Process for the preparation of...

Details Process for the preparation of... Process for the preparation of...

2001-07-26

2004-10-26

Berch, Mark L. (Department: 1624)

Organic compounds -- part of the class 532-570 series

Organic compounds

Pteroyl per se or having -c-, wherein x is chalcogen, bonded...

C546S275400

Reexamination Certificate

active

06809200

ABSTRACT:

This invention relates to a series of pyrazolo[
4,3-
d]pyrimidin-7-one compounds of formula I (as defined below) and intermediates thereof. More notably, most of the compounds of interest are inhibitors of type 5 cyclic guanosine 3′,5′-monophosphate phosphodiesterase (CGMP PDE5) and have utility in a variety of therapeutic areas (such as male erectile dysfunction). A compound of particular interest is 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (hereinafter compound of formula IA).
“Processes for the preparation of compounds of formula I are disclosed in WO 01/27112. In particular, example 132 of WO 01/27112 discloses a displacement reaction for preparing compound IA.”
According to a first aspect of the invention there is provided a process for the preparation of a compound of formula (I):
or a pharmaceutically or veterinarily acceptable salt , pro-drug, polymorph and/or solvate thereof, wherein
Q represents O or NR
5
R
1
represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
2
represents H, halo, cyano, nitro, OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
, SO
2
NR
14
R
15
, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
3
represents H, lower alkyl, alkylHet or alkylaryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
4
represents H, halo, cyano, nitro, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
, NR
16
Y(O)R
17
, N[Y(O)R
17
]
2
, SOR
18
, SO
2
R
19
, C(O)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
Y represents C or S(O)
A represents lower alkylene
Z represents OR
6
, halo, Het or aryl (which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
and SO
2
NR
14
R
15
)
R
10
and R
11
independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR
6
, OC(O)R
7
, C(O)R
6
, C(O)OR
9
, C(O)NR
10
R
11
, NR
12
R
13
, SO
2
NR
14
R
15
and NR
20
S(O)
2
R
21
or Het or aryl optionally substituted with one or more of said latter thirteen groups) or one of R
10
and R
11
may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl
R
10a
and R
11a
independently represent R
10
and R
11
as defined above, except that they do not represent groups that include lower alkyl, Het or aryl, when these three groups are substituted and/or terminated (as appropriate) by one or more substituents that include one or more C(O)NR
10a
R
11a
and/or NR
12
R
13
groups
R
12
and R
13
independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR
6
, C(O)OR
9
, C(O)NR
22
R
23
and NR
24
R
25
), one of R
12
or R
13
may be C(O)-lower alkyl or C(O)Het (in which Het is optionally substituted with lower alkyl), or R
12
and R
13
together represent C
3-7
alkylene (which alkylene group is optionally unsaturated, optionally substituted by one or more lower alkyl groups and/or optionally interrupted by O or NR
26
)
R
14
and R
15
independently represent H or lower alkyl or R
14
and R
15
, together with the nitrogen atom to which they are bound, form a heterocyclic ring
R
16
and R
17
independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR
6
, C(O)OR
9
, C(O)NR
22
R
23
and NR
24
R
25
) or one of R
16
and R
17
may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl
R
5
, R
6
, R
7
, R
8
, R
9
, R
18
, R
19
, R
20
, R
22
, R
23
, R
24
and R
25
independently represent H or lower alkyl
R
18
and R
19
independently represent lower alkyl
R
21
represents lower alkyl or aryl
R
28
represents H, lower alkyl, aryl, C(O)R
27
or S(O)
2
R
28
R
27
represents H, lower alkyl or aryl
R
28
represents lower alkyl or aryl
Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulphur and mixtures thereof
said process comprising reacting a compound of formula (II), (III), (IV) or (V) in the presence of
−
OR
3
and a hydroxide trapping agent or, alternatively, in the case of compounds of formulae (IV) or (V) reacting in the presence of an auxiliary base and a hydroxide trapping agent. An auxiliary base as defined herein means a base other than
−
OR
3
which is used in place of
−
OR
3
.
wherein X is a leaving group and Q and R
1
to R
4
are as defined above.
The term “aryl”, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl, which groups are optionally substituted with one or more substituents selected from aryl (which group may not be substituted by any further aryl groups), lower alkyl, Het, halo, cyano, nitro, OR
6
, OC(O)O)R
7
, C(O)O)R
8
, C(O)O)R
9
, C(O)NR
10a
R
11a
, NR
12a
R
13a
(wherein R
12a
and R
13a
independently represent R
12
and R
13
as hereinbefore defined, except that: (i) they do is not represent C(O)Het in which Het is substituted by one or more substituents that include one or more C(O)NR
10a
R
11a
and/or NR
12a
R
13a
, groups; or (ii) they do not together represent C
3-7
alkylene interrupted by NR
26
) and SO
2
NR
14
R
15
.
The term “Het”, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain one or more heteroatoms selected from nitrogen, oxygen, sulfur and mixtures thereof, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The ring systems may be monocyclic, bicyclic or fused. Each “Het” group identified herein is optionally substituted by one or more substituents selected from halo, cyano, nitro, oxo, lower alkyl (which alkyl group may itself be optionally substituted or terminated as defined below), OR
6
, OC(O)R
7
, C(O)R
8
, C(O)OR
9
, C(O)NR
10a
R
11a
, NR
12a
R
13a
and SO
2
NR
14
R
15
. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbon atom of the Het ring or, where appropriate, at one or more of the heteroatoms.
“Het” groups may also be in the form of an N-oxide.
The heterocyclic ring that R
14
and R
15
(together with the nitrogen atom to which they are bound) may represent may be any heterocyclic ring that contains at least one nitrogen atom, and whic

Affiliated with

Also associated with

Rating

Process for the preparation of... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Process for the preparation of..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Process for the preparation of... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3266143