U.S. patent application number 12/293257 was filed with the patent office on 2009-03-12 for organic compounds.
Invention is credited to David Bryant Batt, Rene Beerli, Guido Bold, Giorgio Caravatti, Timothy Michael Ramsey.
Application Number | 20090069360 12/293257 |
Document ID | / |
Family ID | 38222743 |
Filed Date | 2009-03-12 |
United States Patent
Application |
20090069360 |
Kind Code |
A1 |
Batt; David Bryant ; et
al. |
March 12, 2009 |
Organic Compounds
Abstract
The present invention relates to the discovery that certain
compounds inhibit, regulate and/or modulate tyrosine and
serine/threonine kinase and kinase-like proteins, such as RAF
kinase, a serine/threonine kinase that functions in the MAP kinase
signaling pathway, and is concerned with compositions which contain
these compounds, and methods of using them to treat tyrosine and
serine/threonine kinase and kinase-like dependent diseases, such as
angiogenesis, cancer and cardiac hypertrophy.
Inventors: |
Batt; David Bryant;
(Wayland, MA) ; Beerli; Rene; (Binningen, CH)
; Bold; Guido; (Gipf-Oberfrick, CH) ; Caravatti;
Giorgio; (Bottmingen, CH) ; Ramsey; Timothy
Michael; (Weston, MA) |
Correspondence
Address: |
CARSTENS & CAHOON, LLP
P O BOX 802334
DALLAS
TX
75380
US
|
Family ID: |
38222743 |
Appl. No.: |
12/293257 |
Filed: |
March 14, 2007 |
PCT Filed: |
March 14, 2007 |
PCT NO: |
PCT/US07/06424 |
371 Date: |
September 16, 2008 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
60783175 |
Mar 16, 2006 |
|
|
|
Current U.S.
Class: |
514/275 ;
544/331 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 27/02 20180101; A61P 9/04 20180101; A61P 25/00 20180101; A61P
9/10 20180101; A61P 17/02 20180101; A61P 3/10 20180101; A61P 43/00
20180101; A61P 25/06 20180101; A61P 29/00 20180101; C07D 401/04
20130101 |
Class at
Publication: |
514/275 ;
544/331 |
International
Class: |
A61K 31/506 20060101
A61K031/506; C07D 401/04 20060101 C07D401/04; A61P 35/00 20060101
A61P035/00 |
Claims
1. A compound of formula (I) ##STR00036## or a pharmaceutical
acceptable salt, ester or prodrug thereof for use as a
pharmaceutical wherein each of A.sub.1, A.sub.2, A.sub.3, A.sub.4
is independent selected from N or C--R.sup.3 where R.sup.3
represents H or a substituent moiety of C and where at least one of
A.sub.1, A.sub.2 and A.sub.4 is N; X is a linking moiety selected
from N--H, substituted amino, O or S; R.sup.1 is a substituent of
the aromatic ring and n is an integer from 0 to 4; Y and D are
independently selected from O, S, CH.sub.2, NH, R.sup.6-substituted
C, or R.sup.6-substituted N, R.sup.6 is a substituent of the ring
which contains Y and D and r is an integer from 0 to the maximum
number of available valencies of the ring; R.sup.2 is a substituted
or unsubstituted moiety selected from hydrocarbyl and heterocyclic;
T is selected from H, halogen, O--R.sup.9, S--R.sup.8, SO--R.sup.8,
SO.sub.2--R.sup.8, SO.sub.2--N(R.sup.8).sub.2, SO.sub.2--NR.sup.10
and SO.sub.2-halogen, where R.sup.8 is selected from hydrogen,
substituted or unsubstituted alkyl, cycloalkyl, heterocyclyl or
aryl; and R.sup.9 is substituted or unsubstituted alkyl,
cycloalkyl, or aryl, and NR.sup.10 represents a heterocyclic ring
including the nitrogen; and p is an integer from 0 to 5.
2. A compound of formula (I) ##STR00037## or a pharmaceutically
acceptable salt, ester or prodrug thereof wherein each of A.sub.1,
A.sub.2, A.sub.3, A.sub.4 is independently selected from N or
C--R.sup.3 where R.sup.3 represents H or a substituent moiety of C
and where at least one of A.sub.1, A.sub.2 and A.sub.4 is N; X is a
linking moiety selected from N--H, substituted amino, O or S;
R.sup.1 is a substituent of the aromatic ring and n is an integer
from 0 to 4; Y and D are independently selected from O, S,
CH.sub.2, NH, R.sup.8-substituted C, or R.sup.8-substituted N,
R.sup.6 is a substituent of the ring which contains Y and D and r
is an integer from 0 to the maximum number of available valencies
of the ring; R.sup.2 is a substituted or unsubstituted moiety
selected from hydrocarbyl and heterocyclic; T is selected from H,
halogen, OR.sup.9, S--R.sup.8, SO--R.sup.8 SO.sub.2--R.sup.8,
SO.sub.2--N(R.sup.8).sub.2, SO.sub.2--NR.sup.10 and SO.sub.2--
halogen, where R.sup.8 is selected from hydrogen, substituted or
unsubstituted alkyl, cycloalkyl, heterocyclyl or aryl; and R.sup.9
is substituted or unsubstituted alkyl, cycloalkyl, or aryl, and
NR.sup.10 represents a heterocyclic ring including the nitrogen;
and p is an integer from 0 to 5 and wherein the compound is not:
##STR00038##
3. A compound of claim 1 wherein A.sub.1 and A.sub.2 are N, and
A.sub.3 and A.sub.4 are C--R.sup.3.
4. (canceled)
5. A compound of claim 1 wherein X is N--H.
6. (canceled)
7. (canceled)
8. A compound of claim 1 wherein n is 1.
9. A compound of claim 1 wherein Y is CH.sub.2.
10. A compound of claim 1 wherein D is CH.sub.2.
11. (canceled)
12. (canceled)
13. A compound as claimed in claim 1 wherein R.sup.2 is selected
from substituted or unsubstituted phenyl, imidazolyl, pyrrolyl,
oxazolyl and isoxazolyl.
14. A compound as claimed in claim 1 wherein R.sup.2 phenyl.
15. A compound as claimed in claim 1 wherein p is 1.
16. A compound as claimed in claim 1 wherein p is 1 and T is
located para- to the linking group X.
17. A compound as claimed in claim 1 wherein T is selected from
halogen, O-alkyl, O-alkyl-halogen, SO.sub.2--R.sup.8,
SO.sub.2--NHR.sup.8, SO.sub.2--NR.sup.10 and SO.sub.2-halogen.
18. (canceled)
19. (canceled)
20. (canceled)
21. A compound as claimed in claim 17 wherein T is a moiety
selected from the formulae (i) to (x): where q is an integer from 1
to 4 and s is an integer from 0 to 4 ##STR00039##
22. (canceled)
23. A compound as claimed in claim 1 selected from compounds of the
formulae (II), (III) and (IV):
24. A compound as claimed in claim 23 wherein X is NH.
25. A compound as claimed in claim 23 wherein R.sup.2 is
phenyl.
26. (canceled)
27. (canceled)
28. A compound as claimed in claim 1 of the formula (V):
##STR00040##
29. (canceled)
30. A compound as claimed in claim 1 or 2 selected from compounds
for the formulae (VI), (VII) and (VIII): ##STR00041##
31. (canceled)
32. A compound as claimed in claim 1 or 2 of the formula (IX)
##STR00042##
33. (canceled)
34. (canceled)
35. A compound as claimed in claim 1 of the formula (X)
##STR00043## wherein G represents R.sup.8, NHR.sup.8 or
NR.sup.10.
36. (canceled)
37. A compound as claimed in claim 1 of the formula (XI)
##STR00044##
38. A compound as claimed in claim 1 of the formula (XII)
##STR00045##
39. (canceled)
40. (canceled)
41. (canceled)
42. The compound of any one of claim 1 for use in inhibiting IKK,
PDGF-R, Kdr, c-Src, Her-1, Her-2, c-Kit, c-Abl, Ins-r, Tek, Flt-1,
Flt-3, Flt-4, c-Abi, RAF Kinase, and FGFR-1, Eph receptors (e.g.
EphB4), CDK1, CDK2 and RET activity in a warm-blooded animal.
43. (canceled)
44. A compound as claimed in claim 42 wherein said diseases are
selected from one or more of angiogenesis, cancer, tumour growth,
atherosclerosis, age related macular degeneration, diabetic
retinopathy, inflammatory diseases, neurotraumatic diseases,
chronic neurodegeneration, pain, migraine or cardiac hypertrophy,
and melanoma.
45. (canceled)
46. A compound of claim 1 for use in the treatment of a disease
characterized by an activated mutant B-RAF kinase.
47. (canceled)
48. (canceled)
49. (canceled)
50. (canceled)
51. (canceled)
52. The use as claimed in claim 46 wherein said compound is
administered in combination with at least one other anticancer
agent.
53. (canceled)
54. A pharmaceutical composition comprising a compound of any one
of claim 1.
55. (canceled)
56. (canceled)
57. (canceled)
58. (canceled)
59. (canceled)
60. A pharmaceutical composition of claim 54 additionally
comprising a carrier.
61. A pharmaceutical composition of claim 60 wherein said carrier
is mannitol, a suspension in oil, or a solid carrier.
62. (canceled)
63. (canceled)
64. (canceled)
65. (canceled)
66. (canceled)
67. (canceled)
68. A pharmaceutical composition comprising a compound of claim 1
and at least one anticancer agent.
69. (canceled)
70. (canceled)
71. (canceled)
72. (canceled)
73. A method of treating melanoma, which method comprises (a)
testing melanoma tissue from a patient to determine whether the
melanoma tissue expresses mutant RAF kinase or overexpresses a
wild-type RAF kinase, and (b) treating the patient with an
effective RAF kinase inhibiting amount of a RAF inhibiting compound
as claimed in claim 1 if the melanoma is found to overexpresses a
wild type RAF kinase or express an activating mutant B-RAF
kinase.
74. A method of treating melanoma, which method comprises (a)
testing melanoma tissue from a patient and determining whether the
melanoma tissue overexpresses B-RAF kinase or C-RAF kinase
activity, and (b) treating the patient with an effective RAF kinase
inhibiting amount of a RAF inhibiting compound as claimed in claim
1 if the melanoma tissue is found to overexpress B-RAF kinase or
C-RAF kinase activity.
75. A method of treating melanoma, which method comprises (a)
testing melanoma tissue from a patient and determining whether the
melanoma tissue expresses mutant B-RAF kinase or C-RAF kinase
activity, and (b) treating the patient with an effective RAF kinase
inhibiting amount of a RAF inhibiting compound as claimed in claim
1 if the melanoma tissue is found to express mutant B-RAF
kinase.
76. A method of treating a disease characterized by an activated
mutant B-RAF kinase, which method comprises detecting a mutation in
the B-RAF kinase gene or protein in a tissue sample from a patient
and treating the patient with an effective B-RAF kinase inhibiting
amount of a compound as claimed in claim 1.
77. (canceled)
78. A process for the preparation of a compound of the formula
##STR00046## which process comprises the following reaction scheme:
##STR00047## where step 2 is optional and where carried out T' is a
precursor of T, and R.sup.1' is a precursor of R.sup.1 or is
R.sup.1 and X, R.sup.1, R.sup.2, T and P are as defined in claim
1.
79. A process as claimed in claim 78 wherein X is NH.
80. A process as claimed in claim 78 wherein R.sup.2 is phenyl.
81. A process as claimed in claim 78 wherein p is 1.
82. A process as claimed in claim 78 wherein R.sup.1' is OH.
83. A process as claimed in claim 78 wherein T represents
SO.sub.2-G where G represents R.sup.8, NHR.sup.8 or NR.sup.10 and
R.sup.8 and R.sup.10 are as defined in claim 1.
84. A process as claimed in claim 78 wherein T represents
O--R.sup.9 where R.sup.9 is as defined in claim 1.
85. A process as claimed in claim 84 wherein X--R.sup.2-(T).sub.p
represents ##STR00048##
Description
SUMMARY
[0001] The present invention relates to the discovery that certain
compounds inhibit, regulate and/or modulate tyrosine and
serine/threonine kinase and kinase-like proteins, such as RAF
kinase, a serine/threonine kinase that functions in the MAP kinase
signaling pathway, and is concerned with compositions which contain
these compounds, and methods of using them to treat tyrosine and
serine/threonine kinase and kinase-like dependent diseases, such as
angiogenesis, cancer and cardiac hypertrophy.
BACKGROUND
[0002] Cells communicate various aspects of their extracellular
environment to the nucleus by using various signal transduction
pathways. Many of these, signals are transmitted by protein kinases
which activate various factors through the transfer of phosphate
groups. Disruption of signal transduction by inhibiting appropriate
kinase activity can have a clinical benefit as has been
demonstrated by imatinib, an inhibitor of bcr-abl kinase, which is
marketed as its mesylate salt under the brand GLEEVEC (in the
United States) or GLIVEC.
[0003] The MAP kinase signaling pathway is known in the art as one
of the pathways for growth factors to send their signal to
proliferate from the extracellular environment to the cell nucleus.
The growth factors activate transmembrane receptors located on the
cell surface which in turn start a cascade whereby RAS is activated
and recruits RAF kinase to the membrane where it is activated and
in turn activates MEK kinase which then activates ERK kinase.
Activated ERK kinase can move to the nucleus where it activates
various gene transcription factors. Aberrations in this pathway can
lead to altered gene transcription, cellular growth and contribute
to tumorogenicity by negatively regulating apoptosis and
transmitting proliferative and angiogenic signals. Inhibitors of
RAF kinase have been shown to block signaling through the MAP
kinase signaling pathway.
[0004] The RAF kinase family is known to have three members
designated C-RAF, also known as RAF-1, B-RAF and A-RAF. It has been
reported that B-RAF kinase is commonly activated by one of several
somatic point mutations in human cancer, including 59% of the
melanoma cell lines tested. See, Davies, H. et al, Nature 417,
949-954 (2002). This invention relates to the discovery of a class
of compounds that efficiently inhibit one or more members of the
RAF kinase family.
[0005] The RAF kinase inhibiting property of the compounds makes
them useful as therapeutic agents for the treatment for
proliferative diseases characterized by an aberrant MAP kinase
signaling pathway, particularly many cancers characterized by
overexpression of RAF kinase or an activating mutation of RAF
kinase, such as melanoma having mutated B-RAF, especially wherein
the mutated B-RAF is the V599E mutant. The present invention also
provides a method of treating other conditions characterized by an
aberrant MAP kinase signaling pathway, particularly where B-RAF is
mutated, for example benign Nevi moles having mutated B-RAF, with
the compounds.
DESCRIPTION
[0006] A first aspect of the present invention provides a compound
of formula (I)
##STR00001##
or a pharmaceutical acceptable salt, ester or prodrug thereof for
use as a pharmaceutical wherein [0007] each of A.sub.1, A.sub.2,
A.sub.3, A.sub.4 is independently selected from N or C--R.sup.3
where R.sup.3 represents H or a substituent moiety of C and where
at least one of A.sub.1, A.sub.2 and A.sub.4 is N; [0008] X is a
linking moiety selected from N--H, substituted amino, O or S;
[0009] R.sup.1 is a substituent of the aromatic ring and n is an
integer from 0 to 4; [0010] Y and D are independently selected from
O, S, CH.sub.2, NH, R.sup.8-substituted C, or R.sup.6-substituted
N, [0011] R.sup.6 is a substituent of the ring which contains Y and
D and r is an integer from 0 to the maximum number of available
valencies of the ring; [0012] R.sup.2 is a substituted or
unsubstituted moiety selected from hydrocarbyl and heterocyclic;
[0013] T is selected from H, halogen, O--R.sup.9, S--R.sup.8,
SO--R.sup.8 SO.sub.2--R.sup.8, SO.sub.2--N(R.sup.8).sub.2,
SO.sub.2--N.sup.8R.sup.10 and SO.sub.2-halogen, where R.sup.8 is
selected from hydrogen, substituted or unsubstituted aliphatic,
cycloaliphatic, heterocyclyl or aryl; and R.sup.9 is substituted or
unsubstituted aliphatic; cycloaliphatic, or aryl, and N.sup.a and
R.sup.10 together represent a 4, 5, 6, 7 or 8-membered heterocyclic
ring including the nitrogen N.sup.a; and p is an integer from 0 to
5.
[0014] A second aspect of the invention provides a compound of
formula (I)
##STR00002##
or a pharmaceutically acceptable salt, ester or prodrug thereof
wherein [0015] each of A.sub.1, A.sub.2; A.sub.3, A.sub.4 is
independently selected from N or C--R.sup.3 where R.sup.3
represents H or a substituent moiety of C and where at least one of
A.sub.1, A.sub.2 and A.sub.4 is N; [0016] X is a linking moiety
selected from N--H, substituted amino, O or S; [0017] R.sup.1 is a
substituent of the aromatic ring and n is an integer from 0 to 4;
[0018] Y and D are independently selected from O, S, CH.sub.2, NH,
R.sup.6-substituted C, or R.sup.6-substituted N, [0019] R.sup.6 is
a substituent of the ring which contains Y and D and r is an
integer from 0 to the maximum number of available valencies of the
ring; [0020] R.sup.2 is a substituted or unsubstituted moiety
selected from hydrocarbyl and heterocyclic; [0021] T is selected
from H, halogen, O--R.sup.9, S--R.sup.8, SO--R.sup.8
SO.sub.2--R.sup.8, SO.sub.2--N(R.sup.8).sub.2, SO.sub.2--NR.sup.10
and SO.sub.2-halogen, where R.sup.8 is selected from hydrogen,
substituted or unsubstituted aliphatic, cycloaliphatic,
heterocyclyl or aryl; and R.sup.9 is substituted or unsubstituted
aliphatic, cycloaliphatic, or aryl, and NR.sup.10 represents a
heterocyclic ring including the nitrogen; and p is an integer from
0 to 5 and wherein the compound is not:
##STR00003##
[0022] Preferably R.sup.1 is present (n is not 0) and is
independently selected from halogen, lower alkyl, halo-lower alkyl,
carboxy, esterified carboxy, hydroxy, etherified or esterified
hydroxy, lower alkoxy, phenyl, substituted phenyl, lower alkanoyl,
substituted or unsubstituted amine, amino, mono- or di-substituted
amino, amidino, ureido, mercapto, N-hydroxy-amidino, guanidino,
amidino-lower alkyl, sulfo, sulfamoyl, carbamoyl, cyano,
cyano-lower alkyl, azo (N.dbd.N.dbd.N) and nitro.
[0023] R.sup.1, or each R.sup.1 independently, is preferably
selected from OH, O-alkyl, SH, S-alkyl, halogen, substituted or
unsubstituted amine, CF.sub.3 and C.sub.1-C.sub.4 alkyl. Most
preferably n is 1.
[0024] R.sup.2 is preferably selected from substituted or
unsubstituted aliphatic, alicyclic, or aromatic moieties such as
cycloalkyl, heterocyclylalkyl, phenyl, pyrrole, imidazole,
pyrazole, isoxazole, oxazole, thiazole, pyridazine, pyrimidine,
pyrazine, pyridyl, indole, isoindole, indazole, purine,
indolizidine, quinoline, isoquinoline, quinazoline, pteridine,
quinolizidine. Preferably R.sup.2 is aromatic. In particular
R.sup.2 is selected from substituted or unsubstituted phenyl,
imidazolyl, pyrrolyl, oxazolyl and isoxazolyl, and especially
R.sup.2 is phenyl or substituted phenyl, wherein the substituent
include lower alkyl(C.sub.1-C.sub.6), halogen, OH, lower alkoxy,
NH.sub.2, SH, S-alkyl, SO-alkyl, SO.sub.2-alkyl, NH-alkyl,
N-dialkyl, carboxyl or CF.sub.3.
[0025] Thus preferably X--R2-(T).sub.p represents
##STR00004##
T may preferably be selected from halogen, O-alkyl,
O-alkyl-halogen, SO.sub.2--R.sup.8, SO.sub.2--NHR.sup.8,
SO.sub.2--NR.sup.10 and SO.sub.2-halogen where halogen is
preferably chlorine.
[0026] R.sup.8 and R.sup.9 may preferably be independently selected
from lower alkyl, especially C.sub.1, C.sub.2, C.sub.3 or C.sub.4
alkyl, cycloalkyl, heterocyclolalkyl, lower alkenyl, lower alkynyl,
lower alkoxy, especially methoxy or ethoxy, lower-alkanoyl,
carboxy, amino, mono- or di-substituted amino, a cyclic group, for
example phenyl, pyrrole, imidazole, pyrazole, isoxazole, oxazole,
thiazole, pyridazine, pyrimidine, pyrazine, pyridyl, indole,
isoindole, indazole, purine, indolizidine, quinoline, isoquinoline,
quinazoline, piperidyl, pteridine, quinolizidine piperazinyl,
pyrollidine, morpholinyl and thiomorpholinyl.
[0027] Preferably R8 and R9 are substituted or unsubstituted alkyl
or substituted or unsubstituted aryl. In particular R8 may
represent linear or branched alkyl, cycloalkyl, linear or branched
halo-alkyl, alkoxy, carboxyalkyl, or alkylamino.
[0028] Most preferably R2 is phenyl and T is located para to the
linking group X.
[0029] Where T is O--R9 and R2 is phenyl, preferably T is located
meta to the linking group X.
[0030] Preferably p is 1.
[0031] Particularly preferably T is a moiety selected from the
formulae (i) to (x):
##STR00005##
[0032] Preferably A.sub.1 and A.sub.2 are N, and A.sub.3 and
A.sub.4 are C--R.sup.3. It is especially preferred that A.sub.3 and
A.sub.4 are C--H.
[0033] Preferably X is N--H.
[0034] Preferably R.sup.1 is OH.
[0035] Preferably Y is CH.sub.2. Preferably D is CH.sub.2.
[0036] Preferably each R.sup.3 and R.sup.6 (where present)
respectively are independently selected from hydrogen, halogen,
lower aliphatic (especially lower alkyl), halo-lower alkyl,
carboxy, lower alkoxycarbonyl, hydroxy, etherified or esterified
hydroxy, lower alkoxy, optionally substituted alicyclic group or an
optionally substituted aromatic group, lower alkanoyloxy, lower
alkanoyl, amino, mono- or di-substituted amino, amidino, ureido,
mercapto, N-hydroxy-amidino, guanidino, amidino-lower alkyl, sulfo,
sulfamoyl, carbamoyl, cyano, cyano-lower alkyl, azo (N.dbd.N.dbd.N)
and nitro. Most preferably r is 0. However, where r is not 0,
preferably R.sup.8, or each R.sup.8 independently, is preferably
selected from OH, O-alkyl, SH, S-alkyl, halogen, CF.sub.3 and
C.sub.1-C.sub.4 alkyl.
[0037] In preferred embodiments of the invention the moiety of
formula (I).II
##STR00006##
is a tetrahydroquinoline moiety wherein preferably r=0. Preferably
n=1. Preferably R.sup.1 is OH so that the moiety is a hydroxy
tetrahydroquinoline, most especially
1,2,3,4-tetrahydroquinolin-5-ol (formula (I.III):
##STR00007##
[0038] Preferred compounds include compounds of the formulae (II),
(III) and (IV):
##STR00008##
preferably wherein X is NH, R.sup.2 is phenyl n is 1 and/or p is
1.
[0039] Other preferred compounds have the formula (V):
##STR00009##
preferably wherein A.sub.1 and A.sub.2 are N, and A.sub.3 and
A.sub.4 are C--R.sup.3.
[0040] Further preferred compounds have the formulae (VI), (VII)
and (VIII):
##STR00010##
preferably wherein n is 1.
[0041] Still further preferred compounds have the formula (IX)
##STR00011##
[0042] For compounds of formulae (VI) to (IX) preferably p is 1 and
X is NH.
[0043] Other preferred compounds include:
formula (X)
##STR00012##
wherein G represents R.sup.8, NHR.sup.8 or NR.sup.10 and preferably
wherein X is NH; formula (XI);
##STR00013##
and formula (XII)
##STR00014##
[0044] Preferably in the compound of formula (XII) T is
O--R.sup.9.
[0045] Preferably in compounds (XI) and (XII) X is NH.
[0046] A third aspect of the invention provides a process for the
preparation of a compound of the formula:
##STR00015##
which process comprises the following reaction scheme:
##STR00016##
where step 2 is optional and where carried out T' is a precursor of
T, and R.sup.1' is a precursor of R.sup.1 or is R.sup.1 and X,
R.sup.1, R.sup.2, T and P are as defined in claim 1.
[0047] Preferably X is NH.
[0048] Preferably R.sup.2 is phenyl.
[0049] Preferably p is 1.
[0050] Preferably R.sup.1' is OH.
[0051] In one preferred embodiment T represents SO.sub.2-G where G
represents R.sup.8, NHR.sup.8or NR.sup.10 and R.sup.8 and R.sup.10
are as defined in the first aspect of the invention.
[0052] In another preferred embodiment T represents O--R.sup.9
where R.sup.9 is as defined in the first aspect of the
invention.
[0053] Preferably in the latter embodiment X--R.sup.2-(T).sub.p
represents
##STR00017##
[0054] Another aspect of the present invention is a compound of
formula (I), wherein [0055] A.sub.1, A.sub.2, A.sub.3 and A.sub.4
are N or CR.sub.3, and where at least one of A.sub.1, A.sub.2 and
A.sub.4 is N; [0056] X is N--R.sub.5, O or S; [0057] R.sup.1 is OH,
--O-alkyl, --SH, --S-alkyl, halogen, substituted or unsubstituted
amines, --CF.sub.3 or --C--, --C.sub.4-alkyl; [0058] Y is O, S,
CR.sub.5 or NR.sup.5; [0059] D is O, S, CR.sub.5 or NR.sup.5;
[0060] R.sup.2 is an alkyl, alicycle, heterocycle, aliaromatic,
hetereoaromatic all of which may be substituted or unsubstituted;
[0061] T is H, --SO.sub.2--NH--R.sup.4 or --SO.sub.2--R.sup.4;
[0062] R.sup.4 is H, alkyl or aryl, which may be substituted or
unsubstituted; [0063] R.sup.5 is H or alkyl or C(O)--O--C-Ph;
[0064] n is 0-4; or a tautomer thereof, or a salt thereof.
[0065] Special preference is given to a compound of formula
(I),
wherein [0066] A.sub.1 and A.sub.2 are N; [0067] A.sub.3 and
A.sub.4 are CH; [0068] Y is CH.sub.2 or NR.sup.5 such as
--NH--C(O)--O--C-Ph; [0069] X is NH; [0070] D is CH.sub.2; [0071]
R.sup.1 is OH, Cl, Me or F; [0072] R.sup.2 is phenyl, imidazolyl,
pyrrolyl, oxazolyl or isoxazole, where phenyl may be unsubstituted
or substituted with 1, 2 or 3-OMe groups, Cl, CF.sub.3, --SMe, OH,
--O--[CH.sub.2].sub.2-pyridine, --O--[CH.sub.2].sub.3--Cl or
--O--[CH.sub.2].sub.3-morpholino; and [0073] R.sup.4 is H,
C.sub.2NMe, C.sub.2OH, -Npipeidinyl, Me, Me(t-butyl), C.sub.2COOH
or ethyl(isopropyl); [0074] R.sup.5 is H; [0075] n is 0 or 1; or a
tautomer thereof, or a salt thereof.
[0076] More generally, within the context of the present
disclosure, the general terms used herein to describe compounds of
formulae (I to XII) have the following meanings, unless indicated
otherwise.
[0077] Hydrocarbyl may be defined as having preferably up to 20
carbon atoms, especially up to 12 carbon atoms. Hydrocarbyl groups
may be linear or branched aliphatic, e.g. alkyl, alkenyl or
alkynyl; they may be alicyclic (i.e. aliphatic-cyclic), e.g.
cycloalkyl; they may be aromatic, e.g. phenyl. Hydrocarbyl groups
may contain a combination of two or more moieties selected from
aliphatic, alicyclic and aromatic moieties, e.g. a combination of
at least one alkyl group and an aromatic group. In some instances,
hydrocarbyl groups may be optionally interrupted by one or more
in-chain heteroatoms, for example --O--, thus forming, for example,
an ether linkage.
[0078] A mono- or di-substituted amino moiety may be defined where
the amino is optionally substituted by a hydrocarbyl moiety, the
hydrocarbyl moiety being, for example, selected from lower alkyl,
especially C.sub.1, C.sub.2, C.sub.3 or C.sub.4 alkyl, cycloalkyl,
especially cyclohexyl, alkyl-carboxy, carboxy, lower alkanoyl,
especially acetyl, a carbocyclic group, for example cyclohexyl or
phenyl, a heterocyclic group; where the hydrocarbyl moiety is
unsubstituted or substituted by, for example lower alkyl (C.sub.1,
C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6 or C.sub.7), halogen,
OH, lower alkoxy, NH.sub.2, SH, S-alkyl, SO-alkyl, SO.sub.2-alkyl,
NH-alkyl, N-dialkyl, carboxyl, CF.sub.3, wherein alkyl may be
optionally substituted branched, unbranched or cyclic C.sub.1-6,
interrupted 0-3 times by O, S, N.
[0079] As used herein, the term mercapto defines moieties of the
general structure --S--R.sub.e wherein R.sub.e is selected from H,
alkyl, a carbocylic group and a heterocyclic group as described
herein.
[0080] As used herein, the term guanidino defines moieties of the
general structure --NHR--C(NH)NH.sub.2 and derivatives thereof, in
particular, where hydrogen is replaced by alkyl, e.g. methyl or
ethyl.
[0081] As used herein, the term amidino defines moieties of the
general structure --C(NH)NH.sub.2 and derivatives thereof, in
particular, where hydrogen is replaced by alkyl, e.g. methyl or
ethyl.
[0082] Alkyl preferably has up to 20, more preferably up to 12
carbon atoms and is linear or branched one or more times; preferred
is lower alkyl, especially preferred is C.sub.1-C.sub.4-alkyl, in
particular methyl, ethyl or i-propyl or t-butyl. Where alkyl may be
substituted by one or more substituents. Unsubstituted alkyl,
preferably lower alkyl, is especially preferred.
[0083] Alkyl may be optionally interrupted by one or more in-chain
heteroatoms, for example --O--, thus forming, for example, an ether
linkage.
[0084] Substituted alkyl is alkyl as last defined, especially lower
alkyl, preferably methyl; where one or more, especially up to
three, substituents may be present, primarily from the group
selected from halogen, especially fluorine, amino, N-lower
alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino,
hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower
alkoxycarbonyl. Trifluoromethyl is especially preferred. One class
of compounds includes a substituted alkyl where the alkyl is
substituted with a heterocyclic ring, for example a pyrazine ring,
thus forming an alkylene-het group, i.e. --CH.sub.2-Het, the alkyl
group effectively acting as a linker between the heterocycle and a
second moiety.
[0085] The term "lower" when referring to substituents such as
alkyl, alkoxy, alkyl amine, alkylthio and the like denotes a
radical having up to and including a maximum of 7, especially from
1 up to and including a maximum of 4, carbon atoms, the radicals in
question being unbranched or branched one or more times.
[0086] The alkyl portion of lower alkyl, lower alkoxy, mono- or
di-lower alkyl amino, lower alkyl thio and other substituents with
an alkyl portion is especially C.sub.1-C.sub.4alkyl, for example
n-butyl, sec-butyl, tert-butyl, n-propyl, isopropyl, methyl or
ethyl. Such alkyl substituents are unsubstituted or substituted by
halogen, hydroxy, nitro, cyano, lower alkoxy, C.sub.3, C.sub.4,
C.sub.5, C.sub.6 or C.sub.7 cycloalkyl, amino, or mono- or di-lower
alkyl amino, unless otherwise indicated.
[0087] Halo-lower alkyl, halo-lower alkyloxy, halo-lower alkylthio
and the like refer to substituents having an alkyl portion wherein
the alkyl portion is mono- to completely substituted by halogen.
Halo-lower alkyl, halo-lower alkyloxy, halo-lower alkylthio and the
like are included within substituted lower alkyl, substituted lower
alkoxy, substituted lower alkylthio and the like.
[0088] Among the moieties corresponding to substituted alkyl,
hydroxy-lower alkyl, especially 2-hydroxyethyl, and/or halo-lower
alkyl, especially trifluoromethyl or 2,2,2-trifluoroethyl, are
especially preferred.
[0089] An alicyclic group is a carbocyclic group especially which
comprises 3, 4, 5, 6 or 7 in ring carbon atoms and is non aromatic,
but may be saturated or unsaturated. Preferred alicyclic groups
comprise cycloalkyl groups, which are preferably
C.sub.3-C.sub.10-cycloalkyl, especially, cyclopropyl,
dimethylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl, cycloalkyl being unsubstituted or substituted by one
or more, especially 1, 2 or 3, substituents.
[0090] An aromatic group is heterocyclic or carbocyclic and is
bound via a bond located at an aromatic ring carbon atom of the
radical (or optionally bound via a linking group, such as --O-- or
--CH.sub.2--). Preferably the aromatic group is carbocyclic and has
a ring system of not more than 16 carbon atoms and is preferably
mono- bi- or tri-cyclic and may be fully or partially substituted,
for example substituted by at least two substituents. Preferably,
the aromatic group is selected from phenyl, naphthyl, indenyl,
azulenyl and anthryl, and is preferably in each case unsubstituted
or substituted by lower alkyl, especially methyl, ethyl or
n-propyl, halo (especially fluoro, chloro, bromo or iodo),
halo-lower alkyl (especially trifluoromethyl), hydroxy, lower
alkoxy (especially methoxy), halo-lower alkoxy (especially
2,2,2-trifluoroethoxy), amino-lower alkoxy (especially
2-amino-ethoxy), lower alkyl (especially methyl or ethyl)
carbamoyl, N-(hydroxy-lower alkyl)-carbamoyl (especially
N-(2-hydroxyethyl)-carbamoyl) and/or sulfamoyl-substituted aryl,
especially a corresponding substituted or unsubstituted phenyl.
[0091] A substituted aromatic group is generally an aromatic group
that is substituted with from 1-5, preferably 1 or 2, substituents.
Appropriate substituents include, but are not limited to, amino,
mono- or di-lower alkyl substituted amino, wherein the lower alkyl
substituents may be unsubstituted or further substituted by those
substitutents listed above for alkyl groups, halogen, lower alkyl,
substituted lower alkyl, hydroxy, lower alkoxy, substituted lower
alkoxy, nitro, cyano, mercapto, lower alkylthio, halo-lower
alkylthio, heterocyclyl, heteroaryl, heterocyclylalkyl,
heteroarylalkyl, lower alkanoyl, carbamoyl, and N-mono- or
N,N-di-lower alkyl substituted carbamoyl, wherein the lower alkyl
substituents may be unsubstituted or further substituted.
[0092] A heterocycle is an aromatic ring or ring system having 16
or fewer members, preferably a ring of 5 to 7 members. Heterocycle
also includes a three to ten membered non-aromatic ring or ring
system and preferably a five- or six-membered non-aromatic ring,
which may be fully or partially saturated. In each case the rings
may have 1, 2 or 3 hetero atoms selected from the group consisting
of nitrogen, oxygen and sulfur. The heterocycle is unsubstituted or
substituted by one or more, especially from one to three, for
example one, identical or different substituents. Important
substituents on heterocycle are those selected from the group
consisting of halogen, for example, fluorine or chlorine; mono- or
di-lower alkyl-substituted amino wherein the alkyl groups are
unsubstituted or substituted by halogen, hydroxy, nitro, cyano,
lower alkoxy, C.sub.3-C.sub.7 cycloalkyl, a heterocyclic radical or
a heteroaryl radical; lower alkyl, such as methyl or ethyl;
halo-lower alkyl, such as trifluoromethyl; lower alkoxy, such as
methoxy or ethoxy; halo-lower alkoxy, for example,
trifluoromethoxy; lower alkylthio, such as methylmercapto,
halo-lower alkylthio, such as trifluoromethylthio, a heteroaryl
radical, heteroaryl-lower-alkylene, a heterocyclic radical or
heterocyclic-lower-alkylene.
[0093] Heterocycle especially is a radical selected from the group
consisting of oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl,
thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl,
thianthrenyl, isobenzofuranyl, benzofuranyl, chromenyl,
2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,
imidazolidinyl, berizimidazolyl, pyrazplyl, pyrazinyl,
pyrazolidinyl, pyranyol, thiazolyl, isothiazolyl, dithiazolyl,
oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl,
especially piperidin-1-yl, piperazinyl, especially piperazin-1-yl,
pyridazinyl, morpholinyl, especially morpholino, thiomorpholinyl,
especially thiomorpholino, indolizinyl, isoindolyl, 3H-indolyl,
indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl,
purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl,
octahydroisoquinolyl, benzofuranyl, dibenzofuranyl,
benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl,
quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl,
carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl,
phenoxazinyl, chromenyl, isochromanyl and chromanyl, each of these
radicals being unsubstituted or substituted by one to two radicals
selected from the group consisting of lower alkyl, especially
methyl or tert-butyl, lower alkoxy, especially methoxy, and halo,
especially bromo or chloro. Unsubstituted heterocyclyl, especially
piperidyl, piperazinyl, thiomorpholino or morpholino, is
preferred.
[0094] Halogen is especially fluorine, chlorine, bromine or iodine,
more especially, fluorine, chlorine or bromine, in particular
fluorine.
[0095] Cycloalkyl is preferably C.sub.3-C.sub.10-cycloalkyl,
especially cyclopropyl, dimethylcyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl being
unsubstituted or substituted by one or more, especially 1 to 3,
substituents.
[0096] Heterocyclylalkyl is as cycloalkyl but containing one or
more in-ring heteroatoms and may be exemplified by piperidyl,
piperazinyl, pyrollidine, morpholinyl.
[0097] Esterified carboxy is especially lower alkoxycarbonyl, such
as tert-butoxycarbonyl, iso-propoxycarbonyl, methoxycarbonyl or
ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or
phenyloxycarbonyl.
[0098] Alkanoyl is primarily alkylcarbonyl, especially lower
alkanoyl, e.g. acetyl. In particular, the alkanoyl group may be
substituted by substituents, e.g. CO--R
[0099] Any reference to compounds, salts and the like in the plural
is always to be understood as including one compound, one salt or
the like.
[0100] Throughout the description and claims of this specification,
the words "comprise" and "contain" and variations of the words, for
example "comprising" and "comprises", means "including but not
limited to"; and is not intended to (and does not) exclude other
moieties, additives, components, integers or steps.
[0101] Any asymmetric carbon atoms may be present in the (R)-, (S)-
or (R,S)-configuration, preferably in the (R)- or
(S)-configuration. Radicals having any unsaturation are present in
cis-, trans- or (cis, trans) form. The compounds may thus be
present as mixtures of isomers or as pure isomers, preferably as
enantiomer-pure diastereomers.
[0102] The invention relates also to possible tautomers of the
disclosed compounds.
[0103] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can
be separated into their corresponding isomers in a manner known per
se by, means of suitable separation methods. Diastereomeric
mixtures for example may be separated into their individual
diastereomers by means of fractionated crystallization,
chromatography, solvent distribution, and similar procedures. This
separation may take place either at the level of a starting
compound or in a compound of Formula I or formulae II to XII
respectively. Enantiomers may be separated through the formation of
diastereomeric salts, for example by salt formation with an
enantiomer-pure chiral acid, or by means of chromatography, for
example by HPLC, using chromatographic substrates with chiral
ligands.
[0104] Salts are especially the pharmaceutically acceptable acid
addition salts of compounds of formula (I). Such salts are formed,
for example, by compounds of formula (I) having a basic nitrogen
atom as acid addition salts, preferably with organic or inorganic
acids, especially the pharmaceutically acceptable salts. Suitable
inorganic acids are, for example, hydrohalic acids, such as
hydrochloric acid; sulfuric acid; or phosphoric acid. Suitable
organic acids are, for example, carboxylic, phosphonic, sulfonic or
sulfamic acids, for example acetic acid, propionic acid, octanoic
acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid,
2-hydroxybutyric acid, gluconic acid, glucosemonocarboxylic acid,
fumaric acid, succinic acid, adipic acid, pimelic acid, suberic
acid, azelaic acid, malic acid, tartaric acid, citric acid,
glucaric acid, galactaric acid, amino acids, such as glutamic acid,
aspartic acid, N-methylglycine, acetylaminoacetic acid,
N-acetylasparagine, N-acetylcysteine, pyruvic acid, acetoacetic
acid, phosphoserine, 2- or 3-glycerophosphoric acid, maleic acid,
hydroxymaleic acid, methylmaleic acid cyclohexanecarboxylic acid,
benzoic acid, salicylic acid, 1- or 3-hydroxynaphthyl-2-carboxylic
acid, 3,4,5-trimethoxybenzoic acid, 2-phenoxybenzoic acid,
2-acetoxybenzoic acid, 4-aminosalicylic acid, phthalic acid,
phenylacetic acid, glucuronic acid, galacturonic acid, methane- or
ethane-sulfonic acid, 2-hydroxyethanesulfonic acid,
ethane-1,2-disulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid,
N-cyclohexylsulfamic acid, N-methyl-, N-ethyl- or N-propyl-sulfamic
acid, or other organic protonic acids, such as ascorbic acid.
[0105] For isolation or purification it is also possible to use
pharmaceutically unacceptable salts, for example picrates or
perchlorates. Only the pharmaceutically acceptable salts or the
free compounds (optionally in the form of pharmaceutical
compositions) are used therapeutically, and those are therefore
preferred.
[0106] In view of the close relationship between the novel
compounds in free form and in the form of their salts, including
also those salts which can be used as intermediates, for example in
the purification of the novel compounds or for their
identification, hereinbefore and hereinafter any reference to the
free compounds is also to be understood as including the
corresponding salts, as appropriate and expedient.
[0107] The compounds of the present invention are found to inhibit,
regulate and/or modulate tyrosine and serine/threonine kinase and
kinase-like proteins involved in signal transduction, and
compositions containing the compounds are used in the treatment of
tyrosine and serine/threonine kinase and kinase-like-dependent
diseases, such as angiogenesis, cancer, tumour growth,
atherosclerosis, age related macular degeneration, diabetic
retinopathy, inflammatory diseases, neurofraumatic diseases,
chronic neurodegeneration, pain, migraine or cardiac hypertrophy,
and the like in mammals.
[0108] Specifically, the compounds of the present invention inhibit
IKK, PDGF-R, Kdr, c-Src, Her-1, Her-2', c-Kit, c-Abl, Ins-r, Tek,
Flt-1, Flt-3, Flt-4, c-Abi and FGFR-1, Eph receptors (e.g. EphB4),
CDK1, CDK2 and RET at >70% inhibition at 10 micromole. More
specifically, the compounds inhibit the RAF family of kinases
including mutations with IC50 values in the range of 1-1000 nM.
[0109] Typically, the patient is a mammal, generally a human,
suffering from a disease that is characterized by excessive
signaling through the MAP kinase pathway. This can be measured by
activation state specific antibodies to pathway members by methods
such as Western blot analysis or immunohistochemistry. Such methods
are known to those of skill in the art.
[0110] In general, the disease characterized by excessive signaling
through the MAP kinase signaling pathway is a proliferative
disease, particularly a cancer characterized by increased RAF
kinase activity, for example one which overexpresses wild-type B-
or C-RAF kinase, or that expresses an activating mutant RAF kinase,
for example a mutant B-RAF kinase. Cancers wherein a mutated RAF
kinase has been detected include melanoma, colorectal cancer,
ovarian cancer, gliomas, adenocarcinomas, sarcomas, breast cancer
and liver cancer. Mutated B-RAF kinase is especially prevalent in
many melanomas.
[0111] In accordance with the present invention, a sample of
diseased tissue may taken from the patient, for example, as a
result of a biopsy or resection, and tested to determine whether
the tissue produces a mutant RAF kinase, such as a mutant B-RAF
kinase or overexpresses a wild-type RAF kinase, such as wild-type
B- or C-RAF kinase. If the test indicates that mutant RAF kinase is
produced or that a RAF kinase is overproduced in the diseased
tissue, the patient is treated by administration of an effective
RAF-inhibiting amount of a RAF inhibitor compound described
herein.
[0112] However, it is also possible to downregulate the MAP kinase
signaling pathway with a RAF kinase inhibiting compound If another
kinase in the cascade is the cause of excessive signaling in the
pathway. Thus, the present invention further relates to the
treatment of a disease characterized by excessive signaling in the
MAP kinase signaling pathway attributed to a cause other than an
activating mutation in or overexpression of a RAF kinase.
[0113] Tissue samples are tested by methods generally known in the
art. For example, B-RAF mutations are detected by allele specific
PCR, DHPLC, mass spectropscopy and overexpression of wild-type B-
or C-RAF detected by immunohistochemistry, immunofluorescence, or
Western blot analysis. A particularly useful method of detecting
B-RAF mutations is a polymerase chain reaction based method.
Similar methods are used to determine whether other kinases in the
cascade are mutant or overexpressed.
[0114] A particularly important aspect of this invention relates to
a method of treating melanoma, which comprises (a) testing melanoma
tissue from a patient to determine whether the melanoma tissue
expresses mutant RAF kinase or overexpresses a wild-type RAF kinase
and (b) treating the patient with an effective RAF kinase
inhibiting amount of a RAF-inhibiting compound described herein if
the melanoma tissue is found to overexpress a wild type RAF kinase
or express an activating mutant B-RAF kinase.
[0115] An important aspect of this embodiment relates to a method
of treating melanoma, which comprises (a) testing melanoma tissue
from a patient to determine whether the melanoma tissue
overexpresses B-RAF kinase or C-RAF kinase activity and (b)
treating the patient with an effective RAF kinase inhibiting amount
of a RAF inhibiting compound described herein if the melanoma
tissue is found to overexpress the B-RAF kinase or C-RAF kinase
activity.
[0116] Another important aspect of this embodiment relates to a
method of treating melanoma, which comprises (a) testing melanoma
tissue from a patient to determine whether the melanoma tissue
expresses mutant B-RAF kinase and (b) treating the patient with an
effective RAF kinase inhibiting amount of a RAF inhibiting compound
described herein if the melanoma tissue is found to express mutant
B-RAF kinase.
[0117] Generally, the B-RAF kinase mutation is one of those
described in the Davies et al article cited. These mutations are
summarized in Table 1.
[0118] Thus, the present invention particularly relates to a method
of treating a disease characterized by an activated mutant B-RAF
kinase, which comprises detecting a mutation in the B-RAF kinase
gene or protein in a tissue sample from a patient and treating the
patient with an effective B-RAF kinase inhibiting compound,
especially a compound described herein.
[0119] Hence, the present invention additionally relates to a
compound (for example of formulae I to XII) for use in the
treatment of melanoma. More particularly, the invention relates to
a compound for use in the treatment of a disease characterized by
an activated mutant B-RAF kinase.
TABLE-US-00001 TABLE 1 B-RAF mutation protein change G1388A G463E
G1388T G463V G1394C G465A G1394A G465E G1394T G465V G1403C G468A
G1403A G468E G1753A E585K T1782G F594L G1783C G595R C1786G L596V
T1787G L596R T1796A V599E TG1796-97AT V599D
[0120] Further, the invention provides for the use of a compound
(for example of formulae I to XII) in the manufacture of a
medicament for use in the treatment of melanoma. More specifically,
the invention provides for the use of a compound in the manufacture
of a medicament for use in the treatment of a disease characterized
by an activated mutant B-RAF kinase.
[0121] An important aspect of this invention includes those
instances wherein the mutant B-RAF kinase exhibits a mutation
described in Table 1, especially the V599E mutation.
[0122] A particularly important aspect of this invention includes
those instances wherein disease is melanoma and the mutant B-RAF
kinase exhibits a mutation described in Table 1, especially the
V599E mutation.
[0123] Accordingly, this invention includes a method of treating a
disease characterized by mutant B-RAF kinase, which comprises
detecting a mutation in the B-RAF kinase gene selected from G1388A,
G1388T, G1394C, G1394A, G1394T, G1403C, G1403A, G1753A, T1782G,
G1783C, C1786G, T1787G, T1796A and TG1796-97AT, or corresponding
mutation in the RAF kinase protein, in a tissue sample from a
patient and treating the patient with an effective B-RAF kinase
inhibiting compound described herein.
[0124] The present invention further relates to a method of
inhibiting RAF kinase, which comprises contacting the RAF kinase
with a compound of formula (I), or more specifically with any one
of the compounds of formulae (II) to (XII). Preferably, the RAF
kinase is B- or C-RAF kinase, or a mutant RAF kinase, especially a
mutant B-RAF kinase, particularly the V599E mutant. The RAF kinase
may be isolated or in a cellular environment.
[0125] The compounds of formula (I), and more specifically the
compounds of formulae (II) to (XII) have valuable pharmacological
properties, as described above.
[0126] The compounds of the present invention may be administered
alone or in combination with other anticancer agents, such as
compounds that inhibit tumor angiogenesis, for example, the
protease inhibitors, epidermal growth factor receptor kinase
inhibitors, vascular endothelial growth factor receptor kinase
inhibitors and the like; cytotoxic drugs, such as antimetabolites,
like purine and pyrimidine analog antimetabolites; antimitotic
agents like microtubule stabilizing drugs and antimitotic
alkaloids; platinum coordination complexes; anti-tumor antibiotics;
alkylating agents, such as nitrogen mustards and nitrosoureas;
endocrine agents, such as adrenocorticosteroids, androgens,
anti-androgens, estrogens, anti-estrogens, aromatase inhibitors,
gonadotropin-releasing hormone agonists and somatostatin analogues
and compounds that target an enzyme or receptor that is
overexpressed and/or otherwise involved a specific metabolic
pathway that is upregulated in the tumor cell, for example ATP and
GTP phosphodiesterase inhibitors, protein kinase inhibitors, such
as serine, threonine and tyrosine kinase inhibitors, for example,
Abelson protein tryosine kinase and the various growth factors,
their receptors and kinase inhibitors therefore, such as, epidermal
growth factor receptor kinase inhibitors, vascular endothelial
growth factor receptor kinase inhibitors, fibroblast growth factor
inhibitors, insulin-like growth factor receptor inhibitors and
platelet-derived growth factor receptor kinase inhibitors and the
like; methionine aminopeptidase inhibitors, proteasome inhibitors,
cyclooxygenase inhibitors, for example, cyclooxygenase-1 or -2
inhibitors, and histone deacetylase inhibitors.
[0127] The compound of the present invention may also be
administered together with radiotherapy, immunotherapy, surgical
treatment or combinations thereof. Treatment to maintain the status
of a patient after tumor remission or even chemopreventive
treatment, for example in the case of at-risk patients, is also
possible.
[0128] Compounds according to the invention are intended not only
for the (prophylactic and, preferably, therapeutic) treatment of
human beings, but also for the treatment of other warm-blooded
animals, for example of commercially useful animals, for example
rodents, such as mice, rabbits or rats, or guinea pigs.
[0129] In general, the invention relates also to the use of a
compound of formula (I), and more specifically to the use of
compounds of formulae (II) to (XII), in inhibiting RAF kinase
activity.
[0130] The compounds of the present invention are preferably
administered as an active ingredient in a pharmaceutical
composition. Preference is given to a pharmaceutical composition
which is suitable for administration to a warm-blooded animal,
especially a human being or a commercially useful mammal, which is
suffering from a disease characterized by an aberrant MAP kinase
signaling pathway especially, a tumor disease, most particularly
melanoma, comprising a compound of formula (I), or a pharmaceutical
acceptable salt thereof where salt-forming groups are present, in
an amount that is effective in inhibiting RAF kinase, particularly
a mutant RAF kinase, together with at least one pharmaceutically
acceptable carrier.
[0131] Preference is given also to a pharmaceutical composition for
the prophylactic or, especially, therapeutic treatment of tumor
diseases and other proliferative diseases in a warm-blooded animal,
especially a human being or a commercially useful mammal, which
requires such treatment, especially which is suffering from such a
disease, comprising a novel compound of formula (I), or a
pharmaceutically acceptable salt thereof, as active ingredient in
an amount that is effective prophylactically or, especially,
therapeutically against the mentioned diseases.
[0132] Pharmaceutical compositions comprise from approximately 1%
to approximately 95% active ingredient, dosage forms that are in
single dose form preferably comprising from approximately 20% to
approximately 90% active ingredient, and dosage forms that are not
in single dose, form preferably comprising from approximately 5% to
approximately 20% active ingredient. Unit dose forms are, for
example, dragees, tablets, ampoules, vials, suppositories or
capsules. Other dosage forms are, for example, ointments, creams,
pastes, foams, tinctures, lipsticks, drops, sprays, dispersions,
etc. Examples are capsules comprising from approximately 0.05 g to
approximately 1.0 g of the active ingredient.
[0133] The pharmaceutical compositions of the present invention are
prepared in a manner employing steps which may individually be
known per se, for example by means of conventional mixing,
granulating, confectioning, dissolving or lyophilising
processes.
[0134] Solutions of the active ingredient are preferably used, in
addition also suspensions or dispersions, especially isotonic
aqueous solutions, dispersions or suspensions, which, in the case
of, for example, lyophilised compositions which contain the active
substance alone or together with a carrier, for example mannitol,
can be prepared prior to use. The pharmaceutical compositions may
be sterilised and/or comprise excipients, for example
preservatives, stabilisers, wetting agents and/or emulsifiers,
solubilisers, salts for regulating the osmotic pressure and/or
buffers, and are prepared in a manner known per se, for example by
means of conventional dissolving or lyophilising processes. The
mentioned solutions or suspensions may comprise
viscosity-increasing substances, such as sodium
carboxymethylcellulose, carboxymethylcellulose, dextran,
polyvinylpyrrolidone or gelatin, or solubilisers, for example Tween
80[polyoxyethylene(20)sorbitan monooleate; trade mark of ICI
Americas, Inc, USA].
[0135] Suspensions in oil comprise as the oily component the
vegetable, synthetic or semi-synthetic oils customary for injection
purposes. There may be mentioned as such especially liquid fatty
acid esters, which comprise as the acid component a long-chained
fatty acid having from 8 to 22, especially from 12 to 22, carbon
atoms, for example lauric acid, tridecylic acid, myristic acid,
pentadecylic acid, palmitic acid, margaric acid, stearic acid,
arachidic acid, behenic acid or corresponding unsaturated acids,
for example oleic acid, elaidic acid, erucic acid, brassidic acid
or linoleic acid, optionally with the addition of antioxidants, for
example vitamin E, .beta.-carotene or
3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of those
fatty acid esters has a maximum of 6 carbon atoms and is a mono- or
poly-hydric, for example mono-, di- or tri-hydric, alcohol, for
example methanol, ethanol, propanol, butanol or pentanol or their
isomers, but especially glycol and glycerol. Examples of fatty acid
esters which may be mentioned are, therefore: ethyl oleate,
isopropyl myristate, isopropyl palmitate, "Labrafil M 2375"
(polyoxyethyleneglycerol trioleate from Gattefosse, Paris),
"Labrafil M 1944 CS" (unsaturated polyglycolised glycerides
prepared by alcoholysis of apricot kernel oil and composed of
glycerides and polyethylene glycol ester; Gattefosse, France),
"Labrasol" (saturated polyglycolised glycerides prepared by
alcoholysis of TCM and composed of glycerides and polyethylene
glycol ester; Gattefosse, France) and/or "Miglyol 812"
(triglyceride of saturated fatty acids having a chain length of
from C.sub.8 to C.sub.12 from Hulls AG, Germany), but especially
vegetable oils, such as cottonseed oil, almond oil, olive oil,
castor oil, sesame oil, soybean oil and, more especially, groundnut
oil.
[0136] The preparation of the injection compositions is carried out
in customary manner under sterile conditions, as are also the
introduction thereof, for example, into ampoules or vials and the
sealing of the containers.
[0137] Pharmaceutical compositions for oral administration can be
obtained, for example, by combining the active ingredient with one
or more solid carriers, granulating a resulting mixture, where
appropriate, and processing the mixture or granules, if desired,
where appropriate by addition of additional excipients, to tablets
or dragee cores.
[0138] Suitable carriers are especially fillers, such as sugars,
for example lactose, saccharose, mannitol or sorbitol, cellulose
preparations and/or calcium phosphates, for example tricalcium
phosphate or calcium hydrogen phosphate, also binders, such as
starches, for example corn, wheat, rice or potato starch,
methylcellulose, hydroxypropylmethylcellulose, sodium,
carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if
desired, disintegrators, such as the above-mentioned starches, also
carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic
acid or a salt thereof, such as sodium alginate. Additional
excipients are especially flow conditioners and lubricants, for
example silicic acid, talc, stearic acid or salts thereof, such as
magnesium or calcium stearate, and/or polyethylene glycol, or
derivatives thereof.
[0139] Dragee cores can be provided with suitable, optionally
enteric, coatings, there being used inter alia concentrated sugar
solutions which may contain gum arabic, talc, polyvinylpyrrolidone,
polyethylene glycol and/or titanium dioxide, or coating solutions
in suitable organic solvents or solvent mixtures or, for the
preparation of enteric coatings, solutions of suitable cellulose
preparations, such as acetylcellulose phthalate or
hydroxypropylmethylcellulose phthalate. Colourings or pigments may
be added to the tablets or dragee coatings, for example for
identification purposes or to indicate different doses of active
ingredient.
[0140] Pharmaceutical compositions for oral administration are also
hard gelatin capsules and soft sealed capsules consisting of
gelatin and a plasticiser, such as glycerol or sorbitol. The hard
gelatin capsules may contain the active ingredient in the form of
granules, for example in admixture with fillers, such as corn
starch, binders and/or glidants, such as talc or magnesium
stearate, and optionally stabilisers. In soft capsules the active
ingredient is preferably dissolved or suspended in suitable liquid
excipients, such as fatty oils, paraffin oil or liquid polyethylene
glycols or fatty acid esters of ethylene glycol or propylene
glycol, it likewise being possible to add stabilisers and
detergents, for example of the polyoxyethylenesorbitan fatty acid
ester type.
[0141] Suitable rectally administrable pharmaceutical compositions
are, for example, suppositories that consist of a combination of
the active ingredient with a suppository base. Suitable suppository
bases are, for example, natural or synthetic triglycerides,
paraffin hydrocarbons, polyethylene glycols or higher alkanols.
[0142] For parenteral administration there are suitable,
especially, aqueous solutions of an active ingredient in
water-soluble form, for example in the form of a water-soluble
salt, or aqueous injection suspensions that comprise
viscosity-increasing substances, for example sodium
carboxymethylcellulose, sorbitol and/or dextran and, if desired,
stabilisers. The active ingredient, optionally together with
excipients, can also be in the form of a lyophilisate and can be
made into a solution prior to parenteral administration by the
addition of suitable solvents.
[0143] Solutions used, for example, for parenteral administration
can also be used as infusion solutions.
[0144] Preferred preservatives are, for example, antioxidants, such
as ascorbic acid, or microbicides, such sorbic acid or benzoic
acid.
[0145] The invention relates especially to a process or a method
for treating one of the pathological conditions that is
characterized by an aberrant MAP kinase signaling pathway,
especially a disease responsive to inhibition of RAF kinase,
especially a corresponding tumor disease. The compounds of formula
(I) can be administered prophylactically or therapeutically as such
or in the form of pharmaceutical compositions, preferably in an
amount that is effective against the mentioned diseases, to a
warm-blooded animal, for example a human being, requiring such
treatment, the compounds being used especially in the form of
pharmaceutical compositions. In the case of a body weight of
approximately 70 kg, a daily dose of from approximately 0.1 g to
approximately 5 g, preferably from approximately 0.5 g to
approximately 2 g, of a compound of the present invention is
administered.
[0146] The preferred dosage, composition and preparation of
pharmaceutical formulations (medicaments) to be used in each
particular case are described above.
[0147] The compounds of the present invention are prepared
utilizing methods preferably according to the exemplary reaction
schemes described below, individual steps of the said methods being
known in general terms to those skilled in the art.
[0148] A general scheme showing a process of the present invention
is as described above. A more specific variation of the above
scheme is given below (Scheme G):
##STR00018##
[0149] An example of an R group is one containing sulphur, as
illustrated below in Schemes 1 and 2:
##STR00019##
[0150] A particular example of a reaction of Scheme 1 is shown
below:
##STR00020##
[0151] A third reaction scheme according to the present invention
is shown below:
##STR00021##
[0152] A particular example of reaction Scheme 3 is shown below in
Scheme 4.
##STR00022##
EXAMPLES
[0153] The preparative method will now be illustrated by reference
to the specific preparations of
1-{2-[3-(3-Chloro-propoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydr-
o-quinolin-5-ol and various 1-{2-[3-(sulphonyl, sulphanyl and
sulphonamino)-phehylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-quinolin-5--
ol derivatives.
[0154] Results of melting point tests and mass spectrometric
evaluations are also presented.
1-{2-[3-(3-Chloro-propoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-
-quinolin-5-ol
Intermediate Synthesis
[3-(3-Chloro-propoxy)-phenyl]-(4-chloro-pyrimidin-2-yl)-amine
##STR00023##
[0156] Heating 22.98 g (161.64 mmol)
2-methylsulfanyl-pyrimidin-4-ol in 90 mL DMEU to 100.degree. C.
results in a clear solution. Now, 30 g (161.64 mmol)
3-(3-chloro-propoxy)-phenylamine are added. Heating at 100.degree.
C. is continued for 15 h; A 10 mL fraction of this reaction mixture
is poured onto aqueous sodium bicarbonate and extracted with ethyl
acetate. After evaporation of the solvent the brown oil is
dissolved in 10 mL DMEU and 35 mL POCl.sub.3 are added. After
heating the reaction mixture at 70.degree. C. for 2 h it is
carefully poured onto an aqueous bicarbonate solution. Extraction
with ethyl acetate followed by flash chromatography on silica
(eluent: hexanes ethyl acetate 1:1) affords 1.60 g (yield ca. 50%)
of the title compound as brown oil.
[0157] .sup.1H NMR: (DMSO d.sub.6, 400 MHz): 10.03 (s, 1H), 8.45
(d, 1H), 7.44 (t, 1H), 7.29 (dd, 1H), 7.21 (t, 1H), 6.97 (d, 1H),
6.61 (dd, 1H), 4.07 (t, 2H), 3.80 (t, 2H), 2.18 (quint, 2H).
1-{2-[3-(3-Chloro-propoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-
-quinolin-5-ol
##STR00024##
[0159] A mixture of 200 mg (0.617 mmol)
[3-(3-chloro-propoxy)-phenyl]-(4-chloro-pyrimidin-2-yl)-amine and
100 mg (0.617 mmol) 3-(3-chloro-propoxy)-phenylamine is heated neat
at 100.degree. C. for 20 minutes. With the help of sonication the
resulting resin is dissolved in a mixture of ethyl acetate and
aqueous sodium bicarbonate. The organic layer is dried over sodium
sulfate and evaporated. Chromatography on silica using
dichloromethane/ethyl acetate (10:1) as eluent afforded 160 mg
(yield 58%) of the title compound as yellow foam.
[0160] .sup.1H NMR (DMSO d.sub.6, 400 MHz): 9.43 (s, 1H), 9.13 (s,
br, 1H), 7.91 (d, 1H), 7.47 (m, 1H), 7.17 (d, 1H), 7.04 (t, 1H),
6.90 (t, 1H), 6.72 (d, 1H), 6.51 (d, 1H), 6.42-6.38 (m, 2H), 3.96
(t, 2H), 3.88 (dd, 2H), 3.71 (t, 2H), 2.53 (t, 2H), 2.09 (quint,
2H), 1.78 (m, 2H).
[0161] MS: ES+: 411 (M+1).sup.+ isotop pattern for 1 chlorine
atom.
1-{2-[3-(sulphonyl, sulphanyl and
sulphonamino)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydro-quinolin-5--
ol derivatives
Intermediate Synthesis
##STR00025##
[0162] (4-Chloro-pyrimidine-2-yl)-phenyl-amine
[0163] 2-Phenylamino-pyrimidine-4-ol (1.309 g, 7 mmol) is suspended
in 35 mL of acetonitrile and treated with 3.5 mL (14 mmol) of a 4 m
solution of hydrochloric acid in dioxane (Aldrich) and 1.6 mL (17.5
mmol) phosphorous oxychloride under nitrogen and at room
temperature. The mixture is heated under reflux for 3 hours, cooled
and diluted with ethyl acetate. The resulting solution is washed
with saturated sodium bicarbonate solution and brine, dried over
sodium sulfate and evaporated. The residue is purified by flash
chromatography on silica gel using ethyl acetate/hexane 2:8. The
title compound is obtained in 86% yield (1.5 g): m.p.
134-135.degree. C.; MS (ES+) m/z (M+H).sup.+1 206.
4-(4-Chloro-pyrimidine-2-ylamino)-benzenesulfonyl chloride
[0164] 3.2 mL (48 mmol) Chlorosulfonic acid are cooled to 0.degree.
C. under nitrogen. To this is added
(4-chloro-pyrimidine-2-yl)-phenyl-amine (1.15 g, 5.6 mmol) in small
portions under stirring. After complete addition, the mixture is
stirred 15 minutes at 0.degree. C., 2 hours at room temperature and
15 minutes at 60.degree. C. The yellow solution is cooled and added
slowly onto 100 g of crashed ice. After the ice has completely
melted the solid is filtered off, washed with water and dried under
vacuum. The title compound is obtained in 74% yield (1.26 g): m.p.
192-195.degree. C.; MS (ES+) m/z (M+H).sup.+1 300 (mass of the
corresponding methyl sulfonate since the MS solution was made up in
methanol).
##STR00026##
N-Cyclohexyl-4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidine-2-y-
lamino]-benzenesulfonamide
[0165] A mixture of 560 mg (1.5 mmol)
4-(4-chloro-pyrimidine-2-ylamino)-N-cyclohexyl-benzenesulfonamide
and 225 mg (1.52 mmol) 1,2,3,4-tetrahydro-quinoline-5-ol is heated
without solvent in an oil bath for 15 minutes at 200.degree. C. The
brown viscous mixture is cooled first to room temperature, then
with dry ice, and the solidified material is pulverized. This solid
is stirred with 5% citric acid solution, filtered, re-suspended in
saturated sodium bicarbonate solution, filtered again and finally
washed with water. This material is subjected to a flash
chromatography on silica gel using ethyl acetate/hexane 8:2. Pure
fractions are pooled and evaporated, stirred a few minutes in
methanol, filtered, re-suspended in a mixture of toluene and
diispropyl ether, filtered again and dried under vacuum. The title
compound is obtained in 20% yield (150 mg): m.p. 236-238.degree.
C.; MS (ES+) m/z (M+H).sup.+1 480.
Starting material
4-(4-chloro-pyrimidine-2-ylamino)-N-cyclohexyl-benzenesulfonamide
[0166] 600 mg (2 mmol)
4-(4-Chloro-pyrimidine-2-ylamino)-benzenesulfonyl chloride are
suspended in 60 mL of dichloromethane and treated at room
temperature with 0.57 mL (5 mmol) cyclohexylamine. All the material
goes slowly into solution and after stirring for about 15 minutes
fine needles start to appear. The stirring is continued for a total
of 2 hours then the mixture is diluted with dichloromethane and
washed with 5% citric acid and brine. The organic phase is dried
(Na.sub.2SO.sub.4) and evaporated. The title compound is obtained
in 99% yield (706 mg): m.p. 202-204.degree. C.; MS (ES+) m/z
(M+H).sup.+1 367.
[0167] The following examples are synthesized using an analogous
sequence as described for
N-cyclohexyl-4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidine-2-y-
lamino]-benzenesulfonamide:
TABLE-US-00002 MS (ES+) m/z Comp. name m.p. in .degree. C. (M +
H).sup.+1
4-[4-(5-Hydroxy-3,4-dihydro-2H-quinoline-1-yl)-pyrimidin-2- 124-126
468 ylamino]-N-(3-methyl-butyl)-benzenesulfonamide
N-(2-Dimethylamino-ethyl)-4-[4-(5-hydroxy-3,4-dihydro-2H- 175-177
469 quinoline-1-yl)-pyrimidin-2-ylamino]-benzenesulfonamide
3-{4-[4-(5-Hydroxy-3,4-dihydro-2H-quinoline-1-yl)-pyrimidin-
217-219 470 2-ylamino]-benzenesulfonylamino}-propionic acid
4-[4-(5-Hydroxy-3,4-dihydro-2H-quinoline-1-yl)-pyrimidin-2- 242-245
442 ylamino]-N-(2-hydroxy-ethyl)-benzenesulfonamide ##STR00027##
##STR00028## ##STR00029## ##STR00030##
(3-Chlorophenyl)-[4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine
hydrochloride
##STR00031##
[0168] 2-(3-Chloro-phenylamino)-pyrimidine-4-ol
[0169] 2-Methylsulfanyl-pyrimidine-4-ol (568 mg, 4 mmol) and
3-chloronaniline (0.47 mL, 4 mL) are mixed and heated for 30
minutes to 170.degree. C. The resulting solution is cooled and
triturated with 0.1 m hydrochloric acid, filtered, washed with
water and dried under vacuum. The title compound is obtained in 59%
yield (520 mg): m.p. 250-252.degree. C.; MS (ES+) m/z (M+H).sup.+1
222.
(3-Chloro-phenyl)-(4-chloro-pyrimidine-2-yl)-amine
[0170] 2-(3-Chloro-phenylamino)-pyrimidine-4-ol (444 mg, 2 mmol) is
added in portions to 6 mL phosphorous oxychloride at room
temperature. The mixture is heated to 70.degree. C. for 1 hour,
cooled and the excess phosphorous oxychloride evaporated under
reduced pressure. The residue is dissolved in ethyl acetate washed
with saturated sodium carbonate solution and brine, dried over
sodium sulfate and evaporated. The title compound is obtained in
91% yield (440 mg): m.p. 112-114.degree. C.; MS (ES+) m/z
(M+H).sup.+1 240,242.
(3-Chloro-phenyl)-[4-(3,4-dihydro-2H-quinoline-1-yl)-pyrimidin-2-yl]-amine
hydrochloride
[0171] (3-Chloro-phenyl)-(4-chloro-pyrimidine-2-yl)-amine (360 mg,
1.5 mmol) in 1 mL of dioxane is treated with 223 mg (1.5 mmol)
1,2,3,4-tetrahydro-quinoline-5-ol. The mixture is heated 2 hours at
80.degree. C. and then 18 hours at 100.degree. C. The solvent was
evaporated and the residue suspended in ethyl acetate/hexane 1:1
stirred for a few minutes and filtered. The title compound is
obtained in 29% yield (150 mg): m.p. 250-252.degree. C.; MS (ES+)
m/z (M+H).sup.+1 353.
[0172] The following examples are synthesized using an analogous
sequence as described for
(3-Chlorophenyl)-[4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-amine
hydrochloride. The compounds in the table are isolated as the free
bases.
TABLE-US-00003 MS (ES+) m/z Compound name m.p. .degree. C. (M +
H).sup.+1 1-{2-[4-(Piperidine-1-sulfonyl)-phenylamino]-pyrimidin-4-
126-128 466 yl}-1,2,3,4-tetrahydro-quinolin-5-ol
4-[4-(5-Hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin- 155-158
398 2-ylamino]-benzenesulfonamide
1-[2-(4-Methylsulfanyl-phenylamino)-pyrimidin-4-yl]- 190-192 365
1,2,3,4-tetrahydro-quinoline-5-ol ##STR00032## ##STR00033##
##STR00034##
1-[2-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inolin-5-ol (oxidation product of
1-[2-(4-methylsulfanyl-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inoline-5-ol)
##STR00035##
[0174]
1-[2-(4-Methylsulfanyl-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahy-
dro-quinoline-5-ol (364 mg, 1 mmol) is suspended in 10 mL of
dichloromethane at 0.degree. C. m-chloroperbenzoic acid (FLUKA
25800, 590 mg, 2.4 mmol) is added and the mixture stirred at
0.degree. C. for 45 minutes. 100 mg of Na.sub.2SO.sub.3 are added
and the reaction mixture is then partitioned between
dichloromethane and water. The organic layer is separated and
washed with saturated sodium bicarbonate, water and brine, dried
over sodium sulfate and evaporated. The crude material is purified
first by flash chromatography on silica gel using ethyl acetate and
then by MPLC on a reverse phase column using an acetonitrile/water
gradient containing 0.5% TFA. The title compound is obtained in 6%
yield (25 mg): m.p. 242-245.degree. C.; MS (ES+) m/z (M+H).sup.+1
353.
[0175] Additional compounds within the scope of the present
invention include the following: [0176]
1-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inolin-5-ol [0177]
4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-benzen-
esulfonamide [0178]
1-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inolin-6-ol [0179]
1-[2-(3,5-dimethoxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-quino-
lin-5-ol [0180]
1-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inolin-7-ol [0181]
4-[4-(6-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-N-(2-h-
ydroxy-ethyl)-benzenesulfonamide [0182]
{4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-benze-
nesulfonylamino}-acetic acid [0183]
1-[2-(3,5-dimethoxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-quino-
lin-6-ol [0184]
4-[4-(6-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-benzen-
esulfonamide [0185]
4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-N-(2-h-
ydroxy-ethyl)-3-methyl-benzenesulfonamide [0186]
1-[2-(3-chloro-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-quinolin-5-
-ol [0187]
[4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(3,4,5-trimet-
hoxy-phenyl)-amine [0188]
1-[2-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-q-
uinolin-7-ol [0189]
1-[2-(4-methylsulfanyl-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inolin-5-ol [0190]
1-(2-phenylamino-pyrimidin-4-yl)-1,2,3,4-tetrahydro-quinolin-5-ol
[0191]
1-[2-(3-hydroxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-quinolin--
5-ol [0192]
4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-3-meth-
yl-N-(3-methyl-butyl)-benzenesulfonamide [0193]
4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-N-pyri-
din-4-ylmethyl-benzenesulfonamide [0194]
1-{2-[3-(2-imidazol-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tet-
rahydro-quinolin-5-ol [0195]
1-{2-[3-(3-chloro-propoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydr-
o-quinolin-6-ol [0196]
4-[4-(5-chloro-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-benzene-
sulfonamide [0197]
1-{2-[3-(3-morpholin-4-yl-propoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-t-
etrahydro-quinolin-5-ol [0198]
4-[4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-benzenesulfonami-
de [0199]
4-[4-(6-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamin-
o]-N-(3-methyl-butyl)-benzenesulfonamide [0200]
[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(3,4,5-trimeth-
oxy-phenyl)-amine [0201]
1-{2-[3-(3-chloro-propoxy)-phenylamino]-pyrimidin-4-yl}-1,2,3,4-tetrahydr-
o-quinolin-7-ol [0202]
[4-(7-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(3,4,5-trimeth-
oxy-phenyl)-amine [0203]
4-[4-(6-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-benzene-
sulfonamide [0204]
[4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-yl]-(2,3-dimethoxy-benzyl)--
amine [0205]
4-[4-(5-hydroxy-3,4-dihydro-2H-quinolin-1-yl)-6-methyl-pyrimidin-2-ylamin-
o]-benzenesulfonamide, [0206]
3-[4-(3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino]-phenol
[0207]
4-[4-(6-fluoro-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-pyrimidin-2-ylamino-
]-N-(3-methyl-butyl)-benzenesulfonamide [0208]
1-[2-(3,4,5-trimethoxy-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-qu-
inolin-8-ol [0209]
[1-(2-phenylamino-pyrimidin-4-yl)-1,2,3,4-tetrahydro-quinolin-3-yl]-carba-
mic acid benzyl ester [0210]
1-[2-(4-trifluoromethyl-phenylamino)-pyrimidin-4-yl]-1,2,3,4-tetrahydro-q-
uinolin-5-ol
Dry-Filled Capsules
[0211] 5000 capsules, each comprising as active ingredient 0.25 g
of one of the compounds of formula I mentioned above, are prepared
as follows:
TABLE-US-00004 Composition active ingredient 1250 g talcum 180 g
wheat starch 120 g magnesium stearate 80 g lactose 20 g
Preparation Process
[0212] The mentioned substances are pulverized and forced through a
sieve of 0.6 mm mesh size. 0.33 g portions of the mixture are
introduced into gelatin capsules using a capsule-filling
machine.
[0213] Soft Capsules
[0214] 5000 soft gelatin capsules, each comprising as active
ingredient 0.05 g of one of the compounds of formula (I) mentioned
above, are prepared as follows:
TABLE-US-00005 Composition active ingredient 250 g PEG 400 1 L
Tween 80 1 L
[0215] Preparation Process
[0216] The active ingredient is pulverized and suspended in PEG 400
(polyethylene glycol having an Mr of from approximately 380-420,
Fluka, Switzerland) and Tween.RTM.80 (polyoxyethylene sorbitan
monolaurate, Atlas Chem. Ind. Inc., USA, supplied by Fluka,
Switzerland) and ground in a wet pulverizer to a particle size of
approximately from 1-3 .mu.m. 0.43 g portions of the mixture are
then introduced into soft gelatin capsules using a capsule-filling
machine.
EQUIVALENTS
[0217] While the invention has been described in connection with
what is presently considered to be the most practical and preferred
embodiment, it is to be understood that the invention is not to be
limited to the disclosed embodiment, but on the contrary, is
intended to cover various modifications and equivalent arrangements
included within the spirit and scope of the appended claims.
* * * * *