Studies on the Synthesis of Arylpropionic Acids and their Antiinflammatory Activity

消炎鎮痛劑에 관한 研究

Arylpropionic acid

蔡 東 圭

서울大學校 藥學ᄎ學

(Received March 14

1979)

Dong Kyu Chae

College o f Pharmacy, Seoul National University

Studies on the Synthesis of Arylpropionic their Antiinflammatory A ctivity

Seoul 151t Korea Acids and

Abstract— Eight derivatives of arylpropionic acid, arylcarbonylpro- pionic acid, and arylhydroxybutyric acid were synthesized and their structures were elucidated on the basis of elemental analysis and spect­

ral data. Also their antiinflammatory activities were evaluated by the method of the inhibitory effect on the carrageenin-induced rat paw edema and compared with phenylbutazone. Compound ( I ) exhibited 59% edema inhibition vs control when 100 mg/kg, was orally adminis­

tered, whereas phenylbutazone showed 57.8% for 50mg/kg.

1961

Nicholson, Adams

ibufenac (4-isobutylphenyl acetic acid)

arylalkanoic acid

Nicholson

ibufenac

ibufenac

a-methyl

ibuprofen

recemi

aspirin

16〜 32

.carra­

geenin-induced rat paw edema

phenylbutazone

2’3)

.

aromatic ring

flubiprofen

antiarthritic activity

4-aryl-3-hydroxybutyric acid

Barren

aryl group

-biphenyl

B D H 7538 (4-biphenylyl 3-hydroxybutyric acid)

phenylbutazcme

2. 5

antiinflammatory activity

. biphenyl

alkanoic acid

Hey

W ilk inso n

1940

fenbufen C3~ (4-biphenylcarbonyl) propionic acid〕5)

19

Tomcufcik

aspirin

phenylbutazone

6)

fenbufen

rat

paw edema

fenbufen

/-4-(4-biphenyl) -4-hydroxy-

butyric acid

aspirin, phenylbutazone, indomethacin

..

CH ： CH 3

그 C H — - C H2- ^ - 1

c h 3 CH—COOH 1

F

Ibuprofen Flubiprofen

CH3

>-CH-COOH

< ^ ) - ^ ^ ) - C H 2- C H - C H 2COOH c - c h 2 c h 2 c o o h OH

BDH 7538 Fenbufen

OH

Q rQ r

CH2CH2COOH

d, /-4-(4-Biphenyl)-4~hydroxy butyric acid

著者는 消炎作用을 發現하는 化合物들의 構造的 상관성에 着眼하여

ibuprofen

a-methylarylpropionic acid

benzyl chloride

malonic ester

a-methyl-

arylcarbonylprop

^ acid

methylsuccinic -anhydride8)

iso-butylbenzene, biphenyl, anisole

Friedel-Crafts

-hydroxybutyric acid

arylcarbonylpropionic acid

NaBH4

.

이들의 合成經路는 다음과 같다

. 1. a-Methyl-jS-arylpropionic acid

CH3 R-CH2-C(C02H)2 CH2(C 02C2Hs) 2- r^cH zC I

' RCH2C H (C 0 2C2H5) 2

c h 3

R C H i(C 0 2C2H5)2

c h 3 R

— C H — C O O H

o

NaOEt C H

I

尸

3 Cl

R Cr

I c h 3/

2. CH3—CH COOH I

c h 2 c o o h

r - G

CH 3 COC 1

ᅳ

H

m ethylsuceinic an hy d ride A IC I

in nitrobenzene

fl

0 II C H r •-C H

C\

c k - c > °

II 0

R - (

o -

o c h 3

II I

- c c h 2 c h c o o h

CH3 v

고 = >CH—CH2 c u /

w

3. R — <

) Succinic _anhydride ^ R _ < ^ > - C C H 2C H 2C O O H

1) a-(p-m ethylbenzy 1) propionic a c i d ( I

Ethyl p-Methylbenzylmalonate 100m

無水에탄을

25mZ

1.2g

50

550C

diethylmalonate 8. 0g (0. 05mole)

10

/

methylbenzyl chloride 7. 0g(0. 05mole)

30

.

20mZ

5 m f chloroform

有機層과 합해서 無水

M g S 0

.

bp 176

〜

收得量

：

3.62 (t, 1H ), 3.17 (d, 2H ), 1.19 (t, 6H) 2.28 (s, 3H).

E t h y l m e t h y l - p - m e t h y l b e n z y l m a l o n a t e 無水 ^{E t O H} 1 2 . 5 m / 에 금속 S o d i u m 0 . 6 g 을 溶 解시키고

Ethyl-^m ethylbenzylm alonate 0. 6g (0.025 mole)

30

C H 3I 4. 0g (0.028 mole

5

.

反應液에 물 15m/를 가해 有機層을 분리하고 水層은 5mZ chloroform 으로 抽出 有機層과 合

-

.

，

；

a- ( p-m ethylbenzy 1) propionic acid lOOmZ

ethyl methyl-/

m e thyl benzyl malonate 4. 2g

K O H 3. 3g

ethanol 20m/

2

..

反應시킨다음

ethanol

.

- 1 ^ 0

210-

〜

220oC

15

. 145

150oC/14m m H g

mp. 39

40

收得量

1.8g

cm-1; 3180

2600

2400

1700.

NMR(CDC13)5

；

〜

，

，

Anal. Calcd. for C iiH 14C>

; C, 74.16; H, 7.87; F ou nd

C, 74.38; H , 7.91 2) a-(2,5-Dimethylbenzyl) propionic acid (

)

Ethyl-2. 5-dimethylbenzyl m alonate ethyl-^m ethylbenzylm alonate

sodium 1. 2g, diethylmalonate 8. Gg

2. 5-dimethylbenzyl chloride 7.7 g (0. 05 mole

. bp. 170

1760/13mmHg

9 g (6 5% ), N M R (CDC13) ^ ; 6. 95

(s, 3H ), 4.15 (q, 4 H ), 3. 62 (t, 1H), 3.17 (d, 2H ), 2. 25 (s, 6H ), 1.16 (t, 6 H ),

E t h y l m e t h y l 2，^{5 - d i m} e t h y l b e n z y l m a l o n a t e E t h y l - 2，^{5 - d i m} e t h y l b e n z y l m a l o n a t e 8 . 4 g

(0.03 mole)

C H 3I 4. 9g (0. 035mole)

. b. p. 172

1780/14m m H g

5.2g(60%) NMR(CDC13)5; 6.92 (s, 4H), 4 .18(q, 4H) 3. 26 (s, 2H) 2. 21 (s,6H), 1. 29(s,.

合 成 實 驗

：

3H ) 1. 21 (t, 6H ).

a - (2 ,5-Dimethylbenzyl) propionic acid Ethylmethyl-2, 5-dimethylbenzylmalonate 4 .4g

( I

a-(p-methylbenzyl)propionic acid

162

1650/14mmHg

. mp 58

59

1. 6g

I R d S : 3150

2600

2400

1700. NM R(CD C13) J : 7.0(s, 4H) 2 .50

3 . 16 (m, 3H) 2. 31 (s, 6H) 1. 20 (d, 3H ). Anal. Calcd. for C12H 160 2; C, 75.0; H , 8.33; Found; C, 75.13; H , 8.25.

3) a- (m -Chlorobenzyl) propionic acid ( HI)

E th y l m -C hlorobenzylm alonate

Sodium 1. 2g, diethylmalonate 8. Og, w-chlorobenzyl chloride 8. 05g(0. 05 mole)

.

b .p . 182

1860C 18mmHg, 6.2g(43 .7 % ) N M R (CDC13)5; 7.05

7.25(m

4H) 4.12 (q, 4H) 3. 53(t, 1H) 3 . 18(d, 2H) 1 .15(t, 6H).

Ethyl methyl-w-ChlorobenZylmalonate---Ethyl wz-chlorobenzylmalonate 6g(0. 021 mole), 금속

Sodium 0. 56g

C H 3I 3. 55g(0. 025 mole)

. b.p. 160

1660/18mmHg,

2 .7g (43 % ), NM R(CD C13)

; 7.09

7.22(m , 4H) 4 . 19(q, 4H) 3 .2(s, 2H )1.34(s, 3H) 1. 24 (t, 6H)

a- (m-chlorobenzyl) propionic acid Ethyl methyl-w-chlorobenzylmalonate 2. 7g

( I )

a-(/>-methylbenzyl) propionic acid

. 130

收得量

，

〜

，

8 ： 7. 05

7. 25 (m, 4H) 2.50

3 .1 8 (m, 3H) 1.15(d, 3H) A n al Calcd. for C10H n O 2; C, 60.

45

H , 5.54

Found;C, 60.90

H , 5.31.

4 ) a - M e t h y l - / 3 - ( p - i s o b u t y l b e n z y l ) p r o p i o n i c a c i d ( W ) 의 合成

250m/ flask

nitrobenzene 25mZ

alum inum chloride 5. 6g

5°C

isobutylbenzene 2 .7 g (0.02 mole)

methylsuccinic a n h y d r id e

2. 28g (0.02 mole

.

3

c-HCl 5mZ

30mZ

nitrobenzene

.

3 % sodium carbonate

,

6N-H2S 0

ethanol-H20

. mp. 95

970C, 2. 5g (50%)

IR y S c m

3200

3400

2700

2500

1690

1670. N M R (D M S O -d6)5 : 7.95 and 7. 30 (d, 4H ), 2. 85

3. 62 (m, 3H ), 2. 56 (d, 2H ), 1. 65

2.25 (m, 1H), 1. 34 (d, 3H ), 0. 93 (d, 6H) Anal.

• Calcd. for C15H 20O 3: C, 72. 58

H , 8.06; Found

C, 72.29; H , 8.12

5 ) a - M e t h y l - / 3 - ( p - m e t h o x y b e n z o y l ) p r o p i o n i c a c i d ( V ) 의 合成

(W

anisole 2 . 16g(0. 02 mole

methylsuccinic anhydride 2. 28g (0.02 mole

. mp. 143

1450C,

2 .18g(53% )

IR i^ScnT 1: 3400，2700

2500

1700

1670. N M R (DM SO-d

) J : 7.43 and

. 25(d, 4 H ), 4 .1 5 (s,

H ) 3.15

3.75 (m, 3 H ),

.47 (d, 3H ). Anal. Calcd. for C

H

O

C, 64.86

H , 5.97; Found

C, 65.18;

H , 6. 05.

6 ) a - M e t h y l - / 3 - ( p - p h e n y l b e n z o y 1 ) p r o p i o n i c a c i d ( \ I ) 의 合成

(W

biphenyl 3. 08g(0. 02 mole

methylsuccinic anhydride 2. 28

g (0.02 mole

,

2. 5g (47% ), m p 212

2140C

' IR iS c n r

，

〜

，

6) ^ ：

〜

〜

，

；

：

7) 4- (p-Isobutylphenyl) -4-hydroxybutyric acid(VB)

a) 3- (p-Isobutylbenzoyl) propionic acid

(17

isobutylbenzene 2. 7 g (0.02 mole

succinic anhydride 2g (0. 02 mole

. mp. 110

111°C,

3. 5g (74.8% )

b) 4- (p-Isobutylpheny 1) 4-hydroxybutyric acid

lOOmZ

3-(/>-isobutylbenzoyl) propionic acid 2. 34g(0. 01 mole)

isopro- pyl alcoh

NaBH4 0. 38g (0.01 mole)

30

에서 還流하여 反應을 完決하고 生成된 침전을

10% N a O H

-HC1

Ethyl acetate

.

isopropan

. mp. 64~66°

1.5g (63%)

IRyScm-1: 3400

，

〜

，

〜

，

(t, 1H) 2.37

2*61(m ,4H ) 2.09(q, 2H) 1. 62

2.01 (m, 1H) 0. 90 (d, 6 H ). A n a l Ceded, for

：

：

8) 4- (p-Methoxypheny 1) -4-hydroxybutyric acid (

3- (p-Methoxybenzoyl) propionic acid (10

anisole 2 . 16g (0. 02 mole)

succinic anhydride 2g(0. 02 mole)

.

3. l g (74. 5 % )

4- (/>-Methoxyphenyl) -4-hydroxybutyric acid (\I)

3-(/>-methoxyben- zoyl) propionic acid 2. 08g (0.01 mole), sodium borohydride 0. 38g (0.01 mole

.

1.3g (62% )

K v S c m - 1; 3400

2700-2500, 1760. NM R(CDC13) 8 ：

. 32

6 .9 5 (m, 4H ) 5. 45(t,

H ) 3.83 Table I-Effect of the compounds on carrageenin-induced rat paw edema

Compounds Dose

(mg/kg, po) No. of

rats

Degree of edema a)

Inhibition (% )

Control — 4 0. 83±0. 08 —

I 100 4 0. 34 士 0. 02w 59.0

50 4 0. 53 士 0 .05c) 36.1

표 100 4 0.38 士 0 .02b) 54.2

50 4 0.54 士 0 .05c) 34.9

1 100 4 0.42 士 0 .03c) 49.4

N 100 4 0.43 士 0 .05c) 48.2

V 100 4 0.61 士 0 .05d) 26.5

체 100 4 0. 56 士 0 .04c) 32.5

YU 100 4 0.39 士 0 .03b) 51.8

50 4 0.52 土 0 .04c) 37.3

m 100 4 0.47 土 0 .05c) 43.3

phenylbutazone 50 4 0.35 士 0 .03b) 57.8

a) Mean 士 Standard error b) p 〈0 . 001 vs. control c) p 〈0 . 01 Vi

control d) p < 0 . 02 vs. control

Cs, 3H) 2 .65(t, 2H) 2.2(q, 2H) Anal. Calcd. for C n H 140 14: C, 62.86; H, 6.67. Found: C, 62.57: H, 6.71

표 ^. 動物 實驗 ( C a r r a g e e n i n - i n d u c e d e d e m a t e s t i n r a t s )

W inter

(10’ u)

150

200g female rat 4

16

Comp. I

I

1 % Tween solution

1 % Tween solution (

)

K g

lOOmg

. 1

Plethysmometric apparatus

1 % Carrageenin 0.9%

0. lm

3

.

Carragee­

nin

.

K g

lOOmg

50%

3

(Comp. I

I

Vtt

K g

50mg

.

果는

Table I

. %

考察 및 結論

1) Benzyl chloride

malonic ester synthesis

. 3

arylpropionic acid

Friedel-Crafts

3

arylcarbonylpropionic acid

.

2

arylhydroxybutyric acid

.

.

( I ) a- (/>-Methylbenzyl) propionic acid. ( I ) a-(2 ,5-Dimethylbenzyl) propionic acid, ( 1 ) a- (m-chlorobenzyl) propionic acid, (H ) a-Methyl— — (/>-isobutylbenzoyl) propionic acid, ( V ) a-Methyl-/3-(/>-methoxybenzoyl) propionic acid, (M[) a-Methyl-^S-(/>-phenylbenzoyl) propionic acid, 0 1 ) 4-(/>-Isobutylphenyl)-4-hydroxybutyric acid, (MD) 4-(/>-Methoxyphenyl)-4-hydroxy butyric acid.

2) Carrageenin-induced edema

( I ) ( I ) ( W)

:

.

本 實驗을실시하는데 李晶唆君의 協助에 대하여 감사한다

.

文 獻 ᅳ

1. Boots, Brit. pat. 971,700 [C. A , 61 ， 14591(1964)).

2. S.S. Adams, E .R . Cliffe, B. Lessel, and J. S. Nicholson, Nature, 200 ， 271(1963).

3. idem., J. Pharm. Sci., 56 ， 1686(1967).

4. D. I. Barren, P. J. Bysouth, R. W. Clarke, A. R. Copley, O. Stephenson, D. K. Vallance, and A. M

W ild, J. Med. Chem., 11, 1139(1968).

5. D. H. Hey and R. W ilkinson, J. Chem. Soc.

1030(1940).

6

. A. S. Tomcufcik, R. G. Child, and A. E. Sloboda, Brit. Pat.

1,320,076(1972).

7. idem., J. Pharm. Sci., 66 ， 466(1977).

8

. A. H. Blatt, Org. Syn. Coll., Vol. f l, 560(1960).

9. W . Perkin, J. Chem. Soc.

53 ， 564(1888).

10. C.A . Winter, E. A. Risley, and G. W. Nuss, Proc. Soc. E xp tl. Biol. M ed. ，I l l , 544(1962).

11. idem., J. Pharmacol. Exptl. Therap., 141, 369(1963).

12. J .M . Harris and P .S .J . Spencer, J. Pharm. Pharmacol.

14, 464(1962).