STUDIES IN PHENOXYACETIC ACID ADRENALINES

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l £ 39°7 1 4 * 1 1 3 to 1 9 5 0 t - e d e r e r , S e y m o u r J e r r a l d , I 9 2 I+oL 35

S tu d ie s in phenoxy a c e t i c a c id a d r e n a lin e s o New Y o r k , I 9 I4.9 . 68 t y p e w r i t t e n l e a v e s , 2 9 cm, T h e s i s ( P h o D o ) - New Y o rk U n i v e r ­ s i t y , G r a d u a t e S c h o o l , 19 ^ 0 o . B i b l i o g r a p h y : p 06 6 - b 8 « C 50 721

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S eym our J , L e d e r e r

October Istj AS 40 F eJU’-u^ ^ v7*0

*A d i s s e r t a t i o n I n t h e d e p a r t m e n t o f c h e m i s t r y s u b m i tte d t o t h e f a c u l t y o f t h e G r a d u a te S c h o o l o f A r t s a n d S c ie n c e o f l e v Y o rk U n i v e r s i t y i n p a r t i a l f u l f i l l m e n t o f t h e r e q u i r e m e n t s f o r t h e d e g r e e o f D o e to r o f P h ilo s o p h y " *

TABLE CF CONTENTS

Pag© INTRODUCTORY QUOTATION ................................................... ...............................................................................................

2

........................................................................................................................

3

ACKNOWLEDGEMENT SCOPE

THEORETICAL ....................... H is to ry

........................................................

The R e l a t i o n B etw een P h a r m a c o lo g ic A c t i v i t y a n d C h e m ic a l C o n s t i t u t i o n

....................................................

7

The S y n t h e s i s o f B e ta P h e n e th y la m ln e Type Compounds

..................................... ................ « • . . . « • • •

S te r e o is o m e r is m

20

..................................................

A l i p h a t i c S y m p a th o m im e tic A m in e s

.................

25 28

P h a rm a c o lo g y • • • • • • • • • • • • • • • . . • • • • • . • « » .............. • •

31

..............................

34

U ses o f t h e S y m p a th o m lm e tlc s

PRESENT INVESTIGATION........................................................................

37

EXPERIMENTAL.............................. S y n t h e s i s c£ A d r e n a l i n o z y a c e t i c E s t e r ...................»• S y n t h e s i s o f S y n e p h r l n e o x y a c e t i c E s t e r ...........

56

TABLE CF COMPOUNDS...............................................................................

64

SUMMARY .................................................................................................................... BIBLIOGRAPHY..............................................................................................

a o i o ^

66

45

65

"T he r e a l o b j e c t o f c h e m i s t r y i s n o t t o m ake g o l d , b u t t o p r e p a r e m e d ic in e s • " — P a r a c e l s u s •

1

ACKNOWLEDGMENT TO PROFESSOR JOSEPH B . U SD ERL, FOR HIS KIND COOPERATION IN INITIATING AND ADVISING THIS INVESTIGATION, THE AUTHOR WISHES TO EXPRESS H IS SINCERE APPRECIATION.

SCOPE

I t waa b e l i e v e d t h a t t h e I n t r o d u c t i o n o f a g l y c o l 11c a d d - t y p e l i n k a g e i n t o a d r e n a l i n e w o u ld p r o d u c e a n i n t e r e s t ­ i n g a n d p o s s i b l y p h y s i o l o g i c a l l y a c t i v e co m p o u n d .

I t w as

f o r t h i s r e a s o n t h a t a d r e n a l i n o x y - a e e t i c a c i d ( N - m e tb y la m ln o - m e th y l- ( 4 - h y d r o x y 3 - e t h y l o x y a c e t l e ) - p h e n y l c a r b l n o l ) and i t s

a n a lo g u e s y n e p h r i n e o x y - a c e t l c a c i d ( N -m eth y 1 - am in o ­

m e t h y l - (4 - m e th y l o x y a c e t l e ) - p h e n y l c a r b l n o l w e re p r e p a r e d .

3 -

THEORETICAL H i s t o r y o f t h e S y m p a th o w lm e tlc s The f i e l d o f t h e sy m p a th o m im e tic a m in e s i s a p a r t i c u l a r l y I n t e r e s t i n g o n e s in c e i t r e p r e s e n ts one o f th e m ost s u c c e s s f u l a t t e m p t s t o c o r r e l a t e p h a r m a c o lo g ic a c t i v i t y w i t h c h e m ic a l s tru c tu re *

I n te r e s t i n th e s e

com pounds w h ic h p r o d u c e d a r i s e

i n b l o o d p r e s s u r e was a r o u s e d w hen O l i v e r a n d S c h a e f e r i n 1894 ( 1 ) , a n d S cym onow lcs I n d e p e n d e n t l y i n

1895 ( 2 ) fo u n d t h a t th e e x t r a c t s

o f t h e s u p r a n e a l g la n d s , fo u n d ab o v e th e k id n e y , p ro d u c e d a r i s e i n b l o o d p r a s s u r e w hen i n j e c t e d i n t o t h e b lo o d v e s s e l s o f a n im a ls * A b e l a n d C ra w fo rd i n 1897 ( 3 ) s e p a r a t e d e p i n e p h r i n e i n t h e fo rm o f a p o ly b e n z o y l d e r i v a t i v e l f c l c h , o n d e c o m p o s it io n w i t h s u l f u r i c a c i d , y i e l d s a v e r y a c t i v e s u l f a t e w h ic h i s

th o u g h t t o h a v e b e e n

a fo rm o f F r i e s r e a r r a n g e m e n t o f o n e o f t h e b e n z o y l g r o u p s i n t o th e b en zen e n u c le u s * T ak am ln e was t h e f i r s t t o c r y s t a l l i z e p u r e e p l n e p h r i n e ( 4 ) a n d l a t e r w o rk b y A l d r i c h show ed i t s b e C10Hl o H 0 ( 6 , 6 ) .

t r u e e m p ir ic a l fo rm u la to

F o r t h e n e x t fe w y e a r s w o r k e r s i n t h e f i e l d

p r o p o s e d s e v e r a l s t r u c t u r a l f o r m u l a e f o r e p i n e p h r i n e , t h e m o st p o p u la r b e in g t h e f o llo w in g t h r e e

( 7 ,8 ,9 ,1 0 ) t

H CHOHHHCH

i

ii

CHCHo 0H HHCH* O hi

J e w e t t i n h i e o x i d a t i o n s t u d i e s o b t a i n e d p r o d u c t s w h ic h le a d t o th e p r o o f o f s t r u c t u r e I (1 0 )*

S to le , fo llo w in g

J e w e t t 's l i n e o f r e a s o n i n g , s e t a b o u t t o s y n t h e s i s e com pound I ( U ) * He c o n d e n s e d C h l o r a c e t y l c a t e c h o l w i t h m e th y l am in e g i v i n g t h e m e th y l am in o a o e to c a t e c h o l *

R e d u c tio n o f t h i s com pound g a v e a

com pound w i t h g r e a t a c t i v i t y a p p r o a c h i n g t h a t o f e p i n e p h r in e * The r e a s o n t h a t t h e a c t i v i t y o f S t o l s t s p r o d u c t w as n o t I d e n ­ t i c a l w ith t h a t o f t h e n a t u r a l p ro d u c t can b e e x p la in e d b y th e f a c t t h a t t h e s y n t h e t i c com pound was a m i x t u r e o f d a n d 1 - f o r m s , w h ile t h e n a t u r a l e p i n e p h r i n e i s

o n l y t h e 1- f o r m w h ic h l a tw e n ty

t i m e s m o re a c t i v e t h a n t h e d -fo rm * W ith t h e n a t u r e o f t h e e p i n e p h r i n e m o le c u le e s t a b l i s h e d a g r e a t i n t e r e s t i n t h e b e t a p h e n e t b y l a m in e s w as a r o u s e d *

T y ra m ln e

w as f o u n d t o a c t a s a p r e s s e r a n d b e t a p h e n e t b y l a m in e w as f o u n d among t h e p u t r e f a c t i o n p r o d u c t s o f p r o t e i n s *

I n 1910 B a rg e r a n d

B a le m ade a v e r y c o s q p re h e n s lv e s t u d y o n t h e r e l a t i o n b e tw e e n c h e m ic a l c o n s t i t u t i o n a n d p h a r m a c o lo g ic p r o p e r t i e s o f com pounds p r o d u c in g a r i s e i n b lo o d p r e s s u r e ( 1 2 ) *

T hey In tro d u c e d th e

te r m • s y m p a th o m im e tic " w h ic h I m p l i e s t h a t t h e e f f e c t p r o d u c e d b y su ch a d ru g I s s im ila r t o t h a t o b ta in e d b y e x c i t a t i o n o f th e s y m p a th e tic n e rv e s b y o th e r a g e n c ie s ; su c h a s a n e l e c t r i c a l Im p u ls e * C hen a n d S c h m id t i n 1925 n o t i c e d t h a t t h e p h e n y l l s o p r o p y l am ine s k e l e t o n com pounds p r o d u c e d a r i s e i n b lo o d p r e s s u r e ( I S ) * T h is s t i m u l a t e d much w ork on e p h r e d r l n e a n d r e l a t e d com pounds*

More r e e e n t l y t h e r e h a s b e e n a te n d e n c y t o d i v e r t som e a t t e n t i o n fro m t h e s e com pounds w i t h a b e t a p h e n e tb y l a m in e s t i n c t u r e t o o t h e r t y p e s ; s u c h a s t h e a l i p h a t i c a m in e s a n d com pounds o f t h e l m l d a s o l e ty p e .

T he R e l a t i o n B etw een P h a r m a c o lo g ic A c t i v i t y a n d C h e m ic al C o n e tltu tio n ♦

T he b e t a p h en e t h y l e a l ne s k e le to n , a p p e a r s t o b e t h e b a s i c s t r u c t u r e n e c e s s a r y f o r t h e a c t i v e com pound*

T h is g r o u p i n g ,

a p h e n y l a n d an am in e a n a d j a c e n t c a r b o n a to m s , was o b s e r v e d q u i t e e a r l y to b e one o f t h e m in im al e s s e n t i a l s f o r p r e s s o r a c tiv ity *

Work v l t h t h e a l i p h a t i c a m in e s , t h e i m i d a z o l e s ,

a n d r e l a t e d com pounds h a s , h o w e v e r, a l t e r e d t h e n e c e s s i t y f o r th is

s tru c tu re .

S in c e m o st o f o u r p r e s s o r s a t t h e p r e s e n t a r e

o f t h e b e t a p h e n e th y l am in e t y p e , a n d s i n c e m o s t o f t h e w o rk h a s b e e n done i n t h i s f i e l d , e m p h a s is m i l l b e p l a c e d o n t h e s e com pounds a n d t h e o t h e r m o d i f i c a t i o n s w i l l b e d i s c u s s e d l a t e r in th e p a p e r. A ssu m in g t h e r e s t r i c t i o n s o f th e b e t a p h e n e t h y l am in e s t r u c t u r e , t h e r e a r e a c o n s i d e r a b l e n u m b er o f p o s s i b i l i t i e s fo r s u b s titu tio n .

T h e re a r e t h r e e p o s i t i o n s i n th e p h e n y l

n u c l e u s ; o r t h o , m e ta , a n d p a r a t o t h e a l i p h a t i c c h a i n , t h e a l p h a , a n d b e t a c a rb o n s i n t h e s i d e c h a i n , a n d t h e a m in e n i t r o g e n *

The

e f f e c t s o f v a r i o u s s u b s t i t u e n t s o r c o m b in a tio n s o f s u b s t i t u e n t s o n t h e s k e l e t o n , i t i s a p p a r e n t fro m a s t u d y o f t h e p h a r m a c o lo g ic p r o p e r t i e s , w i l l n o t c o m p l e t e l y d e s t r o y t h e a c t i v i t y a s t h e y do i n m any o t h e r a c t i v e ty p e s *

I t w as a l s o f o u n d t h a t t h e a d d i t i o n

o f tw o o r m o re s u b s t i t u e n t s n a y h a v e a n a d d l t l t i v e e f f e c t * T he e f f e c t o f i n t r o d u c i n g a m e th y l g r o u p i n t h e a l p h a p o s i t i o n

o f t h e s i d e c h a i n c a n b e s e e n b y a c o m p a r is o n o f s e v e r a l p a i r s o f h o m o lo g u e s .

TABLE 1

P re s s o r a c tio n as f r a c t i o n of E p in e p h r in e

S tru c tu re

CHCHCBffi 6 5 2 2 2

C H CHOHCH IH

6 5

2

1 /1 8 3

60 mg/^cg

In tra v e n o u s to ra b b its

1/42&

25 m g^cg

in tr a v e n o u s to ra b b its

8 0 m g /k g

In tra v e n o u s to ra b b its

7 0 mg/^cg

In tra v e n o u s to r a b b its

2

CgHgCHOHCB( CH^ ) HHg

(H 0 )2 C6H3CH° HCH2HH2 ( HO ) C H CH0HCH( HH ) CH Z o 3 2 3

T o x ic ity

1 /6 0

1*2

1/12

I t c a n b e s e e n t h a t th e p r e s e n c e o f t h e a l p h a m e th y l g r o u p re d u c e s th e p r e s s o r a c t i v i t y a n d I n c r e a s e s th e t o x i c p r o p e r tie s o f t h e m o le c u l e .

O r d i n a r i l y t h i s c o m b in a tio n o f e f f e c t s w o u ld b e

a v o i d e d i n t h e c h o i c e o f a new d r u g , b u t i n t h i s c a s e t h e r e i s

a n o t h e r p r o p e r t y c o n f e r r e d b y t h e a l p h a m e th y l g r o u p , t h a t o f g re a t s ta b ility *

T hus i t

i s p o s s i b l e t o u s e t h e a l p h a m e th y l

com pounds b y o r a l a d m i n i s t r a t i o n *

I t m ig h t b e w e l l t o e x p l a i n

a te r m w h ic h s h a l l b e u s e d i n d i s c u s s i n g t h e c h a n g e i n a c t i v i t y on s u b s t i t u t i o n - t h e t h e r a p e u t i c r a t i o *

T h is i s m e r e ly a

r o u g h m e th o d o f d e t e r m i n i n g t h e a p p a r e n t m e d ic a l u s e f u l l n e s s o f a new p r o d u c t a s co m p ared t o t h e o r i g i n a l , i n te r m s o f a c t i v i t y and to x ic ity *

I f we assu m e t h a t t h e n e w ly fo rm e d com pound

i s t w i c e a s a c t i v e a s t h e p a r e n t com pound a n d o n l y o n e * t h i r d a s t o x i c , t h e n t h e t h e r a p e u t i c r a t i o i s t h r e e tim e s tw o , o r s ix * If,

o n t h e o t h e r h a n d , t h e a c t i v i t y i s o n ly o n e - h a l f a n d t h e t o x i c i t y

f o u r tim e s a s g r e a t ,

th e r a t i o

i s o n e -e ig h th *

I n th e c a s e o f th e

a l p h a m e th y l s u b s t i t u t i o n i t c a n b e s e e n t h a t , a l t h o u g h t h e r e i s an a d v e rse th e ra p e u tic r a t i o , th is i s

n o t s e r io u s s in o e th e

m a rg in o f s a f e t y i s g r e a t , a n d t h e new p r o p e r t y o f o r a l a c t i v i t y h a s b e e n ad d ed * E p in e p h r in e i s i n a c t i v e when o r a l l y a d m i n i s t e r e d s o t h a t w hen Chen a n d h i s

c o - w o r k e r s came t o

t h e i r c o n c lu s io n a b o u t th e

a l p h a m e th y l g r o u p , many w o r k e r s becam e I n t e r e s t e d

(1 4 )*

B e ta

p h e n e t h y l am in e i s i n a c t i v e w hen t a k e n o r a l l y , b u t i t s a l p h a m e th y l d e r i v a t i v e , b e n z e d r i n e , i s a c t i v e a n d t h e d i r a t i o n o f a c tiv ity is

c o n s i d e r a b l y e x te n d e d (1 5 )*

A s tu d y o f c o b e fr in

p r o v i d e s I n t e r e s t i n g i n f o r m a t i o n ( 1 6 )* T he f a c t t h a t e p i n e p h r i n e i s n o t o r a l l y a c t i v e w as a t t r i b u t e d t o t h e g r e a t c h e m ic a l a c t i v i t y o f t h e c a t e c h o l - t y p e n u c l e u s a n d t h e r e f o r e i t s p r o b a b l e d e s t r u c t i o n i n t h e a l i m e n t a r y c a n a l*

9

C o b e f r i n , # i i c h i s t h e a l p h a m e th y l e p i n e p h r i n e , i s

o ra lly

a c t i v e s h e e rin g t h a t t h e d i p h e n o l l c p h e n y l d e r i v a t i v e s a r e m o d if ie d j u s t a s a r e t h e n o n p h e n o l lc b y t h e m e th y l o n t h e a l p h a c a rb o n *

C h e n 's w o rk h a s show n t h a t t h e i m p o r t a n t d i f f e r e n c e

a t t r i b u t a b l e t o th e t h r e e c a rb o n I s o p ro p y l c h a in a l s o In c lu d e t h e p r o p e r t y o f e x h i b i t i n g t a c h y p h y l a x i s ( im m u n i s a ti o n t o t h e d r u g a f t e r c o n t i n u e d a d m i n i s t r a t i o n ) a n d t h e te n d e n c y t o show a n a le p tic a c tio n i n v a ry in g d e g re e s*

B e y e r ( 1 7 ) h a s show n t h a t

t h i s change I n p r o p e r tie s a s th e le n g th o f th e s id e c h a in i n ­ c r e a s e s f r o m tw o t o t h r e e c a r b o n s i s d u e t o t h e f a c t t h a t t h e t h r e e c a r b o n c h a i n p l a c e s t h e a m in o g r o u p on a s e c o n d a r y c a r b o n an d t h e s e a m in e s a r e n o t a s r a p i d l y d e a m ln a te d e n z y m a t i c a l l y a s a r e t h o s e on a p r i m a r y c a r b o n ( 1 8 , I P ) * I n tr o d u c tio n o f a lo n g e r r a d i c a l on t h e a lp h a c a rb o n , C0 t o C , p r o d u c e d com pounds w i t h no a o t i v i t y a s f a r a s p r e s s o r ® 3 a c t i o n i s c o n c e r n e d ( 2 0 )* W h ile s t u d y i n g t h e a l p h a p o s i t i e n o n e s h o u l d I n c l u d e t h e c y c llz a tio n p o s s ib ilitie s *

—

qh2

•\ \dimH2 TCIIg Amino ln d a n e

B e ta am in o t e t r a h y d r o n a p h th a le n e I II ( I ) R a i s e d t h e b l o o d p r e s s u r e ; b u t is o f l i t t l e c i r c u l a t o r y s t i m u l a n t ( 2 1 ) , w h ile ( I I ) h a s l i t t l e

10

u s e as a

p re sso r

activity

(22).

S u b s t i t u t i o n o n t h e b e t a c a r b o n a to m h a s b e e n r e s t r i c t e d t o m e th y l, a l k y l , h y d r o x y l , o r k e to n e *

A k e to n e g r o u p o n t h e

b e t a caxfeon i s f o u n d I n a d r e n a l o n e o r k e p h r in e w h ic h h a s o n ly 1 /3 0 0 t o 1 /2 0 0 t h e a c t i v i t y o f t h a t o f t h e c o r r e s p o n d i n g a l c o h o l* T h is p a r t i c u l a r compound i s u s e d a s a h e m o s ta t ( 2 3 ) • W ith t h e a l c o h o l g r o u p one f i n d s t h a t a t l e a s t tw o e f f e c t s m u st b e a t t r i b u t e d t o i t s

p r e s e n c e on t h e b e t a c a rb o n *

T h e re i s

a n a p p r e c i a b l e d e c r e a s e i n a c u te t o x i c i t y a n d a d e c i d e d I n c r e a s e in p re sso r a c tiv ity * TABLE I I

Compound

A c tiv ity

good r i s e

C H CHOHCH WH 6 5 2 2

E q u a ls • p h e d r l n e

T o x i c i t y K*L*D* In tra v e n o u s 4 0 -6 0 m g /k g t o r a b b i t s

3 0 -6 0 m g /k g

W V H(1,V CHS

1 /4 2 5 o f e p i n e p h r i n e

25 m g /k g

C 1 CHOHCH( HH )CH 6 5 2 3

1 /6 0

of e p in e p h rin e

7 5 -9 0 m g /k g

(HO) C H CH CH NHCH 2 6 3 2 2 3

l/l2

of e p in e p h rin e

(HO) C H CHOHCH XHCH 2 6 3 2 3

E p in e p h r in e

11 -

«

T he s t i m u l a t i n g e f f e c t o n t h e n e r v o u s s y s te m i s c o n s i d e r ­ a b l y d e c r e a s e d b y t h e p r e s e n c e o f t h e h y d r o x y l b u t n o t c o m p le t e ly e lim in a te d ( 2 4 ) .

On t h e o t h e r h a n d , t h e p r e s e n c e o f t h e h y d r o x y l

h a s a n e f f e c t on t h e p h y s i c a l p r o p e r t i e s w h ic h l e a v e s t h e d e s o x y a n a lo g u e s w i t h a p r a c t i c a l a d v a n t a g e .

The p h e n y la lk y la m ln e s h a v e

a m uch h i g h e r v a p o r t e n s i o n p e r m i t t i n g t h e i r a d m i n i s t r a t i o n b y in h a la tio n .

T h u s, a lth o u g h p r o p r a d r in e h as a t h e r a p e u ti c r a t i o

tw e n ty - o n e tim e s t h a t o f b e n z e d r i n e , o n e f i n d s b e n z e d r i n e m o re w id e ly u s e d due to i t s

s im p lic ity o f a d m in is tra tio n *

I n t h e c a s e of b e t a m e th y l s u b s t i t u t i o n s one n o t i c e s a s t r i k i n g s i m i l a r i t y t o t h e a l c o h o l i c com pound a s f a r a s p r e s s o r a c t i v i t y an d t o x i c i t y a r e co n c ern ed *

T he I n t r o d u c t i o n o f e i t h e r

g r o u p , b o t h o f w h ic h a r e o f e q u a l m a s s , h a s t h e sam e e f f e c t * TABLE I I I

W H20H(SV CH3

L .D . 2 5 m g /k g

C CHOHCH ( OH. ) HH„ bo o £ 0 H CH(CH )CH(HH )CH 6 5 3 2 3

M .L .D . 8 0 m g /k g L .D . 2 9 0 m g /k g

C H CHOHCH NHCH a n d C H CH(CH CHNHCH b o th p r o d u c e 65 2 5 6 5 3 3 a r i s e o f b l o o d p r e s s u r e , b u t i t i s n o t p o s s i b l e t o co m p are th e s e due t o th e d i s s i m i l a r i t y i n e x p e rim e n ta l c o n d itio n s *

- 12

I t i s i n t e r e s t i n g t o co m p are t h e e f f e c t s o f alp h a, a n d b e ta m e th y la tia n s TABLE IV

to x le lty

a c tiv ity

r e m a rk s

a lp h a

ra is e d

lo w e r e d

o r a lly a c tiv e

b e ta

lo w e r e d

ra is e d

o r a lly In a c tiv e

As t h e s l s e o f t h e a l k y l g r o u p i s i n c r e a s e d t h e p r e s s o r a c t i v i t y d e c r e a s e s a n d t o x i c i t y I n c r e a s e s ( § 6 )# S in c e e i t h e r m e th y l o r h y d r o x y l p r o d u c e s t h e sam e a c t i v i t y , i f b o t h a r e p r e s e n t o n e s h o u l d f i n d t h e sam e ty p e o f a c t i v i t y a s f o u n d i n -C(O H ) ( o r o n d e h y d r a t i o n -C rO ) a n d , I n t e r e s t i n g l y enough* t h e t e r t i a r y a l c o h o l s o f t h e t y p e C! H_C ( oH>CH( NH ) CH o o 2 9 h a v e t h e same o r d e r o f m a g n itu d e o f t o x i c i t y a n d p r e s s o r a c t i v i t y a s t h a t o f t h e k e to n e ( 2 6 ) * X -A lk y la tlo n h a s g e n e r a l ly b e e n r e s t r i c t e d to a s in g l e m e th y l g r o u p .

I n m o s t c a s e s t h e a d d i t i o n o f t h e m e th y l g r o u p

to th e n itr o g e n d e o re a se e p re s s o r a c t i v i t y an d in c re a s e s to x ic ity *

• 13

TABLE V

Compound

Activity

Toxicity In tra v e n o u s 6 0 m g /k g t o r a b b i t s

A

c 6 h 5 chohch 2 «h 2

A i s tw ic e a s a c t i v e

B

C H CaOHCH.MECH6 5 * *

as B.

C

C6H6CH0HCH( HHg )CH3

lm g m .r.0 1 2 5 ag n u e p i n . M .L .D . 7 5 m g /k g

m

D

C H CHOHCH( HHCH )CH 6 5 3 5

l a g m . r .0 1 0 6 mgm. e p i n . M .L .D . 55 m g /k g

m

E

(HO) C H CHOHCH HH 2 6 5 2 2

1*2 e p i n e p h r i n e

L .D . 0 * 5 m g /k g

■

F

(HO) C H CHOHCH HHCH 2 6 3 2 3

B p in e p h r ln e

L .D . 0 * 1 5 m g /k g

•

0

C H CH CH HH. 6 5 2 2 2

2 /1 8 3 e p i n e p h r i n e

4 0 - 5 0 m g /k g

m

TT x&

rw

xj

a

6 5

r» n n u i r e p u u i i Av n A

2

2

®

( ° S

>

° V

a

1 /3 5 0 e p i n e p h r i n e

3

I ° A

1 0 0 m g /k g

P re sso r

4

L .D . 5 5 m g /k g

m

4

L.D* 6 5 ig lc g

m

S

J

C„H CH(CH- )CHKHCH 6 5 5 2 3

P re sso r

w JL

(HO)rtC„H CH CH MH 2 6 3 2 2 2

1 /5 0 e p i n e p h r i n e

T II

(HO C H CH CH HHCH 2 6 3 2 2 3

1 /1 2 e p i n e p h r i n e

M m

(HO) C H CH CH HHC H 2 6 3 2 2 2 5

l / 4 3 e p in e p h rin e

A g a in t h i s a d v e r s e e f f e c t o n t h e t h e r a p e u t i c r a t i o s u f f i c i e n t t o c a u s e a la rm *

is not

I n t h e e a s e o f n o re p in e p h rln e (B ) th e

m e c h a n ism o f a c t i o n i s l e s s l o c a l i s e d t h a n f o r t h e e p i n e p h r i n e ( F ) *

14

I n t h e p h o n y l a I k y la m in a a e r i e s ( 0 , H, I , J , L , K , ) t h e i n c r e a s e i n t o x i c i t y i s le s a an d n ay b e d e o re a s e d and th e a e t l v l t y i s d e c r e a s e d i n some c a s e s (H ) an d i n c r e a s e d i n o t h e r s ( L ) .

As

a g e n e r a l r u l e i t i a r e p o r t e d t h a t V m e tf a y la tio n r e d u c e s t h e a c tiv ity (1 9 ).

I t c a n b e s e e n (M) t h a t a n I n c r e a s e i n t h e l e n g t h

o f t h e c h a i n f ro m 1 t o 2 , d e c r e a s e s t h e a c t i v i t y .

D ia lk y la tlo n

o f t h e am in e g i v e s a d e c r e a s e i n a c t i v i t y a c c o m p a n ie d b y a n In c re a se in to x ic ity (2 7 ).

Q u a r te n a r y ammonium com pounds i n

t h e e p l n e p b r i n e - e p h r e d r i n e s e r i e s p ro d u c e c u r a r e - l i k e a c t i o n i n common w i t h o t h e r t y p e s o f q u a r t e n a r y ammonium s a l t s . I n t h e p h e n y l n u c l e u s i t w as f o u n d t h a t t h e i n t r o d u c t i o n o f a n a l k y l g ro u p i n c r e a s e s t h e t o x i c i t y an d u s u a l l y lo w e r s t h e p r e s s o r p o te n c y .

I f th e r a d i c a l i s la r g e en o u g h , a s w ith b e n z y l,

t h e com pound a c t u a l l y r e v e r s e s i t s a c t i v i t y a n d b eco m es a d e p r e s s o r (2 8 ) •

A m e th y l g r o u p a t t a c h e d t o p r o p r a d r l n e i n e i t h e r

th e m et* o r p a r a p o s i t i o n d e c r e a s e s t h e t h e r a p e u t i c r a t i o o n e t e n t h (29 ) •

W ith n o a l c o h o l i c g r o u p o n t h e s i d e c h a i n , t h e

p r e s e n c e o f t h e m e th y l g r o u p i s n o t s o u n d e s i r a b l e . H a lo g e n s u b s t i t u t i o n h a s show n I n m o st c a s e s a l a r g e d e c r e a s e i n th e th e ra p e u tic r a t i o ex cep t In th e c a se o f p a ra -c h io r p h e n e t h y l am in e w h e re a f a v o r a b l e r a t i o w as o b t a l n e d ( 3 0 ) •

The

n i t r e com pounds a r e r a t e d a t l e s s t h a n o n e - o n e h u n d r e d a n d e i g h t y t h i r d t h a t a t e p l a c p h r l n e a n d t h e p a r a n l t r o p h e n e t h y la m l n e show s a t r a n s i t o r y d e o r e a s e f o l l o w e d b y a m a rk e d r i s e W hich p e r s i s t s f o r ab o u t f i v e m in u te s .

B u t b y f a r t h e m o st i m p o r t a n t p h e n y l

15 -

s u b s t i t u t i o n i n t h e s y n p a th o m lm e tic s i s

i n t h e p h e n o l lo

co m p o u n d s. A l l o f t h e mono h y d ro x y e p h e d r l n e s a c t l i k e e p h r e d r i n e i t s e l f and p o sse ss n e i t h e r q u a l i t a t i v e l y n o r q u a n t i t a t i v e l y th e a c tio n o f e p in e p h r in e .

The m e ta com pound show s a r e v e r s a l

o f t h e a c t i o n o n t h e c i r c u l a t o r y s y s te m , t h e p a r a l a w e a k e r , b u t s t i l l a c t i v e , w h ile t h e a c t i o n o f t h e o r t h o i s a u g m e n t a t i v e . None o f t h e p h e n o l i c com pounds e x h i b i t t a c h y p h y l a x i s a n d d i f f e r i n t h a t l a r g e d o s e s a lw a y s p r o d u c e a r i s e i n b lo o d p r e s s u r e . The i n t r o d u c t i o n o f t h e o n e p h e n o l i c g r o u p i n t o p h e n y l p r o p a n o l a m ln e t e n d s t o c u t down t h e d u r a t i o n o f p r e s s o r r e s p o n s e .

In

m o d if y in g t h e c i r c u l a t o r y e f f e c t s t h e o r t h o p h e n o l i s t h e l e a s t a c t i v e ( 3 1 ) , h o w e v e r, c o n t r a r y t o B a r g e r an d D a le ( 1 2 ) t h e m e ta i s a s tr o n g e r p r e s s o r th a n th e p a ra ( 3 2 ) .

T hus, i t i s e v id e n t,

t h a t m ost o f t h e i n t e n s i f y i n g e f f e c t o f e p in e p h r in e i s b y t h e m e ta p h e n o l l e h y d r o x y l .

c o n ferred

T he s i m u l t a n e o u s s u b s t i t u t i o n

o f tw o h y d r o x y l g r o u p s i n t h e a r o m a t i c n u c l e u s g i v e s a s e r i e s o f a h l c h e p i n e p h r i n e i s a m em ber. has l i t t l e com pound i s

The 2 , 4 d ih y d r o x y compounc

e f f e c t o n th e c i r c u l a t i o n a n d t h e 2 , 3 d ih y d r o x y lik e w is e in a c ti v e ( 3 3 ) .

TABLE VI

Compounds

A c tiv ity as a f ra c tio n o f e p in e p h rin e

T o x io lty

p-H0C6H4CH80HgMH8

1 /7 0 ----------------------------------- ---------------------------

m-HOC H CH„CH„HH„ 6 4 22 2

1 /7 0

m-HOC H CH CH NHCH 6 4 2 2 3

- — - — -------

------------------------in tra v e n L . D . 3 6 0 m g /k g o u s t o n ic e

O-H0 C H CH CH HHCH--------------------------------------6 4 2 2 3

L . D . 180 m g/kg

"

p-HOC H CH CH HHCH--------------------------------------6 4 2 2 3

L . D . 227 m g /k g

*

p-HOC H CHOHCH HHCH 6 4 2 3

1 /1 1 6

M .L .D . 4 00 m g /k g

*

m-HOC H CHOHCH HHCH 6 4 2 3

l/9

3 ,4 ( H 0 ) C H CHOHCH HHCH 2 6 3 2 3 3 ,4 ( H 0 ) C H CHOHCH( HH )CH 2 6 3 2 3

E p in e p h r in e l/l2

— in tra v e n L .D . .1 5 m g /k g o u s t o ra ts M .L .D . 11 m g /k g

T he 3 , 4 d ih y d r o x y com pounds a r e b e s t known a n d b e l o n g t o a c l a s s c o n s i d e r e d toy T a l n t e r a s t r u e s y m p a t h i c o t r o p i c a g e n t s com pounds w h ic h p r o d u c e t h e e f f e o t th r o u g h t h e s y m p a th e t ic n e r v o u s s y s te m ( 3 4 ) .

”

TABLE V II

Name E p in e p h r in e 3*4 D ih y d ro x y F h e n e th y la m ln e 3 , 4 D lh y d ro x y J h e n y lp r o p y la m in e E p ln ln e A rte rn e ro l

Activity

R CHOHCH NHCH 2 3 CH CH NH 2

2

1 1 /7 5 -1 /6 6

2

CH CH CH NH 2 2 2 2 CH-CH NHCH 2 2 5 CH(OH)CH NH 2 2

1 /2 2 0 - 1 /1 8 0 1/12

io A

" 2

A b i g d i f f e r e n c e b e tw e e n th e p h e n o l i c a n d n o n - p h e n o llc com pounds l a

i n t h e i r g ly c e m lc a c t i o n ( t u r n i n g o f m u s c le

a n d l i v e r g ly c o g e n i n t o g l u c o s e ) , t h u s g i v i n g a r i s e i n b lo o d s u g p r* ris e

S y n e p h rln e * w i t h a p h e n o l i c h y d r o x y l * p r o d u c e s a g r e a t

i n b lo o d s u g a r w h i l e e p h r e d r l n e p r o d u c e s t h e r i s e

w ith a v e r y l a r g e q u a n t i t y o f m a t e r i a l *

o n ly

I t w as s u g g e s t e d t h a t

t h e h y p e r g ly c e m ic a c t i o n o f e p h e d r l n e i s a r e s u l t o f I n c r e a s e d e p i n e p h r i n e s e c r e t i o n ( 3 5 )* A s e r i e s 2 .CH_ IJHC H,

E p in in e ty p r e s s o r a c tiv ity o f ( - ) e p in e p h r in e CH NHCH

C H (O H ) 66 11 2 d (-)

E p in e p h r in e

(S u b je c t to c o n fir m a tio n )

1 ( - ) E p in e p h r in e l/lO p ressor a c tiv ity o f ( - ) e p in e p h rin e

T he a l e b h o l l e h y d r o x y l on t h e p h e n y l b e a r i n g c a r b o n a to m i s fo u n d g e n e r a lly t o I n c r e a s e a c t i v i t y and d e c re a s e to x ic ity *

A c o m p a r is o n b s t v s e n s p l n l n e a n d d - a n d 1 - e p l n e p h r i n e show s t h a t d e p e n d in g o n w h ic h p o s i t i o n t h e h y d r o x y l t a k e s o n t h e p h e n y l b e a r i n g c a r b o n a to m , a d i f f e r e n c e I s f o u n d .

If it

i s th e

( - ) e p in e p h rin e th e a c t i v i t y i s d e c re a s e d b y t w o - f i f t h s . E a rtu n g t r i e s t o e x p la in th e d i f f e r e n c e i n r e a c t i v i t y on th e b a s is

o f r e a c t i o n w i t h t h e p r o to p la s m ( 4 8 ) ,

A m o le c u le

w i t h a n a s y m e t r i c c e n t e r r e a c t s w i t h t h e p r o to p la s m t o fo rm a new com pound o r c o m p le x .

S in c e t h e c o n f i g u r a t i o n o f t h e p r o t o ­

p la s m d o e s n o t c h a n g e , t h e p r o d u c t fo rm e d w hen a l e v o r o t a t o r y d ru g u n ite s w ith th e l i v i n g t i s s u e I s d la s te r e o is o m e r ic w ith th e d e x t r o r o t a t o r y d ru g * a l l p o in ts o f n e w .

T h ey a r e d i f f e r e n t com pounds fro m n e a r l y I t is n o t u n lik e ly th a t,

j u s t a s th e p rese n ce

o f t h e d r u g m o le c u le m o d i f i e s t h e n a t u r e o f t h e r e s p o n s e , t h e n a t u r e o f t h e p r o to p la s m r e a c t i o n p r o d u c t a l s o p r e d e t e r m i n e s t h e n a t u r e o f t h e r e s p o n s e c a l l e d f o r t h b y t h e d r u g m o le c u le *

T h is

m eans t h a t t h e d r u g a n d t i s s u e h a v e m u t u a l l y m o d if y in g e f f e c t s . T he p r o b le m o f t h e r e s o l u t i o n o f e p i n e p h r i n e t o o b t a i n t h e m ore a c t i v e 1 - fo r m h a s b e e n c a r r i e d o u t i n a num ber o f w a y s. One o f t h e m o st s a t i s f a c t o r y I n v o l v e s t h e f o l l o w i n g p r o c e d u r e (4 9 )* One m o le o f s y n t h e t i c d - l - e p l n e p h r l n e was m o is te n e d w i t h m e th a n o l a n d I n t r o d u c e d i n t o a h o t m e th a n o l s o l u t i o n o f a l i t t l e m o re t h a n one m o le o f d - t a r t a r l c a d d *

T he a l c o h o l w as d i s t i l l e d o f f u n d e r

r e d u c e d p r e s s u r e a t 3 5 t o 40°C*

A m ass o f c r y s t a l s w as o b t a i n e d ,

w h ic h o n r e c r y s t a l l l s a t l o n fro m a l c o h o l , p r o v e d t o b e s h a r p m e l t ­ in g a n d g a v e t h e h y d r o c h l o r i d e o f 1 - a d r e n a l l n e •

26

P ie k h o lz c a r r i e d o u t t h e r e s o l u t i o n b a s e d o n th e d if fe re n c e in s o l u b i l i t y o f th e o x a la te s in e th a n o l. d e x t r o is o m e r i s

The

r a c e m lz e d b y h e a t i n g w i t h d i l u t e a c i d a n d

t h e 1 f o r a a g a in e x t r a c te d u n t i l t h e r e i s p r a c t i c a l l y a l l 1 -e p ln e p h rin e (5 0 ).

- 27

A l i p h a t i c S y m p ath o m im e tic Amine a

B a r g e r a n d D a le m ade a s t u d y o f a s e r i e s o f a l i p h a t i c a m in e s w h ic h w e re c o n f i n e d l a r g e l y t o t h o s e com pounds h a v in g t h e am in e g r o u p s o n t h e t e r m i n a l c a r b o n o f t h e c h a i n a s w e l l a s some s im p le s e c o n d a r y a m in e s ( 4 0 ) •

T h e i r r e s u l t s show ed

t h a t th e p r e s s o r a c tio n began w ith n - b u ty l and re a c h e d an optim um v a l u e w i t h 1 -a m in e h e x a n e a n d p e r s i s t e d i n h i g h e r m em bers o f t h e s e r i e s *

R e c e n t l y , m o re e x t e n s i v e s t u d i e s h a v e

b e e n m ade o n t h e a l i p h a t i c a m in e s , an d m any com pounds h a v in g t h e am in e g r o u p o n o t h e r t h a n t h e t e r m i n a l g ro u p h a v e b e e n t e s t e d (4 1 ) •

I n s e v e r a l w ays t h e g e n e r a l i z a t i o n r e g a r d i n g t h e

r e l a t i o n s h i p o f s t r u c t u r e to a c t i v i t y I n th e a l i p h a t i c s e r i e s seem s t o b e a r some r e l a t i o n s h i p t o t h o s e i n t h e a r o m a t i c s e r i e s *

U s in g t h e s k e l e t o n

R-C-fc-6-IT^

t h e f o l l o w i n g r e l a t i o n s h i p s seem t o b e o f s o a » v a l u e t 1 )*

The s u b s t i t u t i o n o f a m e th y l g ro u p i n t h e a l p h a p o s itio n in c re a s e s p r e s s o r a c tio n an d i t s d u ra tio n of a c tio n *

S u b s titu tio n o f th e a l k y l s e r i e s r a d i c a l s

g r e a t e r t h a n t h e m e th y l d e c r e a s e s t h e a c t i v i t y m a rk e d ly * 2 )*

T he s u b s t i t u t i o n o f t h e a l k y l g r o u p o n t h e b e t a c a rb o n te n d s to d e c re a s e a c t i v i t y *

28

3 )«

S u b s t i t u t i o n o n t h e am in o n i t r o g e n t e n d s t o d e c re a s e th e a c t i v i t y ; th e e f f e c t i s r e l a t i v e l y s m a ll v l t h t h e m e th y l g r o u p , h u t w i t h l a r g e r g ro u p s, i t i s

q u ite p ro n o u n ced .

One o f t h e a l i p h a t i c a m in e s s o l d to d a y i s T u a n d n e ( 2 -a m in o h e p t a n e ) and a s co m p a re d t o e p i n e p h r i n e t h e p r e s s o r a c t i v i t y i s r a t e d a s t h r e e m ic ro g ra m s o f e p i n e p h r i n e n e e d e d t o g iv e t h e sam e p r e s s o r a c t i v i t y a s o n e m i l l i g r a m

o f a m in e , a n d t h e

d u r a t i o n o f a c t i o n i s much l o n g e r t h a n t h a t o f e p i n e p h r i n e ( 4 2 ) .

The t h i r d ty p e o f s y n p a th o v n im e tlc s t r u c t u r e i m i d a z o le ty p e com pound.

i s th e

A n um ber o f com pounds h a v i n g t h e

i m i d a z o le r i n g a s a p a r t o f t h e i r s t r u c t u r e a r e n a t u r a l l y o c c u r r i n g ; e . g . h i s t a m i n e , p i l o c a r p i n e a n d o t h e r s show d e f i n i t e p h a r m a c o lo g ic p r o p e r t i e s .

T he com pounds w h ic h h a v e

a n y s y m p a th o m im e tic a c t i v i t y a t a l l a r e a l l t h e p a r t i a l l y r e d u c e d 2 - s u b s t i t u t e d i m i d a z o l i n e ty p e ( 4 3 ) .

The 2 - a l k y l a t e d

im id a z o lin e s a l l d i l a t e p e r ip h e r a l v e s s e ls and th e r e b y d e c re a s e t h e b lo o d p r e s s u r e ( 4 4 ) . can

T h e i r a c t i o n , h o w e v e r, i s v e r y w eak a n d

b e d e m o n s tr a te d o n ly w i t h a c o m p a r a t i v e l y h l g i m in im a l

d o s e o f 10 m gm ./kgm .

P r e s e n t i n f o r m a t i o n r e v e a l s t h a t th e

t o x i c i t y in c r e a s e s w ith th e le n g th e n in g o f t h e s i d e c h a in .

The

b a s ic 2 - a lk y la te d im id a z o lin e (b e n z y l) i s a s tr o n g v a s o d ila t o r

29

(

a n d I f t h e h y d ro g e n a t o n i n t h e 4 p o s i t i o n i s r e p l a c e d b y a h y d r o x y l t h e a c t i o n on t h e c i r c u l a t o r y s y s te m i s

re v e rse d *

I t w as fo u n d t h a t t h e lm l da s o l e r i n g s c o u ld n o t h e p a r t i a l l y r e d u c e d t o t h e i m i d a z o l i n e , so t h a t t h e s y n t h e s i s o f t h e s e i m i d a z o l i n e s h a s t o h e b u i l t fro m e t h y l e n e d la m in e ( 4 5 ) «

For

e x a m p le , 2 - m e th y l i m i d a z o l i n e , w h ic h h a s some v a s o d i l a t o r a c t i o n , i s p r e p a r e d fro m t h e d ia c e ta m id e *

CHgCONHCHgCHgMHCOCHg----------»

CH0-NH | * ^ C*CH3 ®2

30-

P h a rm a c o lo g y

The p h a r m a c o l o g i c a l m eth o d o f a e t l o n o f t h e s y m p a th o m lm e tic s i s n o t c l e a r l y u n d e r s t o o d an d a g r e a t d e a l m ore w o rk m a s t b e d o n e b e f o r e c o n c lu s iv e r e s u l t s

can b e o b t a i n e d .

E u le r, in 1938, s ta te d

t h a t e p i n e p h r i n e a c t s d i r e c t l y on t h e e f f e c t o r c e l l s

(1 5 ).

The

d r u g c o n s t r i c t s t h e v e s s e l s o f t h e human p l a c e n t a , w h ic h i s t h o u g h t t o b e v o id o f n e r v e s u p p ly * W h e th e r o r n o t e p i n e p h r i n e a f f e c t s t h e a c c e p t o r s u b s t a n c e of t h e s e c r e t o r y e l e m e n ts o f t h e c e l l s

is not

known* The d u r a t i o n o f a c t i o n o f e p i n e p h r i n e I n t h e b o d y i s d e t e r m in e d b y t h e r a t e o f d e s t r u c t i o n ; t h e d ru g b e i n g o x i d i z e d f a i r l y ra p id ly *

T a i n t e r b e l i e v e s t h a t some o f t h e a m in e s a c t a s

h o rm o n e s , p e n e t r a t i n g t h e r e a c t i v e t i s s u e s t o in d u c e p h y s i o l o g i c a l resp o n se (5 2 ). O th e r s a p p e a r t o a c t r a t h e r a s s u b s t a n c e c o m p e t i t o r s w h ic h , b y b l o c k i n g th e enzym e s y s te m i n a c t i v a t i n g e p i n e p h r i n e , p e r m it it

t o a c c u m u la te i n th e t i s s u e , w i t h r e s u l t i n g p h y s i o l o g i c a l

r e s p o n s e ( 5 3 ,5 4 ,5 5 ) * T he a t t a i n m e n t o f p r e s e n t - d a y k n o w le d g e o f sy m p a th o m im e tic a m in e s i s d u e i n n o s m a ll m e a s u re t o t h e w o rk in g o u t o f r e a s o n a b l y a c c u r a t e r e p r o d u c i b l e p h a r m a c o lo g ic a l t e s t s *

The e a r l y w o rk e rs

i n t h e f i e l d u s e d t h e e f f e c t o n a r t e r i a l b lo o d p r e s s u r e a s a q u a n t i t a t i v e i n d e x o f sy m p a th o m im e tic a c t i v i t y *

The c h o i c e o f

t h i s m eth o d o f t e s t i n g was l o g i c a l , s i n c e t h e m o st p r o m in e n t

f e a t u r e o f a sy m p a th o m lm e ti c a m in e i a i t a a r t e r i a l b lo o d p r e s s u r e *

e f f e c t i n r a i s i n g th e

T h is m eth o d h a s t h e a d v a n ta g e o f e a s e

o f o b s e r v a t i o n a n d i s u s e d e v e n to d a y * A good d e a l o f th e w o rk i n t h e l i t e r a t u r e i s d i f f i c u l t t o i n t e r p r e t q u a n t i t a t i v e l y b e c a u s e o f t h e fo llo w in g re a s o n s t (1}

fa ilu re

to ta k e in to acco u n t th e v a r ia tio n s e x is tin g

b e tw e e n I n d i v i d u a l s o f a g i v e n a n im a l s p e c i e s a n d ( 2 ) t h e fa ilu re

to r e c o g n i z e t h e p r o p e r t y o f ta c h y p h y l a x i s *

E p in e p h r in e i s a sh o rt a c tiv ity ,

an a lm o s t i d e a l s u b s ta n c e s in c e (1 ) i t h a s

(2 ) i t d o es n o t m a n ife s t ta c h y p h y la x is ,

and (3 ) i t g iv e s v e r y c o n s is te n t and r e p r o d u c ib le r e s u l t s

in

a g i v e n i n d i v i d u a l a n im a l* A c t i v i t y i s o f t e n e x p r e s s e d a s an e p in e p h rin e e q u i v a le n t; t h a t

la t h e n um ber o f e p i n e p h r i n e

m ic ro g ra m s e q u i v a l e n t t o o n e m i l l i g r a m o f t h e am ine* T he e f f e c t o f t h e sy m p a th o m im e tic a m in e i n b r i n g i n g a b o u t a s h rin k a g e o f t h e t u r b i n a t e s i s

o f g r e a t im p o r ta n c e *

In

a n im a ls t h e m e th o d m o st com m only u s e d i s t h a t i n v o l v i n g a k y m o g rap h , w i t h t h e a n i m a l 's n a s a l c h a m b e rs s e a l e d . T he a p p a r a t u s p l o t s t h e a c t i o n a n d show s t h e s h r i n k a g e a n d d u r a t i o n o f a c t i o n (5 6 )* T he v a l u e o f t h e s y m p a th o m lm e tic s i n a s th m a i s d u e t o t h e i r a b i l i t y t o b r i n g a b o u t t h e d i l a t i o n s o f t h e b r o n c h i , th u s a l l o w i n g a f r e e p a s s a g e o f a i r t o a n d fro m th e l u n g s .

32

A s th m a tic c o n d i t i o n s

a r e s im u la te d by th e a d m in is tr a tio n o f a d ru g su c h as p ilo c a r p in e w h ic h c o n s t r u c t s t h e b r o n c h i*

T he a n im a l t o be t e s t e d i s i n j e c t e d

a n d t h e d r u g a n t a g o n i z e s th e e f f e c t o f t h e p i l o c a r p i n e , t h u s r e l a x i n g t h e b r o n c h i a n d a l l o w i n g t h e p a s s a g e o f a g r e a t v o lum e o f a ir*

The e f f e c t s a r e r e c o r d e d o n a kym ograph*

33

U ses o f S y m p a th o m lm e tic s (5 7 )

D is o rd e rs o f t h e u p p e r r e s p i r a t o r y t r a e t (n o s e , t h r o a t , a n d s i n u s ) make up t h e m o st f r e q u e n t dem ands f o r t h e co m p o u n d s. T h ey s h r i n k t h e s w o lle n m ucosa o f t h e n o s e t o r e l i e v e t h e b r e a t h i n g , o r th e y o p e n t h e a p e r t u r e s o f t h e s i n u s w id e r t o f a c i l i t a t e d ra in a g e an d s e c r e t i o n .

V a s o c o n s tric tio n i s a

p r o p e r t y o f a l l s y m p a th o m lm e tic s i n common u s e , th o u g h some h a v e s p e c i a l o t h e r a c t i v i t i e s m ak in g th em m o re o r l e s s v a lu a b le .

F o r e x a m p le , a m p h e ta m in e i s v o l a t i l e a n d u s e d i n

i n h a l a t o r s ; p r o p r a d r ln e , on th e o th e r h an d , e x e r t s l e s s c e n tr a l s tim u la tio n . The m o st i m p o r ta n t a r e a o f a p p l i c a t i o n i s i n h y p e r s e n s l t v i t y r e a c t i o n s ; a s th m a , h a y f e v e r , se ru m s i c k n e s s , a n d o th e rs .

T h re e an d f i v e - t e n t h s p e r c e n t o f t h e U . S . p o p u l a t i o n

s u f f e r s fro m a s th m a a n d h a y f e v e r , a n d s e e k s r e l i e f t h r o u g h t h e u s e o f sy m p a th o m im e tic a m in e s .

B r o n c h i a l a s th m a s u f f e r e r s

a r e r e l i e v e d b y t h e u s e o f e p i n e p h r i n e a l m o s t im m e d ia te l y . e p in e p h rin e h a s i t s

fa u lts ;

th e a c tio n i s so b r i e f t h a t i t

m u s t be r e i n j e c t e d e v e r y h a l f - h o u r , i t n e rv o u s n e s s , and a n x i e ty .

causes p a lp ita tio n ,

E p h e d r in e h a s a m ore p r o lo n g e d

a c t i o n a n d c a n be o r a l l y a d m i n i s t e r e d .

I t i s , h o w e v e r, n o t

a s e f f i c i e n t , and c a u se s u n p le a s a n t c e n t r a l s ti m u la t io n s .

34

B ut

T h e r e l a t h e n e e d o f a s e n s i t i v e v a s o p r e s s o r t o ovorooaae v a s o m o to r c o l l a p s e d u r i n g a n o p e r a t i o n w hen t h e b lo o d p r e s s u r e d r o p s a n d m u st b e r a i s e d *

E p in e p h r in e d o e s r a i s e t h e b lo o d

p r e s s u r e , b u t g i v e s a num ber o f u n d e s i r a b l e e f f e c t s ;

su ch a s a

r i s e i n p u l s e r a t e , a n x i e t y , p a l l o r , I n c r e a s e d m e ta b o l is m ,a n d i n c r e a s e d w o rk o f t h e h e a r t . im p ro v e m e n t.

T he n ew er s y n t h e t l o s o f f e r

W ith p a r e d r i n e o r n e o s y n e p h r in e o n e c a n g e t a

5 0 mm. r i s e i n b lo o d p r e s s u r e a f t e r s u b c u t a n e o u s , o r e v e n o r a l d o s e , a n d w ith o u t t h e d i s t u r b i n g a n x i e t y sym ptom s o f e p i n e p h r i n e o r e p h e d rin e .

As a r e s u l t o f a g e n e r a l a n e s t h e t l e f o r s u r g e r y ,

t h e b lo o d p r e s s u r e may f a l l fro m 1 40 t o 8 0 mm., and t h e p u l s e r a t e may r i s e fro m 8 0 t o 1 4 0 .

I n th e e a r ly p e rio d o f t h i s ch an g e,

v a s o c o n s t r i c t o r a c t i o n may b e l i f e - s a v i n g .

A s u it a b le dose o f

p a r e d r in e r e s t o r e s th e p r e s s u r e , o r i f g iv e n s h o r t l y b e f o r e th e a n e s th e tic , p re v e n ts th e f a l l . E p h e d r in e e x e r t s a c e n t r a l s t i m u l a t i o n w h ic h c o u n t e r a c t s th e d e p re s s io n ca u sed by d ru g s su ch as th e b a r b itu r a t e s . A m phetam ine p o s s e s s e s t h e q u a l i t y o f c e n t r a l s t i m u l a t i o n w h ic h i s w id e ly u se d i n n e u r o p s y c h ia tr y . o n t h e i n t e l l e c t , a n d t h e m ood.

I t e x e rc is e s an in flu e n c e

I t s a e tlo n r e s u l t s i n a change

i n t h e q u a l i t y o f p e r s o n a l i t y w h ic h h a s w id e a p p e a l , e v e n th o u g h o n ly te m p o r a r i ly . I t

i s a g e n e ra l p s y c h o lo g ic a l s tim u la n t and

c o r r e c t s p e r s o n a l i t y d e f e c ts su c h a s re ta rd u m . h e s ita tio n .

I n d e c is io n , and

T he f e e l i n g o f t e n s i o n an d a n x i e t y d i s a p p e a r s

t h e r e i s a p e r i o d o f r e l a x a t i o n a n d c a lm .

- 55

T he u s e o f t h i s

compound a l s o r e s u l t s i n t h e a c c e l e r a t i o n o f th o u g h t p r o c e s s e s , a c c o m p a n ie d toy w a k e f u ln e s s * o v e rs le e p in e s s *

I t i s u s e d w id e ly to c o n t r o l

T he a p p l i c a t i o n i n m e n ta l d i s e a s e i s

a l t h o u g h some sy m p a th o m im e tic b e n e f i t s a r e n o te d *

36

lim ite d ,

Present Investigation

R e s e a rc h on sy m p a th o m im e tic a m in e s i s a f i e l d w h ic h i s

q u ite

o l d a n d m a tu r e , s i n c e s t u d i e s o f t h e s e com pounds h a v e b e e n g o in g on f o r p r a c t i c a l l y f i f t y y e a r s .

H o w ev er, d i s c o v e r i e s r e m a in t o

be made n o m a t t e r how t h o r o u g h l y t h i s f i e l d o f a c t i v i t y may h a v e been c u ltiv a te d .

O b j e c t i v e s f o r r e s e a r c h a r e m a n if o l d b e c a u s e

t h e s e a m in e s c o n s t i t u t e one o f t h e m o st i m p o r ta n t g r o u p s i n p r e s e n t d a y t h e r a p y , t h r o u g h t h e i r f u n d a m e n ta l r e l a t i o n s w i t h t h e s y m p a th e t ic s y s t e m . The g ly o o llic a c i d g r o u p w as i n t r o d u c e d i n t o tw o sy m p a th o ­ m im e tic a m in e s t o

s tu d y th e e f f e c t o f t h i s lin k a g e on th e

p r o p e r t i e s o f t h e com pounds,

A c o m p a r is o n b e tw e e n t h e a d r e n a l i n e

a n d a d r e n a l l n o x y - a c e t i c a c i d show s t h a t t h e f o r m e r i s a n a m in e , f o r m in g s a l t s w i t h a c i d s an d s u b s t i t u t e d a m id e s .

T he l a t t e r i s

a n a m in o a c i d e x h i b i t i n g , i n a d d i t i o n t o a l l c f t h e b a s i c p r o p e r t i e s o f th e a d r e ^ l l n e , th e r e a c t i o n s an d s o l u b i l i t y o f an a l i p h a t i c a c id .

The am ino a c i d w i l l b e s o l u b l e i n a c i d an d

b a s e ( a m p h o te r i c ) an d w i l l fo rm b o t h a c i d a n d b a s i c s a l t s .

The

p r e s e n c e o f th e g l y c o l l i c a c i d l i n k a g e , e s p e c i a l l y o r t h o t o a p h e n o l i c g r o u p , m a rk e d ly i n c r e a s e s t h e p o l a r i t y o f t h e com pound a n d s u b s e q u e n tl y i t s

s o l u b i l i t y in w a te r.

T h is may w e ll p r o v e

a v a l u a b l e p r o p e r t y o f t h i s new s e r i e s o f am ino a c i d s . The c h a n g e fro m p h e n o l i c t o g l y c o l l i c a c i d g r o u p in g s h o u ld b r i n g a b o u t p h y s i o l o g i c a l a s w e l l a s c h e m ic a l an d p h y s i c a l 37

changes*

I h s n o l l e g r o u p s a s a w h o le p o s s e s s p o w e r f u l a n t l - b a c t e r l a l

p ro p e rtie s *

The in tr o d u c tio n o f a se co n d p h e n o lic h y d ro x y l g ro u p ,

h o w e v e r, d e c r e a s e s t h e a c t i v i t y t o a b o u t o n e - e i g h th * P h e n o l I t s e l f i f a n t i s e p t i c , g e r m i c i d a l , an d a n e s t h e t i c •

C a te c h o l i s t h e m o st

t o x i c o f t h e t h r e e d l h y d r l c p h e n o ls and c a n b e u s e d o n ly I f o n e o f t h e p h e n o lic g r o u p s i s t i e d u p a s t h e m o n o m eth y l e t h e r , g u a l a c o l , w h ic h i s u s e d i n

th e t r e a t m e n t o f t u b e r c u l o s i s a s a n

in te s ti n a l a n tis e p tic * B ens o l e a d d , w h ic h h a s n o p h e n o l i c g r o u p s o n t h e n u c l e u s , h a s t h e sam e t y p e a n t i s e p t i c a c t i v i t y a s p h e n o l th o u g h t o a l e s s e r d e g r e e , a s w e l l a s a v e r y lo w s y s t e m i c a c t i v i t y , a n d f a t a l i t i e s a r e unknow n w i t h t h i s com pound*

I t h a s a m ild

a n t i - r h e u m a t i c a c t i o n s i m i l a r t o , b u t much w e a k e r t h a n t h a t a t th e o r t h o h y d r o x y c a r b o x y l l c com pound - s a l i c y l i c a c id *

S a lic y lic

a c i d a n d c l o s e l y r e l a t e d com pounds p r e s e n t a n o t h e r s i m p l e i l l u s t r a ­ t i o n o f t h e r e l a t i o n s h i p w h ic h e x i s t s b e tw e e n c h e m lo a l c o n s t i t u t i o n and p h y s io lo g ic a l a c tiv i ty * P h e n o l i s p r a c t i c a l l y i n a c t i v e a n d b e n s o l c a c i d i s som ew hat e f f e o t l v e i n t h e t r e a t m e n t o f a c u t e J o i n t r h e u m a tis m , b u t f a r l e s s e f f e c t i v e t h a n s a l i c y l i c a c id *

The a c t i v i t y o f s a l i c y l i c a c i d

a s a n a n t i - r h e u m a t i c an d a s a n a n t i s e p t i c i s c o m p le t e ly l a c k i n g I n t h e m e ta a n d p a r a I s o m e r s a n d i t

a p p e ars l i k e l y th a t th e

h y d r o x y l a n d c a r b o x y l g ro u p i n t h e o r t h e p o s i t i o n , a s f o u n d i n a d r e n a l l n o x y - a c e t i c a d d , a r e e s s e n t i a l t o Tsaximum a c t i v i t y * S a l i c y l i c a d d a n d m any com pounds d e r i v e d fro m i t p r o d u c e m a rk e d

38

a n t i p y r e t i c a n d a n a l g e s i c e f f e c t s a n d g i v e r e l i e f i n r h e u m a tic f e v e r an d rh e u m a tic t o n s l l l t l s * S a l i c y l i c a c i d h a s b e e n show n a b o v e t o p o s s e s s a s t r u c t u r e w h ic h m akes f o r t h e maximum i n a c t i v i t y , th o u g h i t i s n o t a s y m p a th o m im e tic a g e n t a s i s a d r e n a l i n e *

A d re n a lln o x y -a c e tic

a c i d c o n t a i n s t h e sam e t y p e s t r u c t u r e , a p h e n o l i c g ro u p a n d a c a rb o x y g ro u p o r th o to i t *

I n t h i s c a s e , h o w e v e r, we h a v e a

g l y c o l l i c a c i d g r o u p in g a s f o u n d i n p h e n o x y a c e tlc a c i d r a t h e r t h a n a c a r b o x y l g ro u p a s fo u n d i n b e n z o ic a c id * P h e n o x y a c e tlc a c i d i n c o n c e n t r a t i o n s o f fro m 0 .0 0 2 N t o 0*0026H i s show n t o h a v e t h e sam e r a p i d b a c t e r i a l a c t i o n o n tu b e r c le b a c i l l i in p u re c u ltu r e a s s a l i c y l i c

a c id *

F h en o x y

a c e t i c a c i d sh o w s a p r o lo n g e d h y p e r t h e r m i c a c t i o n w hen u s e d h y p o d e r m i c a l l y i n d o s e s o f 0 * 0 2 0 -0 * 3 0 g ram s p e r kgm* o f b o d y a n d w e i g h t , w i t h n o a c c o m p a n y in g t o x i c e f f e c t *

The h y p e rth e rm ic

a c t i o n a p p e a rs to b e c o n fin e d c h i e f l y to th e th e rm o re g u la tlv e c e n te r and can be e a s i l y and q u ic k ly c o n t r o l l e d .

S o m etim es t h e r e

i s a t e m p e r a t u r e d e c r e a s e im m e d ia te ly a f t e r i n j e c t i o n , a n d t h e n t h e t e m p e r a t u r e g r a d u a l l y I n c r e a s e s t o a maximum i n a b o u t t e n h o u r s ; u s u a l l y 1*4 t o 1*5 d e g r e e s a b o v e t h e o r i g i n a l b o d y t e m p e r a t u r e s , a n d a t ti m e s u p t o 2*6 d e g r e e s ,

The t e m p e r a t u r e

r e m a in s a lm o s t c o n s t a n t f o r e i g h t t o n i n e h o u r s an d t h e n r e t u r n s to th e o r i g i n a l te m p e ra tu re i n a b o u t tw e n ty - th r e e h o u r s .

T h is

t y p e a c t i v i t y s h o u ld becom e o f g r e a t im p o r ta n c e i n th e t r e a t m e n t o f a l l c a s e s i n w h ic h t h e b o d y t e m p e r a t u r e i s

su b n o rm a l*

T he new s e r i e s o f com pounds p r e p a r e d c o n t a i n t h e b e t a

- 39

p h e n e th a n o l am in e s t r u c t u r e w h ic h I s i n d i c a t i v e o f s y m p a th o m im e tic a c tiv ity .

I n a d d i t i o n i t h a s a c a t e c h o l ty p e n u c l e u s ( a l t h o u g h

one p h e n o lic h y d ro x y l g ro u p i s sy m p a th o m im e tic a c t i v i t y .

s u b s t i t u t e d ) th u s e n h a n c in g t h e

The s u b s t i t u t e d p h e n o l c o n t a i n s a

c a r b o x y m e th y l g r o u p t h u s g i v i n g t h e o r t h o h y d ro x y c a r b o x y c o n f i g u r a t i o n w h ic h h a s p r o v e n t o b e e s s e n t i a l f o r t h e g r e a t e s t a c t i v i t y a s a g e r m ic id a l, a n t i s e p t i c , a n t i - p y r e t i c , and a n t i r h e u m a tic a g e n t .

The c a r b o x y l i s a g l y c o l l i c a c i d ty p e an d t h e

h y p e r th e m lc a c t i v i t y o f t h e s e com pounds may becom e e v i d e n t .

The

c o m b in a tio n o f a l l o f t h e s e p o t e n t i a l l y p h y s i o l o g i c a l l y a c t i v e g r o u p in g s on o n e compound may w e l l r e s u l t I n a s y m p a th o m im e tic am in e w ith a n y num ber o f t h e

o th e r ty p e s o f a c t i o n I n c o r p o r a te d ,

o r p o s s i b l y t h e p r o d u c t i o n o f a n e n t i r e l y new c l a s s o f p o t e n c y . A h i g h l y a c t i v e , v e r s a t i l e d r u g s u c h a s t h i s w o u ld f i n d c o u n t l e s s a p p l i c a t i o n s i n p r e s e n t d a y c h e m o - th e r a p y . The s y n t h e s e s o f t h e s e com pounds u s e d o r t h o h y d r o x y p h en o x y a c e t i c a c i d a n d p h e n o x y a c e t i c a c i d a s t h e s t a r t i n g com pounds* T he s t e p s i n t h e s y n t h e s e s I n v o lv e t h e f o r m a t i o n o f t h e r e s p e c t i v e c h l o r a c e t y l p h en o x y a c e t i c a c i d s t h r o u g i t h e P r l e d e l - C r a f t s r e a c t i o n on t h e e t h e r s •

The c h l o r a c e t y l com pounds w e re c o n v e r t e d

i n t o t h e r e s p e c t i v e k e t o - a m ln e s b y c o n d e n s a t i o n w i t h m e th y l a m in e .

T h e s e w e re t h e n r e d u c e d t o t h e a l c o h o l i c a m in e s , a s

shown b e lo w 2

40 -

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The s t a r t i n g com pound, o r t h o h y d r o x y p h en o x y a e e t i c a c i d , v a s p r e p a r e d b y c o n d e n s in g o n e m ole o f c a t e c h o l w i t h one m o le o f mono c h l o r a c e t i e a d d i n t h e p r e s e n c e o f a n e x c e s s o f so d iu m h y d r o x id e *

T he so d iu m s a l t v a s c o n c e r t e d im m e d ia te ly t o t h e

a c id .

41

The f o l l o w i n g s t e p I n t h e schem e o f s y n t h e s i s c a l l s f o r a c o n d e n s a t i o n w ith c h l o r a c e t y l c h l o r i d e I n a F r i e d e l - C r a f t s r e a c tio n to g iv e th e c h lo rk e to n e .

S e v e ra l a tte m p ts a t c a r r y ­

in g th e r e a c t i o n o u t w ith th e f r e e c a rb o x y llc a c id gave p o o r r e su lts.

P r o t e c t i n g t h e a c i d g ro u p a s t h e m e th y l e s t e r g a v e

a w h ite c r y s t a l l i n e p r o d u c t I n a good y i e l d .

On r e c r y s t a l l l z a t l o n

o f t h e r e a c t i o n p r o d u c t t h e e s t e r g ro u p was h y d r o l y z e d . A l l a t te m p ts to c o n d e n s e t h e c h l o r k e t o n e p r e p a r e d a b o v e w i t h m e th y l am in e r e s u l t e d I n t a r r y p r o d u c t s .

The c a r b o x y l g r o u p

w as t i e d u p a s t h e m e th y l e s t e r , b u t t h i s w as fo u n d t o b e u n s ta b le .

T he e t h y l e s t e r was s t a b l e , b u t t h i s

y ie ld e d u n s ta b le

c o n d e n s a t io n p r o d u c t s .

com pound, t o o ,

T he p h e n o l i c g r o u p was

p r o t e c t e d b y e s t e r l f 1 c a t i o n w i t h a c e t y l c h l o r i d e ; t h i s w as o f no h e lp In th e c o n d e n s a tio n .

B o th th e c a r b o x y l l c a n d p h e n o l i c

g r o u p s w e re t i e d u p a s t h e e t h y l e s t e r a n d a c e t a t e c o r r e s p o n d i n g l y an d t h e r e a c t i o n w ith m e th y l a m in e g a v e a c r y s t a l l i n e p r o d u c t w h ic h w as p r o v e n b y a n a l y s i s t o h a v e t h e p h e n o l i c g r o u p f r e e , b u t th e c a rb o x y l g ro u p s t i l l e s t e r l f l e d . The k e to a m ln e was r e d u c e d I n a n a c i d s o l u t i o n w i t h a p a lla d lu m -c h a rc o a l c a t a l y s t to th e a lc o h o llc -a m ln e .

T he

h y d r o c h l o r i d e o f t h i s am in e was p r e p a r e d a n d c h a r a c t e r i s e d by a n a ly s is .

42

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CHOHCH IIHCHg

The p h e n o x y a c e t i c a c i d w h ic h l a t h e s t a r t i n g com pound waa p r e p a r e d f ro m p h e n o l a n d a n e x e e a a o f mono c h l o r a c e t l c a c i d i n a n e x c e a e o f so d iu m h y d r o x id e *

On a c l d l f i c a t i o n , b e c a u s e a n

I n t e n s e o d o r o f p h e n o l was n o t e d , t h e p r e c i p i t a t e was d i e s o l v e d i n e t h e r a n d e x t r a c t e d w i t h so d iu m c a r b o n a te *

A c i d i f i c a t i o n w ith

h y d r o c h l o r i c a c i d g a v e t h e p u r e p h e n o x y a c e tlc a c id *

• 43

As I n t h e c a s e o f t h e o t h e r s e r i e s o f com pounds no s a t i s f a c t o r y p r o d u c t c o u l d b e o b t a i n e d on c o n d e n s a t io n o f th e f r e e a c id an d c h lo r a c e ty l c h lo r id e In th e P r le d e l- C r a f ts re a c tio n *

I t w as n e c e s s a r y t o p r e p a r e t h e m e th y l e s t e r a n d

th u s t h e c o n d e n s a t i o n was c a r r i e d o u t* The r e s u l t i n g c h l o r a c e t y l p h e n o x y a c e t i c a c i d y i e l d e d I n a l l a t t e m p t s a t c o n d e n s a t i o n w i t h m e th y l a m in e , b l a c k p r o d u c t s , an d no a c c e p t a b l e p r o d u c t was o b t a i n e d on p u r i f i c a t i o n * The c a r b o x y l g r o u p w as t h e n p r o t e c t e d b y th e f o r m a t i o n o f t h e m e th y l e s t e r w h ic h , i n t h i s

com pound, was fo u n d t o b e q u i t e

s t a b l e * U n d er c o m p le t e ly a n h y d ro u s c o n d i t i o n s a n d a t a low t e m p e r a t u r e ( -3 0 ° C ) t h e c o n d e n s a t i o n g a v e t h e d e s i r e d com pound, t h e k e to a m in e *

A n a ly s is show ed t h a t t h e m e th y l e s t e r was n o t

h y d ro ly s e d d u r in g th e r e a o tio n * The a l c o h o l i c - a m i n e was p r e p a r e d b y r e d u c t i o n i n a n a c i d medium w i t h a p a l l a d l u m - c h a r c o a l c a t a l y s t * T he f r e e am in e was n o t s t a b l e , an d i t was s e p a r a t e d , p u r i f i e d , a n d a n a l y z e d a s t h e am in e h y d r o c h l o r i d e *

44

EXPERIMENTAL

P r e p a r a tio n o f A d re n a lin o x y a c e tlc E a te r

o-Hydroxy Phenoxy Acetic Acid

F o r t y g ram s o f c h l o r a e e t i c a c i d a n d 55 g ram s o f c a t e c h o l w ere d i s s o l v e d i n 250 c c . o f w a t e r a n d h e a t e d t o re flu x .

A s o l u t i o n o f 4 0 gram s o f so d iu m h y d r o x id e i n

100 c c . o f w a te r w as a d d e d d r o p w ls e a n d t h e r e f l u x c o n t i n u e d f o r tw o h o u r s .

The s o l u t i o n w as c o o l e d t o 60°C an d p o u re d

i n t o a c r a c k e d - ic e - h y d r o c h lo r ic a c id m ix tu re .

The o - h y d rc x y

phenoxy a c e t i c a c id p r e c i p i t a t e d o u t on s ta n d in g . was r e c r y s t a l l i z e d fro m h o t w a t e r . m .p . 1 3 4 ° C.

- 46

T he compound

The y i e l d was 58 g r a m s ,

o-Hydroxy phenoxy methyl acetate T h i r t y - e i g h t g ram a o f o - h y d r o x y p h en o x y a e e t i e a c i d w e re r e f l u x e d w ith 60 cc* o f m e th a n o l a n d 55* o f c o n c e n t r a t e d s u l f u r i c a c i d f o r o n e h o u r a n d th e n p o u r e d i n t o c r a c k e d - l c e w i t h c o n t in u o u s s t i r r i n g *

An o i l s e p a r a t e d o u t a n d i t w as

r e c r y s t a l l i z e d f r o m a n a l c o h o l - w a t e r m ix tu r e * 3 0 gram s*

m. p*

59°C*

47

The y i e l d was

2-Hydroxy 4-chloracetyl phenoxy acetic a d d T h i r t y g ram s a t o - h y d ro x y p h e n o x y m e th y l a c e t a t e w e re d is s o lv e d I n a m ix tu re o f 120 c c . o f c a rb o n d i s u l f i d e and 9 0 g ram s o f c h l o r a c e t y l c h l o r i d e ( f r e s h l y d i s t i l l e d ) . O n e -h u n d re d fifty

gram s o f a n h y d r o u s alu m in u m c h l o r i d e w e re a d d e d r a p i d l y .

The s o l u t i o n was k e p t i n an i c e b a t h a n d c o n s t a n t s t i r r i n g was m a i n t a i n e d th r o u g h o u t t h e a d d i t i o n . o c c u rre d .

In s ta n ta n e o u s r e a c tio n

The m ix t u r e was a llo w e d t o s t a n d u n t i l t h e i n i t i a l

f r o t h i n g s to p p e d a n d w as t h e n h e a t e d w i t h s t i r r i n g u n t i l i t t u r n e d t o a n o r a n g e - y e l lo w v i s c o u s m a s s .

C a re m u st b e t a k e n

to p re v e n t o v e rh e a tin g b e c a u se in e v e ry In s ta n c e a b la c k o r d a rk b ro w n p r o d u c t r e s u l t e d i n v e r y p o o r y i e l d s .

The e n t i r e m ix t u r e

was t h e n p o u r e d s lo w ly i n t o i c e an d h y d r o c h l o r i c a c i d . A b r o w n i s h - w h it e p r e c i p i t a t e s e t t l e d o u t . I t w as f i l t e r e d o f f a n d r e c r y s t a l l i z e d fro m h o t w a t e r w ith t h e u s e o f 5 g ra m s o f D a rc o 0 - 6 0 a s a d e c o l o r i z i n g a g e n t .

Four r e c r y s ta llls a tlo n s

w e re n e c e s s a r y b e f o r e a c o n s t a n t m e l t i n g com pound w h ic h a n a l y s e d c o r r e c t l y was o b t a i n e d .

The y i e l d was 12 g r a m s , m .p . 1 7 2 -1 7 3 °C .

C a lc u la te d

Pound

4 9 .0 6

4 9 .0 5

3 .7 2

3 .7 2

Apalyalsi % C a rb o n % H y d ro g e n

48 -

2-Hydroxy 4-chloracetyl phenoxy methyl acetate Ten gram s o f 2 - h y d ro x y 4 - c h l o r a c e t y l p h e n o x y a c e t i c a c i d an d 10 c c . o f m e th a n o l w e re r e f l u x e d w i t h 1 c c . o f c o n c e n tr a te d s u l f u r i c a c i d f o r 1 h o u r, a n d th e n p o u red i n t o an ic e - w a te r m ix tu r e .

T he m e th y l e s t e r p r e c i p i t a t e d

o u t a n d was r e c r y s t a l l i z e d fro m a n a l c o h o l - m i x t u r e g i v i n g a c r y s t a l l i n e p ro d u c t.

The y i e l d was t e n g r a m s , m .p . 6 1 °C .

C al c ilia te d

Found

Analysisi % C a rb o n % H y d ro g en

5 0 .8 3

5 0 .7 1

4 .2 4

4 .1 1

T he 2 - h y d r o x y 4 - c h l o r a c e t y l p h en o x y m e th y l a c e t a t e w as fo u n d t o b e q u i t e u n s t a b l e , a n d t h e r e f o r e n o t c o n v e n ie n t f o r u s e i n th e m e th y l a m in e c o n d e n s a t i o n .

2-Hydroxy 4-chloracetyl ethyl acetate

T en g ram s o f 2 - h y d r o x y 4 - c h l o r a c e t y l p h en o x y a c e t i c a c i d , 20 cc* o f e t h a n o l , end 2 c c * o f c o n c e n t r a t e d s u l f u r i c a c i d v e r e r e f l u x e d f o r one h o u r a n d p o u r e d I n t o a c r a c k e d lc e - w a te r m ix tu re . am o rp h o u s s o l i d .

The e t h y l e s t e r p r e c i p i t a t e d a s a n R e c r y s t a l l i s a t i o n fro m a n a l c o h o l - w a t e r

m ix t u r e g a v e a c r y s t a l l i n e p r o d u c t* The y i e l d w as 10 g ram s* m *p. 1 2 4 -1 2 5 ° C .

C a lc u la te d

P ound

A n a ly s ls : % c a rb o n

52*70

52*66

% h y d ro g en 4*75

4*68

The e t h y l e s t e r was f o u n d t o b e s t a b l e *

C o n d e n s a tio n s

w i t h m e th y l am in e w e re a t t e m p t e d u n d e r v a r i e d c o n d i t i o n s , y ie l d i n g i n each e a s e a b la c k ta r *

50

2-Acetyloxy 4-chloracetyl phenoxy acetic acid

T en g ra m s of 2 - h y d r o x y 4 - c h l o r a c e t y l p h e n o x y a c e t i c a d d w e re s u s p e n d e d I n 2 0 cc* o f b e n z e n e a n d 5 g ra m s o f a c e t y l c h l o r i d e w ere a d d e d * tw o h o u rs *

T he s o l u t i o n w as r e f l u x e d f o r

T he e x c e s s a c e t y l c h l o r i d e a n d t h e b e n z e n e

w e re rem o v ed b y d i s t i l l a t i o n u n d e r r e d u c e d p r e s s u r e *

A

gum r e m a in e d a n d w as t a k e n u p I n h o t c y c lo h e x a n e a n d I t o The y i e l d was 9 gram s* m*p* 116 C*

r e c r y s t a l l l z e d o n c o o lin g *

C a lc u la te d

Found

A n a ly a I s t % C a rb o n % H y d ro g en

50*13

50*19

3*81

3*69

A ll a tte m p ts to c ondense t h i s

compound w i t h m e th y l am in e

u n d e r v a r i e d c o n d i t i o n s r e s u l t e d i n b l a c k t a r s a n d gums w h ic h c o u l d i n no c a s e b e r e s o l v e d I n t o a n a c c e p t a b l e com pound*

51

2-Acetyloxy 4-chloracetyl phenoxy ethyl acetate T en gram a o f 2 - h y d r o x y 4 - c h l o r a c e t y l p h en o x y e t h y l a c e t a t e w ere d i s s o l v e d i n 20 cc* o f b e n z e n e an d 5 gram s o f a c e t y l c h l o r i d e w e re a d d e d . The s o l u t i o n w as r e f l u x e d f o r tw o h o u r s . T he e x c e s s a c e t y l a c h l o r i d e an d b e n z e n e w ere rem o v e d u n d e r r e d u c e d p r e s s u r e .

A w h ite

c r y s t a l l i n e p r o d u c t r e m a in e d w h ic h w as r e c r y s t a l l i z e d fro m a b e n z e n e -h e x a n e m ix tu re .

The y i e l d was 10 gram s* m .p . 7 6 ° C .

C a lc u la te d

Found

A n a ly s is : % C a rb o n % H y d ro g en

53* 2 2

53*10

4*74

4*73

52

N-Methyl-amlno-methyl-( 4-hydroxy 5-ethyl oxyacetlc)-phenyl k e to n e .

T en g ram s o f 2 - a c e t y l o x y 4 - c h l o r a c e t y l p h e n o x y e t h y l a c e t a t e w ere d i s s o l v e d I n 3 0 c c . o f a b s o l u t e a l c o h o l a n d T h i r t y c c . o f a 2 5 % s o l u t i o n o f a n h y d ro u s

c o o le d to - 40°C .

m e th y l am in e w ere a d d e d a n d t h e s y s te m w as I m m e d ia te ly e v a c u a te d .

I t was t h e n p l a c e d u n d e r a n a tm o s p h e r e o f h y d ro g e n

a n d s h a k e n f o r 4 d a y s a t room t e m p e r a t u r e . p a l e y e llo w

c o lo r.

T he s o l u t i o n was a

The t e m p e r a t u r e was d r o p p e d t o - 3 0 ° C . an d

c a r b o n d i o x i d e w as b u b b le d t h r o u g h u n t i l t h e o d o r o f m e th y l a m in e was g o n e .

I t w as f o u n d a d v a n ta g e o u s t o a d d a few p i e c e s

o f d r y - l c e fro m tim e t o t i m e .

The s o l u t i o n d a r k e n e d s l i g h t l y ,

w as b r o u g h t t o room t e m p e r a t u r e , a n d was c o n c e n t r a t e d t o 10 c c . u n d e r r e d u c e d p r e s s u r e . w e re a d d e d t o t h e s o l u t i o n . a d d e d d r o p w ls e aid

T en c c . o f d i s t i l l e d w a te r

D i l u t e h y d r o c h l o r i c a c i d was

a f t e r t h e f i r s t fe w d r o p s a b l a c k p r e c i p i ­

t a t e came down a n d w as f i l t e r e d o f f a n d r e j e c t e d .

M ore

a d d w as a d d e d d r o p w is e u n t i l t h e s o l u t i o n t u r n e d a l i g h t y e llo w .

The s o l u t i o n w as f i l t e r e d a g a i n , a n d t h e p r e c i p i t a t e

w as r e j e c t e d .

F u r th e r a d d i ti o n o f a c id g av e a g re y -w h ite

p r e c i p i t a t e w h ic h w as p u r i f i e d b y r e p r e c l p l t a t i o n fro m a c i d

53

w i t h ammonium h y d r o x id e *

The y i e l d w as 3 g r a m s , m .p

1 9 0 -1 9 1 ° C .

C a lc u la te d

Found

A n a ly s is : % N itr o g e n

5 .3 9

5 .2 5

The h y d r o c h l o r i d e was f o u n d t o be u n s t a b l e .

54 -

K - M e th y l- a m in o -m e th y l-( 4 - h y d r o x y 3 - e t h y l o x y a c e t l c ) - p h e n y l c a r b ln o l - (A d re n a lln o x y a c e tlc e a t e r ) >

T h re e gram a o f N - m e th y l- a m in o - m e th y l- ( 4 - h y d r o x y 3 - e t h y l o x y a c e t l c ) - p h e n y l k e to n e w ere s u s p e n d e d I n 10 cc* o f 95% e t h a n o l a n d d i s s o l v e d b y t h e a d d i t i o n o f a minimum am ount o f c o n c e n tra te d h y d ro c h lo ric a c id .

The r e d u c t i o n was c a r r i e d

o u t b y s h a k in g f o r s i x h o u r s u n d e r 4 5 p o u n d s o f h y d r o g e n w ith 0*6 g ram s o f p a l l a d l u m - c h a r c o a l c a t a l y s t ( 5 8 ) •

The a l c o h o l

w as d i s t i l l e d o f f u n d e r r e d u c e d p r e s s u r e a n d w h i t e c r y s t a l s o f t h e a m ln o - a lc o h o l h y d r o c h l o r i d e r e m a in e d .

T he h y d r o c h l o r i d e

w as r e c r y s t a l l i s e d fro m a n a l c o h o l - e t h y l a c e t a t e - e t h e r m ix tu r e * The y i e l d was 2*8 g ram s* m*p* 1 5 8 -1 6 0 °C * Cal c u l a t e d

Found

A n a ly s is > % N itro g e n

4*53

4*55

P r e c i p i t a t i o n o f t h e f r e e a m in e fro m t h e h y d r o c h l o r i d e y ie ld e d a b la c k ta r* H y d r o l y s i s o f t h e e s t e r w ith a c i d o r a l k a l i i n

an

a t t e m p t t o o b t a i n th e a d r e n a l i n o x y - a c e t i c a c i d fro m t h e e t h y l e s t e r g a v e a brow n p r e c i p i t a t e w h ic h t a r r e d I m m e d ia te ly on filtra tio n .

55

Preparation of araephrlneoxyacetlc Bateg

- 56 -

Phenoxy acetic acid

T w e n ty - f iv e g ram s o f p h e n o l and 40 gram a o f c h l o r a c e t i e a c i d w e re d i s s o l v e d i n 100 c c . o f w a t e r i n a 3 n e c k , 500 c c . f l a s k e q u ip p e d w i t h a r e f l u x c o n d e n s e r a n d a d r o p p in g f u n n e l .

T he s o l u t i o n w as h e a t e d t o t o i l i n g . F o r t y

gram s o f so d iu m h y d r o x id e i n 100 c c . o f w a t e r w e re a d d e d s lo w ly .

The r e f l u x w as c o n t i n u e d f o r one h o u r .

The m ix t u r e

w as t h e n c o o l e d t o 6 0 °C . a n d p o u r e d i n t o BOO c c . o f c o n c e n ­ t r a t e d h y d ro c h lo ric a c id an d i c e .

On s t a n d i n g o v e r n i g h t

a w h ite c r y s t a l l i n e p r e c i p i t a t e a p p e a r e d a n d on f i l t r a t i o n s m e lle d s t r o n g l y o f p h e n o l .

T he p r e c i p i t a t e w as d i s s o l v e d

i n 100 c c . o f e t h e r a n d e x t r a c t e d w i t h t h r e e 50 c c . p o r t i o n s o f so d iu m c a r b o n a t e .

The t h r e e p o r t i o n s w ere co m b in e d a n d

a c i d i f i e d w ith c o n c e n tra te d h y d ro c h lo ric a c id .

A c ry s ta llin e

p r o d u c t s e p a r a t e d o u t a n d w as r e c r y s t a l l i z e d fro m h o t w a t e r . The y i e l d w as 37 g r a m s , m .p . 9 9 °C .

57-

Methyl phenoxy acetate T h i r t y - a e v e n gram s o f p h e n o x y a c e t i c a c i d , 5 0 c c . o f m e th a n o l,

and 5 c c . o f s u l f u r i c a c i d w e re r e f l u x e d f o r o n e

h o u r a n d t h e s o l u t i o n w as p o u r e d i n t o 2 0 0 c c . o f c r a c k e d - i c e . An o i l s e p a r a t e d o u t a n d was d i s s o l v e d i n 100 c c . o f e t h e r , w ash e d w i t h d i l u t e so d iu m h y d r o x id e a n d d r i e d o v e r a n h y d ro u s so d iu m s u l f a t e .

T he e t h e r was rem o v ed u n d e r r e d u c e d p r e s s u r e

a n d th e r e m a in in g o i l was d i s t i l l e d a t 242°/*753 y i e l d w as 35 g ra m s .

58

mm.

The

Para chloracetyl phenoxy acetic acid T h i r t y - f i v e gram a a t p h e n o x y m e th y l a o e t a t e w e re p la c e d , i n a m ix t u r e o f 140 cc* o f c a r b o n d i s u l f i d e a n d 105 gram s o f c h l o r a c e t y l c h l o r i d e *

The sam e s e t - u p w as u s e d a s t h a t

u s e d f o r t h e p r e p a r a t i o n o f th e 2 - h y d r o x y 4 - c h l o r a c e t y l p h e n o x y a c e t i c a c id *

O n e - h u n d r e d - s e v e n t y - f i v e g ram s o f a n h y d ro u s alum inum

c h l o r i d e w e re a d d e d a n d c a r e was t a k e n to a v o i d e x c e s s f r o t h i n g d u rin g th e a d d itio n *

A co n d en ser s e t f o r d i s t i l l a t i o n re p la c e d

t h e pow der f u n n e l an d t h e r e a c t i o n w as h e a t e d o n a w a te r b a t h f o r 2 0 m in u te s w i t h c o n s t a n t s t i r r i n g . The m ix tu r e s o l i d i f i e d , t u r n e d t o a g o ld e n - b r o w n c o l o r , an d w as p o u r e d i n t o 500 c c * o f a n i c e - h y d r o c h l o r i c a c i d m ix tu re *

T h e re was a n Im m e d ia te

p r e c i p i t a t e o f w h i t e c r y s t a l s w h ic h w ere s u b s e q u e n t l y r e c r y s t a l l i z e d fro m h o t w a t e r w i t h t h e u s e o f 2 g ram s o f D a rc o 0 - 6 0 t o rem ove a s m a l l am ount a t t a r w h ic h h a d fo rm e d *

T he y i e l d w as 20 g ra m s .

m*p* 15 3 —155 C* C a lc u la te d

Found

A n a ly s is % C a rb o n % H y d ro g en

52*25

52* 1 3

3*94

3*91

59

p a r a C h l o r a c e t y l p h e n o x y m e th y l a c e t a t e

T w en ty g ra m s o f p - c h l o r a c e t y l p h en o x y a c e t i c a c i d w e re r e f l u x e d w i t h 35 cc * o f m e th a n o l a n d 3 cc* o f c o n c e r t r a t e d s u l f u r i c a c i d f o r o n e h o u r a n d p o u r e d i n t o 100 cc* o f a n I c e w a te r m i x t u r e .

An o i l s e p a r a t e d o u t a n d c r y s t a l l i z e d on s ta n d in g *

R e c r y s t a l l l z a t i o n fro m a l c o h o l a n d w a t e r y i e l d e d 18 g ram s* m*p* 92°C*

C a lc u la te d

Found

A n a ly s is % C a rb o n % H y d ro g e n

5 4 .1 3

53*99

4 .5 1

4 .4 4

60

N - M e th y l- a m ln o - m e th y l( 4 - m e th y l o x y a c e t l c ) - p h e n o l k e to n e *

T en g ram s o f p a r a c h l o r a c e t y l p h e n o x y m e th y l a c e t a t e w e re d i s s o l v e d i n 20 cc* o f a b s o l u t e a l c o h o l a n d c o o le d t o -3 0 °C .

T h i r t y cc* o f a 25JC s o l u t i o n o f a n h y d ro u s

m e th y l am in e i n a b s o l u t e a l c o h o l w e re a d d e d r a p i d l y * a i r w as r e p l a c e d b y a n a tm o s p h e r e o f h y d r o g e n . s h a k e n f o r 4 d a y s a t room t e m p e r a t u r e .

T he

The m ix t u r e was

C a rb o n d i o x i d e a n d d r y -

i o e w e re u s e d t o e x p e l t h e e x c e s s m e th y l am ine*

T he v o lu m e

waa c o n c e n t r a t e d i n v a c u o t o 10 cc* a n d 1 5 c c . o f d i s t i l l e d w a t e r w e re a d d e d . T he am in e w as p r e c i p i t a t e d b y t h e a d d i t i o n o f d i l u t e h y d r o c h l o r i c a c id *

The f i r s t few d r o p s r e s u l t e d i n

b l a c k t a r s w h ic h w ere r e j e c t e d . The c o l o r o f t h e s o l u t i o n becam e m uch l i g h t e r .

When t h e c o l o r r e a c h e d a p a l e - y e l l o w

t h e a d d i t i o n o f a n o t h e r d r o p o f a c i d g a v e a w h ite p r e c i p i t a t e w h ic h w as p u r i f i e d b y r e p r e c i p l t a t l o n fro m a c i d w i t h ammonium h y d r o x id e *

The y i e l d was 4 gram s* m *p. 1 8 0 -1 8 1 ° C . C a lc u la te d

Found

5*82

5*55

A n a ly s is i % n itro g e n

The h y d r o c h l o r i d e was f o u n d t o b e u n s t a b l e a n d t u r n e d t o a s t l c k y - t a r a lm o s t I n s t a n t a n e o u s l y on p r e c i p i t a t i o n *

M -M e th y l-a m ln o -m e th y l-( 4 - m e th y l o x y a c e t l c ) - p h e n y l c a r b l n o l ( S y n e p h r ln e o x y a c e t lc e a t e r ) F o u r g ram s o f N - m e th y l- a r a in o - m e th y l- ( 4 - m e th y l o x y a c e t i c ) p h e n y l k e to n e w e re s u s p e n d e d i n 30 c c . o f 9 5 # e t h a n o l a n d d i s s o l v e d b y t h e a d d i t i o n o f t h e minimum am ount o f c o n c e n t r a t e d h y d ro c h lo ric a c id .

The r e d u c t i o n w as c a r r i e d o u t b y s h a k i n g f o r

6 h o u r s u n d e r 45 p o u n d s o f h y d ro g e n w ith 0 . 8 g ram s o f p a l l a d i u m c h a rc o a l c a t a l y s t (5 8 ).

T he s o l u t i o n was f i l t e r e d t o rem o v e t h e

c a t a l y s t a n d t h e a l c o h o l was re m o v e d u n d e r r e d u c e d p r e s s u r e , y i e l d i n g w h i t e c r y s t a l s o f t h e a m i n e - a l c o h o l h y d r o c h l o r i d e . T h e se w e re r e c r y s t a l l i z e d fro m a n a l c o h o l - e t h y l a c e t a t e - e t h e r m i x t u r e . The y i e l d was 4 g r a m s , m .p . 1 4 8 -1 5 0 ° C . C a lc u la te d

Found

5 .0 6

5 .1 3

A n a ly s is : % N itr o g e n

T he f r e e am in e w as fo u n d t o b e s t a b l e a n d w as p r e p a r e d b y d i s s o l v i n g 2 g ra m s o f th e h y d r o c h l o r i d e i n d i s t i l l e d w a te r an d p re c lp lta tlx g s

t h e a m in e b y d r o p w is e a d d i t i o n o f d i l u t e

ammonium h y d r o x i d e .

T he i f c i t e com pound w as r e p r e c i p i t a t e d

fro m a n a c i d s o l u t i o n w i t h d i l u t e ammonium h y d r o x i d e . The y i e l d was 1 g ra m . m .p . 1 9 6 °C .

62

A l l a t t e m p t s t o h y d r o l y s e t h e m e th y l e s t e r t o g iv e t h e f r e e am ino a e i d r e s u l t e d i n t a r s v h i e h c o u l d n o t b e re s o lv e d I n to a c e e p ta b le p ro d u c ts .

63

Tabla of compounds

O

R»

'

% C a rb o n F orm ula.

^ H y d ro g e n

M .P . C a l c . F o u n d C a l c . F ound 1 7 3 ° 4 9 .0 1 4 9 .0 5 3 .6 2 3 .7 2

R1 OH

*2 OCHgCOOH

R3 COCHgCl

C10H9 ° 6 C1

OH

OCHACOOCH 2 3 OCH COOC H 2 2 5 OCH COOH 2 OCH COOC H 2 2 6 H

COCH C l

C11H1 1 ° 5 C1

92

5 1 .0 1

5 0 .8 9 4 .2 5

4 .2 2

COCH C l 2 COCH C l 2 COCH C l 2 COCH C l 2 COCH CL 2

C H 0 C l 126 12 1 3 5 C H 0 C l 116 12 11 6 C H 0 C l 75 14 13 6 165 ° 1 0 H9 ° 4C1 92

5 2 .7 0

52*66 4 .7 4

4 .6 5

5 0 .2 1

5 0 .0 1 3 .8 4

3 .9 0

5 3 .2 2

5 3 .1 0 4 .7 4

4 .7 3

5 2 .2 5

5 2 .1 3

3 .9 4 3 .9 1

5 4 .1 3

5 3 .9 9

4 .5 1 4 .4 4

OH OCOCH 3 OCOCHg OCHgCOOH

H

)CH_COOCH 2 3

2

cxxhii0401

% N itr o g e n

OH OH

XJH COOCH 2 3

)CH COOCH 2 3

OCH COOC 2 2 OCH_COOC 2 S H H

H 5 H 5

C H O I 191 COCH.NHCH 2 3 13 17 5 CHOHCH.NHCH 2 3 HC1 C H 0 NCI 1 60 13 10 5 COCH NHCH C10H O N 181 1 2 15 4 3 2 CHOHCH.NHCH 2 3 HCL

C H O N 196 12 17 4 C ioH , ° NCI 1 50 12 18 4

64

C a lc .

F ou n d

6*39

5 .2 5

4 .5 3

4 .6 6

6*62

5 .5 3

5*76

5 .7 6

6 .0 6

5*13

T he h y d r o c h l o r i d e o f t h e e t h y l e a t e r of a d r e n a l l n o x y a c e t l c a c i d a n d t h e m e th y l e s t e r o f s y n e p h r l n e o x y - a c e t l c a c i d w e re p r e p a r e d a n d c h a r a c t e r i z e d b y a n a l y s i s .

A l t o g e t h e r tw e lv e

new com pounds w e re p r e p a r e d . The w ork I n t h i s t h e s i s h a s b e e n p r e s e n t e d b e f o r e t h e M e d ic in a l D i v i s i o n o f The A m eric an C h e m ic a l S o c i e t y a t t h e A t l a n t i c C i t y m e e tin g i n S e p te m b e r, 1 9 4 9 . An a b s t r a c t o f t h i s t h e s i s h a s b e e n s u b m i t t e d t o t h e J o u r n a l o f t h e A m e ric a n C h e m ic a l S o c i e t y . B o th o f t h e h y d r o e h l o r l d e s w e re s u b m i t t e d f o r e x a m in a tio n of p o s s ib le p h y s io lo g ic a l a c t i v i t y .

65 -

B ib lio g ra p h y

(1 )

O liv e r and S c h a e fe r, J . P h y s io l., 1 6 , 1 (1 8 9 4 ); T g . 230 (1 8 9 5 ).

(2 )

S cym onow icz, B u l l . I n t e r n , a c a d . , C r a c a v l , C l a s s e a c i . m a th e t . n a t . 56 ( 1 8 9 5 ) .

(3 )

A b el a n d C r a w f o rd , B u ll* J o h n H o p k in s H o s p ., 8 , 1 5 1 ( 1 8 9 7 ) .

(4 )

T a k a m ln e , Am. J . F h a r m ., 7 5 , 5 2 3 ( 1 9 0 1 ) .

(5 )

A l d r i c h , Am. J . P h y s i o l . , 5 , 4 5 7 ( 1 9 0 1 ) .

(6 )

A l d r i c h , J . Am. Cham, d o c . , 2 7 , 1 0 7 4 ( 1 9 0 5 ) .

(7 )

F u r t h , M o a a ta h , 2 4 , 2 6 1 ( 1 9 0 3 ) .

(8 )

F u r th , B e r ., 3 7 , 1 3 8 8 (1 9 0 4 ).

(9 )

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