Title: N-Aryl (thio) anthranilic acid amide derivatives, their preparation and their use as VEGF
Abstract: Described are compunds of formula (I), wherein W is O or S; X is NR8; Y is CR9R10—(CH2)n wherein R9 and R10 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 SO2; R2 is aryl; R2 is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R2 cannot represent 2-phthalimidyl, and in case of Y=SO2 cannot represent 2,1,3-benzothiadiazol-4-yl; any of R3, R4, R5 and R6, independently of the other, is H or a substituent other than hydrogen; and R7 and R8, 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. ##STR1##
Patent Number: 7,002,022 Issued on 02/21/2006 to Altmann, et al.
| 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; Jürgen (Denzlingen, DE);
Huth; Andreas (Berlin, DE);
Krüger; Martin (Berlin, DE);
Seidelmann; Dieter (Berlin, DE);
Menrad; Andreas (Oranienburg, DE);
Haberey; Martin (Berlin, DE);
Thierauch; Karl-Heinz (Berlin, DE)
|
| Assignee:
|
Novartis AG (Basel, CH);
Schering Aktiengesellschaft (Berlin, DE)
|
| Appl. No.:
|
828951 |
| Filed:
|
April 21, 2004 |
Foreign Application Priority Data
| Current U.S. Class: |
548/335.1; 548/346.1; 514/396 |
| Current Intern'l Class: |
C07C 49/76 (20060101); C07C 49/78.6 (20060101); C07C 49/82 (20060101); C07C 49/82.5 (20060101); C07C 49/88.4 (20060101) |
| Field of Search: |
548/3351,346.1
514/396
|
References Cited [Referenced By]
U.S. Patent Documents
| 3226394 | Dec., 1965 | Schipper.
| |
| Foreign Patent Documents |
| 19830430 | Jan., 2000 | DE.
| |
| 0 947 500 | Oct., 1999 | EP.
| |
| 1189719 | Apr., 1970 | GB.
| |
| 56-161362 | Dec., 1981 | JP.
| |
| 9-59236 | Mar., 1997 | JP.
| |
| 9059236 | Mar., 1997 | JP.
| |
| 10-259176 | Sep., 1998 | JP.
| |
| 96/09294 | Mar., 1996 | WO.
| |
| 96/41795 | Dec., 1996 | WO.
| |
| 98/17648 | Apr., 1998 | WO.
| |
| 95/25723 | Sep., 1998 | WO.
| |
| 99/32477 | Jul., 1999 | WO.
| |
| 99/54284 | Oct., 1999 | WO.
| |
Other References
Japan Tobacco Inc., Chemical Abstracts, 1982; 162351, (JP 56-161362, Dec. 11, 1981).
Inaba et al., Chemical Abstracts 129:310895, Jun. 4, 1999, ( JP 10-259176, Sep.
29, 1998).
Augustin, tiPS. vol. 19, "Antiangiogenic tumour therapy: will it work?" pp. 216-222,
(Jun. 1998).
Hisano et al. Chem. Pharm.Bull., vol. 20, No. 12, "Syntheses and Pharmacological
Activities of 2-Heterocyclic Substituted 4(3H)-Quinazolinone Derivatives,"
pp. 2575-2584, (1972).
Lüddens et al., European Journal of Pharmacology, vol. 344, "Structure—activity
relationship of furosemide-derived compounds as antagonists of cerebellum-specific
GABAA receptors," pp. 269-277, (1998).
Caplus, English Abstract JP9059236, Kawagoe Keiichi, Mar. 1997.
Breier et al., Trends in Cell Biology, vol. 6, "The Role of Vascular Endothelial
Growth Factor in Blood Vessel Formation," pp. 454-456, (Dec. 1996).
Mikhailitsyn et al. Chemical Abstracts, vol. 116, 417373f, p. 771, (1992) XP-002128306.
Shani et al., Pharmacology, vol. 26, "Structure Activity Correlation for Diuretic
Furosemide Congeners," pp. 172-180, (1983).
Tiwari et al., J.Chem.Soc.Pak, vol. 4, No. 2, "Visible Antifertility Compounds—Part
IV: Syntheses of 2-(Phthallmido methylamino)-substituted benzanilides," pp. 115-117, (1982).
Varnavas et al., Pharmazie, vol. 51, "Anthranoyl-anthranilic acid: a template
for the development of a new class of chloecystokinin receptor ligands," pp. 697-700, (1996).
The Condensed Chemical Dictionary, Fifth Edition, p. 114 (1956).
|
Primary Examiner: Desai; Rita
Attorney, Agent or Firm: McNally; Lydia T.
Parent Case Text
This application is a divisional of U.S. application Ser. No. 10/180,289, filed
Jun. 26, 2002 now U.S. Pat No. 6,878,720, which is a divisional of U.S. application
Ser. No. 09/850,434, filed May 7, 2001, now issued as U.S. Pat. No. 6,448,277 B2,
which is a continuation of International Application No. PCT/EP99/08545, filed
Nov. 8, 1999.
Claims
What is claimed is:
1. A compound of formula I,
##STR11##
wherein
W is O or S;
X is NR
8;
Y is CR
9R
10—(CH
2)
n wherein
R
9 and R
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
2;
R
1 is aryl;
R
2 is a imidazolyl;
any of R
3, R
4, R
5 and R
6, independently
of the other, is H or a halogen or aralkyl group; and
R
7 and R
8, independently of each other, are H or lower alkyl;
or a N-oxide or a pharmaceutically acceptable salt thereof.
2. A compound of formula I according to claim 1,
wherein
W is O or S;
X is NR
8;
Y is CHR
9—(CH
2)
n wherein
R
9 is hydrogen or lower alkyl, and
n is an integer of from and including 0 to and including 3; or
Y is SO
2;
R
1 is aryl;
R
2 is a imidazolyl;
any of R
3, R
4, R
5 and R
6, independently
of the other, is H or a halogen or an alkyl group and R
7 and R
8,
independently of each other, are H or lower alkyl;
or a salt thereof.
3. A compound of formula I according to claim 1,
wherein
W is O or S;
X is NR
8;
Y is CHR
9—(CH
2)
n wherein
R
9 is H or lower alkyl, and
n is 0 to 3; or
Y is SO
2;
R
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 alkanoyl-amino, 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 alkyl-phenylthio 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)2) and lower alkylene dioxy bound at adjacent C-atoms
of the ring;
R2 is imidazolyl, of the formula Ib or Ic
##STR12##
wherein
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; and
Q is lower alkyl, hydroxy, lower alkoxy, lower thioalkyl or halogen;
any of R
3, R
4, R
5 and R
6, independently
of the other, is H, fluorine or lower alkyl; and
R
7 and R
8, independently of each other, are H or lower alkyl;
or a N-oxide or a pharmaceutically acceptable salt thereof.
4. A compound of formula I according to claim 1, wherein
W is O;
X is NR
8;
Y is CHR
9—(CH
2)
n wherein
R
9 is H or methyl, and
n is 0;
or Y is SO
2;
R
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
2 is imidazolyl;
any of R
3, R
4, R
5 and R
6, independently
of the other, are H, methyl or chloro; or
R
3 and R
4 together represent methylene dioxy and R
5
and R
6, independently of the other, are H, methyl or chloro; and
R
7 and R
8, independently of each other, are H, fluorine
or methyl;
or a N-oxide or a pharmaceutically acceptable salt thereof.
5. A compound of formula I according to claim 1, wherein
W is O;
X is NR
8;
Y is CHR
9—(CH
2)
n wherein
R
9 is H or methyl, and
n is 0;
or Y is SO
2;
R
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
2 is imidazolyl;
any of R
3, R
4, R
5 and R
6, independently
of the other, is H or methyl; and
R
7and R
8, independently of each other, are H or methyl;
or a N-oxide or a pharmaceutically acceptable salt thereof.
6. A compound of formula I according to claim 1, wherein
W is O;
X is NR
8;
Y is CHR
9—(CH
2)
n wherein
R
9 is H or methyl, and
n is 0;
or Y is SO
2;
R
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
2 is imidazolyl;
any of R
3, R
4, R
5 and R
6, independently
of the other, is H or methyl; and
R
7 and R
8, independently of each other, are H or methyl;
or a salt thereof.
7. A compound of formula I according to claim 1 selected from
2-[(2-imidazolyl)methyl]amino-N-(4-chlorophenyl)benzamide;
or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical preparation, comprising a compound of formula I according
to claim 1, or a N-oxide or a pharmaceutically acceptable salt thereof, or a hydrate
or solvate thereof, and at least one pharmaceutically acceptable carrier.
Description
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.
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).
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).
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.
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.
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.
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.
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.
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.
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
The invention relates the use of a compound of formula I,
##STR2##
wherein
W is O or S;
X is NR8;
Y is CR9R10—(CH2)n wherein
- R9 and R10 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 SO2;
R1 is aryl;
R2 is a mono- or bicyclic heteroaryl group comprising one or
more ring nitrogen atoms with the exception that R2 cannot represent
2-phthalimidyl, and in case of Y=SO2 cannot represent 2,1,3-benzothiadiazol-4-yl;
any of R3, R4, R5 and R6, independently
of the other, is H or a substituent other than hydrogen; and
R7 and R8, 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 general terms used hereinbefore and hereinafter preferably have within the
context of this disclosure the following meanings, unless otherwise indicated:
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.
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.
Any asymmetric carbon atoms (for example in compounds of formula I, wherein R
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.
The invention relates also to possible tautomers of the compounds of formula I.
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.
The index n is preferably 0 or 1, especially 0.
Y is preferably methylene (CH
2) or ethylene (CH
2—CH
2),
most preferably methylene.
"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)
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 isopropoxy 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-trifluoromethylphenyl, 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.
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.
Halogen is especially fluorine, chlorine, bromine, or iodine, especially
fluorine, chlorine, or bromine.
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.
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.
Etherified hydroxy is especially C
8-C
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
8-C
20-alkyloxy,
such as n-decyloxy, halogen-lower alkoxy, such as trifluoromethyloxy or 1,1,2,2-tetrafluoroethoxy.
Esterified hydroxy is especially lower alkanoyloxy, benzoyloxy, lower
alkoxycarbonyloxy, such as tert-butoxycarbonyloxy, or phenyl-lower alkoxycarbonyloxy,
such as benzyloxycarbonyloxy.
Esterified carboxy is especially lower alkoxycarbonyl, such as tert-butoxycarbonyl,
isopropoxycarbonyl, methoxycarbonyl or ethoxycarbonyl, phenyl-lower alkoxycarbonyl,
or phenyloxycarbonyl.
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.
Alkylphenylthio is especially lower alkylphenylthio.
Alkylphenylsulfonyl is especially lower alkylphenylsulfonyl.
Alkylphenylsulfinyl is especially lower alkylphenylsulfinyl.
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.
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.
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, isobenzofuranyl, 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).
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
2 cannot represent
2-phthalimidyl, and in case of Y=SO
2R
2 cannot represent 2,1,3-benzothiadiazol-4-yl.
Preferred is imidazolyl, especially imidazol-4-yl, quinolyl, especially 3-, 4-,
5-quinolyl, naphthyridinyl, especially 3-(1,8-naphthyridinyl) or 4-(1,8-naphthyridinyl),
or especially a moiety of the formula Ib or Ic
##STR3##
wherein
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, 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.
Very preferably R
2 is 3-pyridyl, 4-pyridyl, 4-quinolinyl or 5-quinolinyl.
Most preferably, R
2 is 4-pyridyl.
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.
Preferably, R
7 and R
8 are hydrogen, and R
3,
R
4, R
5 and R
6 each are independently hydrogen,
chloro or fluorine.
Salts are especially the pharmaceutically acceptable salts of compounds of
formula I.
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
acid, 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.
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.
When a basic group and an acid group are present in the same molecule, a compound
of formula 1 may also form internal salts.
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.
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.
The compounds of formula I and N-oxides thereof have valuable pharmacological
properties, as described hereinbefore and hereinafter.
The efficacy of the compounds of the invention as inhibitors of VEGF-receptor
tyrosine kinase activity can be demonstrated as follows:
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 μl 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
2), 3 mM magnesium chloride (MgCl
2), 10 μM sodium
vanadate, 0.25 mg/ml polyethylenglycol (PEG) 20000, 1 mM dithiothreitol and 3 μg/μl
poly(Glu,Tyr) 4:1 (Sigma, Buchs, Switzerland), 8 μM [
33P]-ATP
(0.2 μCi) 1% dimethyl sulfoxide, and 0 to 100 μM 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 μl 0.25 M ethylenediaminetetraacetate
(EDTA) pH 7. Using a multichannel dispenser (LAB SYSTEMS, USA), an aliquot of 20
μl 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
3PO
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 μl Microscint® (β-scintillation counter liquid). IC
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 μmol).
The IC
50-values that can be found with compounds of formula I are in
the range of 0.01 to 100 μM, preferably in the range from 0.01 to 50 μM.
The antitumor efficacy of the compounds of the invention can be demonstrated
in vivo as follows:
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® anaesthesia (Abbott, Switzerland).
Treatment with the test compound is started as soon as the tumor has reached a
mean volume of 100 mm
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.
As an alternative other cell lines may also be used in the same manner, for example:
- the MCF-7 breast adenocarcinoma cell line (ATCC No. HTB 22; see also
J. Natl. Cancer Inst. (Bethesda) 51, 1409-16 [1973]);
- the MDA-MB 468 breast adenocarcinoma cell line (ATCC No. HTB 132; see
also In Vitro 14, 911-15 [1978]);
- the MDA-MB 231 breast adenocarcinoma cell line (ATCC No. HTB 26; see
also J. Natl. Cancer Inst. (Bethesda) 53, 661-74 [1974]);
- the Colo 205 colon carcinoma cell line (ATCC No. CCL 222; see also Cancer
Res. 38, 1345-55 [1978]);
- the HCT 116 colon carcinoma cell line (ATCC No. CCL 247; see also Cancer
Res. 41, 1751-6 [1981]);
- the DU145 prostate carcinoma cell line DU 145 (ATCC No. HTB 81; see
also Cancer Res. 37, 4049-58 [1978]); and
- the PC-3 prostate carcinoma cell line PC-3 (ATCC No. CRL 1435; see also
Cancer Res. 40, 524-34 [1980]).
The inhibition of VEGF-induced KDR-receptor autophosphorylation can be confirmed
with a further in vivo 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°
C. under 5% CO
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° C., recombinant VEGF is added; the final
VEGF concentration is 20 ng/ml). After a further five minutes' incubation at 37°
C., the cells are washed twice with ice-cold PBS (phosphate-buffered saline) and
immediately lysed in 100 μl 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° C.
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™ 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 μg protein per well) are then incubated
in these plates overnight at 4° C. together with an anti-phosphotyrosine 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 μM to 6 μM, preferably 0.005
to 0.5 μM.
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 Abl 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.
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]).
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.
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:
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-(methylsulfonyl)phenyl]thiophene
or diclofenac, is administered in a separate group.
In detail, male Wistar rats (5 animals per group, weighing approximately 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).
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.
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 μl of a 20% yeast suspension in water in the hind paw. The
rats are treated orally with the test compound (3, 10 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.
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 I, 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.
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.
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.
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-β or
IFN-β, an aromatase inhibitor, a classical cytostatic, and an inhibitor of
the interaction of an SH2 domain with a phosphorylated protein.
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.
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.
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.
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;
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.
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.
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 I, wherein
W is O or S;
X is NR8;
Y is CR9R10—(CH2)n wherein
- R9 and R10 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 SO2;
R1 is aryl;
R2 is a mono- or bicyclic heteroaryl group comprising one or
more ring nitrogen atoms with the exception that R2 cannot represent
2-phthalimidyl, and in case of Y=SO2 cannot represent 2,1,3-benzothiadiazol-4-yl;
any of R3, R4, R5 and R6, independently
of the other, is H or a substituent other than hydrogen; and
R7 and R8, independently of each other, are H or lower alkyl;
with the exception of the compound of formula I wherein W is O, X is NR8,
Y is CH2, R1 is 4-chlorophenyl, R2 is 2-pyridyl,
R3, R4, R5, R7 and R8 are
each H and R6 is chloro;
or a N-oxide or a pharmaceutically acceptable salt thereof.
Preferred are compounds of formula I, wherein
W is O or S;
X is NR8;
Y is CHR9—(CH2)n wherein
- R9 is hydrogen or lower alkyl, and
- n is an integer of from and including 0 to and including 3; or
Y is SO2;
R1 is aryl;
R2 is a mono- or bicyclic heteroaryl group comprising one or
more ring nitrogen atoms with the exception that R2 cannot represent
2-phthalimidyl, and in case of Y=SO2 cannot represent 2,1,3-benzothiadiazol-4-yl;
any of R3, R4, R5 and R6, independently
of the other, is H or a substituent other than hydrogen; and
R7 and R8, independently of each other, are H or lower alkyl;
with the exception of the compound of formula I wherein W is O, X is NR8,
Y is CH2, R1 is 4-chlorophenyl, R2 is 2-pyridyl,
R3, R4, R5, R7 and R8 are
each H and R6 is chloro;
or a salt thereof.
In particular, preferred compounds of formula I are those in which
W is O or S;
X is NR8;
Y is CHR9—(CH2)n wherein
- R9 is H or lower alkyl, and
- n is 0 to 3; or
Y is SO2;
R1 is phenyl that is unsubstituted 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)2); and lower
alkylene dioxy bound at adjacent C-atoms of the ring;
R2 is imidazolyl, quinolyl, naphthyridinyl, or a moiety of the
formula Ib or Ic
##STR4##
wherein
- 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 R3, R4, R5 and R6, independently
of the other, is H, fluorine or lower alkyl; and
R7 and R8, independently of each other, are H or lower alkyl;
or a N-oxide or a pharmaceutically acceptable salt thereof.
More specifically, preference is given to a compound of formula I, wherein
W is O;
X is NR8;
Y is CHR9—(CH2)n wherein
- R9 is H or methyl, and
- n is 0;
or Y is SO2;
R1 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 alko
