CA1053257A

CA1053257A - Anti-inflammatory and analgesic stilbene derivatives

Info

Publication number: CA1053257A
Application number: CA231,559A
Authority: CA
Inventors: Takehiro Amano; Teruya Seki; Michitada Sasajima
Original assignee: Taisho Pharmaceutical Co Ltd
Current assignee: Taisho Pharmaceutical Co Ltd
Priority date: 1974-07-16
Filing date: 1975-07-15
Publication date: 1979-04-24
Also published as: GB1465661A; AU8215275A; ES439430A1; JPS5227B2; FR2278332A1; AU470771B2; FR2278332B1; PH11312A; CH610582A5; AR205387A1; SE7508074L; NL7507803A; SE409452B; JPS5111748A; DE2531456A1

Abstract

A B S T R A C T
Process for preparing novel stilbene derivatives represented by the general formula (I) ..........(I) wherein R1 and R2 are independently hydrogen, lower alkyl, lower alkoxy, halo-gen or haloalkyl, and R3 is hydrogen or lower alkyl, which comprises hydro-lysing the compounds represented by the general formula (II)

Description

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) 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

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

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.

.
~ .

.

.., : -1053ZS'7 Scheme (c) 3 I

C=O
Rl CE=CHY l H2N

R3 Meerwein arylation Rl C=O

~ ~ NH2 + YHC=HC ~

1 C=0 CHOH

~ CH=CII~ reduction ~ ~CH=CH

., IR3 CHX

halogenation > ~ CH=CH

cyanation > ~ Cll=CH~

(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

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 ~ .

R ~ CHCO0A
alkylation > ~ CH=CH~

., . :- . . ~ , . .
'' , , ' ' ' ' " . '. "' ' " " ' lOS3ZS7 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~

Rl / C~COOA)z Rl CHCOOH

~ CH=CH~ tnd ~ CH=CH

R2 decarboxylation (R3 is lower alkyl and A is alkyl) An optionally substituted alkyl 3-stilbeneacetateis condensed - ~: . ,, :: . : . . ..

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 - . . .
,.
,, ,. . , . , , - . . .

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.

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

- ~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 ~ , . .

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 :

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

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 .

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 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), , , . , -., .............. : . . . :

.

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 .:

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 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).

:

Claims

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

1. A process for preparing the compounds represented by the general formula (I) ........(I) wherein R1 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) ...........(II) wherein R1 and R2 are same as defined above and M is chosen from -HC(R3)CN
wherein R3 is same as defined above, -CH2C(S)B wherein B is amino; -HC(R3) COOA wherein R3 is same 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 decar-boxlating the product when M is -C(R3)(COOA)2.

2. A process according to claim 1 wherein R1, R2 and R3 are each hydragen.

3. A process according to claim 1 wherein R1 is methyl, and R2 and R3 are each hydrogen.

4. A process according to claim 1 wherein R1 is ethyl, and R2 and R3 are each hydrogen.

5. A process according to claim 1 wherein R3 is methyl, and R1 and R2 are each hydrogen.

6. A process according to claim 1 wherein R1 and R3 are each methyl, and R2 is hydrogen,

7. A process according to claim 1 wherein R1, R2 and R3 are each methyl.

8. A process according to claim 1 wherein R1 is ethyl, R3 is methyl and R2 is hydrogen.

9. A process according to claim 1 wherein R1 is methoxy, R3 is methyl and R2 is hydrogen.

10. A process according to claim 1 wherein R1 is chloro, R3 is methyl and R2 is hydrogen.

11. A process according to claim 1 wherein R1 and R2 are each chloro, and R3 is methyl.

12. A process according to claim 1 wherein R1 is fluoro, R3 is methyl and R2 is hydrogen.

13. A process according to claim 1 wherein R1 is trifluoromethyl, R3 is methyl and R2 is hydrogen.

14. A process according to claim 1 wherein R3 is ethyl, and R1 and R2 are each hydrogen.