Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-13
2002-04-09
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S083000
Reexamination Certificate
active
06369070
ABSTRACT:
This application is a 371 of a PCT/US99/7613 filed Jun. 7, 1999.
Along with surgery and radiotherapy, chemotherapy continues to be an effective therapy for many cancers. In fact, several types of cancer are now considered to be curable by chemotherapy and include Hodgkin's disease, large cell lymphoma, acute lymphocytic leukemia, testicular cancer and early stage breast cancer. 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, 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 which are selective inhibitors of MDR1 or MRP1.
The present invention relates to a compound of formula I:
where:
R is (CH
2
)
m′
CHR
1
NHR
2
, O(CH
2
)
2
NHR
2
, (CH
2
)
m′
COR
3
, NHR
2
, and (CH
2
)
m′
CHR
1
NR
4
R
5
;
R′ is hydrogen, hydroxy, or O(C
1
-C
6
alkyl optionally substituted with phenyl or C
3
-C
7
cycloalkyl);
m and m
1
are independently at each occurrence 0, 1, or 2;
R′ is independently at each occurrence hydrogen or C
1
-C
6
alkyl;
R
2
is hydrogen, COR
6
, CH
2
R
′
, SO
2
R
7
, or a moiety of the formula
R
3
is hydrogen, hydroxy, C
1
-C
6
alkoxy, an amino ester, an amino acid, or NR
4
R
5
;
R
4
is hydrogen or C
1
-C
6
alkyl;
R
5
is hydrogen, C
1
-C
6
alkyl, C
6
-C
10
bicycloalkyl, CH
2
CH(CH
3
)phenyl, CH(CH
3
)CH
2
CO
2
R
1
, aryl, substituted aryl, (CH
2
)
n
CHR
8
NHC(O)OC(CH
3
)
3
, (CH
2
)
n
NH
2
, (CH
2
)
2
NHCOR
6
, (CH
2
)
2
OH, (CH
2
)
q
-heterocycle, (CH
2
)
q
-substituted heterocycle, or R
4
and R
5
combine to form a pyrrolidin-1-yl, piperidin-1-yl, hexamethyleneimin-1-yl, or morpholin-4-yl ring;
n is 1, 2, 3, or 4;
q is 0, 1, 2, or 3;
R
6
is C
1
-C
6
alkyl, substituted C
3
-C
6
cycloalkyl, aryl, substituted aryl, tert-butoxy, (CH
2
)
q
-heterocycle, (CH
2
)
q
-substituted heterocycle, (CH
2
)
n
S(O)
r
R
1
, C(CH
3
)
2
CH
2
N(R
1
)
2
, (CH
2
)
n
CHR
8
NHC(O)OC(CH
3
)
3
, (CH
2
)
n
NCHR
8
NH
2
, (CH
2
)
2
NH-aryl, or NHR
7
;
R
6′
is C
1
-C
6
alkyl, substituted C
3
-C
6
cycloalkyl, aryl, substituted aryl, (CH
2
)
q
-heterocycle, (CH
2
)q-substituted heterocycle, (CH
2
)
n
S(O)
r
R
1
, C(CH
3
)C
2
CH
2
N(R
1)
2
, (CH
2
)
n
CHR
8
NH—C(O)OC(CH
3
)
3
, (CH
2
)
n
CHR
8
NH
2
, or (CH
2
)
2
NH-aryl;
r is 0, 1, or 2;
R
7
is C
1
-C
6
alkyl, phenyl, or substituted phenyl; and
R
8
is hydrogen or CO
2
R
1
; or a pharmaceutical salt or solvate thereof.
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, or a pharmaceutical salt or solvate thereof.
In another embodiment, the present invention relates to 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, or a pharmaceutical salt or solvate thereof, in combination with an effective amount of an oncolytic agent.
The present invention also relates to a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutical salt or solvate thereof, in combination with one or more oncolytics, pharmaceutical carriers, diluents, or excipients therefor.
The current invention concerns the discovery that a select group of compounds, those of formula I, are selective inhibitors of multidrug resistant protein (MRP1) and are thus useful in treating MRP1 conferred multidrug resistance (MDR) in a resistant neoplasm and a neoplasm susceptible to resistance.
The terms “inhibit” as it relates to MRP1 and “inhibiting MRP1” refer to prohibiting, alleviating, ameliorating, halting, restraining, slowing or reversing the progression of, or reducing MRP1's ability to redistribute an oncolytic away from the oncolytic's site of action, most often the neoplasm's nucleus, and out of the cell.
As used herein, the term “effective amount of a compound of formula I” refers to an amount of a compound of the present invention which is capable of inhibiting MRP1. The term “effective amount of an oncolytic” refers to an amount of oncolytic capable of inhibiting a neoplasm, resistant or otherwise.
The term “inhibiting a resistant neoplasm, or a neoplasm susceptible to resistance” refers to prohibiting, halting, restraining, slowing or reversing the progression of, reducing the growth of, or killing resistant neoplasms and/or neoplasms susceptible to resistance.
The term “resistant neoplasm” refers to a neoplasm which is resistant to chemotherapy where that resistance is conferred in part, or in total, by MRP1. Such neoplasms include, but are not limited to, neoplasms of t
Gruber Joseph M.
Kroin Julian S
Norman Bryan H
Dawalt Elizabeth A.
Desai Rita
Eli Lilly and Company
Lee Kirby W.
Rotman Alan L.
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