U.S. patent application number 11/894591 was filed with the patent office on 2008-01-31 for indolyl-3-glyoxylic acid derivatives having antitumor action.
This patent application is currently assigned to Asta Medica Aktiengesellschaft. Invention is credited to Kay Brune, Peter Emig, Eckhard Gunther, Guillaume Le Baut, Bernd Nickel, Dietmar Reichert, Jurgen Schmidt, Istvan Szelenyi.
Application Number | 20080027110 11/894591 |
Document ID | / |
Family ID | 7863398 |
Filed Date | 2008-01-31 |
United States Patent
Application |
20080027110 |
Kind Code |
A1 |
Nickel; Bernd ; et
al. |
January 31, 2008 |
Indolyl-3-glyoxylic acid derivatives having antitumor action
Abstract
The invention relates to the use of N-substituted
indole-3-glyoxylamides of the general formula I as antitumor agents
##STR1## and to a pharmaceutical composition having antitumor
action, characterized in that it contains at least one of the
compounds of the general formula 1, if appropriate also in the form
of the physiologically tolerable acid addition salts or N-oxides.
Furthermore, the invention also includes antitumor agents
comprising as active compound one or more N-substituted
indole-3-glyoxylamides according to the general formula 1 and, if
appropriate, their physiologically tolerable acid addition salts
and, if possible, N-oxides and a pharmaceutically utilizable
carrier and/or diluent or auxiliary substance in the form of
tablets, coated tablets, capsules, solutions for infusion or
ampoules, suppositories, patches, powder preparations which can be
employed by inhalation, suspensions, creams and ointments.
Inventors: |
Nickel; Bernd; (Muhltal,
DE) ; Szelenyi; Istvan; (Schwaig, DE) ;
Schmidt; Jurgen; (Uhidingen Muhihofen, DE) ; Emig;
Peter; (Bruchkobel, DE) ; Reichert; Dietmar;
(Eschau, DE) ; Gunther; Eckhard; (Maintal, DE)
; Brune; Kay; (Marloffstein, DE) ; Le Baut;
Guillaume; (Saint Sebastian/Loire, FR) |
Correspondence
Address: |
ROPES & GRAY LLP;PATENT DOCKETING 39/41
ONE INTERNATIONAL PLACE
BOSTON
MA
02110-2624
US
|
Assignee: |
Asta Medica
Aktiengesellschaft
|
Family ID: |
7863398 |
Appl. No.: |
11/894591 |
Filed: |
August 20, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10309204 |
Dec 4, 2002 |
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11894591 |
Aug 20, 2007 |
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09810604 |
Mar 19, 2001 |
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10309204 |
Dec 4, 2002 |
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09285058 |
Apr 2, 1999 |
6232327 |
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09810604 |
Mar 19, 2001 |
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Current U.S.
Class: |
514/333 ;
514/339; 514/419; 546/168; 546/256; 546/277.4; 548/493 |
Current CPC
Class: |
A61K 31/444 20130101;
A61P 35/00 20180101; A61K 31/4439 20130101; A61K 31/4709 20130101;
C07D 209/14 20130101; C07D 403/12 20130101; A61K 31/4178 20130101;
C07D 401/14 20130101; C07D 401/12 20130101; A61K 31/404 20130101;
A61P 35/04 20180101; A61P 35/02 20180101; A61K 31/496 20130101 |
Class at
Publication: |
514/333 ;
514/339; 514/419; 546/168; 546/256; 546/277.4; 548/493 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/404 20060101 A61K031/404; A61K 31/444
20060101 A61K031/444; A61P 35/00 20060101 A61P035/00; C07D 209/12
20060101 C07D209/12; C07D 401/12 20060101 C07D401/12 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 2, 1998 |
DE |
DE 19814838.0 |
Claims
1. N-substituted indole-3-glyoxylamides of the general formula 1
for use as antitumor agents, ##STR158## where the radicals R,
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Z have the following
meaning: R=hydrogen, (C.sub.1-C.sub.6)-alkyl, where the alkyl group
can be mono- or polysubstituted by the phenyl ring and this phenyl
ring for its part can be mono- or polysubstituted by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, by carboxyl
groups, carboxyl groups esterified with C.sub.1-C.sub.6-alkanols,
trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy
groups, benzyloxy groups and by a benzyl group which is mono- or
polysubstituted in the phenyl moiety by (C.sub.1-C.sub.6)-alkyl
groups, halogen atoms or trifluoromethyl groups, R is further the
benzyloxycarbonyl group (Z group) and the tertiary-butoxycarbonyl
radical (BOC radical), furthermore the acetyl group. R.sub.1 can be
the phenyl ring, which is mono- or polysubstituted by
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkoxy, cyano, halogen,
trifluoromethyl, hydroxyl, benzyloxy, nitro, amino,
(C.sub.1-C.sub.6)-alkylamino, (C.sub.1-C.sub.6)-alkoxycarbonylamino
and by the carboxyl group or by the carboxyl group esterified with
C.sub.1-C.sub.6-alkanols, or can be a pyridine structure of the
formula 2 and its N-oxide[sic] ##STR159## and its N-oxide, where
the pyridine structure is alternatively bonded to the ring carbon
atoms 2, 3 and 4 and can be substituted by the substituents R.sub.5
and R.sub.6. The radicals R.sub.5 and R.sub.6 can be identical or
different and have the meaning (C.sub.1-C.sub.6)-alkyl and the
meaning (C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkoxy,
nitro, amino, hydroxyl, halogen, trifluoromethyl and further are
the ethoxycarbonylamino radical and the group carboxyalkyloxy in
which the alkyl group can have 1-4 C atoms. R.sub.1 can further be
a 2- or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can
be mono- or polysubstituted by the methyl group, furthermore are
[sic] the 2-, 3-, and 4- and 8-quinolyl structure substituted by
(C.sub.1-C.sub.6)-alkyl, halogen, the nitro group, the amino group
and the (C.sub.1-C.sub.6)-alkylamino radical, are [sic] a 2-, 3-,
and [sic] 4-quinolylmethyl group, where the ring carbons of the
pyridylmethyl radical of the quinolyl group and of the
quinolylmethyl radical can be substituted by
(C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkoxy, nitro, amino and
(C.sub.1-C.sub.6)-alkoxycarbonylamino. R.sub.1, in the case in
which R=hydrogen, the methyl or benzyl group and the
benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl
radical (BOC radical) and the acetyl group, can furthermore be the
following radicals: --CH.sub.2COOH; --CH(CH.sub.3)--COOH;
--(CH.sub.3).sub.2--CH--(CH.sub.2).sub.2--CH--COO--;
H.sub.3C--H.sub.2C--CH(CH.sub.3)--CH(COOH)--;
HO--H.sub.2C--CH(COOH)--; phenyl-CH.sub.2--CH(COOH)--;
(4-imidazolyl)-CH.sub.2--CH--(COOH)--;
HN.dbd.(NH.sub.2)--NH--(CH.sub.2).sub.3--CH(COOH)--;
H.sub.2N--(CH.sub.2).sub.4--CH(COOH)--;
H.sub.2N--CO--CH.sub.2--CH--(COOH)--;
HOOC--(CH.sub.2).sub.2--CH(COOH)--; R.sub.1, in the case in which R
is hydrogen, the Z group, the BOC radical, the acetyl or the benzyl
group, can furthermore be the acid radical of a natural or
unnatural amino acid, e.g. the .alpha.-glycyl, the
.alpha.-sarcosyl, the .alpha.-seryl, the .alpha.-phenylalanyl, the
.alpha.-histidyl, the .alpha.-prolyl, the .alpha.-arginyl, the
.alpha.-lysyl, the .alpha.-asparagyl and the .alpha.-glutamyl
radical, where the amino groups of the respective amino acids can
be present unprotected or can be protected. A possible protective
group of the amino function is the carbobenzoxy radical (Z radical)
and the tert-butoxycarbonyl radical (BOC radical) as well as the
acetyl group. In the case of the asparagyl and glutamyl radical
claimed for R.sub.1, the second, unbonded carboxyl group is present
as a free carboxyl group or in the form of an ester with
C.sub.1-C.sub.6-alkanols, e.g. as a methyl, ethyl or as a
tert-butyl ester. Furthermore, R.sub.1 can be the
allylaminocarbonyl-2-methylprop-1-yl group. R and R.sub.1 can
further form, together with the nitrogen atom to which they are
bonded, a piperazine ring of the formula III or a homopiperazine
ring, provided R.sub.1 is an aminoalkylene group, in which
##STR160## R.sub.7 is an alkyl radical, is a phenyl ring which can
be mono- or polysubstituted by (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy, halogen, the nitro group, the amino
function and by the (C.sub.1-C.sub.6)-alkylamino group. R.sub.7 is
furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl
[sic] group. R.sub.2 can be hydrogen and the
(C.sub.1-C.sub.6)-alkyl group, where the alkyl group is mono- or
polysubstituted by halogen and phenyl, which for its part can be
mono- or polysubstituted by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, carboxyl groups, carboxyl groups
esterified with C.sub.1-C.sub.6-alkanols, trifluoromethyl groups,
hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.
The (C.sub.1-C.sub.6)-alkyl group counting as R.sub.2 can further
be substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl
structure, which can both in each case be mono- or polysubstituted
by halogen, (C.sub.1-C.sub.4)-alkyl groups or
(C.sub.1-C.sub.4)-alkoxy groups. R.sub.2 is further the aroyl
radical, where the aryl moiety on which this radical is based is
the phenyl ring, which can be mono- or polysubstituted by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, carboxyl
groups, carboxyl groups esterified with C.sub.1-C.sub.6-alkanols,
trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy
groups or benzyloxy groups. R.sub.3 and R.sub.4 can be identical or
different and are hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkanoyl,
(C.sub.1-C.sub.6)-alkoxy, halogen and benzyloxy. R.sub.3 and
R.sub.4 can furthermore be the nitro group, the amino group, the
(C.sub.1-C.sub.4)-mono or dialkyl-substituted amino group, and the
(C.sub.1-C.sub.6)-alkoxycarbonylamino function or
(C.sub.1-C.sub.6)-alkoxycarbonylamino-(C.sub.1-C.sub.6)-alkyl
function. Z is O and S.
2. N-Substituted indole-3-gloxylamides [sic] according to claim 1
with the formula 1a for use as antitumor agents, ##STR161## where
the radicals R=hydrogen R.sub.1=4-pyridyl, 4-fluorophenyl
R.sub.2=benzyl, 4-chlorobenzyl, 4-fluorobenzyl, 3-pyridylmethyl,
4-bromobenzyl R.sub.3 and R.sub.4=hydrogen and Z is oxygen.
3. Pharmaceutical composition having antitumor action
characterized, in that it contains at least one of the compounds of
the general formula 1 or 1a, optionally also they [sic] as acid
addition salts, for example as salts of mineral acids, such as
hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic
acids, such as, for example, acetic acid, lactic acid, malonic
acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid,
citric acid, embonic acid, methanesulfonic acid, trifluoroacetic
acid, succinic acid and 2-hydroxyethanesulfonic acid [sic] and
possibly their N-oxides.
4. Use of N-substituted indole-3-glyoxylamides of the general
formula 1 or 1a and their physiologically tolerable acid addition
salts for the production of antitumor agents for the treatment of
oncoses using these agents, namely in particular the following
compounds or their salts with physiologically tolerable acids or if
possible their N-oxides: D 24241
N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide D
24843 N-(pyridin-4-yl)-(1-benzylindol-3-yl)-glyoxylamide D 24850
N-(4-fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamide D
24851 N-(pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide
D 25505
N-(pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide HCL
[sic]
5. Antitumor agents comprising as active agent one or more
N-substituted indole-3-gloxylamides according to the general
formula 1 or 1a and optionally their physiologically tolerable acid
addition salts, but in particular one or more compounds according
to claim 4.
6. Antitumor agents comprising as active agent D 24241
N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-indol-3-yl]glyoxylamide or its
hydrochloride
7. Antitumor agents comprising as active agent D 24843
N-(Pyridin-4-yl)-(1-benzylindol-3-yl)glyoxylamide.
8. Antitumor agents comprising as active agent D 24850
N-(4-Fluorophenyl)-[1-(3-pyridylmethyl)-indol-3-yl]glyoxylamide
9. Antitumor agents comprising as active agent D 24851
N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)-indol-3-yl]glyoxylamide
10. Antitumor agent comprising as active agent one or more
N-substituted indole-3-gloxylamides according to the general
formula 1 or 1a and optionally their physiologically tolerable acid
addition salts and, if possible, N-oxides, but in particular one or
more compounds according to claim 4 and 6 to 8 and a
pharmaceutically utilizable excipient and/or diluent or auxiliary
in the form of tablets, coated tablets, capsules, solutions for
infusion or ampoules, suppositories, patches, powder preparations
which can be employed by inhalation, suspensions, creams and
ointments.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 10/309,204, filed Dec. 4, 2002, which is a continuation of U.S.
application Ser. No. 09/810,604, filed Mar. 19, 2001, which is a
continuation of U.S. application Ser. No. 09/285,058, filed Apr. 2,
1999, which claims priority to German Application No. DE
19814838.0, filed Apr. 2, 1998. The entire teachings of the above
referenced applications are incorporated herein by reference and
without disclaimer.
BACKGROUND OF THE INVENTION
[0002] Indole-3-glyoxylamides have a variety of uses as
pharmacodynamically active compounds and a synthetic building
blocks in pharmaceutical chemistry.
[0003] In the patent application Neth.Appl. 6502481, compounds are
described which have an anti-inflammatory and antipyretic activity
profile and analgesic activity.
[0004] In the British Application GB-B 1 028 812, derivatives of
indolyl-3-glyoxylic acid and their amides are used as analgesic,
anticonvulsant and .beta.-adrenergic compounds.
[0005] G. Domschke et al. (Ber. 94, 2353 (1961)) describe
3-indolylglyoxylamides which are not characterized
pharmacologically.
[0006] E. Walton reports in J. Med. Chem., 11, 1252 (1968) on
indolyl-3-glyoxylic acid derivatives which have an inhibitory
action on glycerophosphate dehydrogenase and lactate
dehydrogenase.
[0007] In the European Patent Specification EP 675110,
1H-indole-3-glyoxylamides are described which are profiled as sPLA2
inhibitors and are used in the treatment of septic shock, in
pancreatitis and in the treatment of allergic rhinitis and
rheumatoid arthritis.
[0008] The aim of the present invention is to make available
N-substituted indole-3-glyoxylamides which have an antitumor action
and thus to enrich the available pharmaceutical wealth.
[0009] The compounds mentioned have already been disclosed as
medicaments having antiasthmatic, antiallergic and
immunosuppressant/immunomodulating action in DE-A 19636150 A1.
SUMMARY OF THE INVENTION
[0010] The invention therefore relates to the use of N-substituted
indole-3-glyoxylamides of the general formula 1 for the production
of antitumor agents, antitumor agents having a content of active
substance according to formula 1 and their use for the treatment of
oncoses. ##STR2##
[0011] where the radicals R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
Z have the following meaning:
[0012] R=hydrogen, (C.sub.1-C.sub.6)-alkyl, where the alkyl group
can be mono- or polysubstituted by the phenyl ring and this phenyl
ring for its part can be mono- or polysubstituted by halogen,
(C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl, by carboxyl
groups, carboxyl groups esterified with C.sub.1-C.sub.6-alkanols,
trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy
groups, benzyloxy groups and by a benzyl group which is mono- or
polysubstituted in the phenyl moiety by (C.sub.1-C.sub.6)-alkyl
groups, halogen atoms or trifluoromethyl groups,
[0013] R is further selected from benzyloxycarbonyl (Z group),
tertiary-butoxycarbonyl (BOC radical), and acetyl;
[0014] R.sub.1 can be a phenyl ring, which is mono- or
polysubstituted by (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy, cyano, halogen, trifluoromethyl,
hydroxyl, benzyloxy, nitro, amino, (C.sub.1-C.sub.6)-alkylamino,
(C.sub.1-C.sub.6)-alkoxycarbonylamino or by carboxyl or by carboxyl
esterified with C.sub.1-C.sub.6-alkanols, or R.sub.1 can be a
pyridine structure of the formula 2 ##STR3##
Formula 2
[0015] or an N-oxide thereof, where the pyridine structure is
alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be
substituted by the substituents R.sub.5 and R.sub.6. The radicals
R.sub.5 and R.sub.6 can be identical or different and have the
meaning (C.sub.1-C.sub.6)-alkyl and the meaning
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkoxy, nitro,
amino, hydroxyl, halogen, trifluoromethyl and further are the
ethoxycarbonylamino radical and the group carboxyalkyloxy in which
the alkyl group can have 1-4 C atoms.
[0016] R.sub.1 can further be a 2- or 4-pyrimidinyl heterocycle,
where the 2-pyrimidinyl ring can be mono- or polysubstituted by a
methyl group; a 2-, 3-, 4- or 8-quinolyl structure which may be
substituted by (C.sub.1-C.sub.6)-alkyl, halogen, nitro, amino or
(C.sub.1-C.sub.6)-alkylamino; or a 2-, 3-, or 4-quinolylmethyl
group, where the ring carbons of the pyridylmethyl radical, the
quinolyl group, and the quinolylmethyl radical can be substituted
by (C.sub.1-C.sub.6)-alkyl, (C.sub.1-C.sub.6)-alkoxy, nitro, amino
and (C.sub.1-C.sub.6)-alkoxycarbonylamino;
[0017] R.sub.1, in the case in which R=hydrogen, methyl, benzyl,
benzyloxycarbonyl (Z radical), tert-butoxycarbonyl (BOC radical) or
acetyl, can furthermore be the following radicals:
[0018] --CH.sub.2COOH; --CH(CH.sub.3)--COOH;
--(CH.sub.3).sub.2--CH--(CH.sub.2).sub.2--CH--COO--;
H.sub.3C--H.sub.2C--CH(CH.sub.3)--CH(COOH)--;
HO--H.sub.2C--CH(COOH)--; phenyl-CH.sub.2--CH(COOH)--;
(4-imidazolyl)-CH.sub.2--CH--(COOH)--;
HN.dbd.(NH.sub.2)--NH--(CH.sub.2).sub.3--CH(COOH)--;
H.sub.2N--(CH.sub.2).sub.4--CH(COOH)--;
H.sub.2N--CO--CH.sub.2--CH--(COOH)--; or
HOOC--(CH.sub.2).sub.2--CH(COOH)--;
[0019] R.sub.1, in the case in which R is hydrogen, the Z group,
the BOC radical, acetyl or benzyl, can furthermore be the acid
radical of a natural or unnatural amino acid, e.g. the
.alpha.-glycyl, the .alpha.-sarcosyl, the .alpha.-seryl, the
.alpha.-phenylalanyl, the .alpha.-histidyl, the .alpha.-prolyl, the
.alpha.-arginyl, the .alpha.-lysyl, the .alpha.-asparagyl and the
.alpha.-glutamyl radical, where the amino groups of the respective
amino acids can be present unprotected or can be protected, wherein
a possible protective group of the amino function is carbobenzoxy
(Z radical), tert-butoxycarbonyl (BOC radical) or acetyl and in the
case where R.sub.1 is asparagyl or glutamyl, the second, unbonded
carboxyl group is present as a free carboxyl group or in the form
of an ester with C.sub.1-C.sub.6-alkanols, e.g. as a methyl, ethyl
or as a tert-butyl ester;
[0020] furthermore, R.sub.1 can be the
allylaminocarbonyl-2-methylprop-1-yl group;
[0021] R and R.sub.1 can further form, together with the nitrogen
atom to which they are bonded, a piperazine ring of the formula III
or a homopiperazine ring, provided R.sub.1 is an aminoalkylene
group, in which ##STR4##
[0022] R.sub.7 is an alkyl radical, is a phenyl ring which can be
mono- or polysubstituted by (C.sub.1-C.sub.6)-alkyl,
(C.sub.1-C.sub.6)-alkoxy, halogen, nitro, amino or by
(C.sub.1-C.sub.6)-alkylamino;
[0023] R.sub.7 is furthermore selected from a benzhydryl group or a
bis-p-fluorobenzhydryl group;
[0024] R.sub.2 can be hydrogen and the (C.sub.1-C.sub.6)-alkyl
group, where the alkyl group is mono- or polysubstituted by halogen
and phenyl, which for its part can be mono- or polysubstituted by
halogen, (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.7)-cycloalkyl,
carboxyl, carboxyl esterified with C.sub.1-C.sub.6-alkanols,
trifluoromethyl, hydroxyl, methoxy, ethoxy or benzyloxy;
[0025] where R.sub.2 is (C.sub.1-C.sub.6)-alkyl, it can further be
substituted by the 2-quinolyl group or the 2-, 3- and 4-pyridyl
structure, which can both in each case be mono- or polysubstituted
by halogen, (C.sub.1-C.sub.4)-alkyl or (C.sub.1-C.sub.4)-alkoxy
[[.]];
[0026] R.sub.2 is further the aroyl radical, where the aryl moiety
on which this radical is based is the phenyl ring, which can be
mono- or polysubstituted by halogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, carboxyl, carboxyl esterified with
C.sub.1-C.sub.6-alkanols, trifluoromethyl, hydroxyl, methoxy,
ethoxy or benzyloxy;
[0027] R.sub.3 and R.sub.4 can be identical or different and are
selected from hydrogen, (C.sub.1-C.sub.6)-alkyl,
(C.sub.3-C.sub.7)-cycloalkyl, (C.sub.1-C.sub.6)-alkanoyl,
(C.sub.1-C.sub.6)-alkoxy, halogen and benzyloxy;
[0028] R.sub.3 and R.sub.4 can furthermore be nitro, amino,
(C.sub.1-C.sub.4)-mono or dialkyl-substituted amino,
(C.sub.1-C.sub.6)-alkoxycarbonylamino or
(C.sub.1-C.sub.6)-alkoxycarbonylamino-(C.sub.1-C.sub.6)-alkyl;
[0029] Z is O and S.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] FIG. 1a shows the survival time of animals with murine
leukemia L1210 after intraperitoneal administration of D24851.
[0031] FIG. 1b shows the survival time of animals with murine
leukemia L1210 after oral administration D24851.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The designation alkyl, alkanol, alkoxy or alkylamino group
for the radicals R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5,
R.sub.6, R.sub.7 is normally understood as meaning both
"straight-chain" and "branched" alkyl groups, where "straight-chain
alkyl groups can be, for example, radicals such as methyl, ethyl,
n-propyl, n-butyl, n-pentyl, n-hexyl and "branched alkyl groups"
designate, for example radicals such as isopropyl or tert-butyl.
"Cycloalkyl" is understood as meaning radicals such as, for
example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cycloheptyl.
[0033] The designation "halogen" represents fluorine, chlorine,
bromine or iodine. The designation "alkoxy group" represents
radicals such as, for example, methoxy, ethoxy, propoxy, butoxy,
isopropoxy, isobutoxy or pentoxy.
[0034] The compounds can also be employed s acid addition salts,
for example as salts of mineral acids, such as, for example,
hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic
acids, such as, for example, acetic acid, lactic acid, malonic
acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid,
citric acid, embonic acid, methanesulfonic acid, trifluoroacetic
acid, succinic acid and 2-hydroxyethanesulfonic acid.
[0035] Both the compounds of the formula 1 and their salts are
biologically active.
[0036] The compounds of the formula 1 can be administered in free
form or as salts with physiologically tolerable acids.
[0037] Administration can be performed orally, parenterally,
intravenously, transdermally or by inhalation.
[0038] The invention furthermore relates to pharmaceutical
preparations which contain at least one of the compounds of the
formula 1 or their salts with physiologically tolerable inorganic
or organic acids and, if appropriate, pharmaceutically utilizable
excipients and/or diluents or auxilianes.
[0039] Suitable administration forms are, for example, tablets,
coated tablets, capsules, solutions for infusion or ampoules,
suppositories, patches, powder preparations which can be employed
by inhalation, suspensions, creams and ointments.
[0040] The processes for the production of the compounds according
to the invention are described in the following reaction schemes 1
and 2 and in general procedures. All compounds can be prepared as
described or analogously.
[0041] The compounds of the general formula 1 with Z=O,
R.sub.1=aryl, aralkyl, heteroaryl and heteroaralkyl and
R.sub.2=alkyl, aralkyl and heteroaralkyl are obtainable according
to the following Scheme 1: ##STR5##
[0042] 1st Stage:
[0043] The indol derivative, which can be unsubstituted or
monosubstituted or polysubstituted on C-2 or in the phenyl
structure, is dissolved in a protic, dipolar aprotic or nonpolar
organic solvent, such as, for example, isopropanol,
tetrahydrofuran, dimethyl sulfoxide, dimethylformamide,
dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or
methylene chloride and added dropwise to a suspension of a base
prepared in a three-necked flask under an N.sub.2 atmosphere or
employed in a molar amount or in excess, such as, for example,
sodium hydride, powdered potassium hydroxide, potassium
tert-butoxide, dimethylaminopyridine or sodium amide, in a suitable
solvent. Then the desired alkyl, aralkyl or heteroaralkyl halide,
for example, is added, if appropriate with addition of a catalyst,
such as, for example, copper and the mixture is allowed to react
for some time, for example for 30 minutes to 12 hours, and the
temperature is maintained within a range from 0.degree. C. to
120.degree. C., preferably between 30.degree. C. and 80.degree. C.,
particularly between 50.degree. C. and 65.degree. C. After
completion of the reaction, the reaction mixture is added to water,
the solution is extracted, e.g. with diethyl ether,
dichloromethane, chloroform, methyl tert-butyl ether or
tetrahydrofuran, and the organic phase obtained in each case is
dried with anhydrous sodium sulfate. The organic phase is
concentrated in vacuo, the residue which remains is crystallized by
trituration or the oily residue is purified by recrystallization,
distillation or by column or flash chromatography on silica gel or
alumina. The eluent used is, for example, a mixture of
dichloromethane and diethyl ether in the ratio 8:2 (vol/vol) or a
mixture of dichloromethane and ethanol in the ratio 9:1
(vol/vol).
[0044] 2nd Stage
[0045] The N-substituted indol obtained according to the above
procedure of the 1st Stage is dissolved under a nitrogen atmosphere
in an aprotic or nonpolar organic solvent, such as, for example,
diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane,
toluene, xylene, methylene chloride or chloroform and added to a
solution prepared under a nitrogen atmosphere of a monomolar up to
60% excess amount of oxalyl chloride in an aprotic or nonpolar
solvent, such as, for example, in diethyl ether, methyl tert-butyl
ether, tetrahydrofuran, dioxane, toluene, xylene, methylene
chloride, the temperature being kept between -5.degree. C. and
20.degree. C. The reaction solution is then heated at a temperature
between 10.degree. C. and 130.degree. C., preferably between
20.degree. C. and 80.degree. C., particularly between 30.degree. C.
and 50.degree. C., for a period of 30 minutes to 5 hours and the
solvent is then evaporated. The residue of the
"indolyl-3-glyoxyloyl chloride" formed in this manner which remains
is dissolved in an aprotic solvent such as, for example,
tetrahydrofuran, dioxane, diethyl ether, toluene or alternatively
in a dipolar aprotic solvent, such as, for example,
dimethylformamide, dimethylacetamide or dimethyl sulfoxide, cooled
to a temperature between 10.degree. C. and -15.degree. C.,
preferably between -5.degree. C. and 0.degree. C., and treated in
the presence of an acid scavenger with a solution of the primary or
secondary amine in a diluent. Possible diluents are the solvents
used above for dissolving the indolyl-3-glyoxyloyl chloride. Acid
scavengers used are triethylamine, pyridine, dimethylaminopyridine,
basic ion exchanger, sodium carbonate, potassium carbonate,
powdered potassium hydroxide and excess primary or secondary amine
employed for the reaction. The reaction takes place at a
temperature from 0.degree. C. to 120.degree. C., preferably at
20-80.degree. C., particularly between 40.degree. C. and 60.degree.
C. After a reaction time of 1-3 hours and standing at room
temperature for 24 hours, the hydrochloride of the acid scavenger
is filtered, the filtrate is concentrated in vacuo and the residue
is recrystallized from an organic solvent or purified by column
chromatography on silica gel or alumina. Eluents used are, for
example, a mixture of dichloromethane and ethanol (95:5,
vol/vol).
WORKING EXAMPLES
[0046] According to this general procedure for Stages 1 and 2, on
which synthesis scheme 1 is based, the following compounds were
synthesized which are evident from the following tabulated list
detailing the respective chemical name. In Tables 1a-j on pages
A-J, the structures of these compounds and their melting points can
be seen from the general formula 1 and the substituents
R.sub.1-R.sub.4 and Z:
Example 1
N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl}glyoxyl-amide (D
24241)
[0047] 1st Stage
1-(4-Fluorobenzyl)indole
[0048] A solution of 11.72 g (0.1 mol) of indol in 50 ml of
dimethyl sulfoxide is added to a mixture of 2.65 g of sodium
hybride (0.11 mol, mineral oil suspension) in 100 ml of dimethyl
sulfoxide. The mixture is heated at 60.degree. C. for 1.5 hours,
then allowed to cool and 15.9 g (0.11 mol) of 4-fluorobenzyl
chloride are added dropwise. The solution is warmed to 60.degree.
C., allowed to stand overnight and then poured into 400 ml of water
with stirring. The mixture is extracted a number of times with a
total of 150 ml of methylene chloride, the organic phase is dried
using anhydrous sodium sulfate, filtered and the filtrate is
concentrated in vacuo. The residue is distilled in a high vacuum:
21.0 g (96% of theory) b.p. (0.5 mm): 140.degree. C.
[0049] 2nd Stage
N-(Pyridine-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxyl-amide (D
24241)
[0050] A solution of 4.75 g (21.1 mmol) of 1-(4-fluoro-benzyl)indol
in 25 ml of ether is added dropwise at 0.degree. C. and under
N.sub.2 to a solution of 2.25 ml of oxalyl chloride in 25 ml of
ether. The mixture is heated to reflux for 2 hours and the solvent
is then evaporated. 50 ml of tetrahydrofuran were then added to the
residue, the solution was cooled to -5.degree. C. and treated
dropwise with a solution of 4.66 g (49.5 mmol) of 4-aminopyridine
in 200 ml of THF. The mixture is heated to reflux for 3 hours and
allowed to stand at room temperature overnight. The 4-aminopyridine
hydro-chloride is filtered off with suction, the precipitated is
washed with THF, the filtrate is concentrated in vacuo and the
residue is recrystallized from ethyl acetate.
[0051] Yield: 7.09 g (90% of theory)
[0052] Melting point: 225-226.degree. C.
[0053] Elemental analysis: TABLE-US-00001 Ber. C 70.77 H 4.32 N
11.25 Gef. C 71.09 H 4.36 N 11.26
[0054] Example 2, D 242424
N-(pyridin-4-yl)-(1-methylindol-3-yl)glyoxylamide
[0055] Example 3, D 24834 N
(Pyridin-3-yl)-(1-(4-fluoro-benzyl)indol-3-yl]glyoxylamide
[0056] Example 4, D 24835
N-(Pyridin-3-yl)-(1-benzylindol-3-yl)glyoxylamide
[0057] Example 5, D 24836
N-(Pyridin-3-yl)-[1-(2-chloro-benzyl)indol-3-yl]glyoxylamide
[0058] Example 6, D 24840
N-(4-Fluorophenyl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide
[0059] Example 7, D 24841
N-(4-Nitrophenyl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide
[0060] Example 8, D 24842
N-(2-chloropyridin-3-yl)-[1(4-fluorobenzyl)indol-3-yl]glyoxylamide
[0061] Example 9, D 24843
N-(Pyridin-4-yl)-(1-benzylindol-3-yl)glyoxylamide
[0062] Example 10, D 24848
N-(Pyridin-4-yl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylamide
[0063] Example 11, D 24849
N-(4-Fluorophenyl)-[1-(2-pyridylmethyl)indol-3-yl]glyoxylamide
[0064] Example 12, D 24850
N-(4-Fluorophenyl)-[1(3-pyridylmethyl)indol-3-yl]glyoxylamide
[0065] Example 13, D 24851
N-(Pyridin-4-yl)-[1(4-chlorobenzyl)indol-3-yl]glyoxylamide
[0066] Example 14, D 24852
N-(Pyridin-4-yl)-[1-(2-chlorobenzyl)indol-3-yl]glyoxylamide
[0067] Example 15, D 24853
N-(Pyridin-2-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide
[0068] Example 16, D
N-(Pyridin-4-yl)-[1-(2-pyridylmethyl)indol-3-yl]glyoxylamide
[0069] Example 17, D 24858
(4-Phenylpiperazin-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]glyoxylamide
[0070] Example 18, D 24854
N-(Pyridin-2-yl)-(1-benzylindol-3-yl)glyoxylamide
[0071] Example 19, D 25421
N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-6-ethoxycarbonylaminoindol-3-yl]glyo-
xylamide
[0072] Example 20, D 25422
N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-5-ethoxycarbonylaminoindol-3-yl]glyo-
xylamide
[0073] Example 21, D
N-(Pyridin-4-yl)-[1-(4-fluorobenzyl)-6-cyclopentyloxycarbonylaminoindol-e-
-yl]glyoxylamide
[0074] Example 22, D 25420
4-(Pyridin-4-yl)piperazin-1-yl)-[1-(4-fluorobenzyl)indol-3-yl]-glyoxylami-
de
[0075] Example 23, D 24866
N-(3,4,5-Trimethoxybenzyl)-N-(allylaminocarbonyl-2-methylprop-1-yl)-[1-(4-
-fluorobenzyl)indol-3-yl]glyoxylamide
[0076] Example 24,
N-(Pyridin-4-yl)-[1(4-fluorobenzyl)-5-methoxyindol-3-yl]-glyoxylamide
[0077] Example 25,
N-(Pyridin-4-yl)-[1(4-fluorobenzyl)-5-ethoxycarbonylaminomethylindol-3-yl-
]glyoxylamide
[0078] Starting Substances for the Compounds of the General Formula
1 Prepared According to Synthesis Scheme 1, which are Evident from
Table 1.
[0079] For the synthesis final products TABLE-US-00002 D 24241 D
24242 D 24834 D 24835 D 24836 D 24840 D 24841 D 24842 D 24843 D
24848 D 24849 D 24850 D 24851 D 24852 D 24853 D 24847 D 24858 D
24854 D 25420 D 25422
[0080] Available.
[0081] Furthermore, the compounds of the general formula 1 with
Z=0, R.sub.1=aryl, aralkyl, heteroaryl, heteroaralkyl and the
allylamino-carbonyl-2-methylprop-1-yl group and R.sub.2=alkyl,
arakyl and the heteroaralkyl group are also obtainable according to
the synthesis route of Scheme 2: ##STR6##
[0082] The compounds D 24241, D 24841, D 24840 and D 24834 (2nd
Stage of reaction scheme 2, see also Table 1) and their respective
precursors D 24825, D 24831, D 24832 and D 24833 (1st Stage of
reaction scheme 2, see also Table 2 on page K) were obtained
according to the present Scheme 2.
N-(Pyridin-4-yl)-[1(4-fluorobenzyl)indol-3-yl]-glyoxylamide (D
24241)
[0083] 1st Stage
N-(Pyridin-4-yl)-(indol-3-yl)glyoxylamide
[0084] A solution of 10 g (85.3 mmol) of indole in 100 ml of ether
is added dropwise at 0.degree. C. to a solution of 9 ml of oxalyl
chloride in 100 ml of anhydrous ether. The mixture is kept under
reflux for 3 hours. A suspension of 12 g (127.9 mmol) of
4-aminopyridine in 500 ml of tetrahydrofuran is then added dropwise
at -5.degree. C., the reaction mixture is heated to reflux
temperature with stirring for 3 hours and allowed to stand
overnight at room temp. It is filtered, the precipitate is treated
with water and the dried compound is purified on a silica gel
column (silica gel 60, Merck AG, Darmstadt) using the eluent
methylene chloride/ethanol (10:1, v/v).
[0085] Yield: 9.8 g (43.3% of theory)
[0086] M.p: from 250.degree. C.
[0087] 2nd Stage
N-(Pyridin-4-yl)-[1(4-fluorobenzyl)indol-3-yl]-glyoxylamide (D
24241)
[0088] The N-(pyridin-4-yl)-(indol-3-yl)glyoxylamide obtained
according to the 1st Stage is reacted with 4-fluorobenzyl chloride
according to the "benzylation procedure" (page 5) and the compound
D 24241 obtained is isolated.
[0089] Yield: 41% of theory
[0090] M.p.: 224-225.degree. C.
[0091] Elemental analysis: TABLE-US-00003 Calc. C 70.77 H 4.32 N
11.25 Found C 70.98 H 4.40 N 11.49
[0092] General Procedure for the Preparation of the Compounds of
the General Formula 1 According to Scheme 2
[0093] 1st Stage:
[0094] The indol derivative, which can be unsubstituted or
substituted on C-2 or in the phenyl ring, dissolved in a solvent,
as, for example, indicated above for oxalyl chloride, is added
dropwise at a temperature between -5.degree. C. and +5.degree. C.
to a solution prepared under a nitrogen atmosphere of a monomolar
up to 60% excess amount of oxalyl chloride in an aprotic or
nonpolar solvent, such as, for example, in diethyl ether, methyl
tert-butyl ether, tetrahydrofuran, dioxane or alternatively
dichloromethane. The reaction solution is then heated for 1 to 5
hours to a temperature between 10.degree. C. and 120.degree. C.,
preferably between 20.degree. C. and 80.degree. C., particularly
between 30.degree. C. and 60.degree. C., and the solvent is then
evaporated. The residue of the (indol-3-yl)glyoxyloyl chloride
which remains is dissolved or suspended in an aprotic solvent, such
as, for example, tetrahydrofuran, dioxane, diethyl ether, toluene
or alternatively in a dipolar aprotic solvent, such as, for
example, dimethylformamide, dimethylacetamide or dimethyl
sulfoxide, cooled to a temperature between -10.degree. C. and
+10.degree. C., preferably -5.degree. C. to 0.degree. C., and
treated in the presence of an acid scavenger with a solution of the
primary or secondary amine in a diluent. Possible diluents are the
solvents used for dissolving the "indolyl-3-glyoxyloyl chloride".
Acid scavengers used are triethylamine, pyridine,
dimethylaminopyridine, basic ion exchanger, sodium carbonate,
potassium carbonate, powdered potassium hydroxide and excess
primary or secondary amine employed for the reaction.
[0095] The reaction takes place at a temperature from 0.degree. C.
to 120.degree. C., preferably at 20-80.degree. C., particularly
between 40.degree. C. and 60.degree. C. After a reaction time of
1-4 hours and standing at room temperature for 24 hours, the
mixture is filtered, the precipitate is digested with water,
filtered off with suction and dried in vacuo. The desired compound
is purified by recrystallization in an organic solvent or by column
chromatography on silica gel or alumina. The eluent used is, for
example, a mixture of dichloromethane and ethanol (10:1,
vol/vol).
[0096] 2nd Stage
[0097] The "indol-3-ylglyoxylamide" obtained according to the above
procedure of the 1st Stage is dissolved in a protic, dipoplar
aprotic or nonpolar organic solvent, such as, for example, in
isopropanol, tetrahydrofuran, dimethyl sulfoxide,
dimethylformamide, dimethyl-acetamide, N-methylpyrrolidone,
dioxane, toluene or methylene chloride and added dropwise to a
suspension of a base prepared in a three-necked flask under an
N.sub.2 atmosphere or employed in a molar amount or in excess, such
as, for example, sodium hydride, powdered potassium hydroxide,
potassium tert-butoxide, dimethylaminopyridine or sodium amide in a
suitable solvent. The desired alkyl, aralkyl or heteroaralkyl
halide is then added either undiluted or in a diluent, which was
also used, for example, for dissolving the
"indol-3-ylglyoxylamide", if appropriate with addition of a
catalyst, such as, for example, copper and the mixture is allowed
to react for some time, e.g. for 30 minutes to 12 hours, and the
temperature is kept within a range between 0.degree. C. and
120.degree. C., preferably between 30.degree. C. and 80.degree. C.,
particularly between 50 and 70.degree. C. After completion of the
reaction, the reaction mixture is added to water, the solution is
extracted, for example, with diethyl ether, dichloromethane,
chloroform, methyl tert-butyl ether, tetrahydrofuran or n-butanol
and the organic phase obtained in each case is dried using
anhydrous sodium sulfate.
[0098] The organic phase is concentrated in vacuo, the residue
which remains is crystallized by trituration or the oily residue is
purified by distillation or by column or flash chromatography on
silica gel or alumina. The eluent used is, for example, a mixture
of methylene chloride and diethyl ether in the ratio 8:2 (vol/vol)
or a mixture of methylene chloride and ethanol in the ratio 9:1
(v/v).
[0099] According to this general procedure for stages 1 and 2, on
which the synthesis scheme 2 is based, the compounds D 24241, D
24841, D 24840 and D 24834 were synthesized, which have also
already been prepared according to the synthesis procedure of
reaction scheme 1 and are evidence from Table 1. The relevant
precursors of these compounds can be seen from Table 2 on page K
and L.
[0100] The compounds show a good dose-dependent antitumor action in
the following pharmacological models:
[0101] The indoles, particularly D-24851 and D-24241, are first
apparent in the XTT proliferation test/cytotoxicity test (Table 3
and Table 3a). In this test system, the effect of substances on the
proliferation behavior of tumor cell lines is investigated. In the
course of this, the cytotoxic potential of these substances is
determined. The test method is described in Scudiero et al. 1988,
Cancer Res. 48, 4827.
[0102] The following tumor cell lines were employed in the
investigations:
[0103] The KB cell line an epidermal carcinoma of the oral
cavity,
[0104] The L1210 cell line a lymphatic leukemia of the mouse, the
LNCAP cell line a prostate carcinoma and the SK-OV-3 cell line an
ovarian carcinoma.
[0105] A large number of different indols were active in all four
tumor cell lines, D-24851 and D-24241 showed the strongest actions,
D-24851 being more active than D-24241 (Table 3 and 4).
[0106] In further comparative investigations with D-24851 and
D-24241 in the hollow fiber assay on the nude mouse and on L 1210
(mouse), a strong dose-dependent antitumor action was observed for
both compounds (Table 3 and 5). In the hollow fiber assay, both
compounds were almost equally strongly active, while on L 1210
D24851 was markedly more strongly active after oral and
intraperitoneal administration than D-24241. In comparison with the
antitumor substances available on the market, D-24851 is markedly
more strongly active in many cases in the leukemia model than the
known comparison substances (Table 5).
[0107] A further great advantage of D-24851 in comparison with the
antitumor substances available on the market is the low toxicity of
the compound (Tables 3 and 5). With LD 50 values of 1000 mg/kg p.o.
and >1000 mg/kg i.p., the compound has a great therapeutic
breadth.
[0108] Furthermore, after administration of D-24851 no DNA
fragmentation was observed. In the hematopoiesis test, too, none of
the blood parameters investigated were modified by the
intraperitoneal administration of d-24851.
[0109] In a further chemotherapy model, the Dunning tumor in the
rat, a stoppage of tumor growth and in some animals even tumor
regression was observed after repeated oral administration of
D24851.
[0110] In the KB test on the nude mouse, an antitumor action was
likewise observed after administration of the two indols d-24851
and D-24241 (Tables 3, 3a and 4).
[0111] In the investigations with the tumor cell line L1210, a
lymphatic leukemia of the mouse, a distinct dose-dependent
prolongation of the survival time was seen after intraperitoneal or
oral administration of D 24851 with a 100 and 147 mg/kg multiple
dose (FIG. 1a and FIG. 1b).
[0112] On account of the good therapeutic breadth, which was
demonstrated experimentally, the active substance can be
administered in a higher amount than commercially available tumor
pharmaceuticals.
[0113] Without within to restrict the scope of the invention by the
following details, it can be said that doses from approximately 20
mg up to 500 mg daily are possible orally. In the case of
intravenous administration as an injection or as an infusion, up to
250 mg/day or more can be administered depending on the body weight
of the patient and individual tolerability. TABLE-US-00004 TABLE 3
Composition D-24851 according to Example 13 D-24851
N-(Pyridin-4-yl)-[1-(4-chlorobenzyl)indol-3-yl]glyoxylamide Mod 1
Result. SK-OV-3 KB L1210 LNCaP MCF-7 Tox XTT (.mu.g/ml) EC.sub.50
.apprxeq.0.03 .apprxeq.0.017 .apprxeq.0.017 .apprxeq.0.03 1 .times.
ip (mg/kg) LD.sub.50 =1000 1 .times. per os (mg/kg) LD.sub.50
>1000 Hollow fiber intra- % INH no 56 38 peritoneal action 4
.times. 46 mg/kg ip Hollow fiber intra- % INH 12 60 68 peritoneal 4
.times. 147 mg/kg ip Hollow fiber subcutaneous % INH 44 no action
47 4 .times. 46 mg/kg ip Hollow fiber subcutaneous % INH 35 67 68 4
.times. 147 mg/kg ip In vivo: 1 .times. 681 mg/kg ip % ILS 0 1
.times. 464 mg/kg ip 18 4 .times. 215 mg/kg ip % ILS 13 4 .times.
147 mg/kg ip 94 7 .times. 100 mg/kg ip % ILS 35 7 .times. 147 mg/kg
ip 59 1 .times. 681 mg/kg po % ILS 22 4 .times. 215 mg/kg po 31 7
.times. 100 mg/kg po 63 7 .times. 147 mg/kg po 75 7 .times. 46
mg/kg ip % WHI 33 2 .times. 215 mg/kg po 18
[0114] TABLE-US-00005 TABLE 3a Substance according Tumor cells XTT
to Example KB L 1210 LNCAP SK-OV-3 D Number) EC.sub.50 [.mu.g/ml]
EC.sub.50 [.mu.g/ml] EC.sub.50 [.mu.g/ml] EC.sub.50 [.mu.g/ml] 1 (D
24241) 0.020 0.170 >31.600 0.170 3 (D 24834) 1.75 1.75 9.250
1.750 4 (D 24835) 17.5 1.750 >31.6 9.200 6 (D 24840) 3.100 1.750
>31.6 17.5 9 (D 24843) 0.050 0.090 3.240 1.750 10 (D 24848)
4.060 1.75 >31.6 7.220 11 (D 24849) 4.590 1.750 17.500 4.250 12
(D 24850) >31.6 0.017 >31.6 >31.6 13 (D 24851) 0.017 0.017
0.030 0.030 14 (D 24852) 1.75 1.75 17.5 2.58 15 (D 24853) >31.6
3.1 >31.6 >31.6 16 (D 24847) 4.59 1.75 17.500 4.250 Table 2
17.5 17.5 17.5 17.5 (D 24831)
[0115] Further animal experimental results:
[0116] Stoppage of tumor growth, in some animals even tumor
regression, was observed in the Dunning tumor after administration
of 7.times.100 mg/kg and 7.times.147 mg/kg p.o. of D-24851.
[0117] In comparison with the original form, the testing of the
crystalline form yielded no differences.
[0118] D-24851 causes no DNA fragmentation
[0119] In the hematopoiesis test, none of the blood parameters
investigated were altered by the intraperitoneal administration of
D-24851. TABLE-US-00006 TABLE 4 D 24241
N-(Pyridin-4-yl)-[1-(4-fluorobenzyl) indol-3-yl]glyoxylamide
according to Example 1 Model Result. SK-OV-3 KB L1210 LNCaP MCF-7
Tox XTT (.mu.g/ml) EC.sub.50 .apprxeq.0.17 .apprxeq.0.02
.apprxeq.0.17 >31.6 1 .times. ip (mg/kg) LD.sub.50 .apprxeq.158
1 .times. per os (mg/kg) LD.sub.50 >1000 Hollow fiber intra- %
INH 46 43 no action peritoneal 4 .times. 15.8 mg/kg ip Hollow fiber
subcutaneous % INH 81 68 33 4 .times. 15.8 mg/kg ip In vivo: 1
.times. 14.7 mg/kg ip % ILS no action 1 .times. 30 mg/kg per os %
ILS no action 1 .times. 464 mg/kg per os % ILS 44 4 .times. 30
mg/kg per os % ILS no action 6 .times. 30 mg/kg per os % ILS no
action 14 .times. 30 mg/kg per os % ILS no action 19 .times. 50
mg/kg per os % ILS 50 2 .times. 46.4 mg/kg ip % WHI 22 4 .times.
21.5 mg/kg ip % WHI no action 2 .times. 215 mg/kg po % WHI 47
[0120] TABLE-US-00007 TABLE 5 Comparison of the antitumor action of
D-24851 and D-24241 with standard compounds XTT Tox. L1210 EC 50
Substance mg/kg mg/kg (.mu.g/ml) D-24851 .apprxeq.1000 i.p. 4
.times. 147 i.p. KB .apprxeq. 0.017 94% ILS L1210 .apprxeq. 0.017
SKOV3 .apprxeq. 0.03 LNCAP .apprxeq. 0.03 D-24241 .apprxeq.158 i.p.
19 .times. 50 p.o. KB .apprxeq. 0.02 50% ILS L1210 .apprxeq. 0.07
SKOV3 .apprxeq. 0.17 LNCAP > 31.6 Mitoxantrone 16 i.v. 1 .times.
4.64 i.v. KB - 0.174 144% ILS L1210 < 0.0003 SKOV3 - 0.174 LNCAP
- 0.017 5-Fluorouracil -- 1 .times. 147 i.p. -- 72% ILS 4 .times.
68.1 i.p. 83% ILS Methotrexate -- 1 .times. 53.7 i.p. KB - 0.007
39% ILS L1210 n.d. SKOV3 > 31.6 LNCAP n.d. Etoposide
.apprxeq.158.0 i.p. 1 .times. 46.4 i.p. -- >68.1 i.v. 56% ILS
Ratjadone -16.0 1 .times. 1.47 i.p. KB < 0.003 i.p. 22% ILS
L1210 < 0.003 -30.0 i.v. SKOV3 < 0.003 LNCAP < 0.003
Epothilone B .apprxeq.100.0 i.p. 1 .times. 10 i.p. KB - 0.0002 44%
ILS L1210 - 0.0017 SKOV3 - 0.0031 LNCAP - 0.014 Taxol .apprxeq.158
i.p. 1 .times. 14.7 i.v. KB < 0.003 22% ILS L1210 < 0.003 1
.times. 46.4 i.v. SKOV3 < 0.003 61% ILS LNCAP < 0.003
Vincristine .apprxeq.3.0 i.v. 1 .times. 1.0 i.p. KB < 0.001 29%
ILS L1210 0.004 SKOV3 0.003 LNCAP 0.004 Adriamycin .apprxeq.27.0
i.v. 1 .times. 14.7 i.v. KB 0.15 111% ILS L1210 0.174 SKOV3 0.089
LNCAP 0.17 Cisplatin .apprxeq.16.0 i.p. 1 .times. 3.16 i.p. L1210
0.30 .apprxeq.73.0 p.o. 38.9% ILS Carboplatzin .apprxeq.158.0 1
.times. 100 i.p. -- i.p. 41% ILS .apprxeq.841.0 p.o Lobaplatin
.apprxeq.34.0 i.p. 1 .times. 14.7 i.p. -- 55.0% ILS
Cyclophosphamide .apprxeq.340.7 i.v. 1 .times. 46.4 i.v. -- 40% ILS
Ifosfamide .apprxeq.732 i.p. 1 .times. 316 i.p. -- 89% ILS
Miltefosine .apprxeq.46.4 i.p. no action -- .apprxeq.464-1000
p.o.
[0121] TABLE-US-00008 TABLE 1a Indolylglyoxylamides according to
reaction scheme 1 Formula 1 ##STR7## Example D R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 1 D-24241 H ##STR8## ##STR9## H H O
225-6.degree. C. 2 D-24242 H ##STR10## CH.sub.3 H H O 176.degree.
C. 3 D-24834 H ##STR11## ##STR12## H H O 173.degree. C. 4 D-24835 H
##STR13## ##STR14## H H O 140.degree. C. 5 D-24836 H ##STR15##
##STR16## H H O 185.degree. C.
[0122] TABLE-US-00009 TABLE 1b Indolylglyoxylamides according to
reaction scheme 1 Example R R.sub.1 R.sub.2 R.sub.3 R.sub.4 Z M.p.
6 D-24840 H ##STR17## ##STR18## H H O 199.degree. C. 7 D-24841 H
##STR19## ##STR20## H H O >250.degree. C. 8 D-24842 H ##STR21##
##STR22## H H O 149.degree. C. 9 D-24843 H ##STR23## ##STR24## H H
O 178-180.degree. C. 10 D-24848 H ##STR25## ##STR26## H H O
179.degree. C. 11 D-24849 H ##STR27## ##STR28## H H O 132.degree.
C.
[0123] TABLE-US-00010 TABLE 1c Indolylglyoxylamides according to
reaction scheme 1 Example D R R.sub.1 R.sub.2 R.sub.3 R.sub.4 Z
M.p. 12 D-24850 H ##STR29## ##STR30## H H O 144.degree. C. 13
D-24851 H ##STR31## ##STR32## H H O 262.degree. C. 14 D-24852 H
##STR33## ##STR34## H H O 184.degree. C. 15 D-24853 H ##STR35##
##STR36## H H O 141.degree. C. 16 D-24847 H ##STR37## ##STR38## H H
O 202.degree. C. 17 D-24858 ##STR39## ##STR40## H H O 115.degree.
C. 18 D-24854 H ##STR41## ##STR42## H H O 112-3.degree. C.
[0124] TABLE-US-00011 TABLE 1d Indolylglyoxylamides according to
reaction scheme 1 Example D R R.sub.1 R.sub.2 R.sub.3 R.sub.4 Z
M.p. 19 D-25421 H ##STR43## ##STR44## 6-NHCOOEt H O >250.degree.
C. 20 D-25422 H ##STR45## ##STR46## 5-NHCOOEt H O 183.degree. C. 21
D-25423 H ##STR47## ##STR48## ##STR49## H O 22 D-25420 ##STR50##
##STR51## H H O 160-62.degree. C. 23 D-24866 ##STR52## ##STR53##
##STR54## H H O 139-141.degree. C. 24 D-25561 H ##STR55## ##STR56##
5-OCH.sub.3 H O 188.degree. C. 25 D-25559 H ##STR57## ##STR58##
5-Ch.sub.2--NHCOOEt H O 175-176.degree. C.
[0125] TABLE-US-00012 TABLE 1e Indole-3-glyoxylic acid derivative
according to reaction scheme 1 Formula 1 ##STR59## Example, D- R
R.sub.1 R.sub.2 R.sub.3 R.sub.4 Z M.p. 26 D-50570 H ##STR60##
##STR61## H H O 27 D-51078 H ##STR62## ##STR63## H H O 28 D-49404 H
##STR64## ##STR65## 5-F H O 205-207.degree. C. 29 D-44073 H
##STR66## ##STR67## H H O 192-194.degree. C. 30 D-44072 H ##STR68##
##STR69## H H O 196-198.degree. C. 31 D-44067 H ##STR70## ##STR71##
H H O 219-221.degree. C.
[0126] TABLE-US-00013 TABLE 1f Indole-3-glyoxylic acid derivative
according to reaction scheme 1 Example, D- R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 32 D-44061 H ##STR72## ##STR73## H H O
238-240.degree. C. 33 D-43163 H ##STR74## ##STR75## H H O
203-205.degree. C. 34 D-51273 H ##STR76## ##STR77## H H O
305-307.degree. C. 35 D-44070 H ##STR78## ##STR79## H H O
>250.degree. C. 36 D-49405 H ##STR80## ##STR81## H H O
237-239.degree. C. 37 D-44071 H ##STR82## ##STR83## H H O
154-156.degree. C. 38 D-44089 H ##STR84## ##STR85## H H O
213-215.degree. C. 39 D-44068 H ##STR86## ##STR87## H H O
183-185.degree. C.
[0127] TABLE-US-00014 TABLE 1g Indole-3-glyoxylic acid derivative
according to reaction scheme 1 Example, D- R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 40 D-44066 H ##STR88## ##STR89## H H O
187-189.degree. C. 41 D-49406 H ##STR90## ##STR91## ##STR92## H O
191-193.degree. C. 42 D-49403 H ##STR93## ##STR94## ##STR95## H O
193-195.degree. C. 43 D-44064 H ##STR96## ##STR97## H H O
104-106.degree. C. 44 D-43156 H ##STR98## ##STR99## 6-NO.sub.2 H O
238-240.degree. C. 45 D-43155 H ##STR100## ##STR101## 5-NO.sub.2 H
O 203-205.degree. C. 46 D-43152 H ##STR102## ##STR103## H H O
196-198.degree. C. 47 D-43151 H ##STR104## ##STR105## H H O
141-143.degree. C.
[0128] TABLE-US-00015 TABLE 1h Indole-3-glyoxylic acid derivative
according to reaction scheme 1 Example, D- R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 48 D-43149 H ##STR106## ##STR107## H H O
202-204.degree. C. 49 D-43148 H ##STR108## ##STR109## H H O
183-185.degree. C. 50 D-25505 hydrochloride H ##STR110## ##STR111##
H H O Hydrochlorid 51 D-51133 trifluoroacetate H ##STR112##
##STR113## H H O 251-253.degree. C. Trifluoracetat 52 D-51128 H
##STR114## ##STR115## H H O 173-174.degree. C. 53 D-51077 H
##STR116## ##STR117## H H O 244-245.degree. C. 54 D-51195 H
##STR118## ##STR119## ##STR120## H O 228-230.degree. C. 55 D-51391
H ##STR121## ##STR122## H H O 270-271.degree. C.
[0129] TABLE-US-00016 TABLE 1i Indole-3-glyoxylic acid derivative
according to reaction scheme 1 Example, D- R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 56 D-51393 H ##STR123## ##STR124## H H O Ol
57 D-51394 H ##STR125## ##STR126## H H O 216-218.degree. C. 58
D-51184 H ##STR127## ##STR128## H H O 215-217.degree. C. 59 D-51185
H ##STR129## ##STR130## H H O 241-242.degree. C. 60 D-25463 H
##STR131## ##STR132## H H O .degree. C. 61 D-24584 H ##STR133##
##STR134## H H O .degree. C. 62 D-25320 H ##STR135## ##STR136## H H
O 145-147.degree. C.
[0130] TABLE-US-00017 TABLE 1j Indole-3-glyoxylic acid derivative
according to reaction scheme 1 Example, D- R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 63 D-51396 ##STR137## ##STR138## H H O
137.degree. C. 64 D-44065 ##STR139## ##STR140## H H O
205-207.degree. C. 65 D-43146 ##STR141## ##STR142## H H O
89-91.degree. C. 66 D-43145 ##STR143## ##STR144## H H O
68-70.degree. C. 67 D-25558 ##STR145## ##STR146##
6-NHCOOC.sub.2H.sub.5 H O oil
[0131] TABLE-US-00018 TABLE 2 Indolylglyoxylamides according to
reaction scheme 2 Formula 1 ##STR147## Example, D- R R.sub.1
R.sub.2 R.sub.3 R.sub.4 Z M.p. 1 D-24825 H ##STR148## H H H O
>250.degree. C. 2 D-24831 H ##STR149## H H H O >250.degree.
C. 3 D-24832 H ##STR150## H H H O 233-5.degree. C. 4 D-24833 H
##STR151## H H H O 235.degree. C.
[0132] TABLE-US-00019 TABLE 2a Indolylglyoxylamides according to
reaction scheme 2 Example, D- R R.sub.1 R.sub.2 R.sub.3 R.sub.4 Z
M.p. 5 D-43154 H ##STR152## H 6-NO.sub.2 H O 250.degree. C.(dec.) 6
D-43153 H ##STR153## H 5-NO.sub.2 H O >250.degree. C. 7 D-25319
H ##STR154## H H H O 156-157.degree. C.
[0133] TABLE-US-00020 TABLE 2b Indol-3-glyoxylic acid derivatives
according to reaction scheme 1 Example, D- R R.sub.1 R.sub.2
R.sub.3 R.sub.4 Z M.p. 5 D-43154 H ##STR155## H 6-NO.sub.2 H O
250.degree. C.(dec.) 6 D-43153 H ##STR156## H 5-NO.sub.2 H O
>250.degree. C. 7 D-25319 H ##STR157## H H H O 156-157.degree.
C.
* * * * *