Drugs Affecting the Respiratory System - American Chemical Society

7 Clinically Effective 6-Ethyl-3-(1H-tetrazol-5-yl)chromone (AA-344)

Downloaded by NORTH CAROLINA STATE UNIV on January 17, 2013 | http://pubs.acs.org Publication Date: February 22, 1980 | doi: 10.1021/bk-1980-0118.ch007

AKIRA NOHARA Medicinal Research Laboratories, Central Research Division, Takeda Chemical Industries, Ltd., Yodogawa-ku, Osaka 532, Japan

It is well known that disodium cromoglycate (DSCG), a prophylactic drug for asthma, is a splendid fruit of Fisons ' group effort in the structural modification of a naturally occurring oxygen heterocycle, khellin, which possesses vasodilatory and smooth muscle relaxant properties (1, 2). On the other hand, the dried radix of Scutellaria baicalensis Georg has been used since ancient times in Chinese medicine as a diuretic or an antiallergic drug. Based on this information, Koda et al. studied baicalein (1), a major flavonoid present in the radixes and demonstrated that the flavonoid markedly inhibited the release of the mediators (histamine, SRS-A etc.) induced by the antigen challenge of chopped guinea pig lung which had been sensitized with egg albumin (3, 4). We were interested in these reports, and started our research to improve the antiallergic potency of baicalein. Preliminary structure-activity studies on baicalein and related synthetic compounds revealed that introduction of a carbonyl group at the 3-position of the chromone ring enhanced the antiallergic activity (5). This finding along with the paucity of reports concerning chromone derivatives containing substituents at the 3-position prompted us to initiate a program of chemical investigation on 3-substituted chromones. At that time, several preliminary screening methods for a n t i a l l e r g i c a c t i v i t i e s had been r e p o r t e d . At the beginning o f t h e f o l l o w i n g s t u d i e s , we s e l e c t e d t w o a s s a y m e t h o d s , A and B : A , as m e n t i o n e d a b o v e , t h e m e d i a t o r r e l e a s e from c h o p p e d g u i n e a p i g l u n g (3., 4_) , a n d B , h o m o l o g o u s p a s s i v e cutaneous a n a p h y l a x i s (PCA) i n t h e r a t (6^). As a n i n i t i a l s t e p t o t h e i n t r o d u c t i o n o f a c a r b o n y l g r o u p a t t h e 3 - p o s i t i o n o f t h e c h r o m o n e r i n g , we s t a r t e d w i t h t h e s y n t h e s i s o f 3 - f o r m y l d e r i v a t i v e s on w h i c h o n l y a few r e p o r t s (J7, 8^, 9) h a d b e e n p u b l i s h e d . The 4 - o x o - 4 H - l b e n z o p y r a n - 3 - c a r b o x a l d e h y d e s 2 s y n t h e s i z e d b y o u r own m e t h o d ( 1 0 , 1 1 , 12) w h i c h i s d e s c r i b e d l a t e r , showed a n i n h i b i t o r y

0-8412-0536-l/80/47-118-125$05.00/0 © 1980 American Chemical Society

In Drugs Affecting the Respiratory System; Temple, D.; ACS Symposium Series; American Chemical Society: Washington, DC, 1980.

DRUGS AFFECTING THE


126

RESPIRATORY SYSTEM

a c t i v i t y i n the a s s a y ( A ) , but t h e y were i n a c t i v e i n the PCA a s s a y (_13.) · Compounds o f t y p e 2^ p o s s e s s e d d e s i r a b l e a n t i a l l e r g i c p r o p e r t i e s , b u t w e r e f o u n d t o be h i g h l y t o x i c . T h e r e f o r e , 4 - o x o - 4 H - l - b e n z o p y r a n - 3 - c a r b o x y l i c a c i d s (^) w e r e s e t a s t h e s e c o n d t a r g e t i n o u r a t t e m p t t o s o l v e t h e problems o f t h e t o x i c i t y and p o o r s o l u b i l i t y o f 2. However, the d e s i r e d p r o d u c t s 3 (_l4^ o b t a i n e d b y J o n e s o x i d a t i o n o f 2 w e r e f o u n d t o be i n a c t i v e i n PCA i n r a t s a n d a l s o i n t h e assay (A). On t h e o t h e r h a n d , t h e i s o m e r i c 4 - o x o - 4 H - l - b e n z o p y r a n - 2 - c a r b o x y l i c a c i d w h i c h i s t h e p a r e n t c o m p o u n d o f DSCG was i n a c t i v e i n t h e a s s a y ( A ) , b u t a c t i v e i n PCA i n r a t s . We, t h e r e f o r e , s p e c u l a t e d t h a t t h e d i f f e r e n c e i n t h e b i o l o g i c a l a c t i v i t y b e t w e e n t h e two i s o m e r s m i g h t be b a s e d on the d i f f e r e n c e i n a c i d i t y . W h i l e 4-oxo-4H-l-benzopyran-2c a r b o x y l i c a c i d e x h i b i t e d a h i g h a c i d i t y ( p K a ' 4.15 in d i m e t h y l s u l f o x i d e - H 0 o r pKa 2.96 (_15)) , t h e c o r r e s p o n d i n g 3 - i s o m e r s h o w e d a l o w a c i d i t y ( p K a ' 8.85 i n dimethyl s u l f o x i d e - H 0 (_l4) ) due t o i n t r a m o l e c u l a r h y d r o g e n b o n d i n g . 2

2

I n o r d e r t o e n h a n c e t h e a c i d i t y , a v i n y l o g u e (4a) o f 3? 3-(4-oxo-4H-l-benzopyran-3)acrylic a c i d , i n which the f o r m a t i o n o f t h e h y d r o g e n b o n d i n g b e t w e e n t h e c a r b o x y l and the c a r b o n y l g r o u p s i s s t e r i c a l l y h i n d e r e d , was s y n t h e s i z e d as the t h i r d t a r g e t . As e x p e c t e d , t h e a c r y l i c a c i d (4a) was a s l i g h t l y s t r o n g e r a c i d t h a n ^ J * ( pKa ' 7*25 i n d i m e t h y l s u l f oxide-H20) and p r o v e d t o be Ο.36 t i m e s a s a c t i v e a s DSCG i n t h e r a t PCA t e s t b y i n t r a v e n o u s a d m i n i s t r a t i o n (Jj5 ) · In the n e x t s t e p , some b i o l o g i c a l a c t i v i t i e s w e r e i n v e s t i g a t e d t o c h a r a c t e r i z e t h e p r o f i l e o f 4a. The compound 4a was not a n t a g o n i s t i c t o h i s t a m i n e , s e r o t o n i n o r b r a d y k i n i n , and a l s o s h o w e d no i n h i b i t o r y a c t i v i t y i n t h e a s s a y ( A ) . T h u s , 4a was f o u n d t o be a c t i v e s p e c i f i c a l l y i n t h e r a t PCA t e s t . In a d d i t i o n , t h e f a c t t h a t 4a i s a c t i v e n o t o n l y b y an i n t r a v e n o u s a d m i n i s t r a t i o n r o u t e b u t a l s o b y a n o r a l r o u t e was of p a r t i c u l a r s i g n i f i c a n c e b e c a u s e DSCG i s i n a c t i v e when o r a l l y administered and u s u a l l y h a s t o be a d m i n i s t e r e d by a n i n h a l a t i o n route. T h u s , a n u m b e r o f t h e d e r i v a t i v e s o f 4a w e r e s y n t h e s i z e d a n d t h e p o t e n c i e s s t u d i e d (_l6 ) . R e c e n t l y , a t t e m p t s h a v e b e e n made t o r e p l a c e the c a r b o x y l i c a c i d g r o u p by a t e t r a z o l e g r o u p i n chromones ( 17 ι l 8 ) , x a n t h o n e s (_19) , a n d a t h i o x a n t h o n e d e r i v a t i v e (20), b e c a u s e l H - t e t r a z o l e s g e n e r a l l y show a c i d i t y c o m p a r a b l e w i t h t h e c o r r e s p o n d i n g c a r b o x y l i c a c i d s (21). Since these e x a m p l e s i n d i c a t e t h a t b i o l o g i c a l l y a c t i v e t e t r a z o l e s c a n be obtained from the corresponding b i o l o g i c a l l y a c t i v e carboxy l i c a c i d s , b u t n o t f r o m t h e i n a c t i v e a c i d s , t h e r e was a g o o d chance t h a t the s u b s t i t u t i o n of the t e t r a z o l e group f o r the c a r b o x y l i c a c i d g r o u p i n b i o l o g i c a l l y i n a c t i v e 4-oxo-4H,-lb e n z o p y r a n - 3 - c a r b o x y l i e a c i d s (3) m i g h t g i v e i n a c t i v e com pounds. C o n t r a r y to t h i s assumption, however, 3 - ( l H - t e t r a z o l - 5 - y l ) c h r o m o n e (5a) was f o u n d t o be a c t i v e i n t h e r a t


7.

NOH AR A

127

6-Ethyl-3-(1 H-tetrazol-5-yl)chromone


PCA t e s t a n d more p o t e n t t h a n t h e a c r y l i c a c i d ( 4 a ) . The p h y s i c o - c h e m i c a l p r o p e r t i e s o f 5a d i f f e r e d f r o m t h o s e o f the a c i d (3a). The i n t r a m o l e c u l a r hydrogen bonding between the c a r b o n y l a n d t e t r a z o l e g r o u p s w a s n o t o b s e r v e d i n 5a w h i c h showed a s t r o n g e r a c i d i t y (pKa* 5 · 8 5 i n d i m e t h y l suifoxide-H2Û o r p K a 4 . 3 ) t h a n t h e c o r r e s p o n d i n g 3a a n d a l s o the a c r y l i c a c i d (4a). Hence, an e x t e n s i v e s t u d y on t h e s y n t h e s i s and t h e s t r u c t u r e - a c t i v i t y r e l a t i o n s h i p s o f t h i s o r a l l y e f f e c t i v e s e r i e s o f t e t r a z o l y l c h r o m o n e s 3_ w a s c o n ducted (22). ~" S y n t h e s i s o f 3 - S u b s t i t u t e d Chromones An e a r l i e r i n v e s t i g a t i o n (23) d e m o n s t r a t e d t h a t t h e V i l s m e i e r - H a a c k r e a c t i o n o f t h e ArCOCH^ t y p e compounds g i v e s the m o n o f o r m y l a t e d c o m p o u n d s o r t h e c o r r e s p o n d i n g β-chlorov i n y l a l d e h y d e s . I t was f o u n d , however, t h a t i n t h e c a s e o f o - h y d r o x y a c e t o p h e n o n e s , t h e m e t h y l group was d o u b l y f o r m y l a t e d b y a V i l s m e i e r r e a g e n t t o g i v e o u r f i r s t t a r g e t com pounds, 4-oxo-4H-l-benzopyran-3-carboxaldehydes (2.) i n o n e s t e p ( K ) , 1_1, 12). T h e r e a s o n why d o u b l e f o r m y l a t i o n t o o k p l a c e i n t h e c a s e o f o - h y d r o x y a c e t o p h e n o n e c a n be i n t e r p r e t e d as f o l l o w s ; w h i l e an e n o l a t e d acetophenone r e a c t s w i t h t h e r e a g e n t t o g i v e t h e i n t e r m e d i a t e w h i c h cannot be f u r t h e r formylated, an o-hydroxyacetophenone i n which t h e énolization i s p r o h i b i t e d b y t h e i n t r a m o l e c u l a r h y d r o g e n bonding can be doubly f o r m y l a t e d (Figure l ) . The s e c o n d t a r g e t , 4-oxo-4H-l-benzopyran-3-carboxy1ic a c i d s (3) w e r e o b t a i n e d b y J o n e s o x i d a t i o n o f 2 o r h y d r o l y s i s o f t h e 3 - c a r b o n i t r i l e d e r i v a t i v e s (6) d e s c r i b e d b e l o w ( 1 4 ) . The t h i r d t a r g e t , 3 - ( 4 - o x o - 4 H - l - b e n z o p y r a n - 3 ) a c r y l i c a c i d s (4) w e r e s y n t h e s i z e d g e n e r a l l y b y t h e K n o e v e n a g e l r e a c t i o n o f 3 - c a r b o x a l d e h y d e s (2) w i t h m a l o n i c a c i d il6). In the m e a n t i m e , i t w a s f o u n d t h a t t h e 3 - c a r b o x a l d e h y d e s {2), w h i c h w e r e a b l e t o f u n c t i o n a s β-dialdehyde c o m p o u n d s , w e r e a t t a c k e d b y a m i d e g r o u p s i n some c a s e s , t o g i v e 2(1H)-pyridone derivatives after condensation with malonic acid derivatives. T h u s , c o n d e n s a t i o n o f .2 w i t h m a l o n o d i a m i d e i n p y r i d i n e g a v e i n i t i a l l y a c r y l a m i d e d e r i v a t i v e s which were c o n v e r t e d i n t o 3-carbamoyl-5-(2-hydroxybenzoyl)-2(1H)-pyridones {j) ( 2 4 ) . The f i n a l t a r g e t , 3 - ( l H - t e t r a z o l - 5 - y l ) c h r o m o n e s (5), were s y n t h e s i z e d by t h e r e a c t i o n o f sodium a z i d e i n t h e p r e s e n c e o f anhydrous aluminum c h l o r i d e and 4-oxo-4H-l-benzo p y r a n - 3 - c a r b o n i t r i l e s (£) w h i c h w e r e o b t a i n e d i n o n e s t e p f r o m ^ w i t h h y d r o x y l a m i n e (j22, 23) ( F i g u r e 2 ) . Structure-Activity Relationships A c r y l i c A c i d (4) S e r i e s (22, 16) While t h eparent a c r y l i c

i ntheTetrazole

acid

(4a)

(5.) a n d "~

was, as s t a t e d



DRUGS AFFECTING THE RESPIRATORY SYSTEM

Figure 2.

Synthesis of 3-substituted chromone derivatives


7.

NOHARA


Table

Compd. DSCG 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 51 5m 5n 5o

5Ρ 5q 5r

6-Ethyl-3-(lH-tetrazol-5-yl)chromone

I.

129

R e l a t i v e P o t e n c i e s a g a i n s t Rat P a s s i v e Cutaneous A n a p h y l a x i s (PCA) o f 3 - ( l H - T e t r a z o l - 5 - y l ) c h r o m o n e s (5) , 3 - ( 4 - O x o - 4 H - l - b e n z o p y r a n - 3 ) a c r y l i c A c i d s (4_) , a n d DSCG

, ^ R and P o s i t i o n

Η 8-OMe 6,8-Me 7,8-Benzo 5,6-Benzo 6-Et 6-C1 6-N0 6-n-Pr 6-i-Pr 6-C00Et 7-OMe 6-Me 6-NMe 6-OMe 6-n-Bu 6-n-Hex 6-cyclo-Hex 2

2

2

PCA a s s a y (iv)

3

_ Compd. J

PCA a s s a y ( i v )

1 (standard) 3.5 30

4a

Ο.36

11.6

4c

1.4

4e 4f 4g 4h 4i 4j

0.4 1.1 0.5 0.3 1.4 2.4

41 4m 4n 4o 4

0.3 0.8 1.1 1.3 1.1

8.3 5.0 4.0 4.0 4.0 3.4 3.4 2.9 2.5 2.4 2.3 2.2 1.8 0.6

P

a

0.5

T h e d o s e g i v i n g 50% i n h i b i t i o n ( I D ^ ) * e a c h d r u g w a s c a l c u l a t e d g r a p h i c a l l y from t h e d o s e - i n h i b i t i o n relation ship expressed i n i n h i b i t i o n percent o f t h ebluing areas a g a i n s t doses on a l o g a r i t h m i c s c a l e . At least three d o s e s a n d t h r e e a n i m a l s f o r e a c h d o s e ( i . e . , 12 s p o t s ) were used f o r o b t a i n i n g t h e d o s e - i n h i b i t i o n r e l a t i o n s h i p . r

0


DRUGS AFFECTING THE RESPIRATORY SYSTEM

130 Table

Compd.

I I . Relative

Structure

P o t e n c i e s (DSCG=l) (iv route)

PCA

assay

3

i n R a t PCA

Structure

Assay

PCA


ο

I

03

7.

NOHARA

135

6-Ethyl-3-(1 H-tetrazol-5-yl)chromone

predominantly t h e unchanged drug, b u t i nguinea p i g s , r a b b i t s a n d monkeys, m e t a b o l i t e s whose s t r u c t u r e s a r e s t a t e d l a t e r were found (Table V ) . T h e r e was a l r e a d y a w i d e d i s t r i b u t i o n o f C i n t i s s u e s 10 m i n a f t e r o r a l a d m i n i s t r a t i o n o f t h e d r u g t o r a t s . At t h i s t i m e , t h e * C c o n c n . was h i g h e s t i n t h e s t o m a c h , f o l lowed by k i d n e y , l i v e r , plasma, h e a r t and l u n g , and lowest in t h eb r a i n . A l m o s t a l l o f t h e a d m i n i s t e r e d *C w a s e l i m i n a t e d f r o m t h e b o d y i n 72 h . T h e m a j o r r o u t e o f e x c r e t i o n w a s u r i n e i n the v a r i o u s s p e c i e s except guinea p i g s , i n which t h e dosed was a l m o s t e q u a l l y d i v i d e d b e t w e e n u r i n e a n d f a e c e s . O n l y t r a c e amounts o f t h e u n c h a n g e d d r u g was f o u n d i n u r i n e and b i l e . The major u r i n a r y m e t a b o l i t e s a r e as f o l l o w s : a h y d r o x y ( l £ ) , a - k e t o ( l j ) , β-hydroxy ( l 8 ) , a n d α,β-dihydroxy (19) d e r i v a t i v e s o f AA-344 i n r a t s ; 16 a n d s a l i c y l i c a c i d d e r i v a t i v e (22,) i n g u i n e a p i g s ; 16, 18 a n d a g l u c u r o n i d e (20) i n r a b b i t s ; 16 a n d 20 i n d o g s ; a n d 16 a n d 19 i n m o n k e y s (Table V I ) . 1


lZ

Synthesis

and B i o l o g i c a l

Activities

o f theMetabolites

(32)

I n t h e m e t a b o l i s m s t u d y (29, 30, 3 1 ) i t h e f o l l o w i n g seven m e t a b o l i t e s , 6-(1-hydroxyethy1)-3-(ΙΗ-tetrazo1-5-y1)c h r o m o n e ( 16 ) , 6 - a c e t y l - 3 - ( l H - t e t r a z o l - 5 - y l ) c h r o m o n e ( 17 ) 6 - ( 2 - h y d r o x y e t h y l ) -3-( l H - t e t r a z o l - 5 - y l ) c h r o m o n e ( ΐ£) , 6( 1 , 2 - d i h y d r o x y e t h y l ) - 3 - ( Ι Η - t e t r a z o 1 - 5 - y l ) c h r o m o n e ( 19.) , g l u c u r o n i d e (20) ( t h e s t r u c t u r a l e l u c i d a t i o n i s d e s c r i b e d b e l o w ) , 5 - e t h y l s a l i c y l i c a c i d (21.) a n d 3 - c a r b o x y - 4 - h y d r o x y p h e n y l a c e t i c a c i d (.22), w e r e i d e n t i f i e d i n t h e u r i n e o f r a t s , g u i n e a p i g s , r a b b i t s , dogs and monkeys. T h e s e s e v e n com pounds were s y n t h e s i z e d a n d u s e d a s r e f e r e n c e compounds t o u n e q u i v o c a l l y e s t a b l i s h t h e s t r u c t u r e s o f t h e u r i n a r y metabo l i t e s , and t o a l l o w e v a l u a t i o n o f t h e i r a n t i a l l e r g i c a c t i v i t y (32.)· The s y n t h e t i c r o u t e s a r e shown b e l o w ( F i g u r e 4 ) . B r o m i n a t i o n o f AA-344 w i t h N - b r o m o s u c c i n i m i d e ( N B S ) f o l l o w e d b y a l k a l i n e h y d r o l y s i s g a v e t h e α-hydroxy m e t a b o l i t e ( l j ) ) , w h i c h w a s c o n v e r t e d t o 17 b y J o n e s o x i d a t i o n . While t h e e p o x i d e d e r i v a t i v e (23.) ( r e f e r t o r e f e r e n c e 32) g a v e t h e β-hydroxy m e t a b o l i t e (18) o n c a t a l y t i c hydrogénation, t h e t r e a t m e n t o f 23 w i t h f o r m i c a c i d f o l l o w e d b y h y d r o l y s i s w i t h a q u e o u s a l k a l i y i e l d e d t h e α, β-dihydroxy m e t a b o l i t e (19.). C o n d e n s a t i o n o f AA-344 w i t h m e t h y l 1 - b r o m o - 1 - d e o x y - t r i - 0 a c e t y l -oc-D-g l u c o p y r a n u r o n a t e (24) i nt h e presence o f s i l v e r c a r b o n a t e g a v e a m i x t u r e o f 25a a n d 26a w h i c h w e r e s e p a r a t e d by f r a c t i o n a l r e c r y s t a 1 1 i z a t i o n . The p r o t e c t i n g g r o u p s o f 25a a n d 26a w e r e r e m o v e d w i t h s o d i u m h y d r o x i d e t o g i v e 25b a n d 26b, r e s p e c t i v e l y . T h e s t r u c t u r e s o f t h e g l u c u r o n i d e s w e r e c o n f i r m e d t o b e t h e N - l i s o m e r s , 25a a n d 25b, b y t h e chemical s h i f t s o f t h eg l y c o s y d i c carbons and t h e t e t r a z o l e



2, .0 1.• 5 0, .5 3. .0 1..0

1

Drugs Affecting the Respiratory System - American Chemical Society

Recommend Documents