FR2735470A1 - New nitro- ketone and nitro- oxime cpds. - Google Patents

Abstract

Nitro-ketone and nitro-oxime cpds. of formula NO2CH(R4)C(R3)=CHC(=R2)(R1) (I), their racemates, enantiomers, geometric isomers, and their salts, with the exception of 3-ethyl-4-nitro-1-(pyridin-2-yl) pent-2-en-1-one oxime, are new. R1 = pyridinyl, thiazolyl, quinolinyl, or isoquinolinyl; R2 = O or NOR5; R5 = H or 2-4C alkanoyl; R3 = 1-4C alkyl, or phenyl opt. substd by one or more of halo, 1-4C alkyl, 1-4C alkoxy and/or NO2; and R4 = 1-4C alkyl.

Description

The present invention relates to nitroaliphatic derivatives, their preparation and their therapeutic application.

dans laquelle
R1 représente un hétérocycle choisi parmi les groupes pyridinyle, thiazole, quinoléine et isoquinoléine,
R2 représente soit un atome d'oxygène, soit un groupe =NOh où R5 est un atome d'hydrogène ou un groupe (C2-C4)alcanoyle,
R3 représente soit un groupe (C-C4)alkyle, soit un groupe phényle, soit un groupe phényle substitué par un ou plusieurs substituants choisis parmi les atomes d'halogène et les groupes (C1-C4)alkyle, (C1-C4 > alcoxy et nitro, et R4 représente un groupe (C1-C4)alkyle droit ou ramifié, à l'exception du 3-éthyl-4-nitro-1-(pyridin-2-yl)pent-2-èn-1- one oxime, ainsi que leurs sels d'addition à des acides ou à des bases pharmaceutiquement acceptables.The compounds of the invention correspond to formula (I)

in which
R1 represents a heterocycle chosen from pyridinyl, thiazole, quinoline and isoquinoline groups,
R2 represents either an oxygen atom or a group = NOh where R5 is a hydrogen atom or a (C2-C4) alkanoyl group,
R3 represents either a (C-C4) alkyl group, a phenyl group, or a phenyl group substituted with one or more substituents selected from halogen atoms and (C1-C4) alkyl, (C1-C4) alkoxy groups and nitro, and R4 represents a straight or branched (C1-C4) alkyl group, with the exception of 3-ethyl-4-nitro-1- (pyridin-2-yl) pent-2-en-1-oxime as well as their addition salts with pharmaceutically acceptable acids or bases.

The compounds of formula (I) may exist in the form of pure racemate or enantiomers and / or geometric isomers which are also part of the invention.

Nitroaliphatic compounds are described in European Patent EP 0113106, in Japanese patent applications
JP-92-262858 and JP-93-28832 and in the patent application
WO 9310097.

According to the invention the compounds of formula (I) can be synthesized according to scheme 1.

Diagram 1

<tb><SEP> 1) <SEP> n-butytlithium
<tb><SEP> 1) RICW <SEP> (w)
<tb><SEP> 9 <SEP> R
<tb><SEP> l <SEP> O
<tb><SEP> -l? <<SEP> R3
<tb><SEP> o <SEP> (IV)
<tb><SEP> BI
<tb><SEP> F
<tb><SEP> Rt <SEP> O
<tb> 1 \ <SEP> 95
<tb> Oi <SEP> I4 <SEP> (L)
<tb><SEP> PI
<tb><SEP> 1
<tb><SEP> R4
<tb> (Ib)
<tb><SEP> NOH
<tb><SEP> \ NaH
<tb><SEP> Rz
<tb><SEP> | <SEP> (Rti) 20
<tb><SEP> R4
<tb> ozw <SEP> I (<SEP> (Ic)
<tb><SEP> \ N6R5
<tb><SEP> Rt
<Tb>
(Diethoxyphosphinyl) methyl is reacted with a compound of formula (II) (wherein R1 is as defined above) in the presence of n-butyllithium in an aprotic solvent such as tetrahydrofuran at low temperature and then a compound of formula (III) (wherein R 3 and R 4 are as defined above), the mixture is heated to the reflux temperature and a compound of formula (IV) is obtained which is treated with acetyl chloride in an aprotic solvent such as for example tetrahydrofuran in the presence of a base such as potassium bistrimethylsilyl amide to obtain a compound of formula (V) which is treated with trifluoroacetic anhydride in the presence of a nitrating agent such as nitrate of ammonium in an aprotic solvent such as chloroform and there is obtained a compound of formula (Ia) which corresponds to formula (I) when
R2 is an oxygen atom.

If it is desired to obtain a compound of formula (Ib) which corresponds to formula (I) when R2 is a hydroxyimino group, the nitrocetone of formula (Ia) is treated with hydroxylamine hydrochloride in a mixture of solvents such as chloroform. and methanol.

If it is desired to obtain a compound of formula (Ic) which corresponds to formula (I) when R2 is a group = NOR5 where R5 is a (C2-C4) alkanoyl group, the corresponding compound of formula (Ib) is treated with a compound of formula (R '> 20 wherein R5 is as defined above.

The starting compounds are commercially available or described in the literature or may be prepared according to methods described therein or which are known to those skilled in the art.

Thus the regiospecific nitration process described in Scheme 1 is adapted from that described by P. Dampawan et al.
Synthesis, (1983), 545.

The synthesis of the compounds of formula (IV) is similar to that described by K. Lee et al., Synthesis, (1991), 213.

The oximation process of the compounds of formula (Ia) is adapted from that described in European Patent EP 0113106.

The following examples illustrate the preparation of certain compounds according to the invention.

The microanalyses and the IR and NMR spectra confirm the structure of the compounds obtained.

The numbers of the compounds exemplified refer to those of the table given below which illustrates the chemical structures and the physical properties of some compounds according to the invention.
Example 1 (Compound No. 3) 4-nitro-3-phenyl-1- (pyridin-2-yl) pent-2-en-1-one
1.1. 3-phenyl-1- (pyridin-2-yl) pent-3-en-1-one
To a solution of 8.35 g (55 mmol) of (diethoxyphosphinyl) methyl in 150 ml of tetrahydrofuran is added at -65 ° C, 35 ml (52.5 mmol) of a 1.5 M n-butyllithium solution. in hexane.The reaction medium is left for 1 hour at -70 ° C., a solution of 5.2 g (50 mmol) of pyridine-2-carbonitrile in 50 ml of tetrahydrofuran is added dropwise, the temperature is allowed to the reaction medium rise to 0 ° C and the mixture is maintained at this temperature for 1 hour. Then 6.75 g (50 mmol) of 1-phenylpropan-1-one dissolved in 50 ml of tetrahydrofuran is added dropwise and the mixture is brought to the reflux temperature for 16 hours. After cooling, the reaction medium is hydrolyzed by adding 50 ml of 2N hydrochloric acid and left stirring for 1 hour. The pH is adjusted to 8 by addition of an aqueous solution of sodium bicarbonate, the mixture is decanted and the aqueous phase is extracted with twice 100 ml of ether. The organic phases are combined and washed with a solution of sodium chloride. sodium, dried over magnesium sulfate and the solvent evaporated to dryness. The residue is purified by column chromatography on silica gel, eluting with a cyclohexane: ethyl acetate (9: 1) mixture.

9.04 g of product are obtained in the form of a mixture of two isomers Z and E (78/22) in the form of an oil.

Yield = 76%
1.2. 3-phenyl-1- (pyridin-2-yl) penta-1,3-dienoacetate
l-yl
To 8.1 g (38.6 mmol) of 95% potassium bistrimethylsilyl amide in 150 ml of tetrahydrofuran was added at -70 ° C, 9.04 g (38.1 mmol) of 3-phenyl-1 - (pyridin-2-yl) pent-3-en-1-one. The mixture is left for 1 hour at -70 ° C. with stirring, 3 ml (42 mmol) of acetyl chloride are added dropwise, the temperature of the mixture is allowed to rise to 20 ° C. and left for 1 hour at this point. temperature. The medium is then hydrolyzed with saturated aqueous sodium bicarbonate solution, decanted and extracted with twice 50 ml of ether. The organic phases are combined, dried, the solvent is evaporated under vacuum and the product is obtained. in the form of a mixture of crystals and oil. The crystals are filtered off in cyclohexane and recrystallized from cyclohexane. The oil is purified by chromatography on a column of silica gel, eluting with ethyl acetate: cyclohexane (2: 8). We collect purified oil and crystals.

9.2 g of product are obtained which is used as it is in the next step.

Yield = 86%
Melting point = 118-120 ° C
1.3. 4-nitro-3-phenyl-1- (pyridin-2-yl) pent-2-en-1-one
In a flask containing 6 g (21.5 mmol) of 3-phenyl-1- (pyridin-2-yl) penta-1,3-dien-1-yl acetate and 1.9 g (23.7 mmol) ) of ammonium nitrate in 50 ml of chloroform, 6.7 ml (47.4 mmol) of trifluoroacetic anhydride is added at 0 ° C., the temperature of the reaction medium is allowed to rise to 20 ° C. and it is left to this temperature with stirring for 2 hours. The reaction medium is then poured into 50 ml of ice water and extracted with twice 20 ml of chloroform. The organic phases are combined, dried over magnesium sulphate and the residue is purified by gel column chromatography. of silica eluting with toluene: ethyl acetate (9: 1). A solid is obtained which is recrystallized from a cyclohexane: toluene (9: 1) mixture and dried.

0.95 g of product is obtained in the form of yellow crystals.

Yield = 16%
Melting point = 78 OC
1H NMR (CDCl 3: 1.8 (d, 3H, J = 6Hz), 5.5 (q, 1H, J = 6Hz), 7.2 (m, 2H), 7.3 (m, 3H); 7.4 (m, 1H), 7.75 (t, 1H, J = 7Hz), 7.8 (s, 1H), 7.9 (d, 1H, J = 7Hz), 8.7 (d, 1H, J = SHz).

Example 2 (compounds 1 and 2) 3-ethyl-4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
2.1. 3-ethyl-1- (pyridin-2-yl) pent-3-en-1-one
The product is prepared as described in 1.1 using 5 g (58 mmol) of pentan-3-one.

4.2 g of product are obtained in the form of an oil.

Yield = 44%
2.2. 3-ethyl-1- (pyridin-2-yl) penta-1,3-dien-1-yl acetate
The product is prepared as described in 1.2 from 4.2 g (22 mmol) of 3-ethyl-1- (pyridin-2-yl) pent-3-en-one.

4.6 g of product are obtained in the form of an oil.

Yield = 90%
2.3. 3-ethyl-4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
The product is prepared as described in 1.3 from 1.83 g (7.92 mmol) of 3-ethyl-1- (pyridin-2-yl) penta-1,3-dien-1-acetate. yl.

1 g of product is obtained in the form of a mixture of isomers
Z and E.

Yield = 54%
The Z and E isomers are separated by column chromatography on silica gel, eluting with a cyclohexane: ethyl acetate (9: 1) mixture.

200 mg of isomer E are obtained in the form of an oil and 100 mg of Z isomer in the form of a white solid which is recrystallized from ethanol.

E-isomer (oil): 1H NMR (CDCl3): 1.3 (t, 3H, J = 7Hz) 1.8 (d, 3H, J = 7Hz); 2.35 (m, 2H); 6.7 (q, 1H, J = 7Hz); 7.5 (m, 1H); 7.8 (s, 1H); 7.9 (t, 1H); 8.1 (d, 1H, J = 8 Hz); 8.7 (d, 1H, J = 6Hz) Z isomer (solid): 1H NMR (CDCl3): 1.2 (t, 3H, J = 7Hz); 1.85 (d, 3H, J = 7Hz); 2.75 (q, 2H, J = 7Hz); 5.3 (q, 1H, J = 7Hz); 7.5 (m, 1H); 7.8 (s, 1H); 7.9 (t, 1H, J = 7Hz); 8.1 (d, 1H, J = 7Hz); 8.7 (d, 1H, J = 6Hz)
Melting point of the isomer Z = 66-67 OC
Example 3 (Compound No. 4) 3- (4-Chlorophenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
3.1. 3- (4-chlorophenyl) -1- (pyridin-2-yl) pent-3-en-1-one
The product is prepared as described in 1.1 from 10.34 g (61.3 mmol) of 1- (4-chlorophenyl) propan-1-one.

9.79 g of product are obtained.

Yield = 60%
3.2. 3- (4-chlorophenyl) -1- (pyridin-2-yl) pentaacetate
1,3-dien-1-yl
The product is prepared as described in 1.2 from 9.79 g (36 mmol) of 3- (4-chlorophenyl) -1- (pyridin-2-yl) pent-3-en-1-one.

9.72 g of product is obtained in the form of an oil.

Yield = 86%
3.3. 3- (4-chlorophenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-
l-one
The product is prepared as described in 1.3 from 9.72 g (31 mmol) of 3- (4-chlorophenyl) -1- (pyridin-2-yl) penta-1,3-diene acetate. l-yl.

4.37 g of product are obtained in the form of an oil.

Yield = 44%
1H NMR (CDCl3): 1.8 (d, 3H, J = 6Hz); 5.5 (q, 1H, J = 6Hz); 7.1-7.5 (m, 5H); 7.7 (t, 1H, J = 7Hz); 7.8 (s, 1H); 7.9 (d, 1H, J = 7Hz); 8.7 (d, 1H, J = 7Hz).

Example 4 (Compound No. 5) 3- (4-Methoxyphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
4.1. 3- (4-methoxyphenyl) -1- (pyridin-2-yl) pent-3-en-1-one
The product is prepared as described in 1.1 from 11.5 g (70 mmol) of 1- (4-methoxyphenyl) propan-1-one.

11.44 g of product are obtained in the form of an oil.

Yield = 63%
4.2. 3- (4-methoxyphenyl) -1- (pyridin-2-yl) pentaacetate
1,3-dien-1-yl
The product is prepared as described in 1.2 from 8.3 g (31 mmol) of 3- (4-methoxyphenyl) -1- (pyridin-2-yl) pent-3-en-1-one.

8.79 g of product are obtained in the form of an oil.

Yield = 91%
4.3. 3- (4-methoxyphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-
l-one
The product is prepared as described in 1.3 from 8.79 g (28.44 mmol) of 3- (4-methoxyphenyl) -1 (pyridin-2-yl) penta-1,3-diene acetate. -1-yl.

1.58 g of product are obtained.

Yield = 18%
1H NMR (CDCl 3: 1.8 (d, 3H, J = 6Hz), 3.8 (s, 3H), 5.5 (q, 1H, J = 6Hz), 6.8 (d, 2H, J); = 9Hz), 7.1 (d, 2H, J = 9Hz), 7.4 (m, 1H), 7.6 (s, 1H), 7.8 (t, 1H, J = 7Hz); 7 (d, 1H, J = 7Hz).

Example 5 (Compound No. 6) 3- (4-methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
5.1. 3- (4-methylphenyl) -1- (pyridin-2-yl) pent-3-en-1-one
The product was prepared as described in 1.1 from 9.08 g (61 mmol) of 1- (4-methylphenyl) propan-1-one.

8.03 g of product are obtained in the form of an oil.

Yield = 52%
5.2. 3- (4-methylphenyl) -1- (pyridin-2-yl) penta-1,3-dien-1-yl acetate
The product was prepared as described in 1.2 from 8.03 g (32 mmol) of 3- (4-methylphenyl) -1- (pyridin-2-yl) pent-3-en-1-one.

8.41 g of product is obtained in the form of an oil.

Yield = 90%
5.3. 3- (4-methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-
en-l-one
The product is prepared as described in 1.3 from 8.4 g (28.6 mmol) of 3- (4-methylphenyl) -1- (pyridin-2-yl) penta-1,3-acetate. -dien-l-yl,
3.18 g of product is obtained in the form of an oil.

Yield = 37%
Example 6 (Compound No. 7) 3- (2-Methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
6.1. 3- (2-methylphenyl) -1- (pyridin-2-yl) pent-3-en-1-one
The product is prepared as described in 1.1 from 9.09 g (61.3 mmol) of 1- (2-methylphenyl) propan-1-one.

7.45 g of product are obtained.

Yield = 44%
6.2. 3- (2-methylphenyl) -1- (pyridin-2-yl) penta-1,3-dien-1-yl acetate
The product is prepared as described in 1.2 from 7.45 g (29.6 mmol) of 3- (2-methylphenyl) -1- (pyridin-2-yl) pent-3-en-1-one. .

7.55 g of product are obtained in the form of an oil.

Yield = 87%
6.3. 3- (2-methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-
en-l-one
The product is prepared as described in 1.3 from 7.55 g (25.7 mmol) of 3- (2-methylphenyl) -1- (pyridin-2-yl) penta-1,3-ethyl acetate. dien-1-yl.

2.61 g of product are obtained in the form of two Z isomers and
E in proportion 3: 2 not allocated.

Yield = 34%
1 H NMR (CDCl 3): 1.8 and 1.9 (d, 3H, J = 6 Hz); 2.3 and 2.35 (s, 3H); 5.45 (m, 1H); 7.0 - 7.5 (m, 5H); 7.80 (m, 3H); 8.7 (d, 1H, J = SHz).

Example 7 (Compound No. 8) 3- (2,6-difluorophenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one
It is prepared from 8.94 g (52.5 mmol) of 1- (2,6-difluorophenyl) propan-1-one according to the method described in Example 1.

The product is obtained in the form of an oil.

1H NMR (CDCl 3: 1.8 (d, 3H, J = 6Hz), 5.5 (q, 1H, J = 6Hz), 6.9 (t, 2H, J = 7Hz), 7.4 (t , 1H, J = 7Hz), 7.5 (t, 1H, J = 7Hz) 7.8 (t, 1H, J = 7Hz), 7.9 (d, 1H, J = 7Hz); s, 1H); 8.7 (d, 1H, J = 5z)
Example 8 (Compound No. 9) 5-methyl-4-nitro-3-phenyl-1- (pyridin-2-yl) hex-2-en-1-one
8.1. 5-methyl-3-phenyl-1- (pyridin-2-yl) hex-3-en-1-one
The product is prepared as described in 1.1 from 27.85 g (167 mmol) of 3-methyl-1-phenylbutan-1-one.

28.9 g of product are obtained.

Yield = 65%
8.2. 5-methyl-3-phenyl-1- (pyridin-2-yl) hexa-1,3-acetate
dien-l-yl
The product is prepared as described in 1.2 from 27 g (102 mmol) of 5-methyl-3-phenyl-1- (pyridin-2-yl) hex-3-en-1-one.
22 g of product are obtained in the form of an oil.

Yield = 70%
8.3. 5-methyl-4-nitro-3-phenyl-1- (pyridin-2-yl) hex
2-en-1-one
The product is prepared as described in 1.3 from 2 g (6.5 mmol) of 5-methyl-3-phenyl-1- (pyridin-2-yl) hex-1,3-dien-1-acetate. yl.

0.7 g of product is obtained in the form of an oil.

1 H NMR (CDCl 3): 1.1 (d, 6H, J = 7 Hz); 2.7 (m, 1H); 5.05 (d, 1H, J = 9Hz); 7.2 (m, 2H); 7.3 (m, 3H); 7.4 (m, 1H) 7.75 (t, 1H, J = 7Hz); 7.9 (d, 1H, J = 7Hz); 7.95 (s, 1H); 8.7 (d, 1H, J = SHz)
Yield = 35 S
Example 9 (Compound No. 10) 5,5-dimethyl-4-nitro-3-phenyl-1- (pyridin-2-yl) hex-2-en-1-one
9.1. 5,5-dimethyl-3-phenyl-1- (pyridin-2-yl) hex-3-en-1-one
The product is prepared as described in 1.1 from 19 g (100 mmol) of 3,3-dimethyl-1-phenylbutan-1-one.

6.3 g of product are obtained.

Yield = 21%
9.2. 5,5-dimethyl-3-phenyl-1- (pyridin-2-yl) hexachloroacetate
1,3-dien-1-yl
The product is prepared as described in 1.2 from 6.3 g (22.6 mmol) of 5,5-dimethyl-3-phenyl-1- (pyridin-2-yl) hex-3-en-1 -one
4 g of product are obtained in the form of an oil.

Yield = 53%
9.3. 5,5-dimethyl-4-nitro-3-phenyl-1- (pyridin-2-yl) hex-2-en-1-one
The product is prepared as described in 1.3 from 2.2 g (6.8 mmol) of 5,5-dimethyl-3-phenyl-1- (pyridin-2-yl) hex-1 acetate, dien-3-l-yl.

2 g of product are obtained in the form of an oil.

Yield = 80%
Melting point = 110-114 ° C
Example 10 (Compound No. 11) 5,5-dimethyl-4-nitro-3- (4-chlorophenyl) -1- (pyridin-2-yl) hex-2-en-1-one
The product is prepared according to the method described in Example 1 from 18.83 g (90 mmol) of 3,3-dimethyl-1- (4-chlorophenyl) butan-1-one.

0.6 g of product is obtained in the form of an oil.

1H NMR CDCl3): 1.15 (s, 9H); 5.35 (s, 1H); 7.2 (d, 2H, J = 7Hz); 7.3 (d, 2H, J = 7Hz); 7.4 (m, 1H); 7.8 (t, 1H, J = 7Hz); 7.9 (d, 1H, J = 7Hz); 8.0 (s, 1H); 8.7 (d, 1H, J = 7Hz)
Example 11 (Compound No. 12) 4-nitro-3-phenyl-1- (pyridin-4-yl) pent-2-en-1-one
The product is prepared from pyridine-4-carbonitrile and 1-phenylpropan-1-one according to the method described in Example 1.

The product is obtained in the form of an oil.

1 H NMR (CDCl 3): 1.8 (d, 3H, J = 6 Hz); 5.5 (q, 1H, J = 6Hz); 7-7.5 (m, 6H); 7.8 (d, 2H, J = 6Hz); 8.8 (d, 2H, J = 6Hz)
Example 12 (compound 13) 5-methyl-4-nitro-3-phenyl-1- (pyridin-4-yl) hex-2-en-1-one
It is prepared from 3-methyl-1-phenylbutan-1-one according to the method described in Example 1.

The product is obtained in the form of an oil.

1 H NMR (CDCl 3): 1.1 (d, 3H, J = 6 Hz); 1.2 (d, 3H, J = 6Hz); 2.6 (m, 1H); 5.1 (d, 1H, J = 10 Hz); 7.0 (s, 1H); 7.1-7.3 (m, 5H); 7.6 (d, 2H, J = 6Hz); 8.7 (d, 2H, J = 6Hz)
Example 13 (Compound No. 16) 4-nitro-3-phenyl-1- (pyridin-2-yl) pent-2-en-1-one oxime hydrochloride
4.44 g (15.7 mmol) of 4-nitro-3-phenyl-1- (pyridin-2-yl) pent-2-en-1-one dissolved in a mixture of 45 ml of chloroform and ml of methanol, 2.44 g (35.1 mmol) of hydroxylamine hydrochloride are added. The reaction medium is left stirring at room temperature for 48 hours, evaporated and the crude product is taken up in 30 ml of hydrochloride. chloroform: methanol (95: 5). The mixture is filtered and the residue is suspended in a mixture of 125 ml of chloroform and 25 ml of water. The pH of the aqueous phase is adjusted to 4-5 by addition of sodium bicarbonate, the organic phase is recovered, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol (95: 5) mixture.

1.69 g of product is obtained in base form.

Yield = 36%
Melting point = 115 OC (decomposition)
The hydrochloride is obtained by successive crystallizations of the crude product in a chloroform: methanol mixture and then in methanol.

850 mg of product is obtained in the form of a white powder.

Yield = 13%
Melting point = 160 OC (decomposition)
EXAMPLE 14 (Compound No. 17) 3- (4-Chlorophenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one oxime hydrochloride
The method described in Example 13 is used starting from a mixture of 3 g (21.6 mmol) of 3- (4-chlorophenyl) -4-nitrol- (pyridin-2-yl) pent-2-en 1-one and 1.5 g (21.6 mmol) of hydroxylamine hydrochloride in a mixture of 27 ml of chloroform and 13 ml of methanol.

The hydrochloride is prepared by successive crystallizations in a mixture of chloroform: methanol (95: 5).

0.25 g of product is obtained in the form of a white powder.

Yield = 7%
Melting point = 155 OC (decomposition)
Example 15 (Compound No. 18) 3- (4-Methoxyphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one oxime hydrochloride
A mixture of 1.67 g (5.35 mmol) of 3- (4-methoxyphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one is stirred for 3 days. one and 0.75 g (10.8 mmol) of hydroxylamine hydrochloride in 15 ml of chloroform and 7 ml of methanol. The process is continued according to the method of Example 13, filtered, evaporated and the residue purified by column chromatography on silica gel eluting with a mixture of dichloromethane: methanol (95: 5). It is acidified with 40 ml of 0.1 N hydrochloric acid solution in isopropanol and evaporated. A yellow solid is obtained which is triturated in ethyl acetate and filtered.

0.39 g of hydrochloride is obtained in the form of a white solid.

Yield = 20%
Melting point = 130 OC (decomposition)
Example 16 (Compound No. 19) 3- (4-methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one oxime hydrochloride
The product is prepared from 3.18 g (10.7 mmol) of 3- (4-methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one according to the method described in Example 13.

0.25 g of hydrochloride is obtained.

Yield = 9%
Melting point = 130 OC
Example 17 (compound No. 20) 3- (2-methylphenyl) -4-nitro-1- (pyridin-2-yl) pent-2-en-1-one oxime hydrochloride
The product is prepared in base form according to the method described in Example 13 from 2.61 g (5.8 mmol) of 3- (2-methylphenyl) -4-nitro-1- (pyridin-2) -yl) pent-2-en-1-one. By adding a solution of 0.1 N hydrochloric acid in isopopanol and evaporation, a white solid is obtained which is washed with chloroform and dried.

0.25 g of hydrochloride is obtained.

Yield = 8 t
Melting point = 155 ° C. EXAMPLE 18 (Compound No. 26) 5,5-Dimethyl-4-nitro-3-phenyl-1- (pyridin-2-yl) hex-2-en-1-one oxime
The product is prepared in base form according to the method described in Example 13 starting from 2 g (6.2 mmol) of 5,5-dimethyl-4-nitro-3-phenyl-1- (pyridin-2- yl) hex-2-en-1-one.

0.2 g of product is obtained in the form of a white powder.

Yield = 10%
Melting point = 158-160 C Table

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<tb> Table legend: in the column "Stereochemistry": "/" means that the product is in the form of a mixture of forms E and z.

 in the "Salt" column: "HCl" corresponds to the hydrochloride; the absence of any mention means that the compound is in base form.

in column "F (C)": "oil" means that the products have been characterized by their NMR spectrum. "dec" means fusion with decomposition.

The compounds of the invention have been the subject of pharmacological tests which have shown their importance as active substances in therapeutics.

Thus, these compounds have been studied for their relaxing activity on the isolated rabbit aorta.

The experimental protocol used is a variant of that used by Furchgott et al., 1980, Nature, 288, 373-376.

New Zealand male rabbits ESD with an average weight of 2.5 kg.

are sacrificed by cervical dislocation and exsanguination.

The thoracic aorta is removed quickly and the endothelium removed.

Aorta rings approximately 1 cm long were prepared and installed in 20 ml organ chambers containing oxygenated bicarbonate solution (pH 7.4) at 370 ° C. The tissue is connected to a TRI 110 isometric sensor (Letica) at a basal voltage of 2 g which is connected to an ISO 506 amplifier which allows the recording of voltage variations (Letica model 4006). The preparation is contracted by 3 MM phenylephrine and the relaxing effect of the compounds is measured by adding to the bath cumulative increasing concentrations of between 0.001 and 100 μM of the products to be tested.

At the end of the experiment, a supramaximal concentration of papaverine (100 μM) is added in order to determine the maximum possible relaxation of each preparation.

The absolute values (in grams) of the initial contraction after 3 MM phenylephrine and the contraction after the different cumulative concentrations of compounds are obtained, for each preparation, by difference with the minimum contraction observed 30 minutes after the final addition of 100 MN papaverine. The percentage decrease in contraction, relative to the contraction caused by 3 MN of phenylephrine is calculated for each compound concentration and each preparation. The average values obtained (weighted by the inverse of the standard error at the mean), are analyzed using a mathematical model of sigmoidal curve. The molar concentration is calculated, causing 50% relaxation of the response to the acetylcho line (CE) or its antilogarithm (pCE).

For the compounds of the invention the PUCES are of the order of 7.5 to 4.

The compounds of the invention have also been tested for inhibition of platelet aggregation of blood induced by ADP (adenosine-5'-diphosphate).

The assay is performed according to the method of Born (J. Physiol., (1963), 168, 178-195) on rabbit platelets. The blood is collected by cardiac puncture, and collected on trisodium citrate at 3.8% in the proportions of 1 volume of anti-coagulant solution for 9 volumes of blood. Centrifugation is then carried out at 150xg for 13 minutes, the platelet-rich plasma is removed and the platelets are counted.

The pellet is recentrifuged at 3600xg for 15 minutes to obtain platelet-poor plasma, and the platelet-rich plasma is diluted with platelet-poor plasma to obtain a suspension of 250000-300000. platelets per microliter.

In vitro aggregation is induced by means of ADP at a concentration of 10 M. The optical density variations are recorded by means of an aggregameter (300 ml of platelet-rich plasma per tank, 1100 rpm at 370 ° C.). until the maximum aggregation is exceeded.

For the tests, the compounds of the invention are dissolved in dimethylsulfoxide and incubated for 1 min at 370 ° C. prior to the addition of ADP.

The anti-aggregating action of the compounds is expressed by the Lashes, a concentration which inhibits by 50% the aggregation caused by ADP.

The IC50's of the compounds of the invention in this test are between 0.05 and 500 MM.

The compounds of the invention are vasodilators and behave as potential NO donors.

They can therefore be used for the treatment and / or prevention of stable and unstable angina, cardiac ischemia and heart failure.

For this purpose they may be presented in any suitable form for oral or parenteral administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions, etc. in combination with suitable excipients. They may also be presented in any form suitable for intradermal administration in combination with suitable excipients.

All these forms are dosed to allow administration of 10 to 30 mg, one to several times a day.

Claims (4)

claims 1. Compounds corresponding to formula (I)

 in which R1 represents a heterocycle chosen from pyridinyl, thiazole, quinoline and isoquinoline groups, R2 represents either an oxygen atom or a NOR 'group where R5 is a hydrogen atom or a (C2-C4) alkanoyl group, R3 represents either a (C-C4) alkyl group, a phenyl group, or a phenyl group substituted with one or more substituents selected from halogen atoms and (C1-C4) alkyl, (C1-C4) alkoxy groups and nitro, and R4 represents a straight or branched (C1-C4) alkyl group, with the exception of 3-ethyl-4-nitro-1- (pyridin-2-yl) pent-2-en-1-oxime as pure racemates or enantiomers and / or geometric isomers, as well as their addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds according to claim 1, characterized in that (diethoxyphosphinyl) methyl is reacted with a compound of formula (II)  R1CN (II) (wherein R1 is as defined in claim 1) in the presence of n-butyllithium in an aprotic solvent and then a compound of formula (III) is added

 (wherein R 3 and R 'are as defined in claim 1), heated to reflux temperature and a compound of formula (IV) is obtained

 that is treated with acetyl chloride in an aprotic solvent in the presence of a base to obtain a compound of formula (V)

 that it is treated with trifluoroacetic anhydride in the presence of a nitrating agent in an aprotic solvent and a compound of formula (Ia) is obtained which corresponds to formula (I) when R2 is an oxygen atom,

 (wherein R1, R3 and R4 are as defined in claim 1), then if desired the nitrocetone of formula (Ia) is treated with hydroxylamine hydrochloride to obtain a compound of formula (Ib)

 which corresponds to formula (I) in which R2 is a hydroxyimino group, which compound is optionally treated with a compound of formula  (R5) 2O where R5 is a (C2-C4) alkanoyl group, to obtain a compound of formula (Ic)

 which corresponds to formula (I) in which R2 is a group = NOR5 where R5 is a (C2-C4) alkanoyl group. 3. Medicinal product characterized in that it contains a compound according to claim 1. 4. A pharmaceutical composition characterized in that it contains a compound according to claim 1 in association with any pharmaceutically acceptable excipient.