Synthesis and Quantitative Structure-Activity Relationships of

Chapter 6

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Synthesis and Quantitative Structure—Activity Relationships of Pyridylsulfonylurea Herbicides S. Murai, Y. Nakamura, T. Akagi, N. Sakashita, and T. Haga Central Research Institute, Ishihara Sangyo Kaisha, Ltd., 2-3-1, Nishi-shibukawa, Kusatsu, Shiga 525, Japan

SL-950 (Nicosulfuron, ISO proposed) is a post emergence application herbicide for corn which has a novel type of pyridylsulfonylurea structure. The analogs of SL-950 were synthesized, and their quantitative structure activity relationship analyses was carried out to understand the drug-receptor interaction. The QSAR equations obtained indicates SL-950 is the most effective compound among those examined.

SL-950 i s a p y r i d y l s u l f o n y l u r e a t y p e h e r b i c i d e f o r c o r n w h i c h has N , N - d i m e t h y l c a r b a m o y l g r o u p a t t h e 3 - p o s i t i o n on p y r i d i n e r i n g (compound 19 i n T a b l e I ) and shows a b r o a d h e r b i c i d a l s p e c t r u m a g a i n s t b o t h g r a s s e s and b r o a d l e a f weeds ( 2 ) . For t h e p u r p o s e o f s t u d y i n g 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 e s e p y r i d y l s u l f o n y l u r e a compounds, we p r e p a r e d 55 a n a l o g s o f SL-950, each o f which b e a r s d i f f e r e n t s u b s t i t u e n t s R , R , R , X , X and Z a s shown i n T a b l e I . I n t h i s paper s u b s t i t u e n t s R on t h e 6 - p o s i t i o n o f t h e p y r i d i n e r i n g were t h e o n l y p y r i d i n e s u b s t i t u t i o n s examined. I t was c l e a r from a p r e v i o u s s t u d y t h a t t h e i n t r o d u c t i o n o f s u b s t i t u e n t s i n t o any p o s i t i o n e x c e p t 6 - p o s i t i o n o f p y r i d i n e r i n g of p y r i d y l s u l f o n y l u r e a remarkably decreased the h e r b i c i d a l activity (1). 1

2

3

1

2

3

Synthesis S y n t h e t i c methods o f s u l f o n a m i d e p r e c u r s o r s f o r s u l f o n y l u r e a s a r e summarized i n Scheme I ( 2 ) . P h y s i c o - c h e m i c a l properties of t h e s e s u l f o n a m i d e s and s u l f o n y l u r e a s a r e shown i n r e f e r e n c e (3). S u l f o n a m i d e i n t e r m e d i a t e s f o r compounds 1—35 w i t h o u t any s u b s t i t u e n t a t t h e 6 - p o s i t i o n on p y r i d i n e r i n g were p r e p a r e d by r o u t e A i n scheme I , w h i l ^ p r e c u r s o r s f o r compounds 36—56 w h i c h have a c e r t a i n s u b s t i t u e n t R a t 6 - p o s i t i o n were p r e p a r e d by r o u t e e i t h e r B, C o r D. I n r o u t e B, 2 , 6 - d i c h l o r o n i c o t i n a m i d e s , 3

0097-6156/92/0504-0043$06.00/0 © 1992 American Chemical Society Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

44

SYNTHESIS AND CHEMISTRY OF AGROCHEMICALS III

Table I Synthesized SL-950 Analogs C0N-R

X,

2

y& R

Compd. 1 2 3 4 5 6 7 8

R

1

H 3

3

5

2

5

2

3

9 10

i-C H c-C H -CH CH=CH -CH CH=CH

11 12

-CH C = CH C ii H 9

13 14 15 16 17 18

(CH ) OCH (CH ) 0CH CH C0 CH C6 H5 CH CH CH CH

19 20

3

7

3

7

2

2

2

2

2

2

2

3

2

2

3

2

2

3

3

3

3

3

21 22 23 24 25 26 27 28

C H CH CF 0CH 0CH C0 CH C H

29 30

4-Cl-C H* 2,4-F -C H

C H C H 2

5

2

5

2

R

3

H H H H H H CH CH CH CH

3

H H H H H H H H H H

0CH 0CH 0CH 0CH 0CH 0CH CH CH 0CH 0CH

CH

3

H H H H H H H H H H

0CH 0CH 0CH 0CH 0CH CH 0CH 0CH 0CH 0CH

3

3

3

C H C H5 CH CH CH CH CH CH CH 5

3

3

5

3

3

6

2

6

3

X

1

H H H H H H

3

3

X

0CH CH 0CH CH 0CH 0CH 0CH 0CH 0CH 0CH

H H H H

3

3

3

2

H H H H H H H H H H

2

3

2

2

2

5

2

6

X

R

CH CH C H C H CH CF 2

N^
(Pi

^N^Cl

N SBn |f,g

|a,h,e,f,i y^s.

C0 Me

j or g

2

CONR'R >

(Pi

2

—* (Pi v

2

l , a , b or d

iPl

CONR'R

>

2

m,e

CONR'R

2

JPl

BnO

f , i

3

a,R H

iPl

2

y ^

CONR'R

2

—> iPl 3

R ^N^S0 NH

2

2

N SBn

j[pX

k

3

2

2

2

2

2

c ) NaH,R X/THF, d) N H ( R ' ) R / C H C l

2

2

2

2

R ^N^S0 NHH-

a) S O C l , b ) R ' N H / C H C l ,

2

H0^N^S0 NH-+-

^^CONR^

—*

S0 NH 2

CONR^

— *

HO^N^SBn

/ N

jOf

•

Cl^N^Cl y^

N

/s^CONR'R

KM

Cl^N^Cl

2

y^CONR'R

k

^N^S0 NH +

2

3

2

(Pi

^N^S0 NH4route B

^\CF

2

2

2

e) BnSH,K C0 /DMSO, f ) C l / a q . A c O H , g) N H / C H C 1 , h) MeOH, 2

3

2

3

NEt3/EDC, i ) t - B u N H / C H C l , 2

2

2

1

2

2

2

k) C F C 0 H , 1) I . A I C I 3 / E D C 2.H SO* 3

2

2

j ) Me AlN(R )R /benzene-CH Cl , 2

f

2

2

m) BnOH,K C0 /DMSO, n) c . H C l 2

3

Scheme I Synthetic Routes of Sulfonamides

Baker et al.; Synthesis and Chemistry of Agrochemicals III ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

Synthesis and QSAR of Pyridylsulfonylurea Herbicides

MURAI ET AL.

route

C

/\.C0 H

a,b o r d,e

2

M

CONR'R

2

JPl N SBn

>

Me^N^OH

f,g

—

/^CONR'R

>

2

IoT Me^N^SOzNHz

Me

| a,h,e,f,: C0 Me

C0 Me

2

2

x

Me f T S0 NH-

p,q,k > R0CH

BrH C^N^S0 NH-

2

2

^

2

I

.C0NMe

N

2

S 0 NH

2

C0NMe

2

2

r , s , q, k ,C0 Me 2

Br HC'"N'"S0 NH-f2

FH C^N'"S0 NH

2

J M

2

2

2

2

t C0 Me 2

u,g,k

C0NMe

0HC"N'"S0 NH-h \

0HC^N^S0 NH

2

2

2

2

s,q,k

IS

C0NMe

F HC^N^S0 NH 2

route

2

2

2

D

F C

N

3

CI

F C

N

3

S 0 NH •

v,k

.^C0NMe

— >

x o l F C^N^S0 NH

2

3

2

2

2

) N B S / C C I 4 , p) RONa/ROH, q j N H f R ) R / M e O H , r ) A g N 0 / a c e t o n e - H 0, 1

2

3

) E t N S F / C H C l , t ) AgN0 /EtOH-H 0 u) H 0 ( C H ) OH,TsOH, 2

3

2

2

3

2

2

2

) n - B u L i , ClC0NMe /THF 2

Scheme I Continued

American Chemical Society Library 1155 16th St., N.W. Baker et Washington, al.; Synthesis andD.C. Chemistry of Agrochemicals III 20036

ACS Symposium Series; American Chemical Society: Washington, DC, 1992.

2

47

48


p r e p a r e d from 2 , 6 - d i c h l o r o - 3 - t r i f l u o r o m e t h y l p y r i d i n e by t h e s i d e - c h a i n t r a n s h a l o g e n a t i o n , were t r e a t e d w i t h b e n z y l a l c o h o l to i n t r o d u c e b e n z y l o x y p r o t e c t i n g group a t t h e 6 - p o s i t i o n by a nucleophilic substitution. The 6 - b e n z y l o x y compounds f r e e d from a p p r o x i m a t e l y 10% o f t h e c o r r e s p o n d i n g 2 - b e n z y l o x y i s o m e r , were reacted with benzylmercaptan t o introduce the t h i o e t h e r e a l l i n k a g e a t 2 - p o s i t i o n , which was t o be c o n v e r t e d t o a sulfonamide group. The 6 - h y d r o x y l compounds, o b t a i n e d by d e p r o t e c t i o n o f t h e b e n z y l g r o u p , were r e a c t e d w i t h v a r i o u s n u c l e o p h i l e s t o i n t r o d u c e a s u b s t i t u e n t R a t t h e 6 - p o s i t i o n . By r o u t e B, t h e p r e c u r s o r s f o r compounds 37—41, and 47—53 were p r e p a r e d . P r e c u r s o r s f o r compounds 36, 42 and 43 b e a r i n g a l k y l g r o u p s and compounds 55 and 56 b e a r i n g a l k o x y m e t h y l g r o u p s a s R a t 6p o s i t i o n were p r e p a r e d by t h e f i r s t two methods i n r o u t e C, respectively. S y n t h e t i c methods f o r p r e c u r s o r s f o r t h e 6f l u o r o m e t h y l (compound 44), 6 - f o r m y l (compound 54) and 6d i f l u o r o m e t h y l (compound 45) d e r i v a t i v e s a r e a l s o shown i n r o u t e C. A p r e c u r s o r f o r compound 46 b e a r i n g a t r i f l u o r o m e t h y l group a t 6 - p o s i t i o n was p r e p a r e d a c c o r d i n g t o r o u t e D. The s u l f o n a m i d e p r e c u r s o r s were c o n v e r t e d t o s u l f o n y l u r e a compounds by one o f t h r e e c o u p l i n g p r o c e s s e s shown i n Scheme II. The f i r s t method i s t h e c o n d e n s a t i o n o f t h e a m i n o p y r i m i d i n e s o r a m i n o t r i a z i n e s w i t h t h e p h e n y l Np y r i d y l s u l f o n y l c a r b a m a t e s d e r i v e d from s u l f o n a m i d e precursors. The s e c o n d and t h e t h i r d methods a r e t h e c o n d e n s a t i o n o f t h e sulfonamides with e i t h e r t h e phenyl carbamates o r t h e i s o c y a n a t e s which were d e r i v e d from e i t h e r a m i n o p y r i m i d i n e s o r aminotriazines. 3

3

(1st

method)

y (2nd method) )-N R

z ( 3 r d method)

3

X, w) NaH , (PhO) 2 CO/DMF,

x) H N - ( Q z 2

/AcOEt,

Scheme II Coupling Process


6.


MURAIETAL.

Quantitative Structure A c t i v i t y Relationships A n a l y s e s o f q u a n t i t a t i v 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 were c a r r i e d out by t h e a d a p t i v e l e a s t - s q u a r e s method ( 4 ) . H e r b i c i d a l a c t i v i t i e s o f a f o r e m e n t i o n e d SL-950 a n a l o g s were d i v i d e d i n t o t h r e e c l a s s e s a c c o r d i n g t o the i n t e n s i t y a g a i n s t s o y b e a n , c o c k l e b u r , m o r n i n g - g l o r y , smartweed and pigweed by f o l i a r a p p l i c a t i o n a t t h e r a t i o o f 125 g a . i . / h a . I n T a b l e I I , r a n k 3 means t h e most e f f e c t i v e c l a s s w h i l e rank 1 i n d i c a t e s no herbicidal effect. E q u a t i o n (1) i s t h e b e s t e q u a t i o n ( c o r r e l a t i o n c o e f f i c i e n t i s 0.89 and i s s a t i s f a c t o r y ) o b t a i n e d f o r compounds 1—34 which have no s u b s t i t u e n t s a t t h e 6 - p o s i t i o n on t h e p y r i d i n e r i n g .

L = 1.056 Alog (0.628)

P - 0.279 ( A l o g P ) (2.383) - 0.036 Vw (0.207)

2

- 0.007 Vw (1.033)

1

(R )

2

(R ) - 1.380 I + 1.680 (0.248)

N = 34 ( 3 - g r a d e s ) , Rs = 0.89, e = 0.160, M i s = R s ( l e a v e - o n e - o u t ) = 0.74, Alog P = 1.892

(1 )

3(0)

o p t

In t h e e q u a t i o n ( 1 ) , L r e p r e s e n t s t h e d i s c r i m i n a n t f u n c t i o n and t h e v a l u e i n p a r e n t h e s i s under each term i n d i c a t e s t h e c o n t r i b u t i o n f a c t o r w h i c h i s the v a l u e o f c o e f f i c i e n t m u l t i p l i e d by t h e s t a n d a r d d e v i a t i o n . P h y s i c o - c h e m i c a l p a r a m e t e r s f o r each compound a r e shown i n T a b l e I I . V w ( R ) i s t h e van der Waals volume o f s u b s t i t u e n t R c a l c u l a t e d by B o n d i ' s method ( 5 ) . R i s d e d i c a t e d t o t h e more b u l k y g r o u p i n comparison w i t h R group. V w ( R ) i s t h e van der Waals volume o f R group i n e x c e s s o f t h a t of a m e t h y l g r o u p . I n o t h e r words, i n t h e case o f a h y d r o g e n o r a m e t h y l group as R , V w ( R ) was e s t i m a t e d as 0. A l o g P i s t h e summation of t h e 1o c t a n o l / w a t e r p a r t i t i o n c o e f f i c i e n t s c a l c u l a t e d by C i p p e n ' s method {6) f o r p y r i d i n e r i n g and t h e o t h e r h e t e r o c y c l i c m o i e t y e x c e p t t h e s u l f o n y l u r e a b r i d g e . N i s the number o f compounds. Rs i s t h e Spearman rank c o r r e l a t i o n c o e f f i c i e n t . e i s the d i s p e r s i o n of e r r o r . M i s i s t h e number m i s c l a s s i f i e d . The f i g u r e i n p a r e n t h e s i s a f t e r t h e v a l u e o f M i s i s the number m i s c l a s s i f i e d by two g r a d e s . I i s a dummy p a r a m e t e r f o r h e t e r o c y c l i c m o i e t y , t h a t i s , I i s 0 f o r p y r i m i d i n e and 1 f o r triazine. 1

1

1

2

2

2

2

2


49

50


Table II Physico-chemical Parameters Used for Equations (1) and (2) rank o f a c t i v i t y Compds.

Vw(R') obsd.

1 2

2 2

3 4

3 1 2 2 2 2 2 1

5 6 7 8 9 10 1 1 12 13 14

2 3 3 1 3 2 2 2 2 1 2 2 2 1 1 2 3 1

19 20

3 1

21 22 23 24

3 2 1 2

3 2 1 2

25 26

3 1 2 2 2 2

3 1 2 2 2 2

27 28 29 30

3

Vw(R )

A log P

I

0 .784 1 .125 1 .125

pred.

3 2 2 1 1 2 2 1 3 1

15 16 17 18

2

Vw(R )

3 .45 13 .68 13 .68 23 .91 23 .91 32 .16 34 .14 27 .24 30 .62 30 .62

0 0 0 0 0 0 0 0 0 0

3 .45 3 .45 3 .45 3 .45 3 .45 3 .45 3 .45 3 .45 3 .45 3 .45

2 .298 1 .610 1 .930 1 .899 1 .503 1 .758 1 .960

0 0 0 1 0 0 0 0 0 1

23,.72 44,.37 37,.84 37,.84 42..29 47..37 13.,68 13..68 13.,68 13.,68

0 0 0 0 0 0 0 0 0 0

3,.45 3,.45 3,.45 3,.45 3..45 3..45 3.,45 3.,45 3.,45 3.,45

1 .290 2 .533 0 .758 0 .960 -0,.091 2,.626 1 .596 , 2,.154 1 .466 . 1 .668 .

0 0 0 1 0 0 0 1 0 1

3. 45 3. 45 3. 45 3. 45 3. 45 3. 45 3. 45 3. 45 3. 45 3. 45

1 .951 . 2.,436 2.,638 2.,271 1 ,466 . 2.,154 1 .408 2. 967 3. 562 3. 308

0 0 1 0 0 1 0 0 0 0

23..91 23. 91 23. 91 32. 16 17. 38 17. 38 32. 06 47. 37 56. 16 52. 87

0 10. 25 10. 25 0 0 0 0 0 0 0


6.

MURAIETAL.


Table II Continued rank of

activity 1

Compds.

Vw(R ) obsd. 2 2 1 2 1

2 2 1 2 1

37 38

3 3 1

3 3 1

39 40

3 3

3 3

41 42

3 3 3 3 3

47 48

3 3 3 3 3 3 3 2

3 3 2

49 50

3 3

3 3

31 32 33 34 35 36

43 44 45 46

51 52 53 54 55 56

2

2

3 1 2

3 2 3 2 2

3 2

2

Vw(R )

3

Vw(R )

A log P

I

3 .45 3 .45 3 .45 3 .45 3 .45 13 .67 31 .67 .67 31 , 5,.72 11 .62 ,

2 .040 0 .751 0 .953 2 .404 2 .242 1 .399 1 .563 . 2,.251 1 .775 , 1 .997 ,

0 0 1 0 1 0 0 1 0 0

14,.40

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

pred. 20 .46 24 .16 24 .16 31 .26 20 .46 13 .68 13 .68 13 .68 13,.68 13,.68

6,.80 6..80 6..80 0 6..80 0 0 0 0 0

13,.68 13,.68 13..68 13..68 13..68 13.,68 13.,68 13.,68 13.,68 13..68

0 0 0 0 0 0 0 0 0 0

27..10

2,.298 1 .740 , 2..390 1 .648 . 2..131 2..626 1 ,904 . 2.,389 1 ,611 . 2.,096

13. 68 13. 68 13. 68 13. 68 13. 68 13. 68

0 0 0 0 0 0

38. 84 24. 47 37. 92 15. 15 27. 10 49. 06

2. 416 2. 304 0. 434 1 .649 1 .194 1 .999

13,.67 23..90 15..95 18..98 21 ..93 31 ..67 41 .,89 16. 87


51

52


2

S i n c e the c o e f f i c i e n t s f o r Vw(R') and V w ( R ) a r e n e g a t i v e , t h e l a r g e r R and R d e c r e a s e t h e h e r b i c i d a l a c t i v i t y . The optimum v a l u e f o r A l o g P w i l l e x i s t b e c a u s e t h e e q u a t i o n i s q u a d r a t i c f o r i t . C a l c u l a t e d optimum v a l u e f o r A l o g P i s 1.892. T h i s v a l u e i s l a r g e r than t h e A l o g P f o r SL-950 ( 1 . 4 6 6 ) . However, from t h e f a c t t h a t l a r g e R and R d e c r e a s e t h e a c t i v i t y , t h e r e s u l t o f t h e combined e f f e c t of A l o g P and Vw s u g g e s t s t h a t SL-950 shows t h e h i g h e s t a c t i v i t y . N e x t , we c a r r i e d out a QSAR a n a l y s i s f o r SL-950 a n a l o g s i n c l u d i n g s u l f o n y l u r e a s w h i c h have a s u b s t i t u e n t as R to a n a l y z e t h e c o n t r i b u t i o n by t h a t g r o u p . The b e s t e q u a t i o n (2) f o r compounds 1 — 56 i s o b t a i n e d by t h e p r o c e d u r e shown below. 1

2

1

2

3

L = 0.953 A l o g (0.428)

- 0.028 Vw (0.179)

P - 0.233 ( A l o g P ) (1.449)

2

(R )

- 0.005 Vw (0.716)

3

(R )

2

- 0.013 Vw (1.751)

1

(R )

- 1.436 I + 1.938 (0.211)

N = 56, Rs = 0.89, e = 0.191, R s ( l e a v e - o n e - o u t ) = 0.81, A l o g P

(2)

Mis = 7 ( 0 ) = 2.006

o p t

To o b t a i n e q u a t i o n ( 2 ) , t h e same p a r a m e t e r s as t h a t o f t h e e q u a t i o n (1) were used e x c e p t V w ( R ) w h i c h i s van der Waals volume o f R g r o u p . I t was c o n f i r m e d t h a t t h e r e were no c o r r e l a t i o n s between A l o g P and each Vw. A l l o f t h e terms f o r Vw a r e a g a i n n e g a t i v e and t h e e q u a t i o n i s a l s o q u a d r a t i c f o r A l o g P as was e x p e r i e n c e d f o r t h e e q u a t i o n ( 1 ) . The v a l u e s o f c o n t r i b u t i o n f a c t o r i n d i c a t e t h a t t h e c o n t r i b u t i o n o f V w ( R ) and Vw(R ) i s important. E s p e c i a l l y , V w ( R ) has t h e l a r g e s t c o n t r i b u t i o n f a c t o r among a l l o f the p a r a m e t e r s i n t h e e q u a t i o n . The o r d e r o f f l e x i b i l i t y f o r t h e s i t e o f r e c e p t o r i s R , R, R a c c o r d i n g t o t h e a b s o l u t e v a l u e s o f c o e f f i c i e n t f o r Vw. The optimum v a l u e f o r A l o g P was c a l c u l a t e d t o be 2.006. In t h e e q u a t i o n s (1) and (2) we used a dummy p a r a m e t e r c o n c e r n i n g h e t e r o c y c l e m o i e t y e x c e p t l o g P, i n w h i c h t h e c o n t r i b u t i o n of h e t e r o c y c l e moiety i s p a r t l y i n v o l v e d . With the i n t e n t i o n of a thorough i n v e s t i g a t i o n of the c o n t r i b u t i o n of t h e h e t e r o c y c l i c m o i e t y t o t h e h e r b i c i d a l a c t i v i t y , we c a r r i e d out a n o t h e r QSAR a n a l y s i s u s i n g 15 compounds i n T a b l e I I I b e a r i n g a dimethylcarbamoyl group at the 3 - p o s i t i o n of p y r i d i n e r i n g keeping the l e f t - h a l f of the s t r u c t u r e f i x e d . In Table I I I , X r e p r e s e n t s the s m a l l e r group i n comparison w i t h X group. A c c o r d i n g t o t h e r e s u l t of l e a v e - o n e - o u t p r e d i c t i o n , e q u a t i o n (3) was s e l e c t e d . £ o i n t h e e q u a t i o n i s t h e summation o f Hammett's e l e c t r o n i c p a r a m e t e r s (7) o f each p o s i t i o n o f t h e heterocycle ring. V i s t h e a d d i t i o n o f van der Waals volume o f b o t h X i n e x c e s s o f t h a t o f 0CH and Z i n e x c e s s o f CH. From t h e e q u a t i o n a c e r t a i n e l e c t r o n i c i n t e r a c t i o n between t h e h e t e r o c y c l e r i n g and r e c e p t o r was e l u c i d a t e d i n a d d i t i o n t o t h e s t e r i c e f f e c t f o r X and Z. 3

3

1

3

1

3

2

1

2

1

3

1


1

6.


MURAIETAL.

L = 7.18 Z o (1.37)

~ 1.61 ( Z a ) (5.95)

2

- 0.168 V - 6.15 (1.02)

N = 15, Rs = 0.92, e = 0.217, R s ( l e a v e - o n e - o u t ) = 0.72, Z a

O

P

(3)

Mis = 1(0) t = 2.23

C o n t r i b u t i o n f a c t o r s o f each term show t h a t t h e c o n t r i b u t i o n o f e l e c t r o n i c parameter i s l a r g e r than t h a t of s t e r i c e f f e c t . The optimum v a l u e f o r Z a was c a l c u l a t e d t o be 2.23 from t h e equation.

Table HI Compounds and Physico-chemical Parameters for Equation (3) C0N(CH ) 3

X

2

X

3ompd.

Y

17 18

N N N N N N N N N

1

Y

2

2

rank of a c t i v i t y pred. obsd.

Z a

V

2

1 .91

0

1

3. 03 2. 10 2. 84

0

Z

X

N

CH

CH

0CH

3

2

N N N N N N N N N

N CH N CH CH CH CH CH CH

0CH

3

0CH

3

1

0CH

3

0CH

3

3

2

0CH

3

1

1

2 2 2 2

2 2 2 2

N

CH

CH

N

N

CF

0CH

65 66

N CH

CH

CH

CF

CH

N

0CH

67

CH

CH

N

H

19 26 57 58 59 60 61 62 63 64

N N

1

CH

X

3

3

2

0CH

3

OC2H5

0CH

3

OCHF2

0CH

3

SCH

3

0CH

3

CI 0CHF

SCH

3

2

OCHF2

1

1

SCH

1

2

CH

3

3

3

3

3

3

2. 08 2. 29 2. 13 2. 35 2. 48 2. 16

0 0 0 0 0 0

5.51 7.60

1

1

1 .72

0

1

2

2. 16

CF

3

1

1

1 .79

2.27 5.06

CF

3

1

1

1 .48

0

CF

3

1

1

1 .36

0

0CH

3


53

54


The r e s u l t s o f t h e a f o r e - m e n t i o n e d c o r r e l a t i o n a n a l y s e s c a n be summarized i n t h e r e c e p t o r mapping shown i n Scheme I I I . E q u a t i o n (1) i n d i c a t e s t h a t t h e p y r i d i n e r i n g b i n d s w i t h r e c e p t o r b e a r i n g some h y d r o p h o b i c c h a r a c t e r . Especially the b i n d i n g s i t e o f t h e r e c e p t o r which s u r r o u r d s t h e 3 - p o s i t i o n s u b s t i t u e n t o f p y r i d i n e r i n g c o u l d accomodate o n l y a l i m i t e d numbers o f atoms, e l u c i d a t i n g t h a t m e t h y l g r o u p i s t h e most d e s i r a b l e a s t h e s u b s t i t u e n t R and R . S i n c e t h e s t e r i c c o n t r i b u t i o n o f s u b s t i t u e n t R a s w e l l a s t h a t o f R was f o u n d t o be i m p o r t a n t by e q u a t i o n ( 2 ) , t h e b i n d i n g r e g i o n a r o u n d R can be s i z e - l i m i t e d . From t h e e q u a t i o n (3) were s u g g e s t e d two points. S i n c e an optimum v a l u e e x i s t s f o r t h e e l e c t r o n i c p a r a m e t e r o , t h e r e must be an e l e c t r o n i c i n t e r a c t i o n between t h e h e t e r o c y c l e m o i e t y and r e c e p t o r d i p o l e , and t h a t t h i s i n t e r a c t i o n i s s t e r i c a l l y a f f e c t e d a t the p l a c e near s u b s t i t u e n t X' and n u c l e a r atom Z. 1

2

3

1

3

Scheme III Interpretation of the QSAR Analyses

Conclusion The r e s u l t o f QSAR a n a l y s e s was summarized a s t h e r e c e p t o r mapping i n Scheme I I I . The optimum v a l u e s f o r A l o g P was o b t a i n e d and t h e s t e r i c e f f e c t f o r R', R , R X and Z was observed. An e l e c t r o n i c i n t e r a c t i o n between t h e h e t e r o c y c l e m o i e t y and t h e r e c e p t o r was a l s o s u g g e s t e d from t h e e q u a t i o n ( 3 ) . The t h r e e e q u a t i o n s were c o n s i s t e n t w i t h t h e f a c t t h a t SL-950 was t h e most d e s i r a b l e h e r b i c i d a l compound. 2

3

1


6.

MURAIETAL.

Synthesis and QSAR of Pyridylsulfonylurea Herbicides 55

Literature Cited 1.

2.

3. 4. 5. 6. 7.

Murai, S.; Haga, T . ; Fujikawa, K.; Sakashita, N . ; Kimura, F., Ed.; ACS Symposium Series No. 443; American Chemical Society: Washington, D . C . , 1991; p98. Murai, S.; Haga, T . ; Sakashita, N . ; Honda, C.; Nakamura, Y.; Honzawa, S.; T s u j i i , Y . ; Kimura, F . ; Fujikawa, K.; Nishiyama, R. J. Pestic. Sci., Submitted. Kimura, F . ; Haga, T . ; Sakashita, N.; Honda, C.; Murai, S. European Patent 0 232 067, 1987. Moriguchi, I . ; Komatsu, K. Eur. J. Med. Chem., 1981, 19. Bondi, A. J. Phys. Chem., 68, 1964, 68, 441. Ghose, A. K.; Crippen, G. M. J. Comput. Chem., 1986, 7, 565. Hansch, C.; Leo, A . ; Taft, R. W. Chem. Rev., 1991, 91, 165.

RECEIVED April27,1992


Synthesis and Quantitative Structure-Activity Relationships of

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