U.S. patent application number 11/095433 was filed with the patent office on 2005-08-04 for process for preparing indolinone derivatives.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Jin, Qingwu, Mauragis, Michael A., May, Paul D..
Application Number | 20050171357 11/095433 |
Document ID | / |
Family ID | 33029733 |
Filed Date | 2005-08-04 |
United States Patent
Application |
20050171357 |
Kind Code |
A1 |
Jin, Qingwu ; et
al. |
August 4, 2005 |
Process for preparing indolinone derivatives
Abstract
The present invention refers to a process for preparing
indolinone derivatives of the general formula (VI) as defined in
the specification and intermediates of that process.
Inventors: |
Jin, Qingwu; (Kalamazoo,
MI) ; Mauragis, Michael A.; (Scotts, MI) ;
May, Paul D.; (Kalamazoo, MI) |
Correspondence
Address: |
AGOURON PHARMACEUTICALS, INC.
10777 SCIENCE CENTER DRIVE
SAN DIEGO
CA
92121
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
33029733 |
Appl. No.: |
11/095433 |
Filed: |
March 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11095433 |
Mar 30, 2005 |
|
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10367008 |
Feb 14, 2003 |
|
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60411732 |
Sep 18, 2002 |
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Current U.S.
Class: |
548/181 ;
548/229; 548/311.1; 548/465 |
Current CPC
Class: |
C07D 403/06
20130101 |
Class at
Publication: |
548/181 ;
548/229; 548/311.1; 548/465 |
International
Class: |
C07D 417/02; C07D
413/02; C07D 043/02 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 15, 2002 |
WO |
PCT/US02/04407 |
Claims
What is claimed is:
1. A process for preparing an indolinone of the general formula
(VI) 46wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently
selected from the group consisting of hydrogen, C.sub.1-12 alkyl,
C-.sub.1-12 alkoxy, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl,
C.sub.5-12 heterocyclic group containing 1 to 3 atoms selected from
N, S or O, provided that the heterocyclic group may be partially
unsaturated, but not aromatic, C.sub.6-12 aryloxy, C.sub.6-12
alkaryl, C.sub.6-12 alkaryloxy, halogen, trihalomethyl, hydroxy,
--S(O)R', --SO.sub.2NR'R", --SO.sub.3R', --SR', --NO.sub.2,
--NR'R", --OH, --CN, --C(O)R', --OC(O)R', --NHC(O)R',
--(CH.sub.2).sub.nCO.sub.2R', and --CONR'R"; each R.sup.5 is
independently selected from the group consisting of hydrogen,
C.sub.1-12 alkyl, C.sub.1-12 alkoxy, C.sub.5-12 cycloalkyl,
C.sub.6-12 aryl, C.sub.5-12 heterocyclic group containing 1 to 3
atoms selected from N, S or O, provided that the heterocyclic group
may be partially unsaturated, but not aromatic, C.sub.6-12 aryloxy,
C.sub.6-12 alkaryl, C.sub.6-12 alkaryloxy, halogen, trihalomethyl,
hydroxy, --S(O)R', --SO.sub.2NR'R", --SO.sub.3R', --SR',
--NO.sub.2, --NR'R", --OH, --CN, --C(O)R', --OC(O)R', --NHC(O)R',
--(CH.sub.2).sub.nCO.sub.2R', and --CONR'R"; R.sup.6 is
--NR.sup.8(CH.sub.2).sub.mR.sup.9 or --NR.sup.10R.sup.11; R.sup.8
is hydrogen or C.sub.1-12 alkyl; R.sup.9 is selected from the group
consisting of --NR.sup.10R.sup.11, --OH, --C(O)R.sup.12, C.sub.6-12
aryl, C.sub.5-12 heterocyclic group containing 1 to 3 atoms
selected from N, S or O, --N.sup.+(O.sup.-)R.sup.10, and
--NHC(O)R.sup.13; R.sup.10 and R.sup.11 are independently selected
from the group consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12
cyanoalkyl, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, and C.sub.5-12
heterocyclic group containing 1 to 3 atoms selected from N, S or O;
or R.sup.10 and R.sup.11 may be combined to form a five- or
six-membered heterocyclic group optionally containing 1 to 3 atoms
selected from N, O, or S in addition to the nitrogen atom to which
R.sup.10 and R.sup.11 are bound, provided that the heterocyclic
group formed by R.sup.10 and R.sup.11 may optionally be substituted
by R'; R.sup.12 is selected from the group consisting of hydrogen,
--OH, C.sub.1-12 alkoxy and C.sub.6-12 aryloxy; R.sup.13 is
selected from the group consisting of C.sub.1-12 alkyl, C.sub.1-12
haloalkyl, and C.sub.6-12 aralkyl; R' and R" are independently
selected from the group consisting of hydrogen, C.sub.1-12 alkyl,
C.sub.1-12 cyanoalkyl, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl,
C.sub.5-12 heterocyclic group containing 1 to 3 atoms selected from
N, S or O, provided that the heterocyclic group may be partially
unsaturated, but not aromatic, or in the group --NR'R" the R' and
R" substituents may be combined to form a five- or six-membered
heterocyclic group optionally containing 1 to 3 atoms selected from
N, O, or S in addition to the nitrogen atom to which R' and R" are
bound; J is selected from the group consisting of O, S, and NH; one
of K, L and M is C and the group --C(O)R.sup.6 is bound thereto,
the others of the group of K, L and M are independently selected
from the group consisting of CR.sup.5, CR.sup.5.sub.2, N, NR.sup.5,
O and S; n is 0, 1 or 2; m is 1, 2, 3, or 4; and p is 0, 1 or 2;
the process comprising the steps of reacting a compound of the
general formula (III) 47wherein R* is selected from the group
consisting of --O--C(O)--C.sub.1-4 alkyl,
--O--C(O)--O--(C.sub.1-4)alkyl, --O--C(O)--O-phenyl, provided that
the phenyl may optionally be substituted by 1 to 3 halogen atoms,
--O--C(O)--O--CH.sub.2-phenyl, provided that the phenyl may
optionally be substituted by 1 to 3 halogen atoms; 48with a
compound of general formula (IV) 49and an amine of general formula
(V) HR.sup.6 (V) to form the indolinone of the general formula
(VI).
2. The process of claim 1, wherein 50is selected from the group
consisting of 51
3. The process of claim 1, wherein 52
4. The process of claim 1, wherein R.sup.1 is hydrogen or C.sub.1--
alkyl.
5. The process of claim 1, wherein R.sup.1 is hydrogen.
6. The process of claim 1, wherein R.sup.2 is selected from the
group consisting of hydrogen, fluorine, chlorine, bromine,
C.sub.1-4 alkyl, --O--C.sub.1-4 alkyl, phenyl, --COOH, --CN,
--C(O)CH.sub.3, --SO.sub.2NH.sub.2 and
--SO.sub.2N(CH.sub.3).sub.2.
7. The process of claim 1, wherein R.sup.2 is fluorine.
8. The process of claim 1, wherein R.sup.3 is selected from the
group consisting of hydrogen, C.sub.1-4 alkyl, phenyl,
--O--C.sub.1-4 alkyl and --COOH.
9. The process of claim 1, wherein R.sup.3 is hydrogen or C.sub.1-4
alkyl.
10. The process of claim 1, wherein R.sup.4 is hydrogen.
11. The process of claim 1, wherein R.sup.5 is selected from the
group consisting of hydrogen, C.sub.1-4 alkyl, --C(O)--C.sub.1-4
alkyl, --C(O)phenyl, and phenyl.
12. The process of claim 1, wherein R.sup.5 is hydrogen, or
C.sub.1-4 alkyl.
13. The process of claim 1, wherein R.sup.6 is
--NR.sup.8(CH.sub.2).sub.mR- .sup.9, provided that one or two of
the CH.sub.2 groups can optionally be substituted by --OH or
halogen.
14. The process of claim 1, wherein R.sup.8 is hydrogen or
C.sub.1-4 alkyl.
15. The process of claim 1, wherein m is 2 or 3.
16. The process of claim 1, wherein R.sup.9 is
--NR.sup.10R.sup.11.
17. The process of claim 16, wherein R.sup.10 and R.sup.11 are
hydrogen or C.sub.1-4 alkyl.
18. The process of claim 1, wherein R.sup.9 is a C.sub.5-12
heterocyclic group containing 1 to 3 atoms selected from N, S or
O.
19. The process of claim 18, wherein the heterocyclic group is a
five- to seven-membered heterocyclic group bonded to the
(CH.sub.2).sub.m group via a nitrogen atom and optionally
containing a further heteroatom selected from N, O, and S.
20. The process of claim 19, wherein the heterocyclic group is
selected from the group consisting of 53
21. The process of claim 20, wherein the heterocyclic group is
selected from the group consisting of 54
22. The process of claim 13, wherein R.sup.8 is hydrogen or
C.sub.1-4 alkyl, m is 2 or 3 and R.sup.9 is
--NR.sup.10R.sup.11.
23. The process of claim 22, wherein R.sup.10 and R.sup.11 are
hydrogen or C.sub.1-4 alkyl.
24. The process of claim 13, wherein R.sup.9 is a C.sub.5-12
heterocyclic group containing 1 to 3 atoms selected from N, S or
O.
25. The process of claim 24, wherein the heterocyclic group is a
five- or six-membered heterocyclic group bonded to the
(CH.sub.2).sub.m group via a nitrogen atom and optionally
containing a further heteroatom selected from N, O, and S.
26. The process of claim 25, wherein the heterocyclic group is
selected from the group consisting of 55
27. The process of claim 26, wherein the heterocyclic group is
selected from the group consisting of 56
28. The process of claim 1, wherein the compound of general formula
(VI) is selected from the group consisting of: 57wherein X is
selected from the group consisting of hydrogen, fluorine, chlorine
and bromine.
29. The process of claim 28, wherein X is fluorine.
30. The process of claim 1, wherein the compound of general formula
(VI) is selected from the group consisting of: 5859
Description
[0001] This is a division of U.S. patent application Ser. No.
10/367,008, filed Feb. 14, 2003, which claims the benefit of U.S.
Provisional Application No. 60/411,732, filed Sep. 18, 2002, and
International Application No. PCT/US02/04407, filed Feb. 15, 2002,
the disclosures of which are incorporated herein by reference in
their entireties.
FIELD OF THE INVENTION
[0002] The present invention refers to a process for preparing
indolinone derivatives and intermediates of that process.
BACKGROUND OF THE INVENTION
[0003] A number of indolinone derivatives have been found to
exhibit pharmaceutical activity. Due to the ability to modulate the
protein kinase activity, they have been suggested to treat an
number of conditions such as various types of cancer, mastocytosis,
allergy associated chronic rhinitis, diabetes, autoimmune
disorders, restenosis, fibrosis, psoriasis, von Hippel-Lindau
disease, osteoarthritis, rheumatoid arthritis, angiogensis,
inflammatory disorders, immunological disorders, and cardiovascular
disorders (WO 01/45689, WO 01/60814, WO 99/48868, U.S. Pat. No.
6,316,429, U.S. Pat. No. 6,316,635, U.S. Pat. No. 6,133,305, and
U.S. Pat. No. 6,248,771).
[0004] Among the indolinone derivatives those having an amide group
on a heterocyclic ring condensed with the indolinone have been of
interest. These compounds modulate protein kinase activity and are
thus useful in treating diseases relating to abnormal protein
kinase activity. A process for preparing the amide derivatives is
disclosed in WO 01/60814. An appropriate pyrrole is formylated and
subsequently condensed with a 2-indolinone to give a respective
5-(2-oxo-1,2-dihydroindole-3-ylidenemet- hyl)-1H-pyrrole. If an
amide derivative of the pyrrole is desired, a pyrrole having a
carboxylic acid group is selected. The carboxylic acid group is
reacted with the desired amine in the presence of
dimethylformamide, 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide
and 1-hydroxybenzotriazole. In example 129 a scale-up procedure is
disclosed in which the amidation is conducted in the presence of
dimethylformamide,
benzotriazole-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) and triethylamine.
[0005] It is an object of the present invention to provide an
improved process for preparing indolinone derivatives which have an
amide group on a heterocyclic ring condensed with the
indolinone.
SUMMARY OF THE INVENTION
[0006] The present invention provides a process for preparing an
indolinone of the general formula (VI) 1
[0007] wherein
[0008] R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently
selected from the group consisting of hydrogen, C.sub.1-12 alkyl,
C.sub.1-12 alkoxy, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl,
C.sub.5-12 heterocyclic group containing 1 to 3 atoms selected from
N, S or O, provided that the heterocyclic group may be partially
unsaturated, but not aromatic, C.sub.6-12 aryloxy, C.sub.6-12
alkaryl, C.sub.6-12 alkaryloxy, halogen, trihalomethyl, hydroxy,
--S(O)R', --SO.sub.2NR'R", --SO.sub.3R', --SR', --NO.sub.2,
--NR'R", --OH, --CN, --C(O)R', --OC(O)R', --NHC(O)R',
--(CH.sub.2).sub.nCO.sub.2R', and --CONR'R";
[0009] each R.sup.5 is independently selected from the group
consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12 alkoxy,
C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heterocyclic
group containing 1 to 3 atoms selected from N, S or O, provided
that the heterocyclic group may be partially unsaturated, but not
aromatic, C.sub.6-12 aryloxy, C.sub.6-12 alkaryl, C.sub.6-12
alkaryloxy, halogen, trihalomethyl, hydroxy, --S(O)R',
--SO.sub.2NR'R", --SO.sub.3R', --SR', --NO.sub.2, --NR'R", --OH,
--CN, --C(O)R', --OC(O)R', --NHC(O)R',
--(CH.sub.2).sub.nCO.sub.2R'- , and --CONR'R"; R.sup.6 is selected
from --NR.sup.8(CH.sub.2).sub.mR.sup.- 9 and --NR.sup.10R.sup.11,
provided that optionally one to two of the CH.sub.2 groups may be
substituted by --H or halogen; R.sup.8 is hydrogen or C.sub.1-12
alkyl;
[0010] R.sup.9 is selected from the group consisting of
--NR.sup.10R.sup.11, --OH, --C(O)R.sup.2, C.sub.1-12 aryl,
C.sub.5-12 heterocyclic group containing 1 to 3 atoms selected from
N, S or O, --N.sup.+(O)R.sup.10, and --NHC(O)R.sup.13;
[0011] R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12
cyanoalkyl, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, and C.sub.5-12
heterocyclic group containing 1 to 3 atoms selected from N, S or O;
or R.sup.10 and R.sup.11 may be combined to form a five- or
six-membered heterocyclic group optionally containing 1 to 3 atoms
selected from N, O, or S in addition to the nitrogen atom to which
R.sup.10 and R.sup.11 are bound, provided that the heterocyclic
group formed by R.sup.10 and R.sup.11 may optionally be substituted
by R'
[0012] R.sup.12 is selected from the group consisting of hydrogen,
--OH, C.sub.1-12 alkoxy and C.sub.6-12 aryloxy;
[0013] R.sup.13 is selected from the group consisting of C.sub.1-12
alkyl, C-.sub.1-12 haloalkyl, and C.sub.1-12 aralkyl;
[0014] R' and R" are independently selected from the group
consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12 cyanoalkyl,
C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heterocyclic
group containing 1 to 3 atoms selected from N, S or O, provided
that the heterocyclic group may be partially unsaturated, but not
aromatic, or in the group --NR'R" the R' and R" substituents may be
combined to form a five- or six-membered heterocyclic group
optionally containing 1 to 3 atoms selected from N, O, or S in
addition to the nitrogen atom to which R' and R" are bound;
[0015] The terms "halogen" and "halo" refer to substituents
selected from the group consisting of F, Cl, Br, and I
[0016] J is selected from the group consisting of O, S, and NH;
[0017] one of K, L and M is C and the group --C(O)R.sup.6 is bound
thereto, the others of the group of K, L and M are independently
selected from the group consisting of CR.sup.5, CR.sup.5.sub.2, N,
NRC, O and S;
[0018] n is 0, 1 or 2;
[0019] m is 1, 2, 3, or 4; and
[0020] p is 0, 1 or 2;
[0021] comprising the steps of
[0022] (i) reacting a compound of general formula (I) 2
[0023] wherein R.sup.5, J, K, L, M and p are as defined above,
[0024] Q is selected from the group consisting of 3
[0025] with a compound of general formula (II)
X.sup.2--R (II)
[0026] wherein:
[0027] (a) one of X.sup.1 and X.sup.2 is chlorine, or bromine; and
the other is selected from the group consisting of hydroxy,
--O--C.sub.1-4 alkyl and --O-phenyl; and R is selected from the
group consisting of --C(O)--C.sub.1-4 alkyl,
--C(O)--O--(C.sub.1-4)alkyl, --C(O)--O-phenyl, provided that the
phenyl may optionally be substituted by 1 to 3 halogen atoms,
--C(O)--O--CH.sub.2-phenyl, provided that the phenyl may optionally
be substituted by 1 to 3 halogen atoms, or
[0028] (b) X.sup.1 is chlorine or bromine, X.sup.2 is hydrogen and
R is selected from the group consisting of 4
[0029] or
[0030] (c) X.sup.1 is hydroxy, --O--C.sub.1-4 alkyl and
--O-phenyl,
[0031] X.sup.2 is 5
[0032] and R is 6
[0033] to form a compound of the general formula (III) 7
[0034] wherein R* is --O--R in case (a) of step (i) and --R in
cases (b) and (c) of step (i);
[0035] (ii) reacting the compound of general formula (III) with a
compound of general formula (IV) 8
[0036] wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as
defined above,
[0037] and an amine of general formula (V)
HR.sup.6 (V)
[0038] wherein R.sup.6 is as defined above, to form the indolinone
of the general formula (VI).
[0039] The dashed lines in the heterocyclic ring system mean that
two double bonds are present but their position is not
specified.
[0040] A further embodiment the present invention relates to a
process for preparing a compound of the general formula (III) 9
[0041] wherein
[0042] R.sup.5, J, K, L, M, and p are as defined above;
[0043] comprising the steps of
[0044] (i) reacting a compound of general formula (I) 10
[0045] R.sup.5, J, K, L, M, and p are as defined above;
[0046] with a compound of general formula (II)
X.sup.2--R (II)
[0047] (a) wherein one of X.sup.1 and X.sup.2 is chlorine, or
bromine; and the other is selected from the group consisting of
hydroxy, --O--C.sub.1-4 alkyl and --O-phenyl; and R is selected
from the group consisting of --C(O)--C.sub.1-4 alkyl,
--C(O)O--(C.sub.1-4)alkyl, --C(O)--O-phenyl,
--C(O)--O--CH.sub.2-phenyl, wherein the phenyl can optionally be
substituted by 1 to 3 halogen atoms;
[0048] (b) wherein X.sup.1 is chlorine or bromine, X.sup.2 is
hydrogen and R is selected from the group consisting of 11
[0049] or
[0050] (c) wherein X.sup.1 is hydroxy, --O--C.sub.1-4 alkyl and
--O-phenyl, and X.sup.2 is 12
[0051] and R is 13
[0052] to form a compound of the general formula (III) 14
[0053] wherein R* is --O--R in case (a) of step (i) and --R in
cases (b) and (c) of step (i).
[0054] (ii) reacting the compound of general formula (III) with a
compound of general formula (IV) 15
[0055] wherein R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as
defined above,
[0056] and an amine of general formula (V)
HR.sup.6 (V)
[0057] wherein R.sup.6 is as defined above, to form the indolinone
of the general formula (VI).
[0058] The present invention also refers to a process for preparing
an indolinone of the general formula (VI) 16
[0059] wherein
[0060] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, J, K,
L, M, and p are as defined above;
[0061] comprising the steps of
[0062] reacting a compound of the general formula (III) 17
[0063] R.sup.5, J, K, L, M, and p are as defined above;
[0064] wherein R* is selected from the group consisting of
--O--C(O)--O--C.sub.1-4alkyl, --O--C(O)--O--(C.sub.1-4)alkyl,
--O--C(O)--O-phenyl, provided that the phenyl may optionally be
substituted by 1 to 3 halogen atoms, --O--C(O)--O--CH.sub.2-phenyl,
provided that the phenyl may optionally be substituted by 1 to 3
halogen atoms, 18
[0065] with a compound of general formula (IV) 19
[0066] R.sup.1, R.sup.2, R.sup.3, and R.sup.4 are as defined
above;
[0067] and an amine of general formula (V)
HR.sup.6 (V)
[0068] wherein R.sup.6 is as defined above, to form the indolinone
of the general formula (VI).
[0069] In yet another embodiment compounds of the general formula
(III): 20
[0070] wherein R.sup.5, J, K, L, M, and p are as defined above and
R* is selected from the group consisting of --O--C(O)--C.sub.1-4
alkyl, --O--C(O)--O--(C.sub.1-4)alkyl, --O--C(O)--O-phenyl,
provided that the phenyl may optionally be substituted by 1 to 3
halogen atoms, --O--C(O)--O--CH.sub.2-phenyl, provided that the
phenyl may optionally be substituted by 1 to 3 halogen atoms,
21
[0071] are disclosed. Preferably R* is 22
DETAILED DESCRIPTION OF THE INVENTION
[0072] The present invention provides a process for preparing
indolinone derivatives of general formula (VI). The compounds can
modulate the activity of protein kinases and the compounds
themselves, their pharmaceutically acceptable salts and derivatives
are useful in a wide range of medical applications. Preferred
compounds having the formula (VI), pharmaceutical compositions
containing such compounds and the medical utility of these
compounds have been described, e.g. in WO 01/45689, WO 01/60814, WO
99/48868, U.S. Pat. No. 6,316,429, U.S. Pat. No.
6,316,635,6,133,305, and U.S. Pat. No. 6,248,771, all of which are
incorporated herein by reference in the entirety. Particularly
preferred compounds are described in WO 01/45689 (e.g. compounds 15
and 16) and WO 01/60814 (e.g. in the examples and in Table 1).
[0073] The indolinone compounds have the general formula (VI)
23
[0074] R.sup.1, R.sup.2, R.sup.3, R.sup.4 are independently
selected from the group consisting of hydrogen, C.sub.1-12 alkyl,
C.sub.1-12 alkoxy, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl,
C.sub.5-12 heterocyclic group containing 1 to 3 atoms selected from
N, S or O, provided that the heterocyclic group may be partially
unsaturated, but not aromatic, C.sub.6-12 aryloxy, C.sub.6-12
alkaryl, C.sub.6-12 alkaryloxy, halogen, trihalomethyl, hydroxy,
--S(O)R', --SO.sub.2NR'R", --SO.sub.3R', --SR', --NO.sub.2,
--NR'R", --OH, --CN, --C(O)R', --OC(O)R', --NHC(O)R',
--(CH.sub.2).sub.nCO.sub.2R', and --CONR'R". Preferably R.sup.1 is
hydrogen or C.sub.1-4 alkyl; more preferably R.sup.1 is
hydrogen.
[0075] In a preferred embodiment R.sup.2 is selected from the group
consisting of hydrogen, fluorine, chlorine, bromine, C.sub.1-4
alkyl, --O--C.sub.1-4 alkyl, phenyl, --COOH, --CN, --C(O)CH.sub.3,
--SO.sub.2NH.sub.2 and --SO.sub.2N(CH.sub.3).sub.2; more preferably
R.sup.2 is selected from the group consisting of hydrogen,
fluorine, chlorine, C.sub.1-4 alkyl, --O--C.sub.1-4 alkyl, --CN,
--SO.sub.2NH.sub.2 and --SO.sub.2N(CH.sub.3).sub.2 and even more
preferably R.sup.2 is hydrogen, fluorine, chlorine, and C.sub.1-4
alkyl. Most preferably R.sup.2 is fluorine.
[0076] In a preferred embodiment R.sup.3 is selected from the group
consisting of hydrogen, C.sub.1-4 alkyl, phenyl, C.sub.1-4 alkoxy
and --COOH; more preferably R.sup.3 is hydrogen or C.sub.1-4 alkyl;
most preferably R.sup.3 is hydrogen.
[0077] It is preferred that R.sup.4 is hydrogen.
[0078] Each R.sup.5 is independently selected from the group
consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12 alkoxy,
C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heterocyclic
group containing 1 to 3 atoms selected from N, S or O, provided
that the heterocyclic group may be partially unsaturated, but not
aromatic, C.sub.6-12 aryloxy, C.sub.6-12 alkaryl, C.sub.6-12
alkaryloxy, halogen, trihalomethyl, hydroxy, --S(O)R',
--SO.sub.2NR'R", --SO.sub.3R', --SR', --NO.sub.2, --NR'R", --OH,
--CN, --C(O)R', --OC(O)R', --NHC(O)R',
--(CH.sub.2).sub.nCO.sub.2R'- , and --CONR'R". Preferably R.sup.5
is hydrogen or a C.sub.1-4 alkyl.
[0079] R.sup.6 is is selected from
--NR.sup.8(CH.sub.2).sub.mR.sup.9 and --NR.sup.10R.sup.11, provided
that optionally one to two of the CH.sub.2 groups may be
substituted by --OH or halogen. Preferably R.sup.6 is
--NR.sup.8(CH.sub.2).sub.mR.sup.9. In a preferred embodiment the
CH.sub.2 groups are unsubstituted or one of the CH.sub.2 groups is
substituted by --OH.
[0080] R.sup.8 is hydrogen or C.sub.1-12 alkyl. Preferably R.sup.8
is hydrogen or C.sub.1-4 alkyl, and more preferably R.sup.8 is
hydrogen.
[0081] R.sup.9 is selected from the group consisting of
--NR.sup.10R.sup.11, --OH, --C(O)R.sup.12, C.sub.6-12 aryl,
C.sub.5-12 heterocyclic group containing 1 to 3 atoms selected from
N, S or O, --N.sup.+(O.sup.-)R.sup.10, and --NHC(O)R.sup.13. In one
embodiment R.sup.9 is preferably --NR.sup.10R.sup.11. In a second
embodiment R.sup.9 is preferably a C.sub.5-12 heterocyclic group
containing 1 to 3 atoms selected from N, S or O. Preferably the
heterocyclic group is a five- to seven-membered heterocyclic group
bonded to the (CH.sub.2).sub.m group via a nitrogen atom and
optionally containing a further heteroatom selected from N, O, and
S. Examples of the heterocyclic group are, but are not limited to
24
[0082] Preferably the heterocyclic group is 25
[0083] R.sup.10 and R.sup.11 are independently selected from the
group consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12
cyanoalkyl, C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, and C.sub.5-12
heterocyclic group containing 1 to 3 atoms selected from N, S or O;
or R.sup.10 and R.sup.11 may be combined to form a five- or
six-membered heterocyclic group optionally containing 1 to 3 atoms
selected from N, O, or S in addition to the nitrogen atom to which
R.sup.10 and R.sup.11 are bound, provided that the heterocyclic
group formed by R.sup.10 and R.sup.11 may optionally be substituted
by R'. Preferably R.sup.10 and R.sup.11 are hydrogen or C.sub.1-4
alkyl. More preferably R.sup.10 and R.sup.11 are H.
[0084] R.sup.12 is selected from the group consisting of hydrogen,
--OH, C.sub.1-12 alkoxy and C.sub.6-12 aryloxy. Preferably R.sup.12
is a C.sub.1-4 alkyl.
[0085] R.sup.13 is selected from the group consisting of C.sub.1-12
alkyl, C.sub.1-12 haloalkyl, and C.sub.6-12 aralkyl. Preferably
R.sup.13 is a C.sub.1-4 alkyl.
[0086] R' and R" are independently selected from the group
consisting of hydrogen, C.sub.1-12 alkyl, C.sub.1-12 cyanoalkyl,
C.sub.5-12 cycloalkyl, C.sub.6-12 aryl, C.sub.5-12 heterocyclic
group containing 1 to 3 atoms selected from N, S or O, provided
that the heterocyclic group may be partially unsaturated, but not
aromatic, or in the group --NR'R" the R' and R" substituents may be
combined to form a five- or six-membered heterocyclic group
optionally containing 1 to 3 atoms selected from N, O, or S in
addition to the nitrogen atom to which R' and R" are bound.
Preferably R' and R" are independently a C.sub.1-4 alkyl.
[0087] J is selected from the group consisting of O, S, and NH,
preferably J is NH.
[0088] one of K, L and M is C and the group --C(O)R.sup.6 is bound
thereto, the others of the group of K, L and M are independently
selected from the group consisting of CR.sup.5, CR.sup.5.sub.2, N,
NR.sup.5, O and S. Preferred heterocyclic groups 26
[0089] are 27
[0090] Particularly preferred as the heterocyclic group is 28
[0091] n is 0, 1 or 2.
[0092] m is 1, 2, 3, or 4; preferably m is 2 or 3.
[0093] p is 0, 1 or 2.
[0094] Preferred compounds are shown wherein X is a halogen
2930
[0095] In the first step of the process of the present invention, a
compound of general formula (I) 31
[0096] wherein R.sup.5, R.sup.6, J, K, L, M and p are as defined
above, is reacted with a compound of general formula (II)
X.sup.2--R (II)
[0097] (a) wherein one of X.sup.1 and X.sup.2 is chlorine, or
bromine; and the other is selected from the group consisting of
hydroxy, --O--C.sub.1-4 alkyl and --O-phenyl; and R is selected
from the group consisting of --C(O)--C.sub.1-4 alkyl,
--C(O)--O--(C.sub.1-4)alkyl, --C(O)--O-phenyl, provided that the
phenyl may optionally be substituted by 1 to 3 halogen atoms,
--C(O)--O--CH.sub.2-phenyl, provided that the phenyl may optionally
be substituted by 1 to 3 halogen atoms,
[0098] (b) wherein X.sup.1 is chlorine or bromine, X.sup.2 is
hydrogen and R is selected from the group consisting of 32
[0099] or
[0100] (c) wherein X.sup.1 is hydroxy, --O--C.sub.1-4 alkyl and
--O-phenyl, and X.sup.2 is 33
[0101] and R is 34
[0102] to form a compound of the general formula (III) 35
[0103] wherein R* is OR in case (a) of step (1) and --R in cases
(b) and (c) of first step. In first step, option (c) is
preferred.
[0104] The compounds of general formulae (I) and (II) are either
commercially available or can be prepared by methods well known in
the art. For example, heterocycles having a formyl group can be
obtained by slowly adding POCl.sub.3 to dimethylformamide followed
by addition of the appropriate heterocycle, which is also dissolved
in dimethylformamide. This reaction is described in more detail and
exemplified e.g. in WO 01/60814, which is incorporated herein by
reference.
[0105] The reaction is generally carried out in a polar aprotic
solvent. An aprotic solvent is any solvent that, under normal
reaction conditions, does not donate a proton to a solute. Polar
solvents are those which have a non-uniform distribution of charge.
Generally they include 1 to 3 atoms selected from heteroatom such
as N, S or O. Examples of polar aprotic solvents that can be used
in the invention are ethers such as tetrahydrofuran, diethylether,
methyl tert-butyl ether; nitrile solvents such as acetonitrile; and
amide solvents such as dimethylformamide. Preferably the reaction
solvent is an ether, more preferably the solvent is
tetrahydrofuran. Mixtures of the solvents may also be employed. The
aprotic, polar solvent preferably has a boiling point from
30.degree. C. to 130.degree. C., more preferably from 50.degree. C.
to 80.degree. C. Both components of the reaction are introduced
into a reaction vessel together with the solvent. The reactants may
be added in any order, although it is preferred to add compound I
to a stirred suspension of compound II in a suitable solvent, at
room temperature (18-25.degree. C.). A reactant concentration of
0.3 to 0.5 moles/liter is preferred, although the person of skill
in the art will appreciate that the reaction may be conducted at
different concentrations. The reaction may be conducted at a
temperature of 0.degree. C. up to the reflux temperature of the
solvent. However, it is preferred to conduct the reaction at a
temperature of 25.degree. C. to 80.degree. C. with mechanical
stirring. The progress of the reaction may be monitored by a
suitable analytical method, such as HPLC. Upon completion of the
reaction the reaction mixture is cooled and the intermediate
compound III crystallizes. It is preferred to cool the reaction
mixture to a temperature below room temperature and 0.degree. C. is
most preferred. The intermediate compound III may be separated from
the reaction mixture by methods known to those skilled in the art,
such as centrifuging, and filtration. Intermediate III is a
crystalline solid that is non-hygroscopic and is stable in air at
room temperature.
[0106] The compound of general formula (III) is then reacted in a
second step with a compound of general formula (IV) 36
[0107] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 are as defined
above
[0108] and an amine of general formula (V)
HR.sup.6 (V)
[0109] wherein R.sup.6 is as defined above to form the indolinone
of the general formula (VI). The reaction can be carried out in
solution, using the same solvents used in the first reaction step.
The reaction may be carried out sequentially by reacting compound
III with either compound compound IV or compound V and then adding
the other compound. However, it is preferred that compounds II, IV
and V are introduced into a reaction vessel together with the
solvent. The reactants may be added in any order, although it is
preferred to add compound III to a stirred suspension of compound
IV and the amine V in a suitable solvent, at room temperature
(18-25 IC). A reactant concentration of 0.3 to 0.5 moles/liter is
preferred, although the person of skill in the art will appreciate
that the reaction may be conducted at different concentrations. The
reaction may be conducted at a temperature of 50.degree. C. up to
the reflux temperature of the solvent. However, it is preferred to
conduct the reaction at a temperature of 50.degree. C. to
80.degree. C. with mechanical stirring. The progress of the
reaction may be monitored by a suitable analytical method, such as
HPLC. Upon completion of the reaction, the reaction mixture is
cooled and compound VI crystallizes. It is preferred to cool the
reaction mixture to a temperature below room temperature and
0.degree. C. is most preferred. Compound VI may be separated from
the reaction mixture by methods known to those skilled in the art,
such as centrifuging, and filtration. Although Compound VI obtained
from the process above is often of sufficient purity for medical
use, if desired, compound VI may be further purified by methods
known to those skilled in the art, such as recrystallization.
[0110] If desired the indolinone compounds of general formula (VI)
can be further reacted to their pharmaceutically acceptable salts
or derivatives according to conventional processes.
[0111] The present invention provides a process for preparing
indolinone derivatives, which is more convenient than the prior art
processes. Generally the intermediates are easier to handle.
Furthermore, product isolation is facilitated.
[0112] The following examples serve to illustrate the invention and
should not be construed as limiting. Unless otherwise specified all
percentages, parts, and amounts are based on weight.
EXAMPLES
Example 1
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-yl-
idene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
[0113] 37
[0114]
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde
(14.0 g), N,N-diethylethylenediamine (15.0 g), 5-fluorooxindole
(9.86 g), triethylamine (27 ml), and acetonitrile (250 ml) were
mixed and heated to 60.degree. C. The black slurry was stirred for
18 h at 60.degree. C. (needs mechanical stirrer). The resulting
yellow slurry was cooled to room temperature, diluted with 100 ml
acetonitrile, and filtered. The cake was washed with 3.times.100 ml
acetonitrile and dried overnight at 50.degree. C. under house
vacuum. N-[2-(diethylamino)ethyl]-5-[(Z)-(5-flu-
oro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-
-carboxamide (21.7 g) was obtained with 85% yield.
Example 2
5-[(Z)-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethyl-
amino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
[0115] 38
[0116] A 0.1 L flask fitted with a thermometer, condenser, heating
mantle, nitrogen inlet and magnetic stirring was charged with; 3.0
g 5-Bromooxindole, 3.03 g
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrr-
ole-2-carbaldehyde, 3.24 g N,N-Diethylethylene diamine, 4.23 g
Triethylamine and 30 ml Tetrahydrofuran. The mixture was heated to
60-65.degree. C. for 8 hours, then cooled to ambient temperature.
10 ml Tetrahydrofuran was added to aid stirring and the reaction
mixture was filtered. Drying provided 3.7 g (57.7%) first crop of
5-[(Z)-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[2-(diethy-
lamino)ethyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide. The mother
liquors are cooled to -10.degree. C. for 6 h for an additional 1.9
g (29.6%). .sup.1HNMR (DMSO): .delta. 8.08 (1H,s); 7.75 (1H,s);
7.41 (1H,s); 7.24 (1H,d); 6.81 (1H,d); 3.31 (4H,bs); 2.46 (14H,bm);
0.96 (6H,t).
Example 3
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hy-
droxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
[0117] 39
[0118] A 0.25 L flask fitted with a thermometer, condenser,
magnetic stirring, and nitrogen inlet was charged with 4.92 g
5-Fluorooxindole, 7.0 g 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-
1H-pyrrole-2-carbaldehyd- e, 15.5 g
(R)-1-Amino-3-(4-morpholinyl)-2-propanol, 9.78 g Triethylamine and
88 ml Tetrahydrofuran. The mixture was heated to 60.degree. C. for
16.5 hours. The reaction was cooled to ambient temperature and
filtered. The solids obtained were slurried (3) three successive
times in acetonitrile at 11 ml/g, dried in vacuo to produce a yield
of 3.6 g (25.25%) of
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-
-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carbo-
xamide.
[0119] 1HNMR (DMSO): .delta. 10.86 (1H,bs); 7.75 (1H,d); 7.70
(1H,s); 7.50 (1H,m); 6.88 (2H,m); 4.72 (1H,bs); 3.78 (1H,bs); 3.56
(4H,m); 3.32 (6H, m); 3.15 (1H,m); 2.43 (8H,bm).
Example 4
5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hy-
droxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
[0120] 40
[0121]
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde
(6.8 g, 31.3 mmol), (2S)-1-amino-3-morpholin-4-ylpropan-2-ol (10.0
g, 62.5 mmol), 5-chlorooxindole (5.3 g, 31.6 mmol), and THF (100
ml) were mixed and heated to 60.degree. C. After stirring for 68 h
at 60.degree. C., triethylamine (14 ml) was added and stirred for 5
h at 60.degree. C. Added 4.6 g of
(2S)-1-amino-3-morpholin-4-ylpropan-2-ol, and stirred for 20 h at
60.degree. C. The yellow slurry was cooled to room temperature and
filtered. The cake was washed with 2.times.50 ml THF and dried
overnight at 50.degree. C. under house vacuum.
5-[(Z)-(5-chloro-2-oxo-1,2-
-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylprop-
yl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (5.48 g) was obtained
with 38% yield.
Example 5
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-
-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide
[0122] 41
[0123] A mixture of
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-
-carbaldehyde (4.1 Kg), THF (70.8 Kg), and water (4.7 L) were
heated at 40-50.degree. C. until the solids were dissolved. The
resulting solution was filtered, and then distilled to 40-50. The
mixture was subsequently cooled to 25-30.degree. C. A solution of
1-(2-aminoethyl) pyrrolidine (2.8 Kg) in THF (2.1 L) was added. A
solution of 5-Fluorooxindole (2.9 Kg) in THF (18.8 Kg) was also
added. The mixture was then heated to 45-50.degree. C. for 17 h.
The mixture was cooled, filtered, washed with THF (28 Kg), and
dried at 45-50.degree. C. to afford 5.53 Kg (73%) of
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethy-
l-N-(2-pyrrolidin-1-ylethyl)-1H-pyrrole-3-carboxamide. .sup.1H NMR
(DMSO-d.sub.6) .delta. 2.48 (d, J=8 Hz, 6H), 2.55 (m, 7H), 2.62 (t,
J=8 Hz, 1H), 3.37 (m, 6H), 6.90 (m,1H), 7.00 (m, 1H), 7.57 (t, J=4
Hz, 1H), 7.80 (m, 2H).
Example 6
5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hy-
droxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
[0124] 42
[0125]
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde
(7.0 g, 32.3 mmol), (2R)-1-amino-3-morpholin-4-ylpropan-2-ol (15.5
g, 96.9 mmol), 5-chlorooxindole (5.48 g, 32.6 mmol), triethylamine
(14 ml), and THF (88 ml) were mixed and heated to 60.degree. C. A
red solution formed. After stirring for 16 h at 60.degree. C., the
yellow slurry was cooled to room temperature and filtered. The cake
was washed with 2.times.50 ml of THF and dried overnight at
50.degree. C. under house vacuum.
5-[(Z)-(5-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[-
(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxami-
de (4.36 g) was obtained in 29% yield.
Example 7
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2S)-2-hy-
droxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide
[0126] 43
[0127]
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde
(7.0 g, 32.3 mmol), (2S)-1-amino-3-morpholin-4-ylpropan-2-ol (15.0
g, 64.6 mmol), 5-fluorooxindole (4.93 g, 32.6 mmol), triethylamine
(9.79 g, 96.9 mmol), and THF (88 ml) were mixed and heated to
60.degree. C. After stirring for 24 h at 60.degree. C., the mixture
was cooled to rt and filtered. The cake was washed with 80 ml THF
and dried overnight at 50.degree. C. under house vacuum. A brown
solid (23.2 g) was obtained. The solid was slurried in 350 ml water
for 5 h at room temperature and filtered. The cake was washed with
100 ml water and dried at 50.degree. C. under house vacuum
overnight. 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-in-
dol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimeth-
yl-1H-pyrrole-3-carboxamide (8.31 g) was obtained in 56% yield.
Example 8
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-
-N-(2-morpholin-4-ylethyl)-1H-pyrrole-3-carboxamide
[0128] 44
[0129]
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde
(5.0 g, 23.0 mmol), 4-(2-aminoethyl)morpholine (4.5 g, 34.6 mmol),
5-fluorooxindole (3.47 g, 23.0 mmol), and THF (80 ml) were mixed
and heated to 65.degree. C. After stirring for 24 h at 65.degree.
C., the mixture was cooled to room temperature and filtered. The
cake was washed with 40 ml THF and dried overnight at 50.degree. C.
under house vacuum.
5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethy-
l-N-(2-morpholin-4-ylethyl)-1H-pyrrole-3-carboxamide (8.28 g) was
obtained in 87% yield.
Example 9
(3Z)-3-({3,5-dimethyl-4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl]-1H-pyrr-
ol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-one
[0130] 45
[0131]
4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde
(11.3 g, 51.9 mmol), 4-morpholinopiperidine (15.0 g, 88.2 mmol),
5-fluorooxindole (7.84 g, 51.9 mmol), and THF (126 ml) were mixed
and heated to 66.degree. C. After stirring for 68 h at 66.degree.
C., the mixture was cooled to room temperature and filtered. The
cake was washed with 4.times.20 ml THF and dried overnight at
70.degree. C. under house vacuum.
(3Z)-3-({3,5-dimethyl-4-[(4-morpholin-4-ylpiperidin-1-yl)carbonyl-
]-1H-pyrrol-2-yl}methylene)-5-fluoro-1,3-dihydro-2H-indol-2-one
16.09 g was obtained in 68% yield.
* * * * *