HYDROXY PYRIMIDINE DERIVATIVES

DERIVES HYDROXYLES DE LA PYRIMIDINE

English Abstract

A B S T R A C T
Novel isopropylamino-pyrimidine derivatives of
the general formula:
<IMG>
wherein A4, A5 and A6 each stand for hydrogen or hydroxy
with the proviso that at least one is other than hydrogen
are useful in the field of nervous regeneration and the
treatment of muscular dystrophies.

Claims

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined
as follows:
1. The process for preparing a 2-isopropyl-
amino-pyrimidine derivative of the general formula:
<IMG>
wherein A4, A5 and A6 each stand for hydrogen or hydroxy
with the proviso that at least one of A4, A5 and A6 is
other than hydrogen, which comprises
A. reacting isopropylamine with a 2-thiomethyl-
pyrimidine of the formula:
<IMG>
wherein A4, A5 and A6 are as previously defined, the
reaction being carried out in a non-polar solvent at
a temperature of from about 100° to about 120°C; or
B. reacting a 2-isopropylamino-halogeno-pyrimidine of
the formula:
<IMG>
wherein A'4, A'5 and A'6 stand for hydrogen or halo-
gen, with the proviso that at least one of A'4, A'5
and A'6 is other than hydrogen, with a mineral base
in water at a temperature of from 100° to 150°C; or

C. hydrogenating a compound of the formula:
<IMG>
in the presence of a hydrogenation catalyst, A"4,
A"5 and A"6 stand for hydrogen, aralkyloxy or
alkyloxy with the proviso that at least one of A"4,
A"5 and A"6 is other than hydrogen.
2. Process for preparing 4-hydroxy-2-
isopropylamino-pyrimidine, which comprises reacting
methyl thiouracil with isopropylamine in a non-polar
solvent at a temperature of from 110-120°C.
3. Process for preparing 5-hydroxy-2-
thiomethyl-pyrimidine, which comprises reacting 5-
hydroxy-2-thiomethyl-pyrimidine with isopropylamine in
a non-polar solvent at a temperature of about 105°C.
4. Process for preparing 4,6-dihydroxy-2-
isopropylamino-pyrimidine, which comprises reacting 4,6-
dihydroxy-2-thiomethyl-pyrimidine with isopropylamine in
a non-polar solvent at a temperature of about 110°C.
5. Process for preparing 5-hydroxy-2-
isopropylamino-pyrimidine, which comprises reacting 2-
isopropylamino-5-bromo-pyrimidine with sodium hydroxide
in the presence of copper powder at a temperature of from
130 to 135°C.
6. Process for preparing 4-hydroxy-2-
isopropylamino-pyrimidine, which comprises reacting 2-
isopropylamino-4-chloro-pyrimidine with sodium hydroxide
in the presence of copper powder at a temperature of from
130 to 135°C.

7. Process for preparing 4,6-dihydroxy-2-
isopropylamino-pyrimidine, which comprises reacting 2-
isopropylamino-4,6-dichloro-pyrimidine with sodium
hydroxide in the presence of copper powder at a tempera-
ture of from 130 to 135°C.
8. Process for preparing 5-hydroxy-2-
isopropylamino-pyrimidine, which comprises hydrogenating
2-isopropylamino-5-benzyloxy-pyrimidine in the presence
of palladium catalyst.
9. Process for preparing 4-hydroxy-2-
isopropylamino-pyrimidine, which comprises hydrogenating
2-isopropylamino-4-ethoxy-pyrimidine in the presence of
palladium catalyst.
10. Process for preparing 4,6-dihydroxy-2-
isopropylamino-pyrimidine, which comprises hydrogenating
2-isopropylamino-4,6-dibenzyloxy-pyrimidine in the
presence of palladium catalyst.
11. A 2-isopropylamino-pyrimidine derivative of
the general formula:
<IMG>
wherein A4, A5 and A6 each stand for hydrogen or hydroxy
with the proviso that at least one of A4, A5 and A6 is
other than hydrogen, when prepared by the process defined
in Claim 1 or by an obvious chemical equivalent.
12. The 4-hydroxy-2-isopropylamino-pyrimidine,
when prepared by the process defined in Claims 2, 6 or 9
or by an obvious chemical equivalent.
11

13. The 5-hydroxy-2-isopropylamino-pyrimidine,
when prepared by the process defined in Claims 3, 5 or 8
or by an obvious chemical equivalent.
14. The 4,6-dihydroxy-2-isopropylamino-
pyrimidine, when prepared by the process defined in
Claims 4, 7 or 10 or by an obvious chemical equivalent.
12

Description

l~Z561
-- 1 --
The present invention relates to novel iso-
propylamino-pyrimidine derivatives having interesting
therapeutic activities.
More particularly, the compounds of the present
invention correspond to the following general formula:
~ /CH3
5 ~ />-- \
A6
wherein A4, A5 and A6 each stand for hydrogen or hydroxy
with the proviso that at least one of A4, A5 and A6 is
other than hydrogen.
The novel compounds have been found to be
useful in the field of nervous regeneration and for the
treatment of muscular dystrophies.
The compounds of the present invention may be
prepared by any of the following processes.
In one process, isopropylamine is reacted with
a 2-thiomethyl-pyrimidine of the general formula:
A4
~ N
5~ /~ 3
N
A6
wherein A4, A5 and A6 are as defined previously, the
reaction being carried out in a non-polar solvent at a
20 temperature of about 100 to about 120C.
In another process a 2-isopropylamino-halogeno-
pyrimidine is treated with a mineral base in water at 100
to 150C in the presence of copper in accordance with the
following reaction scheme:

~3'~
-- 2 --
~ N /CH3
wherein A'4, A'5 and A'6 stand for hydrogen or halogen,
with the proviso that at least one of A'4, A'5 and A'6
is other than hydrogen and A4, A5 and A6 are as defined
previously while M is an alkali or alkaline earth metal.
As an example of suitable metals there may be mentioned
sodium, potassium or calcium.
A further process comprises reducing a 2-
isopropylamino aralkyloxy or alkyloxy pyrimidine with
hydrogen under pressure and in the presence of a hydro-
genation catalyst such as palladium in accordance with
the following reaction scheme:
5 ~ /~ \ Pd 5 ~
CH3 N CH3
A"6 A6
wherein A"4, A"5 and A"6 stand for hydrogen, aralkyloxy
or alkyloxy with the proviso that at least one is other
than hydrogen and A4, A5 and A6 are as defined previ-
ously. The preferred aralkyloxy radical is benzyloxy
while the preferred alkyloxy is methoxy, ethoxy, propyl-
oxy and butoxy.
The present invention will be more readily
understood by referring to the following Examples which
are given to illustrate the invention.
EXAMPLE 1
4-hydroxy-2-isopropylamino-pyrimidine
The starting methyl thiouracil is obtained by
reacting methyl iodide with thiouracil in the presence of
sodium methanolate. The methyl thiouracil thus obtained

~32561
20 g. (0.14 mol) is placed in a one litre pressurized
reactor with 200 ml of dry toluene and 200 ml of iso-
propylamine. The reaction is carried on for 24 hours
under pressure, at 110-120C. The resulting mixture is
evaporated to dryness, treated with acetone and diethyl
ether (50/50), filtered, washed with water and recrystal-
lized in isopropyl acetate. There is thus obtained 17 g
(yield 84%) of a white crystalline product melting at
140C, the analysis of which shows a good correspondence
with the formula C7HllN3O. There is also prepared the
hydrochloride of this compound, melting point 233-234C
(Tottoli) which also is a white crystalline product; its
U.V. Spectrum data are:
In water (for hydrochloride) In methanol (for base)
: 266 nm El% = 210 ~ : 293 nm El% = 510
max lcm max lcm
~max : 217 nm lcm ~max : 222 nm lcm
~max 290 nm
The base is a white crystalline product
(molecular weight 153.18), insoluble in water but soluble
in chloroform.
EXAMPLE 2
5-hydroxy-2-isopropylamino-pyrimidine
The method of Example 1 was repeated but 5-
hydroxy-2-thiomethyl-pyrimidine was used. Yield 83%.
The temperature of reaction was 105 C. Melting point
161 C (Tottoli). U.V. Spectrum in water 60/methanol 40 :
~max : 341 nm lcm
max : 241 nm lcm

~3Z561
- 4
EXAMPLE 3
4,6-dihydroxy-2-isopropylamino-pyrimidine
The method of Example l was repeated but 4,6-
dihydroxy-2-thiomethyl-pyrimidine was used. Yield 67%.
Temperature of reaction 110C. Melting point 215-220 C,
with decomposition (Tottoli) for the hydrochloride of
formula C7HllN3O2, HCl. This is a white crystalllne
product insoluble in water at room temperature.
EXAMPLE 4
2-isopropylamino-5-hydroxy-pyrimidine
Into a one litre reactor were poured 80 ml of
- water, 3 g of sodium hydroxide, some copper powder and
4.3 g (0.02 mol) of 2-isopropylamino-5-bromo-pyrimidine;
the reaction mixture was maintained at 130 to 135C for
1 hour under stirring and then at 130 to 140C for about
12 hours, also under stirring.
After filtration off of the copper, the
reaction mixture was extracted twice with chloroform.
The combined extracts were acidified with acetic acid
to pH ~.5 to 7Ø The solution was then saturated with
sodium chloride causing precipitation of the product,
which was collected and washed with water and then with
pentane. The product was then taken up in diethyl ether
and treated with carbon black. The solution was concen-
trated, causing reprecipitation of the product which was
collected and recrystallized from water or from isopropyl
acetate. The crystals were dried to give 2.45 g (yield
80%) of 2-isopropylamino-5-hydroxy-pyrimidine. Ele-
mentary analysis showed the expected empirical formula
7 11 3
The 2-isopropylamino-5-bromo-pyrimidine start-
ing material had been readily obtained by reacting, in
stoichiometric proportions, 2-isopropylamino-pyrimidine
and N-bromo-succinimide in the presence of acetic acid
(yield 84%).

1~3~56~
-- 5
EXAMPLE 5
2-isopropylamino-4-hydroxy-pyrimidine
The method of Example 1 was repeated except
that 2-isopropylamino-4-chloro-pyrimidine was used
instead of 2-isopropylamino-5-bromo-pyrimidine. Yield
was 77% in a white crystalline product melting at 140C
(Tottoli), the analysis of which shows a perfect corre-
spondence with the formula C7HllN3O. Structural analysis
(U.V. Spectrum) confirms the position of the hydroxy
group.
EXAMPLE 6
2-isopropylamino-4,6-dihydroxy-pyrimidine
The method of Example 1 was repeated except
that 2-isopropylamino-4,6-dichloro-pyrimidine was used
instead of 2-isopropylamino-5-bromo-pyrimidine. ~ield
was 73% in a white crystalline product melting at 221-
225C (Tottoli) with decomposition, the analysis of which
shows a perfect correspondence with the formula C7HllO2,
HCl. Structural analysis (U.V. Spectrum) confirms the
position of the hydroxy groups.
EXAMPLE 7
2-isopropylamino-5-hydroxy-pyrimidine
In a pressurized reactor of 2 litre capacity,
preferably cleared by a nitrogen flow, were placed 0.8 g
of 2-isopropylamino-5-benzyloxy-pyrimidine, 40 ml of
methanol and 80 mg of palladium catalyst; hydrogenation
was performed for 2 hours at normal pressure. After
filtration off of the catalyst and evaporation off of the
methanol, the product was taken up in diethyl ether and
the solution was filtered to eliminate insoluble matter.
The diethyl ether was evaporated off and the product was
recrystallized first from water and then from ethyl
acetate. After drying, there was obtained 0.4 g (yield
80%) of 2-isopropylamino-5-hydroxy-pyrimidine. Ele-
mentary analysis showed the expected empirical formula
C7Hl1N3O. Melting point 161 C (Tottoli). U.V. Spectrum

~.,13~5~i~
confirms the structure.
EXAMPLE 8
2-isopropylamino-4-hydroxy-pyrimidine
The method as described in Example 1 was
applied to 2-isopropylamino-4-ethoxy-pyrimidine instead
of 2-isopropylamino-5-benzyloxy-pyrimidine. The yield
was 83~ in a white crystalline product melting at 140C
(Tottoli), the analysis of which confirms the perfect
correspondence with the formula C7HllN3O. U.V. Spectrum
confirms the structure.
EXAMPLE 9
2-isopropylamino-4,6-dihydroxy-pyrimidine
The method as described in Example 1 was
applied to 2-isopropylamino-4,6-dibenzyloxy-pyrimidine
instead of 2-isopropylamino-5-benzyloxy-pyrimidine. The
yield was 78~ in a white crystalline product (hydro-
chloride) melting at 218-221C (Tottoli), with decompo-
sition, the analysis of which confirms the perfect corre-
spondence with the formula C7HllN3O2, HCl. U.V.
Spectrum confirms the structure.
TOXICITY
The acute toxicity (mg/kg) of the compounds of
the invention was determined on mice i.p. and per os and
the values are reported in the following table:
Compound
Route ~ Ex. 1 Ex. 2 Ex. 3
i.p. 200 240 260
per os 205 355 285
PHARMACOLOGY
The pharmacological activity of the compound of
the invention has been researched by the following com-
parative experimentation undertaken on the regeneration
- 30 of the sciatic nerve of the male adult rat (Wistar).

1~L32561
A lesion is made on the sciatic nerve of the
rats by application of a thermosound at -20C for 20
minutes on the nerve. The rats are then treated i.p. by
the reference product or by the compounds of the in-
vention for a predetermined duration. At the end of the
treatment, the rats are killed, the sciatic nerves are
separated and placed in contact with a sery of 70 thin
parallel platinum wires (interval 1 mm) and an electric
signal applied upstream the lesion point is researched on
the platinum wires: the more distant wire where the
signal can be collected gives the regenerated length.
For each tested composition and each duration
of treatment, a batch of 8 rats is used.
Four compositions have been tested i.p.:
Example 1 compound, Example 2 compound, Example 3
compound, all at the i.p. dose of 10 mg/kg and, as a
reference, a mixture of vitamins Bl (500 mg/kg), B6
(500 mg/kg) and B12 (5 mg/kg) which is known in the art
to be the most effective composition in this field.
Controls received no treatment at all. Five batches of
8 animals were used for each duration (7, 11, 14, 17 and
21 days) either for controls or for compounds 1, 2, 3 or
reference mixture.
The results of this experimentation are summa-
rized in the following table together with the figures
obtained for control animals. The lengths of regenerated
nerves are indicated in mm. at the respective day columns
as an average value of the lengths measured for all the
animals of each batch. When no figure appears (17 and 21
days) this means that the regenerated length exceeded the
length of the taken sample.

~ ~25~;~
-- 8 --
Duration (days)
Compound and ~ 7 11 14 17 21
Controls 5.110 2 12.817.8 22.4
Example 1 . 6 614.1 26.3 _ _
10 mg/kg _ 6.814.4 26.1 _ _
Example 3 6 715.6 26.7 _
Bl, B6, B12 8 813 4 15 820 4 23 7
500 mg/kg, 500 mg/kg and 5mg/kg
PRESENTATION - POSOLOGY
These derivatives may be presented in any thera-
peutically acceptable form and, for instance, in tablets
or in gelatine capsules containing 5 mg per dosage unit
together with an excipient; for injectable form, the
product may be dosed in phials containing at least 1 mg
of active ingredient under the form of its hydrochloride
dissolved in water. As to the posology for human use,
oral administration requires from 20 mg to 1 g per diem
whereas injectable form may be administered at doses
between 1 mg to 50 mg per diem.
An example of the tablet form is given here-
under:
- Compound of any of the examples 5 mg
- Lactose 70 mg
- Talc 20 mg
- Magnesium stearate 5 mg
100 mg