4,6-substituted 2,5-dideoxystreptamine aminoglycoside antibiotics

7/29/2019 4,6-substituted 2,5-dideoxystreptamine aminoglycoside antibiotics

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US 20130203693A1

( 1 2 ) Patent Application Publication ( 1 0 ) P u b . N o . : US 2 0 1 3 / 0 2 0 3 6 9 3 A 1( 1 9 ) United S t a t e s

CHAPARIAN t a l . ( 4 3 ) P u b . D a t e : Aug. , 2013( 5 4 ) 4,6-SUBSTITUTED P u b l i c a t i o n C l a s s i ? c at i o n2,5-DIDEOXYSTREPTAMINEAMINOGLYCOSIDE NTIBIOTICS ( 5 1 ) I n t - Cl

C07H 5 / 2 3 4 ( 2 0 0 6 . 0 1 )( 7 1 ) A p p l i c a n t : S e l e c tX P h a r m a c e u t i c a l s , I n c . , B o s t o n , ( 5 2 ) US, l ,MA Us) CPC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C07H 5/234 (2013.01)

USPC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514/40; 536/168( 7 2 ) I n v e n t o r s : M i c h a e l G . CHAPARIAN, a s h i n g t o nT o w n s h i p , MI U S ) ; M i c h a e l B r a d y , ( 5 7 ) ABSTRACTH a v e r h i l l , MA U S ) ; S c o t t M o e ,S u d b u r y , MA U S ) ; Babu RaoR e n i k u n t l a , S h r e W s b u r y , MA U S ) ;S r i n i v a s G a d t h u l a , D u b l i n , OH U S ) ;S r i n i v a s a r a o M e n e n i , S h r e W s b u r y , MA( U S ) ; Venkata S a i PrakashC h a t u r v e d u l a , A l p h a r e t t a , GA U S )

( 7 3 ) A s s i g n e e : S e l e c tX P h a r m a c e u t i c a l s , I n c . , B o s t o n ,MA U S )

( 2 1 ) A p p l . N o . : 1 3 / 7 5 5 , 2 7 5( 2 2 ) F i l e d : J a n . 3 1, 2 0 1 3

R e l a t e d US. p p l i c a t i o n Data( 6 0 ) P r o v i s i o n a l a p p l i c a t i o n N o . 6 1 / 5 9 4 , 6 6 3 , ? l e d o n F e b .3 , 2 0 1 2 .

A m i n o g l y c o s i d e a n t i b i o t i c s o f t h e f o r m u l a

HZN OHR 3

0 0 R 2 ,HZN

R 7A // \N 1 0R 8 R HN R ,OHO OH

a r e d i s c l o s e d . The compounds r e u s e f u l f o r t r e a t i n g b a c t e r i a li n f e c t i o n s , p a r t i c u l a r l y i n f e c t i o n s r e s i s t a n t t o known n t i b io t i c s .


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4,6-SUBSTITUTED2,5-DIDEOXYSTREPTAMINEAMINOGLYCOSIDE ANTIBIOTICSCROSS-REFERENCE TO RELATEDAPPLICATIONS

[ 0 0 0 1 ] T h i s a p p l i c a t i o n c l a i m s p r i o r i t y f r o m Us. p r o v is i o n a l a p p l i c a t i o n 6 1 / 5 9 4 , 6 6 3 , ? l e d F e b . 3 , 2 0 1 2 , t h e e n t i r ec o n t e n t s o f Which a r e i n c o r p o r a t e d h e r e i n by e f e r e n c e .

FIELD OF THE INVENTION[ 0 0 0 2 ] Th e n v e n t i o n r e l a t e s t o a m i n o g l y c o s i d e a n t i b i o t i c s .

BACKGROUND OF THE INVENTION[ 0 0 0 3 ] S i n c e t h e i r ? r s t c l i n i c a l u s e W i t h t h e i n t r o d u c t i o n o fs t r e p t o m y c i n i n 1 9 4 7 , t h e a m i n o g l y c o s i d e s ( A G ) h a v e b e e none f t h e most i m p o r t a n t and i d e l y u s e d c l a s s e s o f a n t i b io t i c s a g a i n s t m o s t g r a m - n e g a t i v e a n d s e r i o u s g r a m - p o s i t i v ei n f e c t i o n s . A m i n o g l y c o s i d e s b i n d t h e A - s i t e o f t h e 30S i b os o m e , b l o c k i n g b a c t e r i a l p r o t e i n s y n t h e s i s t h r o u g h d i s r u p t i o no f n i t i a t i o n and r a n s l a t i o n . AGs r e a c t i v e l y t r a n s p o r t e d i n t ot h e b a c t e r i a l c e l l by a n e n e r g y - r e q u i r i n g p r o c e s s . D e f e c t i v emembrane r o t e i n s r e s u l t i n g f r o m t r a n s l a ti o n a l e r r o r s f u r t h e re n h a n c e t h e a c t i v i t y o f AGs y a l l o W i n g p a s s i v e e n t r y o f h ea n t i b i o t i c i n t o t h e c e l l .[ 0 0 0 4 ] Over h e p a s t s e v e r a l d e c a d e s o f u s e , c l i n i c a l r e s i st a n c e t o t h e A Gs h a s e m e r g e d . A m i n o g l y c o s i d e r e s i s t a n c eg e n er a l l y o c c u r s by o n e o f s e v e r a l m e c h a n i s m s , d e s c r i b e dh e r e i n o r d e r o f c l i n i c a l r e l e v a n c e :

[ 0 0 0 5 ] 1 . E n Z y m e - m e d i a t e d c h e m i c a l m o d i ? c a t i o n o ft h e d r u g b y a m i n o g l y c o s i d e m o d i f y i n g e n Z y m e s(AGME). These enZymes a r e c a r r i e d and t r a n s f e r r e de a s i l y b y p l a s m i d s i n c l i n i c a l i s o l a t e s a n d i n a c t i v a t e AGsb y c h e m i c a l m o d i ? c a t i o n r e s u l t i n g i n g r e a t l y r e d u c e dr i b o s o m a l b i n d i n g . T h r e e g e n e r a l c l a s s e s o f AGMEe x i s t :[ 0 0 0 6 ] a . N - A c e t y l t r a n s f e r a s e s ( A A C ) 4 c a t a l y Z e s

a c e t y l C o A - d e p e n d e n t a c e t y l a t i o n o f a n a m i n o g r o u p[ 0 0 0 7 ] b . O - A d e n y l t r a n s f e r a s e s ( A N T ) 4 c a t a l y Z e sA T P - d e p e n d e n t a d e n y l a t i o n o f h y d r o x y l g r o u p[ 0 0 0 8 ] c . O - P h o s p h o t r a n s f e r a s e s ( A P H ) 4 c a t a l y Z e sA T P - d e p e n d e n t p h o s p h o r y l a t i o n o f a h y d r o x y l g r o u p

[ 0 0 0 9 ] 2 . Reduced p t a k e o r d e c r e a s e d c e l l p e r m e a b i l i t y .Most y p i c a l l y s e e n i n Pseudomonas a e r u g i n o s a ( P a e ) ,t h i s form of e s i s t a n c e i s due o a t r a n s p o r t d e f e c t r e s u l ti n g i n b r o a d , i n t e r m e d i a t e l e v e l r e s i s t a n c e t o a l l t h e AGs.

[ 0 0 1 0 ] 3 . E f ? u x . Drugs a r e pumped u t o f t h e c e l l b e f o r et h e y c a n c a u s e c e l l d e a t h . T h i s g e n e r a l l y r e s u l t s i n broadr e s i s t a n c e to a l l AGs. A Gs a r e a f f e c t e d by o t h g e n e r a la n t i b i o t i c e f ? u x pumps a n d a l s o by AG p e c i ? c p u m p s .[ 0 0 1 1 ] 4 . A l t e r e d r i b o s o m e b i n d i n g s i t e s , t y p i c a l l y b ym e t h y l a t i o n , f a c i l i t a t e d b y 1 6 S RNA e t h y l a s e s . Modi? c a t i o n a t t h e s i t e o f a m i n o g l y c o s i d e i n t e r a c t i o n i n t e rf e r e s W i t h r i b o s o m a l b i n d i n g . These enZymes a r e a l s op l a s m i d m e d i a t e d .

[ 0 0 1 2 ] C o i n c i d e n t W i t h t h e emergence o f AG e s i s t a n c e i st h e r a p i d e m e r g e n c e o f a v a r i e t y o f s e r i o u s g r a m - n e g a t i v ei n f e c t i o n s , m o s t n o t a b l y h o s p i t a l b a s e d ( n o s o c o m i a l ) i n f e ct i o n s . Many of t h e s e i n f e c t i o n s a r e n o t s u s c e p t i b l e t o c u rr e n t l y m a r k e t e d a n d o n c e e f f e c t i v e a n t i b i o t i c s ( a m i n o g l y c os i d e s a n d b e t a - l a c t a m s ) a n d t h u s p o s e a s i g n i ? c a n t a n d u r g e n tneed o r neW r improved n t i b i o t i c s . A m i n o g l y c o s i d e s , havi n g a l o n g h i s t o r y o f e f f e c t i v e u s e a g a i n s t g r a m - n e g a t i v e

A u g . 8 , 2 01 3

i n f e c t i o n s s u c h a s P a e and K l e b s i e l l a pneumoniae ( K p n ) ,seem e l l s u i t e d t o a d d r e s s t h i s problem f compounds can bec r e a t e d t h a t e f f e c t i v e l y overcome h e mo t c l i n i c a l l y r e l e v a n tmechanisms o f AG e s i s t a n c e . I n a d d i t i o n to overcomingr e s i s t a n c e a n d i n c r e a s i n g p o t e n c y a n d s p e c t r u m , i t i s d e s i ra b l e t o i m p r o v e t h e t h e r a p e u t i c i n d e x , p a r t i c u l a r l y b yd e c r e a s i n g t h e n e p h r o t o x i c i t y a n d / o r o t o t o x i c i t y .

SUMMARY OF THE INVENTION[ 0 0 1 3 ] I n o n e a s p e c t t h e i n v e n t i o n r e l a t e s t o compounds o ff o r m u l a I :

IHZN OH

R 3 0 R 2 .HZN 0

R 7A\ /R 8 R l H N o R ,OHO OH

HZN

[ 0 0 1 4 ] W h e r e i n[ 0 0 1 5 ] R 2 i s c h o s e n f r o m iOH n d iNHZ;[ 0 0 1 6 ] R 3 i s c h o s e n f r o m H n d OH;[ 0 0 1 7 ] R 1 i s c h o s e n f r o m H , 4C(:NH)NH2, a n d4 C ( : O ) R l o , W h e r e i n

[ 0 0 1 8 ] R 1 0 i s c h o s e n f r o m i ( C l - C 2 O ) a l k y l , i(C3C l o ) c a r b o c y c l e , i ( C 3 - C 9 ) h e t e r o c y c l e , i ( C 1 - C 8 )a l k y l ( C 3 - C l o ) c a r b o c y c l e , a n d i ( C l - C 8 ) a l k y l ( C 3 - C 9 )h e t e r o c y c l e W h e r e i n[ 0 0 1 9 ] i n s a i d ( C 1 - C 2 O ) a l k y l o r i n t h e ( C l - C 8 ) a l k y l

p o r t i o n o f s a i d ( C l - C 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e o r(Cl-C8)alkyl(C3-C9)heterocycle, on e or tW o4CHi ay b e r e p l a c e d W i t h iNi, tW o4CHi ay e r e p l a c e d by 4C:Ci, nd n e o rt W o 4CH2i ay e r e p l a c e d b y Oi,iSi,iSOi, isozi, 4CECi, a ( C 3 - C l o ) c a rb o c y c l e o r a ( C 3 - C 6 ) h e t e r o c y c l e and[ 0 0 2 0 ] s a i d ( C 1 - C 2 O ) a l k y l , ( C 3 - C l o ) c a r b o c y c l e ,( C 3 - C 9 ) h e t e r o c y c l e , ( C l - C 8 ) a l k y l ( C 3 - C l O ) c a rb o c y c l e , ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r o c y c l e may b ea d d i t i o n a l l y s u b s t i t u t e d W i t h from one o t h r e e s u bs t i t u e n t s c h o s e n i n d e p e n d e n t l y f r o m CH3,ADH, iNHZ, %OOH, :O , iNHCONH2,iNHC(:NH)NH2,4CN r h a l o g en ;[ 0 0 2 1 ] R 5 i s c h o s e n f r o m H , h a l o g e n , N 3 , i ( C l - C 4 )

a l k y n y l a n d iNHRSO, w h e r e i n R 5 0 i s c h o s e n f r o m H ,i ( C 3 - C l o ) c a r b o c y c l e , i ( C 3 - C 9 ) h e t e r o c y c l e , i ( C lC 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e , i ( C l - C 8 ) a l k y l ( C 3 - C 9 )h e t e r o c y c l e a n d t h e d e s h y d r o x y r e s i d u e o f a n a m in o a c i d ;

[ 0 0 2 2 ] R 7 i s c h o s e n f r o m H , i ( C l - C 6 ) a l k y l a n dh y d r o x y - ( C - C 6 ) a l k y l ;

[ 0 0 2 3 ] R 8 i s c h o s e n f r o m i ( C l - C 2 O ) a l k y l , i ( C 3 - C l o )c a r b o c y c l e , i ( C 3 - C 9 ) h e t e r o c y c l e , i ( C l - C 8 ) a l k y l ( C 3C l o ) c a r b o c y c l e , i ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r o c y c l e ,i N R S O R S I , a n d iC(:NH)NH2, h e r e i n


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[ 0 0 2 4 ] R 8 0 a n d R 8 1 a r e c h o s e n i n d e p e n d e n t l y f r o m Ha n d ( C - C 6 ) a l k y l ;[ 0 0 2 5 ] i n s a i d ( C l - C 2 O ) a l k y l o r i n t h e ( C l - C 8 ) a l k y l

p o r t i o n o f s a i d ( C 1 - C 8 ) a l k y l ( C 3 - C l o ) c a r b o c y c l e or( C 1 - C 8 ) a l l < y l ( C 3 - C 9 ) h e t e r o c y c l e , on e r tW o iCHimay b e r e p l a c e d W i t h iNi, tW o 4CHi ay b er e p l a c e d by 4C:Ci, n d o n e o r tW o iCHZi ayb e r e p l a c e d b y 40*, iSi, iSOi, isozi,iCECi, ( C 3 - C 1 O ) c a r b o c y c l e o r a ( C 3 - C 6 ) h e t e r oc y c l e ; a n d[ 0 0 2 6 ] s a i d ( C 1 - C 2 O ) a l k y l , ( C 3 - C l o ) c a r b o c y c l e ,( C 3 - C 9 ) h e t e r o c y c l e , ( C l - C s ) a l k y l ( C 3 - C l o ) c a rb o c y c l e , ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r o c y c l e may b e

a d d i t i o n a l l y s u b s t i t u t e d W i t h from one o t h r e e s u bs t i t u e n t s c h o s e n i n d e p e n d e n t l y f r o m CH3,%H2CH3, iOH, %H2OH, iNHz,%H2NH2, iCOOH, :O, iNHCONH2,iNHC(:NH)NH2, 4CN n d h a l o g e n ;[ 0 0 2 7 ] o r[ 0 0 2 8 ] R 7 a n d R S A , t a k e n t o g e t h e r W i t h t h e n i t r o g e n t oWhich h e y a r e a t t a c h e d , f o r m a ( C 3 - C 9 ) h e t e r o c y c l e , s ai d( C 3 - C 9 ) h e t e r o c y c l e o p t i o n a l l y s u b s t i t u t e d W i t h f r o mone t o t h r e e s u b s t i t u e n t s chosen i n d e p e n d e n t l y from

(:NH)NH2, 4CN n d h a l o g e n ; a n d[ 0 0 2 9 ] A s c h o s e n f r o m a d i r e c t b o n d , i(C:O)i,%(:O)Oi, iNH(C:O)i, i(C:O)NHi,iNH(C:O)NHi, i(C:S)NHi, iNH(C:S)i,a n d iNH(C:S)NHi.

[ 0 0 3 0 ] I n a n o t h e r a s p e c t , t h e i n v e n t i o n r e l a t e s t o method ft r e a t i n g a mammal s u f f e r i n g f r o m a b a c t e r i a l i n f e c t i o n , bya d m i n i s t e r i n g a t h e r a p e u t i c a l l y e f f e c t i v e amount of a comp o u n d d e s c r i b e d a b o v e .[ 0 0 3 1 ] I n a n o t h e r a s p e c t , t h e i n v e n t i o n r e l a t e s t o pharmac e u t i c a l c o m p o s i t i o n s c o m p r i s i n g a p h a r m a c e u t i c a l l y a c c e p ta b l e c a r r i e r and a compound e s c r i b e d a b o v e .

DETAILED DESCRIPTION OF THE INVENTION[ 0 0 3 2 ] I n on e embodiment, t h e i n v e n t i o n r e l a t e s t o a comp o u n d o f t h e f o r m u l a ( I ) shoWn e l o W :

HZN OHR 3

0 0 R 2 ,HZN

R 7//A\ 1 0R s R HN R 50HO OH

[ 0 0 3 3 ] I n some embodiments f t h e i n v e n t i o n , R 2 i s iOH.I n o t h e r e m b o d i m e n t s , R 2 i s iNH2.[ 0 0 3 4 ] I n some embodiments o f t h e i n v e n t i o n , R 3 i s H . I no t h e r e m b o d i m e n t s , R 3 i s iOH.[ 0 0 3 5 ] I n some m b o d i m e n t s o f t h e i n v e n t i o n , R 2 i s iNHZan d R3 i s H.

A u g . 8 , 2 01 3

[ 0 0 3 6 ] I n some embodiments o f t h e i n v e n t i o n , R 1 i s H . I no t h e r e m b o d i m e n t s , R 1 i s 4C(:NH)NH2. I n s t i l l o t h e re m b o d i m e n t s , R 1 i s i C ( : O ) R 1 O .[ 0 0 3 7 ] I n some e m b o d i m e n t s o f t h e i n v e n t i o n , R 1 0 i s ( C 1C 2 O ) a l k y l . I n o t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , R 1 0 i s ( C 3C O ) c a r b o c y c l e . I n some embodiments f t h e i n v e n t i o n , R 1 0 i sa ( C 3 - C 9 ) h e t er o c y c l e . I n some embodiments of h e i n v e n t i o n ,R 1 0 i s a i ( C 1 - C 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e . I n s t i l l o t h e re m b o d i m e n t s o f t h e i n v e n t i o n , R 1 0 i s a i ( C l - C 8 ) a l k y l ( C 3C 9 ) h e t e r o c y c l e . I n some embodiments f t h e i n v e n t i o n , i n t h ea l k y l p o r t i o n o f R 1 0 [ t h a t i s , w h e n R 1 0 i s ( C l - C 2 O ) a l k y l , ( C 1C 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e , o r ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r oc y c l e ] , one o r tW o 4CHi ay be e p l a c e d With iNi. no t h e r embodiments f t h e i n v e n t i o n i n which 1 0 c o n t a i n s a na l k y l p o r t i o n , t W o 4CHi ay e r e p l a c e d b y 4C:Ci. ns t i l l o t h e r embodiments i n which 1 0 c o n t a i n s a n a l k y l p o rt i o n , o n e o r t W o 4CH2i ay e r e p l a c e d by 40*,iSi,iSOi, isozi, 4CECi, a ( C 3 - C l o ) c a r b o c y c l e o r a( C 3 - C 6 ) h e t e r o c y c l e . I n y e t o t h e r e m b o d i m e n t s o f t h e i n v e nt i o n , R 1 O may b e i ( C l - C 2 O ) a l k y l , i ( C 3 - C l o ) c a r b o c y c l e ,i ( C 3 - C 9 ) h e t e r o c y c l e , i ( C l - C 8 ) a l k y l ( C 3 - C l o ) c a r b o c y c l e ,o r i ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r o c y c l e a d d i t i o n a l l y s u b s t it u t e d With o n e , tW o o r t h r e e s u b s t i t u e n t s . I n some embodim e n t s , t h e s e s u b s t i t u e n t s a r e c h o s e n i n d e p e n d e n t l y from%H3, iOH, iNHZ, %OOH, :O , iNHCONH2,iNHC(:NH)NH2,4CN r h a l o g e n .[ 0 0 3 8 ] I n some embodiments o f t h e i n v e n t i o n , R 1 i s%(:O)Rlo. n s o m e o f t h e s e e m b o d i m e n t s, R 1 0 s ( C l - C 1 5 )a l k y l . I n o t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , R 1 0 i s ( C 3 - C 6 )c a r b o c y c l e . I n some embodiments o f t h e i n v e n t i o n , R1 0 s a( C 3 - C 5 ) h e t e r o c y c l e . I n some embodiments o f t h e i n v e n t i o n ,R 1 0 i s a i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) c a r b o c y c l e . I n s t i l l o t h e re m b o d i m e n t s o f t h e i n v e n t i o n , R 1 0 i s a i ( C l - C 3 ) a l k y l ( C 3C 5 ) h e t e r o c y c l e . As b o v e , i n some embodiments f t h e i n v e nt i o n , i n t h e a l k y l p o r t i o n o f R 1 O [ t h a t i s , w h e n R 1 0 i s ( C l - C 1 5 )a l k y l , i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) c a r b o c y c l e , o r i ( C l - C 3 ) a l k y l( C 3 - C 5 ) h e t e r o c y c l e ] , on e o r tW o 4CHi ay be r e p l a c e dW i t h iNi. n o t h e r embodiments f t h e i n v e n t i o n i n whichR 1 0 c o n t a i n s a n a l k y l p o r t i o n , t W o 4CHi ay e r e p l a c e dby 4C:Ci. n s t i l l o t h e r embodiments i n which 1 0 cont a i n s a n a l k y l p o r t i o n , one o r tW o 4CH2i ay be e p l a c e db y 40*, Si, iSOi, iSOZi, 4CECi, ( C 3 - C l o )c a r b o c y c l e o r a ( C 3 - C 6 ) h e t er o c y c l e . I n y e t o t h e r embodim e n t s o f t h e i n v e n t i o n , R 1 O may e i ( C l - C 1 5 ) a l k y l , i(C3C 6 ) c a r b o c y c l e , i ( C 3 - C 5 ) h e t e r o c y c l e , i ( C l - C 3 ) a l k y l ( C 3C 6 ) c a r b o c y c l e , o r i ( C l - C 3 ) a l k y l ( C 3 - C 5 ) h e t e r o c y c l ea d d i t i o n a l l y s u b s t i t u t e d With n e , tW o r t h r e e s u b s t i t u e n t s . I nsome embodiments, t h e s e s u b s t i t u e n t s a r e chosen i n d e p e nd e n t l y f r o m CH3, iOH, iNHZ, 4COOH, :O, iNHCONH2, iNHC(:NH)NH2, iCN r h a l o g e n . I n y e t o t h e re m b o d i m e n t s o f t h e i n v e n t i o n , R 1 0 i s s e l e c t e d f r o m o p t i o n a l l ys u b s t i t u t e d c y c l o p r o p y l , c y c l o b u t y l , c y c l o p e n t y l , c y c l o h e x y l ,p h e n y l , p y r r o l e , i m i d a Z o l e , f u r a n , t e t r a h y d r o f u r a n , p i p e r id i n e , i m i d a Z o l y l m e t h y l a n d ( C l - C 1 O ) a l k y l . I n o t h e r e m b o d im e n t s , R1 0 s ( C l - C 1 O ) a l k y l i n Which one r tW o4CHi ayb e r e p l a c e d W i t h iNi. I n s t i l l o t h e r e m b o d i m e n t s , tW o4CHi ay be r e p l a c e d by 4C:Ci, and one o r tW o4CH2i may b e r e p l a c e d b y iOi, iSi, iSOi,iSOZi r CEO n some embodiments, R 1 0 i s t h e d e sc a r b o x y r e s i d u e o f a n a t u r a l o t - a m i n o a c i d . I n o t h e r embodim e n t s , R 1 0 i s iCH(Rll)i(CH2)niNHRl2. I n s t i l l o t h e rembodiments, R1 0 s i(CH2)niRl3 I n some embodiments,4C(:O)Rlo s 4 - a m i n o - 2 - h y d r o x y b u t y r y l .


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[ 0 0 3 9 ] I n some embodiments, n s Z e r o . I n o t h e r embodiments, n i s o n e . I n o t h e r embodiments, n i s t W o . I n o t h e rembodiments, n s t h r e e . I n o t h e r embodiments, n s f o u r . I no t h e r embodiments, n s ? v e . I n o t h e r embodiments, n s s i x .[ 0 0 4 0 ] I n some e m b o d i m e n t s , R 1 1 i s 40H. I n o t h e re m b o d i m e n t s , R 11 i s iNHZ.[ 0 0 4 1 ] I n some e m b o d i m e n t s , R 1 2 i s H . I n o t h e r embodim e n t s , R 1 2 i s ( C l - C 6 ) h a l o al k y l . I n s t i l l o t h e r e m b o d i m e n t s ,R 1 2 i s iC(:NH)NH2. n y e t o t h e r e m b o d i m e n t s , R 1 2 i s t h edeshydroxy e s i d u e o f a n a t u r a l o t - a m i n o a c i d .[ 0 0 4 2 ] I n some embodiments, R 1 3 i s iOH. I n somee m b o d i m e n t s , R 1 3 i s o p t i o n a l l y s u b s t i t u t e d p h e n y l . I n somee m b o d i m e n t s , R 1 3 i s o p t i o n a l l y s u b s t i t u t e d 5 - o r 6-memberedr i n g h e t e r o c y c l e .[ 0 0 4 3 ] I n some embodiments, R5 i s H . I n some embodim e n t s , R 5 i s h a l o g e n . I n o t h e r e m b o d i m e n t s , R 5 i s iN3. I ns t i l l o t h e r e m b o d i m e n t s , R5 i s ( C l - C 4 ) a l k y n y l . I n somee m b o d i m e n t s , R 5 i s iNHRSO. I n some e m b o d i m e n t s , R 5 i s? u o r i n e .[ 0 0 4 4 ] I n some embodiments o f t h e i n v e n t i o n , R 5 0 i s H . I nsome e m b o d i m e n t s o f t h e i n v e n t i o n , R 5 0 i s ( C 3 - C l o ) c a rb o c y c l e . I n some e m b o d i m e n t s o f t h e i n v e n t i o n , R 5 0 i s ( C 3C 9 ) h e t e r o c y c l e . I n some embodiments f t h e i n v e n t i o n , R 5 0 i si(C - C 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e . I n some m b o d i m e n t s o fth e i n v e n t i o n , R 5 0 i s i ( C 1 - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r o c y c l e . I nsome embodiments o f t h e i n v e n t i o n , R 5 0 i s t h e d e s h y d r o x yr e s i d u e of an a m i n o a c i d . I n some embodiments, R50 i ss e l e c t e d f r o m H , c y c l o p r o p y l , c y c l o p r o p y l m e t h y l , p y r r o l i d in y l , a n d t h e d e s h y d r o x y r e s i d u e o f c i t r u l l i n e o r s e r i n e .[ 0 0 4 5 ] I n some embodiments o f t h e i n v e n t i o n , R7 s H . I nsome embodiments o f t h e i n v e n t i o n , R7 i s ( C l - C 6 ) a l k y l . I nsome embodiments o f t h e i n v e n t i o n , R7 i s h y d r o X y ( C 1 - C 6 )a l k y l .[ 0 0 4 6 ] I n some e m b o d i m e n t s o f t h e i n v e n t i o n , R8 s ( C 1C 2 O ) a l k y l . I n some e m b o d i m e n t s o f t h e i n v e n t i o n , R8 s ( C 3C O ) c a r b o c y c l e . I n some embodiments f t h e i n v e n t i o n , R8 s( C 3 - C 9 ) h e t e r o c y c l e . I n some embodiments o f t h e i n v e n t i o n ,R8 i s i ( C l - C 8 ) a l k y l ( C 3 - C l o ) c a r b o c y c l e . I n some embodim e n t s o f t h e i n v e n t i o n , R 8 i s i ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r oc y c l e . I n some m b o d i m e n t s o f t h e i n v e n t i o n , R8 s C(:NH)NH2. n some embodiments o f t h e i n v e n t i o n , R8 s N R S O R S I .I n some embodiments f t h e i n v e n t i o n , i n t h e a l k y l p o r t i o n o fR 8 [ t h a t i s , W h e n R 8 i s ( C 1 - C 2 O ) a l k y l , i ( C l - C 8 ) a l k y l ( C 3C l o ) c a r b o c y c l e , o r i ( C l - C 8 ) a l k y l ( C 3 - C 9 ) h e t e r o c y c l e ] , oneo r tW o iCHi ay be r e p l a c e d With iNi. I n o t h e rembodiments o f t h e i n v e n t i o n i n Which R8 c o n t a i n s a n a l k y lp o r t i o n , t W o 4CHi ay e r e p l a c e d by 4C:Ci. n s t i l lo t h e r embodiments n Which R8 o n t a i n s an l k y l p o r t i o n , oneo r t W o 4CH2i ay e r e p l a c e d b y iOi,iSi,iSOi,isozi,4CECi, ( C 3 - C l o ) c a r b o c y c l e o r a ( C 3 - C 6 ) h e te r o c y c l e . I n y e t o t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , R 8 mayb e ( C 1 - C 2 O ) a l k y l , ( C 3 - C 1 O ) c a r b o c y c l e , ( C 3 - C 9 ) h e t e r o c y c l e ,i ( C l - C 8 ) a l k y l ( C 3 - C l o ) c a r b o c y c l e , o r i ( C l - C 8 ) a l k y l ( C 3C 9 ) h e t e r o c y c l e a d d i t i o n a l l y s u b s t i t u t e d W i t h o n e , tW o r t h r e es u b s t i t u e n t s . I n some embodiments, t h e s e s u b s t i t u e n t s a r ec h o s e n i n d e p e n d e n t l y f r o m CH3, iCH2CH3, iOH,iCHZOH, iNH2, 4CH2NH2, iCOOH, :O , iNHCONH2, iNHC(:NH)NH2, iCN r h a l o g e n .[ 0 0 4 7 ] I n some embodiments o f t h e i n v e n t i o n , R 8 0 i s H . I no t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , R 8 0 i s ( C - C 6 ) a l k y l .[ 0 0 4 8 ] I n some embodiments o f t h e i n v e n t i o n , R 8 1 i s H . I no t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , R 8 1 i s ( C l - C 6 ) a l k y l .[ 0 0 4 9 ] I n some embodiments of h e i n v e n t i o n , A s a d i r e c tb o n d . I n some embodiments of t h e i n v e n t i o n , A i s

A u g . 8 , 2 01 3

i(C:O)i. I n o t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , A s4C(:O)Oi. n s t i l l o t h e r e m b o d i m e n t s o f t h e i n v e n t i o n , Ai s iNH(C:O)i. n y e t o t h e r embodiments o f t h e i n v e nt i o n , A s i(C:O)NHi. I n some embodiments o f t h ei n v e n t i o n , A s iNH(C:O)NHi. n some embodiments ft h e i n v e n t i o n , A s i(C:S)NHi. n o t h e r e m b o d i m e n t s o ft h e i n v e n t i o n , A s iNH(C:S)i. n some embodiments o ft h e i n v e n t i o n , A s iNH(C:S)NHi.[ 0 0 5 0 ] I n some m b o d i m e n t s o f t h e i n v e n t i o n , R7 n d R S A ,t a k e n t o g e t h e r W i t h t h e n i t r o g e n t o W h i c h t h e y a r e a t t a c h e d ,form a ( C 3 - C 9 ) h e t e r o c y c l e . I n some o f t h e s e embodiments,t h e ( C 3 - C 9 ) h e t e r o c y c l e i s o p t i o n a l l y s u b s t i t u t e d W i t h o n e , tW oo r t h r e e s u b s t i t u e n t s c h o s e n i n d e p e n d e n t l y from CH3,%H2CH3, ADH, %H2OH, iNHz, iCHzNHz,%OOH, :O, iN HCONH2, iNHC(:NH)NH2,%Na n d h a l o g e n .[ 0 0 5 1 ] I n s o m e e m b o d i m e n t s , R 7 a n d R S A , t a k e n t o g e t h e rW i t h t h e n i t r o g e n t o W h i c h t h e y a r e a t t a c h e d , f o r m a ( C 3 - C 6 )h e t e r o c y c l e . I n some e m b o d i m e n t s , t h i s ( C 3 - C 6 ) h e t e r o c y c l em ay be p t i o n a l l y s u b s t i t u t e d W i t h from one o t h r e e s u b s t i t ue n t s c h o s e n i n d e p e n d e n t l y f r o m CH3, iCH2CH3, iOH,%H2OH, iNHz, %H2NH2, iCOOH, :O , iNHCONH2, iNHC(:NH)NH2, 4CN n d h a l o g e n . I n o t h e re m b o d i m e n t s , R 7 a n d R S A , t a k e n t o g e t h e r W i t h t h e n i t r o g e nt o Which t h e y a r e a t t a c h e d , form a p i p e r i d i n e , p i p e r a Z i n e ,t e t r a h y d r o p y r i m i d i n e o r p y r r o l i d i n e , a n y o f Which r e o p t i o na l l y s u b s t i t u t e d W i t h CH3, 4CH2CH3, iOH, 4CH2OH,iNHz, %H2NH2, %OOH, O, iNHCONHz, iNHC(:NH)NH2, 4CN r h a l o g e n .[ 0 0 5 2 ] I n some embodiments, A s a d i r e c t bond and R7 andR 8 a r e c h o s e n i n d e p e n d e n t l y f r o m ( C - C 6 ) a l k y l a n d h y d r o x y( C l - C 6 ) a l k y l .[ 0 0 5 3 ] I n some embodiments f t h e i n v e n t i o n , R7 s H ; A sc h o s e n f r o m a d i r e c t b o n d , i(C:O)i, iC(:O)Oi, n diNH(C:O)i; a n d R 8 i s c h o s e n f r o m ( C 1 - C l 5 ) a l k y l , ( C 3C l o ) c a r b o c y c l e , ( C 3 - C 6 ) h e t e r o c y c l e , i ( C l - C 3 ) a l k y l ( C 3 - C 6 )c a r b o c y c l e , i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) h e t e r o c y c l e , i N ( C H 3 )2iNH2, a n d 4C(:NH)NH2. I n some o f t h e s eembodiments, one o r tW o of t h e iCHi e s i d u e s of t h e( C 1 - C l 5 ) a l k y l o r t h e ( C l - C 3 ) a l k y l p o r t i o n o f th e i ( C l - C 3 )a l k y l ( C 3 - C 6 ) c a r b o c y c l e o r i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) h e t e r oc y c l e may e may e r e p l a c e d W i t h iNi, W o 4CHi aybe e p l a c e d by i-C:Ci, r on e o r tW o 4CH2i ay er e p l a c e d b y iOi, isozi, 4CECi, ( C 5 - C 6 ) c a rb o c y c l e o r a ( C 3 - C 4 ) h e t e r o c y c l e . A d d i t i o n a l l y o r a l t e m at i v e l y , i n some f t h e s e e m b o d i m e n t s , t h e ( C l - C 1 5 ) a l k y l , ( C 3C l o ) c a r b o c y c l e , ( C 3 - C 6 ) h e t e r o c y c l e , i ( C l - C 3 ) a l k y l ( C 3 - C 6 )c a r b o c y c l e , o r i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) h e t e r o c y c l e may b ea d d i t i o n a l l y s u b s t i t u t e d W i t h from one t o t h r e e s u b s t i t u e n t sc h o s e n i n d e p e n d e n t l y f r o m CH3, iCH2CH3, iOH,%H2OH, iNHZ, %OOH, :O, iNHCONH2, iNHC(:NH)NH2, a n d h a l o g e n .[ 0 0 5 4 ] I n some e m b o d i m e n t s , R7 s H ; A s a d i r e c t b o n d ;a n d R 8 i s c h o s e n f r o m iN(CH3)2, iNHZ, a n d iC(:NH)N H 2 .[ 0 0 5 5 ] I n some embodiments f t h e i n v e n t i o n , R7 s H ; A sc h o s e n from d i r e c t bond and i(C:O)i; nd R8 s c h o s e nf r o m ( C 1 - C l 5 ) a l k y l , ( C 3 - C l o ) c a r b o c y c l e , ( C 3 - C 6 ) h e t e r oc y c l e , i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) c a r b o c y c l e , a n d i ( C l - C 3 )a l k y l ( C 3 - C 6 ) h e t e r o c y c l e . I n some f t h e s e e m b o d i m e n t s , t h e( C 1 - C l 5 ) a l k y l , ( C 3 - C 1 O ) c a r b o c y c l e , ( C 3 - C 6 ) h e t e r o c y c l e ,i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) c a r b o c y c l e , o r i ( C l - C 3 ) a l k y l ( C 3C 6 ) h e t e r o c y c l e may e a d d i t i o n a l l y s u b s t i t u t e d W i t h f r o m o n et o t h r e e s u b s t i t u e n t s c h o s e n i n d e p e n d e n t l y f r o m CH3,


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iCH2CH3, ADH, %H2OH, iNHz, %OOH, :O,iNHCONHZ, iNHC(:NH)NH2, a n d h a l o g e n .[ 0 0 5 6 ] I n some embodiments f t h e i n v e n t i o n , R7 s H ; A sc h o s e n f r o m a d i r e c t b o n d , i(C:O)i, iC(:O)Oi, n diNH(C:O)i; n d R8 s ( C 1 - C l 5 ) a l k y l . I n some o f t h e s eembodiments, one r tW o iCHi f h e ( C l - C 1 5 ) a l k y l mayb e r e p l a c e d W i t h iNi, W o 4CHi ay b e r e p l a c e d b yiC:Ci, o r one o r tW o 4CH2i ay b e r e p l a c e d byiOi, SOzi, iCECi, y c l o p e n t y l , c y c l o h e x y l , f u r a no r d i o x o l e . I n s t i l l o t h e r embodiments, t h e ( C 1 - C l 5 ) a l k y l o rr e p l a c e d ( C 1 - C l 5 ) a l k y l may d d i t i o n a l l y b e s u b s t i t u t e d W i t hfrom one t o t h r e e s u b s t i t u e n t s chosen i n d e p e n d e n t l y fromiCH3, iCH2CH3, ADH, iCHzOH, iNHZ, iCOOH,:O, iNHCONHZ, iNHC(:NH)NH2, a n d h a l o g e n .[ 0 0 5 7 ] I n some embodiments f t h e i n v e n t i o n , R7 s H ; A sa d i r e c t b o n d ; a n d R 8 i s ( C l - C 6 ) a l k y l a d d i t i o n al l y s u b s t i t u t e dWith on e t o o r tW o s u b s t i t u e n t s chosen independently fromiOH, iNH2, a n d iNHC(:NH)NH2. I n some o f t h e s ee m b o d i m e n t s , R8 s a m i n o p r o p y l . I n some o f t h e s e embodim e n t s , R5 i s ? u o r i n e . I n some o f t h e s e e m b o d i m e n t s ,i(C:O)RlO s 4 - a m i n o - 2 - h y d r o x y b u t y r y l .[ 0 0 5 8 ] I n some embodiments o f t h e i n v e n t i o n , R 1 0 i ss e l e c t e d f r o m o p t i o n a l l y s u b s t i t u t e d c y c l o p r o p y l , c y c l o b u t y l ,c y c l o p e n t y l , c y c l o h e x y l , p h e n y l , p y r r o l e , i m i d a Z o l e , f u r a n ,t e t r a h y d r o f u r a n , p i p e r i d i n e , i m i d a Z o l y l m e t h y l , ( C - C 0 ) a l k y l[ i n Which one o r tW o 4CHi ay be e p l a c e d W i t h iNi,tW o iCHi ay be e p l a c e d by 4C:Ci, nd one r tW oiCHzi may b e r e p l a c e d b y 40*, iSi, iSOi,iSOZi r iCEC], h e d e s c a r b o x y r e s i d u e o f a n a t u r a lo t - a m i n o a c i d , 4CH(Rll)i(CH2)niNHRl2, a n d i(CH2)niRl3 I n t h e s e embodiments, A s chosen from d i r e c t bonda n d i(C:O)i, a n d R 8 i s c h o s e n f r o m ( C l - C 1 5 ) a l k y l , ( C 3C l o ) c a r b o c y c l e , ( C 3 - C 6 ) h e t e r o c y c l e , i ( C l - C 3 ) a l k y l ( C 3 - C 6 )c a r b o c y c l e , a n d i ( C l - C 3 ) a l k y l ( C 3 - C 6 ) h e t e r o c y c l e . T h e ( CC l 5 ) a l k y l , ( C 3 - C 1 O ) c a r b o c y c l e , ( C 3 - C 6 ) h e t e r o c y c l e , ( C l - C 3 )a l k y l ( C 3 - C 6 ) c a r b o c y c l e , ( C l - C 3 ) a l k y l ( C 3 - C 6 ) h e t e r o c y c l emay be a d d i t i o n a l l y s u b s t i t u t e d W i t h from one to t h r e e s u bs t i t u e n t s c h o s e n i n d e p e n d e n t l y f r o m CH3, iCH2CH3,iOH, iCHzOH, iNHz, %OOH, :O , iNHCONH2,iNHC(:NH)NH2, n d h a l o g e n . I n some f t h e s e embodim e n t s , R 5 i s c h o s e n f r o m H , ? u o r i n e , N3 a n d iNHRSO, a n dR 5 0 i s c h o s e n f r o m H , c y c l o p r o p y l , c y c l o p r o p y l m e t h y l , p y rr o l i d i n y l , a n d t h e d e s h y d r o x y r e s i d u e o f c i t r u l l i n e o r s e r i n e .[ 0 0 5 9 ][ 0 0 6 0 ] T h r o u g h o u t t h i s s p e c i ? c a t i o n t h e t e r m s a n d s u bs t i t u e n t s r e t a i n t h e i r d e ? n i t i o n s .[ 0 0 6 1 ] A l k y l i s i n t e n d e d t o i n c l u d e l i n e a r a n d b r a n c h e dh y d r o c a r b o n s t r u c t u r e s . A c o m b i n a t i o n o f a l k y l W i t hc y c l o a l k y l s u c h a s i(Cl C 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e W o u l db e , f o r e x a m p l e , c y c l o p r o p y l m e t h y l . L o W e r a l k y l r e f e r s t oa l k y l g r o u p s o f from t o 6 c a r b o n a t o m s . Examples o f l o W e ra l k y l g r o u p s i n c l u d e m e t h y l , e t h y l , p r o p y l , i s o p r o p y l , n - b u t y l ,s - b u t y l a n d t - b u t y l , a n d t h e l i k e . P r e f e r r e d a l k y l g r o u p s a r et h o s e o f C 2 0 o r b e l o W . C y c l o a l k y l o r c a r b o c y c l e i n c l u d e sc y c l i c h y d r o c a r b o n g r o u p s o f from 3 t o 8 c a r b o n a t o m s .E x a m p l e s o f c y c l o a l k y l g r o u p s i n c l u d e c - p r o p y l , c - b u t y l ,c - p e n t y l , n o r b o m y l a n d t h e l i k e . A l k y l e n e i s a d i v a l e n t a l k y lr e s i d u e , f o r e x a m p l e p r o p y l e n e i s iCH2CH2CH2i.[ 0 0 6 2 ] Alkoxy o r a l k o x y l r e f e r s t o g r o u p s o f from to 6c a r b o n a t o m s o f a s t r a i g h t , b r a n c h e d , o r c y c l i c c o n ? g u r a t i o nand c o m b i n a t i o n s t h e r e o f a t t a c h e d t o t h e p a r e n t s t r u c t u r et h r o u g h a n o x y g e n . E x a m p l e s i n c l u d e m e t h o x y , e t h o x y , p r o

I n some e m b o d i m e n t s , R 2 i s iNHZ n d R 3 i s H .

A u g . 8 , 2 01 3

p o x y , i s o p r o p o x y , c y c l o p r o p y l o x y , c y c l o h e x y l o x y a n d t h el i k e . LoWer-alkoxy r e f e r s t o g r o u p s c o n t a i n i n g one t o f o u rc a r b o n s .[ 0 0 6 3 ] S i m i l a r l y , a l k y l t h i o r e f e r s t o g r o u p s o f from t o 6c a r b o n a t o m s o f a s t r a i g h t , b r a n c h e d , o r c y c l i c c o n ? g u r a t i o nand c o m b i n a t i o n s t h e r e o f a t t a c h e d t o t h e p a r e n t s t r u c t u r et h r o u g h s u l f u r .[ 0 0 6 4 ] Aryl and e t e r o a r y l mean 5 - o r 6-membered a r om a t i c o r h e t e r o a r o m a t i c r i n g c o n t a i n i n g 0 - 3 h e t e r o a t o m ss e l e c t e d from O , N , o r S ; a b i c y c l i c 9 - o r l0-membereda r o m a t i c o r h e t e r o a r o m a t i c r i n g s y s t e m c o n t a i n i n g 0 - 3 h e teroatoms s e l e c t e d from O, N, o r S ; o r a t r i c y c l i c 1 3 - o rl4-membered a r o m a t i c o r h e t e r o a r o m a t i c r i n g system cont a i n i n g 0 - 3 h e t e r o a t o m s s e l e c t e d from O , N , o r S . Th e a r om a t i c 6 - t o l 4 - m e m b e r e d c a r b o c y c l i c r i n g s i n c l u d e , e . g . ,b e n Z e n e , n a p h t h a l e n e , i n d a n e , t e t r a l i n , a n d ? u o r e n e a n d t h e5 - t o l0-membered r o m a t i c h e t e r o c y c l i c r i n g s i n c l u d e , e . g . ,i m i d a Z o l e , p y r i d i n e , i n d o l e , t h i o p h e n e , b e n Z o p y r a n o n e , t h i aZ o l e , f u r a n , b e n Z i m i d a Z o l e , q u i n o l i n e , i s o q u i n o l i n e , q u i n o x al i n e , p y r i m i d i n e , p y r a Z i n e , t e t r a Z o l e a n d p y r a Z o l e . As u s e dh e r e i n a r y l and h e t e r o a r y l r e f e r t o r e s i d u e s i n Which one o rmore i n g s a r e a r o m a t i c , b u t n o t a l l need e .[ 0 0 6 5 ] A r y l a l k y l a s a s u b s t i t u e n t means an a r y l r i n ga t t a c h e d t o t h e p a r e n t s t r u c t u r e v i a a n a l k y l r e s i d u e . Examplesa r e b e n Z y l , p h e n e t h y l and t h e l i k e . H e t e r o a r y l a l k y l means ah e t e r o a r y l r i n g a t t a c h e d t o t h e p a r e n t s t r u c t u r e v i a a n a l k y lr e s i d u e . E x a m p l e s i n c l u d e , e . g . , p y r i d i n y l m e t h y l , p y r i m i d in y l e t h y l a n d t h e l i k e .[ 0 0 6 6 ] H y d r o c a r b o n means a l i n e a r , b r a n c h e d , o r c y c l i cr e s i d u e c o m p r i s e d o f h y d r o g e n a n d c a r b o n a s t h e o n l ye l e m e n t a l c o n s t i t u e n t s a n d i n c l u d e s a l k y l , c y c l o a l k y l , p o l yc y c l o a l k y l , a l k e n y l , a l k y n y l , a r y l a n d c o m b i n a t i o n s t h e r e o f .E x a m p l e s i n c l u d e b e n Z y l , p h e n e t h y l , c y c l o h e x y l m e t h y l ,c a m p h o r y l a n d n a p h t h y l e t h y l .[ 0 0 6 7 ] U n l e s s o t h e r W i s e s p e c i ? e d , t h e t e r m c a r b o c y c l e i si n t e n d e d t o i n c l u d e r i n g s y s t e m s i n Which h e r i n g a t o m s a r ea l l c a r b o n b u t o f any o x i d a t i o n s t a t e . Thus ( C 3 - C 1 O ) c a rb o c y c l e r e f e r s to b o t h n o n - a r o m a t i c a n d a r o m a t i c s y s t e m s ,i n c l u d i n g s u c h s y s te m s a s c y c l o p r o p a n e , b e n Z e n e a n d c y c l oh e x e n e . C a r b o c y c l e , i f n o t o t h e r W i s e l i m i t e d , r e f e r s t o monoc y c l e s , b i c y c l e s a n d p o l y c y c l e s .[ 0 0 6 8 ] H e t e r o c y c l e means a c y c l o a l k y l o r a r y l r e s i d u e i nWhich one to f o u r of h e c a r b o n s i s r e p l a c e d by a h e t e r o a t o msuch s oxygen, i t r o g e n o r s u l f u r . H e t e r o a r y l s form s u b s e to f e t e r o c y c l e s . E x a m p l e s o f h e t e r o c y c l e s t h a t f a l l W i t h i n t h es c o p e o f t h e i n v e n ti o n i n c l u d e p y r r o l i d i n e , p y r a Z o l e , p y r r o l e ,i n d o l e , q u i n o l i n e , i s o q u i n o l i n e , t e t r a h y d r o i s o q u i n o l i n e , b e nZ o f u r a n , b e n Z o di o x a n , b e n Z o d i o x o l e ( c o m m o n l y r e f e r r e d t oa s m e t h y l e n e d i o x y p h e n y l , W hen c c u r r i n g a s a s u b s t i t u e n t ) ,t e t r a Z o l e , m o r p h o l i n e , t h i a Z o l e , p y r i d i n e , p y r i d a Z i n e , p y r i m id i n e , t h i o p h e n e , f u r a n , o x a Z o l e , o x a Z o l i n e , i s o x a Z o l e , d i o xa n e , t e t r a h y d r o f u r a n a n d t h e l i k e .[ 0 0 6 9 ] Th e t e r m h a l o g e n means ? u o r i n e , c h l o r i n e , b r omine r i o d i n e . I n one embodiment, halogen m ay be u o r i n eor chlorine.[ 0 0 7 0 ] As u s e d h e r e i n , t h e t e r m o p t i o n a l l y s u b s t i t u t e d m ay be used i n t e r c h a n g e a b l y W i t h u n s u b s t i t u t ed o r s u b s t it u t e d . Th e t e r m s u b s t i t u t e d r e f e r s t o t h e r e p l a c e m e n t o fon e o r m o r e hydrogen atoms i n a speci?ed group With as p e c i ? e d r a d i c a l . I n o n e e m b o d i m e n t , l , 2 o r 3 h y d r o g e natoms r e r e p l a c e d W i t h a s p e c i ? e d r a d i c a l . I n t h e c a s e of l k y land c y c l o a l k y l , more t h a n t h r e e hydrogen atoms can ber e p l a c e d b y ? u o r i n e ; i n d e e d , a l l a v a i l a b l e h y d r o g e n a t o m sc o u l d b e r e p l a c e d b y ? u o r i n e .


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[ 0 0 7 1 ] V i r t u a l l y a l l o f t h e c o m p o u n d s d e s c r i b e d h e r e i nc o n t a i n on e r more asymmetric c e n t e r s and h u s g i v e r i s e t oe n a n t i o m e r s , d i a s t e r e o m e r s , a n d o t h e r s t e r e o i s o m e r i c f o r m st h a t m ay be d e ? n e d , i n t e r m s o f a b s o l u t e s t e r e o c h e m i s t r y , a s( R ) - o r ( S ) - . Th e r e s e n t i n v e n t i o n i s meant o i n c l u d e a l l s u c hp o s s i b l e i s o m e r s , a s W e l l a s t h e i r r a c e m i c and p t i c a l l y p u r ef o r m s . O p t i c a l l y a c t i v e ( R ) - a n d ( S ) - i s o m e r s may e p r e p a r e du s i n g c h i r a l s y n t h o n s o r c h i r a l r e a g e n t s , o r r e s o l v e d u s i n gc o n v e n t i o n a l t e c h n i q u e s . When t h e c o m p o u n d s d e s c r i b e dh e r e i n c o n t a i n o l e ? n i c double bonds o r o t h e r c e n t e r s of geom e t r i c a s y m m e t r y , a n d u n l e s s s p e c i ? e d o t h e r W i s e , i t i si n t e n d e d t h a t t h e compounds n c l u d e b o t h E n d Z e o m e t r i ci s o m e r s . L i k e w i s e , a l l t a u t o m e r i c forms a r e a l s o i n t e n d e d t obe i n c l u d e d .[ 0 0 7 2 ] S u b s t i t u e n t s R a r e g e n e r a l l y de?ned When n t r od u c e d a n d r e t a i n t h a t d e ? n i t i o n t h r o u g h o u t t h e s p e c i ? c a t i o na n d i n a l l i n d e p e n d e n t c l a i m s .[ 0 0 7 3 ] Th e term r e s i d u e of an amino a c i d a s used e r e i nr e f e r s t o an amino a c i d ( as de?ned beloW) minus oneh y d r o x y l o r c a r b o x y l t h a t i s c o n s i d e r e d p a r t o f t h e l i n k a g e t ot h e p a r e n t a m i n o g l y c o s i d e s c a f f o l d . W h e n h e r e s i d u e o f t h ea m i n o a c i d i s d e s h y d r o x y , i t W i l l b e m i n u s t h e h y d r o x y l o ft h e a c i d f u n c t i o n . I f t h e amino a c i d h a s t W o c a r b o x y l s ( e . g .g l u t a m i c a c i d ) t h e h y d r o x y c a n b e f r o m e i t h e r c a r b o x y l i ca c i d . W h e n h e r e s i d u e o f t h e amino a c i d i s d e s c a r b o x y ,i t W i l l be minus 4COOH; f t h e amino a c i d h a s tW o c a rb o x y l s , e i t h e r c a r b o x y l i c a c i d c a n b e r e m o v e d . F o r e x a m p l e ,i n t h e m o l e c u l e i l l u s t r a t e d b e l o W :

HZN OH

NH NH 0

0HO onHZN

t h e c i r c l e d r e s i d u e R 1 0 i s t h e d e s c a r b o x y r e s i d u e o f t h e n a t u r a lamino a c i d s e r i n e . S i m i l a r l y i n t h e m o l e c u l e :

t h e c i r c l e d r e s i d u e R 5 0 i s t h e d e s h y d r o x y r e s i d u e o f t h e n a t ur a l amino a c i d c i t r u l l i n e . These and s i m i l a r s t r u c t u r e s o famino c i d s t h a t l a c k a f u n c t i o n a l group t t h e p o i n t of t t a c h

A u g . 8 , 2 01 3

ment o t h e g l y c o s i d e s c a f f o l d a r e r e f e r r e d t o h e r e i n a s r e s id u e s of amino a c i d s . One might l s o r e f e r t o them a s aminoa c i d f r a g m e n t s .[ 0 0 7 4 ] Th e term amino a c i d a s used e r e i n r e f e r s t o t h er a c e m a t e s a n d a l l o p t i c a l i s o m e r s o f t h e f o l l o W i n g n a t u r a l l yo c c u r r i n g o t - a m i n o a c i d s : a l a n i n e , a s p a r a g i n e , a s p a r t i c a c i d ,a r g i n i n e , c i t r u l l i n e , c y s t e i n e , g l u t a m i c a c i d , g l u t a m i n e , g l yc i n e , h i s t i d i n e , i s o l e u c i n e , l e u c i n e , l y s i n e , m e t h i o n i n e , p h en y l a l a n i n e , p r o l i n e , s e r i n e , t h r e o n i n e , t r y p t o p h a n , t y r o s i n e ,v a l i n e , s a r c o s i n e , n o r v a l i n e , n o r l e u c i n e , h o m o s e r i n e , a l l ot h r e o n i n e , h y d r o x y n o r v a l i n e , s t a t i n e , h y d r o x y p r o l i n e , o r n it h i n e , 2 - a m i n o a d i p i c a c i d , p e n i c i l l a m i n e , h o m o c y s t e i n e ,S - m e t h y l c y s t e i n e , e t h i o n i n e a n d p h e n y l g l y c i n e . F o r t h e p u rpose o f t h i s i n v e n t i o n , t h e term amino a c i d a l s o i n c l u d e s as i n g l e n a t u r a l l y o c c u r r i n g [ 3 - a m i n o a c i d , [ 3 - a l a n i n e .[ 0 0 7 5 ] As s e d h e r e i n , and a s Would e u n d e r s t o o d by t h ep e r s o n of k i l l i n t h e a r t , t h e r e c i t a t i o n o f a compoun iu n l e s s e x p r e s s l y f u r t h e r l i m i t e d i i s i n t e n d e d t o i n c l u d e s a l t so f t h a t compound. T h u s , f o r e x a m p l e , t h e r e c i t a t i o n a compound o f f o r m u l a I as d e p i c t e d a b o v e , i n which R 1 i s4C(:NH)NH2, Would i n c l u d e s a l t s i n which R 1 i s4C(:NH)NH3+X_, Wherein X s any c o u n t e r i o n . I n a p a rt i c u l a r e m b o d i m e n t , t h e t e r m compound f f o r m u l a r e f e r st o t h e compound o r a p h a r r n a c e u t i c a l l y a c c e p t a b l e s a l tt h e r e o f .[ 0 0 7 6 ] Th e compounds o f t h e i n v e n t i o n may e p r e s e n t ass a l t s , i . e . c a t i o n i c s p e c i e s . T h e t e r m p h a r m a c e u t i c a l l ya c c e p t a b l e s a l t r e f e r s t o s a l t s Whose c o u n t e r i o n ( a n i o n )d e r i v e s f r o m p h a r r n a c e u t i c a l l y a c c e p ta b l e n o n - t o x i c a c i d si n c l u d i n g i n o r g a n i c a c i d s a n d o r g a n i c a c i d s . S u i t a b l e p h a rm a c e u t i c a l l y a c c e p t a b l e a n i o n s f o r t h e c o m p o u n d s o f t h ep r e s e n t i n v e n t i o n i n c l u d e a c e t a t e , b e n Z e n e s u l f o n a t e ( b e s yl a t e ) , b e n Z o a t e , b i c a r b o n a t e , b i s u l f a t e , c a r b o n a t e , c a m p h o rs u l f o n a t e , c i t r a t e , e t h a n e s u l f o n a t e , f u m a r a t e , g l u c o n a t e ,g l u t a m a t e , g l y c o l a t e , b r o m i d e , c h l o r i d e , i s e t h i o n a t e , l a c t a t e ,m a l e a t e , m a l a t e , m a n d e l a t e , m e t h a n e s u l f o n a t e , m u c a t e ,n i t r a t e , p a m o a t e , p a n t o t h e n a t e , p h o s p h a t e , s u c c i n a t e , s u l f a t e ,t a r t r a t e , t r i ? u o r o a c e t a t e , p - t o l u e n e s u l f o n a t e , a c e t a m i d o b e nZ o a t e , a d i p a t e , a l g i n a t e , a m i n o s a l i c y l a t e , a n h y d r o m e t h y le n e c i t r a t e , a s c o r b a t e , a s p a r t a t e , c a l c i u m e d e t a t e , c a m p h o r a t e ,c a m s y l a t e , c a p r a t e , c a p r o a t e , c a p r y l a t e , c i n n a m a t e , c y c l am a t e , d i c h l o r o a c e t a t e , e d e t a t e ( E D T A ) , e d i s y l a t e , e m b o n a t e ,e s t o l a t e , e s y l a t e , ? u o r i d e , f o r m a t e , g e n t i s a t e , g l u c e p t a t e , g l uc u r o n a t e , g l y c e r o p h o s p h a t e , g l y c o l a t e , g l y c o l l y l a r s a n i l a t e ,h e x y l r e s o r c i n a t e , h i p p u r a t e , h y d r o x y n a p h t h o a t e , i o d i d e , l a ct o b i o n a t e , m a l o n a t e , m e s y l a t e , n a p a d i s y l a t e , n a p s y l a t e , n i c ot i n a t e , o l e a t e , o r o t a t e , o x a l a t e , o x o g l u t a r a t e , p a l m i t a t e , p e c t in a t e , p e c t i n a t e p o l y m e r , p h e n y l e t h y l b a r b i t u r a t e , p i c r a t e ,p i d o l a t e , p r o p i o n a t e , r h o d a n i d e , s a l i c y l a t e , s e b a c a t e , s t e a r a t e ,t a n n a t e , t h e o c l a t e , t o s y l a t e a n d t h e l i k e . A l t h o u g h p h a r m ac e u t i c a l l y a c c e p t a b l e c o u n t e r i o n s W i l l b e p r e f e r r e d f o r p r ep a r i n g 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 t h e r a n i o n s a r e q u i t ea c c e p t a b l e a s s y n t h e t i c i n t e r m e d i a t e s . T h a t i s , p h a r m a c e u t ic a l l y u n d e s i r a b l e a n i o n s , s u c h a s i o d i d e , o x a l a t e , t r i ? u or o m e t h a n e s u l f o n a t e a n d t h e l i k e , may e p r e s e n t When s u c hs a l t s a r e chemical i n t e r m e d i a t e s .[ 0 0 7 7 ] I t W i l l b e r e c o g n i Z e d t h a t t h e compounds o f t h i si n v e n t i o n c a n e x i s t i n r a d i o l a b e l e d f o r m , i . e . , t h e compoundsmay ontain one or more atoms containing an atomic mass ormass number i f f e r e n t f r o m th e atomic mass or mass numberu s u a l l y f o u n d i n n a t u r e . R a d i o i s o t o p e s o f h y d r o g e n , c a r b o n ,p h o s p h o r o u s , ? u o r i n e , a n d c h l o r i n e i n c l u d e 2 H , 3 H , 1 3 C , 1 4 C ,1 5 N, 5 S , 1 8 F , and 6 C l , r e s p e c t i v e l y . Compounds h a t c o n t a i nt h o s e r a d i o i s o t o p e s a n d / o r o t h e r r a d i o i s o t o p e s o f o t h e r a t o m sa r e W i t h i n t h e s c o p e o f h i s i n v e n t i o n . A m on g h e i s o t o p i c a l l ya l t e r e d compounds f t h e i n v e n t i o n , d e u t e r a t e d , i . e . 2 H , co mp o u n d s a r e o f p a r t i c u l a r i n t e r e s t . S e l e c t i v e i n c o r p o r a t i o n o f


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d e u t e r i u m i n p l a c e o f h y d r o g e n ( d e u t e r a t i o n ) h a s t h e u n i q u ee f f e c t o f r e t a i n i n g t h e b i o c h e m i c a l p o t e n c y a n d s e l e c t i v i t y o fp h y s i o l o g i c a l l y a c t i v e c o m p o u n d s W h i l e , i n c e r t a i n i n s t a n c e s ,m o d i f y i n g m e t a b o l i c f a t e t o s u b s t a n t i a l l y a l t e r t h e i r o v e r a l lt h e r a p e u t i c p r o ? l e . I n f a v o u r a b l e c a ses , t h i s m o d i ? c a t i o n h a st h e p o t e n t i a l t o h a v e a p o s i t i v e i m p a c t e f f e c t on a f e t y , e ? ic a c y a n d / o r t o l e r a b i l i t y . [ S e e T h e D e v e l o p m e n t o f D e u t er i u m - C o n t a i n i n g D r u g s b y R o g e r T u n g , I n n o v a t i o n s i nP h a r m a c e u t i c a l T e c h n o l o g y March 2010 and US. a t . N o s .7 , 5 1 4 , 0 6 8 ; 7 , 6 0 8 , 7 3 7 ; 7 , 6 7 8 , 9 1 4 a n d o t h e r s . ] T r i t i a t e d , ie3 H , a n d c a r b o n - 1 4 , i . e . , l 4 C , r a d i o i s o t o p e s a r e i n c e r t a i n c i rc u m s t a n c e s p r e f e r r e d f o r t h e i r e a s e i n p r e p a r a t i o n and e t e c ta b i l i t y . C o m p o u n d s t h a t c o n t a i n i s o t o p e s 1 1 C , 1 3 N , 1 5 O a n d1 8 F a r e W e l l s u i t e d f o r p o s i t r o n e m i s s i o n t o m o g r a p h y . Radiol a b e l e d compounds d e s c r i b e d a b o v e c a n g e n e r a l l y b e p r ep a r e d by methods W e l l knoWn o t h o s e s k i l l e d i n t h e a r t .C o n v e n i e n t l y , s u c h r a d i o l a b e l e d compounds a n b e p r e p a r e db y c a r r y i n g o u t t h e p r o c e d u r e s d i s c l o s e d i n t h e E x a m p l e s a n dS c h e m e s b y s u b s t i t u t i n g a r e a d i l y a v a i l a b l e r a d i o l a b e l e dr e a g e n t f o r a n o n - r a d i o l a b e l e d r e a g e n t .[ 0 0 7 8 ] A l t h o u g h t h i s i n v e n t i o n i s s u s c e p t i b l e t o e m b o d iment n many i f f e r e n t f o r m s , p r e f e r r e d embodiments o f t h ei n v e n t i o n a r e s h o W n . I t s h o u l d b e u n d e r s t o o d , h o W e v e r , t h a tt h e p r e s e n t d i s c l o s u r e i s t o be c o n s i d e r e d a s an exempli?cat i o n o f t h e p r i n c i p l e s o f h i s i n v e n t i o n and s n o t i n t e n d e d tol i m i t t h e i n v e n t i o n t o t h e embodiments l l u s t r a t e d . I t may befound upon x a m i n a t i o n t h a t c e r t a i n members f t h e c l a i m e dg e n u s a r e n o t p a t e n t a b l e t o t h e i n v e n t o r s i n t h i s a p p l i c a t i o n . I nt h i s e v e n t , s u b s e q u e n t e x c l u s i o n s o f s p e c i e s f r o m t h e c o m p a s so f a p p l i c a n t s c l a i m s a r e t o be c o n s i d e r e d a r t i f a c t s o f p a t e n tp r o s e c u t i o n and n o t r e ? e c t i v e o f t h e i n v e n t o r s c o n c e p t o rd e s c r i p t i o n o f h e i r i n v e n t i o n ; t h e i n v e n t i o n e n c o m p a s s e s a l lo f t h e members o f t h e g e n u s ( I ) t h a t a r e n o t a l r e a d y i n t h ep o s s e s s i o n o f h e p u b l i c .[ 0 0 7 9 ] A o m p r e h e n s i v e l i s t o f a b b r e v i a t i o n s u t i l i Z e d b yo r g a n i c c h e m i s t s a p p e a r s i n t h e ? r s t i s s u e o f e a c h volume o ft h e J o u r n a l o f O r g a n i c C h e m i s t r y . T h e i s t , W h i c h s t y p i c a l l yp r e s e n t e d i n a t a b l e e n t i t l e d S t a n d a r d L i s t o f A b b r e v i a t i o n s ,i s i n c o r p o r a t e d h e r e i n b y r e f e r e n c e . T h e f o l l o W i n g a b b r e v i at i o n s a n d t e r m s h a v e t h e i n d i c a t e d m e a n i n g s t h r o u g h o u t :A c : a c e t y lB o c ? - b u t y l o x y c a r b o n y lB r e d e r e c k s R e a g e n t ? e r t - b u t o x y - b i s - ( d i m e t h y l a m i n o )methaneB u : b u t y lD C C : d i c y c l o h e x y l c a r b o d i i m i d eD I P E A I d i i s o p r o p y l e t h y l a m i n eD M A P I d i m e t h y I a m i n o p y r i d i n eD M F : N , N - d i m e t h y l f o r m a m i d e[ 0 0 8 0 ] EDCII ( 3 - ( d i m e t h y l a m i n o ) p r o p y l ) - 3 - e t h y l - c a r b od i i m i d e h y d r o c h l o r i d eE t O A c : e t h y l a c e t a t eH O B t : h y d r o x y b e n Z o t r i a Z o l eH O S U : N - h y d r o x y s u c c i n i m i d e[ 0 0 8 1 ] L i H M D S I I i t h i u m h e x a m e t h y l d i s i l a Z i d eM C P B A I m e t a - C h l o r o p e r o x y b e n Z o i c A c i dM e : m e t h y lMICIminimum n h i b i t o r y c o n c e n t r a t i o nMMP:matrix e t a l l o p r o t e i n a s eNaH:sodium y d r i d e

A u g . 8 , 2 01 3

N H S : N - h y d r o x y s u c c i n i m i d e[ 0 0 8 2 ] P h r p h e n y lP h O H : p h e n o lrt:room e m p e r a t u r es a t d I s a t u r a t e dT B D M S ? - b u t y l d i m e t h y l s i l y lT H F ? e t r a h y d r o f u r a nT I P S ? r i i s o p r o p y l s i l y lT M S ? r i m e t h y l s i l y l[ 0 0 8 3 ] Th e f o l l o W i n g a b b r e v i a t i o n s a r e a l s o u s e d i n t h ed e s c r i p t i o n o f t h e s u b s t i t u e n t s i n t h e t e x t o f h i s a p p l i c a t i o n :

HN H 2 ~ 5 7 i N \ " / N H 20H NHAHB G

H~ i i N \ / \ / N H Z i i AHPDA CPA

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[ 0 0 8 4 ] I t may happen h a t r e s i d u e s i n t h e s u b s t r a t e o f n t e re s t r e q u i r e p r o t e c t i o n a n d d e p r o t e c t i o n d u r i n g t h e s y n t h e s i sp r o c e d u r e . T e r m i n o l o g y r e l a t e d t o p r o t e c t i n g , d e p r o t e c ti n g a n d p r o t e c t e d f u n c t i o n a l i t i e s o c c u r s t h r o u g h o u t t h i sa p p l i c a t i o n . S u c h t e r m i n o l o g y i s W e l l u n d e r s t o o d b y p e r s o n sof k i l l i n t h e a r t and s used n t h e c o n t e x t of r o c e s s e s Whichi n v o l v e s e q u e n t i a l t r e a t m e n t W i t h a s e r i e s o f r e a g e n t s . I n t h a tc o n t e x t , a p r o t e c t i n g group e f e r s t o a group Which s used omask f u n c t i o n a l i t y d u r i n g a p r o c e s s s t e p i n Which t Wouldo t h e r W i s e r e a c t , b u t i n Which r e a c t i o n i s u n d e s i r a b l e . Thep r o t e c t i n g g r o u p p r e v e n t s r e a c t i o n a t t h a t s t e p , b u t may b es u b s e q u e n t l y r e m o v e d t o e x p o s e t h e o r i g i n a l f u n c t i o n a l i t y .Th e e m o v a l o r d e p r o t e c t i o n o c c u r s a f t e r t h e c o m p l e t i o n o ft h e r e a c t i o n o r r e a c t i o n s i n Which t h e f u n c t i o n a l i t y Wouldi n t e r f e r e . T h u s , W hen s e q u e n c e o f r e a g e n t s i s s p e c i ? e d , a s i ti s b e l o W , t h e p e r s o n o f o r d i n a r y s k i l l c a n r e a d i l y e n v i s i o nt h o s e g r o u p s t h a t Would e s u i t a b l e a s p r o t e c t i n g g r o u p s .S u i t a b l e groups f o r t h a t purpose a r e d i s c u s s e d i n s t a n d a r dt e x t b o o k s i n t h e ? e l d o f c h e m i s t r y , s u c h a s P r o t e c t i v e Groupsi n O r g a n i c S y n t h e s i s b y T . W . G r e e n e [ J o h n W i l e y & o n s ,NeW o r k , 1 9 9 1 ] , W h i c h i s i n c o r p o r a t e d h e r e i n b y r e f e r e n c e .[ 0 0 8 5 ] W h i l e i t may b e p o s s i b l e f o r t h e compounds o ff o r m u l a ( I ) t o be a d m i n i s t e r e d a s t h e raW c h e m i c a l , i t i sp r e f e r a b l e t o p r e s e n t them s a 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 .A c c o r d i n g t o a f u r t h e r a sp e c t , t h e p r e s e n t i n v e n t i o n p r o v i d e sa 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 c o m p r i s i n g a compound o f


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f o r m u l a ( I ) o r a 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 o r s o l v a t et h e r e o f , t o g e t h e r W i t h one o r more h a r m a c e u t i c a l l y c a r r i e r st h e r e o f and p t i o n a l l y one r more t h e r t h e r a p e u t i c i n g r e d ie n t s . Th e a r r i e r ( s ) must e a c c e p t a b l e i n t h e s e n s e o f b e i n gc o m p a t i b l e W i t h t h e o t h e r i n g r e d i e n t s o f t h e f o r m u l a t i o n a n dn o t d e l e t e r i o u s to t h e r e c i p i e n t t h e r e o f .[ 0 0 8 6 ] Th e f o r m u l a t i o n s i n c l u d e th o s e s u i t a b l e f o r o r a l ,p a r e n t e r a l ( i n c l u d i n g s u b c u t a n e o u s , i n t r a d e r m a l , i n t r a m u s c ul a r , i n t r a v e n o u s a n d i n t r a a r t i c u l a r ) , r e c t a l a n d t o p i c a l ( i n c l u di n g d e r m a l , b u c c a l , s u b l i n g u a l a n d i n t r a o c u l a r ) a d m i n i s t r at i o n . The mo t s u i t a b l e r o u t e m ay depend upon h e c o n d i t i o na n d d i s o r d e r o f t h e r e c i p i e n t . P a r e n t e r a l p h a r m a c e u t i c a l comp o s i t i o n s , o r a l d o s a g e f o r m s a n d o p i c a l p h a r m a c e u t i c a l co mp o s i t i o n s a r e p r e f e r r e d . T a b l e t s , c a p s u l e s , i n t r a o c u l a r t o p i c a lf o r m u l a t i o n s an d p a r e n t e r a l s o l u t i o n s a r e common amonga m i n o g l y c o s i d e s . Th e o r m u l a t i o n s may o n v e n i e n t l y b e p r es e n t e d i n u n i t d o s a g e f o r m a n d may e p r e p a r e d by n y o f t h emethods W e l l knoWn i n t h e a r t o f p h a r m a c y . A l l methodsi n c l u d e th e s t e p o f b r i n g i n g i n t o a s s o c i a t i o n a compound ff o r m u l a ( I ) o r a 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 o r s o l v a t et h e r e o f ( a c t i v e i n g r e d i e n t ) W i t h t h e c a r r i e r W h i c h c o n s t it u t e s one o r more a c c e s s o r y i n g r e d i e n t s . I n g e n e r a l , t h e f o rm u l a t i o n s a r e p r e p a r e d b y u n i f o r m l y a n d i n t i m a t e l y b r i n g i n gi n t o a s s o c i a t i o n t h e a c t i v e i n g r e d i e n t W i t h l i q u i d c a r r i e r s o r? n e l y d i v i d e d s o l i d c a r r i e r s o r b o t h and t h e n , i f n e c e s s a r y ,s h a p i n g t h e p r o d u c t i n t o t h e d e s i r e d f o r m u l a t i o n .[ 0 0 8 7 ] F o r m u l a t i o n s o f t h e p r e s e n t i n v e n t i o n s u i t a b l e f o ro r a l a d m i n i s t r a t i o n m ay be r e s e n t e d a s d i s c r e t e u n i t s such sc a p s u l e s , c a c h e t s o r t a b l e t s e a c h c o n t a i n i n g a p r e d e t e r m i n e damount of h e a c t i v e i n g r e d i e n t ; a s a poWder r g r a n u l e s ; a s as o l u t i o n o r a suspension n an aqueous l i q u i d o r a non-aqueous l i q u i d ; or a s an o i l - i n - W a t e r l i q u i d emulsion or a Wateri n - o i l l i q u i d e m u l s i o n . Th e a c t i v e i n g r e d i e n t may a l s o b ep r e s e n t e d a s a b o l u s , e l e c t u a r y o r p a s t e .[ 0 0 8 8 ] A a b l e t may e made y c o m p r e s s i o n o r m o l d i n g ,o p t i o n a l l y With one o r more a c c e s s o r y i n g r e d i e n t s . Com

A u g . 8 , 2 01 3

p r e s s e d t a b l e t s may e p r e p a r e d b y c o m p r e s s i n g i n a s u i t a b l emachine t h e a c t i v e i n g r e d i e n t i n a f r e e - ? o w i n g form s u c h a sa poWder r g r a n u l e s , o p t i o n a l l y mixed i t h a b i n d e r , l u b r ic a n t , i n e r t d i l u e n t , l u b r i c a t i n g , s u r f a c e a c t i v e o r d i s p e r si n ga g e n t . Molded a b l e t s may e made by o l d i n g i n a s u i t a b l emachine a m i x t u r e o f t h e poWdered compound m o i s t e n e dW i t h a n i n e r t l i q u i d d i l u e n t . The t a b l e t s may o p t i o n a l l y b ecoated o r scored an d may be formulated s o a s t o provides u s t a i n e d , d e l a y e d o r c o n t r o l l e d r e l e a se o f t h e a c t i v e i n g r e d ie n t t h e r e i n .[ 0 0 8 9 ] F o r m u l a t i o n s 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 c l u d ea q u e o u s a n d n o n - a q u e o u s s t e r i l e i n j e c t i o n s o l u t i o n s Whichmay o n t a i n a n t i - o x i d a n t s , b u f f e r s , b a c t e r i o s t a t s a n d s o l u t e sWhich e n d e r t h e f o r m u l a t i o n i s o t o n i c W i t h t h e b l o o d o f t h ei n t e n d e d r e c i p i e n t . F o r m u l a t i o n s f o r p a r e n t e r a l a d m i n i s t r at i o n a l s o i n c l u d e aqueous and non-aqueous s t e r i l e s u s p e ns i o n s , W h i c h may n c l u d e s u s p e n d i n g a g e n t s a n d t h i c k e n i n ga g e n t s . Th e f o r m u l a t i o n s may b e p r e s e n t e d i n u n i t - d o s e o fm u l t i - d o s e c o n t a i n e r s , f o r e x a m p l e s e a l e d a m p o u l e s a n dv i a l s , and m ay be s t o r e d i n a f r e e Z e - d r i e d ( l y o p h i l i Z e d ) cond i t i o n r e q u i r i n g o n l y t h e a d d i t i o n o f a s t e r i l e l i q u i d c a r r i e r , f o re x a m p l e s a l i n e , p h o s p h a t e - b u f f e r e d s a l i n e ( P B S ) o r t h e l i k e ,i m m e d i a t e l y p r i o r t o u s e . E x t e m p o r a n e o u s i n j e c t i o n s o l ut i o n s a n d s u s p e n s i o n s may e p r e p a r e d f r o m s t e r i l e p o W d e r s ,g r a n u l e s a n d t a b l e t s o f t h e k i n d p r e v i o u s l y d e sc r i b e d .[ 0 0 9 0 ] P r e f e r r e d u n i t dosage f o r m u l a t i o n s a r e t h o s e cont a i n i n g an f f e c t i v e d o s e , a s hereinbeloW e c i t e d , o r an approp r i a t e f r a c t i o n t h e r e o f , o f t h e a c t i v e i n g r e d i e n t .[ 0 0 9 1 ] I t s h o u l d b e u n d e r s t o o d t h a t i n a d d i t i o n t o t h e i n g r ed i e n t s p a r t i c u l a r l y m e n t i o n e d a b o v e , t h e f o r m u l a t i o n s o f h i si n v e n t i o n may i n c l u d e o t h er ag e n t s c o n v e n t i o n a l i n t h e a r th a v i n g r e g a r d t o t h e t y p e o f f o r m u l a t i o n i n q u e s t i o n , f o re x a m p l e t h o s e s u i t 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 may i n c l u d e? a v o r i n g a g e n t s .[ 0 0 9 2 ] T a b l e 1 ( b e l o w ) p r e s e n t s r e p r e s e n t a t i v e members ft h e g e n u s o f t h e i n v e n t i o n :

S u b s t i t u e n t s

Example # ID Code R1 R5 R 2 1 B R8iAiN(R7)i

l SXPl2l2-56"7 F OH OH l l l H ZH E HN H 2 ENWNTNHZO O

l l l H zE HN \ H / H 2

0 NH


9/23


10/23


11/23

US 2 0 1 3 / 0 2 0 3 6 9 3 A1 A u g . 8 , 2 0 1 3

- c o n t i n u e dS u b s t i t u e n t s

Example # ID Code R1 R5 R 2 1 6 ' R8iAiN(R7)i23 SXP1212-56"-41 O F OH OH

NHZ NH; NH

24 SXP1212-56"-42 O F OH OH

N H ; N/\/\NH2H25 SXP1212-56"-43 O F OH OH

NH; N/\H

2 6 2 5 5 4 O F N H 2 H LNHNH 2 > { N

27 2523 O F NH2 HN H ; > N / \ / \ N H 22 8 2524 0 F NH2 H

N H ; NMNHZOH29 2525 O F NH2 H NHHN H 2 %N

[ 0 0 9 3 ] F o r e v a l u a t i o n o f e f ? c a c y , W e a s s e m b l e d p a n e l s o f TABLEr e p r e s e n t a t i v e g r a m - n e g a t i v e p a t h o g e n s , i n c l u d i n gP s e u d o m o n a s a e r u g i n o s a ( P a e , PAWT, ATCC # 2 7 8 5 3 ) ,K l e b s i e l l a p n e u m o n i a e ( K p n , KPWT, ATCC # 7 0 0 6 0 3 ) ,A c i n e l o b a c l e r b a u m a n n i i ( A b a , ABWT, ATCC # B A A - 7 4 7 )a n d E s c h e r i c h i a c o l i ( E c o , ECWT, ATCC # 2 5 9 2 2 ) . T h e s er e f e r e n c e s t r a i n s a r e u s e f u l i n d i c a t o r o r g a n i s m s t o c h a r a c t e ri Z e compound c t i v i t y a g a i n s t b a c t e r i a f r o m a p a t h o g e n i cg e n u s i n t h e a b s e n c e o f m u l t i p l e r e s i s t a n c e m e c h a n i s m s . TW os t r a i n s (PAWT n d ECWT) r e r e f e r e n c e s t r a i n s c i t e d W i t h i nt h e C l i n i c a l a n d L a b o r a t o r y S t a n d a r d s I n s t i t u t e ( C L S I ) S t a nd a r d s f o r s u s c e p t i b i l i t y t e s t i n g b y Minimum n h i b i t o r y Conc e n t r a t i o n ( M I C ) (SXPS2) a n d a r e W e l l s u i t e d f o r q u a l i t yc o n t r o l . ABWT and ECWT r e W i d e l y s u s c e p t i b l e to amin o g l y c o s i d e a n t i b i o t i c s , W h e r e a s PAWT nd KPWT a r b o r as i n g l e a m i n o g l y c o s i d e - m o d i f y i n g e n Z y m e (AGME) h a t t a rg e t s 4 , 6 - s u b s t i t u t e d - 2 - d e o x y s t r e p t a m i n e A G s .

MIC a l u e s o f r e f e r e n c e A Gs g a i n s t i n d i c a t o r s t r a i n s .MIC u g / m L )

S t a n d a r d AG PAWT KPWT ABWT ECWTt o b r a l n y c i n 0 . 2 5 8 0 . 2 5 l

0 . 2 5 - 0 . 1 2 5 - 0 . 2 5s i s o m y c i n 0. 5 1- 2 0 . 2 5 0. 5

0 . 2 5d i b e k a c i n 0 . 5 1 6 0 . 2 5 l - 2

0 . 2 5a r b e k a c i n 0 . 5 0 . 5 0 . 5 lg e n t a l n y c i n l 8 0 . 2 5 - 0 . 5 0. 5a l n i k a c i n l - 2 l 1 2 - 4s t r e p t o m y c i n l 6 l - 2 2 - 4 4k a n a l n y c i n B l 6 l 6 0 . 5 - 1 2neomycin 3 2 4 - 8 0 . 2 5 - 0 . 5 l


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TABLE - c o n t i n u e dMIC a l u e s o f r e f e r e n c e AGs g a i n s t i n d i c a t o r s t r a i n s .

MIC u g / m L )S t a n d a r d AG PAWT KPWT ABWT ECWTk a n a l n y c i n A >6 4 32 1 4s p e c t i n o m y c i n >6 4 6 4 1 6 8 - 1 6

Pseudomonas a e r u g i n o s a i s a p r o m i n e n t n o s o c o m i a l p a t h og e n . I n a d d i t i o n t o i n t r i n s i c a n t i b i o t i c r e s i s t a n c e t o s e v e r a la n t i b i o t i c s , P s e u d o m o n a s h a s a c q u i r e d m u l t i p l e a d d i t i o n a lmechanisms f es i sta n c e . As r e s u l t , t h e r ap e u t i c o p t i o n s f o rt h e t r e a t m e n t o f i n f e c t i o n s c a u s e d by Pseudomonas a e r u g inosa a r e l i m i t e d . We c q u i r e d c l i n i c a l i s o l a t es of Pseudomoh a s a e r u g i n o s a ( M i c r o m y x L L C , K a l a m a z o o , M i c h ) , a n du s e d t h i s p a n e l t o t e s t compounds o r P s e u d o m o n i c i d a l a c t i vi t y . Th e a n e l i n c l u d e s PAWT, W o c l i n i c a l i s o l a t e s W i t h i n t e rm e d i a te a m i n o g l y c o s i d e r e s i s t a n c e ( P R 1 a n d P R 2 ) , a n d at h i r d c l i n i c a l i s o l a t e ( P R 3 ) p o s s e s s i n g h i g h - l e v e l , e ? l l u x - m ed i a t e d , p a n - a m i n o g l y c o s i d e r e s i s t a n c e ( i m p e r m e a b l e ) . F o re a c h s t r a i n and n t i b i o t i c , t h e m e c h a n i s m ( s ) o f e s i s t a n c e Wasi n f e r r e d f r o m t h e r e s i s t a n c e p r o ? l e . Th e r e s e n c e o f s p e c i ? cAGMEs as con?rmed by c o l o n y PCR.

TABLEP o t e n c y o f e f e r e n c e a n d t e s t c o m p o u n d s a g a i n s t P s e u d o m o n a s a e r u g i n o s a

W i l d t y p e a n d r e s i s t a n t s t r a i n s :MI C ( u g / m L )

PAWT PR 1 PR 2 PR 3TOB 0 . 2 5 2 >64 >64DI B 0 . 2 5 - 0 5 4 >64 >64SISO 0 . 2 5 - 0 . 5 4 >64 >64ARB 0. 5 8 8 - 1 6 1 6GEN 1 8 >64 >64AMK 1 - 2 8 8 - 1 6 64STREP 1 6 64 1 6 64KAN-B 1 6 64 >64 >64NEO 32 32 8 - 1 6 >64KAN-A >64 >64 >64 >64SP E >64 >64 >64 >64

SXP1212-56"-7 4 1 6 1 6 12 8SXP1212-56"-8 4 8 8 64SXP1212-56"-16 1 2 - 8


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TABLEM IC a l u e s a g a i n s t E n t e r o b a c t e r i a c e a e

K Z e b s i e Z Z a pneumonia E. c o l iSX P # KPWT K Rl K R 2 KM MIC90 MICg0

SXP1212-56"-16


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p r o t e c t e d W i t h Boc n d a c e t y l g r o u p s , t h e n t h e 5 - p o s i t i o n Wasc o n v e r t e d to 5 - F ( o r t o o t h e r s u b s t i t u e n t s R 5 ) a s d e s c r i b e db e l o w . The c e t yl p r o t e c t i n g g r o u p s Were h e n removed i t hb a s e (e g s o d i u m m e t h o x i d e ) a n d t h e 6 " h y d r o x y l Was o s yl a t e d . D i s p l a c e m e n t W i t h v a r i o u s a m i n e s R 8 - A - N H ( R 7 ) g a v et h e p e n u l t i m a t e p r o d u c t Which Was l e a v e d u n d e r a c i d i c cond i t i o n s t o p r o v i d e 5F-amikcin-NH-AHB-R6"-R8ANR7 a n al o g s :

A u g . 8 , 2 01 3

[ 0 1 0 2 ] T h e g e n e r a l p r o c e d u r e f o r t h e p r o t e c t i o n o f a m i n e sa n d a c e t y l a t i o n o f h e h y d r o x y l s i n t h e k a n a m y c i n a m i n o g l yc o s i d e s i s r e p o r t e d b y S h i t a r a e t a l [ S h i t a r a T , Umemura ,T s u c h i y a T , M a t s u n o T C a r b o h y d r a t e R e s ea r c h 2 7 6 , 7 5 - 8 9( 1 9 9 5 ) ] .[ 0 1 0 3 ] M o d i ? c a t i o n o f t h e R5 h y d r o x y l g r o u p i s g e n e r a l l ya c c o m p l i s h e d a s f o l l o W s : F o r R5 ? u o r o compounds, t h e p r ot e c t e d a m i n o g l y c o s i d e i s d i s s o l v e d i n d i c h l o r o m e t h a n e a n d

SCHEMElHN B HN2 PIN OH 00 BocHN OAc

0 OH o 0A0Mon OH unuOAc 0A0

NH2 0 l.Boc2O BocHN O2 . A C 2 Oo ,H N g

OH OHHO 0 A00 0

o 0HO OH AcO 0A0HZN BocHN

a s . bb

R 5 m o d i ? c a t i o n s( s e e t e x t )

B HN B HN0 BocHN OAc 0 BocHN OH

0 OAc O OHUnOAc 0A0 Mon OH

BocHN 0 BocHN 0o 1 . NaOMe/MeOH o

g 2 T 1 gosy ationR 5 R 5A00 0 TsO O

o 0A00 0A0 HO OHBocHN BocHN

cc ddH N2 HZN OH

0 OH\\\\OH OH s__NHRI O 1 . R A HNR

oHN 2 . d l O X i n ? / H c l

R 5R8ANR7 o

0HO OH

66


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c o o l e d to 2 0 0 C . A o l u t i o n o f d e o x o - ? u o r [ b i s - ( 2 - m e t h o x ye t h y l ) a m i n o s u l f u r t r i ? u o r i d e ] ( D A S T ) i s t h e n a d d e d d r o pWise o v e r 1 5 m i n . The e a c t i o n i s s t i r r e d o v e r n i g h t a t 20 Ca n d t h e e x c e s s r e a g e n t i s q u e n c h e d by t h e a d d i t i o n o f s o l i dNaHCO3. T h e r e a c t i o n i s W o r k e d u p b y W a s h i n g t h e o r g a n i cl a y e r W i t h a q . NaHCO3, a t e r , s o d i u m h y p o c h l o r i t e s o l u t i o n ,a n d t h e n W a t e r . Th e r g a n i c l a y e r i s d r i e d a n d t h e n e v a p o r a t e dt o p r o v i d e t h e R 5 - e p i - ? u o r o - 5 R 5 - d e s o x y a n a l o g s .[ 0 1 0 4 ] F o r R 5 - c h l o r o , bromo n d i o d o c o m p o u n d s , t h e p r ot e c t e d a m i n o g l y c o s i d e i s d i s s o l v e d i n d i c h l o r o m e t h a n e ( 2 0m l ) a n d m e s i t y l e n e s u l f o n y l c h l o r i d e ( 0 . 2 5 m o l e s ) i s a d d e d i nt h e p r e s e n c e o f c a t a l y t i c amount o f D MAP . Th e r e a c t i o nm i x t u r e i s s t i r r e d at r oom e m p e r a t u r e f o r 5 - 6 h o u r s and f t e rc o m p l e t i o n t h e p r o d u c t i s c o n c e n t r a t e d u n d e r vacuum o y i e l da m e s i t y l e n e s u l f o n a t e i n t e r m e d i a t e . F o r c h l o r i d e s , t h e i n t e rm e d i a t e i s d i s s o l v e d i n DMF 1 0 mL) n d L i C l ( 0 . 5 m o l e s ) i sa d d e d . Th e e a c t i o n i s re?uxed t 1 0 0 C . f o r 6 - 8 h o u r s . A f t e rc o m p l e t i o n o f t h e r e a c t i o n , t h e p r o d u c t i s c o n c e n t r a t e d u n d e rvacuum a n d s u s p e n d e d i n W a t e r ( 2 0 mL) a n d e x t r a c t e d W i t hC H 2 C l 2 ( 3 > < 2 5 m L ) . T h e o r g a n i c l a y e r i s W a s h e d W i t h b r i n ea n d d r i e d o v e r a n h y d r o u s Na2SO4 o l l o W e d b y c o n c e n t r a t i o nunder vacuum t o f u r n i s h 5-deoxy 5 - c h l o r o d e r i v a t i v e s . Forb r o m i d e s , t h e i n t e r m e d i a t e i s d i s s o l v e d i n DMF 1 0 mL) n dNaBr 4 m o l e s ) i s a d d e d . Th e e a c t i o n i s r e ? u x e d a t 1 0 0 0 C .f o r 1 8 h o u r s . Work-up o f t h e r e a c t i o n m i x t u r e as above f u rn i s h e s R 5 - d e o x y - R 5 - b r o m o c o m p o u n d s . F o r i o d i d e s , t h ei n t e r m e d i a t e i s d i s s o l v e d i n DMF 1 0 mL) n d N a l ( 6 m o l e s )i s a d d e d . Th e r e a c t i o n i s re?uxed t 1 0 0 0 C . f o r 1 8 h o u r s .Work-up o f t h e r e a c t i o n m i x t u r e as above f u r n i s h e sR 5 - d e o x y - R 5 - i o d o c o m p o u n d s .[ 0 1 0 5 ] F o r R5 a Z i d e s a n d a m i n e s , t h e m e s i t y l e n e s u l f o n a t ei n t e r m e d i a t e o b t a i n e d a s a b o v e i s d i s s o l v e d i n DMF 1 0 mL)a n d NaN3 8 m o l e s ) i s a d d e d . Th e e a c t i o n i s r e ? u x e d a t 1 0 0 0C . f o r 1 8 h o u r s . Work-up o f t h e r e a c t i o n m i x t u r e a s abovef u r n i s h e s 5 - d e o x y - R 5 a Z i d e c o m p o u n d s . T h e R5 d e o x y - R 5a Z i d e ( 5 0 0 mg) c a n b e d i s s o l v e d i n d r y THF ( 1 0 mL) a n dr e d u c e d b y a d d i n g L i A l H 4 i n THF 5 mL) t 1 0 0 C . T h er e a c t i o n i s s t i r r e d f o r 3 h o u r s a t r oom e m p e r a t u r e . A f t e r t h er e a c t i o n i s c o m p l e t e d , t h e r e a c t i o n m i x t u r e i s p a r t i a l l y c o nc e n t r a t e d u n d e r vacuum a n d d i e t h y l e t h e r ( 2 0 mL) p l u s d i l .HCl ( 2 0 % , 1 0 mL) a r e added W i t h s t i r r i n g a t 1 0 0 C . Theo r g a n i c l a y e r i s s e p a r a t e d a n d th e a q u e o u s l a y e r i s W a s h e dW i t h e x c e s s d i e t h y l e t h e r ( 2 > < 2 5 m L ) . Th e c o m b i n e d e t h e rl a y e r s a r e Washed W i t h b r i n e and d i e d o v e r a n h y d r o u sNa2SO4 f o l l o W e d by c o n c e n t r a t i o n u n d e r vacuum o f u r n i s hR5 d e o x y - R 5 - a m i n e c o m p o u n d s . T h e a m i n e c a n b e a l k y l a t e dW i t h t h e h a l i d e o f t h e a p p r o p r i a t e ( C 3 - C 1 O ) c a r b o c y c l e , ( C 3C 9 ) h e t e r o c y c l e , ( C l - C 8 ) a l k y l ( C 3 - C 1 O ) c a r b o c y c l e o r ( C l - C 8 )a l k y l ( C 3 - C 9 ) h e t e r o c y c l e . Or h e amine can be e a c t e d With ana c t i v a t e d e s t e r o f an - B o c - p r o t e c t e d aminoacid t o p r o v i d et h e compounds n w h i c h R 5 0 i s t h e d e s h y d r o x y r e s i d u e o f t h ea m i n o a c i d .[ 0 1 0 6 ] F o r compounds n Which R5 s a n a l k y n e , t h e m e s it y l e n e s u l f o n a t e i n t e r m e d i a t e can be e a c t e d With m e t a l s a l to f t h e a p p r o p r i a t e a l k y n e , s u c h a s s o d i u m a c e t y l i d e .[ 0 1 0 7 ] G e n e r a l p r o c e d u r e f o r d e p r o t e c t i o n o f a c e t y lg r o u p s : To a s o l u t i o n of c ( 8 0 mg) n 5 mL f 30% NaOMei n MeOH W as added, and t h e mixture W as s t i r r e d f o r overn i g h t . The s o l u t i o n Was e u t r a l i Z e d With aq HCl and concen

A u g . 8 , 2 01 3

t r a t e d . Th e e s i d u e Was h o r o u g h l y Washed i t h W a t e r ( 1 0 m l )and d r i e d i n vacuum a t 4 0 0 C . to g i v e compounds dd( ~ 6 0 % ) .[ 0 1 0 8 ] G e n e r a l p r o c e d u r e f o r d e p r o t e c t i o n o f Boc g r o u p s :Compound d d ( 2 0 0 mg) W a s d i s s o l v e d i n d i o x a n e / H C l ( 1 0mL) an d t i r r e d a t 100 . f o r 5 - 6 h r s . Dioxane Was removedunder vac uum an d t h e s o l i d o b t a i n e d Was Washed With i s op r o p y l e t h e r ( 2 > < 1 0 m L ) f o l l o W e d b y C H 2 C l 2 ( 2 > < 1 0 m L ) a n dd r y i n g a t 4 0 0 C . u n d e r vacuum fumished h e ? n a l compoundsmodi?ed t CiR5 o s i t i o n .[ 0 1 0 9 ] T h e g e n e r a l s y n t h e t i c m e t h o d f o r i n c o r p o r a t i o n o fg u a n i d i n e g r o u p s a t a l l a m i n e s o f a m i n o g l y c o s i d es i n v o l v e st h e c o n d i t i o n s r e p o r t e d i n t h e l i t e r a t u r e [ H o s h i H , A b u r a k i S ,l i m u r a S , Y a m a s a k i T , N a i t o T , K a W a g u c h i H h e J o u r n a l o fA n t i b i o t i c s 1 9 9 0 , 8 5 8 - 8 7 2 ] . S e l e c t i v e g u a n i d i n y l a t i o n o fa m i n e s W a s a c h i e v e d b y r e a c t i n g p r o t e c t e d a m i n o g l y c o s i d e sW i t h t h e c o r r e s p o n d i n g e q u i v a l e n t s o f T f N : C ( N H B o c ) 2 .T h u s , f o r e x a m p l e , i f a g u a n i d i n e i s d e s i r e d a t R 1 , compoundh of Scheme o r compound n of Scheme beloW can ber e a c t e d W i t h TfN:C(NHBoc)2 n t h e p r e s e n c e o f a b a s e s u c ha s t r i e t h y l a m i n e i n aqueous s o l u t i o n .[ 0 1 1 0 ] W hen n a l o g s a r e d e s i r e d i n which 1 i s n o t AHB,Scheme 1 c a n b e employed W i t h t h e a p p r o p r i a t e s t a r t i n gm a t e r i a l a a r e p l a c i n g a m i k a c i n . A l t e r n a t i v e l y , one can o ll o W t h e p r o c e d u r e s o f Schemes 2 a n d 3 b e l o W .[ 0 1 1 1 ] S y n t h e s i s o f E x a m p l e s 2 6 - 2 9 i s shoWn n s c h e m a t i cf o r m i n S c h e m e s 2 a n d 3 . A s shoWn n Scheme , t o b r a m y c i nWas ? r s t p r o t e c t e d W i t h Boc and a c e t y l g r o u p s , t h e n t h e5 - p o s i t i o n Was c o n v e r t e d t o 5 - F . The r o t e c t i n g g r o u p s Weret h e n removed. The 3 " and amines Were t h e n c h e l a t e d W i t hZn(OAc)2 and t h e n o n - c h e l a t e d a m i n e s a t 3 , 2 ' and ' Werep r o t e c t e d W i t h Boc r o u p s . Th e " - a m i n e Was r o t e c t e d as i t st r i ? u o r o a c e t a m i d e (TFA m i d e ) a n d th e r e m a i n i n g R 1 - a m i n eW a s c o u p l e d W i t h v a r i o u s c a r b o x y l i c a c i d s , i n c l u d i n g f o re x a m p l e s 2 6 - 2 9 , ( S ) - A H B - B o c . T h e c o u p l i n g ( h > i ) may ea c c o m p l i s h e d by n y o f t h e m e t h o d s W e l l - k n o w n i n t h e a r t o fp e p t i d e s y n t h e s i s . C o n d e n s i n g a g e n t s f o r r e a c t i n g a m i n e sW i t h c a r b o x y l i c a c i d s i n c l u d e c a r b o d i i m i d e s o f v a r i o u s s o r t s ,mixed a n h y d r i d e s , EEDQ, HATU, a n d t h e l i k e . I t i s a l s op o s s i b l e t o p r e - r e a c t t h e c a r b o x y l i c a c i d o f t h e l i n k e r W i t h a na p p r o p r i a t e l e a v i n g g r o u p t o form an a c t i v a t e d e s t e r . A c t iv a t e d e s t e r s d e n o t e e s t e r s Which a r e c a p a b l e of undergoing as u b s t i t u t i o n r e a c t i o n W i t h p r i m a r y o r s e c o n d a r y a m i n e s t oform n a m i d e . Th e e r m i n c l u d e s e s t e r s a c t i v a t e d by e i g hb o r i n g e l e c t r o n W i t h d r a W i n g s u b s t i t u e n t s . E x a m p l e s i n c l u d ee s t e r s o f p h e n o l s , p a r t i c u l a r l y e l e c t r o n e g a t i v e l y s u b s t i t u t e dp h e n o l e s t e r s s u c h a s p e n t a ? u o r o p h e n o l e s t e r s ; O - e s t e r s o fi s o u r e a , s u c h a s a r i s e from i n t e r a c t i o n W i t h c a r b o d i i m i d e s ;O - e s t e r s o f N - h y d r o x y i m i d es a n d N - h y d r o x y h e t e r o c y c l e s ;s p e c i ? c e x a m p l e s i n c l u d e S - t - b u t y l e s t e r s , S - p h e n y l e s t e r s ,S - 2 - p y r i d y l e s t e r s , N - h y d r o x y p i p e r i d i n e e s t e r s , N - h y d r o xy s u c c i n i m i d e e s t e r s , N - h y d r o x y p h t h a l i m i d e e s t e r s a n d N - h yd r o x y b e n Z o t r i a Z o l e e s t e r s .[ 0 1 1 2 ] Th e TFA r o u p Was t h e n c l e a v e d and e p l a c e d W i t ha B o c - g r o u p . T o s y l a t i o n o r m e s i t y l a t i o n o f t h e R6"-OH o ll o W e d b y d i s p l a c e m e n t W i t h v a r i o u s a m i n e s R 8 - A - N H ( R 7 )g a v e t h e p e n u l t i m a t e p r o d u c t Which Was l e a v e d u n d e r a c i d i cc o n d i t i o n s t o p r o v i d e 5 F - t o b r a m y c i n - N H - A H B - R 6 "RSANR7 n a l o g s :


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17/23

A u g . 8 , 2 01 3

OHBocHN

O NHBocOBocHN

HZN FHO O

h

US 2013/0203693 A 11 6

- c o n t i n u e dOHBocHN

TFAO O NHBoc WBocHN

HZNHO O F

HO 0 OH

HZNg

BocHN OH1) NH3eOH2 ) E0020

BocHNO NHBocOOH BOCHN

OE F

O

BocHN

HOHO 0 OHTFAHN

i

BOCHN OHBocHN

O N H B o c&>O 2 ) O H - r e s i nOH BOCHN

o g FR 8 A ( R 7 ) N O

HO 0 OHBocHN

k

[ 0 1 1 3 ] An l t e r n a t i v e r o u t e i s shown n Scheme , W h e r e i nt o b r a m y c i n - Z i n c c o m p l e x W a s r e a c t e d W i t h B o c - a n h y d r i d ea n d t h e n e t h y l t r i ? u o r o a c e t a t e . T h e r e m a i n i n g R l p o s i t i o nWas t h e n a c y l a t e d With AHB-Boc. The 3"-TFA Was c l e a v e dWith a s e , t h e n p r o t e c t e d a s a Boc g r o u p . The R 6 " - O H W ast r e a t e d W i t h m e s i t y l e n e s u l f o n y l c h l o r i d e f o l l o W e d b y d i sp l a c e m e n t o f t h e m e s i t y l e n e s u l f o n a t e W i t h v a r i o u s a m i n e s .

H0

Th e r e e a m i n e s W e r e p r o t e c t e d W i t h B o c , f o l l o W e d b y s e l e ct i v e a c y l a t i o n o f t h e h y d r o x y l g r o u p s , l e a v i n g t h e 5-OHu n p r o t e c t e d . Th e 5-OH Was ? u o r o d e o x y g e n a t e d W i t h DAST[ ( d i e t h y l a m i n o ) s u l f u r t r i ? u o r i d e ] o r DEOXO-FLUOR t og i v e t h e e p i - F - d e s o x y i n t e r m e d i a t e . T h i s m a t e r i a l Was t h e nd e p r o t e c t e d s e q u e n t i a l l y , ? r s t W i t h NaOCH3 a n d t h e n W i t hHC l t o remove t h e B o c - g r o u p s :


18/23


19/23

US 2 0 1 3 / 0 2 0 3 6 9 3 A1 A u g . 8 , 2 0 1 3

- c o n t i n u e dBOCNH OH BOCNH OH

BocNH BocNH8 7O NHBoc%NHBoc

o 0- \ \ O H BOCHN MOH BOCHN

o og O H g O HMesity1SO2O O R8ANR7 O

BocHN BocHNI S

B 0 0 2 0

BOCNH OH BOCNH 0A0BocNH BocNH

o NHBOC& NHBOCo 0- \ \ O H BOCHN -\OACBOCHN

o og O H g O HR8ANR7 O RsANRv oH o w o i r A c O w O A cocHN BocHN

t u

DEOXOFLUOR

BOCNH 0A0 HZ N OHBocNH HZN

o NHBOC 1 ) NH3M6OH o NH20 2)HC1 O. nOAC OCHN . nOH HZN

o og F g FR8ANR7 0 RsANRv 0

A 0 0 0 0 A 0 HowoirBocHN HZN

I n a s p e c i ? c e x a m p l e , SXP-2523 Was s y n t h e s i z e d a s f o l l o w s :[ 0 1 1 4 ] T e t r a h y d r o f u r a n ( 2 5 0 mL) a s a d d e d t o Z n ( O A c ) 2 .2H2O ( 2 9 . 3 g . 1 3 3 . 8 mmol) n a 5 0 0 mL r l e n m e y e r ? a s k ,s W i r l e d f o r 5 m i n , an d h e s o l i d Was o l l e c t e d on f r i t t e d g l a s sBuchner u n n e l and Washed i t h a n o t h e r 250 mL f THF. Th es o l i d Was completely r i e d under vacuum o r 1 hour t 4 0 0 C .T h e d r i e d Z n ( O A c ) 2 . 2 H 2 O a n d t o b r a m y c i n f r e e b a s e ( 2 5 . 0 g ,5 3 . 5 mmol) Were added t o a 3 L round-bottom ?ask ands t i r r e d W i t h m e t h a n o l ( 3 5 0 mL) t room t e m p e r a t u r e f o r 2

W

h o u r s ( a f t e r 2 0 - 2 5 min c l e a r s o l u t i o n Was o b s e r v e d ) . Et3N( 2 2 . 5 mL, 1 6 0 . 5 mmol) Was d d e d W i t h s t i r r i n g , a n d t h e i n i t i a lp r e c i p i t a t e t h a t formed i s s o l v e d W i t h i n 30 min o g i v e a c l e a rs o l u t i o n . B o c - a n h y d r i d e ( 4 6 . 6 g , 2 1 4 . 0 mmol) Was a d d e d t ot h i s s o l u t i o n , and t h e s t i r r i n g Was c o n t i n u e d f o r 1 6 h . Thep r o g r e s s o f t h e r e a c t i o n Was m o n i t o r e d by LC-MS, WhichshoWed a b o u t 1 0 % o f T o b - B o c 5 a s t h e o n l y i m p u r i t y . Th ee x c e s s B o c - a n h y d r i d e Was quenched by t h e a d d i t i o n o f 2 8 %NH4OH ( 3 . 5 mL) a n d s t i r r e d f o r 1 h o u r . V o l a t i l e s Were


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US 2013/0203693 A 1

r e m o v e d b y r o t a r y e v a p o r a t i o n ( b a t h t e m p 4 0 C . ) . T h e s o l i dr e s i d u e Was i s s o l v e d i n n - b u t a n o l ( 5 0 0 mL) n d Washed i t hN H 4 O H z b r i n e ( 2 : 1 , 1 L . 3 > < 3 3 0 m L ) , f o l l o w e d b y b r i n e( 2 > < 3 3 0 m L ) . Then a n e q u a l volume o f W a t e r ( 5 0 0 mL) Wasadded o t h e b u t a n o l l a y e r . The combined a t e r and u t a n o ll a y e r s W e r e e v a p o r a t e d u s i n g a G e n e v a c g R o c k e t E v a p o r a t o r( 4 5 C . , 3 h ) . Th e e s u l t i n g s o l i d W a s s u s p e n d e d i n m e t h a n o l( 6 0 mL) a n d t h e n W a t e r ( 3 0 mL) W a s a d d e d . A g a i n t h ecombined W a t e r and m e t h a n o l l a y e r s Were removed u s i n gGenevac R o c k e t E v a p o r a t o r ( 4 5 C . , 1 8 h ) . T h e s o l i do b t a i n e d Was r e - d i s s o l v e d W i t h m e t h a n o l , and t h e i n s o l u b l eW h i t e c r y s t a l l i n e s o l i d ( N C l ) W a s d i s c a r d e d b y ? l t r a t i o n . Th emethanol a y e r Was o n c e n t r a t e d under vacuum o y i e l d 40 gc r u d e p r o d u c t . T h e m a j o r i m p u r i t y i n T o b - B o c 3 i s T o b - B o c 5 .HPLC i t h a n e v a p o r a t i v e l i g h t s c a t t e r i n g d e t e c t o r (ELSD)R t 4 . 4 mi n ( P h e n o m e n e x - C 1 8 , 5 0 > < 3 mm, 4 p m , g r a d i e n te l u t i o n W i t h 9 5 % a t e r ( 0 . 1 % f o r m i c a c i d ) and 100% methan o l ) ; LC-MS: / Z 7 6 8 . 3 3 ( M + 1 ) o b t a i n e d , 7 6 7 . 8 6 c a l c u l a t e d :TLC N i n h y d r i n ) CH2Cl2:MeOH:28% NH4OH, . 5 : 1 . 0 : 0 . 5 )R f 0 . 2 5 . T h e i m p u r i t y W a s r e m o v e d f r o m t h e p r o d u c t b ys e l e c t i v e l y d i s s o l v i n g t h e p r o d u c t i n W a t e r . T h i s Was c h i e v e db y s t i r r i n g t h e s o l i d W i t h W a t e r ( 3 5 0 mL) o r a t l e a s t 1 h o u r ,f o l l o W e d b y ? l t r a t i o n t h r o u g h a f r i t t e d g l a s s B u c h n e r f u n n e l .T h i s p r o c e d u r e Was e p e a t e d a n o t h e r t h r e e t i m e s ( t o t a l o f f o u rW a s h e s ) u n t i l LC-MS shoWed no r o d u c t i n t h e r e s i d u a l s o l i d .The combined q u e o u s l a y e r s Were o n c e n t r a t e d u s i n g Genev a c R o c k e t E v a p o r a t o r ( 4 5 C . ) t o p r o v i d e 3 2 g ( 7 7 . 9 % y i e l d )of Tob-Boc3 a s a pure White s o l i d .[ 0 1 1 5 ] T o b - B o c 3 ( m ) ( 1 9 . 5 g , 2 5 . 0 m m o l ) W a s c o - e v a p or a t e d W i t h a n h y d r o u s DMF 2 > < 5 0 m L ) . T o a s t i r r e d s o l u t i o no f T o b - B o c 3 i n a n h y d r o u s DMF 7 0 mL) W a s a d d e d e t h y lt r i ? u o r o a c e t a t e ( 3 . 6 2 g , 2 5 . 0 mmol) r o p W i s e a t 5 C . f o r 3 0min. Th e mixture W as t i r r e d a t r oom temperature o r 10 min.The LC-MS f t h e m i x t u r e shoWs c o m p l e t i o n o f t h e r e a c t i o nt o T o b - B o c 3 - T F A ( n ) W i t h a p p r o x i m a t el y 2 - 3 % T o b - B o c 3T F A 2 s i d e p r o d u c t a c c o r d i n g H P L C / E L S D . ( S m a l l - s c a l er e a c t i o n s a t v a r i o u s c o n c e n t r a t i o n s o f T o b - B o c 3 s u g g e s t t h a tt h e amount o f Tob-Boc3-TFA2 b y - p r o d u c t c a n b e s u b s t a nt i a l l y e l i m i n a t e d b y p e r f o r m i n g t h e r e a c t i o n a t 0 . 1 M o bBoc3 i n DMF.) To t h e r e a c t i o n m i x t u r e Were added 1 mL f1M o l u t i o n ofAHB-Boc n DMF 7 6 . 6 m m o l ) , HOBt 4 . 6 g ,7 6 . 6 m m o l ) , 1 - e t h y l - 3 - [ 3 - d i m e t h y l a m i n o p r o p y l ] c a r b o d i i mi d e h y d r o c h l o r i d e ( E D C . H C l ) ( 5 . 8 g , 7 6 . 6 m m o l ) a n d t r i e t h yl a m i n e ( 4 . 2 mL, 7 6 . 6 m m o l ) . Th e i x t u r e Was t i r r e d

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