IP Library › Granted Patent US 9,249,186
Granted Patent B2
US 9,249,186 · App. 14/793,942 · Granted Feb 2, 2016

Cytotoxic peptides and antibody drug conjugates thereof

Inventors: Matthew David Doroski (Mystic, CT); Andreas Maderna (Stony Point, NY); Christopher John O'Donnell (Mystic, CT); Chakrapani Subramanyam (South Glastonbury, CT); Beth Vetelino (North Stonington, CT); Russell George Dushin (Old Lyme, CT); Pavel Strop (San Mateo, CA); Edmund Idris Graziani (Chestnut Ridge, NY)
Assignee: Pfizer Inc.
C07K7/06C07K2319/30
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Quick Facts
Patent No.
US 9,249,186
App. No.
14/793,942
Granted
Feb 2, 2016
Kind
B2
Abstract

The present invention is directed to cytotoxic pentapeptides, to antibody drug conjugates thereof, and to methods for using the same to treat cancer.

Claims (109)

1. A compound of formula IIIa:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

R 11 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

 or —NH 2 ;

R 7 is independently selected for each occurrence from the group consisting of F, Cl, I, Br, NO 2 , CN and CF 3 ;

R 10 is hydrogen, —C 1 -C 10 alkyl, —C 3 -C 8 carbocycle, aryl, —C 1 -C 10 heteroalkyl, —C 3 -C 8 heterocyclo, —C 1 -C 10 alkylene-aryl, -arylene-C 1 -C 10 alkyl, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo), —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkyl, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo), and —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkyl, where aryl on R 10 comprising aryl is optionally substituted with [R 7 ] h ;

h is 1, 2, 3, 4 or 5; and

X is O or S;

R 6 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and

h is 1, 2, 3, 4 or 5.

2. A compound of formula IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

R 11 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

 or —NHL;

L is an antibody;

X is O or S.

3. A compound of formula IIIc:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

R 11′ is —Y—,

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z′ is

 or —NH—;

L is an antibody;

X is O or S.

4. A compound of formula IIId:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

[linker] is a divalent linker;

L is an antibody;

X is O or S.

5. A compound of formula IIc:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

R 1′ is —Y—,

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 carbocyclo)-, —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z′ is

 or —NH—;

L is an antibody;

D is —C(R 4A′ )(R 4B′ )— or is absent;

R 2′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, or is absent if is present;

R 3A′ and R 3B′ are either of the following:

(i) R 3A′ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B′ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R 3B′ is C 2 -C 4 alkylene and forms 5-7 member ring as indicated by ; or

(ii) R 3A′ and R 3B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A′ and R 4B′ are either of the following:

(i) R 4A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A′ and R 4B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

 C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly and C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

 optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

Assignments (1)
ASSIGNEE ADDRESS CORRECTION Recorded Mar 20, 2023
From: PFIZER INC.
To: PFIZER INC.
Reel/Frame 063119/0087 →
Continuity (5)
Continuation 14322262 · Jul 2, 2014
Continuation 13670612 · Nov 7, 2012
Provisional Application 61676423 · Jul 27, 2012
Provisional Application 61561255 · Nov 17, 2011
Related Publication 20150307551A1 · Oct 29, 2015