U.S. patent application number 12/862979 was filed with the patent office on 2010-12-23 for combinations of organic compounds.
This patent application is currently assigned to NOVARTIS AG. Invention is credited to Michael Rugaard JENSEN, Christopher Sean STRAUB, Mary Ann TRAN, Youzhen WANG, Leigh ZAWEL.
Application Number | 20100324083 12/862979 |
Document ID | / |
Family ID | 38015223 |
Filed Date | 2010-12-23 |
United States Patent
Application |
20100324083 |
Kind Code |
A1 |
JENSEN; Michael Rugaard ; et
al. |
December 23, 2010 |
Combinations of Organic Compounds
Abstract
The invention provides a pharmaceutical combination comprising:
a) compounds that inhibit the binding of the Smac protein to IAPs;
and b) a taxane, and a method for treating or preventing a
proliferative disease using such a combination.
Inventors: |
JENSEN; Michael Rugaard;
(Basel, CH) ; STRAUB; Christopher Sean; (Stow,
MA) ; ZAWEL; Leigh; (Hingham, MA) ; TRAN; Mary
Ann; (Somerville, MA) ; WANG; Youzhen;
(Newton, MA) |
Correspondence
Address: |
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
220 MASSACHUSETTS AVENUE
CAMBRIDGE
MA
02139
US
|
Assignee: |
NOVARTIS AG
|
Family ID: |
38015223 |
Appl. No.: |
12/862979 |
Filed: |
August 25, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12158130 |
Jun 19, 2008 |
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PCT/US2006/048163 |
Dec 18, 2006 |
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12862979 |
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60752146 |
Dec 20, 2005 |
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Current U.S.
Class: |
514/300 ;
514/343; 514/365 |
Current CPC
Class: |
A61K 31/425 20130101;
A61K 31/437 20130101; A61K 31/475 20130101; A61K 31/16 20130101;
A61K 31/425 20130101; A61P 35/02 20180101; A61P 43/00 20180101;
A61P 35/00 20180101; A61K 45/06 20130101; A61K 31/475 20130101;
A61K 31/337 20130101; C07D 471/04 20130101; A61K 31/16 20130101;
A61K 2300/00 20130101; A61K 31/337 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/300 ;
514/365; 514/343 |
International
Class: |
A61K 31/437 20060101
A61K031/437; A61K 31/427 20060101 A61K031/427; A61K 31/4439
20060101 A61K031/4439; A61P 35/00 20060101 A61P035/00 |
Claims
1. A pharmaceutical combination comprising: (a) a compound that
inhibit the binding of the Smac protein to Inhibitor of Apoptosis
Proteins (IAPs) of formula (I) ##STR00005## wherein R.sub.1 is H,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkenyl,
C.sub.1-C.sub.4alkynyl or C.sub.3-C.sub.10cycloalkyl, which are
unsubstituted or substituted; R.sub.2 is H, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl or
C.sub.3-C.sub.10cycloalkyl, which are unsubstituted or substituted;
R.sub.3 is H, --CF.sub.3, --C.sub.2F.sub.5, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl, --CH.sub.2-Z,
wherein Z is H, --OH, F, Cl, --CH.sub.3, --CF.sub.3, --CH.sub.2Cl,
--CH.sub.2F or --CH.sub.2OH, or R.sub.2 and R.sub.3, together with
the nitrogen, form a het ring; R.sub.4 is C.sub.1-C.sub.16straight-
or branched-alkyl, C.sub.1-C.sub.16alkenyl, C.sub.1-C.sub.16alkynyl
or --C.sub.3-C.sub.10cycloalkyl, --(CH.sub.2).sub.1-6Z.sub.1,
--(CH.sub.2).sub.0-6aryl and --(CH.sub.2).sub.0-6het, wherein
alkyl, cycloalkyl and phenyl are unsubstituted or substituted,
wherein Z.sub.1 is --N(R.sub.8)--C(O)--C.sub.1-C.sub.10alkyl,
--N(R.sub.8)--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--N(R.sub.8)--C(O)--(CH.sub.2).sub.0-6phenyl,
--N(R.sub.8)--C(O)--(CH.sub.2).sub.1-6het,
--C(O)--N(R.sub.9)(R.sub.10), --C(O)--O--C.sub.1-C.sub.10alkyl,
--C(O)--O--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O--(CH.sub.2).sub.0-6phenyl,
--C(O)--O--(CH.sub.2).sub.1-6het, --O--C(O)C.sub.1-C.sub.10alkyl,
--O--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--O--C(O)--(CH.sub.2).sub.0-6phenyl,
--O--C(O)--(CH.sub.2).sub.1-6het, wherein alkyl, cycloalkyl and
phenyl are unsubstituted or substituted; and het is a 5- to
7-membered heterocyclic ring containing 1-4 heteroatoms selected
from N, O and S, or an 8- to 12-membered fused ring system
including at least one 5- to 7-membered heterocyclic ring
containing 1, 2 or 3 heteroatoms selected from N, O, and S, which
heterocyclic ring or fused ring system is unsubstituted or
substituted on a carbon or nitrogen atom, wherein R.sub.8 is H,
--CH.sub.3, --CF.sub.3, --CH.sub.2OH or --CH.sub.2Cl; R.sub.9 and
R.sub.10 are each independently H, C.sub.1-C.sub.4alkyl,
C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6phenyl, wherein alkyl, cycloalkyl and phenyl
are unsubstituted or substituted, or R.sub.9 and R.sub.10, together
with the nitrogen, form het; R.sub.5 is H, C.sub.1-C.sub.10alkyl,
aryl, phenyl, C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C.sub.1-C.sub.10alkyl--aryl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl-(CH.sub.2).sub.0-6phenyl,
--(CH.sub.2).sub.0-4CH--((CH.sub.2).sub.1-4phenyl).sub.2,
--(CH.sub.2).sub.0-6CH(phenyl).sub.2, -indanyl,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7-cycloalkyl,
--C(O)--(CH.sub.2).sub.0-6phenyl, --(CH.sub.2).sub.0-6C(O)-phenyl,
--(CH.sub.2).sub.0-6het, --C(O)--(CH.sub.2).sub.1-6het, or R.sub.5
is a residue of an amino acid, wherein the alkyl, cycloalkyl,
phenyl and aryl substituents are unsubstituted or substituted; and
U is as shown in formula (II): ##STR00006## wherein n is 0-5; X is
--CH or N; Ra and Rb are independently an O, S or N atom or
C.sub.0-C.sub.8alkyl, wherein one or more of the carbon atoms in
the alkyl chain may be replaced by a heteroatom selected from O, S
or N, and where the alkyl may be unsubstituted or substituted; Rd
is selected from: (a) --Re-Q-(Rf).sub.p(Rg).sub.q; or (b)
Ar.sub.1-D-Ar.sub.2, wherein p and q are independently 0 or 1; Re
is C.sub.1-C.sub.8alkyl or alkylidene and Re which may be
unsubstituted or substituted; Q is N, O, S, S(O), or S(O).sub.2;
Ar.sub.1 and Ar.sub.2 are substituted or unsubstituted aryl or het;
Rf and Rg are each independently H, --C.sub.1-C.sub.10alkyl,
C.sub.1-C.sub.10alkylaryl, --OH, --O--C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--O--(CH.sub.2).sub.0-6aryl, phenyl, aryl, phenyl-phenyl,
--(CH.sub.2).sub.1-6het, --O--(CH.sub.2).sub.1-6het, --OR.sub.11,
--C(O)--R.sub.11, --C(O)--N(R.sub.11)(R.sub.12),
--N(R.sub.11)(R.sub.12), --S--R.sub.11, --S(O)--R.sub.11,
--S(O).sub.2--R.sub.11, --S(O).sub.2--NR.sub.11R.sub.12,
--NR.sub.11--S(O).sub.2--R.sub.12, S--C.sub.1-C.sub.10alkyl,
aryl-C.sub.1-C.sub.4alkyl, het-C.sub.1-C.sub.4-alkyl, wherein
alkyl, cycloalkyl, het and aryl are unsubstituted or substituted,
--SO.sub.2--C.sub.1-C.sub.2alkyl,
--SO.sub.2--C.sub.1-C.sub.2alkylphenyl, --O--C.sub.1-C.sub.4alkyl,
or Rg and Rf form a ring selected from het or aryl; D is --CO--,
--C(O)--C.sub.1-C.sub.7alkylene or arylene, --CF.sub.2--, --O--,
--S(O).sub.r, where r is 0-2, 1,3-dioaxolane or
C.sub.1-C.sub.7alkyl-OH, where alkyl, alkylene or arylene may be
unsubstituted or substituted with one or more halogens, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl or --CF.sub.3,
or D is --N(Rh), wherein Rh is H, C.sub.1-C.sub.7alkyl
(unsubstituted or substituted), aryl,
--O(C.sub.1-C.sub.7cycloalkyl) (unsubstituted or substituted),
C(O)--C.sub.1-C.sub.10alkyl, C(O)--C.sub.o-C.sub.10alkyl-aryl,
C--O--C.sub.1-C.sub.10alkyl, C--O--C.sub.o-C.sub.10alkyl-aryl or
SO.sub.2--C.sub.1-C.sub.10-alkyl,
SO.sub.2-(C.sub.o-C.sub.10-alkylaryl); Rc is H, or Rc and Rd may
together form a cycloalkyl or het, where if Rd and Rc form a
cycloalkyl or het, R.sub.5 is attached to the formed ring at a C or
N atom; R.sub.6, R.sub.7, R'.sub.6 and R'.sub.7 are each
independently H, --C.sub.1-C.sub.10alkyl, --C.sub.1-C.sub.10alkoxy,
aryl-C.sub.1-C.sub.10alkoxy, --OH, --O--C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--O--(CH.sub.2).sub.0-6aryl, phenyl, --(CH.sub.2).sub.1-6het,
--O--(CH.sub.2).sub.1-6het, --C(O)--R.sub.11,
--C(O)--N(R.sub.11)(R.sub.12), --N(R.sub.11)(R.sub.12),
--S(O)--R.sub.11, --S(O).sub.2--R.sub.11,
--S(O).sub.2--NR.sub.11R.sub.12, --NR.sub.11--S(O).sub.2--R.sub.12,
wherein alkyl, cycloalkyl and aryl are unsubstituted or
substituted; and R.sub.6, R.sub.7, R'.sub.6 and R'.sub.7 can be
united to form a ring system, wherein R.sub.11 and R.sub.12 are
independently H, C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6(CH).sub.0-1(aryl).sub.1-2,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.0-6O-fluorenyl,
--C(O)--NH--(CH.sub.2).sub.0-6aryl, --C(O)--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.1-6het, --C(S)--C.sub.1-C.sub.10alkyl,
--C(S)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(S)--O--(CH.sub.2).sub.0-6aryl,
--C(S)--(CH.sub.2).sub.0-6O-fluorenyl,
--C(S)--NH--(CH.sub.2).sub.0-6aryl, --C(S)--(CH.sub.2).sub.0-6aryl,
--C(S)--(CH.sub.2).sub.1-6het, wherein alkyl, cycloalkyl and aryl
are unsubstituted or substituted, or R.sub.11 and R.sub.12 are a
substituent that facilitates transport of the molecule across a
cell membrane, or R.sub.11 and R.sub.12, together with the nitrogen
atom, form het, wherein the alkyl substituents of R.sub.11 and
R.sub.12 may be unsubstituted or substituted by one or more
substituents selected from C.sub.1-C.sub.10alkyl, halogen, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl or --CF.sub.3,
substituted cycloalkyl substituents of R.sub.11 and R.sub.12 are
substituted by one or more substituents selected from a
C.sub.1-C.sub.10alkene, C.sub.1-C.sub.6alkyl, halogen, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl or --CF.sub.3;
and substituted phenyl or aryl of R.sub.11 and R.sub.12 are
substituted by one or more substituents selected from halogen,
hydroxy, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, nitro, --CN,
--O--C(O)--C.sub.1-C.sub.4alkyl and --C(O)--O--C.sub.1-C.sub.4aryl;
or pharmaceutically acceptable salts thereof or (IV) ##STR00007##
wherein R.sub.1 is H; R.sub.2 is H, C.sub.1-C.sub.4alkyl, which is
unsubstituted or substituted by one or more substituents selected
from halogen, --OH, --SH, --OCH.sub.3, --SCH.sub.3, --CN, --SCN and
nitro; R.sub.3 is H, --CF.sub.3, --C.sub.2F.sub.5, --CH.sub.2-Z,
wherein Z is H, --OH, F, Cl, --CH.sub.3, --CF.sub.3, --CH.sub.2Cl,
--CH.sub.2F or --CH.sub.2OH, or R.sub.2 and R.sub.3, together with
the nitrogen, form a C.sub.3-C.sub.6heteroaliphatic ring; R.sub.4
is C.sub.1-C.sub.16straight-chain alkyl,
O.sub.3--C.sub.10branched-chain alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6Z.sub.1, --(CH.sub.2).sub.0-6phenyl and
--(CH.sub.2).sub.0-6het, wherein the alkyl, cycloalkyl and phenyl
substituents are unsubstituted or substituted, wherein Z.sub.1 is
--N(R.sub.9)--C(O)--C.sub.1-C.sub.10alkyl,
--N(R.sub.9)--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--N(R.sub.9)--C(O)--(CH.sub.2).sub.0-6phenyl,
--N(R.sub.9)--C(O)--(CH.sub.2).sub.1-6het,
--C(O)--N(R.sub.10)(R.sub.11), --C(O)--O--C.sub.1-C.sub.10alkyl,
--C(O)--O--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O--(CH.sub.2).sub.0-6phenyl,
--C(O)--O--(CH.sub.2).sub.1-6het, --O--C(O)--C.sub.1-C.sub.10alkyl,
--O--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--O--C(O)--(CH.sub.2).sub.0-6phenyl,
--O--C(O)--(CH.sub.2).sub.1-6het, wherein the alkyl, cycloalkyl and
phenyl substituents are unsubstituted or substituted, wherein
R.sub.9 is H, --CH.sub.3, --CF.sub.3, --CH.sub.2OH or CH.sub.2Cl;
R.sub.10 and R.sub.11 are each independently H,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6phenyl, wherein the alkyl, cycloalkyl and
phenyl substituents are unsubstituted or substituted, or R.sub.10
and R.sub.11, together with the nitrogen, are het; het is a 5- to
7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms
selected from N, O and S, or an 8- to 12-membered fused ring system
including at least one 5- to 7-membered heterocyclic ring
containing 1, 2 or 3 heteroatoms selected from N, O and S, which
heterocyclic ring or fused ring system is unsubstituted or
substituted on a carbon atom by halogen, hydroxy,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, nitro,
--O--C(O)--C.sub.1-C.sub.4alkyl or --C(O)--O--C.sub.1-C.sub.4alkyl
or on a nitrogen by C.sub.1-C.sub.4alkyl,
--O--C(O)--C.sub.1-C.sub.4alkyl or --C(O)--O--C.sub.1-C.sub.4alkyl;
X is CH or N; R.sub.5 is H, C.sub.1-C.sub.10alkyl,
C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C.sub.1-C.sub.10alkyl aryl
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl-(CH.sub.2).sub.0-6phen-
yl, --(CH.sub.2).sub.0-4CH--((CH.sub.2).sub.1-4phenyl).sub.2.
--(CH.sub.2).sub.0-6CH(phenyl).sub.2,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--(CH.sub.2).sub.0-6phenyl, --(CH.sub.2).sub.1-6het,
--C(O)--(CH.sub.2).sub.1-6het, or R.sub.5 is a residue of an amino
acid, wherein the alkyl, cycloalkyl, phenyl and aryl substituents
are unsubstituted or substituted; R.sub.6 is H, methyl, ethyl,
--CF.sub.3, --CH.sub.2OH or --CH.sub.2Cl, or R.sub.5 and R.sub.6,
together with the nitrogen, are het; R.sub.7 and R.sub.8 are cis
relative to the acyl substituent at the one position of the ring
and are each independently H, C.sub.1-C.sub.10alkyl --OH,
--O--C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--O--(CH.sub.2).sub.0-6aryl, phenyl, --(CH.sub.2).sub.1-6het,
--O--(CH.sub.2).sub.1-6het, --N(R.sub.12)(R.sub.13), --S--R.sub.12,
--S(O)--R.sub.12, --S(O).sub.2--R.sub.12,
--S(O).sub.2--NR.sub.12R.sub.13, wherein the alkyl, cycloalkyl and
aryl substituents are unsubstituted or substituted, wherein
R.sub.12 and R.sub.13 are independently H, C.sub.1-C.sub.10alkyl
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6(CH).sub.0-1(aryl).sub.1-2,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)-O--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.0-6O-fluorenyl,
--C(O)--NH--(CH.sub.2).sub.0-6aryl, --C(O)--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.1-6het, wherein the alkyl, cycloalkyl and
aryl substituents are unsubstituted or substituted; or a
substituent that facilitates transport of the molecule across a
cell membrane, or R.sub.12 and R.sub.13, together with the
nitrogen, are het; and aryl is phenyl or naphthyl which is
unsubstituted or substituted; n is 0, 1 or 2; and (b) at least one
taxane.
2. A method for treating or preventing a proliferative disease in a
subject in need thereof, comprising co-administration to said
subject of a therapeutically effective amount of at least one
taxane and a compound that inhibit the binding of the Smac protein
to IAPs of formula (I) or (IV) according to claim 1.
3. A pharmaceutical combination according to claim 1, for use in a
method according to claim 2.
4. A pharmaceutical combination according to claim 1, for use in
the preparation of a medicament for use in a method according to
claim 2.
5. A pharmaceutical combination according to claim 1, wherein agent
a) is N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octa
hydro-pyrrolo[2,3-c]pyridin-1-yl-ethyl]-2-methylamino-propionamide
of formula (III): ##STR00008##
6. A pharmaceutical combination according to claim 1, wherein agent
b) is selected from Paclitaxel, docetaxel, vinorelbine and the
epothilones and combinations thereof.
7. A method for treating a proliferative disease comprising
administering a combination of a taxane and a compound that inhibit
the binding of the Smac protein to IAPs of formula (I) or (IV).
8. A method for treating a proliferative disease comprising
administering a combination of a taxane and a compound selected
from
N--[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-y-
l-ethyl]-2-methylamino-propionamide of formula (III) and
pharmaceutically acceptable salts thereof.
9. A method for treating a proliferative disease comprising
administering a combination of a taxane and a compound that inhibit
the binding of the Smac protein to IAPs of formula (I) or (IV),
wherein the taxane is selected from paclitaxel and docitaxel, and
combinations thereof.
10. A method for treating a proliferative disease selected from
breast, ovarian and lung tumors comprising administering a
combination of a taxane and a compound that inhibit the binding of
the Smac protein to Inhibitor of Apoptosis Proteins (IAPs) of
formula (I) or (IV).
11. A method for treating a proliferative disease selected from
breast, ovarian and lung tumors comprising administering a
combination of a taxane and a compound selected from
N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
-ethyl]-2-methylamino-propionamide of formula (III) and
pharmaceutically acceptable salts thereof.
Description
[0001] The present invention relates to a pharmaceutical
combination comprising compounds that inhibit the binding of the
Smac protein to Inhibitor of Apoptosis Proteins (IAPs) and a
taxane, and the uses of such a combination, e.g., in proliferative
diseases, e.g., tumors, myelomas and leukemias.
[0002] In spite of numerous treatment options for patients with
proliferative diseases, there remains a need for effective and safe
molecularly targeted anti-proliferative agents. Combination of such
exploratory agents with existing therapies sometimes results in a
synergistic interaction and enhanced therapeutic benefit relative
to either agent alone.
SUMMARY OF THE INVENTION
[0003] It has now been found that a combination comprising at least
one compound that inhibits the binding of the Smac protein to IAPs
and a taxane, e.g., as defined below, has a beneficial effect on
proliferative diseases, e.g., tumors, myelomas and leukemias.
DETAILED DESCRIPTION OF THE INVENTION
[0004] The invention relates to a pharmaceutical combination which
comprises. [0005] (a) a taxane; and [0006] (b) a compound (IAP
inhibitor) that inhibits the caspase-9 inhibiting properties of an
IAP; and, optionally, [0007] (c) at least one pharmaceutically
acceptable carrier for simultaneous, separate or sequential use, in
particular, for the treatment of a proliferative disease,
especially a solid tumor disease; a pharmaceutical composition
comprising such a combination; the use of such a combination for
the preparation of a medicament for the treatment of a
proliferative disease; a commercial package or product comprising
such a combination as a combined preparation for simultaneous,
separate or sequential use; and to a method of treatment of a
warm-blooded animal, especially a human. A greater than additive
effect is seen when compounds (a) and (b) are used in
combination.
[0008] Taxanes are microtubule targeting agents that bind to
tubulin and block cell division by interfering with the function of
the mitotic spindle. Taxanes represent a first-line treatment
option for metastatic breast, lung, ovarian and digestive cancers
and are commonly used in the adjuvant setting for breast
cancer.
[0009] Taxanes include Paclitaxel, marketed as TAXOL and docetaxel,
marketed as TAXOTERE. Other taxanes include vinorelbine and the
epothilones, such as epothilone B and patupilone.
[0010] Compounds that inhibit the binding of the Smac protein to
IAPs include compounds of the formula (I):
##STR00001##
wherein [0011] R.sub.1 is H, C.sub.1-C.sub.4alkyl,
C.sub.1-C.sub.4alkenyl, C.sub.1-C.sub.4alkynyl or
C.sub.3-C.sub.10cycloalkyl, which are unsubstituted or substituted;
[0012] R.sub.2 is H, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkenyl,
C.sub.1-C.sub.4alkynyl or C.sub.3-C.sub.10cycloalkyl, which are
unsubstituted or substituted; [0013] R.sub.3 is H, --CF.sub.3,
--C.sub.2F.sub.5, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkenyl,
C.sub.1-C.sub.4alkynyl, --CH.sub.2--Z, wherein Z is H, --OH, F, Cl,
--CH.sub.3, --CF.sub.3, --CH.sub.2Cl, --CH.sub.2F or --CH.sub.2OH,
or [0014] R.sub.2 and R.sub.3, together with the nitrogen, form a
het ring; [0015] R.sub.4 is C.sub.1-C.sub.16straight- or
branched-alkyl, C.sub.1-C.sub.16alkenyl, C.sub.1-C.sub.16alkynyl or
--C.sub.3-C.sub.10cycloalkyl, --(CH.sub.2).sub.1-6Z.sub.1,
--(CH.sub.2).sub.0-6aryl and --(CH.sub.2).sub.0-6het, wherein
alkyl, cycloalkyl and phenyl are unsubstituted or substituted,
[0016] wherein [0017] Z.sub.1 is
--N(R.sub.8)--C(O)--C.sub.1-C.sub.10alkyl,
--N(R.sub.8)--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--N(R.sub.8)--C(O)--(CH.sub.2).sub.0-6phenyl,
--N(R.sub.8)--C(O)--(CH.sub.2).sub.1-6het,
--C(O)--N(R.sub.9)(R.sub.10), --C(O)--O--C.sub.1-C.sub.10alkyl,
--C(O)--O--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O--(CH.sub.2).sub.0-6phenyl,
--C(O)--O--(CH.sub.2).sub.1-6het, --O--C(O)C.sub.1-C.sub.10alkyl,
--O--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--O--C(O)--(CH.sub.2).sub.0-6phenyl,
--O--C(O)--(CH.sub.2).sub.1-6het, wherein alkyl, cycloalkyl and
phenyl are unsubstituted or substituted; and [0018] het is a 5- to
7-membered heterocyclic ring containing 1-4 heteroatoms selected
from N, O and S, or an 8- to 12-membered fused ring system
including at least one 5- to 7-membered heterocyclic ring
containing 1, 2 or 3 heteroatoms selected from N, O, and S, which
heterocyclic ring or fused ring system is unsubstituted or
substituted on a carbon or nitrogen atom, [0019] wherein [0020]
R.sub.8 is H, --CH.sub.3, --CF.sub.3, --CH.sub.2OH or --CH.sub.2Cl;
[0021] R.sub.9 and R.sub.10 are each independently H,
C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6phenyl, wherein alkyl, cycloalkyl and phenyl
are unsubstituted or substituted, or [0022] R.sub.9 and R.sub.10,
together with the nitrogen, form het; [0023] R.sub.5 is H,
C.sub.1-C.sub.10alkyl, aryl, phenyl, C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C.sub.1-C.sub.10alkylaryl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl-(CH.sub.2).sub.0-6phenyl,
--(CH.sub.2).sub.0-4CH--((CH.sub.2).sub.1-4phenyl).sub.2,
--(CH.sub.2).sub.0-6CH(phenyl).sub.2, -indanyl,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7-cycloalkyl,
--C(O)--(CH.sub.2).sub.0-6phenyl, --(CH.sub.2).sub.0-6C(O)-phenyl,
--(CH.sub.2).sub.0-6het, --C(O)--(CH.sub.2).sub.1-6het, or [0024]
R.sub.5 is a residue of an amino acid, wherein the alkyl,
cycloalkyl, phenyl and aryl substituents are unsubstituted or
substituted; and [0025] U is as shown in formula (II):
[0025] ##STR00002## [0026] wherein [0027] n is 0-5; [0028] X is
--CH or N; [0029] Ra and Rb are independently an O, S or N atom or
C.sub.0-C.sub.8alkyl, wherein one or more of the carbon atoms in
the alkyl chain may be replaced by a heteroatom selected from O, S
or N, and where the alkyl may be unsubstituted or substituted;
[0030] Rd is selected from: [0031] (a) --Re-Q-(Rf).sub.p(Rg).sub.q;
or [0032] (b) Ar.sub.1-D-Ar.sub.2, [0033] wherein [0034] p and q
are independently 0 or 1; [0035] Re is C.sub.1-C.sub.8alkyl or
alkylidene and [0036] Re which may be unsubstituted or substituted;
[0037] Q is N, O, S, S(O), or S(O).sub.2; [0038] Ar.sub.1 and
Ar.sub.2 are substituted or unsubstituted aryl or het; [0039] Rf
and Rg are each independently H, --C.sub.1-C.sub.10alkyl,
C.sub.1-C.sub.10alkylaryl, --OH, --O--C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--O--(CH.sub.2).sub.0-6aryl, phenyl, aryl, phenyl-phenyl,
--(CH.sub.2).sub.1-6het, --O--(CH.sub.2).sub.1-6het, --OR.sub.11,
--C(O)--R.sub.11, --C(O)--N(R.sub.11)(R.sub.12),
--N(R.sub.11)(R.sub.12), --S(O)--R.sub.11, --S(O)--R.sub.11,
--S(O).sub.2--NR.sub.11R.sub.12, --NR.sub.11--S(O).sub.2--R.sub.12,
S--C.sub.1-C.sub.10alkyl, aryl-C.sub.1-C.sub.4alkyl,
het-C.sub.1-C.sub.4-alkyl, wherein alkyl, cycloalkyl, het and aryl
are unsubstituted or substituted, --SO.sub.2--C.sub.1-C.sub.2alkyl,
--SO.sub.2--C.sub.1-C.sub.2alkylphenyl, --O--C.sub.1-C.sub.4alkyl,
or [0040] Rg and Rf form a ring selected from het or aryl; [0041] D
is --CO--, --C(O)--C.sub.1-C.sub.7alkylene or arylene,
--CF.sub.2--, --O--, --S(O).sub.r, where r is 0-2, 1,3-dioaxolane
or C.sub.1-C.sub.7alkyl-OH, where alkyl, alkylene or arylene may be
unsubstituted or substituted with one or more halogens, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl or --CF.sub.3,
or [0042] D is --N(Rh), wherein Rh is H, C.sub.1-C.sub.7alkyl
(unsubstituted or substituted), aryl,
--O(C.sub.1-C.sub.7cycloalkyl) (unsubstituted or substituted),
C(O)--C.sub.1-C.sub.10alkyl, C(O)--C.sub.o-C.sub.10alkyl-aryl,
C--O--C.sub.1-C.sub.10alkyl, C--O--C.sub.o-C.sub.10alkyl-aryl or
SO.sub.2--C.sub.1-C.sub.10-alkyl,
SO.sub.2--(C.sub.o-C.sub.10-alkylaryl); [0043] Rc is H, or [0044]
Rc and Rd may together form a cycloalkyl or het, where if Rd and Rc
form a cycloalkyl or het, R.sub.5 is attached to the formed ring at
a C or N atom; [0045] R.sub.6, R.sub.7, R'.sub.6 and R'.sub.7 are
each independently H, --C.sub.1-C.sub.10alkyl,
--C.sub.1-C.sub.10alkoxy, aryl-C.sub.1-C.sub.10alkoxy, --OH,
--O--C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--O--(CH.sub.2).sub.0-6aryl, phenyl, --(CH.sub.2).sub.1-6het,
--O--(CH.sub.2).sub.1-6het, --C(O)--R.sub.11,
--C(O)--N(R.sub.11)(R.sub.12), --N(R.sub.11)(R.sub.12),
--S(O)--R.sub.11, --S(O).sub.2--R.sub.11,
--S(O).sub.2--NR.sub.11R.sub.12, --NR.sub.11--S(O).sub.2--R.sub.12,
wherein alkyl, cycloalkyl and aryl are unsubstituted or
substituted; and [0046] R.sub.6, R.sub.7, R'.sub.6 and R'.sub.7 can
be united to form a ring system, [0047] wherein [0048] R.sub.11 and
R.sub.12 are independently H, C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6(CH).sub.0-1(aryl).sub.1-2,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.0-6O-fluorenyl,
--C(O)--NH--(CH.sub.2).sub.0-6aryl, --C(O)--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.1-6het, --C(S)--C.sub.1-C.sub.10alkyl,
--C(S)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(S)--O--(CH.sub.2).sub.0-6aryl,
--C(S)--(CH.sub.2).sub.0-6O-fluorenyl,
--C(S)--NH--(CH.sub.2).sub.0-6aryl, --C(S)--(CH.sub.2).sub.0-6aryl,
--C(S)--(CH.sub.2).sub.1-6het, wherein alkyl, cycloalkyl and aryl
are unsubstituted or substituted, or [0049] R.sub.11 and R.sub.12
are a substituent that facilitates transport of the molecule across
a cell membrane, or [0050] R.sub.11 and R.sub.12, together with the
nitrogen atom, form het, wherein [0051] the alkyl substituents of
R.sub.11 and R.sub.12 may be unsubstituted or substituted by one or
more substituents selected from C.sub.1-C.sub.10alkyl, halogen, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl or --CF.sub.3;
[0052] substituted cycloalkyl substituents of R.sub.11 and R.sub.12
are substituted by one or more substituents selected from a
C.sub.1-C.sub.10alkene, C.sub.1-C.sub.6alkyl, halogen, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl or --CF.sub.3;
and [0053] substituted phenyl or aryl of R.sub.11 and R.sub.12 are
substituted by one or more substituents selected from halogen,
hydroxy, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, nitro, --CN,
--O--C(O)--C.sub.1-C.sub.4alkyl and --C(O)--O--C.sub.1-C.sub.4aryl;
[0054] or pharmaceutically acceptable salts thereof.
[0055] The general terms used hereinbefore and hereinafter
preferably have within the context of this disclosure the following
meanings, unless otherwise indicated:
[0056] "Aryl" is an aromatic radical having 6-14 carbon atoms,
which may be fused or unfused, and which is unsubstituted or
substituted by 1 or more, preferably 1 or 2 substituents, wherein
the substituents are as described below. Preferred "aryl" is
phenyl, naphthyl or indanyl.
[0057] "Het" refers to heteroaryl and heterocyclic rings and fused
rings containing aromatic and non-aromatic heterocyclic rings.
"Het" is a 5- to 7-membered heterocyclic ring containing 1-4
heteroatoms selected from N, O and S, or an 8- to 12-membered fused
ring system including at least one 5- to 7-membered heterocyclic
ring containing 1, 2 or 3 heteroatoms selected from N, O and S.
Suitable het substituents include unsubstituted and substituted
pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl,
piperazyl, tetrahydropyranyl, morphilino, 1,3-diazapane,
1,4-diazapane, 1,4-oxazepane, 1,4-oxathiapane, furyl, thienyl,
pyrrole, pyrazole, triazole, 1,2,3-triazole, tetrazolyl,
oxadiazole, thiophene, imidazol, pyrrolidine, pyrrolidone,
thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine,
quinoline, isoquinoline, pyridopyrazine, pyrrolopyridine,
furopyridine, indole, benzofuran, benzothiofuran, benzindole,
benzoxazole, pyrroloquinoline and the like. The het substituents
are unsubstituted or substituted on a carbon atom by halogen,
especially fluorine or chlorine; hydroxy; C.sub.1-C.sub.4alkyl,
such as methyl and ethyl; C.sub.1-C.sub.4alkoxy, especially methoxy
and ethoxy; nitro; --O--C(O)--C.sub.1-C.sub.4alkyl or
--C(O)--O--C.sub.1-C.sub.4alkyl or on a nitrogen by
C.sub.1-C.sub.4alkyl, especially methyl or ethyl;
--O--C(O)--C.sub.1-C.sub.4alkyl or --C(O)--O--C.sub.1-C.sub.4alkyl,
such as carbomethoxy or carboethoxy.
[0058] When two substituents together with a commonly bound
nitrogen are het, it is understood that the resulting heterocyclic
ring is a nitrogen-containing ring, such as aziridine, azetidine,
azole, piperidine, piperazine, morphiline, pyrrole, pyrazole,
thiazole, oxazole, pyridine, pyrimidine, isoxazolyl and the
like.
[0059] Halogen is fluorine, chlorine, bromine or iodine, especially
fluorine and chlorine.
[0060] Unless otherwise specified "alkyl" includes straight- or
branched-chain alkyl, such as methyl, ethyl, n-propyl, isopropyl,
n-butyl, sec-butyl, tent-butyl, n-pentyl and branched pentyl,
n-hexyl and branched hexyl and the like.
[0061] A "cycloalkyl" group means C.sub.3-C.sub.10cycloalkyl having
3- to 8-ring carbon atoms and may be, e.g., cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Preferably, cycloalkyl is cycloheptyl. The cycloalkyl group may be
unsubstituted or substituted with any of the substituents defined
below, preferably halo, hydroxy or C.sub.1-C.sub.4alkyl, such as
methyl.
[0062] The amino acid residues include a residue of a standard
amino acid, such as alanine, arginine, asparagine, aspartic acid,
cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine,
leucine, lysine, methionine, phenylalanine, proline, serine,
threonine, tryptophan, tyrosine and valine. The amino acid residues
also include the side chains of uncommon and modified amino acids.
Uncommon and modified amino acids are known to those of skill in
the art [see, e.g., Fields, Tiam and Barany, Synthetic Peptides A
Users Guide, University of Wisconsin Biochemistry Center, Chapter
3, (1992)] and include amino acids, such as 4-hydroxyproline,
5-hydroxylysine, desmosine, beta (.beta.)-alanine, alpha
(.alpha.)-, gamma (.gamma.)- and .beta.-aminobutric acid,
homocysteine, homoserine, citrulline, ornithine, 2- or 3-amino
adipic acid, 6-aminocaproic acid, 2- or 3-aminoisobutric acid,
2,3-diaminopropionic acid, diphenylalanine, hydroxyproline and the
like. If the side chain of the amino acid residue contains a
derivatizable group, such as COOH, --OH or amino, the side chain
may be derivatized by a substituent that reacts with the
derivatizable group. For example, acidic amino acids, like aspartic
and glutamic acid, or hydroxy substituted side chains, like those
of serine or threonine, may be derivatized to form an ester, or
amino side chains may form amide or alkylamino derivatives. In
particular, the derivative may be a substituent that facilitates
transport across a cell membrane. In addition, any carboxylic acid
group in the amino acid residue, e.g., an .alpha.-carboxylic acid
group, may be derivatized as discussed above to form an ester or
amide.
[0063] Substituents that facilitate transport of the molecule
across a cell membrane are known to those of skill in the medicinal
chemistry arts. See, e.g., Gangewar et al., Drug Dis Today, Vol. 2,
pp. 148-155 (1997); and Bundgaard and Moss, Pharma Res, Vol. 7, p.
885 (1990). Generally, such substituents are lipophillic
substituents. Such lipophillic substituents include a
C.sub.6-C.sub.30alkyl, which is saturated, monounsaturated,
polyunsaturated, including methylene-interrupted polyene, phenyl,
phenyl which substituted by one or two C.sub.1-C.sub.8alkyl groups,
C.sub.5-C.sub.9cycloalkyl, C.sub.5-C.sub.9cycloalkyl, which is
substituted by one or two C.sub.1-C.sub.9alkyl groups,
--X.sub.1-phenyl, --X.sub.1-phenyl, which is substituted in the
phenyl ring by one or two C.sub.1-C.sub.8alkyl groups,
X.sub.1--C.sub.5-C.sub.9cycloalkyl or
X.sub.1--C.sub.5-C.sub.9cycloalkyl, which is substituted by one or
two C.sub.1-C.sub.8alkyl groups, where X.sub.1 is
C.sub.1-C.sub.24alkyl, which is saturated, mono-unsaturated or
poly-unsaturated and straight- or branched-chain.
[0064] Unsubstituted is intended to mean that hydrogen is the only
substituent.
[0065] Any of the above defined aryl, het, alkyl, cycloalkyl, or
heterocyclic groups may be unsubstituted or independently
substituted by up to 4, preferably 1, 2 or 3 substituents, selected
from the group consisting of: halo, such as Cl or Br; hydroxy;
lower alkyl, such as C.sub.1-C.sub.31lower alkyl; lower alkyl,
which may be substituted with any of the substituents defined
herein; lower alkenyl; lower alkynyl; lower alkanoyl; alkoxy, such
as methoxy, aryl, such as phenyl or benzyl; substituted aryl, such
as fluoro phenyl or methoxy phenyl; amino; mono- or di-substituted
amino; amino lower alkyl, such as dimethylamino; acetyl amino;
amino lower alkoxy, such as ethoxyamine; nitro; cyano; cyano lower
alkyl; carboxy; esterified carboxy, such as lower alkoxy carbonyl,
e.g., methoxy carbonyl; n-propoxy carbonyl or iso-propoxy carbonyl;
alkanoyl; benzoyl; carbamoyl; N-mono- or N,N-di-substituted
carbamoyl; carbamates; alkyl carbamic acid esters; amidino;
guanidine; urea; ureido; mercapto; sulfo; lower alkylthio;
sulfoamino; sulfonamide; benzosulfonamide; sulfonate; sulfanyl
lower alkyl, such as methyl sulfanyl; sulfoamino; substituted or
unsubstituted sulfonamide, such as benzo sulfonamide; substituted
or unsubstituted sulfonate, such as chloro-phenyl sulfonate; lower
alkylsulfinyl; phenylsulfinyl; phenyl-lower alkylsulfinyl;
alkylphenylsulfinyl; lower alkanesulfonyl; phenylsulfonyl;
phenyl-lower alkylsulfonyl; alkylphenylsulfonyl; halogen-lower
alkylmercapto; halogen-lower alkylsulfonyl, such as especially
trifluoromethane sulfonyl; phosphono (--P(.dbd.O)(OH).sub.2);
hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl;
substituted urea, such as 3-trifluoro-methyl-phenyl urea; alkyl
carbamic acid ester or carbamates, such as ethyl-N-phenyl-carbamate
or --NR.sub.4R.sub.5, wherein [0066] R.sub.4 and R.sub.5 can be the
same or different and are independently H; lower alkyl, e.g.,
methyl, ethyl or propyl, or [0067] R.sub.4 and R.sub.5, together
with the N atom, form a 3- to 8-membered heterocyclic ring
containing 1-4 nitrogen, oxygen or sulfur atoms, e.g., piperazinyl,
pyrazinyl, lower alkyl-piperazinyl, pyridyl, indolyl, thiophenyl,
thiazolyl, n-methyl piperazinyl, benzothiophenyl, pyrrolidinyl,
piperidino or imidazolinyl, where the heterocyclic ring may be
substituted with any of the substituents defined herein.
[0068] Preferably, the above-mentioned alkyl, cycloalkyl, aryl or
het groups may be substituted by halogen, carbonyl, thiol, S(O),
S(O.sub.2), --OH, --SH, --OCH.sub.3, --SCH.sub.3, --CN, --SCN or
nitro.
[0069] Where the plural form is used for compounds, salts,
pharmaceutical preparations, diseases and the like, this is
intended to mean also a single compound, salt or the like.
[0070] It will be apparent to one of skill in the art when a
compound of the invention can exist as a salt form, especially as
an acid addition salt or a base addition salt. When a compound can
exist in a salt form, such salt forms are included within the scope
of the invention. Although any salt form may be useful in chemical
manipulations, such as purification procedures, only
pharmaceutically acceptable salts are useful for pharmaceutically
products.
[0071] Pharmaceutically acceptable salts include, when appropriate,
pharmaceutically acceptable base addition salts and acid addition
salts, e.g., metal salts, such as alkali and alkaline earth metal
salts; ammonium salts; organic amine addition salts; amino acid
addition salts; and sulfonate salts. Acid addition salts include
inorganic acid addition, salts such as hydrochloride, sulfate and
phosphate; and organic acid addition salts, such as alkyl
sulfonate, arylsulfonate, acetate, maleate, fumarate, tartrate,
citrate and lactate. Examples of metal salts are alkali metal
salts, such as lithium salt, sodium salt and potassium salt;
alkaline earth metal salts, such as magnesium salt and calcium
salt, aluminum salt and zinc salt. Examples of ammonium salts are
ammonium salt and tetramethylammonium salt. Examples of organic
amine addition salts are salts with morpholine and piperidine.
Examples of amino acid addition salts are salts with glycine,
phenylalanine, glutamic acid and lysine. Sulfonate salts include
mesylate, tosylate and benzene sulfonic acid salts.
[0072] In view of the close relationship between the compounds in
free form and those in the form of their salts, including those
salts that can be used as intermediates, e.g., in the purification
or identification of the compounds, tautomers or tautomeric
mixtures and their salts, any reference to the compounds
hereinbefore and hereinafter especially the compounds of the
formula (I), is to be understood as referring also to the
corresponding tautomers of these compounds, especially of compounds
of the formula (I), tautomeric mixtures of these compounds,
especially of compounds of the formula (I), or salts of any of
these, as appropriate and expedient and if not mentioned
otherwise.
[0073] Any asymmetric carbon atom may be present in the (R)-, (S)-
or (R,S)-configuration, preferably in the (R)- or
(S)-configuration. Substituents at a ring at atoms with saturated
bonds may, if possible, be present in cis(=Z-) or trans(=E-) form.
The compounds may thus be present as mixtures of isomers or
preferably as pure isomers, preferably as enantiomer-pure
diastereomers or pure enantiomers.
[0074] Compounds within the scope of formula (I) and the process
for their manufacture are disclosed in WO 05/097791 published on
Oct. 20, 2005, which is hereby incorporated into the present
application by reference. A preferred compounds within the scope of
formula (I) is
N--[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-y-
l-ethyl]-2-methylamino-propionamide of formula (III):
##STR00003##
[0075] Additional compounds that inhibit the binding of the Smac
protein to IAPs include compounds of the formula (IV):
##STR00004##
wherein [0076] R.sub.1 is H; [0077] R.sub.2 is H,
C.sub.1-C.sub.4alkyl, which is unsubstituted or substituted by one
or more substituents selected from halogen, --OH, --SH,
--OCH.sub.3, --SCH.sub.3, --CN, --SCN and nitro; [0078] R.sub.3 is
H, --CF.sub.3, --C.sub.2F.sub.5, --CH.sub.2--Z, wherein Z is H,
--OH, F, Cl, --CH.sub.3, --CF.sub.3, --CH.sub.2Cl, --CH.sub.2F or
--CH.sub.2OH, or [0079] R.sub.2 and R.sub.3, together with the
nitrogen, form a C.sub.3-C.sub.6heteroaliphatic ring; [0080]
R.sub.4 is C.sub.1-C.sub.16straight-chain alkyl,
C.sub.3-C.sub.10branched-chain alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6Z.sub.1, --(CH.sub.2).sub.0-6phenyl and
--(CH.sub.2).sub.0-6het, wherein the alkyl, cycloalkyl and phenyl
substituents are unsubstituted or substituted, [0081] wherein
[0082] Z.sub.1 is --N(R.sub.9)--C(O)--C.sub.1-C.sub.10alkyl,
--N(R.sub.9)--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--N(R.sub.9)--C(O)--(CH.sub.2).sub.0-6phenyl,
--N(R.sub.9)--C(O)--(CH.sub.2).sub.1-6het,
--C(O)--N(R.sub.10)(R.sub.11), --C(O)--O--C.sub.1-C.sub.10alkyl,
--C(O)--O--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O--(CH.sub.2).sub.0-6phenyl,
--C(O)--O--(CH.sub.2).sub.1-6het, --O--C(O)--C.sub.1-C.sub.10alkyl,
--O--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--O--C(O)--(CH.sub.2).sub.0-6phenyl,
--O--C(O)--(CH.sub.2).sub.1-6het, wherein the alkyl, cycloalkyl and
phenyl substituents are unsubstituted or substituted, [0083]
wherein [0084] R.sub.9 is H, --CH.sub.3, --CF.sub.3, --CH.sub.2OH
or CH.sub.2Cl; [0085] R.sub.10 and R.sub.11 are each independently
H, C.sub.1-C.sub.4alkyl, C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6phenyl, wherein the alkyl, cycloalkyl and
phenyl substituents are unsubstituted or substituted, or [0086]
R.sub.10 and R.sub.11, together with the nitrogen, are het; [0087]
het is a 5- to 7-membered heterocyclic ring containing 1, 2 or 3
heteroatoms selected from N, O and S, or an 8- to 12-membered fused
ring system including at least one 5- to 7-membered heterocyclic
ring containing 1, 2 or 3 heteroatoms selected from N, O and S,
which heterocyclic ring or fused ring system is unsubstituted or
substituted on a carbon atom by halogen, hydroxy,
C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, nitro,
--O--C(O)--C.sub.1-C.sub.4alkyl or --C(O)--O--C.sub.1-C.sub.4alkyl
or on a nitrogen by C.sub.1-C.sub.4alkyl,
--O--C(O)--C.sub.1-C.sub.4alkyl or --C(O)--O--C.sub.1-C.sub.4alkyl;
[0088] X is CH or N; [0089] R.sub.5 is H, C.sub.1-C.sub.10alkyl,
C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C.sub.1-C.sub.10alkyl-aryl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl-(CH.sub.2).sub.0-6phenyl,
--(CH.sub.2).sub.0-4CH--((CH.sub.2).sub.1-4phenyl).sub.2,
--(CH.sub.2).sub.0-6CH(phenyl).sub.2,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--(CH.sub.2).sub.0-6phenyl, --(CH.sub.2).sub.1-6het,
--C(O)--(CH.sub.2).sub.1-6het, or [0090] R.sub.5 is a residue of an
amino acid, wherein the alkyl, cycloalkyl, phenyl and aryl
substituents are unsubstituted or substituted; [0091] R.sub.6 is H,
methyl, ethyl, --CF.sub.3, --CH.sub.2OH or --CH.sub.2Cl, or [0092]
R.sub.5 and R.sub.6, together with the nitrogen, are het; [0093]
R.sub.7 and R.sub.8 are cis relative to the acyl substituent at the
one position of the ring and are each independently H,
C.sub.1-C.sub.10alkyl, --OH, --O--C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--O--(CH.sub.2).sub.0-6aryl, phenyl, --(CH.sub.2).sub.1-6het,
--O--(CH.sub.2).sub.1-6het, --N(R.sub.12)(R.sub.13),
--S(O)--R.sub.12, --S(O).sub.2--R.sub.12,
--S(O).sub.2--NR.sub.12R.sub.13, wherein the alkyl, cycloalkyl and
aryl substituents are unsubstituted or substituted, [0094] wherein
[0095] R.sub.12 and R.sub.13 are independently H,
C.sub.1-C.sub.10alkyl,
--(CH.sub.2).sub.0-6C.sub.3-C.sub.7cycloalkyl,
--(CH.sub.2).sub.0-6(CH).sub.0-1(aryl).sub.1-2,
--C(O)--C.sub.1-C.sub.10alkyl,
--C(O)--(CH.sub.2).sub.1-6C.sub.3-C.sub.7cycloalkyl,
--C(O)--O-(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.0-6O-fluorenyl,
--C(O)--NH--(CH.sub.2).sub.0-6aryl, --C(O)--(CH.sub.2).sub.0-6aryl,
--C(O)--(CH.sub.2).sub.1-6het, wherein the alkyl, cycloalkyl and
aryl substituents are unsubstituted or substituted; or a
substituent that facilitates transport of the molecule across a
cell membrane, or [0096] R.sub.12 and R.sub.13, together with the
nitrogen, are het; and [0097] aryl is phenyl or naphthyl which is
unsubstituted or substituted; [0098] n is 0, 1 or 2; [0099]
substituted alkyl substituents are substituted by one or more
substituents selected from a double bond, halogen, OH,
--O--C.sub.1-C.sub.6alkyl, --S--C.sub.1-C.sub.6alkyl and
--CF.sub.3; [0100] substituted cycloalkyl substituents are
substituted by one or more substituents selected from a double
bond, C.sub.1-C.sub.6alkyl, halogen, OH, --O--C.sub.1-C.sub.6alkyl,
--S--C.sub.1-C.sub.6alkyl and --CF.sub.3; and [0101] substituted
phenyl or aryl are substituted by one or more substituents selected
from halogen, hydroxy, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy,
nitro, --CN, --O--C(O)--C.sub.1-C.sub.4alkyl and
--C(O)--O--C.sub.1-C.sub.4alkyl.
[0102] Unsubstituted is intended to mean that hydrogen is the only
substituent.
[0103] Halogen is fluorine, chlorine, bromine or iodine, especially
fluorine and chlorine.
[0104] Unless otherwise specified alkyl substituents include
straight- or branched-chain alkyl, such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and branched
pentyl, n-hexyl and branched hexyl and the like.
[0105] Cycloalkyl substituents include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and cycloheptyl.
[0106] Compounds within the scope of formula (VIII) and the process
for their manufacture are disclosed in WO 04/005284, which is
hereby incorporated into the present application by reference.
[0107] In each case where citations of patent applications are
given above, the subject matter relating to the compounds is hereby
incorporated into the present application by reference. Comprised
are likewise the pharmaceutically acceptable salts thereof, the
corresponding racemates, diastereoisomers, enantiomers, tautomers,
as well as the corresponding crystal modifications of above
disclosed compounds where present, e.g., solvates, hydrates and
polymorphs, which are disclosed therein. The compounds used as
active ingredients in the combinations of the invention can be
prepared and administered as described in the cited documents,
respectively. Also within the scope of this invention is the
combination of more than two separate active ingredients as set
forth above, i.e., a pharmaceutical combination within the scope of
this invention could include three active ingredients or more.
[0108] In accordance with the particular findings of the present
invention, there is provided:
1. A pharmaceutical combination comprising: [0109] a) a compound
that inhibit the binding of the Smac protein to IAPs of formula (I)
or (IV); and [0110] b) at least one taxane. 2. A method for
treating or preventing proliferative disease in a subject in need
thereof, comprising co-administration to said subject, e.g.,
concomitantly or in sequence, of a therapeutically effective amount
of a compound that inhibit the binding of the Smac protein to IAPs
of formula (I) or (VIII) and a taxane. Examples of proliferative
diseases include, e.g., tumors, leukemias and myelomas. 3. A
pharmaceutical combination as defined under 1) above, e.g. for use
in a method as defined under 2) above. 4. A pharmaceutical
combination as defined under 1) above for use in the preparation of
a medicament for use in a method as defined under 2) above.
[0111] Utility of the combination of the invention in a method as
hereinabove specified, may be demonstrated in animal test methods,
as well as in clinic, e.g., in accordance with the methods
hereinafter described.
[0112] It has now surprisingly been found that the combination of a
compounds that inhibit the binding of the Smac protein to IAPs and
a taxane possesses therapeutic properties, which render it
particularly useful as a treatment for proliferative diseases.
[0113] In another embodiment, the instant invention provides a
method for treating proliferative diseases comprising administering
to a mammal in need of such treatment a therapeutically effective
amount of the combination of compounds that inhibit the binding of
the Smac protein to IAPs and a taxane or pharmaceutically
acceptable salts or prodrugs thereof.
[0114] In another embodiment, compounds that inhibit the binding of
the Smac protein to IAPs are selected from compounds of formulae
(I) and (IV) as defined above.
[0115] Preferably, the instant invention provides a method for
treating mammals, especially humans, suffering from proliferative
diseases comprising administering to a mammal in need of such
treatment an inhibiting amount of the combination of compounds that
inhibit the binding of the Smac protein to IAPs and a taxane or
pharmaceutically acceptable salts thereof.
[0116] In the present description, the term "treatment" includes
both prophylactic or preventative treatment, as well as curative or
disease suppressive treatment, including treatment of patients at
risk of contracting the disease or suspected to have contracted the
disease, as well as ill patients. This term further includes the
treatment for the delay of progression of the disease.
[0117] The term "curative:, as used herein, means efficacy in
treating ongoing episodes involving proliferative diseases.
[0118] The term "prophylactic" means the prevention of the onset or
recurrence of diseases involving proliferative diseases.
[0119] The term "delay of progression", as used herein, means
administration of the active compound to patients being in a
pre-stage or in an early phase of the disease to be treated, in
which patients, e.g. a pre-form of the corresponding disease is
diagnosed or which patients are in a condition, e.g., during a
medical treatment or a condition resulting from an accident, under
which it is likely that a corresponding disease will develop.
[0120] This unforeseeable range of properties means that the use of
the combination of a compounds that inhibit the binding of the Smac
protein to IAPs and taxanes are of particular interest for the
manufacture of a medicament for the treatment of proliferative
diseases.
[0121] To demonstrate that the combination of a compounds that
inhibit the binding of the Smac protein to IAPs and taxanes is
particularly suitable for the treatment of proliferative diseases
with good therapeutic margin and other advantages, clinical trials
can be carried out in a manner known to the skilled person.
A. Combined Treatment
[0122] A combination which comprises: [0123] (a) a taxane; and
[0124] (b) an IAP inhibitor, in which the active ingredients are
present in each case in free form or in the form of a
pharmaceutically acceptable salt; and, optionally, at least one
pharmaceutically acceptable carrier, will be referred to
hereinafter as a COMBINATION OF THE INVENTION.
[0125] Suitable clinical studies are, e.g., open-label, dose
escalation studies in patients with proliferative diseases. Such
studies prove in particular the synergism of the active ingredients
of the COMBINATION OF THE INVENTION. The beneficial effects can be
determined directly through the results of these studies which are
known as such to a person skilled in the art. Such studies are, in
particular, suitable to compare the effects of a monotherapy using
the active ingredients and a COMBINATION OF THE INVENTION.
Preferably, the dose of: [0126] agent (a) is escalated until the
Maximum Tolerated Dosage is reached; and [0127] agent (b) is
administered with a fixed dose.
[0128] Alternatively, the agent (a) is administered in a fixed dose
and the dose of agent (b) is escalated. Each patient receives doses
of the agent (a) either daily or intermittent. The efficacy of the
treatment can be determined in such studies, e.g., after 12, 18 or
24 weeks by evaluation of symptom scores every 6 weeks.
[0129] The administration of a pharmaceutical COMBINATION OF THE
INVENTION results not only in a beneficial effect, e.g., a
synergistic therapeutic effect, e.g., with regard to alleviating,
delaying progression of or inhibiting the symptoms, but also in
further surprising beneficial effects, e.g., fewer side effects, an
improved quality of life or a decreased morbidity, compared with a
monotherapy applying only one of the pharmaceutically active
ingredients used in the combination of the invention.
[0130] A further benefit is that lower doses of the active
ingredients of the COMBINATION OF THE INVENTION can be used, e.g.,
that the dosages need not only often be smaller but are also
applied less frequently, which may diminish the incidence or
severity of side effects. This is in accordance with the desires
and requirements of the patients to be treated.
[0131] The terms "co-administration" or "combined administration"
or the like as utilized herein are meant to encompass
administration of the selected therapeutic agents to a single
patient, and are intended to include treatment regimens in which
the agents are not necessarily administered by the same route of
administration or at the same time.
[0132] It is one objective of this invention to provide a
pharmaceutical composition comprising a quantity, which is jointly
therapeutically effective at targeting or preventing proliferative
diseases a COMBINATION OF THE INVENTION. In this composition,
agents (a) and (b) may be administered together, one after the
other or separately in one combined unit dosage form or in two
separate unit dosage forms. The unit dosage form may also be a
fixed combination.
[0133] The pharmaceutical compositions for separate administration
of agents (a) and (b) or for the administration in a fixed
combination, i.e., a single galenical composition comprising at
least two combination partners (a) and (b), according to the
invention may be prepared in a manner known per se and are those
suitable for enteral, such as oral or rectal, and parenteral
administration to mammals (warm-blooded animals), including humans,
comprising a therapeutically effective amount of at least one
pharmacologically active combination partner alone, e.g., as
indicated above, or in combination with one or more
pharmaceutically acceptable carriers or diluents, especially
suitable for enteral or parenteral application.
[0134] Suitable pharmaceutical compositions contain, for example,
from about 0.1% to about 99.9%, preferably from about 1% to about
60%, of the active ingredient(s). Pharmaceutical preparations for
the combination therapy for enteral or parenteral administration
are, e.g., those in unit dosage forms, such as sugar-coated
tablets, tablets, capsules or suppositories, or ampoules. If not
indicated otherwise, these are prepared in a manner known per se,
e.g., by means of conventional mixing, granulating, sugar-coating,
dissolving or lyophilizing processes. It will be appreciated that
the unit content of a combination partner contained in an
individual dose of each dosage form need not in itself constitute
an effective amount since the necessary effective amount can be
reached by administration of a plurality of dosage units.
[0135] In particular, a therapeutically effective amount of each of
the combination partner of the combination of the invention may be
administered simultaneously or sequentially and in any order, and
the components may be administered separately or as a fixed
combination. For example, the method of preventing or treating
proliferative diseases according to the invention may comprise:
[0136] (i) administration of the first agent (a) in free or
pharmaceutically acceptable salt form; and [0137] (ii)
administration of an agent (b) in free or pharmaceutically
acceptable salt form, simultaneously or sequentially in any order,
in jointly therapeutically effective amounts, preferably in
synergistically effective amounts, e.g., in daily or intermittently
dosages corresponding to the amounts described herein. The
individual combination partners of the combination of the invention
may be administered separately at different times during the course
of therapy or concurrently in divided or single combination forms.
Furthermore, the term administering also encompasses the use of a
pro-drug of a combination partner that convert in vivo to the
combination partner as such. The instant invention is therefore to
be understood as embracing all such regimens of simultaneous or
alternating treatment and the term "administering" is to be
interpreted accordingly.
[0138] The term "a combined preparation", as used herein, defines
especially a "kit of parts" in the sense that the combination
partners (a) and (b) as defined above can be dosed independently or
by use of different fixed combinations with distinguished amounts
of the combination partners (a) and (b), i.e., simultaneously or at
different time points. The parts of the kit of parts can then,
e.g., be administered simultaneously or chronologically staggered,
that is at different time points and with equal or different time
intervals for any part of the kit of parts. The ratio of the total
amounts of the combination partner (a) to the combination partner
(b) to be administered in the combined preparation can be varied,
e.g., in order to cope with the needs of a patient sub-population
to be treated or the needs of the single.
[0139] The effective dosage of each of the combination partners
employed in the combination of the invention may vary depending on
the particular compound or pharmaceutical composition employed, the
mode of administration, the condition being treated, the severity
of the condition being treated. Thus, the dosage regimen of the
combination of the invention is selected in accordance with a
variety of factors including the route of administration and the
renal and hepatic function of the patient. A clinician or physician
of ordinary skill can readily determine and prescribe the effective
amount of the single active ingredients required to alleviate,
counter or arrest the progress of the condition. Optimal precision
in achieving concentration of the active ingredients within the
range that yields efficacy without toxicity requires a regimen
based on the kinetics of the active ingredients' availability to
target sites.
[0140] Daily dosages for agent (a) or (b) or will, of course, vary
depending on a variety of factors, for example the compound chosen,
the particular condition to be treated and the desired effect. In
general, however, satisfactory results are achieved on
administration of agent (a) at daily dosage rates of the order of
ca. 0.03-5 mg/kg/day, particularly 0.1-5 mg/kg/day, e.g., 0.1-2.5
mg/kg/day, as a single dose or in divided doses. Agents (a) and (b)
may be administered by any conventional route, in particular,
enterally, e.g., orally, e.g., in the form of tablets, capsules,
drink solutions or parenterally, e.g., in the form of injectable
solutions or suspensions. Suitable unit dosage forms for oral
administration comprise from ca. 0.02-50 mg active ingredient,
usually 0.1-30 mg, e.g., agent (a) or (b), together with one or
more pharmaceutically acceptable diluents or carriers
therefore.
[0141] Agent (b) may be administered to a human in a daily dosage
range of 0.5-1000 mg. Suitable unit dosage forms for oral
administration comprise from ca. 0.1-500 mg active ingredient,
together with one or more pharmaceutically acceptable diluents or
carriers therefore.
[0142] The administration of a pharmaceutical combination of the
invention results not only in a beneficial effect, e.g., a
synergistic therapeutic effect, e.g., with regard to inhibiting the
unregulated proliferation of haematological stem cells or slowing
down the progression of leukemias, such as chronic myeloid leukemia
(CML), acute lymphocyte leukemia (ALL) or acute myeloid leukemia
(AML), or the growth of tumors, but also in further surprising
beneficial effects, e.g., less side effects, an improved quality of
life or a decreased morbidity, compared to a monotherapy applying
only one of the pharmaceutically active ingredients used in the
combination of the invention.
[0143] A further benefit is that lower doses of the active
ingredients of the combination of the invention can be used, e.g.,
that the dosages need not only often be smaller but are also
applied less frequently, or can be used in order to diminish the
incidence of side effects. This is in accordance with the desires
and requirements of the patients to be treated.
[0144] Combinations of compounds that inhibit the binding of the
Smac protein to IAPs and taxanes may be combined, independently or
together, with one or more pharmaceutically acceptable carriers
and, optionally, one or more other conventional pharmaceutical
adjuvants and administered enterally, e.g., orally, in the form of
tablets, capsules, caplets, etc. or parenterally, e.g.,
intraperitoneally or intravenously, in the form of sterile
injectable solutions or suspensions. The enteral and parenteral
compositions may be prepared by conventional means.
[0145] The combination of compounds that inhibit the binding of the
Smac protein to IAPs and taxanes can be used alone or combined with
at least one other pharmaceutically active compound for use in
these pathologies. These active compounds can be combined in the
same pharmaceutical preparation or in the form of combined
preparations "kit of parts" in the sense that the combination
partners can be dosed independently or by use of different fixed
combinations with distinguished amounts of the combination
partners, i.e., simultaneously or at different time points. The
parts of the kit of parts can then, e.g., be administered
simultaneously or chronologically staggered, that is at different
time points and with equal or different time intervals for any part
of the kit of parts. Non-limiting examples of compounds which can
be cited for use in combination with the combination of a compounds
that inhibit the binding of the Smac protein to IAPs and taxanes
are cytotoxic chemotherapy drugs, such as cytosine arabinoside,
daunorubicin, doxorubicin, cyclophosphamide, VP-16, or imatinib
etc. Further, the combination of a compounds that inhibit the
binding of the Smac protein to IAPs and taxanes could be combined
with other inhibitors of signal transduction or other
oncogene-targeted drugs with the expectation that significant
synergy would result.
[0146] The COMBINATION OF THE INVENTION can be a combined
preparation or a pharmaceutical composition.
[0147] Moreover, the present invention relates to a method of
treating a warm-blooded animal having a proliferative disease
comprising administering to the animal a COMBINATION OF THE
INVENTION in a quantity which is therapeutically effective against
said proliferative disease.
[0148] Furthermore, the present invention pertains to the use of a
COMBINATION OF THE INVENTION for the treatment of a proliferative
disease and for the preparation of a medicament for the treatment
of a proliferative disease.
[0149] Moreover, the present invention provides a commercial
package comprising as active ingredients COMBINATION OF THE
INVENTION, together with instructions for simultaneous, separate or
sequential use thereof in the delay of progression or treatment of
a proliferative disease.
[0150] Preferred embodiments of the invention are represented by
combinations comprising: [0151] compound I and paclitaxel; [0152]
compound IV and paclitaxel; [0153] compound I and docetaxel; and
[0154] compound IV and docetaxel.
[0155] In further aspects, the present inventions provides: [0156]
a combination which comprises: [0157] (a) a COMBINATION OF THE
INVENTION, wherein the active ingredients are present in each case
in free form or in the form of a pharmaceutically acceptable salt
or any hydrate thereof; and, optionally, [0158] (b) at least one
pharmaceutically acceptable carrier; for simultaneous, separate or
sequential use; [0159] a pharmaceutical composition comprising:
[0160] (a) a quantity which is jointly therapeutically effective
against a proliferative disease of a COMBINATION OF THE INVENTION;
and [0161] (b) at least one pharmaceutically acceptable carrier;
[0162] the use of a COMBINATION OF THE INVENTION for the treatment
of a proliferative disease; [0163] the use of a COMBINATION OF THE
INVENTION for the preparation of a medicament for the treatment of
a proliferative disease; [0164] the use of a COMBINATION OF THE
INVENTION wherein the compound that inhibit the binding of the Smac
protein to IAPs is a compound of formula (I); and [0165] the use of
COMBINATION OF THE INVENTION wherein the compound that inhibit the
binding of the Smac protein to IAPs is a compound of formula
(IV).
[0166] In particular, the present invention relates to a
combination comprising: [0167] (a) a taxane; and [0168] (b) a
compound that inhibit the binding of the Smac protein to IAPs.
[0169] Moreover, in particular, the present invention relates to a
combined preparation, which comprises: [0170] (a) one or more unit
dosage forms of a taxane; and [0171] (b) one or more unit dosage
forms of a compound that inhibit the binding of the Smac protein to
IAPs.
[0172] Furthermore, in particular, the present invention pertains
to the use of a combination comprising: [0173] (a) a taxane; and
[0174] (b) a compound that inhibit the binding of the Smac protein
to IAPs for the preparation of a medicament for the treatment of a
proliferative disease.
B. Diseases to be Treated
[0175] The term "proliferative disease" includes but is not
restricted to tumors, psoriasis, restenosis, sclerodermitis and
fibrosis.
[0176] The term hematological malignancy, refers in particular to
leukemias, especially those expressing Bcr-Abl, c-Kit or HDAC (or
those depending on Bcr-Abl, c-Kit or HDAC) and includes, but is not
limited to, CML and ALL, especially the Philadelphia chromosome
positive acute lymphocyte leukemia (Ph+ALL), as well as
Imatinib-resistant leukemia. Especially preferred is use of the
combinations of the present invention for leukemias, such as CML,
ALL or AML. Most especially preferred is use in diseases which show
resistance to Imatinib and is sold under the name Gleevec.RTM..
[0177] The term "a solid tumor disease" especially means ovarian
cancer, breast cancer, cancer of the colon and generally the
gastrointestinal tract, cervix cancer, lung cancer, e.g.,
small-cell lung cancer and non-small-cell lung cancer, head and
neck cancer, bladder cancer, cancer of the prostate or Kaposi's
sarcoma.
[0178] The combinations according to the invention, that inhibit
the protein kinase activities mentioned, especially tyrosine
protein kinases mentioned above and below, can therefore be used in
the treatment of protein kinase dependent diseases. Protein kinase
dependent diseases are especially proliferative diseases,
preferably benign or especially malignant tumours, e.g., carcinoma
of the kidneys, brain, liver, adrenal glands, bladder, breast,
stomach (especially gastric tumors), ovaries, colon, rectum,
prostate, pancreas, lungs (especially SCLC), vagina or thyroid,
sarcoma, multiple myeloma, glioblastomas and numerous tumours of
the neck and head, as well as leukemias; especially colon carcinoma
or colorectal adenoma, or a tumor of the neck and head, an
epidermal hyperproliferation, especially psoriasis, prostate
hyperplasia, a neoplasia, especially of epithelial character,
preferably mammary carcinoma, or a leukemia. They are able to bring
about the regression of tumours and to prevent the formation of
tumour metastases and the growth of (also micro) metastases. In
addition they can be used in epidermal hyperproliferation, e.g.,
psoriasis; in prostate hyperplasia; and in the treatment of
neoplasias, especially of epithelial character, e.g., mammary
carcinoma. It is also possible to use the combinations of the
present invention in the treatment of diseases of the immune system
insofar as several or, especially, individual tyrosine protein
kinases are involved; furthermore, the combinations of the present
invention can be used also in the treatment of diseases of the
central or peripheral nervous system where signal transmission by
at least one tyrosine protein kinase, especially selected from
those mentioned specifically, is involved.
[0179] In CML, a reciprocally balanced chromosomal translocation in
hematopoietic stem cells (HSCs) produces the Bcr-Abl hybrid gene.
The latter encodes the oncogenic Bcr-Abl fusion protein. Whereas
Abl encodes a tightly regulated protein tyrosine kinase, which
plays a fundamental role in regulating cell proliferation,
adherence and apoptosis, the Bcr-Abl fusion gene encodes as
constitutively activated kinase, which transforms HSCs to produce a
phenotype exhibiting deregulated clonal proliferation, reduced
capacity to adhere to the bone marrow stroma and a reduces
apoptotic response to mutagenic stimuli, which enable it to
accumulate progressively more malignant transformations. The
resulting granulocytes fail to develop into mature lymphocytes and
are released into the circulation, leading to a deficiency in the
mature cells and increased susceptibility to infection.
ATP-competitive inhibitors of Bcr-Abl have been described which
prevent the kinase from activating mitogenic and anti-apoptotic
pathways (e.g., P-3 kinase and STATS), leading to the death of the
Bcr-Abl phenotype cells and thereby providing an effective therapy
against CML. The combinations of the present invention are thus
especially appropriate for the therapy of diseases related to its
overexpression, especially leukemias, such as leukemias, e.g., CML
or ALL.
[0180] In a broader sense of the invention, a proliferative disease
includes hyperproliferative conditions, such as leukemias,
hyperplasias, fibrosis (especially pulmonary, but also other types
of fibrosis, such as renal fibrosis), angiogenesis, psoriasis,
atherosclerosis; and smooth muscle proliferation in the blood
vessels, such as stenosis or restenosis following angioplasty. In
another aspect the combinations of the present invention could be
used to treat arthritis.
[0181] Combinations of the present invention can also be used to
treat or prevent fibrogenic disorders, such as scleroderma
(systemic sclerosis); diseases associated with protein aggregation
and amyloid formation, such as Huntington's disease; inhibition of
the replication of hepatitis C virus and treating hepatitis C
virus; treating tumors associated with viral infection, such as
human papilloma virus; and inhibiting viruses dependent of
heat-shock proteins.
[0182] The combinations of the present invention primarily inhibit
the growth of blood vessels and are thus, e.g., effective against a
number of diseases associated with deregulated angiogenesis,
especially diseases caused by ocular neovascularisation, especially
retinopathies, such as diabetic retinopathy or age-related macula
degeneration; psoriasis; haemangioblastoma, such as haemangioma;
mesangial cell proliferative disorders, such as chronic or acute
renal diseases, e.g., diabetic nephropathy; malignant
nephrosclerosis; thrombotic microangiopathy syndromes or transplant
rejection; or especially inflammatory renal disease, such as
glomerulonephritis, especially mesangioproliferative
glomerulonephritis; haemolytic-uraemic syndrome; diabetic
nephropathy; hypertensive nephrosclerosis; atheroma; arterial
restenosis; autoimmune diseases; diabetes; endometriosis; chronic
asthma; and especially neoplastic diseases (solid tumors, but also
leukemias and other haematological malignancies), such as
especially breast cancer, cancer of the colon, lung cancer
(especially small-cell lung cancer), cancer of the prostate or
Kaposi's sarcoma. Combinations of the present invention inhibit the
growth of tumors and are especially suited to preventing the
metastatic spread of tumors and the growth of micrometastases.
[0183] Combinations of the present invention may in particular be
used to treat: [0184] (i) a breast tumor; an epidermoid tumor, such
as an epidermoid head and/or neck tumor or a mouth tumor; a lung
tumor, e.g., a small cell or non-small cell lung tumor; a
gastrointestinal tumor, e.g., a colorectal tumor; or a
genitourinary tumor, e.g., a prostate tumor, especially a
hormone-refractory prostate tumor; [0185] (ii) a proliferative
disease that is refractory to the treatment with other
chemotherapeutics; or [0186] (iii) a tumor that is refractory to
treatment with other chemotherapeutics due to multi-drug
resistance.
Example 1
[0187] The combination of Docetaxel with a compound of formula
(III) in the ovarian carcinoma line SKOV3 results in significant
synergy in vitro. FIG. 1 indicates anti-proliferative activity of
compound of formula (III) alone (bottom row), Docetaxel alone (most
leftward column) and combinations of the two agents across a dose
range.
[0188] FIG. 2 is the corresponding isobologram at 70% growth
inhibition.
Example 2
[0189] The combination of a compound of formula (III) and
Paclitaxel has superior anti-tumor activity compared to either
agent administered as a single agent in the orthotopic breast
cancer model MDA-MB-231. Established tumors were treated for two
weeks with the dose regimens indicated in FIG. 2.
Example 3
[0190] FIG. 4 indicates anti-proliferative activity of Taxol is
dramatically enhanced by combination with a compound of formula
(III) in the melanoma cell line A375. Top curve shows dose response
of Taxol alone in A375 in three day proliferation assay. Bottom two
curves show Taxol dose response in presence of either 6 .mu.M or 12
.mu.M compound of formula (III).
[0191] The compound of formula (III) has no stand alone activity in
A375 (data not shown).
Example 4
[0192] IAP Inhibitor compounds such as LBW242 display single agent
activity on a limited number of tumor cell lines in vitro. To
determine whether a larger number of cell lines are responsive to
an IAP Inhibitor in combination with Taxol, Taxol dose response
evaluations are performed in the presence or absence of LBW242 with
10-12 tumor cell lines representing the following cancers: lung,
ovarian, melanoma, pancreatic. The criteria used for an assignment
of combination activity--either additivity or synergy--is a minimum
of a five fold potency shift for the IC50 of Taxol in combination
with LBW242 relative to Taxol alone. Tumor cell lines which are
responsive to LBW242 as a monotherapy such as MDA231 and SKOV3 also
exhibit combination activity with Taxol. In all cancer types
tested, tumor cell lines are identified in which the IAP Inhibitor
compound has no single agent activity yet enhances the response to
Taxol. Thus, the range of tumor cell lines sensitive to LBW242 in
combination with a cytotoxic agent is slightly larger than the
range responsive as a single agent.
[0193] LBW242, LCJ917, LCP656 and LCL161 are Smac mimetic small
molecules with nM affinity for the BIR3 domain of XIAP and CIAP1.
As Inhibitor of Apoptosis Proteins (IAPs) are thought to protect
tumor cells from apoptotic cell death, it was anticipated that such
agents would sensitize tumor cells to apoptotic stimuli.
Interestingly, such agents have anti-proliferative/apoptosis
inducing activity as single agents against a narrow range of tumor
cell lines for reasons which remain unclear. To determine whether
the spectrum of tumor cell lines which responded to these agents
would be wider in combination with the cytotoxic drug Taxol, we
subject panels of tumor cell lines representing a number of human
cancers to in vitro combination analyses.
Materials and Methods
[0194] MTS Reagent (#G1111; Promega) in PBS, pH 6-6.5. Phenazine
Methosulfate (PMS) (#P-5812; Sigma). 96 well tissue culture plates
(#3585; Corning Costar). RPMI 1640 cell culture medium (#22400-071;
Invitrogen). Penicillin/Streptomycin (#15140-122; Invitrogen).
Fetal Bovine Serum (#10082-139; Invitrogen). (Note: RPMI 1640+10%
FBS+Penicillin/Streptomycin is "RPMI/10% FBS Complete medium").
0.25% Trypsin-EDTA (#25200-056; Invitrogen). The IAP Inhibitor
compounds LBW242, LCJ917, LCP656 and LCL161 are dissolved in DMSO
at a concentration of 10 mM and stored at -20.degree. C. Tumor Cell
Lines are purchased from ATCC.
MTS Assay
[0195] Cell proliferation/cell death is analyzed in 72 hr.
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-
-2H-tetrazolium, inner salt (MTS) assays. Tumor cell lines are
plated at subconfluent densities in 96 well plate format and
allowed to adhere for 12-16 hr. Cpds are then added according to
the following schemes: i. Chemotherapeutic agents or cytotoxic cpds
(Ctx) are added alone, in an 8-point/10-fold titration scheme from
high to low dose, in triplicate. ii. IAP-inhibitor (NVP-LBW242) is
added alone, at a single fixed dose (dose determined in stand alone
MTS assays) in triplicate. iii. Ctx agent (8-point/10-fold scheme)
and LBW242 (single fixed dose) are added together, simultaneously,
in triplicate. Once all dosing is completed, cells are cultured for
a further 72 hr. and then assayed using the MTS format:
Day -1
[0196] 1. Plate cells in RPMI/10% FBS Complete medium. Set-up Time
0 (T.0) and Experimental (EXP) plates as appropriate for each cell
line. Each plate will contain culture medium (CM) alone (Blank)
wells (200 ul/well). 2. An additional "Blank" plate will contain
Blank wells: the center 24 wells will contain 12 wells with 100 ul
CM/well and 12 wells with 110 ul CM/well. All surrounding wells
will contain 200 ul CM/well. 3. Trypsinize cells at 37.degree.
C./5% CO.sub.2 for up to 5', quench the trypsin with CM and then
plate cells onto 96 well plates at 90 ul/well. Seed cells at
densities appropriate for each cell line (appropriate cell
densities will yield optimal cell growth which is reflected in
T.0OD 490 values between 0.3-0.8). Add 90 ul CM to 6 Blank wells on
the T.0 plate and 200 ul CM to all surrounding wells. Add 200 ul CM
to all outer wells on Exp plates. Culture plates @ 37.degree. C./5%
CO2 for 24 (T.0 plate) to 96 hr. (EXP plates).
Day 0
[0197] 1. Add MTS/PMS reagents to T.0 Plate(s). Mix enough of each
reagent (100 ul 500 uM PMS per 2 ml 333 ug/ml MTS reagent/96 well
plate) for 20 ul/well. Add 20 ul mixture to ea. well & incubate
plate(s) 2 hr. @ 37.degree. C./5% CO2. Read OD 490 nm using SoftMax
Pro software on a Molecular Devices (Sunnyvale, Calif.)
Spectrophotometer. Calculate T.0 values for each cell line to be
assayed by generating the mean value of the OD 490 nm readings from
each cell line's T.0 wells (6/cell line) and subtracting the mean
OD 490 nm values from Blank wells. 2. Dose EXP plate(s) with
appropriate Cdps in triplicate in the schemes shown in FIG. 5.
Incubate plates at 37.degree. C./5% CO2 for 72 hr.
Day 3
[0198] 1. Add MTS/PMS reagents to EXP Plate(s). Mix enough of each
reagent (100 ul 500 uM PMS per 2 ml 333 ug/ml MTS reagent/96 well
plate) for 20 ul/well. Add 20 ul mixture to ea. well & incubate
plate(s) 2 hr. @ 37.degree. C./5% CO2. Read OD 490 nm using SoftMax
Pro software on a Molecular Devices Spectrophotometer. MTS Data is
generated as described below: Calculate % CG by first averaging
triplicate results (subtracting blank medium values) as
follows:
If OD treated>OD T.0, then: % CG=100.times.[(OD treated-OD
T.0)/(OD 72 hr. untreated-OD T.0)]
If ODtreated<OD T.0, then: % CG=100.times.[(OD treated-OD
T.0)/OD T.0]
Selection of IAP Inhibitor Dose Levels
[0199] IAP Inhibitors are used at a single fixed dose of 10 uM (12
uM in earliest assays) in lines where compound shows no effect
(IC50>10 uM) as a single agent.
[0200] IAP Inhibitors are used at a single fixed dose yielding
70-80% control cell growth (% CG) (between IC20-IC30 dose) in lines
where compounds show moderate stand alone activity (IC50 1-10 uM)
as a single agent.
[0201] In most cases, fixed doses in specific cell lines are set by
generating empirical data in MTS assays.
Criteria for Call of Combination Activity
[0202] Combinations exhibiting a.gtoreq.5-fold potency shift in the
IC50 dose as compared with Taxol alone are scored as a combination
activity hits provided that under similar conditions LBW242 by
itself did not result in <70% CG (IC30).
[0203] True assessment of synergy requires fixed ratio titrations
of combination partners and determination of combination indices.
The above criteria do not formally distinguish between synergy and
additivity.
Ovarian Tumor Cell Lines:
[0204] FIG. 5 Taxol+100 nM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in OVCAR-4
[0205] FIG. 6 Taxol+1 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in OVCAR-4
[0206] FIG. 7 Taxol+10 uM
N--[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-y-
l)-ethyl]-2-methylamino-propionamide Combinations in TOV 21G
[0207] FIG. 8 Taxol+80 nM
N--[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-y-
l)-ethyl]-2-methylamino-propionamide Combinations in SKOV-3
Melanoma Cancer Cell Lines:
[0208] FIG. 9 Taxol+10 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-A-pyrrolidin-1-y-
l}-2-oxo-ethyl)-2-methylamino-propionamide Combination in
SKMEL-2
[0209] FIG. 10 Taxol+10 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in SKMEL-2
[0210] FIG. 11 Taxol+10 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in MEWO
[0211] FIG. 12 Taxol+10 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in A375
[0212] FIG. 13 Taxol+1 uM
N-[1-Cyclohexyl-2-(2-{2-[(4-fluoro-phenyl)-methyl-amino]-pyridin-4-yl}-py-
rrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide Combination
in A375
[0213] FIG. 14 Taxol+6 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in A375
[0214] FIG. 15 Taxol+10 uM
N-(1-Cyclohexyl-2-{2-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in A375
[0215] FIG. 16 Taxol+10 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in A375
[0216] FIG. 17 Taxol+1 uM
N-[1-Cyclohexyl-2-(2-{2-[(4-fluoro-phenyl)-methyl-amino]-pyridin-4-yl}-py-
rrolidin-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide Combination
in A375
[0217] FIG. 18 Taxol+10 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in A375
[0218] FIG. 19 Taxol+10 uM
N-(1-Cyclohexyl-2-{2-[5-(4-fluoro-phenoxy)-pyridin-3-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in A375
Lung Tumor Cell Lines:
[0219] FIG. 20 Taxol+10 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in
NCI-H2030
[0220] FIG. 21 Taxol+2 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in NCI-H23
[0221] FIG. 22 Taxol+0.5 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in SK-LU-1
[0222] FIG. 23 Taxol+7 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in
NCI-H441
[0223] FIG. 24
Taxol+N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridi-
n-1-yl)-ethyl]-2-methylamino-propionamide Combination in
NCI-H441
[0224] FIG. 25 Taxol+4 uM
N-(1-Cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-
-2-oxo-ethyl)-2-methylamino-propionamide Combination in A-427
[0225] FIG. 26 Taxol+10 uM
N-[1-Cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo[2,3-c]pyridin-1-yl-
)-ethyl]-2-methylamino-propionamide Combination in A-427
* * * * *