IP Library › Granted Patent US 8,163,698
Granted Patent B2
US 8,163,698 · App. 12/648,446 · Granted Apr 24, 2012

Dolastatin 15 derivatives

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Quick Facts
Patent No.
US 8,163,698
App. No.
12/648,446
Granted
Apr 24, 2012
Kind
B2
Abstract

Compounds of the present invention include cell growth inhibitors which are peptides of Formula I, A-B-D-E-F-(G) r -(K) s -L  (I), and acid salts thereof, wherein A, B, D, E, F, G and K are α-amino acid residues, and s and r are each, independently, 0 or 1. L is a monovalent radical, such as, for example, an amino group, an N-substituted amino group, a β-hydroxylamino group, a hydrazido group, an alkoxy group, a thioalkoxy group, an aminoxy group, or an oximato group. The present invention also includes a method for treating cancer in a mammal, such as a human, comprising administering to the mammal an effective amount of a compound of Formula I in a pharmaceutically acceptable composition.

Claims (186)

1. A compound of the formula

A-B-D-E-F-(G) r -(K) s -L

wherein

r and s are 0;

A is

an α-amino acid derivative of Formula III a ,

wherein R a is hydrogen or unsubstituted C 1 -C 3 -alkyl; R 1 a is C 1 -C 3 -alkyl; R 6 a is methyl, hydroxyl- or methoxy-substituted C 1 -C 3 -alkyl, phenyl, or fluorine- or methoxy-substituted phenyl; and R 7 a is hydrogen or C 1 -C 3 -alkyl;

B is valyl, isoleucyl, or 2-tert-butylglycyl;

D is N-methylvalyl or N-methylisoleucyl;

E is prolyl, thiazolidinyl-4-carbonyl or 3,4-didehydroprolyl;

F is prolyl; and

L is N-benzylamide, N-methoxy-N-benzylamide, tert-butylamide, tert-butyl ester, N-methoxy-N-methylamide, isopropylamide, 5-phenyl isoxasolidinyl, isoxazolidinyl, pentylamide, (R) or (S) phenethylamide, —O-tert-butyl, isoxazolidinyl, 5-phenyl isoxazolidinyl,

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 selected from the group consisting of:

Me 2 Aib-Val-MeVal-Pro-Pro-NHBn

[N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn

Xax Val Xaa Pro Xab isomer 1

Xax Val Xaa Pro Xab isomer 2

Xaz Val Xaa Pro Xab isomer 1

Xaz Val Xaa Pro Xab isomer 2

Xbb Val Xaa Pro Xab

Xbd Val Xaa Pro Xab isomer 1

Xbd Val Xaa Pro Xab isomer 2

Xbg Val Xaa Pro Xab

Xbi Val Xaa Pro Xab isomer 1

Xbi Val Xaa Pro Xab isomer 2

Xbk Val Xaa Pro Xab isomer 1

Xbk Val Xaa Pro Xab isomer 2

Xbl Val Xaa Pro Xab

Xbm Val Xaa Pro Xab

Xbl Val Xaa Pro Xab isomer 1

Xbl Val Xaa Pro Xab isomer 2

Xau Val Xaa Pro Xbp

Xau Val Xaa Pro Xbx

Xbi Val Xaa Pro Xbx isomer 2

Xau Val Xaa Pro Xab isomer 1

Xau Val Xaa Pro Xab isomer 2

Xau Val Xaa Pro Xcb

Xbi Val Xaa Pro Xcb isomer 1

Xbi Val Xaa Pro Xcb isomer 2

Xbi Val Xaa Pro Xcc isomer 1

Xbi Val Xaa Pro Xcc isomer 2

Xbi Val Xaa Pro Xcd

Xbk Val Xaa Pro Xcc isomer 1

Xbk Val Xaa Pro Xcc isomer 2

Xax Val Xaa Pro Xbp isomer 1

Xax Val Xaa Pro Xbp isomer 2

Xbk Val Xaa Pro Xcb isomer 1

Xbk Val Xaa Pro Xcb isomer 2

Xau Val Xaa Pro Xcc

Xau Val Xaa Pro Xcd

Xau Val Xaa Pro Xbp isomer 1

Xau Val Xaa Pro Xbp isomer 2

Xbk Val Xaa Pro Xcd

Xau Val Xaa Pro Xch

Xau Val Xaa Pro XCi

Xau Val Xaa Pro Xck

Xau Val Xaa Pro Xcl

Xau Val Xaa Pro Xcm

Xau Val Xaa Pro Xcn

Xau Val Xaa Pro Xco

Xau Val Xaa Pro Xcp

Xau Val Xaa Pro Xcq

Xau Val Xaa Pro Xcr

Xau Val Xaa Pro Xbr

Xad Val Xaa Xal Xbx

Xau Val Xaa Xal Xbx

Xaw Val Xaa Xal Xbx

Xad Val Xaa Xal Xch

Xau Val Xaa Xal Xch

Xau Val Xaa Xal Xcr

Xau Val Xaa Xan Xbx

Xau Val Xaa Xan Xch

Xau Val Xaa Xan Xer

Xau Ile Xaa Pro Xbx

Xau Ile Xaa Pro Xch

Xau Xcs Xaa Pro Xch

Xau Xcs Xaa Pro Xbx

Xau Val Xct Pro Xch and

Xau Val Xct Pro Xbx;

or a pharmaceutically acceptable salt thereof,

wherein:

Xaa is N-methyl-valine, Xab is Prolyl N-benzylamide, Xau is N,N-dimethyl-2-ethyl-2-phenyl-glycine, Xax is N,N dimethyl-2-[2-fluoro]phenyl-glycine, Xaz is N,N-dimethyl-2-[4-fluoro]phenyl-glycine, Xbb is 2-(R,S)-ethyl-2-phenyl-glycine, Xbd is N,N-dimethyl-2-(R,S)-methyl-2-phenyl-glycine, Xbg is N-isopropyl-2-(R,S)-ethyl-2-phenyl-glycine,Xbi is N,N-dimethyl-2-propyl-2-phenyl-glycine, Xbk is N,N-dimethyl-2-[4-methoxy]phenyl-glycine, Xbl is N-methyl-3-hydroxy-D,L-valine, Xbm is N,N-dimethyl-D,L-2-isopropyl-2-phenyl-glycine, Xbp is proline-isopropylamide, Xbr is proline-N-methoxy-N-benzylamide, Xbx is proline-tert-butylamide, Xcb is proline-pentyl(3)amide, Xcc is proline-(R)-phenethylamide, Xcd is proline-(S)-phenethylamide,

Xch is

Xci is

Xck is

Xcl is

Xcm is

Xcn is

Xco is

Xcp is

Xcq is

Xcr

and

Xct is N-methyl-L-isoleucine.

3. The compound of claim 2 , having the structure:

Me 2 Aib-Val-MeVal-Pro-Pro-NHBn or

[N,N-dimethyl-2-ethyl-2-phenylglycyl]-Val-MeVal-Pro-Pro-NHBn

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , having the structure:

Xax Val Xaa Pro Xab isomer 1

Xax Val Xaa Pro Xab isomer 2

Xaz Val Xaa Pro Xab isomer 1

Xaz Val Xaa Pro Xab isomer 2

Xbb Val Xaa Pro Xab

Xbd Val Xaa Pro Xab isomer 1 or

Xbd Val Xaa Pro Xab isomer 2;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , having the structure:

Xbg Val Xaa Pro Xab

Xbi Val Xaa Pro Xab isomer 1

Xbi Val Xaa Pro Xab isomer 2

Xbk Val Xaa Pro Xab isomer 1 or

Xbk Val Xaa Pro Xab isomer 2;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 , having the structure:

Xbl Val Xaa Pro Xab or

Xbm Val Xaa Pro Xab

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 2 , having the structure:

Xbl Val Xaa Pro Xab isomer 1 or

Xbl Val Xaa Pro Xab isomer 2

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 , having the structure:

Xau Val Xaa Pro Xbp

Xau Val Xaa Pro Xbx

Xbi Val Xaa Pro Xbx isomer 2

Xau Val Xaa Pro Xab isomer 1

Xau Val Xaa Pro Xab isomer 2

Xau Val Xaa Pro Xcb

Xbi Val Xaa Pro Xcb isomer 1

Xbi Val Xaa Pro Xcb isomer 2

Xbi Val Xaa Pro Xcc isomer 1 or

Xbi Val Xaa Pro Xcc isomer 2;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 2 , having the structure:

Xbi Val Xaa Pro Xcd

Xbk Val Xaa Pro Xcc isomer 1

Xbk Val Xaa Pro Xcc isomer 2

Xax Val Xaa Pro Xbp isomer 1

Xax Val Xaa Pro Xbp isomer 2

Xbk Val Xaa Pro Xcb isomer 1

Xbk Val Xaa Pro Xcb isomer 2

Xau Val Xaa Pro Xcc or

Xau Vat Xaa Pro Xcd

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 2 , having the structure:

Xau Val Xaa Pro Xbp isomer 1

Xau Val Xaa Pro Xbp isomer 2 or

Xbk Val Xaa Pro Xcd

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 2 , having the structure:

Xau Val Xaa Pro Xch

Xau Val Xaa Pro Xci

Xau Val Xaa Pro Xck or

Xau Val Xaa Pro Xcl;

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 2 , having the structure:

Xau Val Xaa Pro Xcm

Xau Val Xaa Pro Xcn

Xau Val Xaa Pro Xco

Xau Val Xaa Pro Xcp

Xau Val Xaa Pro Xcq

Xau Val Xaa Pro Xcr

Xau Val Xaa Pro Xbr or

Xau Val Xaa Xal Xbx

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 2 , having the structure:

Xau Val Xaa Xal Xch

Xau Val Xaa Xal Xcr or

Xau Val Xaa Xan Xbx

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 2 , having the structure:

Xau Val Xaa Xan Xch

Xau Val Xaa Xan Xcr

Xau Xaa Pro Xbx or

Xau Ile Xaa Pro Xch;

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 2 , having the structure:

Xau Xcs Xaa Pro Xch or

Xau Xcs Xaa Pro Xbx;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 2 , having the structure:

Xau Val Xct Pro Xch or

Xau Val Xct Pro Xbx;

or a pharmaceutically acceptable salt thereof.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 16, 2013
From: ABBOTT GMBH & CO KG
To: ABBVIE DEUTSCHLAND GMBH & CO KG
Reel/Frame 030805/0023 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 13, 2010
From: JANSSEN, BERND; BARLOZZARI, TERESA; HAUPT, ANDREAS; ZIERKE, THOMAS; KLING, ANDREAS
To: BASF AKTIENGESELLSCHAFT
Reel/Frame 023772/0964 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 12, 2010
From: BASF AKTIENGESELLSCHAFT
To: ABBOTT GMBH & CO. KG
Reel/Frame 023765/0420 →