U.S. patent application number 09/736431 was filed with the patent office on 2001-08-16 for substituted n-benzylindol-3-ylglyoxylic acid derivatives having antitumor action.
Invention is credited to Bacher, Gerald, Emig, Peter, Gunter, Eckhard, Le Baut, Guillaume, Nickel, Bernd, Reichert, Dietmar.
Application Number | 20010014690 09/736431 |
Document ID | / |
Family ID | 7934006 |
Filed Date | 2001-08-16 |
United States Patent
Application |
20010014690 |
Kind Code |
A1 |
Gunter, Eckhard ; et
al. |
August 16, 2001 |
Substituted N-benzylindol-3-ylglyoxylic acid derivatives having
antitumor action
Abstract
The invention relates to novel, substituted
N-benzyl-indol-3-ylglyoxylic acid derivatives of the following
formula and their use for the treatment of oncoses 1 The invention
further relates to their physiologically tolerable acid addition
salts and if possible their N-oxides. In addition, the invention
relates to pharmaceutical preparations containing at least one of
the compounds of the abovementioned formula or their salts or
N-oxides with physiologically tolerable inorganic or organic acids
and, if appropriate, pharmaceutically utilizable vehicles and/or
diluents or excipients and also administration forms of the
compounds of the abovementioned formula containing at least one of
the compounds of this formula or their salts 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: |
Gunter, Eckhard; (Maintal,
DE) ; Emig, Peter; (Bruchkobel, DE) ;
Reichert, Dietmar; (Eschau, DE) ; Le Baut,
Guillaume; (Saint Sebastian/Loire, FR) ; Nickel,
Bernd; (Muhltal, DE) ; Bacher, Gerald;
(Heidelberg, DE) |
Correspondence
Address: |
PILLSBURY WINTHROP LLP
1600 TYSONS BOULEVARD
MCLEAN
VA
22102
US
|
Family ID: |
7934006 |
Appl. No.: |
09/736431 |
Filed: |
December 15, 2000 |
Current U.S.
Class: |
514/339 ;
514/254.09; 514/419; 546/277.4; 548/496 |
Current CPC
Class: |
C07D 401/12 20130101;
A61P 35/00 20180101 |
Class at
Publication: |
514/339 ;
514/419; 514/254.09; 546/277.4; 548/496 |
International
Class: |
A61K 031/4439; C07D
401/00; C07D 209/20 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 23, 1999 |
DE |
199 62 300.7 |
Claims
1. Novel, substituted N-benzylindol-3-ylglyoxylic acid derivatives
having antitumor action of the general formula 1 7Where the
radicals R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and Z have the
following meaning: R=nitro, amino, mono- or
di(C.sub.1-C.sub.6)-alkylamino, mono- or
di(C.sub.1-C.sub.6)-cycloalkylamino, (C.sub.1-C.sub.6)-acylamino,
phenyl (C.sub.1-C.sub.6)-alkylamino, aroylamino, heteroaroylamino,
(C.sub.1-C.sub.6) -alkylsulfonamido, arylsulfonamido, maleimido,
succinimido, phthalimido, benzyloxycarbonylamino (z-amino),
tert-butoxycarbonylamino (boc-amino),
9-fluorenylmethoxy-carbonylamino (Fmoc-amino), triphenylmethylamino
(Tr-amino), 2-(4'-pyridyl)ethoxycarbon- ylamino (Pyoc-amino),
diphenylmethylsilylamino (DPMS-amino), where the radicals for R can
alternatively be substituted on the C atoms 2, 3 and 4 of the
phenyl ring, R can furthermore be, in the case in which
R.sub.1=hydrogen, the methyl or phenylmethyl group and the
benzyloxycarbonyl radical (Z radical), the tert-butoxycarbonyl
radical (BOC radical) and the acetyl group, the following radicals:
--NH--CH.sub.2--COOH; --NH--CH(CH.sub.3)--COOH;
(CH.sub.3).sub.2CH--CH.su- b.2--CH.sub.2--CH(NH)--COOH;
H.sub.3C--CH.sub.2--CH(CH.sub.3)--CH(NH)--COO- H;
HOH.sub.2C--CH(NH)--COOH; phenyl--CH.sub.2--CH(NH)--COOH;
(4-imidazoyl)--CH.sub.2--CH(NH)--COOH;
HN.dbd.C(NH.sub.2)--NH--(CH.sub.2)- .sub.3--CH(NH)--COOH;
H.sub.2N--(CH.sub.2).sub.4--CH(NH)--COOH;
H.sub.2N--CO--CH.sub.2--CH(NH)--COOH;
HOOC--(CH.sub.2).sub.2--CH(NH)--COO- H R.sub.1=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.sub.1 is further
the benzyloxycarbonyl group (Z group) and the
tertiary-butoxycarbonyl radical (Boc radical), furthermore the
acetyl group R.sub.2 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 their N-oxide
[sic] 8and 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 [R.sub.5 and
R.sub.6 in formula 2 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 and trifluoromethyl and further are the
ethoxycarbonylamino radical and the group carboxyalkyloxy in which
the alkyl group can have 1-4 C atoms. R.sub.2 can further be a 2-
or 4-pyrimidinyl heterocycle, where the 2-pyrimidinyl ring can be
mono- or polysubstituted by the methyl group, furthermore can be
the 2-, 3-, 4-, 5-, 6-, 7- 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, can be 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.2 in the case in
which R.sub.1=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.2CH--(CH.sub.2).sub.2--CH(COOH)--;
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.C(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.2 in the case in which
R.sub.1 are [sic] 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.alanyl, the .alpha.-leucyl, the
.alpha.-isoleucyl, 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.2, the second, unbonded carboxyl group is present
as a free carboxyl group or in the form of a carboxyl group
esterified with C.sub.1-C.sub.6-alkanols, e.g. as a methyl, ethyl
or as a tert-butyl ester; furthermore, R.sub.2 can be the
allylaminocarbonyl-2-me- thylprop-1-yl group; [R.sub.1 and R.sub.2
can further form, together with the nitrogen atom to which they are
bonded, a piperazine ring of the formula 3 or a homopiperazine
ring, provided R.sub.2 is an aminoalkylene group, in which 9R.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-fluorobenzhydryl
group. 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 the
(C.sub.1-C.sub.6)-alkoxycarbonylamino-(C.sub.1-C.sub.6)-alkyl
function, Z is 0 and S.
2. N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]-glyoxylamide
(D-68838)
3. N-(Pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]-glyoxylamide
(D-68836)
4. Acid addition salts of the compounds according to claims 1-4 of
the general formula 1 as salts of mineral acids, such as
hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic
acids, in particular acetic acid, lactic acid, malonic acid, maleic
acid, fumaric acid, gluconic acid, glucuronic acid, citric acid,
ascorbic acid, embonic acid, methanesulfonic acid, trifluoroacetic
acid, succinic acid, 2-hydroxy-ethanesulfonic acid, nicotinic acid
and p-toluene-sulfonic acid.
5. Pharmaceutical preparations of the compounds according to claims
1-4 of the general formula 1 containing at least one of the
compounds of the formula 1 or their salts according to claim 3 with
physiologically tolerable inorganic or organic acids and, if
appropriate, pharmaceutically utilizable vehicles and/or diluents
or excipients.
6. Application forms of the compounds according to claims 1-4 of
the general formula 1 containing at least one of the compounds of
the formula 1 or their salts according to claim 3 in the form of
tablets, coated tablets, capsules, solutions for infusion or
ampoules, suppositories, patches, powder preparations which can he
employed by inhalation, suspensions, creams and ointments
7. Use of the compounds according to claims 1-4 of the general
formula 1 for the production of antitumor compositions.
8. Use of compounds according to claims 1-4 of the general formula
1 for the treatment of oncoses.
Description
[0001] The aim of the present invention is to make available novel
compounds from the indol-3-ylglyoxylic acid series of the general
formula 1 which have a good antitumor action and can be employed
for the preparation of antitumor agents; 2
[0002] Where the radicals R, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and
Z have the following meaning
[0003] R=nitro, amino, mono- or di(C.sub.1-C.sub.6)-alkylamino,
mono- or di(C.sub.1-C.sub.6)-cycloalkylamino, (C.sub.1-C.sub.6)
-acylamino, phenyl (C.sub.1-C.sub.6)-alkylamino, aroylamino,
heteroaroylamino, (C.sub.1-C.sub.6)-alkylsulfonamido,
aryl-sulfonamido, maleimido, succinimido, phthalimido,
benzyloxycarbonylamino (Z-amino), tert-butoxy-carbonylamino
(BOC-amino), 9-fluorenylmethoxy-carbonylamino (Fmoc-amino),
triphenylmethylamino (Tr-amino), 2-(4'-pyridyl)ethoxycarbon-
ylamino (Pyoc-amino), diphenylmethylsilylamino (DPMS-amino), where
the radicals for R can alternatively be substituted on the C atoms
2, 3 and 4 of the phenyl ring,
[0004] R can furthermore be, in the case in which R.sub.1=hydrogen,
the methyl or phenylmethyl group and the benzyloxycarbonyl radical
(Z radical), the tert-butoxycarbonyl radical (BOC radical) and the
acetyl group, the following radicals:
[0005] --NH--CH.sub.2--COOH; --NH--CH(CH.sub.3)--COOH;
(CH.sub.3).sub.2CH--CH.sub.2--CH.sub.2--CH(NH)--COOH;
H.sub.3C--CH.sub.2--CH(CH.sub.3)--CH(NH)--COOH;
HOH.sub.2C--CH(NH)--COOH; phenyl--CH.sub.2--CH(NH)--COOH;
(4-imidazoyl)--CH.sub.2--CH(NH)--COOH;
HN.dbd.C(NH.sub.2)--NH--(CH.sub.2).sub.3--CH(NH)--COOH;
H.sub.2N--(CH.sub.2).sub.4--CH(NH)--COOH;
H.sub.2N--CO--CH.sub.2--CH(NH)-- -COOH;
HOOC--(CH.sub.2).sub.2--CH(NH)--COOH
[0006] R.sub.1=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,
[0007] R.sub.1 is further the benzyloxycarbonyl group (Z group) and
the tertiary-butoxycarbonyl radical (Boc radical), furthermore the
acetyl group.
[0008] R.sub.2 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 3
[0009] 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 and trifluoromethyl and further are the ethoxycarbonylamino
radical and the group carboxyalkyloxy in which the alkyl group can
have 1-4 C atoms.
[0010] R.sub.2 can further be a 2- or 4-pyrimidinyl heterocycle,
where the 2-pyrimidinyl ring can be mono- or polysubstituted by the
methyl group, furthermore can be the 2-, 3-, 4-, 5-, 6-, 7- 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, can be 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)-alkoxycarbon- ylamino.
[0011] R.sub.2 in the case in which R.sub.1=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:
[0012] --CH.sub.2COOH; --CH(CH.sub.3)--COOH;
(CH.sub.3).sub.2CH--(CH.sub.2- ).sub.2--CH(COOH)--;
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.C(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)--;
[0013] R.sub.2 in the case in which R.sub.1 are [sic] 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.-alanyl, the .alpha.-leucyl, the .alpha.-isoleucyl, 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.2, the second,
unbonded carboxyl group is present as a free carboxyl group or in
the form of a carboxyl group esterified with
C.sub.1-C.sub.6-alkanols, e.g. as a methyl, ethyl or as a
tert-butyl ester. Furthermore, R.sub.2 can be the
allylaminocarbonyl-2-methylprop-1-- yl group. R.sub.1 and R.sub.2
can further form, together with the nitrogen atom to which they are
bonded, a piperazine ring of the formula 3 or a homopiperazine
ring, provided R.sub.2 is an aminoalkylene group, in which 4
[0014] 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-fluorobenzhydryl
group.
[0015] 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.
[0016] Z is O and S.
[0017] 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. 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. The designation acyl of
the acylamino radicals is to be understood as meaning the groups
formyl, acetyl, propionyl, butyryl, valeryl and isovaleryl. The
designation aroyl of the aroylamino groups represents benzoyl,
naphthoyl, toluoyl, phthaloyl and the group heteroaroyl of the
heteroaroylamino radicals represents nicotinoyl, isonicotinoyl,
thenoyl and furoyl. The designation aryl of the arylsulfonamido
group is understood as meaning phenyl, tolyl and naphthyl.
[0018] The compounds can also be employed as 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, ascorbic acid, embonic acid, methanesulfonic acid,
trifluoroacetic acid, succinic acid, 2-hydroxyethanesulfonic acid,
nicotinic acid and p-toluenesulfonic acid. Both the compounds of
the formula 1 and their salts are biologically active. The
compounds of the formula 1 can be administered in free form or as
salts with physiologically tolerable acids. Administration can be
performed orally, parenterally, intravenously, transdermally or by
inhalation.
[0019] 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 auxiliaries.
[0020] 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.
[0021] The processes for the preparation of the compounds according
to the invention are described in the following reaction schemes 1
and 2 (Stages 1-3) and in general procedures. All compounds can be
prepared as described or analogously.
[0022] The compounds of the general formula 1 with Z.dbd.O,
R.dbd.NO.sub.2 and NH.sub.2 and R.sub.2=aryl, aralkyl and
heteroaryl are obtainable according to the following Scheme 1:
5
[0023] The indole 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. to [sic]
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).
[0024] 2nd stage
[0025] The N-substituted indole 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. The eluent used is, for
example, a mixture of dichloromethane and ethanol (95:5,
vol/vol).
[0026] 3rd stage
[0027] The N-nitrobenzyl-substituted "indoleglyoxylamide" obtained
according to the above procedure (2nd stage) is dissolved in a
protic solvent, such as, for example, methanol, ethanol, propanol,
isopropanol or butanol or in a nonpolar solvent, such as, for
example, tetrahydrofuran, dioxane or glycol dimethyl ether or in a
dipolar aprotic solvent, such as, for example, dimethyl sulfoxide,
dimethylformamide, dimethylacetamide or N-methylpyrrolidone and the
solution is treated with a hydrogenation catalyst such as, for
example, Raney nickel, palladium/carbon or platinum under a
nitrogen atmosphere and with stirring. Hydrogen is passed into the
suspension with moderate shaking at a gas pressure of 1-15 bar,
preferably 2-10 bar, particularly at 4-6 bar and the temperature is
raised to about 20.degree.-80.degree. C., preferably
30.degree.-60.degree. C., particularly to 45.degree.-55.degree. C.
If appropriate, after about 1 hour a further amount of catalyst is
added and the hydrogenation is continued. The hydrogenation was
complete after a reaction time of 4-10 hours. The catalyst was
filtered off under a nitrogen atmosphere, the solvent was
concentrated to dryness in vacuo and the colorless to yellowish
residue was dried in vacuo at 40.degree. C.
WORKING EXAMPLES
[0028] According to this general procedure for stages 1-3, on which
synthesis scheme 1 is based, the following compounds were
synthesized which are evident from the following tabulated list
[sic] detailing the respective chemical name.
Example 1
N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide
(D-68838)
[0029] 1st stage
[0030] 1-(4-Nitrobenzyl)indole
[0031] A mixture of 5.28 g of sodium hydride (0.22 mol, mineral oil
suspension) in 200 ml of dimethyl sulfoxide is treated with a
solution of 23.4 g (0.2 mol) of indole in 100 ml of dimethyl
sulfoxide. It is heated at 65.degree. C. for 1 hour, then allowed
to cool and 37.7 g (0.22 mol) of 4-nitrobenzyl chloride are then
added dropwise. The solution is heated to 60.degree. C., kept at
room temperature for 14 hours and then poured into 700 ml of water
with stirring. The mixture is extracted in portions with a total of
300 ml of methylene chloride, the organic phase is dried using
anhydrous sodium sulfate, filtered and the filtrate is concentrated
in vacuo. The residue is purified on a silica gel column (silica
gel 60, Merck AG, Darmstadt; eluent methylene chloride/ethanol 9:1,
v/v).
[0032] Yield: 43.9 g (87% of theory) MS: m/e 253 (M+H)
[0033] 2nd stage
[0034] N-(Pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide
(D-68836)
[0035] A solution of 4.50 ml of oxalyl chloride in 50 ml of ether
is treated dropwise with a solution of 10.09 g (0.04 mol) of
1-(4-nitrobenzyl)indole in 50 ml of ether at 0.degree. C. [sic] and
under a nitrogen atmosphere. The mixture is heated at reflux
temperature for 2 hours and the solvent is then evaporated. 100 ml
of tetrahydrofuran are added to the residue, it is cooled to
-5.degree. C. and a solution of of [sic] 9.32 g (0.099 mol) of
4-aminopyridine in 400 ml of tetrahydrofuran is added dropwise. The
mixture is heated to reflux for 3 hours and allowed to stand at
room temperature overnight. The 4-aminopyridine hydrochloride is
filtered off with suction, the precipitate is washed with
tetrahydrofuran, the filtrate is concentrated in vacuo and the
residue is recrystallized from ethyl acetate.
[0036] Yield: 13.5 g (84% of theory) MS: m/e 401 (M+H)
[0037] 3rd stage
[0038] N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide
(D-68838)
[0039] A mixture of 200 mg of Raney nickel in 50 ml of dioxane is
treated with a suspension of 320 mg (0.8 mmol) of
N-(pyridin-4-yl)-[1-(4-nitroben- zyl)indol-3-yl]glyoxylamide in a
solvent mixture of 150 ml of dioxane and 20 ml of isopropanol.
Hydrogen is passed into this suspension with shaking at a gas
pressure of 5 bar and the temperature is kept at 30-35.degree. C.
After about 3 hours, a further 400 mg of Raney nickel are added and
the hydrogenation is continued at 35.degree. C. and 5 bar for a
further 8 hours with vigorous shaking. The catalyst is filtered off
under an N.sub.2 atmosphere, the filtrate is concentrated to
dryness in vacuo and the residue is dried in vacuo at 40.degree.
C.
[0040] Yield: 273 mg (92% of theory) MS: m/e 371 (M+H)
[0041] Furthermore, the compounds of the general formula 1 with
Z.dbd.O, R.dbd.NO.sub.2 and NH.sub.2 and R.sub.2=aryl, aralkyl,
heteroaryl, heteroaralkyl and the
allylaminocarbonyl-2-methylprop-1-yl group can also be synthesized
according to the synthesis route of Scheme 2: 6
[0042] 1 st stage
[0043] N-(Pyridin-4-yl)-(indol-3-yl)glyoxylamide
[0044] 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 temperature. 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).
[0045] Yield: 9.8 g (43.3% of theory) MS: m/e 266 (M+H)
[0046] 2nd stage
[0047] N-(Pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide
(D-68836)
[0048] The N-(pyridin-4-yl)-(indol-3-yl)glyoxylamide obtained
according to the 1st Stage (Scheme 2) is reacted with 4-nitrobenzyl
chloride according to the "benzylation procedure" (page 5) and the
compound N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]glyoxylamide
obtained is isolated.
[0049] Yield: 64% of theory MS: m/e 401 (M+H)
[0050] N-(Pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide
(D-68838)
[0051] The
N-(pyridin-4-yl)-[1-(4-nitrobenzyl)indol-3-yl]-glyoxylamide
obtained according to the 2nd Stage (Scheme 2) is catalytically
hydrogenated according to the "hydrogenation procedure" (page 7)
and the compound
N-(pyridin-4-yl)-[1-(4-aminobenzyl)indol-3-yl]glyoxylamide obtained
is isolated.
[0052] Yield: 94% of theory MS: m/e 371 (M+H)
[0053] General procedure for the preparation of the compounds of
the general formula 1 according to Scheme 2
[0054] 1st stage:
[0055] The indole 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 to -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. 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).
[0056] 2nd Stage
[0057] 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, 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. 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.degree. C.
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. The organic
phase is concentrated in vacua, 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).
[0058] 3rd stage
[0059] The N-nitrobenzyl-substituted "indoleglyoxylamide obtained
according to the above procedure (2nd stage) is dissolved in a
protic solvent, such as, for example, methanol, ethanol, propanol
or butanol or in a nonpolar solvent, such as, for example,
tetrahydrofuran, dioxane or glycol dimethyl ether or in a dipolar
aprotic solvent, such as, for example, dimethyl sulfoxide,
dimethylformamide, dimethylacetamide or N-methylpyrrolidone and the
solution is treated with a hydrogenation catalyst such as, for
example, Raney nickel, palladium/carbon or platinum under a
nitrogen atmosphere and with stirring. Hydrogen is passed into the
suspension with moderate shaking at a gas pressure of 1-15 bar,
preferably 2-10 bar, particularly at 4-6 bar and the temperature is
raised to about 20.degree.-80.degree. C., preferably
30.degree.-60.degree. C., particularly to 45.degree.-55.degree. C.
If appropriate, after about 1 hour a further amount of catalyst is
added and the hydrogenation is continued. The hydrogenation was
complete after a reaction time of 4-6 hours. The catalyst was
filtered off under a nitrogen atmosphere, the solvent was
concentrated to dryness and the colorless to yellowish residue was
dried in vacuo at 40.degree. C.
[0060] According to this general procedure for stages 1-3, on which
the synthesis scheme 2 is based, the compounds D-68836 and D-68838
were synthesized, which have also already been prepared according
to the synthesis procedure of reaction scheme 1.
[0061] It was possible to show the activity of the present
compounds in a tubulin polymerization assay. In particular, proof
was provided that D-68838 inhibits the polymerization of tubulin
and thus exerts a destabilizing effect on microtubuli or the
mitotic spindles.
* * * * *