Bifunctional cytotoxic agents

Patent metadata

Field	Value
Publication number	US-10086085-B2
Application number	US-201514605697-A
Country	US
Kind code	B2
Filing date	Jan 26, 2015
Priority date	Jan 27, 2014
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

Cytotoxic dimers comprising CBI-based and/or CPI-based sub-units, antibody drug conjugates comprising such dimers, and to methods for using the same to treat cancer and other conditions.

First claim

We claim:

1. A compound of Formula (I):
F 1 -L 1 -T-L 2 -F 2   (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein:
F 1 and F 2 are each independently selected from ring systems A, and B:

wherein:
each V 1 is independently a bond, O, N(R) or S, for each ring system A in which V 1 appears;
each V 2 is independently O, N(R) or S, for each ring system B in which V 2 appears;
W 1 and W 2 are each independently H, —C 1 -C 5 alkyl or -phenyl, for each ring system A and ring system B in which W 1 and W 2 appear;
each X is independently —OH, —O-acyl, azido, halo, cyanate, thiocyanate, isocyanate, thioisocyanate, or

for each ring system A in which X appears;
each Y is independently selected from the group consisting of H, —C 1 -C 6 alkyl-R A , —C(O)R A , —C(S)R A , —C(O)OR A , —S(O) 2 OR A , —C(O)N(R A ) 2 , —C(S)N(R A ) 2 , and —PO(OR A ) 2 , for each ring system A in which Y appears, wherein each R A is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 , wherein said —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 are optionally substituted with 1 to 3 substituents independently selected from R;
each Z is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl, and wherein said C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl and —C 3 -C 8 carbocyclyl,
are each optionally substituted with 1 to 3 substituents independently selected from R, for each ring system A and ring system B in which Z appears;
L 1 and L 2 are each independently a direct bond;
T is selected from:
—C(A 1 )X 1 -T 2 -X 1 C(B 1 )—, where T 2 is:

wherein each X 1 is independently a bond, —NR E —, —O— or —S—, wherein A 1 and B 1 are each independently ═O or ═S,
wherein R 1 , R 2 , R 3 , and R 4 are each independently R E , or R 1 and R 2 form a ring system, or R 3 and R 4 form a ring system, or both R 1 and R 2 , and R 3 and R 4 , each independently form ring systems, or R 1 and R 3 form a ring system, or R 2 and R 4 form a ring system, or both R 1 and R 3 , and R 2 and R 4 , each independently form ring systems, where said ring systems are independently selected from —C 3 -C 8 carbocyclycl, or R 1 , R 2 , R 3 and R 4 are each bonds to different carbons on D, wherein g and j are each independently an integer from 0 to 50 and m is an integer from 1 to 50, and wherein D is —C 3 -C 8 carbocyclo, —C 3 -C 8 carbocyclo is optionally substituted with —R E , —C(O)R E , —C(O)OR E , —N(R E ) 2 , —N(R)C(O)R E or —N(R)C(O)OR E , and D is additionally optionally substituted by 1 to 2 R, and
-G 1 -T 2 -G 2 -, where G 1 and G 2 are each independently —S(O)X 1 — or —S(O) 2 X 1 ,
wherein each R E is independently selected from the group consisting of H, —C 1 -C 8 alkyl, —C 1 -C 8 heteroalkyl, —C 6 -C 14 aryl, -aralkyl, —C 1 -C 10 heterocyclyl, —C 3 -C 8 carbocyclyl, —C(O)OC 1 -C 8 alkyl, —C(O)N(C 1 -C 8 alkyl) 2 , and —C(O)-halo, and wherein each R E is optionally substituted with 1 to 3 substituents independently selected from R, and wherein each R is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, halo, hydroxyl, alkoxy, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —NO 2 , —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl, wherein two or more R optionally join to form a ring or rings, and wherein said —C 6 -C 14 aryl and —C 6 -C 14 heteroaryl are optionally substituted with 1 to 5 substituents independently selected from —C 1 -C 10 alkyl, —C 1 -C 10 alkoxy, -halo, —C 1 -C 10 alkylthio, -trifluoromethyl, —NH 2 , —NH(C 1 -C 8 alkyl), —N(C 1 -C 8 alkyl) 2 , —C 1 -C 10 alkyl-N(C 1 -C 8 alkyl) 2 , —C 1 -C 3 alkylthio, —NO 2 or —C 1 -C 10 heterocyclyl, for each ring system in which R appears.

2. The compound or a pharmaceutically acceptable salt or solvate of claim 1 , wherein:
each V 1 is independently O or N(R) for each ring system A in which V 1 appears;
each V 2 is independently O or N(R) for each ring system B in which V 2 appears;
W 1 and W 2 are each independently H or —C 1 -C 5 alkyl, for each ring system A and ring system B in which W 1 and W 2 appear;
each X is independently halo, for each ring system A in which X appears;
each Y is independently selected from the group consisting of H, —C(O)R A , —C(O)N(R A ) 2 , and —PO(OR A ) 2 , for each ring system A in which Y appears, wherein each R A is independently selected from the group consisting of H, —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 , wherein said —C 1 -C 20 alkyl, —C 1 -C 8 heteroalkyl, —C 3 -C 8 carbocyclyl and —C 1 -C 20 alkylN(R) 2 are optionally substituted with 1 to 3 substituents independently selected from R; and
T is selected from:
—C(A 1 )X 1 -T 2 -X 1 C(B 1 )—, where T 2 is:

wherein each X 1 is a bond, wherein A 1 and B 1 are each independently ═O, wherein R 1 , R 2 , R 3 , and R 4 are each independently H or R 1 and R 2 form a ring system, or R 3 and R 4 form a ring system, or both R 1 and R 2 , and R 3 and R 4 , each independently form ring systems, or R 1 and R 3 form a ring system, or R 2 and R 4 form a ring system, or both R 1 and R 3 , and R 2 and R 4 , each independently form ring systems, where said ring systems are independently selected from —C 3 -C 8 carbocyclycl, and wherein D is —C 3 -C 8 carbocyclo, —C 3 -C 8 carbocyclo is optionally substituted with —NH 2 , —N(R)C(O)H or —N(R)C(O)OH;
and wherein each R is independently selected from the group consisting of H, —C 1 -C 20 alkyl and —NH 2 .

3. The compound or a pharmaceutically acceptable salt or solvate of claim 1 , wherein two R optionally join to form a ring.

4. The compound or a pharmaceutically acceptable salt or solvate of claim 1 , wherein each V 1 is O, for each ring system A in which V 1 appears; and each Y is independently selected from the group consisting of H, —C(O)N(R A ) 2 , —C(S)N(R A ) 2 , and —PO(OR A ) 2 for each ring system A in which Y appears, wherein each R A is independently selected from the group consisting of H, —C 1 -C 20 alkyl, and —C 1 -C 20 alkylN(R) 2 , and wherein said —C 1 -C 20 alkyl, and —C 1 -C 20 alkylN(R) 2 are optionally substituted with 1 to 3 substituents independently selected from R.

5. The compound or a pharmaceutically acceptable salt or solvate according to claim 1 , wherein one to four W is C 1 -C 3 alkyl.

6. The compound or a pharmaceutically acceptable salt or solvate according to claim 1 , wherein one or two X is chloro.

7. The compound or a pharmaceutically acceptable salt or solvate according to claim 1 , wherein one Y is H or —C(O)C 1 -C 10 alkyl.

8. The compound or a pharmaceutically acceptable salt or solvate according to claim 1 , wherein one to four Z is H.

9. A compound, or a pharmaceutically acceptable salt or solvate thereof, se

Assignees

• Pfizer

Inventors

• Maderna Andreas
• Doroski Matthew David
• Chen Zecheng
• Risley Hud Lawrence
• Casavant Jeffrey Michael
• O'Donnell Christopher John
• Porte Alexander M
• Subramanyam Chakrapani

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61P1/18

  for pancreatic disorders, e.g. pancreatic enzymes · CPC title