N-substituted indole-3-glyoxylamides having anti-asthmatic,...

Details N-substituted indole-3-glyoxylamides having anti-asthmatic,... N-substituted indole-3-glyoxylamides having anti-asthmatic,...

1999-09-30

2002-02-05

McKane, Joseph K. (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S218000, C514S256000, C544S333000, C544S335000, C544S373000, C540S575000

Reexamination Certificate

active

06344467

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to novel N-substituted indole-3-glyoxylamides, processes for their preparation and pharmaceutical uses. The compounds have antiasthmatic, antiallergic and immunosuppressant/immunomodulating properties.
2. Background Information
Indole-3-glyoxylamides have various uses as pharmaco-dynamically active compounds and as synthesis components in the pharmaceutical chemistry.
The Patent Application NL 6502481 describes compounds which have an antiinflammatory and antipyretic profile of action and analgesic activity.
The British Patent GB 1 028 812 mentions derivatives of indolyl-3-glyoxylic acid and its amides as compounds having analgesic, anticonvulsant and &bgr;-adrenergic activity.
G. Domschke et al. (Ber. 94, 2353 (1961)) describe 3-indolylglyoxylamides which are not characterized pharmacologically.
E. Walton et al. in J. Med. Chem. 11, 1252 (1968) report on indolyl-3-glyoxylic acid derivatives which have an inhibitory activity on glycerophosphate dehydrogenase and lactate dehydrogenase.
Euoropean Patent Specification EP 0 675 110 A1 describes 1H-indole-3-glyoxylamides 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.
SUMMARY OF THE INVENTION
The aim of the present invention is to make available novel compounds from the indolyl-3-glyoxylic acid series, which have antiasthmatic and immunomodulating action.
The chemical processes for the preparation of these compounds and pharmaceutical processes for the conversion of the novel compounds into medicaments and heir preparation forms are furthermore described.
The subject matter of the invention comprises compounds of the general formula I,
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.
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
1
can be a phenyl ring which is mono- or polysubstituted by (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, hydroxyl, benzyloxy, nitro, amino, (C
1
-C
6
)-alkylamino, (C
1
-C
6
)-alkoxy-carbonylamino and by a carboxyl group or a carboxyl group esterified by (C
1
-C
6
)-alkanols, or is a pyridine structure of the formula II
 where the pyridine structure is alternatively bonded to the ring carbon atoms 2, 3 and 4 and can be substituted by the substitutents 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 also the meaning (C
3
-C
7
)-cycloalkyl, (C
1
-C
6
)-alkoxy, nitro, amino, hydroxyl, halogen and trifluoromethyl and are furthermore the ethoxycarbonylamino radical and the group carboxyalkyloxy in which the alkyl group can have 1-4 C atoms.
R
1
can furthermore be a 2- or 4-pyrimidinylheterocycle or a pyridylmethyl radical in which CH
2
can be in the 2-, 3-, 4-position where the 2-pyrimidinyl ring can be mono- or polysubstituted by the methyl group, furthermore are the 2-, 3- and 4-quinolyl structure substituted by (C
1
-C
6
)-alkyl, halogen, the nitro group, the amino group and the (C
1
-C
6
)-alkylamino radical, or are a 2-, 3- and 4-quinolylmethyl group, where the ring carbons of the pyridylmethyl and quinolylmethyl radical can be substituted by (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy, nitro, amino and (C
1
-C
6
)-alkoxy-carbonylamino.
R
1
for the case where R is hydrogen 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 in unprotected or protected form. Possible protective groups for the amino function are the carbobenzoxy radical (Z radical) and the tert-butoxycarbonyl radical (BOC radical) and also the acetyl group. In the case of the asparagyl and glutamyl radical claimed for R
1
, the second, nonbonded 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 the methyl, ethyl or as the tert-butyl ester. R
1
can furthermore be the allylaminocarbonyl-2-methylprop-1-yl group. R and R
1
, together with the nitrogen atom to which they are bonded, can furthermore form a piperazine ring of the formula III or a homopiperazine ring if R
1
is an aminoalkylene group in which
R
7
is an alkyl radical, 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, by (C
1
-C
6
)-alkylamino, the benzhydryl group and the bis-p-fluorobenzylhydryl group.
R
2
can be hydrogen or the (C
1
-C
6
)-alkyl group, where the alkyl group can be 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 furthermore be substituted by the 2-quinolyl group and the 2-, 3- and 4-pyridyl structure, which in each case can both be mono- or polysubstituted by halogen, (C
1
-C
4
)-alkyl groups or (C
1
-C
4
)-alkoxy groups. R
2
is furthermore the aroyl radical, where the aroyl 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 by (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, hydroxyl, (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
3
)-alkoxycarbonylamino function or (C
1
-C
3
)-alkcoxycarbonylamino-(C
1
-C
3
)-alkyl function.
Z is O or 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
and R
7
is normally to be understood as meaning “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 and n-hexyl and “branched alkyl groups” designate, for example, radicals such as isopropyl or tert-butyl. “Cycloalkyl” is to be 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 compounds according to the invention can also be present 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, embonic acid, methanesulfonic acid, trifluoroacetic acid and succinic acid.
Both the compounds of the formula I and their salts are biologically active. The compounds of the formula 1 can be administered in free form or as salts with a p

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