Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
lQ4~;31
The present invention relates to a process for pre-
paring compounds represented by the general formula I:
~ ~ -R
~N JJ\N~LX ( I )
2
wherein R is selected from hydrogen, lower alkyl, lower alkenyl,
lower alkynyl, aralkyl and lower alkyl substituted with halogen,
hydroxyl, lower alkoxy, lower alkanoyloxy, vinyloxy, lower ~ -
hydroxyalkoxy, lower cycloalkyl, carboxyl, lower alkoxycarbonyl,
di(lower alkyl)amino or six-membered cyclicamino; and X is O
or S.
All of the compounds prepared according to the process
of the present invention possess at least one of such pharma-
cological activities as anti-inflammatory, anti-ulcerative,
analgetic, antipyretic, antihistaminic and central nervou~
system depressive activities as well as low toxicity, and most
of them possess more than one of the said activities. It is
to be noted, therefore, that certain of the compounds within
the scope of the present invention are useful as new analgesics,
anti-inflammatory agents and central nervous system depressants.
- Mor~ particularly, preferred compounds prepared ac-
cording to the process of the present invention can be repre-
sented by the general formula II:
~ ~ ~ X (II)
~J~ N0
'.
1040631
wherein R is selected from hydrogen, lower alkyl groups having
from one to 6 carbon atoms, lower alkenyl groups having from
3 to 5 carbon atoms, haloallyl, propargyl, cyclopropylmethyl,
lower haloalkyl groups having from one to 3 carbon atoms, lower
txihaloalkyl groups having from one to 3 carbon atoms, acetoxy-
ethyl, lower hydroxyalkyl groups having from 2 to 3 carbon atoms,
lower alkoxyalkyl groups having from 2 to 4 carbon atoms, vinyl-
oxyethyl, hydroxyethoxyethyl, carboxymethyl, ethoxycar~onyl-
methyl, 2,3-epoxypropyl, diethylaminoethyl, 4-methylpiperazino-
ethyl, benzyl, phenethyl and cinnamyl; and X i5 0 or S.
The compounds disclosed herein may be prepared accord-
ing to the process represented by the following reaction scheme.
Reaction scheme
.
+ ACXB ) ~ ~ X
~D NO f~o:2
(III~ (IV) (I)
wherein R and X have the same meanings as defined in the above
formula(l); ~ is selected from amino, lower alXylamino, sub-
stituted lower alkylamino, unsaturated lower alkylamino, sub-
: stituted unsaturated lower alkylamino, aralkylamino, hydroxyl
and lower alkoxy; A and B are the same or dissimilar and are
halogen, amino, lower alkylamino, unsaturated lower alkylamino,
substituted lower alkylamino, substituted unsaturated lower
alkylamino, aralkylamino, lower alkoxy 9 trihalomethyl or
imidazolyl.
In more detail, the process of the presentinvention
- 2 -
:,
, .: .
~ , . .
~ 040631
may be explained by the following reaction scheme (1) and (2).
eaction scheme (
+ aCXb ) ~ ~ X
~ N02 ~ ~2
(III - 1) (IV ~ 1~ (I)
wherein R and X have the same meanings as above; a and b are
the same or dissimilar and are halogen, amino, lower alkory,
trihalomethyl or imidazolyl. Examples of compounds of the
general formula (IV-l) include urea, methylurea, diethylurea,
N-propylurethane, trichloroacetyl chloride, N-ethoxycarbonyl-
imidazole, l,l'carboxyldiimidazole, phosgene, ethyl chlorocar-
bonate, diethyl carbonate, l,l'thiocarbonyldiimidazole and
thiophosgene.
Reaction scheme (2)
- ~ + RNHCXb' ~ ~ ~
N H ~N \N ~ X
~ N2 ~ N02
(III - 2) (IV - 2~ (I)
wherein R and X have the same meanings as above; y is hydrogen
or lower alkyl; and b' is amino or lower alkoxy. Examples of
compounds of the general formula (IV-2) include urea, diethyl-
urea, N-propylurethane and thiourea.
The reactions of the present invention are generally
iO4~631
carried out in an organic solvent such as dimethylformamide,
diglyme, tetrahydrofuran or alcohol. In the preferred procedure,
the reactions should be carried out in the presence of a metal-
lic compound such as metallic sodium, sodium amide and sodium
hydride, or an organic base such as trialkylamine and pyridine,
or an inorganic base such as alkali hydroxide and carbonate.
The first-mentioned metallic compounds are most effective to
enhance the yield of product. The reaction temperature is not
critical, and may be ambient or elevated temperature. However,
the reaction is carried out under ice-cooling when phosgene or
thiophosgene is used as a reagent. The reaction solvent is ~ -
distilled off from the reaction mixture under reduced pressure
and the re~idue obtained is mixed with water to precipitate a
crude product. Recrystallization of this product from an
organic solvent such as acetone or methanol yields pure cry-
stals.
The starting materials represented by the general for-
mula (III) may be prepared in high yield~ by reacting 2-anil-
inonicotinic acid derivatives or 2-anilinonicotinyl chloride
derivative~ with amines or alcohols, but the preparation of
the starting materials is not to be limited to this method.
ComPound:
- Some example of the compounds obtained according to
the process of the present invention and the melting points
thereof are shown in Table I.
--4--
- .. ~ - - - : -
- . . : .
..
~14~631
Table I
. . .
Examples of the compounds obtained by the present invention
O
N-R
NO2 . .
..._
No. X R Melt(ng)potnt
. .. _ .
1 0 -H 302 - 303
_ ,.
2 " -CH3 234 - 235
. .. _ __. ._
3 u -C2H5 210 - 211
. .
: 4 ll -CH2CH2CH3 184 - 185
. CH
-CH~H3 217 - 218
: 6 ll -CH2CH2CH2CH3 146 - 147
7 -CH2CH~CH3 . 199 - 200
8 ,. -CH2CH2CH2CH2CH3 150 - 151
_. . . _
~ 9 ,. -CH2CH=CH2 192 - 193
; . CH
~ _ .................. -CH2CH=C~cH33 _ 178 - 179
11 .l -CH2CH=CHCl 217 - 218
.
12 ll -CH2C=CH 239 - 240
13 -CH2 ~ . 165 - 166 .
_5_
16~40631
.
Compound X R Meltlng)point
. . .. . .: -
14 0 -CH2CH2Cl 202 - 203
. . .,
l 15 ¦ " -CH2CH2F 233 - 234
_. . ____ _
16 ll -CH2C~3 228 - 229
__ ~
17 ll -CH2CH2CH2Cl -159 - 160
. .
18 ll -CH2CH20H 212 - 213
.
19 n -CH2CH2CH20H 173 - 174
. . : '
, 20 . -CH2C~H~CH2 201 - 202.
. 21 . -CH2CH20COCH3 195 - 196
. . . .' -, .
22 ll -CH20CH3 184 - 186 : .
.
23 -CH2CH20C2H5 163 - 164
24 -CHzCH20CH-CH2 182 - 183
.l -CH2CH20CH2CH20H 176 - 178
:
26 .l -CH2COOH 244 - 245
27 ~~ l -CH2COOC2Hs 200 - 201 :~ : ;
28 -CH2cHz-N~c2Hss. (Hydrochloride~
29 u -tH2CH2-N N-CH3(Hydrochloride)
. .
3D _ _ -CH2 ~ 219 - 220
- -
~Q4Q631
. .. .
L~mp~d X R Mel ti (g )oi n~
31 0 -CH2CH2~ 227 - 228
. . .
32 " -CH2CH=CH~ 191 - 1 g2
..
33 S -CH3 265- 266
. - .
34 n -C2Hs . 239 - 240
ll -CH2CH2CH3 190 - 191
. .
36 -CH2Ct1=CH2 : 248 - 250
37 ll -C~t2C--CH 209 - 210
38 -CH~2~ 199- 200
39 . ~ -CH2CF3 242 - 243
.
-CH2~ 224- 22
.
- Pharmacolo~ical activiti~ ~ 40 6 31
With respect to numerous compounds of the present
invention, the acute toxicity was tested to ensure their
safety, and further central nervous system depressive, anti-
inflammatory and analgetic effects were tested to prove thair
excellent activities. The results of each test are indicated
in Table II. Each test was conducted in the following manner.
(1) Acute toxicity
Each test compound suspended in 0.5~ tragacanth-
saline solution was administered intraperitoneally or orallyto dd-strain male mice (16-24 g). The lethal dose was e~ti-
mated from the death of animals 72 hours after administration.
(2) Anti-inflammatory effect
A group of five Wistar-strain male rats (100-150 g)
were orally administered with each test compound suspended in
0.5~ tragacanth-saline solution. After 30 minutes 0. ~-1.0~
carrageenin suspended in the water for injection was injected
subcutaneously to a hind paw. After 3 hours the carrageenin -~
edema wa~ measured by volume and the inhibition percentage
was determined with respect to the results for the control
animals. The inhibition percentages were shown with the nota-
tion~ as follows~
less than 15%: + 31-45%: ++ more than 61~: ++++
16-30~: + 46-60~ +
(3) Analgetic effect
Each test compound suspended in 0.5~ tragacanth-saline
solution was orally administered to dd-strain male mice (lo~
20 g~. After one hour o.6% acetic acid solution was intra-
peritoneally iniected in a volume of 0.1 ml/10 g The writhing
- 8 -
' , ' ' ~ ' ' -, ' ' '
.
104~631
syndrome was observed for 10 minutes from 30 minutes after
the injec-tion~ and 50~ analgetic effective dose (ED50) and
its 95~ confidential limits wer~ calculated by ~itchfield-
Wilcoxon's method.
(4) Central nervous system depressive effect
Each test compound suspended in 0.5~ tragacanth-
saline s~lution was injected intraperitoneally to dd-strain
male mice ~16-24 g). The disappearance of righting reflex
was observed under noiseless circumstances. The dose required
for the disappearance of righting reflex is indicated with
the following notations:
more than 1,000 (mg/kg~: - 100-30 (mg/kg~: ++
1,000-300 (mg/kg~: + 30-10 (mg/kg): +++
300-100 rmg/kg): + less than 10 (mg/kg~: +++~
,
_ 9 _
,
~04Q63~
Table II
_ . .... __
Anti-inflammatory, Analgetic and Central Nervous System Depressive Effects, and
Acute Toxicity of the Object Compounds of General Formula:
O
N-R
NO2
l _ .
anti-inflam- analgetic C N S acute
matory effect depres- toxicity
.e ff e~t EDso sive ~mg/k9)
Standard compounds dose(mg~kg) (9SgC.L.) effect
10(mg/kg) i.p.
phenylbutazone * +lll3 4~5) ~~00-1000 1
flufenam~c acid + +(131-245) 300-1000
aminopyrine + +(43PO-753 0) /100-300
methaqualone / / / ~+300-1000
diazepam + + / _ 300-1000
Known analogous compounds anti-inflam- analgetic C N S acute
matory eff~ct depres- toxicity
N-R2effect ED50 sive ~mglkg)
N ~ N ~ dose(mg/kg)(95%C L;) effect .
Rl
: Rl R2 100 50 2G 10 _ i.p. P
: ~ CF ¦ -C2H5 ~ +ut ~+ +~ (210 51.4) +~ 600 665
_ _ __
-CH3 ¦+~+ ++ +~ ++ (2.7 18.5) + >1000 >1000 . .
~ Br -CH2CH2CH3 ¦+H+ +* ~ ~+ ~2 9 ;37 0) >1000 /
--10--
1~4~631
.. _ . _ . ............. .
anti-inflam-ana1getic C N S acute
matory effect depres- toxici~y
effect ED50 sive (mg/kg)
X R dose(mg~kg)(95%C.L.) effect
(mg/kg)
100 S0 .20 10 i.p. p.o.
,__ ._. ... .. __ .__ .. _ .
0 -CH2CH20C2Hs * ** ** * (0.06-0.44) ~+ >1000 /
__ . ._
., -CH2COOH - / * + /(13.5 80.9) + >1000 >2000 ~:~ . . _ .. _ . .
. " -CH2COOC2Hs ++ *+ * *(17.3 117) + lOOQ ~2000
_ .__ .... _
-CH2 ~ +x+ ** *+ *(0.63 4.56) _ 1000 2000
! -
: n -CH2CH2 ~ + - / >100 + >1000 >2000
. ._. . . .
-CH2C0 ~ Cl + / / / >100 >1000 >2000
. ,..... .. _ .. .. _ ~_ _
: S -CH~ / ~* / +* (0.23 1.55) >1000 >2000
,~ . . . _ .__
-C2Hs / ~* / ~* -0.2 ++ ~1000 ~2000
-CH2CH2CH3 / + / + ~100 _ >1000 >2000
. . .~
-CH2CF3 / *+ / t~+~o.o7 o.377) ~ >1000 2000
.
--12--
1~4¢~;31
.
Object compounds anti-inflam- analgetic C N S acute
O matory effect depres-toxicity
~N-R effect ED50 sive(mg/kg)
~N~N'l X dose(mg/kg) (95C.L.) effect
f ~ (mg/kg)
~JL NO2
X R 100 50 20 10 i.p. p.o.
.... _ . ... ~. _
-CH3 ** ** ** **(o.o;170,542) l 200- 2000
*It 0.113 300- 1000-
-C2H5 I +~++~+(0.027-0.476 + 1000 200n
-CH2CH2CH3 +* * +~ **(1.05-6.40) _ 1000 >2000
..
-CH~CcH3 ~* +~ ** +~ 2 15 * >1000 /
CH 3 1
-CH2CH~CH3 * * * /(1.20-8.30) + 1000 >2000
-CH2~ ~* +x+ +~*~K+ (0.048-0.298' ____ 300 250O _
. , _ _
_ -CH2CH=CH2 +* *~ +~ +*(1,20566,40) * 300- >2000
ll -cH2~H=c'cH3 *~ ff* +~ ~+(0.18-1.02) 2aoSOO >2000
_
-CH2C_CH +~+ +~ m +~ 1 15 + >1000 >2000 r
-CH2CH2Cl *+ +~ ** ++ O 19 _ >1000 >2000
-CH2CH2F +It +~+ ~+ *+ ~i 0.01 * 100- 2000
-CH2CF3 ++ ~+ ~ ~+ 1 28 _ >1000 >2000
-CH2CH20H * * / /(o.o54-l2.l5) ~>lOOC >2000
-CH2CH2CH20H +H~ +~ ~ * -1.0 + >~Oû >2000 ,
-CH2CH20COCH3 * ~ / / ¦(0.06-C.433 _ 2000 l
.
=11 -
: . .
. -
.
1~4~;3~
~ he present invention is illustrated hereinafter but
not limited to these Examples.
Example
To a solution of 3.0 g of N-(n-propyl)-2-!m-nitro-
anilino~nicotinamide and 25 ml of tetrahydrofuran was added
0.5 g of 50% sodium hydride, and the whole was stirred for
15 minutes. To this was further added dropwise under cooling
5.4 g of ethyl chlorocarbonate. The mixture was allowed to
stand for one hour and then refluxed for 10 hours. After
10 the reaction was complete, the solvent was distilled off
from the resulting mixture under reduced pressure. To the
residue thus obtained was added water to precipitate a crude
product. This product was recrystallized from methanol to
yield 2.5 g of 1-(m-ni~rophenyl)-3-n-propylpyrido [2,3-d~pyri-
midine-2,4(1H,3H~-dione as pale yellow prisms, melting at 184-
185C. Analysls-Calculated for C16 H14N404: C, 58.89; H,
4.32: ~, 17.17. Found: C, 58.95; H, 4.31; N, 17.09.
Example 2
To a solution of 3.0 g of N-allyl-2-(m-nitroanilino)
20 nicotinamide and 25 ml of tetrahydrofuran was ~dded 1.0 g of
approximately 50~ sodium hydride, and the wh~le was stirred
for 30 minutes. To this was further added dropwise under
cooling 16 g of 30~ phosgene-toluene solution. The mixture
was stirred for one hour and then refluxed for 2 l-ours. After
the reaction was finished, the solvent was di~tilled off from
the resulting mixture under reduced pressurer To the residue
thus obtained was added water to precipitate a crude product.
This product was recrystallized from ethyl acetate to yield
: , . .
,. . -
104~ti31
2.8 g of 1-!m-nitrophenyl)-3-allylpyrido ~2,3-~ pyrimidine-2,
4~1H,3H)-dione as colourless needles, melting at 188-189C.
Analysis-Calculated for C16H12N404: C, 59.26; H, 3.73; N,
17.28. Found: C, 59.21; H, 3.69; N, 17.34.
Example 3
To a solution of 2.7 g of N-methyl-2-(m-nitroanilino)
nicotinamide and 20 ml of dry diglyme we~e added o.6 g oE 5~
sodium hydride and 5.9 g of diethyl carbonate, and the mixture
was refluxed for 12 hours. After the reaction was complete,
the solvent was distilled off from the resulting mixture under
reduced pressure to leave a residue, to which was added water
to precipitate a crude product. Recrystallization of this
product from methanol gave 2.6 g of 1-(m-nitrophenyl~-3-methyl-
pyrido ~2,3-~ pyrimidine-2,4(lH,3H~-dione as colourless prisms,
melting at 234-235C. Analysis-Calculated for C14H1oN404:
C, 56.38; H, 3.38; N, 18.79. Found: C, 56.45: H, 3.36; N, 18.72.
Example 4
To a solution of 2.9 g of N-ethyl-2-(m-nitroanilino)
nicotinamide and 50 ml of tetrahydrofuran were added 1 g of
50~o sodium hydride and 4.9 g of l,l'carbonyldiimidazole, and
the mixtur~ was stirred for on~ hour and then refluxed for
5 hours. After the reaction was finished, the solvent was
remo~ed from the mixture under reduced ~?ressure. To the
residue thus obtained was added ice-cold water to yield a
precipitate. This product was recrystallized from methanol
to give 2.6 g of 1-(m-nitrophenyl~-3-ethylpyrid~ 2,3-~ pyrimi-
dine-2,4(1H,3H)-dione as colourless needlesS melting at 193- - -
195C. Analysis-Calculated for C15H12N404: C, 57.69; H, 3.87:
- 14 -
.
104~tj31
N, 17.94. Found: C, 57.65; H, 3.82, N, 17.89.
Example 5
To a solution of 1.25 g of N-methyl-2-(m-nitroanilino)
nicotinamide and 20 ml of tetrahydrofuran was added o.48 g of
approximately 5~ sodium hydride and the mixture was stirred
for 30 minutes. To the mixture was further added dropwise
2.3 g of thiophosgene under cooling with ice and the requltant
mixture was allowed to stand for 30 minutes at room temperature.
The excess of thiophosgene was decomposed by adding methanol- _
ammonia qolution. The solvent was distilled off from the
mixture to give a residue, to which was added water to preci-
pitate a crude product. Recrystallization of this product
from acetone gave 1.2 g of pure 1-(m-nitrophenyl)-3-methyl-
2-thio-4-oxo-1,2,3,4-tetrahydropyrido~2,3-d~pyrimidine as
pale yellow prisms, melting at 265-266C. Analysis-Calculated
for C14HloN403S: C, 53.51; H, 3.21; N, 17.83. Found: C,
53.63; H, 3.19; N, 17.69.
Example 6.
To a solution of 2.9 g of 2-(m-nitroanilino~nicotinic
acid ethyl ester and 20 ml of dimethylformamide was added o.48
g of 55% sodium hydride and the whole was stirred for one hour
at room temperature. To this was further added 10.3 g of
N-methylurethane, and the mixture was reacted at 100C for
20 hours. After the reaction was complete, the solid preci-
pitate was produced and filtered off. The filtrate was con-
centrated under reduced pressure to leave a residue, to which
was added water to yield a crude product. This product was
collected by filtration and than recrystallized from methanol
.
:: . . :
.
104~ti 31
to give 1.4 g of 1-~m-nitrophenyl~-3-methylpyrido~2,3-~ py-
rimidine-2,4(lH,3H~-dione as pale yellow prisms, melting at
234-235C. Analysis-Calculated for C14Hlo~404: C, 56.38;
H, 3.38: N, 18.79. Found: C, 56.32; H, 3.39; N, 18.68.
Example 7
To a solution of 2.7 g of 2-(m-nitroanilino~nicotinic
acid methyl ester and 20 ml of dimethylformamide was added
o.48 g of 55~ sodium hydride, and the whole was stirred for
one hour at room temperature. To this was added 6 g of urea
and the mixture was reacted at 160C for 15 hours. After the
reaction was complete, the solid precipitate was produced and
filtered off. The filtrate was concentrated under reduced
pressure to leave a residue, to which was added water to yield
a crude product. This product was recrystallized from di-
methylormamide to yield 1.5 g of l-(m-nitrophenyl~pyrido
~2,3-~ pyrimidine-2,4(1H~3H~-dione as colourless prisms, melt-
ing at 302-303C. Analysis-Calculated for C13~N404: C, 54.~3;
H, 2.84: N, 19.71. Found: C, 54.81; H, 2.81; N, 19.67.
Example 8
To a solution of 2.9 g of 2-(m~nitroanilino~nicotinic
- acid ethyl eQter and 20 ml of dimethylformamide was added o.48
y of sodium hydride, and the whole was stirred for one hour
at room temperature. To this was further added 11.7 g of
N-ethylurethane and the mixture was reacted for 15 hours at
100C~ After the reaction was complete, the solid precipitate
was produced and filtered off. The filtrate was concentrated
under reduced pressure to leave a residue, to which was added
water to precipitate a crude product. This product was re-
- 16 -
104~)~31
crystallized from methanol to yield 1.3 g of l-(m-nitrophenyl~
-3-ethylpyrido~2,3-~ pyrimidine-2,4!1H,3~-dione as pale
yellow prisms, melting at 210-211C. Analysis-Calculated
for C H12N404: C, 57-69; H, 3-87; N, 17-94- Found: C,
57.59; H, 3.82; N, 17.89.
-~ 17 -
