CA1079731A - 2,4-diamino-pyrimidine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of the formula (II):

Description

10~9731 The present invention relates to pyrimidine deriYatives, their preparation and composition~ containing them.
United States Patent No. 3t723,429 discloses inter alia that compounds of the formula (I):

H2N ~ ~2 (I) B - O - A ~ X N
CH3 C~3 wherein A i8 a divalent aliphatic group and ~ i~ an optionally -sub~tituted hydrocarbon group have antimicrobial activity. Such compounds are not particularly well di~tributed in the body after oral admini~tration to mammal~ and ~o it would be of advantage if a olaa~
of compounds of similar activity could be found that were better distributed but not more toxic after oral administration. Such a group of compounds has now been discovered.
Accordingly the present invention provides the compounds of the formula (II):
~2~ \
Ar - Y - X - O ~ NH2 (II) R

and pharmaceutically acceptable salts thereof wherein R is a h~drogen atom or a methyl or ethyl group; X is an alkylene group of 1 to 10 carbon atoms; Y is 0, S or a bond; and Ar is an aryl group.

~179731 The ~kYlene group X may be Qtraight or branched chain but is moæt suitably straight chainad. Particularly euitable group9 X include tho~e of the formula -(C~2)n- where n i~ an integer of from 1 to 6.
Most suitably Y i8 an oxygen atom.
Suitable groups ~r include phenyl, naphthyl, anthranyl, phen~nthryl and phenyl substituted by from 1 to 5 group~ selected from fluorine, chlorine, bromine, lower alkoxyl, lower acyloxyl, lower ~ kyl, lower alksnyl, C5 6 cycloalkyl, C5 6 cycloalkenyl or lower alkylthio.
When used herein the term 'lower' means that the group contains 1-6 carbon atom~.
Particularly ~uitable compound~ of the formula (II) include those of the formula (III):

Ar - O - (C~2)m ~ ~ (III) R

and pharmaceutically aoceptable salt~ thereof wherein R and Ar are as defined in relation to formula (II) and m is 1, 2, 3 or 4.
Favoured values for the group Ar inolude the phenyl and naphthyl groups and phenyl substituted by one more more groups selected from chlorine, bromine, lower alkoxyl, lower alkyl, lower alkenyl, C5 6 cyclo-~lkyl and C5 6 cycloalkenyl.

- ., :: ,: .
,. ~ :
: :

` 107973~L

One particularly suitable sub-group of compounds of the formulae (II) and (III) is that wherein R is a hydrogen atom.
Another particularly suitable sub-group of compounds of the formulae (II) and (III) is that wherein R is a methyl group.
Certain favoured compounds of the formulae (II) and (III) include those wherein Ar is a phenyl, mono-, di- or tri-substi-tu-ted phenyl especially phenyl substituted by cyclohexyl or cyclopentyl and optionally substituted by a further 1 or 2 groups.

Particularly favoured compounds of the formulae (II) and (III) include those wherein Ar is a group of the sub-formula (a):

~ .

2 ~ ~a) ; wherein R1 is a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxyl group and R2 is a hydrogen, fluorine, chlorine or bromine atom or a methyl or methoxyl group.
Most suitably Rl is a hydrogen, chlorine or bromine atom.
Most suitably R2 is a hydrogen, chlorine or bromine atom.
Cert~in preEerred moieties of the sub-formula ~a) are those of the sub-formula (b):

R3 ~
Cl ~ (b) .. ~ :

:i ' , . - , , . . ' ~'~' ' ' - ~' .

:. . . : , '" , ' " ' ' , ., ~ .

73~

~herein ~3 i9 a hydrogen, ~luorine, chlorine or bromine a~om or a methyl or methoxyl group.
~lore sui~ably ~3 i8 A hydsogsn, cnlorine or bra~ine atom.
Pr~er~bly ~3 i~ a hydrogen ~om.
The acid addition salts of the compound~ of the formula (II) may be any formed with a pharmaceutically acceptable inorganic or organic acid such a~ hydrochloric, orthopho~phorio, acetic, succinic, lactic, citric, fumaric, tartaric or the like acid.
In a further aspect the present inventiorl provides a prooe~s for the preparation of the oompounds of the formula (II) and their aalt~
whioh prooe~ comprises the reaotion of a aompound of the formula (IV)~

~2N~

~ ~ ~ NH2 (IV) ~ N

or a basio salt thereof wherein R is a hydrogen atom or a methyl or ethyl group; and a oompound of the formula (V):

~r -- Y -- X - Z tv) wherein Ar, Y and X are ae defined in relation to formula (II) and Z is a ~roup re~dily displaceable by a nuoleophile.

, ~ ,. . , . ~ . :

: .-: . . .

~079731 An Plternative proces~ of this invention for the preparation of those compoundc of the formula (II) wherein Y i~ 0 compriae~
the reaction of a compound of the formula (VI):

Z - X - O ~ 9--NH2 (V l ) R

wherein R and X are as defined in relation to formula (II) and Z iB a8 defined in relation to formula (V) with a compound of the formula (VII):

Ar - 0~ (VII) or a basic salt thereof wherein Ar i~ as defined in relation to formula (II).
Suitable group8 Z inolude Cl, ~r, I, OS02C~3, OS02C6H4C~3 and the like.
Suitable ba0ic ~alts of the compounds of the formulae tIV) or (VII) include alkall metal salts ~uch as the ~odium salt and o~her simllar solts.
The preceding reaotions are normally ca~ied out in relatlvely polar organic sol~ent~ suoh a~ dimethylformamide, dimethyl~ulphoxide, acetonitrile and the like.

, . .

. . ~

1~79~73~

Normally the condensationa are performed at a non-extreme temperature ~uch as -20C to 180C, more u~ually from 10C to 100C~
for example from 25C to 60Co The present invention also provides a pharmaceutical composition which comprise~ a compound of the formula (II) and a phar~aceutically acceptable carTier.
Most suitably the composition will be adapted for oral or injectable administration. Preferred compositions will be adapted for oral administration.
The compositions may be formulated by conventional method~, for example as described in United Stated Patent No. 3,723,429.
Particularly suitable compositions of thi~ invention include tablet~, ¢ap~ules and other unit doasge form~ whioh contain from 5 m~ to 500 m~ of active compound. Suoh compo~itiona may be admlni~tered once or more time~ a dsy in order to provide a daily do~e of 20 -1000 mg and more ueually 50 - 500 mg for a 70 kg adult.
The compo~itions of this invention m~y be used to treat malaria and/or bacterial infections. ~he compositions are of e~pecial usefulness as they are able to effectively treat malarial infections which are resistant to many conventional anti-malarial agents. ~he eood oral absorpt~on properties of the compositions of this invention are an additional advantage that allows for their easy u~e.

.. . ............... .
, ' '' ~, : . ~ ' -~, .

The compositions of this invention may also be used to treat bacterial infection as they possess antibacterial activity, ~or example against gram positive bacteria such as Staphylococcus aureaus and against gram negative bacteria such as Escherichla coli and Proteus mirabilis.
If desired the compositions of this invention may also contain an antibacterially active sulphonamide such as sulphamethoxazole.
The hydroxy compounds of the formula (IV) may be prepared by the method of R. Hull, Journal of the Chemical Society, 1965, 2033.
The following Examples illustrate the invention:

-~L~79~73~

2,4-Diamino-6-methyl-5-(4-chloro-2-cyclohexy~heno 2,4-Diamino-6-methyl-5-hydroxypyrim1dine dihydrochloride (2.13 g~
was added to a solution prepared from sodium (0.8 g) and ethanol (30 ml) and ~tirred at room temperature for one hour. 4-Chloro-2-cyclohex~}-phenoxypropyl bromide (3.32 g) wa~ added portionwi~e and the reaction mixture was ~tirred overnight. Th~ reaction was heated at 50C for 24 hour~, cooled, filtered and the filtrate evaporated. ~he residue wa~ triturated with acetone and filtered. The crude product w2s dissolved in ethanol and a few drops of concentrated ~Cl added whereupon the product crystallised a~ a white solid. The product wa~ recrystallised from methanol/ethanol (1.65 g; 4~/o), m.p. 246 - 7C~ Analysis indieated that the product wa~ a monohydroehloride, po~ibly n monobydrn~e, : ~ .
: , , , , . ' '' .
, , ',~ ' - . :

: .
.:
-:

~07973~

~ing the method of Ex~mple 1, the compound~ of the formula:
~2N

Ar (CH2)n ~ ~H2. HCl were prepared:

Ar n ~ M.P~ C
Sol~ent

3,4-dichlorophenyl 1 aq. aoetone 240 l-naphthyl 1 ethanol 252-3 (~ 2) l-phenanthryl 1 methanol 259-60 (MeO~) -pentaohlorophenoxy 3 DMF ~eOH/H20 279 2,3,4,6-tetraohlorophenoxy 3 aq. methanol 305-7 2,4,6-tri¢hlorophenoxy 3 aq. metha~ol 270-1 2,4-dlohlorophenoxy 3 aq. ethanol 234-5 2,3-diohlorophenox~ 3 aq. ethanol 280-1 2-(prop-2-eny1)-4-bromophenoxy 3 methanol/ethanol 230-1 2-bromophenoxy 3 methanol/e-thanol 259-61 2-(prop-2-eny1)-4-mRtho~yphenox~ 3 ethanol 232 3,4,5-trimethoxyphenoxy 3 ethanol 255-6 (~H20) 3,4,5-trimethoxyphenoxy 4 methanol/etha~ol 231~2 _ 10_ :
~ .
.~

::~07973~

Ar n ~3~5L~ 2~ M-P C
Solvent 2,6-dimethoxypheno~y 3 MeOH/EtOH/H20 248-50 (~ 2~
2,6-dimethoxyphenoxy 2 ethanol 240-2 2,3-dimethoxyphenoxy 3 aq. ethanol 23~-5 3,4,5-trimethoxyphenyl 3 aq. ethanol 245-6 3,4,5-trimethoxyphenyl 2 aq. ethanol 250-1 3,4-dimethoxyphenyl 2 water 227-8 3,4,5-trimethoxyphenyl 1 ethanol 236-7 2-methoxyphenyl 1 aq. ethanol 23~
2-thioeth~lphenyl 1 aq. ethanol 233-40 phenoxy 4 ethanol 2~5-6 (~2) phenoxy 6 ethanol 240 (~ 2~
2,4,6-triohlorophenoxy 4 ethanol 269-71 2,4,5-triohlorophenoxy 6 ethanol 231-2 (~ 2) phenoxy 8 aoetone 2345

4-methoxyphenoxy 8 ethanol 255-6 phenoxy 10 ethanol 262 2-ohlorophenoxy 10 methanol/ethanol 239-40 (~2) 2,6-dimethoxyphenoxy 10 ethanol 229-30 (~ 2) .,~......................... , : . . .:.
:~. .. . : , , ,,, ` . .. , . ; ' : ',', ' .'": , ', .

~07~731 Using the method of Example l,the ¢ompounds o the formula:

~2~
~ - N
Ar - (CH2)n - O ~ ~ ~H2-were prepared:

Ar n C~etallisation .P. C
Sol~ent l-naphthyl 1 ethanol 189 t1-~H20) l-phenanthryl 1 aq. ethanol 253-4 (2HCl) pentachlorophenoxy 3 aq. methanol 253-4 3,4,5-trLmethoxyphenyl 1 aq. ethanol 245 3,4,5-trimethoxyphenyl 2 aq. ethanol 242 (H20) phenoxy 10 ethanol 174-5 t ~2) 3,4-dimethoxyphenyl 2 ethanol 238-9 . .
,: .
: . . . . . . . . . .
''. . ~

~ , .
' ~9~3~

~xnmple 4 hnrmncolo~y The compound of Example 1 wa~ administered to A ~roup of mice at n dose of 160 mg/kg. ~o de~th~ occured indicating that the compound ~as le99 acutely toxic thAn pyrimethami~le. After orsl admini~tration to mice in a standard antimalarial test (Rnne Test) the compound of Example 1 was found to be half as active a9 pyrimethamine.

'';

,

Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSTVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a compound of formula (II) (II) and pharmaceutically acceptable salts thereof wherein R is a hydrogen atom or a methyl or ethyl group; X is an alkylene group of 1 to 10 carbon atoms; Y is O, S or a bond; and Ar is an aryl group, which comprises (i) reacting a compound of the formula (IV) (IV) or a basic salt thereof wherein R is a hydrogen atom or a methyl or ethyl group, with a compound of the formula (V) Ar - Y - X - Z (V) wherein Ar, Y and X are as defined in relation to formula (II) and Z is a group readily displaceable by a nucleophile; or (ii) when Y is an oxygen atom, reacting a compound of formula (VI) (VI) wherein R and X are as defined in relation to formula (II) and Z is a group readily displaceable by a nucleophile, with a compound of the formula (VII) Ar - OH (VII) or a basic salt thereof wherein Ar is as defined in relation to formula (II), and recovering the required compound of formula (II) and where required preparing a pharmaceutically acceptable salt thereof.

2. A process for the preparation of a compound of formula (II) as claimed in claim 1(i), wherein in the formulae (V) and (II) X is -(CH2)n-where n is an integer from 1 to 6.

3. A process for the preparation of a compound of formula (II) as claimed in claim 1(i), wherein in the forrnulae (V) and (II) Y is an oxygen atom.

4. A process for the preparation of a compound of formula (II) as claimed in claim 1(i), wherein Ar in formulae (V) and (II) is phenyl, naphthyl, anthranyl, phenanthryl or phenyl substituted by from 1 to 5 groups selected from fluorine, chlorine, bromine, lower alkoxyl, lower acyloxyl, lower alkyl, lower alkenyl, C5-6 cycloalkyl, C5-6 cycloalkenyl or lower alkylthio.

5. A process for the preparation of a compound of formula (II) as claimed in claim 1(i), 2 or 3, wherein Ar in formulae (V) and (II) is a phenyl or naphthyl group or phenyl substituted by one, two or three groups selected from chlorine, bromine, lower alkoxyl, lower alkyl, lower alkenyl, C5-6 cycloalkyl and C5-6 cycloalkenyl.

6. A process as claimed in claim 2, 3 or 5, wherein R is hydrogen or methyl in formulae (IV) and (II).

7. A process as claimed in claim 1(i), 2 or 3, wherein Ar in formulae (V) and (II) is phenyl substituted by a cyclohexyl group.

8. A process as claimed in claim 1(i), 2 or 3, wherein Ar in formulae (V) and (II) is a phenyl group substituted in the 2 position by cyclo-hexyl and further substituted by R1 and R2, wherein each of R1 and R2 is H, F, Cl, Br, methyl or methoxy.

9. A process as claimed in claim 1(i), 2 or 3, wherein Ar in formulae (V) and (II) is a phenyl group substituted in the 2 position by cyclohexyl, in the 4 position by chloro and further by R3 which is H, F, Cl, Br, methyl or methoxyl.

10. A compound of the formula (II) (II) and pharmaceutically acceptable salts thereof wherein R is a hydrogen atom or a methyl or ethyl group; X is an alkylena group of 1 to 10 carbon atoms;
Y is O, S or a bond; and Ar is an aryl group, when prepared by the process of claim 1 or an obvious chemical equivalent.

11. A process for the preparation of the salt 2,4-diamino-6-methyl--5-(4-chloro-2-cyclohexylphenoxypropyloxy)pyrimidine monohydrochloride which comprises reacting the sodium salt of 2,4-diamino-6-methyl-5-hydroxy-pyrimidine with 4-chloro-2-cyclohexylphenoxypropyl bromide in a solvent, treating the crude product with HCl and recovering the required salt.

12. 2,4-diamino-6-methyl-5-(4-chloro-2-cyclohexylphenoxypropyloxy)-pyrimidine monohydrochloride, when prepared by the process of claim 11 or an obvious chemical equivalent.

13. A process for the preparation of a salt of formula wherein Aro, n and R have the following values:

which comprises reacting the sodium salt of the corresponding compound of formula wherein R is as defined, with the corresponding compound of formula Aro - (CH2)n - Br wherein Aro and n are as defined, in a solvent; treating the crude product with HCl and recovering the required salt.

14. A compound of the formula wherein Aro, n and R have the following values:

when prepared by the process of claim 13 or an obvious chemical equivalent.