Note: Descriptions are shown in the official language in which they were submitted.
~ ^ ~
~3~i3~
This invention relates to new pharmaceutical compounds and in par-
ticular it relates to n.ew pharmaceutical compounds which possess analgesic pro-
perties. In addition certain of the compounds also possess anti-inflammatory
properties and/or are inhibitors of prostaglandin synthetase.
It will be appreciated that certain of the new compounds defined below
possess at least one asymmetric carbon atom and may therefore exist in racemic
and optically active forms, namely those compounds of formula I wherein R , R2 or
R is a radical con~aining an asymmetric carbon atom. It is to be understood
that this specificati.on relates to those racemic and optically active forms, of
such compounds, which possess the useful properties mentioned hereinbelow, it
W h
being well ~nw~n in the general art how to prepare optically active forms by
~ resolution o the corresponding racemate or by synthesis from optically active
starting materials, and how to determine their pharmacological properties by the
standard described hereinbelow.
According to the invention, therefore, there is provided a process for
the manufacture of a 1,3,5-triazine-2,6-dione of the formula:
:, O
. .~ ~ N CoR3
Rl_ N /~
~N R
O
wherein Rl is a Cl 6-alkyl radical or a C3 6-cycloalkyl radical; R2 is a Cl 4-
g 1-4 alkoxy radical, a C3 8-cycloalkyl C
radical, a C5 1O-alkyl radical wherein the linking ~-carbon atom is secondary,
or a phenyl or phenyl Cl 4-alkyl radical optionally bearing an aromatic substi-
tuent selected from halogen atoms, Cl ~-alkyl and Cl 4-alkoxy radicals; and R3
is a methyl radical; or a pharmaceutically acceptable base-addition salt thereof.
-- 1 --
.. ~
~3~3~
A particular value for Rl when it is a Cl 6-alkyl radical is, for ex-
ample, a methyl, ethyl, isopropyl, n-propyl or isobutyl radical; and when it is
a C3 6-cycloalkyl radical is, for example, a cyclohexyl radical.
A partic~llar value for R2 when it is a Cl 4-alkyl radical bearing a
Cl 4-alkoxy radical is, for examplc, a 2-methoxy- or 2-ethoxy-ethyl radical;
and when it is a C3 6-alkenyl radical is, for example, an allyl or 2-methylallylradical.
A particular value for R2 when it is a C3 8-cycloalkyl radical is, for
~ example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or norbornyl radical;
-~ 10 and when it is a C5 1O radical wherein the linking ~-carbon atom is secondary,
; is, for example, a pent-2-yl, pent-3-yl, hex-2-yl, hex-3-yl or hept-4-yl radical,
of which latter values, a pent-3-yl radical is especially preferred.
A particular value for a phenyl-Cl ~-alkyl radical is, for example, a
benzyl, l-(phenyl)ethyl or 2-(phenyl)ethyl radical.
A particular value for an aromatic substituent which may be present
when R2 is a phenyl or phenyl-Cl 4-alkyl radical is, for example:
when it is a halogen substituent, a fluorine, chlorine or bromine
atom;
when i~ is a Cl 4-alkyl substituent, a methyl radical; and
when it is a Cl 4-alkoxy substituent, a methoxy radical.
Specific values for R2 when it is an optionally substituted phenyl or
;~
phenyl-Cl 4-alkyl radical are, for example, phenyl~ benzyl, l-(phenyl)ethyl,
2-(phenyl)ethyl, 4-chlorophenyl, 4-methylphenyl, 3-methoxyphenyl and 4-chloro-
benzyl radicals.
It is preferred that when Rl and R2 are both alkyl radicals, the radi-
cals taken together number four or more carbon atoms.
A particular base-addition salt of a compound of formula I is, for
-- 2 --
,
;,A
~L3~35
example, an alkali metal or alkaline earth metal salt, for example a sodium,
potassium, calcium or magnesium salt, an aluminium salt, for example an aluminium
hydroxide di-salt, a copper salt or a complex therewith, or a salt with an or-
ganic base affording a pharmaceuti.cally acceptable cation, for example tri-
ethanolamine or benzylamine.
It will be apparent that within the above definition there are com-
prised various particular and distinct groups, namely those compounds of formulaI, or pharmaceutically acceptable base-addition salts thereof, wherein one of
Rl, R2 and R3 has one of the above defined particular or specific values, and
the remainder of Rl, R2 and R3 have any of the above defined general, particularor specific values. However, specific groups of compounds which are of particu-
lar interest comprise those compounds of formula I wherein:-
~a) R is a straight chain Cl 6-alkyl radical, for example a methyl,
ethyl or n-propyl radical, or Rl is a C3 6-cycloalkyl radical; and R is a
C5 1O-alkyl radical, wherein the linking ~-carbon atom is secondary;
(b) Rl is a Cl 6-alkyl or C3 6-cycloalkyl radical; and R2 is a pent-2-yl
radical, or a C6 1O-alkyl radical wherein the l.inking ~-carbon atom is secondary,
for example a hex-3-yl or hept-4-yl radical;
(c) R is a Cl 6-alkyl or C3 6-cycloalkyl radical; and
R is a C6 1O-alkyl radical wherein the linking ~-carbon a~om is secondary;
(d) Rl is a Cl 6-alkyl or C3 6-cycloalkyl radical; and
R2 is a phenyl or phenyl-Cl 4-alkyl radical optionally substituted as defined
hereinbefore;
(e) Rl is a Cl 6-alkyl or C3 6-cycloalkyl radical; and
R2 is a C3 8-cycloalkyl radical; and
(f) R is a Cl 6-alkyl or C3 6-cycloalkyl radical; and
R is a C3 6-alkenyl radical or a Cl 4-alkyl radical bearing a Cl 4-alkoxy
~3~35
radical;
and in each group R is a methyl radical; together with the pharmaceuti-
cally acceptable base-addition salts thereof.
Preferred groups of compounds of formula I comprise those compounds
whcrein:
(a) R is an isopropyl or n-propyl radical;
(b) R2 is a pent-3-yl, llex-3-yl or cyclohexyl radical; or
(c) R is a methyl radical;
and, in each group, the remainder of Rl, R2 and R3 have any of the previously
defined values; together with the pharmaceutically acceptable base-addition salts
thereof.
Yet further preferred groups of compounds of formula I comprise those
~; compounds wherein Rl, R2 and R3 all have the values defined in (a), (b) and (c)
immediately above; or wherein two of Rl, R2 and R3 have the values defined in
(a), (b) or (c) immediately above, and the other of Rl, R2 and R3 has any of thevalues previously defined; together with the pharmaceutically acceptable base-
`~ addition salts thereof.
Specific compounds of formula I are described hereinafter in the Ex-
amples, and, of these, particularly preferred compounds are l-isopropyl-4-(N-
acetyl)cyclopropylamino-tetrahydro~1,3,5-triazine-2,6-dione, 1-isopropyl-4-[(N-
acetyl)-pent-3-ylamino]-tetrahydro-1,3,5-triazine-2,6-dione and 1-isopropyl-4-
~N-acetyl)-cyclohexylamino-tetrahydro-lJ3,5-triazine-2,6-dione; and the pharma-
ceutically acceptable base-addition salts thereof.
The compounds of formula I may be obtained by any process applicable
to the manufacture of analogous chemical compounds. Such processes are provided
according to the invention and are illustrated by the following, wherein R , R
and R have the meanings defined hereinbefore:-
. -- 4 --
"A,,
3L~3~3S
~a~ acylating a compound of the formula:-
o
- N II
~ N
by reaction with an acylating agent derived from an acid of the formula
1~ C02~1.
A particularly suitable acylating agent is, for example, an acid
halide, for example the acid chlorlde or bromide, the anhydride or a mixed an-
hydride with formic acid, derived from an acid of the formula R3Co2H.
The reaction may be-carried out in the presence of a diluent or
solvent, for example a hydrocarbon, for example toluene or xylene. An excess
of the acylating agent is preferably used, and may itself serve as diluent or
solvent. In either case the reaction is conveniently carried out at a tem-
perature in the range, for example, 15 - 150C., and preferably, at an elevated
temperature in the range, for example, 80 - 150C.
It will be appreciated that, when an anhydride is used as the acylat-
ing agent, the parent acid of the formula R3Co2H is also formed, and may be con-
;~ veniently removed by distillation.
The starting materials of formula II may be obtained, as described inthe Examples, by reaction of an amine of the formula R2.NH2 with a 4-alkylthio-
1,3,5-triazine derivative of the formula:-
o
N
III
N
O
-- 5 --
,
,, .. ... ~ .
-'~ .' ' - '' ~ ':' '
: , ' '
,','
3l13~35
wherein R4is a Cl 4-alkyl radical, for example a methyl radical. The amine of
the formula R2-Nll2 is conveniently used in the form of its salt wi*h a Cl 4-
alkanoic acid, for example in the form of its acetate salt, and the reaction is
preferably carried out at a tempcrature in the range, for example, 100 - 250C.
A suitable solvent or diluent, or example dimethylformamide, may conveniently
be used.
The 4-alkylthio compounds of formula III may be made by well known
procedures for the synthesis of analogous 1,3,5-triazine~2,6-diones, for example
as described in United Kingdom patent specification No. 1 435 585 or No.
1 397 888.
~b) Rearranging a compound of the formula:-
O /COR
\ N
lN/ ~ NHR IV
\
N
by the influence of heat.
The rearrangement is preferably carried out by heating at a tempera-
ture in the range, for example, 60 - 200~C~, and may optionally be carried out
in the presence of a high boiling diluent or solvent, for example xylene.
The process is particularly suitable for the preparation of compounds
of formula I wherein R3 is a methyl radical and in which case the required
starting materials of formula IV may be obtained by reaction of a compound of
formula II with ketene, preferably at or near room temperature and in a diluent
or solvent, for example methylene chloride. In many cases, it is convenient to
prepare the compound of formula IV in situ, and use it without purification in
process (b~. The remaining starting materials of formula IV may be obtained
-- 6 --
~L3~3~
in analogous manner using the appropriate substituted ketene of the formula
R5.CII=C=0 wherein R5 is a Cl 3-alkyl radical.
The compo~mds of formula I are moderately acidic and react with weak
bases, for example alkali metal hydrogen carbonates, to form the corresponding
alkali metal salts.
Nhereafter when a pharmaceutically acceptable base-addition salt is
required acompoundofformula I is reacted with a suitable base.
The analgesic properties of the compounds of formula I may be de-
monstrated in a standard test measuring the inhibition of writhing in mice in-
duced by an intraperitoneal injection of acetylcholineJ using the procedure of
Hackett and Buckett ~European J. Pharmacology, 1975, 30, 280). In general com-
pounds of formula I show significant activity in this test at an oral dose of
50 mg./kg., or less, without any overt toxic effects at the active dose~ and
preferred compounds of formula I, for example, l-isopropyl-4- L (N-acetyl)-pent-
3-ylamino]-tetrahydro-1,3,5-triazine-2,6-dione, show significant activity at an
oral dose of 5 mg./kg. or much less.
In addition to analgesic properties, certain of the compounds of
formula I possess anti-inflammatory properties which may be demonstrated using
either or both of the following standard tests:-
~a) ~djuvant induced arthritis in rats, using a similar procedure to that
of B.B. Newbould ~British Journal of Pharmacology, 1963, 21, 127);
(b~ Carrageenin induced oedema in rats, using a similar procedure to that
of C.A. Winter et alia [Proceedings of the Society of Experimental Biology (New
York), 1962, 111, 544~.
In general, compounds of formula I possessing anti-inflammatory pro-
perties show activity in either or both of the above tests at an oral dose of
50mg./kg. or less, given as a daily dose for 14 days in test (a) or as a single
o~.'
- 7 -
,;~ ' ,:
:,
~13~35
dose in test ~b), without overt toxic effects at the active dose.
Compounds possessing good anti-inflammatory properties are, for ex-
ample, l-ethyl-4-~N-acetyl)-n-propylamino-, l-n-propyl-4-~N-acetyl)-n-propyl-
amino-, and l-isopropyl-4-~N-acety])benzylamino-tetrahydro-1,3,5-triazine-2,6-
dione.
Certain of the compounds of formula I also possess the property of
inhibiting the enzyme prostaglandin synthetase. This property may be demon-
strated in a standard in vitro test which involves the use of prostaglandin
synthetase isolated from the ram seminal vesicle. The compounds of formula I
which inhibit prostaglandin synthetase, in general do so at an in vitro concen-
tration of 10 3M or less. A representative compound of formula I which inhibits
the enzyme prostaglandi~synthetase is, for cxample, l-isopropyl-4-~N-acetyl)-
benzylamino-tetrahydro-1,3,5-triazine-2,6-dione. It is known, that inhibitors
of prostaglandin synthetase, for example indomethacin or flufenamic acid, are
clinically effective in the treatment of adverse conditions associated with ab-
normally high tissue levels of prostaglandins, for example dysmenorrhoea or
menorrhagia, and in the treatment of painful inflammatory joint diseases, for
example arthritis and osteoarthritis.
~hen used to produce the aforementioned pharmacological effects in
warm blooded animals the compounds of formula I may be administered as follows:-
(a) for analgesic effects, at a daily oral dose of for example, 0.1 -
25 mg./kg. (in humans this is equivalent to a total daily dose of, for example,
2.5 - 625 mg.);
(b~ for anti-inflammatory effects, at a daily oral dose of, for example,
1 - 50 mg./kg. of a compound of formula I possessing anti-inflammatory proper-
ties; (in humans this is equivalent to a total daily dose of, for example,
25 - 1250 mg.);
(c) to inhibit prostaglandin synthetase n vi~o, at a daily dGse of, for
example, 1 - 50 mg./kg. of a compound of formula I possessing the property of
inhibiting prostaglandin synthetase; (in humans this is equivalent to a total
daily dose of, for example 25 - 1250 mg.).
The abovc total da:ily dose may conveniently be glven in divided, but
not necessari]y equal doses and the compound of formula I may be replaced by
an equivalent amount of a suitable base-addition salt.
The invention is illustrated, but not limited, by the following Ex-
amples in which yields, where given, are not to be construed as necessarily the
maximum attainable:-
Example 1
~ propyl-4-cyclopropylaminotetrahydro-1,3,5-triazine-2,6-dione
(4.0g.) was heated under reflux in acetic anhydride (50 ml.) for 3 hours. The
excess of acetic anhydride was then removed in vacuo and the residue obtained
was triturated with n-hexan0 containing a little ether. The brown solid which
formed was separated and recrystallised from a mixture of carbon tetrachloride
and petroleum ether (b.p. 60 - 80C.), giving l-isopropyl-4-(N-acetyl)cyclo-
propylamino-tetrahydro-1,3,5-triazine-2,6-dione in 55 % yield, m.p. 118 - 119C.
The starting material was obtained as follows:-
0 l-lsopropyl-4-methylthiotetrahydro-1,3,5-triazine-2,6-dione (6.0 g.)
: ~obtained as described in United Kingdom patent specification No. 1 435 585)
and cyclopropylamine acetate (17.85 g.) were heated together and stirred at
150C. for 3 hours. The mixture was then cooled and water (150 ml.) was added.
The whi~e solid which formed was collected, washed with water and dried to give
~ l-isopropyl-4-cyclopropylaminotetrahydro-1,3,5-triazine 2,6-dione, m.p. 237 -
'': 239C-
_ g _
Example 2
: In a similar manner to that described in Example 1 the following com-
pounds of formula I wherein R3 is a methyl radical were obtained in yields of
60 - 90 % by acylating a compound of formula II with acetic anhydride:-
Compound m.p.
No. R R (C.)
_ _
1 n-propyl n-propyl 117 - 118
2 i-propyl allyl 108 - 109
. 3 ethyl n-propyl 129 - 131
4 i-propyl2-methylallyl 96 - 97
i-propyl benzyl 152 - 153
6 i-propyl phenyl 199 - 201
7 i-propyl2-methoxyethyl 77 - 78
i-propyl3,3-dimethylbutyl 138 - 139
The necessary starting materials of formula II were obtained in an
analogous manner to that described in Example 1 by reacting the appropriate
~-~ 4-methylthio compound of formula III, wherein R4 is a methyl radical, with an
8 - 10 molar excess of the appropri.ate amine as its acetate:-
Intermediate m.p.
No. R R . ~-C :
1 n-propyl n-propyl 249 - 250
2 i-propyl allyl 182 - 183
3 ethyl n-propyl 248 - 250
4 i-propyl2-methylallyl 181 - 182
. 5 i-propyl ben~yl 251 - 254
6 i-propyl phcnyl 272 - 274
: 7 i-propyl2-methoxyethyl 98 - 100
8 i-propyl3,3-dimethylbutyl 216 - 218 _
- 10 -
.
, .
,
,, ,
~31~35
Example 3
Using a similar procedu~e to that described in Example 1 the following
compounds of formula I wherein Rl is an isopropyl radical and R3 is a me~hyl
radical l~ere obtained in yields of 40 - 90 %, by reacting a compound of formula
II with an excess of acetic anhydride:-
Compound 2 m.p.
No. R _ (C.)
9 cyclohexyl 129 - 131
l-(phenyl)ethyl syrup
[Mote (a)]
11 pent-3-yl 85 - 88
12 hex-3-yl syrup
[Note (b)]
13 hept-4-yl syrup
[Note (c)]
14 4-chlorophenyl 248 - 250
4-methylphenyl 214 - 216 _
Notes: syrups were homogeneous by TLC analysis (SiO2:
acetic acid/ethyl acetate/toluene 2:80:18 v/v) and had the following
characteristic NMR spectra [determined a~ 60~1z in CDC13 solution using
tetram~thyl silane (TMS) as internal standard]:-
(a), ~(ppm): 1.4, 1.5 [doublet (d), 6 protons, (CH3)2CH]; 1.77,
1.9 [doublet (d), 3 protons, C_3CHPh); 2.0 [singlet (s), 3 pro~GnS, N.COCH3];
4.7 - 5.3 [multiplet (m), 1 proton, (CH3)2CH]; 6.5 - 6.9 [quartet (q), l proton,
CH3CHPh]; 7.26 [singlet (s), 5 aromatic protons];
(b), ~(ppm) (lOOMHz): 0.86 - 1.0 [t, 6 protons, CH3~CH2)2CHCH2CH3];
1.15 - 1.35 ~m, 2 protons, CH3C_2CH2CHCH2CH3); 1.42 - 1.50 [d, 6 protons,
~CH3)2CH]; 1-65 - 2-35 (m, 4 protons, CH3CH2CH2CHCH2CH3); 2-43 ~s, 3 protons,
N-COCll3); 4-05 - 4.40 [m, 1 proton, Cll3(cH2)2CHCll2CH3]; 4-8 - 5-2 [m, l proton,
(Cl13)2Cll];
(c), ~(ppm): 0.7 - l.l (t, 6 protons, Cll3Cll2Cll2CH-); 1.1 - 1.7 (m, 4 pro-
tons, Cll3CH2Cll2CH); 1.42 - 1.53 [d, 6 protons, (l-l3)2CH]; 1.77 - 2.35 (m, 4 pro-
tons, Cl-l3CI-l2CH2CII); 2.47 (s, 3 protons, N.C()Ctl3); 4.05 - 4.60 (m, 1 proton,
C~13CH2CH2CH); 4.73 - 5.40 [m, 1 proton, (Cll3)2CH].
The necessary starting materials of formula II were obtained in an
analogous manner to that described in Example 1 by reacting 1-isopropyl-4-
methylthio-tetrahydro-1,3,5-triazine-2,6-dione with a 1.5 - 2.0 molar excess of
the appropriate amine as its acetate:-
Intermediate m.p.
No. _ R (C.)
9 cyclohexyl 253 - 258
l-(phenyl)ethyl 169 - 171
11 pent-3-yl 253 - 256
12 hex-3-yl syrup
[Note (a)]
13 hept-4-yl syrup
[Note (b)]
14 4-chlorophenyl 248 - 250
4-methylphenyl 286 - 288
Notes: syrups were homogeneous by TLC analysis (SiO2:
acetic acid/ethyl acetate/toluene; 2"35:63v/v) and had the following
characteristic NMR spectra ~determined at 60MHz in CDC13 solution using TMS
as internal standard]:-
(a), ~(ppm): 0.77 - 1.17 (t, 6 protons, C~13CH2CH2.CHCH2C~l3);
1.42 and 1.52 (~, 6 protons, (CH3)2CH]; 1.17 - 2.07 (m, 6 protons,
CH3CH2CH2.CHCH2CH3); 3.62 - 4.32 [m(broad), lp, CH3CH2CH2.CHCH2CH3);
,:
~ - 12 -
~3~ X
4.72 - 5.37 ~m, 1 proton, (CH3)2CH], 8.17 [d(broad)J 1 proton, NH];
(b), ~ppm): 0.7 - 9.1 (t, 6 protons, CH3CH2CH2CII); 1-1 - 1-9 ~m, 8
protons, Cll3CH2CII2C~I); 1.4 - 1.53 [d, 6 protons, (Cll3)2CH]; 3.6 - 4.3 [m(broad),
1 proton~ CH3CII2CII2C~I~; 4.7 - 5.3 [m, 1 proton, (Cll3)2CII]-
Example 4
A suspension of l-isopropyl-4-(N-acetyl)cyclohexylamino-tetrahydro-
1,3,5-triazine-2,6-dione (10 mM) in a mixture of water (50 ml.) and 1,2-dimethoxy-
ethane (10 ml.) was prepared. Sodium hydrogen carbonate (10 mM.) in water (50
ml.) was then added to the stirred suspension. After 1 hour at room temperature
tha solution was filtered and the filtrate evaporated in vacuo. l'he solid resi-
due was then triturated with a little 1,2-dimethoxyethane to give the sodium salt
of l--isopropyl-4-(N-acetyl)cyclohexylamino-tetrahydro-1,3,5-triazine-2,6-dione
in essentially quantitative yield as a white solid, having a satisfactory micro-
analysis.
.~:
,~
, ~ .
,~
- - 13 -
,
~,.`j
,
, .
;,
