U.S. patent application number 11/708840 was filed with the patent office on 2007-07-05 for indolylmaleimide derivatives.
Invention is credited to Rainer Albert, Nigel Graham Cooke, Sylvain Cottens, Claus Ehrhardt, Jean-Pierre Evenou, Richard Sedrani, Peter Von Matt, Jurgen Wagner, Gerhard Zenke.
Application Number | 20070155817 11/708840 |
Document ID | / |
Family ID | 27358348 |
Filed Date | 2007-07-05 |
United States Patent
Application |
20070155817 |
Kind Code |
A1 |
Albert; Rainer ; et
al. |
July 5, 2007 |
Indolylmaleimide derivatives
Abstract
Indolylmaleimide derivatives comprising either a substituted
phenyl, naphthyl, tetrahydronaphthyl, quinazolinyl, quinolyl,
isoquinolyl or pyrimidinyl residue have interesting pharmaceutical
properties, e.g. in the treatment and/or prevention of T-cell
mediated acute or chronic inflammatory diseases or disorders,
autoimmune diseases, graft rejection or cancer.
Inventors: |
Albert; Rainer; (Basel,
CH) ; Cooke; Nigel Graham; (Oberwill, CH) ;
Cottens; Sylvain; (Witterswil, CH) ; Ehrhardt;
Claus; (Lorrach, DE) ; Evenou; Jean-Pierre;
(St. Louis, FR) ; Sedrani; Richard; (Basel,
CH) ; Von Matt; Peter; (Biel- Benken, CH) ;
Wagner; Jurgen; (Bottmingen, CH) ; Zenke;
Gerhard; (Rheinfelden, DE) |
Correspondence
Address: |
NOVARTIS;CORPORATE INTELLECTUAL PROPERTY
ONE HEALTH PLAZA 104/3
EAST HANOVER
NJ
07936-1080
US
|
Family ID: |
27358348 |
Appl. No.: |
11/708840 |
Filed: |
February 20, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10660442 |
Sep 11, 2003 |
7220774 |
|
|
11708840 |
Feb 20, 2007 |
|
|
|
10007368 |
Nov 5, 2001 |
6645970 |
|
|
10660442 |
Sep 11, 2003 |
|
|
|
60246400 |
Nov 7, 2000 |
|
|
|
60283705 |
Apr 13, 2001 |
|
|
|
Current U.S.
Class: |
514/414 |
Current CPC
Class: |
C07D 231/12 20130101;
C07D 233/56 20130101; C07D 249/08 20130101; C07D 471/10 20130101;
C07D 403/04 20130101; C07D 401/14 20130101; A61K 45/06 20130101;
C07D 405/14 20130101; A61P 37/06 20180101; A61P 29/00 20180101;
C07D 403/14 20130101 |
Class at
Publication: |
514/414 |
International
Class: |
A61K 31/405 20060101
A61K031/405 |
Claims
1-11. (canceled)
12. A compound of formula I ##STR38## wherein R.sub.a is H;
C.sub.1-4alkyl; or C.sub.1-4alkyl substituted by OH, NH.sub.2,
NHC.sub.1-4alkyl or N(C.sub.1-4alkyl).sub.2; R.sub.b is H; or
C.sub.1-4alkyl; R is a radical of formula (a), (b), (c), (e) or (f)
##STR39## wherein each of R.sub.1, R.sub.4, R.sub.7, R.sub.11 and
R.sub.14 is a heterocyclic residue, NR.sub.16R.sub.17 wherein
R.sub.16 and R.sub.17 form together with the nitrogen atom to which
they are bound a heterocyclic residue; or a radical of formula
.alpha. --X--R.sub.c--Y (.alpha.) wherein X is a direct bond, O, S
or NR.sub.18 wherein R.sub.18 is H or C.sub.1-4alkyl, R.sub.c is
C.sub.1-4alkylene or C.sub.1-4alkylene wherein one CH.sub.2 is
replaced by CR.sub.xR.sub.y wherein one of R.sub.x and R.sub.y is H
and the other is CH.sub.3, each of R.sub.x and R.sub.y is CH.sub.3
or R.sub.x and R.sub.y form together --CH.sub.2--CH.sub.2--, and Y
is bound to the terminal carbon atom and is a heterocyclic residue;
each of R.sub.2, R.sub.3, R.sub.5, R.sub.6, R.sub.12,
R.sub.13R.sub.15 and R'.sub.15, independently, is H, halogen,
C.sub.1-4alkyl, CF.sub.3, OH, SH, NH.sub.2, C.sub.1-4alkoxy,
C.sub.1-4alkylthio, NHC.sub.1-4alkyl, N(C.sub.1-4alkyl).sub.2 or
CN; E is --N.dbd. and G is --CH.dbd. and ring A is optionally
substituted, or a salt thereof.
13. A compound according to claim 12, wherein the heterocyclic
residue as R.sub.1, R.sub.4, R.sub.7, R.sub.11, R.sub.14 or Y or
formed, respectively, by NR.sub.16R.sub.17 or NR.sub.19R.sub.20, is
a three to eight membered saturated, unsaturated or aromatic
heterocyclic ring comprising 1 or 2 heteroatoms, and optionally
substituted on one or more ring carbon atoms and/or on a ring
nitrogen atom when present.
14. A compound according to claim 13 wherein the heterocyclic
residue as R.sub.1, R.sub.4, R.sub.7, R.sub.11, R.sub.14 or Y or
formed, respectively, by NR.sub.16R.sub.17 or NR.sub.19R.sub.20, is
a residue of formula (.gamma.) ##STR40## wherein the ring D is a 5,
6 or 7 membered saturated, unsaturated or aromatic ring; X.sub.b is
--N--, --C.dbd. or --CH--; X.sub.c is --N.dbd., --NR.sub.f--,
--CR.sub.f'.dbd. or --CHR.sub.f'-- wherein R.sub.f is a substituent
for a ring nitrogen atom and is selected from C.sub.1-6alkyl; acyl;
C.sub.3-6cycloalkyl; C.sub.3-6cycloalkyl-C.sub.1-4alkyl; phenyl;
phenyl-C.sub.1-4alkyl; a heterocyclic group; and a residue of
formula .beta. --R.sub.21--Y' (.beta.) wherein R.sub.21 is
C.sub.1-4alkylene or C.sub.2-4alkylene interrupted by O and Y' is
OH, NH.sub.2, NH(C.sub.1-4alkyl) or N(C.sub.1-4alkyl).sub.2; and
R.sub.f' is a substituent for a ring carbon atom and is selected
from C.sub.1-4alkyl; C.sub.3-6cycloalkyl optionally further
substituted by C.sub.1-4alkyl; ##STR41## wherein p is 1, 2 or 3;
CF.sub.3; halogen; OH; NH.sub.2; --CH.sub.2--NH.sub.2;
--CH.sub.2--OH; piperidin-1-yl; and pyrrolidinyl; the bond between
C.sub.1 and C.sub.2 is either saturated or unsaturated; each of
C.sub.1 and C.sub.2, independently, is a carbon atom which is
optionally substituted by one or two substituents selected among
those indicated above for a ring carbon atom; and the line between
C.sub.3 and X.sub.b and between C.sub.1 and X.sub.b, respectively,
represents the number of carbon atoms as required to obtain a 5, 6
or 7 membered ring D.
15. A compound according to claim 14, wherein D is a piperazinyl
ring optionally C- and/or N-substituted as specified in claim
14.
16. A compound according to claim 12 wherein R is a radical of
formula (e) or (f).
17. A process for the preparation of a compound of formula I
according to claim 12 which process comprises a) reacting a
compound of formula II ##STR42## wherein R.sub.a, R.sub.b and ring
A are as defined in claim 1, with a compound of formula III
R--CH.sub.2--CO--NH.sub.2 (III) wherein R is as defined in claim 1,
b) reacting a compound of formula IV ##STR43## wherein R.sub.a,
R.sub.b and ring A are as defined in claim 1, with a compound of
formula V R--CO--CO--OCH.sub.3 (V) wherein R is as defined in claim
1; or c) converting in a compound of formula I a substituent
R.sub.1, R.sub.4, R.sub.7, R.sub.11, or R.sub.14 into another
substituent R.sub.1, R.sub.4, R.sub.7, R.sub.11 or R.sub.14 and,
where required, converting the resulting compound of formula I
obtained in free form to a salt form or vice versa, as
appropriate.
18. A pharmaceutical composition comprising a compound of formula I
according to claim 12 in free form or pharmaceutically acceptable
salt form in association with a pharmaceutically acceptable diluent
or carrier therefor.
19. A combination comprising a) an inhibitor of PKC and of T-cell
activation and proliferation and b) at least one second agent
selected from an immunosuppressant, immunomodulatory,
anti-inflammatory, antiproliferative or anti-diabetic drug.
20. A method for preventing or treating disorders or diseases
mediated by T lymphocytes and/or PKC in a subject in need of such
treatment, which method comprises administering to said subject an
effective amount of a compound of formula I according to claim 12
or a pharmaceutically acceptable salt thereof.
21. Method according to claim 20 for preventing or treating T cell
mediated acute or chronic autoimmune or inflammatory diseases or
acute or chronic transplant rejection of organ or tissue allo- or
xenografts in a subject in need of such treatment, which method
comprises administering to said subject an effective amount of a
compound of formula I according to claim 1 or a pharmaceutically
acceptable salt thereof.
Description
[0001] The present invention relates to indolylmaleimide
derivatives, process for their production and pharmaceutical
compositions containing them.
[0002] More particularly the present invention provides a compound
of formula I ##STR1## wherein [0003] R.sub.a is H; C.sub.1-4alkyl;
or C.sub.1-4alkyl substituted by OH, NH.sub.2, NHC.sub.1-4alkyl or
N(di-C.sub.1-4alkyl).sub.2; [0004] R.sub.b is H; or C.sub.1-4alkyl;
[0005] R is a radical of formula (a), (b), (c), (d), (e) or (f)
##STR2## wherein [0006] each of R.sub.1, R.sub.4, R.sub.7, R.sub.8,
R.sub.11, and R.sub.14 is OH; SH; a heterocyclic residue;
NR.sub.16R.sub.17 wherein each of R.sub.16 and R.sub.17,
independently, is H or C.sub.1-4alkyl or R.sub.16 and R.sub.17 form
together with the nitrogen atom to which they are bound a
heterocyclic residue; or a radical of formula .alpha.
--X--R.sub.c--Y (.alpha.) [0007] wherein X is a direct bond, O, S
or NR.sub.18 wherein R.sub.18 is H or C.sub.1-4alkyl, [0008]
R.sub.c is C.sub.1-4alkylene or C.sub.1-4alkylene wherein one
CH.sub.2 is replaced by CR.sub.xR.sub.y wherein one of R.sub.x and
R.sub.y is H and the other is CH.sub.3 each of R.sub.x and R.sub.y
is CH.sub.3 or R.sub.x and R.sub.y form together --CH--CH.sub.2--,
and [0009] Y is bound to the terminal carbon atom and is selected
from OH, a heterocyclic residue and --NR.sub.19R.sub.20 wherein
each of R.sub.19 and R.sub.20 independently is H,
C.sub.3-6cycloalkyl, C.sub.3-6cycloalkyl-C.sub.1-4alkyl,
aryl-C.sub.1-4alkyl or C.sub.1-4alkyl optionally substituted on the
terminal carbon atom by OH, or R.sub.19 and R.sub.20 form together
with the nitrogen atom to which they are bound a heterocyclic
residue; [0010] each of R.sub.2, R.sub.3, R.sub.5, R.sub.6,
R.sub.9, R.sub.10, R.sub.12, R.sub.13, R.sub.15 and R'.sub.15,
independently, is H, halogen, C.sub.1-4alkyl, CF.sub.3, OH, SH,
NH.sub.2, C.sub.1-4alkoxy, C.sub.1-4alkylthio, NHC.sub.1-4alkyl,
N(di-C.sub.1-4alkyl).sub.2 or CN; [0011] either E is --N.dbd. and G
is --CH.dbd. or E is --CH.dbd. and G is --N.dbd.; and [0012] ring A
is optionally substituted.
[0013] Any alkyl or alkyl moiety in e.g. alkoxy may be linear or
branched. Halogen may be F, Cl, Br or I, preferably F or Cl. Any
aryl may be phenyl or naphthyl, preferably phenyl.
[0014] By heterocyclic residue as R.sub.1, R.sub.4, R.sub.7,
R.sub.8, R.sub.11, R.sub.14 or Y or formed, respectively, by
NR.sub.16R.sub.17 or NR.sub.19R.sub.20, is meant a three to eight,
preferably five to eight, membered saturated, unsaturated or
aromatic heterocyclic ring comprising 1 or 2 heteroatoms,
preferably selected from N, O and S, and optionally substituted.
Suitable examples include e.g. pyridyl, e.g. 3- or 4-pyridyl,
piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl, homopiperidyl,
piperazinyl, homopiperazinyl, morpholin-4-yl, imidazolyl,
imidazolidinyl, pyrrolyl or pyrrolidinyl, optionally substituted,
e.g. mono- or polysubstituted. When the heterocylic residue is
substituted, this may be on one or more ring carbon atoms and/or on
a ring nitrogen atom when present. Examples of a substituent on a
ring carbon atom include e.g. C.sub.1-4alkyl e.g. CH.sub.3;
C.sub.3-6cycloalkyl e.g. cyclopropyl, optionally further
substituted by C.sub.1-4alkyl; ##STR3## wherein p is 1, 2 or 3,
preferably 1; CF.sub.3; halogen; OH; NH.sub.2;
--CH.sub.2--NH.sub.2; --CH.sub.2--OH; piperidin-1-yl; or
pyrrolidinyl. Examples of a substituent on a ring nitrogen atom are
e.g. C.sub.1-6alkyl; acyl, e.g. R'.sub.x--CO wherein R'.sub.x is H,
C.sub.1-6alkyl or phenyl optionally substituted by C.sub.1-4alkyl,
C.sub.1-4alkoxy or amino, e.g formyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkyl-C.sub.1-4alkyl; phenyl; phenyl-C.sub.1-4alkyl
e.g. benzyl; a heterocyclic residue, e.g. as disclosed above, e.g.
an aromatic heterocyclic residue comprising 1 or 2 nitrogen atoms;
or a residue of formula .beta. --R.sub.21--Y' (.beta.) wherein
R.sub.21 is C.sub.1-4alkylene or C.sub.2-4alkylene interrupted by O
and Y' is OH, NH.sub.2, NH(C.sub.1-4alkyl) or
N(C.sub.1-4alkyl).sub.2.
[0015] C.sub.2-4alkylene interrupted by O may be e.g.
--CH.sub.2CH.sub.2O--CH.sub.2--CH.sub.2--.
[0016] When the substituent on a cyclic nitrogen is a heterocyclic
residue, it may be a five or six membered saturated, unsaturated or
aromatic heterocyclic ring comprising 1 or 2 heteroatoms,
preferably selected from N, O and S. Examples include e.g. 3- or
4-pyridyl, piperidyl, e.g. piperidin-1-yl, 3- or 4-piperidyl,
homopiperidyl, piperazinyl, homopiperazinyl, pyrimidinyl,
morpholin-4-yl, imidazolyl, imidazolidinyl, pyrrolyl or
pyrrolidinyl,
[0017] When R.sub.a is substituted C.sub.1-4alkyl, the substituent
is preferably on the terminal carbon atom.
[0018] When ring A is substituted, it may be mono- or
polysubstituted, preferably monosubstituted, the substituent(s)
being selected from the group consisting of e.g. halogen, OH,
C.sub.1-4alkoxy, e.g. OCH.sub.3, C.sub.1-4alkyl, e.g. CH.sub.3,
NO.sub.2, CF.sub.3, NH.sub.2, NHC.sub.1-4alkyl,
N(di-C.sub.1-4alkyl).sub.2 and CN. For example, ring A may be a
residue of formula ##STR4## wherein [0019] R.sub.d is H;
C.sub.1-4alkyl; or halogen; and [0020] R.sub.e is OH; NO.sub.2;
NH.sub.2; NHC.sub.1-4alkyl; or N(di-C.sub.1-4alkyl).sub.2.
[0021] Preferably R.sub.d is in position 1; preferably R.sub.e is
in position 3.
[0022] When R.sub.c has a CH.sub.2 replaced by CR.sub.xR.sub.y, it
is preferably the CH.sub.2 bearing Y.
[0023] Examples of heterocyclic residue as R.sub.1, R.sub.4,
R.sub.7, R.sub.8, R.sub.11, R.sub.14 or Y or formed, respectively,
by NR.sub.16R.sub.17 or NR.sub.19R.sub.12, include e.g. a residue
of formula (.gamma.) ##STR5## wherein [0024] the ring D is a 5, 6
or 7 membered saturated, unsaturated or aromatic ring; [0025]
X.sub.b is --N--, --C.dbd. or --CH--; [0026] X.sub.c is --N.dbd.,
--NR.sub.f--, --CR.sub.f'.dbd. or --CHR.sub.f'-- wherein R.sub.f is
a substituent as indicated above for a ring nitrogen atom, and
R.sub.f' is a substituent as indicated above for a ring carbon
atom; [0027] the bond between C.sub.1 and C.sub.2 is either
saturated or unsaturated; [0028] each of C.sub.1 and C.sub.2,
independently, is a carbon atom which is optionally substituted by
one or two substituents selected among those indicated above for a
ring carbon atom; and [0029] the line between C.sub.3 and X.sub.b
and between C.sub.1 and X.sub.b, respectively, represents the
number of carbon atoms as required to obtain a 5, 6 or 7 membered
ring D.
[0030] A preferred residue of formula (.gamma.) is one wherein the
ring D forms a 1.4-piperazinyl ring optionally C- and/or
N-substituted as indicated.
[0031] Representative examples of a residue of formula (.gamma.)
are e.g. 3- or 4-pyridyl; piperidin-1-yl; 1-N--(C.sub.1-4alkyl)- or
-(.omega.-hydroxy-C.sub.1-4alkyl)-3-piperidyl; morpholin-4-yl;
imidazolyl; pyrrolidinyl; 1-piperazinyl; 2-C.sub.1-4alkyl- or
C.sub.3,6cycloalkyl-1-piperazinyl ; 3-C.sub.1-4alkyl- or
--C.sub.3-6cycloalkyl-1-piperazinyl; 2,2- or 3,5- or 2,5- or
2,6-di(C.sub.1-4alkyl)-1-piperazinyl;
3,4,5-tri-(C.sub.1-4alkyl)-1-piperazinyl; 4-N--(C.sub.1-4alkyl) or
-(.omega.-hydroxy-C.sub.1-4alkyl)- or
-dimethylamino-C.sub.1-4alkyl)-1-piperazinyl;
4-N-pyridin-4-yl-1-piperazinyl; 4-N-phenyl- or
C.sub.3-6cycloalkyl-1-piperazinyl; 4-N--(C.sub.1-4alkyl) or
-(.omega.-hydroxy-C.sub.1-4alkyl)-3-C.sub.1-4alkyl- or
-3,3-di(C.sub.1-4alkyl)-1-piperazinyl;
4-N-(1-C.sub.1-4alkyl-C.sub.3-6cycloalkyl)-1-piperazinyl;
4-N-formyl-1-piperazinyl; 4-N-pyrimidin-2-yl-1-piperazinyl; or
4-N--C.sub.1-4alkyl-1-homopiperazinyl.
[0032] The compounds of formula I may exist in free form or in salt
form, e.g. addition salts with e.g. organic or inorganic acids, for
example, hydrochloric acid, acetic acid, when R.sub.1, R.sub.4,
R.sub.7, R.sub.8, R.sub.11 or R.sub.14 and/or R.sub.2, R.sub.3,
R.sub.5, R.sub.6, R.sub.9, R.sub.10, R.sub.12, R.sub.13 or R.sub.15
comprises an optionally substituted amino group or a heterocyclic
residue which can form acid addition salts.
[0033] It will be appreciated that the compounds of formula I may
exist in the form of optical isomers, racemates or
diastereoisomers. For example, a ring carbon atom bearing a
substituent in the heterocyclic residue as R.sub.1, R.sub.4,
R.sub.7, R.sub.8, R.sub.11, R.sub.14 or Y or formed, respectively,
by NR.sub.16R.sub.17 or NR.sub.19R.sub.20, is asymmetric and may
have the D- or L-configuration. It is to be understood that the
present invention embraces all enantiomers and their mixtures.
Similar considerations apply in relation to starting materials
exhibiting assymetric carbon atoms as mentioned.
[0034] In the compounds of formula I, the following significances
are preferred individually or in any sub-combination: [0035] 1.
R.sub.a is H or CH.sub.3; [0036] 2. R.sub.b is H; [0037] 3. Ring A
is unsubstituted; or is substituted by methyl in position 7; [0038]
4. Preferred heterocyclic residue as formed by NR.sub.16R.sub.17 is
e.g. piperazin-1-yl optionally N-substituted, e.g. by
C.sub.1-4alkyl, .omega.-hydroxy-C.sub.1-4alkyl,
w-dimethylamino-C.sub.1-4alkyl, C.sub.5-6cycloalkyl,
C.sub.1-4alkyl-C.sub.5-6cycloalkyl, an aromatic heterocyclic
residue comprising 1 or 2 nitrogen atoms, e.g. pyridyl or
pyrimidin-2-yl, or a residue of formula .beta. as defined above
and/or optionally C-substituted, e.g. by CH.sub.3 e.g. in positions
2, and/or 3 and/or 5 and/or 6 and/or 2,2 or 3,3 or by ##STR6## e.g.
in position 2 or 3; piperidin-1-yl optionally C-substituted, e.g.
in position 4, by NH.sub.2, --CH.sub.2--NH.sub.2 or piperidin-1-yl,
or in position 3, e.g. by OH or NH.sub.2; or pyrrolidinyl
optionally C-substituted in position 3 by OH or NH.sub.2; [0039] 5.
R.sub.18 is H or CH.sub.3; [0040] 6. R.sub.c is C.sub.1-4alkylene
or C.sub.1-4alkylene wherein the terminal CH.sub.2 is replaced by
CR.sub.xR.sub.y wherein R.sub.x and R.sub.y form together
--CH.sub.2--CH.sub.2--; [0041] 7. X is O; [0042] 8. The radical of
formula (.alpha.) is O--CH.sub.2--CH.sub.2--Y; [0043] 9. Each of
R.sub.19 and R.sub.20 is H, C.sub.1-4alkyl, e.g. methyl,
C.sub.1-4alkyl substituted on the terminal carbon atom by OH, e.g.
--CH.sub.2--CH.sub.2--OH, or cyclopropyl; [0044] 10. Preferred
heterocyclic residue as formed by NR.sub.19R.sub.20 is e.g.
piperazin-1-yl optionally N-substituted by C.sub.1-4alkyl or a
residue of formula .beta.; piperidin-1-yl;
1-(C.sub.1-4alkyl)-piperidin-3-yl; 3- or 4-pyridyl; imidazolyl;
pyrrolidinyl; or morpholin-4-yl; [0045] 11. Each of R.sub.1,
R.sub.4, R.sub.7, R.sub.8, R.sub.11, or R.sub.14, independently, is
1-N-methyl-piperidin-yl; 4-methyl-piperazin-1-yl;
4-methyl-1-homopiperazinyl; 4-(2-hydroxyethyl)-piperazin-1-yl; or
--X'--C.sub.1, 2 or 3-alkylene-NR.sub.19R.sub.20 wherein X' is a
direct bond, O or NH; [0046] 12. In the residue of formula
(.alpha.) either each of R.sub.2 and R.sub.3 is H or one of R.sub.2
and R.sub.3 is H and the other is F, Cl, CH.sub.3, OH, OCH.sub.3 or
CF.sub.3; [0047] 13. In the residue of formula (.alpha.) R.sub.2 is
OH; [0048] 14. In the residue of formula (b) either each of R.sub.5
and R.sub.6 is H or one of R.sub.5 and R.sub.6 is H and the other
is F, Cl, CH.sub.3, OCH.sub.3 or CF.sub.3; [0049] 15. In the
residue of formula (b) R.sub.4 is a radical of formula (.alpha.) or
NR.sub.16R.sub.17; [0050] 16. In the residue of formula (d) either
each of R.sub.9 and R.sub.10 is H or one of R.sub.9 and R.sub.10 is
H and the other is F, Cl, CH.sub.3, OCH.sub.3 or CF.sub.3;
preferably R.sub.10 is H and R.sub.9 is in position 5, 6, 7 or 8,
preferably in position 6; [0051] 17. In the residue of formula (e)
each of R.sub.12 and R.sub.13 is H; [0052] 18. In the residue of
formula (e) one of R.sub.12 and R.sub.13 is H and the other is F,
Cl, CH.sub.3, OCH.sub.3 or CF.sub.3; [0053] when E is --N.dbd. and
G is H--H.dbd., preferably R.sub.13 is H and R.sub.12 is in
position 6 or 7; [0054] when E is --CH.dbd. and G is --N.dbd.,
preferably R.sub.13 is H and R.sub.12 is in position 7; [0055] 19.
In the residue of formula (f) R.sub.15 is H, CH.sub.3 or Cl, e.g.
in position 5 or 6; [0056] 20. In the residue of formula (f)
R'.sub.15 is H or CH.sub.3, e.g. in position 5, preferably H;
[0057] 21. R is a radical of formula (d), (e) or (f).
[0058] The present invention also includes a process for the
preparation of a compound of formula I which process comprises
[0059] a) reacting a compound of formula II ##STR7## [0060] wherein
R.sub.a, R.sub.b and ring A are as defined above, [0061] with a
compound of formula III R--CH.sub.2--CO--NH.sub.2 (III) [0062]
wherein R is as defined above, [0063] b) reacting a compound of
formula IV ##STR8## [0064] wherein R.sub.a, R.sub.b and ring A are
as defined above, [0065] with a compound of formula V
R--CO--CO--OCH.sub.3 (V) [0066] wherein R is as defined above; or
[0067] c) converting in a compound of formula I a substituent
R.sub.1, R.sub.4, R.sub.7, R.sub.8, R.sub.11, or R.sub.14 into
another substituent R.sub.1, R.sub.4, R.sub.7, R.sub.8, R.sub.11,
or R.sub.14 and, where required, converting the resulting compound
of formula I obtained in free form to a salt form or vice versa, as
appropriate.
[0068] Process steps a) and (b) may conveniently be effected in the
presence of a strong base, e.g. t-BuOK. When compounds of formula
III or V comprising an OH group which should not participate to the
reaction are used, such OH group is in protected form. The
OH-protecting group may be removed according to methods known in
the art at the end of condensation step a) or b). Process step c)
may be carried out according to known methods: for example when
R.sub.1, R.sub.4, R.sub.7, R.sub.8, R.sub.11, or R.sub.14 comprises
a final OH group, this OH group may be replaced by the desired
--NR.sub.16R.sub.17 or --NR.sub.19R.sub.20.
[0069] Compounds of formula II may be prepared by reacting the
corresponding indol compound with an oxalyl halogenide, e.g.
chloride, or with a monoalkyl oxalyl chloride under basic
conditions, e.g. as disclosed in Example 28.
[0070] Compounds of formula III or V, used as starting materials,
may be prepared in accordance with known methods, e.g. by
introducing the desired substituent R.sub.1, R.sub.4, R.sub.7,
R.sub.8, R.sub.11, or R.sub.14, respectively, in a compound of
formula III' or V' R'--CH.sub.2--CO--NH.sub.2 (III')
R''--CO--CO--OCH.sub.3 (V') wherein each of R'or R'' is
respectively a radical of formula (a), (b), (c), (d), (e) or (f),
each of which comprising a leaving group, e.g. halogen, in place of
R.sub.1, R.sub.4, R.sub.7, R.sub.8, R.sub.11 or R.sub.14.
[0071] Alternatively, compounds of formula III wherein R is a
radical of formula (a), (b) or (c), R.sub.1, R.sub.4 or R.sub.7
being a radical of formula (.alpha.), may be prepared in accordance
with known methods by reacting a compound of formula III' wherein
R' is respectively a radical of formula (a), (b) or (c), each of
which comprising OH in place of R.sub.1, R.sub.4 or R.sub.7, with a
compound of formula X.sub.a--X--R.sub.c--Y wherein X.sub.a is a
leaving group, e.g. Cl, and X, R.sub.c or Y are as defined
above.
[0072] Compounds of formula I wherein R is a radical of formula (e)
wherein E is --N.dbd., G is --CH.dbd. and R.sub.11 is
--O--R.sub.c--Y or --S-R.sub.c--Y may also be prepared by reacting
together a compound of formula II as defined above with a compound
of formula III' wherein R' is a radical of formula (e') ##STR9##
wherein R.sub.12 and R.sub.13 are as defined above and X.sub.a is a
leaving group, e.g. halogen, and with a compound of formula VI
R'.sub.11H (VI) wherein R'.sub.11 is --O--R.sub.c--Y or
--S--R.sub.c--Y. This reaction may be carried out in accordance
with know methods, e.g. as disclosed in Example 28 below.
[0073] Compounds of formula I wherein R is a radical of formula (d)
or (f) wherein R.sub.8 or R.sub.14 is --O--R.sub.c--Y or
--S--R.sub.c--Y may also be prepared by reacting together a
compound of formula II as defined above with a compound of formula
III'' wherein R'' is a radical of formula (d') or (f') ##STR10##
wherein R.sub.9, R.sub.10, R.sub.15 and R'.sub.15 are as defined
above and X.sub.a is a leaving group, e.g. halogen, and with a
compound of formula VI' A-H (VI) wherein A is --O--R.sub.c--Y or
--S--R.sub.c--Y. This reaction may be carried out in accordance
with know methods.
[0074] Insofar as the production of the starting materials is not
particularly described, the compounds are known or may be prepared
analogously to methods known in the art or as described
hereafter.
[0075] The following Examples are illustrative of the
invention.
RT=room temperature
THF=tetrahydrofuran
FCC=flash column chromatography
TBAF=tetrabutyl ammonium fluoride
BINAP=2,2'-bis(diphenylphosphino1,1'-binaphthyl
EXAMPLE 1
3(1.H.-Indol-3-yl)-4-[3-(2-dimethylamino-ethoxy)-5-hydroxy-phenyl]-pyrrole-
-2,5-dione
[0076] ##STR11##
[0077] A solution of 400 mg (0.58 mmol) of
3-(1.H.-indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-5-triphenylmethoxy-
-phenyl]-pyrrole-2,5-dione in 5 mL of 33% dimethylamine in ethanol
is stirred overnight at RT. The reaction mixture is diluted with
ethyl acetate. The resulting mixture is washed with saturated
aqueous sodium bicarbonate. The layers are separated and the
aqueous layer is extracted with three portions of ethyl acetate.
The combined organic solution is washed with saturated brine, dried
over anhydrous sodium sulfate, filtered and concentrated under
reduced pressure. The residue is filtered through a plug of silica
gel (70:30 ethyl acetate/methanol) to afford
3-(1.H.-Indol-3-yl)-4-[3-(2-dimethylamino-ethoxy)-5-triphenylmethoxy-phen-
yl]-pyrrole-2,5-dione, which is immediately used in the next step
without further purification.
[0078] To a solution of 370 mg (0.58 mmol) of
3-(1.H.-Indol-3-yl)-4-[3-(2-dimethylamino-ethoxy)-5-triphenylmethoxy-phen-
yl]-pyrrole-2,5-dione in 5 mL of methanol is added 251 mg (1.46
mmol) of para-toluenesulfonic acid. After stirring for 2 h at room
temperature, the mixture is diluted with ethyl acetate and washed
with saturated aqueous sodium bicarbonate. The aqueous layer is
extracted with three portions of ethyl acetate. The combined
organic layers are washed with saturated brine, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue is purified by column chromatography on
silica gel (7:3 ethyl acetate/methanol) to afford the title
compound as an orange foam.
[0079] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 11.89 (s, 1H),
11.00 (s, 1H), 9.45 (s, 1H), 7.98 (s, 1H), 7.43 (d, J=8.0 Hz, 1H),
7.08 (t, J=7.4 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.50 (m, 2H), 6.34
(s, 1H), 6.30 (s, 1H), 3.69 (t, J=5.9 Hz, 2H), 2.35 (t, J=5.9 Hz,
2H), 2.06 (s, 6H); MS (EI, negative ionization) m/z 390
[M-H].sup.-, (EI, positive ionization) m/z 392 [M+H].sup.+
[0080]
3-(1.H.-Indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-5-hydroxy-p-
henyl]-pyrrole-2,5-dione, used as starting material, may be
prepared as follows:
a) [3-(2-Triisopropylsilyloxy-ethoxy)-5-hydroxy-phenyl]-acetic acid
methyl ester
[0081] A mixture of 9.39 g (51.5 mmol) of
(3,5-dihydroxy-phenyl)-acetic acid methyl ester (prepared according
to U. Eder, G. Sauer, G. Haffer, G. Neef, R. Wiechert, U.S. Pat.
No. 4,066,674), 11.38 g (61.8 mmol) of
1-bromo-2-triisopropylsilyloxy-ethane and 14.50 g (51.5 mmol) of
cesium carbonate is stirred at RT for 1 hour and at 60.degree. C.
for another hour. The reaction mixture is then treated with
saturated aqueous sodium carbonate and extracted with ethyl
acetate. The layers are separated and the organic layer is washed
three times with saturated aqueous sodium carbonate. The aqueous
layers are combined and extracted three times with ethyl acetate.
The combined organic solutions are then washed with saturated
brine, dried, filtered and concentrated under reduced pressure. The
residue is purified by column chromatography on silica gel (85:15
hexane/ethyl acetate then 70:30 hexane/ethyl acetate and finally
pure ethyl acetate) to afford above title compound as a yellow oil.
MS (EI, negative ionization) m/z 381 [M-H].sup.-, (EI, positive
ionization) m/z 405 [M+Na].sup.+
b)
2-[3-(2-Triisopropylsilyloxy-ethoxy)-5-hydroxy-phenyl]-acetamide
[0082] A mixture of 3.9 g (10.2 mmol) of the compound of step a)
and 40 mL of concentrated aqueous ammonia is stirred at RT for 2
days and the solvents are removed under reduced pressure. The
residue is dissolved in ethyl acetate and filtered through a plug
of silica gel. The filtrate is reduced under reduced pressure. The
residue is dissolved in a minimum of ethyl acetate and n-hexane is
added upon which the desired product crystallized, affording above
title compound after filtration and drying.
[0083] MS (EI, negative ionization) m/z 366 [M-H].sup.-, (EI,
positive ionization) m/z 390 [M+Na].sup.+
c)
2-[3-(2-Triisopropylsilyloxy-ethoxy)-5-triphenylmethoxy-phenyl]-acetami-
de
[0084] A solution of 1.6 g (4.38 mmol) of compound b), 3.7 g (13.27
mmol) of triphenyl chloromethane, 3.7 mL (26.69 mmol) of
triethylamine and 535 mg (4.38 mmol) of dimethylaminopyridine in 50
mL of dichloromethane is stirred at room temperature for 2 hours.
Saturated aqueous sodium bicarbonate is added and the mixture is
extracted with three portions of ethyl acetate. The combined
organic layers are washed twice with saturated aqueous sodium
bicarbonate and once with saturated brine, dried over anhydrous
sodium sulfate, filtered and concentrated under reduced pressure.
The residue is purified by column chromatography on silica gel (1:2
n-hexane/ethyl acetate followed by 100% ethyl acetate) to afford
the title compound c) as a white foam. .sup.1H NMR (DMSO-d.sub.6,
400 MHz) .delta. 7.46-7.20 (m, 16H), 6.81 (s, 1H), 6.38 (s, 1H),
6.28 (s, 1H), 5.92 (s, 1H), 3.81 (dd, J=4.5, 4.7 Hz, 2H), 3.68 (dd,
J=4.5, 4.7 Hz, 2H), 3.13 (s, 2H), 1.11-0.91 (m, 21H); MS (EI,
negative ionization) m/z 608 [M-H].sup.-, (EI, positive ionization)
m/z 632 [M+Na].sup.+
d)
3-(1.H.-Indol-3-yl)-4-[3-(2-triisopropylsilyloxy-ethoxy)-5-triphenylmet-
hoxy-phenyl]-pyrrole-2,5-dione
[0085] To a stirred solution of 2.5 g (4.12 mmol) of compound c)
and 1.3 g (6.40 mmol) of (1.H.-indol-3-yl)-oxo-acetic acid methyl
ester in 18 mL of THF is added 20.6 mL (20.6 mmol) of a 1M solution
of t-BuOK in THF at room temperature. The reaction mixture is
heated to 60.degree. C. for 45 minutes and then allowed to cool to
RT. Saturated aqueous sodium bicarbonate is added and the resulting
mixture is diluted with ethyl acetate. The layers are separated.
The aqueous layer is extracted three times with ethyl acetate. The
combined organic solutions are washed twice with saturated aqueous
sodium bicarbonate and once with saturated brine, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue is purified by column chromatography on
silica gel (2:1 n-hexane/ethyl acetate followed by 100% ethyl
acetate) to afford the title compound d) as an orange foam. .sup.1H
NMR (DMSO-d.sub.8, 400 MHz) .delta. 11.90 (s, 1H), 10.95 (s, 1H),
7.93 (s, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.37-7.20 (m, 15H), 7.11 (dd,
J=7.4, 7.6 Hz, 1H), 6.74 (t, J=7.6 Hz, 1H), 6.56 (s, 1H), 6.33(s,
1H), 6.16 (d, J=8.0 Hz, 1H), 6.07 (t, J=2.1 Hz, 1H), 3.65 (dd,
J=4.1, 5.1 Hz, 2H), 3.39 (m, 2H), 1.04-0.87 (m, 21H); MS (EI,
negative ionization) m/z 761 [M-H], 518 [M-Ph.sub.3C].sup.-, (EI,
positive ionization) m/z 785 [M+Na].sup.+
e)
3-(1.H.-Indol-3-yl)-4-[3-(2-hydroxy-ethoxy)-5-triphenylmethoxy-phenyl]--
pyrrole-2,5-dione
[0086] To a stirred, cooled (0.degree. C.) solution of 1.8 compound
d) in 15 mL of THF is added 7.1 mL (7.1 mmol) of a 1M solution of
TBAF in THF. After 45 minutes, saturated aqueous sodium bicarbonate
is added, and the resulting mixture is diluted with ethyl acetate.
The layers are separated. The aqueous layer is extracted with three
portions of ethyl acetate. The combined organic layers are washed
twice with saturated aqueous sodium bicarbonate and once with
saturated brine, dried over anhydrous sodium sulfate, filtered and
concentrated under reduced pressure. The residue is purified by
column chromatography on silica gel (1:1 n-hexane/ethyl acetate) to
afford the title compound e) as an orange foam.
[0087] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 11.89 (s, 1H),
10.95 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
7.40-7.20 (m, 15H), 7.13 (dd, J=7.4, 7.6 Hz, 1H), 6.77 (dd, J=7.2,
7.8 Hz, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 6.20 (d, J=8.0 Hz, 1H),
6.08 (t, J=2.1 Hz, 1H), 4.66 (s, 1H), 3.37 (s, 4H); MS (EI,
negative ionization) m/z 605 [M-H].sup.-, 362 [M-Ph.sub.3C].sup.-,
(EI, positive ionization) m/z 629 [M+Na].sup.+, 645 [M+K].sup.+
f)
3-(1.H.-Indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-5-triphenylmetho-
xy-phenyl]-pyrrole-2,5-dione
[0088] A mixture of compound e), 1.0 g (5.74 mmol) of
methanesulfonic anhydride and 0.76 mL (9.42 mmol) of pyridine in 20
mL of THF is stirred at room temperature for 1 hour. Saturated
aqueous sodium bicarbonate is added, and the resulting mixture is
diluted with ethyl acetate. The layers are separated. The aqueous
layer is extracted with three portions of ethyl acetate. The
combined organic layers are washed twice with saturated aqueous
sodium bicarbonate and once with saturated brine, dried over
anhydrous sodium sulfate, filtered and concentrated under reduced
pressure. The residue is purified by column chromatography on
silica gel (1:2 n-hexane/ethyl acetate followed by 100% ethyl
acetate) to afford the title compound f) as an orange oil.
[0089] The compounds of formula X.sub.1 ##STR12##
[0090] wherein R.sub.1 and R.sub.2 are as defined in Table 1, may
be prepared by following the procedure of Example 1 but using the
appropriate starting materials. Starting materials which do not
comprise a OH substituent will be prepared without the protecting
steps as indicated in Example 1. TABLE-US-00001 TABLE 1 Example
R.sub.1 R.sub.2 R.sub.3 R.sub.a M.S. Data 2 OH H H H M.sup.+ 304 3
--O--(CH.sub.2).sub.3--N(CH.sub.3).sub.2 H H H MH.sup.+ 390 4
--O--CH.sub.2--4-pyridyl H H H MH.sup.+ 396 5
--O--CH.sub.2--3-pyridyl H H H MH.sup.+ 396 6
--O--CH.sub.2--CH.sub.2--OH H H H M.sup.+ 348 7
--O--CH.sub.2--CH.sub.2-piperidin-1-yl H H H MH.sup.+ 416 8
--O--CH.sub.2--CH.sub.2-(4-methyl-piperazin-1-yl) H H H MH.sup.+
431 9 --O--CH.sub.2--CH.sub.2-(morpholin-4-yl) H H H MH.sup.+ 418
10 --O--CH.sub.2--CH.sub.2-[4-(2-hydroxyethyl)-piperazin-1-yl] H H
H MH.sup.+ 461 11 --O--CH.sub.2--CH.sub.2-(imidazol-1-yl) H H H
MH.sup.+ 399 12 --O--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2 H H H
MH.sup.+ 376 13 ##STR13## H H H MH.sup.+ 406 14 ##STR14## H H H
MH.sup.+ 482 15
--O--CH.sub.2--CH.sub.2--N(CH.sub.2--CH.sub.2--OH).sub.2 H H H
MH.sup.+ 436 16 --O--CH.sub.2--CH.sub.2-(pyrrolidin-1-yl) H H H
MH.sup.+ 402 17 --O--CH.sub.2-(1-methyl-piperidin-3-yl) H H H
MH.sup.+ 416 18 --CH.sub.2--N(CH.sub.3).sub.2 H H H MH.sup.+ 346 19
--O--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2 --O--CH.sub.2--CH.sub.3
H H M.sup.+ 419 20 --O--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2
--O--CH.sub.3 H H MH.sup.+ 406 21 -(4-methyl-piperazin-1-yl) H
--O--CH.sub.3 H (M + H).sup.+ 417 22 -(4-methyl-piperazin-1-yl) H H
H (M + H).sup.+ 387 23 -(4-methyl-piperazin-1-yl) H H CH.sub.3 (M +
H).sup.+ 401 24 -(4-methyl-piperazin-1-yl) H CH.sub.3 H (M +
H).sup.+ 401 25 -(4-methyl-piperazin-1-yl) H CH.sub.3 CH.sub.3 (M +
H).sup.+ 415 26 -(4-methyl-piperazin-1-yl) H Cl H (M + H).sup.+ 421
27 -(4-methyl-piperazin-1-yl) H Cl CH.sub.3 (M + H).sup.+ 435
EXAMPLE 28
3-(1.H.-Indol-3-yl)-4-[3-(2-dimethylamino-ethoxy)-naphthalen-1-yl]-pyrrole-
-2,5-dione
[0091] ##STR15##
[0092] A suspension of 2.10 g (4.41 mmol) of
3-(1.H.-indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-naphthalen-1-yl]-p-
yrrole-2,5-dione in 20 mL of a 33% solution of dimethylamine in
ethanol is stirred at room temperature overnight. The solvents are
removed under reduced pressure. The product is crystallized from
1:1 acetonitrile/water, filtered and washed with 1:1
acetonitrile/water, diethylether and n-hexane. This procedure
affords the title compound as a red-orange crystalline solid.
[0093] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 11.84 (s,
1H).sub.1 11.13 (s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.62
(d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.39 (t, J=7.4 Hz, 1H), 7.31 (d,
J=8.2 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 7.12 (s, 1H), 6.92 (dd,
J=7.4, 7.6 Hz, 1H), 6.46 (dd, J=7.4, 7.6 Hz, 1H), 6.25 (d, J=8.2
Hz, 1H), 4.16 (m, 2H), 2.63 (dd, J=5.5, 5.7 Hz, 2H), 2.20(s, 6H);
.sup.13C NMR (DMSO-d.sub.6, 100 MHz) .delta. 173.3, 173.2, 156.3,
137.1, 136.6, 135.3, 132.2, 131.6, 128.6, 128.1, 127.7, 127.3,
126.4, 125.6, 124.7, 122.8, 121.9, 121.3, 120.7, 112.9, 109.2,
105.9, 66.8, 58.4, 46.4; IR (KBr) 3244, 1698, 1629, 1597, 1220,
1039.
[0094]
3-(1.H.-Indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-naphthalen--
1-yl]-pyrrole-2,5-dione, used as starting materials may be prepared
as follows:
a) 1-Bromo-3-(2-triisopropylsilyloxy-ethoxy)-naphtalene
[0095] A stirred mixture of 4.38 g (19.6 mmol) of
1-bromo-naphtalen-3-ol (prepared according to the procedure of M.
S. Newman, V. Sankaran, D. R. Olson, J. Am. Chem. Soc. 1976, 98,
3237-3242). 5.52 g (19.6 mmol) of
1-bromo-2-triisopropylsilyloxy-ethane, 13.56 g (98.1 mmol) of
potassium carbonate and 1.45 g (3.9 mmol) of tetrabutylammonium
iodide in 50 mL of dimethylformamide is heated to 60.degree. C. for
4 hours. Then an additional 0.55 g (2.0 mmol) of
1-bromo-2-triisopropylsilyloxy-ethane are added and stirring is
continued for another hour at 60.degree. C., after which TLC
analysis indicated complete consumption of 1-bromo-naphthalen-3-ol.
The mixture is allowed to cool to room temperature and brine is
added. The resulting solution is extracted with ethyl acetate. The
organic solution is washed twice with brine and the combined
aqueous layers are back extracted with ethyl acetate. The organic
layers are combined, dried, filtered and concentrated under reduced
pressure. The oily brown residue is purified by column
chromatography on silica gel (97.5:2.5 n-hexane/diethylether) to
afford above title compound as a brown solid.
b) Oxo-[3-(2-triisopropylsilyloxy-ethoxy)-naphthalen-1-yl]-acetic
acid methyl ester
[0096] To a stirred, cooled (-78.degree. C.) solution of 1.59 g the
compound of step a) in 15 mL of THF is added 2.6 mL (4.13 mmol) of
a 1.6 M solution of n-BuLi in n-hexane. The resulting mixture is
stirred for 1 h and a solution of 886 mg (7.50 mmol) of
dimethyloxalate in 5 mL of THF is added dropwise. After stirring
the reaction mixture for 30 minutes at -78.degree. C., it is warmed
to 0.degree. C., and stirring is continued at that temperature for
3 hours. Thereafter an additional. 132 mg (1.12 mmol) of
dimethyloxalate in 1 mL of THF is added. Stirring is continued for
1 h at 0.degree. C., and the reaction is quenched by the addition
of saturated aqueous ammonium chloride. Ethyl acetate is added and
the layers are separated. The organic layer is washed twice with
saturated brine. The aqueous layers are combined and extracted one
more time with ethyl acetate. The combined organic solutions are
dried, filtered and concentrated under reduced pressure. The
residue is purified by column chromatography on silica gel (95:5
n-hexane/diethylether) to afford above title compound as a yellow
oil.
c)
3-(1.H.-Indol-3-yl)-4-[3-(2-triisopropylsilanyloxy-ethoxy)-naphthalen-1-
-yl]-pyrrole-2,5-dione
[0097] To a solution of 1.070 g the compound of step b) and 0.436 g
(2.50 mmol) of 2-(1.H.-Indol-3-yl)-acetamide in 10 mL of THF is
added at RT 12.5 mL (12.5 mmol) of a 1M solution of t-BuOK in THF.
After the addition is complete the mixture is heated to 60.degree.
C. for 4 hours and then allowed to cool to room temperature.
Saturated aqueous sodium bicarbonate is added and the resulting
mixture is extracted with ethyl acetate. The organic layer is
washed twice with saturated brine. The aqueous layers are combined
and extracted with ethyl acetate. The combined organic extracts are
dried, filtered and concentrated under reduced pressure. The
residue is purified by column chromatography on silica gel (60:40
n-hexane/ethyl acetate) to afford above title compound as a
red-range solid.
[0098] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 11.85 (s,
1H).sub.1 11.15 (s, 1H), 7.98 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.60
(d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.39 (dd, J=7.4, 7.6 Hz, 1H), 7.31
(d, J=8.0 Hz, 1H), 7.15 (m, 2H), 6.92 (dd, J=7.4, 7.6 Hz, 1H), 6.44
(dd, J=7.4, 7.8 Hz, 1H), 6.26 (d, J=8.0 Hz, 1H), 4.18 (m, 2H), 4.03
(dd, J=4.3, 4.5 Hz, 2H), 1.16-0.92 (m, 21H); IR (KBr) 3346, 1710
cm.sup.-1; MS (EI, negative ionization) m/z 553 [M-H].sup.-, (EI,
positive ionization) m/z 574 [2M+K+H].sup.2+, 577 [M+Na].sup.+
d)
3-(1.H.-Indol-3-yl)-4-[3-(2-hydroxy-ethoxy)-naphthalen-1-yl]-pyrrole-2,-
5-dione
[0099] To a stirred, cooled (0.degree. C.) solution of 807 mg (1.45
mmol) of the compound of step c) in 10 mL of THF is added 4.4 mL
(4.40 mmol) of a 1M solution of TBAF in THF. After 1 hour,
saturated aqueous sodium bicarbonate is added, and the resulting
mixture is extracted with ethyl acetate. The organic layer is
washed twice with saturated brine. The aqueous layers are combined
and extracted with ethyl acetate. The combined ethyl acetate
solutions are dried, filtered and concentrated under reduced
pressure. The residue is purified by column chromatography on
silica gel (ethyl acetate) to afford above title compound as a
red-orange solid.
[0100] .sup.1H NMR (DMSO-dd, 400 MHz) .delta. 11.85 (s, 1H), 11.15
(s, 1H), 7.97 (s, 1H), 7.84 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.4 Hz,
1H), 7.45 (d, J=1.8 Hz, 1H), 7.38 (dd, J=7.2, 7.6 Hz, 1H), 7.31 (d,
J=8.0 Hz, 1H), 7.15 (m, 2H), 6.92 (dd, J=7.4, 7.6 Hz, 1H), 6.47
(dd, J=7.4, 7.8 Hz, 1H), 6.29 (d, J=8.2 Hz, 1H), 4.92 (t, J=5.5 Hz,
1H), 4.11 (m, 2H), 3.76 (m, 2H); IR (KBr) 1705 cm.sup.-1; MS (EI,
negative ionization) m/z 397 [M-H].sup.-, (EI, positive ionization)
m/z 418 [2M+K+H].sup.2+, 421 [M+Na].sup.+
e)
3-(1H.-Indol-3-yl)-4-[3-(2-methanesulfonyloxy-ethoxy)-naphthalen-1-yl]--
pyrrole-2,5-dione
[0101] A mixture of 1.99 g (5.00 mmol) of the compound of step d),
2.18 g (12.50 mmol) of methanesulfonic anhydride and 1.6 mL (19.80
mmol) of pyridine in 25 mL of THF is heated to 60.degree. C. for 1
hour. The reaction mixture is allowed to cool to RT and is
filtered. The filtrate is concentrated under reduced pressure. The
product is then crystallized from diethylether, filtered and washed
with one portion of diethylether, two portions of water and another
portion of diethylether. This procedure affords above title
compound as red-orange crystals. .sup.1H NMR (DMSO-d.sub.6, 400
MHz) .delta. 11.83 (s, 1H), 11.14 (s, 1H), 7.96 (d, J=2.5 Hz, 1H),
7.84 (d, J=8.2 Hz, 1H), 7.61 (d, J=8.2 Hz, 1H). 7.50 (d, J=2.1 Hz,
1H), 7.40 (dd, J=7.4, 7.6 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.16 (m,
2H), 6.92 (dd, J=7.4, 7.8 Hz, 1H), 6.46 (t, J=7.6 Hz, 1H), 6.28 (d,
J=8.2 Hz, 1H), 4.57 (dd, J=3.9, 4.1 Hz, 2H), 4.39 (m, 2H), 3.21 (s,
3H); MS (EI, negative ionization) m/z 475 [M-H].sup.-, (EI,
positive ionization) m/z 499 [M+Na].sup.+
[0102] The compounds of formula X.sub.2 ##STR16##
[0103] wherein R.sub.3 is as defined in Table 2, may be prepared by
following the procedure of Example 28 but using the appropriate
starting materials. TABLE-US-00002 TABLE 2 Ex. R.sub.3 R M.S. Data
29 --O--CH.sub.2--CH.sub.2--(pyrrolidin-1-yl) H MH.sup.+ 452 30
##STR17## H MH.sup.+ 456 31 --O--CH3 H (M - H).sup.- 367 32 OH H (M
- H).sup.- 353 33 --O--(CH.sub.2).sub.3--N(CH.sub.3).sub.2 H
MH.sup.+ 440 34 --O--(CH.sub.2).sub.2--N(CH.sub.3)--cyclopropyl H
MH.sup.+ 452 35 --O--(CH.sub.2).sub.2--N(CH.sub.3)--cyclopropyl
CH.sub.3 MH.sup.+ 466 36 --O(CH.sub.2).sub.2NH--cyclopropyl
CH.sub.3 (M + H).sup.+ 452 37 ##STR18## H (M + H).sup.+ 438.2 (M -
H).sup.- 436.3 38 ##STR19## CH.sub.3 (M + H).sup.+ 452.3 39
(4-methyl-piperazin-1-yl) H (M + H).sup.+ 437 (M - H).sup.- 435 40
(4-methyl-piperazin-1-yl CH.sub.3 (M + H).sup.+ 451 41
1-piperazinyl H (M + H).sup.+ 423 (M - H).sup.- 421 42
1-piperazinyl CH.sub.3 (M + H).sup.+ 437 (M - H).sup.- 435 43
--(4-formyl-piperazin-1-yl) CH.sub.3 (M + H).sup.+ 465 (M +
Na).sup.+ 487 44 O--(CH.sub.2).sub.2--(piperidin-1-yl) H (M +
H).sup.+ +466 45 O--(CH.sub.2).sub.2--N(CH.sub.3)(n-Bu) H (M +
H).sup.+ +468 46 O--(CH.sub.2).sub.2--NH--cyclohexyl H (M +
H).sup.+ +480 47 O--(CH.sub.2).sub.2--(4-methyl- H (M + H).sup.+
+480 piperidin-1-yl) 48 O--(CH.sub.2).sub.2--(rac-2-methyl- H (M +
H).sup.+ +466 pyrrolidin-1-yl) 49 O--(CH.sub.2).sub.2--(4-hydroxy-
H (M + H).sup.+ +482 piperidin-1-yl) 50
O--(CH.sub.2).sub.2--((S)-2- H (M + H).sup.+ +482
hydoxymethyl-pyrrolidin-1-yl) 51
O--(CH.sub.2).sub.2--[4-(piperidin-1- H (M + H).sup.+ +549
yl)-piperidin-1-yl] 52 O--(CH.sub.2).sub.2--(rac-3-hydroxy- H (M +
H).sup.+ +482 piperidin-1-yl)
[0104] The compounds of Examples 48 and 52 which are racemates may
also be prepared in the form of pure cis or trans enantiomers using
the corresponding cis or trans starting materials. The same applies
to the cis isomer of Example 50: it may also be prepared as a
racemate or in pure trans form.
EXAMPLE 53
3-[3-(2-hydroxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-4-1.H.-indol-3-
-yl)-pyrrole-2,5-dione
[0105] ##STR20##
[0106]
3-[3-(2-t.butoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-4-(1.-
H.-indol-3-yl)-pyrrole-2,5-dione is treated with TFA/H.sub.2O (5
ml, 95/5) at RT for 15 min. The reaction mixture is poured into
ice-cold saturated aqueous NaHCO.sub.3 solution and the resulting
suspension is extracted with ethyl acetate. Pure title compound is
obtained as orange powder after purification on silica gel using
cyclo-hexane/ethyl acetate (2/1) as mobile phase. MH.sup.+: 403
(ES.sup.+)
[0107] .sup.1H NMR (400 MHz, DMSO-de) .delta. 11.84 (bs, 1H), 10.96
(s, 1H), 7.95 (d, 1H, J=1.47 Hz), 7.37 (d, 1H, J=8.32 Hz), 7.03 (t,
1H, J=7.34 Hz), 6.72 (d, 1H, J=2.44 Hz), 6.67 (t, 1H, J=7.33 Hz),
6.62 (d, 1H, J=2.69 Hz), 6.45 (d, 1H, J=8.07 Hz), 4.77 (t, 1H,
J=5.38 Hz), 3.87 (m, 2H), 3.62 (q, 2H, J=5.38 Hz), 2.67 (m, 2H),
2.34 (m, 1H), 2.06 (m, 1H), 1.59 (m, 1H), 1.49 (m, 1H), 1.36 (m,
2H)
[0108]
3-[3-(2-t.butoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-4-(1.-
H.-indol-3-yl)-pyrrole-2,5-dione, used as starting materials, is
prepared as follows:
a) 8-bromo-6-acetyltetralin
[0109] To AlCl.sub.3 (9.9 g, 75 mmol) is added dropwise
6-acetyltetralin (5.25 g, 30 mmol) under mechanical stirring at RT.
After 20 minutes at 70.degree. C. the reaction is cooled to RT and
treated in small portions with Br.sub.2 (5.76 g [=1.86 ml], 36
mmol) over a period of 30 minutes. After that the mixture is
stirred for further 60 minutes at 85.degree. C. After cooling down
to RT and addition of ice-water (450 ml) the compound is extracted
with methylene chloride and purified on silica gel using a mixture
of cyclo-hexane/ethyl acetate 211 to 1/1 obtaining the product as a
pale yellow solid.
b) 8-bromo-tetralin-6-yl acetate
[0110] Compound of step a) (7.28 g, 28.75 mmol) is dissolved in
CH.sub.2Cl.sub.2 (60 ml). 2 equivalents. m-chloroperbenzoic acid
(11.7 g, FLUKA 25800, 70%) is added at RT and after addition of
sodium sulfate (5 g) the reaction mixture is treated with
trifluoromethanesulfonic acid (250 .mu.l, 2.88 mmol). The reaction
is kept at RT for 16 hours. After thin layer control,
m-chloroperbenzoic acid (2.25 g, 11 mmol), sodium sulfate (2 g) and
trifluoromethanesulfonic acid (50 .mu.l, 0.57 mmol) is added to the
reaction (2 times within 6 hours). The organic layer is filtered
and extracted 3 times with an aqueous sodium thiosulfite solution.
The compound is purified on silica gel using a mixture of
cyclo-hexane/ethyl acetate 2/1 to 1/1 obtaining the product as
colorless oil.
c) 5,6,7,8-tetrahydro-4-bromo-2-naphthol
[0111] Compound of step b) (6.1 g, 22.66 mmol) is added to MeOH
(200 ml) at RT. 1N sodium methoxide in methanol (22.7 ml) is
stirred for 15 min. Amberlite IR-120 (H.sup.+-form) is added to the
mixture until the reaction mixture becomes neutral. The ion
exchanger is filtered off, the solvent is evaporated and the crude
product is isolated without any further purification as a pale
yellow solid.
d) 2-(2-t.butoxy-ethoxy)-4-bromo-5,6,7,8-tetrahydro-naphthalene
[0112] Compound of step c) (2.8 g, 12.33 mmol) is added to THF (100
ml) at RT. Triphenyl-phosphine (16.82 g, 64.13 mmol) and (after 10
minutes) diisopropylazodicarboxylate (11.66 ml, 59.2 mmol) are
added and the mixture is stirred for 14 hours. The solvent is
removed and the residue is purified on silica gel using cyclohexane
(100%) to cyclohexane/-methylene chloride (1/1) as mobile phase,
obtaining the product as a pale yellow solid.
e)
3-(2-t.butoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl-oxo-acetic
acid methyl ester
[0113] Compound of step d) (2.61 g, 7.96 mmol) is dissolved in dry
THF (70 ml) at RT and cooled down to -70.degree. C. Butyllithium
(5.5 ml, 8.76 mmol, 1.6 M in hexane) is added dropwise to the
reaction mixture under inert atmosphere (argon). A solution of
dimethyl oxalate (1.9 g, 15.92 mmol) in 5 ml dry THF is added to
the reaction mixture and the reaction is warmed up to RT. The
reaction mixture is poured into Titrisol buffer solution (pH 7) and
extracted with ethyl acetate. The organic layer is dried and the
compound is purified on silica gel using cyclohexane/methylene
chloride 1/2 as mobile phase obtaining the product as white
solid.
f)
3-[3-(2-t.butoxy-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-4-(1.H.-in-
dol-3-yl)pyrrole-2,5-dione
[0114] Compound of step e) (1 g, 2.99 mmol) and indole-3-acetamide
(270 mg, 1.49 mmol) is added to THF (10 ml) and heated up to
reflux. t.-BuOK (6 ml, 6 mmol, 1 M in THF) is added dropwise under
argon and the reaction is kept at reflux for 1 hour. The reaction
mixture is diluted with ethyl acetate and extracted with saturated
aqueous NaHCO.sub.3 solution. The organic layer is dried and the
compound is isolated as an orange solid after removal of the
solvent without any further purification.
EXAMPLE 54
3-[3-(2-Dimethylamino-ethoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-4-(1.H-i-
ndol-3-yl)-pyrrole-2,5-dione
[0115] ##STR21##
[0116] The compound of example 53 (380 mg, 0.94 mmol) is suspended
in methylene chloride (20 ml) containing 225 .mu.l pyridine (2.8
mmol). After addition of methanesulfonic anhydride (393 mg, 2.26
mmol) the reaction mixture is kept at RT for 14 hours. The reaction
is extracted with 1N HCl in water, the organic layer is dried over
sodium sulfate and the solvent is removed under reduced pressure.
The residue is dissolved in THF and then treated with an aqueous
solution of dimethylamine (2.5 ml). After 96 hours the solvent is
removed and pure title compound is obtained as an orange powder
after silica gel chromatography (methanol/ethylacetate 1/1 as
mobile phase). MH.sup.+: 430 (ES.sup.+)
[0117] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.11.87 (bs, 1H),
10.99 (s, 1H), 7.98 (t, 1H, J=0.40 Hz), 7.39 (d, 1H, J=8.07 Hz),
7.05 (t, 1H, J=7.34 Hz), 6.75 (d, 1H, J=2.44 Hz), 6.68 (t, 1H,
J=7.33 Hz), 6.63 (d, 1H, J=2.69 Hz), 6.44 (d, 1H, J=8.07 Hz), 3.98
(m, 2H), 2.70 (m, 2H), 2.63 (m, 2H), 2.40 (m, 1H), 2.23 (s, 6H),
2.12 (m, 1H), 1.63 (m, 1H), 1.53 (m, 1H), 1.41 (m, 2H)
EXAMPLE 55A
3-(1.H.-Indol-3-yl)-4-[3-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naph-
thalen-1-yl]-pyrrole-2,5-dione
[0118] The title compound is prepared by condensing
2-[3-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-1-yl]-acetam-
ide with (1.H.-indol-3-yl)-oxo-acetic acid methyl ester in analogy
to example 53 (step q. MH.sup.+: 441 (ES.sup.+)
EXAMPLE 55B
3-(1-Methyl-1.H.-indol-3-yl)-4-[3-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrah-
ydro-naphthalen-1-yl]-pyrrole-2,5-dione
[0119] The title compound is prepared by condensing
2-[3-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-1-yl]-acetam-
ide with (1-methyl-1.H.-indol-3-yl)-oxo-acetic acid methyl ester in
analogy to example 53 (step f). MH.sup.+: 455 (ES.sup.+)
##STR22##
[0120]
2-[3-(4-methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-1-yl--
acetamide, used as starting material, is prepared as follows:
a) 5-Bromo-7-methoxy-1,2,3,4-tetrahydro-naphthalene
[0121] 5,6,7,8-tetrahydro-4-bromo-2-naphthol (7 g, 30.8 mmol; step
c) in example 29) is dissolved in dry acetone (100 ml) and treated
with K.sub.2CO.sub.3 (15 g, 0.11 mol) and methyliodide (7.25 ml,
0.13 mmol). The reaction mixture is kept at RT over night. After
filtration and removal of the solvent the residue is purified over
silica gel (methylene chloride/cyclohexane 1/1) affording the
compound as a white solid.
b) (3-Methoxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-acetic acid ethyl
ester
[0122] To a solution of compound of step a) (2.75 g, 11.4 mmol) in
DMF (110 ml) ZnBr.sub.2 (3.4 g, 14.8 mmol), are added
.alpha.-(tributylstannyl)acetate (5.5 g, 14.8 mmol) and
dichlorobis(tri-o-tolylphosphine)-palladium. The reaction is kept
under argon at 80.degree. C. over night. DMF is removed under
reduced pressure and the crude residue is dissolved in ethyl
acetate and extracted with aqueous NaHCO.sub.3 (6%). The organic
layer is dried, concentrated and purified on silica gel (methylene
chloridelcyclohexane 1/1) affording the pure compound.
c) (3-Hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-acetic acid ethyl
ester
[0123] DL-Methionine (1.11 g, 7.5 mmol) and compound of step b) is
dissolved in methanesulfonic acid (9 ml) and kept at RT over night.
The reaction is poured into a ice-cold saturated NaCl solution and
extracted 3 times with methylene chloride. The organic layer is
dried, concentrated and purified on silica gel (methylene
chloride/methanol 95/5) affording the pure compound.
d)
(3-Trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-1-yl)-acet-
ic acid ethyl ester
[0124] To a solution of compound of step c) (940 mg, 4 mmol) in
pyridine (2 ml) trifluoromethane-sulfonic anhydride (720 .mu.l, 4.4
mmol) is added at 0.degree. C. The reaction mixture is kept at RT
over night. The reaction is poured into a ice-cold water and
extracted 3 times with diethyl ether. The organic layer is dried,
concentrated and purified on silica gel (methylene chloride)
affording the compound.
e)
[3-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-1-yl]-acetic
acid ethyl ester
[0125] ##STR23##
[0126] To a solution of compound of step d) (0.5 g, 1.36 mmol) in
dry THF (10 ml) K.sub.3PO.sub.4 (405 mg, 1.90 mmol),
N-methylpiperazine (180 .mu.l, 163 mmol),
tris(dibenzylideneacetoneacetone)-dipalladium(0) (60 mg, 0.07 mmol)
and 2-(di-t-butylphosphino)biphenyl (21 mg, 0.07 mmol) are added
under argon. The reaction is kept under argon at 80.sup.0 C for 24
hours. After filtration DMF is removed under reduced pressure and
the crude residue is purified on silica gel (methylene
chloride/methanol 9515) affording the pure compound.
[0127] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.68 (d, 1H,
J=2.44 Hz), 6.59 (d, 1H, J=2.20 Hz), 4.15 (q, 2H, J=7.34 Hz), 3.55
(s, 2H), 3.17 (t, 4H, J=5.13 Hz), 2.75 (t, 2H, J=5.87 Hz), 2.60 (t,
2H, J=6.11 Hz), 2.57 (t, 4H, J=4.90 Hz), 2.35 (s, 3H), 1.77 (m,
4H), 1.25 (t, 3H, J=7.10 Hz)
f)
2-[3-(4-Methyl-piperazin-1-yl]-5,6,7,8-tetrahydro-naphthalen-1-yl]-acet-
amide
[0128] A solution of compound of step e) (394 mg, 1.2 mmol) in
methanol/NH.sub.3 (4 molar) is transferred into an autoclave and
kept at 120.sup.0 C for 48 hours. After cooling the reaction is
concentrated and the crude residue is purified on silica gel
(methylene chloride/methanol 90/105) affording the pure title
compound.
EXAMPLE 56
3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrol-
e-2,5-dione
[0129] ##STR24##
[0130] 2-[2-(4-methyl-piperazin-1-yl)quinazolin-4-yl]-acetamide
(213 mg, 0.75 mmol) and 3-indoleglyoxylic acid methyl ester (167
mg, 1.1 eq.) are dissolved in THF (15 mL). To the suspension is
added dropwise at 0.degree. C. t-BuOK 1.0 M in THF (2.25 mL, 3.0
eq.). The mixture is stirred at RT overnight. A second portion of
glyoxalate (30 mg, 0.2 eq.) and t-BuOK (0.5 mL) are added and the
mixture is stirred at RT for 24 h. AcOEt is added and the organic
phase is washed with aqueous NaHCO.sub.3 1.0 M and brine. The
organic phase is dried over Na.sub.2SO.sub.4 and evaporated. The
residue is purified by FCC (Et.sub.2O/MeOH/aqueous NH.sub.4OH
90:10:1) to afford the title compound as an orange-red powder.
ESI-MS: 437 [M-H].sup.+;
[0131] .sup.1H NMR (DMSO, 400 MHz) .delta. 2.13 (s, 3H), 2.16 (m,
4H), 3.69 (m, 4H), 6.35 (d, J=8.0 Hz, 1H), 6.64 (dd, J=7.8, 7.4 Hz,
1H), 7.02 (dd, J=7.6, 7.4 Hz, 1H), 7.10 (dd, J=7.8, 7.2 Hz, 1H),
7.38 (d, J=8.2 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.63-7.73 (m, 2H),
8.13 (s, 1H), 11.29 (br s, 1H), 12.01 (br s, 1H). The resulting
compound is dissolved in ethanol and 1.2 equivalents of acetic acid
are added. The solvent is evaporated under reduced pressure
yielding the acetate salt.
2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide
[0132] ##STR25## used as starting material may be prepared as
follows:
[0133] a) To a suspension of 1H,3H-quinazolin-2,4-dione (10.0 g,
61.7 mmol) in POCl.sub.3 (37.0 mL) is added dropwise
N,N-dimethylaniline (7.8 mL, 1.0 eq.). The mixture is heated to
110.degree. C. and kept at reflux for 35 h. The solution is cooled
to RT and poured onto an ice-water mixture. The precipitate is
filtered off and washed with H.sub.2O. The solid is redissolved in
AcOEt and washed with H.sub.2O and brine. The organic phase is
dried over Na.sub.2SO.sub.4 and evaporated to afford crude
2,4-dichloro-quinazoline which can be recrystallized from
toluene/pentane. EI-MS: 198 [M-H].sup.+, 163 [M--Cl].sup.+;
[0134] b) Ethyl acetoacetate (5.08 mL, 2.0 eq.) dissolved in THF
(25 mL) is added dropwise to a suspension of NaH (60%, 1.04 g, 1.3
eq.) in THF (25 mL) at 0.degree. C. The solution is stirred 30 min.
at 0.degree. C. and the solvent is evaporated. The residue is
redissolved in toluene (125 mL) and 2,4-dichloro-quinazoline (4.0
g, 20.0 mmol) is added. The mixture is stirred 30 min. at reflux
and the toluene is evaporated. The oily residue is redissolved in
aqueous NH.sub.4OH 25% (80 mL) and stirred overnight at RT. All
volatile materials are evaporated and the residue is taken up in
AcOEt (80 mL). The suspension is heated at reflux for 15 min.,
cooled to 0.degree. C. and filtered to afford
2-(2-chloro-quinazolin-4-yl)-acetamide as a white solid.
[0135] EI-MS: 221 [M].sup.+178; IR (KBr) .nu..sub.max 3302, 3138,
1681, 1542, 1388, 1287, 948, 771;
[0136] .sup.1H NMR (DMSO, 400 MHz) .delta. 4.21 (s, 2H), 7.24 (br
s, 1H), 7.75-7.84 (m, 2H), 7.97 (d, J=8.4 Hz, 1H), 8.08 (dd, J=8.4,
7.5 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H)
[0137] c) 2-(2-chloro-quinazolin-4-yl)-acetamide (221 mg, 1.0 mmol)
is dissolved in 1-methyl-2-pyrrolidinone (2.0 mL) and
N-methylpiperazine (555 .mu.L, 5.0 eq.) is added. The mixture is
heated 45 min. at 50.degree. C. AcOEt is added and the suspension
is filtered to afford
2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide as a
white solid.
[0138] ESI-MS: 284 [M-H].sup.+, 241; .sup.1H NMR (DMSO, 400 MHz)
.delta. 2.24 (s, 3H), 2.40 (m, 4H), 3.86 (m, 4H), 3.98 (s, 2H),
7.12 (br s, 1H), 7.24 (dd, J=8.2, 7.5 Hz, 1H), 7.49 (d, J=8.4 Hz,
1H), 7.63-7.72 (m, 2H), 7.95 (d, J=8.2 Hz, 1H);
[0139] The compounds of formula X.sub.3 ##STR26##
[0140] wherein R.sub.1, R.sub.5, R.sub.6 and R.sub.7 are as defined
in Table 3 below, may be prepared by following the procedure of
Example 56 but using the appropriate starting materials. The
compounds may also be converted into the acetate salt as disclosed
for the compound of Example 56, where appropriate. TABLE-US-00003
TABLE 3 R.sub.6 (position 7 R.sub.7 (position 5 Ex. R.sub.5 R.sub.1
or 8) or 6) M.S. Data 57 --OCH.sub.3 H H H M.sup.+ 370 (EI) 58
--N(CH.sub.3).sub.2 H H H M.sup.+ 383 (EI) 59
--O--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2 H H (M - H).sup.- 426
(ES.sup.-) 60 --O--CH.sub.2--CH.sub.2--OH H H H (M - H).sup.- 399
(ES.sup.-) 61 --HN--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2 H H H (M
- H).sup.- 425 (ES.sup.-) 62 --O-(1-methyl-piperidin-4-yl) H H H (M
- H).sup.- 452 (ES.sup.-) 63
--O--(CH.sub.2).sub.3--N(CH.sub.3).sub.2 H H H (M + H).sup.+ 442
(ES.sup.+) 64 --N(CH.sub.3)--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2
H H H (M - H).sup.- 439 (ES.sup.-) 65 -(4-methyl-piperazin-1-yl) H
7-OCH.sub.3 H (M - H).sup.- 467 (ES.sup.-) 66
-(4-methyl-piperazin-1-yl) H 8-CH.sub.3 H (M - H).sup.- 451
(ES.sup.-) 67 -(4-methyl-piperazin-1-yl) H 7-OCH.sub.3 6-OCH.sub.3
(M - H).sup.- 497 (ES.sup.-) 68 -(4-methyl-piperazin-1-yl) H H 6-Cl
(M - H).sup.- 471 (ES.sup.-) 69 -(4-methyl-piperazin-1-yl) H 7-Cl H
(M - H).sup.- 471 (ES.sup.-) 70 -1-piperazinyl H H H (M - H).sup.-
423 (ES.sup.-) 71 morpholin-4-yl H H H (M - H).sup.- 424 (ES.sup.-)
72 -(4-methyl-piperazin-1-yl) H H 6-CH.sub.3 (M - H).sup.- 451
(ES.sup.-) 73 -[4-(2-hydroxyethyl)-piperazin- H H H (M - H).sup.-
1-yl] 467 (ES.sup.-) 74 -(4-methyl-piperazin-1-yl) H H 6-F M.sup.+
456 (EI) 75 (cis) 3,5-dimethyl-1-piperazinyl H H H (M - H).sup.-
451 (ES.sup.-) 76 -4-N-(pyridin-4-yl)-1- H H H (M - H).sup.-
piperazinyl 500 (ES.sup.-) 77 (rac.) 3-methyl-piperazin-1-yl H H H
(M - H).sup.- 437 (ES.sup.-) 78 -(4-methyl-piperazin-1-yl) H H
6-OCH.sub.3 (M - H).sup.- 467 (ES.sup.-) 79
-(4-methyl-piperazin-1-yl) H H 6-OH MH+ 455 80
-(4-benzyl-piperazin-1-yl) H H H MH+ 515 81 (trans)
2,5,-dimethyl-1- H H H MH+ 453 piperazinyl 82
-[4-(2-dimethylamino-ethyl)- H H H MH+ 496 piperazin-1-yl] 83
4-phenyl-piperazin-1-yl H H H (M - H).sup.- 499 84
4-ethyl-piperazin-1-yl H H H MH.sup.+ 453 85
4-isopropyl-piperazin-1-yl H H H M.sup.+ 466 86
-(4-methyl-piperazin-1-yl) H 7-F H MH.sup.+ 457 87
-(4-methyl-piperazin-1-yl) CH.sub.3 H 6-Cl MH.sup.+ 487 88
1-piperazinyl CH.sub.3 H 6-Cl MH.sup.+ 473 89 (cis)
3,5-dimethyl-piperazin-1- H H 6-Cl MH+ 487 yl 90 (cis)
3,5-dimethyl-1-piperazinyl CH.sub.3 H 6-Cl MH+ 501 91 (cis)
3,4,5-trimethyl-1- H H 6-Cl MH+ 501 piperazinyl 92 (cis)
3,4,5-trimethyl-1- CH.sub.3 H 6-Cl MH.sup.+ 515 piperazinyl 93
-(4-methyl-piperazin-1-yl) H H 5-CH.sub.3 MH.sup.+ 453 94
-(4-ethyl-piperazin-1-yl) H H 6-Cl MH.sup.+ 487 95
-(4-isopropyl-1-piperazin-1-yl) H H 6-Cl MH.sup.+ 501 96
-(4-ethyl-piperazin-1-yl) CH.sub.3 H 6-Cl MH.sup.+ 501 97
-(4-isopropyl-piperazin-1-yl) CH.sub.3 H 6-Cl MH.sup.+ 515 98
-(4-cyclopropyl-piperazin-1-yl) H H H MH.sup.+ 465 99
-(4,7-diaza-spiro[2.5]oct-7-yl) H H H MH.sup.+ 451, MNa.sup.+ 473
100 -(4,7-diaza-spiro[2.5]oct-7-yl) CH.sub.3 H H MH.sup.+ 465,
MK.sup.+ 503 101 -(4-cyclopropyl-piperazin-1-yl) CH.sub.3 H H
MH.sup.+ 479 102 -(4-methyl-4,7-diaza- H H H MH.sup.+ 465
spiro[2.5]oct-7-yl) 103 -(4-methyl-3,3-diethyl- H H H MH.sup.+ 495
piperazin-1-yl) 104 --(4-methyl-4-7-diaza- CH.sub.3 H H MH.sup.+
479; MNa.sup.+ spiro[2.5]oct-7-yl) 501 105 -(4-methyl-3,3-diethyl-
CH.sub.3 H H MH.sup.+ 509 piperazin-1-yl) 106
-4-(1-methyl-cyclopropyl)-1- H H H MH.sup.+ 479 piperazinyl 107
-4-(1-methyl-cyclopropyl)-1- CH.sub.3 H H MH.sup.+ 493; MNa.sup.+
piperazinyl 515 108 1-piperazinyl CH.sub.3 H H MH.sup.+ 439 109
-(4-methyl-piperazin-1-yl) CH.sub.3 H H (M + H).sup.+ 453 110
-(4-methyl-piperazin-1-yl) 2-hydroxyethyl H 6-Cl (M + H).sup.+ 517
111 (4-N-methyl-1- H H 6-Cl (M + H).sup.+ 487 homopiperazinyl) 112
-(4-t-butyl-piperazin-1-yl) H H 6-Cl (M + H).sup.+ 515 113
3-methyl-piperazin-1-yl CH.sub.3 H 6-Cl (M + H).sup.+ 487 114
-(4-t-butyl-piperazin-1-yl) CH.sub.3 H 6-Cl (M + H).sup.+ 519 115
-(4-methyl-4,7-diaza- CH.sub.3 H 6-Cl (M + H).sup.+ 499
spiro[2.5]oct-7-yl) 116 3-R-methyl-piperazin-1-yl CH.sub.3 H 6-Cl
(M + H).sup.+ 487 117 3-S-methyl-piperazin-1-yl CH.sub.3 H 6-Cl (M
+ H).sup.+ 487 118 3,3-dimethyl-1-piperazinyl CH.sub.3 H 6-Cl (M +
H).sup.+ 501 119 3,3-dimethyl-1-piperazinyl H H 6-Cl (M + H).sup.+
487 120 3,3-dimethyl-1-piperazinyl CH.sub.3 H H (M + H).sup.+ 467
121 3,3-dimethyl-1-piperazinyl H H H (M - H).sup.- 451 122
-(4-methyl-piperazin-1-yl) 2-(CH.sub.3).sub.2N- H 6-Cl (M +
H).sup.+ 544 ethyl
[0141] The compound of Example 77 which is a racemate may also be
prepared in the form of pure cis or trans enantiomer using the
corresponding cis or trans starting materials. The same applies to
the cis isomers of Examples 75, and 89 to 92 and to the trans
isomer of Example 81: they may also be prepared as a racemate or in
pure trans or cis form, respectively, using the corresponding
starting materials. Compounds of Examples 116 and 117 may also be
prepared as a racemate or in the corresponding S or R isomer
form.
[0142] The compounds of formula X.sub.4 ##STR27##
[0143] wherein R, R.sub.1 and R.sub.2 are as defined in Table 4
below, may be prepared by following the procedure of Example 56 but
using the appropriately substituted (1.H.-indol-3-yl)-oxo-acetic
acid ethyl ester. TABLE-US-00004 TABLE 4 M.S. Data(ESI- Ex. R
R.sub.1 R.sub.2 MS) 123 4-F H H 457 [M + H].sup.+ 124 4-OMe H H 469
[M + H].sup.+ 125 5-F H H 457 [M + H].sup.+ 126 5-OMe H H 469 [M +
H].sup.+ 127 5-Cl H H 473 [M + H].sup.+ 128 6-F H H 457 [M +
H].sup.+ 129 7-F H H 457 [M + H].sup.+ 130 6-OCH.sub.3 H H 469 [M +
H].sup.+ 131 6-Cl H H 473, 475 [M + H].sup.+ 132 5-Br H H 517, 519
(M.sup.+) 133 4-CH.sub.3 H H 453 [M + H].sup.+ 134 4-Cl H H 473,
475 [M + H].sup.+ 135 5-CH.sub.3 H H 453 [M + H].sup.+ 136 7-Br H H
517, 519 [M + H].sup.+ 137 7-Cl H H 473, 475 [M + H].sup.+ 138
6-CH.sub.3 H H 453 [M + H].sup.+ 139 7-CH.sub.3 H H 453 [M +
H].sup.+ 140 7-OCH.sub.3 H H 469 [M + H].sup.+ 141 4-Br H H 517,
519 [M + H].sup.+ 142 6-Br H H 517, 519 [M + H].sup.+ 143 H
CH.sub.3 CH.sub.3 MH.sup.+ 467 144 H H CH.sub.3 MH.sup.+ 453 145
5-OH H H MH.sup.+ 455 146 5-NO.sub.2 H H MH.sup.+ 484 147
5-NHCH.sub.3 H H MH.sup.+ 468 148 5-NH.sub.2 H H MH.sup.+ 454
EXAMPLES 149A AND 149B
[0144] The compounds are prepared by following the procedure of
Example 56 but using the appropriately substituted
(1.H.-indol-3-yl)-oxo-acetic acid methyl ester. ##STR28##
[0145] Example 149A Example 149B
[0146] M.sup.+ 486 M.sup.+ 500
[0147] (7-Fluoro-1.H.-indol-3-yl)-oxo-acetic acid methyl ester,
used as starting material may be prepared as follows:
[0148] 7-Fluoroindole (0.147 g, 1.09 mmol) is dissolved in dry THF
(5 ml) and the solution cooled to 0.degree. C. A solution of 2M
oxalyl chloride in dichloromethane (0.65 mL, 1.31 mmol) is added
and the mixture is stirred for a further 10 min at 0.degree. C. and
then 4 h at room temperature. The mixture is cooled to 0.degree. C.
and methanol (10 ml) is added. The mixture is stirred for a further
18 h at room temperature. The mixture is evaporated to dryness
under reduced pressure, the solid residue is washed with a mixture
of ethyl acetate:hexane (1:1) and dried under high vacuum to afford
(7-fluoro-1.H.-indol-3-yl)-oxo-acetic acid methyl ester. The
product is used without further purification.
[0149] ESI-MS: 220 [M-H].sup.+
[0150] The corresponding substituted (1.H.-indol-3-yl)-oxo-acetic
acid methyl ester, used as starting materials in the preparation of
examples 123-148 were prepared in an analogous way from the
corresponding indoles.
[0151] The compounds of formula X.sub.5 ##STR29##
[0152] wherein R, R.sub.1 and R.sub.2 are as defined in Table 5
below, may be prepared by following the procedure of Example 56 but
using the appropriately substituted (1.H.-indol-3-yl)-oxo-acetic
acid methyl ester. TABLE-US-00005 TABLE 5 Ex. R.sub.14 R.sub.15
R'.sub.15 R.sub.1 M.S. Data 150 -(4-N-methyl)-1- H H H [M +
H].sup.+ 389 piperazinyl 151 -(4-N-methyl)-1- H H CH.sub.3 [M +
H].sup.+ 403 piperazinyl 152 -3,5-dimethyl-1- H H H [M + H].sup.+
403 piperazinyl 153 -3,5-dimethyl-1- H H CH.sub.3 [M + H].sup.+ 417
piperazinyl 154 -(4-N-methyl)-1- 5-CH.sub.3 H H [M + H].sup.+ 403
piperazinyl 155 -(4-N-methyl)-1- 5-CH.sub.3 H CH.sub.3 [M +
H].sup.+ 417 piperazinyl 156 -(4-N-methyl)-1- 6-CH.sub.3 H H [M +
H].sup.+ 403 piperazinyl 157 -(4-N-methyl)-1- 6-CH.sub.3 H CH.sub.3
[M + H].sup.+ 417 piperazinyl 158 -(4-N-methyl)-1- 6-CH.sub.3
5-CH.sub.3 CH.sub.3 [M + H].sup.+ 431 piperazinyl 159
-(4-N-methyl)-1- 6-CH.sub.3 5-CH.sub.3 H [M + H].sup.+ 417
piperazinyl 160 -(4-N-methyl)-1- 5-Cl H CH.sub.3 [M + H].sup.+ 437
piperazinyl 161 -(4-N-methyl)-1- 5-Cl H H [M + H].sup.+ 423
piperazinyl
EXAMPLE 162
3-[2-(2-dimethylamino-ethoxy)-quinolin-4-yl]-4-(1.H.-indol-3-yl)-pyrrole-2-
,5-dione
[0153] ##STR30##
[0154] 2-(2-chloro-quinolin-4-yl)-acetamide (110 mg, 0.5 mmol),
methyl 3-indoleglyoxylate (102 mg, 0.5 mmol) and
N,N-dimethylaminoethanol (508 .mu.L, 10 eq.) are dissolved in dry
THF (5.0 mL) at 1.0 M t.-BuOK (2.5 mL, 5 eq.) is added and the
reaction is stirred at 80.degree. C. overnight. The mixture is
allowed to cool to RT, diluted with AcOEt (20 mL) and washed with
H.sub.2O (10 mL) and brine (5 mL). The organic phase is dried over
Na.sub.2SO.sub.4 and evaporated. The residue is purified by FCC
(AcOEt/EtOH/28% NH.sub.4OH 90:9:1) to afford a red powder, which
can be recrystallized from CH.sub.2Cl.sub.2/Et.sub.2O to give the
pure title compound.
[0155] .sup.1H NMR (DMSO, 400 MHz) .delta. 2.20 (s, 6H), 2.67 (m,
2H), 4.51 (m, 2H), 6.38 (d, J=8.4 Hz, 1H), 6.53 (dd, J=8.4, 7.5 Hz,
1H), 6.95 (m, 2H), 7.21 (dd, J=8.4, 7.5 Hz, 1H), 7.34 (d, J=8.4 Hz,
1H), 7.57 (dd, J=8.4, 7.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.78 (d,
J=8.4 Hz, 1H), 8.00 (s, 1H), 11.20 (br s, 1H), 11.92 (br s,
1H);
[0156] ES-MS: 427 [M+H].sup.+
2-(2-chloro-quinolin-4-yl)-acetamide
[0157] ##STR31## used as starting material may be prepared as
follows:
[0158] a) 2-(2-chloroquinolin-4-yl)-acetic acid methyl ester may be
prepared as disclosed in EP-A1-0 364 327 and Indian J. Chem. 1994,
33B, 747-751.
[0159] b) 2-(2-chloro-quinolin-4-yl)-acetic acid methyl ester (100
mg, 0.42 mmol) is suspended in 28% NH.sub.4OH (2.0 mL). The mixture
is stirred at RT overnight. The solvent is evaporated to afford
2-(2-chloro-quinolin-4-yl)-acetamide as a solid.
[0160] .sup.1H NMR (DMSO, 300 MHz) d 3.88 (s, 2H), 7.16 (br s, 1H),
7.30 (s, 1H), 7.65 (dd, J=8.4, 7.5 Hz, 1H), 7.70 (br s, 1H), 7.80
(dd, J=8.4, 7.5 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 8.12 (d, J=8.4 Hz,
1H)
EXAMPLE 163
3-(1.H.-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinolin-4-yl]-pyrrole--
2,5-dione
[0161] ##STR32##
[0162] 2-[2-(4-methyl-piperazin-1-yl)-quinolin-4-yl]-acetamide (200
mg, 0.70 mmol) and methyl 3-indoleglyoxylate (143 mg, 0.70 mmol)
are dissolved in DMF (7.0 mL) at 0.degree. C. 1.0 M t-BuOK (3.52
mL, 5 eq.) is added and the reaction is stirred at 80.degree. C.
overnight. The mixture is cooled to RT, diluted with
CH.sub.2Cl.sub.2 (40 mL) and washed with H.sub.2O (2.times.10 mL)
and brine (5 mL). The organic phase is dried over Na.sub.2SO.sub.4
and evaporated. The residue is purified by FCC (AcOEt/H.sub.2O/AcOH
7:1:1) to afford the acetate salt. The salt is redissolved in AcOEt
(20 mL) and washed with saturated aqueous NaHCO.sub.3 (2.times.10
mL). The organic phase is dried over Na.sub.2SO.sub.4 and
evaporated to afford the title compound as a red powder.
[0163] .sup.1H NMR (DMSO, 400 MHz) .delta. 2.22 (s, 3H), 2.37 (m,
4H), 3.62 (m, 4H), 6.63 (dd, J=8.4, 7.5 Hz, 1H), 6.74 (d, J=8.4 Hz,
1H), 6.95-7.05 (m, 2H), 7.10 (s, 1H), 7.34 (d, J=8.4 Hz, 1H),
7.41-7.50 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.85 (s, 1H), 10.77 (br
s, 1H), 11.48 (br s, 1H);
[0164] ES-MS: 438 [M+H].sup.+
2-[2-(4-methyl-piperazin-1-yl)-quinolin-4-yl]-acetamide
[0165] ##STR33## used as starting material may be prepared as
follows:
[0166] 2-(2-chloro-quinolin-4-yl)-acetamide (500 mg, 2.27 mmol) is
dissolved in 1-methyl-2-pyrrolidinone (3.0 mL). N-methylpiperazin
(1.3 mL, 5 eq.) is added and the reaction is stirred at 80.degree.
C. for 48 h. AcOEt (20 mL) is added and the precipitate is purified
by FCC (AcOEt/EtOH/28% NH.sub.4OH 80:18:1) to afford
2-[2-(4-methyl-piperazin-1-yl)-quinolin-4-yl]-acetamide as a
solid.
[0167] .sup.1H NMR (DMSO, 400 MHz) .delta. 2.25 (s, 3H), 2.47 (m,
4H), 3.67 (m, 4H), 3.77 (s, 2H), 7.00 (br s, 1H), 7.16 (s, 1H),
7.22 (dd, J=8.4, 7.5 Hz, 1H), 7.50 (dd, J=8.4, 7.5 Hz, 1H), 7.56
(m, 2H), 7.85 (d, J=8.4 Hz, 1H);
[0168] ES-MS: 285 [M+H].sup.+
[0169] The compounds of formula X.sub.6 ##STR34##
[0170] wherein R.sub.6 and R.sub.9 are as defined in Table 6 below,
may be prepared by following the procedure of Example 162 or 163
but using the appropriate starting materials. TABLE-US-00006 TABLE
6 Position- Ex. R.sub.8 R.sub.9 R.sub.a M.S Data 164 Cl H H 374 (M
+ H).sup.+ 165 --OCH.sub.3 6-CH.sub.3 H 384 (M + H).sup.+ 166
--O--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2 6-CH.sub.3 H 441 (M +
H).sup.+ 167 --O--(CH.sub.2).sub.3--N(CH.sub.3).sub.2 6-CH.sub.3 H
455 (M + H).sup.+ 168 --OCH.sub.3 H H 370 (M + H).sup.+ 169
--OCH.sub.3 7-CH.sub.3 H 384 (M + H).sup.+ 170
--O--CH.sub.2--CH.sub.2--N(CH.sub.3).sub.2 7-CH.sub.3 H 441 (M +
H).sup.+ 171 -(4-N-methyl)-1-piperazinyl 7-CH.sub.3 H 452 (M +
H).sup.+ 172 -(4-N-methyl)-1-piperazinyl 7-CH.sub.3 CH.sub.3 466 (M
+ H).sup.+ 173 -(4-N-methyl)-1-piperazinyl H CH.sub.3 438 (M +
H).sup.+ 174 -(4-N-methyl)-1-piperazinyl 6-CH.sub.3 H 452 (M +
H).sup.+ 175 -(4-N-methyl)-1-piperazinyl 6-CH.sub.3 CH.sub.3 466 (M
+ H).sup.+ 176 -(4-N-cyclopentyl)-1- H CH.sub.3 506 (M + H).sup.+
piperazinyl 177 -(4-N-cyclopentyl)-1- H H 492 (M + H).sup.+
piperazinyl 178 -(4-N-3-hydroxypropyl)-1- H H 482 (M + H).sup.+
piperazinyl 179 -(4-N-3-dimethylamino- H H 509 (M + H).sup.+
propyl) 180 -(4-N-pyrimidin-2-yl)-1- CH.sub.3 H 516 (M + H).sup.+
piperazinyl
EXAMPLE 181
3-(1.H.-Indol-3-yl)-4-[3-(4-methyl-piperazin-1-yl)-Isoquinolin-1-yl]-pyrro-
le-2,5-dione
[0171] ##STR35##
[0172]
3-(3-Chloro-isoquinolin-1-yl)-4-(1.H.-indol-3-yl)-pyrrole-2,5-dion-
e (110 mg, 0.30 mmol) is suspended in N-methylpiperazine (2.5 ml)
and kept at 130.degree. C. for 24 hours. The excess of
N-methylpiperazine is removed at high vacuo at 60.degree. C. and
the residue is dissolved in ethyl acetate and extracted with 0.5N
aqueous H.sub.2O. The deep orange aqueous phase is adjusted to pH 9
with 1N NaOH and extracted with ethyl acetate. The organic phase is
separated, dried with Na.sub.2SO.sub.4, concentrated and purified
on silica gel using methylene chloride/methanol/acetic acid.sub.50%
(9/1/0.25) as mobile phase. The fractions with the title compound
are collected and extracted with aqueous NaHCO.sub.3 solution (6%).
The organic phase is separated, dried with Na.sub.2SO.sub.4, and
concentrated to give pure title compound as orange powder.
MH.sup.+: 438 (ES.sup.+) .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta.11.88 (s, 1H), 11.14 (broad, 1H), 8.04 (s, 1H), 7.68 (d, 1H,
J=8.56 Hz), 7.65 (d, 1H, J=9.05 Hz), 7.45 (t, 1H, J=8.07 Hz), 7.31
(d, 1H, J=8.07 Hz), 7.08 (s, 1H, J=8.33 Hz), 7.08 (t, 1H, J=8.31
Hz), 6.94 (t, 1H, J=8.07 Hz), 6.50 (t, 1H, J=7.34 Hz), 6.16 (d, 1H,
J=8.07 Hz), 3.53 (m, 4H), 2.30 (m, 4H), 2.14 (s, 3H)
[0173]
3-(3-Chloro-isoquinolin-1-yl)-4-(1.H.-indol-3-yl)-pyrrole-2,5-dion-
e, used as starting material, may be prepared as follows:
[0174] a) (3-chloro-isoquinolin-1-yl)acetic acid ethyl ester may be
prepared as disclosed by T. Kametani et al. in Chem. Pharm. Bull.,
15(5), 704 (1967).
[0175] b) (3-chloro-isoquinolin-1-yl)-acetic acid ethyl ester (2.5
g, 10 mmol) is dissolved in 4N NH.sub.3/MeOH (50 ml). The solution
is transferred into an autoclave and kept at 120.degree. C. for 48
hours. After cooling to RT the solvent is removed and the resulting
crude product is purified on silica gel using methylene chloride
(100%).fwdarw.methylene chloride/methanol (95/5) as eluent,
affording 2-(3-chloro-isoquinolin-1-yl)acetamide as a pale yellow
solid.
[0176] c) 2-(3-chloro-isoquinolin-1-yl)-acetamide (440 mg, 2.5
mmol) and methyl 3-indoleglyoxalate (1.0 g, 5 mmol) are added to
THF (10 ml) and heated up to reflux. t-BuOK (10 ml, 10 mmol, 1 M in
THF) is added dropwise under argon and the reaction is kept at
reflux for 1 hour. The reaction mixture is diluted with ethyl
acetate and extracted with saturated aqueous NaHCO.sub.3 solution.
The organic layer is dried over sodium sulfate and the compound is
isolated after treatment with diethylether and filtration as an
orange solid. MH.sup.+: 375 (ES.sup.+)
[0177] .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 12.04 (s, 1H),
11.30 (s, 1H), 8.14 (s, 1H), 8.11 (s, 1H), 7.99 (d, 1H, J=8.32 Hz),
7.95 (d, 1H, J=8.56 Hz), 7.75 (t, 1H, J=8.33 Hz), 7.50 (t, 1H,
J=8.33 Hz), 7.32 (d, 1H, J=8.07 Hz), 6.92 (t, 1H, J=8.07 Hz), 6.48
(t, 1H, J=7.33 Hz), 5.96 (d, 1H, J=8.07 Hz)
EXAMPLE 182
3-(1-Methyl-1.H.-indol-3-yl)-4-[3-(4-methyl-piperazin-1-yl)-isoquinolin-1--
yl]-pyrrole-2,5-dione
[0178] ##STR36##
[0179] 2-[3-(4-Methyl-piperazin-1-yl)-isoquinolin-1-yl]-acetamide
(710 mg, 2.5 mmole) and methyl (1-methylindolyl)-3-glyoxalate (1.1
g, 5 mmol) are reacted in THF in the presence of t-BuOK at reflux
according to the procedure disclosed in Example 181 c) above. The
title compound is isolated as disclosed in Example 181 c).
MH.sup.+: 452 (ES.sup.+)
[0180] 2-[3-(4-Methyl-piperazin-1-yl)-isoquinolin-1-yl]-acetamide,
used as starting material, may be prepared as follows:
[0181] a) (3-Chloro-isoquinolin-1-yl)acetic acid ethyl ester (13 g,
50 mmol) is dissolved in dioxane (150 ml) under argon. To this
solution BINAP (1.3 g, 2 mmol), palladium(II)acetate (1.3 g, 4
mmol), N-methylpiperazine (11 ml, 0.1 mol) and t.-BuONa (5.4 g, 55
mmol) is added (under argon) and the reaction is kept under reflux
for 30 minutes. After cooling the reaction is diluted with
methylene chloride (300 ml) and extracted with 0.5 N aqueous HCl
(300 ml). After filtration the aqueous phase is adjusted to pH 8.5
with solid sodium bicarbonate and extracted with methylene chloride
(3.times.). The combined organic phases are dried
(Na.sub.2SO.sub.4) and concentrated. The resulting crude is
purified on silica gel using methylene chloride
(100%)->methylene chloride/methanol (90/10) as eluent obtaining
the product as a pale yellow solid.
[0182] b) To a solution of
[3-(4-Methyl-piperazin-1-yl)-isoquinolin-1-yl]-acetic acid ethyl
ester (1.7 g, 5.4 mmol) in DMF, formamide (0.72 ml, 18.1 mmol) is
added under argon. After heating up to 100.degree. C. 5.4N MeONa in
methanol (1 ml) is added in 10 portions (0.1 ml each) over a period
of 45 minutes. After 60 minutes at 100.degree. C. the reaction is
cooled to RT and diluted with isopropanol (100 ml). The solvents
are removed under reduced pressure, the residue is dissolved in
ethyl acetate and extracted with aqueous sodium bicarbonate
solution (5%). The organic phase is dried (Na.sub.2SO.sub.4) and
concentrated. The resulting crude is purified on silica gel using
methylene chloride/methanol (90/10->80120) as eluent obtaining
the product as a white solid.
[0183] The compounds of formula X.sub.7 ##STR37##
[0184] wherein R.sub.a, R.sub.c, R.sub.8 and R.sub.9 are as defined
in Table 7 below, may be prepared by following the procedure of
Example 181 but using the appropriate starting materials.
TABLE-US-00007 TABLE 7 Posit- ion- Ex. R.sub.8 R.sub.9 R.sub.a
R.sub.c M.S Data 183 -(4-N-methyl)-1-piperazinyl H H CH.sub.3 452
(M + H).sup.+ 184 -(4-N-methyl)-1-piperazinyl H H F 456 (M +
H).sup.+ 185 -1-piperazin H H F 442 (M + H).sup.+ 186
-(4-N-methyl)-1- H H F 470 (M + H).sup.+ homopiperazinyl 187
-(4-N-methyl)-1- H H H 452 (M + H).sup.+ homopiperazinyl 188
(rac.)-(3-methyl-piperazin- H H H 438 (M + H).sup.+ 1-yl) 189
1-piperazinyl H H H 424 (M + H).sup.+ 190 (4-N-isopropyl)-1- H H H
466 (M + H).sup.+ piperazinyl 191 3-methyl-1-piperazinyl H H H 438
(M + H).sup.+ 192 -(4-N-methyl)-1-piperazinyl H CH.sub.3 F 470 (M +
H).sup.+ 193 -(4-N-methyl)-1-piperazinyl H CH.sub.3 H 452 (M +
H).sup.+ 194 -(4-N-methyl)-1-plperazinyl H CH.sub.3 CH.sub.3 466 (M
+ H).sup.+ 195 -(4-N-methyl)-1-piperazinyl 7-Cl H H 473 (M +
H).sup.+ 196 -(4-N-methyl)-1-piperazinyl 7-Cl CH.sub.3 H 487 (M +
H).sup.+
[0185] The compounds of formula I in free form or in
pharmaceutically acceptable salt form exhibit valuable
pharmacological properties, e.g. inhibiting Protein Kinase C (PKC),
e.g. PKC isoforms like .alpha., .beta., .delta., .epsilon., .eta.
or .theta. activity, inhibiting T-cell activation and
proliferation, e.g. by inhibiting production by T-cells or
cytokines, e,g, IL-2, by inhibiting the proliferative response of
T-cells to cytokines, e.g. IL-2, e.g. as indicated in in vitro and
in vivo tests and are therefore indicated for therapy.
In Vitro
1. Protein Kinase C Assay
[0186] The compounds of formula I are tested for their activity on
different PKC isoforms according to a published method (D. Geiges
et al. Biochem. Pharmacol. 1997; 53:865-875) The assay is performed
in a 96-well polypropylene microtiterplate (Costar 3794) that has
been previously siliconized with Sigmacote (Sigma SL-2). The
reaction mixture (50 .mu.l) contains 10 .mu.l of the relevant PKC
isozyme together with 25 .mu.l of the test compound and 15 .mu.l of
a mix solution that contains 200 .mu.g/ml protamine sulfate, 10 mM
Mg(NO.sub.3).sub.2, 10 .mu.M ATP (Boehringer 519987) and 3750 Bq of
.sup.33P-ATP (Hartmann Analytic SFC301, 110 TBq/mmol) in 20 mM
Tris-buffer pH 7.4+0.1% BSA. Incubation is performed for 15 min at
32.degree. C. in a microtiterplate shaking incubator (Biolabo
Scientific Instruments). Reaction is stopped by adding 10 .mu.l of
0.5 M Na.sub.2EDTA, pH 7.4. 50 .mu.l of mixture are pipetted onto a
pre-wetted phosphocellulose paper (Whatmann 3698-915) under gentle
pressure. Non-incorporated ATP is washed away with 100 .mu.l
bi-dist H.sub.2O. The paper is washed twice in 0.5% H.sub.3PO.sub.4
for 15 min followed by 5 min in EtOH. Thereafter the paper is dried
and placed in an omnifilter (Packard 6005219), and overlayed with
10 .mu.l/well of Microscint-O (Packard 6013611) before counting in
a Topcount radioactivity counter (Packard). IC.sub.50 measurement
is performed on a routine basis by incubating a serial dilution of
inhibitor at concentrations ranging between 1-1000 .mu.M according
to the method described above. IC.sub.50 value are calculated from
the graph by sigmoidal curve fitting.
2. Protein Kinase C .theta. Assay
[0187] Human recombinant PKC.theta. is used under the assay
conditions as described above. In this assay, compounds of formula
I inhibit PKC .theta. with an IC.sub.50.ltoreq.1 .mu.M. Compound of
Example 56 inhibits PKC.theta. in this assay with an
IC.sub.50<10 nM.
3. Protein Kinase Ca Assay
[0188] Human recombinant PKC.alpha. was obtained from Oxford
Biomedical Research and is used under the assay conditions as
described under Section A.1 above: Compound of Example 100 inhibits
PKC.alpha. in this assay with an IC.sub.50 of 39.+-.15 nM.
4. Protein Kinase CB1 Assay
[0189] Human recombinant PKC.beta.1 was obtained from Oxford
Biomedical Research and is used under the assay conditions as
described under Section A.1 above. Compound of Example 163 inhibits
PKC.beta.1 in this assay with an IC.sub.50 of 8.+-.2 nM.
5. Protein Kinase C.delta. Assay
[0190] Human recombinant PKC.delta. was obtained from Oxford
Biomedical Research and is used under the assay conditions as
described under Section A.1 above. Compound of Example 181 inhibits
PKC.delta. in this assay with an IC.sub.50 of 18.+-.8 nM.
6. Protein Kinase C.epsilon. Assay
[0191] Human recombinant PKC.epsilon. was obtained from Oxford
Biomedical Research and is used under the assay conditions as
described under Section A.1 above. Compound of Example 139 inhibits
PKC.epsilon. in this assay with an IC.sub.50 of 20.+-.7 nM.
7. Protein Kinase C.eta. Assay
[0192] Human recombinant PKC.eta. was obtained from PanVera and is
used under the assay conditions as described under Section A.1
above. Compound of Example 85 inhibits PKC.eta. in this assay with
an IC.sub.50 of 50.+-.9 nM.
8. CD28 Costimulation Assay
[0193] The assay is performed with Jurkat cells transfected with a
human interleukin-2 promoter/reporter gene construct as described
by Baumann G et al. in Transplant. Proc. 1992; 24:43-8, the
.beta.-galactosidase reporter gene being replaced by the luciferase
gene (de Wet J., et al., Mol. Cell. Biol. 1987, 7(2), 725-737).
Cells are stimulated by solid phase-coupled antibodies or phorbol
myristate acetate (PMA) and the Ca.sup.++ ionophore ionomycin as
follows. For antibody-mediated stimulation Microlite TM1 microtiter
plates (Dynatech) are coated with 3 .mu.g/ml goat anti-mouse IgG Fc
antibodies (Jackson) in 55 .mu.l phosphate-buffered saline (PBS)
per well for three hours at room temperature. Plates are blocked
after removing the antibodies by incubation with 2% bovine serum
albumin (BSA) in PBS (300 .mu.l per well) for 2 hours at room
temperature. After washing three times with 300 .mu.l PBS per well,
10 .mu.g/ml anti-T cell receptor antibodies (WT31, Becton &
Dickinson) and 300 ng/ml anti-CD28 antibodies (15E8) in 50 .mu.l 2%
BSA/PBS are added as stimulating antibodies and incubated overnight
at 4.degree. C. Finally the plates are washed three times with 300
.mu.l PBS per well. Seven three-fold serial dilutions of test
compounds in duplicates in assay medium (RPMI 1640/10% fetal calf
serum (FCS) containing 50 .mu.M 2-mercaptoethanol, 100 units/ml
penicillin and 100 .mu.g/ml streptomycin) are prepared in separate
plates, mixed with transfected Jurkat cells (clone K22 290_H23) and
incubated for 30 minutes at 37.degree. C. in 5% CO.sub.2. 100 .mu.l
of this mixture containing 1.times.10.sup.5 cells are then
transferred to the antibody-mated assay plates. In parallel 100
.mu.l are incubated with 40 ng/ml PMA and 2 .mu.M ionomycin. After
incubation for 5.5 hours at 37.degree. C. in 5% CO.sub.2, the level
of luciferase is determined by bioluminescence measurement. The
plates are centrifuged for 10 min at 500 g and the supernatant is
removed by flicking. Lysis buffer containing 25 mM Tris-phosphate,
pH 7.8, 2 mM DTT, 2 mM 1,2-diaminocyclohexane-N,N,N',N-tetraacetic
acid, 10% (v/v) glycerol and 1% (v/v) Triton X-100 is added (20
.mu.l per well). The plates are incubated at room temperature for
10 minutes under constant shaking. Luciferase activity is assessed
with a bioluminescence reader (Labsystem, Helsinki, Finland) after
automatic addition of 50 .mu.l per well luciferase reaction buffer
containing 20 mM Tricine, 1.07 mM
(MgCO.sub.3).sub.4Mg(OH).sub.2x5H.sub.2O, 2.67 mM MgSO.sub.4, 0.1
mM EDTA, 33.3 mM DTT, 270 .mu.M coenzyme A, 470 .mu.M luciferin
(Chemie Brunschwig AG), 530 .mu.M ATP, pH 7.8. Lag time is 0.5
seconds, total measuring time is 1 or 2 seconds. Low control values
are light units from anti-T cell receptor- or PMA-stimulated cells,
high controls are from anti-T cell receptor/anti-CD28- or
PMA/ionomycin-stimulated cells without any test sample. Low
controls are subtracted from all values. The inhibition obtained in
the presence of a test compound is calculated as percent inhibition
of the high control. The concentration of test compounds resulting
in 50% inhibition (IC.sub.50) is determined from the dose-response
curves. In this assay, compounds of formula I inhibit anti-T cell
receptor/anti-CD28 and PMA/ionomycin stimulated Jurkat cells with
an IC.sub.50.ltoreq.1 .mu.M. Compound of Example 56 has an
IC.sub.50 of 42.+-.12 nM in this assay.
9. Allogeneic Mixed Lymphocyte Reaction (MLR)
[0194] The two-way MLR is performed according to standard
procedures (J. Immunol. Methods, 1973, 2, 279 and Meo T. et al.,
Immunological Methods, New York, Academic Press, 1979, 227-39).
Briefly, spleen cells from CBA and BALB/c mice (1.6.times.10.sup.5
cells from each strain per well in flat bottom tissue
culture-microtiter plates, 3.2.times.10.sup.5 in total) are
incubated in RPMI medium containing 10% FCS, 100 U/ml penicillin,
100 .mu.g/ml streptomycin (Gibco BRL, Basel, Switzerland), 50 .mu.M
2-mercaptoethanol (Fluka, Buchs, Switzerland) and serially diluted
compounds. Seven three-fold dilution steps in duplicates per test
compound are performed. After four days of incubation 1 .mu.Ci
.sup.3H-thymidine is added. Cells are harvested after an additional
five-hour incubation period, and incorporated .sup.3H-thymidine is
determined according to standard procedures. Background values (low
control) of the MLR are the proliferation of BALB/c cells alone.
Low controls are subtracted from all values. High controls without
any sample are taken as 100% proliferation. Percent inhibition by
the samples is calculated, and the concentrations required for 50%
inhibition (IC.sub.50 values) are determined. In this assay,
Compound of Example 56 has an IC.sub.50 of 168.+-.20 nM.
B. In Vivo
Rat Heart Transplantation
[0195] The strain combination used: Male Lewis (RT.sup.1 haplotype)
and BN (RT.sup.1 haplotype). The animals are anaesthetised using
inhalational isofluorane. Following heparinisation of the donor rat
through the abdominal inferior vena cava with simultaneous
exsanguination via the aorta, the chest is opened and the heart
rapidly cooled. The aorta is ligated and divided distal to the
first branch and the brachiocephalic trunk is divided at the first
bifurcation. The left pulmonary artery is ligated and divided and
the right side divided but left open. All other vessels are
dissected free, ligated and divided and the donor heart is removed
into iced saline.
[0196] The recipient is prepared by dissection and cross-clamping
of the infra-renal abdominal aorta and vena cava. The graft is
implanted with end-to-side anastomoses, using 10/0 monofilament
suture, between the donor brachiocephalic trunk and the recipient
aorta and the donor right pulmonary artery to the recipient vena
cava. The clamps are removed, the graft tethered retroabdominally,
the abdominal contents washed with warm saline and the animal is
closed and allowed to recover under a heating lamp. Graft survival
is monitored by daily palpation of the beating donor heart through
the abdominal wall. Rejection is considered to be complete when
heart beat stops. Increases of graft survival are obtained in
animals treated with a compound of formula I administered orally at
a daily dose of 1 to 30 mg/kg. Thus compound of Example 100
significantly increases the graft survival when administered at a
dose of 30 mg/kg/day.
[0197] The compounds of formula I are, therefore, useful in the
treatment and/or prevention of diseases or disorders mediated by T
lymphocytes and/or PKC, e.g. acute or chronic rejection of organ or
tissue allo- or xenografts, atherosclerosis, vascular occlusion due
to vacular injury such as angioplasty, restenosis, hypertension,
heart failure, chronic obstructive pulmonary disease, CNS diseases
such as Alzheimer disease or amyotrophic lateral sclerosis, cancer,
infectious diseases such as AIDS, septic shock or adult respiratory
distress syndrome, ischemia/reperfusion injury e.g. myocardial
infarction, stroke, gut ischemia, renal failure or hemorrhage
shock, or traumatic shock. The compounds of formula I are also
useful in the treatment and/or prevention of T-cell mediated acute
or chronic inflammatory diseases or disorders or autoimmune
diseases e.g. rheumatoid arthritis, osteoarthrits, systemic lupus
erythematosus, Hashimoto's thyroidis, multiple sclerosis,
myasthenia gravis, diabetes type I or II and the disorders
associated therewith, respiratory diseases such as asthma or
inflammatory lung injury, inflammatory liver injury, inflammatory
glomerular injury, cutaneous manifestations of
immunologically-mediated disorders or illnesses, inflammatory and
hyperproliferative skin diseases (such as psoriasis, atopic
dermatitis, allergic contact dermatitis, irritant contact
dermatitis and further eczematous dermatitises, seborrhoeic
dermatitis), inflammatory eye diseases, e.g. Sjoegren's syndrome,
keratoconjunctivitis or uveitis, inflammatory bowel disease,
Crohn's disease or ulcerative colitis. For the above uses the
required dosage will of course vary depending on the mode of
administration, the particular condition to be treated and the
effect desired. In general, satisfactory results are indicated to
be obtained systemically at daily dosages of from about 0.1 to
about 100 mg/kg body weight. An indicated daily dosage in the
larger mammal, e.g. humans, is in the range from about 0.5 mg to
about 2000 mg, conveniently administered, for example, in divided
doses up to four times a day or in retard form.
[0198] The compounds of formula I may be administered by any
conventional route, in particular enterally, e.g. orally, e.g. in
the form of tablets or capsules, or parenterally, e.g. in the form
of injectable solutions or suspensions, topically, e.g. in the form
of lotions, gels, ointments or creams, or in a nasal or a
suppository form. Pharmaceutical compositions comprising a compound
of formula I in free form or in pharmaceutically acceptable salt
form in association with at least one pharmaceutical acceptable
carrier or diluent may be manufactured in conventional manner by
mixing with a pharmaceutically acceptable carrier or diluent. Unit
dosage forms for oral administration contain, for example, from
about 0.1 mg to about 500 mg of active substance.
[0199] Topical administration is e.g. to the skin. A further form
of topical administration is to the eye.
[0200] The compounds of formula I may be administered in free form
or in pharmaceutically acceptable salt form e.g. as indicated
above. Such salts may be prepared in conventional manner and
exhibit the same order of activity as the free compounds.
[0201] In accordance with the foregoing the present invention
further provides: [0202] 1.1 A method for preventing or treating
disorders or diseases mediated by T lymphocytes and/or PKC, e.g.
such as indicated above, in a subject in need of such treatment,
which method comprises administering to said subject an effective
amount of a compound of formula I or a pharmaceutically acceptable
salt thereof; [0203] 1.2 A method for preventing or treating acute
or chronic transplant rejection or T-cell mediated inflammatory or
autoimmune diseases, e.g. as indicated above, in a subject in need
of such treatment, which method comprises administering to said
subject an effective amount of a compound of formula I or a
pharmaceutically acceptable salt thereof; [0204] 2. A compound of
formula I, in free form or in a pharmaceutically acceptable salt
form for use as a pharmaceutical, e.g. in any of the methods as
indicated under 1.1 and 1.2 above. [0205] 3. A pharmaceutical
composition, e.g. for use in any of the methods as in 1.1 and 1.2
above comprising a compound of formula I in free form or
pharmaceutically acceptable salt form in association with a
pharmaceutically acceptable diluent or carrier therefor. [0206] 4.
A compound of formula I or a pharmaceutically acceptable salt
thereof for use in the preparation of a pharmaceutical composition
for use in any of the method as in 1.1 and 1.2 above.
[0207] Compounds of formula I may be administered as the sole
active ingredient or together with other drugs in immunomodulating
regimens or other anti-inflammatory agents e.g. for the treatment
or prevention of allo- or xenograft acute or chronic rejection or
inflammatory or autoimmune disorders. For example, they may be used
in combination with cyclosporines, or ascomycines or their
immunosuppressive analogs or derivatives, e.g. cyclosporin A.
cyclosporin G, FK-506, ABT-281, ASM 981; an mTOR inhibitor, e.g.
rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin etc.; corticosteroids;
cyclophosphamide; azathioprine; methotrexate; an accelerating
lymphocyte homing agent, e.g. FTY 720; leflunomide or analogs
thereof; mizoribine; mycophenolic acid; mycophenolate mofetil;
15-deoxyspergualine or analogs thereof; immunosuppressive
monoclonal antibodies, e.g., monoclonal antibodies to leukocyte
receptors, e.g., MHC, CD2, CD3, CD4, CD 11a/CD18, CD7, CD25, CD 27,
B7, CD40, CD45, CD58, CD 137, ICOS, CD150 (SLAM), OX40, 4-1BB or
their ligands, e.g. CD154; or other immunomodulatory compounds,
e.g. a recombinant binding molecule having at least a portion of
the extracellular domain of CTLA4 or a mutant thereof, e.g. an at
least extracellular portion of CTLA4 or a mutant thereof joined to
a non-CTLA4 protein sequence, e.g. CTLA4Ig (for ex. designated ATCC
68629) or a mutant thereof, e.g. LEA29Y, or other adhesion molecule
inhibitors, e.g. mAbs or low molecular weight inhibitors including
LFA-1 antagonists, Selectin antagonists and VLA-4 antagonists.
Compounds of formula I may also be administered together with an
antiproliferative drug, e.g. a chemotherapeutic drug, e.g. in
cancer treatment, or with an anti-diabetic drug in diabetes
therapy.
[0208] In accordance with the foregoing the present invention
provides in a yet further aspect: [0209] 5. A method as defined
above comprising co-administration, e.g. concomitantly or in
sequence, of a therapeutically effective amount of an inhibitor of
PKC and of T-cell activation and proliferation, e.g. a compound of
formula I in free form or in pharmaceutically acceptable salt form,
and a second drug substance, said second drug substance being an
immunosuppressant, immunomodulatory, anti-inflammatory,
antiproliferative or anti-diabetic drug, e.g. as indicated above.
[0210] 6. A therapeutic combination, e.g. a kit, comprising a) an
inhibitor of PKC and of T-cell activation and proliferation, e.g. a
compound of formula I in free form or in pharmaceutically
acceptable salt form, and b) at least one second agent selected
from an immunosuppressant, immunomodulatory, anti-inflammatory,
antiproliferative and anti-diabetic drug. Component a) and
component b) may be used concomitantly or in sequence. The kit may
comprise instructions for its administration.
[0211] Where an inhibitor of PKC and of T-cell activation and
proliferation, e.g. a compound of formula I, is administered in
conjunction with other immunosuppressive/immunomodulatory,
anti-inflammatory, antiproliferative or anti-diabetic therapy, e.g.
for preventing or treating acute or chronic graft rejection or
inflammatory or autoimmune disorders as hereinabove specified,
dosages of the co-administered immunosuppressant, immunomodulatory,
anti-inflammatory, antiproliferative or anti-diabetic compound will
of course vary depending on the type of co-drug employed, e.g.
whether it is a steroid or a cyclosporine, on the specific drug
employed, on the condition being treated and so forth.
[0212] A preferred compound according to the invention is e.g. the
compound of Example 56.
* * * * *