Derivatives of uncialamycin, methods of synthesis and their use as antitumor agents

Patent metadata

Field	Value
Publication number	US-9777013-B2
Application number	US-201414911881-A
Country	US
Kind code	B2
Filing date	Aug 14, 2014
Priority date	Aug 14, 2013
Publication date	Oct 3, 2017
Grant date	Oct 3, 2017

Abstract

In one aspect, the present disclosure provides new analogs of uncialamycin of formulae (I) and (II). The present disclosure also provides novel synthetic pathways to obtaining uncialamycin and analogs thereof. Additionally, the present disclosure also describes methods of use of uncialamycin and analogs thereof. In another aspect, the present disclosure provides antibody-drug conjugates comprising the compounds of formulae (I) and (II).

First claim

The invention claimed is:

1. A compound of the formula:

wherein:
Y 1 is —O(CH 2 ) m Y′, —NH(CH 2 ) m Y′, —S(CH 2 ) m Y′, or —(CH 2 ) m NR 1 R 2 , or is taken together with Z 1 as defined below;
wherein:
Y′ is hydroxy, halo, mercapto, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C≦12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , or substituted alkylamino (C1-12) ;
m is 1, 2, 3, 4, 5, or 6; and
R 1 and R 2 are each independently selected from hydrogen, hydroxy, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) ; a monovalent amine protecting group, —C(O)O(CH 2 ) n S-A 1 , —C(O)O(CH 2 ) n S(O)-A 1 , or —C(O)O(CH 2 ) n S(O) 2 -A 1 ,
wherein:
A 1 is aryl (C6-12) , substituted aryl (C6-12) , or

wherein:
A 2 is alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkoxy (C1-12) , substituted alkoxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) , dialkylamino (C2-12) , or substituted dialkylamino (C2-12) ; wherein A 2 is not —CO 2 H, —CO 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —C(O)NH 2 , and —OC(O)CH 3 ; and

n is 1, 2, 3, 4, or 5; or

R 1 and R 2 are taken together and are divalent amine protecting group, alkanediyl (C1-12) , alkylaminodiyl (C1-8) ; alkoxydiyl (C1-8) ; or a substituted version of either of these groups; or
Y 1 is taken with Z 1 and is alkylaminodiyl (C1-8) substituted alkylaminodiyl (C1-8) ; -alkanediyl (C1-6) -NZ 2 -alkanediyl (C1-6) , or -substituted alkanediyl (C1-6) -NZ 2 -substituted alkanediyl (C1-6) ,
wherein:
Z 2 is hydrogen, an amine protecting group, acyl (C6-12) , substituted acyl (C6-12) , —C(O)O(CH 2 ) n S-A 3 , or —C(O)O(CH 2 ) n S(O) 2 -A 3 , and
wherein:
A 3 is aryl (C6-12) , substituted aryl (C6-12) , or

wherein:
 A 4 is alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , acyloxy (C1-12) , substituted acyloxy (C1-12) , alkoxy (C1-12) , substituted alkoxy (C1-12) , alkylamino (C1-12) , substituted alkylamino (C1-12) , dialkylamino (C2-12) , or substituted dialkylamino (C2-12) , wherein A 4 is not —CO 2 H, —CO 2 CH 3 , —OCH 3 , —OCH 2 CH 3 , —C(O)CH 3 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —C(O)NH 2 , and —OC(O)CH 3 ;

Z 1 is absent, hydrogen or taken together with Y 1 as defined above;
R 3 and Z 2 are each independently selected from hydrogen, hydroxy, halo, amino, cyano, nitro, phosphate, or mercapto, or
alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , amido (C1-12) , or a substituted version of any of these groups;

o is 1, 2, or 3;
R 4 is hydrogen, alkyl (C1-12) , a monovalent amine protecting group, or substituted alkyl (C1-12) ;
R 5 , R 6 , and R 7 are each independently hydrogen, hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 ; or
alkyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups;
wherein:
X 1 is a hydroxy protecting group;
X 2 and X 3 are independently selected from hydrogen, a monovalent amine protecting group, or when X 2 and X 3 are taken together form a divalent amine protecting group; and
X 4 is a thiol protecting group;

R 8 is hydroxy, amino, or mercapto; or
alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; and
R 9 , R 10 , R 11 , and R 12 are each independently selected from hydrogen, hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 , or
alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups; or Y 2 —R 13 ;
wherein:
X 1 is alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , or a hydroxy protecting group;
X 2 and X 3 are independently selected from hydrogen, alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , a monovalent amine protecting group, or when X 2 and X 3 are taken together form a divalent amine protecting group;
X 4 is alkyl (C1-12) , substituted alkyl (C1-12) , alkenyl (C2-12) , substituted alkenyl (C2-12) , alkynyl (C2-12) , substituted alkynyl (C2-12) , aryl (C6-12) , substituted aryl (C6-12) , aralkyl (C7-12) , substituted aralkyl (C7-12) , heteroaryl (C1-12) , substituted heteroaryl (C1-12) , heterocycloalkyl (C2-12) , substituted heterocycloalkyl (C2-12) , acyl (C1-12) , substituted acyl (C1-12) , or a thiol protecting group;
Y 2 is alkanediyl (C1-12) or substituted alkanediyl (C1-12) ; and
R 13 is hydroxy, amino, mercapto, —OX 1 , —NX 2 X 3 , or —SX 4 , or heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , alkylthio (C1-12) , amido (C1-12) , or a substituted version of any of these groups;

p and q are each independently 1 or 2; and
Z 3 is hydrogen, hydroxy, halo, amino, cyano, nitro, phosphate, or mercapto, or
alkyl (C1-12) , alkenyl (C2-12) , alkynyl (C2-12) , aryl (C6-12) , aralkyl (C7-12) , heteroaryl (C1-12) , heterocycloalkyl (C2-12) , acyl (C1-12) , alkoxy (C1-12) , acyloxy (C1-12) , alkylamino (C1-12) , dialkylamino (C2-12) , amido (C1-12) , or a substituted version of any of these groups;

provided that Y 1 is not —NHMe or —NHCH 2 CH 2 NH 2 ; or

a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the formula is further defined as:

Assignees

• Univ Rice William M
• Bristol Myers Squibb Co
• Scripps Research Inst

Inventors

• Nicolaou Kyriacos C
• Lu Min
• Mandal Debashis
• Gangwar Sanjeev
• Chowdari Naidu S
• Poudel Yam B

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61K47/6851

  the antibody targeting a determinant of a tumour cell · CPC title

• A61K9/0021

  Intradermal administration, e.g. through microneedle arrays or needleless injectors · CPC title