Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
i O S ~2~7
For reducing the drawbacks of steroid series anti-in~lammatory
agents, arylacetic acid series compounds~ such as 2-(4-isobutylphenyl)acetic
acid, 2-(4_isobutylphenyl)propionic acid, 2-(2-fluoro-4-biphen~l)propionic
acid, 2-(3-phenoxyphenyl)propionic acid and 2-(3-benzo~lphenyl)propionic acid
have been developed recently.
Among them, 2-(4_isobutylphenyl)propionic acid has been used fre-
quentl~ and extensivel~ to treat inflammation by reducing inflammation and
relieving pain in such diseases as rheumatoid arthritis, osteo arthritis,
gout, infectious arthritis and rheumatic fever for its excellent anti-inflam_
mator~ and analgesic activity and its low toxicity.
On the other hand, as the stilbene derivatives which is similar to
the compounds of this invention in their chemical structures, the following
compounds are disclosed:
(1) 4-stilbeneacetic acid; inhibitor of coenzyme A and cholesterol and lipid
increasing factors, (Arch Intern, Pharmacodynamie, 109, 400 (1957) ),
(2) 2-stilbeneacetic acid; a proposed intermediate for the preparation of
benzylisoquinoline, (J. Am, Chem. Soc , 64, 2962 (1942) ),
(3) 4_stilbeneacrylic acid; Potential anti-ch~lesterinemic a~ti-rheumatic
drug, (J, Am, Chem. Soc., 79, 3514 (1957), United States Patent 2,885,434),
(4) 4_(4-stilbene)butanoic acid; anti-inflammatory, analgesic and Y~nti-
pyretic compound, (Belgian Patent 667,498),
(5) 4,4'~stilbenedi~arboxylic acid and 3,5-stilbenedicarbox~lic acid; photo_
sensitive synthetic polyamido resins, (United States Patent 2,997,391), and
(6) 4-(p, o, or m_fluorostyryl~salicylic acid and 5-(p, o, or m_fluoro-
9tyryl)_9alic~1ic acid; anti_inflammatory, analgesic and antipyretic com_
pounds, (United States Patent 3,657,430).
~i The compounds of items (4) and (6) are reported to have anti-
inflammatory, analgesic and antipyretic activity, however, practical des-
cription of pharmacological and ~herapeutic activit~ has not been found.
Thi~ invention-relates to a process for preparing new s~ilbene
,~
.- . , . . ,- ~ , . . - . - - . .
- . .. , .: .
10~3257
derivatives. More particularly, this invention concerns with a process for
preparing novel stilbene derivatives represented by the general fornula (I)
R3
CHCOOH
~ ~3 ~
wherein ~ and R2 are independently hydrogen, lower alkyl, lower alkoxy,
halogen or haloalkyl, and R3 is hydrogen or lower alkyl, which comprises
hydrolysing the compounds represented by the general formula (II)
M
CH ~I ~ II
wherein Rl and R2 are as defined above and M is chosen from -HC(R3)CH wherein
R3 is same as defined above, -CH2C(S)B wherein B is amino~ -HC(R3)COOA where-
in R3 ls as defined above and A is alkyl, or -C(R3)(COOA)2 wherein R3 and A
are same as defined above, in water, an organic solvent or a mixture thereof
in the presence of acid or alkali, and further decarboxylating the product
when M is -C(R3)(COOA)2-
This invention seeks to provide novel stilbene derivatives possess-
ing excellent anti-inflammatory and analgesic activity.
"
. This invention also seeks to provide novel stilbene derivatives, the
- toxicity of which ls extremely low.
,
This invention further provides novel stilbene derivatives by simple
and ¢onvenient preparing procedure.
Through our systematlc pharmacological screening of newly-synthesized
-~ various oompounds, it was found tha~ the compounds represented by the general
formula (I) have excellent anti-inflammatory and analgesic activity, and low
toxicity. For example, 2-(3-stilbene)propionic aoid, one of the compounds of
this 1nvention, is about 1.5 times more effective than 2-(4-isobutylphenyl)-
propior~o acid in anti-inflammatory and analgesic actlvity. Moreover, LD50
value of 2-(3-stilbene)propionic acid in mice is 2152 m~iXg
: L~
~ - 2 -
'If ' ' ' ' ' . ' : ~
,', . ' , ' ,' . '.. ' , ', , ' '' ' .: ' , ' . ' . ' ' ' " : '' '
lOS3ZS7
orally which is about twofold higher than that of 2-(4-isobutylphenyl)-
propionic acid.
In this specification and claims, the terms "lower alkyl" and
"lower alkoxy" re~er to each group having 1-5 carbon atoms which group may be
straight or branched. The term "halogen" may be chloro, bromD, fluoro, or
iodo and "haloaLkyl" means halogenated lower alkyl such as trifluoromethyl,
etc.
The compounds of the present invention may be prepared by processes
well known in the art. mese processes produce novel compounds, therefore,
10 such novel compounds and processes for the preparation thereof are also part
of the present invention.
The following schemes are suitable for preparing the compounds of
this invention. In these representations, Rl, R2 and R3 are usually as here-
inbefore defined for general for$ula (I), and various reactions, such as,
hydrolysis, alkylation, halogenation, cyanation, reduction, decarboxylation,
esterification, Meerwein arylation, condensation and Willgerodt reaction,
may be carried out in the usual manner.
Scheme (I) R
13 R
CHCN
/ CHCOOH
(II~
20 The compounds (IIa) are preferably hydrolyzed in water, an organic solvent
or a mixture thereof in the presence of an acid or a base at 20-120C. As
an acid, a mineral acid such as hydrochloric acid and sulfuric acid is suit-
able. An alk~li n~tal hydroxide such as sodium hydroxide and potassium
hydroxide is preferably used as a base. As an organic solvent, a water-
soluble solvent, such as lower alcohols, tetrahydrofuran and dioxane etc.
may be employed. Particularly, in the presence of an acid such as sulfuric
~ _ 3
~ ,,~, ~, . ..
- . .
,
' ~ ' ' ' ' ' ' : - , ' :
~OS3~S7
acid, acetic acid is frequently used as a suitable solvent in the form of
the mixture with water or as it is.
The intermediate CIIa) can be prepared by the processes of Schemes
~a), (b) and ~c).
Scheme (a?
R
~CH2CN
R ~ CH=CHY I H2N
2 Meerwein arylation and
optional alkylation
., ~
'., Rl ~ CH2CN
"3~=9--NH2 + YHC=HC~
.,,'. R2 ,
,,;~
., 1 CHCN
~3CH~CH~ ~ ~
.1 R2 ~:
, (Y is hydrogen or carboxy)
The alkylation may be carried out by reacti.ng an optionally
substituted 3-stilbeneacetonitrile with an alkali metal hydride such as sodium
. hydride or an alkali metal alcoholate and further with an alkyl halide or
dialkyl sulfate.
: ., : . .
., , ,. - .
- . : : . . . .
.~ ~ ,. .
S3~5~7
Scheme (b) R13
Rl C112
~CH=CHY l H2N
R2
R
R 13 Meerwein arylation
~ NH2 ~ YHC=HC C~
R
: !3 : .
CHCN
cyanation > / / ~H=CH ~
2 ~ :
~Rl and R2 are hydrogen, lower alkoxy, halogen or haloalkyl, Y is hydrogen or
j carboxy and X is halogen)
For instance, an optionally substituted 3-alkylstilbene may be
I converted into the corresponding 3 haloalkylstilbene with a N-halosuccinimide,
;l 10 such as N-bromosuccinimide and thus produced halide is reacted with sodium or
potassium cyanide to give the corresponding stilbeneacetonitrile.
.
~ .
- 5 -
.
.., : -
1053ZS'7
Scheme (c) 3
I
C=O
Rl CE=CHY l H2N
R3 Meerwein arylation
Rl C=O
~ ~ NH2 + YHC=HC ~
R2 IR3 IR3
1 C=0 CHOH
~ CH=CII~ reduction ~ ~CH=CH
., IR3
CHX
halogenation > ~ CH=CH
2 R
1HCN
cyanation > ~ Cll=CH~
R2
(R3 is lower alkyl, Y is hydrogen or carboxy and X is halogen)
An optionally substituted alkanoylstilbene is reduced to thecorresponding 3~ hydroxyalkyl)stilbene with sodium borohydride, lithium
alu~inum hydride, lithium borohydride or aluminum isopropoxide. The obtained
hydroxy compound may be converted into the corresponding 3-Cl-haloalkyl)
1, stilbene by reaction with a halide of phosphorus or sulfur, for instance,
phosphorus oxychloride or thionylchloride, or a similar bromide.
..
.~ . .
.~ .
~053~S7
Scheme (2)
Rl cC=Ho S
~ Wi llRerodt~ Cll=C~I ~H~CB
2 R2
H COOH
Rl / 2
hydrolysis ~~ 3CH=CH -
~B is amino)
An optionally substituted acetylstilbene is converted into the
corresponding 3-stilbeneacetothioamide by the usual manner of Willgerodt
reaction or Willgerodt-Kinder reaction, that is, by refluxing or heating in
sealed vessels at 130 - 230 C with sulfur and an amine, preferably a secon-
dary amine, more favorably, a cyclic secondary amine such as morpholine.
Hydrolysis of 3-stilbeneacetothioamide is carried out in the same manner as
described in Scheme
Scheme (3)
Rl / CH2COOH Rl OOA
~H=CH~ esterification~ ~ - CH=CH~
~2 ~2
~ .
13
R ~ CHCO0A
alkylation > ~ CH=CH~
., . :- . . ~ , . .
'' , , ' ' ' ' " . '. "' ' " " '
lOS3ZS7
IR3
CHCOOH
hydrolysis> ~ CH=CH
(R3 is lower alkyl and A is alkyl)
Esterification may be carried out by heating or refluxing ~n op-
tionally substituted 3~stilbeneacetic acid with an ester-constitutive alcohol
in the presence of a mineral acid such as sulfuric acid, hydrochloric acid or
a strong organic acid e.g. p-toluenesulfonic acid. Further~ benzene or
toluene may be added into the reaction mixture for removing eliminated water
azeotropically.
Alkylation and hydrolysis are carried out in the same manner as
described in Scheme Ca) and Scheme Cl), respectively.
Scheme C4~
~, Rl CH2COOA
H=CH ~ \ condensation >
~ AO
R
Rl CH~COoA)2
~CH=CH~ alkvlation~
R3 R3
Rl / C~COOA)z Rl CHCOOH
~ CH=CH~ tnd ~ CH=CH
R2 decarboxylation
R2
(R3 is lower alkyl and A is alkyl)
An optionally substituted alkyl 3-stilbeneacetateis condensed
-- 8 --
- ~: . ,, :: . : . . ..
105;~'~S7
with dialkylcarbonate in the presence of an alkali metal alcoholate. ~le
obtained dialkyl 3-styrylphenylmalonate is alkylated and hydrolysed in the
same manner as described above. Decarboxylation is carried out by treating
the corresponding 3-styrylphenylmalonic acid at an elevated temperature, pre-
ferably, at 80 - 250C.
. An optionally substituted 3-stilbeneacetic acid ester may be
prepared by condensing an appropriate alcohol with the corresponding 3-stil-
beneacetic acid, 3-stilbeneacetic anhydride or 3-stilbeneacetic acid halide.
If necessary, the salts of 3-stilbeneacetic acids can be easily
prepared by reacting the acids with organic and inorganic bases.
The following compounds are typical of the active compounds of the
general formula ~I), but do not limit the invention in any way.
Compound No.
~1) 3-stilbeneacetic acid
(2) 2'-methyl-3-stilbeneacetic acid
3) 4'-methyl-3-stilbeneacetic acid
, C4~ 4'-ethyl-3-stilbeneacetic acid
5) 2-C3-stilbene)propionic acid
6) 2-C2'-methyl-3-stilbene)propionic acid
(7~ 2-(4'-methyl-3-stilbene)propionic acid
8) 2-(2',5'-dimethyl-3-stilbene)propionic acid
C9) 2-C4'-ethyl-3-stilbene)propionic acid
(10) 2-C4'-methoxy-3-stilbene)propionic acid
Cll) 2-(3'-chloro-3-stilbene)propionic acid
(12) 2-C4'-chloro-3-stilbene)propionic acid
~13) 2-(2',6'-dichloro-3-stilbene)propionic acid
14) 2-C4'-fluoro-3-stilbene~propionic acid
C15) 2-(3'-trifluoromethyl-3-stilbene)propionic acid
C16) 2-C3-stilbene)butyric acid
_ g _ - ~
,, '
. ~ .
: . . ~ , .
- lOS3~57
Example 1
3-stilbeneacètonîtrile
A mixture of 55 g of 3-methylstilbene~ 45 g of N-bromosuccinimide
and 0.2 g of benzoyl peroxide in 250 ml of benzene was refluxed for 3 hours
with stirring. The reaction mixture was added with 300 ml of isopropyl ether
and cooled in ice bath. Precipitated succinimide was filtered off and the
filtrate was washed with 5 % sodium hydroxide solution and water successively
and dried with anhydrous calcium sulfate. Evaporating the solyent gave 80 g
of pale yellowish oil. The oil was added with a solution of 20 g of sodium
cyanide in 70 ml of water and 300 ml of ethanol and was refluxed for 6 hours
with stirring. After evaporating the ethanol, the reaction ~ixture ~as added
with 500 ml of ethyl ether, washed with water and saturated sodium chloride
solution and dried, successively. The brown oil which was obtained by evaporat-
ing ether was refined by silica gel column chromatography ~eluting solvent:
n-hexane - benzene mixture) and recrystallized from methanol in colorless plate
to give 37 g of 3-stilbeneacetonitrile, m.p. 54 - 55C.
3-stilbeneacetic acid (1)
To a solution of lQ g of sodium hydroxide in 20 ml of ~ater and
40 ml of methanol, 3.9 g of 3-stilbeneacetonitrile was added and refluxed for
12 hours. After evaporation of the methanol, 50 ml of water and 50 ml of
concentrated hydrochloric acid were added to the reaction mixtureJ which was
extracted twice by each 100 ml of chloroform of 40C. The extract was washed
with water and dried. Then, the chloroform was removed by distillation giving
crystalline precipitate of the objective compound. The precipitate was re-
crystallized from benzene in colorless plate to afford 3.8 g of 3-stilbene-
acetic acid, m.p. 183 - 184C. Analysis C16 H14 2' Calcd: C, 80.64%;
H, 5.92%, Found: CJ 80.41%J H, 6.05%.
~xample 2
3-stilbeneacetic acid ~1)
To 50 ml of 60 % sulfuric acid, 4.4 g of 3-stilbeneacetonitrile
-- 10 --
- . . .
,.
,, ,. . , . , , - . . .
1053ZS7
was added and stirred at 70C for 6 hours. After coolingJ 120 ml of water
was added to the reaction mixture. Separated precipitate was filtered, washed
with water and recrystallized from ethanol to give 3.6 g of 3-stilbeneacetic
acid.
Example 3
3-acetylstilbene
To a suspension of 162 g of 3-aminoacetophenone, 300 ml of concen-
trated hydrochloric acid and 200 ml of water, was added a solution o 83 g of
sodium nitrite in 150 ml of water with stirring at -10 - -5C during one hour
period. An ice cooled solution of 167 g of styrene in 1.5 liter of acetone
was added to the solution of the diazonium salt. The mixture was cooled to
;~ ~15 - -10C, and then 101 g of sodium bicarbonate was added. After evolution
of carbon dioxide ceased, 5.0 g of cupric chloride dihydrate was added to
the mixture with vigorous stirring, and nitrogen evolution was observed. The
temperature of the xeaction mixture was controlled so that nitrogen evolved
smoothly. Ater the evolution ceased~ the organic layer was separated and
concentrated. The residual oil was dissolved in ethyl ether, and washed with
2 N hydrochloric acid, water, 10 % sodium hydroxide aqueous solution, and
~t saturated sodium chloride solution successively, and dried over anhydrous
calcium sulfate. After removal of the ether, a solution of 120 g of sodium
Z
hydroxide in one liter of methanol was added to the resulting oil. The mix-
ture was refluxed for 20 minutes, and concen~rated to a volume of 500 ml under
; reduced pressure, and added to ethyl ether. The ethereal solution was washed
.
with saturated sodium chloride solution, dried over anhydrous calcium sulfate,
and concentrated. The residue was crystallized from 700 ml of isopropyl ether
to give 126 g of 3-acetylstilbene, m.p. 80 - 81C.
I 2-~3-stilbene)proPionitrile
t ~ To a suspension of 54 g of 3-acetylstilbene in 500 ml of methanol -
was added 7.6 g of sodium borohydride with stirring at 0C. The temperature
o the reaction mixture was elevated to 20C, and stirring was conti~ued until
i. - 11 -
~(~53~57
the suspension became a clear homogeneous solution at 20C. After the
solution was stirred another one hour at 40C, 100 ml of water was added and
methanol was removed under reduced pressure. The separated oil was extracted
with ethyl ethe~, and washed with saturated sodium chloride solution, dried
over anhydrous calcium sulfate and concentrated to give 3-(1-hydroxyethyl)
stilbene as a pale yellow oil.
To a solution of ~he crude 3-Cl-hydroxyethyl)stilbene in 500 ml of
benzene, was dropped 30 ml of thionyl chloride with stirring at 5C. The
mixture was allowed to stand at room temperature for 2 hours, then evaporated
under reduced pressure.
The resulting crude 3-(1-chloroethyl)stilbene was mixed with 30 g
of sodium cyanide and 200 ml of di~ethyl sulfoxide, and stirred at 60 - 65C
for 6 hours. The reaction mixture was cooled and mixed with one liter of water9
followed by extraction with ethyl ether. The ethereal solution was washed
with water and saturated sodium chloride solution, dried and concentrated to
give crude 2-(3-stilbene)propionitrile in the form of a viscous brown oil.
2-C3-stilbene~propionic acid C5
-; A solution of 200 g of sodium hydroxide in 300 ml of water and 400
ml of methanol was added to the crude 2-C3-stilbene~propionitrile. The mixture
~` 20 was refluxed for 12 hours and poured on to one kilogram of ice, then acidified
with concentrated hydrochloric acid to separate a dark brown oil, which was
dissolved in ethyl ether. The ethereal solution was extracted with 10 %
potassium hydroxide aqueous solution. The aqueous layer was acidified ~ith
concentrated hydrochloric acid, followed by extraction with ethyl ether. The
ethereal solution was washed ~ith saturated sodium chloride solution, dried
oYer anhydrous calcium sulfate, decolorized with active charcoal, and filtered.
, After evaporation of t~e ether, the resulting colorless oil was crystallized
from isopropyl ether to give 29.2 g of 2-(3-stilbene)propionic acid, m.p.
120 - 121~C.
The compounds listed in Table 1 were prepared by the similar pro-
cedure i]lustrated in Example 3.
- 12 -
- : . . . .
.- - ,. : . . - . . ~,
, :, . .
. . .: , . . .
- ~053;~S7
Table 1
~3 CH CH~
Z
Example R R ~H3 CH3
No. 1 2 -COOH3 -~HCN -CHCOOH
melting point ( C)
:
4 2'-CH3 H oil oil 88 - 89
4'-CH3 H 92 - 93 71 - 72 133 - 134
6 4'-OCH3 H 84 106 - 107 165 - 166
7 3'-Cl H 80 - 83 oil 117 - 118
8 4'-Cl H 104 - 105 81 - 83 132 - 133
9 2'-C1 6'-C1 72 - 73 oil 79 - 80
~ Analysis
it Example 4. 2-C2'-~eth~l-3-stilbenelproplonic acid C6S C18 H18 2'
~ Calcd: C, 81.17%; H, 6.81%J Found: C, 81.31%; H, 6.79%
;s Example 5. 2-(4~-methyl-3-stilbene)proplonic acid ~7~ C18 H18 2~
Calcd: C, 81.17%; H, 6.81%, Pound: C, 81.35%; H, 6.64%
Example 6. 2-(4'-methoxy-3-stilbene)propionic acid (lO)C18 H18 03,
Calcd: C, 76.57%; H, 6.43%, Found: C, 76.52%; H, 6.54%
Example 7. 2-C3'-chloro-3-stilbene)propionic acid (11) C17 H15 2 Cl,
Calcd: C, 71.20%; H, 5.27%, Found: C, 71.15%; H, 5.16%
Example 8. 2-C4'-chloro-3-stilbene)propionic acid (12) C17 H15 2 Cl,
Calcd: C, 71.20%; H, 5.27%, Found: C, 71.24%; H, 5.20%
! ExampIe 9. 2-(2',6'-dichloro-3-stilbene)propionic acid (13) C17 H14 2 C12,
Calcd: C, 63.57%; H, 4.39%, Found: C~ 63.37%; H, 4.26%
31 Example 10
3-acetyl-4'-fluorostilbene
i~
To a suspension of 13.4 g of 4-fluoroaniline, 30 ml of concentrated
13 -
~ , . .
S;3ZS7
hydrochloric acid, and 20 ml of water, was added a solution of 8.3 g of sodium
nitrite in 20 ml of water with stirring at -10 - -5C during 20 minutes
period. A suspension of 29.0 g of 3-acetylcinnamic acid in 300 ml of acetone
was added to the solution of diazonium salt. The mixture was cooled to -15 -
-10C, then 10.1 g of sodium bicarbonate was added. After evolution of carbon
dioxide ceased, 2.0 g of cupric chloride di~ydrate was added to the mixture
with vigorous stirring. The temperature of the reaction mixture was controlled
so that nitrogen evolved smoothly. After the evolution ceased J 15.0 g of
sodium bicarbonate and 50 ml of ~ater was added, stirred at room temperature
until the evolution of carbon dioxide ceased, and followed by acidification
with concentrated hydxochloric acid. The organic layer was sepaxated and con-
centrated to give a dark brown oil containing crystalline 3-acetylcinnamic acid,which was recovered by filtration. The filtrate was dissolved in ethyl etherJ
washed with 2N hydrochloric acidJ 10 % sodium hydroxide solution and saturated
sodium chloride solution, dried over anhydrous calcium sulfate. After removal
of the etherJ the resulting dark brown oil was crystallized from isopropyl
ether to give 10.4 g of 3-acetyl-4'-fluorostilbene as needle, m.p. 94 - 95C.
-~ 2-~4'_fluoro-3-stilbene~propionitrile and
2-~4'-fluoro-3-stilbene)propionic acid C14)
2e By the procedure exemplified in Example 3J 3-acetyl-4'-fluoro- -
, stilbene was converted to 2-C4'-fluoro-3-stilbene~propionitrileJ a pale yellow
oil, which ~as hydrolysed to 2-C4'-fluoro-3-stilbene)pxopionic acid, m.p.
119 - 121C. Analysis C17 H15 2 F, Calcd: C, 75.54%; H, 5.59%, Found:
C, 75.29%; H, 5.44%
The compounds listed in Table 2 were prepared by the similar
procedure illustrated in Example 10~
~.
" : .
1053~57
Table 2
~ CH=CH
,
Example Rl 2 ~ - ~H3 ~H3
No. -COCH3- HCN -~HCOOH
melting point C~ C)
11. 4'-C2H5 H oil oil 119 - 120
12. 3'-CF3 H 85 - 86 oil 75 - 76
13. 2'-CH3 s~-CH3 oil oil 72 - 74
Analysis
Example 11. 2-C4'-ethyl-3-stilbene~propionic acid (9~ C19 H20 2'
Calcd: C, 81.39~; H, 7.19%, Found: C9 81.35%; H, 7.23%
Exam~le 12. 2-(3'-trifluoromethyl-3-stilbene~propionic acid (15) Cl8 H15 2 F3,
Calcd: C, 67.49%; H, 4.72%, Found: C, 67.28%; HJ 4.66%
t Example 13. 2-(2',5'-dimethyl-3-stilbene)propionic acid ~8) Clg H20 2'
t Calcd: C, 81.39%; H, 7.19%, Found: C, 81.31%; H, 7.27%
Example 14
4'-methyl-3-stilbeneacetonitrile
To a suspension of 15.9 g of 3-aminoben~eneacetonitrile, 30 ml of
concentrated hydrochloric acid, and 20 ml of water, was added a solution of
8.3 g of sodium nitrite in 20 ml of water with stirring at -10 - -5C during
20 minutes period. An ice-cooled solution of 24.4 g sf methylcinnamic acid in
1 200 ml of acetone was added to the solution of diazonium salt. The mixture
.t was cooled to -15 - -10C, and then 10.0 g of sodium bicarbonate was added.
After evoIution of carbon dioxide ceas0d, 2.0 g of cupric chloride dihydrate
~as added to the mixture with vigorous stirring. The temperature of the
!- reaction mixture was controlled so ~hat nitrogen evolved smoothly. After the
e~olution ceased, 15.0 g of sodium bicarbonate was added to the reaction mix-
ture, which was stirred at 20C until evolution of carbon dioxide ceased, and
- 15 -
:
. . , . . - . ~ ~ - . : .. .
" ~' ' ,. ~ .
., ,
- 1053'~57
acidified with concentrated hydrochloric acid. The organic layer was separat-
ed and concentrated. The residual oil was dissolved in ethyl ether and washed
with 2 N hydrochloric acid, water~ 10 % sodium hydroxide aqeuous solution,
and saturated sodium chloride solution successively, and dried over anhydrous
calcium sulfate. The solvent was evaporated to give crude 4'-methyl-3-stil-
beneacetonitrile in the form of a viscous brown oil.
4'-methyl-3-stilbeneacetic acid C3)
A mixture of the crude 4l-methy1-3-stilbeneacetonitrile, 200 ml of
concentrated hydrochloric acid and 100 Ml of acetic acid was refluxed for 7
hours. The reaction mixture was added to one liter of ice-water to separate
a dark brown oil, which was dissolved in ethyl ether. T~e ethereal solution
was extracted with lO % potassium hydroxide aqueous solution. The aqueous
layer was acidified with concentrated hydrochloric acid, followed by extraction
with ethyl ether. The ethereal solution was washed with saturated sodium
chloride solution, dried over anhydrous calcium sulfate, decolorized with
active charcoal, and filtered. After evaporation of the ether, the resulting
pale yellow solid was recrystallized from ben~ene to give 14.0 g of 4'-methyl-
3-stilbeneacetic acid, m.p. 191 - 193C. Analysis: Caclulated for C17 H1602:
, C, 80.92 %, H, 6.39 %. Found: C, 80.89%; H, 6.33%.
`~ 20 Example 15
2-C3-stilbene~propionitrile
~ Under nitrogen atmosphere, 10 ml of ethyl ether was added dropwise
;1 to a mixture of 4.4 g of 3-s~ilbeneacetonitrile and 0.8 g of sodium hydride
as 60 % dispersion in minelal oill, and 40 ml of N,N-dimethylformamide ~DMF)
was further added dropwise into the mixture cooled in ice bath with stirring.
After evolution of hydrogen gas became moderate, the reaction temperature was
elevated to room temperature. Then, the mixture was stirred for 4 hours at
! the same temperature and cooled again in ice bath. Under ice-cooling, a
solution of 3.2 g of methyl iodide in 20 ml of DMF was added dropwise to the
reaction mixture, which was stirred for 3 hours at room temperature after con-
- 16 -
,: . .
1053Z~'7
clusion of the exnthermic reaction. The reaction mixture was poured into 100
ml of water and extracted three times with each 50 ml of chloroform. The
extract was washed with water and dried. The chloroform was distilled off
and the obtained pale yellowish oil was refined by silica gel column chromato-
graphy (eluting solvent : n-hexane - benzene mixture) and recr~stallized from
isopropyl ether and further from methanol to giYe 3.2 g of 2-C3-stilbene)
propionitrile, m.p. 71 - 72C, colorless fine plate.
2-~3-stilbene)~ropionic acid C5)
A mixture of 2.4 g of 2-C3-stilbene)propionitrile, 6 g of potassium
hydroxide, 15 ml of water and 25 ml of dioxane was refluxed for 10 hours with
stirring. After evaporating dioxane azeotropically with 100 ml of water, the
reaction mixture was added with 30 ml of concentrated hydrochloric acid and
extracted twice with each 50 ml of chloroform. The extract was washed with
water and dried. The chloroform was distilled off giving objective crystalline
precipitateJ which was recrystallized from cyclohexane in colorless needle to
give 1.8 g of 2-C3-stilbene)propionic acid, m.p. 121 - 122C. Analysis
C17 H16 2' Calcd: C, 80.92%; H, 6.39%, Found: C, 80.75%; H, 6.44%
Example 16
3-stilbeneacetothiomorpholide
A mixture of 22.2 g of 3-acetylstilbene, 4.8 g of sulfur, and 20
ml of morpholine was refluxed for 12 hours. After removal of morpholine, the
l .
resulting yellow oil was crystallized from ethanol to give 27.1 g of 3-stil-
beneacetothiomorpholide, m.p. 105 - 107C.
3-stilbeneacetic acid(l)
A solution of 60 g of sodium hydroxide in 80 ml of water and 120
ml of methanol was mixed with 22.6 g of 3-stilbeneacetothiomorpholide. The
mixture was refluxed for 8 hours, follo~ed by acidification ~ith 2 N hydro-
1 chloric acid to precipitate pale yello~ po~der, which was extracted with
-j ethyl ether. The ethereal solution was washed with water and saturated sodium
1 30 chloride solution, dried over anhydrous calcium sulfate, and concentrated to
e
1 7
.
1053'~57
give a pale yellow solid, which was recrystallized from benzene to give 13.6
g of 3-stilbeneacetic acid, m.p. 183 - 184C.
Example 17
2'-methyl-3-stilbeneacetic acid C2)
A mixture of 5.6 g of 3-acetyl-2'-methylstilbene, 1.2 g of sulfur,
and 5 ml of morpholine was refluxed for 10 hours. After remo~al of morpholine,
a solution of 2 ml of sulfuric acid in 2 ml of water and 8 ml of acetic acid
was added to the resulting dark brown oil. The mixture was refluxed for 5
hours, then mixed with 100 ml of ~ater, followed by extraction with benzene.
The benzene solution was washed with water, then extracted with 10 % potassium
hydroxide aqueous solution. The aqueous solution was acidified with concen-
trated hydrochloric acid, then extracted with ethyl ether. The ethereal
solution was washed with saturated sodium chloride solution, dried over
anhydrous calcium sulfate and concentrated to give a yellow oil, which was
crystallized from isopropyl ether to give 3.6 g of 2'-methyl-3-stilbeneacetic
acid, m.p. 119C. Analysis C17 H16 2' Calcd: C, 8n.92%; H, 6.39%,
Found: C, 80.78%; H, 6.46%.
Example 18
4'-ethyl-3-st~lbeneacetic acid C42
B~ the procedure exemplified in Example 17~ 3-ac~tyl-4'-ethylstil-
bene was converted to 4'-ethyl-3-stilbeneacetic acid, m.p. 189C. Analysis
' C18 Hl8 2' Calcd: C, 81.17%; H, 6.81%, Found: C, 81.28%; H, 6.75%
Example 19
methyl-3-stilbeneacetate (17)
.. .. .
To a suspension of 9.0 g of 3-stilbeneacetic acid in 50 ml of
methanol was dropped 5 ml of thionyl chloride with stirring at 0C. The
reaction mixture was stirred at room t~mperature for one hour and refluxed for
another one hour, then concentrated under reduced pressure to give a pale
yellow solid, which was dissol~ed in benzene, washed with saturated sodium bi-
carbonate solution and ~ater, successi~ely, and dried over anh~drous calcium
- 18 -
1053~57
sulfate. The solvent was evaporated to give a solid, which was recrystallized
from methanol to give 8.7 g of methyl 3-stilbeneacetatel m.p. 82C. Analysis
C17 Hl6 2~ Calcd: C, 80.92%; H, 6.39%; Found: C, 80.88%; H, 6.42%
methyl 2-(3-stilbene~propionate Cl9)
To a suspension of 8.4 g of methyl 3-stilbeneacetate and 1.3 g of
sodium hydride ~about 60% dispersion in mineral oil) in 70 ml of ethyl ether,
was dropped 25 ml of hexamethylphosphoric triamide with stirring at 0C during
40 minutes period. The reaction mixture became dark red with evolution of
hydrogen. After the evolution ceased, the reaction mixture was refluxed for
30 minutes, then treated with 4.7 g of iodomethane with stirring at 0C for
3 hours. The resulting pale yellow mixture was added with lO0 ml of ice-water,
followed by extraction with ethyl ether. The ethereal solution ~as washed
with saturated sodium chloride solution, dried over anhydrous calcium sulfate,
and concentrated to give a yellow oil, which was chromatographed on silicagel
column with n-hexane - chloroform Cl:l) to give 4.6 g of methyl 2-C3-stilbene)
propionate. Crystallization from methanol gave almost colorless fine needle,
~ m.p. 78 - 79C.
'~ 2-(3-stilbene)propionic acid (5)
A mixture of 2.7 g of methyl 2-(3-stilbene)propionate, 2.0 g of
sodium hydroxide, 10 ml of water, and 20 ml of methanol was refluxed for 5
hours, then acidified with concentrated hydrochloric acid, followed by extrac-
tion with ethyl ether. The ethereal solution was washed with water and
.~ .
saturated sodium chloride solution, dried over anhydrous calcium sulfate,
and concentrated to give 2-(3-stilbene)propionic acid, which was recrystalliz-
ed from isopropyl ether to give 2.2 g of fine needle, m.p. 119 - 120C.
Example 20
Ethyl 3-stilbeneacetate (18)
; A mixture of 11.9 g of 3-stilbeneacetic acid, 3 ml of sulfuric
acid, and lO0 ml of ethanol was refluxed for 6 hours, then concentrated to a
volume of 30 ml. The residue was dissolved in ethyl ether, washed with wa~er,
- 19 .` ~ : :
, -:
- lOS;~Z57
saturated sodium bicarbonate aqueous solution~ and saturated sodium chloride
solution, then dried over anhydrous calcium sulfate. After removal of the
ether, the resulting yellow solid was recrystalli~ed from n-hexane to give
11.6 g of ethyl 3-stilbeneacetate, m.p. 38 - 40C. Analysis C18 ~18 2'
Calcd: C, 81.17%; H~ 6.81%, Found: C, 81.16%; H, 6.70%
Diethyl 3-styrylphenylmalonate
A solution of sodium ethoxide from 0.70 g of sodium and 20 ml of
; ethanol was added to a mixture of 8.Q g of ethyl 3-stilbeneacetate and 30 ml
of diethyl carbonate with stirring at 20~C. The reaction mixture was heated
at 100 - 110C for 3 hours in order to remove the ethanol used as solvent and
formed by condensation. Then, the excess diethyl carbonate was distilled
under reduced pressure at the temperature. A solution of 5 ml of acetic acid
in 50 ml of ice-water was added to the residue, followed by extraction with
ethyl ether. The ethereal solution was washed with sa~urated sodium bicarbon-
ate solution and saturated sodium chloride solutioh, dried over anhydrous
calcium sulfate, and concentrated to give a yellow oil, which was chromato-
graphed on a column of silica gel with chloroformto gi~e 7.1 g of pure diethyl
~, 3-styrylphenylmalonate in the form of a pale yellow oil.
Diethyl ethyl(3-styrylphenyl)malonate
A solution of 6.8 g of diethyl 3-styrylphenylmalonate in 30 ml of
ethanol was added to a solution of sodium ethoxide from 0.46 g of sodium and
50 ml of ethanol with stirring at 20C. The mixture was refluxed for 30
minutes, and cooled. A solution of 3 ml of iodoethane in 10 ml of ethanol was
added to the moxture with stirring at 20C, and it was refluxed for 6 hours,
i then concentrated under reduced pressure. The residue was dissolved in ethyl
ether, washed with 10~ sodium hydroxide aqueous solution and saturated sodium
chloride solution, then dried over anhydrous calcium sulfate. Evaporation of
the eth~r gaYe 6.7 g of diethrl eth~l-C3~styrylphenyl~alonate as a yellow oil.
2-(3-stil~ène)butyric acid Cl6)
A solution of 20 g of potassium hydroxide in 20 ml of ~ater and 20
.: '
- 20 - ~
, . . . . . . .
1~5;~Z57
ml of ethanol was added to 6.0 g of diethyl ethyl~3-styrylphenyl)malonate and
refluxed for 6 hours. The reaction mixture was concentrated, and acidified
with 200 ml of 20 % sulfuric acid, refluxed for 12 hours. Then, the reaction
mixture was extracted with ethyl ether, and the ethereal solution was ~ashed
~ith water and dried. Evaporation of the ether gave precipitate. The pre-
cipitate was crystallized from n-hexane to glve 2.1 g of 2-C3-stilbene)butyric
acid, m.p. 110 - 112C. Analysis C18 1118 2' Calcd: C, 81.17%; H, 6.81%,
Found: C, 80.99%; H, 6.73%.
Example 21
By the same manner as described in Example 1,
2-C3-stilbene)propionic acid ~5),
2-(4'-methoxy-3-stilbene~propionic acid Cl) .
2-~3'-chloro-3-stilbene)propionic acid ~11),
2-(4'-chloro-3-stilbene)propionic acid C12),
2-C2',6'-dichloro-3-stilbene)propionic acid C13),
2-~4'-fluoro-3-stilbene)propionic acid (14),
2-C3'-trifluoromethyl-3-stilbene)propionic acid C15) and
2-C3-stilbene)butyric acid C16) can be prepared.
Example 22
By the same manner as described in Example 3 or 10,
2-(3-stilbene)butyric acid ~16) can be prepared.
; Example 23
By the same manner as described in Example 14, or Examples 14 and
3-stilbeneacetic acid (1),
2'-methyl-3-stilbeneacetic acid ~2),
4'-ethyl-3-stilbeneacetic acid ~4~
2-C2'-methyl-3-stilbene)propionic acid C6), -
; 2-~4'-methyl-3-stilbene~propionic acid C7),
2-C2',5'-dimethyl-3-stilbenelpropionic acid C8),
- 21 -
, , . , -., .............. : . . . :
.
lOS;~57
2-~4'-ethyl-3-stilbene)propionic acid C9?
2-C4'-methoxy-3-stilbene)propionic acid ~10)
2-C3'-chloro-3-stilbene)propionic acid (11)
2-C4'-chloro-3-stilbenelpropionic acid C12)
2-C2',6l-dichloro-3-stilbene)propionic acid ~13)
- 2-C4'-fluorG-3-stilbene)propionic acid C14)
2-C3'-trifluoromethyl-3-stilbene)propionic acid Cl5) and
2-C3-stilbene)butyric acid C16) can be prepared.
Example 24
By the same manner as described in Examples 16 or 17J
4'-methyl-3-stilbeneacetic acid (3) can be prepared.
Example 25
By the same manner as described in Example 19,
2-(2'-methyl-3-stilbene)propionic acid C6)
2-(4'-methyl-3-stilbene)propionic acid C7)
2-C2',5'-dimethyl-3-stilbene~propionic acid C8)
2-C4'-ethyl-3-stilbene)propionic acid (9)
2-(4'-methoxy-3-stilbene)propionic acid Cl
2-(3'-chloro-3-stilbene)propionic acid Cll
2-(4'-chloro-3-stilbene~propionic acid C12)
2-(2',6'-dichloro-3-stilbene)propionic acid C13)
2-~4'-fluoro-3-stilbene)propionic acid (14)
2-(3'-trifluoromethyl-3-stilbene)propionic acid C15) and
2-C3-stilbene)butyric acid C16) can be prepared.
Example 26
By the same manner as described in Example 20,
2-C3-stilbene)propionic acid (5)
2-~2'-methyl-3-stilbene)propionic acid C6)
2-(4'-methyl-3-stilbene)propionic acid (?)
2-~2',5'-dimethyl-3-stilbene)propionic acid C8)
~ 22 -
-............. . . . . . . .
~05~i~57
2-(4'-ethyl-3-stilbene)propionic acid (9)
2-C4'-methoxy-3-stilbene)propionic acid Clo~
2-C3'-chloro-3-stilbene)propionic acid ~11)
2-(4'-chloro-3-stilbene)propionic acid ~12)
2-(2',6'-dichloro-3-stilbene)propionic acid ~13)
2-(4'-fluoro-3-stilbene)propionic acid C14) and
2-(3'-trifluoromethyl-3-stilbene)propionic acid (15) can be prepared.
Example A
Approximate acute toxicity of the compounds of the present inven-
tion was tested in each group of three DDY-strain male mice wPighing 22 - 24 g.
Each 1000 mg/Kg of the compounds were administered in mice orally as suspen-
sions in 0.5 % CMC solution. After 2 days from the administration, no
lethality was obserYed for all test compounds.
Further, more precisely, acute toxicity of 2-C3-stilbene)propionic
acid and 2-(4-isobutylphenyl)propionic acid was investigated in each group of
ten DDY-strain male mice. After 7 days from the similar administration in
various doses C800 - 3000 mg/Kg), LD50 values were calculated from the obtain-
ed lethality by Litchfield and ~ilcoxon method CJ. Pharmacol. Exptl. Therap.,
96, 99 C1949)) and are shown as follows:
Compound LD50 (mg/Kg) ;
2-(3-stilbene)propionic acid 2152
2-(4-isobutylphenyl~propionic acid 1100
- Example B
Anti-inflammatory activity was tested by the method of Winter et al.
(J. Pharmacol. Exptl. Therap., 141, 369 (1963)) with slight modification. Male
~istar rats being 6 weeks old C6 rats per group~ were injected in the plantar
surace of left hind paw with 0.1 ml of sterile 1 % carrageenin solution. The
testing compounds suspended in the solution containing 0.5 % CMC, 0.1 % Tween
80 and 0.9 % sodium chloride were administered orall~ one hour before
carrageenin injec~ion. As control, the above solution was administered in the
- 23 -
.:
l~S;~57
same way. Until six hours after the carrageenin injection, the foot volumes
were measured by plethymorgraph at one hour intervals. The edema volumes
were determined by difference of foot volumes before and after carrageenin
injection. Inhibitive percents of testing compounds on carrageenin edema were
calculated from the plethysmorgan area of ede~a ~olumes. The obtained results
are shown in Table 3.
Table 3 InhibitiYe Ef~ect on Rat Carrageenin-induced Edema
Compound
No. dose ~mg/Kg~ inhibition (%)
14.1
~5) 40 37.1
56.4
100 60.8
(1) 100 29.8
C6) 100 26.0
' (10) 100 23.6
~ 20 15.7
;' 2-C4-isobutylphenyl)
propionic acid 40 33 5
8Q 40.0 -
Example C
Analgesic Activity was investigated by acetic acid writhing test
of Koster et al. CFed. Proc. 18, 412 (1959)) with slight modification. Ten
DDY-strain male mice weighing 20 - 24 g were used in each group. The test
~$~ compounds were administered orally as suspension in 0.5 % CMC solution, and 30
minutes later 0.7 ~ acetic acid solution C70 mg/Kg) was injected intraperiton~
eally. After five minutes from the acetic acid injection, the total number of
3 writhing per animal was counted for 10 min. Analgesic activity was expressed
~; as inhibition percent and each ED50 was calculated by the Litchfield and
j Wilcoxon method. The obtained results are shown in Table 4.
i - 24
.
. .~ . . .,, . - . ~ , .,
,. , -, : ,, - , . :
,, . ~ .
lQS3~S~
Table 4
Inhibiti~e Effect on Mouse ~rithing Number by Acetic Acid Injection
Compound
No. dose Cmg/Kg) . inhibition ~%~ ED50
16.8
~5) loo 36.3 130
200 71.8
15.9
c6~ loo 31.2 160
200 60.1
8.7
o ~7) loo 28.2 195
200 48.5
6.0
o) loo 24.2 193
200 51.7
11.5
Cll) loo 24.6
203 30-3
19.5
(12) loo 29.g
200 44.2
19.5 -
3) loo 33.0
200 42.0
loo 29.1
2-(4-isobutylphenyl) 200 36.3
propionic acid
300 48.2 >300
400* 89.3
* In a dose of 400 mg/Kg of 2-(4-isobutylphenyl)propionic acid, significant
ataxia was observed in the mice, whereas such undesirable side effects were not
observed in doses of 400 mg/Kg and 1000 mg/Kg of the compound ~5).
:
- 25 -
