Note: Descriptions are shown in the official language in which they were submitted.
3~
The present invention relates to (2-pyrimidinyl-thio)
-alkanoic acid amides and their preparation.
t2-pyrimidinyl-thio) alkanoic acids, their esters,
amides and hydrazides, are described in the United States
Patent 3,814,761, and are stated to have an antilipemic
effect. The substituted amides, which are the subject of
the present invention, are structurally new and have a
much lower toxicity, ln relation to their activity, than
the compounds described in the patent cited.
The amides of the present invention have the formula
(I): 2
Y R
~ ~ S-CH2-C-N \ (I)
where Y is halogen; Rl is halogen, a radical of formula:
R4 R5 6
I ~ R
- N ~
where R4 is hydrogen or alkyl of 1 to 4 carbon atoms,
and R5 and R6, which may be the same or different, are
hydrogen, halogen, methyl or methoxy, a radical oE formula:
NHCH2 ~
~ , ''~,
) ;~, '
L23~
or a radical of formula:
R7 R8
- ~ - CH-CH2OH
where R7 and X8, which may be the same or different,
stand for hydrogen or alkyl of 1 to 4 carbon atoms; and
R2 and R3, which may be the same or different, ~ ~ .
represent straight or branched alkyl or alkenyl of up to
10 carbon atoms, cycloalkyl of up to 10 carbon atoms, or
straight or branched hydroxyalkyl or mercaptoalkyl of 2 to
5 carbon atoms, or R2 and R3 may be joined to form
with the adjacent nitrogen a heterocyclic saturated 5 or 6
membered ring which may contain another hetero atoml and :~
R may also represent hydrogen.
Particularly preferred compounds of the invention are
compounds of the formula (I) in which: Y is chlorine,~ `-
Rl is a R5
~ R6 ~-
NH ~
residue (where R5 and R6 have the aforestated
meanings), or a benzylamine residue, and R2 and R3, ;.
which may be the same or different, are straight or ;;
branched alkyl or alkenyl of up to 10 carbon atoms, :. `
straight or branched hydroxyalkyl or mercaptoalkyl of 2 to .
5 carbon atoms, and R2 may also represent hydrogen. ; -~
- 3
~f .~`.:
~.. .
,, ., . . ' ` , . . . ,: , . ~ , . . . :
23(:~
Exarnples of R radicals of formula:
R5
R6
_-_ NH ~
are radicals corresponding to the following amines:
aniline, 2,3-xylidine, 4-chloro-aniline, 4-methoxy-
aniline, 2,4,6-trimethyl-aniline, 3,4-dichloro-aniline,
4-fluoro-aniline, 3-trifluoromethyl-aniline, and
4-phenyl-aniline. Other preferred radicals of formula
-NR R3 are the benzylamine residue, -NH-CH2CH2OH
and -N-CH2CH2OH groups.
CH3
According to a feature of the invention, the compounds
of formula (I) are prepared by reacting an acid derivative
of the formula:
Y ~ N~ S-CH2-COX (II)
~ N
Rl
with an amine of the formula:
HN'' (III)
~ R3
where Y, Rl, R2, and R3 are as defined above, and X
represents halogen (preferably chlorine) or a
O-CO-OC2H5 residue.
When X represents chlorine, the acyl chloride of
formula (II) is obtained by treatment of the corresponding
. ."''
.
- 4 -
w ~3, f, ' , ~:
-
~ .
. . . . .
~.
3~
(2-pyrimidinyl-thio)-alkanoic acid wi.th SOCl2 or oxalyl chlo-
ride in benzene solution. The compounds of formula (II) so
obtained need not be isloated but may be treated directly
with the amine of formula (III), when necessary in the presence
of tertiary bases.
When , o~ the other hand, the compound of formula
(II) is a mixed anhydride (X = O-CO-OC2~l5), it is prepared
by the treatment of the corresponding (2-pyrimidinyl-thio)-
alkanoic acid with ethyl chlorocarbonate in the presence of a
tertiary base (preferably triethylamine), in a solvent such as
tetrahydrofuran, chloroform or acetone. In this case also the ~
compound of formula (II) need not be isolated and may be di- -
rectly transformed into the final product of formula (I) by
reaction with the desired amine of formula ~III).
Alternatively, the compounds of formula (I) may
be prepared by dorect treatment of the corresponding (2-pyrimi-
dinyl-thio)-alkanoic acid with 2 mols of an amine of formula
(III), 2 mols of triethylamine and 2 mols of BF3-etherate~ in
benzene or toluene solution, and refluxing, the mixture being ~ .
kept in an anhydrous condition with MgS04, using the technique
described by J. Tani, J. Dine and I. Inouf in Synthesis, 714,
1975. -
In the particular case where the -NR2R3 group in
the compound of formula (I) represents a ~-hydroxyalkylamine
residue, the preparation may be carried out by reacting the
corresponding acid with an aziridine of the formula:
,'~ ': . : .: , :. ,i
~8~23~
Cll2 CH-R9
\ N /
1 1 0
where R9 and R10 each represent hydrogen or alkyl of 1
to 3 carbon atoms and R10 may also denote -CH2CH20H.
The compounds of formula (I) in which Y denotes
chlorine and Rl is as defined above but is not halogen,
may be obtained by treating an amide of a (4,6-dichloro-
2-pyrimidinyl-thio)-alkanoic acid of formula:
Cl R2
-CH2-C-N ~ 3 V
N
Cl
where R2 and R3 are as defined above with two
equivalents of an amine of formula: .
R1 _ H VI
where Rl is as defined above but is not halogen, with
fusion.
The (4,6-dichloro-2-pyrimidinyl-thio)-alkanoic acids
of the formula (VII) may be prepared by acid hydrolysis of
the corresponding esters (VIII), obtainable for example by
the method described in United States Patent 3,814,761, by
condensation of sodium thiobarbiturate with a bromo-ester
of formula (IX) and subsequent reaction with POC13:
'~`'' ' ~';
,N s~ ~ HO
,N~ S-CE~-COOEt
N srC~12-CooEt ~ ¦r
OH ) ~ N
OH
Cl\ N ~ S-CH2-COOE-t Cl N ~ S-cH2-cooH
POCl3 ~ N H2O ~ N
Cl H~ C1
(VI I I ) (VI I )
where R and n have the aforesaid meanings and Et denotes
an ethyl residue.
The compounds of the present invention are all much
less toxic than the corresponding free acids. For example
the [4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]
-(N-~-hydroxy-ethyl)-acetamide, administered in a single
dose, orally, to mice, did not cause the death of any
animal, at a dosage corresponding to the LDloo for the ~ `
corresponding [4-chloro-6-~2,3-xylidino)-2-pyrimidinyl- ~;
thio]-acetic acid. E4-Chloro-6-(2,3-xylidino)-2
-pyrimidinyl-thiol-(N~-hydroxyethyl)-acetamide at
5g/kg/bodyweight did not cause the death of any animal ;
among rats or mice, male or female, while the
[4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio]-acetic acid
administered orally gave, for male mice, a LD50 of 1155
mg/kg (9703-1374) calculated according to the method of
Litchfield and Wilcoxon. ;
' ' '
-- 7 --
~ ~ . .
:. - . : - .
.. . . .
23~3
In the same ~ay, the compounds of the formula:
Cl ~ N ~ SCH2COX
N
NH
~ CH3
2 2 )2; NH(CH2CH2CH20H); -NH(CH CH CH C
-NHCH(CH3)CH2CH; -NH(CH2CH3); -NH(CH2CH2CH3);
-NH(CH2CH2CH2CH3); or -N(CH2CH3)2 did not cause, at Sg/kg/body-
weight, the death of any animal. Toxicological researches,
medium term, show that, with equal dosage, /4-chloro-6-(2,3-
xylidino)-2-pyrimldinyl-thio/-(N-3-hydroxyethyl)acetamide is
less toxic than the /4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-
thio/-acetic acid, particularly on the liver. The notable
reduction of toxicity shown by the compounds of the present
invention, particularly those containing alkyl or hydroxy-alkyl
chains of up to four carbon atoms, is not accompanied by any
diminution in activity compared with the relevant free acid. ~ ;~
The compounds reduce the concentration oE triglycerides and
cholesterol in the blood serum of normal rats or rats treated
with a hypercholesterolizing diet. In particular, with the
Buchanan test (in which the pharmacological preparation is
administered to normal rats for four days and analysis of the
- 8 -
serum cholesterol is carried out on the fifth day), compounds
which lower the serum cholesterol by at least 20~ at a dose of
400 mg/kg are consid~red as active. A standard preparation, re-
presented by Chlofibrate, at a dose of 200 ~g/kg, reduces by
20% the serum cholesterol level. With this test, wi-th varying
values of X, the following resul-ts were obtained:
~reduction of serum
X dose:mg/kg cholesterol level
OH 50 30.28
NHCH2CH2OH 56 30.70
N(CH2CH2OH)2 64 28.70
NHCH(CH3)CH2H 59 31.20 ~ -
NH(C 2)3CH3 58 35.00
NHCH2CH3 54 24.20
N(C2H5)2 54 15.00
NHC3H7 56 21.00
NH(CH2)2CH2OH 50 15.00
NH(CH2)3CH2OH 50 19.00
In the blood serum of normal rats or those on a hyper-
cholesterol diet, treated with /4-chloro-6-(2,3-xylidino)-2-
pyrimidinyl-thio/-(N-B-hydroxyethyl)-acetamide abnormal steroids,
perhaps derived from the synthetic path for cholesterol, did not
appear.
An appropriate dosage for the compounds of the
invention is 10 to 200 mg of the active principle as a single
_ g _
3~)
dose. Useful pharmaceutical forms are:
_psules: composition per 100 mg
/4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-B-
hydroxyethyl)-acetamide 50 mg
lactose 49 mg
magnesium stearate 1 mg
Tablets: composition per 100 mg
/4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-~-
hydroxyethyl)-acetamide 50 mg
10 starch 27 mg
lactose 18 mg
talc 4 mg
magnesium stearate 1 mg
The analytical data on the compounds described in the
Examples are shown in Table 1 below.
Example 1
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-~-hydroxyethyl)
-acetamide. ~;
To a suspension of /4-chloro-6-(2,3-xylidino)-2- ~-
pyrimidinyl-thio/-acetic acid (60 g.) in chloroform (1200 ml.),
at ambient temperature, ethylene-imine (5.4 ml.) in chloroform
(60 ml.) was added and the solution was heated to boiling for
four hours. The mixture was cooled to ambient temperature,
another 2.7 ml. ethylene-imine in chloroform (30 ml. ) was added,
and the mixture was heated for another four hours. After a
final
-- 10 --
-: . : -: . . .. . . . .
L230
addition of 1.35 ml. ethylene-imine in chloroform (15 ml.) and
a further heatin~ to boiling for Eour hours, the mixture was
concentrated to a small volume (300 ml.). The precipitated
solid was filtered off and recrystallized several times from
acetone. 40 g. o~ /4-cnloro-6-~2,3-xylidino)-2-pyrimidinyl-
thio7-(N-~-hydroxyethyl)-acetamide were obtained, m.p. 150-151C.
Using the same method the ~ollowing compounds were
prepared:
Example 2
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-th o/-(~,N-bis-~-
hydroxyethyl)-acetamide, m.p. 166-167C. (acetone).
Example 3
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-N-(~-methyl-~-
hydroxyethyl)-acetamide, m.p. 170-172C. (acetone).
Example 4
/4-Chloro-6-(_-chloroanilino)-2-pyrimidinyl-thio/-N-~-hydroxy-
ethyl)-acetamide. m.p. 145-147C. (ethanol/water).
Example 5
/4-Chloro-6-benzylamino-2-pyrimidinyl-thio/-(N-~-hydroxyethyl)-
acetamide, m.p. 117-119C.(ethanol/water).
Example 6
/4-Chloro-6-anilino-2-pyrimidinyl-thio/-(N-~-hydroxyethyl)-
acetamide, m.p. 136-138C. (ethanol/water).
Example 7
/4-Chloro-6-(p-methoxyanilino)-2-pyrimidinyl-thio/-(N-~-hydroxy-
3~
ethyl)-acetamide, m.p. 119-121C.(methanol/water).
Example 8
a) Ethyl/~-Chloro-6-(N-met;yl-N-~-hydroxyethylamino)-
2-pyrimidinylthio/-acetate.
A mixture of ethyl (4.6-dichloro-2-pyrimidinyl-thio)
-acetate (16 g.), anhydrous sodium carbonate (3.7 g.~, N-metnyl-
amino-ethanol (5.9 ml.) in ethanol (100 ml.) was heated to
boiling, with agitation, for 16 hours. The rnixture was filtered
and water (400 ml.) added to cause precipitation. The mixture
was then left for 60 minutes at 0C. The solid precipitate was
filtered off and recrystallised from ethanol/water. 13 g. of
et'nyl/~-Chloro-6-(N-methyl-N-~-hydroxyethylamine)-2-pyrimidinyl-
tnio7-acetate were obtained, m.p. 73-74C.
b) /4-Chloro-6-(N-methyl-N-~-hydroxyethylamino)-2-
pyrimidinyl-thio/-acetic acid.
A solution of 5.6 g. of the above-described ester
in 30 ml. ethanol, with an addition of 0.7 g. NaOH in 8 ml.
water, was boiled for two minutes, then diluted with 160 ml.
water and extracted with ether. The aqueous phase was acidified
with 17.6 ml. of HCl lN and evaporated to dryness. From
crystallisation of the residue from about 60 ml. acetone,~ 4g.
of the desired acid was obtained, m.p. 188-190C.
c) /~-Chloro-6-(N-methyl-N-~ hydroxyethylamino)-2-
pyrimidinyl-thlo/-(N-~-hydroxyethyl)-acetaMide, : . :
Operating as in Example 1, by reaction of etnylene-
; "
- ~8123~
imine with ~ -Chloro-6-(N-methyl-N-~-hydroxye-thylamino)-2-
pyrimidinyl-thio/acetic acid, the corresponding N-~-hydroxy-
ethyl-amide was obtained, in a good yield, m.p. 119-121C.
(ethyl acetate).
Example 9
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thiO/-(N-~-hydroxy-
ethyl)-acetamide.
To the solution of ~-chloro-6-(2,3-xylidino)-2-
pyrimidinyl-thio/-acetic acid (85 g.), triethylamine (45 ml.),
in anhydrous chloroform (750 ml.), cooled to -5QC, 35 ml. of
ethyl chlorocarbonate and then 22 ml. of ethanolamine were
added with stirring while the temperature was kept below +10C.
The reaction mixture was washed with water (350 ml.),- and dried
over sodium sulphate and the solvent was removed under reduced
pressure. The residue was washed with benzene (500 ml.) and
crystallised several times from acetone. 55 g. of /4-chloro-
6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-~-hydroxyethyL)-
acetamide were obtained, identical with the compound prepared
as in Example 1.
Using the same method tne following compounds were
prepared:
Example 10
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-ethyl)-
acetamide, m.p. 191-19 2C. (acetone).
Example 11
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-tnio/-(~-n-propyl)-
--- 13 -
.
.. .
.. . : .. . . ;, ..
:: ~
~638~
acetamide, m.p. 146-148C. ~benzene).
Example 12
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-i-propyl)-
acetamide, m.p. 156-158C. (benzene).
~xample 13
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio~-(N-n-butyl)-
acetamide, m.p. 137-139C. (diethyl ether).
Example 14
~-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio7-(N-n-hexyl)-
acetamide, m.p. 116-118C. (benzene/hexane).
Example 15
: .
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-n-octyl)~
acetamide, m.p. 144-146C. (benzene).
Example 16
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio7-(N-allyl)- ~ ;
acetamide, m.p. 143-145C. (benzene/hexane).
Example 17
~ .
/~-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-cyclohexyl)-
acetamide, m.p. 156-158C. (acetone).
Example 18
~4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thi~ -(N,N-diethyl)-
acetamide, m.p. 104-106C. (ethyl acetate/hexane).
Example 19
. .
~-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thi 7- (N-~-mercapto-
ethyl)-acetamide, m.p. 117-119C. (ethyl acetate/hexane).
- 14 -
LZ3~ . .
Example 20
/~-Chloro-6-(2,3-xylidino)-2 pyrimidinyl-thio7-(N-morpholino)-
acetamide, m.p. 106-108C. (ethyl acetate/hexane).
Example 21
/~-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio7-(N-piperidino)-
acetamide, m.p. 113-115C. (methylene chloride/hexane).
Example 22
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-3-hydroxy-
propyl)-acetamide, m.p. 122-124C. (ethyl acetate).
Example 23
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-4-hydroxy-
butyl)-acetamide, m.p. 84-86C. (ethyl acetate).
Using the method described in Example 9 the compounds
of Examples 2-7 were again prepared.
Example 24
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thio/-(N-n-butyl-
acetamide.
A mixture of /4-chloro-6-(2,3-xylidino)-2-pyrimidinyl-
thio/-acetic acid (1.6 g.), triethylamine (1.4 ml.), n-butyl-
amine (730 mg.), 47~ BF3-etherate (2.68 ml.) in anhydrous
benzene (.78 ml.) was heated to boiling for 24 hours. The
solvent for tne reaction was dehydrated by passing through a
Soxhlet extractor containing magnesium sulphate. The reaction
mixture washed with 10~ NaOH, then with HCl, and finally with
water to neutrality. It was dehydrated over sodium sulphate
- 15 -
and the solvent evaporated ln vacuo. ~he compound obtained
was identical with that of Example 13.
Example 25
a) (4,6-Dichloro-2-pyrimidinyl-thio)-acetic acid.
A solution of the ethyl ester of the (4,6-dichloro-2-pyrimidinyl
-thio)-acetic acid (4 g.) in a mixture of ~lacial acetic acids
(40 ml.) and HCl 37~ (8 ml.) was heated to boiling ~or three
hours. After cooling to 0C, water and ice were added and the
solid precipitate filtered off. This was purified by ether
extraction of an aqeous solution of its sodium salt. This was
then acidified, so that the acid could be filtered off again.
It was then washed with water to neutrality and dried under
vacuum over P205. On crystallisation from chloroform 2.5 g. of
(4,6-dichloro-2-pyrimidinyl-thio)-acetic acid was obtained,
m.p. 120-122C.
b) (4,6-Dichloro-2-pyrimidinyl-thio)-(~ -hydroxyethyl)
-acetamide.
To a suspension of (4,6-dichloro-2-pyrirnidinyl-thio)
-acetic acid (2.390 g.) in anhydrous benzene (24 ml.), 1.27 ml.
of oxalyl chloride in anhydrous benzene (6 ml.) was added at
room temperature. The reaction mixture was heated, with agita-
tion, to 40C., for 30 minutes and held for another 10 minutes
at 60C. The solvent was evaporated under vacuum to give an
oily residue, which was taken up again in anhydrous chloroform
(50 ml.). The chloroform solution was added drop by drop to a
- 16 -
- .:- : ~ . :
3~
solution of ethanoLamine (1.~ ml.) in anhydrous chloroform
(40 ml.) while the temperature was kept at about 15C. The
mixture was held at ambient temperature for 60 minutes and the
separated solid was then filtered off. The filtrate was
evaporated under vacuum to obtain a residue which was crystal-
lised from ethyl acetate/hexane (1.5 g.), m.p. 95-96C.
Using the same method the following compounds were
prepared:
Example 26
(4,6-Dichloro-2-pyrimidinyl-thio)-(N-~-mercaptoethyl)-
acetamide, m.p. 88-90C. (ethyl acetate/hexane).
Example 27
(4,6-Dichloro-2-pyrimidinyl-thio)-(N-butyl)-acetamide, m.p.
109-111C. (ethyl acetate/hexane).
Example 28
/4-Chloro-6-(2,3-xylidino)-2-pyrimidinyl-thi_/-(N-~-hydroxy-
ethyl)-acetamide.
A mixture of (4,6-dichloro-2-pyrimidinyl-thio)-(N-R-
hydroxyethyl)-acetamide, obtained as in Example 25, (0.490 g.)
and 2,3-dimethylaniline (0.434 ml.) was heated until melted
by immersion in an oil bath (T:110C.) for 10 minutes. The
solid residue thus obtained was cooled and crystallised from
acetone, to gi~e 0.400 g. of /4-chloro-6-(2,3-xylidino)-2-
pyrimidinyl-thi_/-(N-B-hydroxyethyl)-acetamide, identical with
that made according to Example 1.
Using the same method the compounds of Examples 2 to
7 and 10 to 23 were also prepared.
- 17 -
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