Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-09
2001-08-21
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S354000
Reexamination Certificate
active
06277850
ABSTRACT:
The present invention relates to pyrrolylquinoxalinediones of the formula I
and their tautomeric and isomeric forms, and their physiologically tolerated salts, where the variables have the following meaning:
R
1
hydrogen, C
1
-C
6
-alkyl, substituted by hydroxyl or carboxyl,
R
2
hydrogen, C
1
-C
6
-alkyl, C
2
-C
6
-alkenyl, C
2
-C
6
-alkynyl, a chlorine, fluorine or bromine atom, a trihalomethyl, cyano or nitro group or SO
2
—C
1
-C
4
-alkyl,
R
3
COOH or a radical which can be hydrolyzed to the carboxyl group,
n 1 or 2.
The invention furthermore relates to processes for their preparation and to their use for controlling diseases.
Derivatives of quinoxaline-2,3(1H, 4H)-dione of the formula A
have been described in several publications, such as EP-A-374 534 and EP-A-260 467, as glutamate antagonists. Many known derivatives are unsubstituted in the heterocyclic quinoxaline fragment (A with R
1
, R
2
=hydrogen). Furthermore, derivatives in which R
1
in A is a radical which is not hydrogen are also known. Thus, EP-A-377 112 and EP-A-374 534 have disclosed N-hydroxyquinoxalines (A; R
1
=OR
4
). EP-A-315 959, DE-A-41 35 871, WO 91/13 878 and WO 92/07 847 describe alkyl radicals as R
1
in A, it also being possible for the alkyl chain to be substituted by acids, esters or amides.
Quinoxalinedione derivatives of the formula A which have a heterocycle as substituent R
3
are likewise known. Thus, EP-A-556 393 describes imidazoles, triazoles and pyrazoles. Quinoxalinedione derivatives having a pyrrolyl radical as R
3
are disclosed in EP-A-572 852 and WO 95/35 289. DE-A-43 400 45 mentions pyrrole derivatives which have a urea residue as glutamate antagonists.
The known pyrrolylquinoxalinedione compounds are still not always entirely satisfactory with regard to their pharmacological effect. It is an object of the present invention to provide pyrrolylquinoxalinedione derivatives with improved activity and, at the same time, good physiological tolerability.
We have found that this object is achieved by the pyrrolylquinoxalinediones of the formula I mentioned at the outset.
The radicals R
1
-R
3
in formula I have the following meanings:
R
1
is hydrogen or branched or unbranched C
1
-C
6
-alkyl, substituted by hydroxyl or carboxyl, eg. hydroxyethyl or carboxymethyl. C
1
-C
6
-Alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl. In the case of the hydroxyl-substituted compounds, alkyl is preferably C
2
-C
6
-alkyl.
R
2
is hydrogen, C
1
-C
6
-alkyl, eg. as mentioned above, C
2
-C
6
-alkenyl or—alkynyl, eg. vinyl, ethynyl, propenyl, isopropenyl, fluorine, chlorine, bromine, trihalomethyl, eg. trichloromethyl or trifluoromethyl, cyano or nitro, and SO
2
—C
1
-C
4
-alkyl, where the alkyl radical has the abovementioned meanings. Particularly preferred radicals R
2
are hydrogen, chlorine, trifluoromethyl or nitro.
R
3
is a carboxyl group COOH or a radical which can be hydrolyzed to the carboxyl group, eg. an amide group, a carboxylic anhydride group or, in particular, an ester group COOR
4
where R
4
is C
1
-C
4
-alkyl, eg. COOCH
3
or COOC
2
H
5
. In the case of two adjacent carboxyl groups, they may form a cyclic anhydride. Particularly preferred for the pharmacological effect is the free COOH group or its salts.
The variable n is 1 or 2, in particular 1.
The substituent(s) R
3
can be located in the position meta, para or ortho to the urea residue. The para and/or meta position is preferred.
Particularly preferred compounds are those where
R
1
is hydrogen,
R
2
is hydrogen, chlorine, a trifluoromethyl or nitro group,
R
3
is COOH and
n is 1 or 2.
Further particularly preferred compounds are those where
R
1
— is CH
2
COOH or —CH
2
CH
2
OH,
R
2
is hydrogen, chlorine, a trifluoromethyl or nitro group,
R
3
is COOH, and
n is 1 or 2.
The compounds I according to the invention can be prepared as shown in reaction scheme 1.
This entails amino-substituted oumnoxalinediones of the formula II being reacted with a 1,4-dicarbonyl compound or cyclic acetals derived therefrom (III and VI) with elimination of water to give the pyrroles I and IV. The processes used for this are the conventional ones described, for example, in A. R. Katritzky and C. W. Rees, “Comprehensive Heterocyclic Chemistry”, Vol.4, Part 306, pages 313 et seq., in C. Ferri, “Reaktionen der organischen Synthese”, Thieme Verlag 1978, pages 708 et seq., or in EP-A-572 852 and DE-A-43 400 45. The pyrrole synthesis is normally catalyzed by acid and takes place in the presence of acetic acid or toluenesulfonic acid. The acid can also act as solvent if used in larger amounts. However, it is generally customary to carry out the reaction in a solvent such as toluene or in a mixture of solvents such as toluene/dimethylformamide at from 50 to 150° C., preferably 100 to 150° C., or in concentrated acetic acid at from 50° C. to the boiling point.
If the dicarbonyl compound employed, for example compound III in scheme 1, has an amino group, this is protected beforehand. Known protective groups such as amides, urethanes or benzyl radicals can be employed, and trifluoroacetyl is preferably used. Other possible protective groups and introduction methods are indicated in Th. W. Green and P. G. M. Wuts, “Protective Groups in Organic Synthesism”, Wiley&Sons 1991, Chapter 7. The protective groups are removed in a conventional way after the pyrrole ring has been synthesized, resulting in the amine V. Elimination of the amide protective group preferably takes place with acids or bases such as lithium hydroxide in a solvent or solvent mixtures such as tetrahydrofuran/water at from 10 to 60° C., preferably 20 to 30° C.
The amines of the formula V can then be reacted in a conventional way with isocyanates to give the compounds of the formula I according to the invention, it also being possible to use in place of the isosocyanate the corresponding anilines which, in this case, are reacted in a known manner with phosgene or analogous compounds, such as carbonyl diimidazole, to give the isocyanates in situ. These and similar processes are described, for example, in Houben-Weyl, “Methoden der organischen Chemier”, Vol. E4, pages 334 et seq.
In place of the amide III, it is also possible to employ the corresponding aldehyde which is subsequently converted, in a reductive amination, into the amines V.
The pyrrolylquinoxalinediones according to the invention can be obtained directly by starting from the aniline compounds II and using the acetals VI. The procedure for this is similar to that for preparing the pyrroles V.
The ester in the urea derivative I can be converted into the corresponding acid with acids or bases. This preferably takes place with bases such as lithium hydroxide in solvent mixtures such as tetrahydrofuran/water at 20 to 30° C.
The compounds according to the invention which are mentioned by way of example in the table can be prepared by the abovementioned synthetic route:
TABLE 1
I
get,0001
R
3
= COOH
R
1
R
2
n
Position
CH
2
CH
2
OH
H
1
para
CH
2
CH
2
OH
H
1
meta
CH
2
CH
2
OH
H
1
ortho
CH
2
CH
2
OH
Cl
1
para
CH
2
CH
2
OH
Cl
1
meta
CH
2
CH
2
OH
Cl
1
ortho
CH
2
CH
2
OH
CF
3
1
para
CH
2
CH
2
OH
CF
3
1
meta
CH
2
CH
2
OH
CF
3
1
ortho
CH
2
CH
2
OH
NO
2
1
para
CH
2
CH
2
OH
NO
2
1
meta
CH
2
CH
2
OH
NO
2
1
ortho
CH
2
CH
2
OH
H
2
para/meta
CH
2
CH
2
OH
Cl
2
para/meta
CH
2
CH
2
OH
CF
3
2
para/meta
CH
2
CH
2
OH
NO
2
2
para/meta
CH
2
CH(OH)CH
3
H
1
para
CH
2
CH(OH)CH
3
H
1
meta
CH
2
CH(OH)CH
3
Cl
1
para
CH
2
CH(OH)CH
3
Cl
1
meta
CH
2
CH(OH)CH
3
CF
3
1
para
CH
2
CH(OH)CH
3
CF
3
1
meta
CH
2
CH(OH)CH
3
NO
2
1
para
CH
2
CH(OH)CH
3
NO
2
1
meta
CH
2
CH(OH)CH
3
H
2
para/meta
CH
2
CH(OH)CH
3
Cl
2
para/meta
CH
2
CH(OH)CH
3
CF
3
2
para/meta
CH
2
CH(OH)CH
3
NO
2
2
para/meta
CH
2
CH
2
CH
2
OH
H
1
para
CH
2
CH
2
CH
2
OH
H
1
meta
CH
2
CH
2
CH
2
OH
Cl
1
para
CH
2
CH
2
CH
2
OH
Cl
1
meta
CH
2
CH
2
CH
2
OH
CF
3
1
para
CH
2
CH
2
CH
2
OH
CF
3
1
meta
CH
2
CH
2
CH
2
OH
NO
2
1
para
CH
2
CH
2
CH
2
OH
NO
2
1
meta
CH
2
CH
2
CH
2
OH
H
2
para/meta
CH
2
CH
2
CH
2
OH
Cl
2
para/meta
CH
2
CH
2
CH
2
OH
CF
3
2
para/meta
CH
2
C
Behl Berthold
Hofmann Hans-Peter
Lubisch Wilfried
Szabo Laszlo
Abbott Laboratories
Bernhardt Emily
Keil & Weinkauf
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