US2004176405A1PendingUtilityA1
Methods and compounds for inhibitting MRP1
Priority: Dec 22, 1999Filed: Mar 10, 2004Published: Sep 9, 2004
Est. expiryDec 22, 2019(expired)· nominal 20-yr term from priority
C07D 471/04A61P 35/00
49
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Claims
Abstract
The present invention further relates to a method of inhibiting MRP1 in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I).
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of formula I:
where:
A is a C 3 -C 8 cycloalkyl, optionally substituted 1-3 times with a C 1 -C 4 alkyl;
het is a five (5) membered heterocyclic ring comprising N and a second heteroatom selected from N, O, or S;
wherein the non-fused carbon atom of the heteroaryl ring may be optionally substituted with R b : C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted heterocycle, an amino acid ester, CH 2 OH, CH 2 O-heterocycle, halo, CH 2 N 3 , CH 2 SR 1 , CH 2 NR 4 R 6 , OR 1 , SR 13 , S(CH 2 ) k -phenyl, or NR 4 R 6 ; provided that when het is pyrazole or imidazole, the saturated nitrogen of the het ring may be optionally substituted with R a : C 1 -C 4 alkyl;
k is 0, 1, 2, 3, or 4;
n is 0, 1, or 2;
p is 0 or 1;
q is 0, 1, or 2;
r is 0, 1, or 2;
t is 0, 1, 2, 3, or 4;
u is 0, 1, 2, 3, or 4;
Y is -E-C(O)R 3 , -E-CH═CHR 13 , -E-C(OH)R 13 , -E-NR 4 R 5 , -E-OR 2 , -E-S(O) q R 13 , -E-SO 2 NR 4 R 6 , —C(R 11 )=NR 6 , or an optionally substituted heterocycle;
E is a bond or —C(R 11 )(R 11 )—;
R 1 is independently at each occurrence hydrogen or C 1 -C 6 alkyl;
R 2 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, or optionally substituted heterocycle, C(O)-aryl, or (CH 2 ) 2 NR 4 R 5 ;
R 3 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, OR 13 , or NR 4 R 6 ;
R 4 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, optionally substituted (C 1 -C 6 alkyl)-aryl, optionally substituted aryl, or R 4 and R 5 , R 6 , R 6′ combine to form ═CR 1 R 14 ;
R 5 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, optionally substituted heterocycle, optionally substituted C 3 -Cg cycloalkyl, optionally substituted C 6 -C 10 bicycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C 1 -C 4 alkyl)-heterocycle, C(O)C(O)R 13 , C(O)R 7 , CH 2 R 7 , SO 2 R 8 , a moiety of the formula
or R 4 and R 5 , together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
R 6 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 bicycloalkyl, optionally substituted (C 1 -C 4 alkyl)aryl, optionally substituted aryl, optionally substituted (C 1 -C 4 alkyl)-heterocyc]e, optionally substituted heterocycle, or R 4 and R 6 , together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
R 6′ is independently at each occurrence hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 bicycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C 1 -C 4 alkyl)heterocycle, optionally substituted heterocycle, (C 1 -C 4 alkyl)-OR 13 ;
wherein the (C 1 -C 4 alkyl) of the (C 1 -C 4 alkyl)-OR 13 may be optionally substituted from 1 to 2 times with C 1 -C 4 alkyl, optionally substituted aryl, optionally substituted heterocycle;
or R 4 and R 6′ , together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
R 7 is independently at each occurrence optionally substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 4 alkoxy)-aryl, (C 1 -C 4 alkoxy)-heterocycle, (C 1 -C 4 alkoxy)SiCH 3 , optionally substituted (C 3 -C 8 cycloalkyl), optionally substituted (C 1 -C 4 alkyl)-(C 3 -Cg cycloalkyl), optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, diphenylmethyl, optionally substituted (C 1 -C 4 alkyl)-CO-aryl, optionally substituted CO-aryl, optionally substituted (C 1 -C 4 alkyl)-heterocycle, optionally substituted CH═CH-heterocycle, optionally substituted phenoxy, optionally substituted heterocycle, optionally substituted (C 1 -C 4 alkyl)-phenoxy, (CH 2 ) t S(O) t R 1 , (CH 2 ) t C(R 12 )(R 9 )N(R 16 )(R 15 ), (CH 2 ) t C(R 12 )(R 9 )O(R 17 ), (CH 2 ) t C(R 12 )(R 9 )S(R 17 ), or NR 4 R 6 ′;
R 8 is independently at each occurrence optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted (C 1 -C 4 alkyl)-heterocycle, or optionally substituted heterocycle;
R 9 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -Cg cycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, (CH 2 ) u4 C 1 -C 6 alkoxy), optionally substituted (CH 2 ) u —O—(C 3 -C 8 cycloalkyl), optionally substituted (CH 2 ) u —(C 1 -C 4 alkoxy)-aryl, optionally substituted (CH 2 ) u —O-aryl, optionally substituted (CH 2 ) u —O-heterocycle, (C 1 -C 4 alkyl)-CO 2 —(C 1 -C 6 alkyl), optionally substituted (C 1 -C 4 alkyl)-CO 2 —(C 3 -C 8 cycloalkyl), optionally substituted (C 1 -C 4 alkyl)CO 2 —(C 1 -C 4 alkyl)-aryl, optionally substituted (C 1 -C 4 alkyl)-CO 2 -aryl, optionally substituted (C 1 -C 4 alkyl)-CO 2 -heterocycle, or R 9 and R 12 can combine to form a C 3 -C 8 cycloalkyl;
R 10 is 0 to 4 substituents from the aryl ring independently at each occurrence hydrogen, halo, C(O)R 3 , cyano, optionally substituted heterocycle, optionally substituted aryl, C≡C—R 1 , C 1 -C 4 alkoxy, (C 1 -C 4 alkyl)-phenyl, NR 19 R 20 , or C 2 -C 6 alkenyl;
R 11 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, optionally substituted heterocycle, optionally substituted (C 1 -C 4 alkyl)heterocycle, optionally substituted aryl, or optionally substituted (C 1 -C 4 alkyl)-aryl;
R 12 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alky], optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 4 alkyl)aryl, optionally substituted aryl, optionally substituted (C 1 -C 4 alkyl)-heterocycle or optionally substituted heterocycle;
R 13 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, Optionally substituted aryl, CO 2 CH 2 CO 2 CH 2 CH 3 , or optionally substituted heterocycle;
R 14 is independently at each occurrence C 1 -C 6 alkyl or optionally substituted (C 1 -C 4 alkyl)-aryl;
R 15 is independently at each occurrence hydrogen, C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 bicycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, optionally substituted (C 1 -C 4 allyl)-heterocycle, optionally substituted heterocycle, C(O)OR 13 , SO 2 R 8 , C(O)R 18 , or a moiety of the formula
R 16 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted aryl, optionally substituted heterocycle, or —COR 8 ; or R 16 and R 15 , together with the nitrogen to which they are attached, combine to form an optionally substituted N-heterocycle;
R 17 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, COR 18 , optionally substituted heterocycle, optionally substituted (C 1 -C 4 alkyl)-heterocycle, optionally substituted C 1 -C 6 alkoxy, optionally substituted (C 1 -C 4 alkoxy)-aryl, optionally substituted (C 1 -C 4 alkoxy)-heterocycle, (C 1 -C 4 alkyl)-N(R 1 )(R 1 ), or an amino acid ester;
R 18 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted (C 1 -C 4 alkyl)-aryl, optionally substituted aryl, optionally substituted heterocycle, (C 1 -C 4 alkyl)-NHCO 2 —(C 1 -C 4 alkyl), or optionally substituted (C 1 -C 4 alkyl)-heterocycle;
R 19 is independently at each occurrence hydrogen, or optionally substituted C 1 -C 6 alkyl;
R 20 is independently at each occurrence hydrogen, optionally substituted C 1 -C 6 alkyl, CH 201 , CO—(C 1 -C 4 alkyl); or a pharmaceutical salt thereof.
2 . The compound of claim 1 where het is
3 . The compound of claim 1 where het is
4 . The compound of any one of claims 1 - 3 where A is 1,3-cyclohexyl.
5 . The compound of any one of claims 14 where n is 0.
6 . The compound of any one of claims 1 - 5 where o is 0 or 1.
7 . The compound of any one of claims 1 - 6 where Y is E-NR 4 R 5 .
8 . The compound of claim 7 where R 5 is COR 7 .
9 . The compound of claim 8 where R 7 is optionally substituted heterocycle.
10 . The compound of claim 8 where R 7 is optionally substituted CO-aryl.
11 . The compound of claim 8 where R 7 is optionally substituted CO-heteroaryl.
12 . The compound of claim 8 where R 7 is. (CH 2 ) t C(R 12 )(R 9 )N(R 16 )(R 15 ).
13 . The compound of any one of claims 1 - 12 where R b is C 1 -C 6 alkyl.
14 . The compound of claim 13 where R b is methyl.
15 . The compound of any one of claims 1 - 14 where R 10 is halo.
16 . The compound of claim 15 where R 10 is chloro.
17 . The compound of claim 16 where R 10 is 9-chloro.
18 . The compound of claim 17 selected from the group consisting of N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide, N-[(3S,1R) 3(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide, N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-imidazolo[5,4-c]quinolin-5-yl))cyclohexyl]methyl}benzamide, N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2(4-fluorophenyl)-2-hydroxyacetamide, N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide, and N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamde.
19 . A method of inhibiting MRP1 in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, as defined in claim 1 , or a pharmaceutical salt thereof.
20 . The method according to claim 19 where the mammal is a human.
21 . The method of any one of claims 19 - 20 where het is
22 . The method of any one of claims 19 - 20 where het is
23 . The method of any one of claims 19 - 22 where A is 1,3-cyclohexyl.
24 . The method of any one of claims 19 - 23 where n is 0.
25 . The method of any one of claims 19 - 24 where o is 0 or 1.
26 . The method of any one of claims 19 - 25 where Y is E-NR 4 R 5 .
27 . The method of claim 26 where R 5 is COR 7 .
28 . The method of claim 27 where R 7 is optionally substituted heterocycle.
29 . The method of claim 27 where R 7 is optionally substituted CO-aryl.
30 . The method of claim 27 where R 7 is optionally substituted CO-heteroaryl.
31 . The method of claim 27 where R 7 is (CH 2 ) t C(R 12 )(R 9 )N(R 16 )(R 15 ).
32 . The method of any one of claims 19 - 31 where R b is C 1 -C 6 alkyl.
33 . The method of claim 32 where R b is methyl.
34 . The method of any one of claims 19 - 33 where R 10 is halo.
35 . The method of claim 34 where R 10 is chloro.
36 . The method of claim 35 where R 10 is 9-chloro.
37 . The method of claim 36 selected from the group consisting of N-[(3S,1R) 3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide, N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-imidazolo[5,4-c]quinolin-5-yl))cyclohexyl]methyl}benzamide, N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide, N-[(3S,1R) 3 -(9-chloro-3-methyl-4-oxo-SH-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-fluorophenyl)-2-hydroxyacetamide, N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4 acetylpiperazinyl)-2-phenylacetamide, and N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide.
38 . A method of inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance, in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, as defined in claim 1 , or a pharmaceutical salt thereof; in combination with an effective amount of one or more oncolytic agents.
39 . The method according to claim 38 where the mammal is a human.
40 . The method according to claim 39 where the oncolytic(s) is selected from:
camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone, doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside.
41 . The method according to claim 39 where the neoplasm is of the Wilm's type, bladder, bone, breast, lung(small-cell), testis, or thyroid or the neoplasm is associated with acute lymphoblastic and myeloblastic leukemia, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.
42 . The method of any one of claims 3941 where het is
43 . The method of any one of claims 3941 where het is
44 . The method of any one of claims 3943 where A is 1,3-cyclohexyl.
45 . The method of any one of claims 3944 where n is 0.
46 . The method of any one of claims 39 - 45 where o is 0 or 1.
47 . The method of any one of claims 3946 where Y is E-NR 4 R 5 .
48 . The method of claim 47 where R 5 is COR 7 .
49 . The method of claim 48 where R 7 is optionally substituted heterocycle.
50 . The method of claim 48 where R 7 is optionally substituted CO-aryl.
51 . The method of claim 48 where R 7 is optionally substituted CO-heteroaryl.
52 . The method of claim 48 where R 7 is (CH 2 ) t C(R 12 )(R 9 )N(R 16 )(R 15 ).
53 . The method of any one of claims 39 - 52 where R b is C 1 -C 6 alkyl.
54 . The method of claim 53 where R b is methyl.
55 . The method of any one of claims 39 - 54 where R 10 is halo.
56 . The method of claim 55 where R 10 is chloro.
57 . The method of claim 56 where R 10 is 9-chloro.
58 . The method of claim 57 selected from the group consisting of N-[(3S,1R)-3-(9-chloro-3-methyl oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-piperidylacetamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(2-chloro(4-pyridyloxy))acetamide, N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-imidazolo[5,4-c]quinolin-5-yl))cyclohexyl]methyl}benzamide, N-{[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}benzamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-hydroxy-2-phenylacetamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-fluorophenyl)-2-hydroxyacetamide, N-{[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]methyl}-3-pyridylcarboxamide, N-[(3S,1R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide, and N-[(1S,3R)-3-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl))cyclohexyl]-2-(4-acetylpiperazinyl)-2-phenylacetamide.
59 . A pharmaceutical formulation comprising a compound of formula I, as defined in claim 1 , or a pharmaceutical salt thereof; in combination with one or more pharmaceutical carriers, diluents, or excipients therefor.
60 . A pharmaceutical formulation comprising:
(a) a compound of formula I, as defined in claim 1 , or a pharmaceutical salt thereof; (b) one or more oncolytic agents; and (c) one or more pharmaceutical carriers, diluents, or excipients therefor.
61 . The formulation according to claim 60 where the oncolytic(s) is selected from: camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone, doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside.
62 . A use of a compound of formula I, as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance in a mammal.
63 . A use of a compound of formula I, as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting MRP1.
64 . A use of a compound of formula I, as defined in claim 1 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting MRP1 conferred MDR in a resistant neoplasm, or a neoplasm susceptible to resistance in a mammal.
65 . A use of a compound of formula I, as defined in claim 1 , in therapy.
66 . A pharmaceutical composition for inhibiting MRP1 in a mammal which comprises an effective amount of a compound of formula I, as defined in claim 1 , or a pharmaceutical salt thereof.
67 . The composition according to claim 66 where the mammal is a human.
68 . A pharmaceutical composition for inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance, in a mammal which comprises administering to a mammal in need thereof an effective amount of a compound of formula I, as defined in claim 1 , or a pharmaceutical salt thereof; in combination with an effective amount of one or more oncolytic agents.
69 . The composition according to claim 68 where the mammal is a human.
70 . The composition according to claim 69 where the oncolytic(s) is selected from: camptosar, melphalan, paclitaxel, vinorelbine, mitoxantrone, doxorubicin, daunorubicin, epirubicin, vincristine, and etopsoside.
71 . The composition according to claim 69 where the neoplasm is of the Wilm's type, bladder, bone, breast, lung(small-cell), testis, or thyroid or the neoplasm is associated with acute lymphoblastic and myeloblastic leukemia, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.Join the waitlist — get patent alerts
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