Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
2001-06-21
2004-05-04
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
Reexamination Certificate
active
06730786
ABSTRACT:
This invention relates to a novel process for the production of 4-alkylpiperazinylsulfonylphenyl- and 4-alkylpiperazinylsulfonyl pyridinyldihydropyrazolo[4,3-d]pyrimidin-7-one derivatives, and, in particular, the anti-impotence drug, sildenafil and analogues thereof.
Sildenafil (5-[2-ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one),
is the active ingredient in Viagra™. The compound, which was originally disclosed in European patent application EP 463 756, has been found to be particularly useful in the treatment of inter alia male erectile dysfunction (see international patent application WO 94/28902).
Multi-step syntheses for the production of sildenafil are described in EP 463 756. An improved process for its production is described in a later application (European patent application EP 812 845), the final step of which involves an internal cyclisation under basic, neutral or acidic conditions.
We have now found that sildenafil and analogues thereof may be made via a novel process, as described hereinafter, which process has advantages over the processes described in the above-mentioned prior art documents.
According to a first aspect of the invention, there is provided a process for the production of compounds of general formula I:
wherein
A represents CH or N;
R
1
represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
2
and R
4
independently represent lower alkyl;
R
3
represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R
5
, R
6
, R
7
, R
8
, R
9
, R
11a
and R
11b
independently represent H or lower alkyl;
R
10a
and R
10b
either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl,
which process comprises the dehydrogenation of a compound of general formula II,
wherein A, R
1
, R
2
, R
3
and R
4
are as defined above,
which process is referred to hereinafter as “the process of the invention”.
According to a second aspect of the invention, there is provided a process for the production of compounds of general formula I:
wherein
A represents CH or N;
R
1
represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
2
and R
4
independently represent lower alkyl;
R
3
represents lower alkyl, which alkyl group is optionally interrupted by oxygen; Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R
5
, R
6
, R
7
, R
8
, R
9
, R
11a
and R
11b
independently represent H or lower alkyl;
R
10a
and R
10b
either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl;
with the proviso that the compound of formula I is not sildenafil;
which process comprises the dehydrogenation of a compound of general formula II,
wherein A, R
1
, R
2
, R
3
and R
4
are as defined above,
which process is referred to hereinafter as “the process of the invention”.
According to a third aspect of the invention, there is provided a process for the production of compounds of general formula I:
wherein
A represents CH;
R
1
represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
2
and R
4
independently represent lower alkyl;
R
3
represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R
5
, R
6
, R
7
, R
8
, R
9
, R
11a
and R
11b
independently represent H or lower alkyl;
R
10a
and R
10b
either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl;
with the proviso that the compound of formula I is not sildenafil;
which process comprises the dehydrogenation of a compound of general formula II,
wherein A, R
1
, R
2
, R
3
and R
4
are as defined above,
which process is referred to hereinafter as “the process of the invention”.
According to a fourth aspect of the invention, there is provided a process for the production of compounds of general formula I:
wherein
A represents N;
R
1
represents H, lower alkyl (which alkyl group is optionally interrupted by O), Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted (and/or, in the case of lower alkyl, optionally terminated) by one or more substituents selected from halo, cyano, nitro, lower alkyl, OR
5
, C(O)R
6
, C(O)OR
7
, C(O)NR
8
R
9
, NR
10a
R
10b
and SO
2
NR
11a
R
11b
;
R
2
and R
4
independently represent lower alkyl;
R
3
represents lower alkyl, which alkyl group is optionally interrupted by oxygen;
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and sulfur;
R
5
, R
6
, R
7
, R
8
, R
9
, R
11a
and R
11b
independently represent H or lower alkyl;
R
10a
and R
10b
either independently represent, H or lower alkyl or, together with the nitrogen atom to which they are attached, represent azetidinyl, pyrollidinyl or piperidinyl,
which process comprises the dehydrogenation of a compound of general formula II,
wherein A, R
1
, R
2
, R
3
and R
4
are as defined above,
which process is referred to hereinafter as “the process of the invention”.
The compounds of general formulae I and II can be represented by the formulae IA and IB and IIA and IIB as detailed hereinafter. The novel process according to the present invention includes compounds of the formulae IA, IB, IIA and IIB.
The term “aryl”, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl and the like.
Het groups may be fully saturated, partly unsaturated, wholly aromatic, partly aromatic and/or bicyclic in character. Het groups that may be mentioned include groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl, piperazinyl, thienyl and furanyl.
The point of attachment of any Het group may be via any atom in the ring system including (where appropriate) a heteroatom. Het groups may also be present in the N- or S-oxidised form.
The term “lower alkyl” (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, includes C
1-6
alkyl (e.g. C
1-4
alkyl). Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be
Bunnage Mark Edward
Levett Philip Charles
Thomson Nicholas Murray
Benson Gregg C.
Ford John M.
Jones James T.
Pfizer Inc
Richardson Peter C.
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