Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-02
2001-05-15
Rotman, Alan L. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S278100, C546S256000
Reexamination Certificate
active
06232327
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
Indole-3-glyoxylamides have a variety of uses as pharmacodynamically active compounds and as synthetic building blocks in pharmaceutical chemistry.
2. Background Information
In the patent application Neth. Appl. 6502481, compounds are described which have an anti-inflammatory and antipyretic activity profile and analgesic activity.
In the British Application GB-B 1 028 812, derivatives of indolyl-3-glyoxylic acid and their amides are used as analgesic, anticonvulsant and &bgr;-adrenergic compounds.
G. Domschke et al. (Ber. 94, 2353 (1961)) describes [sic] 3-indolylglyoxylamides which are not characterized pharmacologically.
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.
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.
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.
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
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.
where the radicals R, R
1
, R
2
, R
3
, R
4
and Z have the following meaning:
R=hydrogen, (C
1
-C
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
1
-C
6
)-alkyl, (C
3
-C
7
)-cycloalkyl, by carboxyl groups, carboxyl groups esterified with C
1
-C
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
1
-C
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
1
can be the phenyl ring, which is mono- or polysubstituted by (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, cyano, halogen, trifluoromethyl, hydroxyl, benzyloxy, nitro, amino, (C
1
-C
6
)-alkylamino, (C
1
-C
6
)-alkoxycarbonylamino and by the carboxyl group or by the carboxyl group esterified with C
1
-C
6
-alkanols, or can be a pyridine structure of the formula 2 and its N-oxide [sic]
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
5
and R
6
. The radicals R
5
and R
6
can be identical or different and have the meaning (C
1
-C
6
)-alkyl and the meaning (C
3
-C
7
)-cycloalkyl, (C
1
-C
6
)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and further are the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
R
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
1
-C
6
)-alkyl, halogen, the nitro group, the amino group and the (C
1
-C
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
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, nitro, amino and (C
1
-C
6
)-alkoxycarbonylamino.
R
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
2
COOH; —CH(CH
3
)—COOH; —(CH
3
)
2
—CH—(CH
2
)
2
—CH—COO—; H
3
C—H
2
C—CH(CH
3
)—CH(COOH)—; HO—H
2
C—CH(COOH)—; phenyl—CH
2
—CH(COOH)—; (4-imidazolyl)—CH
2
—CH—(COOH)—; HN═C(NH
2
)—NH—(CH
2
)
3
—CH(COOH)—; H
2
N—(CH
2
)
4
—CH(COOH)—; H
2
N—CO—CH
2
—CH—(COOH)—; HOOC—(CH
2
)
2
—CH(COOH)—;
R
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 &agr;-glycyl, the &agr;-sarcosyl, the &agr;-alanyl, the &agr;-leucyl, the &agr;-isoleucyl, the &agr;-seryl, the &agr;-phenylalanyl, the &agr;-histidyl, the &agr;-prolyl, the &agr;-arginyl, the &agr;-lysyl, the &agr;-asparagyl and the &agr;-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
1
, the second, unbonded carboxyl group is present as a free carboxyl group or in the form of an ester with C
1
-C
6
-alkanols, e.g. as a methyl, ethyl or as a tert-butyl ester.
Furthermore, R
1
can be the allylaminocarbonyl-2-methylprop-1-yl group.
R and R
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
1
is an aminoalkylene group, in which
R
7
is an alkyl radical, is a phenyl ring which can be mono- or polysubstituted by (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, halogen, the nitro group, the amino function and by the (C
1
-C
6
)-alkylamino group. R
7
is furthermore the benzhydryl group and the bis-p-fluorobenzylhydryl [sic] group.
R
2
can be hydrogen and the (C
1
-C
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
1
-C
6
)-alkyl, (C
3
-C
7
) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C
1
-C
6
-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups. The (C
1
-C
6
)-alkyl group counting as R
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
1
-C
4
)-alkyl groups or (C
1
-C
4
)-alkoxy groups. R
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
1
-C
6
) -alkyl, (C
3
-C
7
) -cycloalkyl, carboxyl groups, carboxyl groups esterified with C
1
-C
6
-alkanols, trifluoromethyl groups, hydroxyl groups, methoxy groups, ethoxy groups or benzyloxy groups.
R
3
and R
4
can be identical or different and are hydrogen, (C
1
-C
6
)-alkyl, (C
3
-C
7
) -cycloalkyl, (C
1
-C
6
) -alkanoyl, (C
1
-C
6
) -alkoxy, halogen and benzyloxy. R
3
and R
4
can furthermore be the nitro group, the amino group, the (C
1
-C
4
)-mono or dialkyl-substituted amino group, and the (C
1
-C
6
)-alkoxycarbonylamino function or (C
1
-C
6
)-alkoxycarbonylamino-(C
1
-C
6
)-alkyl function.
Z is O and S.
The designation alkyl, alkanol, alkoxy or alkylamino group for the radicals R, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
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.
The designation “
Brune Kay
Emig Peter
Gunther Eckhard
Nickel Bernd
Reichert Dietmar
Asta Medica Aktiengesellschaft
Desai Rita
Rotman Alan L.
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