2-propen-1-yl) amino-3-phenylisoxazole:

  320.4 g of 5-amino-3-phenylisoxane are dissolved

  zole obtained in the manner described in Example 1- (2) and

  242.6 g of pyridine in 2 liters of chloroform.

  The resulting mixture is cooled to below -5 ° C. A solution of 282.3 g of methacryloyl chloride

  in 300 ml of chloroform is added to the resulting solution.

  at room temperature in the range of -5 ° C. to -10 ° C. After the addition, the reaction mixture is added at -50 ° C. for 2 hours. Then, the chloroform is evaporated under reduced pressure and the resulting residue is dissolved in the mixture. ethyl acetate The resulting solution is strained with a

  dilute solution of hydrochloric acid, a solution of

  sodium bicarbonate and finally with a saturated aqueous saline solution After drying over anhydrous magnesium sulfate, the drying agent is removed, and then the ethyl acetate

  is evaporated under reduced pressure The residue is recrystallized

  in a mixture of ethyl acetate / methanol (4: 1) to

  provide 5- (2-methyl-2-propen-1-yl) amino-3-phenylisoxa

zole (P f 180 183 C).

(2) Compound N 15:

  27.4 g of 5- (2-methyl-2-propenol) are dissolved.

  oyl) amino-3-phenylisoxazole obtained in step (1) and

  17.1 g of pyrrolidine in 100 ml of ethanol and then heated.

  the refluxing solution for 8 hours.

  pore ethanol under reduced pressure Ethyl acetate and

  water added to the residue The layer of ethyl acetate

  is separated, washed with an aqueous saline solution

  turkey and dried over anhydrous sodium sulphate

  desiccation is removed and the residue is evaporated under

  sion to provide raw crystals.

  crystallisation in a mixture of ethyl acetate / hexane,

  24.5 g of the desired compound N 15 (P f 106.5 -

  107.50 C) in a first step then 7.5 g in a second crop. Mass: M 299 (C 7 H 2 N 302)

17 21 3 2>

  The following compounds are synthesized as described in Example 3 except that one chooses

  a starting compound corresponding to a predicted compound.

Compound N Yield P f o C

82.0 112.5 114

11 84.3 147.5 148.5

12 79.0 129.0 131

13 82.6 190 191.5

14 79.04 170 172

16 84.1 125 126

EXAMPLE 4

  Synthesis of 5- (3-piperazino-2-methyl-1-propionyl) amino-3-

  phenylisoxazole (compound N 17):

  1.72 g of piperazine and 3.5 g of dihydrochloride -

  of piperazine are dissolved in 60 ml of ethanol is added

  to this solution of 5- (2-methyl-2-propen-1-yl) amino-3-phenol

  nylisoxazole obtained in Example 3- (1) The system of

  The reaction is heated at 70 ° C for 15 hours, then

  The mixture is cooled to room temperature. Ethanol is evaporated under reduced pressure and water is added to the residue. Next, chloroform is added to the layer.

  water to extract the chloroform

  is dried over anhydrous sodium sulphate After

  under reduced pressure, the residue is purified by

  alumina column chromatography (elution with benzene

  zene) to provide 2.79 g of the desired product P f 142.5 -

144.5 C.

EXAMPLE 5 Synthesis of 5- (3-dimethylamino-2-methyl-1-1-pro-Dionyl) amino

  3-phenylisoxazole (compound N 18):

  11.41 g of 5- (2-methyl-2-propen-1-yl) amino-

  3-phenylisoxazole obtained in Example 3 (1), 13.6 g (20 ml) of dimethylamine and 100 ml of methanol are introduced into an autoclave. The mixture is stirred at room temperature.

  for 12 hours, then methanol and dimethyl-

  excess amine are evaporated under reduced pressure to leave an oil This oil is dissolved in ether and gaseous hydrochloric acid is introduced into the system while it is cooled to 5 C The resulting crystals are filtered and the solid is recrystallized from an ethanol / ether mixture to obtain 13.2 g (yield

  2%) of the hydrochloride of the desired compound (P f 85 -

87 OC).

EXAMPLE 6

  Synthesis of 5- (3-diethylamino-2-methyl-11-propionyl) amino

  3-phenylisoxazole (compound N 19):

  3.00 g of 5- (2-methyl-2-propen-1-yl) amino-

  3-phenylisoxazole obtained in Example 3- (1) are mixed with 21.2 g of diethylamine.

  reflux for 7 hours, excess diethylamine is

  pores under reduced pressure and leaves an oil which is

  chromatographed on silica gel using as a developing agent a mixture of chloroform / ethyl acetate (20: 1) to obtain the compound provided under

form of an oil.

Mass: M + 301.

  The compound N 118 is obtained in the indicated manner.

  above, except that we react with the di-

  thylamine a derivative of 5-aminoisoxazole selected according

  of the expected compound Yield: 56.8%, P f: 93 94 C.

EXAMPLE 7

  Synthesis of 5- (3-di-n-oropyvlamino-2-methyl lrorionyl) amine

  no-3-phenylisoxazole (Compound N 20): The procedure described in Example 6 is repeated except that the diethylamine is replaced by di-npropylamine to obtain 2.53 g (58.43% ) of the compound

  This compound is dissolved in acetone.

  equimolar content of fumaric acid is added to the solution.

  and the mixture is stirred at room temperature and then concentrated to precipitate the fumaric acid salt of the desired compound P 79 820 C.

EXAMPLE 8

  Synthesis of 5- (3-dimethylamino-2-methyl-1-propionyl) amino

  3-methylisoxazole (compound N 21): (1) 5- (2-methyl-2-propen-1-yl) amino-3-methylisoxazole: 0 g of 5-amino-3-methylisoxazole and 10.32 g

  (14.2 ml) of triethylamine are dissolved in 100 ml of chlorine

  methylene chloride The resulting solution is cooled to a temperature below 5 ° C. A solution of 9.96 ml

  of methacryloyl chloride in 30 ml of

  Thylene is added dropwise to the solution. After stirring the reaction mixture at room temperature

  for 12 hours, this mixture is washed with water and separated

  on anhydrous magnesium sulphate Methyl chloride

  It is evaporated under reduced pressure and leaves 5- (2-

  methyl-2-propen-1-yl) amino-3-methylisoxazole The yield

  after recrystallization was 10.62 g (mp: 9899 ° C).

(2) Compound N 21:

  5 g of 5- (2-methyl-2-propen-1-yl) amino-3-

  methylisoxazole obtained in step (1) and 10 ml of dimethyl

  thylamine are dissolved in methanol After stirring the reaction mixture at room temperature in a

  tube sealed for 12 hours, methanol and dimethyl-

  excess amine are evaporated under reduced pressure and

  leave the desired compound having a P f of 64 -

  66 C The resulting crystals are dissolved in ether and gaseous hydrochloric acid is introduced into the system to precipitate it after recrystallization

  methanol / ether mixture, the hydrochloride having a P f.

139 140 C is obtained.

EXAMPLE 9

  Synthesis of 5- (3-piperidino-1-deionyl) amino-3-methyliso-

  xazole (compound N 22): (1) The procedure described in Example 1- (3) is repeated except that 5-amino-3-phenylisoxazole is replaced by

  5-amino-3-methylisoxazole to give 5- (3-bromo-1-

  propionyl) amino-3-methylisoxazole (P 133 133 C)

21.28 g (65.8%).

  (2) 19.8 g of the compound obtained in step (1) and 21.7 g of piperidine are added to 300 ml of benzene. The mixture is

  heated at reflux for 2 hours and then cooled to

  The benzene layer is dried over anhydrous sodium sulphate and concentrated under water.

  reduced pressure to provide crude crystals These crystals

  Crude levels are recrystallized from a benzene / hexane mixture (1: 2) and yield 17.45 g of the compound N 22, P f:

63 650 C, Yield: 86.5%.

EXAMPLE 10

  Synthesis of 5- (3-piperidino-1-Dromionyl) amino-3-methyl-4-

  phenylisoxazole (compound N 23): (1) 5-amino-3-methyl-4-phenylisoxazole: 79.7 g of 1-cyano-1-phenyl-2-propanone are

* dissolved in 250 ml of pyridine is added 39.5 g of chlorine

  hydroxylamine hydrate to the solution The reaction mixture

  It is stirred at room temperature for 12 hours and then at 550 ° C. for 6 hours. When the reaction is complete, the pyridine is evaporated under reduced pressure and

  a mixture of water / ether is added to the residue.

  The crude crystals are collected and recrystallized from carbon tetrachloride to give 78.5 g of 5-amino-3-methyl. The resulting crystals are collected under reduced pressure and dried over an anhydrous Glauber salt. -4-phenylisoxazole (P f:

67 70 C) Yield: 90.1%.

  (2) 5- (3-bromo-1-propionyl) amino-3-methyl-4-phenylisoxazole: 26.2 g of 5-amino-3-methyl-4-phenylisoxazole obtained in step (1) and 14 3 g of pyridine are dissolved in 120 ml of chloroform. 30.9 g of 3-bromopropionyl chloride are added dropwise to the solution while cooling to a value of less than 5 ° C. After stirring the reaction mixture at 60.degree. 4 hours, this reaction mixture is cooled to room temperature and the chloroform layer is washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to give

  get raw crystals These raw crystals are recreated

  in a mixture of benzene / ethyl acetate to

  provide 21.83 g of 5- (3-bromo-1-propionyl) amino-3-methyl-

4-phenylisoxazole P 130 133 C.

  (3) Compound N 23: 9 g of the compound obtained in step (2) are suspended in 300 ml of benzene. 17.9 g of piperidine are added dropwise to the suspension at ambient temperature. The mixture is refluxed for 3 hours, the reaction mixture is cooled to room temperature and the benzene layer is washed with saturated aqueous saline solution. The benzene layer is dried over anhydrous sodium sulphate and evaporated under reduced pressure.

  reduced pressure to obtain crude crystals

  crude levels are recrystallized from an acetate mixture

  ethyl / methanol to provide 19.07 g (yield: 90.0%).

  of the desired compound (P f 126 128 C).

EXAMPLE 11

  Synthesis of 5- (3-dimethylamino-2-methyl-1-propionyl) amino

  3-nhényl-4-iso Dro Dpylisoxazole (compound N 24): (1) 5-amino-4isopropyl-3-phenylisoxazole: 12.94 g of small pieces of sodium are added

  to 120 ml of anhydrous ether A mixture of 48.30 g of benzonitrile

  trile and 39.0 g of 3-methylbutyronitrile is added dropwise to the system and the reaction mixture is stirred at room temperature for 4 hours.

  water carefully and separate the ethereal layer.

  After drying over anhydrous magnesium sulphate, the ether is evaporated off under reduced pressure and leaves 79.6 g of crude crystals. 79.6 g of the crude crystals obtained are dissolved in ml of ethanol. A solution of 35.64 g of chlorhydrate of hydroxylamine in 250 ml of a mixed solvent mixture

  Ethanol / H2 (2: 3) is added dropwise to the solution.

  After stirring the reaction mixture for 12 hours, the ethanol is evaporated under reduced pressure. Ether is added to the residue. After drying over magnesium sulphate, the ether is evaporated under reduced pressure to give the mixture.

  obtain 53.55 g of oil The oil is separated by

  high performance liquid separating matography (chlorine

  roform: ethyl acetate = 10: 1) to obtain 23.43 g of -amino-4-iso-dropyl-3-phenylisoxazole.

  (2) 5- (2-methyl-2-propen-1-yl) amino-4-isopropyl-3-phenyl-

  isoxazole: 5-amino-4-isopropyl-3-phenylisoxazole obtained in step (1) and 2.75 g of triethylamine are dissolved in 50 ml of chloroform The resulting solution

  is cooled to a temperature below 100 ° C.

  3.10 g of methacryloyl chloride in 10 ml of chloroform is added dropwise to the solution. After stirring the reaction mixture at room temperature for 12 hours, the reaction mixture is washed with water and dried over sodium sulfate. anhydrous magnesium The chloroform is distilled off under reduced pressure and ether is added to the residue obtained to precipitate

  5- (2-methyl-2-propen-1-yl) amino-4-isopropyl-3-phenyl-

  isoxazole in the form of white crystals Yield: 1.56 g

(23.3%).

(3) Compound N 24:

  1.51 g of 5- (2-methyl-2-nropen-1) are dissolved

  oyl) amino-4-isopropyl-3-n-phenylisoxazole obtained in step (2) in 80 ml of chloroform. A large excess of

  dimethylamine to the solution, and the reaction mixture is stirred

  at room temperature in a sealed tube

  12 hours; excess chloroform and dimethylamine are evaporated to obtain the desired compound as an oil This oil is dissolved in acetone and a

  equimolar amount of fumaric acid is added to this

  ci to obtain its fumarate Yield: 2.35 g, P f:

1610 C.

EXAMPLE 12

  Synthesis of 5- (3-pyrrolidino-2-methyl-1-propionl) amino-3-

  phenyl-4-isopropylisoxazole (compound N 25):

  2.0 g of 5- (2-methyl-2-propen-1-yl) amino-4-

  isopropyl-3-phenylisoxazole obtained in Example 11- (2) and

  0.63 g of pyrrolidine are dissolved in 50 ml of benzene.

  The resulting solution is refluxed for 24 hours.

  When the reaction is complete, the reaction mixture

  The reaction mixture is cooled to room temperature, washed with water and dried over anhydrous magnesium sulfate.

  benzene is evaporated under reduced pressure and leaves

  The crystals are filtered and dried under reduced pressure to yield 2.25 g (yield:

  89.07%) of the desired compound P f: 104 106 C.

Mass: M 341 (C 20 H 27 N 302).

EXAMPLE 13

  Synthesis of 5- (3-pyrrolidino-2-methyl-1-propionyl) amino-3-

  phenyl-4-bromoisoxazole (compound N 26):

  2.50 g of 5- (3-pyrrolidino-2-methyl-1-propionic acid)

  nyl) amino-3-phenylisoxazole obtained in Example 3- (4) are dissolved in 50 ml of chloroform. 1.93 g of N-bromosuccinimide are added to the solution while stirring.

  The reaction system is then stirred at room temperature.

  binder for 10 hours, washed with water and dried over anhydrous magnesium sulfate The drying agent is removed then the chloroform is evaporated under reduced pressure Ethyl acetate is added to the residue and the mixture is stirred for the crystals precipitate The crystals are filtered and dried under reduced pressure to obtain 0.6 g

  of the desired compound P 68 700 C (tartrate).

EXAMPLE 14

  Synthesis of 5- / N-methyl-N- (3-dimethylamino-2-methyl-1-pro

  pionvl) 3-amino-henylisoxazole (Compound N 27): (1) 5-Formylamino-3-phenylisoxazole: 96.0 g of 5-amino-3-phenylisoxazole obtained in

  Example 1 (2) is added to 400 ml of formic acid.

  After heating the mixture at reflux for 1.5 hours, the

  The reaction mixture is poured into a large amount of water.

  The crystals thus formed are filtered and dried under

  reduced after recrystallization from chloroform

  71.03 g (62.9%) of 5-formylamino-3-phenylisomer were collected.

  xazole P f: 1120 C. (2) 5-N-methylamino-3-phenylisoxazole: 22.82 g of aluminolithic hydride are added to

  anhydrous tetrahydrofuran A solution of 75.5 g of 5-

  formylamino-3-phenylisoxazole obtained in step (1) in 500 ml of tetrahydrofuran is added dropwise to

  the suspension above, with stirring at 150 ° C.

  tation of the reaction mixture at room temperature

  for 3 hours, water is then carefully added

  to decompose the excess aluminolithic hydride.

  A mineral material thus formed is filtered and washed several times with tetrahydrofuran The washing solutions are combined with the filtrate The tetrahydrofuran is evaporated to dryness under reduced pressure The resulting residue

  is recrystallized from benzene and provides 57.2 g of 5-N-

  methylamino-3-phenylisoxazole Yield: 81.9% P f: 112 o C.

  (3) 5-ZN-methyl-N- (2-methyl-2-propen-1-yl) lamino-3-phenyl-

  isoxazole: 16.0 g of 5-N-methylamino-3-phenylisoxazole obtained in step (2) and 18.58 g of triethylamine are added to chloroform. 20 ml of chloroform containing 19 ml of chloroform are introduced dropwise into this solution. 24 g of methacryloyl chloride at a temperature below

14354

   C. After stirring the reaction system at ambient temperature for 12 hours, the reaction mixture is washed with water, then with dilute hydrochloric acid and finally with water and then dried over anhydrous magnesium sulphate. The chloroform is evaporated under pressure. reduced and the residue is purified

  chromatography on silica gel using chlorine

  form to obtain 5-F N-methyl-N- (2-methyl-2-propen-1

  oyl) 7-amino-3-phenylisoxazole Yield: 15.54 g (69.7%).

Mp 60 61 C.

(4) Compound N 27

  4.50 g of 5-lN-methyl-N- (2-methyl-2-propen-1)

  7-amino-3-phenylisoxazole obtained in step (3) are dissolved in 100 ml of benzene.

  de-dimethylamine to the solution while cooling to 0 C.

  After stirring the reaction mixture at room temperature in a sealed tube for 12 hours, excess benzene and dimethylamine are removed and the residue is purified by silica gel chromatography (chloroform: methanol) to obtain 5.18 g of the compound sought in the form of an oil This oil is dissolved in acetone and an equimolar amount of fumaric acid is added

  to the solution to obtain the fumarate of the product.

M.p .: 108 109 C.

  According to the same procedure as described above,

  the oil compound N 51 is prepared. Yield: 51.7%.

EXAMPLE 15

  Synthesis of 5-F N-methyl-N- (3-pyrrolidino-2-methyl-1-propionic)

  nyl) 3-aminophenylisoxazole (compound NO 28):

  4.00 g of 5-f N-methyl-N- (2-methyl-1-propen-1)

  oyl) 7-amino-3-phenylisoxazole obtained in Example 14- (3)

  and 1.41 g of pyrrolidine are added to 80 ml of benzene.

  After heating the mixture under reflux for 24 hours, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate, and the benzene is then evaporated off under reduced pressure. The oil thus obtained is purified by chromatography on silica gel using a chloroform / methanol (10: 1); we get the product

sought in the form of an oil.

  M + / e mass 313, 243, 140, 103, 84 (C 18 H 23 N 302) NMR (free base) 6 (CDCl 3>: 1.19 (3H 1, d, J = 7Hz, CH 3 CH 1.5 2.0 (4H, m, CH 2 -CH 2 -CH 2 -CH 2), 2.3 2.7 (6H, m, CH 2 N), 2.7 3, 2 (1H,

  m, -CHCH 3); 3.40 (3H, s, CH 3 N); 6.53 (1H, s, = C-H); 7,3-

H 3 H

  7.6 (3H, m, = C-C 1 -H H) 7.68.0 (2H, m, = HH Fumarate P f 144 1450C. The following compounds are synthesized from

  described in this example, except that pyrrolidine

  dine is followed by piperidine, heptamethyleneimine, hexamethyleneimine, 2,5-dimethylpyrrolidine, N-ethyl-N-benzylamine or cycloheptylamine. The following compounds can thus be prepared synthetically:

Compound NO 119.

  5-l-N-methyl-N (3-pyrperidino-2-methyl-1-yloplanyl) -7-amino

  3-Phenyl isoxazole Oil Yield: 60.4% δ (CDCl 3): 1.13 (3H, d, J = 7H 4z, CH 3 CH); 1, 2 1, 8 (6H, m, -CH 2 CH 2 CH 2 CH 2 CH 2) 2.3 2, 7 (6H, m, N-CH 2) 2.7 3, 2 (1 H, m, CH 3 CHCH 2) 6.48 (1H, s, = CH 1); 7.3 7.6 (3H, m, H 2H)

= C 7.6 7.9 (2H, m, = -

  HH Mass: M + 327 (C 9 H 25 N 0) mp 115 117 o C (fumarate) omiose NO 120 - / W-methyl-N (3-hexamethyleneamino-2-methyl-1-propionyl) 1-7 amino 3Dhenylisoxazole Oil Yield: 45.1% NMR 6 (CD C 13): 1.11 (3H, d, J = 7.0Hz, CH 3 CH-); 1.3 1.7 (8H, m, -CH 2 CH 2 CH 2 CH 2 CH 2 CH 2-); 2.4 2.7 (6H, m, CH 2 N); 2.7 3.1 (1H, m, CH 3 CHCH 2); 3.40 (3H, s, N-CH 3); 6.47 (1H, s, = C-H);

H H

  7.25 7.6 (3H, m, = C H) 7.69.9 (2H, m, = C)

H H

  Mass M: 341 (C 20 H 27 N 302) P f: 144 147 C (fumarate) The following compounds are synthesized according to the procedure described in this example except

  that 5-ZN-methyl-N- (2-methyl-1-propen-1-yl) 7-amino-3-

  phenylisoxazole is replaced by a derivative of 5-aminoiso-

  xazole chosen according to the desired compound.

  The following compounds are synthesized from

  described in this example except that 5-N-

  Compound NP f (C) Yield (%) 121 132-134 (fumarate) 49 122 oil (mass: M + 341) 3.4 123 oil (mass: M 377) 4.2 124 oil (mass: M 355) 46 Compound NP f (C) Yield (%) 44 oil 90.2 oil (mass: M 449) 90.5 143 oil (mass: M + 313) 85.7 146 1480 C (fumarate) oil (mass: M + 299) 70, 1,144,145 C (fumarate) thyl-N- (2-methyl-1-dl-D-1-yl) -7-amino-3-ph-6-nylisoxazole and

  pyrrolidone are replaced by a 5-aminoisoxane derivative

  zole chosen according to the desired compound and piperidin

  ne, respectively, in this example.

EXAMPLE 16

  Synthesis of 5-N-methyl-N- (3-diethylamino-2-methyl-1-pro-

  nionvl) lamino-3-phenylisoxazole (compound N 29):

  5-Ak-methyl-N- (2-methyl-2-propen-1)

  oylamino-3-phenylisoxazole obtained in Example 14- (3) are introduced into a 500 ml flask. 200 ml of diethylamine are added thereto. 1.2 ml of liquid is then added to the mixture.

  After heating the mixture at reflux

  After 28 hours, the reaction mixture is freed of

  excess diethylamine by evaporation under high pressure

  To the resulting oil is added normal hydrochloric acid and the mixture is extracted twice with ethyl ether. The aqueous solution is adjusted to pH 9 with 28% aqueous ammonia and extracted with water. The ether layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is removed and the residue is evaporated under reduced pressure.

  reduced pressure; 58.6 g of the compound

  The oil is dissolved in 300 ml of acetone. 23.7 g of fumaric acid are added to the solution. The mixture is stirred and then allowed to stand.

  for the crystals to precipitate The crystals are fil-

  very, washed with a small amount of acetone and dried Compound NP f (o C) Yield (%) oil (mass: M + 361) 75 128 P f 67 70 C 61 (mass: M + 361) 133 oil (mass: M + 357) 68

  under reduced pressure; 64.4 g of fumigant

  spleen of the desired compound Yield: 72.3% P f: 113.5 -

1140 C.

  NMR (free base) 6 (CD C 13): 0.97 (6H, t, J = 7.0Hz, CH 3 -CH 2); 1.12 (3H, d, J = 6Hz, CH 3 CH-); 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3) 2); 3.42 (3H, s, CH 3 N); 6.52 (1H, s, = C-H); 7.4 7.6 (3H, m,

H H

= C O H); 7.6 8.0 (2H, m, = C)

H

  Mass: M + 315, 299, 149, 143, 140, 115, 103 (C 18 H 25 N 302)

(free base) -

  The following compounds are synthesized from

  described in this example except that diethyl-

  amine is replaced by dipropylamine, isopropylamine

  pylamrine, tert-butylamine or N-ethyl-N-propyl-

amine in this example.

Compound N 30.

  N-methyl-N- (3-di-n-propyl-2-methyl-1-propionyl) -7-amino-3-phenyloxazole: m.p. 553, 313, 243, m.p. 174, 154, 114 (C 20 H 29 N 302) 1H NMR (CDCl 3): 1.13 (6H, t, J = 8.0Hz, CH 3 CH 2 CH 2); 3 H, d, J = 6.0 Hz, CH 3 CH-); 1.0 1.7 (4H, m, CH 3 CH 2 CH 2); 2.1 2.6 (6H, m, CH 2 N); 2.6 3.1 (1H, m, CH 2 CHCH 3); 3.42 (3H, s, N-CH 3); 6.47 (1H, s, = C-H); 7.3 7.6 (3H, m,

H H

= C / H); 7.6, 7.9 (2H, m, = C H)

H H

  Compound NP f (C) 31 53 55 (dl-tartrate) 32 180 181 (dl-tartrate) 124 79 81 (fumarate) The following compounds are synthesized according to the procedure described in this example except that - / N Methyl-N (2-methyl-2-propen-1-yl) -Jamino-3-phenyliso-

  xazole is replaced by 5-fluorobenzyl-N- (2-methyl-2-propyl)

  pèn-1-oyllêmino-3-phenylisoxazole and that diethylamnine

  or dipropylamine is used in this example.

  Compound NO Yield (% 42 oil <mass M + 391) 41.2 43 oil 33.8 The following compounds are synthesized according to the procedure described in this example except that the

  5- (4-methoxybenzyl) -N (2-methyl-1-pro-en-1-alkyl) amino

  3-phenylisoxazole, 5-Z (3,4-dimethoxybenzyl) -N (2-methyl)

  2-ethyl-1-propenyl-7-amino-3-yl-phenylisoxazole, the 5-lN

  nyl-N - '(2-methyl-2-propen-1-yl) -amino-3-phenylisoxazole or

  5β-Tr-N-phenyl-N (2-methyl-2-propen-1-yl) -Zamino-3- <1, 1-

  dimethyl-1-ethyl) isoxazole and diethylamine are used

in this example.

  Comoose NO 49 -P'N-O-N, N-3-diethylamino-2-methyl-1-propionyl) 7-amino-3-oenylisoxazole Oil Compound NO Yield (%) 46 Oil <M + mass 421) 76.0

<C 25 H 3104 N 3)

47 oil (mass M + 451) 72.9

(C 26 H 3304 N 3)

-50 oil (mass Me 357) 43.4

(21 H 3123

  Yield: 98.4% RN 6 (CDCl 3): 0.91 (6H, t, J = 7.0 Hz CH 2 CH 3); 1. 08 (3H, d, J = 6.0Hz, CH 3 CH-); 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3) 2); 6.83 (1H, s, = C-H); 7.42 (5H, s, -N);

H H

  7.3 7.6 (3H, m, = C-H); 7.6, 7.9 (2H, m, = C)

H H

  Mass: M 377 (C 23 H 27 N 302) The following compounds are synthesized according to

  the procedure of this example except that 5- (2-methyl-

  2-propen-1-oyl) amino-3- (4-chlorophenyl) isoxazole and a

  chosen according to the next intended compound are

in this example.

Compound N P f (C) Yield (%)

107 109 31

  116 179 181 (fumarate) 26 117 128 130 (fumarate) The following compounds are synthesized according to the procedure described in this example except that the

  5- / R-methyl-N- (2-methyl-2-propen-1-yl) amino-3-phenyliso-

  xazole is replaced by a chosen 5-aminoisoxazole derivative

  depending on the next compound provided in this example.

  Compound N 127 N-methyl-N- (3-diethylamino-2-methyl-1-propionyl) 7 amino

3- (2-chlorophenyl) isoxazole.

  Oil Yield: 77% NMR 6 (CDCT 3): 0.97 (6H, t, J = 8Hz, CH 2 CH 3); 1.13 (3H, d, J = 7Hz, CH 3 CH); 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3) 2); 3.43 (3H, s, e CH 3); 6, 66 (1H, s, = C-H) 7, 37.6 (3H, M, Cl H = C-H); 7, 6 7, 9 (1H, m, = C (Y H Mass: M + 349 (H NO OC Ci)

18 to 24 3 2

  Comoose No. 129-N-methyl-N (3-diethylamino-2-methyl-1-fluo-Dionyl) -7-amino-3 (3-chlorothenyl) isoxazole M.p. 46 -48.5-C Yield 67% NMR 6 (CDCl 3) 13) 0.95 (6H, t, J = 8Hz, NCH 2, p H 13); 1.20 (3H, d, J = 8.0, CH 3 CH-); 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3 2 2) 3.44 (3H, s, NCH 3) 6.54 (1H, s, = CH); 7.3 7.9 (4H, m, H ci

= C èH)

  H H Mass: 349 (C 18 H 2 N O 2) n O 130

  5-LF-methyl-N (3-diethylamino-2-methyl-1-propionyl) amino

  3- (2-Methylphenyl) isoxazole Oil Yield: 75% NMR 6 (CDCl 3>: 0.95 (3H, t, J = 8.0Hz, -NCH 29 -H 13) 1.13 (3H) , d, CH 3 J = 8.0 Hz, 2.50 (3H, s,) 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3) 2) y 3, 41 (3H, s, NCH 3): 6.40 (1H, s, = CH 1)

CH 3 H

7.1 7.7 (4H, M, = C H)

Mass: 4329 (C 9 H 27 N 0)

14354

  Com Dose NO Yield () 131 oil <mass M + 329) 54

(C 19 H 27 N 302)

132 oil (mass: M + 329)

(C 19 H 27 N 302) + 7

134 oil (mass M + 345) 7

(19 H 27 N 303)

138 oil (mass M 357) 24.7

(C 2 H 1 N 03

  119 1200 C (fumarate) oil <mass M + 329) 56.4

(C 19 H 27 N 302)

99 1010 C (fumarate)

142 oil (mass M 343) 51.6.

<C 20 H 29 N 302)

  1170 C (fumarate) 146 oil (mass M + 301) 80.8

(C 17 H 23 N 302)

96,980 C (fumarate)

EXAMPLE 17

  synthesis of 5-F N (2-methyl-1-pro Dvl) -N (3-x-nitrrolidino)

  methyl-1-orooionyl) 17-amino-3-phenylisoxazole (com Rosè NO 33): (1) 5 (2-methyl-1-propionyl) amino-3-Dhenylisoxazole

  The procedure described in Example 1- (3) is

  except that 3-bromo-1-propionyl chloride is replaced by 2-methyl-1-deionyl chloride

  obtain 5 (2-methyl-1-propionyl) -amino-3-phenylisoxazole.

  Yield 71.65%, mp 188 1900 C. (2) 5- (2-methyl-1-propyl) amino-3-phenylisoxazole

  3.95 g of aluminum hydride are suspended

  sithic acid in 200 ml of anhydrous tetrahydrofuran

  20.0 g of 5- (2-methyl-1-p-Dropionyl) amino-3-phenylisoxazole obtained in step (1) and 200 ml of tetrahydrofuran are added.

  Anhydrous is added dropwise.

  After 12 hours, water is added thereto to decompose the aluminolithic hydride and the resulting solid is filtered and washed thoroughly with tetrahydrofuran.

  filtrate Tetrahydrofuran is evaporated under high pressure

  and the resulting residue is recrystallized from a

  ether / hexane to give 5- (2-methyl-1-propyl)

  3-amino-n-phenylisoxazole Yield: 11.88 g (63.14%).

M.p .: 46,470 C.

  (3) 5-N-2-methyl-1-propyl) -N- (2-methyl-2-propen-1-yl) -1-

amino-3-phenylisoxazole:

* The procedure described in Example 14- (3) is

  except that 3-methylamino-3-phenylisoxazole is

  replaced by 5-f N- (2-methyl-1-ropyl) -amino-3-phenyliso-

  obtained in step (2) to obtain 5- (N- (2-methyl)

  1-ethyl-1-propyl) -N- (2-methyl-2-propen-1-yl) -amino-3-phenylisobutyl

  xazole with a yield of 87.05% at 43 ° C. (4) Compound N 33: The procedure described in Example 15 is repeated except that 5-ZN-methylN- (2-methyl) -2-propen-1-oyl) l

  amino-3-phenylisoxazole is replaced by 5-EN- (2-methyl-

  1-propyl) -N- (2-methyl-2-propen-1-yl) Jamino-3-phenylisoxazole obtained in step 43); the comoosé N 33 is thus obtained with a yield of 83.2% P f: 75 76 o C.

EXAMPLE 18

  Synthesis of 5-F N- (2-methyl-1-oro-Dyl) -N- (3-dimethylamino) -2-

  methyl-1-Drononyl) 1-amino-3-tdhenylisoxazole (com Dosage N 34):

  The procedure described in Example 14 is repeated

  (4) except that 5-ZN-methyl-N- (2-methyl-2-propen-1)

  oyl) lamino-3-phenylisoxazole is replaced by 5- / F- {2-

  methyl-1-propyl) -N- (2-methyl-2-oro-Dn-1-yl) amino-3-phenyl-

  isoxazole obtained in Example 17- (3); the compound N 34 is thus obtained in the form of an oil with a yield of

  84.2% The oil is converted into its fumarate according to a

  conventional thode P f: 90 930 C. Mass: M 329 (C 19 H 27 N 302)

EXAMPLE 19

  Synthesis of 5-N- (2,2-dimethyl-1-propyl) -N- (3-diethylamino-2-methyl-propionyl) 7-amino-3-phenylisoxazole (Compound N 36): (1) N- (2,2-Dimethyl-1-propionyl) 7-amino-3-phenylisoxazole: The procedure described in Example 1- (3) is repeated.

  except that 3-bromopropion chloride is replaced

  with 2,2-dimethylpropionyl chloride so that

  obtain 5-N- (2,2-dimethyl-1-propionyl) 7-amino-3-phenyl-

  isoxazole with a yield of 89.2%.

  Mp: 134 1350C. (21 5-N- (2,2-dimethyl-1-propyl) 3-amino-phenylisoxazole:

  The procedure described in Example 17 is repeated.

  (2) except that 5-ZC- (2-methyl-1-pro) is replaced

  pionyl) lamino-3-phenylisoxazole by 5-F N- (2,2-dimethyl)

  1-propionyl) 7-amino-3-phenylisoxazole to obtain 5-r N-

  (2,2-dimethyl-1-propyl) 7-amino-3-phenylisoxazole with a

  53.2% P f: 102 104 o C. (3) 5-N- (2,2-dimethyl-1-propyl) -N- (2-methyl-2-propen-1-yl) 7 amino-3-phenylisoxazole:

  The procedure described in Example 14 is repeated

  (3) except that 3-methylamino-3-phenylisoxazole is

  replaced by 5-N- (2,2-dimethyl-1-propyl) 7-amino-3-phenyl-

  isoxazole obtained in step (2) to obtain the 5- / N- (2,2-

  dimethyl-1-propyl) -N- (2-methyl-2-propen-1-yl) 7-amino-3-phenol

  nylisoxazole. (4) Compound N 36: The procedure described in Example 16 is repeated

  except that 5-f N-methyl- (2-methyl-2-propen-1-yl) 7-

  amino-3-phenylisoxazole is replaced by 5-ZR- (2,2-dimethyl)

  1-ethyl-propyl) -N- (2-methyl-2-propen-1-yl) 7-amino-3-phenyl

  isoxazole obtained in step (3) to obtain the compound

  expected with a yield of 67.5% P f: 80 82 C.

  Mass: M + 371 (C 22 H 33 N 302) The procedure described in step (4) of this example is repeated except that diethylamine is replaced

  with pyrrolidine, isopropylamine or tert-bu-

  tylamine to obtain the following compounds: Compound N P f (Oc) Yield (%)

91 93 62.1

37 80 82 86.5

38 140 142 59.7

(Ditartrate)

EXAMPLE 20

  Synthesis of 5-ZN-benzyl-N- (3-pyrrolidino-2-methyl-1-propionic)

  nvyl) 7-amino-3-phenylisoxazole (compound N 39)

  (1) 5-ZN-benzyl-N- (2-methyl-2-propen-1-yl) 7-amino-3-phenyl

  isoxazole: The procedure described in Example 14- (3) is repeated except that 5-N-methylamino-3-phenylisoxazole is replaced by 5-N-benzylamino-3-phenylisoxazole for

  obtain 5-lN-benzyl-N- (2-methyl-2-propen-2-yl) 7-amino-3-

  phenylisoxazole with a yield of 73.7%.

  Mp: 95,970 C. (2) Compound N 39: The procedure described in Example 15 is repeated except that 5-lN-methyl-N- (2-methyl-2-propen-1-ol) ) l 7

  amino-3-phenylisoxazole is replaced by 5-lN-benzyl-N-

  (2-methyl-2-propen-1-yl) 7-amino-3-phenylisoxazole obtained in step (1) to obtain the desired compound under

  form of an oil, with a yield of 81.8%.

  Mp: 117 118 C (fumarate) Mass: M + 389 (C 24 H 27 N 302)

EXAMPLE 21

  Synthesis of 5-F N-benzyl-N-f 3- (4- (2-chlorophenyl) piperazino)

  2-methyl-1-propionyl 7-amino-3-phenylisoxazole (Coated)

N 40)

  The procedure described in Example 20- (2) is repeated except that the pyrrolidine is replaced by 4- (2-chloro-1-phenyl) piperazine so as to obtain the expected compound with a yield of 63.3% Pf: 47 48 o C.

EXAMPLE 22

  Synthesis of 5-lN-benzyl-N- (3-dimethylamino-2-methyl-1-pro-

  pionvl) 7 amino-3-phenylisoxazole (compound N 41): The procedure described in Example 14- (4) is

  repeated except that 5- (N-methyl-N- (2-methyl-2-propene)

  1-oyl) 7-amino-3-phenylisoxazole is replaced by 5-lN-

  benzyl-N- (2-methyl-2-propen-1-yl) -lamino-3-phenylisoxazole and the benzene is replaced by dichloromethane to obtain the desired compound as an oil

with a yield of 98.7%.

Mass: M + 363 (C 22 H 25 N 302)

  M.p .: 82 85 C (dl-tartrate) (recrystallized from acetone);

tone).

EXAMPLE 23

  Synthesis of 5- / N-phenyl-N- (3-pyrrolidino-2-methyl-1-propionic acid)

  nyl) 3-amino-phenylisoxazole (compound N 48): (1) 5-N-phenylamino-3-phenylisoxazole:

  30 g of acetophenone and 60 g of

  After cooling the system to 0 ° C. and stirring, a solution of 26 g of titanium tetrachloride in benzene is added dropwise over a period of 30 minutes when the addition is complete. completed, the reaction is continued at room temperature

  12 hours The resulting mineral salt is removed by filtration.

  and the filtrate is evaporated under reduced pressure; 44 g of oil are collected and this oil is distilled

  under pressure reduce and provides 30.52 g of an enaminoacetone

  Phenone P e: 84-89 C / 120.0 Pa (0.9 mm Hg) Yield:

64.5%.

  0 g of the enaminoacetophenone thus obtained

  50 ml of ethyl acetate are dissolved in 30 ml of a solution of

  13.0 g of phenyl isothiocyanate in acetylene

  After heating the mixture under reflux for 1.5 hours, the ethyl acetate is evaporated under reduced pressure. The residue obtained is

  dissolved in 200 ml of methanol and the hydrochloride of

  xylamine and 13 g of anhydrous sodium acetate are added

  to the resulting solution After refluxing the mixture

  After 2 hours, the reaction mixture is evaporated under reduced pressure. A mixture of water and methylene chloride is added to the residue and the resulting solution is extracted with methylene chloride.

  Methylene is dried with anhydrous magnesium sulfate.

  The desiccant is removed by filtration and then

  Methylene chloride is evaporated under reduced pressure.

  The resulting residue is dissolved in methacrylate

  hot nol and the solution is cooled to provide

  4.38 g of 5-N-phenylamino-3-phenylisoxazole.

M.p .: 130,131 C.

  (2) 5- N -phenyl-N- (2-methyl-2-propen-1-yl) 7-amino-3-phenyl

  isoxazole: The procedure described in Example 14- (3) is repeated except that 5-N-methylamino-3-phenylisoxazole is replaced by the 5-N-phenylamino-3-phenylisoxazole obtained

  in step (1) to obtain 5-lN-phenyl-N- (2-methyl-2-

  propen-1-oyl) 7-amino-3-phenylisoxazole with a yield of

68.1%.

P: 83.84C.

(3) Compound N 48:

  The procedure described in Example 15 is repeated

  except that 5-lN-phenyl-N- (2-methyl-2-propen-1

  oyl) lamino-3-phenylisoxazole is used to obtain the

  desired compound in the form of an oil Yield: 98.4%.

-Mass: M 375 (C 23 H 25 N 302) -

  Pf of dl-tartrate: 102 106 o C (recrystallized from

Xane).

EXAMPLE 24

  Synthesis of 5- (3-Diperidino-3-methyl-1-propionyl) amino-3-phenylisoxazole (Compound N 52): (1) 5-F N- (3-methyl-2-propen-1-yl) 7 amino-3-phenylisoxazole: 320.4 g of 5-amino-3-phenylisoxazole are dissolved in 6 liters of chloroform. 275.6 g of powdered anhydrous sodium carbonate (800 ml of chloroform containing 250.9 g of chloroform) are added to this solution. Crotonoyl chloride is added dropwise with stirring After heating

  of the mixture for 7 hours, the reaction mixture is

  cooled to room temperature and the crystals formed are separated by filtration The chloroform layer is washed

  with water and then dried over anhydrous magnesium sulfate.

  The desiccant is removed and the chloroform is

  evaporated under reduced pressure The residue obtained is recreated

  in a mixture of benzene / ethyl acetate (1 :):

  5-ZN- (3-methyl-2-propen-1-oyl) -7-amino

  3-phenylisoxazole Yield: 187.3 g (43.7%)

M.p .: 155,157 C.

(2) Compound N 52:

  34.3 g of 5-lN- (3-methyl-2-propen-1-yl) 7 amino-

  3-phenylisoxazole obtained in step (1) and 25.6 g of

  Rinse are dissolved in 50 ml of ethanol. After refluxing the mixture for 30 hours, the reaction mixture is cooled to room temperature and then acidified with

  diluted hydrochloric acid is added

  thylate to the mixture and remove the impurities After removing the ethyl acetate layer, a solution is added

  aqueous sodium carbonate to alkalize the system.

  An oil thus separated is extracted with acetate acetate.

  The ethyl acetate layer is dried over anhydrous sodium sulfate. The drying agent is removed and then the ethyl acetate is evaporated; 39.6 g of residue are thus collected. This residue is dissolved under heat in a mixture.

  solvent comprising 40 ml of benzene and 270 ml of hexane.

  The solution is cooled and allowed to stand. The crystals thus formed are filtered off and dried under reduced pressure; the desired compound is thus collected with a yield of 24.6 g (52.4%)

P: 94.955C.

  The procedure described above is repeated except that a starting material selected according to the intended final composition is used to obtain the following compounds: ## EQU1 ## Yield NP (f) Yield (%) 53 100.5-102 (recrystallization 74.0 in benzene-hexane) 54 134.5-136 (ibid) 69.1 55 175.5-176.5 (recrystall 83.1

in the case of

  cool isopropyl) 56 170-172 (hydrochloride: 68.5 recrystallization from ether-ethyl acetate)

EXAMPLE 25

  Synthesis of 5- (3-oxo-3- (4-methyl-diazazine) -1-methyl-1-pro

  17-amino-3-phenylisoxazole (comnose N 59): (1) 1- (2-buten-1-yl) -4-methylpiperazine:

  0 g of 4-methylpiperazine and 22.3 g of

  ethylamine are dissolved in 200 ml of chloroform 23.0 g of crotonoyl chloride are added dropwise to the solution at a temperature below 5 C After

  The mixture is stirred at room temperature for 12 hours.

  The chloroform layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent

  is removed and the chloroform is evaporated under high pressure

  pick; 34.1 g of an oil are thus collected. This oil is distilled under reduced pressure and gives 1- (2-buten-1-yl) -4-methylpiperazine P e: 94,980 C / 66.7 Pa.

(0.5 mm Hg) Yield: 79.7%.

  (2) Compound N 59: 5.15 g of sodium amide was added to 200 ml of anhydrous benzene. 19.2 g of 5-amino-3-phenylisoxazole crystals were added to the mixture.

  of a solution of 20.2 g of 1- (2-buten-1-yl) -4-methyl-

  piperazine obtained in step (1) in anhydrous benzene are added little by little to the above mixture The mixture is heated at reflux for 3 hours and then cooled to room temperature and added with water, introduced with

  precaution to wash the benzene layer The benzene layer

  The drying agent is removed and the benzene is evaporated under anhydrous magnesium sulfate.

  reduced pressure; 39.4 g of an oil are thus collected.

  This oil is purified by chromatography on silica gel using a mixture of chloroform / methanol (10: 1)

  to obtain the desired compound as an oil.

Yield: 40.6%.

P: 79820 ° C (dl-tartrate).

EXAMPLE 26

  Synthesis of 5-Z-3-oxo-3- (4-phenylaminazine) -1-methyl-1

  Pronvyl 7-amino-3-Dhenylisoxazole (Compound N 60): 3.9 g of sodium amide are suspended

  in 200 ml of anhydrous benzene is added 16.0 g of 5-amino

  Crystalline 3-phenylisoxazole in suspension while stirring.

  23.0 g of 1- (2-buten-1-yl) are then added to this mixture.

  4-phenylpiperazine After stirring the mixture at room temperature

  At room temperature for 48 hours, this reaction mixture is washed with water. Magnesium sulfate anhydrous is added

  to the mixture to dry it The drying agent is then

  it is then removed and the benzene is evaporated under reduced pressure.

  The residue obtained is purified by gel chromatography.

  silica: 28.34 g of the desired compound are collected.

Yield: 72.6.

M.p .: 154 155.5 C.

EXAMPLE 27

  Synthesis of 5- (3-oxo-3-moroholino-1-methyl-1-propyl) amino

  3-phenylisoxazole (compound NO 58): 0.46 g of sodium amide is added to 200 ml of anhydrous benzene 19.0 g of isoxazole are added little by little while stirring. The resulting suspension is added dropwise with 18.4 g of 1- (2-buten-1-yl) morpholine in 50 ml of anhydrous benzene The reaction mixture is

  heated at reflux for 12 hours, then cooled to room temperature

  room temperature and added water introduced with

  deposit to wash the benzene layer After drying the mixture on anhydrous magnesium sulphate and then eliminated

  the drying agent, the benzene is evaporated under

  The resulting residue is purified by means of an alumina with benzene as the solvent. Ether is added to the resulting oil to obtain crystals.

  are filtered and dried to provide the desired compound.

Yield: 23.4 g (62.5%).

P f: 100 103 C.

Mass: M + 315 (C 17 H 21 N 303)

  The procedure described in Example 27 is

  except that 1- (2-buten-1-yl) morpholine is

  replaced by 1- (2-buten-1-yl) piperidine, 1- (2-butenediol)

  1-oyl) pyrrolidine, 1- (2-methyl-2-propen-1-yl) piperidine

  or 1- (2-methyl-2-propen-1-yl) pyrrolidine so as to obtain

  contain the following compounds: Compound N Yield (%) P f (OC)

57 73.3 104 106

61 88.5 156 158

62 29.2 118 120

63 29.4 83 85

EX 4 EMPLE 28.

  Synthesis of 5- (N-Methyl) -N- (3-oxo-3-pyrrolidino-1-methyl-1-

  Dropy 1) 7-amino-3-yenylisoxazole (compound N 64): 0.56 g of sodium amide is added to 200 ml

  anhydrous benzene is then added 25 g of 5-N-methyl-

  Amino-3-phenylisoxazole 50 ml of a solution of 24.0 g of (2-buten-1-yl) pyrrolidine in anhydrous benzene are added dropwise to the system. After refluxing the mixture for 12 hours, reaction mixture is cooled to room temperature Water is added thereto

  to wash the benzene layer After drying the mixture

  on anhydrous magnesium sulfate, the drying agent

  is removed and the benzene is distilled under reduced pressure.

  Ether is added to the formed residue to obtain crystals. These crystals are filtered and dried under pressure.

  scaled down; 25.2 g of the desired compound are thus collected.

Rendt-ment: 56.3%.

M.p .: 137,138 C (fumarate).

EXAMPLE 29

  Synthesis of 5- (3-piperidino-3-methyl-1-dropyl) amino-3-phenol

  Nylisoxazole (compound N 77): 200 mg of aluminolithic hydride are added to ml of anhydrous ether 60 ml of a solution comprising 1.6 g

  of 5-ZN- (3-piperidino-2-methyl-1-propionyl) 7-amino-3-phenyl-

  Isoxazole in anhydrous ether is added dropwise into the system, with stirring After refluxing the mixture for 17 hours, a small amount of water is added and the precipitates formed are filtered and

  washed with ether The washing solution is combined with the

  After removal of the drying agent, the ether is distilled off under reduced pressure and leaves crystals. These crystals are recrystallized from benzene and dried.

  provide 1.43 g of the desired compound.

Yield: 96%.

Mp 99,100C.

Mass: M + 299 (C 18 H 25 N 30).

  In the same manner as above, the following compounds are obtained: Compound N 87: - (3-O -rolidino-1-methyl-1-1-propyl) amino-3-phenylisoxazole: m.p. 87.5 88.5 ° C Yield: 79.2% Mass: M 285 (C 17 H 23 N 30) Compound N Yield (%) P f (oc) 82.0 157-158 (oxalate) 72 81.0 152-153 (oxalate) 113 34 , 6 oil

EXAMPLE 30

  Synthesis of 5- (3-Mor-Dholino-1-pro-Dyl) amino-3-phenylisoxa

zole (compound N 66):

  A 70% solution of dihydrobis (2-methoxy-

  ethoxy) sodium aluminate J Na A 1 H 2 (OCH 2 CH 2 OCH 3) 27 in benzene is dissolved in 200 ml of anhydrous benzene A

  solution of N- (3-morpholino-1-propionyl) amino-3-phenyl-

  isoxazole in 150 ml of anhydrous benzene is added drop

  to the solution above After shaking the system

  at room temperature for 12 hours, water is added thereto and the precipitates thus formed are separated by filtration. The benzene layer is washed with water and

  dried over anhydrous magnesium sulfate The desiccating agent

  cation is separated by filtration and the filtrate is evaporated

  under reduced pressure; the product is thus collected

  sought as an oil Yield: 98.36 g (98.3%).

  The oil is dissolved in acetone An equimolar amount

  re of fumaric acid is added to the solution to make

precipitate the crystals.

  Mp: 170 C (fumarate) Mass: M 287 (C 16 H 2 N 302) In the same manner as above, the following compounds are prepared: Compound N Solvent Yield (%) P f (C) 67 benzene-tetra 69 101 103 hydrofuran

68 "57.8 99 101

  69 benzene 90.7 77 80 70 ether 50.7 86 88 71 benzene 56.9 oil 83 ether 74.8 125.5 127.5 84 benzene 94.6 66 (citrate: decomp) 85 "88.1 75 (citrate : decomp) 86 benzene-ether 23.6 126 127.5

  EXAMPLE 31 Synthesis of 5- (3-pyrrolidino-3-methyl-1-propyl) amino-3-

phenylisoxadole (compound 4 n 76)

  19.5 g of 5- (3-pyrrolidino-3-methyl-1-propionyl) amino-3-

  phenylisoxadole are dissolved in 250 ml of anhydrous benzene.

  70% dihydrobis (mnthoxyethoxy) sodium aluminate

  Benzene diluted with 250 ml of anhydrous benzene is added dropwise

To the above solution at a temperature of 5 to 10 ° C. After stirring the reaction mixture at room temperature for 12 hours, ml of water are added and the precipitates thus formed are separated by filtration. The benzene layer is washed at room temperature. water After drying over anhydrous magnesium sulphate followed by removal of the drying agent, the benzene is evaporated under reduced pressure and the residue obtained

  is purified by silica gel column chromatography.

  this; 10.97 g of the desired compound are thus collected.

Yield: 80.7%.

  66.6 ° C. In the manner described above, the following compounds are prepared: Cmposition N Yield (%) P f (C)

81 76.8 79 82

82 81.6 82 83

73 57.9 76 77

74 85 86.5 87.5

75 75.4 101 102

76 80.7 64 66.5

78 89.3 145 147

79 96.8 oil

77.4 118 119

EXAMPLE 32

  Synthesis of 5- / N-benzyl-N- (3-pyrrolidino-3-methyl-1-oro-Dyl) 7-

  amino-3-Dhenylisoxazole (compound N 98): 1.51 g of sodium amide is added to 150 ml

  Then 7.38 g of 5- (3-pyrrolidine) are added.

  rolidino-3-methyl-1-propyl) amino-3-phenylisoxazole and the mixture is heated under reflux for 1.5 hours.

  heating, the mixture is cooled to room temperature

  5.51 g of benzyl bromide are added dropwise.

  After stirring the reaction system at 50 ° C for 12 hours, it is poured onto a saturated aqueous salt solution and the benzene layer is washed with saturated aqueous saline solution. This benzene layer is dried over anhydrous magnesium sulfate and the drying agent. The benzene is evaporated under reduced pressure and the residue obtained is purified by chromatography on silica gel using a mixture of hexane / acetone / NH 3 (350: 2); In this way, the desired product is obtained in the form

of an oil.

  Yield: 4.5 g (46.4%) M + Mass: M 375 (C 24 H 29 N 30)

Mp: 1570C (fumarate).

  By proceeding as indicated above, the following compounds are prepared: Compound N 107: N -benzyl-N- (3-pyrrolidino-1-methyl-1-pro-Dyl) -7-amino-3-phenylisoxazole: Yield: 41.0% w: 142 o C (fumarate)

Mass: M 375 (C 24 H 29 N 30).

EXAMPLE 33

  Synthesis of 5 N-benzyl-N- (3-pyrrolidino-1-methyl-1-propyl) -7-

  amino-3-phenyl-4-bromoisoxazole (compound N 112):

  2.20 g of 5-lN-benzyl-N- (3-pyrrolidino-1-methyl)

  thyl-1-oropyl) 7-amino-3-phenylisoxazole are dissolved in

  chloroform is added 1.25 g of N-bromosuccinimide

  portioned into the solution The reaction mixture

  is stirred at room temperature for 24 hours,

  Compound N Yield (%) P f (o C) 88 65 146 148 (fumarate) 89 52.7 170 171 (fumarate) 70.2 176 (decompose fumarate) 91 78.5 130 131 (fumarate) 92 55.4 157 (fumarate decomp) 93 65.9 55 (hydrochloride) 94 85 146 147 (oxalate) 71.0 80 81 (fumarate) 96 78.2 163.5 (fumarate) 97 71.7 150 154 (hydrochloride) 99 96.7 55 (fumarate) 74.9 80 (citrate) 101 61 96 97 (citrate) 102 84 63 (citrate decomp) 103 94 60 (citrate) 104 50.2 64 (hydrochloride) 35.9 oil 106 26.9 oil 108 58 , 1 oil 109 65.9 oil 25, 3 oil 111 36.6 oil 114 21.8 oil

  water to wash the chloroform layer after

  on anhydrous magnesium sulphate followed by removal

  drying agent, the chloroform is evaporated under reduced pressure and the resulting residue is purified by chromatography on silica gel using a mixture of toluene / triethylamine (15: 1); thus 630 mg of the

  compound N 112 in the form of an oil.

Yield 23.7%.

EXAMPLE 34

  Synthesis of 5-F N-methyl-N- (3-nyrrolidino-2-methyl-1-propionic)

  nyl) lamino-3- (2-chlorophenyl) isoxazole (comnose N 126): (1) 5-amino-3 (2-chlorophenyl) isoxazole: 100 ml of anhydrous ether are introduced into a quadricol and then 3 is added, 43 g of 50% sodium hydride to obtain a suspension A solution of 50 g of 2-chlorobenzonitrile and 38 ml of acetonitrile in 50 ml of ether is added dropwise to the suspension in one hour.

  2-hour period After heating the mixture to

  20.5 hours, the reaction mixture is cooled

  di at room temperature and added water Then

  ethyl acetate is added to the mixture.

  ethyl acetate is dried over anhydrous magnesium sulfate

  and the drying agent is removed. The residue is evaporated.

  pored under reduced pressure and provides 2-chlorophenyl-3-

  crude iminopropionitrile in the form of an oil.

  The crude 2-chlorophenyl-3-imino-dropionitrile thus obtained is dissolved in 300 ml of ethanol. 50.5 g of hydroxylamine hydrochloride are added to the solution and the mixture is stirred at ambient temperature for 21 hours.

  hours The crystals thus formed are separated by

  and the filtrate is evaporated under reduced pressure; we

  So collects an oil of water and ethyl acetate.

  are added to this oil to carry out the extraction with ethyl acetate The layer of ethyl acetate is

  dried over anhydrous calcium sulphate and the desiccant

  cation is removed after concentration under pressure

  This oil is purified by column chromatography on silica gel using silica gel.

  methylene chloride; this gives 5-amino-3- (2-

  chlorophenyl) isoxazole Yield: 18.7 g (2.7%). M.p .: 64 650 C. (2) 5formylamino-3- (2-chlorophenyl) isoxazole 13.31 g of 5-amino-3- (2chlorophenyl) isoxazole are introduced into a flask 100 ml of acid are added thereto

  formic and the reaction mixture is heated to 1000.degree.

  After 2 hours, the reaction mixture is poured on

  a mixture of water and ice so that the crystals form

  The crystals are filtered, washed thoroughly with water and dissolved in ethyl acetate. The resulting ethyl acetate layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is removed

  and the residue is concentrated under reduced pressure; we ob-

  thus holds a solid This one is purified by ehromatogra-

  silica gel using methylene chloride;

  7.4 g of 5-formylamino-3- (2-chlorophenyl) are thus obtained.

isoxazole Yield: 51%.

Mass: M + 212

Mp 112-113.5 ° C.

  (3) 5-methylamino-3- (2-chlorophenyl) isoxazole:

  6 g of 5-formylamino-3- (2-chlorophenyl) isoxa

  zole are dissolved in 100 ml of toluene.

  sodium drobis (2-methoxyethoxy) aluminate in toluene is added slowly to the stirred solution until

  the starting material is consumed When the reaction

  After completion, water is added to the reaction mixture.

  and the crystals thus formed are separated by

  The toluene layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the toluene is evaporated under reduced pressure.

  reduced pressure; 5.8 g of 5-methyl-

  amino-3- (2-chlorophenyl) isoxazole as an oil.

  Yield 98.6% Mass: M + 208 Pf: 80.5 ° 82.5 ° C. (4) Proceeding as described in Example 14- (3) except that 5-N-methylamino-3 -phenylisoxazole is replaced by 5-N-methylamino-3- (2chlorophenyl) isoxazole,

  5-N-methyl-N- (2-methyl-2-propen-1-yl) lamino-

  3- (2-chlorophenylisoxazole in the form of a Rende-

52%.

Mass: M 276.

(5) Compound N 126:

  The procedure described in Example 15 is repeated

  except that 5- / 2-methyl-N- (2-methyl-2-propene)

  1-oyl) 7-amino-3-Dhenylisoxazole is replaced by 5-F N-

  methyl-N- (2-methyl-2-propnen-1-yl) lamino-3- (2-chlorophenyl) isoxazole to give the expected compound Yield:%. Mass: M + 347 (C 18 H 2202 N 3 C 1)

EXAMPLE 35

  Synthesis of 5-F N-methyl-N- (3-orthrolidino-2-methyl-1-propionic)

  nyl) 7-amino-4-iso Drop 1--3-Dhenylisoxazole (Compound N 137): (1) The procedure described in Example 14- (1) is repeated except that the amino-3- phenylisoxazole is replaced by 5-amino-4-isopropyl-3-phenylisoxazole obtained in Example 11- (1) so as to obtain 5-formylamino-4-iso-

propyl-3-phenylisoxazole.

Yield: 58.9%.

Mp 106,108 C.

  (2) The procedure described in Example 14- (2) is repeated

  except that 5-formylamino-3-phenylisoxazole is replaced by

  placed with 5-formylamino-4-isogropyl-3-phenylisoxazole

  to obtain 5-N-methylamino-4-isopropyl-3-phenylisoxa

  zole. Yield: 85.0 X.p. 102 103 o C. (3) The procedure described in Example 14- (3) is repeated except that 5-N-methylamino-3-phenylisoxazole is

  replaced by 5-N-methylamino-4-iso Dropylamino-3-phenyl-

  isoxazole to obtain 5-Z-methyl-N- (2-methyl-2-propen-1-yl) 7-amino-4-isopropylamino-3-phenylisoxazole Yield:

76.6%.

  Mass: M + 268 (C 17 H 20 N 202) (4) Compound N 137:

  The procedure described in Example 15 is repeated

  except that 5 / N-methyl-N- (2-methyl-1-propene)

  1-oyl) Jamino-3-phenylisoxazole is replaced by 5-1 N-

  methyl-N- (2-methyl-1-oropen-1-yl) amino-4-isopropyl-3-

  phenylisoxazole to obtain the desired compound Rende-

79.4%.

Mass: M + 355 (free base) (oil)

M.p .: 141,142C (fumarate).

  The procedure described above is repeated except that the pyrrolidine is replaced by Diperidine to obtain the following compound: Comoose N 136: P: 134 136 C (fumarate) Yield: 80.8% (free base)

EXAMPLE 36

  Synthesis of 5-i-ethyl-N- (3-niueridino-2-methyl-1-tropio)

  nyl) 7 amino-3-uhenylisoxazole (compound N 139): (1) 20 g of 5-amino-3-phenylisoxazole are introduced into

  one bottle of 100 ml of nyridine and then 50 ml of acetic anhydride

  The resulting mixture is heated at 85 ° C. with stirring for 8.5 hours. The reaction mixture is cooled to room temperature and methanol is added thereto. The reaction mixture is evaporated under pressure.

  Ethanol is added to the resulting residue and the mixture is

  The mixture is again evaporated under reduced pressure. This procedure is repeated several times. The residue obtained is

2514354 '

  dissolved in 250 ml of anhydrous tetrahydrofuran is added

  g of aluminolithic hydride to the solution while cooling

  The reaction mixture is stirred at room temperature for 1.5 hours. Then, ethyl acetate is added to the reaction mixture to decompose the hydride.

  excess aluminolithic acid 30 ml of water are added and the

  mine by filtration the solid thus formed The filtrate is

  dried over anhydrous magnesium sulfate The desiccating agent

  The mixture is removed and the residue is evaporated under

  pick; 27.0 g of residue are thus collected. This residue is recrystallized from a mixture of hexane / toluene to give 5-ethylamino-3-phenylisoxazole. Yield: 9.35 g

(39.7%).

P.I: 115,116 C.

  (2) The procedure described in Example 14- (3) is repeated if

  it is only 5-N-methylamino-3-phenylisoxazole is replaced

  placed by 5-N-ethylamino-3-phenylisoxazole to obtain

  5-lN-ethyl-N- (2-methyl-2-propen-1-yl) 7-amino-3-phenyl

Isoxazole Yield: 88.1%.

  (3) Compound N 139: The procedure described in the example is repeated

  except that 5-ZN-methyl-N- (2-methyl-1-propen-1)

  7-amino-3-phenylisoxazole is replaced by 5-N-ethyl-

  N- (2-methyl-1-propen-1-yl) 7-amino-3-phenylisoxazole and that the pyrrolidine is replaced by piperidine to obtain the desired product Yield: 76.3% Mass: M + 341 (C 20 H 27 N 302)

M.p .: 131133C (fumarate).

EXAMPLE 37

  Synthesis of 5- / N-propyl-N- (3-pyldidin-2-methyl-1-propionic acid)

  nvl) 3-amino-phenylisoxazole (Compound N 141): (1) The procedure described in Example 36- (1) is repeated

  except that acetic anhydride is replaced by

  propionic hydride to obtain 5-propylamino-3-

isoxazole.

  Yield: 21.7 g (85.8%) Mp: 107.109 o C Mass: M + / e 202 (C 12 H 14 N 20) (2) The procedure described in Example 36- (2) is repeated except that 5-ethylamino-3-phenylisoxazole is replaced by 5-propylamino-3-phenylisoxazole to obtain

  5-lN-propyl-N- (2-methyl-2-propen-1-yl) 7-amino-3-phenyl-

isoxazole.

Yield: 91.4%.

  (3) Compound N 141 The procedure described in Example 36- (3) is

  repeated except that N-ethyl-N- (2-methyl-2-propene)

  1-oyl) lamino-3-phenylisoxazole is replaced by 5- / N-pro-

  pyl-N- (2-methyl-2-propen-1-yl) 7-amino-3-phenylisoxazole

  to obtain the desired compound Yield: 75.3%.

  Mass: M 355 (C 21 H 29 N 302) m.p .: 123 125 C (fumarate)

EXAMPLE 38

  Synthesis of 5-N-methyl-N- (3-diethylamino-3-methyl-1-dibenzyl)

  pionvl) lamino-3-henlisoxazole (comose NO 144):

  (1) 6.0 g of 5-N- (3-methyl-2-propen-1-yl) amino-3-phenyl-

  isoxazole are dissolved in 300 ml of acetonitrile 12.5 g of a mixture of potassium fluoride and alumina (KF:

  At 1203: H 20 = 34:52:14) are added to the resulting solution.

  aunt to obtain a suspension 4.17 g of iodine

  After stirring the reaction mixture at room temperature for 15 hours, the mixture of potassium fluoride and alumina is filtered off and the acetonitrile is evaporated.

  is added to the oil thus obtained. The acetate layer of

  Thyl is washed with water and dried over anhydrous magnesium sulfate. The drying agent is removed and the mother liquor is evaporated under reduced pressure; we thus collect

  5- (N-methyl-N- (3-methyl-2-propen-1-yl) 7-amino-3-phenyl-

  isoxazole in the form of an oil.

Yield: 5.85 g (91.8%).

(2) Compound NI 144:

  The procedure described in Example 16 is repeated

  except that 5- N-methyl-N- (2-methyl-2-propene)

  1-oyl) 2-amino-3-phenylisoxazole is replaced by 5-ZN-methyl-N- (3-methyl-2-propen-1-yl) 7-amino-3-phenylisoxazole

  to obtain the desired compound as an oil.

Yield: 94.0%.

Mass: M + / e 315 (C 18 H 25 N 302)

P: 118 1200 C (fumarate).

EXAMPLE 39

  Synthesis of (+) - 5-N-methyl-N- (3-diethylamino-2-methyl-1-

  propionyl) Yamino-3-phenylisoxazole (compound N 147): (1) 199.0 g of methyl methacrylate are introduced into a

  500 ml flask 205.6 ml of diethyl ether are then added.

  amine then 11.3 ml of acetic acid are added and

  the reaction at 100 ° C. with stirring for 48 hours

  the reaction is complete, the reaction mixture is

  on a mixture of ice and water and acidified with the help of

  H Cl 6 N with cooling The resulting solution is ex-

  treated with toluene and the aqueous layer is alkalinized with 28% ammonia and extracted with ethyl ether The ether layer is washed with water and dried over anhydrous magnesium sulfate The drying agent

  is removed and the ether is evaporated under reduced pressure.

  The residue is distilled under reduced pressure and provides

  162.7 g of methyl 3-diethylamino-2-methylpropionate.

Yield: 47.2%

P: 75 76 C / 1570 Pa (12 mm Hg).

  (2) 35.0 g of magnesium and 800 ml of tetrahydro-

  Anhydrous furan in a 5 liter quadricol A solution

  188.1 g of ethyl bromide in 270 ml of tetrahydrofuran

  A solution of 174.5 g of D (+) - amethylbenzylamine in tetrahydrofuran is added dropwise.

  added dropwise to the solution of ethyl bromide

  magnesium obtained while the internal temperature is kept below 15 ° C. When the addition is complete, the mixture is stirred at room temperature for 30 minutes. A solution of methyl 3-diethylamino-2-methylpropionate in tetrahydrofuran is added dropwise to the mixture. Previous system at a temperature below C When the addition is complete, the mixture is stirred at room temperature for 30 minutes and then heated

  at reflux for 4.5 hours Then the mixture is cooled

  di at room temperature Water is then added

  Toluene is added to the mixture and the mixture is washed with water three times. The toluene layer is

  dried over anhydrous magnesium sulfate and the desiccant

  cation is separated by filtration The filtrate is evaporated

  under reduced pressure and provides 168.4 g of (+) - N-Z (+) - l-

  (1-phenylethyl) 7-3-diethylamino-2-methylpropanamide

89.2%.

25 + 27.9 (CHCl 3, C = 0.62).

  The diastereomer obtained is resolved by chroma-

  silica gel graphing using CH C 113: And OH: NH 4 OH to

  28% (600: 20: 1) to obtain 24.5 g of (+) - N-1 (+) - 1- (1-phenyl)

  N-methylethyl) 7-3-diethylamino-2-methylpropanamide of purity

greater than 99%.

  J + 81.6 (CH C 13, C = 0.711).

C 37 = (O H 013,

  Purity is confirmed by chromatographic analysis

gas phase graph.

  FID Column: O 3 mm, 2 m, Temperature: 210 C, Filling mass: 15% FFAP

Support: Chromosorb WHP.

  (3) 24 g of (+) - N-1 (+) - 1- (1-phenylethyl) -3-diethylamino-2-

  methylpropanamide are loaded into a 300 ml vial.

  128 ml of a complex is slowly added dropwise

  boron trifluoride / methanol (BF 3.2 CH 30 H) while cooling

  The mixture was stirred at an external temperature of 100 ° C. for 3 hours, then the reaction liquid was poured on ice and its pH was adjusted to 8 with 28% aqueous ammonia. The mixture is extracted with ether. The ethereal layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is filtered off and the ether is filtered off.

  evaporated under reduced pressure; an oil is thus obtained.

  This oil is purified by chromatography on silica gel using a mixture of methylene chloride and methanol (10: 1) as a developing agent to obtain

  4.63 g of methyl (+) - 3-diethylamino-2-methylpropionate.

Yield: 29.2%.

2 to 5 e 28.20 (CH C 13 C = O, 621)

(4) Compound N 147: -

  In a 200 ml flask, 50 ml of

  anhydrous tetrahydrofuran and 1.29 g of magnesium.

  Ethyl bromide (4.76 ml) in tetrahydrofuran (10 ml) is added dropwise. The mixture is stirred at room temperature for 30 minutes.

  9.25 g of N-methylamino-3-phenylisoxazole in tetra-

  hydrofuran is added dropwise into the mixture.

  When the addition is complete, the mixture is stirred at room temperature for 30 minutes. A solution of methyl (+) - 3-diethylamino-2-methylpropionate (4.60 g) in tetrahydrofuran is added dropwise to the mixture. addition, the mixture is refluxed

during 3 hours.

  When the reaction is complete, the water is

  added to the reaction mixture and the resulting aqueous solution

  The aqueous solution is extracted with toluene. Normal hydrochloric acid is added to the toluene layer and the mixture is extracted with normal hydrochloric acid. The hydrochloric acid layer is washed with toluene. 28% ammonia is added. at the hydrochloric acid layer

  to alkalinize it (p H 9) and extract the resulting solution.

  The toluene layer is washed with water and dried over anhydrous magnesium sulfate. The drying agent is removed by filtration and the toluene is evaporated under reduced pressure. The residue is conecentered.

* under high vacuum and provides 6.60 g of the desired product.

Yield: 78.8%.

   1/25 + 63.4 (CHCl 3, C-0.708) Mp: 106.5 107.5 ° C (fumarate) ia 25 + 51.40 (CH 3 COCH 3, C = 0.432) Elemental analysis: Calc C 61, 24 H 6.77 N 9.74 found 63.24 6.91 9.89 NMR 6 (CDC 13): 0.95 (3H, t, J = 8Hz, NCH 2 CH 3); 1.12 (3H, d, J = 8Hz, CH 3 CH-); 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3) 2); 3.42 (3H, s, NCH 3); 6.49 (1H, s, = C-H); 7.3 7.6 (3H, m,

H H

  = C <H); 7.6 7.9 (2H, m, = CH) HH Mass M + 315 (C 18 H 25 N 302)

EXAMPLE 40

  Synthesis of (-) - 5-EN-methyl-N- (3-diethylamino-2-methyl-1-

  oro ionyl) 7-amino-3-phenylisoxazole (Compound N 148): (1) The procedure is as described in Example 39- (2) except that D - (+) - amethylbenzylamine is replaced by L - (-) - α-methylbenzylamine to give 30.8 g of

  (-) - N-Z (-) - 1 (1-phenylethyl) 7-3-diethylamino-2-methylpropa

namide.

  Purity: greater than 99% (GC chromatography

  zeuse) 83.1 (CHC 13, C = 0.603) (2) The procedure is as described in Example 31- (3)

  except that (+) - N-1 (+) - 1- (1-phenylethyl) -3-diethyl-

  amino-2-methylpropanamide is replaced by (-) - N-E (-) - 1-

  (1-phenylethyl) -1-diethylamino-2-methylpropanamide for

  obtain methyl (-) - 3-diethylamino-2-methylpropionate.

Yield: 4.83 g (49.2%).

  a 28.4 (CH C 13, C = 0.828) (3) Compound N 148: The procedure is as indicated in the example

  39- (4) except that (+) - 3-diethylamino-2-methylpropionic

  methyl nate is replaced by (-) - 3-diethylamino-2-

  methylpropionate to give (-) - 5-f'N-methyl-

  N- (3-diethylamino-2-methyl-1-propionyl) amino-3-phenyliso-

xazole Yield: 82.9%.

  Zla 64.60 (CH C 13, C = 0.608) Mp: 107.5 108.5 C (fumarate) and E 725 48.1 (fumarate) (CH 3 COCH 3, C = 0.563) NMR 5 (CDCl 3 ): 0.94 (3H, t, J = 8Hz, NCH 2 CH 3); 1.12 (3H, d, J = 8.0 Hz, CH 3 CH-); 2.0 3.2 (7H, m, CH 3 CHCH 2 N (CH 2 CH 3) 2); 3.40 (3H, s, NCH 3); 6.47 (1H, s, = C-H); 7.3 7.6 (3H, m,

H H

= C -H); 7.6, 7.9 (2H, m, = CH)

H H

+ -

Mass M 315 (C 18 H 25 N 302)

EXAMPLE 41

  Synthesis of the (+) and (-) isomers of 5- / M- (3-pyrrolidino)

  2-methyl-1-propionyl) lamino-3-phenylisoxazole (compounds N 149 and N 150): 15.0 g of d- (+) - tartaric acid are dissolved in 150 ml of ethanol. , 24 g

  5-N- (3-pyrrolidino-2-methyl-1-propionyl) -amino-3-phenyl-

  isoxazole and the mixture is stirred to obtain a homogeneous solution The solution is stirred at room temperature to provide crystals These crystals are filtered, iavés

  repeatedly with ethanol and dried under

  The crystals are recrystallized twice

  methanol and provide 13.3 g of d- (+) - tar-

compound N 150.

  2 to 5 + 84.0 (MeOH, C = 1.00), ZaD Pf: 157 158 C Mass: M + 299 (C 17 H 16 N 302) The mother liquor remaining after the filtration of the crystals is combined with the solution ethanolic wash. The ethanol is evaporated under reduced pressure The oil obtained is dissolved in water The solution is neutralized with sodium hydrogen carbonate and extracted with acetate

  The extract is dried over magnesium sulfate

  Hydrate and the drying agent is removed. The ethyl acetate is evaporated under reduced pressure; 149 g of an oil are thus collected. This oil has an optical rotation power of Da 725 61.8 (Me OH, C = 1.0 O).

  12.86 g of the oil to a solution of 6.45 g of l - (-) -

  tartaric acid in 65 ml of ethanol to obtain a homogeneous solution The solution is stirred and allowed to stand for the crystals to develop The crystals are filtered,

  washed thoroughly with ethanol and dried under pressure

  The crystals are recrystallized twice from methanol and give 14.55 g of 1 - (-) - tartrate.

  (-) - 5-N- (3-pyrrolidino-2-methyl-1-propionyl) amino-3-

  isoxazole. Yield 5 83.20 (MeOH, C = 1.00), mp: 157 158 C Mass: M + 299 (C 17 H 16 N 302)

EXAMPLE 42

  Synthesis of 5-F N-methyl-N- (3-diethylamino-2-ethyl-1-D)

  pionvl) 7-amino-3-phenylisoxazole (Compound N 151): (1) 141.5 g of diethyl ethylmalonate are dissolved in 300 ml of ethanol in a 2 liter quadricol A solution of 50.3 g of KOH in 440 ml of ethanol is added dropwise while the internal temperature is maintained at

  O 5 C After stirring the mixture at room temperature

  during 18 hours, the ethanol is evaporated under pressure

  The residue is added to the residue (300 ml of water) and the mixture is extracted with benzene. The pH 2 of the aqueous layer is adjusted to 2 with 6N hydrochloric acid and the mixture is extracted with ether. Ethereal is washed with water and dried over anhydrous magnesium sulfate. The drying agent is removed and then the ether is evaporated under reduced pressure; 118.9 g (92.5%) of ethylmalonate are thus collected.

  of monoethyl is introduced 118.9 g of this monoethyl ester.

  only in a quadricol of 1 liter is added drop by drop

  101.3 ml of diethylamine at an internal temperature of 5 -

  10 C When the addition is complete, add drop to

  drop 85 ml of 35% formalin in the mixture and ef-

  perform the reaction at room temperature for 56

  Then, 70 ml of a solution is added dropwise.

  aqueous solution of 14 g of potassium carbonate in the

  reaction mixture to form two layers The top layer

  is removed and the lower layer is extracted

  with ether The extract is combined with the top layer

  dried and dried over anhydrous magnesium sulphate.

  drying is filtered off Ether is evaporated

  pored under reduced pressure The residue is distilled under

  reduced pressure and provides ethyl 2-ethylacrylate.

Yield 84.04 g (81.7%).

  Mp: 56-590 ° C / 3600 Pa (27 mm Hg).

  (2) To a 200 ml flask, 50.0 g of 2-ethyl-

  ethyl acrylate and 44.4 ml of diethylamine 2.57 ml of acetic acid are introduced into the mixture. The reaction mixture

  is heated at 1000 C for 48 hours, then the

  excess ethylamine is evaporated under reduced pressure The residue is acidified with normal hydrochloric acid

  while the system is cooled, then extracted with ether.

  The aqueous layer is alkalinized (p H 9) using ammonia

  The ether layer was washed with water and dried over anhydrous magnesium sulfate. The drying agent was separated by filtration and the ether was dissolved.

  evaporated under reduced pressure; an oil is thus collected.

  This oil is distilled under reduced pressure and provides ethyl 3diethylamino-2-ethylpropionate Yield

  12.8 g (16.3%) P e 110.11 IC / 326 Pa (32 mm Hg).

  (3) Compound N 151: Introduced into a 100 ml vial 0.966 g

  of magnesium and 10 ml of anhydrous tetrahydrofuran

  5.20 g of ethyl bromide in tetrahydrofuran

  The mixture is added dropwise to the mixture while it is cooled with ice. When the addition is complete, the mixture is stirred at room temperature.

  for 30 minutes A solution of 6.99 g of 5-N-methyl-

  amino-3-phenylisoxazole in tetrahydrofuran is added

  After the addition is complete, the mixture is stirred at room temperature for 30 minutes.

  Then add dropwise to the solution.

  a solution of 3-diethylamino-2-ethylpropionate of

  thyl in tetrahydrofuran while cooling the system with ice The reaction mixture is stirred

  at room temperature for 30 minutes, then warm

  it was refluxed for 6 hours; we add water and

  luene to the reaction mixture and the resulting solution is acidified with normal hydrochloric acid.

  careful mixing, the aqueous layer is separated, alkaline

  with 28% ammonia (p H 9) and then extracted with ethyl ether The ethereal layer is washed with water

  and dried over anhydrous magnesium sulfate.

  Drying is filtered off and the ether is evaporated under reduced pressure. The resulting oil is concentrated under high vacuum and provides the title compound as a

oil Yield: 1.66 g (25.1 X).

  Mass: M +/- 329 (C 19 H 2702 N 3) 1.58 g of oil and 0.612 g of fumaric acid are added to 100 ml of acetone and the mixture is stirred to obtain a solution. acetone under reduced pressure A small amount of a mixture of acetone and hexane (1: 1) is added to the resulting oil and the resulting solution is allowed to stand for the crystals to develop. These crystals are filtered, washed in the ether

  and dried under reduced pressure Yield: 1.57 g.

Mp: 111-113C.

REFERENCE EXAMPLE 1.

  (1) The procedure is as described in Example 23- (1)

  except that acetophenone is replaced by 3,3-di-

  methyl-butan-2-one to obtain 5-N-phenylamino-3- (1,1-

dimethyl-1-ethyl) isoxazole.

M.p .: 144,145 C.

  (2) The procedure is as described in Example 14- (3) except that 5-N-methylamino-3-phenylisoxazole is

  replaced by 5-N-phenylamino-3- (1,1-dimethyl-1-ethyl) -

  isoxazole to give 5-N-phenyl-N- (2-methyl-2-propene)

  1-oyl) 7-amino-3- (1,1-dimethyl-1-ethyl) isoxazole.

REFERENCE EXAMPLE 2.

  The procedure is as described in Example - (1) to obtain the following compounds: Compound Yield P e O 01 C / Pa) P f (c)

CH 3 CH = CHCOND 77.6 92.5 94 / 80.0

CH 3 CH = CHCONJ 80.7 75 78 / 57.3

CH 3 CH = CHCON N-O 90.3 118 120 C

CH 3 CH = CHCONF O 79.3 99.5 104/26,

CH 2 CI-CON 3 D 89.5 820 / 80.0

% -3 CH 3

CH 2 = C-CONJ 74.4 96 98 / 80.0

CH 3

REFERENCE EXAMPLE 3.

  6.88 g of 50% sodium hydride are suspended in a anhydrous solution. A solution of 21.13 g of p-chlorobenzonitrile, 7.09 g of anhydrous acetonitrile and 1.5 ml of t-chlorobenzonitrile are added. Butanol in 170 ml of anhydrous ether is added dropwise to the suspension.

  reflux for 26 hours, then the reaction mixture is cooled

  at room temperature The ethereal layer is

  washed with water and dried over anhydrous magnesium sulfate.

  The drying agent is removed. The ether is evaporated under reduced pressure and the residue is recrystallized from

  ether; 22.07 g of p-chlorophenyl-3 are thus collected.

  Iminopropionitrile Yield: 80.2%.

  Fifty grams of ethanol are dissolved in 500 ml of ethanol.

  chlorophenyl-3-iminopropionitrile thus obtained.

  8.75 g of hydroxylamine hydrochloride in 50 ml of water is added dropwise to the resulting solution and the mixture is refluxed for 5 hours. When the reaction is complete, the ethanol is evaporated under pressure.

  reduced and the residue obtained is extracted with the acetate of

  The extract is washed with water and dried over anhydrous magnesium sulfate. The drying agent is removed and the ethyl acetate is evaporated under reduced pressure. The residue obtained is recrystallized from benzene and gives 14.81 g. 5-amino-3- (4-chlorophenyl) -isoxazole Yield: 6%. Repeat the procedure described in the example

  8- (1) except that 5-amino-3-methylisoxazole is replaced by

  placed with 5-amino-3- (4-chlorophenylisoxazole to obtain

  5.8 g of 5- (2-methyl-2-propen-1-yl) amino-3- (4-chloro)

  phenyl) isoxazole Yield: 98.5%.

REFERENCE EXAMPLE 4.

  The procedure described in Example 34- (1) is repeated except that 2-chlorobenzonitrile is replaced by 3-chlorobenzonitrile, 2-methylbenzonitrile,

  3-methylbenzonitrile, 4-methylbenzonitrile or 4-methyl-

  thoxybenzonitrile to obtain 5-aminoiso-

  following Xazole: Yield P f (o C) (<) -amino-3- (3-chlorophenyl) isoxazole 54 108 109 5-amino-3- (2-methylphenyl) isoxazole 18 98 99 -amino3- (3-methylphenyl) isoxazole 23 54 55 -amino-3- (4-methylphenyl) isoxazole 68 145.5 147.0 -amino-3- (4-methoxyphenyl) isoxazole 50 128 130

REFERENCE EXAMPLE 5.

  Repeat the procedure described in the example

  34- (2) except that 5-amino-3- (2-chlorophenyl) isoxa

  zole is replaced by 5-amino-3- (3-chlorophenyl) isoxazole,

  5-amino-3- (2-methylphenyl) isoxazole, 5-amino-3- (3-methyl)

  5-amino-3- (4-methylphenyl) isoxazole or 5-amino-3- (4-methylphenyl) isoxazole or 5-amino-3- (4-methoxyphenyl) isoxazole to give -formylamino-3- (3chlorophenyl) isoxazole, 5-formylamino-

  3- (2-methylphenyl) isoxazole, 5-formylamino-3- (4-methyl)

  phenyl) isoxazole or 5-formylamino-3- (4-methoxyphenyl) -

isoxazole. Yield P f (C)

(%) ___

  -formylamino-3- (3-chlorophenyl) isoxazole -formylamino-3- (2-methylphenyl) -isoxazole -formylamino-3- (4-methylphenyl) -isoxazole formylamino-3- (4-methoxyphenyl) -isoxazole

REFERENCE EXAMPLE 6.

134.55.5

oil

141 143

  Repeat the procedure described in the example

  34- (3) except that 5-formylamino-3- (2-chlorophenyl) -

  isoxazole is replaced by 5-formylamino-3- (3-chlorophenyl)

  nyl) isoxazole or 5-formylamino-3- (4-chlorophenyl) isoxazole

  zole to obtain the following compounds: Yield P f (C) _ _ 1 r_ methylamino-3- (3-chlorophenyl) -isoxazole

  5-methylamino-3- (4-chlorophenyl) -

isoxazole

87 88.5

158 159.5

(Mass:

M + 208)

REFERENCE EXAMPLE 7.

  3.44 g of 5-formylamino-3- (4-methyl-

  phenyl) isoxazole in 100 ml of anhydrous ether 0.7 g of aluminolithic hydride are added portionwise to the mixture at room temperature. When the addition is complete, the

  The reaction is carried out at room temperature for 2 hours.

  Then, the ethyl acetate is added to the reaction mixture.

  to break down the excess aluminolithic hydride.

  Ethyl acetate and water are added and the resulting solid is filtered off. The ethyl acetate layer is separated and dried over anhydrous magnesium sulfate. The drying agent is removed and the acetate is removed. ethyl is evaporated under reduced pressure; we collect

  a quantitative amount of 5-methylamino-3- (4-methylphenyl)

nyl) crystalline isoxazole.

  Mass: M + 188 (C 1 H 12 N 20) Using the procedure described above, the following compounds are obtained: Yield P f (o C) -N-methylamino-3- (2-methylphenyl) -

isoxazole 100 -

  5-N-methylamino-3- (4-methoxyphenol)

  nyl) isoxazole 100 103 104,5-N-methylamino-3- (4-chlorophenyl) isoxazole 100 122 123.5

REFERENCE EXAMPLE 8.

  The procedure described in Example 14- (3) is repeated except that 5-N-methylamino-3-phenylisoxazole

  is replaced by 5-N-methylamino-3- (3-chlorophenyl) isoxazole, 5-N-methylamino-3- (4-chlorophenyl) isoxazole, -N-methylamino-

  3- (2-methylphenyl) isoxazole, 5-N-methyl-

  amino-3- (3-methylphenyl) isoxazole, 5-N-methylamino-3- (4-

  methylphenyl) isoxazole or 5-N-methylamino-3- (4-methoxy)

  phenyl) isoxazole to obtain the following compounds: Yield P f (C)

  5-N-methyl-N- (2-methyl-2-propene)

1-oyl) 7 amino-3- (3-chlorophenyl) -

  isoxazole 40 oil-N-methyl-N- (2-methyl-2-propene)

1-oyl) lamino-3- (4-chlorophenyl) -

  isoxazole 51.7 69 71 - / - methyl-N- (2-methyl-2-propene)

  1-oyl) 7 amino-3- (2-methylphenyl) -

  isoxazole 40 oil - / N-methyl-N- (2-methyl-2-propen-1-yl) 7-amino-3- (3-methylphenyl) -isoxazole 77 oil - / N-methyl-N- (2-methyl-2) propen-

  1-oyl) 7-amino-3- (4-methylnenyl) -

isoxazole 43 oil

  5-N-methyl-N- (3-methyl-2-propene)

  1-amino) 7-amino-3- (4-methoxyphenyl) -

isoxazole 74 oil

REFERENCE EXAMPLE 9.

  N-methylamino-3-phenyloxazole. Synthesized 5-N-methylamino-3-phenylisoxazole

  in Examples 14- (1) and (2) can be prepared by way of

  thesis also according to the following method: 400 mg of 5-amino-3-phenylisoxazole are dissolved in 5 ml of ethanol. 2 ml of 35% formalin

  the solution The reaction is carried out at room temperature

  After stirring for 7 hours 400 mg of borosodium hydride powder are added portionwise to the reaction mixture while cooling with ice.

  reaction by cooling for a further 2 hours.

  methylene chloride and water are added to the

  reaction mixture and the mixture is extracted with chlorine

  methylene chloride The methylene chloride layer is

  dried over anhydrous magnesium sulfate The desiccating agent

  cation is removed by filtration Methylene chloride

  is evaporated under reduced pressure. The residue obtained is

  by silica gel chromatography using

  methylene chloride; thus collecting 5-N-methyl-

amino-3-phenylisoxazole.

Yield: 199 mg (45.7%).

  By performing a melting point test on

  the mixture of this product with the product obtained in the

  Figure 14- (2) shows a lowering of the melting point.

  The two products coincide with each other with respect to

  their infrared absorption spectrum and their

  The procedure described above is repeated except that 5-amino-3-phenylisoxazole is replaced by 5-amino-3- (3-methylphenyl) isoxazole and that the % is replaced by acetaldehyde to give the following compounds: Yield (X) -N-methylamino-3- (3-methylphenyl) isoxazole 24 -Naminoamino-3-phenylisoxazole 47.4

Claims (1)

1 Derivatives of 5-aminoisoxazole characterized in that they are represented by the following general formula: ## STR1 ## in which R 1 represents a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom, R 2 is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group; phenyl, R 3 is hydrogen, C 1 -C 5 alkyl, phenyl or benzyl which may be substituted with halogen or lower alkoxy, 4 and R 5 are each a hydrogen atom or a lower alkyl group, one of the radicals A and B represents a carbonyl group and the other represents a methylene group which may be substituted with a lower alkyl group; or A and B each represent a methylene group which may be substituted with lower alkyl, and D is -N (wherein R 6 is hydrogen or C 1 -C 6 alkyl, and R 7 is C 1-6 alkyl); 1-6, cycloalkyl or benzyl), morpholino, hexamethyleneimino, heptamethyleneimino, pyrrolidino which may be substituted with one or more lower alkyl groups, piperazino be substituted with a lower alkyl group, a phenyl or phenylhalogen group or a piperidino group which may be substituted with a phenyl group or a benzyl group, as well as their non-toxic salts. 2 Derivatives of 5-aminoisoxazole according to claim 1, characterized in that R 1 is a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group or a halogen atom, R 2 is a hydrogen atom, hydrogen or a lower alkyl group, R 3 is a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group or a benzyl group, one of the radicals R 4 and R 5 is an atom of hydrogen and the other is a hydrogen atom or a lower alkyl group, A is a carbonyl group or a methylene group which may be substituted with a lower alkyl group, B is a methylene group which may be substituted with a lower alkyl group, D is a R 6 -N group (wherein R 6 and R 7 each represent a C 1 -C 6 alkyl group), a piperidino group, a hexamethyleneimino group or a pyrrolidino group which may be substituted with one or more lower alkyl groups, as well as their salt s non-toxic. 3 Derivatives of 5-aminoisoxazole according to Claim 2, characterized in that the lower alkyl group and the halogen atom in the radical R 1 are a methyl group and a chlorine atom respectively, the the lower alkyl group of the radical R 2 is an isopropyl group, the C 1 -C 5 alkyl group of the radical R 3 is a methyl, ethyl, n-propyl, secbutyl or neopentyl group, the lower alkyl group in the radicals R 4 or R 5 is methyl, the lower alkyl group in radical B is methyl, the alkyl group of R 6 and R 7 in D is methyl, ethyl or n-propyl and the lower alkyl group is Substituent of the pyrrolidino group in D is a methyl group, as well as their non-toxic salts. 4 Derivatives of 5-aminoisoxazole according to Claim 1, characterized in that R 1 is a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group or a halogen atom, R 2 is a dicarboxylic acid atom, hydrogen, R 3 is a C 1 -C 3 alkyl group or a phenyl group, A is a carbonyl group, R 4 is a hydrogen atom, R 5 is a lower alkyl group, BR / m 6 is a group methylene and D is a group -N (in which R 6 and R 7 are each a C 1 -C 4 alkyl group), a pyrrolidino group, a piperidino group or a hexamethyleneamino group, as well as their non-toxic salts. 5-Aminoisoxazole derivatives according to Claim 4, characterized in that the lower alkyl group and the halogen atom in the radical R 1 are respectively a methyl group and a chlorine atom, R 3 is methyl, ethyl or n-propyl, R 5 is methyl, and R 6 and R 7 are ethyl or n-propyl, and their non-toxic salts. 5-Aminoisoxazole derivatives according to Claim 5, characterized in that the methyl group in the radical R 1 is placed in the ortho position of the dienyl group and the chlorine in the radical R 1 is placed in the ortho or meta position of the phenyl group, as well as their non-toxic salts. 7 5-IN-methyl-N- (3-pyrrolidino-2-methyl-1-propionyl) lamino-3-phenylisoxazole, as well as its non-toxic salts. 8-N-methyl-N- (3-diethylamino-2-methyl-1-propionyl) -3-amino-phenylisoxazole, as well as its non-toxic salts. N-methyl-N- (3-di-n-propylamino-2-methyl-1-propionyl) -amino-3-phenylisoxazole, as well as its non-toxic salts. 5-N-phenyl-N- (3-diethylamino-2-methyl-1-propionyl) -amino-3-phenylisoxazole, as well as its non-toxic salts. 5-Z-N-methyl-N- (3-piperidino-2-methyl-1-propionyl) -amino-3-phenylisoxazole, as well as its non-toxic salts. 5-N-methyl-N- (3-hexamethyleneimino-2-methyl-1-propionyl) -7-amino-3-phenylisoxazole, as well as its non-toxic salts. 5-N-methyl-N- (3-diethylamino-2-methyl-1-propionyl) amino-3- (2-chlorophenyl) isoxazole, as well as its non-toxic salts. 5-N-methyl-N- (3-diethylamino-2-methyl-1-propionyl) amino-3- (3-chlorophenyl) isoxazole, as well as its non-toxic salts. 5-N-methyl-N- (3-diethylamino-2-methyl-1-propionyl) -7-amino-3- (2-methylphenyl) isoxazole, and its non-toxic salts - 16 Process for the production of 5-friend derivatives noisoxazole represented by the general formula: ## STR1 ## wherein R 1 is a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group, a lower alkoxy group; or a halogen atom, R 2 is a hydrogen atom, a halogen atom, a lower alkyl or phenyl group, R 3 is a hydrogen atom, a C 1 to C 5 alkyl group, a group phenyl or a benzyl group which may be substituted with a halogen atom or one or more alkoxy groups, R 4 and R 5 each represent a hydrogen atom or a lower alkyl group, B 'is a methylene group which may be substituted with an R 6 lower alkyl group, and D is a group -N (in R 7 where R 6 is a hydrogen atom or a C 1 -C 6 alkyl group and R 7 is a C 1 -C 6 alkyl group, a cycloalkyl group or a benzyl group), a morpholino group, a hexamethyleneimino group, a heptamethyleneimino group, a pyrrolidino group which may be substituted with at least one lower alkyl group, a piperazino group which may be substituted with a lower alkyl, phenyl or phenylhalogen group, or a piperidino group which may be substituted with a phenyl or benzyl group and their non-toxic salts; , characterized in that a compound represented by the general formula R 1 X / t R 2 NN COR R 3 is reacted in which R 1, R 2 and R 3 are as defined above and R is a group represented by the formula: R 8 R 4 IIC = C-C = C-H (wherein R 8 is a hydrogen atom or a lower alkyl group) or a group of formula: X 8 R-1 1 XC C IIHR 5 (in which R 4, R 5 and R 8 are as defined above and X is a halogen atom), with a compound represented by the general formula: H-D and, optionally, subjecting the resulting product to optical resolution. A process for producing 5-aminoisoxazole derivatives represented by the general formula: wherein R 1 is a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom, R 2 is a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl group, R 3 is a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group or a benzyl group which may be substituted with a halogen atom or one or more lower alkoxy groups, R 4 is a hydrogen atom or a lower alkyl group, A'-is a methylene group which may be substituted with a lower alkyl group, and D represents a group R -N (wherein R 6 is a hydrogen atom or a R 7 is a C 1 alkyl group at C 6 and R 7 is a C 1 -C 6 alkyl group, a cycloalkyl group or a benzyl group); morpholino group, a hexamethyleneimino group, a heptamethyleneimino group, a pyrrolidino group which may be substituted with at least one lower alkyl group, a piperazino group which may be substituted with a lower alkyl group, a phenyl or phenylhalogen group, o or a piperidino group which can be substituted with a phenyl or benzyl group, as well as their non-toxic salts, characterized in that a compound represented by the general formula R 1 R 2 N NH R 3 in which R 1, R 2 is reacted is reacted and R 3 are as defined above, with a compound of the general formula: R 8 R 4 IIHC = C CO D wherein D is as defined above and R 8 is a hydrogen atom or a lower alkyl group, and, optionally, subjecting the resulting product to optical resolution. Process for the production of 5-aminoisoxazole derivatives represented by the general formula: R 1 R 2 R 4 NN-NA "C -B" -D 0 / I 1 R 3 R 5 wherein R 1 is a group lower alkyl, a phenyl group which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom, R 2 is a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl group, R 3 is a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group or a benzyl group which may be substituted with a halogen atom or one or more alkoxy groups, R 4 and R 5 are each a hydrogen atom or a lower alkyl group, one of the radicals A "and B" is a methylene group and the other is a methylene group which may be substituted with a lower alkyl group, and D is R -N (wherein R 6 is hydrogen or R 7 is C 1 -C 6 alkyl and R 7 is a group C 1 -C 6 alkyl, a cycloalkyl group or a benzyl group), a morpholino group, a hexamethyleneimino group, a heetamethyleneimino group, a pyrrolidino group which may be substituted with at least one lower alkyl group, a piperazino group which may be substituted with a lower alkyl group, a phenyl or phenylhalogen group, or a piperidino group which may be substituted with a dienyl or benzyl group, as well as their non-toxic salts, characterized in that a compound represented by the formula wherein R 1, R 2, R 3, R 4, R 5 and D are as defined above and B 'is a methylene group which may be substituted with a lower alkyl group, or a compound represented by the general formula: ## STR1 ## wherein R 1, R 2, R 3, R 4 and D are as defined above and A 'is a methylene group which can be sub- is substituted with a lower alkyl group, and optionally, the resulting product is subjected to optical resolution. A process for producing 5-aminoisoxazole derivatives represented by the general formula: wherein R 1 is a lower alkyl group, a phenyl group which may be substituted with lower alkyl, lower alkoxy or halogen, R 2 is hydrogen, halogen, lower alkyl or phenyl, R'3 is alkyl. C 1 to C 5, an oenyl group or a benzyl group which may be substituted with a halogen atom or one or more lower alkoxy groups, R 4 and R 5 are each a hydrogen atom or a lower alkyl group, one of the radicals A "and B" is a methylene group and the other is a methylene group which may be substituted with a lower alkanoyl group, and D is a group -N (wherein R 6 R 7 is a hydrogen atom or a C 1 to C 6 alkyl group and R 7 is a C 1 to C 6 alkyl group, a cycloalkyl or a benzyl group), a morpholino group, a hexamethyleneimino group, a heptamethyleneimino group, a pyrrolidino group which may be substituted with at least one lower alkyl group, a piperazino group which may be substituted with an alkyl group. lower, phenyl or phenyl-halogen, or a piperidino group which may be substituted with a phenyl or benzyl group, as well as their non-toxic salts, characterized in that a compound represented by the general formula R 1 RR is reacted Wherein R 1, R 2, R 4, R 5, A ", B" and D are as defined above, with a compound of the general formula ## STR2 ## wherein R 1, R 2, R 4, R 5, A ", B" and D are as defined above. R'3 -X 3- wherein X is a halogen atom and R'3 is as defined above, and optionally subjecting the resulting compound to an optical revolution. A process for producing 5-aminoisoxazole derivatives represented by the general formula: wherein R 1 is a lower alkyl group, a phenyl group which may be substituted with a lower alkyl group or a halogen atom, R 2 is a hydrogen atom, a halogen atom, a lower alkyl group or a phenyl group, R 3 is a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group or a benzyl group which may be substituted with a halogen atom or one or more lower alkoxy groups, one of R'4 and R'8 is an atom of hydrogen and the other represents a lower alkyl group R, and D is a group -N (wherein R 6 is R 7 is a hydrogen atom or a C 1 -C 6 alkyl group and R 7 is a group C 1 -C 6 alkyl, a cycloalkyl group or a benzyl group), a morpholino group, a hexamethyleneimino group, a heptamethyleneimino group, a pyrrolidino group which may be substituted with at least one lower alkyl group, a piperazino group which may be substituted with a lower alkyl, phenyl or phenyl halogen group, or a piperidino group which may be substituted with a phenyl group or benzyl, as well as their non-toxic salts, characterized in that a compound represented by the general formula R 1 R NNHR 3 in which R 1, R 2 and R 3 are as defined above, is reacted with a compound represented by the general formula: RI 8 R 4 1 8 1 4 D CH CH COOR   wherein D, R'4 and R'8 are as defined above and R is a lower alkyl group.