U.S. patent application number 09/850434 was filed with the patent office on 2002-02-14 for n-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as vegf receptor tyrosine kinase inhibitors.
Invention is credited to Altmann, Karl-Heinz, Bold, Guido, Ferrari, Stefano, Furet, Pascal, Haberey, Martin, Hofmann, Francesco, Huth, Andreas, Kruger, Martin, Manley, Paul William, Menrad, Andreas, Mestan, Jurgen, Seidelmann, Dieter, Thierauch, Karl-Heinz, Wood, Jeanette Marjorie.
Application Number | 20020019414 09/850434 |
Document ID | / |
Family ID | 10842150 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020019414 |
Kind Code |
A1 |
Altmann, Karl-Heinz ; et
al. |
February 14, 2002 |
N-aryl(thio)anthranilic acid amide derivatives, their preparation
and their use as VEGF receptor tyrosine kinase inhibitors
Abstract
1 Described are compounds of formula (I), wherein W is O or S; X
is NR.sub.8; Y is CR.sub.9R.sub.10-(CH.sub.2)n wherein R.sub.9 and
R.sub.10 are independently of each other hydrogen or lower alkyl,
and n is an integer of from and including 0 to and including 3; or
Y is SO.sub.2; R.sub.1 is aryl; R.sub.2 is a mono- or bicyclic
heteroaryl group comprising one or more ring nitrogen atoms with
the exception that R.sub.2 cannot represent 2-phthalimidyl, and in
case of Y.dbd.SO.sub.2 cannot represent 2,1,3-benzothiadiazol-4-yl;
any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently of the
other, is H or a substituent other than hydrogen; and R.sub.7 and
R.sub.8, independently of each other, are H or lower alkyl; or a
N-oxide or a pharmaceutically acceptable salt thereof for the
preparation of a pharmaceutical product for the treatment of a
neoplastic disease which responds to an inhibition of the VEGF
receptor tyrosine kinase activity. The compounds of formula (I) can
be used for the treatment e.g. of a neoplastic disease, such as a
tumor disease, of retinopathy and age-related macular
degeneration.
Inventors: |
Altmann, Karl-Heinz;
(Reinach, CH) ; Bold, Guido; (Gipf-Oberfrick,
CH) ; Furet, Pascal; (Thann, FR) ; Manley,
Paul William; (Arlesheim, CH) ; Wood, Jeanette
Marjorie; (Biel-Benken, CH) ; Ferrari, Stefano;
(Muttenz, CH) ; Hofmann, Francesco; (Bottmingen,
CH) ; Mestan, Jurgen; (Denzlingen, DE) ; Huth,
Andreas; (Berlin, DE) ; Kruger, Martin;
(Berlin, DE) ; Seidelmann, Dieter; (Berlin,
DE) ; Menrad, Andreas; (Oranienburg, DE) ;
Haberey, Martin; (Berlin, DE) ; Thierauch,
Karl-Heinz; (Berlin, DE) |
Correspondence
Address: |
THOMAS HOXIE
NOVARTIS CORPORATION
PATENT AND TRADEMARK DEPT
564 MORRIS AVENUE
SUMMIT
NJ
079011027
|
Family ID: |
10842150 |
Appl. No.: |
09/850434 |
Filed: |
May 7, 2001 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
09850434 |
May 7, 2001 |
|
|
|
PCT/EP99/08545 |
Nov 8, 1999 |
|
|
|
Current U.S.
Class: |
514/300 ;
514/311; 514/357; 546/122; 546/176; 546/336 |
Current CPC
Class: |
A61P 43/00 20180101;
C07D 213/56 20130101; A61P 35/00 20180101; A61K 31/47 20130101;
C07D 233/54 20130101; C07D 213/89 20130101; C07D 215/12 20130101;
A61P 17/00 20180101; C07D 405/12 20130101; A61K 31/415 20130101;
A61K 31/44 20130101; A61P 27/02 20180101; C07D 213/64 20130101;
C07D 213/38 20130101 |
Class at
Publication: |
514/300 ;
514/311; 514/357; 546/122; 546/176; 546/336 |
International
Class: |
C07D 471/02; C07D
215/14; C07D 211/22; A61K 031/47; A61K 031/4409; A61K 031/4745 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 10, 1998 |
GB |
9824579.8 |
Claims
What is claimed is:
1. Use of a compound of formula I, 11wherein W is O or S; X is
NR.sub.8; Y is CR.sub.9R.sub.10-(CH.sub.2).sub.n wherein R.sub.9
and R.sub.10 are independently of each other hydrogen or lower
alkyl, and n is an integer of from and including 0 to and including
3; or Y is SO.sub.2; R.sub.1 is aryl; R.sub.2 is a mono- or
bicyclic heteroaryl group comprising one or more ring nitrogen
atoms with the exception that R.sub.2 cannot represent
2-phthalimidyl, and in case of Y.dbd.SO.sub.2 cannot represent
2,1,3-benzothiadiazol-4-yl; any of R.sub.3, R.sub.4, R.sub.5 and
R.sub.6, independently of the other, is H or a substituent other
than hydrogen; and R.sub.7 and R.sub.8, independently of each
other, are H or lower alkyl; or a N-oxide or a pharmaceutically
acceptable salt thereof for the preparation of a pharmaceutical
product for the treatment of a neoplastic disease which responds to
an inhibition of the VEGF receptor tyrosine kinase activity.
2. Use of a compound of formula I, wherein the radicals and symbols
have the meanings as defined in claim 1, or a N-oxide or a
pharmaceutically acceptable salt thereof for the preparation of a
pharmaceutical product for the treatment of retinopathy or
age-related macula degeneration.
3. A method for the treatment of a neoplastic disease which
responds to an inhibition of the VEGF-receptor tyrosine kinase
activity, which comprises administering a compound of formula I or
a N-oxide or a pharmaceutically acceptable salt thereof, wherein
the radicals and symbols have the meanings as defined in claim 1,
in a quantity effective against the said disease, to a warm-blooded
animal requiring such treatment.
4. A method for the treatment of retinopathy or age-related macular
degeneration, which comprises administering a compound of formula I
or a N-oxide or a pharmaceutically acceptable salt thereof, wherein
the radicals and symbols have the meanings as defined in claim 1,
in a quantity effective against said diseases, to a warm-blooded
animal requiring such treatment.
5. A compound of formula I, wherein W is O or S; X is NR.sub.8; Y
is CR.sub.9R.sub.10-(CH.sub.2).sub.n wherein R.sub.9 and R.sub.10
are independently of each other hydrogen or lower alkyl, and n is
an integer of from and including 0 to and including 3; or Y is
SO.sub.2; R.sub.1 is aryl; R.sub.2 is a mono- or bicyclic
heteroaryl group comprising one or more ring nitrogen atoms with
the exception that R.sub.2 cannot represent 2-phthalimidyl, and in
case of Y.dbd.SO.sub.2 cannot represent 2,1,3-benzothiadiazol-4-yl;
any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently of the
other, is H or a substituent other than hydrogen; and R.sub.7 and
R.sub.8, independently of each other, are H or lower alkyl; with
the exception of the compound of formula I wherein W is 0, X is
NR.sub.8, Y is CH.sub.2, R.sub.1 is 4-chlorophenyl, R.sub.2 is
2-pyridyl, R.sub.3, R.sub.4, R.sub.6, R.sub.7 and R.sub.8 are each
H and R.sub.6 is chloro; or a N-oxide or a pharmaceutically
acceptable salt thereof.
6. A compound of formula I according to claim 5, wherein W is O or
S; X is NR.sub.8; Y is CHR.sub.9-(CH.sub.2).sub.n wherein R.sub.9
is hydrogen or lower alkyl, and n is an integer of from and
including 0 to and including 3; or Y is SO.sub.2; R.sub.1 is aryl;
R.sub.2 is a mono- or bicyclic heteroaryl group comprising one or
more ring nitrogen atoms with the exception that R.sub.2 cannot
represent 2-phthalimidyl, and in case of Y.dbd.SO.sub.2 cannot
represent 2,1,3-benzothiadiazol-4-yl; any of R.sub.3, R.sub.4,
R.sub.5 and R.sub.6, independently of the other, is H or a
substituent other than hydrogen; and R.sub.7 and R.sub.8,
independently of each other, are H or lower alkyl; with the
exception of the compound of formula I wherein W is O, X is
NR.sub.8, Y is CH.sub.2, R.sub.1 is 4-chlorophenyl, R.sub.2 is
2-pyridyl, R.sub.3, R.sub.4, R.sub.5, R.sub.7 and R.sub.8 are each
H and R.sub.6 is chloro; or a salt thereof.
7. A compound of formula I according to claim 5, wherein W is O or
S; X is NR.sub.8; Y is CHR.sub.9-(CH.sub.2).sub.n wherein R.sub.9
is H or lower alkyl, and n is 0 to 3; or Y is SO.sub.2; R.sub.1 is
phenyl that is unsubsituted or substituted by up to three
substituents selected from amino, mono- or disubstituted amino
wherein the substituents are selected independently from lower
alkyl, hydroxy-lower alkyl, phenyl-lower alkyl, lower alkanoyl,
benzoyl and substituted benzoyl wherein the phenyl radical is
substituted by one or two substituents selected from nitro, amino,
halogen, N-lower alkylamino, N,N-di-lower alkylamino, hydroxy,
cyano, carboxy, lower-alkoxycarbonyl, lower alkanoyl and carbamoyl,
and phenyl-lower alkoxycarbonyl wherein the phenyl radical radical
is substituted by one or two substituents selected from nitro,
amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino,
hydroxy, cyano, carboxy, lower-alkoxycarbonyl, lower alkanoyl and
carbamoyl; lower alkyl; substituted lower alkyl where up to three
substituents are present independently selected from the group
containing halogen, N-lower alkylamino, N,N-di-lower alkylamino,
N-lower alkanoylamino, hydroxy, cyano, carboxy, lower
alkoxycarbonyl and phenyl-lower alkoxycarbonyl; hydroxy, lower
alkoxy; phenyl-lower alkoxy; phenyloxy; halogen-lower alkoxy, lower
alkanoyloxy; benzoyloxy; lower alkoxycarbonyloxy; phenyl-lower
alkoxycarbonyloxy; nitro; cyano; carboxy; lower alkoxycarbonyl;
phenyl-lower alkoxycarbonyl; phenyloxycarbonyl; lower
alkylcarbonyl; carbamoyl; N-mono- or N,N-disubstituted carbamoyl
that is substituted by one or two substituents independently
selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower
alkyl, at the terminal nitrogen atom; amidino; guanidino; mercapto;
sulfo; lower alkylthio; phenylthio; phenyl-lower alkylthio; lower
alkylphenylthio; lower alkylsulfinyl; phenylsulfinyl; phenyl-lower
alkylsulfinyl; lower alkylphenylsulfinyl; lower alkanesulfonyl;
phenylsulfonyl; phenyl-lower alkylsulfonyl; lower
alkylphenylsulfonyl; lower alkenyl; lower alkanoyl; halogen-lower
alkylmercapto; halogen-lower alkylsulfonyl; dihydroxybora
(-B(OH).sub.2); and lower alkylene dioxy bound at adjacent C-atoms
of the ring; R.sub.2 is imidazolyl, quinolyl, naphthyridinyl, or a
moiety of the formula Ib or Ic 12wherein r is 0 to 2; A, B, D, and
E are, independently of one another, N or CH, with the stipulation
that not more than 2 of these radicals are N; preferably; and Q is
lower alkyl, hydroxy, lower alkoxy, lower thioalkyl or halogen; any
of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently of the
other, is H, fluorine or lower alkyl; and R.sub.7 and R.sub.8,
independently of each other, are H or lower alkyl; or a N-oxide or
a pharmaceutically acceptable salt thereof.
8. A compound of formula I according to claim 5, wherein W is O; X
is NR.sub.8; Y is CHR.sub.9-(CH.sub.2).sub.n wherein R.sub.9 is H
or methyl, and n is 0; or Y is SO.sub.2; R.sub.1 is phenyl,
naphthyl or 5,6,7,8-tetrahydronaphthyl which is in each case either
unsubstituted or independently substituted by one or two
substituents selected from the group comprising halogen; lower
alkyl; lower alkoxy; hydroxy; phenyl; phenoxy; halogen-lower
alkoxy; halogen-lower alkyl; lower alkoxycarbonyl; N-lower alkyl
carbamoyl; lower alkylsulfinyl; lower alkanesulfonyl; and lower
alkoxycarbonyl lower alkyl; R.sub.2 is imidazolyl, quinolyl,
naphthyridinyl, 2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl; any
of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently of the
other, are H, methyl or chloro; or R.sub.3 and R.sub.4 together
represent methylene dioxy and R.sub.5 and R.sub.6, independently of
the other, are H, methyl or chloro; and R.sub.7 and R.sub.8,
independently of each other, are H, fluorine or methyl; or a
N-oxide or a pharmaceutically acceptable salt thereof.
9. A compound of formula I according to claim 5, wherein W is O; X
is NR.sub.8; Y is CHR.sub.9-(CH.sub.2).sub.n wherein R.sub.9 is H
or methyl, and n is 0; or Y is SO.sub.2; R.sub.1 is phenyl which is
either unsubstituted or independently substituted by one or two
substituents selected from the group comprising halogen; lower
alkyl; halogen-lower alkyl; lower alkylsulfinyl; and lower
alkanesulfonyl; R.sub.2 is imidazolyl, quinolyl, naphthyridinyl,
2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl; any of R.sub.3,
R.sub.4, R.sub.5 and Re.sub.6, independently of the other, is H or
methyl; and R.sub.7 and R.sub.8, independently of each other, are H
or methyl; or a N-oxide or a pharmaceutically acceptable salt
thereof.
10. A compound of formula I according to claim 5, wherein W is O; X
is NR.sub.8; Y is CHR.sub.9-(CH.sub.2).sub.n wherein R.sub.9 is H
or methyl, and n is 0; or Y is SO.sub.2; R.sub.1 is phenyl which is
either unsubstituted or independently substituted by one or two
substituents selected from the group comprising halogen; lower
alkyl; halogen-lower alkyl; lower alkylsulfinyl; and lower
alkanesulfonyl; R.sub.2 is imidazolyl, quinolyl,
2-methyl-pyridin-4-yl or 4-pyridyl; any of R.sub.3, R.sub.4,
R.sub.5 and R.sub.6, independently of the other, is H or methyl;
and R.sub.7 and R.sub.8, independently of each other, are H or
methyl; or a salt thereof.
11. A compound of formula I according to claim 5, wherein W is O; X
is NR.sub.8; Y is CH.sub.2; R.sub.1 is phenyl, naphthyl or
5,6,7,8-tetrahydronaphthyl which is in each case either
unsubstituted or independently substituted by one or two
substituents selected from the group comprising halogen; lower
alkyl; lower alkoxy; hydroxy; phenyl; phenoxy; halogen-lower
alkoxy; lower alkoxycarbonyl; N-lower alkyl carbamoyl; and lower
alkoxycarbonyl lower alkyl; R.sub.2 is 4-pyridyl; any of R.sub.3,
R.sub.4, R.sub.5 and R.sub.6, independently of the other, are H,
methyl or chloro; or R.sub.3 and R.sub.4 together represent
methylene dioxy and R.sub.5 and R.sub.6, independently of the
other, are H, methyl or chloro; and R.sub.7 and R.sub.8 are H; or a
N-oxide or a pharmaceutically acceptable salt thereof.
12. A compound of formula I according to claim 5 selected from
2-[(4-pyridyl)methyl]amino-N-(4-trifluoromethylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-fluoro-4-methylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-chloro-3-trifluoromethylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-chloro-5-trifluoromethylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)-6-methylbenzamide;
and 2-[(4-quinolyl)methyl]amino-N-(4-chloromethylphenyl)benzamide;
or a pharmaceutically acceptable salt thereof.
13. A compound of formula I according to claim 5 selected from
2-[(4-pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]benzamid-
e; 2-[(4-pyridyl)methyl]amino-N-phenylbenzamide;
2-[(4-pyridyl)methyl]amin-
o-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]am-
ino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-[3,5-(bistrifluoromethyl)phenyl]benzamide;
2-1(4-pyridyl)methyl]amino-N-[3,4-bis-(trifluoromethyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]benzami-
de;
2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-[3-(1 ,1
-dimethylethyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-(3cyanophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-methylthio)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-(3-acetylaminophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-[3-[(aminocarbonyl)amino]phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide;
5-methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzami-
de;
3-methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benza-
mide;
4,5-difluoro-2-[(4-pyridyl)methylamino-N-[3(trifluoromethyl)phenylbe-
nzamide;
2-[(4pyridyl)methyl]amino-N'-methyl-N'-[3-(trifluoromethyl)phenyl-
]benzamide;
2-[(4-pyridyl)methyl]amino-[(3-methylsulphonyl)phenyl]benzamid- e;
2-[(4-pyridyl)methyl]amino-N-[(3-methylsulphinylphenyl]benzamide;
2-1(4-pyridyl)methyl]amino-N-[4-(1 ,
-dimethylethyl)phenylbenzamide;
2-[(4-pyridyl)methyl]amino-N-(3-chlorophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-bromophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-methylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-benzoylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide;
2-[(3-pyridyl)methyl]amino-[N-3-(trifluoromethyl)phenylbenzamide;
2-[(4-quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;
2-[(5-quinolinyl)methyl]amino-[3-(trifluoromethyl)phenyl]benzamide;
2-[(4-(2-methyl)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenylbenzamid-
e;
2-[(4-(1,2-dihydro-2-oxo)pyridyl)methyl]amino-N-3-(trifluoromethyl)phen-
yl)-benzamide;
2-[(4quinolinyl)methyl]amino-N-(4-chlorophenyl)benzamide;
2-[(2-imidazolyl)methyl]amino-4(4chlorophenyl)benzamide;
2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenylbenzamide;
2-[2-(3-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenylbenzamide;
2-[1-methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzami-
de;
2-[(1oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzami-
de; and
2-[(4-pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benz-
amide; or a pharmaceutically acceptable salt thereof.
14. A compound of formula I according to claim 5 selected from
2-[(4-pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamide;
6-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
6-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
3,4-methylendioxy-6-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
4,5-dimethyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-/(7-hydroxynaphthyl)benzamide;
2-1(4-pyridyl)methyl]amino-N-(8-hydroxy-2-naphthyl)benzamide;
4-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
5-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(5,6,7,8-tetrahydronaphthyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-biphenyl)benzamide;
5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(naphthyl)benzamide;
2-[(4-pyridyl)methyl]am- ino-N-(2-napthyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(4-methoxyphenyl)- benzamide;
2-[(4-pyridyl)methyl]amino-N-[4-(trifluoromethoxy)phenyl]benzam-
ide; 2-[(4-pyridyl)methyl]amino-1(4-methoxy-2-naphthyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-bromo-2-naphthyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-[4-(isopropoxycarbonyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-[4-(trifluoromethoxy)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-[4-(isopropylcarbamoyl)phenyl]benzamide;
2-[(4-pyridyl)methyl]amino-N-(3-chloro-4-methylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-(2-methylphenyl)benzamide;
2-[(4-pyridyl)methyl]amino-N-[3-(methoxycarbonylmethyl)phenyl]benzamide;
and 2-[(4-pyridyl)methyl]amino-N-(4-phenoxyphenyl)benzamide; or a
pharmaceutically acceptable salt thereof.
15. A compound of formula I according to any one of claims 5 to 14,
or a N-oxide thereof or a pharmaceutically acceptable salt of such
a compound, for use in a method for the treatment of the human or
animal body.
16. A pharmaceutical preparation, comprising a compound of formula
I according to any one of claims 5 to 14, or a N-oxide or a
pharmaceutically acceptable salt thereof, or a hydrate or solvate
thereof, and at least one pharmaceutically acceptable carrier.
17. A process for the preparation of a compound of formula I
according to claim 5, or a N-oxide or a pharmaceutically acceptable
salt thereof, characterized in that a) for the synthesis of a
compound of the formula I wherein X represents NR.sub.8, where
R.sub.8 is hydrogen and Y represents CHR.sub.9-(CH.sub.2).sub.n,
each as indicated for a compound of formula I, and the remaining
symbols W, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and
R.sub.7 are as defined for a compound of the formula I, an aniline
derivative of the formula II 13wherein W, R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as defined for a compound
of the formula I, is reacted with a carbonyl compound of the
formula III R.sub.2-(CH.sub.2).sub.n-C(R.sub.9).dbd.O (III)wherein
n, R.sub.2 and R.sub.9 are as defined for a compound of the formula
I in the presence of a reducing agent; or b) for the synthesis of a
compound of the formula I wherein X is SO.sub.2 and the remaining
symbols R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, W and X are as defined for a compound of the formula I, an
aniline derivative of the formula II as defined under process
variante a) is reacted with an acid of the formula IVa
R.sub.2-Y--OH (IVa)or a reactive derivative thereof; or with a
compound of formula IVb, R.sub.2-Y-Hal' (IVb)wherein Hal' is
chloro, bromo or iodo; or c) for the synthesis of compounds of the
formula I wherein X represents NR.sub.8, Y represents
CR.sub.9R.sub.10-(CH.sub.2).sub.n and the remaining symbols
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and
R.sub.8 are as defined for a compound of the formula I, a halogen
derivative of the formula V 14wherein Hal represents iodine,
bromine or chlorine and W, R.sub.1, R.sub.3, R.sub.4, R.sub.5,
R.sub.6 and R.sub.7 are as defined for a compound of the formula I,
is reacted with am amine of the formula VI
R.sub.2-(CH.sub.2).sub.n-C(R.sub.9)(R.sub.10)-NHR.sub.8 (VI)wherein
n, R.sub.2, R.sub.8, R.sub.9 and R.sub.10 are as defined for a
compound of the formula I in the presence of an appropriate
catalyst in an inert solvent in the presence of an aprotic base;
where the starting compounds defined in a), b) or c) may also be
present with functional groups in protected form if necessary
and/or in the form of salts, provided a salt-forming group is
present and the reaction in salt form is possible; any protecting
groups in a protected derivative of a compound of the formula I are
removed; and, if so desired, an obtainable compound of formula I is
converted into another compound of formula I or a N-oxide thereof,
a free compound of formula I is converted into a salt, an
obtainable salt of a compound of formula I is converted into the
free compound or another salt, and/or a mixture of isomeric
compounds of formula I is separated into the individual isomers.
Description
[0001] The invention relates to new benzamide derivatives,
processes for the preparation thereof, the application thereof in a
process for the treatment of the human or animal body, the use
thereof--alone or in combination with one or more other
pharmaceutically active compounds--for the treatment especially of
a neoplastic disease, such as a tumor disease, of retinopathy and
age-related macular degeneration; a method for the treatment of
such a disease in animals, especially in humans, and the use of
such a compound--alone or in combination with one or more other
pharmaceutically active compounds--for manufacture of a
pharmaceutical preparation (medicament) for the treatment of a
neoplastic disease, of retinopathy and age-related macular
degeneration.
[0002] Certain diseases are known to be associated with deregulated
angiogenesis, for example diseases caused by ocular
neovascularisation, such as retinopathies (including diabetic
retinopathy), age-related macula degeneration, psoriasis,
haemangioblastoma, haemangioma, arteriosclerosis, an inflammatory
disease, such as a rheumatoid or rheumatic inflammatory disease,
especially arthritis, such as rheumatoid arthritis, or other
chronic inflammatory disorders, such as chronic asthma, arterial or
post-transplantational atherosclerosis, endometriosis, and
especially neoplastic diseases, for example so-called solid tumours
and liquid tumours (such as leucemias).
[0003] According to recent findings, at the centre of the network
regulating the growth and differentiation of the vascular system
and its components, both during embryonic development and normal
growth and in a wide number of pathological anomalies and diseases,
lies the angiogenic factor known as "Vascular Endothelial Growth
Factor" (=VGEF; originally termed "Vascular Permeability Factor",
=VPF), along with its cellular receptors (see Breier, G., et al.,
Trends in Cell Biology 6, 454-6 [1996] and references cited
therein).
[0004] VEGF is a dimeric, disulfide-linked 46-kDa glycoprotein and
is related to "Platelet-Derived Growth Factor" (PDGF). It is
produced by normal cell lines and tumor cell lines, is an
endothelial cell-specific mitogen, shows angiogenic activity in in
vivo test systems (e.g. rabbit cornea), is chemotactic for
endothelial cells and monocytes, and induces plasminogen activators
in endothelial cells, which are then involved in the proteolytic
degradation of extracellular matrix during the formation of
capillaries. A number of isoforms of VEGF are known, which show
comparable biological activity, but differ in the type of cells
that secrete them and in their heparin-binding capacity. In
addition, there are other members of the VEGF family, such as
"Placenta Growth Factor" (PLGF) and VEGF-C.
[0005] VEGF receptors are transmembranous receptor tyrosine
kinases. They are characterized by an extracellular domain with
seven immunoglobulin-like domains and an intracellular tyrosine
kinase domain. Various types of VEGF receptor are known, e.g.
VEGFR-1, VEGFR-2, and VEGFR-3.
[0006] A large number of human tumors, especially gliomas and
carcinomas, express high levels of VEGF and its receptors. This has
led to the hypothesis that the VEGF released by tumor cells could
stimulate the growth of blood capillaries and the proliferation of
tumor endothelium in a paracrine manner and thus, through the
improved blood supply, accelerate tumor growth. Increased VEGF
expression could explain the occurrence of cerebral oedema in
patients with glioma. Direct evidence of the role of VEGF as a
tumor angiogenesis factor in vivo has been obtained from studies in
which VEGF expression or VEGF activity was inhibited. This was
achieved with antibodies which inhibit VEGF activity, with
dominant-negative VEGFR-2 mutants which inhibited signal
transduction, or with the use of antisense-VEGF RNA techniques. All
approaches led to a reduction in the growth of glioma cell lines or
other tumor cell lines in vivo as a result of inhibited tumor
angiogenesis.
[0007] Angiogenesis is regarded as an absolute prerequisite for
those tumors which grow beyond a maximum diameter of about 1-2 mm;
up to this limit, oxygen and nutrients may be supplied to the tumor
cells by diffusion. Every tumor, regardless of its origin and its
cause, is thus dependent on angiogenesis for its growth after it
has reached a certain size.
[0008] Three principal mechanisms play an important part in the
activity of angiogenesis inhibitors against tumors: 1) Inhibition
of the growth of vessels, especially capillaries, into avascular
resting tumors, with the result that there is no net tumor growth
owing to the balance that is achieved between apoptosis and
proliferation; 2) Prevention of the migration of tumor cells owing
to the absence of blood flow to and from tumors; and 3) Inhibition
of endothelial cell proliferation, thus avoiding the paracrine
growth-stimulating effect exerted on the surrounding tissue by the
endothelial cells which normally line the vessels.
[0009] Surprisingly, it has now been found that benzamide
derivatives of formula I, described below, are a new class of
compounds that have advantageous pharmacological properties and
inhibit, for example, the activity of the VEGF receptor tyrosine
kinase, the growth of tumors and VEGF-dependent cell proliferation,
or the treatment of especially inflammatory rheumatic or rheumatoid
diseases, such as rheumatoid arthritis, and/or pain, or the other
diseases mentioned above and below.
[0010] The compounds of formula I open up, for example, an
unexpected new therapeutic approach, especially for diseases in the
treatment of which, and also for the prevention of which, an
inhibition of angiogenesis and/or of the VEGF receptor tyrosine
kinase shows beneficial effects.
FULL DESCRIPTION OF THE INVENTION
[0011] The invention relates the use of a compound of formula I,
2
[0012] wherein
[0013] W is O or S;
[0014] X is NR.sub.8;
[0015] Y is CR.sub.9R.sub.10-(CH.sub.2).sub.n wherein
[0016] R.sub.9 and R.sub.10 are independently of each other
hydrogen or lower alkyl, and
[0017] n is an integer of from and including 0 to and including 3;
or
[0018] Y is SO.sub.2;
[0019] R.sub.1 is aryl;
[0020] R.sub.2 is a mono- or bicyclic heteroaryl group comprising
one or more ring nitrogen atoms with the exception that R.sub.2
cannot represent 2-phthalimidyl, and in case of Y.dbd.SO.sub.2
cannot represent 2,1,3-benzothiadiazol-4-yl;
[0021] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, is H or a substituent other than hydrogen; and
[0022] R.sub.7 and R.sub.8, independently of each other, are H or
lower alkyl;
[0023] or a N-oxide or a pharmaceutically acceptable salt thereof
for the preparation of a pharmaceutical product for the treatment
of a neoplastic disease which responds to an inhibition of the VEGF
receptor tyrosine kinase activity.
[0024] The general terms used hereinbefore and hereinafter
preferably have within the context of this disclosure the following
meanings, unless otherwise indicated:
[0025] The prefix "lower" denotes a radical having up to and
including a maximum of 7, especially up to and including a maximum
of 4 carbon atoms, the radicals in question being either linear or
branched with single or multiple branching.
[0026] Where the plural form is used for compounds, salts, and the
like, this is taken to mean also a single compound, salt, or the
like.
[0027] Any asymmetric carbon atoms (for example in compounds of
formula I, wherein R.sub.9 is lower alkyl) may be present in the
(R)-, (S)- or (R,S)-configuration, preferably in the (R)- or
(S)-configuration. The compounds may thus be present as mixtures of
isomers or as pure isomers, preferably as enantiomer-pure
diastereomers.
[0028] The invention relates also to possible tautomers of the
compounds of formula I.
[0029] Lower alkyl is preferably alkyl with from and including 1 up
to and including 7, preferably from and including 1 to and
including 4, and is linear or branched; preferably, lower alkyl is
butyl, such as n-butyl, sec-butyl, isobutyl, tert-butyl, propyl,
such as n-propyl or isopropyl, ethyl or preferably methyl.
[0030] The index n is preferably 0 or 1, especially 0.
[0031] Y is preferably methylene (CH.sub.2) or ethylene
(CH.sub.2--CH.sub.2), most preferably methylene.
[0032] "Aryl" is an aromatic radical which is bound to the molecule
via a bond located at an aromatic ring carbon atom of the radical.
In a preferred embodiment, aryl is an aromatic radical having 6 to
14 carbon atoms, especially phenyl, naphthyl, tetrahydronaphthyl,
fluorenyl or phenanthrenyl, and is unsubstituted or substituted by
one or more, preferably up to three, especially one or two
substituents, especially selected from amino, mono- or
disubstituted amino, halogen, alkyl, substituted alkyl, hydroxy,
etherified or esterified hydroxy, nitro, cyano, carboxy, esterified
carboxy, alkanoyl, benzoyl, carbamoyl, N-mono- or N,N-disubstituted
carbamoyl, amidino, guanidino, ureido, mercapto, sulfo, lower
alkylthio, phenyl, phenoxy, phenylthio, phenyl-lower alkylthio,
alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl, phenyl-lower
alkylsulfinyl, alkylphenylsulfinyl, lower alkanesulfonyl,
phenylsulfonyl, phenyl-lower alkylsulfonyl, alkylphenylsulfonyl,
lower alkenyl, lower alkanoyl, halogen-lower alkylmercapto,
halogen-lower alkylsulfonyl, such as especially trifluoromethane
sulfonyl, dihydroxybora (-B(OH).sub.2), heterocyclyl, and lower
alkylene dioxy bound at adjacent C-atoms of the ring, such as
methylene dioxy; aryl is preferably phenyl or naphthyl, which in
each case is either unsubstituted or independently substituted by
one or two substituents selected from the group comprising halogen,
especially fluorine, chlorine, or bromine; hydroxy; hydroxy,
etherified by lower alkyl, e.g. methyl, or by halogen-lower alkyl,
e.g. trifluoromethyl; esterified carboxy, especially lower alkoxy
carbonyl, e.g. methoxy carbonyl, n-propoxy carbonyl or iso-propoxy
carbonyl; N-mono-substituted carbamoyl, in particular carbamoyl
monosubstituted by lower alkyl, e.g. methyl, n-propyl or isopropyl;
lower alkyl, especially methyl, ethyl or propyl; substituted alkyl,
especially lower alkyl, e.g. methyl or ethyl, substituted by lower
alkoxy carbonyl, e.g. methoxy carbonyl or ethoxy carbonyl;
halogen-lower alkyl, especially trifluoromethyl; lower
alkylsulfinyl, such as methylsulfinyl, and lower alkanesulfonyl,
such as methane sulfonyl. Aryl is preferably 3- or 4-chlorophenyl,
3-bromophenyl, 4-phenoxyphenyl, 2, 3- or 4-methylphenyl,
4-methoxyphenyl, 3- or 4-tert-butylphenyl, 4-n-propylphenyl,
4-trifluoromethylphenyl, 3-trifluoromethylphenyl,
3-trifluoromethoxyphenyl, 3,4-(trifluoromethyl)phenyl,
3-fluoro-4-methylphenyl, 3-chloro-4-methylphenyl,
4-chloro-3-trifluoromet- hylphenyl,
3-chloro-5-trifluoromethylphenyl, 4-methylsulfinylphenyl,
4-methanesulfonylphenyl, 4-biphenyl, naphthyl, 2-naphthyl;
tetrahydronaphthyl, in particular 5,6,7,8-tetrahydronaphthyl;
hydroxynaphthyl, in particular 7-hydroxynaphthyl, 8-hydroxynaphthyl
or 8-hydroxy-2-naphthyl; methoxynaphthyl, in particular
4-methoxy-2-naphthyl; halonaphthyl, in particular 4-chloronaphthyl
or 3-bromo-2-naphthyl.
[0033] Mono- or disubstituted amino is especially amino substituted
by one or two radicals selected independently of one another from
lower alkyl, such as methyl; hydroxy-lower alkyl, such as
2-hydroxyethyl; phenyl-lower alkyl; lower alkanoyl, such as acetyl;
benzoyl; substituted benzoyl, wherein the phenyl radical is
especially substituted by one or more, preferably one or two,
substituents selected from nitro, amino, halogen, N-lower
alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower
alkoxycarbonyl, lower alkanoyl, and carbamoyl; and phenyl-lower
alkoxycarbonyl, wherein the phenyl radical is unsubstituted or
especially substituted by one or more, preferably one or two,
substituents selected from nitro, amino, halogen, N-lower
alkylamino, N,N-di-lower alkylamino, hydroxy, cyano, carboxy, lower
alkoxycarbonyl, lower alkanoyl, and carbamoyl; and is preferably
N-lower alkylamino, such as N-methylamino, hydroxy-lower
alkylamino, such as 2-hydroxyethylamino, phenyl-lower alkylamino,
such as benzylamino, N,N-di-lower alkylamino, N-phenyl-lower
alkyl-N-lower alkylamino, N,N-di-lower alkylphenylamino, lower
alkanoylamino, such as acetylamino, or a substituent selected from
the group comprising benzoylamino and phenyl-lower
alkoxycarbonylamino, wherein the phenyl radical in each case is
unsubstituted or especially substituted by nitro or amino, or also
by halogen, amino, N-lower alkylamino, N,N-di-lower alkylamino,
hydroxy, cyano, carboxy, lower alkoxycarbonyl, lower alkanoyl,
carbamoyl or aminocarbonylamino.
[0034] Halogen is especially fluorine, chlorine, bromine, or
iodine, especially fluorine, chlorine, or bromine.
[0035] In the preferred embodiment, alkyl has up to a maximum of 12
carbon atoms and is especially lower alkyl, especially methyl, or
also ethyl, n-propyl, isopropyl, or tert-butyl.
[0036] Substituted alkyl is alkyl as last defined, especially lower
alkyl, preferably methyl; where one or more, especially up to
three, substituents may be present, primarily from the group
selected from halogen, especially fluorine, amino, N-lower
alkylamino, N,N-di-lower alkylamino, N-lower alkanoylamino,
hydroxy, cyano, carboxy, lower alkoxycarbonyl, and phenyl-lower
alkoxycarbonyl. Trifluoromethyl is especially preferred.
[0037] Etherified hydroxy is especially C.sub.8-C.sub.20alkyloxy,
such as n-decyloxy, lower alkoxy (preferred), such as methoxy,
ethoxy, isopropyloxy, or n-pentyloxy, phenyl-lower alkoxy, such as
benzyloxy, or also phenyloxy, or as an alternative or in addition
to the previous group C.sub.8-C.sub.20alkyloxy, such as n-decyloxy,
halogen-lower alkoxy, such as trifluoromethyloxy or
1,1,2,2-tetrafluoroethoxy.
[0038] Esterified hydroxy is especially lower alkanoyloxy,
benzoyloxy, lower alkoxycarbonyloxy, such as
tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy, such as
benzyloxycarbonyloxy.
[0039] Esterified carboxy is especially lower alkoxycarbonyl, such
as tert-butoxycarbonyl, isopropoxycarbonyl, methoxycarbonyl or
ethoxycarbonyl, phenyl-lower alkoxycarbonyl, or
phenyloxycarbonyl.
[0040] Alkanoyl is primarily alkylcarbonyl, especially lower
alkanoyl, e.g. acetyl. N-mono- or N,N-disubstituted carbamoyl is
especially substituted by one or two substituents independently
selected from lower alkyl, phenyl-lower alkyl, and hydroxy-lower
alkyl, at the terminal nitrogen atom.
[0041] Alkylphenylthio is especially lower alkylphenylthio.
[0042] Alkylphenylsulfonyl is especially lower
alkylphenylsulfonyl.
[0043] Alkylphenylsulfinyl is especially lower
alkylphenylsulfinyl.
[0044] Heterocyclyl is especially a five or six-membered
heterocyclic system with 1 or 2 heteroatoms selected from the group
comprising nitrogen, oxygen, and sulfur, which may be unsaturated
or wholly or partly saturated, and is unsubstituted or substituted
especially by lower alkyl, such as methyl; a radical selected from
2-methylpyrimidin-4-yl, oxazol-5-yl, 2-methyl-1,3dioxolan-2-yl,
1H-pyrazol-3-yl, and 1-methyl-pyrazol-3-yl is preferred.
[0045] Aryl in the form of phenyl which is substituted by lower
alkylene dioxy bound to two adjacent C-atoms, such as
methylenedioxy, is preferably 3,4-methylenedioxyphenyl.
[0046] Heteroaryl refers to a heterocyclic moiety that is
unsaturated in the ring binding the heteroaryl radical to the rest
of the molecule in formula I and is preferably mono-, bi- or
tricyclic, preferably mono- or bicyclic; where at least in the
binding ring, but optionally also in any annealed ring, one or
more, preferably 1 to 4, most preferably 3 or 4, carbon atoms are
replaced each by a heteroatom selected from the group consisting of
nitrogen, oxygen and sulfur; where the binding ring preferably has
5 to 12, more preferably 5 to 7 ring atoms; and may be
unsubstituted or substituted by one or more, especially one or two,
substitutents selected from the group defined above as
substitutents for aryl, most preferably by lower alkyl, such as
methyl; preferably heteroaryl is selected from thienyl, furyl,
pyranyl, thianthrenyl, isobenzoiuranyl, benzofuranyl, chromenyl,
2H-pyrrolyl, pyrrolyl, lower-alkyl substituted imidazolyl,
benzimidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl,
isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, triazolyl,
tetrazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, cinnolinyl,
pteridinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl,
phenanthrolinyl and furazanyl; more preferably selected from the
group consisting of triazolyl, especially 1,2,4-triazolyl,
1,2,3-triazolyl or 1,3,4-triazolyl, pyridyl, especially 2-, 3 or
4-pyridyl, indolyl, especially 3-indolyl, lower-alkylthiazolyl,
especially 2-(4-methylthiazolyl), pyrrolyl, especially 1-pyrrolyl,
lower alkylimidazolyl, especially 4-(1-methylimidazolyl),
4-(2-methylimidazolyl) or 4-(5-methylimidazolyl), benzimidazolyl,
such as 1-benzimidazolyl, or tetrazolyl, such as
5-(1,2,3,4-tetrazolyl).
[0047] A mono- or bicyclic heteroaryl group comprising one or more
ring nitrogen atoms is preferably a heteroaryl group as defined
above for heteroaryl, with the proviso that preferably at least one
nitrogen is present as ring heteroatom in the binding ring (that
is, the ring from which the bond starts that binds the heteroaryl
moiety to the rest of the molecule) and with the exception that
R.sub.2 cannot represent 2-phthalimidyl, and in case of
Y.dbd.SO.sub.2 R.sub.2 cannot represent 2,1,3-benzothiadiazol-4-yl.
Preferred is imidazolyl, especially imidazol-4-yl, quinolyl,
especially 3-, 4-, 5quinolyl, naphthyridinyl, especially
3-(1,8-naphthyridinyl) or 4-(1,8-naphthyridinyl), or especially a
moiety of the formula Ib or Ic 3
[0048] wherein
[0049] r is 0 to 2,
[0050] A, B, D, and E are, independently of one another, N or CH,
with the stipulation that not more than 2 of these radicals are N;
preferably, each of A, B, D and E is CH; and Q is lower alkyl,
especially methyl, hydroxy, lower alkoxy, especially methoxy, lower
thioalkyl, especially methylthio, or halogen, especially fluoro,
chloro or bromo.
[0051] Very preferably R.sub.2 is 3-pyridyl, 4-pyridyl,
4-quinolinyl or 5-quinolinyl. Most preferably, R.sub.2 is
4-pyridyl.
[0052] A substituent other than hydrogen is preferably selected
from amino, mono- or disubstituted amino, halogen, alkyl,
substituted alkyl, hydroxy, etherified or esterified hydroxy,
nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl,
N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino,
mercapto, sulfo, lower alkylthio, phenylthio, phenyl-lower
alkylthio, alkylphenylthio, lower alkylsulfinyl, phenylsulfinyl,
phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, lower
alkanesulfonyl, phenylsulfonyl, phenyl-lower alkylsulfonyl,
alkylphenylsulfonyl, lower alkenyl, lower alkanoyl, halogen-lower
alkylmercapto, halogen-lower alkylsulfonyl, such as especially
trifluoromethane sulfonyl and heterocyclyl. Two substitutents other
than hydrogen bound at adjacent C-atoms of the ring can also
represent lower alkylene dioxy, such as methylene dioxy ethylene
dioxy. Preferably, a substituent other than hydrogen is lower alkyl
or halogen, especially methyl, chloro or fluoro.
[0053] Preferably, R.sub.7 and N are hydrogen, and R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 each are independently hydrogen,
chloro or fluorine.
[0054] Salts are especially the pharmaceutically acceptable salts
of compounds of formula I.
[0055] Such salts are formed, for example, as acid addition salts,
preferably with organic or inorganic acids, from compounds of
formula I with a basic nitrogen atom, especially the
pharmaceutically acceptable salts. Suitable inorganic acids are,
for example, halogen acids, such as hydrochloric acid, sulfuric
acid, or phosphoric acid. Suitable organic acids are, for example,
carboxylic, phosphonic, sulfonic or sulfamic acids, for example
acetic acid, propionic acid, octanoic acid, decanoic acid,
dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic
acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic
acid, tartaric acid, citric acid, amino acids, such as glutamic
acid or aspartic acid, maleic acid, hydroxymaleic acid,
methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic
acid, benzoic acid, salicylic acid, 4-aminosalicylic acid, phthalic
acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or
ethane-sulfonic acid, 2-hydroxyethanesulfonic add,
ethane-1,2-disulfonic acid, benzenesulfonic acid,
2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2-, 3-
or 4-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric
acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl-,
N-ethyl- or N-propyl-sulfamic acid, or other organic protonic
acids, such as ascorbic acid.
[0056] In the presence of negatively charged radicals, such as
carboxy or sulfo, salts may also be formed with bases, e.g. metal
or ammonium salts, such as alkali metal or alkaline earth metal
salts, for example sodium, potassium, magnesium or calcium salts,
or ammonium salts with ammonia or suitable organic amines, such as
tertiary monoamines, for example triethylamine or
tri(2-hydroxyethyl)amine, or heterocyclic bases, for example
N-ethyl-piperidine or N,N'-dimethylpiperazine.
[0057] When a basic group and an acid group are present in the same
molecule, a compound of formula 1 may also form internal salts.
[0058] For isolation or purification purposes it is also possible
to use pharmaceutically unacceptable salts, for example picrates or
perchlorates. For therapeutic use, only pharmaceutically acceptable
salts or free compounds are employed (where applicable in the form
of pharmaceutical preparations), and these are therefore
preferred.
[0059] In view of the close relationship between the novel
compounds in free form and those in the form of their salts,
including those salts that can be used as intermediates, for
example in the purification or identification of the novel
compounds, any reference to the free compounds hereinbefore and
hereinafter is to be understood as referring also to the
corresponding salts, as appropriate and expedient.
[0060] The compounds of formula I and N-oxides thereof have
valuable pharmacological properties, as described hereinbefore and
hereinafter.
[0061] The efficacy of the compounds of the invention as inhibitors
of VEGF-receptor tyrosine kinase activity can be demonstrated as
follows:
[0062] Test for activity against VEGF-receptor tyrosine kinase. The
test is conducted using Flt-1 VEGF-receptor tyrosine kinase. The
detailed procedure is as follows: 30 .mu.l kinase solution (10 ng
of the kinase domain of Flt-1, Shibuya et al., Oncogene 5, 519-24
[1990]) in 20 mM Tris.HCl pH 7.5, 3 mM manganese dichloride
(MnCl.sub.2), 3 mM magnesium chloride (MgCl.sub.2), 10 .mu.M sodium
vanadate, 0.25 mg/ml polyethylenglycol (PEG) 20000, 1 mM
dithiothreitol and 3 .mu.g/.mu.l poly(Glu,Tyr) 4:1 (Sigma, Buchs,
Switzerland), 8 .mu.M [.sup.33P]-ATP (0.2 .mu.Ci) ,1% dimethyl
sulfoxide, and 0 to 100 .mu.M of the compound to be tested are
incubated together for 10 minutes at room temperature. The reaction
is then terminated by the addition of 10 .mu.l 0.25 M
ethylenediaminetetraacetate (EDTA) pH 7. Using a multichannel
dispenser (LAB SYSTEMS, USA), an aliquot of 20 )l is applied to a
PVDF (=polyvinyl difluoride) Immobilon P membrane (Millipore, USA),
through a Millipore microtiter filter manifold and connected to a
vacuum. Following complete elimination of the liquid, the membrane
is washed 4 times successively in a bath containing 0.5% phosphoric
acid (H.sub.3PO.sub.4) and once with ethanol, incubated for 10
minutes each time while shaking, then mounted in a Hewlett Packard
TopCount Manifold and the radioactivity measured after the addition
of 10 .mu.l Microscint.RTM. (.beta.-scintillation counter liquid).
IC.sub.50-values are determined by linear regression analysis of
the percentages for the inhibition of each compound in three
concentrations (as a rule 0.01, 0.1, and 1 .mu.mol). The
IC.sub.50-values that can be found with compounds of formula I are
in the range of 0.01 to 100 .mu.M, preferably in the range from
0.01 to 50 .mu.M.
[0063] The antitumor efficacy of the compounds of the invention can
be demonstrated in vivo as follows:
[0064] In vivo activity in the nude mouse xenotransplant model:
female BALB/c nude mice (8-12 weeks old), Novartis Animal Farm,
Sisseln, Switzerland) are kept under sterile conditions with water
and feed ad libitum. Tumors are induced either by subcutaneous
injection of tumor cells into mice (for example, Du 145 prostate
carcinoma cell line (ATCC No. HTB 81; see Cancer Research 37,
4049-58 (1978)) or by implanting tumor fragments (about 25 mg)
subcutaneously into the left flank of mice using a 13-gauge trocar
needle under Forene.RTM. anaesthesia (Abbott, Switzerland).
Treatment with the test compound is started as soon as the tumor
has reached a mean volume of 100 mm.sup.3. Tumor growth is measured
two to three times a week and 24 hours after the last treatment by
determining the length of two perpendicular axes. The tumor volumes
are calculated in accordance with published methods (see Evans et
al., Brit. J. Cancer 45, 466-8 [1982]). The antitumor efficacy is
determined as the mean increase in tumor volume of the treated
animals divided by the mean increase in tumor volume of the
untreated animals (controls) and, after multiplication by 100, is
expressed as T/C %. Tumor regression (given in %) is reported as
the smallest mean tumor volume in relation to the mean tumor volume
at the start of treatment. The test compound is administered daily
by gavage.
[0065] As an alternative other cell lines may also be used in the
same manner, for example:
[0066] the MCF-7 breast adenocarcinoma cell line (ATCC No. HTB 22;
see also J. Natl. Cancer Inst. (Bethesda) 51, 1409-16 [19731);
[0067] the MDA-MB 468 breast adenocarcinoma cell line (ATCC No. HTB
132; see also In Vitro 14, 911-15 [1978]);
[0068] the MDA-MB 231 breast adenocarcinoma cell line (ATCC No. HTB
26; see also J. Natl. Cancer Inst. (Bethesda) 53, 661-74
[1974]);
[0069] the Colo 205 colon carcinoma cell line (ATCC No. CCL 222;
see also Cancer Res. 38, 1345-55 [1978]);
[0070] the HCT 116 colon carcinoma cell line (ATCC No. CCL 247; see
also Cancer Res. 41, 1751-6 (1981]);
[0071] the DU145 prostate carcinoma cell line DU 145 (ATCC No. HTB
81; see also Cancer Res. 37, 4049-58 [1978]); and
[0072] the PC-3 prostate carcinoma cell line PC-3 (ATCC No. CRL
1435; see also Cancer Res. 40, 524-34 [1980]).
[0073] The inhibition of VEGF-induced KDR-receptor
autophosphorylation can be confirmed wit a further in vitro
experiment in cells: transfected CHO cells, which permanently
express human VEGF receptor (KDR), are seeded in complete culture
medium (with 10% fetal calf serum=FCS) in 6-well cell-culture
plates and incubated at 37.degree. C. under 5% CO.sub.2 until they
show about 80% confluency. The compounds to be tested are then
diluted in culture medium (without FCS, with 0.1% bovine serum
albumin) and added to the cells. (Controls comprise medium without
test compounds). After two hours' incubation at 37.degree. C.,
recombinant VEGF is added; the final VEGF concentration is 20
ng/ml). After a further five minutes' incubation at 37.degree. C.,
the cells are washed twice with ice-cold PBS (phosphate-buffered
saline) and immediately lysed in 100 .mu.l lysis buffer per well.
The lysates are then centrifuged to remove the cell nuclei, and the
protein concentrations of the supernatants are determined using a
commercial protein assay (BIORAD). The lysates can then either be
immediately used or, if necessary, stored at -20.degree. C.
[0074] A sandwich ELISA is carried out to measure the KDR-receptor
phosphorylation: a monoclonal antibody to KDR (for example Mab
1495.12.14; prepared by H. Towbin) is immobilized on black ELISA
plates (OptiPlate.TM. HTRF-96 from Packard). The plates are then
washed and the remaining free protein-binding sites are saturated
with 1% BSA in PBS. The cell lysates (20 .mu.g protein per well)
are then incubated in these plates overnight at 4.degree. C.
together with an antiphosphotyrosine antibody coupled with alkaline
phosphatase (PY20:AP from Transduction Laboratories). The (plates
are washed again and the) binding of the antiphosphotyrosine
antibody to the captured phosphorylated receptor is then
demonstrated using a luminescent AP substrate (CDP-Star, ready to
use, with Emerald II; TROPIX). The luminescence is measured in a
Packard Top Count Microplate Scintillation Counter (Top Count). The
difference between the signal of the positive control (stimulated
with VEGF) and that of the negative control (not stimulated with
VEGF) corresponds to VEGF-induced KDR-receptor phosphorylation
(=100%). The activity of the tested substances is calculated as %
inhibition of VEGF-induced KDR-receptor phosphorylation, wherein
the concentration of substance that induces half the maximum
inhibition is defined as the ED50 (effective dose for 50%
inhibition). Compounds of formula I here preferably show ED50
values in the range of 0.001 .mu.M to 6 .mu.M, preferably 0.005 to
0.5 .mu.M.
[0075] A compound of formula I or a N-oxide thereof inhibits to
varying degrees also other tyrosine kinases involved in signal
transduction which are mediated by trophic factors, for example AbI
kinase, kinases from the Src family, especially c-Src kinase, Lck,
and Fyn; also kinases of the EGF family, for example, c-erbB2
kinase (HER-2), c-erbB3 kinase, c-erbB4 kinase; insulin-like growth
factor receptor kinase (IGF-1 kinase), especially members of the
PDGF-receptor tyrosine kinase family, such as PDGF-receptor kinase,
CSF-1-receptor kinase, Kit-receptor kinase and VEGF-receptor
kinase; and also serine/threonine kinases, all of which play a role
in growth regulation and transformation in mammalian cells,
including human cells.
[0076] The inhibition of c-erbB2 tyrosine kinase (HER-2) can be
measured, for example, in the same way as the inhibition of EGF-R
protein kinase (see House et al., Europ. J. Biochem. 140, 363-7
[1984]). The erbB2 kinase can be isolated, and its activity
determined, using methods known per se (see T. Akiyama et al.,
Science 232, 1644 [1986]).
[0077] On the basis of these studies, a compound of formula I
according to the invention shows therapeutic efficacy especially
against disorders dependent on protein kinase, especially
proliferative diseases.
[0078] The usefulness of a compound of the formula I in the
treatment of arthritis as an example of an inflammatory rheumatic
or rheumatoid disease can be demonstrated as follows:
[0079] The well-known rat adjuvant arthritis model (Pearson, Proc.
Soc. Exp. Biol. 91, 95-101 (1956)) is used to test the
anti-arthritic activity of compounds of the formula I, or salts
thereof. Adjuvant Arthritis can be treated using two different
dosing schedules: either (i) starting time of immunisation with
adjuvant (prophylactic dosing); or from day 15 when the arthritic
response is already established (therapeutic dosing). Preferably a
therapeutic dosing schedule is used. For comparison, a
cyclooxygenase-2 inhibitor, such as
5-bromo-2-(4-fluorophenyl)-3-[4-(meth- ylsulfonyl)phenyl]thiophene
or diclofenac, is administered in a separate group.
[0080] In detail, male Wistar rats (5 animals per group, weighing
epproximately 200 g, supplied by Iffa Credo, France) are injected
i.d. (intra-dermally) at the base of the tail with 0.1 ml of
mineral oil containing 0.6 mg of lyophilised heat-killed
Mycobacterium tuberculosis. The rats are treated with the test
compound (3, 10 or 30 mg/kg p.o. once per day), or vehicle (water)
from day 15 to day 22 (therapeutic dosing schedule). At the end of
the experiment, the swelling of the tarsal joints is measured by
means of a mico-calliper. Percentage inhibition of paw swelling is
calculated by reference to vehicle treated arthritic animals (0%
inhibition) and vehicle treated normal animals (100%
inhibition).
[0081] The activity of compounds of the formula I against pain can
be shown in the following model of nociception (pain). In this
model, the hyperalgesia caused by an intra-planar yeast injection
is measured by applying increased pressure to the foot until the
animal vocalizes or withdraws its foot from the applied pressure
pad. The model is sensitive to COX inhibitors, and diclofenac at 3
mg/kg is used as a positive control.
[0082] Method: The baseline pressure required to induce
vocalization or withdrawal of the paw of male Sprague Dawley rats
(weighing approximately 180 g, supplied by Iffa Credo, France) is
measured (2 hours before treatment), followed by an intra-planar
injection of 100 .mu.l of a 20% yeast suspension in water in the
hind paw. The rats are treated orally with the test compound (3, 1
0 or 30 mg/kg), diclofenac (3 mg/kg) or vehicle (saline) p.o. 2
hours later (time point 0 hours), and the pressure test is repeated
1 and 2 hours after dosing. Using the standard apparatus supplied
by Ugo Basile, Italy, the pressure required to induce vocalisation
or paw withdrawal of the compound-treated rats at these time points
is compared to that of vehicle-treated animals.
[0083] On the basis of these studies, a compound of formula I
surprisingly is appropriate for the treatment of inflammatory
(especially rheumatic or rheumatoid) diseases and/or pain. The
compounds of the formula 1, especially IA, (or an N-oxide thereof)
according to the invention also show therapeutic efficacy
especially against other disorders dependent on protein kinase,
especially proliferative diseases.
[0084] On the basis of their efficacy as inhibitors of
VEGF-receptor tyrosine kinase activity, the compounds of the
formula I primarily inhibit the growth of blood vessels and are
thus, for example, effective against a number of diseases
associated with deregulated angiogenesis, especially diseases
caused by ocular neovascularisation, especially retinopathies, such
as diabetic retinopathy or age-related macula degeneration,
psoriasis, haemangioblastoma, such as haemangioma, mesangial cell
proliferative disorders, such as chronic or acute renal diseases,
e.g. diabetic nephropathy, malignant nephrosclerosis, thrombotic
microangiopathy syndromes or transplant rejection, or especially
inflammatory renal disease, such as glomerulonephritis, especially
mesangioproliferative glomerulonephritis, haemolytic-uraemic
syndrome, diabetic nephropathy, hypertensive nephrosclerosis,
atheroma, arterial restenosis, autoimmune diseases, acute
inflammation, fibrotic disorders (e.g. hepatic cirrhosis),
diabetes, endometriosis, chronic asthma, arterial or
post-transplantational atherosclerosis, neurodegenerative disorders
and especially neoplastic diseases (solid tumours, but also
leucemias and other "liquid tumours", especially those expressing
c-kit, KDR or flt-1), such as especially breast cancer, cancer of
the colon, lung cancer (especially small-cell lung cancer), cancer
of the prostate or Kaposi's sarcoma. A compound of formula I (or an
N-oxide thereof) inhibits the growth of tumours and is especially
suited to preventing the metastatic spread of tumours and the
growth of micrometastases.
[0085] A compound of formula I can be administered alone or in
combination with one or more other therapeutic agents, possible
combination therapy taking the form of fixed combinations or the
administration of a compound of the invention and one or more other
therapeutic agents being staggered or given independently of one
another, or the combined administration of fixed combinations and
one or more other therapeutic agents. A compound of formula I can
besides or in addition be administered especially for tumor therapy
in combination with chemotherapy, radiotherapy, immunotherapy,
surgical intervention, or a combination of these. Long-term therapy
is equally possible as is adjuvant therapy in the context of other
treatment strategies, as described above. Other possible treatments
are therapy to maintain the patient's status after tumor
regression, or even chemopreventive therapy, for example in
patients at risk.
[0086] Therapeutic agents for possible combination are especially
one or more cytostatic or cytotoxic compounds, for example a
chemotherapeutic agent or several selected from the group
comprising an inhibitor of polyamine biosynthesis, an inhibitor of
protein kinase, especially of serine/threonine protein kinase, such
as protein kinase C, or of tyrosine protein kinase, such as
epidermal growth factor receptor tyrosine kinase, a cytokine, a
negative growth regulator, such as TGF-.beta. or IFN-.beta., an
aromatase inhibitor, a classical cytostatic, and an inhibitor of
the interaction of an SH2 domain with a phosphorylated protein.
[0087] A compound according to the invention is not only for the
(prophylactic and preferably therapeutic) management of humans, but
also for the treatment of other warm-blooded animals, for example
of commercially useful animals, for example rodents, such as mice,
rabbits or rats, or guinea-pigs. Such a compound may also be used
as a reference standard in the test systems described above to
permit a comparison with other compounds.
[0088] In general, the invention relates also to the use of a
compound of formula I or a N-oxide thereof for the inhibition of
VEGF-receptor tyrosine activity, either in vitro or in vivo.
[0089] A compound of formula I or a N-oxide thereof may also be
used for diagnostic purposes, for example with tumors that have
been obtained from warm-blooded animal "hosts", especially humans,
and implanted into mice to test them for decreases in growth after
treatment with such a compound, in order to investigate their
sensitivity to the said compound and thus to improve the detection
and determination of possible therapeutic methods for neoplastic
diseases in the original host.
[0090] With the groups of preferred compounds of formula I and
N-oxides thereof mentioned hereinafter, definitions of substituents
from the general definitions mentioned hereinbefore may reasonably
be used, for example, to replace more general definitions with more
specific definitions or especially with definitions characterized
as being preferred;
[0091] Furthermore, the invention relates to the use of a compound
of formula I, wherein the radicals and symbols have the meanings as
defined above, or a N-oxide or a pharmaceutically acceptable salt
thereof for the preparation of a pharmaceutical product for the
treatment of retinopathy or age-related macula degeneration.
[0092] Furthermore, the invention relates to a method for the
treatment of a neoplastic disease which responds to an inhibition
of the VEGF-receptor tyrosine kinase activity, which comprises
administering a compound of formula I or a N-oxide or a
pharmaceutically acceptable salt thereof, wherein the radicals and
symbols have the meanings as defined above, in a quantity effective
against the said disease, to a warm-blooded animal requiring such
treatment.
[0093] Furthermore, the invention relates to a method for the
treatment of retinopathy or age-related macular degeneration, which
comprises administering a compound of formula I or a N-oxide or a
pharmaceutically acceptable salt thereof, wherein the radicals and
symbols have the meanings as defined above, in a quantity effective
against said diseases, to a warm-blooded animal requiring such
treatment The invention relates in particular to a compound of
formula 1, wherein
[0094] W is O or S;
[0095] X is NR.sub.8;
[0096] Y is CR.sub.9R.sub.10-(CH.sub.2).sub.n wherein
[0097] R.sub.9 and R.sub.10 are independently of each other
hydrogen or lower alkyl, and
[0098] n is an integer of from and including 0 to and including 3;
or
[0099] Y is SO.sub.2;
[0100] R.sub.1 is aryl;
[0101] R.sub.2 is a mono- or bicyclic heteroaryl group comprising
one or more ring nitrogen atoms with the exception that R.sub.2
cannot represent 2-phthalimidyl, and in case of Y.dbd.SO.sub.2
cannot represent 2,1,3-benzothiadiazol-4-yl;
[0102] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, is H or a substituent other than hydrogen; and
[0103] R.sub.7 and R.sub.8, independently of each other, are H or
lower alkyl;
[0104] with the exception of the compound of formula I wherein W is
O, X is NR.sub.8, Y is CH.sub.2, R.sub.1 is 4-chlorophenyl, R.sub.2
is 2-pyridyl, R.sub.3, R.sub.4, R.sub.5, R.sub.7 and R.sub.8 are
each H and R.sub.6 is chloro;
[0105] or a N-oxide or a pharmaceutically acceptable salt
thereof.
[0106] Preferred are compounds of formula I, wherein
[0107] W is O or S;
[0108] X is NR.sub.8;
[0109] Y is CHR.sub.9-(CH.sub.2).sub.n wherein
[0110] R.sub.9 is hydrogen or lower alkyl, and
[0111] n is an integer of from and including 0 to and including 3;
or
[0112] Y is SO.sub.2;
[0113] R.sub.1 is aryl;
[0114] R.sub.2 is a mono- or bicyclic heteroaryl group comprising
one or more ring nitrogen atoms with the exception that R.sub.2
cannot represent 2-phthalimidyl, and in case of Y.dbd.SO.sub.2
cannot represent 2,1,3-benzothiadiazol-4-yl;
[0115] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, is H or a substituent other than hydrogen; and
[0116] R.sub.7 and R.sub.8, independently of each other, are H or
lower alkyl;
[0117] with the exception of the compound of formula I wherein W is
0, X is NR.sub.8, Y is CH.sub.2, R.sub.1 is 4-chlorophenyl, R.sub.2
is 2-pyridyl, R.sub.3, R.sub.4, R.sub.5, R.sub.7 and R.sub.8 are
each H and R.sub.6 is chloro;
[0118] or a salt thereof.
[0119] In particular, preferred compounds of formula I are those in
which
[0120] W is O or S;
[0121] X is NR.sub.8;
[0122] Y is CHR.sub.9-(CH.sub.2).sub.n wherein
[0123] R.sub.9 is H or lower alkyl, and
[0124] n is 0 to 3; or
[0125] Y is SO.sub.2;
[0126] R.sub.1 is phenyl that is unsubsituted or substituted by up
to three substituents selected from amino, mono- or disubstituted
amino wherein the substituents are selected independently from
lower alkyl, hydroxy-lower alkyl, phenyl-lower alkyl, lower
alkanoyl, benzoyl and substituted benzoyl wherein the phenyl
radical is substituted by one or two substituents selected from
nitro, amino, halogen, N-lower alkylamino, N,N-di-lower alkylamino,
hydroxy, cyano, carboxy, lower-alkoxycarbonyl, lower alkanoyl and
carbamoyl, and phenyl-lower alkoxycarbonyl wherein the phenyl
radical radical is substituted by one or two substituents selected
from nitro, amino, halogen, N-lower alkylamino, N,N-di-lower
alkylamino, hydroxy, cyano, carboxy, lower-alkoxycarbonyl, lower
alkanoyl and carbamoyl; lower alkyl; substituted lower alkyl where
up to three substituents are present independently selected from
the group containing halogen, N-lower alkylamino, N,N-di-lower
alkylamino, N-lower alkanoylamino, hydroxy, cyano, carboxy, lower
alkoxycarbonyl and phenyl-lower alkoxycarbonyl; hydroxy, lower
alkoxy; phenyl-lower alkoxy; phenyloxy; halogen-lower alkoxy, lower
alkanoyloxy; benzoyloxy; lower alkoxycarbonyloxy; phenyl-lower
alkoxycarbonyloxy; nitro; cyano; carboxy; lower alkoxycarbonyl;
phenyl-lower alkoxycarbonyl; phenyloxycarbonyl; lower
alkylcarbonyl; carbamoyl; N-mono- or N,N-disubstituted carbamoyl
that is substituted by one or two substituents independently
selected from lower alkyl, phenyl-lower alkyl and hydroxy-lower
alkyl, at the terminal nitrogen atom; amidino; guanidino; mercapto;
sulfo; lower alkylthio; phenylthio; phenyl-lower alkylthio; lower
alkylphenylthio; lower alkylsulfinyl; phenylsulfinyl; phenyl-lower
alkylsulfinyl; lower alkylphenylsulfinyl; lower alkanesulfonyl;
phenylsulfonyl; phenyl-lower alkylsulfonyl; lower
alkylphenylsulfonyl; lower alkenyl; lower alkanoyl; halogen-lower
alkylmercapto; halogen-lower alkylsulfonyl; dihydroxybora
(-B(OH).sub.2); and lower alkylene dioxy bound at adjacent C-atoms
of the ring;
[0127] R.sub.2 is imidazolyl, quinolyl, naphthyridinyl, or a moiety
of the formula Ib or Ic 4
[0128] wherein
[0129] r is 0 to 2;
[0130] A, B, D, and E are, independently of one another, N or CH,
with the stipulation that not more than 2 of these radicals are N;
preferably; and
[0131] Q is lower alkyl, hydroxy, lower alkoxy, lower thioalkyl or
halogen;
[0132] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, is H, fluorine or lower alkyl; and
[0133] R.sub.7 and R.sub.8, independently of each other, are H or
lower alkyl;
[0134] or a N-oxide or a pharmaceutically acceptable salt
thereof.
[0135] More specifically, preference is given to a compound of
formula I, wherein
[0136] W is O;
[0137] X is NR.sub.8;
[0138] Y is CHR.sub.9-(CH.sub.2).sub.n wherein
[0139] R.sub.9 is H or methyl, and
[0140] n is 0;
[0141] or Y is SO.sub.2;
[0142] R.sub.1 is phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl
which is in each case either unsubsituted or independently
substituted by one or two substituents selected from the group
comprising halogen; lower alkyl; lower alkoxy; hydroxy; phenyl;
phenoxy; halogen-lower alkoxy; halogen-lower alkyl; lower
alkoxycarbonyl; N-lower alkyl carbamoyl; lower alkylsulfinyl; lower
alkanesulfonyl; and lower alkoxycarbonyl lower alkyl;
[0143] R.sub.2 is imidazolyl, quinolyl, naphthyridinyl,
2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl; any of R.sub.3,
R.sub.4, R.sub.5 and R.sub.6, independently of the other, are H,
methyl or chloro; or
[0144] R.sub.3 and R.sub.4 together represent methylene dioxy and
R.sub.5 and R.sub.6, independently of the other, are H, methyl or
chloro; and
[0145] R.sub.7 and R.sub.8, independently of each other, are H,
fluorine or methyl;
[0146] or a N-oxide or a pharmaceutically acceptable salt
thereof.
[0147] Even more specifically, preference is given to a compound of
formula I, wherein
[0148] W is O;
[0149] X is NR.sub.8
[0150] Y is CHR.sub.9-(CH.sub.2).sub.n wherein
[0151] R.sub.9 is H or methyl, and
[0152] n is 0;
[0153] or Y is SO.sub.2;
[0154] R.sub.1 is phenyl which is either unsubstituted or
independently substituted by one or two substituents selected from
the group comprising halogen; lower alkyl; halogen-lower alkyl;
lower alkylsulfinyl; and lower alkanesulfonyl;
[0155] R.sub.2 is imidazolyl, quinolyl, naphthyridinyl,
2-methyl-pyridin-4-yl, 3-pyridyl or 4-pyridyl;
[0156] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, is H or methyl; and
[0157] R.sub.7 and R.sub.8, independently of each other, are H or
methyl;
[0158] or a N-oxide or a pharmaceutically acceptable salt
thereof.
[0159] Mostly preferred are compounds of formula I wherein
[0160] W is O;
[0161] X is NR.sub.8
[0162] Y is CHR.sub.9-(CH.sub.2).sub.n wherein
[0163] R.sub.9 is H or methyl, and
[0164] n is 0;
[0165] or Y is SO.sub.2;
[0166] R.sub.1 is phenyl which is either unsubstituted or
independently substituted by one or two substituents selected from
the group comprising halogen; lower alkyl; halogen-lower alkyl;
lower alkylsulfinyl; and lower alkanesulfonyl;
[0167] R.sub.2 is imidazolyl, quinolyl, 2-methyl-pyridin-4-yl or
4-pyridyl;
[0168] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, is H or methyl; and
[0169] R.sub.7 and R.sub.8, independently of each other, are H or
methyl;
[0170] or a salt thereof.
[0171] Especially preferred are compounds of formula I wherein
[0172] W is O;
[0173] X is NR.sub.8;
[0174] Y is CH.sub.2;
[0175] .sub.1 is phenyl, naphthyl or 5,6,7,8-tetrahydronaphthyl
which is in each case either unsubstituted or independently
substituted by one or two substituents selected from the group
comprising halogen; lower alkyl; lower alkoxy; hydroxy; phenyl;
phenoxy; halogen-lower alkoxy; lower alkoxycarbonyl; N-lower alkyl
carbamoyl; and lower alkoxycarbonyl lower alkyl;
[0176] R.sub.2 is 4-pyridyl;
[0177] any of R.sub.3, R.sub.4, R.sub.5 and R.sub.6, independently
of the other, are H, methyl or chloro; or
[0178] R.sub.3 and R.sub.4 together represent methylene dioxy and
R.sub.5 and R.sub.6, independently of the other, are H, methyl or
chloro; and
[0179] R.sub.7 and R.sub.8 are H;
[0180] or a N-oxide or a pharmaceutically acceptable salt
thereof.
[0181] More special preference is given to a compound of formula I
such as is mentioned in the Examples below, or a pharmaceutically
acceptable salt thereof, especially a compound of the formula I or
a salt thereof specifically mentioned in the Examples.
[0182] High preference is given to a compound selected from
[0183]
2-[(4-pyridyl)methyl]amino-N-(4-trifluoromethylphenyl)benzamide;
[0184] 2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
[0185] 2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)benzamide;
[0186]
2-[(4-pyridyl)methyl]amino-N-(3-fluoro-4-methylphenyl)benzamide;
[0187]
2-[(4-pyridyl)methyl]amino-N-(4-chloro-3-trifluoromethylphenyl)benz-
amide;
[0188]
2-[(4-pyridyl)methyl]amino-N-(3chloro-5-trifluoromethylphenyl)benza-
mide;
[0189]
2-[(4-pyridyl)methyl]amino-N-(4-methylphenyl)-6-methylbenzamide;
and
[0190] 2-[(4-quinolyl)methyl]amino-N-(4-chlorophenyl)benzamide;
[0191] or a pharmaceutically acceptable salt thereof.
[0192] Furthermore, high preference is given to a compound selected
from
[0193]
2-[(4-pyridyl)methyl]amino-N-(3-fluoro-(4-trifluoromethyl)phenyl]be-
nzamide;
[0194] 2-1(4-pyridyl)methyl]amino-N-phenylbenzamide;
[0195]
2-[(4-pyridyl)methyl]amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]be-
nzamide;
[0196]
2-[(4-pyridyl)methyl]amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]be-
nzamide;
[0197]
2-[(4-pyridyl)methyl]amino-N-[3,5-(bistrifluoromethyl)phenyl]benzam-
ide;
[0198]
2-[(4-pyridyl)methyl]amino-N-[3,4-bis-(trifluoromethyl)phenyl]benza-
mide;
[0199]
2-[(4-pyridyl)methyl]amino-N-[3-methoxy-5-(trifluoromethyl)phenyl]b-
enzamide;
[0200]
2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;
[0201]
2-[(4-pyridyl)methyl]amino-N-[3-(1,1-dimethylethyl)phenyl]benzamide-
;
[0202] 2-[(4-pyridyl)methyl]amino-N(3-cyanophenyl)benzamide;
[0203]
2-[(4-pyridyl)methyl]amino-N-[(3-methylthio)phenyl]benzamide;
[0204]
2-[(4-pyridyl)methyl]amino-N-(3-acetylaminophenyl)benzamide;
[0205]
2-[(4-pyridyl)methyl]amino-N-[3-1(aminocarbonyl)amino]phenylbenzami-
de;
[0206]
2-[(4-pyridyl)methylamino-N-[3-(dimethylamino)phenyl]benzamide;
[0207]
5-methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]b-
enzamide;
[0208]
3-methyl-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]be-
nzamide;
[0209]
4,5-difluoro-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)pheny-
lbenzamide;
[0210]
2-[(4-pyridyl)methyl]amino-N-methyl-N-[3-(trifluoromethyl)phenyl]be-
nzamide;
[0211]
2-[(4-pyridyl)methyl]amino-N-1(3-methylsulphonyl)phenyl)benzamide;
[0212]
2-[(4-pyridyl)methyl]amino-N-[(3-methylsulphinylphenyl]benzamide;
[0213]
2-[(4-pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide-
;
[0214] 2-[(4-pyridyl)methyl]amino-N(3-chlorophenyl)benzamide;
[0215] 2-[(4-pyridyl)methyl]amino-N(3-bromophenyl)benzamide;
[0216] 2-[(4-pyridyl)methyl]amino-(3-methylphenyl)benzamide;
[0217] 2-[(4-pyridyl)methyl]amino-N(3-benzoylphenyl)benzamide;
[0218]
2-[(4-pyridyl)methyl]amino-N-3-(aminocarbonyl)phenyl]benzamide;
[0219]
2-[(3-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;
[0220]
2-[(4-quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamid-
e;
[0221]
2-[(5-quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamid-
e;
[0222]
2-[(4-(2-methyl)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]b-
enzamide;
[0223]
2-1(4(1,2dihydro-2-oxo)pyridyl)methylamino-N-[3-(trifluoromethyl)ph-
enyl]benzamide;
[0224]
2-1(4-quinolinyl)methylamino-N-(4-chlorophenyl)benzamide;
[0225]
2-1(2-imidazolyl)methyl]amino-N-(4-chlorophenyl)benzamide;
[0226]
2-[2-(4-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;
[0227]
2-[2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide;
[0228]
2-[1-methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]b-
enzamide;
[0229]
2-[(1-oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]ben-
zamide; and
[0230]
2-1(4-pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benza-
mide;
[0231]
2-[(4-pyridyl)methyl]amino-N-(4-chloronaphthyl)benzamide;
[0232]
6-methyl-2-[(4-pyridyl)methyl]amino-AL(4-chlorophenyl)benzamide;
[0233]
6-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
[0234]
3,4-methylendioxy-6-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benz-
amide;
[0235]
4,5-dimethyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide-
;
[0236]
5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;
[0237]
2-[(4-pyridyl)methyl]amino-N-(4-n-propylphenyl)benzamide;
[0238]
2-[(4-pyridyl)methyl]amino-N-(7-hydroxynaphthyl)benzamide;
[0239]
2-[(4-pyridyl)methyl]amino-N-(8-hydroxy-2-naphthyl)benzamide;
4-chloro-2-.(4pyridyl)methyl]amino-N-(4chlorophenyl)benzamide;
[0240]
5-methyl-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
[0241]
2-[(4-pyridyl)methyl]amino-N-(5,6,7,8tetrahydronaphthyl)benzamide;
[0242] 2-[(4-pyridyl)methyl amino-N-(4-biphenyl)benzamide;
[0243]
5-chloro-2-[(4-pyridyl)methyl]amino-N-(4-chlorophenyl)benzamide;
[0244] 2-[(4-pyridyl)methyl]amino-N-(naphthyl)benzamide;
[0245] 2-[(4-pyridyl)methyl]amino-N-(2-napthyl)benzamide;
[0246] 2-[(4-pyridyl)methyl]amino-N-(4-methoxyphenyl)benzamide;
[0247]
2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethoxy)phenyl]benzamide;
[0248]
2-[(4-pyridyl)methyl]amino-N-(4-methoxy-2-naphthyl)benzamide;
[0249]
2-[(4-pyridyl)methyl]amino-N-(3-bromo-2-naphthyl)benzamide;
[0250]
2-[(4-pyridyl)methyl]amino-N-[4-(isopropoxycarbonyl)phenyl]benzamid-
e;
[0251]
2-[(4-pyridyl)methyl]amino-N-[4-(trifluoromethoxy)phenyl]benzamide;
[0252]
2-[(4-pyridyl)methyl]amino-N-[4-(isopropylcarbamoyl)phenyl]benzamid-
e;
[0253]
2-[(4-pyridyl)methyl]amino-N-(3-chloro-4-methylphenyl)benzamide;
[0254] 2-[(4-pyridyl)methyl]amino-N-(2-methylphenyl)benzamide;
[0255]
2-1(4-pyridyl)methyl]amino-N-[3-(methoxycarbonylmethyl)phenyl]benza-
mide;
[0256] 2-[(4-pyridyl)methylamino-N-(4-phenoxyphenyl)benzamide;
[0257] or a pharmaceutically acceptable salt thereof.
[0258] A compound of the invention may be prepared by processes
that, though not applied hitherto for the new compounds of the
present invention, are known per se, especially a process
characterized in that
[0259] a) for the synthesis of a compound of the formula I wherein
X represents NR.sub.8, where R.sub.8 is hydrogen and Y represents
CHR.sub.9-(CH.sub.2)1, each as indicated for a compound of formula
I, and the remaining symbols R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5 and R.sub.6 are as defined for a compound of the formula I,
an aniline derivative of the formula II 5
[0260] wherein W, R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and
R.sub.7 are as defined for a compound of the formula I, is reacted
with a carbonyl compound of the formula III
R.sub.2-(CH.sub.2).sub.n-C(R.sub.9).dbd.O (III)
[0261] wherein n, R.sub.2 and R.sub.9 are as defined for a compound
of the formula I in the presence of a reducing agent; or
[0262] b) for the synthesis of a compound of the formula I wherein
Y is SO.sub.2 and the remaining symbols R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, W and X are as defined for a
compound of the formula I, an aniline derivative of the formula II
as defined under process variante a) is reacted with an acid of the
formula IVa
R.sub.2-Y--OH (IVa)
[0263] or a reactive derivative thereof; or with a compound of
formula IVb,
R.sub.2-Y-Hal' (IVb)
[0264] wherein Hal' is chloro, bromo or iodo; or
[0265] c) for the synthesis of compounds of the formula I wherein X
represents NR.sub.8, Y represents CR.sub.9R.sub.10(CH.sub.2)n and
the remaining symbols R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7 and R.sub.8 are as defined for a compound of the
formula I, a halogen derivative of the formula V. 6
[0266] wherein Hal represents iodine, bromine or chlorine and W,
R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as
defined for a compound of the formula I, is reacted with an amine
of the formula VI
R.sub.2-(CH.sub.2).sub.n-C(R.sub.9)(R.sub.10)--NHR.sub.8 (VI)
[0267] wherein n, R.sub.2, R.sub.8, R.sub.9 and R.sub.10 are as
defined for a compound of the formula I in the presence of an
appropriate catalyst such as a palladium catalyst, for example as
generated in situ from tris(dibenzylideneacetone)-dipalladium[0]
and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl in an inert solvent
such as toluene, in the presence of an aprotic base such as sodium
t-butoxide or caesium carbonate, or a nickel catalyst, such as
dibromobis(bipyridyl)-ni- ckel[2] in a sovent such as
isopropylmethyl ketone, or a copper catalyst, such as
copper(l)iodide in a solvent such as dimethylformamide;
[0268] d) for the synthesis of compounds of the formula I wherein X
represents NR.sub.8, Y represents CH.sub.2, W is 0, R.sub.2 is
4-pyridyl, R.sub.7 and R.sub.8 are each H and and R.sub.1, R.sub.3,
R.sub.4, R.sub.5 and R.sub.6 are as defined for a compound of the
formula I, a compound of formula VII 7
[0269] wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined
for a compound of the formula I and R.sub.1, is lower alkyl, is
reacted with a compound of formula VIII
H.sub.2NR.sub.1 (VIII)
[0270] wherein R.sub.1 is as defined for a compound of formula I in
the presence of trimethylaluminium in an inert solvent, e.g.
toluol;
[0271] where the starting compounds defined in a), b), c) or d) may
also be present with functional groups in protected form if
necessary and/or in the form of salts, provided a salt-forming
group is present and the reaction in salt form is possible;
[0272] any protecting groups in a protected derivative of a
compound of the formula I are removed;
[0273] and, if so desired, an obtainable compound of formula I is
converted into another compound of formula I or a N-oxide thereof,
a free compound of formula I is converted into a salt, an
obtainable salt of a compound of formula I is converted into the
free compound or another salt, and/or a mixture of isomeric
compounds of formula I is separated into the individual
isomers.
[0274] Detailed description of the process variants:
[0275] In the more detailed description of the process below,
R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7,
R.sub.8, R.sub.9, R.sub.10 X, Y and W are as defined for compounds
of formula I, unless otherwise indicated.
[0276] Process a) (reductive alkylation)
[0277] The carbonyl compound of the formula III may also be present
in the form of reactive derivative; however, the free aldehyde or
ketone is preferred.
[0278] Reactive derivatives of the compounds of formula III are,
for example, corresponding bisulfite adducts or especially
semiacetals, acetals, semiketals or ketals of compounds of formula
III with alcohols, for example lower alkanols; or thioacetals or
thioketals of compounds of formula III with mercaptans, for example
lower alkanesulfides.
[0279] The reductive alkylation is preferably carried out with
hydrogenation in the presence of a catalyst, especially a noble
metal catalyst, such as platinum or especially palladium, which is
preferably bonded to a carrier material, such as carbon, or a heavy
metal catalyst, such as Raney nickel, at normal pressure or at
pressures of from 0.1 to 10 MegaPascal (MPa), or with reduction by
means of complex hydrides, such as borohydrides, especially alkali
metal cyanoborohydrides, for example sodium cyanoborohydride, in
the presence of a suitable acid, preferably relatively weak acids,
such as lower alkanecarboxylic acids, especially acetic acid, or a
sulfonic acid, such as p-toluenesulfonic acid; in customary
solvents, for example alcohols, such as methanol or ethanol, or
ethers, for example cyclic ethers, such as tetrahydrofuran, in the
presence or absence of water.
[0280] Process b) (condensation)
[0281] In this process the reagents introducing the radical
R.sub.2Y-- contain either a free sulfo group (formula IVa) or are
in the form of a reactive derivative thereof, for example in the
form of a derived activated ester or reactive anhydride, or in the
form of a reactive cyclic amide, or contain the sulfo group in the
form of a sulfonic acid halide (formula IVb). Reactive derivatives
may also be formed in situ.
[0282] In formula IVb Hal' is preferably chlorine or bromine. The
reaction is carried out in a suitable solvent, e.g.
dichloromethane, e.g. at room temperature or the reflux temperature
of the solvent, in the presence of a suitable amine, e.g.
N-ethyldichlorophosphite, and optionally
4-dimethylaminopyridine.
[0283] The amino group of compounds of formula II that participates
in the reaction preferably is in free form, especially when the
sulfonyl group reacting therewith is present in reactive form; it
may, however, itself have been derivatised, for example by reaction
with a phosphite, such as diethylchlorophosphite, 1,2-phenylene
chlorophosphite, ethyldichlorophosphite, ethylene chlorophosphite
or tetraethylpyrophosphite. A derivative of such a compound having
an amino group is, for example, also a carbamic acid halide or an
isocyanate, the amino group that participates in the reaction being
substituted by halocarbonyl, for example chlorocarbonyl, or
modified in the form of an isocyanate group, respectively.
[0284] The condensation of activated esters, reactive anhydrides or
reactive cyclic amides with the corresponding amines is customarily
carried out in the presence of an anorganic base, such as an
alkaline metal hydrogencarbonate of carbonate, or especially an
organic base, for example simple tri-lower alkylamines, for example
triethylamine or tributylamine, or one of the above-mentioned
organic bases. If desired, a condensation agent is additionally
used, for example as described for free carboxylic acids.
[0285] The condensation is preferably carried out in an inert,
aprotic, preferably anhydrous, solvent or solvent mixture, for
example in a carboxylic acid amide, for example formamide or
dimethylformamide, a halogenated hydrocarbon, for example methylene
chloride, carbon tetrachloride or chlorobenzene, a ketone, for
example acetone, a cyclic ether, for example tetrahydrofuran or
dioxane, an ester, for example ethyl acetate, or a nitrile, for
example acetonitrile, or in a mixture thereof, as appropriate at
reduced or elevated temperature, for example in a temperature range
of from approximately -40.degree. to approximately +100.degree. C.,
preferably from approximately -10.degree. to approximately
+70.degree. C., and when arylsulfonyl esters are used also at
approximately from +100.degree. to +200.degree. C., especially at
temperatures of from 10.degree. to 30.degree. C., and if necessary
under an inert gas atmosphere, for example a nitrogen or argon
atmosphere.
[0286] Aqueous, for example alcoholic, solvents, for example
ethanol, or aromatic solvents, for example benzene or toluene, may
also be used. When alkali metal hydroxides are present as bases,
acetone may also be added where appropriate.
[0287] Process c) (amination)
[0288] The amination process is preferably carried out as an
Ullmann type reaction using a copper catalyst, such as copper[0] or
a copper[I] compound such as copper[I]oxide, copper[I] bromide or
copper[1]iodide in the presence of a suitable base (such as a metal
carbonate, for example potassium carbonate) to neutralise the acid
generated in the reaction. This reaction is reviewed in Houben-Weyl
"Methoden der Organischen Chemie", Band 11/1, page 32-33. 1958, in
Organic Reactions, Volume 14, page 19-24, 1965 and by J. Lindley
(1984) in Tetrahedron, Volume 40, page 1433-1456. The amount of
catalyst is typically in the range of 1 to 20 mole percent. The
reaction is carried out in an inert, aprotic solvent such as an
ether (for example dimethoxyethane or dioxan) or an amide (for
example dimethylformamide or N-methylpyrrolidone), under an inert
atmosphere in the temperature range of 60-180.degree. C.
[0289] An alternative amination process involves using a Group VIII
element, where the metal core of the catalyst should be a
zero-valent transition metal, such as palladium or nickel, which
has the ability to undergo oxidative addition to the Aryl-Halogen
bond. The zero valent state of the metal may be generated in situ
from the N-[II] state. The catalyst complexes may include chelating
ligands, such as alkyl, aryl or heteroaryl derivatives of phoshines
or biphosphines, imines or arsines. Preferred cataysts contain
palladium or nickel. Examples of such catalysts include
palladium[II]chloride, palladium[II]acetate,
tetrakis(triphenylphosphine)palladium[0] and
nickel[II]acetylacetonate. The metal catayst is typically in the
range of 0.1 to 10 mole percent. The chelating ligands may be
either monodentate, as in the case for example of
trialkyphosphines, such as tributylphosphine, triaryl phosphines,
such as tri-(ortho-tolyl)phosphine, and triheteroaryl phosphines,
such as tri-2-furylphosphine; or they may be bidentate such as in
the case of 2,2'-bis9diphenylphosphino)-1,1'binaphthyl,
1,2-bis(diphenylphosphino)ethane,
1,1'-bis(diphenylphosphino)ferrocene and
1-(N,N-dimethyl-amino)-1'-(dicyclohexylphosphino)biphenyl. The
supporting ligand may be added may be complexed to the metal centre
in the form of a metal complex prior to being added to the reaction
mixture or may be added to the reaction mixture as a separate
compound. The supporting ligand is typically present in the range
0.01 to 20 mole percent It is often necessary to add a suitable
base to the reaction mixture, such as a trialkylamine (for example
diisoprpylethylamine or 1,5-diazabicyclo[5,4,0]undec-5-ene), a
Group I alkali metal alkoxide (for example potassium
tertiary-butoxide) or carbonate (for example caesium carbonate) or
potassium phosphate. The reaction is typically carried out in an
inert aprotic solvent such as an ether (for example dimethoxyethane
or dioxan) or an amide (for example dimethylformamide or
N-methylpyrrolidone), under an inert atmosphere in the temperature
range of 60-180.degree. C.
[0290] The amination Is preferably carried out in an inert,
aprotic, preferably anhydrous, solvent or solvent mixture, for
example in a carboxylic acid amide, for example dimethylformamide
or dimethylacetamide, a cyclic ether, for example tetrahydrofuran
or dioxane, or a nitrile, for example acetonitrile, or in a mixture
thereof, at an appropriate temperature, for example in a
temperature range of from approximately 40.degree. to approximately
180.degree. C., and if necessary under an inert gas atmosphere, for
example a nitrogen or argon atmosphere.
[0291] Process d) (amidation)
[0292] In this process first a dimethylaluminium amide is prepared
in situ from Me.sub.3Al and an appropriate amine. Then the esters
to be treated are added and the reaction is carried out at a
temperature between 20.degree. C. and 150.degree. C., preferably
between 100.degree. C. and 120.degree. C., e.g. at 110.degree. C.,
depending on the reactivity of the amide and the ester, in an inert
solvent like benzene, toluene, xylene, tetrahydrofuran,
C.sub.6-C.sub.10 alkanes, or a mixture thereof.
[0293] N-Oxides can be obtained in a known matter by reacting a
compound of formula I with hydrogen peroxide or a peracid, e.g.
3-chloroperoxy-benzoic acid, in an inert solvent, e.g.
dichloromethane, at a temperature between -10.degree. C. and
+35.degree. C., e.g. 0.degree. C. or room temperature.
[0294] Protecting groups
[0295] If one or more other functional groups, for example carboxy,
hydroxy, amino, or mercapto, are or need to be protected in a
compound of formulae II, III and/or IV, because they should not
take part in the reaction, these are such groups as are usually
used in the synthesis of peptide compounds, and also of
cephalosporins and penicillins, as well as nucleic acid derivatives
and sugars.
[0296] The protecting groups may already be present in precursors
and should protect the functional groups concerned against unwanted
secondary reactions, such as acylations, etherifications,
esterifications, oxidations, solvolysis, and similar reactions. It
is a characteristic of protecting groups that they lend themselves
readily, i.e. without undesired secondary reactions, to removal,
typically by solvolysis, reduction, photolysis or also by enzyme
activity, for example under conditions analogous to physiological
conditions, and that they are not present in the end-products.The
specialist knows, or can easily establish, which protecting groups
are suitable with the reactions mentioned hereinabove and
hereinafter.
[0297] The protection of such functional groups by such protecting
groups, the protecting groups themselves, and their removal
reactions are described for example in standard reference works,
such as J. F. W. McOmie, "Protective Groups in Organic Chemistry",
Plenum Press, London and New York 1973, in T. W. Greene,
"Protective Groups in Organic Synthesis", Wiley, New York 1981, in
"The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer),
Academic Press, London and New York 1981, in "Methoden der
organischen Chemie" (Methods of organic chemistry), Houben Weyl,
4th edition, Volume 15/l, Georg Thieme Verlag, Stuttgart 1974, in
H. -D. Jakubke and H. Jescheit, "Aminosuren, Peptide, Proteine"
(Amino acids, peptides, proteins), Verlag Chemie, Weinheim,
Deerfield Beach, and Basel 1982, and in Jochen Lehmann, "Chemie der
Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of
carbohydrates: monosaccharides and derivatives), Georg Thieme
Verlag, Stuttgart 1974.
[0298] Additional process steps
[0299] In the additional process steps, carried out as desired,
functional groups of the starting compounds which should not take
part in the reaction may be present in unprotected form or may be
protected for example by one or more of the protecting groups
mentioned hereinabove under "protecting groups". The protecting
groups are then wholly or partly removed according to one of the
methods described there.
[0300] Salts of a compound of formula I with a salt-forming group
may be prepared in a manner known per se. Acid addition salts of
compounds of formula I may thus be obtained by treatment with an
acid or with a suitable anion exchange reagent. A salt with two
acid molecules (for example a dihalogenide of a compound of formula
1) may also be converted into a salt with one acid molecule per
compound (for example a monohalogenide); this may be done by
heating to a melt, or for example by heating as a solid under a
high vacuum at elevated temperature, for example from 130 to
170.degree. C., one molecule of the acid being expelled per
molecule of a compound of formula I.
[0301] Salts can usually be converted to free compounds, e.g. by
treating with suitable basic agents, for example with alkali metal
carbonates, alkali metal hydrogencarbonates, or alkali metal
hydroxides, typically potassium carbonate or sodium hydroxide.
[0302] Stereoisomeric mixtures, e.g. mixtures of diastereomers, can
be separated into their corresponding isomers in a manner known per
se by means of suitable separation methods. Diastereomeric mixtures
for example may be separated into their individual diastereomers by
means of fractionated crystallization, chromatography, solvent
distribution, and similar procedures. This separation may take
place either at the level of a starting compound or in a compound
of formula I itself. Enantiomers may be separated through the
formation of diastereomeric salts, for example by salt formation
with an enantiomer-pure chiral acid, or by means of chromatography,
for example by HPLC, using chromatographic substrates with chiral
ligands.
[0303] A compound of formula I, wherein W is O, can be converted
into the respective compound wherein W is S, for example, by using
an appropriate sulfur compound, e.g. using reaction with Lawesson's
reagent
(2,4-bis-(4-methoxyphenyl)2,4-dithioxo-1,2,3,4-dithiaphosphetan) in
a halogenated carbon hydrate, such as dichloromethane, or an
aprotic solvent, such as toluene or xylene, at temperatures from
about 30.degree. C. to reflux.
[0304] A compound of the formula I wherein any one or both of
R.sub.7 and R.sub.9 is hydrogen and is part of a sulfonamide (Y is
SO.sub.2) bond can be converted to the respective compound wherein
R.sub.7 and/or R.sub.9 is lower alkyl by reaction e.g. with a diazo
lower alkyl compound, especially diazomethane, in an inert solvent,
preferably in the presence of a noble metal catalyst, especially in
dispersed form, e.g. copper, or a noble metal salt, e.g.
cupper(I)-chloride or copper(II)-sulfate. Also reaction with lower
alkylhalogenides is possible, or with other leaving group carrying
lower alkanes, e.g. lower alkyl alcohols esterified by a strong
organic sulfonic acid, such as a lower alkane sulfonic acid
(optionally substituted by halogen, such as fluoro), an aromatic
sulfonic acid, for example unsubstituted or substituted
benzene-sulfonic acid, the substituents preferably being selected
from lower alkyl, such as methyl, halogen, such as bromo, and/or
nitro, e.g. esterified by methane sulfonic acid, trimethane
sulfonic acid or p-toluol sulfonic acid.
[0305] Also, in a compound of the formula I wherein R.sub.8 is
hydrogen and Y is CR.sub.9R.sub.10(CH.sub.2).sub.n, the alkylation
may be made with such alkylating agents.
[0306] In both cases, the alkylation takes place especially in
aqueous solution and/or in the presence of polar solvents,
typically alcohols, for example methanol, ethanol, isopropanol, or
ethylene glycol, ethers, typically dioxane, amides, typically
dimethylformamide, or phenols, typically phenol, and also under
non-aqueous conditions, in non-polar solvents, typically benzene
and toluene, or in benzene/water emulsions, where applicable in the
presence of acidic or basic catalysts, for example leaches,
typically sodium hydroxide solution, or in the presence of
solid-phase catalysts, typically aluminium oxide, that have been
doped with hydrazine, in ethers, for example diethylether,
generally at temperatures from about 0.degree. C. to the boiling
temperature of the corresponding reaction mixture, preferably
between 20.degree. C. and reflux temperature, if necessary under
increased pressure, e.g. in a sealed tube, a temperature in excess
of boiling point also being possible, and/or under inert gas,
typically nitrogen or argon.
[0307] It should be emphasized that reactions analogous to the
conversions mentioned in this chapter may also take place at the
level of appropriate intermediates.
[0308] General Process conditions
[0309] All process steps described here can be carried out under
known reaction conditions, preferably under those specifically
mentioned, in the absence of or usually in the presence of solvents
or diluents, preferably such as are inert to the reagents used and
able to dissolve these, in the absence or presence of catalysts,
condensing agents or neutralisiing agents, for example ion
exchangers, typically cation exchangers, for example in the H.sup.+
form, depending on the type of reaction and/or reactants at
reduced, normal, or elevated temperature, for example in the range
from -100.degree. C. to about 190.degree. C., preferably from about
-80.degree. C. to about 150.degree. C., for example at -80 to
-60.degree. C., at room temperature, at -20 to 40.degree. C. or at
the boiling point of the solvent used, under atmospheric pressure
or in a closed vessel, where appropriate under pressure, and/or in
an inert atmosphere, for example under argon or nitrogen.
[0310] Salts may be present in all starting compounds and
transients, if these contain salt-forming groups. Salts may also be
present during the reaction of such compounds, provided the
reaction is not thereby disturbed.
[0311] At all reaction stages, isomeric mixtures that occur can be
separated into their individual isomers, e.g. diastereomers or
enantiomers, or into any mixtures of isomers, e.g. racemates or
diastereomeric mixtures, typically as described under "Additional
process steps".
[0312] In certain cases, typically in hydrogenation processes, it
is possible to achieve stereoselective reactions, allowing for
example easier recovery of individual isomers.
[0313] The solvents from which those can be selected which are
suitable for the reaction in question include for example water,
esters, typically lower alkyl-lower alkanoates, e.g diethyl
acetate, ethers, typically aliphatic ethers, e.g. diethylether, or
cyclic ethers, e.g. tetrahydrofuran, liquid aromatic hydrocarbons,
typically benzene or toluene, alcohols, typically methanol, ethanol
or 1- or 2-propanol, nitrites, typically acetonitrile, halogenated
hydrocarbons, typically dichloromethane, acid amides, typically
dimethylformamide, bases, typically heterocyclic nitrogen bases,
e.g. pyridine, carboxylic acids, typically lower alkanecarboxylic
acids, e.g. acetic acid, carboxylic acid anhydrides, typically
lower alkane acid anhydrides, e.g. acetic anhydride, cyclic,
linear, or branched hydrocarbons, typically cyclohexane, hexane, or
isopentane, or mixtures of these solvents, e.g. aqueous solutions,
unless otherwise stated in the description of the process. Such
solvent mixtures may also be used in processing, for example
through chromatography or distribution.
[0314] The invention relates also to those forms of the process in
which one starts from a compound obtainable at any stage as a
transient and carries out the missing steps, or breaks off the
process at any stage, or forms a starting material under the
reaction conditions, or uses said starting material in the form of
a reactive derivative or salt, or produces a compound obtainable by
means of the process according to the invention and processes the
said compound in situ. In the preferred embodiment, one starts from
those starting materials which lead to the compounds described
hereinabove as preferred, particularly as especially preferred,
primarily preferred, and/or preferred above all.
[0315] In the preferred embodiment, a compound of formula I is
prepared according to or in analogy to the processes and process
steps defined in the Examples.
[0316] The compounds of formula I, including their salts, are also
obtainable in the form of hydrates, or their crystals can include
for example the solvent used for crystallization (present as
solvates).
[0317] Pharmaceutical preparations, methods, and uses
[0318] The present invention relates also to pharmaceutical
compositions that comprise a compound of formula I or a N-oxide
thereof as active ingredient and that can be used especially in the
treatment of the diseases mentioned at the beginning. Compositions
for enteral administration, such as nasal, buccal, rectal or,
especially, oral administration, and for parenteral administration,
such as intravenous, intramuscular or subcutaneous administration,
to warm-blooded animals, especially humans, are especially
preferred. The compositions comprise the active ingredient alone
or, preferably, together with a pharmaceutically acceptable
carrier. The dosage of the active ingredient depends upon the
disease to be treated and upon the species, its age, weight, and
individual condition, the individual pharmacokinetic data, and the
mode of administration.
[0319] The invention relates also to pharmaceutical compositions
for use in a method for the prophylactic or especially therapeutic
management of the human or animal body, to a process for the
preparation thereof (especially in the form of compositions for the
treatment of tumors) and to a method of treating tumor diseases,
especially those mentioned hereinabove.
[0320] The invention relates also to processes and to the use of
compounds of formula I or N-oxides thereof for the preparation of
pharmaceutical preparations which comprise compounds of formula I
or N-oxides thereof as active component (active ingredient).
[0321] In the preferred embodiment, a pharmaceutical preparation is
suitable for administration to a warm-blooded animal, especially
humans or commercially useful mammals suffering from a disease
responsive to an inhibition of angiogenesis or of VEGF-receptor
tyrosine kinase, for example psoriasis or especially a neoplastic
disease, and comprises an effective quantity of a compound of
formula I or N-oxides thereof for the inhibition of angiogenesis or
of VEGF-receptor tyrosine kinase, or a pharmaceutically acceptable
salt thereof, if salt-forming groups are present, together with at
least one pharmaceutically acceptable carrier.
[0322] A pharmaceutical composition for the prophylactic or
especially therapeutic management of neoplastic and other
proliferative diseases of a warm-blooded animal, especially a human
or a commercially useful mammal requiring such treatment,
especially suffering from such a disease, comprising as active
ingredient in a quantity that is prophylactically or especially
therapeutically active against the said diseases a novel compound
of formula I or N-oxides thereof, is likewise preferred.
[0323] The pharmaceutical compositions comprise from approximately
1% to approximately 95% active ingredient, single-dose
administration forms comprising in the preferred embodiment from
approximately 20% to approximately 90% active Ingredient and forms
that are not of single-dose type comprising in the preferred
embodiment from approximately 5% to approximately 20% active
ingredient Unit dose forms are, for example, coated and uncoated
tablets, ampoules, vials, suppositories, or capsules. Further
dosage forms are, for example, ointments, creams, pastes, foams,
tinctures, lip-sticks, drops, sprays, dispersions, etc. Examples
are capsules containing from about 0.05 g to about 1.0 g active
ingredient.
[0324] The pharmaceutical compositions of the present invention are
prepared in a manner known per se, for example by means of
conventional mixing, granulating, coating, dissolving or
lyophilizing processes.
[0325] Preference is given to the use of solutions of the active
ingredient, and also suspensions or dispersions, especially
isotonic aqueous solutions, dispersions or suspensions which, for
example in the case of lyophilized compositions comprising the
active ingredient alone or together with a carrier, for example
mannitol, can be made up before use. The pharmaceutical
compositions may be sterilized and/or may comprise excipients, for
example preservatives, stabilizers, wetting agents and/or
emulsifiers, solubilizers, salts for regulating osmotic pressure
and/or buffers and are prepared in a manner known per se, for
example by means of conventional dissolving and lyophilizing
processes. The said solutions or suspensions may comprise
viscosity-increasing agents, typically sodium
carboxymethylcellulose, carboxymethylcellulose, dextran,
polyvinylpyrrolidone, or gelatins, or also solubilizers, e.g. Tween
80.RTM. [polyoxyethylene(20)sorbitan mono-oleate; trademark of ICI
Americas, Inc, USA].
[0326] Suspensions in oil comprise as the oil component the
vegetable, synthetic, or semi-synthetic oils customary for
injection purposes. In respect of such, special mention may be made
of liquid fatty acid esters that contain as the acid component a
long-chained fatty acid having from 8 to 22, especially from 12 to
22, carbon atoms, for example lauric acid, tridecylic acid,
myristic acid, pentadecylic acid, palmitic acid, margaric acid,
stearic acid, arachidic acid, behenic acid or corresponding
unsaturated acids, for example oleic acid, elaidic acid, erucic
acid, brassidic acid or linoleic acid, if desired with the addition
of antioxidants, for example vitamin E, .beta.-carotene or
3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these
fatty acid esters has a maximum of 6 carbon atoms and is a
monovalent or polyvalent, for example a mono-, di- or trivalent,
alcohol, for example methanol, ethanol, propanol, butanol or
pentanol or the isomers thereof, but especially glycol and
glycerol. As fatty acid esters, therefore, the following are
mentioned: ethyl oleate, isopropyl myristate, isopropyl palmitate,
"Labrafil M 2375" (polyoxyethylene glycerol trioleate from
Gattefoss, Paris), "Labrafil M 1944 CS" (unsaturated polyglycolized
glycerides prepared by alcoholysis of apricot kernel oil and
consisting of glycerides and polyethylene glycol ester; Gattefoss,
France), "Labrasol" (saturated polyglycolized glycerides prepared
by alcoholysis of TCM and consisting of glycerides and polyethylene
glycol ester; Gattefoss, France), and/or "Miglyol 812"
(triglyceride of saturated fatty acids of chain length C.sub.8 to
C.sub.12 from Huls AG, Germany), but especially vegetable oils such
as cottonseed oil, almond oil, olive oil, castor oil, sesame oil,
soybean oil and more especially groundnut oil.
[0327] The manufacture of injectable preparations is usually
carried out under sterile conditions, as is the filling, for
example, into ampoules or vials, and the sealing of the
containers.
[0328] Pharmaceutical compositions for oral administration can be
obtained, for example, by combining the active ingredient with one
or more solid carriers, if desired granulating a resulting mixture,
and processing the mixture or granules, if desired or necessary, by
the inclusion of additional excipients, to form tablets or tablet
cores.
[0329] Suitable carriers are especially fillers, such as sugars,
for example lactose, saccharose, mannitol or sorbitol, cellulose
preparations, and/or calcium phosphates, for example tricalcium
phosphate or calcium hydrogen phosphate, and also binders, such as
starches, for example corn, wheat, rice or potato starch,
methylcellulose, hydroxypropyl methylcellulose, sodium
carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or, if
desired, disintegrators, such as the above-mentioned starches, also
carboxymethyl starch, crosslinked polyvinylpyrrolidone, alginic
acid or a salt thereof, such as sodium alginate. Additional
excipients are especially flow conditioners and lubricants, for
example silicic acid, talc, stearic acid or salts thereof, such as
magnesium or calcium stearate, and/or polyethylene glycol, or
derivatives thereof.
[0330] Tablet cores can be provided with suitable, optionally
enteric, coatings through the use of, inter alia, concentrated
sugar solutions which may comprise gum arabic, talc,
polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,
or coating solutions in suitable organic solvents or solvent
mixtures, or, for the preparation of enteric coatings, solutions of
suitable cellulose preparations, such as acetylcellulose phthalate
or hydroxypropylmethyl cellulose phthalate. Dyes or pigments may be
added to the tablets or tablet coatings, for example for
identification purposes or to indicate different doses of active
ingredient.
[0331] Pharmaceutical compositions for oral administration also
include hard capsules consisting of gelatin, and also soft, sealed
capsules consisting of gelatin and a plasticizer, such as glycerol
or sorbitol. The hard capsules may contain the active ingredient in
the form of granules, for example in admixture with fillers, such
as corn starch, binders, and/or glidants, such as talc or magnesium
stearate, and optionally stabilizers. In soft capsules, the active
ingredient is preferably dissolved or suspended in suitable liquid
excipients, such as fatty oils, paraffin oil or liquid polyethylene
glycols or fatty acid esters of ethylene or propylene glycol, to
which stabilizers and detergents, for example of the
polyoxyethylene sorbitan fatty acid ester type, may also be
added.
[0332] Pharmaceutical compositions suitable for rectal
administration are, for example, suppositories that consist of a
combination of the active ingredient and a suppository base.
Suitable suppository bases are, for example, natural or synthetic
triglycerides, paraffin hydrocarbons, polyethylene glycols or
higher alkanols.
[0333] For parenteral administration, aqueous solutions of an
active ingredient in water-soluble form, for example of a
water-soluble salt, or aqueous injection suspensions that contain
viscosity-increasing substances, for example sodium
carboxymethylcellulose, sorbitol and/or dextran, and, if desired,
stabilizers, are especially suitable. The active ingredient,
optionally together with excipients, can also be in the form of a
lyophilizate and can be made into a solution before parenteral
administration by the addition of suitable solvents.
[0334] Solutions such as are used, for example, for parenteral
administration can also be employed as infusion solutions.
[0335] Preferred preservatives are, for example, antioxidants, such
as ascorbic acid, or microbicides, such as sorbic acid or benzoic
acid.
[0336] The invention relates likewise to a process or a method for
the treatment of one of the pathological conditions mentioned
hereinabove, especially a disease which responds to an inhibition
of the VEGF-receptor tyrosine kinase or an inhibition of
angiogenesis, especially a corresponding neoplastic disease or also
psoriasis. The compounds of formula I or N-oxides thereof can be
administered as such or especially in the form of pharmaceutical
compositions, prophylactically or therapeutically, preferably in an
amount effective against the said diseases, to a warm-blooded
animal, for example a human, requiring such treatment. In the case
of an individual having a bodyweight of about 70 kg the daily dose
administered is from approximately 0.1 g to approximately 5 9,
preferably from approximately 0.5 g to approximately 2 g, of a
compound of the present invention.
[0337] The present invention relates especially also to the use of
a compound of formula I, or a pharmaceutically acceptable salt
thereof, especially a compound of formula I or N-oxides thereof
which is said to be preferred, or a pharmaceutically acceptable
salt thereof, as such or in the form of a pharmaceutical
formulation with at least one pharmaceutically acceptable carrier
for the therapeutic and also prophylactic management of one or more
of the diseases mentioned hereinabove, especially a neoplastic
disease or also psoriasis, more especially if the disease responds
to an inhibition of angiogenesis or an inhibition of VEGF-receptor
tyrosine kinase.
[0338] The present invention relates especially also to the use of
a compound of formula I or N-oxides thereof, or a pharmaceutically
acceptable salt thereof, especially a compound of formula I which
is said to be preferred, or a pharmaceutically acceptable salt
thereof, as such or in the form of a pharmaceutical formulation
with at least one pharmaceutically acceptable carrier for the
therapeutic and also prophylactic management of one or more of the
diseases mentioned hereinabove, preferably a disease which responds
to an inhibition of VEGF-receptor tyrosine kinase or an inhibition
of angiogenesis, especially a neoplastic disease or also psoriasis,
more especially if the said disease responds to an inhibition of
VEGF-receptor tyrosine kinase or angiogenesis.
[0339] The present invention relates especially also to the use of
a compound of formula I or N-oxides thereof, or a pharmaceutically
acceptable salt thereof, especially a compound of formula I which
is said to be preferred, or a pharmaceutically acceptable salt
thereof, for the preparation of a pharmaceutical formulation for
the therapeutic and also prophylactic management of one or more of
the diseases mentioned hereinabove, especially a neoplastic disease
or also psoriasis, more especially if the disease responds to an
inhibition of VEGF-receptor tyrosine kinase or angiogenesis.
[0340] The preferred dose quantity, composition, and preparation of
pharmaceutical formulations (medicines) which are to be used in
each case are described above.
[0341] Starting materials
[0342] New starting materials and/or intermediates, as well as
processes for the preparation thereof, are likewise the subject of
this invention. In the preferred embodiment, such starting
materials are used and reaction conditions so selected as to enable
the preferred compounds to be obtained.
[0343] Starting materials of the formula II, III, IVa, IVb, V, VI,
VII and VIII are known, are commercially available, or can be
synthesized in analogy to or according to methods that are known in
the art.
[0344] For example, an aniline of the formula II can be prepared
from a nitro compound of the formula IX, 8
[0345] wherein R.sub.1, R.sub.3 to R.sub.7 and W have the meanings
as given under formula I.
[0346] The reduction preferably takes place in the presence of a
suitable reducing agent, such as tin(lI) chloride or hydrogen in
the presence of an appropriate catalyst, such as Raney nickel (then
preferably the hydrogen is used under pressure, e.g. between 2 and
20 bar) or PtO.sub.2, in an appropriate solvent, e.g. an alcohol,
such as methanol. The reaction temperature is preferably between 0
and 80.degree. C., especially 15 to 30.degree. C.
[0347] A nitro compound of the formula IX is accessible by reaction
of an acid of the formula X, 9
[0348] wherein W is oxygen and R.sub.3 to R.sub.6 are as defined
above, or an activated derivative thereof, is reacted with an amine
of the formula XI,
HNR.sub.1R.sub.7 (XI)
[0349] wherein R.sub.1 and R.sub.7 are as defined under formula I,
e.g. in the presence of a coupling agent, such as
dicyclohexylcarbodiimide, at a temperature between 0.degree. C. and
50.degree. C., preferably at room temperature.
[0350] If required, W.dbd.O can be changed to W.dbd.S with
Lawesson's agent, as described above for the analogous conversion
of a compound of formula I with W =0 into one with W.dbd.S.
[0351] It would also be possible to first reduce the nitro compound
of the formula X to the corresponding aniline compound under
reaction conditions analogous to those for the reduction of nitro
compounds of the formula IX and then react the resulting anilino
compound with the amino compound of formula XI under analogous
conditions as decribed above. However, it may then be nesessary to
protect the aniline amino group.
[0352] An anthranilic acid derivative of the formula VII is
accesible through the reductive amination reaction of a compound of
formula XII 10
[0353] wherein R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are as defined
for a compound of the formula I and R.sub.11 is lower alkyl or
aryl, by first reacting the compound of formula XII with
4-pyridine-carbaldehyde and then with a reducing agent, e.g. sodium
cyanotrihydrido-borate, in a one-step procedure in a lower alkanol,
e.g. methanol, ethanol or propanol, at a temperature between
0.degree. C. and 50.degree. C., e.g. at room temperature.
[0354] The reaction sequence of first obtaining an imine starting
from the amine of formula XII and then reducing it can also be
accomplished in separate reaction steps. Reagents which can be used
to add hydrogen to an imine double bond include borane in
tetrahydrofuran, LiAlH.sub.4, NaBH.sub.4, sodium in ethanol and
hydrogen in the presence of a catalyst.
[0355] All remaining starting materials of are known, capable of
being prepared according to known processes, or commercially
obtainable; in particular, they can be prepared using processes as
described in the Examples.
[0356] In the preparation of starting materials, existing
functional groups which do not participate in the reaction should,
if necessary, be protected. Preferred protecting groups, their
introduction and their removal are described under "protecting
goups" or in the Examples.
EXAMPLES
[0357] The following Examples serve to illustrate the invention
without limiting the invention in its scope.
[0358] Temperatures are measured in degrees celsius (.degree. C.).
Unless otherwise indicated, the reactions take place at room
temperature.
[0359] Preparation of Intermediates:
[0360] 1. Intermediate 1a:
2-Nitro-N-(4-trifluoromethylphenyl)benzamide
[0361] A solution containing 2-nitrobenzoyl chloride (Fluka, Buchs,
Switzerland) (1.97 mL, 15 mmol) and 4-dimethylaminopyridine (Fluka,
Buchs, Switzerland) (10 mg) in dichloromethane (10 mL) is added to
a stirred mixture of 4-aminobenzotrifluoride (Fluka, Buchs,
Switzerland) (2.66 g, 16.5 mmol) and triethylamine (1.90 g, 18.8
mmol) in dichloromethane (100 mL) under an argon atmosphere and the
mixture is stirred for 16 hours at 25.degree. C. The stirred
mixture is then treated with a saturated aqueous solution of sodium
hydrogen carbonate (50 mL) and then extracted with dichoromethane
(2.times.50 mL). The combined extracts are dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by column chromatography on silica gel, eluent 10-50% ethyl acetate
in hexane, to give the title compound as a colourless crystalline
solid.
[0362] Intermediate 1b:
2-Nitro-N-[3-fluoro-(4-trifluoromethyl)phenyl]benz- amide
[0363] A solution of 4-amino-2-fluorobenzotrifluoride (Fluorochem,
Derbyshire, England; 14.4 g, 75 mmol) in ethyl acetate (150 mL) was
added to a stirred solution of sodium hydroxide (3.30 g, 82.5 mmol)
in water, at room temperature. This stirred solution was then
treated dropwise over 30 minutes with a solution of 2-nitrobenzoyl
chloride (11.0 mL, 82.5 mmol) in dry ethyl acetate (110 mL). The
resulting mixture was then stirred overnight at ambient
temperature. The mixture is then extracted with ethyl acetate
(3.times.100 mL). The combined extracts are sequentially washed
with water (2.times.100 mL), hydrochloric aciid (2.times.100 mL of
2M), water (2.times.100 mL), saturated aqueous sodium hydrogen
carbonate solution (2.times.100 mL) and saturated aqueous sodium
chloride (1.times.100 mL), dried (Na.sub.2SO.sub.4), filtered and
the solvent is evaporated off under reduced pressure to yield the
crude product which is purified by recrystallisation from ethyl
acetate-hexane to give the title compound as a colourless
crystalline solid, m.p. 185-189.degree. C.
[0364] The following compounds are prepared analogously by
utilising the appropriate amine (the supplier of which is e.g.
Fluka or Aldrich, both Buchs, Switzerland, or mentioned in
parenthesis):
[0365] (1c) 2-Nitro-N-(4-chlorophenyl)benzamide, utilizing
4-chloroaniline,
[0366] (1d) 2-Nitro-N-(4-methylphenyl)benzamide, utilizing
4-methylaniline,
[0367] (1e) 2-Nitro-N-(3-fluoro-4-methylphenyl)benzamide, utilizing
3-fluoro-4-methylaniline (Riedel-de Haen, Seelze, Germany),
[0368] (1f)
2-Nitro-N-[4-chloro-(3-trifluoromethyl)phenyl]benzamide, utilising
4-chloro-3-(trifluoromethyl)benzenamine,
[0369] (1g)
2-Nitro-N-[3-chloro-(5-trifluoromethyl)phenyl]benzamide, utilizing
3-amino-5-chlorobenzotrifluoride, prepared from
4-amino-3-chloro-5-nitrobenzotrifluoride (Maybridge Chemical Co.
Ltd.) as described in European Patent Application EP 0 516
297),
[0370] (1h)
2-Nitro-N-[4-fluoro-(3-trifluoromethyl)phenyl]benzamide, utilizing
4-fluoro-3-(trifluoromethyl)benzenamine,
[0371] (1i)
2-Nitro-N-[3-fluoro-(5-trifluoromethyl)phenyl]benzamide, utilizing
3-fluoro-5-trifluoromethyl)benzenamine (Fluorochem, Derbyshire,
England),
[0372] (1j) 2-Nitro-N-[3,5-(bis-trifluoromethyl)phenyl]benzamide,
utilizing 3,5-(bistrifluoromethyl)benzenamine,
[0373] (1k) 2-Nitro-N-[3,4-(bis-trifluoromethyl)phenyllbenzamide,
utilizing 3,4-(bistrifluoromethyl)benzenamine,
[0374] (1k)
2-Nitro-N-[3-methoxy-(5-trifluoromethyl)phenyl]benzamide, utilizing
3-methoxy-5-(trifluoromethyl)benzenamine,
[0375] (1m) 2-Nitro-N-[3-(trifluoromethyl)phenyl]benzamide,
utilizing 3-(trifluoromethyl)benzenamine,
[0376] (1n) 2-Nitro-N-[3-(1,1-dimethyl)ethyl)phenyl]benzamide,
utilizing 3-tert-butylaniline,
[0377] (1o) 2-Nitro-N-(3-cyanophenyl)benzamide, utilizing
3-cyanobenzenamine,
[0378] (1p) 2-Nitro-N-(3-methylthiophenyl)benzamide, utilizing
3-methylthiobenzenamine,
[0379] (1q) 2-Nitro-N-[3-[(1-oxoethyl)amino]phenyl]benzamide,
utilizing 3-methylthiobenzenamine (Pfaltz and Bauer Inc,
Connecticut, USA),
[0380] (1r) 2-Nitro-N-[3-[(aminocarbonyl)amino]phenyl]benzamide,
utilising 3-aminophenylurea (Bayer Organica, Leverkusen,
Germany),
[0381] (1s) 2-Nitro-N-[3-(dimethylamino)phenyl]benzamide, utilising
N,N-dimethyl-1,3-benzenediamine, dihydrochloride (Lancaster
Synthesis, Lancashire, England),
[0382] (1t)
5-Methoxy-2-nitro-N-[3-(trifluoromethyl)phenyllbenzamide, utilising
5-methoxy-2-nitrobenzoyl chloride (which may be prepared as
described by Sami Khan and LaMontagne, J. Med. Chem.
1979;22:1005-1008, from 5-methoxy-2-nitrobenzoic acid) and
3-(trifluoromethyl)benzenamine,
[0383] (1u)
3-Methyl-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide, utilising
3-methyl-2-nitrobenzoyl chloride (which may be prepared as
described by Edge et al, J. Chem. Soc. Perkin Trans. 1 1982;
1701-1714, from 3-methyl-2-nitrobenzoic acid) and
3-(trifluoromethyl)benzenamine,
[0384] (1v)
4,5-Difluoro-2-nitro-N-[3-(trifluoromethyl)phenyl]benzamide,
utilising 4,5-difluoro-2-nitrobenzoyl chloride prepared from
4,5-difluoro-2-nitrobenzoic acid as described in German Patent
Application DE 3717904.
[0385] (1w)
2-Nitro-N-methyl-N-[3-(trifluoromethyl)phenyl]benzamide, utilizing
N-methyl-3-(trifluoromethyl)benzenamine prepared as described by
Berbalk et al, Monatshefte Chemie 1976;107: 401-404, from
3-(trifluoromethyl)benzenamine,
[0386] (1x) 2-Bromo-N-[3-(trifluoromethyl)phenyl]benzamide,
utilising 2-bromobenzoyl chloride in lieu of 2-nitrobenzoyl
chloride and 3-(trifluoromethyl)benzenamine.
[0387] Intermediate 1v:
2-Nitro-N-[(3-methylsulphonyl)phenyl]benzamide
[0388] 3-Chloroperoxybenzoic acid (71.8 g of 55%, 229 mmol ) is
added to a stirred mixture of
2-Nitro-N-(3-methylthiophenyl)benzamide (intermediate 1p; 22.0 g,
76.3 mmol) in dichloromethane (1 L) at 0.degree. C. The resulting
mixture is then stirred at 35.degree. C. for 70 hours. The mixture
is then washed sequentially with aqueous sodium hydroxide
(2.times.100 mL) and aqueous sodium thiosulphate (2.times.50 mL of
10%). The organic phase is dried (Na.sub.2SO.sub.4), filtered and
the solvent is evaporated off under reduced pressure to yield the
crude product which is purified by column chromatography on silica
gel, eluent 50% ethyl acetate in hexane and recrystallised from
diisopropyl ether to give the title compound as a colourless
crystalline solid, m.p. 172-173.degree. C.
[0389] 2. Intermediate 2a:
2-Amino-N-(4-trifluoromethylphenyl)benzamide
[0390] A solution of intermediate 1 a (1.92 g, 6.19 mmol) in
methanol (200 mL) is hydrogenated at 5 bar over Raney nickel (400
mg) at 21.degree. C. The calculated amount of hydrogen is taken up
in 1 hour. The mixture is then filtered and the solvent is
evaporated off under reduced pressure to yield the crude product
which is purified by recrystallisation from dichloromethane-hexane
to give the title compound as a colourless crystalline solid, m.p.
160-161.degree. C.
[0391] The following compounds are prepared analogously by
utilising the appropriate amine:
[0392] (2b)
2-Amino-N-[3-fluoro-4-(trifluoromethyl)phenyl]benzamide, m.p.
135-137.degree. C., utilising intermediate 1b. (2c)
2-Amino-N-(4-chlorophenyl)benzamide, m.p. of the hydrochloride salt
156-173.degree. C., utilising intermediate 1c.
[0393] (2d) 2-Amino-N-(4-methylphenyl)benzamide, utilising
intermediate 1d.
[0394] (2e) 2-Amino-N-(3-fluoro-4-methylphenyl)benzamide, m.p.
149-151.degree. C., utilising intermediate 1e.
[0395] (2f)
2-Amino-N-[4-chloro-3-(trifluoromethyl)phenyl]benzamide, m.p.
148-150.degree. C., utilising intermediate 1f.
[0396] (2g) 2-Amino
N-[3-chloro-5-(trifluoromethyl)phenyl]benzamide, m.p.
174-175.degree. C., utilising intermediate 1g.
[0397] (2h)
2-Amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]benzamide, m.p.
159-162.degree. C., utilising intermediate 1h.
[0398] (2i)
2-Amino-N-[3-fluoro-5-(trifluoromethyl)phenyl]benzamide, m.p.
142-144.degree. C., utilising intermediate 1i.
[0399] (2j) 2-Amino-N-[3,5-(bis-trifluoromethyl)phenyl]benzamide,
m.p. 192-193.degree. C., utilising intermediate 1j.
[0400] (2k) 2-Amino-N-[3,4-(bis-trifluoromethyl)phenyl]benzamide,
utilising intermediate 1k.
(21)2-Amino-N-[3-methoxy-5-(trifluoromethyl)ph- enyl]benzamide,
m.p. 125-126.degree. C., utilising intermediate 1l.
[0401] (2m) 2-Amino-N-[3-(trifluoromethyl)phenyl]benzamide, m.p.
131-133.degree. C., utilising intermediate 1m.
[0402] (2n) 2-Amino-N-[3-(1,1-dimethyl)ethyl)phenyl]benzamide, m.p.
84-86.degree. C., utilising intermediate 1n.
[0403] (2o) 2-Amino-N-(3-cyanophenyl)benzamide, m.p.
161-163.degree. C., utilising intermediate 1o.
[0404] (2p) 2-Amino-N-(3-methylthiophenyl)benzamide, m.p.
88-90.degree. C., utilising intermediate 1p.
[0405] (2q) 2-Amino-N-[3-[(1-oxoethyl)amino]phenyl]benzamide, m.p.
132-134.degree. C., utilising intermediate 1q.
[0406] (2r) 2-Amino- N-[3-[(aminocarbonyl)amino]phenyl]benzamide,
m.p. 187-189.degree. C., utilising intermediate 1r.
[0407] (2s) 2-Amino-N-[3-(dimethylamino)phenyl]benzamide, m.p.
109-110.degree. C., utilising intermediate 1s.
[0408] (2t)
2-Amino-5-methoxy-N-[3-(trifluoromethyl)phenyl]benzamide, m.p.
98-99.degree. C., utilising intermediate 1t.
[0409] (2u)
2-Amino-3-methyl-N-[3-(trifluoromethyl)phenyl]benzamide, m.p.
103-108.degree. C., utilising intermediate 1u.
[0410] (2v)
2-Amino-4,5difluoro-N-[3-(trifluoromethyl)phenyl]benzamide, m.p.
198-200.degree. C., utilising intermediate 1v.
[0411] (2w)
2-Amino-N'-methyl-N'-[3-(trifluoromethyl)phenyl]benzamide, m.p.
61-64.degree. C., utilising intermediate 1w.
[0412] Intermediate 2x:
2-Amino-N-[(3-methylsulphonyl)phenyl]benzamide
[0413] A solution of intermediate 1y (22.0 g, 68.7 mmol) in
methanol (1500 mL) is hydrogenated at 7 bar over 10% palladium on
carbon (1.0 g) at 22.degree. C. The calculated amount of hydrogen
is taken up in 1 hour. The mixture is then filtered and the solvent
is evaporated off under reduced pressure to yield the crude product
which is purified by column chromatography on silica gel, eluent
ethyl acetate and recrystallisation from diisopropyl ether-hexane
to give the title compound as a colourless crystalline solid, m.p.
190-193.degree. C.
[0414] Intermediate 2v: 2-Amino-
[(3-methylsulphinyl)phenyl]benzamide
[0415] A solution of intermediate 2p (2.58 g, 10 mmol) in ethanol
(100 mL) is added dropwise over 30 min to a stirred solution of
sodium metaperiodate (2.25 g, 10.5 mmol) mixed solvent (100 ml of
ethanol and 100 ml of H.sub.2O) at 0.degree. C. The mixture is
stirred at 5.degree. C. for 17 hours and then diluted with water
(600 mL) and extracted with dichloromethane (3.times.150 mL). The
combined extracts are dried (Na.sub.2SO.sub.4), filtered and the
solvent is evaporated off under reduced pressure to yield the crude
product which is purified by column chromatography on silica gel,
eluent ethyl acetate and recrystallised from
isopropanol-diisopropylether to give the title compound as a
colourless crystalline solid, m.p. 117-121.degree. C.
[0416] Intermediate 2z: 2-Amino
N[4-(1,1-dimethyl)ethyl)phenyl]benzamide
[0417] A solution of 4-tert-butylaniline (9.00 g, 60.3 mmol) in
dimethylformamide (20 mL) is added to a stirred solution of isatoic
anhydride (9.75 g, 60 mmol) in dimethylformamide (80 mL) at
100.degree. C. The mixture is stirred at 100.degree. C. for 4
hours. The solvent is then evaporated off under reduced pressure to
give a residue which is dissolved in ethyl acetate (300 mL) and
washed with saturated aqueous ammonium chloride solution. The
solution is dried (Na.sub.2SO.sub.4), filtered and the solvent is
evaporated off under reduced pressure to yield the product which is
purified by column chromatography on silica gel, eluent 10% ethyl
acetate in hexane and recrystallised from t butylmethyl
ether-cyclohexane to give the title compound as a colourless
crystalline solid, m.p. 132-134.degree. C.
[0418] The following compounds are prepared analogously by
utilising the appropriate amine:
[0419] (2aa) 2-Amino-N-(3-chlorophenyl)benzamide, m.p. 136-137C,
utilizing 3-chloroaniline;
[0420] (2ab) 2-Amino-1(3-bromophenyl)benzamide, m.p.
150-153.degree. C., utilizing 3-bromoaniline;
[0421] (2ac) 2-Amino-N-(3-methylphenyl)benzamide, m.p.
115-117.degree. C., utilizing 3-methylaniline;
[0422] (2ad) 2-Amino-N-(3-benzoylphenyl)benzamide, as a yellow oil,
utilizing (3-aminophenyl)phenylmethanone;
[0423] (2ae) 2-Amino-N-[(3-aminocarbonyl)phenyl]benzamide,
utilizing 3-aminobenzamide.
[0424] Intermediate 2af:
2-Amino-N-(4-methylphenyl)-6-methylbenzamide
[0425] (i) 2-{((1,1-Dimethylethoxy)carbonyl]amino)-6-methylbenzoic
acid
[0426] A stirred solution of 2-amino-6-methylbenzoic acid (9.90 g,
65.5 mmol), triethylamine (12.4 mL, 9.00 g, 89.10 mmol) in dry
dimethylformamide (300 mL) under an argon atmosphere, is treated
with di-t-butyl dicarbonate (19.44 g, 89.1 mmol) and stirred at
18.degree. C. for 18 hours. The solvent is evaporated off under
reduced pressure to give a residue which is treated with aqueous
citric acid solution (100 mL of 10%) and extracted with
dichloromethane (2.times.100 mL). The combined extracts are dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the product which is purified by
column chromatography on silica gel, eluent 5% methanol in
dichloromethane and recrystallised from t-butylmethyl ether-hexane
to give the title compound as a colourless crystalline solid.
[0427] (ii)
N-(4-Methylphenyl)-2-{[(1,1-dimethylethoxy)carbonyl]amino]-6-m-
ethylbenzamide
[0428] Firstly N-methylmorpholine (6.15 mL, 5.64 g, 55.8 mmol) and
then O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (10.15 g, 26.8 mmol) are added to a stirred
mixture of 2-{[(1 ,1-dimethylethoxy)carbonyl]amino)-6-methylbenzoic
acid (5.60 g, 22.3 mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry
dimethylformamide (110 mL) under an argon atmosphere, and stirred
at 18.degree. C. for 16 hours. The solvent is evaporated off under
reduced pressure to give a residue which is treated with aqueous
sodium hydrogen carbonate solution (200 mL of 10%) and extracted
with dichloromethane (3.times.100 mL). The combined extracts are
washed with aqueous citric acid solution (100 mL of 10%), dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by column chromatography on silica gel, eluent 20% ethyl acetate in
hexane, and recrystallised from tert-butylmethyl ether-hexane to
give the title compound as a colourless crystalline solid, m.p.
250.degree. C.
[0429] (iii) 2-Amino-N-(4-methylphenyl)-6-methylbenzamide,
hydrochloride
[0430] A stirred solution of
N-(4-methylphenyl)-2-{[(1,1-dimethylethoxy)ca-
rbonyl]amino)-6-methylbenzamide (1.67 g, 4.90 mmol) in methanol (4
mL) under an argon atmosphere, is treated with a saturated solution
of hydrogen chloride in dioxane (30 mL) and stirred at 18.degree.
C. for 210 minutes. The solvent is evaporated off under reduced
pressure to give the crude product which is purified by
recrystallisation from methanol - di-isopropyl ether to give the
title compound as a colourless crystalline solid, m.p.
217-220.degree. C.
EXAMPLES
Example 1:
[0431]
2-[(4-Pyridyl)methyl]amino-N-[4-(trifluoromethyl)phenyl]benzamide
[0432] Sodium cyanoborohydride (0.80 g of 90%, 11.5 mmol) is added
in portions over 30 minutes to a stirred mixture of acetic acid
(0.15 mL), 4-pyridinecarboxaldehyde (1.00 g, 3.57 mmol) and
intermediate 2a (1.00 g, 3.57 mmol) in methanol (15 mL) at
25.degree. C. under an argon atmosphere. The mixture is stirred for
16 hours, diluted with dichloromethane (100 mL) and treated with a
saturated aqueous solution of sodium hydrogen carbonate (50 mL).
The mixture is stirred for an additional 5 min and then extracted
with dichoromethane (3.times.50 mL). The combined extracts are
dried (Na.sub.2SO.sub.4), filtered and the solvent is evaporated
off under reduced pressure to yield the crude product that is
purified by column chromatography on silica gel, eluent 33% ethyl
acetate in hexane, and recrystallised from 2-propanol - hexane to
give the title compound as a colourless crystalline solid, m.p.
171-175.degree. C. and having the following physical
characteristics: .sup.1H-NMR (DMSO-d.sub.6) d 4.49 (d, J=6.1 Hz,
2H), 6.56 (d, J=8.4 Hz, 1H), 6.66 (t, J=8.5 Hz, 1H), 7.26 (t, J=8.4
Hz, 1H), 7.33 (d, J=5.9 Hz, 2H), 7.71 (d, J=8.5 Hz, 2H), 7.72 (m,
1H), 7.90 (t, J=6.1 Hz, 1H), 7.96 (d, J=8.5 Hz, 2H), 8.49 (d, J=5.9
Hz, 2H) and 10.46 (s, 1H).
[0433] The following compounds are prepared analogously by
utilising the appropriate amine:
Example 2:
[0434]
2-[(4-Pyridyl)methyl]amino-N-[3-fluoro-(4-trifluoromethyl)phenyl]be-
nzamide, m.p. 162-164.degree. C., utilising intermediate 2b.
Example 3:
[0435] 2-[(4-Pyridyl)methyl]amino-N-phenylbenzamide, m.p.
160-161.degree. C., utilising 2-aminobenzanilide.
Example 4:
[0436] 2-[(4-Pyridyl)methyl]amino-N-(4chlorophenyl)benzamide, m.p.
134-139.degree. C., utilising intermediate 2c.
Example 5:
[0437] 2-1(4-Pyridyl)methyl]amino-1(4-methylphenyl)benzamide,
utilising intermediate 2d.
Example 6:
[0438]
2-[(4-Pyridyl)methyl]amino-N-(3-fluoro-4-methylphenyl)benzamide is
prepared utilising intermediate 2e. Following purification by
chromatography (silica gel, eluent 33% ethyl acetate in hexane),
the base is dissolved in ethyl acetate and treated with a solution
of hydrogen chloride in dichloromethane. The precipitated product
is filtered off and recrystallized from dichloromethane-hexane to
afford the dihydrochloride salt, m.p. 116-124.degree. C.
Example 7:
[0439]
2-[(4-Pyridyl)methyl]amino-N-[4-chloro-3-(trifluoromethyl)phenyl]be-
nzamide, m.p. 162-172.degree. C., utilising intermediate 2f.
Example 8:
[0440]
2-[(4-Pyridyl)methyl]amino-N-[3-chloro-5-(trifluoromethyl)phenyl]be-
nzamide, m.p. 190-194.degree. C., utilising intermediate 2g.
Example 9:
[0441]
2-1(4-Pyridyl)methyl]amino-N-[4-fluoro-3-(trifluoromethyl)phenyl]be-
nzamide, m.p. 183-185.degree. C., utilising intermediate 2h.
Example 10:
[0442]
2-[(4-Pyridyl)methyl]amino-N-13-fluoro-5-(trifluoromethyl)phenyl]be-
nzamide, m.p. 196-197.degree. C., utilising intermediate 2i.
Example 11:
[0443]
2-[(4-Pyridyl)methyl]amino-N-[3,5-(bistrifluoromethyl)phenylbenzami-
de, m.p. 180-185.degree. C., utilising intermediate 2j.
Example 12:
[0444]
2-(4-Pyridyl)methyl]amino-N-[3,4-(bistrifluoromethyl)phenylbenzamid-
e, utilising intermediate 2k.
Example 13:
[0445]
2-[(4-Pyridyl)methyl]amino-[3-methoxy-5-(trifluoromethyl)phenyl]ben-
zamide, m.p. 134-136.degree. C., utilising intermediate 2l.
Example 14:
[0446]
2-[(4-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,
m.p. 157-159.degree. C., utilising intermediate 2m.
Example 15:
[0447] 2-[(4-Pyridyl)methyl]amino-[3-(1,1
-dimethylethyl)phenyl]benzamide, m.p. 144-147.degree. C., utilising
intermediate 2n.
Example 16:
[0448] 2-[(4-Pyridyl)methyl]amino-N-(3 cyanophenyl)benzamide, m.p.
157-160.degree. C., utilising intermediate 2o.
Example 17:
[0449] 2[(4-Pyridyl)methyl]amino-N-(3-methylthio)phenyl]benzamide,
m.p. 138-142.degree. C., utilising intermediate 2p.
Example 18:
[0450] 2-[(4-Pyridyl)methyl]amino-N-(3-acetylaminophenyl)benzamide,
m.p. 157-158.degree. C., utilising intermediate 2q.
Example 19:
[0451]
2-[(4-Pyridyl)methyl]amino-N-3-[(aminocarbonyl)amino]phenyl]benzami-
de, m.p. 200-202.degree. C., utilising intermediate 2r.
Example 20:
[0452]
2-[(4-Pyridyl)methyl]amino-N-[3-(dimethylamino)phenyl]benzamide,
m.p. 152-154.degree. C., utilising intermediate 2s.
Example 21:
[0453]
5-Methoxy-2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]b-
enzamide, m.p. 175-178.degree. C., utilising intermediate 2t.
Example 22:
[0454]
3-Methyl-2-[(4-pyridyl)methyl]amino-N-[3(trifluoromethyl)phenyl]ben-
zamide is prepared utilising intermediate 2u.
[0455] Following purification by column chromatography (silica gel,
eluent: 33% hexane in ethyl acetate) the base is dissolved in ethyl
acetate and treated with a solution of hydrogen chloride in
dichloromethane. The precipitated product is filtered off and
recrystallized from ethyl acetate to afford the dihydrochloride
salt, m.p. 94-98.degree. C.
Example 23:
[0456]
4,5-Difluoro-2-[(4-pyridyl)methylamino-N-[3-(trifluoromethyl)phenyl-
]benzamide, m.p. 175-178.degree. C., utilising intermediate 2v.
Example 24:
[0457]
2-[(4-Pyridyl)methyl]amino-N-methyl-N-[3-(trifluoromethyl)phenyl]be-
nzamide, m.p. 127-128.degree. C., utilising intermediate 2w.
Example 25:
[0458]
2-[(4-Pyridyl)methyl]amino-N-[(3-methylsulphonyl)phenyl]benzamide,
m.p. 178-184.degree. C., utilising intermediate 2x.
Example 26:
[0459]
2-[(4-Pyridyl)methyl]amino-N-[(3-methylsulphinylphenyl]benzamide,
m.p. 175-178.degree. C., utilising intermediate 2y.
Example 27:
[0460]
2-[4-Pyridyl)methyl]amino-N-[4-(1,1-dimethylethyl)phenyl]benzamide,
m.p. 168-170.degree. C., utilising intermediate 2z.
Example 28:
[0461] 2-[(4-Pyridyl)methyl)amino-i(3-chlorophenyl)benzamide, m.p.
131-133.degree. C., utilising intermediate 2aa.
Example 29:
[0462] 2-[(4-Pyridyl)methyl]amino-4(3-bromophenyl)benzamide, m.p.
156-159.degree. C., utilising intermediate 2ab.
Example 30:
[0463] 2-[(4-Pyridyl)methyl]amino-N-(3-methylphenyl)benzamide, m.p.
139-140.degree. C., utilising intermediate 2ac.
Example 31:
[0464] 2-[(4-Pyridyl)methyl]amino-i(3-benzoylphenyl)benzamide, m.p.
168-169.degree. C., utilising intermediate 2ad.
Example 32:
[0465]
2-[(4-Pyridyl)methyl]amino-N-[3-(aminocarbonyl)phenyl]benzamide,
m.p. 195-203.degree. C., utilising intermediate 2ae.
Example 33:
[0466]
2-[(4-Pyridyl)methyl]amino-N-(4-methylphenyl)-6-methylbenzamide,
m.p. 162-163.degree. C., utilising intermediate 2af.
[0467] The following compounds are prepared by a method analogous
to that described in Example 14, by utilising the appropriate
aldehyde:
Example 34:
[0468]
2-[(3-Pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,
m.p. 140-142.degree. C., utilising 3-pyridinecarboxaldehyde.
Example 35:
[0469]
2-[(4-Quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamid-
e, m.p. 191-193.degree. C., utilising 4quinolinecarboxaldehyde.
Example 36:
[0470]
2-[(5-Quinolinyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]benzamid-
e, m.p. 176-178.degree. C., utilising 5-quinolinecarboxaldehyde
prepared as described by Wommack et al, J.Het.Chem. 1969;6:243-245,
from 5-aminoquinoline.
Example 37:
[0471]
2-1(4-(2-Methyl)pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]b-
enzamide, m.p. 146-147.degree. C., utilising
2-methyl-4-pyridinecarboxalde- hyde prepared as described by Boehm
et al, J. Med. Chem. 1996;39:3929-3937 from
2-methyl-4-cyanopyridine, which was in turn prepared by the method
of Ashimori et al, Chem. Pharm. Bull. 1990;38:2446-2458 from
2-methylpyridine-1-oxide.
Example 38:
[0472]
2-[(4-(1,2-Dihydro-2-oxo)pyridyl)methyl]amino-N-[3-(trifluoromethyl-
)phenyl] benzamide, m.p. 183-185.degree. C., utilising
1,2-dihydro-2-oxo-4-pyridinecarboxaldehyde prepared as described by
Ren, Sakai and Nakanishi, J. Amer. Chem. Soc. 1997;119:3619-3620
from 2-hydroxy-4-methylpyridine.
Example 39:
[0473] 2-[(4-Quinolinyl)methyl]amino-N-(4-chlorophenyl)benzamide,
m.p. 178-209.degree. C., is prepared by a method analogous to that
described in Example 4, by utilising
4-quinoline-carboxaldehyde.
Example 40:
[0474] 2-[(2-Imidazolyl)methyl]amino-N-(4chlorophenyl)benzamide,
m.p. 181-184.degree. C., is prepared by a method analogous to that
described in Example 4, by utilising
1H-imidazole-2-carboxaldehyde.
Example 41:
[0475]
2-[2-(4-Pyridyl)ethyl]amino-)N-[3-(trifluoromethyl)phenyl]benzamide
4-Pyridineethanamine (Maybridge Chemical Co, Cornwall, England;
0.31 9, 2.5 mmol) is added to a stirred mixture of
2-bromo-N-[3-(trifluoromethyl)- phenyl]benzamide (intermediate 1x;
1.72 g, 5 mmol), powdered potassium carbonate (0.35 9, 2.5 mmol)
and copper(1)iodide (Fluka, Buchs, Switzerland; 0.48 g, 2.5 mmol)
in dimethylformamide (10 mL). The resulting mixture is then purged
with argon and subsequently heated at 160.degree. C. under an argon
atmosphere for 15 hours. The mixture is cooled, treated with water
(100 mL) and extracted with ethyl acetate (3.times.80 mL). The
combined extracts are washesdwith an aqueous solution of ammonia
(2.times.10%), dried (Na.sub.2SO.sub.4), filtered and the solvent
is evaporated off under reduced pressure to yield the crude product
which is purified by column chromatography on silica gel, eluent
50% ethyl acetate in hexane and recrystallised from ethyl
acetate-hexane to give the title compound as a colourless
crystalline solid, m.p. 151-152.degree. C.
[0476] The following compounds are prepared by a method analogous
to that described in Example 41, by utilising the appropriate
amine:
Example 42:
[0477]
2-[2-(3-Pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]benzamide,
m.p. 102-103.degree. C., utilising 3-pyridineethanamine (Maybridge
Chemical Co, Cornwall, England).
Example 43:
[0478]
2-[1-Methyl-2-(3-pyridyl)ethyl]amino-N-[3-(trifluoromethyl)phenyl]b-
enzamide, utilising 1-(3-pyridyl)-2-propylamine prepared as
described by in J. Amer. Chem. Soc. 1997;119:3619-3620.
Example 44:
[0479]
2-[(1-Oxido-4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)phenyl]ben-
zamide 3-Chloroperoxybenzoic acid (2.06 g of 70%, 8.4 mmol) is
added to a stirred mixture of
2-[(4-pyridyl)methyl]amino-N-[3-(trifluoromethyl)pheny- l]benzamide
(Example 14; 1.86 g, 5 mmol) in dichloromethane (50 mL) at 0C. The
resulting mixture is then stirred at room temperature for 15 hours.
The mixture is diluted with dichloromethane (100 mL) and washed
sequentially with aqueous sodium hydroxide (2.times.100 mL) and
aqueous sodium thiosulphate (2.times.50 mL of 10%). The organic
phase is dried (Na.sub.2SO.sub.4), filtered and the solvent is
evaporated off under reduced pressure to yield the crude product
which is purified by column chromatography on silica gel, eluent
20% ethanol in ethyl acetate, and recrystallised from ethyl
acetate-hexane to give the title compound as a colourless
crystalline solid, m.p. 181-184.degree. C.
Example 45:
[0480]
2-[(4-Pyridyl)methyl]methylamino-N-[3-(trifluoromethyl)phenyl]benza-
mide Sodium cyanoborohydride (0.55 g, 14.1 mmol) is added to a
stirred mixture of paraformaldehyde (0.82 g, 27.3 mmol) and
2-[(4-pyridyl)methyl]amino-M-[3-(trifluoromethyl)phenyl]-benzamide
(Example 14; 1.03 g, 2.78 mmol) in tetrahydrofuran (30 mL) at
20.degree. C. under an argon atmosphere. The resulting mixture is
then treated dropwise with trifluoroacetic acid (15 mL) and stirred
at room temperature for 20 hours. The mixture diluted with ice-cold
aqueous sodium hydroxide (100 mL of 5M) and extracted with
dichloromethane (3.times.100 mL). The organic phase is dried
(Na.sub.2SO.sub.4), filtered and the solvent is evaporated off
under reduced pressure to yield the crude product which is purified
by column chromatography on silica gel, eluent ethyl acetate, to
give the title compound as a colourless crystalline solid.
Example 46:
[0481]
2-[(4-Pyridyl)methyl]methylamino-N-(4-chloronaphthyl)benzamide 0.75
ml Trimethylaluminium (2M in toluene) is added to a suspension of
266 mg 4-chloro-1-naphthylamine in 1 mL toluene. After 10 minutes a
cold solution of 242 mg methyl N-(4-pyridylmethyl)-anthranilate in
2 mL toluene is added. The mixture is stirred for 1 hour at room
temperature and for 1 hour under reflux. After cooling to room
temperature saturated NaHCO.sub.3 solution is added and the mixture
extracted with ethyl acetate. The extract is washed with water and
saturated sodium chloride solution and concentrated. The residue is
crystallized with ethyl acetate to give the title compound as a
solid with m.p. 137.degree. C.
[0482] Stage 46.1: N-(4-pyridylmethyl)-anthranilate
[0483] 3 mL Acetic acid and 8.6 g 4-pyridinecarbaldehyde are added
to a solution of 7.5 g methyl anthranilate in 300 mL methanol. The
mixture is stirred for 12 hours under nitrogen atmosphere at room
temperature. 5.7 g Sodium cyanotrihydridoborate (85%) is added and
the mixture is stirred for 3 hours at room temperature. Additional
1.14 g sodium cyanotrihydridoborate (85%) is added and the mixture
is stirred for 12 hours at room temperature. The solvent is
evaporated and the residue dissolved in ethyl acetate and washed
with saturated NaHCO.sub.3 solution and saturated sodium chloride
solution. The organic extract is concentrated and purified with
hexane/ethyl acetate (1:1) on silica gel to yield methyl
N-(4-pyridylmethyl)-anthranilate with m.p. 86.degree. C.
Examples 47-72
[0484] The compounds of Examples 47-72 were prepared in an
analogous manner by reductive amination followed by amidation with
an amine and trimethylaluminium as described in Example 46. The
used anthranilic esters are commercially available or are described
below.
[0485] Synthesis of the starting material for Example 47:
[0486] 2-Methyl-nitrobenzoic acid is reacted with
trimethylsilydiazomethan- e to yield methyl
2-methyl-6-nitrobenzoate with m.p. 44-45.degree. (Chem. Pharm.
Bull., Vol. 29, 1475 (1981)). Methyl 2-methyl-6-nitrobenzoate is
hydrogenated in methanol in the presence of palladium, 10% on
carbon powder, at room temperature and atmospheric pressure to give
methyl 2-methyl-6-aminobenzoate.
Synthesis of the starting material for Example 48
[0487] 2-Amino-6-chlorobenzoic acid is reacted with
trimethylsilyldiazomethane to yield methyl 2-amino-6-chlorobenzoate
( Chem. Pharm. Bull. Vol. 29, 1475 (1981)).
Synthesis of the starting material for Example 49
[0488] 3,4-Methylenedioxy-6-nitrobenzaldehyde is converted to
methyl 3,4-methylenedioxy-6-nitrobenzoate in methanol in the
presence of sodium cyanide and manganese dioxide (Synthetic
Commun., 27(7), 1281-1283 (1997)). Methyl
3,4-methylenedioxy-6-nitrobenzoate is hydrogenated in ethanol in
the presence of palladium, 10% on carbon powder, at room
temperature and atmospheric pressure to give methyl
3,4-methylenedioxy-6-aminobenzoate.
Synthesis of the starting material for Example 50
[0489] 0.41 g Sodium nitrite in water is added to 1 g
4,5-dimethyl-2-nitroaniline in 3 mL conc. HCl and stirred for 1
hour at +4.degree. C. This solution is added to a mixture of 0.67 g
copper (I) cyanide, 0.98 g sodium cyanide, 0.32 g sodium carbonate,
25 mL of water and 3 mL toluene. The mixture is stirred for 12
hours at room temperature and worked up to give 0.45 g
4,5-dimethyl-2-nitrobenzonitrile. 4,5-Dimethyl-2-nitrobenzonitrile
is reduced with iron powder in acetic acid to yield
4,5-dimethyl-2-aminobenzonitrile. 4,5-Dimethyl-2-aminobenzo-
nitrile is heated at reflux for 12 hours in conc. HCl to give
4,5-dimethyl-2-aminobenzoic acid. 4,5-Dimethyl-2-aminobenzoic acid
is reacted with trimethylsilyldiazomethane to yield methyl
4,5-dimethyl-2-aminobenzoate (Chem. Pharm. Bull. Vol. 29, 1475
(1981)).
1TABLE 1 Examples 47-72 The following compounds are compounds of
formula I wherein W is O, X is NH, Y is CH.sub.2, R.sub.2 is
4-pyridyl; R.sub.6 and R.sub.7 are H. Ex. R.sub.1 R.sub.3 R.sub.4
R.sub.5 mp. 47 4-chlorophenyl methyl H H 190 48 4-chlorophenyl
chloro H H 183-185 49 4-chlorophenyl H --O--CH.sub.2--O-- 50
4-chlorophenyl H methyl methyl 51 4-n-propylphenyl H chloro H 52
4-n-propylphenyl H H H 53 7-hydroxynaphthyl H H H 54 8-hydroxy-2- H
H H 235 naphthyl 55 4-chlorophenyl H H chloro 186 56 4-chlorophenyl
H methyl H 127 57 5,6,7,8-tetrahydro- H H H 116 naphthyl 58
4-biphenyl H H H 135-136 59 4-chlorophenyl H chloro H 206-207 60
naphthyl H H H 61 2-napthyl H H H 159-160 62 4-methoxyphenyl H H H
63 3-trifluoromethoxy- H H H phenyl 64 4-methoxy-2- H H H 152-154
naphthyl 65 3-bromo-2- H H H 130-132 naphthyl 66 4-(isopropoxy- H H
H H 70 carbonyl)-phenyl 67 4-trifluoromethoxy- H H H phenyl 68
4-(isopropyl- H H H 79 carbamoyl)-phenyl 69 3-chloro-4- H H H 143
methylphenyl 70 2-methylphenyl H H H 143 71 3-(methoxy- H H H
carbonylmethyl)- phenyl 72 4-phenoxyphenyl H H H
Example 73:
[0490] Test for activity against Flt-1 VEGF-receptor tyrosine
kinase
[0491] The test is conducted using Flt-1 VEGF-receptor tyrosine
kinase, as described hereinabove. The IC.sub.50 values determined
are given below, insofar as they have been accurately recorded:
2TABLE 2 Test for activity against Flt-1 VEGF-receptor tyrosine
kinase Title compound from Example IC.sub.50(.mu.M) 4 0.18 5 0.26 7
0.56
Example 74: Soft capsules
[0492] 5000 soft gelatin capsules, each comprising as active
ingredient 0.05 g of one of the compounds of formula I mentioned in
the preceding Examples, are prepared as follows:
3 Composition Active ingredient 250 g Lauroglycol 2 liters
[0493] Preparation process: The pulverized active ingredient is
suspended in Lauroglykol.RTM. (propylene glycol laurate, Gattefoss
S. A., Saint Priest, France) and ground in a wet pulverizer to
produce a particle size of about 1 to 3 .mu.m. 0.419 g portions of
the mixture are then introduced into soft gelatin capsules using a
capsule-filling machine.
* * * * *