Patent-US 4847265-Clopidogrel and Salts Such as Clopidogrel Hydrogen Sulfate; Anticoagulants

8/10/2019 Patent-US 4847265-Clopidogrel and Salts Such as Clopidogrel Hydrogen Sulfate; Anticoagulants

1/11

United States Patent [ 1 9 1

Badorc e t a l .

4 , 8 4 7 , 2 6 5

J u l . 1 1 , 1 9 8 9

[ 1 1 ] P a t e n t N u m b e r :

[ 4 5 ] Date o f P a t e n t :

[ 5 4 ] DEXTRO-ROTATORY ENANTIOMER OF

METHYL ALPHA-5

(4,5,6,7-TETRAHYDRO

( 3 , 2 - C )

THIENO

PYRIDYL)

(Z-CHLOROPHENYD-ACETATE

AND

THE

PHARMACEUTICAL COMPOSITIONS

CONTAINING IT

[ 7 5 ] I n v e n t o r s : A l a i n

B a d o r c ,

R o q u e t t e s ; D a n i e l

F r h e l ,

T o u l o u s e , b o t h o f

F r a n c e

[ 7 3 ] A s s i g n e e : S a n o ? , F r a n c e

[ 2 1 ] A p p l . N o . : 1 5 5 , 5 5 0

[ 2 2 ] F i l e d : F e b . 1 2 , 1 9 8 8

[ 3 0 ]

F o r e i g n A p p l i c a t i o n P r i o r i t y D a t a

Feb. 1 7 ,

1987 [FR] France

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

. 87

02025

Nov.

2 7 ,

1987

[FR] France

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

.

87

16516

[ 5 1 ] I n t .

cu . . . . . . . . . . . . . . . . . .

. .

A61K 31/44;

CO7D

495 /04

[ 5 2 ]

U.S.C1. . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. 514/301;

546/ 1 1 4

[ 5 8 ] F i e l d of Search . . . . . . . . . . . . . . . . . . . . . . . . . 546/114;

514/301

[ 5 6 ]

R e f e r e n c e s

C i t e d

U . S . PATENT DOCUMENTS

4,529,596

7 / 1 9 8 5 Aube rt e t

a l .

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

.

546/ 1 1 5

FOREIGN

PATENT DOCUMENTS

0099802 7/1983

European

P a t . O f f . .

OTHER PUBLICATIONS

F i e s e r

e t a l . , Advanced O r g . Chem-Reinhold P u b l i s h

i n g

C o . ,

N . Y . ,

( 1 9 6 1 ) ,

p p .

8 5 - 8 8 .

P r i m a r y Examiner-Mary C . L e e

A s s i s t a n t Examiner-Bernard

.

Dentz

A t t o r n e y , A g e n t ,

o r Firm-Wegner

& B r e t s c h n e i d e r

[ 5 7 ] ABSTRACT

The

p r e s e n t

i n v e n t i o n

r e l a t e s

t o

t h e d e x t r o - r ot a t o r y

e n a n t i o m e r o f Formula

COOCH3

U

5 C l

a n d i t s p h a r m a c e u t i c a l l y a c c e p t a b l e s a l t s w i t h

p l a t e l e t

a g g r e g a t i o n

i n h i b i t i n g

a c t i v i t y .

T h e i n v e n t i o n

a l s o

r e l a t e s t o a p r o c e s s f o r

t h e

p r e p a r a

t i o n o f t h i s

compound

s t a r t i n g f r o m

t h e

r a c e m a t e a n d

t h e p h a r ma c e u t i c a l c o m p o s i t i o n s c o n t a i n i n g i t .

7

C l a i m s ,

N0 D r a w i n g s


2/11

4 , 8 4 7 , 2 6 5

1

DEXTRO-ROTATORY ENANTIOMER

OF

METHYL

ALPHA-5 (4,5,6,7-TETRAHYDRO ( 3 , 2 - C )

THIENO PYRI D YL)

(2-CHLOROPHENYD-ACETATE AND

THE

PHARMACEUTICAL COMPOSITIONS

CONTAINING

IT

The

p r e s e n t i n v e n t i o n

r e l a t e s t o

t h e d e x t r o - r o t a t o r y

e n a n t i o m e r

o f m e t h y l a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2

c ) t h i e n o p y ri d y l ) ( 2 - c h l o r o p h e n y l ) - a ce t a t e , a p r o c e s s

f o r

i t s

p r e p a r a t i o n a n d p h a r m a c e u t i c a l c o m p o s i t i o n s

c o n t a i n i n g

i t .

The co mpound o f t h e i n v e n t i o n

c o r r e s p o n d s

t o t h e

f o l l o w i n g f o r m u l a ( I ) :

COOCH; ( I )

N

5

C l

i n which t h e

C

s a n

a s y m m e t r i c c a r b o n

a t o m . I n f a c t ,

t h i s

f o r m u l a

r e p r e s e n t s b o t h

t h e d e x t r o - r o t a t o r y m o l e

c u l e

c l a i m e d a s w e l l a s i t s

l e v o - r o t a t o r y

e n a n t i o m e r .

The

r a c e m i c

m i x t u r e

c o r r e s p o n d i n g

t o

t h i s

f o r m u l a

was

d e s c r i b e d

i n

t h e F r e n c h p a t e n t

a p p l i c a t i o n

p u b l i s h e d

u n d e r

t h e

No.

2

5 3 0 2 4 7 .

H e r e a f t e r

t h e d e x t r o - r o t a t o ry

e n a n t i o m e r c l a i m e d a c c o r d i n g

t o t h e i n v e n t i o n w i l l

b e

d e s i g n a t e d

b y I d a n d t h e l e v o - r o t a t o r y e n a n t i o m e r

b y

I 1 .

I t

i s

known h a t t h e o p t i c a l r o t a t o r y

power

o f a

c o m

pound

d e p e n d s o n

t h e

s o l v e n t i n which t

i s

m e a s u r e d

and on i t s c o n c e n t r a t i o n

i n

t h i s

s o l v e n t . The o p t i c a l

r o t a t o r y

p o w e r

o f t h e d e x t r o - r ot a t o r y

i s o m e r a c c o r d i n g

t o

t h e i n v e n t i o n

i s

p o s i t i v e

i n

m e t h a n o l i c

s o l u t i o n .

I n

a n u n e x p e c t e d

manner

o n l y

t h e

d e x t r o - r o t a t o r y

e n a n t i o m e r

I d e x h i b i t s a

p l a t e l e t


i n h i b i t i n g

a c t i v i t y ,

t h e


e n a n t i o m e r I 1

b e i n g

i n a c t i v e .

M o r e o v e r , t h e

i n a c t i v e

l e v o - r o t a t o r y e n a n t i o m e r I 1 i s

t h e l e s s

w e l l

t o l e r a t e d

o f

t h e two e n a n t i o m e r s .

The

i n v e n t i o n a l s o

r e l a t e s

t o t h e a d d i t i o n s a l t s o f t h e

compounds o f f o r m u l a ( 1 4 )

w i t h

p h a r m a c e u t i c a l l y a c

c e p t a b l e m i n e r a l o r o r g a n i c a c i d s .

The compound ( I d )

i s a n

o i l

w h e r e a s i t s

h y d r o c h l o

r i d e e x i s t s a s a w h i t e powder. The

o i l y

p r o d u c t s

a r e

u s u a l l y d i f ? c u l t t o p u r i f y a n d

i t

i s

p r e f e r a b l e t o

u s e

f o r

t h e

p r e p a r a t i o n

o f p h a r m a c e u t i c a l c o mp o s i t i o n s c r y s t a l

l i n e p r o d u c t s

which

c a n

u s u a l l y

b e p u r i ? e d

b y

r e c r y s

t a l l i z a t i o n .

However,

i t

h a s been o b s e r v e d

i n t h e p r e s e n t c a s e

t h a t s o m e o f t h e

s a l t s o f compound

1 4 ) u s u a l l y

p r e c i p i

t a t e i n an amorphous form and/

r

t h a t t h e y a r e hygro

s c o p i c ,

a p r o p e r t y

which

makes

them

i f ? c u l t t o h a n d l e

on

an

i n d u s t r i a l s c a l e . T h u s ,

t h e

s a l t s o f c a r bo x y l i c a c i d

a n d

s u l f o n i c

a c i d s

c l a s s i c a l l y u s e d i n

pharmacy

h a v e

b e e n p r e p a r e d , a c i d s s u c h a s a c e t i c ,

b e n z o i c , f u ma r i c ,

m a l e i c , c i t r i c ,

t a r t a r i c , g e n t i s i c ,

m e t h a n e - s u l f o n i c ,

e t h a n e s u l f o n i c , b e n z e n e s u l f o n i c

a n d

l a u ry l s u l f o n i c a c i d s

a s

w e l l

a s t h e s a l t s

o f

d o b e s i l i c a c i d ( m . p . =70 C . ) and

p a r a - t o l u e n e s u l f o n i c

a c i d

( m . p . = 5 l C . ) , t h e p u r i ? c a

t i o n

o f which

proved t o b e

d i f ? c u l t .

Among h e m i n e r a l a n d

o r g a n i c

a c i d s a l t s o f t h e d e x

t r o - r o t a t o r y i s o m e r o f

t h e

compound o f F o r m u l a

( 1 4 )

s a l t s

h a v e b e e n f o u n d

which

c r y s t a l l i z e e a s i l y , a r e

n o t

h y g r o s c o p i c and a r e s u f f i c i e n t l y

w a t e r - s o l u b l e a s

t o

1 5

20

2 5

3 5

4 5

5 5

6 5

2

The p r e s e n t

i n v e n t i o n t h u s

r e l a t e s more p a r t i c u l a r l y

t o t h e h y d r o g e n

s u l f a t e ,

t h e t a u r o c h o l a t e a n d t h e h y d r o

b r o m i d e o f t h e d e x t r o - r o t a t o r y e n a n t i o m e r o f m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l ) ( 2

c h l o r o p h e n y l ) - a c e t a t e .

These

a l t s a r e

p r e p a r e d

i n

a s t a n d a r d manner by t h e

a c t i o n o f

t h e

c o r r e s p o n d i n g a c i d on t h e b a s e i n

s o l u t i o n

i n

a s o l v e n t

f r o m which

t h e y

p r e c i p i t a t e s p o n t a n e o u s l y

o r a f t e r

a d d i t i o n

of

a n o n - s o l v e n t

o f

t h e

s a l t .

The e x t r o - r o t a t o r y i s o m e r o f

m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7

t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

( 2 - c h l o r o p h e n y l ) - a c e

t a t e c a n b e p r e p a r e d by

f o r m i n g

t h e

s a l t

o f t h e r a c e m i c

compound w i t h a n

o p t i c a l l y a c t i v e a c i d i n a

s o l v e n t ,

r e p e a t e d

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

o f

t h e s a l t u n t i l a

p r o d u c t o f

c o n s t a n t o p t i c a l r o t a t o r y power i s

o b t a i n e d ,

f o l l o w e d

by

t h e l i b e r a t i o n o f t h e

d e x t r o - r o t a t o r y i s o m e r

f r o m

i t s

s a l t s by a

b a s e ; i f

r e q u i r e d , a s a l t i s

formed

between

t h e


i s o m e r a n d a p h a r ma c e u t i c a l l y a c c e p t

a b l e a c i d .

The

o p t i c a l l y

a c t i v e a c i d may a d v a n t a g e o u s l y b e

l e v o - r o t a t o r y camphor-lO-sulfonic

a c i d .

One

and

t h e

same o l v e n t ma y be u s e d f o r s a l t forma

t i o n

a n d r e c r y s t a l l i z a t i o n : a c e t o n e

i s i d e a l l y

s u i t e d i n

t h i s

c a s e .

The h i r a l , l e v o - r o t a t o r y c a m p h o r - O - s u l f o n i c a c i d o f

Formula I 1 1 )

i s allowed o

r e a c t i n a n

i n e r t

s o l v e n t w i t h

t h e r a c e m i c

m i x t u r e o f

Formula

( I )

a c c o r d i n g

t o

t h e

f o l l o w i n g

r e a c t i o n

s c h e m e :

COOCH3

N 8

+

5 C l

( 1 )

H3C CH3

i H Z

\

SO3H \

( I I I )

COOCH3

I ?

N+

5

C l

I l l a

CH3 5 0 3

HJC CH2

=0

S a l t

f o r m a t i o n m a y be c a r r i e d o u t

i n

s o l v e n t s

such

a s

a l c o h o l s ,

k e t o n e s ,

d i m e t h y l f o r m a m i d e .

T h e

s a l t

p r e c i p i

t a t e s s p o n t a n e o u s l y o r

i s

i s o l a t e d

by s a l t i n g o u t o r evap

o r a t i o n

o f

t h e s o l v e n t . A

i x t u r e o f two

d i a s t e r e o i s o


3/11

4 , 8 4 7 , 2 6 5

3

i s e n r i c h e d i n

t h e s a l t

o f


i s o m e r o f

c o m p o u n d ( I ) . A f t e r e a c h r e c r y s t a l l i z a t i o n t h e o p t i c a l

r o t a t o r y power [ ( 1 1 1 7 2 0 o f t h e p r e c i p i t a t e i s m e a s u r e d a t

2 0 C .

i n methanol a t

a c o n c e n t r a t i o n

v a r y i n g

between

1 . 5

and

2 g/ 0 0

m l .

When

h e

[ 1 1 1 1 3 2 0

s t o p s i n c r e a s i n g t h e

b a s e

o f

Formula

I D )

i s

l i b e r a t e d

f r o m

t h e

s a l t

( I I I a )

by

t h e a c t i o n o f a

b a s e such a s

sodium o r

p o t a s s i u m

hydro

gen c a r b o n a t e

i n

a q u e o u s

media a t

t e m p e r a t u r e s

v a r y

i n g b e t w e e n

5

C .

a n d

2 0 C .

E v a p o r a t i o n o f

t h e ? l t r a t e

o f t h e

? r s t

r e c r y s t a l l i z a t i o n IV f t e r t h e

c r y s t a l s

o f

t h e

p r e c i p i t a t e d s a l t ( I I I a ) h a v e b e e n ? l t e r e d o f f , g i v e s a

m i x t u r e

e n r i c h e d i n t h e s a l t o f ( I 1 ) e n a n t i o m e r .

The

b a s i ? c a t i o n

o f

t h i s m i x t u r e o f d i a s t e r e o i s o m e r i c

s a l t s

w i t h a weak a s e such a s sodium

o r

p o t a s s i u m

hydrogen

c a r b o n a t e i n a q u e o u s

s o l u t i o n

a t t e m p e r a t u r e s v a r y i n g

between 5

C .

and

2 0 C . l e a d s t o

a m i x t u r e of h e two

e n a n t i o m e r s

( 1 4 )

p l u s ( I 1 ) e n r i c h e d i n t h e l e v o - r o t a t o r y

e n a n t i o m e r ( I 1 ) .

T h i s m i x t ur e ( I d ) + ( I 1 ) e n r i c h e d i n e n a n t i o m e r ( I 1 )

i s

a l l o w e d t o

r e a c t

w i t h


c a m p h o r - l O - s u l

f o n i c a c i d which w i l l

b e d e s i g n a t e d

a s ( 1 1 . 1 ) i n

a

s o l v e n t

a c c o r d i n g t o

t h e f o l l o w i n g r e a c t i o n

s c h e m e :

CH3 S 0 3 1 1

Hsc CH2

=0

( L i )

+ I I )

( I I ) >

( L )

w i t h

( 1 ] )

( I L )

i n e x c e s s

( I I )

d e x t r o - r o t a t o r y )

COOCH3

I

N+

5 Cl

1 1 1

C H ; 5 ' 0 3

H3C CH2

The

r y s t a l l i n e

m i x t u r e

o f d i a s t e r e o i s o m e r i c s a l t s

( I I I b )

o b t a i n e d

i s

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

r o t a t o r y

power

[ 1 1 1 0 2 0

o f

t h e p r e c i p i t a t e

r e m a i n s

c o n

s t a n t .

As p r e v i o u s l y

m e n t i o n e d

t h e o p t i c a l r o t a t o r y

power [ 0 . 1 0 2 0

o f

t h e d i a s t e r e o i s o m e r i c s a l t ( I I I b ) i s d e

t e r m i n e d

a f t e r

e a c h r e c r y s t a l l i z a t i o n .

The

l i b e r a t i o n o f

t h e s t e r e o i s o me r i c ( I 1 ) f r o m i t s

s a l t

i s

c a r r i e d

o u t

i n a s t a n d a r d manner, l i k e t h a t

f o r

com

p o u n d

( I d ) .

L e v o - ro t a t o r y c o m p h o r - l O - s u l f o n i c

a c i d

( 1 1 1 ) may b e

o b t a i n e d

from c o m m e r c i a l l y

a v a i l a b l e am

L I I

2 5

3 0

3 5

4

C H 3 C H 3

S I O 3 H

H s C

C H 2 S O 3 - N H 4 E B

3 0

C H 2

( V ) ( 1 1 1 )

An

q u e o u s

s o l u t i o n

o f

t h e

ammonium a l t ( V ) i s c h r o

matographed on a n A m b e r l i t e

IRN-77

r e s i n .

A f t e r

l y

o p h i l i z a t i o n

o f t h e

e l u a t e

c a m p h o r - l O - s u l f o n i c a c i d o f

F o r m u l a ( I 1 1 )

i s

r e c o v e r e d .

The

n t i r e s e q u e n c e o f t h e p r o c e s s i s shown c h e m a t i

c a l l y b e l o w :

( I )

+

1 1 1 )

_

acetone

make

| - - - . - ' ' - - 1 a l k a l i n e ; I d ) +

I )

on)

+

Li?fPlLQYb a q u e o u s ( I I ) i n e x c e s s

NaHCO3

r e c r y s t a l l i s a t i o n

a c e t o n e + ( H 4 ) a c e t o n e

/

( 1 1 1 ) p u r e ( 1 1 1 1 , )

make l k a l i n e

w i t h r e c r y s t a l l i s a t i o n

aqueous NaHCO3 a c e t o n e

/

[E ( 1 1 1 1 , ) p u r e

d e x t r o < r o t a t o r y

e n a n t i o m e r

make

a l k a l i n e

w i t h

a q u e o u s N a l - I C O ;


e n a n t i o m e r

Each

o f t h e p u r e e n a n t i o m e r s ( I d )

a n d

( 1 ; ) may b e

c o n v e r t e d

i n t o a s a l t by

means o f

t h e s t a n d a r d methods:

f o r

e x a m p l e ,

t h e

h y d r o c h l o r i d e s

a r e p r e p a r e d b y t h e

a d d i t i o n o f a s o l u t i o n o f hydrogen c h l o r i d e g a s i n d i

e t h y l e t h e r t o a

s o l u t i o n

o f ( 1 4 ) o r ( I 1 ) i n

d i e t h y l

e t h e r .

DETERMINATION OF THE ENANTIOMERIC

P U RIT Y

OF

THE

DEXTRO-ROTATORY

1 4 ) AND

LEVO-ROTATORY I 1 ) ENANTIOMERS

Two

methods have

b e e n u s e d :

p r o t o n NMR p e c t r o s c o p y

w i t h

t h e a d d i t i o n o f

a

c h i r a l r a r e e a r t h

h i g h

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

s t a t i o n a r y

p h a s e .

( a ) P r o t o n

NMR p e c t r o s c o p y w i t h t h e

a d d i t i o n

o f

a

c h i r a l r a r e e a r t h

The

e n a n t i o m e r i c p u r i t y

( o p t i c a l

pu

r i t y ) was d e t e r m i n e d by 1H

6 0

MHz

NMR

p e c t r o s

copy i n t h e p r e s e n c e o f a r a r e e a r t h c h i r a l complex

a c c o r d i n g t o t h e method d e s c r i b e d by G . M. WHITE

SIDES e t a l .

( J .

Am. Chem. S o c . 1 9 7 4 7 9 6 ,

1 0 3 8 ) .

I n t h e

r a c e m i c p r o d u c t

( I ) ,

t h e

h y d r o g e n

a t t a c h e d

t o

t h e

asymmetric

c e n t r e

i n

t h e

a . p o s i t i o n

t o t h e

e s t e r

f u n c t i o n a p p e a r s a s a s i n g l e t ( c h e m i c a l s h i f t 8:4.87


4/11

4 , 8 4 7 , 2 6 5

5

t h y 1 e n e ) - d - c a m p h o r a t o e u r o p i u m

( 1 1 1 ) ] t o

t h e p r o b e

c o n t a i n i n g a s o l u t i o n o f t h e r a c e m a t e

( I )

i n CDC13 e a d s

t o t h e r e s o l u t i o n

o f

t h e i n i t i a l

s i n g l e t

i n t o t w o ,

w e l l

s e p a r a t e d

s i n g l e t s

c o r r e s p o n d i n g t o

t h e p r o t o n o f e a c h

o f t h e

two

e n a n t i o m e r s ( I d ) a n d ( 1 1 ) .

When

t h e m o l a r

r a t i o

o f

r a r e e a r t h complex/compound ( I ) = 0 . 4 , t h e

s e p a r a t i o n

b e t w e e n t h e two

s i n g l e t s

i s a b o u t 6 H z .

With

e a c h

o f t h e

two e n a n t i o m e r s

p r e p a r e d , ( I d )

a n d

( 1 1 ) ,

t h e

same procedure was u s e d a s f o r

t h e

racemate

( I ) .

The

s m a l l e r

c h e m i c a l

s h i f t

c o r r e s p o n d s

t o t h e p r o

ton

o f t h e d e x t r o - r o t a t o r y

e n a n t i o m e r ( I d )

a n d

t h e

l a r g e r c h e m i c a l s h i f t t o

t h e

l e v o - r o t a t o r y e n a n t i o m e r

( 1 1 )

The

r e c i s i o n

o f

t h e method was d e t e r m i n e d by c o m

p a r i n g t h e 1 H

( 6 0

MHz) NMR p e c t r a o b t a i n e d w i t h

and

w i t h o u t a d d i t i o n o f

t h e

r a re e a r t h

complex f o r

e a c h

o f t h e t w o . e n a n t i o m e r s ( I d ) a n d ( I 1 ) i n t h e

p u r e

s t a t e o r

a s m i x t u r e s

c o n t a i n i n g

i n c r e a s i n g q u a n t i t i e s o f o n e o f

t h e

e n a n t i o m e r s . I t

was

o b s e r v e d

t h a t i t

was p o s s i b l e t o

d e t e c t

e a s i l y

more

t h a n 5%

by

w e i g h t o f

o n e

e n a n t i o

mer i n t h e p r e s e n c e o f t h e o t h e r .

( b )

H i g h

p r e s s u r e

l i q u i d

c h r o m a t o g r a p h y

u s i n g a

c h i r a l

s t a t i o n a r y

p h a s e

The

t u d y

was c o n d u c t e d w i t h a

l i q u i d c h r o m a t o g r a p h HP-1084

u s i n g

a

UV e t e c t o r

a t

2 1 5

nm. The

c h i r a l

s t a t i o n a r y p h a s e

was

DEAE i l i c a

( 1 0 m i c r o n s )

o n t o

w h i c h w a s g r a ft e d a l p h a - l a c i d g l y

c o p r o t e i n ( 0 . 4 x 1 0 0 mm) (ENANTIOPAC

R - L K B ) .

The m o bi l e p h a s e c o n s i s t e d

o f a n a q u e o u s

p h o s p h a t e

b u f f e r

m i x t u r e 8 mM NaH2PO4/Na2HPO4) o n t a i n i n g

0 . 1 M o f N a C l , a d j u s t e d t o p H = 7 . 4 , a n d 15% o f i s o p r o

p a n o l

( v / v ) . The f l o w r a t e

was ?xed a t

0 . 3 ml/minute

and

t h e t e m p e r a t u r e

o f

t h e

column

was m a i n t a i n e d a t

1 8 - 2 0 C . U n d e r t h e s e

c o n d i t i o n s , t h e


e n a n t i o m e r ( I d )

h a s a

r e t e n t i o n

t i m e o f 4 5

m i n u t e s and

t h e l e v o - r o t a t o ry

e n a n t i o m e r

( I 1 )

h a s

a r e t e n t i o n

t i m e o f

3 5 m i n u t e s .

The p r e c i s i o n o f

t h e

d e t e r m i n a t i o n o f

t h e o p t i c a l

p u r i t y o f t h e two e n a n t i o m e r s was e s t i m a t e d by

c h r o m a t o g r a p h i n g e a c h o f t h e two e n a n t i o m e r s ( I d ) a n d

( 1 1 )

p r e p a r e d

e i t h e r a l o n e o r a s a

m i x t u r e

c o n t a i n i n g

i n c r e a s i n g

amounts o f one o f

t h e

e n a n t i o m e r s . I t was

observed

t h a t i t

was e a s y t o

d e t e c t :

2%

w e i g h t / w e i g h t ) o f e n a n t i o m e r ( L 1 )

i n

e n a n t i o m e r

( I 1 )

4 % w e i g h t / e i g h t ) o f

e n a n t i o m e r

( 1 1 ) i n

e n a n t i o m e r

( I d )

Under

t h e s e

c o n d i t i o n s i t

may be c o n c l u d e d t h a t t h e

o p t i c a l

p u r i t y o f

t h e

two e n a n t i o m e r s ( I d ) a n d ( 1 ; ) o b

t a i n e d

a c c o r d i n g

t o t h e e x a m p l e s

i s

a t

l e a s t

e q u a l t o 96%

f o r t h e d e x t r o - r o t a t o r y

e n a n t i o m e r

( I d ) a n d a t

l e a s t

e q u a l t o 98% f o r t h e l e v o - r o t a t o ry e n a n t i o m e r

( I 1 ) .

The

f o l l o w i n g

e x a m p l e s a r e n o n - r e s t r i c t i v e and a r e

p r e s e n t e d

t o i l l u s t r a t e t h e p r e s e n t i n v e n t i o n .

EXAMPLE

S a l t s

o f d e x t r o - r o t a r y

m e t h y l - a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

(2-chl orop heny l)-acetate

( a )

l e v o - r o t a t o r y c a m p h o r - l O - s u l f o n i c a c i d

A

olumn

o f

A m b e r l i t e IRN-77 r e s i n

i s p r e p a r e d

a n d

t e s t e d

b y

p a s s i n g 1N h y d r o c h l o r i c a c i d t h r o u g h i t a n d

t h e n

by

w a s h i n g

t h i s column

o f

a c i d i ? e d r e s i n

a b u n

d a n t l y

w i t h

w a t e r .

L e v o - r o t a t o r y

ammonium

c a m p h o r

1 0 - s u l f o n a t e

i s d i s s o l v e d i n a minimum o f water and

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

2 0

2 5

3 5

4 5

5 5

6 5

6

W h i t e c r y s t a l s , m.p.= 1 9 8

( c = 2 . 0 7 5 g / 1 0 0 m l w a t e r ) .

( b )

C a m p h o r - l O - s u l f o n i c

a c i d s a l t o f m e t h y l a l p h a

5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o

p y r i d y l ) ( 2 - c h l o r o

p h e n y l ) - a c e t a t e ( S R

2 5 9 9 0 B ) .

3 2

g

( 0 . 0 9 9 4

m o l e )

o f

r a c e m i c m e t h y l a l p h a - 5 ( 4 , 5 , 6 , 7

t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l ) ( 2 - c h l o r o p h e n y l ) - a c e

t a t e a r e d i s s o l v e d i n

1 5 0 ml

o f a c e t o n e . 9 . 9 5 g

( 0 . 0 3 9 7

m o l e ) o f l e v o - r o t a t c a m p h o r - l O - s u l f o n i c

a c i d

monohy

d r a t e

a r e a d d e d . T h e c l e a r s o l u t i o n i s l e f t t o s t a n d

a t

r o o m t e m p e r a t u r e .

A f t e r

4 8

h o u r s

some c r y s t a l s have

f o r m e d . The

r e a c t i o n

m i x t u r e i s c o n c e n t r a t e d

t o

5 0 ml

and e f t

t o s t a n d

a t r o o m e m p e r a t u r e f o r 24

h o u r s .

The

c r y s t a l s o b t a i n e d

a r e

f i l t e r e d o f f , washed w i t h

a c e t o n e

and d r i e d

( y i e l d :

55% on

t h e b a s i s o f t h e

s t a r t i n g

r a c e

m a t e ) .

W h i t e c r y s t a l s ,

m.p.= 1 6 5

( c =

1 . 5 8 g /

1 0 0 m l ; m e t h a n o l ) .

The c r y s t a l s

o b t a i n e d

above a r e

r e d i s s o l v e d

i n

t h e

minimum o f

b o i l i n g a c e t o n e ( 5 0 m l ) . The c r y s t a l s o b

t a i n e d

a f t e r c o o l i n g

a r e

? l t e r e d

o f f , washed

w i t h

a c e - 1

t o n e a n d

d r i e d

( y i e l d :

8 8 % ) .

White c r y s t a l s ,

m.p.=

1 6 5

( 0 : 1 . 6 8

g / 1 0 0

m l ;

m e t h a n o l ) .

( c ) D e x t r o - r o t a t o r y

m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y

d r o ( 3 , 2 - c ) t h i e n o p y r i d y l ) ( 2 - c h l o r o p h e n y l ) - a c e t a t e .

1 2 g

( 0 . 0 2 2 m o l e ) o f

t h e p u r e

p r o d u c t

o b t a i n e d i n ( b )

a r e d i s s o l v e d

i n

a m i n i mu m

o f

w a t e r . A f t e r c o o l i n g

t o 5

C . ,

t h e a q u e o u s

s o l u t i o n

o b t a i n e d

i s

made a l k a l i n e

w i t h

a s a t u r a t e d aqueous

s o l u t i o n o f

sodium

hydrogen

c a r

b o n a t e . The

a l k a l i n e a q u e o u s

p h a s e i s e x t r a c t e d w i t h

d i c h l o r o m e t h a n e . T h e

o r g a n i c

e x t r a c t s

a r e

d r i e d over

a n h y d r o u s s o d i u m s u l f a t e . On e v a p o r a t i o n

o f t h e s o l

v e n t a c o l o r l e s s o i l i s o b t a i n e d ( q u a n t i t a t i v e y i e l d ) . O i l ,

[ a ] D 2 =

+ 5 1 . 5 2 ( c =

1 . 6 1

g / l 0 0 m l ;

m e t h a n o l ) .

( d )

T h e

h y d r o c h l o r i d e o f

m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t

r a h y d r o ( 3 , 2 - c ) t h i e n o

p y r i d y l )

( 2 - c h l o r o p h e n y l ) - a c e t a t e

( d e x t r o - r o t a t o r y )

( S R 2 5 9 9 0 A ) .

7

g

( 0 . 0 2 2 8 m o l e ) o f d e x t r o - r o t a t o r y

m e t h y l

a l p h a

5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

( 2 - c h l o r o

p h e n y l ) - a c e t a t e

a r e

d i s s o l v e d i n

1 0 0

ml o f

d i e t h y l e t h e r .

3 0 ml

o f

a s o l u t i o n o f 1N HCl n d i e t h y l e t h e r a re added

a n d t h e

c r y s t a l s

o b t a i n e d a r e ? l t e r e d

o f f . The c r y s t a l s

a r e

washed

w i t h d i e t h y l

e t h e r and d r i e d ( y i e l d :

9 4 % ) .

W h i t e

c r y s t a l s ,

m . p . = l 1 7

C . , [ a ] D 2 = +6223

( c =

1 . 8 2

g / 1 0 0 m l ; m e t h a n o l ) .

( e )

The

h y d r o g e n

s u l f a t e

o f d e x t r o - r o t a t o r y m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o

p y r i d y l ) ( 2

c h l o r o p h e n y D - a c e t a t e ( S R 2 5 9 9 0 C ) .

8 0 0

ml

o f

a s a t u r a t e d

aqueous

s o l u t i o n

o f

sodium

b i c a r b o n a t e a r e

added t o a

s u s p e n s i o n

o f

200

g o f

SR

2 5 9 9 0

B

i n 8 0 0 ml o f d i c h l o r o m e t h a n e .

A f t e r

v i g o r o u s

s h a k i n g , t h e

o r g a n i c p h a s e i s

s e p a r a t e d , d r i e d o v e r s o

dium s u l f a t e and t h e s o l v e n t i s removed under reduced

p r e s s u r e .

The

r e s i d u e i s d i s s o l v e d i n

5 0 0

ml o f i c e - c o l d

a c e t o n e and 2 0 . 7 ml

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

( 9 3 . 6 4 % , d =

. 8 3 )

a r e a d d e d d r o p - w i s e . The r e c i p i t a t e

f o r m e d i s i s o l a t e d by

? l t r a t i o n

a n d washed w i t h

1 , 0 0 0

m l

of

a c e t o n e , then d r i e d i n a vacuum oven a t 5 0

C .

1 3 9 grams

o f

a n a l y t i c a l l y p u r e w h i t e c r y s t a l s a r e

t h u s

o b t a i n e d

w i t h

a

m e l t i n g

p o i n t o f 1 8 4 C . E m p i r i c a l

f o r m u l a : C16H16ClNO2S.H2SO4 [ 0 . ] ; 3 2 0 :

+ 5 . 1 0

( c = 1 . 8 9 1 g / 1 0 0 m l ; m e t h a n o l ) .

( f ) T h e

h y d r o b r o m i d e

o f


m e t h y l

a l

p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l ) ( 2

c h l o r o p h e n y l ) - a c e t a t e

( S R 2 5 9 9 0 D ) .

c . ,

[ a ] D 2 0 =

+ 2 4 . 6 7

c . , MDZO: +2415


5/11

4 , 8 4 7 , 2 6 5

7

ml o f

d i c h l o r o m e t h a n e .

The

r e s i d u e o b t a i n e d

a f t e r

s e p a

r a t i o n o f t h e o r g a n i c

p h a s e ,

d r y i n g a n d e v a p o r a t i o n

o f

t h e s o l v e n t

i s

d i s s o l v e d i n

1 5 0

ml o f d i e t h y l o r d i i s o p r o

p y l

e t h e r , a n d

4 . 4

ml o f

a

48% ( w t / v ) a q u e o u s s o l u t i o n

o f hydrobromic

a c i d a r e added

d r o p - w i s e .

The

r e c i p i

t a t e

formed

i s i s o l a t e d .

After

d r y i n g ,

1 4 . 4 g of c r y s t a l s

a r e o b t a i n e d

w i t h

a m e l t i n g p o i n t

o f

1 1 1 C .

( y i e l d

9 9 % ) .

1 3 . 4 g o f t h e s e c r y s t a l s

a r e r e c r y s t a l l i z e d from a

mix

t u r e

o f i s o p r o p y l

e t h e r

( 1 0 0 m l )

a n d i s o p r o p a n o l

( 1 5 0

m l ) t o g i v e 1 0 . 2

g

o f a n a l y t i c a l l y p u r e h y d r o b r o m i d e :

m . p . = l 4 0 C . ;

e m p i r i c a l f o r m u l a : C 1 6 H 1 6 C l N O 2 S . H B r

[ a ] D 2 = +5923 ( c = 2 . 0 9 g / 0 0 m l ; m e t h a n o l ) .

( g ) The t a u r o c h o l a t e o f

d e x t r o - r o t a t o r y m e t h y l a l =

p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l ) ( 2

c h l o r o p h e n y l ) - a c e t a t e

( S R

2 5 9 9 0 E ) .

The

sodium

s a l t

o f t a u r o c h o l i c a c i d

i s

chromato

g r a p h e d on

A m b e r l i t e

IRN-77 r e s i n by

e l u t i n g w i t h

w a t e r . The

f r a c t i o n s

o b t a i n e d a r e l y o p h i l i z e d .

3 g ( 0 . 0 0 5 4 m o l e ) o f SR 25990B

a r e

t r e a t e d with a

s a t u r a t e d

a q u e o u s

s o l u t i o n

o f

sodium

b i c a r b o n a t e

a n d

t h e m i x t u r e i s e x t r a c t e d

w i t h

d i c h l o r o m e t h a n e .

The

o r g a n i c p h a s e i s s e p a r a t e d ,

d r i e d

o v e r

s o d i u m

s u l f a t e

a n d

e v a p o r a t e d

t o d r y n e s s .

The

f r e e b a s e o b t a i n e d

i s

t a k e n

u p i n

3 0 ml

o f i s o p r o p a n o l ; 2 . 8 g ( 0 . 0 0 5 4 m o l e ) o f

t a u r o c h o l i c

a c i d

d i s s o l v e d

i n

1 0 0 ml o f i s o p r o p a n o l

a r e

a d d e d t o t h i s s o l u t i o n . The m i x t u r e

i s

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

a t r o o m t e m p e r a t u r e ,

t h e n

e v a p o r a t e d t o d r y n e s s . The

r e s i d u e

s o l i d i f e d on

b e i n g

t r i t u r a t e d

w i t h

e t h e r .

3 . 5

g

o f

b e i g e c r y s t a l s a r e o bt a i n e d .

m.p.=

1 2 0 C .

[ a ] D 2 + = 3 9 . 5 3

( c = 1 . 7 9 l g / 1 0 0 m l o f m e t h a n o l ) .

C 1 6 H 1 6 C l N O 2 S . C z 6 H 4 5 N O 7 S ; C , H , N

a n a l y s e s

i n

a g r e e m e n t w i t h t h e o r y .

EXAMPLE

S a l t s

o f l e v o - r o t a t o r y

m e t h y l


p y r i d y l )


( a )

S a l t

o f d - c a m p h o r - l O - s u l f o n i c a c i d ( S R

2 5 9 8 9 B )

A f t e r

s e p a r a t i o n

o f SR

2 5 9 9 0 B

i n Example

l - b t h e

s o l v e n t

i s e v a p o r a t e d

f r o m

t h e

a c e t o n e ? l t r a t e o b t a i n e d .

The r e s i d u e

i s

t a k e n up i n w a t e r and

d i e t h y l

e t h e r .

The e t h e r e a l p h a s e i s d e c a n t e d . The a q u e o u s p h a s e

i s

c o o l e d

t o 5 C . and

made

l k a l i n e

with

a s a t u r a t e d a q u e

o u s s o l u t i o n

of

sodium b i c a r b o n a t e .

The

aqueous a l k a

l i n e p h a s e

i s e x t r a c t e d w i t h d i e t h y l

e t h e r . The

e t h e r e a l

e x t r a c t s a r e

pooled and d r i e d over

anhydrous sod ium

s u l f a t e .

On e v a p o r a t i o n o f t h e s o l v e n t a n o i l

i s

o b t a i n e d

w h i c h - i s p u r i ? e d b y ? l t r a t i o n t h r o u g h a b e d o f s i l i c a

( e l u a n t :

d i e t h y l

e t h e r ) .

A o l o u r l e s s

o i l i s

r e c o v e r e d

c o n s i s t i n g o f

a m i x t u r e

o f a b o u t 65%

o f t h e l e v o - r ot a

t o r y

e n a n t i o m e r and 35%

o f t h e d e x t r o - r o t a t o r y

e n a n

t i o m e r ,

p r o p o r t i o n s d e t e r m i n e d

b y m e a n s

o f 1 H ( 6 0

MHz) NMR

p e c t r o s c o p y

a f t e r

t h e a d d i t i o n

o f

c h i r a l ,

r a re e a r t h c o m p l e x .

1 6 . 6 6 g

( 0 . 0 5 1 7

m o l e )

o f t h e m i x t u r e

t h u s o b t a i n e d

a r e

d i s s o l v e d

i n 7 0

ml

o f

a c e t o n e . 7 . 7 7 g ( 0 . 0 3 1 0 m o l e ) o f


c a m p h o r - I O - s u l f o n i c

a c i d

m o n o h y d r a t e

a r e a d d e d .

The

homogeneous

m i x t u r e

i s

l e f t t o

s t a n d

o v e r n i g h t a t room

t e m p e r a t u r e .

The c r y s t a l s o b t a i n e d

a r e ? l t e r e d o f f , washed

w i t h

a c e t o n e and d r i e d

( y i e l d :

44% b a s e d

on t h e m i x t u r e ) .

The

c r y s t a l s o b t a i n e d

a r e

d i s s o l v e d i n a minimum of

2 0

3 5

6 0

6 5

8

a c e t o n e and d r i e d .

White

c r y s t a l s , m.p.= 1 6 7 C . ,

[ a ] D 2 0 = 2 4 . 8 5 ( c : 1 . 7 9 g / 1 0 0

m l ;

m e t h a n o l ) .

( b ) L e v o - r o t a t o r y m e t h y l a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y

d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

( 2 - c h l o r o p h e n y l ) - a c e t a t e .

1 1 . 3

g

( 0 . 0 2 0 4 m o l e ) o f

t h e c a m p h o r - I O - s u l f o n a t e

obtained

n

( a )

are dissolved i n a minimum

f

water. The

aqueous

s o l u t i o n

o b t a i n e d i s cooled t o 5

C .

and made

a l k a l i n e with a s a t u r a t e d

aqueous

s o l u t i o n o f

sodium

h y d r o g e n c a r b o n a t e . The a l k a l i n e a q u e o u s p h a s e i s

e x t r a c t e d

w i t h d i c h l o r o m e t h a n e .

The

o r g a n i c

s o l u t i o n

i s d r i e d and h e s o l v e n t i s e v a p o r a t e d . A o l o u r l e s s

o i l

i s

i s o l a t e d

( q u a n t i t a t i v e

y i e l d ) .

O i l [ a ] D 2 = 5 0 . 7 4

( c :

1 . 5 8 g / 1 0 0 m l ; m e t h a n o l ) .

( 0 )

T h e h y d r o c h l o r i d e o f l e v o - r o t a t o r y m e t h y l a l p h a

5 ( 4 , 5 , 6 , 7 t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

( 2 - c h l o r o

p h e n y l ) - a c e t a t e ( S R 2 5 9 8 9 A ) .

P r e p a r e d a c c o r d i n g t o t h e

method

d e s c r i b e d i n Ex

a m p l e 1 ( d ) . Y i e l d :

9 4 % .

W h i t e c r y s t a l s , m . p . = 1 1 7

( c : 1 . 8 0

g / 1 0 0

m l ;

m e t h a n o l ) .

( d )

The h y d r o g e n s u l f a t e o f l e v o - r o t a t o r y m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

( 2

c h l o r o p h e n y l ) - a c e t a t e ( S R

2 5 9 8 9 C ) .

7 0

g

( 0 . 1 2 6 m o l e )

o f t h e camphor s u l f o n a t e

SR

2 5 9 8 9

B b t a i n e d a r e t r e a t e d

a s

d e s c r i b e d i n ( a )

above

with a

s a t u r a t e d a q u e o u s

s o l u t i o n

o f

sodium b i c a r b o n a t e i n

t h e

p r e s e n c e

o f

d i c h l o r o m e t h a n e . The

o r g a n i c p h a s e

i s

s e p a r a t e d ,

d r i e d

o v e r

sodium s u l f a t e

and e v a p o r a t e d t o

d r y n e s s .

The

r e s i d u e

i s

t a k e n up

i n 3 0 0

ml o f a c e t o n e

a n d

7 . 2

ml

0 . 1 2 6 m o l e )

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 a r e

a d d e d d r o p - w i s e .

A f t e r b e i n g

s t i r r e d t h e c r y s t a l s

formed a r e ? l t e r e d o f f and washed with a c e t o n e . 4 7 . 8 g

o f w h i t e

c r y s t a l s

a r e o b t a i n e d . m.p.= 1 8 2

C .

Mb: - 5 1 . 6 1 ( c = 2 . 0 4 4 g / 1 0 0 m l ; m e t h a n o l ) . The

a n a l y s i s ( C , H , N ) a r e i n a g r e e m e n t w i t h t h e o r y .

PHARMACOLOGICAL STUDY

T h e p l a t e l e t a g g r e g a t i o n i n h i b i t i n g a c t i v i t y a n d

t h e

t o x i c i t y o f t h e s e new

compounds

were compared t o

t h o s e

o f t h e r a c e m i c m i x t u r e

d e s c r i b e d i n t h e

French

P a t .

N o . 8 2 . 1 2 5 9 9 ( P u b l i c a t i o n N o . 2 5 3 0 2 4 7 ) .

A e s c r i p t i o n w i l l n ow be g i v e n o f t h e

r e s u l t s

o f t h i s

s t u d y w h i c h d e m o n s t r a t e s a n o t h e r a d v a n t a g e o f t h e

i n v e n t i o n , n a m e l y t h a t t h e

s a l t s

o f t h e


i s o m e r have a b e t t e r t h e r a p e u t i c

i n d e x

t h a n t h e s a l t

o f

t h e r a c e m i c m i x t u r e ;

i n

f a c t ,

t h e l e v o - r o t a t o r y

i s o m e r

e x h i b i t s a l m o s t

n o

p l a t e l e t


i n h i b i t i n g a c t i v

i t y

a n d i t s t o x i c i t y i s m a r k e d l y h i g h e r

t h a n

t h a t

o f

i t s


h o m o l o g u e .

The

l a t e l e t


i n h i b i t i n g

a c t i v i t i e s

a n d

t h e

. a n t i t h r o m b o t i c a c t i v i t i e s

o f

t h e compounds were s t u d

i e d i n

t h e

r a t by s t a n d a r d m e t h o d s .

The c t i v i t y

o n

t h e


o f p l a t e s i n d u c e d b y

ADP r c o l l a g e n was

determined

e x - v i v o .

The p r o d u c t s d i s s o l v e d

i n e t h a n o l

( 2 0 0 m g / m l )

a n d

d i l u t e d

i n w a t e r c o n t a i n i n g gum r a b i c (5%-wt/v) were

a d m i n i s t e r e d

by

t h e

o r a l

r o u t e

t o

groups o f

?ve f e m a l e

r a t s o f

t h e CD COBS t r a i n , w e i g h i n g

2 5 0 - 3 0 0

g ,

i n

amounts o f 1 0

ml

o f s u s p e n s i o n p e r

k i l o g r a m

two h o u r s

b e f o r e b l o o d

s a m p l e s

were t a k e n .

The b l o o d s a m p l e s were

t a k e n

from a n i m a l s a n e s t h e

t i z e d w i t h d i e t h y l o t h e r by p u n c t u r e o f t h e a b d o m i n a l

a o r t a and placed

over

a 3.8%

aqueous

s o l u t i o n of

s o

dium

c i t r a t e

( 1

v o l /

9

v o l u m e s

o f

b l o o d ) .

The

p l a t e l e t

r i c h

p l a s m a

was t h e n i s o l a t e d by c e n t r i f u g a t i o n a t

2 0 0

g

f o r 1 0 m i n u t e s .


6/11

4 , 8 4 7 , 2 6 5

9

The

a g g r e g a t i n g

s o l u t i o n s

u s e d

w e r e : a

5 0 0

uM q u e o u s

s o l u t i o n

o f

ADP

m a r k e t e d b y

B o e h r i n g e r

Mannheim

( ? n a l

c o n c e n t r a t i o n 2 . 5 u M ) , a n d

a s o l u t i o n

o f c o l l a g e n

m a r k e t e d by Sigma

( t y p e 1 ) a t a

c o n c e n t r a t i o n o f

0 . 2 5

g /

1 0 0 m l i n

3 %

a c e t i c a c i d ( v / v )

( ? n a l

c o n c e n t r a t i o n

1 2 . 5 u g / m l ) .

The a g g r e g a t i o n o f t h e p l a t e l e t s was m o n i t o r e d

a s

d e s c r i b e d

i n

t h e

method by

G. V.

R .

Born

i n

N a t u r e

1 9 4 , p . 9 2 7 ( 1 9 6 7 ) u s i n g a C o u l t r o n i c s

g g r e g o m e t e r

a t a

t e m p e r a t u r e

o f 3 7 C . and a g i t a t i o n o f 9 0 0

r p m .

F o r

a g g r e g a t i o n w i t h

ADP,

h e a g g r e g o m e t e r g e n e r

a t e s a curve r e p r e s e n t i n g a p l a t e l e t aggregation a s mea

s u r e d b y a

c h a n g e i n

o p t i c a l d e n s i t y . The

h e i g h t o f t h i s

c u r v e i s

de?ned

a s t h e h e i g h t

o f a g g r e g a t i o n .

The p e r

c e n t a g e

o f a g g r e g a t i o n

i s t h e

r e l a t i o n

b e t w e e n t h e

a g

g r e g at i o n h e i g h t m e a s u r e d a n d t h e h e i g h t c o r r e s p o n d

i n g

t o

100% a g g r e g a t i o n X

1 0 0 .

The p e r c e n t a g e o f i n h i

b i t i o n

i s d e t e r m i n e d by t h e r e l a t i o n :

C o n t r o l a g g r e g a t i o n h e i g h t

2 0

The r e s u l t s

o b t a i n e d

f o r t h e


w i t h

ADP

f o r

t h e h y d r o c h l o r i d e

o f t h e r a c e m i c m i x t u r e (PCR

4 0 9 9 ) ,

t h e

h y d r o g e n

s u l f a t e s o f

t h e d e x t r o - r o t a t o r y ( S R

2 5 9 9 0 C ) a n d l e v o - r o t a t o r y (SR 5 9 8 9

C )

i s o m e r s on

h e

o n e h a n d , a n d

f o r

PCR

0 9 9

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

t h e


( S R 2 5 9 9 0

A )

a n d l e v o - r o t a t o r y

(SR

2 5 9 8 9

A)

on

t h e

o t h e r , a r e shown n

T a b l e

I ;

t h e y

d e m o n s t r a t e

t h a t

t h e l e v o - r o t a t o r y i s o m e r

i s

i n a c t i v e

and

t h a t


i s o m e r i s

a t l e a s t a s a c t i v e

a s

the

racemate.

TABLE

DOSE QUANTITY

%

IN

PRO-

mg /K g

o f b a s e

I - I I B I

DUCT

P.O a d m i n i s t e r e d TION

P

% AGGRE

GATION

C o n t r o l s

4 2 . 4 +/ . 5

PCR

0 9 9

4 . 4 8 3 . 8 4 2 9 . 8 +/ . 4 3 0 0 . 0 1

( r a c e m a t e )

8 . 9 7 7 . 6 9 1 7 . 2

+/

. 2 5 9 0 . 0 0 1

1 7 . 9

1 5 . 3 8 1 1 . 1 +/-

. 3 7 4

0 . 0 0 1

SR

25989C

20 1 5 . 3 8

4 1 . 0

+/

. 5

3

n . s

40

3 0 . 7 6 3 7 . 1 +/

. 7 1 3 n . s

SR 25990C 1 . 2 5 0 . 9 6

3 9 . 4 +/

. 3

7

n . s

2 . 5 1 . 9 2

2 8 . 4

+/ . 3 3 3

0 . 0 1

5 3 . 8 4 1 4 . 0

+/

. 6

6 7

0 . 0 0 1

1 0 7 . 6 9 8 . 5

+/

1 . 6 8 0 0 . 0 0 1

C o n t r o l s

3 3 . 8 +/ . 3

SR 25990E 1 0 3 . 8 4 9 . 6

+/

7 2 0 . 0 0 1

2 0

7 . 6 9 4 +/ . 6 8 8 0 . 0 0 1

AGGREGA

TION

HEIGHT

C o n t r o l s 1 0 3 +/

PCR

0 9 9 2 . 5

2 . 1 4

8 6 +/ 1 7 0 . 0 5

( r a c e m a t e ) 5

4 . 2 8

7 2 +/ 3 0

0 . 0 5

1 2 . 5 1 0 . 7 1 3 2 +/

6 9

0 . 0 0 1

SR

25989A 2 5 2 2 . 4 6

1 0 1 +/

2

n . s

SR

25990A

2 . 5

2 . 2 5

6 7

+/ 3 5

0 . 0 1

5 4 . 4 9

2 6

+/ 7 5 0 . 0 0 1

1 2 . 5

1 1 . 2 3 1 9 +/-

4

8 2 0 . 0 0 1

2 5

2 2 . 4 6 1 1 +/ 8 9

0 . 0 0 1

mean

o f

r e s u l t s +/ s t a n d a r d

e r r o r o f t h e mean (SEM)

Student

t e s t

'aggregation h e i g h t i n

m m :

mean +/- SEM n = )

n . s .

n o t s i g n i ? c a n t

F o r

t h e

a g g r e g a t i o n w i t h

c o l l a g e n ,

t h e

p e r c e n t a g e

o f

i n h i b i t i o n

i s t h e

d i f f e r e n c e

o f t h e s l o p e s o f t h e c u r v e s

r e p r e s e n t i n g

t h e

v a r i a t i o n o f

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

3 5

4 5

5 0

5 5

6 5

1 0

1 0 0 . The

r e s u l t s

shown

i n T a b l e

I I d e m o n s t r a t e a g a i n

t h a t o n l y

t h e

d e x t r o - r o t a t o r y i s o m e r i s

a c t i v e w h e r e a s

t h e s a l t s h a v e c o m p a r a b l e a c t i v i t i e s .

TABLE I

QUAN

DOSE TIT Y % IN

PRO- m g / K g o f

b a s e

a d -

I - I I B I

DUCT

R0

m i n i s t e r e d

SLOPE TION

P

Controls _ 4 . 8 +/ . 3

PCR

0 9 9

4 . 4 8 3 . 8 4 3 . 6

+/ . 2 2 5

0 . 0 5

( r a c e m a t e )

8 . 9 7 7 . 6 9 2 . 7 +/ . 3 4 4 0 . 0 1

1 7 . 9

1 5 . 3 8 1 . 5 +/- . 3

6 9

0 . 0 0 1

SR

25989C 2 0

1 5 . 3 8 4 . 3 +/- . 2 1 0 n . s

4 0 3 0 . 7 6 4 . 0

+/

. 2

1 7 n . s

SR 25990C 1 . 2 5 0 . 9 6 4 . 5

+/

. 3

6

n . s

2 . 5 1 . 9 2 4 . 1 +/ . 2 1 5

n . s

5

3 . 8 4

2 . 3 +/ . 1 5 2

0 . 0 0 1

1 0

7 . 6 9 1 . 7 +/

. 3 6 5 0 . 0 0 1

C o n t r o l s

3 . 5

+/ . 1

SR

25990E 1 0 3 . 8 4 2 . 1 +/

. 5

4 0 0 . 0 5

2 0 7 . 6 9 1 . 4

+/-

0 . 4 6 0

0 . 0 1

C o n t r o l s 3 . 9 7 +/

. 2 9

PCR

099 2 . 5

2 . 1 4 3 . 1 3 +/ . 3 3 2 1

n . s

( r a c e m a t e ) 5

4 . 2 8

2 . 9 4 +/ . 3 4

2 6

0 . 0 5

1 2 . 5 1 0 . 7 1

2 . 1 9

+/ . 4 2 4 5 0 . 0 1

SR

5 9 8 9 . 4 2 5 2 2 . 4 6 4 . 3 2

+/ . 2 9 1 0

n . s

SR

25990A

2 . 5 2 . 2 5

3 . 0 5 +/-

. 1 9

2 3

0 . 0 5

5

4 . 4 9

1 . 2 4 +/

. 2 2

6 9

0 . 0 0 1

1 2 . 5 1 1 . 2 3

0 . 8 6 +/

. 1 4

7 8 0 . 0 0 1

2 5

2 2 . 4 6 0 . 7 4 +/ . 1 3 8 1 0 . 0 0 1

Student t e s t

n . s . n o t s i g n i ? c a n t

The

a n t i t h r o m b o t i c

a c t i v i t y o f t h e s e compounds

h a s

a l s o

been s t u d i e d

i n

t h e t e s t of venous thrombosis o n a

screw t h r e a d d e s c r i b e d by Kumada .

e t

a l . i n

Throm b.

Res

1 8 p .

1 8 9 ( 1 9 8 0 ) .

Female

r a t s o f t h e

same

t y p e a s

t h o s e p r e v i o u s l y

d e s c r i b e d , i n g r o u p s o f

1 0

a n i m a l s , were

a n e s t h e t i z e d

with

d i e t h y l e t h e r

and

h e i r

vena

cava

was

s o l a t e d

a f t e r

a b d o m i n a l i n c i s i o n .

A

e t a l l i c

screw t h r e a d 2 1 mm o n g

c o n s i s t i n g o f

a

d e n t i s t s

d r i l l , m a r k e t e d b y Dyna

( F r a n c e ) s i z e

N o . 3 0 ,

was i n t r o d u c e d

i n t o

t h e lumen o f

t h i s v e i n j u s t

below

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

w i t h o u t damaging h e

w a l l ; 1 9

t o 2 0 mm f t h e l e n g t h o f

t h e screw t h r e a d a r e

i m p l a n t e d and

t h e r e m a i n i n g

1 mm

p r o t r u d e s

through

t h e c l o s e d stomach i n t o t h e e x t e r i o r .

The t h r o m b i f o r m e d r a p i d l y a n d f i v e h o u r s l a t e r ,

u n d e r p e n t o b a r b i t a l a n e s t h e s i a , t h e abdomen i s

r e

o p e n e d a n d

l i g a t u r e s a r e

p l a c e d

a b o v e

a n d

below t h e

s c r e w t h r e a d which i s withdrawn a f t e r l o n g i t u d i n a l

i n c i s i o n

o f t h e

v e i n a n d

t h e

i s o l a t e d t h r o m b u s

i s

w e i g h e d .

The

r e s u l t s which a r e p r e s e n t e d i n T a b l e I I I show

t h a t t h e l e v o - r o t a t o ry i s o m e r i s i n a c t i v e i n t h i s

t e s t ,

i n

c o n t r a s t

t o

t h e

d e x t r o - r o t a t o r y isomer and t h e r a c e

mate.

TABLE I I

DOSE

r u g / K g

QUAN- VARIA

PRO- P.0 T I T Y

WEIGHT f

TION

DUCT

a d m i n .

o f b a s e t h r o m b i % P

C o n t r o l s

3 . 9 +/- . 3

PCR 0 9 9

4 . 4 8 3 . 8 4 2 . 1 7

+/ . 2 4 4 4 0 . 0 0 1

( r a c e m a t e )

8 . 9 7 7 . 6 9 1 . 3 9

+/

. 1 5

6 4

0 . 0 0 1

1 7 . 9

1 5 . 3 8

1 . 0 0

+/- . 1 9

7 4

0 . 0 0 1

SR 25989C 4 0 3 0 . 7 6 4 . 1 7 +/ . 4 2

7

n . s

SR 25990C 1 . 2 5

0 . 9 6 3 . 1 1 +/ . 3 2

2 0 n . s

2 . 5 1 . 9 2

2 . 2 9 +/ . 2 2 4 1

0 . 0 1

5 3 . 8 4

1 . 7 1

+/

. 2 4

5 6

0 . 0 1


7/11

4 , 8 4 7 , 2 6 5

1 1

TABLE I I - c o n t i n u e d

DOSE

mg/Kg

QUAN- VARIA

PRO- P.O TIT Y

WEIGHT f

TION

DUCT

a d m i n . o f b a s e t h r o m b i P

C o n t r o l s

3 . 7 8

+/- 0 . 3 6

SR

2 5 9 9 0 1 5

1 0 3 . 8 4 1 . 4 8 +/ . 1 5 6 0 0 . 0 0 1

2 0 7 . 6 9

1 . 1 8 +/

. 1 5 6 8 0 . 0 0 1

' = weight

of

thrombi

i n

mg +/- t a n d a r d

e r r o r of t h e mean

P

= testofXruskal-Wallis

For

t h e

t o x i c o l o g i c a l s t u d y ,

t h e compounds w e r e

a d m i n i s t e r e d by

t h e o r a l

r o u t e i n

t h e form

o f

a

s u s p e n

s i o n i n t h e same volume of water made up

t o

10%

( w t / v ) w i t h gum a r a b i c t o g r o u p s o f

1 0

f a s t e d

f e m a l e

r a t s o f

t h e S p r a g u e Dawley t r a i n w e i g h i n g 1 2 0 t o 1 3 5

g r a m s .

The

number o f dead

a n i m a l s

was

d e t e r m i n e d

1 4 d a y s

a f t e r t h e a d m i n i s t r a t i o n

o f

t h e compound

u n d e r s t u d y .

The e t h a l

d o s e s

t h u s d e t e r m i n e d , e x p r e s s e d i n

w e i g h t

o f t h e

s a l t

a d m i n i s t e r e d , a r e p r e s e n t e d

i n T a b l e I V ;

t h e s e

r e s u l t s

show

on

t h e

one

hand

t h a t

t h e

t o x i c i t y

o f t h e

r a c e m i c

m i x t u r e

i s

s i m i l a r t o t h a t o f

t h e


i s o m e r w h e r e a s t h e d e x t r o - ro t a t o r y i s o m e r i s

m a r k e d l y

l e s s t o x i c , a n d , o n t h e o t h e r h a n d ,

t h a t

t h e

t o x i c i t y

d e

p e n d s on t h e n a t u r e

o f

t h e a c i d

u s e d

t o form t h e s a l t .

TABLE IV

D 0 ABSOLUTE LETHAL

PRODUCTS

D

0 ( ) D 0 _DOSE

PCR 0 9 9 1 3 1 8 1 6 1 5 1 9 7 9 2 0 0 0

( r a c e m a t e )

( 1 4 4 8 - 1 7 4 7 )

SR 5 9 8 9

A

1 2 5 9 1 7 0 2 2 2 9 9 2 0 0 0

( 1 4 4 3 - 1 7 9 7 )

SR

5 9 9 0 A 3 0 5 5 4 3 1 6 6 1 3 7 5 0 0 0

( 3 5 6 9 - 5 7 0 5 )

SR 2 5 9 9 0

C

2 2 5 7

2 5 9 1

2 9 7 4 4 0 0 0

( 2 3 7 2 - 2 8 0 5 )

SR 2 5 9 9 0

D 2 6 3 4 4 2 6 8

6 9 1 4

5 0 0 0

( 3 5 8 1 - 6 0 1 2 )

( ) = con?dence i n t e r v a l

The

p h a r m a c o l o g i c a l s t u d y j u s t

p r e s e n t e d h a s

dem

o n s t r a t e d t h e i n t e r e s t i n g i n h i b i t o r y

p r o p e r t i e s

t o w a r d s

p l a t e l e t a g g r e g a t i o n

o f

t h e compound I d

a n d t h e

a b

sence of any

a c t i v i t y

of t s isomer

1 1 .

The m e d i c i n e o f

t h e

i n v e n t i o n can be made a v a i l a b l e

f o r

o r a l

a d m i n i s t r a t i o n

i n t h e form

o f

t a b l e t s , s u g a r =

c o a t e d

t a b l e t s , c a p s u l e s ,

d r o p s ,

g r a n u l e s o r a

s y r u p .

I t

c a n

a l s o be

made a v a i l a b l e f o r

r e c t a l

a d m i n i s t r a t i o n i n

t h e f o r m

o f s u p p o s i t o r i e s o r

f o r p a r e n t e r a l a d m i n i s t r a

t i o n

i n

t h e

form

o f a n

i n j e c t a b l e

s o l u t i o n .

Each u n i t d o s e

c o n t a i n s

a d v a n t a g e o u s l y

from

0 . 0 0 1

g

t o 0 . 1 0 0 g o f t h e

d e r i v a t i v e

o f t h e i n v e n t i o n ,

and

t h e

d a i l y

d o s e s

t o be


ma y

a r y

from

0 . 0 0 1

g o

0 . 5 0 0

g o f

a c t i v e i n g r e d i e n t

d e p e n d i n g on

h e

a g e o f

t h e

p a t i e n t a n d t h e s e v e r i t y

o f

t h e d i s o r d e r t o b e t r e a t e d .

Some

p h a r m a c e u t i c a l f o r m u l a t i o n s o f

t h e

m e d i c i n e o f

1 5

20

2 5

3 0

3 5

4 5

5 0

5 5

6 5

1 2

t h e i n v e n t i o n w i l l

be

g i v e n below a s n o n - r e s t r i c t i v e

e x a m p l e s .

( 1 )

T a b l e t s

A c t i v e i n g r e d i e n t :

0 . 0 1 0

g

E x c i p i e n t :

l a c t o s e ,

p o w d e r e d

s u g a r , r i c e - s t a r c h , a l g i n i c

a c i d , m a g n e s i u m s t e a r a t e

( 2 ) S u g a r - c o a t e d

t a b l e t s

A c t i v e i n g r e d i e n t : 0 . 0 0 5 g

E x c i p i e n t :

magnesium s t e a r a t e , m a i z e s t a r c h , gum

a r a

b i c ,

s h e l l a c , w h i t e

s u g a r ,

g l u c o s e ,

w h i t e w a x ,

c a r

n a u b a w a x , p a r a f f i n ,

c o c h i n e a l .

( 3 )

C a p s u l e s

A c t i v e

i n g r e d i e n t :

0 . 0 2 5 g

E x c i p i e n t : m a g n e s i u m s t e a r a t e , m a i z e s t a r c h , l a c t o s e .

( 4 ) I n j e c t a b l e s o l u t i o n

A c t i v e i n g r e d i e n t :

0 . 0 5 0

g

i s o t o n i c s a l i n e q . s . p . 3

m l ,

( 5 ) S u p p o s i t o r i e s

A c t i v e i n g r e d i e n t : 0 . 0 3 0 g

S e m i - s y n t h e t i c t r i g l y c e r i d e s

q . s . p .

l s u p p o s i t o r y .

On a c c o u n t o f i t s

i n t e r e s t i n g i n h i b i t o r y

p r o p e r t i e s

t o w a r d s

p l a t e l e t


a n d

i t s

i n t e r f e r e n c e

i n

t h e

mechanism

o f

f o r m a t i o n

o f a r t e r i a l

and venous throm

b o s e s , t h e

m e d i c i n e

o f t h e i n v e n t i o n c a n b e u s e f u l l y


i n t h e

t r e a t m e n t

a n d p r e v e n t i o n o f p l a t e l e t

d i s o r d e r s due t o

e x t r a c o p o r e a l b l o o d c i r c u i t s

o r t h e

c o n s e q u e n c e o f

c o m p l i c a t i o n s

i n a t h e r o m a .

We l a i m :

1 .

D e x t r o - r o t a t o r y

i s o m e r o f

m e t h y l

a l p h a - 5 ( 4 , 5 , 6 , 7

t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l ) ( 2 - c h l o r o p h e n y l ) - a c e

t a t e s u b s t a n t i a l l y s e p a r a t e d f r o m t h e l e v o - r o t a t o r y

i s o

mer

a n d i t s p h a r m a c e u t i c a l l y a c c e p t a b l e s a l t s .

2 . H y d r o c h l o r i d e o f


i s o m e r o f

m e t h y l a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )

( 2 - c h l o r o p h e n y l ) - a c e t a t e s u b s t a n t i a l l y

s e p a r a t e d

f r o m

t h e l e v o - r o t a t o r y i s o m e r .

3 .

Hydrogen

u l f a t e

o f t h e d e x t r o - r ot a t o r y i s o m e r o f

m e t h y l


p y r i d y l )

( 2 - c h l o r o p h e n y l ) - a c e t a t e s u b s t a n t i a l l y

s e p a r a t e d

f r o m

t h e l e v o - r o t a t o r y i s o m e r.

4 .

H y d r o b r o m i d e

o f


i s o m e r

o f

m e t h y l a l p h a - 5 ( 4 , 5 , 6 , 7 - t e t r a h y d r o ( 3 , 2 - c ) t h i e n o p y r i d y l )


s u b s t a n t i a l l y

s e p a r a t e d f r o m

t h e l e v o - r o t a t o r y i s o m e r.

5 . T a u r o c h o l a t e o f t h e d e x t r o - ro t a t o ry i s o m e r o f

m e t h y l a l p h a - 5 ( 4 , 5 , 6 , 7 t e t r a h y d r o ( 3 , 2 - c ) t h i e n o

p y r i d y l )


s u b s t a n t i a l l y

s e p a r a t e d f r o m

t h e l e v o - r ot a t o r y

i s o m e r .

6 .

P h a r ma c e u t i c a l c o m p o s i t i o n which

c o m p r i s e s a n

e f f e c t i v e

p l a t e l e t


i n h i b i t i n g

amount

o f

a

compound f c l a i m 1 a n d a p h a r ma c e u t i c a l l y

a c c e p t a b l e

c a r r i e r .

7 .

Composition

a c c o r d i n g t o

c l a i m

6 , c o m p r i s i n g u n i t

d o s e s c o n t a i n i n g

from

0 . 0 0 1

g o

0 . 1 0 0

g

o f

a c t i v e i n g r e

d i e n t .

* * i i i


8/11

US004847265C1

( 1 2 )

EX PARTE REEXAMINATION

CERTIFICATE

7 5 7 1 s t )

United S t a t e s P a t e n t

Badore e t a ] .

US

4 , 8 4 7 , 2 6 5

C1

J u n . 2 9 ,

2 0 1 0

( 1 0 ) Number:

( 4 5 ) C e r t i ? c a t e I s s u e d :

( 5 4 )

DEXTRO-ROTARORY ENANTIOMER OF

METHYL LPHA-5 (4,5,6,7-TETRAHYD RO

( 3 , 2 - C )

THIENO PYRIDYL)

(2-CHLOROPHENYL)-ACETA TE

AND

THE

PHARMACEUTICAL

COMPOSITIONS

CONTAINING IT

( 7 5 ) I n v e n t o r s : A l a i n B a d o r e , R o q u e t t e s

( F R ) ; D a n i e l

F r h e l , T o u l o us e ( F R )

( 7 3 )

A s s i g n e e :

S a n o ? - A v e n t i s , P a r i s ( F R )

R e e x a m i n a t i o n

R e q u e s t :

N o . 9 0 / 0 0 9 , 4 7 4 , J u n . 1 , 2 0 0 9

Reexamination

C e r t i ? c a t e f o r :

P a t e n t N o . : 4 , 8 4 7 , 2 6 5

I s s u e d :

J u l .

1 1 ,

1 9 8 9

A p p l .

N o . : 0 7 / 1 5 5 , 5 5 0

F i l e d : F e b . 1 2 , 1988

( 3 0 ) F o r e i g n

A p p l i c a t i o n

P r i o r i t y D a t a

Feb.

1 7 , 1987 (FR) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. .

87 02025

Nov.

2 7 ,

1987 (FR)

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

. . 87

1 6 5 1 6

( 5 1 )

I n t .

C 1 .

C07]

1 / 0 0 ( 2 0 0 6 . 0 1 )

C07D 4 9 5 / 0 0 ( 2 0 0 6 . 0 1 )

C07D

4 9 5 / 0 4

( 2 0 0 6 . 0 1 )

(52)

US.

Cl.

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 4 /30 1 ;

546/ 1 1 4

(58)

Field of Classi?cation

S e a r c h

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

. . None

S e e

a p p l i c a t i o n ? l e

f o r c o m p l e t e

s e a r c h h i s t o r y .

( 5 6 )

R e f e r e n c e s C i t e d

U . S . PATENT DOCUMENTS

3 , 2 8 7 , 2 2 1 A 1 1 / 1 9 6 6 M u l l e r

3 , 3 2 9 , 5 7 0

A

7 / 1 9 6 7 A l l a i s

3 , 3 9 1 , 1 8 9

A 7 / 1 9 6 8 M u l l

3 , 7 9 6 , 7 4 9 A 3 / 1 9 7 4 H o l d r e g e

3 , 8 3 2 , 3 8 8

A

8 / 1 9 7 4 L o r e n z

4 , 0 5 1 , 1 4 1 A 9 / 1 9 7 7 C a s t a i g n e

4 , 0 7 2 , 6 9 8 A

2 / 1 9 7 8 H y l t o n

e t a 1 .

4 , 1 1 5 , 4 3 9

A 9 / 1 9 7 8 Aoki

4 , 1 1 5 , 5 6 8

A 9 / 1 9 7 8

C h a k r a b a r t i e t

a 1 .

4 , 2 4 2 , 3 6 0

A 1 2 / 1 9 8 0 P a i l e r

4 , 2 5 8 , 1 9 2

A

3 / 1 9 8 1

Okamoto

4 , 3 3 2 , 8 1 9 A

6 / 1 9 8 2

E t s c h e n b e r g

4 , 5 2 9 , 5 9 6

A

7 / 1 9 8 5 A u b e r t e t a l .

5 , 9 8 9 , 5 7 8 A

1 1 / 1 9 9 9

B e r n a t

6 , 2 4 8 , 7 2 9

B1 6 / 2 0 0 1

C o n i g l i o

6 , 4 9 5 , 6 9 1 B1

1 2 / 2 0 0 2

Horne

FOREIGN PATENT DOCUMENTS

CA 1194875

1 0 / 1 9 8 5

E P

0099802 7 / 1 9 8 3

FR

82 12599 7/1982

FR 87

02025

2/1987

FR

8 7 1 65 16 l l / l 9 8 7

OTHER PUBLICATIONS

C u s a c k , e t

a l . C h a r a c t e r i s t i c s

Of

ADP R e c e p t o r s ,

A d v a n c e d E x p e r i m e n t a l M e d i c i n e And B i o l o g y ,

v o l .

1 9 2 ,

2 9 4 3 9

( 1 9 8 5 ) . [ D X 1 7 6 ] E n g l i s h .

R e i s t e t a l . ,

V e r y

S l o W C h i r a l

I n v e r s i o n o f

C l o p i d o g r e l

i n

R a t s : a P h a r m a c o k i n e t i c and M e c h a n i s t i c I n v e s t i g a t i o n ,

2 8

D r u g M e t a b .

&

i s p o s . 1 4 0 5 . [ P X 1 5 1 ] E n g l i s h .

W i l e n

e t

a l . ,

S t r a t e g i e s

I n O p t i c a l R e s o l u t i o n s ,

3 3

T e t r a h e

d r o n 2 7 2 5

( 1 9 7 7 ) .

[ P X 8 5 4 ] E n g l i s h .

J a c q u e s e t a l . , E n a n t i o m e r s , R a c e m a t e s a n d R e s o l u t i o n s ,

C h a p t e r 7 , J o h n

W i l e y

a n d

S o n s , 1 9 8 1 . [DDX 4 9 2 ,

DDX

4 9 2 D , D D X 9 2 E ]

E n g l i s h .

E l i e l , R a c e m i c M o d i ? c a t i o n s ,

S t e r e o c h e m i s t r y

o f C a r b o n

C o m p o u n d s ,

C h . 4 , p p . 3 1 4 8 6 ( 1 9 6 2 ) .

[DTX

1 9 3 0 ] E n g l i s h .

V r i e s e t a l . , The

F a m i l y

Approach o R e s o l u t i o n

o f

Race

m a t e s ,

A n g e W . C h e m .

I n t l .

E d .

2 3 4 9 ( 1 9 9 8 ) .

[ P X 8 5 2 ]

E n g l i s h .

Ohm

t

a l . ,

E f f e c t o f A n t i p l a t e l e t A g e n t s on Outcomes f o r

E l d e r l y

P a t i e n t s

W i t h

T r a u m a t i c I n t r a c r a n i a l H e r m o r r h a g e ,

5 8 J . T r a u m a 5 1 8 ( O h m ) .

[ P X

1 8 2 ] E n g l i s h .

R a v i n , L . , e t a l . , C h a p . 7 5 : P r e f o r m u l a t i o n , R e m i n g t o n s

P h a r m a c e u t i c a l S c i e n c e s , 1 8 t h e d .

1 9 9 0 . [ P X

1 5 4 ] E n g l i s h .

C a p r i e S t e e r i n g C o m m i t t e e ,

R a n d o m i z e d B l i n d e d

T r a i l

o f


V e r s u s A s p i r i n i n

P a t i e n t s a t R i s k

o f

I s c h a e m i c

E v e n t s , 3 4 8 T h e

L a n c e t

( 1 9 9 6 ) . [ P X 2 6 0 , DDX

4 7 8 ]

E n g l i s h .

Yusuf

t a l . , E f f e c t s o f C l o p i d o g r e l i n A d d i t i o n

t o A s p i r i n i n

P a t i e n t s W i t h

A c u t e C o r o n o r y S y n d r o m e s , 3 4 5

N .

E n g l .

J .

M e d .

4 9 4

( 2 0 0 1 ) . [DDX 6 1 ] E n g l i s h .

T i c l i d

L a b e l P a c k a g e I n s e r t , W i t h

b l a c k

b o x

W a r n i n g . [ P X

1 8 3 ] E n g l i s h .

B e t r a n d e t

a l . , D o u b l e i B l i n d

S t u d y o f

t h e

S a f e t y o f C l o p i

d o g r e l i n

c o m b i n a t i o n

W i t h

A s p i r i n

. . . 1 0 2 C i r c u l a t i o n

6 2 4 ( A u g . 2 0 0 0 ) . [ D T X 7 5 9 ] E n g l i s h .

FDAs P o l i c y S t a t e m e n t

F o r The D e v e l o p m e n t o f

NeW

S t e

r e o i s o m e r i c

D r u g s h t t p / / WWW. d a .

g o v /

d e r /

u i d a n c e / t e r e

o . h t m

( M a y 1 , 1 9 9 2 ) . [ P T X 1 8 8 ] E n g l i s h .

C a n c e r ,

e t a l . , T r e n d s I n t h e

D e v e l o p m e n t

o f C h i r a l D r u g s ,

D r u g D i s c o v e r y

T o d a y 1 0 5 4 1 0

( 2 0 0 4 ) . [ D T X

4 0 3 2 ] E n g l i s h .

M a Z u e , e t a l . , A g e n t s a n d A c t i o n , T o x i c o l o g i c a l

S t u d i e s

o f

S t u d i e s

o f T i c l o p i d i n e

i n

L a b o r a t o r y A n i m a l s , v o l .

1 5 :

1 2 6 4 1 3 5 ( 1 9 8 4 ) . [DDX 2 ] E n g l i s h .

P a n a k ,

e t a l . , T i c l o p i d i n e : A r o m i s e f o r t h e P r e v e n t i o n a n d

T r e a t m e n t

o f T h r o m b o s i s a n d

i t s

C o m p l i c a t i o n s , Haemo

s t a t s i s ,

1 3 S u p p l . 1 ,

p p . 1 4 5 4

( 1 9 8 3 ) . [DDX 2 2 ]

E n g l i s h .

( C o n t i n u e d )

P r i m a r y

E x a m i n e r i E v e l y n

H u a n g

( 5 7 ) A BS T RACT

The

p r e s e n t i n v e n t i o n

r e l a t e s

t o t h e d e x t r o - r o t a t o r y e n a n t i

o m e r

of

Formula

coocH3

a n d i t s p h a r m a c e u t i c a l l y

a c c e p t a b l e s a l t s W i t h

p l a t e l e t a g g r e

g a t i o n i n h i b i t i n g a c t i v i t y .

The i n v e n t i o n a l s o r e l a t e s t o a p r o c e s s f o r t h e p r e p a r a t i o n

of

t h i s

compound

s t a r t i n g

f r o m

t h e r a c e m a t e

a n d

t h e

p h a r m a

c e u t i c a l

c o m p o s i t i o n s

c o n t a i n i n g i t .


9/11

US

4 , 8 4 7 , 2 6 5

C1

P a g e

2

OTHER PUBLICATIONS

F e l i s t e , R . ,

e t a l . , B r o a d S p e c t r u m

a n t i i p l a t e l e t a c t i v i t y o f

T i c l o p i d i n e

a n d PCR 4 0 9 9 . . . , T h r o m b o s i s

R e s .

4 8 :

4 0 3 4 4 1 5

( 1 9 8 7 ) .

[DDX

6 8 ]

E n g l i s h .

S a v i , e t

a l . , B i n d i n g o f i 2 i M e t h y l t h i o

ADP t o

R a t

P l a t e l e t s i E f f e c t

o f C l o p i d o g r e l

a n d T i c l o p i d i n e , J . P h a r m .

E x p . T h e r a p e u t i c s

2 6 9 :

7 7 2 4 7 7 7 ( 1 9 9 4 ) .

[DDX

1 6 9 ]

E n g l i s h .

A d a m s ,

B r e s l o f f ,

e t a l . ,

P h a r m a c o l o g i c a l

D i f f e r e n c e s

B e t W e e n . . . , 1 9 7 6 , J . P h a r m . P h a r m a c .

2 8 ,

2 5 6 . [DDX 3 6 6 ]

E n g l i s h .

F a s c o ,

P r i n c i p e ,

R

n d S

W a r f a r i n

I n h i b i t i o n , J .

B i o l o g i c a l

C h e m i s t r y , v o l .

2 5 7 ,

N o . 9 , 1 9 8 2 4 8 9 2 4 1 9 0 1 . [DDX 3 6 7 ]

E n g l i s h .

B a n i t t ,

e t a l . , R e s o l u t i o n o f

F l e c a i n i d e , J . M e d . C h e m . ,

1 9 8 6 v o l . 2 9 ,

N o . 2 , 2 9 9 4 3 0 2 .

[DDX 3 6 8 ]

E n g l i s h .

D r i o t ,

M a f f r a n d a n d V a l l e e ,

P l a t e l e t i S u b e n d o t h h e l i u m

I n t e r a c t i o n :

E f f e c t o f

T i c l o p i d i n e , T h r o m p . a n d H a e m o s t a

s i s , N o . 1 ,

v o l .

5 0 ,

J u l . 4 ,

1 9 8 3 . [DDX 3 7 3 ] E n g l i s h .

R a i t e r i , e t

a l . , F u n c t i o n a l

E v i d e n c e f o r T W o S t e r e o h c e m i

c a l l y D i f f e r e n t

A l p h a i 2

A d r e n o r e c e p t o r s . . . , J . P h a r m . E x p .

T h e r a p . , v o l .

2 2 4 ,

N o .

2 3 , 1 9 8 3 .

[DDX 4 5 ]

E n g l i s h .

K l a a s s e n a n d

D o u l l ,

C h a p t e r 2 ,

E v a l u a t i o n

o f S a f e t y : T o x i

c o l o g i c

e v a l u a t i o n , i n C a s a r e t t a n d D o u l l s T o x i c o l o g y , 2 d

E d .

( 1 9 8 0 ) . [DDX 8 2 ] E n g l i s h .

M i s l o W ,

K u r t . I n t r o d u c t i o n t o S t e r e o c h e m i s t r y ,

W.A. Ben

j a m i n

I n c . ,

NeW

Y o r k ,

A m s t e r d a m ,

1 9 6 6 . [DDX

4 8 8 ]

E n g l i s h .

J a c q u e s , e t a l . , E n a n t i o m e r s ,

R a c e m a t e s

a n d R e s o l u t i o n s ,

C h a p t e r

5 , F o r m a t i o n

a n d S e p a r a t i o n

o f

D i a s t e r e o m e r s ,

( J o h n W i l e y a n d

S o n s ,

1 9 8 1 ) . [ D T X 4 8 9 ] E n g l i s h .

M i l l s

e t a l . , C l o p i d o g r e l

I n h i b i t s

t h e B u i l d i n g o f ADP

na

l o g u e s . . . , A r t e r i o s c l e r o s i s a n d T h r o m b b o s i s ,

v o l .

1 2 . , N o . 4 ,

A p r . 1 9 9 2 . [DDX 2 6 ] E n g l i s h .

Leon

M B , e t

a l . ,

A

C l i n i c a l

T r i a l

Comparing

T h r e e

A n t i

t h r o m b o t i c i D r u g R e g i m e n s a f t e r C o r o n a r y i A r t e r y S t e n t

i n g , NEJM 3 9 , 1 6 6 5 ( 1 9 9 8 ) . [DDX 7 3 ] E n g l i s h .

H a r r i s ,

G . ,

S t u d y R a i s e s

Q u e s t i o n s o n P l a v i x

S a f e t y ,

NeW

Y o r k T i m e s , J a n .

2 0 , 2 0 0 5 . [DDX

8 5 2 ] E n g l i s h .

T h e M e r c k I n d e x ( 1 1 t h

e d .

1 9 8 9 ) , e x c e r p t s .

[PTX

1 0 6 2 ]

E n g l i s h .

A l b e r t , A . ,

S e l e c t i v e

T o x i c i t y ,

5 t h e d . , p .

2 5 , Chapman

n d

H a l l , L o n d o n ( 1 9 7 3 ) .

[DDX 1 3 4 , D D X

1 1 3 4 E ] E n g l i s h .

C o l m a n ,

e t

a l . ,

I d e n t i ? c a t i o n

o f T W o D i s t i n c t A d e n o s i n e

D i p h o s p h a t e R e c e p t o r s i n Human P l a t e l e t s , T r a n s . Am.

A s s . P h y s .

9 3 : 3 0 5 i 3 l 0

( 1 9 8 0 ) . [DDX 1 3 0 4 ] E n g l i s h .

G o l d s t e i n , e t

a l . ,

P r i n c i p l e s

o f Drug

A c t i o n :

The B a s i s o f

P h a r m a c o l o g y ,

S e c o n d E d i t i o n , 1 9 7 4

( N Y ,

J o h n

W i l e y &

S o n s ) . [DDX 3 0 5 , 1 3 0 5 A ] E n g l i s h .

NeWman,

O p t i c a l

r e s o l u t i o n

P r o c e d u r e s

f o r

C h e m i c a l Com

p o u n d s , v o l . 1 , M a n h a t t a n

C o l l e g e , R i v e r s d a l e ,

NY

1 9 7 8 ) .

[ D D X 1 3 1 9 ] E n g l i s h .

B o u c h e r ,

M . ,

e t a l . ,

A C r i t i c a l A p p r a i s a l

o f t h e CURE

T r i a l ,

The

C a n a d i a n J .

o f C l i n . P h a r m . , v o l . 1 1 ( 1 ) : 1 5 6 4 6 7 ,

( 2 0 0 4 ) .

[ D D X 1 6 1 6 ]

E n g l i s h .

L a n g e , R i c h a r d A . ,

e t a l . ,

A n t i p l a t e l e t

T h e r a p h y

f o r

I s c h e m i c

H e a r t D i s e a s e , NeW n g l a n d J o u r n a l

o f

M e d i c i n e ,

3 5 0 ( 3 ) : 2 7 7 4 8 0 , 2 0 0 4 . [DDX

6 2 7 ]

E n g l i s h .

S c h l e i n i t Z ,

M . D . , e t

a l .

C l o p i d o g r e l V e r s u s A s p i r i n

f o r S e c

o n d a r y

P r o h y l a x i s

o f V a s c u l a r E v e n t s , Am. J . M e d . ,

1 1 6 ( 1 2 ) : 7 9 7 4 8 0 6 , 2 0 0 4 . [ D D x 1 6 3 8 ]

E n g l i s h .

S c h o m i g ,

A . ,

e t a l . ,

A R a n d o m i Z e d

C o m p a r i s o n

o f

A n t i

p l a t e l e t

a n d A n t i c o a g u l a n t T h e r a p y , NEJM, 3 4 : 1 0 8 4 4 8 9 ,

1 9 9 6 . [DDX

6 3 9 ]

E n g l i s h .

S y b e r t Z , A l p h a

a n d B e t a

A n d r e n o c e p t o r

B l o c k i n g

P r o p e r

t i e s o f L a b e t a l o l

J . Pharmacognomy

a n d E x p . T h e r s . 2 1 8

( 2 ) ,

4 3 5

( 1 9 8 1 ) . 1 3 8 .

[DDX

1 9 2 9 , 1 9 2 9 B ,

PTX 3 2 0 ]

E n g l i s h .

Commit

C o l l .

G r p . ,

A d d i t i o n

o f


t o

A s p i r i n ,

The

L a n c e t ,

v o l .

3 6 6 ,

I s s u e 9 7 9 7 , N o v . 2 0 0 5 , p p . 1 4 5 0 .

[ D D X 2 6 0 1 ] E n g l i s h .

B h a t t , e t a l . , C l o p i d o g r e l a n d A s p i r i n

v e r s u s

A s p i r i n A l o n e

f o r t h e

P r e v e n t i o n o f a t h e r o t h r o m b o t i c

E v e n t s , NEJM

( 2 0 0 6 ) 3 5 4 . [DDX 2 6 0 2 ] E n g l i s h .

P f e f f e r , e t a l . , T h e C h a r i s m a o f

S u b g r o u p s

a n d t h e S u b

g r o u p s

o f CHARISMA, NeW

E n g l a n d

J o u r n a l o f

M e d i c i n e

( 2 0 0 6 ) ,

1 7 4 4 .

[DDX

2 6 0 3 ]

E n g l i s h .

P a t r o n o ,

e t

a l . ,

LowiDose

A s p i r i n

f o r t h e P r e v e n t i o n o f

A t h e r o t h r o m b o s i s , NeW E n g l a n d J o u r n a l

o f

M e d i c i n e ,

3 5 3 ,

2 3 7 3 ( 2 0 0 5 ) . [DDX

6 1 5 ]

E n g l i s h .

T e c h n i c a l d e s r i p t i o n : P l a v i x ( c l o p i d o g r e l

b i s u l f a t e

t a b l e t s ) .

[ D D X 7 0 4 ] E n g l a n d .

O r a n g e

Book L i s t i n g i A p p r o v e d D r u g P r o d u c t s r e :

4 5 2 9 5 9 6

P a t e n t ,

1 9 t h

E d i t i o n ,

1 9 9 9 .

[DDX

1 9 9 8 ]

E n g l i s h .

T r a n s l a t i o n o f A r t i c l e L611*7 o f I n d u s t r i a l P r o p e r t y . [D DX

4 0 3 3 ] E n g l i s h

( T r a n s l a t i o n ) .

T h b a u l t ,

J McEWen, J McGraW,

A . ,

B o u l o u x ,

C . , J a c o b ,

C . ,

C h i g o t ,

C . , I r v i n e , A . , K i n d e r m a n s , M . ,

M a f f r a n d ,

J . P . ,

R o n c u c c i ,

R . , PCR 4 0 9 9 , A NeW

A n t i i t h r o m b ot i c D r u g .

E v a l u a t i o n o f

T o l e r a n c e

a n d

P h a r m a c o l o g i c a l A c t i v i t y ,

T h r o m b o s i s R e s e a r c h , S u p p l . V I

a t

1 4 4 ( N o . 2 8 6 )

( 1 9 8 6 ) .

T h b a u l t , J . , B o u l o u x , C . ,

M c E W e n ,

J . ,

M c G r a W , A . , J a c o b ,

C . , I r v i n e , A . , K i n d e r m a n s , M . , M a f f r a n d ,

J

P . , R o n c u c c i ,

R . ,

PCR

4 0 9 9 , A

NeW

A n t i i t h r o m b o t i c

D r u g .

E v a l u a t i o n o f

T o l e r a n c e a n d P h a r m a c o l o g i c a l A c t i v i t y , ( S 6 4 7 3 1 A ) .

R.W.

Colman a n d W.R.

F i g u r e s , C h a r a c t e ri s t i c s

o f anADP

r e c e p t o r

m e d i a t i n g

p l a t e l e t

a c t i v a t i o n ,

M o l e c u l a r a n d C e l l u

l a r B i o c h e m i s t r y 5 9 : 1 0 1 4 1

1 1

( 1 9 8 4 ) .

E . J .

A r i e n s ,

S t e r e o c h e m i s t r y ,

a

B a s i s f o r

S o p h i s t i c a t e d

Nonsense i n

P h a r m a c o k i n e t i c s

a n d C l i n i c a l P h a r m a c o l o g y ,

E u r .

J . C l i n . P h a r m a c o l . 2 6 : 6 6 3 i 6 6 8 ( 1 9 8 4 ) .

W i l l i a m s a n d

L e e ,

I m p o r t a n c e o f D r u g E n a n t i o m e r s i n

C l i n i c a l P h a r m a c o l o g y , D r u g s 3 0 : 3 3 3 i 3 5 4

( 1 9 8 5 ) .

P h a r m a c e u t i c a l

M a n u f a c t u r i n g G u i d e l i n e s , 1 9 8 5

E d i t i o n

( W i t h t r a n s l a t i o n ) , e d i t e d b y T h e

S o c i e t y

o f t h e J a p a n e s e

P h a r ma c o p o e i a a n d p u b l i s h e d

O c t . 2 2 ,

1 9 8 5

b y Y a k u g y o

J i h o i S a a ( T h e


T i m e s

C o m p a n y ) .

The C e n t e r f o r Drug E v a l u a t i o n a n d R e s e a r c h o f

t h e

Food

a n d

Drug d m i n i s t r a t i o n

d i s t r i b u t e d

G u i d e l i n e f o r S u b m i t

t i n g S u p p o r t i n g D o c u m e n t a t i o n i n D r u g A p p l i c a t i o n s f o r t h e

M a n u f a c t u r e o f

Drug S u b s t a n c e s , D a t e d F e b . 1 9 8 7 .

G o l d s t e i n , AranoW a n d K a p l a n , P r i n c i p l e s o f

D r u g A c t i o n :

T h e B a s i s o f P h a r m a c o l o g y , 2D

E D . (NeW o r k ,

J o h n W i l e y

&

o n s 1 9 7 4 ) .

W . S o u d j i n , A d v a n t a g e s a n d

D i s a d v a n t a g e s i n

t h e A p p l i c a

t i o n

of

B i o r e a c t i v e Racemates o r

Speci?c Isomers

a s

D r u g s ,

i n

S t e r e o c h e m i s t r y a n d

B i o l o g i c a l A c t i v i t y

o f

D r u g s

( L o n d o n , B l a c k W e l l

S c i e n t i ? c P u bl i c a t i o n s 1 9 83 ) . p p .

894102.

K a r r e r , P . , O r g a n i c C h e m i s t r y ,

S e c o n d

E d . ( N e W Y o r k :

E l s e v i e r P ub l . C o . 1 9 4 6 ) .

G r a h a m , D . G . ,

C a t e c h l o l a m i n e T o x i c i t y : A

r o p o s a l

f o r

t h e

M o l e c u l a r P a t h o g e n e s i s o f

M a n g a n e s e N e u r o t o x i c i t y a n d

P a r k i n s o n s D i s e a s e ,

N e u r o t o x i c o l o g y

5 : 8 3 4 9 6

( 1 9 8 4 ) .

C o t Z i a s ,

G . C . , e t a l . , M o d i ? c a t i o n o f

P a r k i n s o n i C h r o n i c

T r e a t m e n t W i t h L i D o p a , NeW

E n g .

J . Of

M e d i c i n e

2 8 0 : 3 3 7 i 3 4 5

( 1 9 6 9 ) .


10/11

US

4 , 8 4 7 , 2 6 5

C1

P a g e 3

G o u l d , P . L . ,

S a l t

s e l e c t i o n f o r b a s i c d r u g s , I n t e r n a t i o n a l

J o u r n a l

f o r


3 3 1 2 0 1 4 2 1 7

( 1 9 8 6 ) .

B e r g e ,

S . M . ,

B i g h l e y ,

L . D . ,

a n d

M o n k h o u s e , D . C . , P h a r

m a c e u t i c a l S a l t s ,

J o u r n a l o f

P h a r m a c e u t i c a l S c i e n c e s

6 6 1 1 4 1 9

( 1 9 7 7 ) .

F e i s e r a n d F e i s e r , A d v a n c e d

O r g a n i c

C h e m i s t r y ( R e i n g o l d

P u b l .

C o .

1 9 6 1 ) , p p . 8 5 4 8 8 .

D i

Minno

G , e t

a l .

C e r b o n e

A M ,

M a t t i o l i P L ,

T u r c o S ,

I o v i n e C ,

M a n c i n i

M. F u n c t i o n a l l y t h r o m b a s t h e n i c

s t a t e i n

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

J .

C l i n

I n v e s t .

1 9 8 5

F e b ; 7 5 ( 2 ) 3 2 8 * 3 8 .

L e h m a n n ,

P . A . , R o d r i g u e s

d e

M i r a n d a ,

a n d A r i e n s , E . J . ,

S t e r e o s e l e c t i v i t y a n d A f f i n i t y

i n M o l e c u l a r P h a r ma c o l o g y ,

i n J u c k e r ( e d . ) , P r o g r e s s

i n

D r u g R e s e a r c h , 2 0 ,

1 4 7 7

( 1 9 7 6 ) .

C e n t e r f o r

Drug E v a l u a t i o n a n d R e s e a r c h

L i s t

o f

Patent-US 4847265-Clopidogrel and Salts Such as Clopidogrel Hydrogen Sulfate; Anticoagulants

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Transcript of Patent-US 4847265-Clopidogrel and Salts Such as Clopidogrel Hydrogen Sulfate; Anticoagulants