Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-12-17
2004-08-17
Shah, Mukund J. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C544S112000
Reexamination Certificate
active
06777551
ABSTRACT:
The present invention relates to a process for the preparation of sulphonamide-substituted imidazotriazinones.
It is known that compounds which are able to inhibit cyclic guanosine 3′,5′-monophosphate-metabolizing phosphodiesterases (cGMP PDEs) can be employed for the treatment of impotence (cf., for example, EP-B 0 702 555; K. Murray, Drugs, News & Perspectives 6 (1993), 150).
In WO 99/24433, sulphonamide-substituted imidazotriazinones are described as potent inhibitors of either one or more of the cyclic guanosine 3′,5′-monophosphate-metabolizing phosphodiesterases (cGMP PDEs). According to the nomenclature of Beavo and Reifsnyder (Trends in Pharmacol. Sci. 11, 150-155, 1990), these cGMP PDEs are the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.
According to WO 99/24433, the sulphonamide-substituted imidazotriazinones described therein are prepared from corresponding 2-ethoxyphenyl-substituted imidazotriazinones by reaction with chlorosulphonic acid and subsequent reaction with an appropriate amine, as is illustrated by the following scheme (R
1
to R
6
here have the meanings indicated in WO 99/24433):
In this process, highly reactive chlorosulphonic acid has to be used as a reagent. Moreover, the imidazotriazinonesulphonyl chlorides formed as intermediates are sensitive to hydrolysis, which, in particular in the conversion of this preparation process to the industrial scale, can lead to not inconsiderable yield variations.
It was therefore the object of the present invention to make available a process for the preparation of sulphonamnide-substituted imidazotriazinones in which the disadvantages of the above process known from the prior art are avoided.
This object is achieved according to the present invention by a process as in claim 1. In particular, in the process according to the invention as in claim 1 the use of chlorosulphonic acid is avoided by introduction of the sulphonic acid via a reaction with sulphuric acid and subsequent reaction with thionyl chloride. Moreover, the reaction with thionyl chloride and the subsequent reaction with an amine is carried out in a one-pot process, so that the imidazotriazinonesulphonyl chloride intermediate, which is sensitive to hydrolysis, does not need to be isolated. By means of this, yield variations on account of partial hydrolysis of this intermediate can be excluded. As a result of these advantages, the process according to the invention is much simpler to carry out on the industrial scale than the process described in WO 99/124433.
The process according to the invention comprises the preparation of compounds of the formula (I)
in which
R
1
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
2
represents straight-chain alkyl having up to 4 carbon atoms,
R
3
and R
4
are identical or different and represent a straight-chain or branched alkyl chain having up to 5 carbon atoms, which is optionally substituted up to two times in an identical or different manner by hydroxyl or methoxy,
or
R
3
and R
4
, together with the nitrogen atom, form a piperidinyl, morpholinyl or thiomorpholinyl ring or a radical of the formula
in which
R
7
denotes hydrogen, formyl, straight-chain or branched acyl or alkoxycarbonyl each having up to 6 carbon atoms, or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally mono- to disubstituted, in an identical or different manner, by hydroxyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, or denotes C
3-8
-cycloalkyl,
and the heterocycles mentioned under R
3
and R
4
, formed together with the nitrogen atom, are optionally mono- to disubstituted, in an identical or different manner, if appropriate also geminally, by hydroxyl, formyl, carboxyl, straight-chain or branched acyl or alkoxycarbonyl each having up to 6 carbon atoms,
and/or the heterocycles mentioned under R
3
and R
4
, formed together with the nitrogen atom, are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally mono- to disubstituted, in an identical or different manner, by hydroxyl or carboxyl,
and/or the heterocycles mentioned under R
3
and R
4
, formed together with the nitrogen atom, are optionally substituted by piperidinyl or pyrrolidinyl linked via N,
R
5
and R
6
are identical or different and represent hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms,
characterized in that compounds of the formula (II)
in which
R
1
, R
2
, R
5
and R
6
have the meanings indicated above,
are reacted with sulphuric acid to give compounds of the formula (III)
in which
R
1
, R
2
, R
5
and R
6
have the meanings indicated above,
and then with thionyl chloride and the product thus obtained is reacted in situ in an inert solvent with an amine of the formula (IV)
in which
R
3
and R
4
have the meaning indicated above,
and, if appropriate, reacted to give the corresponding salts, hydrates or N-oxides.
According to a preferred embodiment of the present invention, in the case of the reactants and the final product of the process according to the invention
R
1
denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
2
denotes straight-chain alkyl having up to 4 carbon atoms,
R
3
and R
4
identically to or differently from one another denote a straight-chain or branched alkyl chain having up to 5 carbon atoms, which is optionally substituted up to two times in an identical or different manner by hydroxyl or methoxy,
or
R
3
and R
4
, together with the nitrogen atom, form a piperidinyl or morpholinyl ring or a radical of the formula
in which
R
7
denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally mono- or disubstituted, in an identical or different manner, by hydroxyl, straight-chain or branched alkoxy each having up to 4 carbon atoms, or denotes C
3-6
-cycloalkyl, and the heterocycles mentioned under R
3
and R
4
, formed together with the nitrogen atom, are optionally mono- or disubstituted, in an identical or different manner, if appropriate also geminally, by hydroxyl, straight-chain or branched acyl or alkoxycarbonyl each having up to 4 carbon atoms, optionally by straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally mono- or disubstituted, in an identical or different manner, by hydroxyl,
R
5
and R
6
identically to or differently from one another denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms.
According to a particularly preferred embodiment of the present invention, in the case of the reactants and the final product of the process according to the invention
R
1
denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R
2
denotes straight-chain alkyl having up to 4 carbon atoms,
R
3
and R
4
identically to or differently from one another denote methyl or ethyl, which are optionally substituted up to two times in an identical or different manner by hydroxyl,
or
R
3
and R
4
, together with the nitrogen atom, form a piperidinyl or morpholinyl ring or a radical of the formula
in which
R
7
denotes hydrogen, methyl or ethyl, which is optionally mono- or disubstituted, in an identical or different manner, by hydroxyl, methoxy or ethoxy, or denotes cyclopentyl or cyclohexyl,
and the heterocycles mentioned under R
3
and R
4
, formed together with the nitrogen atom, are optionally mono- or disubstituted, in an identical or different manner, if appropriate also seminally, by hydroxyl, methyl or ethyl,
R
5
and R
6
identically to or differently from one another denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms.
According to a particularly preferred embodiment of the present invention, in the case of the reactants an
Gehring Reinhold
Heilmann Werner
Nowakowski Marc
Wahl Karl-Heinz
Balasubramanian Venkataraman
Bayer Aktiengesellschaft
Pellegrino Susan M.
Shah Mukund J.
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