Methods and compounds for inhibiting MRP1

Details Methods and compounds for inhibiting MRP1 Methods and compounds for inhibiting MRP1

2002-05-21

2004-06-01

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S293000, C514S232800, C514S255050, C514S228500, C514S256000, C544S126000, C544S060000, C544S405000, C544S333000, C544S361000, C546S083000, C546S082000

Reexamination Certificate

active

06743794

ABSTRACT:

BACKGROUND
Along with surgery and radiotherapy, chemotherapy continues to be an effective therapy for many cancers. In fact, several types of cancer, such as Hodgkin's disease, large cell lymphoma, acute lymphocytic leukemia, testicular cancer and early stage breast cancer, are now considered to be curable by chemotherapy. Other cancers such as ovarian cancer, small cell lung and advanced breast cancer, while not yet curable, are exhibiting positive response to combination chemotherapy.
One of the most important unsolved problems in cancer treatment is drug resistance. After selection for resistance to a single cytotoxic drug, cells may become cross resistant to a whole range of drugs with different structures and cellular targets, e.g., alkylating agents, antimetabolites, hormones, platinum-containing drugs, and natural products. This phenomenon is known as multidrug resistance (MDR). In some types of cells, this resistance is inherent, while in others, such as small cell lung cancer, it is usually acquired.
Such resistance is known to be multifactorial and is conferred by at least two proteins: the 170 kDa P-glycoprotein (MDR1) and the more recently identified 190 kDa multidrug resistance protein (MRP1). Although both MDR1 and MRP1 belong to the ATP-binding cassette superfamily of transport proteins, they are structurally very different molecules and share less than 15% amino acid homology. Despite the structural divergence between the two proteins, by 1994 there were no known consistent differences in the resistance patterns of MDR1 and MRP1 cell lines. However, the association, or lack thereof, of MRP1 and resistance to particular oncolytics is known. See Cole, et. al., “Pharmacological Characterization of Multidrug Resistant MRP-transfected Human Tumor Cells”,
Cancer Research,
54:5902-5910, 1994. Doxorubicin, daunorubicin, epirubicin, vincristine, paclitaxel, mitoxantrone, melphalan, and etoposide are substrates of MRP1, i.e., MRP1 can bind to these oncolytics and redistribute them away from their site of action, the nucleus, and out of the cell. Id. and Marquardt, D., and Center, M. S.,
Cancer Research,
52:3157, 1992.
Doxorubicin, daunorubicin, and epirubicin are members of the anthracycline class of oncolytics. They are isolates of various strains of Streptomyces and act by inhibiting nucleic acid synthesis. These agents are useful in treating neoplasms of the bone, ovaries, bladder, thyroid, and especially the breast. They are also useful in the treatment of acute lymphoblastic and myeloblastic leukemia, Wilm's tumor, neuroblastoma, soft tissue sarcoma, Hodgkin's and non-Hodgkin's lymphomas, and bronchogenic carcinoma.
Vincristine, a member of the vinca alkaloid class of oncolytics, is an isolate of a common flowering herb, the periwinkle plant (
Vinca rosea
Linn). The mechanism of action of vincristine is still under investigation but has been related to the inhibition of microtubule formation in the mitotic spindle. Vincristine is useful in the treatment of acute leukemia, Hodgkin's disease, non-Hodgkin's malignant lymphomas, rhabdomyosarcoma, neuroblastoma, and Wilm's tumor.
Etoposide, a member of the epipodophyllotoxin class of oncolytics, is a semisynthetic derivative of podophyllotoxin. Etoposide acts as a topoisomerase inhibitor and is useful in the therapy of neoplasms of the testis, and lung.
It is presently unknown what determines whether a cell line will acquire resistance via a MDR1 or MRP1 mechanism. Due to the tissue specificity of these transporters and/or in the case where one mechanism predominates or is exclusive, it would be useful to have a selective inhibitor of that one over the other. Furthermore, when administering a drug or drugs that are substrates of either protein, it would be particularly advantageous to coadminister an agent that is a selective inhibitor of that protein. It is, therefore, desirable to provide compounds that are selective inhibitors of MDR1 or MRP1.
SUMMARY OF THE INVENTION
The present invention relates to a compound of formula:
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
-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, 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)-heterocycle, 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
-C
8
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 substitu

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