Compounds of the formula ##STR1## IN WHICH R is aminocarbonylphenyl in which amino is --NH.sub.2, pyrrolidino, piperidino or morpholino, and Ar is phenyl substituted with chloro, fluoro, trifluoromethyl, methylenedioxy or one or more methoxy. The compounds are prepared by reacting 2-Ar-4-chloropyrimidin-6-yl ethylacetate with ##STR2## and then reacting that reaction product with hydroxylamine hydrochloride. The compounds possess vasodilatatory, anti-ulcerous, respiratory analeptic, hypotensive, diuretic, anti-depressive, analgesic, anti-inflammatory and neurotropic properties.

Our U.S. Ser. No. 299,672, filed Oct. 24, 1972, now U.S. Pat. No. 
3,876,636, issued Apr. 8, 1975 discloses pyrimidin-6-yl acethydroxamic 
acids, corresponding to the general formula Io 
##STR3## 
IN WHICH: 
R.sub.1 and R.sub.2 are each alkyl radicals having 1 to 3 carbon atoms or 
form, together with the nitrogen atom to which they are attached, a 
heterocyclic radical selected from the radicals: pyrrolidino, piperldino, 
hexamethyleneimino and morpholino, and 
Ar.sub.1 represents a phenyl radical which may be mono or polysubstituted, 
by a halogen atom selected from fluorine, chlorine and bromine, by a 
methoxy or a methylcarbonyloxy radical, by a CF.sub.3 residue or by a 
methylenedioxy radical. 
The present addition concerns compounds of the same type, corresponding to 
the formula I: 
##STR4## 
in which: 
R represents an aminocarbonylphenyl radical, in which the amino group may 
be primary or tertiary and carrying, in the latter case, a heterocyclic 
radical selected from the following: pyrrolidino, piperidino and 
morpholino; and 
Ar represents a phenyl ring substituted by a halogen atom selected from 
chlorine and fluorine, by a trifluoromethyl group, by a methylenedioxy 
radical or by one or more methoxy groups. 
The process according to the invention consists in reacting an acetic ester 
of formula II: 
##STR5## 
with hydroxylamine hydrochloride of formula III: 
EQU NH.sub.2 OH, HCl (III) 
r and Ar having in formula II, the same significance as in formula I. 
The reaction is effected in a methanolic medium, at the reflux temperature 
of methanol, and in the presence of sodium methylate. 
The acetic esters of formula II are obtained by condensation of a 
derivative of (4-chloro-pyrimidin-6-yl) ethyl acetate of formula IV: 
##STR6## 
with an amine of formula V: 
##STR7## 
R and Ar having in these formulas the same significance as in formula (I). 
The condensation is conducted in an acetic acid medium at 80.degree. - 
90.degree. C and in the presence of concentrated hydrochloric acid.

The following preparation is given by way of example to illustrate the 
invention. 
EXAMPLE: 
[(2-p-chlorophenyl 4-p-aminocarbonylanilino) pyrimidin-6-yl] acethydroxamic 
acid. 
Code No. 72 553 
1st Stage: [(2-p-chlorophenyl-4-p-aminocarbonyl anilino) pyrimidin-6-yl] 
ethyl acetate. 
Code No. 72 333 
A solution of 93.5g (0.3 mol) of (2-p-chlorophenyl-4-chloro) pyrimidin-6-yl 
ethyl acetate, 40.8g (0.3 mol) of p-aminocarbonyl aniline and 1.5 c.c. of 
concentrated hydrochloric acid in 600 c.c. of acetic acid, is heated for 
one hour at 90.degree. C. The solution is then diluted with 2 l of water 
and alkalinised with concentrated ammonia. The product is filtered and 
recrystallized from 2 l of methanol. 
83 g. of product are recovered, which corresponds to a yield of 68%. 
Empirical formula: C.sub.21 H.sub.19 Cl N.sub.4 O.sub.3 
______________________________________ 
Elementary analysis: 
C H N 
______________________________________ 
Calculated % 
61.39 4.66 13.64 
Found % 61.37 4.76 13.47 
______________________________________ 
2nd Stage: [(2-p-chlorophenyl-4-p-aminocarbonyl anilino) pyrimidin-6-yl] 
acethydroxamic acid. 
Code No. 72 553 
A solution of 10.4g (0.15 mol) of hydroxylamine hydrochloride in 150 c.c. 
of methanol is added to a solution of 6.9g. of sodium in 200 c.c. of 
methanol. The mixture is left for 30 minutes, and then the salt formed is 
filtered off. 61.5g. (0.15 mol) of the ester obtained in the preceding 
stage is added to the filtrate and the suspension formed is heated under 
reflux for 21/2 hours. The mixture is then diluted with 1 l of water and 
acidified just to a pH of about 3 with concentrated hydrochloric acid and 
returned to neutrality by adding a solution of sodium bicarbonate. The 
product is filtered and recrystallized from 400 c.c. of 90% alcohol. 
11 g of product is obtained, which corresponds to a yield of 20%. 
Empirical formula: C.sub.19 H.sub.16 Cl N.sub.5 O.sub.3 
______________________________________ 
Elementary analysis: 
C H N 
______________________________________ 
Calculated % 
57.36 4.05 17.61 
Found % 57.19 4.14 17.44 
______________________________________ 
The compounds listed in the following Tables I and II have been prepared 
according to the mode of operation of the first and second stages of the 
Example, respectively. 
TABLE I 
__________________________________________________________________________ 
##STR8## 
Melt- 
Molec- 
ing 
Code Empirical 
ular 
Point 
Yield 
Elementary Analysis 
No. Ar R Formula Weight 
(.degree. C) 
(%) C H N 
__________________________________________________________________________ 
72 242 
##STR9## 
##STR10## C.sub.21 H.sub.19 ClN.sub.4 O.sub.3 
410.85 
218 83 Calc. % Found 
61.39 61.31 
4.66 4.54 
13.64 13.83 
72 223 
##STR11## 
##STR12## C.sub.25 H.sub.25 ClN.sub.4 O.sub.3 
464.94 
209 64 Calc. % Found 
64.58 64.59 
5.42 5.55 
12.05 11.91 
72 244 
##STR13## 
##STR14## C.sub.25 H.sub.25 ClN.sub.4 O.sub.4 
480.94 
204 58 Calc. % Found 
62.43 62.40 
5.24 5.33 
11.65 11.43 
72 232 
##STR15## 
##STR16## C.sub.25 H.sub.27 ClN.sub.4 O.sub.3 
478.96 
185 61 Calc. % Found 
65.19 65.23 
5.68 5.90 
11.70 11.77 
72 369 
##STR17## 
##STR18## C.sub.21 H.sub.19 ClN.sub.4 O.sub.3 
410.85 
179 53 Calc. % Found 
61.39 61.59 
4.66 4.74 
13.64 13.56 
72 699 
##STR19## 
##STR20## C.sub.21 H.sub.19 FN.sub.4 O.sub.3 
394.39 
166 56 Calc. % Found 
63.95 64.06 
4.86 4.67 
14.21 14.30 
72 735 
##STR21## 
##STR22## C.sub.22 H.sub.19 F.sub.3 N.sub.4 O.sub.3 
444.40 
180 63 Calc. % Found 
59.45 59.42 
4.31 4.35 
12.61 12.42 
72 746 
##STR23## 
##STR24## C.sub.22 H.sub.19 F.sub.3 N.sub.4 O.sub.3 
444.40 
191 56 Calc. % Found 
59.45 59.25 
4.31 4.44 
12.61 12.55 
72 728 
##STR25## 
##STR26## C.sub.26 H.sub.25 F.sub.3 N.sub.4 
498.493 
204 63 Calc. % Found 
62.64 62.70 
5.06 5.25 
11.24 11.08 
72 193 
##STR27## 
##STR28## C.sub.26 H.sub.25 F.sub.3 N.sub.4 O.sub.4 
514.49 
188 44 Calc. % Found 
60.69 60.63 
4.90 4.95 
10.89 10.93 
72 729 
##STR29## 
##STR30## C.sub.27 H.sub.27 F.sub.3 N.sub.4 O.sub.3 
512.52 
181 58 Calc. % Found 
63.27 63.23 
5.31 5.35 
10.93 11.07 
72 567 
##STR31## 
##STR32## C.sub.24 H.sub.26 N.sub.4 O.sub.6 
466.48 
164 66 Calc. % Found 
61.79 61.71 
5.62 5.75 
12.01 11.83 
72 566 
##STR33## 
##STR34## C.sub.24 H.sub.25 N.sub.4 O.sub.6 
466.48 
238 38 Calc. % Found 
61.79 61.72 
5.62 5.76 
12.01 11.97 
72 587 
##STR35## 
##STR36## C.sub.28 H.sub.32 N.sub.4 O.sub.7 
536.57 
200 80 Calc. % Found 
62.67 62.70 
6.01 6.04 
10.44 10.39 
72 586 
##STR37## 
##STR38## C.sub.29 H.sub.34 N.sub.4 O.sub.6 
534.57 
160 65 Calc. % Found 
65.16 65.06 
6.41 6.44 
10.48 10.45 
730030 
##STR39## 
##STR40## C.sub.22 H.sub.20 N.sub.4 O.sub.5 
420.41 
178 80 Calc. % Found 
62.85 62.66 
4.80 4.98 
13.33 13.13 
730055 
##STR41## 
##STR42## C.sub.26 H.sub.26 N.sub.4 O.sub.6 
490.49 
179 17 Calc. % Found 
63.66 63.55 
5.34 5.42 
11.42 
__________________________________________________________________________ 
11.22 
TABLE II 
__________________________________________________________________________ 
##STR43## 
Melt- 
Molec- 
ing 
Code Empirical 
ular 
point 
Yield 
Elementary analysis 
No. Ar R form formula weight 
(.degree. C) 
(%) C H N 
__________________________________________________________________________ 
72 583 
##STR44## 
##STR45## base C.sub.19 H.sub.16 ClN.sub.5 O.sub.3 
397.81 
260 37 Calc. % Found 
57.36 57.45 
4.05 4.25 
17.61 17.41 
72 319 
##STR46## 
##STR47## base C.sub.25 H.sub.22 ClN.sub. 
451.90b.3 
203 20 Calc. % Found 
61.13 60.98 
4.91 5.20 
15.50 15.33 
72 308 
##STR48## 
##STR49## base C.sub.24 H.sub.24 Cl N.sub.5 O.sub.3 
465.93 
220 30 Calc. % Found 
61.86 61.86 
5.12 5.24 
15.03 14.87 
72 506 
##STR50## 
##STR51## base C.sub.19 H.sub.16 Cl N.sub.5 O.sub.3 
397.81 
230 42 Calc. % Found 
57.36 57.52 
4.05 4.18 
17.61 17.45 
72 595 
##STR52## 
##STR53## hydro- chloride 
C.sub.23 H.sub.23 Cl.sub.2 N.sub.5 O.sub.3 
488.37 
210 29 Calc. % Found 
56.56 56.77 
4.75 4.72 
14.34 14.15 
72 262 
##STR54## 
##STR55## base C.sub.23 H.sub.22 Cl N.sub.5 O.sub.4 
467.90 
210 30 Calc. % Found 
59.04 58.84 
4.74 4.84 
14.97 14.83 
72 722 
##STR56## 
##STR57## base C.sub.19 H.sub.16 F N.sub.5 O.sub.3 
381.36 
237 52 Calc. % Found 
59.84 59.71 
4.23 4.30 
18.37 18.31 
72 837 
##STR58## 
##STR59## base C.sub.20 H.sub.16 F.sub.3 N.sub.5 O.sub.3 
431.37 
224 71 Calc. % Found 
55.68 55.56 
3.74 3.91 
16.24 16.09 
72 836 
##STR60## 
##STR61## base C.sub.20 H.sub.16 F.sub.3 N.sub.5 O.sub.3 
431.37 
210 64 Calc. % Found 
55.63 55.86 
3.74 3.92 
16.24 16.08 
72 753 
##STR62## 
##STR63## base C.sub.24 H.sub.22 F.sub.3 N.sub.5 O.sub.3 
485.46 
145 49 Calc. % Found 
59.38 59.20 
4.57 4.66 
14.43 14.33 
730022 
##STR64## 
##STR65## base C.sub.25 H.sub.24 F.sub.3 N.sub.5 O.sub.3 
499.48 
150 6 Calc. % Found 
60.11 60.41 
4.84 5.27 
14.02 14.14 
72 795 
##STR66## 
##STR67## base C.sub.24 H.sub.22 F.sub.3 N.sub. 
501.46b.4 
160 7 Calc. % Found 
57.48 57.57 
4.42 4.54 
13.97 13.82 
72 601 
##STR68## 
##STR69## base C.sub.22 H.sub.23 N.sub.5 O.sub.6 
453.44 
222 31 Calc. % Found 
58.27 58.48 
5.11 5.11 
15.45 15.27 
72 791 
##STR70## 
##STR71## base C.sub.22 H.sub.23 N.sub.5 O.sub.6 
453.44 
210 17 Calc. % Found 
58.27 58.07 
5.11 5.31 
15.43 15.34 
72 635 
##STR72## 
##STR73## base C.sub.26 H.sub.29 N.sub.5 O.sub.7 
523.53 
198 44 Calc. % Found 
59.64 59.44 
5.58 5.51 
13.38 13.20 
72 629 
##STR74## 
##STR75## base C.sub.27 H.sub.31 N.sub.5 O.sub.6 
521.56 
179 28 Calc. % Found 
62.17 62.37 
5.99 5.87 
13.43 13.30 
730056 
##STR76## 
##STR77## Hydro- chloride 
C.sub.20 H.sub.18 Cl N.sub.5 O.sub.5 
443.84 
200 30 Calc. % Found 
54.12 53.92 
4.09 4.28 
15.78 15.98 
730192 
##STR78## 
##STR79## Hydro- chloride 
C.sub.24 H.sub.24 Cl N.sub.5 O.sub.6 
513.93 
260 22 Calc. % Found 
56.09 56.28 
4.51 4.69 
13.62 
__________________________________________________________________________ 
13.69 
The compounds of formula (I) have been tested on animals in the laboratory 
and have been shown to possess vasodilatatory, anti-ulcerous, respiratory 
analeptic, hypotensive, diuretic, antidepressive, analgesic, 
anti-inflammatory and neurotropic properties. 
1. Vasodilatatory properties. 
The compounds of formula I are capable of augmenting the flow of the 
coronary vessels of the isolated heart of a guinea-pig, when said 
compounds are added in the perfusion liquid of said organ. 
By way of example, the following Table III lists the percentage 
augmentation of the flow of the isolated heart of a guinea-pig, obtained 
by the addition of certain compounds of formula I, in a concentration of 1 
.mu.g/ml, in the perfusion liquid. 
TABLE III 
______________________________________ 
Percentage augmentation 
Code No. of of flow of isolated heart 
Compound tested 
of guinea-pig (%) 
______________________________________ 
72 753 70 
72 601 140 
730056 50 
730192 160 
72 791 82 
______________________________________ 
2. Anti-ulcerous properties. 
The compounds of formula I, administered by intraduodenal means, reduce the 
extent of ulceration provoked by tying of the pylorus of a rat (Shay 
ulcers). 
Thus, the compound of Code No. 72 722, administered by intraduodenal means, 
in a dose of 50 mg/Kg, provokes a reduction of Shay ulcers by 50%. 
3. Respiratory analeptic properties. 
The compounds of formula (I), administered by intraveinous or intraduodenal 
means to an anaesthetised guinea-pig, are capable of opposing the 
respiratory depression provoked by morphine. 
By way of example, following the administration of 100 mg/Kg/i.d. of the 
compound of Code No. 72 262, there is observed in the anaesthetised 
guinea-pig a percentage augmentation of 140% in the amplitude of the 
respiratory movements. 
As well, the administration of the compounds of Code No. 72 791 provokes, 
under the same conditions, an augmentation of 25% in the respiratory 
frequency and of 55% in the amplitude of the respiratory movements. 
Finally, following the administration of 100 mg/Kg/i.d. of the compound of 
Code No. 72 629, there is observed, in the anaesthetised guinea-pig, a 
percentage augmentation of 100% in the amplitude of the respiratory 
movements. 
4. Hypotensive properties. 
Administered by intraveinous means to the anaesthetised rat, the compounds 
of formula (I), provoke a lowering of the arterial pressure. 
By way of example, the following Table (IV) lists the results obtained 
following the administration of 2mg/Kg/i.v. of different compounds of 
formula (I). 
TABLE IV 
______________________________________ 
Percentage diminution 
Code No. of of arterial pressure 
Duration of 
compound tested 
(%) effect (mn) 
______________________________________ 
72 262 .congruent.35 30 
730 192 .congruent.60 50 
72 629 .congruent.70 45 
72 795 .congruent.35 20 
______________________________________ 
5. Diuretic properties. 
The compounds of formula (I), administered by oral means to the mouse, 
simultaneously with a volume of 1 ml of an isotonic solution of sodium 
chloride per 25 g. of the corporeal weight of the mouse, are capable of 
provoking an augmentation of the volume of urine emitted by reference to 
control animals, the volume being measured for 6 hours following 
administration. 
Thus, the administration of 25 mg/Kg/p.o. of the compounds of Code Nos. 72 
308 and 72 319, produced an augmentation of urinary elimination of 60 and 
70%, respectively. 
6. Anti-depressive properties. 
The compounds of formula (I) preventatively administered by oral means to 
the mouse, are capable of opposing the ptosis provoked by the injection of 
reserpine. 
Thus, following the administration of 100 mg/Kg/p.o. of the compound of 
Code No. 730 192, there is observed, in the mouse, a reduction of 55% in 
the ptosis provoked by the injection of reserpine. 
7. Analgesic properties. 
The compounds of formula (I) administered by oral means to the mouse, are 
capable of reducing the number of painful stretchings caused by the 
intraperitoneal injection of phenylbenzoquinone. 
Thus, following the oral administration of 100 mg/Kg of the compounds of 
Code No. 72 635, there is observed a percentage diminution of 50% in the 
number of painful stretchings caused by the intraperitoneal injection of 
phenylbenzoquinone. 
8. Anti-inflammatory properties. 
These properties are shown by a diminution of the local oedema provoked in 
a rat by the sub-plantar injection of a phlogogenic agent, such as 
carraghenine, following the oral administration of the compounds of 
formula (I). 
Thus, following the administration of the compound of Code No. 72 791, in a 
dose of 100 mg/Kg/p.o. there is observed a percentage diminution of the 
sub-plantar oedema of 65%. 
9. Neurotropic properties. 
a. Inhibitory action of monoamine oxidase: 
The compounds of formula I, administered by oral means to the mouse 
pre-treated by an inhibitory substance of monoamine oxidase (I.M.A.O.), 
potentialising 5-hydroxytryptophane, tryptamine and DOPA 
(.beta.-(3,4dihydroxyphenyl)-.alpha.-alanine). -.beta.- alanine). 
Thus, the DE 50 of the compound of Code No. 72 553, in the potentialisation 
of 5-hydroxytryptophane, of tryptamine and that of DOPA, are respectively 
24 mg/Kg/p.o., 35 mg/Kg/p.o. and 65 mg/Kg/p.o. 
b. Antianoxic action. 
This activity has been researched in the mouse in the oxyprive anoxia test 
and in the rat in the cortical electric silence (S.E.C.) test. 
Oxyprive anoxia test on the mouse. 
Injected by intraduodenal means, the compounds of formula I augment the 
survival time of mice placed in an enclosure short of oxygen. 
By way of example, the administration of 100 mg/Kg/i.p. of the compound of 
Code No. 72 553 produced an augmentation of 54% of the survival time of 
mice placed in an enclosure short of oxygen. 
Cortical electric silence test. 
The compounds of formula I, injected by intraperitoneal means to an 
anaesthetised and curarised rat, placed under artificial respiration and 
subjected to anoxia with nitrogen, augmented the delay in appearance of 
the cortical electric silence. 
Thus, there is observed a significant delay in the appearance of the S.E.C. 
following the administration of 100 mg/Kg/i.p. of the compound of Code No. 
72 553 and a diminution in the recuperation time of cortical 
electrogenesis following the administration of a dose of 25 mg/Kg/i.p. 
Amnesia tests provoked by oxyprive anoxia or by maximal electric shock. 
Administered by intraperitoneal means, the compounds of formula I protect a 
rat subjected to a passive shunning test (box with two compartments of 
GIURGEA) from the amnesia effects of oxyprive anoxia or an electric shock. 
By way of example, the administration of 100 mg/Kg/i.p. of the compound of 
Code No. 72 553 protected the rat against amnesia provoked by anoxia and 
by electric shock by 86 and 80% respectively. 
This being, it may be remarked, that the compounds according to the 
invention possess original properties in relation to those of the 
compounds of formula (Io) described in the above-referenced application. 
In effect, whilst the compounds of formula (Io) show essentially analgesic 
and anti-inflammatory properties and are deprived of cardiovascular and 
neurotropic activities, the compounds of the present invention possess 
vasodilatatory properties (augmentation of the flow of the coronary 
vessels of the isolated heart of a guinea-pig) and hypotensive properties 
(lowering of the arterial pressure of an anaesthetised rat) as well as 
interesting neurotropic properties since, as indicated above, they 
exercise a potentialisation action on 5-hydroxytryptophane, on tryptamine 
and on DOPA on the mouse pre-treated with I.M.A.O., manifest an antianoxic 
activity and are active in a memory test. 
Furthermore the compounds of formula I have litle toxicity, in that there 
is not observed a single case of mortality following the administration of 
2000 mg/Kg/p.o. of the above-described compounds. 
It has resulted that, for the compounds of formula I, the difference 
between the pharmacologically active doses listed above and the lethal 
doses is sufficiently great to permit the application of these derivatives 
in therapeutics. 
The compounds of formula I are useful in the treatment of circulatory 
insufficiencies, gastro-duodenal ulcers, respiratory insufficiencies, 
hypertensions, oedemas, depressions, diverse originating pains, painful 
inflammations and cerebral deficits. 
They may be administered by oral means in the form of tablets, sugar-coated 
pills or gelules containing 50 to 400 mg. of active ingredient (1 to 6 a 
day), in the form of drops containing 0.5 to 5% of active ingredient (20 
to 60 drops - 1 to 3 times a day), by parenteral means in the form of 
injectable ampoules containing 10 to 250 mg. of active ingredient (1 to 3 
a day) or by rectal means in the form of suppositories containing 25 to 
200 mg. of active ingredient (1 to 3 a day). 
Accordingly, the present invention also comprises a therapeutic composition 
comprising a compound of the general formula I, together with a 
therapeutically acceptable carrier.