U.S. patent application number 16/167567 was filed with the patent office on 2019-02-07 for medicaments for the treatment or prevention of fibrotic deiseases.
The applicant listed for this patent is Boehringer Ingelheim International GmbH. Invention is credited to Trixi Brandl, Nveed Chaudhary, Georg Dahmann, Matthias Grauert, Armin Heckel, John Edward Park, Gerald Juergen Roth.
Application Number | 20190038600 16/167567 |
Document ID | / |
Family ID | 36602118 |
Filed Date | 2019-02-07 |
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United States Patent
Application |
20190038600 |
Kind Code |
A1 |
Park; John Edward ; et
al. |
February 7, 2019 |
MEDICAMENTS FOR THE TREATMENT OR PREVENTION OF FIBROTIC
DEISEASES
Abstract
The present invention relates to the use of indolinones of
general formula ##STR00001## substituted in the 6 position, wherein
R.sub.1 to R.sub.5 and X are defined as in claim 1, the isomers and
the salts thereof, particularly the physiologically acceptable
salts thereof, as a medicament for the prevention or treatment of
specific fibrotic diseases.
Inventors: |
Park; John Edward;
(Warthausen, DE) ; Roth; Gerald Juergen; (Biberach
an der Riss, DE) ; Heckel; Armin; (Biberach an der
Riss, DE) ; Chaudhary; Nveed; (Southampton, GB)
; Brandl; Trixi; (Allschwil, CH) ; Dahmann;
Georg; (Warthausen-Birkenhard, DE) ; Grauert;
Matthias; (Biberach an der Riss, DE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Boehringer Ingelheim International GmbH |
Ingelheim am Rhein |
|
DE |
|
|
Family ID: |
36602118 |
Appl. No.: |
16/167567 |
Filed: |
October 23, 2018 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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14982179 |
Dec 29, 2015 |
10154990 |
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16167567 |
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14184821 |
Feb 20, 2014 |
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14982179 |
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12645151 |
Dec 22, 2009 |
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14184821 |
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11275223 |
Dec 20, 2005 |
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12645151 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61K 9/08 20130101; A61K 45/06 20130101; A61K 9/2018 20130101; C07D
295/155 20130101; C07D 209/34 20130101; A61P 43/00 20180101; A61K
31/4178 20130101; A61K 31/445 20130101; A61K 31/4045 20130101; A61K
31/5377 20130101; A61K 9/2866 20130101; A61K 31/404 20130101; A61K
47/38 20130101; A61K 9/0031 20130101; A61K 31/496 20130101; A61K
9/02 20130101; A61K 9/1623 20130101; A61K 31/551 20130101; A61K
9/0078 20130101; C07D 295/215 20130101; C07D 401/12 20130101; A61K
9/0019 20130101; A61K 31/454 20130101; A61K 31/495 20130101; A61K
47/10 20130101; C07D 403/12 20130101; A61K 31/44 20130101; A61K
9/0075 20130101; A61K 9/10 20130101; A61K 31/404 20130101; A61K
2300/00 20130101; A61K 31/44 20130101; A61K 2300/00 20130101; A61K
31/445 20130101; A61K 2300/00 20130101; A61K 31/496 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/4045 20060101
A61K031/4045; A61K 31/5377 20060101 A61K031/5377; A61K 31/496
20060101 A61K031/496; A61K 31/4178 20060101 A61K031/4178; A61K
31/454 20060101 A61K031/454; C07D 403/12 20060101 C07D403/12; A61K
31/551 20060101 A61K031/551; A61K 45/06 20060101 A61K045/06; C07D
209/34 20060101 C07D209/34; C07D 401/12 20060101 C07D401/12; C07D
295/215 20060101 C07D295/215; C07D 295/155 20060101 C07D295/155;
A61K 31/495 20060101 A61K031/495; A61K 31/445 20060101 A61K031/445;
A61K 31/44 20060101 A61K031/44; A61K 31/404 20060101
A61K031/404 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 24, 2004 |
EP |
04030770.4 |
Claims
1. A method for treating fibrosis in rheumatoid arthritis,
comprising administering to patient in need thereof a
therapeutically effective amount of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methy-
l-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
or a salt thereof.
2. The method of claim 1 wherein
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone is in
the form of a monoethanesulfonate salt.
3. The method of claim 1 further comprising administering an
additional pharmacologically active substance selected from the
group consisting of anticholinergic agents, beta-2 mimetics,
steroids, PDE-IV inhibitors, p38 MAP kinase inhibitors, NK1
antagonists, LTD4 antagonists, EGFR inhibitors and
endothelin-antagonists.
4. The method of claim 3, wherein the
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, or salt
thereof, and the additional pharmacologically active substance
together comprise a pharmaceutical composition that further
comprises one or more pharmaceutically acceptable carriers or
excipients.
Description
[0001] The present invention relates to a new use of indolinones of
general formula
##STR00002##
substituted in the 6 position, the tautomers, the diastereomers,
the enantiomers, the mixtures thereof and the salts thereof,
particularly the physiologically acceptable salts thereof.
BACKGROUND
[0002] Compounds of the above general formula I, the tautomers, the
diastereomers, the enantiomers, the mixtures thereof and the salts
thereof, particularly the physiologically acceptable salts thereof,
have been described in WO 01/27081 and WO 04/13099 as having
valuable pharmacological properties, in particular an inhibiting
effect on various kinases, especially receptor tyrosine kinases
such as VEGFR2, PDGFR.alpha., PDGFR.beta., FGFR1, FGFR3, EGFR,
HER2, IGF1R and HGFR, as well as complexes of CDK's (Cyclin
Dependent Kinases) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,
CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1,
D2, D3, E, F, G1, G2, H, I and K) and to viral cyclin (cf. L.
Mengtao in J. Virology 71(3), 1984-1991 (1997)), and on the
proliferation of cultivated human cells, in particular endothelial
cells, e.g. in angiogenesis, but also on the proliferation of other
cells, in particular tumour cells.
[0003] However, none of these compounds have been described for
their use in the treatment or prevention of the fibrotic diseases
referred to in the present invention.
[0004] Remodeling is a normal response to tissue injury and
inflammation that is observed in many tissues throughout the body.
After resolution of the inflammation and repair of tissue damage,
the tissue is generally returned to its original condition.
Excessive uncontrolled tissue repair or the failure to stop
remodeling when it is no longer required leads to condition known
as fibrosis. Fibrosis is characterized by excessive deposition of
extracellular matrix components and overgrowth of fibroblasts.
Fibrosis can occur in all tissues but is especially prevalent in
organs with frequent exposure to chemical and biological insults
including the lung, skin, digestive tract, kidney, and liver (Eddy,
1996, J Am Soc Nephrol, 7(12):2495-503; Dacic et al., 2003, Am J
Respir Cell Mol Biol, 29S: S5-9; Wynn, 2004, Nat Rev Immunol,
4(8):583-94). Fibrosis often severely compromises the normal
function(s) of the organ and many fibrotic diseases are, in fact,
life-threatening or severely disfiguring, such as idiopathic
pulmonary fibrosis (IPF), liver cirrhosis, scleroderma, or renal
fibrosis. Treatment options for these diseases are often limited to
organ transplantation, a risky and expensive procedure.
[0005] A large body of literature implicates the platelet-derived
growth factor (PDGF), fibroblast growth factor (FGF), vascular
endothelial growth factor (VEGF), epidermal growth factor (EGF),
and transforming growth factor beta (TGFb) growth factor families
in the induction or persistence of fibrosis (Levitzki, Cytokine
Growth Factor Rev, 2004, 15(4):229-35; Strutz et al., Kidney Intl,
2000, 57:1521-38; Strutz et al., 2003, Springer Semin Immunopathol,
24:459-76; Rice et al., 1999, Amer J Pathol, 155(1):213-221;
Broekelmann et al., 1991, Proc Nat Acad Sci, 88:6642-6; Wynn, 2004,
Nat Rev Immunol, 4(8):583-94).
[0006] PDGF, EGF and FGF family members are potent mitogens for
mesenchymal cells such as smooth muscle cells, myofibroblasts and
fibroblasts (Benito et al., 1993, Growth Regul 3(3):172-9; Simm et
al, 1998, Basic Res Cardiol, 93(S3):40-3; Klagsburn, Prog Growth
Factor Res, 1989, 1(4):207-35; Kirkland et al., 1998, J Am Soc
Nephrol, 9(8):1464-73), the very cells which supplant normal tissue
in fibrosis and are believed to play a role in tissue remodeling
(Abboud, 1995, Annu Rev Physiol., 57:297-309; Jinnin et al., 2004,
J Cell Physiol, online; Martinet et al., 1996, Arch Toxicol
18:127-39; Desmouliere, Cell Biology International, 1995, 19:471-6;
Jelaska et al., Springer Semin Immunopathol, 2000, 21:385-95).
[0007] Inhibition of PDGF attenuates both liver fibrosis and lung
fibrosis in experimental models, suggesting fibrosis in different
organs may have a common origin (Borkham-Kamphorst et al., 2004,
Biochem Biophys Res Commun; Rice et al., 1999, Amer J Pathol,
155(1):213-221). An EGF receptor kinase inhibitor was also active
in this lung fibrosis model. Three-fold overexpression of an EGF
family member, HB-EGF, in mouse pancreas islets was sufficient to
cause development of fibrosis in both the exocrine and endocrine
compartments (Means et al., 2003, Gastroenterology,
124(4):1020-36).
[0008] Similarly, FGF1/FGF2-deficient mice show dramatically
decreased liver fibrosis after chronic carbon tetrachloride (CCl4)
exposure (Yu et al., 2003, Am J Pathol, 163(4):1653-62). FGF
expression is increased in human renal interstitial fibrosis where
it strongly correlates with interstitial scarring (Strutz et al.,
2000, Kidney Intl, 57:1521-38) as well as in a model of
experimental lung fibrosis (Barrios et al., 1997, Am J Physiol, 273
(2 Pt 1):L451-8), again lending credence to the idea that fibrosis
in various tissues has a common basis.
[0009] In addition, elevated levels of VEGF have been observed in
several studies in persons with asthma (Hoshino et al., 2001, J
Allergy Clin Immunol 107:1034-39; Hoshino et al. 2001, J Allergy
Clin Immunol 107:295-301; Kanazawa et al. 2002, Thorax 57:885-8;
Asai et al., J Allergy Clin Immunol 110:571-5, 2002; Kanazawa et
al., 2004, Am J Respir Crit Care Med, 169:1125-30). Inducible
expression of VEGF in a transgenic mouse model induces an
asthma-like phenotype, edema, angiogenesis and smooth muscle
hyperplasia (Lee et al., 2004, Nature Med 10:1095-1103).
[0010] Finally, TGFb stimulates production of extracellular matrix
proteins including fibronectin and collagens and is believed to
play an important role in fibrosis in many tissues (Leask et al.,
2004, FASEB J 18(7):816-27; Bartram et al., 2004, Chest
125(2):754-65; Strutz et al., 2003, Springer Semin Immunopathol,
24:459-76; Wynn, 2004, Nat Rev Immunol, 4(8):583-94). Inhibitors of
TGFb production and signaling pathways are active in a number of
fibrosis animal models (Wang et al., 2002, Exp Lung Res, 28:405-17;
Laping, 2003, Curr Opin Pharmacol, 3(2):204-8).
[0011] As summarized above, several growth factors are upregulated
in fibrosis and the inhibition of a single factor seems to reduce
the severity of fibrosis in the fibrosis models.
SUMMARY OF THE INVENTION
[0012] Surprisingly, we found that the compounds of above general
formula I are effective in the treatment or prevention of specific
fibrotic diseases.
[0013] The present invention thus relates to the use of the
compounds of above general formula I for the preparation of a
medicament for the treatment or prevention of specific fibrotic
diseases.
[0014] The present invention also relates to a method for the
treatment or prevention of specific fibrotic diseases, by
administration to a patient in need thereof of a pharmaceutical
composition comprising a compound of above general formula I,
together with a pharmaceutically suitable carrier. The expression
"patient" is meant to comprise the mammalian animal body,
preferably the human body.
[0015] The present invention further relates to a pharmaceutical
composition for the treatment or prevention of specific fibrotic
diseases which comprises a compound of above general formula I
alone or in combination with one or more further therapeutic
agents.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
[0016] FIG. 1A depicts lung tissue removed from a rat from a
control group of the experiment described in Example B1(A) which
received saline and vehicle (0.1% Natrosol) instead of bleomycin
intratracheally.
[0017] FIG. 1B depicts lung tissue removed from a rat from a group
of the experiment described in Example B1(A) which was treated
intratracheally with bleomycin and vehicle.
[0018] FIG. 1C depicts lung tissue removed from a rat from a group
of the experiment described in Example B1(A) which were treated
with bleomycin and also treated with Compound (m).
[0019] FIGS. 2 and 3 depict the results experiments described in
Example B1(B) to determine the effect of Compound (m) on expression
of fibrotic marker genes (procollagen I and fibronectin,
respectively) following bleomycin-induced pulmonary fibrosis.
[0020] FIG. 4A depicts lung tissue removed from a rat from a
control group of the experiment described in Example B2 which
received saline and vehicle (0.1% Natrosol) instead of bleomycin
intratracheally.
[0021] FIG. 4B depicts lung tissue removed from a rat from a group
of the experiment described in Example B2 which was treated
intratracheally with bleomycin and vehicle.
[0022] FIG. 4C depicts lung tissue removed from a rat from a group
of the experiment described in Example B2 which were treated with
bleomycin and also treated with Compound (u).
[0023] FIGS. 5 and 6 depict the results experiments described in
Example B2 to determine the effect of Compound (u) on expression of
fibrotic marker genes (procollagen I and fibronectin, respectively)
following bleomycin-induced pulmonary fibrosis.
DETAILED DESCRIPTION OF THE INVENTION
[0024] In accordance with the present invention, the compounds of
above general formula I are the compounds
##STR00003##
[0025] in which
[0026] X denotes an oxygen or sulphur atom,
[0027] R.sub.1 denotes a hydrogen atom or a prodrug group such as a
C.sub.1-4-alkoxycarbonyl or C.sub.2-4-alkanoyl group,
[0028] R.sub.2 denotes a carboxy group, a straight-chain or
branched C.sub.1-6-alkoxy-carbonyl group, a
C.sub.4-7-cycloalkoxy-carbonyl or an aryloxycarbonyl group,
[0029] a straight-chain or branched C.sub.1-6-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
phenyl, heteroaryl, carboxy, C.sub.1-3-alkoxy-carbonyl,
aminocarbonyl, C.sub.1-3-alkylamino-carbonyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl group,
[0030] a straight-chain or branched C.sub.2-6-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
chlorine atom or a hydroxy, C.sub.1-3-alkoxy, amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group,
[0031] an aminocarbonyl or methylaminocarbonyl group, an
ethylaminocarbonyl group optionally substituted in the 2 position
of the ethyl group by a hydroxy or C.sub.1-3-alkoxy group or a
di-(C.sub.1-2-alkyl)-aminocarbonyl group,
[0032] R.sub.3 denotes a hydrogen atom, a C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, trifluoromethyl or heteroaryl group,
[0033] a phenyl or naphthyl group, a phenyl or naphthyl group mono-
or disubstituted by a fluorine, chlorine, bromine or iodine atom,
by a trifluoromethyl, C.sub.1-3-alkyl or C.sub.1-3-alkoxy group,
whilst in the event of disubstitution the substituents may be
identical or different and wherein the abovementioned unsubstituted
as well as the mono- and disubstituted phenyl and naphthyl groups
may additionally be substituted
[0034] by a hydroxy, hydroxy-C.sub.1-3-alkyl or
C.sub.1-3-alkoxy-C.sub.1-3-alkyl group,
[0035] by a cyano, carboxy, carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylamino-carbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group,
[0036] by a nitro group,
[0037] by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino or amino-C.sub.1-3-alkyl group,
[0038] by a C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino,
C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino-C.sub.1-3-alkyl
or aryl-C.sub.1-3-alkylsulphonylamino group,
[0039] by a cycloalkylamino, cycloalkyleneimino,
cycloalkyleneiminocarbonyl, cycloalkyleneimino-C.sub.1-3-alkyl,
cycloalkyleneiminocarbonyl-C.sub.1-3-alkyl or
cycloalkyleneiminosulphonyl-C.sub.1-3-alkyl group having 4 to 7
ring members in each case, whilst in each case the methylene group
in position 4 of a 6- or 7-membered cycloalkyleneimino group may be
replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl,
--NH or --N(C.sub.1-3-alkyl) group,
[0040] or by a heteroaryl or heteroaryl-C.sub.1-3-alkyl group,
[0041] R.sub.4 denotes a C.sub.3-7-cycloalkyl group,
[0042] whilst the methylene group in the 4 position of a 6- or
7-membered cycloalkyl group may be substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group or
replaced by an --NH or --N(C.sub.1-3-alkyl) group,
[0043] or a phenyl group substituted by the group R.sub.6, which
may additionally be mono- or disubstituted by fluorine, chlorine,
bromine or iodine atoms, by C.sub.1-5-alkyl, trifluoromethyl,
hydroxy, C.sub.1-3-alkoxy, carboxy, C.sub.1-3-alkoxycarbonyl,
amino, acetylamino, C.sub.1-3-alkyl-sulphonyl-amino, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
aminosulphonyl, C.sub.1-3-alkyl-aminosulphonyl,
di-(C.sub.1-3-alkyl)-aminosulphonyl, nitro or cyano groups, wherein
the substituents may be identical or different and wherein
[0044] R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0045] a cyano, nitro, amino, C.sub.1-5-alkyl,
C.sub.3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or
heteroaryl group,
[0046] the group of formula
##STR00004##
[0047] wherein the hydrogen atoms bound to a nitrogen atom may in
each case be replaced independently of one another by a
C.sub.1-3-alkyl group,
[0048] a C.sub.1-3-alkoxy group, a
C.sub.1-3-alkoxy-C.sub.1-3-alkoxy, phenyl-C.sub.1-3-alkoxy,
amino-C.sub.2-3-alkoxy, C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.2-3-alkoxy,
phenyl-C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
C.sub.5-7-cycloalkyleneimino-C.sub.2-3-alkoxy or
C.sub.1-3-alkylmercapto group,
[0049] a carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl,
N--(C.sub.1-5-alkyl)-C.sub.1-3-alkylaminocarbonyl,
phenyl-C.sub.1-3-alkylamino-carbonyl,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino-carbonyl,
piperazinocarbonyl or N--(C.sub.1-3-alkyl)-piperazinocarbonyl
group,
[0050] a C.sub.1-3-alkylaminocarbonyl or
N--(C.sub.1-5-alkyl)-C.sub.1-3-alkylaminocarbonyl group wherein an
alkyl moiety is substituted by a carboxy or
C.sub.1-3-alkoxycarbonyl group or in the 2 or 3 position by a
di-(C.sub.1-3-alkyl)-amino, piperazino,
N--(C.sub.1-3-alkyl)-piperazino or a 4- to 7-membered
cycloalkyleneimino group,
[0051] a C.sub.3-7-cycloalkyl-carbonyl group,
[0052] wherein the methylene group in the 4 position of the 6- or
7-membered cycloalkyl moiety may be substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group or
replaced by an --NH or --N(C.sub.1-3-alkyl) group,
[0053] a 4- to 7-membered cycloalkyleneimino group wherein
[0054] a methylene group linked to the imino group may be replaced
by a carbonyl or sulphonyl group or
[0055] the cycloalkylene moiety may be fused to a phenyl ring or
one or two hydrogen atoms may each be replaced by a C.sub.1-3-alkyl
group and/or
[0056] in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be substituted by a
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino group or
[0057] may be replaced by an oxygen or sulphur atom, by a
sulphinyl,
[0058] sulphonyl, --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group,
[0059] a C.sub.1-4-alkyl group substituted by the group R.sub.7,
wherein
[0060] R.sub.7 denotes a C.sub.3-7-cycloalkyl group,
[0061] whilst the methylene group in the 4 position of a 6- or
7-membered cycloalkyl group may be substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group or
replaced by an --NH or --N(C.sub.1-3-alkyl) group or
[0062] in a 5- to 7-membered cycloalkyl group a --(CH.sub.2).sub.2
group may be replaced by a --CO--NH group, a --(CH.sub.2).sub.3
group may be replaced by a --NH--CO--NH or --CO--NH--CO group or a
--(CH.sub.2).sub.4 group may be replaced by a --NH--CO--NH--CO
group, whilst in each case a hydrogen atom bound to a nitrogen atom
may be replaced by a C.sub.1-3-alkyl group,
[0063] an aryl or heteroaryl group,
[0064] a hydroxy or C.sub.1-3-alkoxy group, an amino,
C.sub.1-7-alkylamino, di-(C.sub.1-7-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkyl-amino, phenyl-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino or
di-(phenyl-C.sub.1-3-alkyl)-amino group, an
.omega.-hydroxy-C.sub.2-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-.omega.-hydroxy-C.sub.2-3-alkyl-amino,
di-(.omega.-hydroxy-C.sub.2-3-alkyl)-amino,
di-(.omega.--(C.sub.1-3-alkoxy)-C.sub.2-3-alkyl)-amino or
N-(dioxolan-2-yl)-C.sub.1-3-alkyl-amino group,
[0065] a C.sub.1-3-alkylcarbonylamino-C.sub.2-3-alkyl-amino or
C.sub.1-3-alkylcarbonylamino-C.sub.2-3-alkyl-N--(C.sub.1-3-alkyl)-amino
group,
[0066] a C.sub.1-3-alkylsulphonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino-C.sub.2-3-alkyl-amino or
C.sub.1-3-alkylsulphonylamino-C.sub.2-3-alkyl-N--(C.sub.1-3-alkyl)-amino
group,
[0067] a hydroxycarbonyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-hydroxycarbonyl-C.sub.1-3-alkyl-amino
group,
[0068] a guanidino group wherein one or two hydrogen atoms may each
be replaced by a C.sub.1-3-alkyl group,
[0069] a group of formula
--N(R.sub.8)--CO--(CH.sub.2).sub.n--R.sub.9 (II),
[0070] wherein
[0071] R.sub.8 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0072] n denotes one of the numbers 0, 1, 2 or 3 and
[0073] R.sub.9 denotes an amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N--(C.sub.1-4-alkyl)-phenylamino, benzylamino,
N--(C.sub.1-4-alkyl)-benzylamino or C.sub.1-4-alkoxy group, a 4- to
7-membered cycloalkyleneimino group, whilst in each case the
methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group may be replaced by an oxygen or sulphur
atom, by a sulphinyl, sulphonyl, --NH, --N(C.sub.1-3-alkyl),
--N(phenyl), --N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group,
or, if n denotes one of the numbers 1, 2 or 3, it may also denote a
hydrogen atom, a group of formula
--N(R.sub.10)--(CH.sub.2).sub.m--(CO).sub.o--R.sub.11 (III),
[0074] wherein
[0075] R.sub.10 denotes a hydrogen atom, a C.sub.1-3-alkyl group, a
C.sub.1-3-alkylcarbonyl, arylcarbonyl,
phenyl-C.sub.1-3-alkyl-carbonyl, C.sub.1-3-alkylsulphonyl,
arylsulphonyl or phenyl-C.sub.1-3-alkylsulphonyl group,
[0076] m denotes one of the numbers 1, 2, 3 or 4,
[0077] o denotes the number 1 or, if m denotes one of the numbers
2, 3 or 4, o may also denote the number 0 and
[0078] R.sub.11 denotes an amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N--(C.sub.1-4-alkyl)-phenylamino, benzylamino,
N--(C.sub.1-4-alkyl)-benzylamino, C.sub.1-4-alkoxy or
C.sub.1-3-alkoxy-C.sub.1-3-alkoxy group, a
di-(C.sub.1-4-alkyl)-amino-C.sub.1-3-alkylamino group optionally
substituted in the 1 position by a C.sub.1-3-alkyl group or a 4- to
7-membered cycloalkyleneimino group, wherein the cycloalkylene
moiety may be fused to a phenyl ring or in each case the methylene
group in the 4 position of a 6- or 7-membered cycloalkyleneimino
group may be replaced by an oxygen or sulphur atom, by a sulphinyl,
sulphonyl, --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group,
[0079] a C.sub.4-7-cycloalkylamino,
C.sub.4-7-cycloalkyl-C.sub.1-3-alkylamino or
C.sub.4-7-cycloalkenylamino group wherein position 1 of the ring is
not involved in the double bond and wherein the abovementioned
groups may each additionally be substituted at the amino-nitrogen
atom by a C.sub.5-7-cycloalkyl, C.sub.2-4-alkenyl or
C.sub.1-4-alkyl group,
[0080] a 4- to 7-membered cycloalkyleneimino group, wherein
[0081] the cycloalkylene moiety may be fused to a phenyl group or
to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or
pyrimidino group optionally substituted by a fluorine, chlorine,
bromine or iodine atom, by a nitro, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy or amino group, and/or
[0082] one or two hydrogen atoms may each be replaced by a
C.sub.1-3-alkyl, C.sub.5-7-cycloalkyl or phenyl group and/or
[0083] the methylene group in the 3 position of a 5-membered
cycloalkyleneimino group may be substituted by a hydroxy,
hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkoxy or
C.sub.1-3-alkoxy-C.sub.1-3-alkyl group,
[0084] the methylene group in the 3 or 4 position of a 6- or
7-membered cycloalkyleneimino group may in each case be substituted
by a hydroxy, hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkoxy,
C.sub.1-3-alkoxy-C.sub.1-3-alkyl, carboxy,
C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkyl-amino group or
[0085] may be replaced by an oxygen or sulphur atom, by a
sulphinyl, sulphonyl, --NH, --N(C.sub.1-3-alkyl-), --N(phenyl),
--N(phenyl-C.sub.1-3-alkyl-), --N(C.sub.1-3-alkyl-carbonyl-),
--N(C.sub.1-4-alkyl-hydroxy-carbonyl-),
--N(C.sub.1-4-alkoxy-carbonyl-), --N(benzoyl-) or
--N(phenyl-C.sub.1-3-alkyl-carbonyl-) group,
[0086] wherein a methylene group linked to an imino-nitrogen atom
of the cycloalkyleneimino group may be replaced by a carbonyl or
sulphonyl group or in a 5- to 7-membered monocyclic
cycloalkyleneimino group or a cycloalkyleneimino group fused to a
phenyl group the two methylene groups linked to the imino-nitrogen
atom may each be replaced by a carbonyl group,
[0087] or R.sub.6 denotes a C.sub.1-4-alkyl group which is
substituted by a carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group or by a 4- to 7-membered cycloalkyleneiminocarbonyl
group,
[0088] an N--(C.sub.1-3-alkyl)-C.sub.2-4-alkanoylamino group which
is additionally substituted in the alkyl moiety by a carboxy or
C.sub.1-3-alkoxycarbonyl group,
[0089] a group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0090] wherein
[0091] R.sub.12 denotes a hydrogen atom, a C.sub.1-6-alkyl or
C.sub.3-7-cycloalkyl group or a C.sub.1-3-alkyl group terminally
substituted by a phenyl, heteroaryl, trifluoromethyl, hydroxy,
C.sub.1-3-alkoxy, aminocarbonyl, C.sub.1-4-alkylamino-carbonyl,
di-(C.sub.1-4-alkyl)-aminocarbonyl, C.sub.1-3-alkyl-carbonyl,
C.sub.1-3-alkyl-sulphonyl-amino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkyl-sulphonylamino,
C.sub.1-3-alkyl-aminosulphonyl or
di-(C.sub.1-3-alkyl)-aminosulphonyl group and
[0092] p denotes one of the numbers 0, 1, 2 or 3 and
[0093] R.sub.13 assumes the meanings of the abovementioned group
R.sub.7, or, if p denotes one of the numbers 1, 2 or 3, it may also
denote a hydrogen atom,
[0094] a group of formula
--N(R.sub.14)--(CH.sub.2).sub.q--(CO).sub.r--R.sub.15 (V),
[0095] wherein
[0096] R.sub.14 denotes a hydrogen atom, a C.sub.1-4-alkyl group, a
C.sub.1-3-alkylcarbonyl, arylcarbonyl,
phenyl-C.sub.1-3-alkylcarbonyl, heteroarylcarbonyl,
heteroaryl-C.sub.1-3-alkylcarbonyl, C.sub.1-4-alkylsulphonyl,
arylsulphonyl, phenyl-C.sub.13-alkylsulphonyl, heteroarylsulphonyl
or heteroaryl-C.sub.13-alkyl-sulphonyl group,
[0097] q denotes one of the numbers 1, 2, 3 or 4,
[0098] r denotes the number 1 or, if q is one of the numbers 2, 3
or 4, it may also denote the number 0 and
[0099] R.sub.15 assumes the meanings of the abovementioned group
R.sub.7, a group of formula
--N(R.sub.16)--SO.sub.2--R.sub.17 (VI),
[0100] wherein
[0101] R.sub.16 denotes a hydrogen atom or a C.sub.1-4-alkyl group
optionally terminally substituted by a cyano,
trifluoromethyl-carbonylamino or
N--(C.sub.1-3-alkyl)-trifluoromethyl-carbonyl-amino group and
[0102] R.sub.17 denotes a C.sub.1-3-alkyl group, an amino group
substituted by a
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl-carbonyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl-sulphonyl group and a
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl group,
[0103] or an N--(C.sub.1-3-alkyl)-C.sub.1-5-alkylsulphonylamino or
N--(C.sub.1-3-alkyl)-phenylsulphonylamino group wherein the alkyl
moiety is additionally substituted by a cyano or carboxy group,
[0104] wherein all the single-bonded or fused phenyl groups
contained in the groups mentioned under R.sub.6 may be mono- or
disubstituted by fluorine, chlorine, bromine or iodine atoms, by
C.sub.1-5-alkyl, trifluoromethyl, hydroxy, C.sub.1-3-alkoxy,
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-4-alkylamino-carbonyl, di-(C.sub.1-4-alkyl)-amino-carbonyl,
aminosulphonyl, C.sub.1-3-alkyl-aminosulphonyl,
di-(C.sub.1-3-alkyl)-aminosulphonyl,
C.sub.1-3-alkyl-sulphonylamino, nitro or cyano groups, wherein the
substituents may be identical or different, or two adjacent
hydrogen atoms of the phenyl groups may be replaced by a
methylenedioxy group,
[0105] and
[0106] R.sub.5 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0107] wherein by an aryl group is meant a phenyl or naphthyl group
optionally mono- or disubstituted by a fluorine, chlorine, bromine
or iodine atom, by a cyano, trifluoromethyl, nitro, carboxy,
aminocarbonyl, C.sub.1-3-alkyl or C.sub.1-3-alkoxy group and
[0108] by a heteroaryl group is meant a monocyclic 5- or 6-membered
heteroaryl group optionally substituted by a C.sub.1-3-alkyl group
in the carbon skeleton, wherein
[0109] the 6-membered heteroaryl group contains one, two or three
nitrogen atoms and
[0110] the 5-membered heteroaryl group contains an imino group
optionally substituted by a C.sub.1-3-alkyl or
phenyl-C.sub.1-3-alkyl group, an oxygen or sulphur atom or
[0111] an imino group optionally substituted by a C.sub.1-3-alkyl
or phenyl-C.sub.1-3-alkyl group or an oxygen or sulphur atom and
additionally a nitrogen atom or
[0112] an imino group optionally substituted by a C.sub.1-3-alkyl
or phenyl-C.sub.1-3-alkyl group and two nitrogen atoms,
[0113] and moreover a phenyl ring may be fused to the
abovementioned monocyclic heterocyclic groups via two adjacent
carbon atoms and the bonding takes place via a nitrogen atom or via
a carbon atom of the heterocyclic moiety or a fused phenyl
ring,
[0114] some or all of the hydrogen atoms in the abovementioned
alkyl and alkoxy groups or in the alkyl moieties contained in the
above-defined groups of formula I optionally being replaced by
fluorine atoms,
[0115] the saturated alkyl and alkoxy moieties with more than 2
carbon atoms which are present in the groups defined hereinbefore
also include the branched isomers thereof, such as for example the
isopropyl, tert.butyl, isobutyl group, unless otherwise stated,
and
[0116] additionally the hydrogen atom of any carboxy group present
or a hydrogen atom bound to a nitrogen atom, e.g. a hydrogen atom
of an amino, alkylamino or imino group or a saturated N-heterocycle
such as the piperidinyl group, may each be replaced by a group
which can be cleaved in vivo.
[0117] By a group which can be cleaved in vivo from an imino or
amino group is meant, for example, a hydroxy group, an acyl group
such as the benzoyl or pyridinoyl group or a C.sub.1-16-alkanoyl
group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or
hexanoyl group, an allyloxycarbonyl group, a
C.sub.1-16-alkoxycarbonyl group such as the methoxycarbonyl,
ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,
butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl,
hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl,
decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or
hexadecyloxycarbonyl group, a phenyl-C.sub.1-6-alkoxycarbonyl group
such as the benzyloxycarbonyl, phenylethoxycarbonyl or
phenylpropoxycarbonyl group, a
C.sub.1-3-alkylsulphonyl-C.sub.2-4-alkoxycarbonyl,
C.sub.1-3-alkoxy-C.sub.2-4-alkoxy-C.sub.2-4-alkoxycarbonyl or
R.sub.eCO--O--(R.sub.fCR.sub.g)--O--CO group wherein
[0118] R.sub.e denotes a C.sub.1-8-alkyl, C.sub.5-7-cycloalkyl,
phenyl or phenyl-C.sub.1-3-alkyl group,
[0119] R.sub.f denotes a hydrogen atom, a C.sub.1-3-alkyl,
C.sub.5-7-cycloalkyl or phenyl group and
[0120] R.sub.g denotes a hydrogen atom, a C.sub.1-3-alkyl or
R.sub.eCO--O--(R.sub.fCR.sub.g)--O group wherein R.sub.e to R.sub.g
are as hereinbefore defined,
[0121] wherein additionally the amino group may be a phthalimido
group, whilst the abovementioned ester groups may also be used as a
group which can be converted in vivo into a carboxy group.
[0122] One sub-group of compounds of general formula I which
deserves special mention comprises those wherein
[0123] X, R.sub.1 and R.sub.3 to R.sub.5 are as hereinbefore
defined and
[0124] R.sub.2 denotes a straight-chain or branched
C.sub.1-6-alkoxy-carbonyl group, a C.sub.4-7-cycloalkoxycarbonyl or
a aryloxycarbonyl group,
[0125] a straight-chain or branched C.sub.1-6-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
phenyl, heteroaryl, carboxy, C.sub.1-3-alkoxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl group,
[0126] a straight-chain or branched C.sub.2-6-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
chlorine atom or a hydroxy, C.sub.1-3-alkoxy, amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group,
[0127] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0128] A second sub-group of compounds of general formula I which
deserves special mention comprises those wherein
[0129] X, R.sub.1 and R.sub.3 to R.sub.5 are as hereinbefore
defined and
[0130] R.sub.2 denotes an aminocarbonyl or methylaminocarbonyl
group, an ethylaminocarbonyl group optionally substituted in the 2
position of the ethyl group by a hydroxy or C.sub.1-3-alkoxy group
or a di-(C.sub.1-2-alkyl)-aminocarbonyl group,
[0131] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0132] A third sub-group of compounds of general formula I which
deserves special mention comprises those wherein
[0133] X, R.sub.1 to R.sub.3 and R.sub.5 are as hereinbefore
defined and
[0134] R.sub.4 denotes an R.sub.7--(C.sub.1-4-alkyl)-phenyl group,
wherein
[0135] R.sub.7 denotes an amino, C.sub.1-7-alkylamino,
di-(C.sub.1-7-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkyl-amino, phenyl-C.sub.1-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino or
di-(phenyl-C.sub.1-3-alkyl)-amino group,
[0136] or a phenyl group substituted by the group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0137] wherein R.sub.12, p and R.sub.13 are as hereinbefore
defined,
[0138] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0139] Preferred compounds of general formula I are those
wherein
[0140] R.sub.1 and R.sub.3 are as hereinbefore defined and
[0141] X denotes an oxygen atom,
[0142] R.sub.2 denotes a carboxy group, a straight-chain or
branched C.sub.1-6-alkoxy-carbonyl group, a
C.sub.5-7-cycloalkoxycarbonyl or a phenoxycarbonyl group,
[0143] a straight-chain or branched C.sub.1-3-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
phenyl, heteroaryl, carboxy, C.sub.1-3-alkoxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl group,
[0144] a straight-chain or branched C.sub.2-3-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
chlorine atom, by a hydroxy, C.sub.1-3-alkoxy, amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group,
[0145] an aminocarbonyl or methylaminocarbonyl group, an
ethylaminocarbonyl group optionally substituted in the 2 position
of the ethyl group by a hydroxy or C.sub.1-3-alkoxy group or a
di-(C.sub.1-2-alkyl)-aminocarbonyl group,
[0146] R.sub.4 denotes a C.sub.3-7-cycloalkyl group,
[0147] whilst the methylene group in the 4 position of a 6- or
7-membered cycloalkyl group may be substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group or
replaced by an --NH or --N(C.sub.1-3-alkyl) group,
[0148] or a phenyl group substituted by the group R.sub.6, which
may additionally be mono- or disubstituted by fluorine, chlorine or
bromine atoms, by C.sub.1-3-alkyl, trifluoromethyl, hydroxy,
C.sub.1-3-alkoxy, carboxy, C.sub.1-3-alkoxycarbonyl, amino,
acetylamino, aminocarbonyl, C.sub.1-3-alkyl-aminocarbonyl,
di-(C.sub.1-3-alkyl)-aminocarbonyl, nitro or cyano groups, wherein
the substituents may be identical or different and wherein
[0149] R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0150] a cyano, nitro, amino, C.sub.1-5-alkyl,
C.sub.3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or
heteroaryl group,
[0151] the group of formula
##STR00005##
[0152] wherein a hydrogen atom bound to the nitrogen atom may be
replaced by a C.sub.1-3-alkyl group,
[0153] a C.sub.1-3-alkoxy group, an amino-C.sub.2-3-alkoxy,
C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.2-3-alkoxy,
phenyl-C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
pyrrolidino-C.sub.2-3-alkoxy, piperidino-C.sub.2-3-alkoxy or
C.sub.1-3-alkylmercapto group, a carboxy, C.sub.1-4-alkoxycarbonyl,
aminocarbonyl, C.sub.1-3-alkyl-amino-carbonyl,
phenyl-C.sub.1-3-alkylamino-carbonyl or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino-carbonyl
group,
[0154] a C.sub.3-7-cycloalkyl-carbonyl group,
[0155] wherein the methylene group in the 4 position of the 6- or
7-membered cycloalkyl moiety may be replaced by an --NH or
--N(C.sub.1-3-alkyl) group,
[0156] a 4- to 7-membered cycloalkyleneimino group, wherein
[0157] a methylene group linked to the imino group may be replaced
by a carbonyl or sulphonyl group or
[0158] one or two hydrogen atoms may each be replaced by a
C.sub.1-3-alkyl group and/or
[0159] in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be substituted by a
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino group or
[0160] may be replaced by an oxygen or sulphur atom, by a
sulphinyl, sulphonyl, --NH or --N(C.sub.1-3-alkyl) group,
[0161] a C.sub.1-4-alkyl group terminally substituted by the group
R.sub.7, wherein
[0162] R.sub.7 denotes a C.sub.5-7-cycloalkyl group,
[0163] whilst the methylene group in the 4 position of a 6- or
7-membered cycloalkyl group may be replaced by an --NH or
--N(C.sub.1-3-alkyl) group or in a 5- to 7-membered cycloalkyl
group a --(CH.sub.2).sub.2 group may be replaced by a --CO--NH
group, a --(CH.sub.2).sub.3 group may be replaced by a
--NH--CO--NH-- or a --(CH.sub.2).sub.4 group may be replaced by a
--NH--CO--NH--CO group, whilst in each case a hydrogen atom bound
to a nitrogen atom may be replaced by a C.sub.1-3-alkyl group,
[0164] a phenyl or heteroaryl group,
[0165] a hydroxy or C.sub.1-3-alkoxy group, an amino,
C.sub.1-6-alkylamino, di-(C.sub.1-6-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkyl-amino, phenyl-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino or
di-(phenyl-C.sub.1-3-alkyl)-amino group,
[0166] a .omega.-hydroxy-C.sub.2-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-.omega.-hydroxy- --C.sub.2-3-alkyl-amino,
di-(.omega.-hydroxy-C.sub.2-3-alkyl)-amino,
di-(.omega.--(C.sub.1-3-alkoxy)-C.sub.2-3-alkyl)-amino or
N-(dioxolan-2-yl)-C.sub.1-3-alkyl-amino group,
[0167] a C.sub.1-3-alkylcarbonylamino-C.sub.2-3-alkyl-amino or
C.sub.1-3-alkylcarbonylamino-C.sub.2-3-alkyl-N--(C.sub.1-3-alkyl)-amino
group,
[0168] a C.sub.1-3-alkylsulphonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino- --C.sub.2-3-alkyl-amino or
C.sub.1-3-alkylsulphonylamino-C.sub.2-3-alkyl-
--N--(C.sub.1-3-alkyl)-amino group,
[0169] a hydroxycarbonyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-hydroxycarbonyl-C.sub.1-3-alkyl-amino
group
[0170] a guanidino group wherein a hydrogen atom may be replaced by
a C.sub.1-3-alkyl group,
[0171] a group of formula
--N(R.sub.8)--CO--(CH.sub.2).sub.n--R.sub.9 (II),
[0172] wherein
[0173] R.sub.8 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0174] n denotes one of the numbers 0, 1, 2 or 3 and
[0175] R.sub.9 denotes an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, phenylamino, benzylamino or
C.sub.1-4-alkoxy group, a 5- to 7-membered cycloalkyleneimino
group, wherein the methylene group in position 4 of the piperidino
group may be replaced by an oxygen or sulphur atom, by
[0176] an --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group, or, if n
denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen
atom,
[0177] a group of formula
--N(R.sub.10)--(CH.sub.2).sub.m--(CO).sub.o--R.sub.11 (III),
[0178] wherein
[0179] R.sub.10 denotes a hydrogen atom, a C.sub.1-3-alkyl group, a
C.sub.1-3-alkylcarbonyl or C.sub.1-3-alkylsulphonyl group,
[0180] m denotes one of the numbers 1, 2 or 3,
[0181] o denotes the number 1 or, if m is one of the numbers 2 or
3, o may also denote the number 0 and
[0182] R.sub.11 denotes an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, C.sub.1-4-alkoxy or
C.sub.1-3-alkoxy-C.sub.1-3-alkoxy group or a 5- to 7-membered
cycloalkyleneimino group, wherein the methylene group in position 4
of the piperidino group may be replaced by an oxygen or sulphur
atom, by an --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group,
[0183] a C.sub.4-7-cycloalkylamino or C.sub.4-7-cycloalkenylamino
group wherein position 1 of the ring is not involved in the double
bond,
[0184] a 4- to 7-membered cycloalkyleneimino group, wherein
[0185] the cycloalkylene moiety may be fused to a phenyl group
or
[0186] one or two hydrogen atoms may each be replaced by a
C.sub.1-3-alkyl group and/or
[0187] the methylene group in position 3 of the pyrrolidino group
may be substituted by a hydroxy or C.sub.1-3-alkoxy group,
[0188] in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be substituted by a
hydroxy, hydroxy-C.sub.1-3-alkyl, C.sub.1-3-alkoxy, carboxy,
C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino group or
[0189] may be replaced by an oxygen or sulphur atom, by a
sulphinyl,
[0190] sulphonyl, --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(phenyl-C.sub.1-3-alkyl), --N(C.sub.1-3-alkyl-carbonyl),
--N(C.sub.1-4-alkoxy-carbonyl), --N(benzoyl) or
--N(phenyl-C.sub.1-3-alkyl-carbonyl) group,
[0191] wherein a methylene group linked to an imino-nitrogen atom
of the cycloalkyleneimino group may be replaced by a carbonyl or
sulphonyl group or in a 5- to 6-membered monocyclic
cycloalkyleneimino group or a cycloalkyleneimino group fused to a
phenyl group the two methylene groups linked to the imino-nitrogen
atom may each be replaced by a carbonyl group,
[0192] or R.sub.6 denotes a C.sub.1-4-alkyl group which is
terminally substituted by a carboxy, C.sub.1-3-alkoxycarbonyl,
aminocarbonyl, C.sub.1-3-alkylaminocarbonyl or
di-(C.sub.1-3-alkyl)-aminocarbonyl group or by a 4- to 7-membered
cycloalkyleneiminocarbonyl group,
[0193] a group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0194] wherein
[0195] R.sub.12 denotes a hydrogen atom, a C.sub.1-3-alkyl,
C.sub.5-7-cycloalkyl, phenyl-C.sub.1-3-alkyl or
heteroaryl-C.sub.1-3-alkyl group and
[0196] p denotes one of the numbers 0, 1, 2 or 3 and
[0197] R.sub.13 assumes the meanings of the abovementioned group
R.sub.7, or, if p denotes one of the numbers 1, 2 or 3, it may also
denote a hydrogen atom,
[0198] a group of formula
--N(R.sub.14)--(CH.sub.2).sub.q--(CO).sub.r--R.sub.15 (V),
[0199] wherein
[0200] R.sub.14 denotes a hydrogen atom, a C.sub.1-4-alkyl group, a
C.sub.1-3-alkylcarbonyl, phenylcarbonyl,
phenyl-C.sub.1-3-alkylcarbonyl, heteroarylcarbonyl,
heteroaryl-C.sub.1-3-alkylcarbonyl, C.sub.1-4-alkylsulphonyl,
phenylsulphonyl,
phenyl-C.sub.1-3-alkyl-sulphonyl-heteroarylsulphonyl or
heteroaryl-C.sub.1-3-alkyl-sulphonyl group,
[0201] q denotes one of the numbers 1, 2, 3 or 4,
[0202] r denotes the number 1 or, if q is one of the numbers 2, 3
or 4, it may also denote the number 0 and
[0203] R.sub.15 assumes the meanings of the abovementioned group
R.sub.7,
[0204] a group of formula
--N(R.sub.16)--SO.sub.2--R.sub.17 (VI),
[0205] wherein
[0206] R.sub.16 denotes a hydrogen atom or a C.sub.1-4-alkyl group
optionally terminally substituted by a cyano,
trifluoromethyl-carbonylamino or
N--(C.sub.1-3-alkyl)-trifluoromethyl- -carbonyl-amino group and
[0207] R.sub.17 denotes a C.sub.1-3-alkyl group,
[0208] an amino group substituted by a
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl-carbonyl or
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkyl-sulphonyl group and a
di-(C.sub.1-3-alkyl)-aminocarbonyl-C.sub.1-3-alkyl group,
[0209] wherein all the single-bonded or fused phenyl groups
contained in the groups mentioned under R.sub.6 may be mono- or
disubstituted by fluorine, chlorine or bromine atoms, by
C.sub.1-3-alkyl, trifluoromethyl, hydroxy, C.sub.1-3-alkoxy,
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkyl-aminocarbonyl, aminosulphonyl,
C.sub.1-3-alkyl-aminosulphonyl, nitro or cyano groups, wherein the
substituents may be identical or different, or two adjacent
hydrogen atoms of the phenyl groups may be replaced by a
methylenedioxy group, and
[0210] R.sub.5 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0211] whilst by a heteroaryl group as mentioned above is meant a
pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furyl,
thienyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl or triazolyl
group optionally substituted in the carbon skeleton by a
C.sub.1-3-alkyl group wherein a hydrogen atom bound to a nitrogen
atom may be replaced by a C.sub.1-3-alkyl or phenyl-C.sub.1-3-alkyl
group and wherein the 5-membered heteroaryl groups containing at
least one imino group are bound via a carbon or nitrogen atom,
[0212] a hydrogen atom bound to a nitrogen atom in the
abovementioned groups may be replaced by a group which can be
cleaved in vivo, particularly by an acetyl or tert.butoxycarbonyl
group,
[0213] the carboxy groups contained in the abovementioned groups
may each be substituted by a group which can be cleaved in vivo and
may occur, for example, in the form of the tert.butoxycarbonyl
group,
[0214] some or all of the hydrogen atoms in the abovementioned
alkyl and alkoxy groups or in the alkyl moieties contained in the
above-defined groups of formula I optionally being replaced by
fluorine atoms and
[0215] the saturated alkyl and alkoxy moieties contained in the
abovementioned groups, which contain more than 2 carbon atoms, may
be straight-chain or branched, unless otherwise stated,
[0216] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0217] One subgroup of preferred compounds of general formula I
deserving special mention comprises those wherein
[0218] X, R.sub.1 and R.sub.3 to R.sub.5 are as hereinbefore
defined and
[0219] R.sub.2 denotes a straight-chain or branched
C.sub.1-6-alkoxy-carbonyl group, a C.sub.5-7-cycloalkoxycarbonyl or
a phenoxycarbonyl group,
[0220] a straight-chain or branched C.sub.1-3-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
phenyl- carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group,
[0221] a straight-chain or branched C.sub.2-3-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
hydroxy, C.sub.1-3-alkoxy, amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group,
[0222] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0223] A second sub-group of preferred compounds of general formula
I deserving special mention comprises those wherein
[0224] X, R.sub.1 and R.sub.3 to R.sub.5 are as hereinbefore
defined and
[0225] R.sub.2 denotes an aminocarbonyl or methylaminocarbonyl
group, an ethylaminocarbonyl group optionally substituted in the 2
position of the ethyl group by a hydroxy or C.sub.1-3-alkoxy group
or a di-(C.sub.1-2-alkyl)-aminocarbonyl group,
[0226] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0227] A third sub-group of preferred compounds of general formula
I deserving special mention comprises those wherein
[0228] X, R.sub.1 to R.sub.3 and R.sub.5 are as hereinbefore
defined and
[0229] R.sub.4 denotes an R.sub.7-(n-C.sub.1-4-alkyl)-phenyl group,
wherein
[0230] R.sub.7 denotes an amino, C.sub.1-6-alkylamino,
di-(C.sub.1-6-alkyl)-amino, phenylamino,
N-phenyl-C.sub.1-3-alkyl-amino, phenyl-C.sub.1-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino or
di-(phenyl-C.sub.1-3-alkyl)-amino group,
[0231] or a phenyl group substituted by the group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0232] wherein R.sub.12, p and R.sub.13 are as hereinbefore
defined,
[0233] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0234] Particularly preferred compounds of general formula I are
those wherein
[0235] X denotes an oxygen atom,
[0236] R.sub.1 denotes a hydrogen atom,
[0237] R.sub.2 denotes a carboxy group, a straight-chain or
branched C.sub.1-4-alkoxycarbonyl group or a phenoxycarbonyl
group,
[0238] a straight-chain or branched C.sub.1-3-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
phenyl, carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group,
[0239] a straight-chain or branched C.sub.2-3-alkoxy-carbonyl group
which is terminally substituted in the alkyl moiety by a hydroxy,
C.sub.1-3-alkoxy, amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group,
[0240] an aminocarbonyl or methylaminocarbonyl group, an
ethylaminocarbonyl group optionally substituted in the 2 position
of the ethyl group by a hydroxy or C.sub.1-3-alkoxy group or a
di-(C.sub.1-2-alkyl)-aminocarbonyl group,
[0241] R.sub.3 denotes a C.sub.1-4-alkyl group or a phenyl group
which may be substituted by a fluorine, chlorine or bromine atom,
by a trifluoromethyl, C.sub.1-3-alkyl, hydroxy or C.sub.1-3-alkoxy
group,
[0242] R.sub.4 denotes a C.sub.5-6-cycloalkyl group,
[0243] wherein the methylene group in position 4 of the cyclohexyl
group may be substituted by an amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group or replaced by an --NH or
--N(C.sub.1-3-alkyl) group,
[0244] a phenyl group, a phenyl group disubstituted by
C.sub.1-3-alkyl, C.sub.1-3-alkoxy or nitro groups, wherein the
substituents may be identical or different, or
[0245] a phenyl group substituted by the group R.sub.6, which may
additionally be substituted by a fluorine, chlorine or bromine atom
or by an amino or nitro group, wherein R.sub.6 denotes a fluorine,
chlorine or bromine atom,
[0246] a C.sub.1-3-alkyl, C.sub.1-3-alkoxy, nitro, amino or
C.sub.5-6-cycloalkyl group,
[0247] a pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl
group bound via a carbon atom, wherein the abovementioned
heteroaromatic groups in the carbon skeleton may be substituted by
a C.sub.1-3-alkyl group or a hydrogen atom bound to a nitrogen atom
may be replaced by a C.sub.1-3-alkyl or phenyl-C.sub.1-3-alkyl
group,
[0248] the group of formula
##STR00006##
[0249] a carboxy, C.sub.1-4-alkoxycarbonyl,
phenyl-C.sub.1-3-alkyl-amino-carbonyl or
C.sub.5-7-cycloalkyl-carbonyl group,
[0250] a 5 or 6-membered cycloalkyleneimino group, wherein
[0251] the methylene group in position 4 of the piperidino group
may be replaced by an oxygen or sulphur atom, by an --NH or
--N(C.sub.1-3-alkyl) group,
[0252] an unbranched C.sub.1-3-alkyl group terminally substituted
by the group R.sub.7, wherein
[0253] R.sub.7 denotes a C.sub.5-7-cycloalkyl group,
[0254] wherein in a 5 or 6-membered cycloalkyl group a
--(CH.sub.2).sub.2 group may be replaced by a --CO--NH group, a
--(CH.sub.2).sub.3 group may be replaced by an --NH--CO--NH-- or a
--(CH.sub.2).sub.4 group may be replaced by an --NH--CO--NH--CO
group, whilst in each case a hydrogen atom bound to a nitrogen atom
may be replaced by a C.sub.1-3-alkyl group,
[0255] a phenyl or pyridinyl group or a pyrrolyl, pyrazolyl,
imidazolyl or triazolyl group bound via a carbon or nitrogen atom,
wherein the abovementioned heteroaromatic groups in the carbon
skeleton may be substituted by a C.sub.1-3-alkyl group or a
hydrogen atom bound to a nitrogen atom may be replaced by a
C.sub.1-3-alkyl group,
[0256] a hydroxy or C.sub.1-3-alkoxy group,
[0257] an amino, C.sub.1-6-alkylamino, di-(C.sub.1-6-alkyl)-amino,
phenylamino, N-phenyl-C.sub.1-3-alkylamino,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino group,
[0258] a .omega.-hydroxy-C.sub.2-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-.omega.-hydroxy-C.sub.2-3-alkylamino,
di-(.omega.-hydroxy-C.sub.2-3-alkyl)-amino or
di-(.omega.--(C.sub.1-3-alkoxy)-C.sub.2-3-alkyl)-amino group,
[0259] a C.sub.1-3-alkylcarbonylamino-C.sub.2-3-alkyl-amino or
C.sub.1-3-alkylcarbonylamino-C.sub.2-3-alkyl-N--(C.sub.1-3-alkyl)-amino
group,
[0260] a C.sub.1-3-alkylsulphonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino- --C.sub.2-3-alkylamino or
C.sub.1-3-alkylsulphonylamino-
--C.sub.2-3-alkyl-N--(C.sub.1-3-alkyl)-amino group,
[0261] a hydroxycarbonyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-hydroxycarbonyl-C.sub.1-3-alkyl-amino
group,
[0262] a guanidino group wherein a hydrogen atom may be replaced by
a C.sub.1-3-alkyl group,
[0263] a group of formula
--N(R.sub.8)--CO--(CH.sub.2).sub.n--R.sub.9 (II),
[0264] wherein
[0265] R.sub.8 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0266] n denotes one of the numbers 0, 1, 2 or 3 and
[0267] R.sub.9 denotes an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino or C.sub.1-4-alkoxy group, a 5- or
6-membered cycloalkyleneimino group, wherein the methylene group in
position 4 of the piperidino group may be replaced by an --NH,
--N(C.sub.1-3-alkyl) or --N(C.sub.1-3-alkyl-carbonyl) group, or, if
n denotes one of the numbers 1, 2 or 3, R.sub.9 may also denote a
hydrogen atom,
[0268] a group of formula
--N(R.sub.10)--(CH.sub.2).sub.m--(CO).sub.o--R.sub.11 (III),
[0269] wherein
[0270] R.sub.10 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0271] m denotes one of the numbers 1, 2 or 3,
[0272] o denotes the number 1 or, if m is one of the numbers 2 or
3, o may also denote the number 0 and
[0273] R.sub.11 denotes an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino, C.sub.1-4-alkoxy or
methoxy-C.sub.1-3-alkoxy group or a 5- or 6-membered
cycloalkyleneimino group, wherein the methylene group in position 4
of the piperidino group may be replaced by an --NH,
--N(C.sub.1-3-alkyl) or --N(C.sub.1-3-alkyl-carbonyl) group,
[0274] an azetidino, pyrrolidino, piperidino,
2,6-dimethyl-piperidino, 3,5-dimethyl-piperidino or azepino group,
wherein
[0275] the methylene group in position 3 of the pyrrolidino group
may be substituted by a hydroxy group,
[0276] the methylene group in position 4 of the piperidino group
may be substituted by a hydroxy, hydroxy-C.sub.1-3-alkyl or
C.sub.1-3-alkoxy group or
[0277] may be replaced by an oxygen or sulphur atom, by a
sulphinyl, sulphonyl, --NH, --N(C.sub.1-3-alkyl),
--N(C.sub.1-3-alkyl-carbonyl), --N(benzoyl) or
--N(phenyl-C.sub.1-3-alkyl-carbonyl) group,
[0278] wherein a methylene group linked to an imino-nitrogen atom
of the pyrrolidino, piperidino or piperazino group may be replaced
by a carbonyl group,
[0279] or R.sub.6 denotes a straight-chain C.sub.1-3-alkyl group
which is terminally substituted by a carboxy or
C.sub.1-3-alkoxy-carbonyl group,
[0280] a group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0281] wherein
[0282] R.sub.12 denotes a hydrogen atom, a C.sub.1-3-alkyl or
phenyl-C.sub.1-3-alkyl group,
[0283] p denotes one of the numbers 0, 1 or 2 and
[0284] R.sub.13 denotes an amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, benzylamino,
N--(C.sub.1-3-alkyl)-benzylamino,
C.sub.1-3-alkoxy-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkoxy-C.sub.1-3-alkylamino,
di-(2-methoxy-ethyl)-amino,
di-(.omega.-hydroxy-C.sub.2-3-alkyl)-amino or
aminocarbonyl-methyl-N-(methyl)-amino group,
[0285] a pyrrolyl, pyrazolyl or imidazolyl group bound via a
nitrogen atom and optionally substituted by a C.sub.1-3-alkyl
group,
[0286] a pyrrolidino, piperidino, morpholino, thiomorpholino or a
piperazino group optionally substituted in the 4 position by a
C.sub.1-3-alkyl, phenyl-C.sub.1-3-alkyl, C.sub.1-3-alkylcarbonyl or
C.sub.1-4-alkoxycarbonyl group or, if n denotes the number 1 or 2,
it may also denote a hydrogen atom,
[0287] a group of formula
--N(R.sub.14)--(CH.sub.2).sub.q--(CO).sub.r--R.sub.15 (V),
[0288] wherein
[0289] R.sub.14 denotes a hydrogen atom, a C.sub.1-4-alkyl,
C.sub.1-3-alkyl-carbonyl, phenylcarbonyl,
phenyl-C.sub.1-3-alkylcarbonyl, furyl-carbonyl, pyridinyl-carbonyl,
furyl-C.sub.1-3-alkylcarbonyl, pyridinyl-C.sub.1-3-alkylcarbonyl,
C.sub.1-4-alkylsulphonyl, phenylsulphonyl or
phenyl-C.sub.1-3-alkylsulphonyl group,
[0290] q denotes one of the numbers 1, 2 or 3,
[0291] r denotes the number 1 or, if q is one of the numbers 2 or
3, it may also denote the number 0 and
[0292] R.sub.15 denotes an amino, C.sub.1-4-alkylamino,
di-(C.sub.1-4-alkyl)-amino, phenylamino,
N--(C.sub.1-4-alkyl)-phenylamino, benzylamino or
N--(C.sub.1-4-alkyl)-benzylamino group,
[0293] or a group of formula
--N(R.sub.16)--SO.sub.2--R.sub.17 (VI),
[0294] wherein
[0295] R.sub.16 denotes a hydrogen atom or a C.sub.1-3-alkyl group
optionally terminally substituted by a cyano,
trifluoromethyl-carbonylamino or
N--(C.sub.1-3-alkyl)-trifluoromethyl-carbonyl-amino group and
[0296] R.sub.17 denotes a C.sub.1-3-alkyl group,
[0297] wherein all the single-bonded or fused phenyl groups
contained in the groups mentioned under R.sub.6 may be substituted
by a fluorine, chlorine or bromine atom, by a methyl,
trifluoromethyl, methoxy, nitro or cyano group and
[0298] R.sub.5 denotes a hydrogen atom,
[0299] wherein a hydrogen atom bound to a nitrogen atom in the
abovementioned groups may be replaced by an acetyl or
tert.butoxycarbonyl group,
[0300] the carboxy groups contained in the abovementioned groups
may also be present in the form of the tert.butoxycarbonyl
precursor group and
[0301] the saturated alkyl and alkoxy moieties contained in the
abovementioned groups, which contain more than 2 carbon atoms, may
be straight-chain or branched, unless otherwise stated,
[0302] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0303] One subgroup of particularly preferred compounds of general
formula I deserving special mention comprises those wherein
[0304] X, R.sub.1, R.sub.3 and R.sub.5 are as hereinbefore
defined,
[0305] R.sub.2 denotes a straight-chain or branched
C.sub.1-4-alkoxycarbonyl group or a phenoxycarbonyl group,
[0306] a straight-chain or branched C.sub.1-3-alkoxycarbonyl group,
which is terminally substituted in the alkyl moiety by a phenyl-
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group, or
[0307] a straight-chain or branched C.sub.2-3-alkoxy-carbonyl
group, which is terminally substituted in the alkyl moiety by a
hydroxy, C.sub.1-3-alkoxy, amino, C.sub.1-3-alkylamino or
di-(C.sub.1-3-alkyl)-amino group, and
[0308] R.sub.4 denotes an R.sub.7-(n-C.sub.1-3-alkyl)-phenyl group,
wherein
[0309] R.sub.7 denotes an amino, C.sub.1-6-alkylamino,
di-(C.sub.1-4-alkyl)-amino, .omega.-hydroxy-C.sub.2-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-.omega.-hydroxy-C.sub.2-3-alkyl-amino,
di-(.omega.-hydroxy-C.sub.2-3-alkyl)-amino or
di-(.omega.--(C.sub.1-3-alkoxy)-C.sub.2-3-alkyl)-amino group,
[0310] or a phenyl group substituted by the group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0311] wherein R.sub.12, p and R.sub.13 are as hereinbefore
defined,
[0312] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0313] A second subgroup of particularly preferred compounds of
general formula I deserving special mention comprises those
wherein
[0314] X, R.sub.1, R.sub.3 and R.sub.5 are as hereinbefore
defined,
[0315] R.sub.2 denotes an aminocarbonyl or methylaminocarbonyl
group, an ethylaminocarbonyl group optionally substituted in the 2
position of the ethyl group by a hydroxy or C.sub.1-3-alkoxy group
or a di-(C.sub.1-2-alkyl)-aminocarbonyl group and
[0316] R.sub.4 denotes a R.sub.7-(n-C.sub.1-3-alkyl)-phenyl group,
wherein
[0317] R.sub.7 denotes an amino, C.sub.1-6-alkylamino,
di-(C.sub.1-4-alkyl)-amino, .omega.-hydroxy-C.sub.2-3-alkyl-amino,
N--(C.sub.1-3-alkyl)-.omega.-hydroxy- -C.sub.2-3-alkyl-amino,
di-(.omega.-hydroxy-C.sub.2-3-alkyl)-amino or
di-(.omega.--(C.sub.1-3-alkoxy)-C.sub.2-3-alkyl)-amino group,
[0318] or a phenyl group substituted by the group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0319] wherein R.sub.12, p and R.sub.13 are as hereinbefore
defined,
[0320] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0321] Most particularly preferred compounds of general formula I
are those wherein
[0322] X denotes an oxygen atom,
[0323] R.sub.1 and R.sub.5 each denote a hydrogen atom,
[0324] R.sub.2 denotes a methoxycarbonyl, ethoxycarbonyl or
aminocarbonyl group,
[0325] R.sub.3 denotes a phenyl group and
[0326] R.sub.4 denotes a phenyl group monosubstituted by the group
R.sub.6, wherein
[0327] R.sub.6 denotes an N-methyl-imidazol-2-yl group,
[0328] an unbranched C.sub.1-3-alkyl group which is terminally
substituted by a C.sub.1-4-alkylamino, di-(C.sub.1-4-alkyl)-amino,
piperidino or 2,6-dimethyl-piperidino group,
[0329] a group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0330] wherein R.sub.12 denotes a C.sub.1-3-alkyl group,
[0331] p denotes one of the numbers 1 or 2 and
[0332] R.sub.13 denotes a di-(C.sub.1-3-alkyl)-amino group,
[0333] or a group of formula
--N(R.sub.14)--(CH.sub.2).sub.q--(CO).sub.r--R.sub.15 (V),
[0334] wherein
[0335] R.sub.14 denotes a C.sub.1-3-alkyl-carbonyl or
C.sub.1-3-alkylsulphonyl group,
[0336] q denotes one of the numbers 1, 2 or 3,
[0337] r denotes the number 1 or, if q is one of the numbers 2 or
3, r may also denote the number 0 and
[0338] R.sub.15 denotes a di-(C.sub.1-3-alkyl)-amino group,
[0339] wherein the saturated alkyl moieties contained in the
abovementioned groups which contain more than 2 carbon atoms may be
straight-chain or branched, unless otherwise stated,
[0340] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0341] A subgroup of most particularly preferred compounds of
general formula I deserving special mention comprises those
wherein
[0342] X, R.sub.1, R.sub.3 and R.sub.5 are as hereinbefore
defined,
[0343] R.sub.2 denotes a methoxycarbonyl or ethoxycarbonyl group
and
[0344] R.sub.4 denotes a
di-(C.sub.1-3-alkyl)-amino-C.sub.1-3-alkylphenyl group or a phenyl
group substituted by the group of formula
--N(R.sub.12)--CO--(CH.sub.2).sub.p--R.sub.13 (IV),
[0345] wherein R.sub.12, p and R.sub.13 are as hereinbefore
defined,
[0346] the tautomers, the diastereomers, the enantiomers, the
mixtures thereof and the salts thereof.
[0347] The following are mentioned as examples of particularly
preferred compounds: [0348] (a)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone, [0349] (b)
3-Z-[(1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamo-
yl-2-indolinone, [0350] (c)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone, [0351] (d)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone, [0352] (e)
3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methyl-
ene]-6-ethoxycarbonyl-2-indolinone, [0353] (f)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone, [0354] (g)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone, [0355] (h)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone, [0356] (i)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone, [0357] (j)
3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-2-indolinone, [0358] (k)
3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-
-2-indolinone, [0359] (l)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone, [0360] (m)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-2-indolinone, [0361] (n)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl
amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
[0362] (o)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, [0363] (p)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, [0364] (q)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, [0365] (r)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-methoxycarbonyl-2-indolinon and [0366] (s)
3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbony-
l-2-indolinone,
[0367] their tautomers, their stereoisomers or the physiologically
acceptable salts thereof.
[0368] Another subgroup of compounds of general formula I comprises
those wherein
[0369] X denotes an oxygen or sulphur atom,
[0370] R.sub.1 denotes a hydrogen atom or a prodrug group such as a
C.sub.1-4-alkoxycarbonyl or C.sub.2-4-alkanoyl group,
[0371] R.sub.2 denotes a carboxy group, a straight-chain or
branched C.sub.1-6-alkoxycarbonyl group, a
C.sub.5-7-cycloalkoxycarbonyl or phenyl-C.sub.1-3-alkoxycarbonyl
group, an aminocarbonyl or C.sub.1-2-alkylaminocarbonyl group or,
if R.sub.4 does not denote an aminosulphonyl-phenyl or
N--(C.sub.1-5-alkyl)-C.sub.1-3-alkylaminocarbonyl-phenyl group, a
di-(C.sub.1-2-alkyl)-aminocarbonyl group,
[0372] R.sub.3 denotes a hydrogen atom, a C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, trifluoromethyl or heteroaryl group,
[0373] a phenyl or naphthyl group, a phenyl or naphthyl group mono-
or disubstituted by a fluorine, chlorine, bromine or iodine atom,
by a trifluoromethyl, C.sub.1-3-alkyl or C.sub.1-3-alkoxy group,
whilst in the event of disubstitution the substituents may be
identical or different and wherein the abovementioned unsubstituted
as well as the mono- and disubstituted phenyl and naphthyl groups
may additionally be substituted by a hydroxy,
hydroxy-C.sub.1-3-alkyl or C.sub.1-3-alkoxy-C.sub.1-3-alkyl
group,
[0374] by a cyano, carboxy, carboxy-C.sub.1-3-alkyl,
C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylamino-carbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group,
[0375] by a nitro group,
[0376] by an amino, C.sub.1-3-alkylamino,
di-(C.sub.1-3-alkyl)-amino or amino-C.sub.1-3-alkyl group,
[0377] by a C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino,
C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino-C.sub.1-3-alkyl,
C.sub.1-3-alkylsulphonylamino,
C.sub.1-3-alkylsulphonylamino-C.sub.1-3-alkyl,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylsulphonylamino-C.sub.1-3-alkyl
or aryl-C.sub.1-3-alkylsulphonylamino group,
[0378] by a cycloalkylamino, cycloalkyleneimino,
cycloalkyleneiminocarbonyl, cycloalkyleneimino-C.sub.1-3-alkyl,
cycloalkyleneiminocarbonyl-C.sub.1-3-alkyl or
cycloalkyleneiminosulphonyl-C.sub.1-3-alkyl group having 4 to 7
ring members in each case, whilst in each case the methylene group
in position 4 of a 6- or 7-membered cycloalkyleneimino group may be
replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl,
--NH or --N(C.sub.1-3-alkyl) group,
[0379] or by a heteroaryl or heteroaryl-C.sub.1-3-alkyl group,
[0380] R.sub.4 denotes a C.sub.3-7-cycloalkyl group,
[0381] whilst the methylene group in the 4 position of a 6- or
7-membered cycloalkyl group may be substituted by an amino,
C.sub.1-3-alkylamino or di-(C.sub.1-3-alkyl)-amino group or
replaced by an --NH or --N(C.sub.1-3-alkyl) group,
[0382] or a phenyl group substituted by the group R.sub.6, which
may additionally be substituted by a fluorine, chlorine, bromine or
iodine atom, by a C.sub.1-5-alkyl, trifluoromethyl,
C.sub.1-3-alkoxy, carboxy, C.sub.1-3-alkoxycarbonyl,
aminosulphonyl, nitro or cyano group, wherein
[0383] R.sub.6 denotes a hydrogen, fluorine, chlorine, bromine or
iodine atom,
[0384] a cyano, nitro, C.sub.1-5-alkyl, C.sub.3-7-cycloalkyl,
trifluoromethyl, phenyl, tetrazolyl or heteroaryl group,
[0385] a C.sub.1-3-alkoxy group optionally substituted by 1 to 3
fluorine atoms, a C.sub.1-3-alkoxy-C.sub.1-3-alkoxy,
phenyl-C.sub.1-3-alkoxy, amino-C.sub.2-3-alkoxy,
C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
di-(C.sub.1-3-alkyl)-amino-C.sub.2-3-alkoxy,
phenyl-C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino-C.sub.2-3-alkoxy,
C.sub.5-7-cycloalkyleneimino-C.sub.2-3-alkoxy or
C.sub.1-3-alkylmercapto group,
[0386] a carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkyl-amino-carbonyl,
N--(C.sub.1-5-alkyl)-C.sub.1-3-alkylaminocarbonyl,
phenyl-C.sub.1-3-alkylamino-carbonyl,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino-carbonyl,
piperazinocarbonyl or N--(C.sub.1-3-alkyl)-piperazinocarbonyl
group,
[0387] a C.sub.1-3-alkylaminocarbonyl or
N--(C.sub.1-5-alkyl)-C.sub.1-3-alkylaminocarbonyl group wherein an
alkyl moiety is substituted by a carboxy or
C.sub.1-3-alkoxycarbonyl group or is substituted in the 2 or 3
position by a di-(C.sub.1-3-alkyl)-amino, piperazino,
N--(C.sub.1-3-alkyl)-piperazino or a 4- to 7-membered
cycloalkyleneimino group,
[0388] a 4- to 7-membered cycloalkyleneimino group, wherein
[0389] a methylene group linked to the imino group may be replaced
by a carbonyl or sulphonyl group or the cycloalkylene moiety may be
fused to a phenyl ring or
[0390] one or two hydrogen atoms may each be replaced by a
C.sub.1-3-alkyl group and/or
[0391] in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be substituted by a
carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino group or
[0392] may be replaced by an oxygen or sulphur atom, by a
sulphinyl,
[0393] sulphonyl, --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group,
[0394] a C.sub.1-4-alkyl group which may be substituted
[0395] by a hydroxy or C.sub.1-3-alkoxy group,
[0396] by an amino, C.sub.1-7-alkylamino,
di-(C.sub.1-7-alkyl)-amino,
di-N--(C.sub.1-3-alkyl)-amino-C.sub.2-3-alkylamino,
tri-N,N,N'--(C.sub.1-3-alkyl)-amino-C.sub.2-3-alkylamino,
phenylamino, N-phenyl-C.sub.1-3-alkyl-amino,
phenyl-C.sub.1-3-alkylamino,
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino or
di-(phenyl-C.sub.1-3-alkyl)-amino group,
[0397] by a C.sub.1-3-alkylcarbonylamino,
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkylcarbonylamino,
C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-C.sub.1-3-alkoxycarbonyl-C.sub.1-3-alkylamino
group,
[0398] by a C.sub.4-7-cycloalkylamino,
C.sub.4-7-cycloalkyl-C.sub.1-3-alkylamino or
C.sub.4-7-cycloalkenylamino group wherein position 1 of the ring is
not involved in the double bond and wherein the abovementioned
groups may each additionally be substituted at the amino-nitrogen
atom by a C.sub.1-3-alkyl group wherein some or all of the hydrogen
atoms are replaced by fluorine atoms, by a C.sub.5-7-cycloalkyl,
C.sub.2-4-alkenyl or C.sub.1-4-alkyl group,
[0399] by a 4- to 7-membered cycloalkyleneimino group, wherein
[0400] a methylene group linked to the imino group may be replaced
by a carbonyl or sulphonyl group or
[0401] the cycloalkylene moiety may be fused to a phenyl group or
to an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or
[0402] pyrimidino group optionally substituted by a fluorine,
chlorine, bromine or iodine atom, by a nitro, C.sub.1-3-alkyl,
C.sub.1-3-alkoxy or amino group or
[0403] one or two hydrogen atoms may each be replaced by a
C.sub.1-3-alkyl, C.sub.5-7-cycloalkyl or phenyl group and/or
[0404] in each case the methylene group in the 4 position of a 6-
or 7-membered cycloalkyleneimino group may be substituted by a
hydroxy, carboxy, C.sub.1-4-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl, di-(C.sub.1-3-alkyl)-aminocarbonyl,
phenyl-C.sub.1-3-alkylamino or
N--(C.sub.1-3-alkyl)-phenyl-C.sub.1-3-alkylamino group or
[0405] may be replaced by an oxygen or sulphur atom, by a
sulphinyl,
[0406] sulphonyl, --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group,
[0407] by a carboxy, C.sub.1-3-alkoxycarbonyl, aminocarbonyl,
C.sub.1-3-alkylaminocarbonyl or di-(C.sub.1-3-alkyl)-aminocarbonyl
group or
[0408] by a 4- to 7-membered cycloalkyleneiminocarbonyl group,
[0409] an amino, pyrrolidino, piperidino, morpholino, benzoylamino
or N--(C.sub.1-3-alkyl)-benzoylamino group,
[0410] an N--(C.sub.1-3-alkyl)-C.sub.2-4-alkanoylamino group which
is additionally substituted in the alkyl moiety by a carboxy or
C.sub.1-3-alkoxycarbonyl group,
[0411] a group of formula
--N(R.sub.8)--CO--(CH.sub.2).sub.n--R.sub.9 (II),
[0412] wherein
[0413] R.sub.8 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0414] n denotes one of the numbers 0, 1, 2 or 3 and
[0415] R.sub.9 denotes an amino, C.sub.1-4-alkylamino, phenylamino,
N--(C.sub.1-4-alkyl)-phenylamino, benzylamino,
N--(C.sub.1-4-alkyl)-benzylamino or di-(C.sub.1-4-alkyl)-amino
group, a 4- to 7-membered cycloalkyleneimino group, whilst in each
case the methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group may be replaced by an oxygen or sulphur
atom, by a sulphinyl,
[0416] sulphonyl, --NH, --N(C.sub.1-3-alkyl), --N(phenyl),
--N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group, or, if n
denotes one of the numbers 1, 2 or 3, it may also denote a hydrogen
atom,
[0417] a group of formula
--N(R.sub.10)--(CH.sub.2).sub.m--(CO).sub.o--R.sub.11 (III),
[0418] wherein
[0419] R.sub.10 denotes a hydrogen atom, a C.sub.1-3-alkyl group, a
C.sub.1-3-alkylcarbonyl, arylcarbonyl,
phenyl-C.sub.1-3-alkylcarbonyl, C.sub.1-3-alkylsulphonyl,
arylsulphonyl or phenyl-C.sub.1-3-alkylsulphonyl group,
[0420] m denotes one of the numbers 1, 2, 3 or 4,
[0421] o denotes one of the numbers 0 or 1 and
[0422] R.sub.11 denotes an amino, C.sub.1-4-alkylamino,
phenylamino, N--(C.sub.1-4-alkyl)-phenylamino, benzylamino,
N--(C.sub.1-4-alkyl)-benzylamino or di-(C.sub.1-4-alkyl)-amino
group, a 4- to 7-membered cycloalkyleneimino group, wherein the
cycloalkylene moiety may be fused to a phenyl ring or in each case
the methylene group in the 4 position of a 6- or 7-membered
cycloalkyleneimino group may be replaced by an oxygen or sulphur
atom, by a sulphinyl, sulphonyl, --NH, --N(C.sub.1-3-alkyl),
--N(phenyl), --N(C.sub.1-3-alkyl-carbonyl) or --N(benzoyl) group, a
C.sub.1-3-alkoxy group or a
di-(C.sub.1-4-alkyl)-amino-C.sub.1-3-alkylamino group optionally
substituted in the 1 position by a C.sub.1-3-alkyl group,
[0423] or an N--(C.sub.1-3-alkyl)-C.sub.1-5-alkylsulphonylamino or
N--(C.sub.1-3-alkyl)-phenylsulphonylamino group wherein the alkyl
moiety is additionally substituted by a cyano or carboxy group,
[0424] wherein all the single-bonded or fused phenyl groups
contained in the groups mentioned under R.sub.6 may be mono- or
disubstituted by fluorine, chlorine, bromine or iodine atoms, by
C.sub.1-5-alkyl, trifluoromethyl, C.sub.1-3-alkoxy, carboxy,
C.sub.1-3-alkoxycarbonyl, aminosulphonyl, nitro or cyano groups,
wherein the substituents may be identical or different, or two
adjacent hydrogen atoms of the phenyl groups may be replaced by a
methylenedioxy group,
[0425] and
[0426] R.sub.5 denotes a hydrogen atom or a C.sub.1-3-alkyl
group,
[0427] wherein by an aryl group is meant a phenyl or naphthyl group
optionally mono- or disubstituted by a fluorine, chlorine, bromine
or iodine atom, by a trifluoromethyl, C.sub.1-3-alkyl or
C.sub.1-3-alkoxy group and
[0428] by a heteroaryl group is meant a monocyclic 5- or 6-membered
heteroaryl group optionally substituted by a C.sub.1-3-alkyl group,
wherein the 6-membered heteroaryl group contains one, two or three
nitrogen atoms and the 5-membered heteroaryl group contains an
imino group optionally substituted by a C.sub.1-3-alkyl group, an
oxygen or sulphur atom or an imino group optionally substituted by
a C.sub.1-3-alkyl group and an oxygen or sulphur atom or one or two
nitrogen atoms, and moreover a phenyl ring may be fused to the
abovementioned monocyclic heterocyclic groups via two adjacent
carbon atoms, the saturated alkyl and alkoxy moieties present in
the groups defined above which contain more than 2 carbon atoms
also include the branched isomers thereof such as, for example, the
isopropyl, tert.butyl or isobutyl group, unless otherwise stated,
and
[0429] additionally any carboxy, amino or imino group present may
be substituted by a group which can be cleaved in vivo, the isomers
and the salts thereof.
[0430] A further subgroup of compounds of general formula I which
deserves special mention is the subgroup wherein the substituent in
the 6 position of the substituted indolinone of general formula I
comprises a substituted amido group.
[0431] The above exemplified compounds, their tautomers, their
stereoisomers or the physiologically acceptable salts thereof, as
well as their manufacturing process, have been described in WO
01/27081, the content of which is incorporated herein by
reference.
[0432] Further compounds in accordance with the above general
formula I which are preferred within the meaning of the present
invention are the following compounds: [0433] (t)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [0434] (u)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, [0435]
(v)
3-Z-[1-(3-cyano-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0436] (w)
3-Z-[1-(3-methoxy-4-(N-dimethylaminomethylcarbonyl-N
methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0437] (x)
3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [0438] (y)
3-Z-[1-(4-(N--(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N--
methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0439] (z)
3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-amino-methylcarbonyl)-N-methyl-amino)--
anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0440]
(aa)
3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-ph-
enyl-methylene]-6-methoxycarbonyl-2-indolinone [0441] (ab)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-amino)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [0442] (ac)
3-Z-[1-(4-(N-((4-methyl-[1,4]diazepan-1-yl)-methylcarbonyl)-N-methyl-amin-
o)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0443] (ad)
3-Z-[1-(4-(N-((1-methyl-piperidin-4-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0444]
(ae)
3-Z-[1-(2,3-dimethyl-4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amin-
o)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0445] (af)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0446] (ag)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0447] (ah)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [0448] (ai)
3-Z-[1-(4-(N-((3-dimethylamino-propyl)-aminocarbonyl)-N-methyl-amino)-ani-
lino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0449]
(aj)
3-Z-[1-anilino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0450] (ak)
3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methy-
lene]-6-methoxycarbonyl-2-indolinone [0451] (al)
3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[0452] (am)
3-Z-[1-(4-(4-methylpiperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6--
carboxy-2-indolinone [0453] (an)
3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-carboxy-2-indo-
linone [0454] (ao)
3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy--
2-indolinone [0455] (ap)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-carboxy-2-indolinone [0456] (aq)
3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene-
]-6-carboxy-2-indolinone [0457] (ar)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-carboxy-2-indolinone [0458] (as)
3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-me
amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone [0459]
(at)
3-Z-[1-(4-(N--(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N--
methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone
[0460] (au)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ca-
rboxy-2-indolinone [0461] (av)
3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-carb indolinone [0462]
(aw) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-ca
ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolino [0463] (ax)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(carboxy-ethyl)-phenyl)-m-
ethylene]-6-methoxycarbonyl-2-indolinone [0464] (ay)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-carboxy-ethyl)-phenyl)-m-
ethylene]-6-methoxycarbonyl-2-indolinone [0465] (az)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-ca
ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone [0466]
(ba)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmet-
hylcarbamoyl-2-indolinone [0467] (bb)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylc-
arbamoyl-2-indolinone [0468] (bc)
3-Z-[1-((1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethyl-
carbamoyl-2-indolinone [0469] (bd)
3-Z-[1-(trans-4-dimethylamino-cyclohexylamino)-1-phenyl-methylene]-6-ethy-
lmethylcarbamoyl-2-indolinone [0470] (be)
3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmet-
hylcarbamoyl-2-indolinone [0471] (bf)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethylmethylcarbamoyl-2-indolinone [0472] (bg)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone
[0473] (bh)
3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2--
indolinone [0474] (bi)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethylmethylcarbamoyl-2-indolinone [0475] (bj)
3-Z-[1-(3-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylca-
rbamoyl-2-indolinone [0476] (bk)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethylmethylcarbamoyl-2-indolinone [0477] (bl)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulponyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone [0478] (bm)
3-Z-[1-anilino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone
[0479] (bn)
3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarb-
amoyl-2-indolinone [0480] (bo)
3-Z-[1-(4-((2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmet-
hylcarbamoyl-2-indolinone [0481] (bp)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethylmethylcarbamoyl-2-indolinone [0482] (bq)
3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-
-6-ethylmethylcarbamoyl-2-indolinon [0483] (br)
3-Z-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarba-
moyl-2-indolinone [0484] (bs)
3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-i-
ndolinone [0485] (bt)
3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-amino)-anil-
ino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone [0486]
(bu)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylca-
rbamoyl-2-indolinone [0487] (bv)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone [0488]
(bw)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethylcarbamoyl-2-indolinone [0489] (bx)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylme-
thylcarbamoyl-2-indolinone [0490] (by)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethylcarbamoyl-indolinone [0491] (bz)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylcarbamo-
yl-2-indolinone [0492] (ca)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethylcarbamoyl-2-indolinone [0493] (cb)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethylcarbamoyl-2-indolinone [0494] (cc)
3-Z-[1-(4-carbamoyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-
-indolinone [0495] (cd)
3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylen-
e]-6-ethylmethylcarbamoyl-2-indolinone [0496] (ce)
3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylen-
e]-6-ethylmethylcarbamoyl-2-indolinone [0497] (cf)
3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylen-
e]-6-ethylcarbamoyl-2-indolinone [0498] (cg)
3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene-
]-6-ethylmethylcarbamoyl-2-indolino [0499] (ch)
3-Z-[1-(4-(N-ethyl-N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-
-methylene]-6-ethylmethylcarbamoyl-2-indolinone [0500] (ci)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-diethylcarbamoyl-2-indolinone [0501]
(cj)
3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl--
methylene]-6-ethylmethylcarbamoyl-2-indolinone [0502] (ck)
3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene-
]-6-ethylcarbamoyl-2-indolinone [0503] (cl)
3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylen-
e]-6-ethylmethylcarbamoyl-2-indolinone [0504] (cm)
3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl--
methylene]-6-ethylcarbamoyl-2-indolinone [0505] (cn)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone [0506] (co)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methyle-
ne]-6-methoxycarbonyl-2-indolinone [0507] (cp)
3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-methoxycarbonyl-2-ind-
olinone [0508] (cq)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-methylene]-6-methoxycarbonyl-2-indolinone [0509] (cr)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-methylene]-6-ethylcarbamoyl-2-indolinone [0510] (cs)
3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-ethylcarbamoyl-2-indo-
linone [0511] (ct)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethylcarbamoyl-2--
indolinone [0512] (cu)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-
-6-ethylcarbamoyl-2-indolinone,
[0513] their tautomers, their stereoisomers or the physiologically
acceptable salts thereof.
[0514] These compounds may be prepared analogously to the compounds
of WO 01/27081 and using the methods described hereafter.
[0515] Abbreviations used:
[0516] HOBt=1-hydroxy-1H-benzotriazole
[0517]
TBTU=O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium-tetrafluorobo-
rate
[0518] DEPC=diethyl pyrocarbonate
[0519] n.d.=not determined
Examples (t) to (al)
[0520] The following compounds of general formula II are prepared
analogously to the compounds described in WO 01/27081:
##STR00007##
TABLE-US-00001 Melting Mass point Example A B R.sup.6 Formula
spectrum [.degree. C.] R.sub.f-value* (t) --H --H
--O(CH.sub.2).sub.2--NMe.sub.2 C.sub.27H.sub.27N.sub.3O.sub.4 456
n.b. 0.30 [m - H].sup.- (A) (u) --H --H ##STR00008##
C.sub.31H.sub.33N.sub.5O.sub.4 540 [m + H].sup.+ 250- 252 0.60 (B)
(v) --CN --H --N(Me)--(CO)--CH.sub.2--NMe.sub.2
C.sub.29H.sub.27N.sub.5O.sub.4 510 163- 0.35 [m + H].sup.+ 165 (A)
(w) --OMe --H --N(Me)--(CO)--CH.sub.2--NMe.sub.2
C.sub.20H.sub.30N.sub.4O.sub.5 515 160- 0.40 [m + H].sup.+ 163 (A)
(x) --H --H --N(Me)--(CO)--CH.sub.2--NMe.sub.2
C.sub.26H.sub.24N.sub.4O.sub.4 457 221 0.45 [m + H].sup.+ (C) (y)
--H --H ##STR00009## C.sub.24H.sub.21N.sub.3O.sub.3 542 [m +
H].sup.+ 265 n.d. (z) --H --H ##STR00010##
C.sub.30H.sub.32N.sub.4O.sub.6 545 [m + H].sup.+ 199- 202 0.40 (A)
(aa) --H --H ##STR00011## C.sub.29H.sub.25N.sub.5O.sub.4 508 [m +
H].sup.+ 271 0.45 (A) (ab) --H --H --NH--(CO)--CH.sub.2--NMe.sub.2
C.sub.27H.sub.26N.sub.4O.sub.4 471 250- 0.50 [m + H].sup.+ 255 (A)
(ac) --H --H ##STR00012## C.sub.32H.sub.35N.sub.5O.sub.4 554 [m +
H].sup.+ 180- 185 0.50 (D) (ad) --H --H ##STR00013##
C.sub.32H.sub.34N.sub.4O.sub.4 539 [m + H].sup.+ 190- 193 0.40 (D)
(ae) --CH.sub.3 --CH.sub.3 ##STR00014##
C.sub.32H.sub.35N.sub.5O.sub.4 554 [m + H].sup.+ 254- 257 0.50 (C)
(af) --H --H ##STR00015## C.sub.30H.sub.31N.sub.5O.sub.4 526 [m +
H].sup.+ 170- 175 0.40 (A) (ag) --H --H ##STR00016##
C.sub.30H.sub.31N.sub.5O.sub.4 526 [m + H].sup.+ 205- 208 0.40 (A)
(ah) --H --H --N(Me)--(CO)--(CH.sub.2).sub.3--NMe.sub.2
C.sub.30H.sub.32N.sub.4O.sub.4 511 166- 0.40 [m - H].sup.- 170 (C)
(ai) --H --H --N(Me)--(CO)--NH--(CH.sub.2).sub.3--NMe.sub.2
C.sub.30H.sub.33N.sub.5O.sub.4 528 166- 0.30 [m + H].sup.+ 170 (E)
(aj) --H --H --H C.sub.23H.sub.18N.sub.2O.sub.3 371 275- 0.80 [m +
H].sup.+ 280 (C) (ak) --H --H --N(SO.sub.2Me)--CH.sub.3
C.sub.25H.sub.23N.sub.3O.sub.5S 478 278- 0.70 [m + H].sup.+ 282 (C)
*Solvents: (A): silica gel, methylene chloride/methanol 9:1 (B):
aluminum oxide, methylene chloride/methanol 20:1 (C): silica gel,
methylene chloride/methanol/ammonia 9:1:0.1 (D): silica gel,
methylene chloride/methanol/ammonia 5:1:0.01 (E): silica gel,
methylene chloride/methanol/ammonia 9:1:0.01
[0521] The following compound is prepared analogously: [0522] (al)
3-Z-(1-cyclohexylamino-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone
[0523] R.sub.f value: 0.60 (silica gel, methylene
chloride/methanol=9:1)
[0524] Melting point: 236-243.degree. C.
C.sub.23H.sub.24N.sub.2O.sub.3
[0525] Mass spectrum: m/z=377 [m+H].sup.+
Examples (am) to (av)
[0526] The following compounds of general formula III are prepared
analogously to the compounds described in WO 01/27081:
##STR00017##
TABLE-US-00002 Melting Mass point Example R.sup.6 Formula spectrum
[.degree. C.] R.sub.f-value* (am) ##STR00018##
C.sub.28H.sub.28N.sub.4O.sub.3 467 [m - H].sup.- 275 0.50 (A) (an)
--CH.sub.2--NHMe C.sub.24H.sub.21N.sub.3O.sub.3 398 287 0.70 [m -
H].sup.- (A) (ao) ##STR00019## C.sub.27H.sub.25N.sub.3O.sub.4 454
[m - H].sup.- 335 0.70 (A) (ap)
--N(SO.sub.2Me)--(CH.sub.2).sub.2--NMe.sub.2
C.sub.27H.sub.28N.sub.4O.sub.5S 519 280 0.70 [m - H].sup.- (A) (aq)
##STR00020## C.sub.27H.sub.27N.sub.3O.sub.5 596 [m + Na].sup.+
256-257 0.75 (ar) ##STR00021## C.sub.30H.sub.31N.sub.5O.sub.4 526
[m + H].sup.+ 346 0.60 (A) (as) ##STR00022##
C.sub.29H.sub.28N.sub.4O.sub.5 513 [m + H].sup.+ 237-238 0.70 (A)
(at) ##STR00023## C.sub.30H.sub.33N.sub.5O.sub.4 528 [m + H].sup.+
238-240 0.50 (A) (au) --O(CH.sub.2).sub.2--NMe.sub.2
C.sub.26H.sub.25N.sub.3O.sub.4 444 n.b. 0.35 [m + H].sup.+ (B)
*Solvents: (A): reversed phase RP8, methanol/brine (5%) = 4:1 (B):
silica gel, methylene chloride/methanol 4:1
[0527] The following compound is prepared analogously: [0528] (av)
3-Z-(1-cyclohexylamin-1-phenyl-methylene)-6-carboxy-2-indolinone
[0529] Rf value: 0.50 (silica gel, methylene
chloride/methanol=9:1)
[0530] Melting point: 347-350.degree. C.
[0531] C.sub.22H.sub.22N.sub.2O.sub.3
[0532] Mass spectrum: m/z=363 [m+H].sup.+
Examples (aw) to (az)
[0533] (aw)
3-Z-[1-(3-(dimethylaminomethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-m-
ethylene]-6-methoxycarbonyl-2-indolinone [0534] (ax)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-
-methylene]-6-methoxycarbonyl-2-indolinon [0535] (ay)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl-
)-methylene]-6-methoxycarbonyl-2-indolinone [0536] (az)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-m-
ethylene]-6-methoxycarbonyl-2-indolinone
[0537] Preparation of the Starting Compounds:
[0538] (I.1)
1-acetyl-3-(1-hydroxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6--
methoxycarbonyl-2-indolinone 6.00 g
1-acetyl-6-methoxycarbonyl-2-indolinone, 6.30 g
3-(2-ethoxycarbonyl-ethyl)-benzoic acid (preparation analogously to
Tetrahedron 1997, 53, 7335-7340) and 9.10 g TBTU are dissolved in
80 ml of dimethylformamide, 13.5 ml diisopropylmethylamine and 4.34
g HOBt are added and the mixture is stirred for 12 hrs at ambient
temperature. After this time the solvent is removed, diluted
hydrochloric acid is added and the residue is recrystallized from
methylene chloride/methanol.
[0539] Yield: 10.6 g (94% of theory)
[0540] R.sub.f value: 0.50 (silica gel, methylene
chloride/methanol=19:1)
[0541] Melting point: 80-84.degree. C.
[0542] C.sub.24H.sub.23NO.sub.7
[0543] Mass spectrum: m/z=438 [m+H].sup.+
[0544] The following compounds are prepared analogously:
[0545] (I.2)
1-acetyl-3-(1-hydroxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-
-methoxycarbonyl-2-indolinone prepared from
1-acetyl-6-methoxycarbonyl-2-indolinone and
4-(2-methoxycarbonyl-ethyl)-benzoic acid (preparation analogously
to Tetrahedron 1997, 53, 7335-7340)
[0546] R.sub.f value: 0.60 (silica gel, methylene
chloride/methanol=19:1)
[0547] Melting point: 188-192.degree. C.
[0548] C.sub.23H.sub.21NO.sub.7
[0549] Mass spectrum: m/z=422 [m-H].sup.-
[0550] (II.1)
1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6--
methoxycarbonyl-2-indolinone 7.17 g
trimethyloxoniumtetrafluoroborate are slowly added to a solution of
10.6 g
1-acetyl-3-(1-hydroxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6--
methoxycarbonyl-2-indolinone (starting material I.1) and 12.5 ml
ethyldiisopropylamine in 100 ml methylene chloride. After stirring
for 4 hrs at ambient temperature another 3.50 g
trimethyloxoniumtetrafluoroborate are added and the mixture is
stirred for 12 hrs at ambient temperature. After that time the
mixture is washed twice with water, the organic phase is dried over
magnesium sulphate and the solvent is removed. The residue is
purified over a silica gel column with methylene chloride/methanol
(97:3) as eluant.
[0551] Yield: 4.56 g (42% of theory)
[0552] R.sub.f value: 0.90 (silica gel, methylene
chloride/methanol=20:1)
[0553] C.sub.25H.sub.25NO.sub.7
[0554] Mass spectrum: m/z=452 [m+H].sup.+
[0555] The following compounds are prepared analogously:
[0556] (II.2)
1-acetyl-3-(1-methoxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-
-methoxycarbonyl-2-indolinone prepared from
1-acetyl-3-(1-hydroxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-
-methoxycarbonyl-2-indolinone (starting material I.2)
[0557] R.sub.f value: 0.80 (silica gel, methylene
chloride/methanol=19:1) Melting point: 112-117.degree. C.
[0558] C.sub.24H.sub.23NO.sub.7
[0559] Mass spectrum: m/z=438 [m+H].sup.+
[0560] (III.1)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3-(2-ethoxycarbonyl-ethyl)-ph-
enyl)-methylene]-6-methoxycarbonyl-2-indolinone
[0561] 1.2 g
1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6--
methoxycarbonyl-2-indolinone (starting material II.1) and 0.32 g
4-(dimethylaminomethyl)-aniline are dissolved in 10 ml of
dimethylformamide and stirred for 3 days at 110.degree. C. After
cooling the solvent is evaporated, the residue is taken up in 5 ml
of methanol and 200 mg 20 percent sodiumethylat-solution in ethanol
are added. The mixture is stirred for 1.5 hrs at ambient
temperature, the solvent is removed and the residue is taken up in
water. The aqueous phase is three times extracted with ethyl
acetate and the combined organic phases are dried over sodium
sulphate. After evaporation of the solvent the residue is purified
over a silica gel column with methylene chloride/methanol (9:1) as
eluant.
[0562] Yield: 0.33 g (35% of theory),
[0563] R.sub.f value: 0.35 (silica gel, methylene
chloride/methanol=9:1)
[0564] Melting point: 129-134.degree. C.
[0565] C.sub.31H.sub.33N.sub.3O.sub.5
[0566] Mass spectrum: m/z=528 [m+H].sup.+
[0567] The following compounds are prepared analogously:
[0568] (III.2)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-ethoxycarbonyl-ethyl)--
phenyl)-methylene]-6-methoxycarbonyl-2-indolinone
[0569] prepared from
1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6--
methoxycarbonyl-2-indolinone (starting material II.1)
[0570] R.sub.f value: 0.30 (silica gel, methylene
chloride/methanol=9:1)
[0571] Melting point: 174-177.degree. C.
[0572] C.sub.32H.sub.35N.sub.3O.sub.5
[0573] Mass spectrum: m/z=542 [m+H].sup.+
(III.3)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-ethoxycarbonyl-
-ethyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone
[0574] prepared from
1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene)-6--
methoxycarbonyl-2-indolinone (starting material II.1)
[0575] R.sub.f value: 0.45 (silica gel, methylene
chloride/methanol=9:1)
[0576] Melting point: 102.degree. C.
[0577] C.sub.32H.sub.30N.sub.4O.sub.5
[0578] Mass spectrum: m/z=551 [m+H].sup.+
(III.4)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-methoxycarbonyl-e-
thyl)-phenyl)-methylene]-6-methoxycarbonyl-2-indolinone
[0579] prepared from
1-acetyl-3-(1-methoxy-1-(4-(2-methoxycarbonyl-ethyl)-phenyl)-methylene)-6-
-methoxycarbonyl-2-indolinone (starting material II.2)
[0580] R.sub.f value: 0.50 (silica gel, methylene
chloride/methanol=9:1)
[0581] Melting point: 226-229.degree. C.
[0582] C.sub.30H.sub.31N.sub.3O.sub.5
[0583] Mass spectrum: m/z=512 [m-H].sup.-
[0584] Preparation of the Final Compounds:
[0585] The following compounds of general formula IV are prepared
analogously to the compounds described in WO 01/27081, starting
from the above mentioned starting materials:
##STR00024##
TABLE-US-00003 Melting Starting Mass point Example R.sup.3 R.sup.6
compound Formula spectrum [.degree. C.] R.sub.f value* (aw)
##STR00025## --CH.sub.2--NMe.sub.2 III.1
C.sub.29H.sub.29N.sub.3O.sub.5 500 [m + H].sup.+ 163- 167 0.40 (A)
(ax) ##STR00026## --(CH.sub.2).sub.2--NMe.sub.2 III.2
C.sub.30H.sub.31N.sub.3O.sub.5 514 [m + H].sup.+ 248- 255 0.35 (A)
(ay) ##STR00027## ##STR00028## III.3 C.sub.30H.sub.26N.sub.4O.sub.5
523 [m + H].sup.+ 184- 190 0.35 (A) (az) ##STR00029##
--CH.sub.2--NMe.sub.2 III.4 C.sub.29H.sub.29N.sub.3O.sub.5 498 [m -
H].sup.- 190- 195 0.20 (B) *Solvents: (A): Reversed Phase RP8,
methanol/brine (5%) = 4:1 (B): silica gel, methylene
chloride/methanol 9:1
Examples (ba) to (cn)
[0586] Preparation of the Starting Compounds:
[0587] (IV) 3-(1-hydroxy-1-phenyl-methylene)-6-carboxy-2-indolinone
11.0 g
1-acetyl-3-(1-methoxy-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone
(preparation described in WO 01/27081) are dissolved in 500 ml of
methanol and 160 ml of 1N sodium hydroxide solution are added. The
mixture is stirred for 1 hr at ambient temperature and for 6 hrs at
reflux. After that time another 20 ml of 1N sodium hydroxide
solution are added and the mixture is stirred for another 3 hrs at
reflux. 160 ml of 1N hydrochloric acid are added, the resulting
residue is filtered off and dried at 100.degree. C. The residue is
used without further purification.
[0588] Yield: 7.60 g (86% of theory)
(V.1)
3-(1-hydroxy-1-phenyl-methylene)-6-(N-ethyl-methylcarbamoyl)-2-indol-
inone
[0589] 5.50 g
3-(1-hydroxy-1-phenyl-methylene)-6-carboxy-2-indolinone (starting
material IV), 7.54 g TBTU, 3.60 g HOBt and 17.1 ml
ethyldiisopropylamine are dissolved in 200 ml of dimethylformamide.
2.70 ml of a 94-percent solution of N-methyl-ethylamine are added
and the mixture is stirred for 12 hrs at ambient temperature. After
that time the solvent is evaporated and the residue is purified
over a silica gel column with methylene chloride/methanol/ammonia
(9:1:0.1) as eluant.
[0590] Yield: 6.10 g (97% of theory)
[0591] R.sub.f value: 0.35 (silica gel, methylene
chloride/methanol/ammonia=9:1:0.1)
[0592] C.sub.19H.sub.18N.sub.2O.sub.3
[0593] Mass spectrum: m/z=323 [m+H].sup.+
[0594] The following compound is prepared analogously:
(V.2)
3-(1-hydroxy-1-phenyl-methylene)-6-ethylcarbamoyl-2-indolinone
[0595] prepared from
3-(1-hydroxy-1-phenyl-methylene)-6-carboxy-2-indolinone (starting
material IV) und ethylamine C.sub.18H.sub.16N.sub.2O.sub.3
[0596] Mass spectrum: m/z=309 [m+H].sup.+
[0597] Preparation of the Final Compounds:
[0598] (ba)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-(N-ethyl-
-methylcarbamoyl)-2-indolinone 250 mg
3-(1-hydroxy-1-phenyl-methylene)-6-(N-ethyl-methylcarbamoyl)-2-indolinone
(starting material V.1) and 382 mg
4-(2-dimethylamino-ethyl)-aniline are dissolved in 3 ml of
tetrahydrofuran, 569 ml trimethylsilylimidazole are added and the
mixture is stirred at 170.degree. C. in a microwave oven. After
cooling the solvent is evaporated and the residue is taken up in
water. The residue is filtered off and vacuum-dried at 90.degree.
C.
[0599] Yield: 0.18 g (50% of theory),
[0600] R.sub.f value: 0.30 (silica gel, methylene
chloride/methanol/ammonia=9:1:0.1)
[0601] Melting point: 195-200.degree. C.
[0602] C.sub.29H.sub.32N.sub.4O.sub.2
[0603] Mass spectrum: m/z=469 [m+H].sup.+
[0604] The following compounds of general formula V are prepared
analogously to the above compound (ba), following the procedures
described in WO 01/27081:
##STR00030##
TABLE-US-00004 Melting Mass point Example X R.sup.4 Formula
spectrum [.degree. C.] R.sub.f value* (bb) --CH.sub.3 ##STR00031##
C.sub.28H.sub.30N.sub.4O.sub.2 455 [m + H].sup.+ 239-243 0.35 (A)
(bc) --CH.sub.3 ##STR00032## C.sub.25H.sub.30N.sub.4O.sub.2 419 [m
+ H].sup.+ 267-271 0.35 (B) (bd) --CH.sub.3 ##STR00033##
C.sub.27H.sub.34N.sub.4O.sub.2 447 [m + H].sup.+ 133-138 0.30 (B)
(be) --CH.sub.3 ##STR00034## C.sub.31H.sub.36N.sub.4O.sub.3 513 [m
+ H].sup.+ 191-196 0.45 (B) (bf) --CH.sub.3 ##STR00035##
C.sub.33H.sub.39N.sub.5O.sub.3 554 [m + H].sup.+ 258-262 0.40 (B)
(bg) --CH.sub.3 ##STR00036## C.sub.33H.sub.38N.sub.6O.sub.3 567 [m
+ H].sup.+ 214-218 0.20 (B) (bh) --CH.sub.3 ##STR00037##
C.sub.25H.sub.29N.sub.3O.sub.2 404 [m + H].sup.+ 239-242 0.70 (A)
(bi) --CH.sub.3 ##STR00038## C.sub.31H.sub.35N.sub.5O.sub.3 526 [m
+ H].sup.+ 237-240 0.30 (B) (bj) --CH.sub.3 ##STR00039##
C.sub.30H.sub.34N.sub.4O.sub.2 483 [m + H].sup.+ 105-108 0.40 (B)
(bk) --CH.sub.3 ##STR00040## C.sub.30H.sub.33N.sub.5O.sub.3 512 [m
+ H].sup.+ 208-211 0.40 (B) (bl) --CH.sub.3 ##STR00041##
C.sub.30H.sub.35N.sub.5O.sub.4S 562 [m + H].sup.+ 197-201 0.40 (B)
(bm) --CH.sub.3 ##STR00042## C.sub.25H.sub.23N.sub.3O.sub.2 398 [m
+ H].sup.+ 296-301 0.40 (B) (bn) --CH.sub.3 ##STR00043##
C.sub.28H.sub.30N.sub.4O.sub.2 455 [m + H].sup.+ 243-247 0.30 (A)
(bo) --H ##STR00044## C.sub.28H.sub.30N.sub.4O.sub.2 455 [m +
H].sup.+ 328-332 0.30 (A) (bp) --CH.sub.3 ##STR00045##
C.sub.32H.sub.37N.sub.5O.sub.3 540 [m + H].sup.+ 224-228 0.25 (A)
(bq) --CH.sub.3 ##STR00046## C.sub.27H.sub.28N.sub.4O.sub.4S 505 [m
+ H].sup.+ 265-269 0.40 (B) (br) --CH.sub.3 ##STR00047##
C.sub.27H.sub.25N.sub.3O.sub.4 456 [m + H].sup.+ 254-257 0.60 (B)
(bs) --CH.sub.3 ##STR00048## C.sub.26H.sub.23N.sub.3O.sub.4 442 [m
+ H].sup.+ 316-321 0.10 (B) (bt) --CH.sub.3 ##STR00049##
C.sub.30H.sub.33N.sub.5O.sub.5S 576 [m + H].sup.+ 258-262 0.35 (B)
(bu) --H ##STR00050## C.sub.28H.sub.30N.sub.4O.sub.3 471 [m +
H].sup.+ 308-311 0.35 (B) (bv) --H ##STR00051##
C.sub.32H.sub.36N.sub.6O.sub.3 553 [m + H].sup.+ 279-283 0.60 (C)
(bw) --H ##STR00052## C.sub.29H.sub.33N.sub.5O.sub.4S 548 [m +
H].sup.+ 213-217 0.35 (B) (bx) --CH.sub.3 ##STR00053##
C.sub.29H.sub.32N.sub.4O.sub.3 485 [m + H].sup.+ 218-222 0.40 (A)
(by) --H ##STR00054## C.sub.29H.sub.31N.sub.5O.sub.3 498 [m +
H].sup.+ 130-134 0.35 (D) (bz) --H ##STR00055##
C.sub.27H.sub.28N.sub.4O.sub.2 441 [m + H].sup.+ 341-344 0.45 (D)
(ca) --H ##STR00056## C.sub.30H.sub.33N.sub.5O.sub.3 512 [m +
H].sup.+ 266-270 0.40 (D) (cb) --H ##STR00057##
C.sub.31H.sub.35N.sub.5O.sub.3 526 [m + H].sup.+ 198-202 0.40 (D)
(cc) --CH.sub.3 ##STR00058## C.sub.26H.sub.24N.sub.4O.sub.3 441 [m
+ H].sup.+ 290-295 0.25 (B) (cd) --CH.sub.3 ##STR00059##
C.sub.32H.sub.37N.sub.5O.sub.3 540 [m + H].sup.+ 120-126 0.40 (B)
(ce) --CH.sub.3 ##STR00060## C.sub.31H.sub.33N.sub.5O.sub.3 524 [m
+ H].sup.+ 100-105 0.50 (B) (cf) --H ##STR00061##
C.sub.30H.sub.31N.sub.5O.sub.3 510 [m + H].sup.+ 288-292 0.40 (A)
(cg) --CH.sub.3 ##STR00062## C.sub.32H.sub.35N.sub.5O.sub.3 538 [m
+ H].sup.+ 157-163 0.30 (B) (ch) --CH.sub.3 ##STR00063##
C.sub.32H.sub.37N.sub.5O.sub.3 540 [m + H].sup.+ 162-169 0.20 (B)
(ci) --CH.sub.2CH.sub.3 ##STR00064## C.sub.34H.sub.40N.sub.6O.sub.3
581 [m + H].sup.+ 195-198 0.50 (E) (cj) --CH.sub.3 ##STR00065##
C.sub.32H.sub.35N.sub.5O.sub.3 538 [m + H].sup.+ 238-242 0.35 (B)
(ck) --H ##STR00066## C.sub.31H.sub.33N.sub.5O.sub.3 524 [m +
H].sup.+ 127-130 0.50 (D) (cl) --H ##STR00067##
C.sub.31H.sub.35N.sub.5O.sub.3 526 [m + H].sup.+ 250-253 0.40 (D)
(cm) --H ##STR00068## C.sub.32H.sub.35N.sub.5O.sub.3 524 [m +
H].sup.+ 217-220 0.40 (D) (cn) --H ##STR00069##
C.sub.29H.sub.33N.sub.5O.sub.4S 560 [m - H].sup.- 171-175 0.45 (D)
*Solvents: (A): silica gel, methylene chloride/methanol 9:1 (B):
silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (C):
aluminum oxide, methylene chloride/methanol 9:1 (D): aluminum
oxide, methylene chloride/methanol 19:1 (E): Reversed Phase RP8,
acetonitrile/water/trifluoroacetic acid = 1:1:0.01
Examples (co) to (cq)
[0605] Preparation of the Starting Compounds:
(VI)
1-acetyl-3-(1-ethoxy-methylene)-6-methoxycarbonyl-2-indolinone
[0606] 8.00 g 1-acetyl-6-methoxycarbonyl-2-indolinone and 17.2 ml
triethyl orthoformate are dissolved in 70 ml of acetic anhydride
and stirred for 5.5 hrs at 110.degree. C. After cooling the residue
is filtered off, washed with ether and vacuum-dried at 100.degree.
C.
[0607] Yield: 8.80 g (89% of theory)
[0608] R.sub.f value: 0.35 (silica gel, petrol ether/methylene
chloride/ethylacetate=5:4:1)
[0609] Melting point: 187-189.degree. C.
[0610] C.sub.15H.sub.15NO.sub.5
[0611] Mass spectrum: m/z=290 [m+H].sup.+
[0612] Preparation of the Final Compounds:
[0613] The following compounds of general formula VI are prepared
analogously to the compounds described in WO 01/27081:
##STR00070##
TABLE-US-00005 Melting Mass point R.sub.f Example R.sup.6 Formula
spectrum [.degree. C.] value* (co) --NMe--(CO)--CH.sub.2--NMe.sub.2
C.sub.22H.sub.24N.sub.4O.sub.4 409 250-255 0.40 [m + H].sup.+ (A)
(cp) --CH.sub.2--NMe.sub.2 C.sub.20H.sub.21N.sub.3O.sub.3 352
234-238 035 [m + H].sup.+ (A) (cq) ##STR00071##
C.sub.25H.sub.29N.sub.5O.sub.4 464 [m + H].sup.+ 203-207 0.45 (A)
*Solvents: (A): silica gel, methylene chloride/methanol/ammonia
9:1:0.1
Examples (cr) to (cu)
[0614] Preparation of the Starting Compounds:
(VII) 3-(1-hydroxy-methylene)-6-carboxy-2-indolinone
[0615] 5.00 g
1-acetyl-3-(1-ethoxy-methylene)-6-methoxycarbonyl-2-indolinone
(starting material VI) are dissolved in 150 ml of methanol and 86.4
ml of 1N sodium hydroxide solution are added. The mixture is
refluxed for 8.5 hrs. After that time 86.4 ml of 1N hydrochloric
acid are added. The residue is filtered off and dried at 90.degree.
C.
[0616] Yield: 2.50 g (71% of theory)
[0617] C.sub.10H.sub.7NO.sub.4
[0618] Mass spectrum: m/z=206 [m+H].sup.+
[0619] (VIII) 3-(1-hydroxy-methylene)-6-ethylcarbamoyl-2-indolinone
400 mg 3-(1-hydroxy-methylene)-6-carboxy-2-indolinone (starting
material VII), 689 mg TBTU, 291 mg HOBt and 1.35 ml triethylamine
are dissolved in 20 ml of dimethylformamide. At 0.degree. C. 1.95
ml of a 2M ethylamine-solution in THF are added and the mixture is
stirred for additional 12 hrs at ambient temperature. After that
time the solvent is evaporated and the residue is purified over a
silica gel column with methylene chloride/ethanol/acetic acid
(5:1:0.01) as eluant.
[0620] Yield: 160 mg (35% of theory)
[0621] R.sub.f value: 0.20 (silica gel, methylene
chloride/ethanol/acetic acid=5:1:0.01)
[0622] Melting point: 146-150.degree. C.
[0623] C.sub.12H.sub.12N.sub.2O.sub.3
[0624] Mass spectrum: m/z=233 [m+H].sup.+
[0625] Preparation of the Final Compounds:
(cr)
3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-
-anilino)-methylene]-6-ethylcarbamoyl-2-indolinone
[0626] 160 mg 3-(1-hydroxy-methylene)-6-ethylcarbamoyl-2-indolinone
(starting material VIII) and 543 mg
N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylendiamine
are dissolved in 3 ml of tetrahydrofuran, 506 ml
trimethylsilylimidazole are added and the mixture is stirred for 25
minutes at 170.degree. C. in a microwave oven. After cooling the
solvent is evaporated and the residue is purified over an aluminum
oxide column (activity 2-3) with methylene chloride/ethanol (19:1)
as eluant. The residue is recrystallized from ether and
vacuum-dried at 80.degree. C.
[0627] Yield: 0.17 g (52% of theory),
[0628] R.sub.f value: 0.60 (aluminum oxide, methylene
chloride/methanol=9:1)
[0629] Melting point: 255-260.degree. C.
[0630] C.sub.26H.sub.32N.sub.6O.sub.3
[0631] Mass spectrum: m/z=477 [m+H].sup.+
[0632] The following compounds of general formula VII are prepared
analogously to the above compound (ct), following the procedures
described in WO 01/27081:
##STR00072##
TABLE-US-00006 Melting Mass point R.sub.f Example X R.sup.4 Formula
spectrum [.degree. C.] value* (cs) --H ##STR00073##
C.sub.23H.sub.27N.sub.5O.sub.3 422 [m + H].sup.+ 280-283 0.70 (A)
(ct) --H ##STR00074## C.sub.24H.sub.28N.sub.4O.sub.2 405 [m +
H].sup.+ 245-248 0.80 (A) (cu) --H ##STR00075##
C.sub.25H.sub.31N.sub.5O.sub.3 450 [m + H].sup.+ 130 0.40 (B)
*Solvents: (A): aluminum oxide, methylene chloride/methanol 9:1
(B): silica gel, methylene chloride/ethanol/ammonia 5:2:0.01
[0633] Tautomers, stereoisomers or physiologically acceptable salts
of these compounds are also contemplated within the scope of the
present invention, and may be obtained using the methods described
in WO 01/27081, the content of which is herein incorporated by
reference.
[0634] A particularly preferred compound is the
monoethanesulphonate salt of
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino-
)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone,
disclosed for example in WO 04/13099, the content of which is
incorporated herein by reference.
[0635] The metabolites of the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate and the prodrugs of this compound or of these metabolites
obtained via, for example, chemical or non-chemical derivatization
of the entire molecule or of one or more chemical groups on the
molecule, are also contemplated compounds within the meaning of the
present invention. In this matter, reference is made to WO
04/13099, which describes metabolites and prodrugs of the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulph-
onate.
[0636] The following list of specific compounds is illustrative of
the present invention, without constituting any limitation of its
scope: [0637] (1)
3-Z-(1-anilino-1-phenyl-methylene)-6-ethoxycarbonyl-2-indolinone
[0638] (2)
3-Z-[1-(4-nitro-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indol-
inone [0639] (3)
3-Z-[1-(4-fluoro-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolin-
one [0640] (4)
3-Z-[1-(4-chloro-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolin-
one [0641] (5)
3-Z-[1-(4-iodo-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0642] (6)
3-Z-[1-(4-cyano-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolino-
ne [0643] (7)
3-Z-[1-(4-methoxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolin-
one [0644] (8)
3-Z-[1-(4-ethoxy-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolino-
ne [0645] (9)
3-Z-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0646] (10)
3-Z-[1-(4-methyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolino-
ne [0647] (11)
3-Z-[1-(4-methylmercapto-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2--
indolinone [0648] (12)
3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-ind-
olinone [0649] (13)
3-Z-[1-(4-(isopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [0650] (14)
3-Z-[1-(4-(anilinomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0651] (15)
3-Z-[1-(4-(propylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbon-
yl-2-indolinone [0652] (16)
3-Z-[1-(4-(butylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbony-
l-2-indolinone [0653] (17)
3-Z-[1-(4-(isobutylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0654] (18)
3-Z-[1-(4-(cyclohexylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [0655] (19)
3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbon-
yl-2-indolinone [0656] (20)
3-Z-[1-(4-((N-ethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0657] (21)
3-Z-[1-(4-((N-methyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-
-6-ethoxycarbonyl-2-indolinone [0658] (22)
3-Z-[1-(4-((N-isopropyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0659] (23)
3-Z-[1-(4-((N-ethyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0660] (24)
3-Z-[1-(4-((N-ethyl-N-isopropyl-amino)-methyl)-anilino)-1-phenyl-methylen-
e]-6-ethoxycarbonyl-2-indolinone [0661] (25)
3-Z-[1-(4-(dipropylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0662] (26)
3-Z-[1-(4-(diisopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0663] (27)
3-Z-[1-(4-((N-benzyl-N-ethyl-amino)-methyl)-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0664] (28)
3-Z-[1-(4-(dibenzylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0665] (29)
3-Z-[1-(4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-anilino)-1-phenyl-methylen-
e]-6-ethoxycarbonyl-2-indolinone [0666] (30)
3-Z-[1-(4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylen-
e]-6-ethoxycarbonyl-2-indolinone [0667] (31)
3-Z-[1-(4-(azepan-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbo-
nyl-2-indolinone [0668] (32)
3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [0669] (33)
3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [0670] (34)
3-Z-[1-(4-(thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-etho-
xycarbonyl-2-indolinone [0671] (35)
3-Z-[1-(4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0672] (36)
3-Z-[1-(4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0673] (37)
3-Z-[1-(4-(acetylamino-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbo-
nyl-2-indolinone [0674] (38)
3-Z-[1-(4-(2-amino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0675] (39)
3-Z-[1-(4-(2-methylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0676] (40)
3-Z-[1-(4-(2-ethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbo-
nyl-2-indolinone [0677] (41)
3-Z-[1-(4-(2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [0678] (42)
3-Z-[1-(4-(2-piperidin-1-yl-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0679] (43)
3-Z-[1-(4-(2-acetylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0680] (44)
3-Z-[1-(4-(3-amino-propyl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl--
2-indolinone [0681] (45)
3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0682] (46)
3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methyl-
ene]-6-ethoxycarbonyl-2-indolinone [0683] (47)
3-Z-[1-(4-(N-methylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl--
methylene]-6-ethoxycarbonyl-2-indolinone [0684] (48)
3-Z-[1-(4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [0685] (49)
3-Z-[1-(4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-
-methylene]-6-ethoxycarbonyl-indolinone [0686] (50)
3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-indolinone [0687] (51)
3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0688] (52)
3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino]-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-indolinone [0689] (53)
3-Z-[1-(4-(N-(2-amino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [0690] (54)
3-Z-[1-(4-(N-(2-methylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phe-
nyl-methylene]-6-ethoxycarbonyl-indolinone [0691] (55)
3-Z-[1-(4-(N-(2-diethylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-ph-
enyl-methylene]-6-ethoxycarbonyl-indolinone [0692] (56)
3-Z-[1-(4-(N-acetyl-N-(2-aminoethyl)-amino)-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0693] (57)
3-Z-[1-(4-(N-acetyl-N-(2-methylamino-ethyl)-amino)-anilino)-1-phenyl-meth-
ylene]-6-ethoxycarbonyl-2-indolinone [0694] (58)
3-Z-[1-(4-(N-acetyl-N-(2-methylamino-propyl)-amino)-anilino)-1-phenyl-met-
hylene]-6-ethoxycarbonyl-2-indolinone [0695] (59)
3-Z-[1-(4-(N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [0696] (60)
3-Z-[1-(4-(N-acetyl-N-(aminocarbonylmethyl)-amino)-anilino)-1-phenyl-meth-
ylene]-6-ethoxycarbonyl-2-indolinone [0697] (61)
3-Z-[1-(4-(N-acetyl-N-(dimethylaminocarbonylmethyl)-amino)-anilino)-1-phe-
nyl-methylene]-6-ethoxycarbonyl-indolinone [0698] (62)
3-Z-[1-(4-(N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-indolinone [0699] (63)
3-Z-[1-(4-(N-methyl-N-(aminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-
-6-ethoxycarbonyl-2-indolinone [0700] (64)
3-Z-[1-(4-(N-methyl-N-(methylaminocarbonyl)-amino)-anilino)-1-phenyl-meth-
ylene]-6-ethoxycarbonyl-2-indolinone [0701] (65)
3-Z-[1-(4-(N-methyl-N-(dimethylaminocarbonyl)-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [0702] (66)
3-Z-[1-(4-(N-methyl-N-(piperidin-1-yl-carbonyl)-amino)-anilino)-1-phenyl--
methylene]-6-ethoxycarbonyl-2-indolinone [0703] (67)
3-Z-[1-(4-(N-(2-aminoethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [0704] (68)
3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-ph-
enyl-methylene]-6-ethoxycarbonyl-2-indolinone [0705] (69)
3-Z-[1-(4-(N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phe-
nyl-methylene]-6-ethoxycarbonyl-2-indolinone [0706] (70)
3-Z-[1-(4-(N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0707] (71)
3-Z-[1-(4-(N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0708] (72)
3-Z-[1-(4-(N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0709] (73)
3-Z-[1-(4-(N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0710] (74)
3-Z-[1-(4-(N-(2-(morpholin-4-yl)-ethyl)-N-methylsulphonyl-amino)-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0711] (75)
3-Z-[1-(4-(N-(aminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-1-ph-
enyl-methylene]-6-ethoxycarbonyl-2-indolinone [0712] (76)
3-Z-[1-(4-(N-(methylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino-
)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0713] (77)
3-Z-[1-(4-(N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0714] (78)
3-Z-[1-(4-(N--(N-(2-dimethylamino-ethyl)-N-methyl-amino)-carbonylmethyl)--
N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-i-
ndolinone [0715] (79)
3-Z-[1-(4-(N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0716] (80)
3-Z-[1-(4-(N-(pyrrolidin-1-yl-carbonylmethyl)-N-m
sulphonyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolino-
ne [0717] (81)
3-Z-[1-(4-(N-(piperidin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino)-ani-
lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0718] (82)
3-Z-[1-(4-(N-(piperazin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino)-ani-
lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0719] (83)
3-Z-[1-(4-(N-((morpholin-4-yl)-carbonylmethyl)-N-methylsulphonyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0720]
(84)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0721] (85)
3-Z-[1-(4-(3-dimethylamino-propoxy)-anilino)-1-phenyl-methylene]-6-ethoxy-
carbonyl-2-indolinone [0722] (86)
3-Z-[1-(4-(aminocarbonylmethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0723] (87)
3-Z-[1-(4-(2-aminocarbonyl-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [0724] (88)
3-Z-[1-(4-(pyridin-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2--
indolinone [0725] (89)
3-Z-[1-(4-(pyridine-3-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0726] (90)
3-Z-[1-(4-(pyridin-4-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2--
indolinone [0727] (91)
3-Z-[1-(4-(N-acetyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxy-
carbonyl-2-indolinone [0728] (92)
3-Z-[1-(4-(N-ethylcarbonyl-N-(dimethylaminocarbonyl-methyl)-amino)-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0729] (93)
3-Z-[1-(carbamoylmethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-i-
ndolinone [0730] (94)
3-Z-[1-(4-dimethylcarbamoylmethyl-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [0731] (95)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethoxycarbonyl-2--
indolinone [0732] (96)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-propylidene]-6-ethoxycarbonyl--
2-indolinone [0733] (97)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-butylidene]-6-ethoxycarbonyl-2-
-indolinone [0734] (98)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-
-6-ethoxycarbonyl-2-indolinone [0735] (99)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-ethylidene-
]-6-ethoxycarbonyl-2-indolinone [0736] (100)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-propyliden-
e]-6-ethoxycarbonyl-2-indolinone [0737] (101)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-butylidene-
]-6-ethoxycarbonyl-2-indolinone [0738] (102)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-me-
thylene]-6-ethoxycarbonyl-2-indolinone [0739] (103)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-pr-
opylidene]-6-ethoxycarbonyl-2-indolinone [0740] (104)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-bu-
tylidene]-6-ethoxycarbonyl-2-indolinone [0741] (105)
3-Z-[1-(4-tetrazol-5-yl-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone
[0742] (106)
3-Z-[1-(4-tetrazol-5-yl-anilino)-ethylidene]-6-ethoxy-carbonyl-2-indolino-
ne [0743] (107)
3-Z-[1-(4-tetrazol-5-yl-anilino)-propylidene]-6-ethoxycarbonyl-2-indolino-
ne [0744] (108)
3-Z-[1-(4-tetrazol-5-yl-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinon-
e [0745] (109)
3-Z-[1-(4-carboxy-anilino)-methylene]-6-ethoxycarbonyl-2-indolinone
[0746] (110)
3-Z-[1-(4-carboxy-anilino)-propylidene]-6-ethoxycarbonyl-2-indolinone
[0747] (111)
3-Z-[1-(4-carboxy-anilino)-butylidene]-6-ethoxycarbonyl-2-indolinone
[0748] (112)
3-Z-[1-(4-(N-(3-dimethylamino-propionyl)-N-dimethylaminocarbonylmethyl-am-
ino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0749] (113)
3-Z-[1-(4-(N-(4-dimethylamino-butyryl)-N-dimethylaminocarbonylmethy-
l-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0750] (114)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(2-dimethylamino-ethylsu-
lphonyl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0751] (115)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(3-dimethylamino-propylsulphon-
yl)-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0752] (116)
3-Z-[1-(4-((2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-
-ethoxycarbonyl-2-indolinone [0753] (117)
3-Z-[1-(4-((2-methoxy-ethyl)-amino-methyl)-anilino-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [0754] (118)
3-Z-[1-(4-((2-dimethylamino-ethyl)-amino-methyl)
anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0755]
(119)
3-Z-[1-(4-((3-dimethylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methy-
lene]-6-ethoxycarbonyl-2-indolinone [0756] (120)
3-Z-[1-(4-((N-tert.butoxycarbonyl-2-amino-ethyl)-amino-methyl)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0757] (121)
3-Z-[1-(4-((N-tert.butoxycarbonyl-3-amino-propyl)-amino-methyl)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0758] (122)
3-Z-[1-(4-((2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-e-
thoxycarbonyl-2-indolinone [0759] (123)
3-Z-[1-(4-((3-amino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [0760] (124)
3-Z-[1-(4-((2-acetylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylen-
e]-6-ethoxycarbonyl-2-indolinone [0761] (125)
3-Z-[1-(4-((3-acetylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0762] (126)
3-Z-[1-(4-((2-methylsulphonylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-
-methylene]-6-ethoxycarbonyl-indolinone [0763] (127)
3-Z-[1-(4-((3-methylsulphonylamino-propyl)-amino-methyl)-anilino)-1-pheny-
l-methylene]-6-ethoxycarbonyl-indolinone [0764] (128)
3-Z-[l-(4-(N--(N-tert.butoxycarbonyl-2-amino-ethyl)-N-methyl-amino-methyl-
)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0765]
(129)
3-Z-[1-(4-(N-(2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-met-
hylene]-6-ethoxycarbonyl-2-indolinone [0766] (130)
3-Z-[1-(4-(N-(2-acetylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phen-
yl-methylene]-6-ethoxycarbonyl-indolinone
[0767] (131)
3-Z-[1-(4-(N-(2-methylsulphonylamino-ethyl)-N-methyl)-amino-methyl)-anili-
no)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0768] (132)
3-Z-[1-(4-(carboxymethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-eth-
oxycarbonyl-2-indolinone [0769] (133)
3-Z-[1-(4-(ethoxycarbonylmethyl-amino-methyl)-anilino)-1-phenyl-methylene-
]-6-ethoxycarbonyl-2-indolinone [0770] (134)
3-Z-[1-(4-(carbamoylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-e-
thoxycarbonyl-2-indolinone [0771] (135)
3-Z-[1-(4-(dimethylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methy-
lene]-6-ethoxycarbonyl-2-indolinone [0772] (136)
3-Z-[1-(4-(methylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0773] (137)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-amino-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0774] (138)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-nitro-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0775] (139)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-acetylamino-an-
ilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0776]
(140)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methylsulphony-
lamino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0777] (141)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-cyano-an-
ilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0778]
(142)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-hydroxy-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0779] (143)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methoxy-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0780] (144)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-ethoxycarbonyl-
-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0781]
(145)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carboxy-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0782] (146)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carbamoyl-anil-
ino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0783] (147)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-chloro-anilino-
)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0784] (148)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-fluoro-anilino-
)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0785] (149)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-bromo-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0786] (150)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-met
amino)-3-methyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinon-
e [0787] (151)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-trifluoromethy-
l-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0788]
(152)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dibromo-anil-
ino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0789] (153)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dichloro-ani-
lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0790]
(154)
3-Z-[1-(4-(dimethylaminomethyl)-3-amino-anilino)-1-phenyl-methylene]-6-et-
hoxycarbonyl-2-indolinone [0791] (155)
3-Z-[1-(4-(dimethylaminomethyl)-3-nitro-anilino)-1-phenyl-methylene]-6-et-
hoxycarbonyl-2-indolinone [0792] (156)
3-Z-[1-(4-(dimethylaminomethyl)-3-acetylamino-anilino)-1-phenyl-methylene-
]-6-ethoxycarbonyl-2-indolinone [0793] (157)
3-Z-[1-(4-(dimethylaminomethyl)-3-(methylsulphonylamino)-anilino)-1-pheny-
l-methylene]-6-ethoxycarbonyl-2-indolinone [0794] (158)
3-Z-[1-(4-(dimethylaminomethyl)-3-cyano-anilino)-1-phenyl-methylene]-6-et-
hoxycarbonyl-2-indolinone [0795] (159)
3-Z-[1-(4-(dimethylaminomethyl)-3-hydroxy-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [0796] (160)
3-Z-[1-(4-(dimethylaminomethyl)-3-methoxy-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [0797] (161)
3-Z-[1-(4-(dimethylaminomethyl)-3-(ethoxycarbonyl)-anilino)-1-phenyl-meth-
ylene]-6-ethoxycarbonyl-2-indolinone [0798] (162)
3-Z-[1-(4-(dimethylaminomethyl)-3-carboxy-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [0799] (163)
3-Z-[1-(4-(dimethylaminomethyl)-3-carbamoyl-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0800] (164)
3-Z-[1-(4-(dimethylaminomethyl)-3-chloro-anilino)-1-phenyl-methylene]-6-e-
thoxycarbonyl-2-indolinone [0801] (165)
3-Z-[1-(4-(dimethylaminomethyl)-3-fluoro-anilino)-1-phenyl-methylene]-6-e-
thoxycarbonyl-2-indolinone [0802] (166)
3-Z-[1-(4-(dimethylaminomethyl)-3-bromo-anilino)-1-phenyl-methylene]-6-et-
hoxycarbonyl-2-indolinone [0803] (167)
3-Z-[1-(4-(dimethylaminomethyl)-3-methyl-anilino)-1-phenyl-methylene]-6-e-
thoxycarbonyl-2-indolinone [0804] (168)
3-Z-[1-(4-(dimethylaminomethyl)-3-trifluoromethyl-anilino)-1-phenyl-methy-
lene]-6-ethoxycarbonyl-2-indolinone [0805] (169)
3-Z-[1-(4-(dimethylaminomethyl)-3,5-dibromo-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0806] (170)
3-Z-[1-(4-(dimethylaminomethyl)-3,5-dichloro-anilino)-1-phenyl-methylene]-
-6-ethoxycarbonyl-2-indolinone [0807] (171)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0808]
(172)
3-Z-[1-(4-(N-(imidazo-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phe-
nyl-methylene]-6-ethoxycarbonyl-2-indolinone [0809] (173)
3-Z-[1-(4-(N-(phthalimido-2-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0810] (174)
3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methyl-
ene]-6-ethoxycarbonyl-2-indolinone [0811] (175)
3-Z-[1-(4-(N-acetylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl--
methylene]-6-ethoxycarbonyl-2-indolinone [0812] (176)
3-Z-[1-(4-(N-methylsulphonylaminomethylcarbonyl-N-methyl-amino)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0813] (177)
3-Z-[1-(4-(N--((N-(2-methoxyethyl)-N-methyl-amino)-methylcarbonyl)-N-meth-
yl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0814] (178)
3-Z-[1-(4-(N--((N-(2-dimethylaminoethyl)-N-methyl-amino)-methylcarbonyl)--
N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0815] (179)
3-Z-[1-(4-(N-((di-(2-hydroxyethyl)-amino)-methylcarbonyl)-N-methyl-amino)-
-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0816]
(180)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0817] (181)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-ethylid-
ene]-6-ethoxycarbonyl-2-indolinone [0818] (182)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-propyli-
dene]-6-ethoxycarbonyl-2-indolinone [0819] (183)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-butylid-
ene]-6-ethoxycarbonyl-2-indolinone [0820] (184)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-methylene]-6-ethoxycarbonyl-2-in-
dolinone [0821] (185)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-ethylidene]-6-ethoxycarbonyl-2-i-
ndolinone [0822] (186)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-propylidene]-6-ethoxycarbonyl-2--
indolinone [0823] (187)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-butylidene]-6-ethoxycarbonyl-2-i-
ndolinone [0824] (188)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0825] (189)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [0826] (190)
3-Z-[1-(4-((imidazolidin-2,4-dion-5-ylidene)-methyl)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [0827] (191)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0828] (192)
3-Z-[1-(4-(N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene-
]-6-ethoxycarbonyl-2-indolinone [0829] (193)
3-Z-[1-(4-(2-oxo-pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-e-
thoxycarbonyl-2-indolinone [0830] (194)
3-Z-[1-(4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phen-
yl-methylene]-6-ethoxycarbonyl-2-indolinone [0831] (195)
3-Z-[1-(4-(N-cyanomethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methy-
lene]-6-ethoxycarbonyl-2-indolinone [0832] (196)
3-Z-[1-(4-(2-(imidazol-4-yl)-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxy-
carbonyl-2-indolinone [0833] (197)
3-Z-[1-(4-((2-(N-benzyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0834]
(198)
3-Z-[1-(4-cyclohexylamino-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0835] (199)
3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [0836] (200)
3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [0837] (201)
3-Z-[1-(N-methyl-piperidine-4-yl-amino)-1-phenyl-methylene]-6-ethoxycarbo-
nyl-2-indolinone [0838] (202)
3-Z-[1-(4-(imidazol-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [0839] (203)
3-Z-[1-(4-((4-hydroxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene-
]-6-ethoxycarbonyl-2-indolinone [0840] (204)
3-Z-[1-(4-((4-methoxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene-
]-6-ethoxycarbonyl-2-indolinone [0841] (205)
3-Z-[1-(4-benzyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolino-
ne [0842] (206)
3-Z-[1-(4-(N-(3-trifluoroacetylamino-propyl)-N-methylsulphonyl-amino)-ani-
lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0843]
(207)
3-Z-[1-(4-(4-tert.butoxycarbonyl-piperazin-1-yl-methyl)-anilino)-1-phenyl-
-methylene]-6-ethoxycarbonyl-2-indolinone [0844] (208)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0845] (209)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0846] (210)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-amino-ani-
lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0847]
(211)
3-Z-[1-(4-((3-(N-benzyl-N-methyl-amino)-propyl)-N-methylsulphonyl-amino)--
anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0848]
(212)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [0849] (213)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butyryl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [0850] (214)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isobutyryl-amino)-anilino)-1-pheny-
l-methylene]-6-ethoxycarbonyl-2-indolinone [0851] (215)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [0852] (216)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-amino-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0853] (217)
3-Z-[1-(4-(4-hydroxymethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methy-
lene]-6-ethoxycarbonyl-2-indolinone [0854] (218)
3-Z-[1-(4-(2-(4-hydroxy-piperidin-1-yl)-ethyl)-anilino)-1-phenyl-methylen-
e]-6-ethoxycarbonyl-2-indolinone [0855] (219)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0856] (220)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0857] (221)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0858] (222)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0859] (223)
3-Z-[1-(4-((imidazolidin-2,4-dion-5-yl)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0860] (224)
3-Z-[1-(4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-anilino)-1-phenyl-methylen-
e]-6-ethoxycarbonyl-2-indolinone [0861] (225)
3-Z-[1-(4-(cyclohexylyl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0862] (226)
3-Z-[1-(4-(cyclohexyl-carbonyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [0863] (227)
3-Z-[1-(4-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbony-
l-2-indolinone [0864] (228)
3-Z-[1-(4-(N-(n-hexyl)-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-
-6-ethoxycarbonyl-2-indolinone [0865] (229)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino)-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0866] (230)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-anilino-
)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0867] (231)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(pyridine-3-carbonyl)-amino)-anili-
no)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0868] (232)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(phenyl-acetyl)-amino)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0869] (233)
3-Z-[1-(4-(imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0870] (234)
3-Z-[1-(4-(1-ethyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [0871] (235)
3-Z-[1-(4-(1-benzyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0872] (236)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-amino)-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0873] (237)
3-Z-[1-(4-(N-((4-benzyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0874]
(238)
3-Z-[1-(4-(N-(pyrrolidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0875] (239)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-bromo-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0876] (240)
3-Z-[1-(4-(5-methyl-imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [0877] (241)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-isopropyl-amino)-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0878] (242)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-benzyl-amino)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0879] (243)
3-Z-[1-(4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [0880] (244)
3-Z-[1-(4-(N--((N-aminocarbonylmethyl-N-methyl-amino)-methylcarbonyl)-N-m-
ethyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0881] (245)
3-Z-[1-(4-(N--((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)--
anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0882]
(246)
3-Z-[1-(4-(N-(di-(2-methoxyethyl)-amino-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0883]
(247)
3-Z-[1-(4-(N-((2-(4-tert.butoxycarbonyl-piperazin-1-yl)-ethyl)-carbonyl)--
N-methyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0884] (248)
3-Z-[1-(4-(N-((2-(piperidin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0885] (249)
3-Z-[1-(4-(N-((2-(N-benzyl-N-methyl-amino)-ethyl)-carbonyl)-N-methyl-amin-
o)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0886] (250)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-isopropyl-amino)-anilino)-1-ph-
enyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0887] (251)
3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0888] (252)
3-Z-[1-(4-(N-((4-tert.butoxycarbonyl-piperazin-1-yl)-methylcarbonyl)-N-is-
opropyl-amino)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone
[0889] (253)
3-Z-[1-(4-(N--((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-benzyl-amino)--
anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0890]
(254)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-benzyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethoxycarbonyl-2-indolinone [0891] (255)
3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-benzyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0892] (256)
3-Z-[1-(4-(1,2,4-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-etho-
xycarbonyl-2-indolinone [0893] (257)
3-Z-[1-(4-(1,2,3-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-etho-
xycarbonyl-2-indolinone [0894] (258)
3-Z-[1-(4-(1,2,3-triazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-etho-
xycarbonyl-2-indolinone [0895] (259)
3-Z-[1-(4-((N-aminocarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phen-
yl-methylene]-6-ethoxycarbonyl-2-indolinone [0896] (260)
3-Z-[1-(4-((di-(2-methoxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0897] (261)
3-Z-[1-(4-((di-(2-hydroxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-ethoxycarbonyl-2-indolinone [0898] (262)
3-Z-[1-(4-((N-ethoxycarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phe-
nyl-methylene]-6-ethoxycarbonyl-2-indolinone [0899] (263)
3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [0900] (264)
3-Z-[1-(4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl--
methylene]-6-ethoxycarbonyl-2-indolinone [0901] (265)
3-Z-[1-(4-((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0902] (266)
3-Z-[1-(4-((N-(tert.butoxycarbonyl-3-amino-propyl)-N-methyl-amino)-methyl-
)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0903]
(267)
3-Z-[1-(4-((N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0904] (268)
3-Z-[1-(4-((N-(dimethylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-
-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0905] (269)
3-Z-[1-(4-((N-propyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-
-6-ethoxycarbonyl-2-indolinone [0906] (270)
3-Z-[1-(4-((N-(2-dimethylamino-ethyl)-N-methyl-amino)-methyl)-anilino)-1--
phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0907] (271)
3-Z-[1-(4-((N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0908] (272)
3-Z-[1-(4-((N-(2-methoxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-
-methylene]-6-ethoxycarbonyl-2-indolinone [0909] (273)
3-Z-[1-(4-((N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-
-methylene]-6-ethoxycarbonyl-2-indolinone [0910] (274)
3-Z-[1-(4-((N-(dioxolan-2-yl-methyl)-N-methyl-amino)-methyl)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0911] (275)
3-Z-[1-(4-(3-oxo-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-et-
hoxycarbonyl-2-indolinone [0912] (276)
3-Z-[l-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)--
1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0913] (277)
3-Z-[1-(4-(N-((2-(piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilin-
o)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0914] (278)
3-Z-[1-(4-((N-(3-amino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl--
methylene]-6-ethoxycarbonyl-2-indolinone [0915] (279)
3-Z-[1-(4-(N-(3-methylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0916] (280)
3-Z-[1-(4-Ureidomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-in-
dolinone [0917] (281)
3-Z-[1-(4-guanidinomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [0918] (282)
3-Z-[1-(4-(N-methylsulphonyl-aminomethyl)-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [0919] (283)
3-Z-[1-(4-(4-benzoyl-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]--
6-ethoxycarbonyl-2-indolinone [0920] (284)
3-Z-[1-(4-((N-(3-acetylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [0921] (285)
3-Z-[1-(4-((N-(3-methylsulphonylamino-propyl)-N-methyl-amino)-methyl)-ani-
lino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [0922]
(286)
3-Z-[1-(4-((N-carboxymethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-met-
hylene]-6-ethoxycarbonyl-2-indolinone [0923] (287)
3-Z-(1-anilino-1-phenyl-methylene)-6-methoxycarbonyl-2-indolinone
[0924] (288)
3-Z-[1-(4-nitro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-in-
dolinone [0925] (289)
3-Z-[1-(4-fluoro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolin-
one [0926] (290)
3-Z-[1-(4-chloro-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolin-
one [0927] (291)
3-Z-[1-(4-bromo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolino-
ne [0928] (292)
3-Z-[1-(4-iodo-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinon-
e [0929] (293)
3-Z-[1-(4-cyano-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolino-
ne [0930] (294)
3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indoli-
none [0931] (295)
3-Z-[1-(4-methoxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indoli-
none [0932] (296)
3-Z-[1-(4-ethoxy-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolin-
one [0933] (297)
3-Z-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [0934] (298)
3-Z-[1-(4-methylmercapto-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-
-indolinone [0935] (299)
3-Z-[1-(4-(isopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [0936] (300)
3-Z-[1-(4-(anilinomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [0937] (301)
3-Z-[1-(4-(isobutylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [0938] (302)
3-Z-[1-(4-(cyclohexylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [0939] (303)
3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbo-
nyl-2-indolinone [0940] (304)
3-Z-[1-(4-((N-methyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [0941] (305)
3-Z-[1-(4-((N-isopropyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [0942] (306)
3-Z-[1-(4-((N-ethyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]--
6-methoxycarbonyl-2-indolinone [0943] (307)
3-Z-[1-(4-((N-ethyl-N-isopropyl-amino)-methyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [0944] (308)
3-Z-[1-(4-(dipropylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [0945] (309)
3-Z-[1-(4-(diisopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [0946] (310)
3-Z-[1-(4-((N-benzyl-N-ethyl-amino)-methyl)-anilino)-1-phenyl-methylene]--
6-methoxycarbonyl-2-indolinone [0947] (311)
3-Z-[1-(4-(dibenzylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [0948] (312)
3-Z-[1-(4-(3,6-dihydro-2H-pyridin-1-yl-methyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [0949] (313)
3-Z-[1-(4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [0950] (314)
3-Z-[1-(4-(azepan-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycarb-
onyl-2-indolinone [0951] (315)
3-Z-[1-(4-(2-amino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [0952] (316)
3-Z-[1-(4-(2-methylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [0953] (317)
3-Z-[1-(4-(2-ethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycarb-
onyl-2-indolinone [0954] (318)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [0955] (319)
3-Z-[1-(4-(2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [0956] (320)
3-Z-[1-(4-(2-piperidin-1-yl-ethyl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [0957] (321)
3-Z-[1-(4-(2-acetylamino-ethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [0958] (322)
3-Z-[1-(4-(3-amino-propyl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-
-2-indolinone [0959] (323)
3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [0960] (324)
3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [0961] (325)
3-Z-[1-(4-(N-ethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [0962] (326)
3-Z-[1-(4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-2-indolinone [0963] (327)
3-Z-[1-(4-(N-dipropylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-indolinone [0964] (328)
3-Z-[1-(4-(N--((N-ethyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0965]
(329)
3-Z-[1-(4-(N--((N-ethyl-N-propyl-amino)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0966]
(330)
3-Z-[1-(4-(N--((N-methyl-N-propyl-amino)-methylcarbonyl)-N-methyl-amino)--
anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0967]
(331)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-ethyl-amino)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-2-indolinone [0968] (332)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-propyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-indolinone [0969] (333)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-butyl-amino)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-2-indolinone [0970] (334)
3-Z-[1-(4-(N-(2-amino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [0971] (335)
3-Z-[1-(4-(N-(2-diethylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-ph-
enyl-methylene]-6-methoxycarbonyl-indolinone [0972] (336)
3-Z-[1-(4-(N-acetyl-N-(2-aminoethyl)-amino)-anilino)-1-phenyl-methylene]--
6-methoxycarbonyl-2-indolinone [0973] (337)
3-Z-[1-(4-(N-acetyl-N-(2-methylamino-ethyl)-amino)-anilino)-1-phenyl-meth-
ylene]-6-methoxycarbonyl-2-indolinone [0974] (338)
3-Z-[1-(4-(N-acetyl-N-(3-methylamino-propyl)-amino)-anilino)-1-phenyl-met-
hylene]-6-methoxycarbonyl-2-indolinone [0975] (339)
3-Z-[1-(4-(N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [0976] (340)
3-Z-[1-(4-(N-acetyl-N-(aminocarbonylmethyl)-amino)-anilino)-1-phenyl-meth-
ylene]-6-methoxycarbonyl-2-indolinone [0977] (341)
3-Z-[l-(4-(N-acetyl-N-(piperidin-1-yl-carbonylmethyl)-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-indolinone [0978] (342)
3-Z-[1-(4-(N-methyl-N-(aminocarbonyl)-amino)-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [0979] (343)
3-Z-[1-(4-(N-methyl-N-(methylaminocarbonyl)-amino)-anilino)-1-phenyl-meth-
ylene]-6-methoxycarbonyl-2-indolinone [0980] (344)
3-Z-[1-(4-(N-methyl-N-(dimethylaminocarbonyl)-amino)-anilino)-1-phenyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [0981] (345)
3-Z-[1-(4-(N-methyl-N-(piperidin-1-yl-carbonyl)-amino)-anilino)-1-phenyl--
methylene]-6-methoxycarbonyl-2-indolinone [0982] (346)
3-Z-[1-(4-(N-(2-ethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phe-
nyl-methylene]-6-methoxycarbonyl-2-indolinone [0983] (347)
3-Z-[1-(4-(N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [0984] (348)
3-Z-[1-(4-(N-(2-pyrrolidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0985] (349)
3-Z-[1-(4-(N-(2-piperidin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0986] (350)
3-Z-[1-(4-(N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0987] (351)
3-Z-[1-(4-(N-(2-(4-morpholin-1-yl)-ethyl)-N-methylsulphonyl-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0988] (352)
3-Z-[1-(4-(N-(ethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0989] (353)
3-Z-[1-(4-(N-(diethylaminocarbonylmethyl)-N-methylsulphonyl-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0990] (354)
3-Z-[1-(4-(N-(pyrrolidin-1-yl-carbonylmethyl)-N-methylsulphonyl-amino)-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0991]
(355)
3-Z-[1-(4-(N-(piperidin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino)-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0992]
(356)
3-Z-[1-(4-(N-(piperazin-1-yl-carbonylmethyl)-N-methyl-sulphonyl-amino)-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0993]
(357)
3-Z-[1-(4-(N-((morpholin-4-yl)-carbonylmethyl)-N-methylsulphonyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [0994]
(358)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [0995] (359)
3-Z-[1-(4-(3-dimethylamino-propoxy)-anilino)-1-phenyl-methylene]-6-methox-
ycarbonyl-2-indolinone [0996] (360)
3-Z-[1-(4-(aminocarbonylmethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [0997] (361)
3-Z-[1-(4-(2-aminocarbonyl-ethyl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [0998] (362)
3-Z-[1-(4-(pyridin-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-
-indolinone [0999] (363)
3-Z-[1-(4-(pyridine-3-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [1000] (364)
3-Z-[1-(4((N-phenethyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [1001] (365)
3-Z-[1-(4-(N-acetyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methox-
ycarbonyl-2-indolinone [1002] (366)
3-Z-[1-(4-(N-ethylcarbonyl-N-(dimethylaminocarbonyl-methyl)-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1003] (367)
3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [1004] (368)
3-Z-[1-(4-carboxymethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2--
indolinone [1005] (369)
3-Z-[1-(4-carbamoylmethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [1006] (370)
3-Z-[1-(4-dimethylcarbamoylmethyl-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [1007] (371)
3-Z-[1-(4-tetrazol-5-yl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2--
indolinone [1008] (372)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-methoxycarbonyl-2-
-indolinone [1009] (373)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-ethylidene]-6-methoxycarbonyl--
2-indolinone [1010] (374)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-propylidene]-6-methoxycarbonyl-
-2-indolinone [1011] (375)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-butylidene]-6-methoxycarbonyl--
2-indolinone [1012] (376)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-
-6-methoxycarbonyl-2-indolinone [1013] (377)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-ethylidene-
]-6-methoxycarbonyl-2-indolinone
[1014] (378)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-propyliden-
e]-6-methoxycarbonyl-2-indolinone [1015] (379)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-butylidene-
]-6-methoxycarbonyl-2-indolinone [1016] (380)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-me-
thylene]-6-methoxycarbonyl-2-indolinone [1017] (381)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-et-
hylidene]-6-methoxycarbonyl-2-indolinone [1018] (382)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-pr-
opylidene]-6-methoxycarbonyl-2-indolinone [1019] (383)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-bu-
tylidene]-6-methoxycarbonyl-2-indolinone [1020] (384)
3-Z-[1-(4-tetrazol-5-yl-anilino)-methylene]-6-methoxycarbonyl-2-indolinon-
e [1021] (385)
3-Z-[1-(4-tetrazol-5-yl-anilino)-ethylidene]-6-methoxycarbonyl-2-indolino-
ne [1022] (386)
3-Z-[1-(4-tetrazol-5-yl-anilino)-propylidene]-6-methoxycarbonyl-2-indolin-
one [1023] (387)
3-Z-[1-(4-tetrazol-5-yl-anilino)-butylidene]-6-methoxycarbonyl-2-indolino-
ne [1024] (388)
3-Z-[1-(4-carboxy-anilino)-methylene]-6-methoxycarbonyl-2-indolinone
[1025] (389)
3-Z-[1-(4-carboxy-anilino)-ethylidene]-6-methoxycarbonyl-2-indolinone
[1026] (390)
3-Z-[1-(4-carboxy-anilino)-propylidene]-6-methoxycarbonyl-2-indolinone
[1027] (391)
3-Z-[1-(4-carboxy-anilino)-butylidene]-6-methoxycarbonyl-2-indolinone
[1028] (392)
3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-anilino)-1-methyl-methylene]-6--
methoxycarbonyl-2-indolinone [1029] (393)
3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-anilino)-1-meth-
yl-methylene]-6-methoxycarbonyl indolinone [1030] (394)
3-Z-[1-(4-((benzo(1,3)dioxol-5-yl-methyl)-methyl-amino-methyl)-anilino)-1-
-methyl-methylene]-6-methoxycarbonyl-2-indolinone [1031] (395)
3-Z-[1-(4-(N-phenethyl-N-methyl-aminomethyl)-anilino)-1-methyl-methylene]-
-6-methoxycarbonyl-2-indolinone [1032] (396)
3-Z-[1-(4-(N-(3,4-dimethoxy-benzyl)-N-methyl-amino-methyl)-anilino)-1-met-
hyl-methylene]-6-methoxycarbonyl indolinone [1033] (397)
3-Z-[1-(4-(N-(4-chloro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1034] (398)
3-Z-[1-(4-(N-(4-methylbenzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [1035] (399)
3-Z-[1-(4-(N-(4-fluoro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1036] (400)
3-Z-[1-(4-(N-(4-bromo-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [1037] (401)
3-Z-[1-(4-(N-(3-dimethylamino-propionyl)-N-dimethylaminocarbonylmethyl-am-
ino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1038] (402)
3-Z-[1-(4-(N-(4-dimethylamino-butyryl)-N-dimethylaminocarbonylmethy-
l-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1039] (403)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(2-dimethylamino-ethylsulphony-
l)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1040] (404)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-(3-dimethylamino-propylsulphon-
yl)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1041] (405)
3-Z-[1-(4-((2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-
-methoxycarbonyl-2-indolinone [1042] (406)
3-Z-[1-(4-((2-methoxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-
-methoxycarbonyl-2-indolinone [1043] (407)
3-Z-[1-(4-((2-dimethylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [1044] (408)
3-Z-[1-(4-((3-dimethylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methy-
lene]-6-methoxycarbonyl-2-indolinone [1045] (409)
3-Z-[1-(4-((N-tert.butoxycarbonyl-2-amino-ethyl)-amino-methyl)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1046] (410)
3-Z-[1-(4-((N-tert.butoxycarbonyl-3-amino-propyl)-amino-methyl)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1047] (411)
3-Z-[1-(4-((2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1048] (412)
3-Z-[1-(4-((3-amino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6--
methoxycarbonyl-2-indolinone [1049] (413)
3-Z-[1-(4-((2-acetylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [1050] (414)
3-Z-[1-(4-((3-acetylamino-propyl)-amino-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1051] (415)
3-Z-[1-(4-((2-methylsulphonylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl indolinone [1052] (416)
3-Z-[1-(4-((3-methylsulphonylamino-propyl)-amino-methyl)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl indolinone [1053] (417)
3-Z-[1-(4-(N--(N-tert.butoxycarbonyl-2-amino-ethyl)-N-methyl-amino-methyl-
)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1054] (418)
3-Z-[1-(4-(N-(2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-met-
hylene]-6-methoxycarbonyl-2-indolinone [1055] (419)
3-Z-[1-(4-(N-(2-acetylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phen-
yl-methylene]-6-methoxycarbonyl indolinone [1056] (420)
3-Z-[1-(4-(N-(2-methylsulphonylamino-ethyl)-N-methyl-amino-methyl)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1057] (421)
3-Z-[1-(4-(carboxymethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-met-
hoxycarbonyl-2-indolinone [1058] (422)
3-Z-[1-(4-(ethoxycarbonylmethyl-amino-methyl)-anilino)-1-phenyl-methylene-
]-6-methoxycarbonyl-2-indolinone [1059] (423)
3-Z-[1-(4-(carbamoylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1060] (424)
3-Z-[1-(4-(dimethylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methy-
lene]-6-methoxycarbonyl-2-indolinone [1061] (425)
3-Z-[1-(4-(methylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1062] (426)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-amino-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1063] (427)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-nitro-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1064] (428)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-acetylamino-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1065]
(429)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methylsulphony-
lamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1066] (430)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-cyano-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1067]
(431)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-hydroxy-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1068] (432)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methoxy-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1069] (433)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-ethoxycarbonyl-
-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1070]
(434)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carboxy-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1071] (435)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-carbamoyl-anil-
ino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1072]
(436)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-chloro-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1073] (437)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-fluoro-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1074] (438)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-bromo-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1075] (439)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-methyl-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1076] (440)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3-trifluoromethy-
l-anilino)-1-phenyl-methylene]-methoxycarbonyl-2-indolinone [1077]
(441)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dibromo-anil-
ino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1078]
(442)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-3,5-dichloro-ani-
lino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1079]
(443)
3-Z-[1-(4-(dimethylaminomethyl)-3-amino-anilino)-1-phenyl-methylene]-6-me-
thoxycarbonyl-2-indolinone [1080] (444)
3-Z-[1-(4-(dimethylaminomethyl)-3-nitro-anilino)-1-phenyl-methylene]-6-me-
thoxycarbonyl-2-indolinone [1081] (445)
3-Z-[1-(4-(dimethylaminomethyl)-3-acetylamino-anilino)-1-phenyl-methylene-
]-6-methoxycarbonyl-2-indolinone [1082] (446)
3-Z-[1-(4-(dimethylaminomethyl)-3-methylsulphonylamino-anilino)-1-phenyl--
methylene]-6-methoxycarbonyl-2-indolinone [1083] (447)
3-Z-[1-(4-(dimethylaminomethyl)-3-cyano-anilino)-1-phenyl-methylene]-6-me-
thoxycarbonyl-2-indolinone [1084] (448)
3-Z-[1-(4-(dimethylaminomethyl)-3-hydroxy-anilino)-1-phenyl-methylene]-6--
methoxycarbonyl-2-indolinone [1085] (449)
3-Z-[1-(4-(dimethylaminomethyl)-3-methoxy-anilino)-1-phenyl-methylene]-6--
methoxycarbonyl-2-indolinone [1086] (450)
3-Z-[1-(4-(dimethylaminomethyl)-3-ethoxycarbonyl-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [1087] (451)
3-Z-[1-(4-(dimethylaminomethyl)-3-carboxy-anilino)-1-phenyl-methylene]-6--
methoxycarbonyl-2-indolinone [1088] (452)
3-Z-[1-(4-(dimethylaminomethyl)-3-carbamoyl-anilino)-1-phenyl-methylene]--
6-methoxycarbonyl-2-indolinone [1089] (453)
3-Z-[1-(4-(dimethylaminomethyl)-3-chloro-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1090] (454)
3-Z-[1-(4-(dimethylaminomethyl)-3-fluoro-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1091] (455)
3-Z-[1-(4-(dimethylaminomethyl)-3-bromo-anilino)-1-phenyl-methylene]-6-me-
thoxycarbonyl-2-indolinone [1092] (456)
3-Z-[1-(4-(dimethylaminomethyl)-3-methyl-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1093] (457)
3-Z-[1-(4-(dimethylaminomethyl)-3-trifluoromethyl-anilino)-1-phenyl-methy-
lene]-6-methoxycarbonyl-2-indolinone [1094] (458)
3-Z-[1-(4-dimethylaminomethyl-3,5-dibromo-anilino)-1-phenyl-methylene]-6--
methoxycarbonyl-2-indolinone [1095] (459)
3-Z-[1-(4-(dimethylaminomethyl)-3,5-dichloro-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [1096] (460)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(2-hydrox-
y-ethoxy)-carbonyl]-2-indolinon [1097] (461)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(ethoxyca-
rbonyl-methoxy)-carbonyl]-2-indolinone [1098] (462)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(carboxy--
methoxy)-carbonyl]-2-indolinone [1099] (463)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(carbamoy-
l-methoxy)-carbonyl]-2-indolino [1100] (464)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-[(2-hydroxy-ethoxy) carbonyl]-2-indolinone [1101]
(465)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-[(ethoxycarbonyl-methoxy)-carbonyl]-2-indolinone
[1102] (466)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-
-phenyl-methylene]-6-[(carboxy-methoxy) carbonyl]-2-indolinone
[1103] (467)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-
-phenyl-methylene]-6-[(carbamoyl-methoxy)-carbonyl]-2-indolinone
[1104] (468)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-
-phenyl-methylene]-6-[(2-methoxy-ethoxy)-carbonyl]-2-indolinone
[1105] (469)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-
-phenyl-methylene]-6-[(2-dimethylamino-ethoxy)-carbonyl]-2-indolinone
[1106] (470)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-[(2-(N-tert.butoxycarbonyl-amino)-ethoxy)-carbonyl]-2-indol-
inone [1107] (471)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-[(2-amino-ethoxy) carbonyl]-2-indolinone [1108]
(472)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-[(2,2,2-trifluoroethoxy)-carbonyl]-2-indolinone
[1109] (473)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-am-
ino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1110] (474)
3-Z-[1-(4-(N-(imidazo-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1111] (475)
3-Z-[1-(4-(N-(phthalimido-2-yl-methylcarbonyl)-N
methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1112] (476)
3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [1113] (477)
3-Z-[1-(4-(N-acetylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl--
methylene]-6-methoxycarbonyl-indolinone [1114] (478)
3-Z-[1-(4-(N-methylsulphonylaminomethylcarbonyl-N-methyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1115] (479)
3-Z-[1-(4-(N--((N-(2-methoxyethyl)-N-methyl-amino)-methylcarbonyl)-N-meth-
yl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1116] (480)
3-Z-[1-(4-(N--((N-(2-dimethylaminoethyl)-N-methyl-amino)-methylcarbonyl)--
N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinon-
e [1117] (481)
3-Z-[1-(4-(N-((di-(2-hydroxyethyl)-amino)-methylcarbonyl)-N-methyl-amino)-
-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1118]
(482)
3-Z-[1-(4-tert.butoxycarbonylmethyl-anilino)-1-phenyl-methylene]-6-methox-
ycarbonyl-2-indolinone [1119] (483)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1120] (484)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-ethylid-
ene]-6-methoxycarbonyl-2-indolinone [1121] (485)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-propyli-
dene]-6-methoxycarbonyl-2-indolinone [1122] (486)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-butylid-
ene]-6-methoxycarbonyl-2-indolinone [1123] (487)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-methylene]-6-methoxycarbonyl-2-i-
ndolinone [1124] (488)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-ethylidene]-6-methoxycarbonyl-2--
indolinone [1125] (489)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-propylidene]-6-methoxycarbonyl-2-
-indolinone [1126] (490)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-butylidene]-6-methoxycarbonyl-2--
indolinone [1127] (491)
3-Z-[1-(4-tert.butyloxycarbonyl-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [1128] (492)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino)-anilino)-1-phenyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [1129] (493)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1130] (494)
3-Z-[1-(4-(N-methyl-acetylamino)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [1131] (495)
3-Z-[1-(4-(imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [1132] (496)
3-Z-[1-(4-((N-(dioxolan-2-yl-methyl)-N-methyl-amino)-methyl)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl 2-indolinone [1133] (497)
3-Z-[1-(4-(N-benzyl-N-methyl-amino-methyl)-anilino)-1-methyl-methylene]-6-
-carbamoyl-2-indolinone
[1134] (498)
3-Z-[1-(4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-anilino)-1-meth-
yl-methylene]-6-carbamoyl-2-indolinone [1135] (499)
3-Z-[1-(4-((benzo(1,3)dioxol-5-yl-methyl)-methyl-amino-methyl)-anilino)-1-
-methyl-methylene]-6-carbamoyl-2-indolinone [1136] (500)
3-Z-[1-(4-(N-phenethyl-N-methyl-amino-methyl)-anilino)-1-methyl-methylene-
]-6-carbamoyl-2-indolinone [1137] (501)
3-Z-[1-(4-(N-(3,4-dimethoxy-benzyl)-N-methyl-amino-methyl)-anilino)-1-met-
hyl-methylene]-6-carbamoyl-2-indolinone [1138] (502)
3-Z-[1-(4-(N-(4-chloro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-m-
ethylene]-6-carbamoyl-2-indolinone [1139] (503)
3-Z-[1-(4-(N-(4-methyl-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-m-
ethylene]-6-carbamoyl-2-indolinone [1140] (504)
3-Z-[1-(4-(N-(4-fluoro-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-m-
ethylene]-6-carbamoyl-2-indolinone [1141] (505)
3-Z-[1-(4-(N-(4-bromo-benzyl)-N-methyl-amino-methyl)-anilino)-1-methyl-me-
thylene]-6-carbamoyl-2-indolinone [1142] (506)
3-Z-[1-(4-((N-(2-methoxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-2-indolinone [1143] (507)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-[(2-amino--
ethoxy)-carbonyl]-2-indolinone [1144] (508)
3-Z-[1-(4-((N-(3-methylsulfonylamino-propyl)-N-methyl-amino)-methyl)-anil-
ino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1145]
(509)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoy-
l-2-indolinone-trifluoroacetate [1146] (510)
3-Z-(1-anilino-1-phenyl-methylene)-6-carbamoyl-2-indolinone [1147]
(511)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2--
indolinone-trifluoroacetate [1148] (512)
3-Z-[1-(4-(2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-
-2-indolinone-trifluoroacetate [1149] (513)
3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoy-
l-2-indolinone-trifluoroacetate [1150] (514)
3-Z-[1-(4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]--
6-carbamoyl-2-indolinone-trifluoroacetate [1151] (515)
3-Z-[1-(4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methyle-
ne]-6-carbamoyl-2-indolinone-trifluoroacetate (516)
3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2--
indolinone-trifluoroacetate [1152] (517)
3-Z-[1-(4-(amino-methyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indol-
inone-trifluoroacetate [1153] (518)
3-Z-[1-(4-(2,6-dimethylpiperidin-1-yl-methyl)-anilino)-1-phenyl-methylene-
]-6-carbamoyl-2-indolinone-trifluoroacetate [1154] (519)
3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamo-
yl-2-indolinone-trifluoroacetate [1155] (520)
3-Z-[1-(3-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl--
2-indolinone-trifluoroacetate [1156] (521)
3-Z-[1-(3-(N-methyl-N-ethyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-c-
arbamoyl-2-indolinone-trifluoroacetate [1157] (522)
3-Z-[1-(3-(methylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2--
indolinone-trifluoroacetate [1158] (523)
3-Z-[1-(3-hydroxymethyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indoli-
none [1159] (524)
3-Z-[1-(4-(methoxycarbonylmethyl-aminomethyl)-anilino)-1-phenyl-methylene-
]-6-carbamoyl-2-indolinone-trifluoroacetate [1160] (525)
3-Z-[1-(4-(N-methylsulphonyl-N-(dimethylaminocarbonyl-methyl)-amino)-anil-
ino)-1-phenyl-methylene]-6-carbamoyl 2-indolinone [1161] (526)
3-Z-[1-(4-(N-acetyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-
-2-indolinone [1162] (527)
3-Z-[1-(3,4-dimethoxy-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolino-
ne [1163] (528)
3-Z-[1-(4-(morpholin-4-yl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-ind-
olinone-trifluoroacetate [1164] (529)
3-Z-[1-(4-acetylamino-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolino-
ne [1165] (530)
3-Z-[1-(4-amino-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone
[1166] (531)
3-Z-[1-(4-N-methyl-N-acetyl-amino-anilino)-1-phenyl-methylene]-6-carbamoy-
l-2-indolinone [1167] (532)
3-Z-[1-(4-ethoxycarbonyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indol-
inone [1168] (533)
3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone
[1169] (534)
3-Z-[1-(4-benzylcarbamoyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indo-
linone [1170] (535)
3-Z-[1-(cyclohexyl-amino)-1-phenyl-methylene]-6-carbamoyl-2-indolinone
[1171] (536)
3-Z-[1-(4-amino-cyclohexyl-amino)-1-phenyl-methylene]-6-carbamoyl-2-indol-
inone-trifluoroacetate [1172] (537)
3-Z-[1-(N-methyl-piperidine-4-yl-amino)-1-phenyl-methylene]-6-carbamoyl-2-
-indolinone-trifluoroacetate [1173] (538)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-methyl-methylene]-6-carbamoy-
l-2-indolinone-trifluoroacetate [1174] (539)
3-Z-[1-(3-dimethylaminomethyl-anilino)-1-methyl-methylene]-6-carbamoyl-2--
indolinone-trifluoroacetate [1175] (540)
3-Z-[1-(4-(N-methyl-N-benzyl-aminomethyl)-anilino)-1-methyl-methylene]-6--
carbamoyl-2-indolinone-trifluoroacetate [1176] (541)
3-Z-[1-(4-(N-methylsulphonyl-N-(2-dimethylamino-ethyl)-amino)-anilino)-1--
methyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate [1177]
(542)
3-Z-[1-(4-chloro-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone
[1178] (543)
3-Z-[1-(3-chloro-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone
[1179] (544)
3-Z-[1-(4-methoxycarbonyl-anilino)-1-methyl-methylene]-6-carbamoyl-2-indo-
linone [1180] (545)
3-Z-[1-(4-carboxy-anilino)-1-methyl-methylene]-6-carbamoyl-2-indolinone
[1181] (546)
3-Z-[1-(4-methyl-3-nitro-anilino)-1-methyl-methylene]-6-carbamoyl-2-indol-
inone [1182] (547)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-propyl-methylene]-6-carbamoy-
l-2-indolinone-trifluoroacetate [1183] (548)
3-Z-[1-(3-dimethylaminomethyl-anilino)-1-propyl-methylene]-6-carbamoyl-2--
indolinone-trifluoroacetate [1184] (549)
3-Z-[1-(4-(N-methyl-N-benzyl-aminomethyl)-anilino)-1-propyl-methylene]-6--
carbamoyl-2-indolinone-trifluoroacetate [1185] (550)
3-Z-[1-(4-(N-methylsulphonyl-N-(2-dimethylamino-ethyl)-amino)-anilino)-1--
propyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate [1186]
(551)
3-Z-[1-(4-chloro-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone
[1187] (552)
3-Z-[1-(3-chloro-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone
[1188] (553)
3-Z-[1-(4-methoxycarbonyl-anilino)-1-propyl-methylene]-6-carbamoyl-2-indo-
linone [1189] (554)
3-Z-[1-(4-carboxy-anilino)-1-propyl-methylene]-6-carbamoyl-2-indolinone
[1190] (555)
3-Z-[1-(4-methyl-3-nitro-anilino)-1-propyl-methylene]-6-carbamoyl-2-indol-
inone [1191] (556)
3-Z-[1-(3-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-carbamoy-
l-2-indolinone-trifluoroacetate [1192] (557)
3-Z-[1-(3-(diethylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-
-indolinone-trifluoroacetate [1193] (558)
3-Z-[1-(3-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2--
indolinone-trifluoroacetate [1194] (559)
3-Z-[1-(3-(N-methyl-N-benzyl-aminomethyl)-anilino)-1-phenyl-methylene]-6--
carbamoyl-2-indolinone-trifluoroacetate [1195] (560)
3-Z-[1-(3-(butylaminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-i-
ndolinone-trifluoroacetate [1196] (561)
3-Z-[1-(3-(aminomethyl)-anilino)-1-phenyl-methylene]-6-carbamoyl-2-indoli-
none-trifluoroacetate [1197] (562)
3-Z-[1-(3-(N-(3-dimethylaminopropyl)-N-methyl-amino-methyl)-anilino)-1-ph-
enyl-methylene]-6-carbamoyl-2-indolinone-trifluoroacetate [1198]
(563)
3-Z-[1-(3-(N-(2-dimethylaminoethyl)-N-methyl-aminomethyl)-anilino)-1-phen-
yl-methylene]-6-carbamoyl-indolinone-trifluoroacetate [1199] (564)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [1200] (565)
3-Z-[1-(4-bromo-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indolino-
ne [1201] (566)
3-Z-[1-(3-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [1202] (567)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [1203] (568)
3-Z-[1-(4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-anilino)-1-phenyl-methyl-
ene]-6-ethoxycarbonyl-2-indolinone [1204] (569)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethoxyca-
rbonyl-2-indolinone [1205] (570)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [1206] (571)
3-Z-[1-(4-tert.butyloxycarbonyl-anilino)-1-phenyl-methylene]-6-ethoxycarb-
onyl-2-indolinone [1207] (572)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [1208] (573)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulponyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [1209] (574)
3-Z-[1-(4-(4-methyl-piperazin-1-yl)-anilino)-1-phenyl-methylene]-6-ethoxy-
carbonyl-2-indolinone [1210] (575)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [1211] (576)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethoxycarbonyl-2-indolinone [1212] (577)
3-Z-[1-(4-(N-methyl-acetylamino)-anilino)-1-phenyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [1213] (578)
3-Z-[1-(4-(N-methyl-methylsulphonylamino)-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [1214] (579)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [1215] (580)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino-
)-1-phenyl-methylene]-6-ethoxycarbonyl-2-indolinone [1216] (581)
3-Z-[1-(4-(imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [1217] (582)
3-Z-[1-(4-(tetrazol-5-yl)-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-
-indolinone [1218] (583)
3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6--
ethoxycarbonyl-2-indolinone [1219] (584)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-
-methylene]-6-ethoxycarbonyl-2-indolinone [1220] (585)
3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-ethoxyc-
arbonyl-2-indolinone [1221] (586)
3-Z-[1-(4-(N-methyl-N-phenethyl-aminomethyl)-anilino)-1-phenyl-methylene]-
-6-ethoxycarbonyl-2-indolinone [1222] (587)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethoxycarbonyl-2-indolinone [1223] (588)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-ethoxycarbonyl-2-indolinone [1224] (589)
3-Z-[1-(4-(N-tert.butoxycarbonyl-N-ethyl-aminomethyl-anilino)-1-phenyl-me-
thylene]-6-ethoxycarbonyl-2-indolinone [1225] (590)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-ethyl-methylene]-6-ethoxycar-
bonyl-2-indolinone [1226] (591)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
ethyl-methylene]-6-ethoxycarbonyl-2-indolinone [1227] (592)
3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [1228] (593)
3-Z-[1-(4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [1229] (594)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1230] (595)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1231] (596)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1232] (597)
3-Z-[1-(4-(N-acetyl-N-dimethylaminocarbonylmethyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-2-indolinone [1233] (598)
3-Z-[1-(4-(N-dimethylaminocarbonylmethyl-amino)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1234] (599)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1235] (600)
3-Z-[1-(4-(N-methylaminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1236] (601)
3-Z-[1-(4-((imidazolidin-2,4-dion-5-ylidene)-methyl)-anilino)-1-phenyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [1237] (602)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N
methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1238] (603)
3-Z-[1-(4-(N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-methylene-
]-6-methoxycarbonyl-2-indolinone [1239] (604)
3-Z-[1-(4-(2-oxo-pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1240] (605)
3-Z-[1-(4-(N-aminocarbonylmethyl-N-methylsulphonyl-amino)-anilino)-1-phen-
yl-methylene]-6-methoxycarbonyl-2-indolinone [1241] (606)
3-Z-[1-(4-(thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-meth-
oxycarbonyl-2-indolinone [1242] (607)
3-Z-[1-(4-(1,1-dioxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1243] (608)
3-Z-[1-(4-(N-cyanomethyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methy-
lene]-6-methoxycarbonyl-2-indolinone [1244] (609)
3-Z-[1-(4-(N-tert.butoxycarbonyl-ethylaminomethyl)-anilino)-1-phenyl-meth-
ylene]-6-methoxycarbonyl-2-indolinone [1245] (610)
3-Z-[1-(4-(N-benzyl-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6--
methoxycarbonyl-2-indolinone [1246] (611)
3-Z-[1-(4-(1-oxo-thiomorpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]--
6-methoxycarbonyl-2-indolinone [1247] (612)
3-Z-[1-(4-(2-(imidazol-4-yl)-ethyl)-anilino)-1-phenyl-methylene]-6-methox-
ycarbonyl-2-indolinone [1248] (613)
3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [1249] (614)
3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [1250] (615)
3-Z-[1-(4-((2-(N-benzyl-N-methyl-amino)-ethyl)-N-methylsulphonyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1251]
(616)
3-Z-[1-(4-cyclohexylamino-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [1252] (617)
3-Z-[1-(4-(pyridin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [1253] (618)
3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [1254] (619)
3-Z-[1-(4-(imidazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [1255] (620)
3-Z-[1-(N-methyl-piperidine-4-yl-amino)-1-phenyl-methylene]-6-methoxycarb-
onyl-2-indolinone [1256] (621)
3-Z-[1-(4-(imidazol-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [1257] (622)
3-Z-[1-(4-((4-hydroxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene-
]-6-methoxycarbonyl-2-indolinone [1258] (623)
3-Z-[1-(4-((4-methoxy-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene-
]-6-methoxycarbonyl-2-indolinone [1259] (624)
3-Z-[1-(4-benzyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolin-
one [1260] (625)
3-Z-[1-(4-(N-(3-trifluoroacetylamino-propyl)-N-methylsulphonyl-amino)-ani-
lino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1261]
(626)
3-Z-[1-(4-tert.butoxycarbonylmethyl-anilino)-1-phenyl-methylene]-6-ethoxy-
carbonyl-2-indolinone [1262] (627)
3-Z-[1-(4-tert.butoxycarbonyl-anilino)-1-ethyl-methylene]-6-ethoxycarbony-
l-2-indolinone [1263] (628)
3-Z-[1-(4-(4-tert.butoxycarbonyl-piperazin-1-yl-methyl)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-indolinone
[1264] (629)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [1265] (630)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulponyl-amino)-3-nitro-anil-
ino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1266]
(631)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-amino-ani-
lino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1267]
(632)
3-Z-[1-(4-((3-(N-benzyl-N-methyl-amino)-propyl)-N-methylsulphonyl-amino)--
anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1268]
(633)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-3-chloro-an-
ilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1269]
(634)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-2-indolinone [1270] (635)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-methoxycarbonyl-2-indolinone [1271] (636)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-2-indolinone [1272] (637)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butyryl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1273] (638)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isobutyryl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-2-indolinone [1274] (639)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1275] (640)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-amino-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1276] (641)
3-Z-[1-(4-(4-hydroxymethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methy-
lene]-6-methoxycarbonyl-2-indolinone [1277] (642)
3-Z-[1-(4-(2-(4-hydroxy-piperidin-1-yl)-ethyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [1278] (643)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1279] (644)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1280] (645)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-phenylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1281] (646)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1282] (647)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1283] (648)
3-Z-[1-(4-((imidazolidin-2,4-dion-5-yl)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1284] (649)
3-Z-[1-(4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-anilino)-1-phenyl-methylen-
e]-6-methoxycarbonyl-2-indolinone [1285] (650)
3-Z-[1-(4-(cyclohexylyl-methyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [1286] (651)
3-Z-[1-(4-(cyclohexyl-carbonyl)-anilino)-1-phenyl-methylene]-6-methoxycar-
bonyl-2-indolinone [1287] (652)
3-Z-[1-(4-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbon-
yl-2-indolinone [1288] (653)
3-Z-[1-(4-(N-(n-hexyl)-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [1289] (654)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1290] (655)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1291] (656)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(pyridine-3-carbonyl)-amino)-anili-
no)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1292] (657)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(phenyl-acetyl)-amino)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1293] (658)
3-Z-[1-(4-(N-ethyl-N-methyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-m-
ethoxycarbonyl-2-indolinone [1294] (659)
3-Z-[1-(4-(imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl--
2-indolinone [1295] (660)
3-Z-[1-(4-(1-ethyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [1296] (661)
3-Z-[1-(4-(1-benzyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [1297] (662)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-amino)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1298] (663)
3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1299] (664)
3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1300] (665)
3-Z-[1-(4-(N-((4-benzyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1301]
(666)
3-Z-[1-(4-(N-(pyrrolidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1302] (667)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-bromo-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1303] (668)
3-Z-[1-(4-(5-methyl-imidazol-4-yl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [1304] (669)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-isopropyl-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1305] (670)
3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-benzyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1306] (671)
3-Z-[1-(4-(N-butyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1307] (672)
3-Z-[1-(4-(N--((N-aminocarbonylmethyl-N-methyl-amino)-methylcarbonyl)-N-m-
ethyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1308] (673)
3-Z-[1-(4-(N--((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)--
anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1309]
(674)
3-Z-[1-(4-(N-(di-(2-methoxyethyl)-amino-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1310]
(675)
3-Z-[1-(4-(N-((2-(4-tert.butoxycarbonyl-piperazin-1-yl)-ethyl)-carbonyl)--
N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinon-
e [1311] (676)
3-Z-[1-(4-(N-((2-(piperidin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1312] (677)
3-Z-[1-(4-(N-((2-(N-benzyl-N-methyl-amino)-ethyl)-carbonyl)-N-methyl-amin-
o)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1313] (678)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-isopropyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-indolinone [1314] (679)
3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1315] (680)
3-Z-[1-(4-(N-((4-tert.butoxycarbonyl-piperazin-1-yl)-methylcarbonyl)-N-is-
opropyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1316] (681)
3-Z-[1-(4-(N--((N-benzyl-N-methyl-amino)-methylcarbonyl)-N-benzyl-amino)--
anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1317]
(682)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-benzyl-amino)-anilino)-1-pheny-
l-methylene]-6-methoxycarbonyl-2-indolinone [1318] (683)
3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-benzyl-amino)-anilino)-1-p-
henyl-methylene]-6-methoxycarbonyl-2-indolinone [1319] (684)
3-Z-[1-(4-(1,2,4-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-meth-
oxycarbonyl-2-indolinone [1320] (685)
3-Z-[1-(4-(1,2,3-triazol-2-yl-methyl)-anilino)-1-phenyl-methylene]-6-meth-
oxycarbonyl-2-indolinone [1321] (686)
3-Z-[1-(4-(1,2,3-triazol-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-meth-
oxycarbonyl-2-indolinone [1322] (687)
3-Z-[1-(4-((N-aminocarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phen-
yl-methylene]-6-methoxycarbonyl [1323] (688)
3-Z-[1-(4-((di-(2-methoxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1324] (689)
3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [1325] (690)
3-Z-[1-(4-((di-(2-hydroxy-ethyl)-amino)-methyl)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1326] (691)
3-Z-[1-(4-((N-ethoxycarbonylmethyl-N-methyl-amino)-methyl)-anilino)-1-phe-
nyl-methylene]-6-methoxycarbonyl-indolinone [1327] (692)
3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [1328] (693)
3-Z-[1-(4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-anilino)-1-phenyl--
methylene]-6-methoxycarbonyl-2-indolinone [1329] (694)
3-Z-[1-(4((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1330] (695)
3-Z-[1-(4-((N-(tert.butoxycarbonyl-3-amino-propyl)-N-methyl-amino)-methyl-
)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1331] (696)
3-Z-[1-(4-((N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1332] (697)
3-Z-[1-(4-((N-(dimethylcarbamoyl-methyl)-N-methyl-amino)-methyl)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1333] (698)
3-Z-[1-(4-methyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolin-
one [1334] (699)
3-Z-[1-(4-((N-propyl-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-
-6-methoxycarbonyl-2-indolinone [1335] (700)
3-Z-[1-(4-((N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-
-methylene]-6-methoxycarbonyl-2-indolinone [1336] (701)
3-Z-[1-(4-((N-(2-dimethylamino-ethyl)-N-methyl-amino)-methyl)-anilino)-1--
phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1337] (702)
3-Z-[1-(4-((N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1338] (703)
3-Z-[1-(4-(3-oxo-piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-me-
thoxycarbonyl-2-indolinone [1339] (704)
3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethoxy-carbonyl-2-indoli-
none [1340] (705)
3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-in-
dolinone [1341] (706)
3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-
-2-indolinone [1342] (707)
3-Z-[1-(4-carboxymethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl-2-i-
ndolinone [1343] (708)
3-Z-[1-(4-carboxy-anilino)-1-ethyl-methylene]-6-ethoxy-carbonyl-2-indolin-
one [1344] (709)
3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-methoxyc-
arbonyl-2-indolinone [1345] (710)
3-Z-[1-(4-butylaminomethyl-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-
-2-indolinone [1346] (711)
3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethoxycarbonyl--
2-indolinone [1347] (712)
3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-carbamoyl-2-ind-
olinone [1348] (713)
3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)--
1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1349] (714)
3-Z-[1-(4-(N-((2-(piperazin-1-yl)-ethyl)-carbonyl)-N-methyl-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1350] (715)
3-Z-[1-(4-(N-propyl-aminomethyl)-anilino)-1-phenyl-methylene]-6-methoxyca-
rbonyl-2-indolinone [1351] (716)
3-Z-[1-(4-((N-(3-amino-propyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl--
methylene]-6-methoxycarbonyl-2-indolinone [1352] (717)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-methoxy-
carbonyl-2-indolinone [1353] (718)
3-Z-[1-(3-cyano-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-
-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1354] (719)
3-Z-[1-(3-methoxy-4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilin-
o)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1355] (720)
3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methyl-
ene]-6-methoxycarbonyl-2-indolinone [1356] (721)
3-Z-[1-(4-(N--(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N--
methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1357] (722)
3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-amino-methylcarbonyl)-N-methyl-amino)--
anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1358]
(723)
3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-ph-
enyl-methylene]-6-methoxycarbonyl-2-indolinone [1359] (724)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-amino)-anilino)-1-phenyl-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1360] (725)
3-Z-[1-(4-(N-((4-methyl-[1,4]diazepan-1-yl)-methylcarbonyl)-N-methyl-amin-
o)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1361] (726)
3-Z-[1-(4-(N-((1-methyl-piperidin-4-yl)-methylcarbonyl)-N-methyl-am-
ino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1362] (727)
3-Z-[1-(2,3-dimethyl-4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl-
)-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1363] (728)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-amino)-anilino)-1-
-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1364] (729)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-carbonyl)-N-methyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1365] (730)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-methoxycarbonyl-2-indolinone [1366] (731)
3-Z-[1-(4-(N-((3-dimethylamino-propyl)-aminocarbonyl)-N-methyl-amino)-ani-
lino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone [1367]
(732)
3-Z-[1-anilino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1368] (733)
3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-meth-
ylene]-6-methoxycarbonyl-2-indolinone [1369] (734)
3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
[1370] (735)
3-Z-[1-(4-(4-methylpiperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6--
carboxy-2-indolinone [1371] (736)
3-Z-[1-(4-methylaminomethyl-anilino)-1-phenyl-methylene]-6-carboxy-2-indo-
linone [1372] (737)
3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-carboxy--
2-indolinone [1373] (738)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-carboxy-2-indolinone [1374] (739)
3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene-
]-6-carboxy-2-indolinone [1375] (740)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-carboxy-2-indolinone [1376] (741)
3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-p-
henyl-methylene]-6-carboxy-2-indolinone [1377] (742)
3-Z-[1-(4-(N--(N-(2-dimethylamino-ethyl)-N-methyl-aminomethylcarbonyl)-N--
methyl-amino)-anilino)-1-phenyl-methylene]-6-carboxy-2-indolinone
[1378] (743)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-c-
arboxy-2-indolinone [1379] (744)
3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-carboxy-2-indolinone
[1380] (745)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-pheny-
l)-methylene]-6-methoxycarbonyl-2-indolinone [1381] (746)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-
-methylene]-6-methoxycarbonyl-2-indolinone [1382] (747)
3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl-
)-methylene]-6-methoxycarbonyl-2-indolinone [1383] (748)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-met-
hylene]-6-methoxycarbonyl-2-indolinone
[1384] (749)
3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmet-
hylcarbamoyl-2-indolinone [1385] (750)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylc-
arbamoyl-2-indolinone [1386] (751)
3-Z-[1-((1-methyl-piperidin-4-yl)-amino-1-phenyl-methylene]-6-ethylmethyl-
carbamoyl-2-indolinone [1387] (752)
3-Z-[1-(trans-4-dimethylamino-cyclohexylamino)-1-phenyl-methylene]-6-ethy-
lmethylcarbamoyl-2-indolinone [1388] (753)
3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylmet-
hylcarbamoyl-2-indolinone [1389] (754)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-propionyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethylmethylcarbamoyl-2-indolinone [1390] (755)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone
[1391] (756)
3-Z-[1-cyclohexylamino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-
-indolinone [1392] (757)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethylmethylcarbamoyl-2-indolinone [1393] (758)
3-Z-[1-(3-diethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylca-
rbamoyl-2-indolinone [1394] (759)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethylmethylcarbamoyl-2-indolinone [1395] (760)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone [1396] (761)
3-Z-[1-anilino-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone
[1397] (762)
3-Z-[1-(4-ethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarb-
amoyl-2-indolinone [1398] (763)
3-Z-[1-(4-((2-diethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-ethylmet-
hylcarbamoyl-2-indolinone [1399] (764)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethylmethylcarbamoyl-2-indolinone [1400] (765)
3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-
-6-ethylmethylcarbamoyl-2-indolinone [1401] (766)
3-Z-[1-(4-methoxycarbonyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarba-
moyl-2-indolinone [1402] (767)
3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-i-
ndolinone [1403] (768)
3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-amino)-anil-
ino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-indolinone [1404]
(769)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylca-
rbamoyl-2-indolinone [1405] (770)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone [1406]
(771)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1--
phenyl-methylene]-6-ethylcarbamoyl-2-indolinone [1407] (772)
3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-ethylme-
thylcarbamoyl-2-indolinone [1408] (773)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-pheny-
l-methylene]-6-ethylcarbamoyl-2-indolinone [1409] (774)
3-Z-[1-(4-dimethylaminomethyl-anilino)-1-phenyl-methylene]-6-ethylcarbamo-
yl-2-indolinone [1410] (775)
3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-me-
thylene]-6-ethylcarbamoyl-2-indolinone [1411] (776)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-m-
ethylene]-6-ethylcarbamoyl-2-indolinone [1412] (777)
3-Z-[1-(4-carbamoyl-anilino)-1-phenyl-methylene]-6-ethylmethylcarbamoyl-2-
-indolinone [1413] (778)
3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylen-
e]-6-ethylmethylcarbamoyl-2-indolinone [1414] (779)
3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylen-
e]-6-ethylmethylcarbamoyl-2-indolinone [1415] (780)
3-Z-[1-(4-((4-methyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylen-
e]-6-ethylcarbamoyl-2-indolinone [1416] (781)
3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene-
]-6-ethylmethylcarbamoyl-2-indolinone [1417] (782)
3-Z-[1-(4-(N-ethyl-N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-
-methylene]-6-ethylmethylcarbamoyl-2-indolinone [1418] (783)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-diethylcarbamoyl-2-indolinone [1419]
(784)
3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl--
methylene]-6-ethylmethylcarbamoyl-2-indolinone [1420] (785)
3-Z-[1-(4-((4-ethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl-methylene-
]-6-ethylcarbamoyl-2-indolinone [1421] (786)
3-Z-[1-(4-(N-(2-diethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylen-
e]-6-ethylmethylcarbamoyl-2-indolinone [1422] (787)
3-Z-[1-(4-((cis-3,5-dimethyl-piperazin-1-yl)-carbonyl)-anilino)-1-phenyl--
methylene]-6-ethylcarbamoyl-2-indolinone [1423] (788)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-
-phenyl-methylene]-6-ethylcarbamoyl-2-indolinone [1424] (789)
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino)-methyle-
ne]-6-methoxycarbonyl-2-indolinone [1425] (790)
3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-methoxycarbonyl-2-ind-
olinone [1426] (791)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-methylene]-6-methoxycarbonyl-2-indolinone [1427] (792)
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-methylene]-6-ethylcarbamoyl-2-indolinone [1428] (793)
3-Z-[1-(4-dimethylaminomethyl-anilino)-methylene]-6-ethylcarbamoyl-2-indo-
linone [1429] (794)
3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-methylene]-6-ethylcarbamoyl-2--
indolinone [1430] (795)
3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-methylene]-
-6-ethylcarbamoyl-2-indolinone
[1431] as well as their tautomers, their stereoisomers or the
physiologically acceptable salts thereof.
[1432] The compounds of general formula I, their tautomers, their
stereoisomers or the physiologically acceptable salts thereof are
thus suitable for the prevention or treatment of a specific
fibrotic disease selected from the group consisting of:
[1433] Fibrosis and remodeling of lung tissue in chronic
obstructive pulmonary disease (COPD), chronic bronchitis, and
emphysema;
[1434] Lung fibrosis and pulmonary diseases with a fibrotic
component including but not limited to idiopathic pulmonary
fibrosis (IPF), giant cell interstitial pneumonia (GIP),
sarcodosis, cystic fibrosis, respiratory distress syndrome (ARDS),
granulomatosis, silicosis, drug-induced lung fibrosis (for example,
induced by drugs such as bleomycin, bis-chloronitrosourea,
cyclophosphamide, amiodarone, procainamide, penicillamine, gold or
nitrofurantoin), silicosis, asbestosis, systemic scleroderma;
[1435] Fibrosis and remodeling in asthma;
[1436] Fibrosis in rheumatoid arthritis;
[1437] Virally induced hepatic cirrhosis, for example hepatitis
C;
[1438] Radiation-induced fibrosis;
[1439] Restenosis, post angioplasty;
[1440] Renal disorders including chronic glomerulonephritis, renal
fibrosis in patients receiving cyclosporine and renal fibrosis due
to high blood pressure;
[1441] Diseases of the skin with a fibrotic component including but
not limited to, scleroderma, sarcodosis, systemic lupus
erythematosus;
[1442] Excessive scarring.
[1443] In a preferred embodiment in accordance with the present
invention, the compounds of general formula I, their tautomers,
their stereoisomers or the physiologically acceptable salts thereof
are especially suitable for the prevention or treatment of
idiopathic pulmonary fibrosis.
BIOLOGICAL ACTIVITY
[1444] The following experimental results illustrate the present
invention without representing a limitation of its scope.
Example B1
[1445] In the following experiments of Example B1, Example A
denotes the compound
3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-methyl-amino)-anilino-
)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, which is
compound (m) of the list of the preferred compounds.
[1446] (A) Effect of a representative compound on lung morphology
following bleomycin-induced pulmonary fibrosis.
[1447] Materials and Methods
[1448] Bleomycin sulfate (Bleomycin HEXAL.TM.) was purchased from a
local pharmacy.
[1449] Bleomycin Administration and Treatment Protocols
[1450] All experiments were performed in accordance with German
guidelines for animal welfare, performed by persons certified to
work with animals and approved by the responsible authorities. Male
Wistar rats were intratracheally injected with Bleomycin sulfate
(10 U/kg body weight in 300 .mu.l saline) or saline alone (saline
control) using a catheter (0.5 mm internal diameter, 1.0 mm
external diameter) through the nasal passage, following exposure to
the anaesthetic Isofluorane for 5 minutes. The following day, the
rats were orally treated with Example A (compound (m)) or saline
suspended in 1 ml 0.1% Natrosol. Control rats were administered 1
ml 0.1% Natrosol (vehicle control).
[1451] A total of 25 rats were investigated and were grouped and
treated as shown in Table 1.
TABLE-US-00007 TABLE 1 Intratracheal No. of Treatment instillation
animals Compound Schedule Bleomycin 10 U/kg 10 Example A Days 1-21
(Compound (m)) Bleomycin 10 U/kg 10 Vehicle only Days 1-21 Saline
(300 .mu.l) 5 Vehicle only Days 1-21
[1452] 21 days following bleomycin instillation, the rats were
killed with a lethal intraperitoneal injection of Narcoren.TM.
(Pentobarbital Sodium, Rhone Merieux). The lungs were then removed,
blotted dry and half was snap frozen in liquid nitrogen and stored
at -80.degree. C. The other half was fixed in 4% formalin for
subsequent paraffin embedding and histology.
[1453] Histology
[1454] The lung tissues fixed in 4% formalin were embedded into
paraffin and 5 m sections were cut using a microtome (Leica SM200R)
and placed on poly-L-lysine coated slides. The sections were then
dried onto the slides (60.degree. C. 2 hours) and then left to cool
at room temperature. Collagen deposition was assessed using
Masson's Trichrome staining.
[1455] Results
[1456] FIG. 1A shows the result obtained with the control group,
which received saline and the vehicle instead of bleomycin
intratracheally.
[1457] Rats treated intratracheally with bleomycin and the vehicle
developed severe lung fibrosis, as seen in FIG. 1B. The alveoli
have been largely replaced by fibroblasts and extracellular matrix
and the normal lung structure is nearly obliterated.
[1458] Daily treatment of bleomycin-treated rats with 50 mg/kg of
Example A (compound (m)) showed a consistent, nearly complete
reversal of lung fibrosis in this model. A typical example is shown
in FIG. 1C. Alveoli are intact and little or no fibroblast
infiltration or extracellular matrix deposition has occurred.
Normal lung structure has been maintained, which is evidenced by a
comparison of FIG. 1C with FIG. 1A.
[1459] (B) Effect of a representative compound on expression of
fibrotic marker genes following bleomycin-induced pulmonary
fibrosis.
[1460] mRNA Extractions and Synthesis of cDNA
[1461] One part of the frozen lung tissue dedicated to
investigation of gene expression was cut into small pieces using a
sterile scalpel blade. Approximately 100 mg of tissue was then
placed into a 2 ml Eppendorf tube and 1.5 ml of Trizol (Invitrogen)
was added. A sterile tungsten carbide bead (Qiagen) was then added
to the tube and the tube was placed in a Retsch MM300 Tissue
disruptor (Qiagen) at a frequency of 30.0 Hz for 8 minutes. After
this time, the bead was removed and the sample centrifuged at 12000
rpm for 10 minutes to remove tissue debris. The RNA was extracted
using a modified version of the manufacturer's protocol supplied
with Trizol. Briefly, 0.3 ml chloroform was added to the tube and
the tube shaken vigorously and then left to incubate at room
temperature for 5 minutes, after which the tube was centrifuged for
15 minutes at 12000 rpm at 4.degree. C. The upper colorless aqueous
phase was then collected and added to 750 .mu.l isopropanol. This
was then shaken vigorously and stored at -80.degree. C. overnight.
The samples were then incubated at room temperature for 15 minutes,
after which they were centrifuged for 40 minutes at 12000 rpm at
4.degree. C. The supernatant was then removed and 500 .mu.l of 70%
ethanol was added to wash the pellet then the sample was
centrifuged for 10 minutes at 12000 rpm an 4.degree. C., this wash
step was repeated twice, after which the pellet was left to dry for
10-15 minutes. Finally the pellet was resuspended in 20 .mu.l RNase
free water and stored at -80.degree. C. The concentration of each
sample was then measured using a spectrophotometer.
[1462] Using the Superscript.TM. III (Invitrogen, Paisley, UK)
RT-first strand synthesis kit, 2 .mu.g of each mRNA sample was
reversed transcribed using a modified version of the manufacturer's
protocol. Briefly, a mixture of 2 .mu.g RNA, 1 .mu.l random hexamer
primers (50 ng/.mu.l), 1 .mu.l dNTP mix (10 mM) was made up to 10
.mu.l with DEPC-treated water and incubated at 65.degree. C. for 5
minutes, after which it was placed on ice for 5 minutes. Following
this, to each reaction, 2 .mu.l RT buffer (10.times.), 4 .mu.l
MgCl.sub.2 (25 mM), 2 .mu.l DTT (0.1M), 1 .mu.l RNaseOUT.TM. (40
U/.mu.l) and 1 .mu.l SuperScript.TM. III enzyme (200 U/.mu.l) was
added and the mixture placed in a thermal cycler (Applied
Biosystems) under the following conditions: 25.degree. C. for 10
minutes, 50.degree. C. for 50 minutes and 85.degree. C. for 5
minutes, after which 1 .mu.l of RNase H was added and incubated at
37.degree. C. for 20 minutes. The synthesized cDNA was diluted to 5
ng/.mu.l using the assumption that the RT reaction fully
transcribed all of the mRNA to cDNA and was a concentration of 100
ng/.mu.l.
[1463] Investigation of Gene Expression Using Real Time PCR
[1464] Gene expression was investigated in each of the samples
using the Applied Biosystems 7700 sequence detection system.
Primers for the 18S endogenous control and TGFb1 were purchased as
pre-developed assay reagent kits, whereas primers and probes (see
Table 2 below) for pro-collagen I and fibronectin were designed
using PrimerExpress.TM. (Applied Biosystems), ensuring that at
least one of the primers or probes in each set overlapped an
intron/exon junction, thus eliminating the possibility of
amplifying any contaminating genomic DNA in the cDNA sample. The
purchased PDARs also amplified only cDNA.
TABLE-US-00008 TABLE 2 Target Sequence Fibronectin Forward 5'-GAT
GCC GAT CAG AAG TTT GGA-3' Reverse 5'-TCG TTG GTC GTG CAG ATC TC-3'
Probe 5'-FAM-CTG CCC AAT GGC TGC CCA TGA-TAMRA-3' Pro- Forward
5'-CAG ACT GGC AAC CTG Collagen I AAG AAG TC-3' Reverse 5'-TCG CCC
CTG AGC TCG AT-3' Probe 5'-FAM-CTG CTC CTC CAG GGC TCC AAC
GA-TAMRA3'
[1465] Real Time PCR was carried out in 25 .mu.l reactions, using
25 ng (5 .mu.l) of cDNA per reaction. A quantitative PCR core kit
was purchased (Eurogentec) and a master-mix was made up as follows
for 100 reactions: 500 .mu.l 10.times. reaction buffer, 500 .mu.l
MgCl.sub.2 (50 mM), 200 .mu.l dNTP mix solution (5 mM), 25 .mu.l
Hot Goldstar enzyme, 75 .mu.l 18S PDAR, 22.5 .mu.l forward primer,
22.5 .mu.l reverse primer, 15 .mu.l probe and 640 .mu.l DEPC
treated water. 20 .mu.l of this master-mix was then added to 25ng
(5 .mu.l) target cDNA. Each analysis was carried out in
triplicate.
[1466] In order to quantify the gene expression, a standard curve
was constructed for each primer set and was included on each plate.
The standards were made up of a mix of all the cDNA's under
investigation; this mix of cDNA's was serially diluted 10, 20, 50,
100, 100 times. A standard curve was constructed of the obtained
C.sub.T (Cycle at which amplification reaches a set Threshold)
against the LOG.sub.10 of the dilution factor. Curves were drawn
for the target gene and the 18S rRNA endogenous control. The
C.sub.T value for both targets for each of the samples was then
converted to a fold dilution using the standard curve and the
target gene value was normalized to the 18S gene value.
[1467] Statistics
[1468] All statistical analyses were carried out using GraphPad
Prism V 4.02 software. Comparisons were made using a non-parametric
T-test (Mann-Whitney U test) and a significant value was considered
to be p0.05.
[1469] Results
[1470] The results are shown in FIGS. 2 (procollagen I) and 3
(fibronectin). Each data point represents RNA isolated from the
lung of a single rat.
[1471] Intratracheal administration of bleomycin and subsequent
treatment with vehicle only showed large increases in procollagen I
and fibronectin gene expression in the lung, as seen in FIGS. 2 and
3, consistent with the histologically apparent lung fibrosis seen
in FIG. 1B.
[1472] Daily treatment of Bleomycin-treated rats with 50 mg/kg of
Example A (compound (m)) showed a significant (p.ltoreq.0.0001)
inhibition of expression of fibrotic marker genes in this model, as
seen in FIGS. 2 and 3.
[1473] This experiment thus demonstrates that expression of
fibrotic markers, and therefore deposition of extracellular matrix,
may be dramatically reduced by treatment with Example A (compound
(m)).
Example B2
[1474] In the following experiments of Example B2, the compound
3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a-
nilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, which
is compound (u) of the list of the preferred compounds, was
used.
[1475] All the methods employed are the same as the methods
described in the experiments of Example B1, however using compound
(u) instead of compound (m).
[1476] (A) Effect of a representative compound on lung morphology
following bleomycin-induced pulmonary fibrosis.
[1477] Samples were prepared from rats treated as outlined in above
Table 1 of experimental Example B1 (A).
[1478] Results
[1479] FIG. 4A shows the result obtained with the control group,
which received saline and the vehicle instead of bleomycin
intratracheally.
[1480] Rats treated intratracheally with bleomycin and the vehicle
developed severe lung fibrosis, as seen in FIG. 4B. The alveoli
have been largely replaced by fibroblasts and extracellular matrix
and the normal lung structure is nearly obliterated.
[1481] Daily treatment of bleomycin-treated rats with 50 mg/kg of
compound (u) showed a consistent, nearly complete reversal of lung
fibrosis in this model. A typical example is shown in FIG. 4C.
Alveoli are intact and little or no fibroblast infiltration or
extracellular matrix deposition has occurred. Normal lung structure
has been maintained, which is evidenced by a comparison of FIG. 4C
with FIG. 4A.
[1482] (B) Effect of a representative compound on expression of
fibrotic marker genes following Bleomycin-induced pulmonary
fibrosis.
[1483] The experiment was carried out using the methods as outlined
above for Example B1 (B).
[1484] The results are shown in FIG. 5 (procollagen I) and FIG. 6
(TGFb). Each data point represents RNA isolated from the lung of a
single rat.
[1485] Intratracheal administration of bleomycin and subsequent
treatment with vehicle only showed large increases in procollagen I
and TGFb gene expression in the lung, as seen in FIGS. 5 and 6,
consistent with the histologically apparent lung fibrosis seen in
FIG. 1B.
[1486] Daily treatment of bleomycin-treated rats with 50 mg/kg of
(compound (u) showed a significant (p<0.0001) inhibition of
expression of fibrotic marker genes in this model, as seen in FIGS.
5 and 6.
[1487] This experiment also demonstrates that expression of
fibrotic markers, and therefore deposition of extracellular matrix,
may be dramatically reduced by treatment with another compound
representative of this invention, namely compound (u).
[1488] By reason of their biological properties the compounds
according to the invention may be used in monotherapy or in
conjunction with other pharmacologically active compounds. Such
pharmacologically active compounds may be compounds which are, for
example, also pharmacologically active in the treatment of
fibrosis. Such pharmacologically active compounds may also be
substances with a secretolytic, broncholytic and/or
anti-inflammatory activity.
[1489] In a preferred embodiment in accordance with the present
invention, such pharmacologically active compounds are preferably
selected from the group consisting of anticholinergic agents,
beta-2 mimetics, steroids, PDE-IV inhibitors, p38 MAP kinase
inhibitors, NK.sub.1 antagonists, LTD4 antagonists, EGFR inhibitors
and endothelin-antagonists.
[1490] Anticholinergic agents may preferably be selected from the
group consisting of the tiotropium salts, oxitropium salts,
flutropium salts, ipratropium salts, glycopyrronium salts and
trospium salts.
[1491] Beta-2 mimetics may preferably be selected from the beta-2
mimetics disclosed, for example, in U.S. Pat. No. 4,460,581, which
is incorporated herein by reference.
[1492] PDE-IV inhibitors may preferably be selected from the group
consisting of enprofyllin, theophyllin, roflumilast, ariflo
(cilomilast), CP-325,366, BY343, D-4396 (Sch-351591), AWD-12-281
(GW-842470),
N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethox-
ybenzamide, NCS-613, pumafentine,
(-)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbe-
nzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide,
(R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrol-
idone,
3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N'--[N-2-cyano-S-methyl-iso-
thioureido]benzyl)-2-pyrrolidone,
cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carbonic
acid],
2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyph-
enyl)cyclohexan-1-one,
cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1--
ol],
(R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-yliden-
]acetate,
(S)-(-)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-y-
liden]acetate, CDP840, Bay-198004, D-4418, PD-168787, T-440,
T-2585, arofyllin, atizoram, V-11294A, Cl-1018, CDC-801, CDC-3052,
D-22888, YM-58997, Z-15370,
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4--
triazolo[4,3-a]pyridine and
9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-
-triazolo[4,3-a]pyridine. These compounds may be used, as
available, in the form of their racemates, enantiomers or
diastereoisomers, or in the form of pharamacologically acceptable
acid addition salts thereof, or in the form of their solvates
and/or hydrates.
[1493] Steroids may preferably be selected from the group
consisting of prednisolone, prednisone, butixocortpropionate,
RPR-106541, flunisolid, beclomethasone, triamcinolone, budesonid,
fluticasone, mometasone, ciclesonid, rofleponid, ST-126,
dexamethasone,
6.alpha.,9.alpha.-difluoro-17.alpha.-[(2-furanylcarbonyl)oxy]-11.beta.-hy-
droxy-16.alpha.-methyl-3-oxo-androsta-1,4-dien-17.beta.-carbothionic
acid (S)-fluoromethylester, and
6.alpha.,9.alpha.-difluoro-11.beta.-hydroxy-16.alpha.-methyl-3-oxo-17.alp-
ha.-propionyloxy-androsta-1,4-diene-17.beta.-carbothionic acid
(S)-(2-oxo-tetrahydro-furan-3S-yl)ester. These compounds may be
used, as available, in the form of their racemates, enantiomers or
diastereoisomers, or in the form of pharamacologically acceptable
acid addition salts thereof, or in the form of their solvates
and/or hydrates.
[1494] p38 MAP kinase inhibitors may preferably be selected from
the group consisting of the p38 Kinase inhibitors that are
disclosed for instance in U.S. Pat. No. 5,716,972, U.S. Pat. No.
5,686,455, U.S. Pat. No. 5,656,644, U.S. Pat. No. 5,593,992, U.S.
Pat. No. 5,593,991, U.S. Pat. No. 5,663,334, U.S. Pat. No.
5,670,527, U.S. Pat. Nos. 5,559,137, 5,658,903, U.S. Pat. No.
5,739,143, U.S. Pat. No. 5,756,499, U.S. Pat. No. 6,277,989, U.S.
Pat. No. 6,340,685, and U.S. Pat. No. 5,716,955 and PCT
applications WO 92/12154, WO 94/19350, WO 95/09853, WO 95/09851, WO
95/09847, WO 95/09852, WO 97/25048, WO 97/25047, WO 97/33883, WO
97/35856, WO 97/35855, WO 97/36587, WO 97/47618, WO 97/16442, WO
97/16441, WO 97/12876, WO 98/25619, WO 98/06715, WO 98/07425, WO
98/28292, WO 98/56377, WO 98/07966, WO 98/56377, WO 98/22109, WO
98/24782, WO 98/24780, WO 98/22457, WO 98/52558, WO 98/52559, WO
98/52941, WO 98/52937, WO 98/52940, WO 98/56788, WO 98/27098, WO
98/47892, WO 98/47899, WO 98/50356, WO 98/32733, WO 99/58523, WO
99/01452, WO 99/01131, WO 99/01130, WO 99/01136, WO 99/17776, WO
99/32121, WO 99/58502, WO 99/58523, WO 99/57101, WO 99/61426, WO
99/59960, WO 99/59959, WO 99/00357, WO 99/03837, WO 99/01441, WO
99/01449, WO 99/03484, WO 99/15164, WO 99/32110, WO 99/32111, WO
99/32463, WO 99/64400, WO 99/43680, WO 99/17204, WO 99/25717, WO
99/50238, WO 99/61437, WO 99/61440, WO 00/26209, WO 00/18738, WO
00/17175, WO 00/20402, WO 00/01688, WO 00/07980, WO 00/07991, WO
00/06563, WO 00/12074, WO 00/12497, WO 00/31072, WO 00/31063, WO
00/23072, WO 00/31065, WO 00/35911, WO 00/39116, WO 00/43384, WO
00/41698, WO 00/69848, WO 00/26209, WO 00/63204, WO 00/07985, WO
00/59904, WO 00/71535, WO 00/10563, WO 00/25791, WO 00/55152, WO
00/55139, WO 00/17204, WO 00/36096, WO 00/55120, WO 00/55153, WO
00/56738, WO 01/21591, WO 01/29041, WO 01/29042, WO 01/62731, WO
01/05744, WO 01/05745, WO 01/05746, WO 01/05749, WO 01/05751, WO
01/27315, WO 01/42189, WO 01/00208, WO 01/42241, WO 01/34605, WO
01/47897, WO 01/64676, WO 01/37837, WO 01/38312, WO 01/38313, WO
01/36403, WO 01/38314, WO 01/47921, WO 01/27089, DE 19842833, and
JP 2000 86657 whose disclosures are all incorporated herein by
reference in their entirety.
[1495] Of particular interest for the combinations according to the
invention are those p38 inhibitors disclosed in U.S. Pat. No.
6,277,989, U.S. Pat. No. 6,340,685, WO 00/12074, WO 00/12497, WO
00/59904, WO 00/71535, WO 01/64676, WO 99/61426, WO 00/10563, WO
00/25791, WO 01/37837, WO 01/38312, WO 01/38313, WO 01/38314, WO
01/47921, WO 99/61437, WO 99/61440, WO 00/17175, WO 00/17204, WO
00/36096, WO 98/27098, WO 99/00357, WO 99/58502, WO 99/64400, WO
99/01131, WO 00/43384, WO 00/55152, WO 00/55139, and WO 01/36403.
In a preferred embodiment the p38 kinase inhibitor is selected from
the compounds of following formula (I) as disclosed in WO
99/01131
##STR00076##
[1496] wherein
[1497] R.sub.1 is 4-pyridyl, pyrimidinyl, 4-pyridazinyl,
1,2,4-triazin-5-yl, quinolyl, isoquinolinyl, or quinazolin-4-yl
ring, which ring is substituted with Y--R.sub.a and optionally with
an additional independent substituent selected from C.sub.1-4
alkyl, halogen, hydroxyl, C.sub.1-4 alkoxy, C.sub.1-4 akylthio,
C.sub.1-4 aklylsulfinyl, CH.sub.2OR.sub.12, amino, mono and
di-C.sub.1-6 alkyl substituted amino, an N-heterocyclyl ring which
ring has from 5 to 7 members and optionally contains an additional
heteroatom selected from oxygen, sulfur or NR.sub.15,
N(R.sub.10)C(O)R.sub.b or NHR.sub.a;
[1498] Y is oxygen or sulfur;
[1499] R.sub.4 is phenyl, naphth-1-yl or naphthyl, or a heteroaryl,
which is optionally substituted by one or two substituents, each of
which is independently selected, and which, for a 4-phenyl,
4naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is
halogen, cyano, nitro, C(Z)NR.sub.7R.sub.17, C(Z)OR.sub.16,
(CR.sub.10R.sub.20).sub.vCOR.sub.12, SR.sub.5, SOR.sub.5,
OR.sub.12, halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl,
ZC(Z)R.sub.12, NR.sub.10C(Z)R.sub.16, or
(CR.sub.10R.sub.20).sub.vNR.sub.10R.sub.20 and which, for other
positions of substitution, is halogen, cyano,
C(Z)NR.sub.13R.sub.14, C(Z)OR.sub.3,
(CR.sub.10R.sub.20).sub.mCOR.sub.3, S(O).sub.mR.sub.3, OR.sub.3,
halo-substituted-C.sub.1-4 alkyl, C.sub.1-4 alkyl,
(CR.sub.10R.sub.20).sub.m''R.sub.10C(Z)R.sub.3,
NR.sub.10S(O).sub.m'R.sub.8, NR.sub.10S(O).sub.m'NR.sub.7R.sub.17,
ZC(Z)R.sub.3 or (CR.sub.10R.sub.20).sub.m''NR.sub.13R.sub.14;
[1500] Z is oxygen or sulfur;
[1501] n is an integer having a value of 1 to 10;
[1502] m is 0, or integer 1 or 2;
[1503] m' is an integer having a value of 1 or 2;
[1504] m'' is 0, or an integer having a value of 1 to 5;
[1505] v is 0, or an integer having a value of 1 to 2;
[1506] R.sub.2 is --C(H)(A)(R.sub.22);
[1507] A is optionally substituted aryl, heterocyclyl, or
heteroaryl ring, or A is substituted C.sub.1-10 alkyl;
[1508] R.sub.22 is an optionally substituted C.sub.1-10 alkyl;
[1509] R.sub.a is aryl, arylC.sub.1-6 alkyl, heterocyclic,
heterocyclylC.sub.1-6 alkyl, heteroaryl, heteroarylC.sub.1-6alkyl,
wherein each of these moieties may be optionally substituted;
[1510] R.sub.b is hydrogen, C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl,
aryl, aryl C.sub.1-4 alkyl, heteroaryl, heteroarylC.sub.1-4 alkyl,
heterocyclyl, or heterocyclylC.sub.1-4 alkyl, wherein each of these
moieties may be optionally substituted;
[1511] R.sub.3 is heterocyclyl, heterocyclyl C.sub.1-10 alkyl or
R.sub.8;
[1512] R.sub.5 is hydrogen, C.sub.1-4 alkyl, C.sub.2-4 alkenyl,
C.sub.2-4 alkynyl or NR.sub.7R.sub.17, excluding the moieties
SR.sub.5 being SNR.sub.7R.sub.17 and SOR.sub.5 being SOH;
[1513] R.sub.6 is hydrogen, a pharmaceutically acceptable cation,
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, aryl, aryl C.sub.1-4 alkyl,
heteroaryl, heteroaryl C.sub.1-4 alkyl, heterocyclyl, aryl, or
C.sub.1-10 alkanoyl;
[1514] R.sub.7 and R.sub.17 is each independently selected from
hydrogen or C.sub.1-4 alkyl or R.sub.7 and R.sub.17 together with
the nitrogen to which they are attached form a heterocyclic ring of
5 to 7 members which ring optionally contains an additional
heteroatom selected from oxygen, sulfur or NR.sub.15;
[1515] R.sub.8 is C.sub.1-10 alkyl, halo-substituted C.sub.1-10
alkyl, C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-7
cycloalkyl, C.sub.5-7 cycloalkenyl, aryl, aryl C.sub.1-10 alkyl,
heteroaryl, heteroaryl C.sub.1-10 alkyl,
(CR.sub.10R.sub.20).sub.nOR.sub.11,
(CR.sub.10R.sub.20).sub.nS(O).sub.mR.sub.18,
(CR.sub.10R.sub.20).sub.nNHS(O).sub.2R.sub.18,
(CR.sub.10R.sub.20).sub.nNR.sub.13R.sub.14; wherein the aryl,
arylalkyl, heteroaryl, heteroaryl alkyl may be optionally
substituted;
[1516] R.sub.9 is hydrogen, C(Z) R.sub.11 or optionally substituted
C.sub.1-10 alkyl, S(O).sub.2R.sub.18, optionally substituted aryl
or optionally substituted aryl C.sub.1-4 alkyl;
[1517] R.sub.10 and R.sub.20 is each independently selected from
hydrogen or C.sub.1-4 alkyl;
[1518] R.sub.11 is hydrogen, C.sub.1-10 alkyl, C.sub.3-7
cycloalkyl, heterocyclyl, heterocyclyl C.sub.1-10 alkyl, aryl,
arylC.sub.1-10 alkyl, heteroaryl or heteroaryl C.sub.1-10 alkyl,
wherein these moieties may be optionally substituted;
[1519] R.sub.12 is hydrogen or R.sub.16;
[1520] R.sub.13 an R.sub.14 is each independently selected from
hydrogen or optionally substituted C.sub.1-4 alkyl, optionally
substituted aryl or optionally substituted arylC.sub.1-4 alkyl, or
together with the nitrogen which they are attached form a
heterocyclic ring of 5 to 7 members which ring optionally contains
an additional heteroatom selected from oxygen, sulfur or
NR.sub.9;
[1521] R.sub.15 is R.sub.10 or C(Z)--C.sub.1-4 alkyl;
[1522] R.sub.16 is C.sub.1-4 alkyl, halo-substituted-C.sub.1-4
alkyl, or C.sub.3-7 cycloalkyl;
[1523] R.sub.18 is C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl,
heterocyclyl, aryl, aryl.sub.1-10alkyl, heterocyclyl,
heterocyclyl-C.sub.1-10alkyl, heteroaryl or heteroaryl.sub.1-10
alkyl; [1524] or a pharmaceutically acceptable salt thereof.
[1525] NK1 antagonists may preferably be selected from the group
consisting of
N-[2-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-2-{4-cyclopropylmethyl-piper-
azin-1-yl}-N-methyl-2-phenyl-acetamide (BIIF 1149), CP-122721,
FK-888, NKP 608C, NKP 608A, CGP 60829, SR 48968 (Saredutant), SR
140333 (Nolpitantium besilate/chloride), LY 303 870 (Lanepitant),
MEN-11420 (Nepadutant), SB 223412, MDL-105172A, MDL-103896,
MEN-11149, MEN-11467, DNK 333A, SR-144190, YM-49244, YM-44778,
ZM-274773, MEN-10930, S-19752, Neuronorm, YM-35375, DA-5018,
Aprepitant (MK-869), L-754030, CJ-11974, L-758298, DNK-33A, 6b-I,
CJ-11974, TAK-637, GR 205171 and the arylglycine amide derivates of
general formula (VIII)
##STR00077##
[1526] wherein
[1527] R.sup.1 and R.sup.2 together with the N-atom they are bound
to form a ring of formula
##STR00078##
[1528] wherein r and s independently denote the number 2 or 3;
[1529] R.sup.6 denotes H, --C.sub.1-C.sub.5-alkyl,
C.sub.3-C.sub.5-alkenyl, propinyl, hydroxy(C.sub.2-C.sub.4)alkyl,
methoxy(C.sub.2-C.sub.4)alkyl,
di(C.sub.1-C.sub.3)alkylamino(C.sub.2-C.sub.4)alkyl,
amino(C.sub.2-C.sub.4)alkyl, amino, di(C.sub.1-C.sub.3)alkylamino,
monofluoro-up to perfluoro(C.sub.1-C.sub.2)alkyl,
N-methylpiperidinyl, pyridyl, pyrimidinyl, pyrazinyl or
pyridazinyl,
[1530] R.sup.7 denotes any of the groups defined under (a) to (d):
[1531] (a) hydroxy [1532] (b) 4-piperidinopiperidyl,
[1532] ##STR00079## [1533] wherein R.sup.16 and R.sup.17
independently denote H, (C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.6)cycloalkyl, hydroxy(C.sub.2-C.sub.4)alkyl,
dihydroxy(C.sub.2-C.sub.4)alkyl,
(C.sub.1-C.sub.3)alkoxy(C.sub.2-C.sub.4)alkyl,
phenyl(C.sub.1-C.sub.4)alkyl or
di(C.sub.1-C.sub.3)alkylamino(C.sub.2-C.sub.4)alkyl, and
[1534] R.sup.8 denotes H,
[1535] optionally in the form of enantiomers, mixtures of
enantiomers or the racemates.
[1536] The compounds of formula (VIII) mentioned hereinbefore are
described in WO 96/32386, WO 97/32865 and WO 02/32865. The
disclosure of these international patent applications is
incorporated herein by reference in its entirety.
[1537] LTD4 antagonists may preferably be selected from the group
consisting of montelukast,
1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy--
2-propyl)phenyl)thio)methylcyclopropane-acetate,
1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phen-
yl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-a-
cetate, pranlukast, zafirlukast,
[2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetate-
, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078,
VUF-K-8707 and L-733321. These compounds may be used, as available,
in the form of their racemates, enantiomers or diastereoisomers, or
in the form of pharamacologically acceptable acid addition salts
thereof, or in the form of their solvates and/or hydrates.
[1538] EGFR inhibitors may preferably be selected from the group
consisting of
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-y-
l]amino}-7-cyclopropylmethoxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-
-yl]amino}-7-cyclopropylmethoxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten--
1-yl]amino}-7-cyclopropylmethoxy-chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]a-
mino}-7-cyclopentyloxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-y-
l)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-y-
l)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-chinazoline-
,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morph-
olin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl-
)-ethoxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten--
1-yl]amino}-7-cyclopentyloxy-chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-
-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]--
1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-am-
ino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten--
1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten--
1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amin-
o]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-o-
xo-2-buten-1-yl]amino}-7-cyclopentyloxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten--
1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten--
1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-ethinyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vin-
ylcarbonyl)amino]-chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrim-
idine,
3-cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)--
1-oxo-2-buten-1-yl]amino}-7-ethoxy-chinoline,
4-{[3-chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonyl--
ethyl)amino]methyl}-furan-2-yl)chinazoline,
4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-
-oxo-2-buten-1-yl]amino}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-y-
l]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]--
1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-o-
xo-2-buten-1-yl]amino}-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl-
)-ethoxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl-
)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl-
)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidi-
n-1-yl]-ethoxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-
-4-yloxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7--
methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohex-
an-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-c-
hinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methox-
y-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperid-
in-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidi-
n-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-chinazo-
line,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperid-
in-4-yloxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-ch-
inazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-ylox-
y)-7-hydroxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methox-
y-ethoxy)-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamin-
o]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylami-
no]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulfonylami-
no]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetyl-
amino-ethoxy)-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methan-
sulfonylamino-ethoxy)-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperid-
in-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yl-
oxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carb-
onyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]--
N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulfonyl]--
N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexa-
n-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)--
7-ethoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)--
7-(2-methoxy-ethoxy)-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-ylo-
xy]-7-(2-methoxy-ethoxy)-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy-
)-7-methoxy-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-ylo-
xy]-7-methoxy-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-chinazo-
line,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbo-
nyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)c-
arbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino-
]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-pi-
peridin-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperid-
in-4-yloxy}-7-(2-methoxy-ethoxy)-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-chin-
azoline,
4-[(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-meth-
oxy-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)-7-meth-
oxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-meth-
oxy-ethoxy)-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-y-
loxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy-
)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-
-amino]-cyclohexan-1-yloxy}-7-methoxy-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7--
methoxy-chinazoline,
4-[(3-Ethinyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-y-
loxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)-
carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl-
]-piperidin-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]-
hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)-
carbonyl]-piperidin-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-
-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperid-
in-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-
-piperidin-4-yloxy}-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-ami-
no)-cyclohexan-1-yloxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cycl-
ohexan-1-yloxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-ylo-
xy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-a-
mino)-cyclohexan-1-yloxy]-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-y-
loxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl-
]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl-
)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidin-4-yloxy)--
7-methoxy-chinazoline,
4-[(3-chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-
-chinazoline, Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62. These
compounds may be used, as available, in the form of their
racemates, enantiomers or diastereoisomers, or in the form of
pharamacologically acceptable acid addition salts thereof, or in
the form of their solvates and/or hydrates.
[1539] These compounds are disclosed in the prior art, e.g. in WO
96/30347, WO 97/02266, WO 99/35146, WO 00/31048, WO 00/78735, WO
01/34574, WO 01/61816, WO 01/77104, WO02/18351, WO 02/18372, WO
02/18373, WO 02/18376, WO 02/50043, WO 03/082290, Cancer Research
2004, 64:11 (3958-3965), Am J Health-Syst Pharm 2000, 57(15),
2063-2076, Clinical Therapeutics 1999, 21(2), 309-318, WO 98/50433,
and WO 95/20045.
[1540] Endothelin-antagonists may preferably be selected from the
group consisting of tezosentan, bosentan, enrasentan, sixtasentan,
T-0201, BMS-193884, K-8794, PD-156123, PD-156707, PD-160874,
PD-180988, S-0139 and ZD-1611. Any reference to
endothelin-antagonists within the scope of the present invention
includes a reference to the salts, preferably pharmacologically
acceptable acid addition salts, or derivatives which may be formed
from the endothelin-antagonists.
[1541] These combinations may be administered either simultaneously
or sequentially.
[1542] For pharmaceutical use the compounds according to the
invention are preferably used for warm-blooded vertebrates,
particularly humans, in doses of 0.0001-100 mg/kg of body
weight.
[1543] These compounds may be administered either on their own or
in conjunction with other active substances by intravenous,
subcutaneous, intramuscular, intraperitoneal or intranasal route,
by inhalation, or transdermally, or orally, whilst aerosol
formulations are particularly suitable for inhalation.
[1544] For administration they are formulated with one or more
conventional inert solid, semisolid or liquid carriers e.g. with
starch, different types of cellulose, lactose, mannitol, sorbitol,
glucose, calcium phosphate, hard fat, fatty alcohols, glycerol,
medium chained triglycerides and related esters, polyethylene
glycol, refined specialty oils, water, water/ethanol,
water/glycerol, water/sorbitol, water/polyethylene glycol,
propylene glycol, and/or functional excipients, e.g. with
polyvinylpyrrolidone, hydroxypropylmethylcellulose, sodium
carboxymethylcellulose, sodium starch glycolate, silicon dioxide,
polysorbates, poloxamers, gelucires, magnesium stearate, citric
acid, tartaric acid, or suitable mixtures thereof in conventional
galenic preparations such as plain or coated tablets, capsules,
powders, injectable solutions, ampoules, suspensions, solutions,
sprays or suppositories.
[1545] The following examples of formulations illustrate the
present invention without representing a limitation of its
scope.
Example F1: Coated Tablet Containing 75 mg of Active Substance
[1546] Composition
TABLE-US-00009 1 tablet core contains: active substance 75.0 mg
calcium phosphate 131.0 mg polyvinylpyrrolidone 10.0 mg
carboxymethylcellulose sodium 10.0 mg silicon dioxide 2.5 mg
magnesium stearate 1.5 mg 230.0 mg
[1547] Preparation (Direct Compression)
[1548] The active substance is mixed with all components, sieved
and compressed in a tablet-making machine to form tablets of the
desired shape. [1549] Weight of core: 230 mg [1550] Appearance of
core: 9 mm, biconvex
[1551] The tablet cores thus produced are coated with a film
consisting essentially of hydroxypropylmethylcellulose. [1552]
Weight of coated tablet: 240 mg.
Example F2: Tablet Containing 100 mg of Active Substance
[1553] Composition
TABLE-US-00010 1 tablet contains: active substance 100.0 mg lactose
80.0 mg corn starch 34.0 mg hydroxypropylmethylcellulose 4.0 mg
magnesium stearate 2.0 mg 220.0 mg
[1554] Preparation (Wet Granulation)
[1555] The active substance, lactose and starch are mixed together
and uniformly moistened with an aqueous solution of the
hydroxypropylmethylcellulose. After the moist composition has been
screened (2.0 mm mesh size) and dried in a rack-type drier at
50.degree. C. it is screened again (1.5 mm mesh size) and the
lubricant is added. The finished mixture is compressed to form
tablets. [1556] Weight of tablet: 220 mg [1557] Appearance of
tablet: 10 mm, flat faced with bevelled edges and breaking notch on
one side.
Example F3: Tablet Containing 150 mg of Active Substance
[1558] Composition
TABLE-US-00011 1 tablet contains: active substance 150.0 mg lactose
85.0 mg microcrystalline cellulose 40.0 mg polyvinylpyrrolidone
10.0 mg silicon dioxide 10.0 mg magnesium stearate 5.0 mg 300.0
mg
[1559] Preparation (Dry Granulation)
[1560] The active substance mixed with lactose,
polyvinylpyrrolidone, and parts of the microcrystalline cellulose,
magnesium stearate is compacted e.g. on a roller compactor. The
ribbons are broken up in fine granules through a screen with a mesh
size of 0.8 mm. After subsequent sieving through a screen with a
mesh size of 0.5 mm and blending with the remaining components,
tablets are pressed from the mixture. [1561] Weight of tablet: 300
mg [1562] Appearance of tablet: 10 mm, flat
Example F4: Hard Gelatine Capsule Containing 150 mg of Active
Substance
[1563] Composition
TABLE-US-00012 1 capsule contains: active substance 150.0 mg
lactose 85.0 mg microcrystalline cellulose 40.0 mg
polyvinylpyrrolidone 10.0 mg silicon dioxide 10.0 mg magnesium
stearate 5.0 mg 300.0 mg
[1564] Preparation
[1565] The active substance mixed with lactose,
polyvinylpyrrolidone, and parts of the microcrystalline cellulose,
magnesium stearate is compacted e.g. on a roller compactor. The
ribbons are broken up in fine granules through a screen with a mesh
size of 0.8 mm. After subsequent sieving through a screen with a
mesh size of 0.5 mm and blending with the remaining components, the
finished mixture is packed into size 1 hard gelatine capsules.
[1566] Capsule filling: approx. 300 mg [1567] Capsule shell: size 1
hard gelatine capsule.
Example F5: Suppository Containing 150 mg of Active Substance
TABLE-US-00013 [1568] 1 suppository contains: active substance
150.0 mg polyethyleneglycol 1500 800.0 mg polyethyleneglycol 6000
850.0 mg polyoxyl 40 hydrogenated castor oil 200.0 mg 2,000.0
mg
[1569] Preparation
[1570] After the suppository mass has been melted the active
substance is homogeneously distributed therein and the melt is
poured into chilled moulds.
Example F6: Suspension Containing 50 mg of Active Substance
TABLE-US-00014 [1571] 100 ml of suspension contains active
substance 1.00 g carboxymethylcellulose sodium 0.10 g methyl
p-hydroxybenzoate 0.05 g propyl p-hydroxybenzoate 0.01 g glucose
10.00 g glycerol 5.00 g 70% sorbitol solution 20.00 g flavouring
0.30 g dist. water ad 100 ml
[1572] Preparation
[1573] The distilled water is heated to 70.degree. C. The methyl
and propyl p-hydroxybenzoates together with the glycerol and sodium
salt of carboxymethylcellulose are dissolved therein with stirring.
The solution is cooled to ambient temperature and the active
substance is added and homogeneously dispersed therein with
stirring. After the sugar, the sorbitol solution and the flavouring
have been added and dissolved, the suspension is evacuated with
stirring to eliminate air.
[1574] Thus, 5 ml of suspension contains 50 mg of active
substance.
Example F7: Ampoule Containing 10 mg Active Substance
[1575] Composition
TABLE-US-00015 active substance 10.0 mg 0.01N hydrochloric acid
q.s. double-distilled water ad 2.0 ml
[1576] Preparation
[1577] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with sodium chloride, filtered sterile
and transferred into a 2 ml ampoule.
Example F8: Ampoule Containing 50 mg of Active Substance
[1578] Composition
TABLE-US-00016 active substance 50.0 mg 0.01N hydrochloric acid
q.s. double-distilled water ad 10.0 ml
[1579] Preparation
[1580] The active substance is dissolved in the necessary amount of
0.01 N HCl, made isotonic with sodium chloride, filtered sterile
and transferred into a 10 ml ampoule.
Example F9: Capsule for Powder Inhalation Containing 5 mg of Active
Substance
TABLE-US-00017 [1581] 1 capsule contains active substance 5.0 mg
lactose for inhalation 15.0 mg 20.0 mg
[1582] Preparation
[1583] The active substance is mixed with lactose for inhalation.
The mixture is packed into capsules in a capsule-making machine
(weight of the empty capsule approx. 50 mg).
[1584] weight of capsule: 70.0 mg
[1585] size of capsule=size 3
Example F10: Solution for Inhalation for a Hand-Held Nebuliser
Containing 2.5 mg Active Substance
TABLE-US-00018 [1586] 1 spray contains active substance 2.500 mg
benzalkonium chloride 0.001 mg 1N hydrochloric acid q.s.
ethanol/water (50/50) ad 15.000 mg
[1587] Preparation
[1588] The active substance and benzalkonium chloride are dissolved
in ethanol/water (50/50). The pH of the solution is adjusted with
1N hydrochloric acid. The resulting solution is filtered and
transferred into suitable containers for use in hand-held
nebulisers (cartridges).
[1589] Contents of the container: 4.5 g
Sequence CWU 1
1
6121DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 1gatgccgatc agaagtttgg a 21220DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
2tcgttggtcg tgcagatctc 20321DNAArtificial SequenceDescription of
Artificial Sequence Synthetic probe 3ctgcccaatg gctgcccatg a
21423DNAArtificial SequenceDescription of Artificial Sequence
Synthetic primer 4cagactggca acctgaagaa gtc 23517DNAArtificial
SequenceDescription of Artificial Sequence Synthetic primer
5tcgcccctga gctcgat 17623DNAArtificial SequenceDescription of
Artificial Sequence Synthetic probe 6ctgctcctcc agggctccaa cga
23
* * * * *