US2005113398A1PendingUtilityA1
2,4-pyrimidinediamine compounds and uses as anti-proliferative agents
Priority: Aug 7, 2003Filed: Aug 6, 2004Published: May 26, 2005
Est. expiryAug 7, 2023(expired)· nominal 20-yr term from priority
A61K 31/506C07D 413/12C07D 417/12C07D 405/12C07D 403/12C07D 417/14C07D 498/04C07D 401/14A61K 31/4353A61P 35/04C07D 239/48C07D 413/14A61K 31/505C07D 401/12A61P 35/00A61P 43/00
66
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention provides 2,4-pyrimidinediamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferative diseases such as tumorigenic cancers.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting proliferation of a cancer cell, comprising contacting the cancer cell with an effective amount of a 2,4-pyrimidinediamine compound according to structural formula (I):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
L 1 and L 2 are each, independently of one another, selected from a lower alkyldiyl linker, a lower alkylene linker and a covalent bond;
R 2 is selected from the group consisting of lower alkyl optionally substituted with an R b group,
where Y is NH, O or CH 2 ;
R 2′ is hydrogen, methyl or lower alkyl;
R 4′ is hydrogen, methyl or lower alkyl;
R 4 is selected from the group consisting of lower alkyl optionally monosubstituted with an R a or R b group, lower cycloalkyl optionally monosubstituted with an R a or R b group, lower cycloheteroalkyl optionally substituted at one or more ring carbon and/or heteroatoms with an R a or R b group, —(CR a R a ) n —R b ,
where D is ——(CR 7 R 7 ) m —,
where Z 1 is N or CH and Z 2 is O, S, NH, S(O) 2 ;
R 5 is selected from the group consisting of halo, fluoro and —CF 3 ;
R 6 is hydrogen;
each R 7 is independently selected from the group consisting of hydrogen, methyl, lower alkyl and halo;
each R 8 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —OR a , —(CH 2 ) n —NR c R c , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —C(O)OR a , —C(S)OR a , halo, —CF 3 and —OCF 3 ;
each R 9 is independently selected from the group consisting of hydrogen, lower alkyl, —OR a , —(CH 2 ) n —NR c R c , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —C(O)—NR c R c , —C(S)—NR c R c , —S(O) 2 —NR c R c , —NHC(O)R a , —NHC(S)R a , —C(O)—NH—(CH 2 ) n —NR c R c , —C(S)—NH—(CH 2 ) n —NR c R c , halo, —CF 3 , —OCF 3 ,
each R 10 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —(CH 2 ) n —NR c R c , —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , halo, —CF 3 , —OCF 3 ,
each R 11 is independently selected from the group consisting of —OR a , —NR c R c and —NR a R d ;
each R 12 is independently selected from the group consisting of lower alkyl, arylalkyl, —OR a , —NR c R c , —C(O)R a , —C(O)OR a and —C(O)NR c R c ;
each R 13 is independently selected from the group consisting of lower alkyl, hydroxy, lower alkoxy, methoxy, —C(O)NR c R c and —C(O)NH 2 ;
each R 15 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloakyl and phenyl;
each R 16 is independently selected from the group consisting of hydrogen, methyl, lower alkyl, lower cycloalkyl, lower branched alkyl and lower cycloalkylmethyl;
each R 17 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and R d or, alternatively, R 17 may be taken together with R 18 to form an oxo (═O) group;
each R 18 is independently selected from the group consisting of hydrogen, lower alkyl and methyl or, alternatively, R 18 may be taken together with R 17 to form an oxo (═O) group;
each R 19 is independently selected form the group consisting of hydrogen, lower alkyl, methyl and R d ;
each R 20 is independently selected from the group consisting of hydrogen, lower alkyl, methyl and R d ;
each m is independently an integer from 1 to 3;
each n is independently an integer from 1 to 3;
each R a is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, phenyl and benzyl;
each R b is independently selected from the group consisting of —OR a , —CF 3 , —OCF 3 , —NR c R c , —C(O)R a , —C(S)R a , —C(O)OR a , —C(S)OR a , —C(O)NR c R c , —C(S)NR c R c , —S(O) 2 NR c R c , —C(O)NR a R d , —C(S)NR a R d and —S(O) 2 NR a R d ;
each R c is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, or, alternatively, two R c s may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NR a , NR a —C(O)R a , NR a —C(O)OR a and NR a —C(O)NR a ; and
each R d is independently selected from lower mono-hydroxyalkyl and lower di-hydroxyalkyl,
with the provisos that:
(i) when R 2 is
then R 9 and R 10 are not both simultaneously lower alkoxy or methoxy, or when R 2 is 3,4,5-trimethoxyphenyl or 3,4,5-tri(loweralkoxy)phenyl, then R 4 is
(ii) when R 2 is lower alkyl, then R 4 is
(iii) when R 4 is
and L 2 is lower alkylene, then R 2 is other than 3-(1,3-oxazolyl)phenyl;
(iv) when R 4 is
where R 15 is t-butyl and R 2 is
then at least two of R 8 , R 9 and R 10 or R 8 , R 9 and R 13 are other than hydrogen;
(v) when R 4 is
where R 15 is t-butyl and R 2 is
where R 8 and R 9 are each hydrogen, then R 10 is other than —(CH 2 ) n —OH or —O(CH 2 ) n —R b where R b is selected from —NR c R c , —C(O)R a , —C(O)NR c R c and —C(O)NR a R d .
2 . The method of claim 1 in which L 1 and L 2 are each a covalent bond.
3 . The method of claim 2 in which R 5 is fluoro.
4 . The method of claim 3 in which R 2′ and R 4′ are each hydrogen.
5 . The method of claim 3 in which R 2′ is hydrogen and R 4′ is methyl.
6 . The method of claim 3 in which R 2 is
7 . The method of claim 6 in which R 4 is selected from unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted cyclohexyl
where R e and R f are selected from (C1-C3) alkanyl and methyl and R g is benzyl.
8 . The method of claim 7 in which R 8 is hydrogen; R 9 is selected from
and R 10 is other than
9 . The method of claim 8 in which R 10 is selected from hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro.
10 . The method of claim 8 in which R 12 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)OCH 2 CH 3 .
11 . The method of claim 8 in which R 8 is hydrogen; R 9 is other than
and R 10 is selected from
12 . The method of claim 11 in which R 9 is selected from hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro.
13 . The method of claim 11 in which R 12 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)CH 2 CH 3 .
14 . The method of claim 8 in which R 9 is other than
and R 10 is other than
15 . The method of claim 14 in which R 8 and R 9 are each hydrogen and R 10 is —OCH 2 NHR a .
16 . The method of claim 14 in which R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen, methyl, methoxy, hydroxymethyl, trifluoromethyl and chloro, with the proviso that at least two of R 8 , R 9 and R 10 are other than hydrogen.
17 . The method of claim 7 in which the 2,4-pyrimidinediamine compound is selected from any compound in any one of TABLEs 1A-1D having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
18 . The method of claim 3 in which R 4 is
19 . The method of claim 18 in which R a is hydrogen and R 15 is selected from lower branched alkyl and lower cycloalkyl.
20 . The method of claim 18 in which R 15 is t-butyl or cyclopropyl.
21 . The method of claim 18 in which R 2 is
22 . The method of claim 21 in which R 8 is hydrogen; R 9 is selected from
and R 10 is other than
23 . The method of claim 22 in which R 10 is selected from methyl, trifluoromethyl and chloro.
24 . The method of claim 22 in which R 12 of R 9 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)CH 2 CH 3 .
25 . The method of claim 21 in which R 8 is hydrogen; R 9 is other than
and R 10 is selected from
26 . The method of claim 25 in which R 9 is selected from hydrogen, methyl, trifluoromethyl and chloro.
27 . The method of claim 25 in which R 12 of R 10 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)CH 2 CH 3 .
28 . The method of claim 18 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 2 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
29 . The method of claim 3 in which R 4 is lower alkyl.
30 . The method of claim 29 in which the lower alkyl is branched.
31 . The method of claim 30 in which R 4 is i-propyl or t-butyl.
32 . The method of claim 30 in which R 2 is
33 . The method of claim 32 in which R 8 is hydrogen; R 9 is selected from
and R 10 is other than
34 . The method of claim 33 in which R 10 is selected from hydrogen, methyl, trifluoromethyl and chloro.
35 . The method of claim 33 in which R 12 of R 9 is methyl.
36 . The method of claim 32 in which R 8 is hydrogen; R 9 is hydrogen and R 10 is selected from
37 . The method of claim 36 in which R 12 is methyl.
38 . The method of claim 18 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 3 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
39 . The method of claim 3 in which R 4 is selected from
40 . The method of claim 39 in which R 19 and R 20 are different from one another such that the carbon atom to which they are bonded is chiral.
41 . The method of claim 40 in which the 2,4-pyrimidinediamine compound is a racemate of R and S enantiomers.
42 . The method of claim 40 which the 2,4-pyrimidinediamine compound is enriched in the R enantiomer.
43 . The method of claim 42 in which the 2,4-pyrimidinediamine compound is substantially free of the S enantiomer.
44 . The method of claim 40 in which the 2,4-pyrimidinediamine compound is enriched in the S enantiomer.
45 . The method of claim 44 in which the 2,4-pyrimidinediamine compound is substantially free of the R enantiomer.
46 . The method of claim 39 in which R 2 is
47 . The method of claim 46 in which R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo, chloro and —OCH 2 C(O)NHR a , with the proviso that at least one of R 8 , R 9 or R 10 is other than hydrogen.
48 . The method of claim 46 in which R 8 is hydrogen; R 9 is selected from
and R 10 is selected from hydrogen, methyl and chloro.
49 . The method of claim 48 in which R 12 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)OCH 2 CH 3 .
50 . The method of claim 46 in which R 8 is hydrogen, R 9 is selected from hydrogen, methyl and chloro; and R 10 is selected from
51 . The method of claim 50 in which R 12 is selected from methyl, —C(O)CH 3 , —C(O)OCH 3 and —C(O)OCH 2 CH 3 .
52 . The method of claim 46 in which the substituents on the R 4 and R 2 groups are independently selected from any combinations described in TABLE 4 or TABLE 6.
53 . The method of claim 46 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 4 or TABLE 6 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
54 . The method of claim 3 in which R 4 is
55 . The method of claim 54 in which D is selected from —CH 2 —CH 2 —, —CF 2 —CF 2 , —CH 2 — and —CF 2 —.
56 . The method of claim 54 in which R 2 is
57 . The method of claim 56 in which R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, fluoro, —OCH 2 C(O)NHR a , —OCH 2 C(O)NR c R c , —OCH 2 C(O)OR a , trifluoromethyl and —O(CH 2 ) n OH, with the proviso that at least one of R 8 , R 9 or R 10 is other than hydrogen.
58 . The method of claim 54 which is selected from any compound in TABLE 5 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
59 . The method of claim 3 in which R 2 is
60 . The method of claim 59 in which R 11 is selected from any R 11 group listed in TABLE 7.
61 . The method of claim 59 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 7 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
62 . The method of claim 3 in which R 4 is
63 . The method of claim 62 in which R 2 is
64 . The method of claim 63 in which each R 8 , R 9 and R 10 is selected such that the compound is not an N2,N4-bis(substituted phenyl)-2,4-pyrimidinediamine.
65 . The method of claim 63 in which each R 8 , R 9 and R 10 is, independently of the others, selected from hydrogen, lower alkyl, methyl, hydroxy, trifluoromethoxy, lower linear alkoxy, halo, —O(CH 2 ) n NR c R c , —OCH 2 C(O)NHR a , —OCH 2 C(O)NR c R c and —OCH 2 C(O)OR a .
66 . The method of claim 65 in which R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen, methyl, trifluoromethyl, methoxy, trifluoromethoxy, and chloro, with the proviso that at least one of R 8 , R 9 and R 10 on both of R 2 and R 4 is other than hydrogen.
67 . The method of claim 66 in which at least two of R 8 , R 9 and R 10 on both of R 2 and R 4 are other than hydrogen.
68 . The method of claim 63 in which R 8 and R 9 of R 2 are each hydrogen; R 10 of R 2 is —OCH 2 C(O)NR c R c or —OCH 2 C(O)NHR a ; R 8 and R 10 of R 4 are, independently of one another, selected from hydrogen, methyl and chloro; and R 9 of R 4 is selected from hydroxy,
69 . The method of claim 63 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 8 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
70 . The method of claim 3 in which R 2 is
71 . The method of claim 70 in which R 4 is
where D is —CH 2 CH 2 —.
72 . The method of claim 71 in which R 8 , R 9 and R 10 are each, independently of one another, selected from hydrogen, methyl, methoxy, fluoro and chloro.
73 . The method of claim 71 which is selected from any compound in TABLE 10 having an IC 50 of <20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
74 . The method of claim 3 in which R 2 is
75 . The method of claim 74 in which R 4 is
76 . The method of claim 75 in which R 16 is selected from hydrogen, lower linear alkanyl, lower branched alkanyl, lower cyclic alkanyl and lower cyclicalkanylmethyl.
77 . The method of claim 75 in which the 2,4-pyrimidinediamine compound is selected from any compound in TABLE 13 having an IC 50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
78 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is selected from any compound illustrated in TABLES 1-14 having an IC 50 of ≦20 μM against at least one tumor cell line in an in vitro antiproliferation assay.
79 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ia):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
m is as integer ranging from 1 to 3;
R 21 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halogen and chloro;
R 22 is selected from hydrogen, lower alkoxy, methoxy, halogen, chloro,
R 23 is selected from hydrogen, methyl, lower alkyl, lower alkoxy, methoxy, halogen, chloro, trifluomethyl, —OCH 2 C(O)NHR a ,
and
R 24 is selected from hydrogen and methyl,
with the provisos that (i) when R 22 is
then R 23 is other than
and (ii) when R 23 is
then R 22 is other than
80 . The method of claim 79 in which R 21 and R 22 are each hydrogen and R 23 is selected from —OCH 2 C(O)NHR a ,
81 . The method of claim 79 in which R 22 is selected from hydrogen methoxy, chloro,
82 . The method of claim 81 in which R 12 is methyl.
83 . The method of claim 79 in which R 21 is hydrogen and R 22 is
where R 12 is methyl.
84 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ib):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R 15 is selected from t-butyl and cyclopropyl;
R 21 , R 22 and R 23 are as defined in claim 79 .
85 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ic):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R 14 is selected from i-propyl and t-butyl; and
R 21 , R 22 and R 23 are as defined in claim 79 .
86 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Id):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
Z 1 is selected from N and CH;
Z 2 is selected from NH, O, S and S(O) 2 ;
R 16 is selected from hydrogen and methyl;
R 19 is as defined in claim 1;
R 20 is as defined in claim 1;
R 24 is as defined in claim 79;
R 41 is selected from hydrogen, lower alkyl, methyl; hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl and —CH 2 OH;
R 42 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy, —OCH 2 C(O)NHR a ,
where R 12 is as defined in claim 1; and
R 43 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, chloro, trifluoromethyl, trifluoromethoxy, —OCH 2 C(O)NHR a , —OCH 2 C(O)OR a ,
where R 12 is as defined in claim 1 ,
with the provisos that:
(i) when R 42 is
then R 43 is other than
and
(ii) when R 43 is
then R 42 is other than
87 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ie):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein Z 1 , Z 2 , R 16 , R 19 , R 20 , R 24 , R 41 , R 42 and R 43 are as defined in claim 86 .
88 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (If):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
Z 3 is selected from N and CH;
p is 0 or 1;
R 7 is selected from hydrogen and fluoro;
R 24 is as defined in claim 79;
R 51 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo, trifluoromethyl, CH 2 OH and —C(O)OCH 3 ;
R 52 is selected from hydrogen, lower alkyl, methyl, hydroxy, lower alkoxy, methoxy, halo, trifluoromethyl, CH 2 OH and —OCH 2 C(O)NR a R a where R a is as defined in claim 1; and
R 53 is selected from hydrogen, lower alkyl, methyl, lower alkoxy, methoxy, halo, trifluoromethyl, CH 2 OH, —OCH 2 C(O)OR a and —OCH 2 C(O)NHR a where R a is as defined in claim 1 .
89 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ig):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R 28 is hydrogen or methyl;
R 16 is as defined in claim 86; and
R 21 , R 22 , R 23 and R 24 are as defined in claim 79 .
90 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ih):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R 24 is as defined in claim 79;
R 61 is selected from H and Cl;
R 62 is selected from —CH 2 NHBoc, —CH 2 NH 2 , —C(O)NH 2 , —C(O)NH—CH 2 —C(O)OH, —C(O)NH—CH 2 —C(O)OMe and —C(O)NH—CH 2 CH 2 —N(Et) 2 ;
R 63 is selected from H and Cl;
R 71 is H;
R 72 is selected from H, OMe, Cl and —C(O)NH 2 ; and
R 73 is selected from H, OMe and Cl.
91 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ii):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
each R 24 is independently as defined in claim 79; and
R 30 is selected from alkanyl and alkenyl.
92 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ij):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R 24 is as defined in claim 79;
R 81 is selected from hydrogen, methyl and methoxy;
R 82 is selected from hydrogen, methoxy and chloro; and
R 83 is selected from methyl, methoxy, halo and fluoro.
93 . The method of claim 1 in which the 2,4-pyrimidinediamine compound is a compound according to structural formula (Ik), (Il), (Im) or (In):
including prodrugs, salts, hydrates, solvates and N-oxides thereof, wherein:
R 91 , if present, is hydrogen;
R 92 , if present, is selected from lower alkoxy, methoxy, halo, chloro and fluoro;
R 93 , if present, is selected from lower alkoxy, methoxy, halo and chloro; and
R 96 is selected from hydrogen, lower linear alkanyl, lower branched alkanyl, lower cycloalkanyl and lower cycloalkanylmethyl.
94 . The method of claim 1 in which the cancer cell is a tumor cell.
95 . The method of claim 94 in which the tumor cell is a bladder, lung, colon, breast, prostate, pancreatic, ovarian or hepatic tumor cell.
96 . The method of claim 1 which is practiced in vivo as a therapeteutic approach towards the treatment of cancer.
97 . The method of claim 96 in which the cancer is a metastatic tumor.
98 . The method of claim 97 in which the cancer is selected from the group consisting of breast, colon, pancreatic, lung, neural, esophageal, gastric, and melanoma.
99 . The method of claim 96 in which the compound is administered in the form of a pharmaceutical composition.
100 . The method of claim 99 in which the compound is administered orally or intravenously.
101 . The method of claim 100 in which the subject is a human.Join the waitlist — get patent alerts
Track US2005113398A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.