US2018355025A1PendingUtilityA1
Monomethylvaline compounds having phenylalanine side-chain modifications at the c-terminus
Est. expiryJul 7, 2025(expired)· nominal 20-yr term from priority
A61P 9/10A61P 37/06A61P 9/00A61P 43/00A61P 37/02A61P 7/00A61P 3/10A61P 37/00A61P 5/14A61P 37/08A61P 35/00A61P 25/00A61P 35/02A61P 31/00A61P 27/02A61P 1/00A61P 19/00A61P 11/00A61P 13/12A61P 17/00A61P 21/00A61K 38/00A61K 47/6849C07K 7/02A61K 47/65C07K 7/06A61K 47/6811C07K 16/2878C07K 5/10C07K 5/0205C07K 16/00Y02A50/30
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Claims
Abstract
Auristatin peptide analogs of MeVal-Val-Dil-Dap-Phe (MMAF) are provided having C-terminal phenylalanine residue side chain replacements or modifications which are provided alone or attached to ligands through various linkers. The related conjugates can target specific cell types to provide therapeutic benefit.
Claims
exact text as granted — not AI-modified1 . A compound having the formula:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, X 1 -aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
R 5 is selected from the group consisting of H and methyl;
or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 7 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 5 carbocycle, aryl, X 1 -aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O—(C 1 -C 8 alkyl);
each X 1 is independently C 1 -C 10 alkylene; and
the moiety —NR 9 Z 1 has the formula:
wherein
R 10 is selected from the group consisting of:
wherein
R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, aryylC 2 -C 20 alkenyl, aryylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ;
X 2 is selected from the group consisting of N, NR 16 , S, and O; and each R 16 is independently H or C 1 -C 20 alkyl; or
R 10 has the formula:
wherein
R 12 is selected from the group consisting of C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, aryylC 2 -C 20 alkenyl arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ; and
each R 16 is independently H or C 1 -C 20 alkyl;
R 11 is H; and
Z 2 is COZ 3 R 19 , wherein
Z 3 is O, S, NH, or NR 20 , wherein R 20 is C 1 -C 8 alkyl;
R 19 is H, C 1 -C 20 alkyl aryl, C 3 -C 8 heterocycle, —(X 1 O) v —R 22 , or —(X 1 O) v —CH(R 23 ) 2 ;
v is an integer ranging from 1-1000;
R 22 is H or C 1 -C 8 alkyl;
each R 23 is independently H, COOH, —(CH 2 ) l —N(R 24 ) 2 , —(CH 2 ) l —SO 3 H or —(CH 2 ) l —SO 3 —C 1 -C 8 alkyl;
each R 24 is independently H, C 1 -C 8 alkyl or —(CH 2 ) l —COOH; and
l is an integer ranging from 0 to 6.
2 - 12 . (canceled)
13 . The compound of claim 1 , wherein R 10 is selected from the group consisting of:
wherein R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, amino, formyl, phenyl, E-2-phenylethenyl, Z-2-phenylethenyl, and 2-phenylethynyl; or
R 10 has the formula:
wherein R 12 is selected from the group consisting of C 1 -C 20 alkyl, halogen, amino, formyl, phenyl, E-2-phenylethenyl, Z-2-phenylethenyl, and 2-phenylethynyl.
14 . The compound of claim 1 , wherein the moiety —NR 9 Z 1 is selected from the group consisting of:
15 - 16 . (canceled)
17 . The compound of claim 1 , wherein the moiety —NR 9 Z 1 is an amino acid selected from the group consisting of 4-chloro-phenylalanine, 4-fluoro-phenylalanine, 4-nitro-phenylalanine, tryptophan, tyrosine, benzothiazol-2-yl-alanine, O-t-butyl-tyrosine, and 3-(p-acetylphenyl)alanine.
18 - 27 . (canceled)
28 . A compound having the formula:
L-((LU) 0-1 -(D) 1-4 ) p
or a pharmaceutically acceptable salt or solvate thereof
wherein,
L- is a Ligand Unit;
LU is a Linker Unit;
p is an integer of from 1 to about 20; and
D is a drug moiety having Formula D:
wherein,
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, C 1 -C 8 alkyl-aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, X 1 -aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
R 5 is selected from the group consisting of H and methyl;
or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 7 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, X 1 -aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O—(C 1 -C 8 alkyl);
each X 1 is independently C 1 -C 10 alkylene; and
the moiety —NR 9 Z 1 has the formula:
wherein
R 10 is selected from the group consisting of:
wherein
R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ;
X 2 is selected from the group consisting of N, NR 16 , S, and O; and
each R 16 is independently H or C 1 -C 20 alkyl; or
R 10 has the formula:
wherein
R 12 is selected from the group consisting of C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl, arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ; and
each R 16 is independently H or C 1 -C 20 alkyl;
R 11 is H; and
Z 2 is COZ 3 R 19 , wherein
Z 3 is O, S, NH, or NR 20 , wherein R 20 is C 1 -C 8 alkyl;
R 19 is H, C 1 -C 20 alkyl aryl, C 3 -C 8 heterocycle, —(X 1 O) v —R 22 , or —(X 1 O) v —CH(R 23 ) 2 ;
v is an integer ranging from 1-1000;
R 22 is H or C 1 -C 8 alkyl;
each R 23 is independently H, COOH, —(CH 2 ) l —N(R 24 ) 2 , —(CH 2 ) l —SO 3 H or —(CH 2 ) l —SO 3 —C 1 -C 8 alkyl;
each R 24 is independently H, C 1 -C 8 alkyl or —(CH 2 ) l —COOH; and
l is an integer ranging from 0 to 6.
29 . The compound of claim 28 , having the formula:
L-LU-D or a pharmaceutically acceptable salt or solvate thereof.
30 . A compound having the formula:
LU-(D) 1-4
or a pharmaceutically acceptable salt or solvate thereof
wherein,
LU- is a Linker Unit; and
D is a drug moiety having the Formula D:
wherein:
R 2 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 3 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl C 1 -C 8 alkyl-aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, X 1 -aryl, C 1 -C 8 alkyl-(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
R 5 is selected from the group consisting of H and methyl;
or R 4 and R 5 jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a and R b are independently selected from the group consisting of H, C 1 -C 8 alkyl and C 3 -C 8 carbocycle and n is selected from the group consisting of 2, 3, 4, 5 and 6;
R 6 is selected from the group consisting of H and C 1 -C 8 alkyl;
R 7 is selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 carbocycle, aryl, X 1 -aryl, X 1 —(C 3 -C 8 carbocycle), C 3 -C 8 heterocycle and X 1 —(C 3 -C 8 heterocycle);
each R 8 is independently selected from the group consisting of H, OH, C 1 -C 8 alkyl, C 3 -C 8 carbocycle and O—(C 1 -C 8 alkyl);
each X 1 is independently C 1 -C 10 alkylene; and
the moiety —NR 9 Z 1 has the formula:
wherein
R 10 is selected from the group consisting of:
wherein
R 12 is selected from the group consisting of H, C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl, arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ;
X 2 is selected from the group consisting of N, NR 16 , S, and O and each R 16 is independently H or C 1 -C 20 alkyl; or
R 10 has the formula:
wherein
R 12 is selected from the group consisting of C 1 -C 20 alkyl, halogen, aryl, arylC 1 -C 20 alkyl, arylC 2 -C 20 alkenyl, arylC 2 -C 20 alkynyl, OR 16 , N(R 16 ) 2 and —C(O)R 16 ; and
each R 16 is independently H or C 1 -C 20 alkyl;
R 11 is H; and
Z 2 is COZ 3 R 19 , wherein
Z 3 is O, S, NH, or NR 20 , wherein R 20 is C 1 -C 8 alkyl;
R 19 is H, C 1 -C 20 alkyl, aryl, C 3 -C 8 heterocycle, —(X 1 O) v —R 22 , or —(X 1 O) v —CH(R 23 ) 2 ;
v is an integer ranging from 1-1000;
R 22 is H or C 1 -C 8 alkyl;
each R 23 is independently H, COOH, —(CH 2 ) l —N(R 24 ) 2 , —(CH 2 ) l —SO 3 H or —(CH 2 )i-SO 3 —C 1 -C 8 alkyl;
each R 24 is independently H, C 1 -C 8 alkyl or —(CH 2 ) l —COOH; and
l is an integer ranging from 0 to 6.
31 . The compound according to claim 28 , having Formula Ia′:
Ab-(A a -W w —Y y -(D) 1-4 ) p Ia′
or a pharmaceutically acceptable salt or solvate thereof, wherein:
Ab is an antibody,
A is a Stretcher unit,
a is 0 or 1,
each W is independently an Amino Acid unit,
w is an integer ranging from 0 to 12,
Y is a Spacer unit, and
y is 0, 1 or 2.
32 . The compound according to claim 31 having the formula:
Ab-(D) p .
33 . The compound of claim 31 , wherein the antibody is attached to the drug moiety through a cysteine residue of the antibody.
34 . The compound of claim 33 wherein p is 2 to 5.
35 . The compound of claim 31 wherein p is 2 to 8.
36 . (canceled)
37 . The compound of claim 33 having the formula:
wherein L is an antibody and R 17 is C 1 -C 10 alkylene-, —C 3 -C 8 carbocyclo-, —O—(C 1 -C 8 alkyl)-, -arylene-, —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 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-, —(CH 2 CH 2 O) r —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer of from 1-10.
38 . The compound of claim 37 having the formula:
wherein w and y are each 0.
39 . The compound of claim 37 wherein D has the formula:
40 . The compound of claim 31 having the formula:
41 . The compound of claim 31 having the formula:
42 . The compound of claim 31 having the formula:
43 . The compound of claim 40 wherein D has the formula:
44 . The compound of claim 31 having the formula:
45 . The compound of claim 31 wherein w is an integer ranging from 2 to 12.
46 . The compound of claim 31 wherein w is 2.
47 . The compound of claim 46 wherein W w is -valine-citrulline-.
48 - 49 . (canceled)
50 . The compound of claim 31 , wherein the antibody is a monoclonal antibody.
51 - 52 . (canceled)
53 . The compound of claim 31 , wherein the antibody is a humanized antibody.
54 . The compound of claim 31 , wherein the antibody is an antibody fragment.
55 - 114 . (canceled)Join the waitlist — get patent alerts
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