LES 2,4-DIAMINO-5-BENZYLPYRIMIDINES, PROCEDE POUR LEUR PREPARATION ET PRODUITS PHARMACEUTIQUES QUI EN CONTIENNENT

2,4-DIAMINO-5-BENZYLPYRIMIDINES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS

Abrégé anglais

ABSTRACT OF THE DISCLOSURE
New 2,4-diamino-5-benzylpyrimidines, process
for their preparation and pharmaceutical compositions
containing these compounds.

Revendications

The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A process for the preparation of 2,4-diamino-5-
benzylpyrimidine of the general formula
<IMG> I
in which R represents an alkyl group having from 1 to 4 carbon
atoms or a halogen atom, said process being selected from the
group consisting of:
(A) by reaction of a 2,4-diamino-5-hydroxymethylpyrimidine of
the formula
<IMG> II
with a methoxyphenol of the formula
<IMG> III
wherein R is as defined above, and, if desired, con-
verting the compound of formula III into a pharma-
cologically acceptable acid addition salt;
(B) formylating a hydrocinnamic acid ester of the general
formula
<IMG> IV

wherein R has the meaning specified above and X represents
an alkyl group having from 1 to 4 carbon atoms, with ethyl
formate in the presence of sodium, condensing the compound
obtained with guanidine in an alkaline medium and reacting
the resulting 2-amino-4-hydroxy-5-(substituted benzyl)-
pyrimidine with phosphorus oxychloride, reacting the chlor-
ine compound obtained with ammonia and, if desired, conver-
ting the resulting compound into its pharmacologically
acceptable acid addition salt; or
(C) reacting a .beta.-amino-acrylonitrile of the formula
<IMG> V
in which R represents an alkyl group having from 1 to 4
carbon atoms or a halogen atom and R ' represents an aniline
group which may be substituted or a morpholine group, with
guanidine in alcoholic solution under conditions of heating
under reflux, distilling off the alcohol and heating to
boiling the product remaining behind after removal of the
alcohol, which product has the general formula
VI
<IMG>
in which R has the meaning specified above, in alcoholic
hydrochloric acid so that the methoxy methyl group is split
off and the product is converted into the desired 2,4-
diamino-5-benzylpyrimidine compound and, if desired, con-
verting the resulting compound into its pharmacologically
acceptable acid addition salt.

2. A process as defined in claim 1 wherein said process
is (A).
3. A process as defined in claim 1 wherein said process
is (B).
4. A process as defined in claim l wherein said process
is (C).
5. A process as defined in claim 2 wherein the reaction
is carried out in glacial acetic acid and in the presence of
concentrated hydrochloric acid.
6. A process as defined in claim 2 wherein R represents
a methyl or ethyl group.
7. A process as defined in claim 3 wherein R represents
a methyl or ethyl group.
8. A process as defined in claim 4 wherein R represents
a methyl or ethyl group.
9. A process as defined in claim 2 wherein R represents
a chlorine or bromine atom.
10. A process as defined in claim 3 wherein R represents
a chlorine or bromine atom.
11. A process as defined in claim 4 wherein R represents
a chlorine or bromine atom.
12. A 2,4-diamino-5-benzylpyrimidine of the general
formula
<IMG> I
11

in which R represents an alkyl group having from 1 to 4 carbon
atoms or a halogen atom, or a pharmacologically acceptable
acid addition salt thereof, whenever produced by the process
of claim 1, or an obvious chemical equivalent thereof.
13. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, wherein R represents a methyl or ethyl group, whenever
produced by the process of claim 6 or an obvious chemical
equivalent thereof.
14. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, wherein R represents a methyl or ethyl group, whenever
produced by the process of claim 7 or an obvious chemical
equivalent thereof.
15. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, wherein R represents a methyl or ethyl group, whenever
produced by the process of claim 8 or an obvious chemical
equivalent thereof.
16. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, wherein R represents a chlorine or bromine atom, whenever
produced by the process of claim 9 or an obvious chemical
equivalent thereof.
17. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, wherein R represents a chlorine or bromine atom, whenever
produced by the process of claim 10 or an obvious chemical
equivalent thereof.
18. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, wherein R represents a chlorine or bromine atom, whenever
produced by the process of claim 11 or an obvious chemical
equivalent thereof.
12

19. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, in the form of its addition salt with hydrochloric acid,
hydrobromic acid, sulphuric acid, acetic acid, tartaric acid,
fumaric acid, maleic acid or ascorbic acid, whenever produced
by the process of claim 2 or an obvious chemical equivalent
thereof.
20. A 2,4-diamino-5-benzylpyrimidine as defined in claim .
12, in the form of its addition salt with hydrochloric acid,
hydrobromic acid, sulphuric acid, acetic acid, tartaric acid,
fumaric acid, maleic acid or ascorbic acid, whenever produced
by the process of claim 3 or an obvious chemical equivalent
thereof.
21. A 2,4-diamino-5-benzylpyrimidine as defined in claim
12, in the form of its addition salt with hydrochloric acid,
hydrobromic acid, sulphuric acid, acetic acid, tartaric acid,
fumaric acid, maleic acid or ascorbic acid, whenever produced
by the process of claim 4 or an obvious chemical equivalent
thereof.
13

Description

~55~9~
This invention relates to new benzylpyrimidines,
to a process for their preparation and to pharmaceutical
compositions containing them.
In particular, the invention relates to new 2,4-
diamino-5-benzylpyrimidines of the general formula
R
~ C~2 ~ ~ I
32N1N; J OC33
in which R represents an alkyl group having from 1 to 4 carbon
atoms or a halogen atom, and to their pharmacologically
acceptable acid addition salts.
The invention also relates to a process for the
preparation of such 2,4-diamino-5-benzylpyrimidines and their
salts, in which 2,4-diamino-5-hydroxymethylpyrimidine of the
formula
NH2
~ f H2-OH
~ N ~ II
H2N
is reacted with a methoxyphenol of the yeneral formula
OH
R ~ OCH3
- 2 -

~(~55a~
in which R represents an alkyl yroup haying from 1 to 4
carbon atoms or a halogen atom, and, if desired, the resulting
compound is converted into a pharmacologically acceptable acid
addition salt.
In a preferred embodiment of the invention, the
reaction is carried out by heating in glacial acetic acid in
the presence of concentrated hydrochloric acid. A reaction
of this kind has been described, for example, in German
Offenlegungsschrift No. 2,249,532.
The invention further provides a process for the
preparation of such 2,4-diamino-5-benzylpyrimidines, in which
a hydrocinnamic acid ester of the general formula
R
3 2 ~ ~3 C~2 CH2 C 0 X IV
CH30
' .' .
in which R represcnts an alkyl group having from 1 to 4 carbon
atoms or a halogcn atom and X represents an alkyl group having
from 1 to 4 carbon atoms is formylated with ethyl formate in
the presence of sodium, the compound obtained is condensed with
guanidine in an alkaline medium and the resulting 2-amino-4-
hydroxy~5-(substituted henzyl)-pyrimidine is reacted with
phosphorus oxychloride and the chlorine compound thereby
obtained is reacted with a~nonia and, if desired, the resulting
compound is converted into its pharmacologically acceptable
acid addition salt.
The invention also relates to a proc~ss for the
preparation of such 2,4-diamino-5-benzylpyrimidine5 in which a
~-am.inoacrylonitrile of the formula
. -.
.

~s~
CH3-0-CH2 0 _ ~ CIM V
CH30
in which R represents an alkyl group having from 1 to ~ carbon
atoms or a halogen atom and R' represents an aniline group
which may be substituted or a morpholine group; is reacted
~ith guanidine in alcoholic solution under conditions of
heating under refluxl the alcoho] is distilled off and the
product left behind after removal of the alcohol, which has the
general formula
N ~ C ~ ~ O-C~I -OC~ VI
~ M~J OCH3
in which R has the meaning already specified, ls heated to
boiling in alcoholic hydrochloric acid so tha-t the methoxy
methyl group is split off, the compound is converted into the
desired 2,4-diamino-5-benzylpyrimidine compound and, if desired,
this compound is then converted into a pharmacologically
acceptable acid addition salt.
In the ye~e~al formula (I), the subs-tituent R repre-
sents a straight or branched chain alkyl group having from 1
to 4 carbon atoms, e.g. a methyl, ethyl, M-propyl, isopropyl,
n-butyl or isobutyl group. Cornpounds in which R is a methyl
or ethyl group are preferred. X represents a halogen atom,

1135S4~
e.g. a chlorine, bromine or iod~ne atom. Compounds in which
represents a chlorine or bromine atom are preferred.
The compounds according to the invention, represented
by the general formula (I), and their salts, are new compounds.
Specific examples of pharmacologically acceptable acid
addition salts include the salts of the compounds with hydro-
chloric acid, hydrobromic acid, sulphuric acid, acetic acid,
tartaric acid, fumaric acid, maleic acid and ascorbic acid.
The compounds according to the invention have a good
antibacterial action which is comparable to and in part
superior to that of the known compound, 2,4-diamino-5-(3',4',5'-
trimethoxybenzyl)-pyrimidine which is also known as trimethoprim.
Their toxicity, however, is considerably lower than that of
trimethoprim so that the compounds according to the invention
have a better therapeutic quotient, i.e. a wider therapeutic
range.
The antibacterial activity can be further improved
by combining the compounds according to the invention with
sulphonamides, e.g. sulphadiazine, sulphadiamidine, sulpha-
methoxazole, sulphaquinoxaline, sulphadinemethoazine, sulpho-
merazine and sulphamethoxydiazine.
The invention therefore also relates to a pharma-
ceutical composition which, in addition to the usual auxiliary
substances and excipi.ents, contains at least one of the com-
pounds of the general formula (I).
For application in the dry form, the following combin-
ations may be used as excipients: Cellulose, dextrose, corn
starch, saccharose, talcum, magnesium stearate, calcium hydro-
gen phosphate, lactose~ gelatine and polyvinyl pyrrolidine.
Suitable auxiliary agents for application in the liquid form
include, for example, solutions or suspensions of carboxymethyl-

1~554~
cellulose, cellulose, sorbitol, saccharose, caramel and
flavourings in water. For parenteral administration, compounds
of the formula (I) are suitable in the form of buffer solutions.
The invention will be further described with the aid
of the following Examples.
EXAMPLE 1
.
Preparation of 2,4-dlamino-5-(3'-methoxy-4'-h~rdroxy-
5'-methyl-benzyl)-pyrimidine and its hydrochloride
-
51.0 g (0.36 mol) of 2,4-diamino-5-hydroxymethyl-pyrimidine
and 49.4 g (0.36 mol) of 2~methyl-6-methoxy-phenol in 3.5 1 of
glacial acetic acid and 110 ml of concentrated hydrochloric
acid were heated to 100C for 5 hours in a 5 1 flask. A
precipitate which formed in the ~rly stages of the reaction
slowly dissolved. At the end of the reaction time, the acetic
acid and hydrochloric acid were distilled off except for a
residual volume of about 250 ml, 300 ml of water were added to
the residue and the solution was extracted twice with 150 ml
portions of chloroform. The aqueous phase was then evaporated
to dryness under vacuum and the residue was stirred up with
about 200 ml of acetone until a homogeneous suspension was
obtained. The precipitate was suction filtered, washed with
a small ~uantity of acetone and dried at 100C.
Crude yield: 85.3 g.
The salt was dissolved in hot water by conversion of the
hydrochloride into the base, and the solution was carefully
neutralized with saturated sodium bicarbonate solution with
stirring. The greasy precipitate first formed was filtered off
and a further quantity of sodium bicarbonate solution was added
to the filtrate. The precipitated base was then recrystallized
from 20 to 30% aqueous alcohol.
Melting point: 189 to 193C.
- 6 -

4~8
The hydrochloride melted at 241 to 243C.
13 17 4 2
Calculated:
C 50.98% H 5.35% Cl 12.54% N 19.82% O 11.32%
Found:
C 51.11% H 5.45% Cl 13.51% N 19.46% O 10.84%
EXAMPLE 2
Preparation of 2,4-diamino-5-(3'-bromo-4'-hydroxy-
5'-methoxy-benzyl)-pyrimidine
62.2 g of 3-bromo-4-methyl-dihydroxymethylene-5-methoxy-
ben~aldehyde, 37.8 g oE anilinopropionitrile, 45 ml of dimethyl-
sulphoxide and 110 ml of tert.-butanol were introduced into a
500 ml flask and heated until completely dissolved. When the
solution had cooled to 10 C, 19.4 g of potassium tert.-butylate
were added portionwise at such a rate that the reaction temper-
ature did not rise above 25C. When all the potassium tert.-
butylate had been added, the reaction mixture was heated to
40-50C for 5 hours and the tert.-butanol and dimethylsulphoxide
were then distilled o~f under vacuum. The residue was taken
up with 300 ml of methylene chloride and the methylene chloride
layer was washed with water, dehydrated over sodium sulphate
and evaporated to dryness.
The crude yield was: 28.2 g.
This quantity was heated to boiling together with 41 g of
guanidine hydrochloride in 440 ml of ethanol. To the resulting
solution were added dropwise 69.4 ml of a 30% sodium methylate
solution over a period of 40 minutes and the mixture was then
kept at boiling point for a further 6 hours. The sodium
chloride precipitate was filtered off and the alcohol was
distilled off. The oil left behind was taken up with a mixture
of 50 ml of ethanol and 150 ml of water and acidi~ied to pH 1

1(35S~
with concentrated hydrochloric acid. The solution was gently
heated to boiling and, after removal of undissolved consti-
tuents, the solution was made alkaline with ammonia. The
precipitate obtained was suction filtered and recrystallized
from ethanol.
The melting point was 229C.
C12H13N4 O2Br
Calculated:
C 44,32% H 5.03% Br 24.57% N 17.23% O 9.84%
Found:
C 44.39% H 4.37% Br 25.03% N 16.70% O 9.53%.