U.S. patent application number 10/886955 was filed with the patent office on 2005-01-13 for combination of src kinase inhibitors and chemotherapeutic agents for the treatment of proliferative diseases.
Invention is credited to Lee, Francis Y..
Application Number | 20050009891 10/886955 |
Document ID | / |
Family ID | 34135068 |
Filed Date | 2005-01-13 |
United States Patent
Application |
20050009891 |
Kind Code |
A1 |
Lee, Francis Y. |
January 13, 2005 |
Combination of SRC Kinase inhibitors and chemotherapeutic agents
for the treatment of proliferative diseases
Abstract
Compositions and methods are disclosed which are useful of the
treatment and prevention of proliferative disorders.
Inventors: |
Lee, Francis Y.; (Yardley,
PA) |
Correspondence
Address: |
STEPHEN B. DAVIS
BRISTOL-MYERS SQUIBB COMPANY
PATENT DEPARTMENT
P O BOX 4000
PRINCETON
NJ
08543-4000
US
|
Family ID: |
34135068 |
Appl. No.: |
10/886955 |
Filed: |
July 8, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60485779 |
Jul 9, 2003 |
|
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|
Current U.S.
Class: |
514/369 ;
514/370 |
Current CPC
Class: |
A61K 31/426 20130101;
A61P 35/00 20180101; A61K 31/427 20130101; A61P 43/00 20180101;
A61K 45/06 20130101; A61K 31/427 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/426 20130101 |
Class at
Publication: |
514/369 ;
514/370 |
International
Class: |
A61K 031/427; A61K
031/426 |
Claims
What is claimed is:
1. A method for the treatment of proliferative diseases, including
cancer, which comprises administering to a mammalian specie in need
thereof a synergistically, therapeutically effective amount of (1)
at least one anti-proliferative cytotoxic agent(s) and 2) a
compound of formula I, 4where Q is thiazole; Z is a single bond;
X.sub.1 and X.sub.2 together form .dbd.O; R.sub.1 is (1) hydrogen
or R.sub.6, where R.sub.6 is alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl,
heterocyclo, or heterocycloalkyl, each of which is unsubstituted or
substituted with Z.sub.1, Z.sub.2 and one or more groups Z.sub.3;
(2) --OH or --OR.sub.6; (3) --SH or --SR.sub.6; (4) --C(O).sub.2H,
--C(O).sub.qR.sub.6, or --O--C(O).sub.qR.sub.6, where q is 1 or 2;
(5) --SO.sub.3H or --S(O).sub.qR.sub.6; (6) halo; (7) cyano; (8)
nitro; (9) --Z.sub.4--NR.sub.7R.sub.8; (10) --Z.sub.4--N(R.sub.9)
--Z.sub.5--NR.sub.10R.sub.11; (11)
--Z.sub.4--N(R.sub.12)--Z.sub.5--R.sub- .6; (12) --P(O)
(OR.sub.6).sub.2; R.sub.2 is hydrogen, R.sub.6, --Z.sub.4--R.sub.6,
or --Z.sub.13--NR.sub.7R.sub.8; R.sub.3 is --Z.sub.4--R.sub.6
wherein Z.sub.4 is a single bond and R.sub.6 is heteroaryl which is
unsubstituted or substituted with Z.sub.1, Z.sub.2 and one or more
groups Z.sub.3 R.sub.4 and R.sub.5 are each independently (1)
hydrogen or R.sub.6; (2)
--Z.sub.4--N(R.sub.9)--Z.sub.5--NR.sub.10R.s- ub.11; (3)
--N(R.sub.9)Z.sub.4R.sub.6; or (4) together with the nitrogen atom
to which they are attached complete a 3- to 8-membered saturated or
unsaturated heterocyclic ring which is unsubstituted or substituted
with Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may
optionally have fused to it a benzene ring itself unsubstituted or
substituted with Z.sub.1, Z.sub.2 and Z.sub.3; R.sub.7, R.sub.8,
R.sub.9, R.sub.10, R.sub.11 and R.sub.12 (1) are each independently
hydrogen or R.sub.6; (2) R.sub.7 and R.sub.8 may together be
alkylene, alkenylene or heteroalkyl, completing a 3- to 8-membered
saturated or unsaturated ring with the nitrogen atom to which they
are attached, which ring is unsubstituted or substituted with
Z.sub.1, Z.sub.2 and Z.sub.3; or (3) any two of R.sub.9, R.sub.10
and R.sub.11 may together be alkylene or alkenylene completing a 3-
to 8-membered saturated or unsaturated ring together with the
nitrogen atoms to which they are attached, which ring is
unsubstituted or substituted with Z.sub.1, Z.sub.2 and Z.sub.3;
R.sub.13 is (1) cyano; (2) nitro; (3) --NH.sub.2; (4) --NHOalkyl;
(5) --OH; (6) --NHOaryl; (7) --NHCOOalkyl; (8) --NHCOOaryl; (9)
--NHSO.sub.2alkyl; (10) --NHSO.sub.2aryl; (11) aryl; (12)
heteroaryl; (13) --Oalkyl; or (14) --Oaryl; R.sub.14 is (1)
--NO.sub.2; (2) --COOalkyl; or (3) --COOaryl; R.sub.15 is (1)
hydrogen; (2) alkyl; (3) aryl; (4) arylalkyl; or (5) cycloalkyl;
Z.sub.1, Z.sub.2 and Z.sub.3 are each independently (1) hydrogen or
Z.sub.6, where Z.sub.6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl,
cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aralkyl,
alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a
group (i) which is itself substituted by one or more of the same or
different groups (i); or (iii) a group (i) or (ii) which is
substituted by one or more of the following groups (2) to (16) of
the definition of Z.sub.1, Z.sub.2 and Z.sub.3; (2) --OH or
--OZ.sub.6; (3) --SH or --SZ.sub.6; (4) --C(O).sub.qH,
--C(O).sub.qZ.sub.6, or --O--C(O).sub.qZ.sub.6; (5) --SO.sub.3H,
--S(O).sub.qZ.sub.6; or S(O).sub.qN(Z.sub.9)Z.sub.6; (6) halo; (7)
cyano; (8) nitro; (9) --Z.sub.4--NZ.sub.7Z.sub.8; (10)
--Z.sub.4--N(Z.sub.9)--Z.sub.5--NZ.sub.7- Z.sub.8; (11)
--Z.sub.4--N(Z.sub.10)--Z.sub.5--Z.sub.6; (12)
--Z.sub.4--N(Z.sub.10)--Z.sub.5--H; (13) oxo; (14)
--O--C(O)--Z.sub.6; (15) any two of Z.sub.1, Z.sub.2, and Z.sub.3
may together be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the atoms to
which they are attached; or (16) any two of Z.sub.1, Z.sub.2, and
Z.sub.3 may together be --O--(CH.sub.2).sub.r--O--, where r is 1 to
5, completing a 4- to 8-membered ring together with the atoms to
which they are attached; Z.sub.4 and Z.sub.5 are each independently
(1) a single bond; (2) --Z.sub.11--S(O).sub.qZ.sub.12--; (3)
--Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5)
--Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7)
--Z.sub.11--O--C(O)--Z.sub.12--; or (8)
--Z.sub.11--C(O)--O--Z.sub.12--; Z.sub.7, Z.sub.8, Z.sub.9 and
Z.sub.10 (1) are each independently hydrogen or Z.sub.6; (2)
Z.sub.7 and Z.sub.8, or Z.sub.6 and Z.sub.10, may together be
alkylene or alkenylene, completing a 3- to 8-membered saturated or
unsaturated ring together with the atoms to which they are
attached, which ring is unsubstituted or substituted with Z.sub.1,
Z.sub.2 and Z.sub.3; or (3) Z.sub.7 or Z.sub.8, together with
Z.sub.9, may be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the nitrogen
atoms to which they are attached, which ring is unsubstituted or
substituted with Z.sub.1, Z.sub.2 and Z.sub.3; Z.sub.11 and
Z.sub.12 are each independently (1) a single bond; (2) alkylene;
(3) alkenylene; or (4) alkynylene; and Z.sub.13 is (1) a single
bond; (2) --Z.sub.11--S(O).sub.q--Z.sub.12--; (3)
--Z.sub.11--C(O)--Z.sub.12--; (4) --Z.sub.11--C(S)--Z.sub.12--; (5)
--Z.sub.11--O--Z.sub.12--; (6) --Z.sub.11--S--Z.sub.12--; (7)
--Z.sub.11--O--C(O)--Z.sub.12--; (8) --Z.sub.11--C(O)--Z.sub.12--;
(9) --C(NR.sub.13)--; (10) --C(CHR.sub.14)--; or (11)
--C(C(R.sub.14).sub.2) provided said compound is other than a
compound of formula (vii) 5where R.sub.3e is pyridyl or pryimidinyl
optionally substituted with halogen or alkyl; R.sub.50 and R.sub.51
are each independently hydrogen, halogen or alkyl; R.sub.52 and
R.sub.53 are each independently hydrogen, halogen, alkyl or
haloalkyl; R.sub.54 and R.sub.56 are each independently hydrogen,
halogen, alkyl, nitro or amino; R.sub.55 is hydrogen, halogen,
alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, or
alkoxycarbonyl; and n is zero or 1.
2. A compound of claim 1 wherein R.sub.1 is hydrogen, halo, alkyl,
aryl, alkoxy, alkoxycarbonyl, or aryloxycarbonyl.
3. A compound of claim 2 wherein R.sub.1 is hydrogen.
4. A compound of claim 3 wherein R.sub.2 is hydrogen.
5. A compound of claim 4 wherein R.sub.4 is hydrogen.
6. A compound of claim 5 wherein R.sub.5 is an aryl group which is
substituted with Z.sub.1, Z.sub.2 and one or more groups
Z.sub.3.
7. A compound of claim 6 wherein R.sub.1 is hydrogen or alkyl,
R.sub.2 and R.sub.4 are independently hydrogen or alkyl, and
R.sub.5 is aryl which is unsubstituted or substituted with Z.sub.1,
Z.sub.2 and one or more groups Z.sub.3.
8. A compound of claim 7 wherein R.sub.5 is aryl which is
unsubstituted or independently substituted with one or more alkyl
or halo.
9. A compound of claim 8 wherein R.sub.3 is heteroaryl substituted
optionally substituted with Z.sub.1 and Z.sub.2 and substituted
with at least one group Z.sub.3 where Z.sub.3 is Z.sub.6.
10. A compound of claim 9 wherein Z.sub.6 is heterocyclo optionally
substituted with one or more hydroxyalkyl.
11. The method according to claim 1, wherein the Compound of
Formula I is
'N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-m-
ethyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.
12. The method according to claim 1 wherein the antiproliferative
cytotoxic agent is administered following administration of the
Formula I compound.
13. The method according to claim 1, wherein the antiproliferative
cytotoxic agent is administered prior to the administration of the
Formula I compound.
14. The method according to claim 1 wherein the antiproliferative
cytotoxic agent is administered simultaneously with the formula 1
compound.
15. The method according to claim 1 for the treatment of cancerous
solid tumors.
16. The method according to claim 1 for the treatment of refractory
tumors.
17. The method according to claim 1 wherein the anti-proliferative
cytotoxic agent is selected from the group consisting of a
microtubule-stabilizing agent, a microtubule-disruptor agent, an
alkylating agent, an anti-metabolite, epidophyllotoxin, an
antineoplastic enzyme, a topoisomerase inhibitor, procarbazine,
mitoxantrone, inhibitors of cell cycle progression, radiation and a
platinum coordination complex.
18. The method according to claim 17 wherein the anti-proliferative
cytotoxic agent is paclitaxel.
19. A pharmaceutical composition for the treatment of cancer which
comprises a synergistic combination of at least one
anti-proliferative cytotoxic agent and a compound of claim 1, and a
pharmaceutically acceptable carrier.
20. The composition according to claim 19 for the treatment of
cancerous solid tumors.
21. The composition according to claim 19 for the treatment of
refractory tumors.
22. The composition according to claim 19 wherein the
antiproliferative cytotoxic agent is paclitaxel.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims benefit to provisional application
U.S. Ser. No. 60/485,779 filed Jul. 9, 2003. The entire teachings
of the referenced application are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] This invention relates to the fields of oncology and
improved chemotherapy regimens.
BACKGROUND OF THE INVENTION
[0003] The disclosure of each literature article and published
patent document referred to herein is incorporated by reference
herein in its entirety.
[0004] The National Cancer Institute has estimated that in the
United States alone, 1 in 3 people will be struck with cancer
during their lifetime. Moreover, approximately 50% to 60% of people
contracting cancer will eventually succumb to the disease. The
widespread occurrence of this disease underscores the need for
improved anticancer regimens for the treatment of malignancy.
[0005] Due to the wide variety of cancers presently observed,
numerous anticancer agents have been developed to destroy cancer
within the body. These compounds are administered to cancer
patients with the objective of destroying or otherwise inhibiting
the growth of malignant cells while leaving normal, healthy cells
undisturbed. Anticancer agents have been classified based upon
their mechanism of action.
[0006] One type of chemotherapeutic is referred to as a metal
coordination complex. It is believed this type of chemotherapeutic
forms predominantly inter-strand DNA cross links in the nuclei of
cells, thereby preventing cellular replication. As a result, tumor
growth is initially repressed, and then reversed. Another type of
chemotherapeutic is referred to as an alkylating agent. These
compounds function by inserting foreign compositions or molecules
into the DNA of dividing cancer cells. As a result of these foreign
moieties, the normal functions of cancer cells are disrupted and
proliferation is prevented. Another type of chemotherapeutic is an
antineoplastic agent. This type of agent prevents, kills, or blocks
the growth and spread of cancer cells. Still other types of
anticancer agents include nonsteroidal aromastase inhibitors,
bifunctional alkylating agents, etc.
[0007] The present invention is directed to Src Kinase Inhibitors
that act synergistically when used in combination with certain
conventional chemotherapeutic agents.
SUMMARY OF THE INVENTION
[0008] The present invention provides a synergistic method for the
treatment of anti-proliferative diseases, including cancer, which
comprises administering to a mammalian specie in need thereof a
synergistically, therapeutically effective amount of: (1) at least
one anti-proliferative agent and/or one anti-proliferative
cytotoxic agent and (2) a compound of formula I wherein 1
[0009] wherein Q, Z, N, X.sub.1 and X.sub.2 R.sub.1, R.sub.2,
R.sub.3, R.sub.4, R.sub.4, are defined below, or pharmaceutically
acceptable salt or hydrate thereof.
[0010] A compound of Formula I is represented by
'N-(2-Chloro-6-methylphen-
yl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-
-5-thiazolecarboxamide and pharmaceutically acceptable salts
thereof.
[0011] Suitable anti-proliferative agents for use in the methods of
the invention, include, without limitation, alkylating agents
(including, without limitation, nitrogen mustards, ethylenimine
derivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracil
mustard, Chlormethine, Cyclophosphamide (Cytoxan@), Ifosfamide,
Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine,
Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,
Streptozocin, Dacarbazine, and Temozolomide; antimetabolites
(including, without limitation, folic acid antagonists, pyrimidine
analogs, purine analogs and adenosine deaminase inhibitors),
Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine,
6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
Pentostatine, and Gemcitabine; natural products and their
derivatives (for example, vinca alkaloids, antitumor antibiotics,
enzymes, lymphokines and epipodophyllotoxins): Vinblastine,
Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin,
Doxorubicin, Epirubicin, Idarubicin, Ara-C, paclitaxel (paclitaxel
is commercially available as Taxol@), Mithramycin,
Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons
(especially IFN-a), Etoposide, and Teniposide; navelbene, CPT-11,
anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide,
ifosamide, and droloxafine and radiation.
[0012] The present invention further provides a pharmaceutical
composition for the synergistic treatment of cancer which comprises
at least one anti-proliferative agent, and a compound of Formulas
I, and a pharmaceutically acceptable carrier.
[0013] In another embodiment of the invention the antiproliferative
agent is administered simultaneous with or before or after the
administration of a compound of Formulas I.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] FIGS. 1A and 1B show the combination chemotherapy with
compound 1 and paclitaxel in vivo (A) and in vitro (B) versus the
PC3 human prostate carcinoma.
DETAILED DESCRIPTION OF THE INVENTION
[0015] In accordance with the present invention, methods for the
scheduled administration of Src Kinase inhibitors in synergistic
combination(s) with at least one additional anti-neoplastic agent
for the treatment and prevention of proliferative diseases are
provided.
[0016] Thus, in an embodiment of the invention, the
chemotherapeutic method of the invention comprises the
administration of Src Kinase Inhibitors of Formulas I in
combination with other anti-cancer agents. The Src Kinase
Inhibitors disclosed herein, when used in combination with at least
one other anti-cancer agent(s) demonstrate superior cytotoxic
activity.
[0017] A Src Kinase Inhibitors for use in the methods of the
invention is a compound of Formula I wherein 2
[0018] where
[0019] Q is thiazole;
[0020] Z is a single bond;
[0021] X.sub.1 and X.sub.2 together form .dbd.O;
[0022] R.sub.1 is
[0023] (1) hydrogen or R.sub.6, where R.sub.6 is alkyl, alkenyl,
alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
cycloalkenylalkyl, aryl, aralkyl, heterocyclo, or heterocycloalkyl,
each of which is unsubstituted or substituted with Z.sub.1, Z.sub.2
and one or more groups Z.sub.3;
[0024] (2) --OH or --OR.sub.6;
[0025] (3) --SH or --SR.sub.6;
[0026] (4) --C(O).sub.2H, --C(O).sub.qR.sub.6, or
--OC(O).sub.qR.sub.6, where q is 1 or 2;
[0027] (5) --SO.sub.3H or --S(O).sub.qR.sub.6;
[0028] (6) halo;
[0029] (7) cyano;
[0030] (8) nitro;
[0031] (9) --Z.sub.4--NR.sub.7R.sub.8;
[0032] (10) --Z.sub.4--N (R.sub.9)--Z.sub.5--NR.sub.10R.sub.11;
[0033] (11) --Z.sub.4--N(R.sub.12) --Z.sub.5-R.sub.6;
[0034] (12) --P(O) (OR.sub.6).sub.2;
[0035] R.sub.2 is hydrogen, R.sub.6, --Z.sub.4--R.sub.6, or
--Z.sub.13--NR.sub.7R.sub.8;
[0036] R.sub.3 is --Z.sub.4--R.sub.6 wherein Z.sub.4 is a single
bond and R.sub.6 is heteroaryl which is unsubstituted or
substituted with Z.sub.1, Z.sub.2 and one or more groups
Z.sub.3
[0037] R.sub.4 and R.sub.5 are each independently
[0038] (1) hydrogen or R.sub.6;
[0039] (2) --Z.sub.4--N(R.sub.9)--Z.sub.5--NR.sub.10R.sub.11;
[0040] (3) --N(R.sub.9)Z.sub.4R.sub.6; or
[0041] (4) together with the nitrogen atom to which they are
attached complete a 3- to 8-membered saturated or unsaturated
heterocyclic ring which is unsubstituted or substituted with
Z.sub.1, Z.sub.2 and Z.sub.3, which heterocyclic ring may
optionally have fused to it a benzene ring itself unsubstituted or
substituted with Z.sub.1 Z.sub.2 and Z.sub.3;
[0042] R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11 and
R.sub.12
[0043] (1) are each independently hydrogen or R.sub.6;
[0044] (2) R.sub.7 and R.sub.8 may together be alkylene, alkenylene
or heteroalkyl, completing a 3- to 8-membered saturated or
unsaturated ring with the nitrogen atom to which they are attached,
which ring is unsubstituted or substituted with Z.sub.1, Z.sub.2
and Z.sub.3; or
[0045] (3) any two of R.sub.9, R.sub.10 and R.sub.11 may together
be alkylene or alkenylene completing a 3- to 8-membered saturated
or unsaturated ring together with the nitrogen atoms to which they
are attached, which ring is unsubstituted or substituted with
Z.sub.1, Z.sub.2 and Z.sub.3;
[0046] R.sub.13 is
[0047] (1) cyano;
[0048] (2) nitro;
[0049] (3) --NH.sub.2;
[0050] (4) --NHOalkyl;
[0051] (5) --OH;
[0052] (6) --NHOaryl;
[0053] (7) --NHCOOalkyl;
[0054] (8) --NHCOOaryl;
[0055] (9) --NHSO.sub.2alkyl;
[0056] (10) --NHSO.sub.2aryl;
[0057] (11) aryl;
[0058] (12) heteroaryl;
[0059] (13) --Oalkyl; or
[0060] (14) --Oaryl;
[0061] R.sub.14 is
[0062] (1) --NO.sub.2;
[0063] (2) --COOalkyl; or
[0064] (3) --COOaryl;
[0065] R.sub.15 is
[0066] (1) hydrogen;
[0067] (2) alkyl;
[0068] (3) aryl;
[0069] (4) arylalkyl; or
[0070] (5) cycloalkyl;
[0071] Z.sub.1, Z.sub.2 and Z.sub.3 are each independently
[0072] (1) hydrogen or Z.sub.6, where Z.sub.6 is (i) alkyl,
alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,
cycloalkenylalkyl, aryl, aralkyl, alkylaryl, cycloalkylaryl,
heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself
substituted by one or more of the same or different groups (i); or
(iii) a group (i) or (ii) which is substituted by one or more of
the following groups (2) to (16) of the definition of Z.sub.1,
Z.sub.2 and Z.sub.3;
[0073] (2) --OH or --OZ.sub.6;
[0074] (3) --SH or --SZ.sub.6;
[0075] (4) --C(O).sub.qH, --C(O).sub.qZ.sub.6, or
--O--C(O).sub.qZ.sub.6;
[0076] (5) --SO.sub.3H, --S(O).sub.qZ.sub.6; or
S(O).sub.qN(Z.sub.9)Z.sub.- 6;
[0077] (6) halo;
[0078] (7) cyano;
[0079] (8) nitro;
[0080] (9) --Z.sub.4--NZ.sub.7Z.sub.8;
[0081] (10) --Z.sub.4--N(Z.sub.9)--Z.sub.5--NZ.sub.7Z.sub.8;
[0082] (11) --Z.sub.4--N(Z.sub.10)--Z.sub.5--Z.sub.6;
[0083] (12) --Z.sub.4--N(Z.sub.10) --Z.sub.5--H;
[0084] (13) oxo;
[0085] (14) --O--C(O)--Z.sub.6;
[0086] (15) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together
be alkylene or alkenylene completing a 3- to 8-membered saturated
or unsaturated ring together with the atoms to which they are
attached; or
[0087] (16) any two of Z.sub.1, Z.sub.2, and Z.sub.3 may together
be --O--(CH.sub.2).sub.r--O--,where r is 1 to 5, completing a 4- to
8-membered ring together with the atoms to which they are
attached;
[0088] Z.sub.4 and Z.sub.5 are each independently
[0089] (1) a single bond;
[0090] (2) --Z.sub.11--S(O).sub.q--Z.sub.12--;
[0091] (3) --Z.sub.11--C(O)--Z.sub.12--;
[0092] (4) --Z.sub.11--C(S)--Z.sub.12--;
[0093] (5) --Z.sub.11--O--Z.sub.12--;
[0094] (6) --Z.sub.11--S--Z.sub.12--;
[0095] (7) --Z.sub.11--O--C(O)--Z.sub.12--; or
[0096] (8) --Z.sub.11--C(O)--O--Z.sub.12--;
[0097] Z.sub.7, Z.sub.8, Z.sub.9 and Z.sub.10
[0098] (1) are each independently hydrogen or Z.sub.6;
[0099] (2) Z.sub.7 and Z.sub.8, or Z.sub.6 and Z.sub.10, may
together be alkylene or alkenylene, completing a 3- to 8-membered
saturated or unsaturated ring together with the atoms to which they
are attached, which ring is unsubstituted or substituted with
Z.sub.1, Z.sub.2 and Z.sub.3; or
[0100] (3) Z.sub.7 or Z.sub.8, together with Z.sub.9, may be
alkylene or alkenylene completing a 3- to 8-membered saturated or
unsaturated ring together with the nitrogen atoms to which they are
attached, which ring is unsubstituted or substituted with Z.sub.1,
Z.sub.2 and Z.sub.3;
[0101] Z.sub.11 and Z.sub.12 are each independently
[0102] (1) a single bond;
[0103] (2) alkylene;
[0104] (3) alkenylene; or
[0105] (4) alkynylene; and
[0106] Z.sub.13 is
[0107] (1) a single bond;
[0108] (2) --Z.sub.11--S(O).sub.q--Z.sub.12--;
[0109] (3) --Z.sub.11--C(O) --Z.sub.12--;
[0110] (4) -Z.sub.11--C(S)--Z.sub.12--;
[0111] (5) --Z.sub.11--O--Z.sub.12--;
[0112] (6) --Z.sub.11--S--Z.sub.12--;
[0113] (7) --Z.sub.11--O--C(O)--Z.sub.12--;
[0114] (8) --Z.sub.11--C(O)--O--Z.sub.12--;
[0115] (9) --C (NR.sub.13)--;
[0116] (10) --C(CHR.sub.14)--; or
[0117] (11) --C(C(R.sub.14).sub.2)--;
[0118] provided said compound is other than a compound of formula
(vii) 3
[0119] where
[0120] R.sub.3e is pyridyl or pryimidinyl optionally substituted
with halogen or alkyl;
[0121] R.sub.50 and R.sub.5, are each independently hydrogen,
halogen or alkyl;
[0122] R.sub.52 and R.sub.53 are each independently hydrogen,
halogen, alkyl or haloalkyl;
[0123] R.sub.54 and R.sub.56 are each independently hydrogen,
halogen, alkyl, nitro or amino;
[0124] R.sub.55 is hydrogen, halogen, alkyl, haloalkyl, alkoxy,
haloalkoxy, alkylthio, haloalkylthio, or alkoxycarbonyl; and
[0125] n is zero or 1.
[0126] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.1 is hydrogen, halo, alkyl,
aryl, alkoxy, alkoxycarbonyl, or aryloxycarbonyl.
[0127] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.1 is hydrogen.
[0128] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.2 is hydrogen.
[0129] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.4 is hydrogen.
[0130] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.5 is an aryl group which is
substituted with Z.sub.1, Z.sub.2 and one or more groups
Z.sub.3.
[0131] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.1 is hydrogen or alkyl,
R.sub.2 and R.sub.4 are independently hydrogen or alkyl, and
R.sub.5 is aryl which is unsubstituted or substituted with Z.sub.1,
Z.sub.2 and one or more groups Z.sub.3.
[0132] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.5 is aryl which is
unsubstituted or independently substituted with one or more alkyl
or halo.
[0133] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein R.sub.3 is heteroaryl substituted
optionally substituted with Z.sub.1 and Z.sub.2 and substituted
with at least one group Z.sub.3 where Z.sub.3 is Z.sub.6.
[0134] In another embodiment, the present invention is directed to
a method for the treatment of proliferative diseases, comprising
the compound of formula I wherein Z.sub.6 is heterocyclo optionally
substituted with one or more hydroxyalkyl.
[0135] In another embodiment, the present invention is directed to
a use of the compound of formula I which comprises a
synergistically, therapeutically effective amount of (1) at least
one anti-proliferative agent(s) and 2) a compound of formula I.
[0136] In another embodiment, the invention is directed to a method
for the treatment of proliferative diseases, wherein the
anti-proliferative agent is selected from the group consisting of
selected from the group consisting of an anthracycline drug, a
vinca drug, a mitomycin, a bleomycin, a cytotoxic nucleoside, a
taxane, an epothilone, discodermolide, a pteridine drug, a diynene,
an aromatase inhibitor and a podophyllotoxin.
[0137] In another embodiment, the invention is directed to a method
for the treatment of proliferative diseases, wherein the
anti-proliferative agent is selected from carboplatin, doxorubicin,
and CPT-11.
[0138] In another embodiment, the invention is directed to a
pharmaceutical composition for the treatment of cancer which
comprises a synergistic combination of at least one
anti-proliferative agent and a compound of formula I, and a
pharmaceutically acceptable carrier.
[0139] In another embodiment, the invention is directed to a
pharmaceutical composition wherein the antiproliferative agent is
one or more agent selected from the group consisting of a
microtubule-stabilizing agent, a microtubule-disruptor agent, an
alkylating agent, an anti-metabolite, epidophyllotoxin, an
antineoplastic enzyme, a topoisomerase inhibitor, procarbazine,
mitoxantrone, inhibitors of cell cycle progression, a platinum
coordination complex, an anthracycline drug, a vinca drug, CDK
inhibitors, a mitomycin, a bleomycin, a cytotoxic nucleoside, a
taxane, an epothilone, discodermolide, a pteridine drug, a diynene,
an aromatase inhibitor and a podophyllotoxin.
[0140] The terms "alk" or "alkyl" refer to straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8
carbon atoms. The expression "lower alkyl", refers to alkyl groups
of 1 to 4 carbon atoms.
[0141] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups of 2 to 10, or 2 to 4, carbon atoms having at
least one double bond. Where an alkenyl group is bonded to a
nitrogen atom, it is preferred that such group not be bonded
directly through a carbon bearing a double bond.
[0142] The term "alkynyl" refers to straight or branched chain
hydrocarbon groups of 2 to 10, or 2 to 4, carbon atoms having at
least one triple bond. Where an alkynyl group is bonded to a
nitrogen atom, it is preferred that such group not be bonded
directly through a carbon bearing a triple bond.
[0143] The term "alkylene" refers to a straight chain bridge of 1
to 5 carbon atoms connected by single bonds (e.g.,
--(CH.sub.2).sub.x-- wherein x is 1 to 5), which may be substituted
with 1 to 3 lower alkyl groups.
[0144] The term "alkenylene" refers to a straight chain bridge of 2
to 5 carbon atoms having one or two double bonds that is connected
by single bonds and may be substituted with 1 to 3 lower alkyl
groups. Exemplary alkenylene groups are --CH.dbd.CH--CH.dbd.CH--,
--CH.sub.2--CH.dbd.CH--, --CH.sub.2--CH.dbd.CH--CH.sub.2--,
--C(CH.sub.3).sub.2CH.dbd.CH-- and
--CH(C.sub.2H.sub.5)--CH.dbd.CH--.
[0145] The term "alkynylene" refers to a straight chain bridge of 2
to 5 carbon atoms that has a triple bond therein, is connected by
single bonds, and may be substituted with 1 to 3 lower alkyl
groups. Exemplary alkynylene groups are --C.ident.C--,
--CH.sub.2--C.ident.C--, --CH(CH.sub.3)--C.ident.C-- and
--C.ident.C--CH(C.sub.2H.sub.5)CH.sub.2--- .
[0146] The terms "ar" or "aryl" refer to aromatic cyclic groups
(for example 6 membered monocyclic, 10 membered bicyclic or 14
membered tricyclic ring systems) which contain 6 to 14 carbon
atoms. Exemplary aryl groups include phenyl, naphthyl, biphenyl and
anthracene.
[0147] The terms "cycloalkyl" and "cycloalkenyl" refer to cyclic
hydrocarbon groups of 3 to 12 carbon atoms.
[0148] The terms "halogen" and "halo" refer to fluorine, chlorine,
bromine and iodine.
[0149] The term "unsaturated ring" includes partially unsaturated
and aromatic rings.
[0150] The terms "heterocycle", "heterocyclic" or "heterocyclo"
refer to fully saturated or unsaturated, including aromatic (i.e.
"heteroaryl") cyclic groups, for example, 4 to 7 membered
monocyclic, 7 to 11 membered bicyclic, or 10 to 15 membered
tricyclic ring systems, which have at least one heteroatom in at
least one carbon atom-containing ring. Each ring of the
heterocyclic group containing a heteroatom may have 1, 2, 3 or 4
heteroatoms selected from nitrogen atoms, oxygen atoms and/or
sulfur atoms, where the nitrogen and sulfur heteroatoms may
optionally be oxidized and the nitrogen heteroatoms may optionally
be quaternized. The heterocyclic group may be attached at any
heteroatom or carbon atom of the ring or ring system.
[0151] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,
imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,
isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,
isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl,
oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,
4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl
sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and
tetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the
like.
[0152] Exemplary bicyclic heterocyclo groups include
benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl,
quinolinyl-N-oxide, tetrahydroisoquinolinyl, isoquinolinyl,
benzimidazolyl, benzopyranyl, indolizinyl, benzofuryl, chromonyl,
coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,
furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,1-b]pyridinyl
or furo[2,3-b]pyridinyl), dihydroisoindolyl, dihydroquinazolinyl
(such as 3,4-dihydro-4-oxo-quinazolinyl), benzisothiazolyl,
benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl,
benzotriazolyl, benzpyrazolyl, dihydrobenzofuryl,
dihydrobenzothienyl, dihydrobenzothiopyranyl,
dihydrobenzothiopyranyl sulfone, dihydrobenzopyranyl, indolinyl,
isochromanyl, isoindolinyl, naphthyridinyl, phthalazinyl,
piperonyl, purinyl, pyridopyridyl, quinazolinyl,
tetrahydroquinolinyl, thienofuryl, thienopyridyl, thienothienyl,
and the like.
[0153] The term "heteroaryl" refers to aromatic heterocyclic
groups.
[0154] Exemplary heteroaryl groups include pyrrolyl, pyrazolyl,
imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl,
isothiazolyl, furyl, thienyl, oxadiazolyl, pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, triazolyl, triazinyl, and the like.
[0155] Where q is 1 or 2, "--C(O).sub.qH" denotes --C(O)--H or
--C(O)--OH; "--C(O).sub.qR.sub.6" or "--C(O).sub.qZ.sub.6" denote,
respectively, --C(O)--R.sub.6 or --C(O) --OR.sub.6, or
--C(O)--Z.sub.6 or --C(O)--OZ.sub.6; "--O--C(O).sub.qR.sub.6" or
"--O--C(O).sub.qZ.sub.6" denote, respectively, --O--C(O)--R.sub.6
or --O--C(O)--OR.sub.6, or --O--C(O)--Z.sub.6 or
--O--C(O)--Z.sub.6; and "--S(O).sub.qR.sub.6" or
"--S(O).sub.qZ.sub.6" denote, respectively, --SO--R.sub.6 or
--SO.sub.2--R.sub.6, or --SO--Z.sub.6 or --SO.sub.2--Z.sub.6.
[0156] When a group is referred to as being optionally substituted,
it may be substituted with one to five, or with one to three,
substituents such as F, Cl, Br, I, trifluoromethyl,
trifluoromethoxy, hydroxy, lower alkoxy, cycloalkoxy,
heterocyclooxy, oxo, lower alkanoyl, aryloxy, lower alkanoyloxy,
amino, lower alkylamino, arylamino, aralkylamino, cycloalkylamino,
heterocycloamino, disubstituted amines in which the two amino
substituents independently are selected from lower alkyl, aryl or
aralkyl, lower alkanoylamino, aroylamino, aralkanoylamino,
substituted lower alkanoylamino, substituted arylamino, substituted
aralkylanoylamino, thiol, lower alkylthio, arylthio, aralkylthio,
cycloalkylthio, heterocyclothio, lower alkylthiono, arylthiono,
aralkylthiono, lower alkylsulfonyl, arylsulfonyl, aralkylsulfonyl,
sulfonamide (e.g., SO.sub.2NH.sub.2), substituted sulfonamide,
nitro, cyano, carboxy, carbamyl (e.g., CONH.sub.2), substituted
carbamyl (e.g., CONH-lower alkyl, CONH-aryl, CONH-aralkyl or cases
where there are two substituents on the nitrogen independently
selected from lower alkyl, aryl or aralkyl), lower alkoxycarbonyl,
aryl, substituted aryl, guanidino, and heterocyclos (e.g., indolyl,
imidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl,
pyrimidyl and the like). Where noted above that the substituent is
further substituted, it will be substituted with F, Cl, Br, I,
optionally substituted lower alkyl, hydroxy, optionally substituted
lower alkoxy, optionally substituted aryl, or optionally
substituted aralkyl.
[0157] All stereoisomers of the Formula I compounds of the instant
invention are contemplated, either in admixture or in pure or
substantially pure form. The definition of the formula I compounds
embraces all possible stereoisomers and their mixtures. The Formula
I definitions very particularly embrace the racemic forms and the
isolated optical isomers having the specified activity.
[0158] Compounds of the formula I may in some cases form salts
which are also within the scope of this invention. Reference to a
compound of the formula I herein is understood to include reference
to salts thereof, unless otherwise indicated. The term "salt(s)",
as employed herein, denotes acidic and/or basic salts formed with
inorganic and/or organic acids and bases. Zwitterions (internal or
inner salts) are included within the term "salt(s)" as used herein
(and may be formed, for example, where the R substituents comprise
an acid moiety such as a carboxyl group). Also included herein are
quaternary ammonium salts such as alkylammonium salts.
Pharmaceutically acceptable (i.e., non-toxic, physiologically
acceptable) salts useful, although other salts are useful, for
example, in isolation or purification steps which may be employed
during preparation. Salts of the compounds of the formula I may be
formed, for example, by reacting a compound I with an amount of
acid or base, such as an equivalent amount, in a medium such as one
in which the salt precipitates or in an aqueous medium followed by
lyophilization.
[0159] Exemplary acid addition salts include acetates (such as
those formed with acetic acid or trihaloacetic acid, for example,
trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides, hydrobromides, hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates,
2-naphthalenesulfonates, nicotinates, nitrates, oxalates,
pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as
those formed with sulfuric acid), sulfonates (such as those
mentioned herein), tartrates, thiocyanates, toluenesulfonates,
undecanoates, and the like.
[0160] Exemplary basic salts (formed, for example, where the R
substituents comprise an acidic moiety such as a carboxyl group)
include ammonium salts, alkali metal salts such as sodium, lithium,
and potassium salts, alkaline earth metal salts such as calcium and
magnesium salts, salts with organic bases (for example, organic
amines) such as benzathines, dicyclohexylamines, hydrabamines,
N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and
salts with amino acids such as arginine, lysine and the like. The
basic nitrogen-containing groups may be quaternized with agents
such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl,
diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g.
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0161] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound which, upon administration to a subject,
undergoes chemical conversion by metabolic or chemical processes to
yield a compound of the formula I, or a salt and/or solvate
thereof. Solvates of the compounds of formula I may be
hydrates.
[0162] All stereoisomers of the present compounds, such as those
which may exist due to asymmetric carbons on the R substituents of
the compound of the formula I, including enantiomeric and
diastereomeric forms, are contemplated within the scope of this
invention. Individual stereoisomers of the compounds of the
invention may, for example, be substantially free of other isomers,
or may be admixed, for example, as racemates or with all other, or
other selected, stereoisomers. The chiral centers of the present
invention can have the S or R configuration as defined by the IUPAC
1974 Recommendations.
[0163] Throughout the specification, groups and substituents
thereof are chosen to provide stable moieties and compounds.
[0164] The combination of compounds is a synergistic combination.
Synergy, as described for example by Chou and Talalay, Adv. Enzyme
Regul. 22:27-55 (1984), occurs when the effect of the compounds
when administered in combination is greater than the additive
effect of the compounds when administered alone as a single agent.
In general, a synergistic effect may be clearly demonstrated at
suboptimal concentrations of the compounds. Synergy can be in terms
of lower cytotoxicity, increased efficacy, or some other beneficial
effect of the combination compared with the individual
components.
[0165] "Therapeutically effective amount" is intended to include an
amount of a compound of the present invention alone or an amount of
the combination of compounds claimed or an amount of a compound of
the present invention in combination with other active ingredients
effective to treat the inflammatory diseases described herein.
[0166] A "synergistically, therapeutically effective amount" is a
therapeutically effect amount which is provided by a synergistic
combination.
[0167] A particular Src Kinase inihibitor for use in the methods of
the invention is Compound 1:
'N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxy-
ethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide.
[0168] Compound 1, an exemplary Src Kinase inhibitor of the
invention, competes with ATP for the ATP-binding site in the kinase
domain of selected protein tyrosine kinases (PTKs), potently
inhibits the Src family kinases (SFKs, including: Fyn, Yes, Yrk,
Blk, Fgr, Hck, Lyn, and Frk subfamily members Frk/Rak and
Iyk/Bsk).
[0169] In another embodiment of the invention a compound of
Formulas I is administered in conjunction with at least one
anti-neoplastic agent.
[0170] As used herein, the phrase "anti-neoplastic agent" is
synonymous with "chemotherapeutic agent" and/or "anti-proliferative
agent" and refers to compounds that prevent cancer, or
hyperproliferative cells from multiplying. Anti-proliferative
agents prevent cancer cells from multiplying by: (1) interfering
with the cell's ability to replicate DNA and (2) inducing cell
death and/or apoptosis in the cancer cells.
[0171] Classes of compounds that may be used as anti-proliferative
cytotoxic agents and/or anti-proliferative agents include the
following:
[0172] Alkylating agents (including, without limitation, nitrogen
mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas
and triazenes): Uracil mustard, Chlormethine, Cyclophosphamide
(Cytoxan@), Ifosfamide, Melphalan, Chlorambucil, Pipobroman,
Triethylene-melamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, and
Temozolomide.
[0173] Antimetabolites (including, without limitation, folic acid
antagonists, pyrimidine analogs, purine analogs and adenosine
deaminase inhibitors): Methotrexate, 5-Fluorouracil, Floxuridine,
Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate,
Pentostatine, and Gemcitabine.
[0174] Natural products and their derivatives (for example, vinca
alkaloids, antitumor antibiotics, enzymes, lymphokines and
epipodophyllotoxins): Vinblastine, Vincristine, Vindesine,
Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin,
Idarubicin, Ara-C, paclitaxel (paclitaxel is commercially available
as Taxol.RTM.), Mithramycin, Deoxyco-formycin, Mitomycin-C,
L-Asparaginase, Interferons (especially IFN-a), Etoposide, and
Teniposide.
[0175] Other anti-proliferative cytotoxic agents and/or
anti-proliferative agents are navelbene, CPT-11, anastrazole,
letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide,
and droloxafine.
[0176] The phrase "radiation therapy" includes, but is not limited
to, x-rays or gamma rays which are delivered from either an
externally applied source such as a beam or by implantation of
small radioactive sources.
[0177] Microtubule affecting agents interfere with cellular mitosis
and are well known in the art for their anti-proliferative
cytotoxic activity. Microtubule affecting agents useful in the
invention include, but are not limited to, allocolchicine (NSC
406042), Halichondrin B (NSC 609395), colchicine (NSC 757),
colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC
376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel
(Taxol.RTM., NSC 125973), Taxol.RTM. derivatives (e.g., derivatives
(e.g., NSC 608832), thiocolchicine NSC 361792), trityl cysteine
(NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate
(NSC 67574), natural and synthetic epothilones including but not
limited to epothilone A, epothilone B, epothilone C, epothilone D,
desoxyepothilone A, desoxyepothilone B,
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R-
*,16S*]]-7-11-dihydroxy-8,8,10,12,16-pentamethyl-3-[l-methyl-2-(2-methyl-4-
-thiazolyl)ethenyl]-4-aza-17 oxabicyclo
[14.1.0]heptadecane-5,9-dione (disclosed in U.S. Pat. No.
6,262,094, issued Jul. 17, 2001),
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazol-
yl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4-17-dioxabic-
yclo[14.1.0]- heptadecane-5,9-dione (disclosed in U.S. Ser. No.
09/506,481 filed on Feb. 17, 2000, and examples 7 and 8 herein),
[1S 1R*,3R*(E),7R*,10S*,11R*,12R*,
16S*]]-7,11-dihydroxy-8,8,10,12,16-pentame-
thyl-3-[1-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-4-aza-17oxabicyclo[14.1.-
0]-heptadecane-5,9-dione,
[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[-
2-(Aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16--
pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione, and
derivatives thereof; and other microtubule-disruptor agents.
Additional antineoplastic agents include, discodermolide (see
Service, (1996) Science, 274:2009) estramustine, nocodazole, MAP4,
and the like. Examples of such agents are also described in the
scientific and patent literature, see, e.g., Bulinski (1997) J.
Cell Sci. 110:3055 3064; Panda (1997) Proc. Natl. Acad. Sci. USA
94:10560-10564; Muhlradt (1997) Cancer Res. 57:3344-3346; Nicolaou
(1997) Nature 387:268-272; Vasquez (1997) Mol. Biol. Cell.
8:973-985; Panda (1996) J. Biol. Chem 271:29807-29812.
[0178] In cases where it is desirable to render aberrantly
proliferative cells quiescent in conjunction with or prior to
treatment with the chemotherapeutic methods of the invention,
hormones and steroids (including synthetic analogs):
17a-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,
Fluoxymesterone, Dromostanolone propionate, Testolactone,
Megestrolacetate, Methylprednisolone, Methyl-testosterone,
Prednisolone, Triamcinolone, hlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,
Leuprolide, Flutamide, Toremifene, Zoladex can also be administered
to the patient.
[0179] Also suitable for use in the combination chemotherapeutic
methods of the invention are antiangiogenics such as matrix
metalloproteinase inhibitors, and other VEGF inhibitors, such as
anti-VEGF antibodies and small molecules such as ZD6474 and SU6668
are also included. Anti- Her2 antibodies from Genetech may also be
utilized. A suitable EGFR inhibitor is EKB-569 (an irreversible
inhibitor). Also included are Imclone antibody C225 immunospecific
for the EGFR, and src inhibitors.
[0180] Also suitable for use as an antiproliferative cytostatic
agent is Casodex.TM. which renders androgen-dependent carcinomas
non-proliferative. Yet another example of a cytostatic agent is the
antiestrogen Tamoxifen which inhibits the proliferation or growth
of estrogen dependent breast cancer. Inhibitors of the transduction
of cellular proliferative signals are cytostatic agents. Examples
are epidermal growth factor inhibitors, Her-2 inhibitors, MEK-1
kinase inhibitors, MAPK kinase inhibitors, PI3 inhibitors, Src
kinase inhibitors, and PDGF inhibitors.
[0181] As mentioned, certain anti-proliferative agents are
anti-angiogenic and antivascular agents and, by interrupting blood
flow to solid tumors, render cancer cells quiescent by depriving
them of nutrition. Castration, which also renders androgen
dependent carcinomas non-proliferative, may also be utilized.
Starvation by means other than surgical disruption of blood flow is
another example of a cytostatic agent. A particular class of
antivascular cytostatic agents is the combretastatins. Other
exemplary cytostatic agents include MET kinase inhibitors, MAP
kinase inhibitors, inhibitors of non-receptor and receptor tyrosine
kinases, inhibitors of integrin signaling, and inhibitors of
insulin-like growth factor receptors.
[0182] Also suitable are anthracyclines (e.g., daunorubicin,
doxorubicin), cytarabine (ara-C; Cytosar-U.RTM.); 6-thioguanine
(Tabloid.RTM.), mitoxantrone (Novantrone.RTM.) and etoposide
(VePesid.RTM.),amsacrine (AMSA), and all-trans retinoic acid
(ATRA).
[0183] Thus, the present invention provides methods for the
synergistic treatment of a variety of cancers, including, but not
limited to, the following:
[0184] carcinoma including that of the bladder (including
accelerated and metastatic bladder cancer), breast, colon
(including colorectal cancer), kidney, liver, lung (including small
and non-small cell lung cancer and lung adenocarcinoma), ovary,
prostate, testes, genitourinary tract, lymphatic system, rectum,
larynx, pancreas (including exocrine pancreatic carcinoma),
esophagus, stomach, gall bladder, cervix, thyroid, and skin
(including squamous cell carcinoma);
[0185] hematopoietic tumors of lymphoid lineage including leukemia,
acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell
lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's
lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burketts
lymphoma;
[0186] hematopoietic tumors of myeloid lineage including acute and
chronic myelogenous leukemias, myelodysplastic syndrome, myeloid
leukemia, and promyelocytic leukemia;
[0187] tumors of the central and peripheral nervous system
including astrocytoma, neuroblastoma, glioma, and schwannomas;
[0188] tumors of mesenchymal origin including fibrosarcoma,
rhabdomyoscarcoma, and osteosarcoma; and
[0189] other tumors including melanoma, xenoderma pigmentosum,
keratoactanthoma, seminoma, thyroid follicular cancer, and
teratocarcinoma.
[0190] The present invention provides methods for the synergistic
treatment of a variety of non-cancerous proliferative diseases. The
invention is used to treat GIST, Breast cancer, pancreatic cancer,
colon cancer, NSCLC, CML, and ALL, sarcoma, and various pediatric
cancers.
[0191] The compounds of the present invention are useful for the
treatment of cancers such as chronic myelogenous leukemia (CML),
gastrointestinal stromal tumor (GIST), small cell lung cancer
(SCLC), non-small cell lung cancer (NSCLC), ovarian cancer,
melanoma, mastocytosis, germ cell tumors, acute myelogenous
leukemia (AML), pediatric sarcomas, breast cancer, colorectal
cancer, pancreatic cancer, prostate cancer and others known to be
associated with protein tyrosine kinases such as, for example, SRC,
BCR-ABL and c-KIT. The compounds of the present invention are also
useful in the treatment of cancers that are sensitive to and
resistant to chemotherapeutic agents that target BCR-ABL and c-KIT,
such as, for example, Gleevec.RTM. (STI-571).
[0192] In another embodiment of this invention, a method is
provided for the synergistic treatment of cancerous tumors.
Advantageously, the synergistic method of this invention reduces
the development of tumors, reduces tumor burden, or produces tumor
regression in a mammalian host.
[0193] Methods for the safe and effective administration of most of
these chemotherapeutic agents are known to those skilled in the
art. In addition, their administration is described in the standard
literature.
[0194] For example, the administration of many of the
chemotherapeutic agents is described in the "Physicians' Desk
Reference" (PDR), e.g., 1996 edition (Medical Economics Company,
Montvale, N.J. 07645-1742, USA); the disclosure of which is
incorporated herein by reference thereto.
[0195] A compound of Formula I for use in the methods of the
present invention include:
'N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-
-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide;
and pharmaceutically acceptable salts, solvates and hydrates
thereof.
[0196] The compounds of Formula I may be prepared by the procedures
described in PCT publication, WO 00/62778 published Oct. 26,
2000.
[0197] The present invention also encompasses a pharmaceutical
composition useful in the treatment of cancer, comprising the
administration of a therapeutically effective amount of the
combinations of this invention, with or without pharmaceutically
acceptable carriers or diluents. The synergistic pharmaceutical
compositions of this invention comprise an anti-proliferative agent
or agents, a formula I compound, and a pharmaceutically acceptable
carrier. The methods entail the use of a neoplastic agent in
combination with a Formula I compound. The compositions of the
present invention may further comprise one or more pharmaceutically
acceptable additional ingredient(s) such as alum, stabilizers,
antimicrobial agents, buffers, coloring agents, flavoring agents,
adjuvants, and the like. The antineoplastic agents, Formula I,
compounds and compositions of the present invention may be
administered orally or parenterally including the intravenous,
intramuscular, intraperitoneal, subcutaneous, rectal and topical
routes of administration.
[0198] For oral use, the antineoplastic agents, Formula I compounds
and compositions of this invention may be administered, for
example, in the form of tablets or capsules, powders, dispersible
granules, or cachets, or as aqueous solutions or suspensions. In
the case of tablets for oral use, carriers which are commonly used
include lactose, corn starch, magnesium carbonate, talc, and sugar,
and lubricating agents such as magnesium stearate are commonly
added. For oral administration in capsule form, useful carriers
include lactose, corn starch, magnesium carbonate, talc, and sugar.
When aqueous suspensions are used for oral administration,
emulsifying and/or suspending agents are commonly added.
[0199] In addition, sweetening and/or flavoring agents may be added
to the oral compositions. For intramuscular, intraperitoneal,
subcutaneous and intravenous use, sterile solutions of the active
ingredient(s) are usually employed, and the pH of the solutions
should be suitably adjusted and buffered. For intravenous use, the
total concentration of the solute(s) should be controlled in order
to render the preparation isotonic.
[0200] For preparing suppositories according to the invention, a
low melting wax such as a mixture of fatty acid glycerides or cocoa
butter is first melted, and the active ingredient is dispersed
homogeneously in the wax, for example by stirring. The molten
homogeneous mixture is then poured into conveniently sized molds
and allowed to cool and thereby solidify.
[0201] Liquid preparations include solutions, suspensions and
emulsions. Such preparations are exemplified by water or
water/propylene glycol solutions for parenteral injection. Liquid
preparations may also include solutions for intranasal
administration.
[0202] Aerosol preparations suitable for inhalation may include
solutions and solids in powder form, which may be in combination
with a pharmaceutically acceptable carrier, such as an inert
compressed gas.
[0203] Also included are solid preparations which are intended for
conversion, shortly before use, to liquid preparations for either
oral or parenteral administration. Such liquid forms include
solutions, suspensions and emulsions.
[0204] The compounds of Formula I, as well as the anti-neoplastic
agents, described herein may also be delivered transdermally. The
transdermal compositions can take the form of creams, lotions,
aerosols and/or emulsions and can be included in a transdermal
patch of the matrix or reservoir type as are conventional in the
art for this purpose.
[0205] The combinations of the present invention may also be used
in conjunction with other well known therapies that are selected
for their particular usefulness against the condition that is being
treated.
[0206] If formulated as a fixed dose, the active ingredients of the
combination compositions of this invention are employed within the
dosage ranges described below. Alternatively, the anti-neoplastic,
and Formula I compounds may be administered separately in the
dosage ranges described below. In another embodiment of the present
invention, the antineoplastic agent is administered in the dosage
range described below following or simultaneously with
administration of the Formula I compound in the dosage range
described below.
[0207] Table 1 sets forth chemotherapeutic combinations and
exemplary dosages for use in the methods of the present invention.
Where "Compound of Formula I" appears, any of the variations of
Formula I set forth herein are contemplated for use in the
chemotherapeutic combinations.
1 TABLE 1 CHEMOTHERAPEUTIC DOSAGE COMBINATION mg/m.sup.2 (per dose)
Compound of Formula I + 0.1-100 mg/m2 Cisplatin 5-150 mg/m2
Compound of Formula I + 0.1-100 mg/m2 Carboplatin 5-1000 mg/m2
Compound of Formula I + 0.1-100 mg/m2 Radiation 200-8000 cGy
Compound of Formula I + 0.1-100 mg/m2 CPT-11 5-400 mg/m2 Compound
of Formula I + 0.1-100 mg/m2 Paclitaxel 40-250 mg/m2 Compound of
Formula I + 0.1-100 mg/m2 Paclitaxel + 40-250 mg/m2 Carboplatin
5-1000 mg/m2 Compound of Formula I + 0.1-100 mg/m2 5FU and
optionally + 5-5000 mg/m2 Leucovorin 5-1000 mg/m2 Compound of
Formula I + 0.1-100 mg/m2 Epothilone 1-500 mg/m2 Compound of
Formula I + 0.1-100 mg/m2 Gemcitabine 100-3000 mg/m2 Compound of
Formula I + 0.1-100 mg/m2 UFT and optionally + 50-800 mg/m2
leucovorin 5-1000 mg/m2 Compound of Formula I + 0.1-100 mg/m2
Gemcitabine + 100-3000 mg/m2 Cisplatin 5-150 mg/m2 Compound of
Formula I + 0.1-100 mg/m2 UFT + 50-800 mg/m2 Leucovorin 5-1000
mg/m2 Compound of Formula I + 0.1-100 mg/m2 Cisplatin + 5-150 mg/m2
paclitaxel 40-250 mg/m2 Compound of Formula I + 0.1-100 mg/m2
Cisplatin + 5-150 mg/m2 5FU 5-5000 mg/m2 Compound of Formula I +
0.1-100 mg/m2 Oxaliplatin + 5-200 mg/m2 CPT-11 4-400 mg/m2 Compound
of Formula I + 0.1-100 mg/m2 5FU + 5-5000 mg/m2 CPT-11 and
optionally + 4-400 mg/m2 leucovorin 5-1000 mg/m2 Compound of
Formula I + 0.1-100 mg/m2 5FU + 5-5000 mg/m2 radiation 200-8000 cGy
Compound of Formula I + 0.1-100 mg/m2 radiation + 200-8000 cGy 5FU
+ 5-5000 mg/m2 Cisplatin 5-150 mg/m2 Compound of Formula I +
0.1-100 mg/m2 Oxaliplatin + 5-200 mg/m2 5FU and optionally + 5-5000
mg/m2 Leucovorin 5-1000 mg/m2 Compound of Formula I + 0.1-100 mg/m2
paclitaxel + 40-250 mg/m2 CPT-11 4-400 mg/m2 Compound of Formula I
+ 0.1-100 mg/m2 paclitaxel + 40-250 mg/m2 5-FU 5-5000 mg/m2
Compound of Formula I + 0.1-100 mg/m2 UFT + 50-800 mg/m2 CPT-11 and
optionally + 4-400 mg/m2 leucovorin 5-1000 mg/m2
[0208] In the above Table 1, "5FU" denotes 5-fluorouracil,
"Leucovorin" can be employed as leucovorin calcium, "UFT" is a 1:4
molar ratio of tegafur:uracil, and "Epothilone" is a compound
described in WO 99/02514 or WO 00/50423, both incorporated by
reference herein in their entirety.
[0209] While Table 1 provides exemplary dosage ranges of the
Formula I compounds and certain anticancer agents of the invention,
when formulating the pharmaceutical compositions of the invention
the clinician may utilize dosages as warranted by the condition of
the patient being treated. For example, Compound 1 may be
administered at 25-60 mg/m2 every 3 weeks. Compound 2, may be
administered at a dosage ranging from 25-500 mg/m2 every three
weeks for as long as treatment is required. Dosages for cisplatin
are 75-120 mg/m2 administered every three weeks. Dosages for
carboplatin are within the range of 200-600 mg/m2 or an AUC of
0.5-8 mg/ml.times.min; or an AUC of 4-6 mg/ml.times.min. When the
method employed utilizes radiation, dosages are within the range of
200-6000 cGY. Dosages for CPT-11 are within 100-125 mg/m2, once a
week. Dosages for paclitaxel are 130-225 mg/m2 every 21 days.
Dosages for gemcitabine are within the range of 80-1500 mg/m2
administered weekly. UFT is used within a range of 300-400 mg/m2
per day when combined with leucovorin administration. Dosages for
leucovorin are 10-600 mg/m2 administered weekly.
[0210] The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being
treated. Determination of the proper dosage for a particular
situation is within the skill of the art. Generally, treatment is
initiated with smaller dosages which are less than the optimum dose
of the compound. Thereafter, the dosage is increased by small
amounts until the optimum effect under the circumstances is
reached. For convenience, the total daily dosage may be divided and
administered in portions during the day if desired. Intermittent
therapy (e.g., one week out of three weeks or three out of four
weeks) may also be used.
[0211] Certain cancers can be treated effectively with compounds of
Formula I and a plurality of anticancer agents. Such triple and
quadruple combinations can provide greater efficacy. When used in
such triple and quadruple combinations the dosages set forth above
can be utilized. Other such combinations in the above Table I can
therefore include "Compound 1" in combination with (1)
mitoxantrone+prednisone; (2) doxorubicin+carboplatin; or (3
herceptin+tamoxifen. 5-FU can be replaced by UFT in any of the
above combinations.
[0212] When employing the methods or compositions of the present
invention, other agents used in the modulation of tumor growth or
metastasis in a clinical setting, such as antiemetics, can also be
administered as desired.
[0213] The present invention encompasses a method for the
synergistic treatment of cancer wherein a neoplastic agent and a
Formula I compound are administered simultaneously or sequentially.
Thus, while a pharmaceutical formulation comprising antineoplastic
agent(s) and a Formula I compound may be advantageous for
administering the combination for one particular treatment, prior
administration of the anti-neoplastic agent(s) may be advantageous
in another treatment. It is also understood that the instant
combination of antineoplastic agent(s) and Formula I compound may
be used in conjunction with other methods of treating cancer (such
as cancerous tumors) including, but not limited to, radiation
therapy and surgery. It is further understood that a cytostatic or
quiescent agent, if any, may be administered sequentially or
simultaneously with any or all of the other synergistic therapies.
It is further understood that the routes of administration may vary
between the compounds of Formula I and the antineoplastic.
[0214] The combinations of the instant invention may also be
co-administered with other well known therapeutic agents that are
selected for their particular usefulness against the condition that
is being treated. Combinations of the instant invention may
alternatively be used sequentially with known pharmaceutically
acceptable agent(s) when a multiple combination formulation is
inappropriate.
[0215] The chemotherapeutic agent(s) and/or radiation therapy can
be administered according to therapeutic protocols well known in
the art. It will be apparent to those skilled in the art that the
administration of the chemotherapeutic agent(s) and/or radiation
therapy can be varied depending on the disease being treated and
the known effects of the chemotherapeutic agent(s) and/or radiation
therapy on that disease. Also, in accordance with the knowledge of
the skilled clinician, the therapeutic protocols (e.g., dosage
amounts and times of administration) can be varied in view of the
observed effects of the administered therapeutic agents (i.e.,
antineoplastic agent(s) or radiation) on the patient, and in view
of the observed responses of the disease to the administered
therapeutic agents.
[0216] In the methods of this invention, a compound of Formula I is
administered simultaneously or sequentially with an
anti-proliferative agent and/or radiation. Thus, it is not
necessary that the chemotherapeutic agent(s) and compound of
Formula I, or the radiation and the compound of Formula I, be
administered simultaneously or essentially simultaneously. The
advantage of a simultaneous or essentially simultaneous
administration is well within the determination of the skilled
clinician.
[0217] Also, in general, the compound of Formula I, and
chemotherapeutic agent(s) do not have to be administered in the
same pharmaceutical composition, and may, because of different
physical and chemical characteristics, have to be administered by
different routes. For example, the compound of Formula I may be
administered orally to generate and maintain good blood levels
thereof, while the chemotherapeutic agent(s) may be administered
intravenously. The determination of the mode of administration and
the advisability of administration, where possible, in the same
pharmaceutical composition, is well within the knowledge of the
skilled clinician. The initial administration can be made according
to established protocols known in the art, and then, based upon the
observed effects, the dosage, modes of administration and times of
administration can be modified by the skilled clinician.
[0218] The particular choice of compound of Formula I and
anti-proliferative cytotoxic agent(s) or radiation will depend upon
the diagnosis of the attending physicians and their judgment of the
condition of the patient and the appropriate treatment
protocol.
[0219] If the compound of Formula I and the anti-neoplastic
agent(s) and/or radiation are not administered simultaneously or
essentially simultaneously, then the initial order of
administration of the compound of Formula I, and-the
chemotherapeutic agent(s) and/or radiation, may be varied. Thus,
for example, the compound of Formula I may be administered first
followed by the administration of the antiproliferative agent(s)
and/or radiation; or the antiproliferative agent(s) and/or
radiation may be administered first followed by the administration
of the compound of Formula I. This alternate administration may be
repeated during a single treatment protocol. The determination of
the order of administration, and the number of repetitions of
administration of each therapeutic agent during a treatment
protocol, is well within the knowledge of the skilled physician
after evaluation of the disease being treated and the condition of
the patient. For example, the anti-neoplastic agent(s) and/or
radiation may be administered initially, especially if a cytotoxic
agent is employed. The treatment is then continued with the
administration of the compound of Formula I and optionally followed
by administration of a cytostatic agent, if desired, until the
treatment protocol is complete.
[0220] Thus, in accordance with experience and knowledge, the
practicing physician can modify each protocol for the
administration of a component (therapeutic agent--i.e., compound of
Formula I, anti-neoplastic agent(s), or radiation) of the treatment
according to the individual patient's needs, as the treatment
proceeds.
[0221] The attending clinician, in judging whether treatment is
effective at the dosage administered, will consider the general
well-being of the patient as well as more definite signs such as
relief of disease-related symptoms, inhibition of tumor growth,
actual shrinkage of the tumor, or inhibition of metastasis. Size of
the tumor can be measured by standard methods such as radiological
studies, e.g., CAT or MRI scan, and successive measurements can be
used to judge whether or not growth of the tumor has been retarded
or even reversed. Relief of disease-related symptoms such as pain,
and improvement in overall condition can also be used to help judge
effectiveness of treatment.
[0222] In order to facilitate a further understanding of the
invention, the following examples are presented primarily for the
purpose of illustrating more specific details thereof. The scope of
the invention should not be deemed limited by the examples, but to
encompass the entire subject matter defined by the claims.
[0223] Experimental Protocol
[0224] Compounds:
[0225] The following designations are used to identify the test
compounds throughout the examples:
[0226] Compound 1:
[0227]
!N-(2-Chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperaziny-
l]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide;
[0228] Chemicals and Solutions:
[0229] Unless specified, chemicals and solutions used for the
maintenance of cell culture were obtained from GIBCO/BRL. Sterile
tissue culture ware was obtained from Corning, N.Y. All other
reagents were from Sigma or Fisher at the highest grade
available.
[0230] Drug Administration:
[0231] For PO and IV administration to mice, the Src inhibitor was
dissolved in a mixture of propylene glycol/water (50:50). The
volume of all compounds administered was 0.01 ml/gm of mice.
[0232] In Vivo Antitumor Testing:
[0233] The human tumor xenografts were maintained in Balb/c nu/nu
nude or scid mice (Harlan, Indianapolis). Tumors were propagated as
subcutaneous transplants using tumor fragments obtained from donor
mice.
[0234] The required number of animals needed to detect a meaningful
response were pooled at the start of the experiment and each was
given a subcutaneous implant of a tumor fragment (.about.50 mg)
with a 13-gauge trocar. For treatment of early-stage tumors, the
animals were again pooled before distribution to the various
treatment and control groups. For treatment of animals with
advanced-stage disease, tumors were allowed to grow to the
pre-determined size window (tumors outside the range were excluded)
and animals were evenly distributed to various treatment and
control groups. Treatment of each animal was based on individual
body weight. Treated animals were checked daily for treatment
related toxicity/mortality. Each group of animals was weighed
before the initiation of treatment (Wt1) and then again following
the last treatment dose (Wt2). The difference in body weight
(Wt2-Wt1) provides a measure of treatment-related toxicity. Tumor
response was determined by measurement of tumors with a caliper
twice a week, until the tumors reach a predetermined "target" size
of 1 gm. Tumor weights (mg) were estimated from the formula:
Tumor weight=(length.times.width2).div.2
[0235] Antitumor activity was evaluated at the maximum tolerated
dose (MTD) which is defined as the dose level immediately below
which excessive toxicity (i.e. more than one death) occurred. The
MTD was frequently equivalent to OD. When death occurs, the day of
death was recorded. Treated mice dying prior to having their tumors
reach target size were considered to have died from drug toxicity.
No control mice died bearing tumors less than target size.
Treatment groups with more than one death caused by drug toxicity
were considered to have had excessively toxic treatments and their
data were not included in the evaluation of a compound's antitumor
efficacy.
[0236] Tumor response end-point was expressed in terms of tumor
growth delay (T-C value) and tumor growth inhibition (% T/C). Tumor
growth delay is defined as the difference in time (days) required
for the treated tumors (T) to reach a predetermined target size
compared to those of the control group (C). For this purpose tumor
weight of a group is expressed as medium tumor weight (MTW).
[0237] To estimate tumor cell kill, the tumor volume doubling time
was first calculated with the formula:
TVDT=Median time (days) for control tumor weight to reach target
size-Median time (days) for control tumor weight to reach half the
target size
[0238] And,
Log cell kill (Lck)=T-C.div.(3.32.times.TVDT)
[0239] To estimate tumor growth inhibition, the MTW at the end of
treatment is determined for the treated group (T) and the untreated
control group (C). Inhibition is expressed as the ratio (%) of
treated (T)/control (C).
[0240] Cures were also used to assess activity. A mouse was
considered cured when no mass larger than 35 mg was present at the
site of tumor implant after a number of days post-treatment had
elapsed equivalent to >10 TVDTs in that experiment. Therapeutic
results were reported at the optimal dose (OD) and results were not
used if more than one death occurred in the treated group. A
maximum tolerated dose (MTD), although often synonymous with the
OD, is defined as a dose immediately below that causing
unacceptable toxicity (i.e. more than one death), or in the absence
of any deaths, was assumed when accompanied by >20% body weight
loss. There were typically 8 mice per treatment and control
groups.
[0241] Activity for cytotoxic agents is defined as the attainment
of tumor growth delay equivalent to .about.1 Lck or
3.32.times.TVDT. For cytostatic agents, activity is defined as
attainment of growth inhibition .about.50% T/C (MTW) at the end of
the treatment period.
EXAMPLE 1
Synergistic Combination of Compound 1 with a Tubulin Interacting
Antimitotic Agent (Examplified by Paclitaxel)in the Treatment of
Solid Malignancies In Vivo
[0242] The combined antitumor effects of compound 1 and paclitaxel
was evaluated in the PC3 human prostate carcinoma xenografts in
nude mice compound 1 was administered orally, twice-a-day,
5-day-on, 2-day-off, for a total of 14 days (2qd.times.7).
Paclitaxel was administered iv, weekly.times.3. Single agent
compound 1 at a dose of 10 mpk produced a % T/C of 58% and growth
delay (T-C) of 4.5 days (FIG. 1A). Single agent paclitaxel at a
dose of 18 mpk elicited T-C of 22.5 days. The combined regimen
produced antitumor effect that was more than additive of the
individual effects of the single agent alone with a T-C of 37.2
days which was significantly better than the effects of either
single agent alone (P=0.05). However, combination of the two agents
in vitro produced only additive effect in a clonogenic cell
survival assay (FIG. 1B). These results suggest that the in vivo
synergistic interaction of compound 1 and paclitaxel may involve a
mechanism that does not directly stem from the tumor cells
themselves.
[0243] FIG. 1:
[0244] In FIG. 1A (A) Mice bearing the PC3 prostate carcinoma were
treated when tumors reached .about.100 mg. Compounds were
administered as follows: compound 1 was administered orally (PO),
twice-a-day for 14 days (2QD.times.14), with a 2 day break
following every 5 days of treatment (5-day-on, 2-day-off).
Paclitaxel was administered IV and was given weekly for 3 weeks.
Treatment with both agents was begun on the same day, paclitaxel
being given 1 hour after the first of two daily doses of compound
1. Each symbol represents the median tumor weight of a group of 8
mice. (B) PC3 cells in exponential growth phase were first exposed
to compound 1 for 48 hr followed by paclitaxel for a further 16 hr.
Cells were then washed and processed for colony formation assay.
Line of additivity depicts the level of cytotoxicity if the two
combined agents yield additive cytotoxicity and is the product of
the surviving fractions of each agent given alone. Src family
kinases play an important role in mitotic progression of cells from
G2 to Mitotic (M) phases of the cell cycle, which may explain the
synergistic interaction of Src inhibitors with antimitotic agents
such as paclitaxel.
[0245] The present invention is not limited to the embodiments
specifically described above, but is capable of variation and
modification without departure from the scope of the appended
claims.
* * * * *