US2020399259A1PendingUtilityA1
Phosphonamidates that are BCL Family Antagonists for Use in Clinical Management of Conditions Caused or Mediated by Senescent Cells and for Treating Cancer
Est. expiryApr 30, 2038(~11.8 yrs left)· nominal 20-yr term from priority
C07D 413/14A61P 35/00C07F 9/6533C07F 9/650952
61
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Claims
Abstract
This disclosure provides compounds with Bcl inhibitory activity based on a new chemical scaffold. Phosphonamidate compounds typically include a P-phenyl phosphonamidate moiety which is substituted with an N-aryl or N-heteroaryl group. The P-phenyl phosphonamidate moiety may be optionally substituted at phosphorus with thio (═S) instead of oxo (═O), and/or with a thioxy group or a second amino group instead of an oxy group. One of the heteroatoms attached to phosphorus may be cyclically linked to the N-substituted nitrogen atom that is attached to the phosphorus to provide a heterocyclic ring. By incorporating such a cyclic constraint between two phosphorus substituents of the core linking moiety, a favorable binding conformation may be promoted in the compounds. Selected compounds promote apoptosis in senescent cells, and can be developed for treating senescent-related conditions, such as osteoarthritis, ophthalmic disease, pulmonary disease, and atherosclerosis. Selected compounds promote apoptosis in cancer cells, and can be developed as chemotherapeutic agents.
Claims
exact text as granted — not AI-modified1 .- 20 . (canceled)
21 . A method of selectively eliminating senescent cells or cancer cells from a target tissue, comprising contacting the tissue with a compound according to Formula (VIa):
wherein:
X 1 is O or S;
R 1 is selected from SR 21 , OR 21 , and NR 21 R 22 ;
R 3 is selected from hydrogen and C 1 to 6 alkyl;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 4 is selected from CH and N;
Z 6 is selected from O, CHC(O)R 18a , and CH(CH 2 ) p R 18a wherein p is 0-6 and each R 18a is independently selected from —OR, —N(R) 2 , —OP(═O)(OH) 2 , and —OP(═O)(OR) 2 wherein each R is independently H or alkyl;
R 14 and R 16 are independently selected from hydrogen and halogen;
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 18 , R 19 , R 21 , R 22 and R 52 are independently selected from hydrogen and C 1 to 6 alkyl; and
R 51 is C 1 to 6 alkyl,
and salt forms thereof.
22 . The method of claim 21 , wherein the compound is selected from the following table:
Compound
R 1
R 3
R 4
R 14
R 16
R 17
R 18
R 19
Z 4
Z 6
1
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O
2
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH
3
OCH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O
4
OCH 2 CH 3
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O
5
OCH 2 CH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O
6
OCH 2 CH 3
CH 3
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O
7
OCH 2 CH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOH
8
OH
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
O
9
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHCH 2 OH
10
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHCH 2 OPO(OH) 2
11
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
CHOPO(OH) 2 .
23 . A method of selectively eliminating senescent cells or cancer cells from a target tissue, comprising contacting the tissue with a compound according to Formula (VIb):
wherein:
X 1 is O or S;
R 1 is selected from SR 21 , OR 21 , and NR 21 R 22 ;
R 3 is selected from hydrogen and C 1 to 6 alkyl;
Y 2 is selected from —OR 52 , —N(R 52 ) 2 and —OP(═O)(R 52 ) 2 ;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 4 is selected from CH and N;
R 14 and R 16 are independently selected from hydrogen and halogen;
R 17 is selected from SO 2 R 52 , COR 52 , CO 2 R 52 , CONR 51 R 52 , CONR 52 SO 2 R 51 and SO 2 NR 51 R 52 ;
R 18 , R 19 , R 21 , R 22 and R 52 are independently selected from hydrogen and C 1 to 6 alkyl; and
R 51 is C 1 to 6 alkyl,
and salt form thereof.
24 . The method of claim 23 , wherein the compound is selected from the following table:
Compound
R 1
R 3
R 4
R 14
R 16
R 17
R 18
R 19
Z 4
Y 2
12
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
13
OCH 2 CH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
14
OCH 2 CH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
15
OCH 2 CH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
16
OCH 2 CH 3
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
17
OCH 2 CH 3
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
18
OCH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
19
OCH 3
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
20
OCH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
21
OCH 3
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
22
OCH 3
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
23
OCH 3
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
24
OH
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
25
OH
H
NO 2
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
26
OH
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
27
OH
H
SO 2 CH 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2
28
OH
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
OH
29
OH
H
SO 2 CF 3
F
Cl
SO 2 CH 3
CH 3
CH(CH 3 ) 2
N
N(CH 3 ) 2 .
25 . The method of claim 21 , wherein the compound has the structure shown in Formula (VIIa):
wherein:
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
Z 6 is selected from O and CH(CH 2 ) p R 18a wherein p is 0-6 and R 18a is selected from —OR, —N(R) 2 , —OP(═O)(OH) 2 , and —OP(═O)(OR) 2 wherein each R is independently H or C 1 to 6 alkyl;
R 3 and R 21 are independently selected from hydrogen and C 1 to 6 alkyl;
R 14 is selected from H and F; and
R 51 is C 1 to 6 alkyl,
and salt forms thereof.
26 . The method of claim 23 , wherein the compound has the structure shown in Formula (VIIb):
wherein:
Y 2 is selected from —OR 52 , —N(R 52 ) 2 , and —OP(═O)(OR 52 ) 2 ;
R 4 is selected from NO 2 , SO 2 CH 3 , SO 2 CF 3 and COR 51 ;
R 3 and R 21 are independently selected from hydrogen and C 1 to 6 alkyl;
R 14 is selected from H and F;
R 51 is C 1 to 6 alkyl; and
R 52 is selected from hydrogen and C 1 to 6 alkyl,
and salt forms thereof.
27 . A method of selectively eliminating senescent cells or cancer cells from a target tissue, comprising contacting the tissue with a compound selected from one of the following structures:
28 . The method of claim 21 , wherein R 1 is OR 21 .
29 . The method of claim 21 , wherein R 3 is hydrogen.
30 . The method of claim 21 , wherein R 4 is NO 2 .
31 . The method of claim 21 , wherein R 14 is halogen.
32 . The method of claim 21 , wherein R 16 is halogen.
33 . The method of claim 21 , wherein R 17 is SO 2 R 52 .
34 . The method of claim 21 , wherein R 18 is C 1 to 6 alkyl.
35 . The method of claim 21 , wherein R 19 is C 1 to 6 alkyl.
36 . The method of claim 21 , wherein Z 4 is N.
37 . The method of claim 21 , wherein Z 6 is selected from O and CH(CH 2 ) p R 18a , wherein R 18a is selected from —OH and —OP(═O)(OH) 2 .
38 . The method of claim 23 , wherein R 1 is OR 21 .
39 . The method of claim 23 , wherein R 3 is hydrogen.
40 . The method of claim 23 , wherein R 4 is selected from NO 2 , SO 2 CH 3 , and SO 2 CF 3 .
41 . The method of claim 23 , wherein R 14 is halogen.
42 . The method of claim 23 , wherein R 16 is halogen.
43 . The method of claim 23 , wherein R 17 is SO 2 R 52 .
44 . The method of claim 23 , wherein R 18 is C 1 to 6 alkyl.
45 . The method of claim 23 , wherein R 19 is C 1 to 6 alkyl.
46 . The method of claim 23 , wherein Z 4 is N.
47 . The method of claim 23 , wherein Y 2 is selected from —OH and —N(C 1 to 6 alkyl) 2 .Cited by (0)
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