34 Journal o , f M e d l c u m l C‘hemLstp 197.5, Vol 18, ?io I
Studies on Antianaphylactic Agents .4.I Synthesis and Struct ure- Ac tivi ty Relationships of 3-(4-0xo-4H-l-benzopyran-3)acrylic Acids, a New Series of Antiallergic Substances, and Some Related Compounds Akira Xohara.* Hisashi Kuriki, Taketoshi Saijo, Kiyoshi Ukawa. ‘I’adakazu Murata. Morio Kanno. and Yasushi Sanno Mmficinai Research Luboratories, Central Rrsearch L)ii;ision. Takedn ‘ h r m i c n lIndustr:c,. L ! t i . . l ’ o d o ~ a iat - k u O s a k a ,5:j2. ilnljnri Rec,r.iccd F e b r u a n 2.5. 197-1 The syntheses of trans-3-(l-oxo-4H-l-benzop?ran-3iacr?li(,acid and a number ot analogs shown to be highly active in antiallergic bioassays are described. These compounds are of possible value in the treatment of asthma. The structural requirements for biological activity are discussed with reference to the type of the substituents on the chromone ring or positions of linkage of the acrylic acid on the pi’rone ring.
The dried radix of Scutellaria baicalensis Georg has been used from ancient times in Chinese medicine as a diuretic or antiallergic drug. Recently, Koda. et al., showed that biacalein ( l a ) . one of the flavonoids present in this radix, and its water-soluble derivative, sodium baicalein-6-phosphate lb, possess antianaphylactic activity in experimental animals.* . 3 The preliminary structureactivity studies on baicalein and related synthetic compounds revealed that the introduction of a carbonyl group a t the 3 position of the chromone ring enhanced the antiallergic activity.4 Starting from this observation, $-oxo4H-1-benzopyran-3-carboxaldehydes2 5 . 6 and 4-oxo-3H-1benzopyran-3-carboxylic acids 3 5 were synthesized but were found to be inactive in inhibiting the passive cutaneous anaphylaxis (PCA)’ in the rat.
“W KO
R
Scheme I
0
h-P
COOH
0
q
\
HO la
CHO
c i ‘
0 2
R=H
b I1
=
II
-I’-Oh300"; mass spectrum m / e 248 (&I*), trans-Methyl 3-(7-Methoxy-4-0~0-4H-l-benzopyran-3)acrylate. To a solution of trans-3-(7-hydroxy-4-oxo-4H-l-benzopyran3)acrylic acid (7b, 1.00 g, 4.31 mmol) in DMSO (30 ml) were added Me2S04 (1.00 ml, 10.6 mmol) and anhydrous KzC03 (2.07 g, 15 mmol). The mixture was stirred a t room temperature for 2 hr. Additional Me2SOI (0.5 ml, 5.3 mmol) and anhydrous KzC03 (1.03 g, 7 mmol) were then added. After a n additional 1-hr period, the reaction mixture was poured into ice-water (200 g ) . The resulting precipitate was collected and recrystallized from MeZCO to afford 425 mg (38.1%) of light yellow scales. m p 164-168". Anal. (C14H1205) C, H .
56 Journal of Medicinal Chemistry 1975, Vol. 18, ,Vo. 1
.\,'ohnra, car ni
Table I. trans-3-(4-0~0-4H-l-benzopyran-3)acrylic Acids
COOH 0
R and Compd
pos it1 on
H Yield,
MP,
c
Formula"
Method
PCA
of p r e p
assayb
B
4
5a
H
5b 5c 5d
6-Me 6-Et
5e 5f 5g 5h 5i
5j 5k 51 5m 7a
7b 7c 7d
7e 7f
6 - H -Pr 6 - i -Pr
6- 1 1 -Bu 6 -Cl 6 -0Me 6 -COOH 6 -KO2 6 -NMe2 6 . 8 -Me, 6 . 8 -Br? 5 -OH 'i-OH
6.7-(OAc), 6.7 -(OH), 7 -0Me 6 -NH,
253-254 d e c 260-261 d e c 230.5-232.5 d e c 205-207 220-222 d e c 211-212 281-282 d e c 261-262 d e c 316-317.5 d e c 274-218 d e c 240.5-242.5 d e c 286-288 d e c 2755277 d e c 284--285 d e c 288-290 d e c 246-247 d e c >,300 264.5- 265.5 225-227
c 12H8 0 4
74 63 46 42.9 74.8 43 67
Ci5Hi404 Cl,H1,0, C18ifi0, C1?H,ClO,j
nn 1 1
C13HiO05
1
Ooi
c 11Hi2 0 J
38 67.7 47.7 43.6 33.9 52 48 13
Ci3H80,
c 1 ?Hl?O-i C12H,Br201 c 1?H& C12HEOI Cj&l@s
73.9
C13H100, Ci2HeN04
c 1ZH7NO6 C14H iSNO.l
IC
C
I I I I
B F3
I
I I I I I
B
A B B B E C
I
B B
1
C
I I
C C C C C D
(
c
c ('
____ aAll compounds were analyzed for C, H, and N.hID50 mg/kg value: A, less than 1 mg/kg; B,1-3 mg/kg; C. 4-10 mg/kg; D, 10-20 mg/kg; E, more than 20 mg/kg. CSee Experimental Section. -~
Table 11. M i s c e l l a n e o u s Compounds
_____-.
of light yellow microcrystals. mp 140.5-142". Anal ( C ~ i H 1 8 0 6C.) H. Method t~an~~-3-(Benzo[h]chromon-~-~l~acrylic Acid ( 9 ) . A mixture oi' 8 (810 mg. 2.2 mmol!. AcOH (10 ml), and 6 r\a HzS04 (10 mli was Yield. of PCA heated at 120" for 4 hr. After cooling the mixture. a precipitate Compd Mp, 'C Formula' prep assayb was collected by filtration. Recrystallization of the crude solid from MezCO afforded 150 mg (25%) of yellow prisms. m p 261-6 144- 146 I E 262" dec. 9 261-262 d e c i C Nethod 11. trans-3-(2-Methyl-4-oxo-4~-l-benzopyran11 232-234 11' E 3)acrylic Acid (11). A mixture of 3-acetylchromone (10,10 1.13 8. 6 mmol!. malonic acid (936 mg. 9 mmol), and 2-methvlimidazole 12 216-217 d e c I1 E (1.20 g. 14.6 mmol) was fused a t 120" for 4 min. The reaction mix13 14 9.- 1 50 IIC E ture was cooled and was extracted with H20 and then 5% 238-240 14 I D NaHC03 aqueous solution. The combined extract was made acid206-208 15 ( E ic with concentrated HC1 to precipitate crude 1I . Recrystalliza168-169 16 L D tion of the crude material from MezCO afforded 503 my (38.4'7~I 17c 169-173 ( E of pale yelloR- crystals: m p 292-23.1" dec: ir (KRr) :3000-2500 (CO*H), 1695 ( C 0 2 H ) . 1650 cm-' ( C O ) ; nmr (DhISO-ds) i, ('a 8.12 (1 H, In, chromone H5), 7.48 (1 H , d . J = 16.5 Hz. H.: 01 I! 1 See Table I. footnotes ( I - ( acrylic acid), 7.18 (1 H. d . J = 1 6 5 Hz, H,, of acrylic acid), 7 . 3 . 7.8 (3 H, m, chromone H 6 . 7 . 8 ) . 2.63 (3 H. s, CH3). tran~s-5-('i-lvIethox~-4-oxo-1H-l-benzopyran-3)acr~lic Acid ci~-2-Benzyl-3-(4-oxo--1H-l-benzopyran-:~)acryli~ Acid (13). A (7e). A suspension of trans-methyl 3-(7-methoxy-4-oxo-4H-l-hen- mixture of 2a5.6,10(3.83 g. 22 mmol), benzylmalonic acid (5.24 g. zopyran-3)acrylate (:?OO mp. 1.15 mmol) in concentrated HCI (20 2F, mmoll. and 2-methylimidazole (5.3 g ) was fused at 110" for :30 ml) was heated a t 90" for 1 hr and the reaction mixture was then min. HzO and EtOA4c were then added t o the cooled reaction diluted with HzO (30 m l ) . The resulting precipitate was collected mixture. The EtOAc layer was extracted with 5 7 ~N a H C 0 3 aqueand recrystallized from DMF-MezCO (1:2l to afford 160 mg ous solution. The combined water solution was acidified with con(
