Carboline derivatives as cGMP phosphodiesterase inhibitors

Details Carboline derivatives as cGMP phosphodiesterase inhibitors Carboline derivatives as cGMP phosphodiesterase inhibitors

2001-05-16

2002-10-08

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252180, C514S256000, C514S275000, C514S292000, C544S332000, C544S335000, C544S361000, C546S085000

Reexamination Certificate

active

06462047

ABSTRACT:

FIELD AND BACKGROUND OF THE INVENTION
This invention relates to a series of carboline derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to their use as therapeutic agents. In particular, the invention relates to carboline derivatives which are potent and selective inhibitors of cyclic guanosine 3′, 5′-monophosphate specific phosphodiesterase (cGMP-specific PDE), and in particular PDE5, and have utility in a variety of therapeutic areas where such inhibition is considered beneficial, including the treatment of cardiovascular disorders and erectile dysfunction.
SUMMARY OF THE INVENTION
The present invention provides compounds represented by formula (I):
wherein
A represents a 5- or 6-membered heteroaryl group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur;
R
0
represents hydrogen or halogen;
R
1
is selected from the group consisting of
hydrogen,
nitro (NO
2
),
trifluoromethyl,
trifluoromethoxy,
halogen,
cyano (CN),
a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur, optionally substituted with C(═O)OR
a
or C
1-4
alkyl,
C
1-6
alkyl, optionally substituted with OR
a
,
C
1-3
alkoxy,
C(═O)R
a
,
O—C(═O)R
a
,
C(═O)OR
a
,
C
1-4
alkyleneHet,
C
1-4
alkyleneC(═O)OR
a
,
O—C
1-4
alkylene-C(═O)OR
a
,
C
1-4
alkylene-O—C
1-4
alkylene-C(═O)OR
a
,
C(═O)NR
a
SO
2
R
c
,
C(═O) C
1-4
alkyleneHet,
C
1-4
alkylene NR
a
R
b
,
C
2-6
alkenyleneNR
a
R
b
,
C(═O)NR
a
R
b
,
C(═O)NR
a
R
c
,
C(═O)NR
a
C
1-4
alkyleneOR
b
,
C(═O)NR
a
C
1-4
alkyleneHet,
OR
a
,
OC
2-4
alkylene NR
a
R
b
,
OC
1-4
alkylene-CH(OR
a
)CH
2
—NR
a
R
b
,
O—C
1-4
alkyleneHet,
O—C
2-4
alkylene-OR
a
,
O—C
2-4
alkylene-NR
a
—C(═O)—OR
b
,
NR
a
R
b
,
NR
a
C
1-4
alkyleneNR
a
R
b
,
NR
a
C(═O)R
b
,
NR
a
C(═O)NR
a
R
b
,
N(SO
2
C
1-4
alkyl)
2
,
NR
a
(SO
2
C
1-4
alkyl),
SO
2
NR
a
R
b
,
and OSO
2
trifluoromethyl;
R
2
is selected from the group consisting of hydrogen, halogen, OR
a
, C
1-6
alkyl, NO
2
, and NR
a
R
b
;
or R
1
and R
2
are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
R
3
is selected from the group consisting of hydrogen, halogen, NO
2
, trifluoromethoxy, C
1-6
alkyl, OC
1-6
alkyl, and C(═O)OR
a
;
R
4
is hydrogen,
or R
3
and R
4
are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
Het represents a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulfur, and is optionally substituted with C
1-4
alkyl;
R
a
and R
b
can be the same or different, and are independently selected from hydrogen and C
1-6
alkyl;
R
c
represents phenyl or C
4-6
cycloalkyl, wherein the phenyl or C
4-6
cycloalkyl can be optionally substituted with one or more halogen atoms, one or more C(═O)OR
a
, or one or more OR
a
;
n is an integer 1, 2, or 3;
m is an integer 1 or 2;
and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof.
In a preferred embodiment, R
2
is hydrogen, n and m are the integer 1, and the compounds are represented by the formula (II):
wherein
A represents a 5- or 6-membered heteroaryl group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur;
R
0
, R
4
, R
a
, R
b
, R
c
, and Het are as defined above;
R
1
is selected from the group consisting of
hydrogen,
NO
2
,
halogen,
CN,
a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur, optionally substituted with C(═O)OR
a
or C
1-4
alkyl,
C
1-6
alkyl optionally substituted with OR
a
,
C
1-3
alkoxy,
C(═O)OR
a
,
C
1-4
alkyleneHet,
O—C
1-4
alkylene-C(═O)OR
a
,
C
1-4
alkyleneNR
a
R
b
,
C(═O)NR
a
R
b
,
C(═O)NR
a
R
c
,
OR
a
,
OC
2-4
alkyleneNR
a
R
b
,
O—C
1-4
alkyleneHet,
NR
a
R
b
,
and NR
a
C
1-4
alkyleneNR
a
R
b
;
R
3
is selected from the group consisting of hydrogen and OCH
3
;
R
4
is hydrogen,
or R
3
and R
4
together form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one heteroatom;
and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof.
The term alkyl or alkylene as used herein contains the indicated number of carbon atoms and includes straight chained and branched alkyl or alkylene groups, typically methyl, methylene, ethyl, ethylene, and straight chain and branched propyl, propylene, butyl, and butylene groups. The term alkenylene as used herein contains the indicated number of carbon atoms and includes straight chained and branched alkenylene groups, like ethyenylene.
The term halogen as used herein includes fluorine, bromine, chlorine, and iodine groups.
The term 5- or 6-membered heteroaryl group as used herein includes, for example, thiophene, furan, pyrrole, imidazole, pyrimidine, and pyridine.
The term 5- or 6-membered heterocyclic group as used herein includes 5- or 6-membered heterocycloalkyl and heteroaryl groups, e.g., morpholinyl, piperidyl, pyrrolidinyl, or piperazinyl.
Preferably A is a thiophenyl, furyl, pyrimidinyl, pyridyl, or imidazolyl group. Most preferably, A represents a pyridyl group.
When A represents a thiophenyl group, R
1
preferably is selected from a group consisting of hydrogen, NO
2
, C
1-4
alkyleneNR
a
R
b
, e.g., CH
2
NMe
2
, and C
1-4
alkyleneHet, wherein Het is optionally substituted by C
1-4
alkyl, e.g., a pyrrolidinylmethyl or N-methyl piperazinylmethyl group. Me is an abbreviation for methyl, i.e., CH
3
.
When A represents a furyl group, R
1
preferably is hydrogen or C
1-4
alkyleneNR
a
R
b
, e.g., CH
2
NMe
2
.
When A represents a pyrimidine group, R
1
preferably is hydrogen or NH
2
.
When A represents a pyridine group, R
1
preferably represents hydrogen, a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur, optionally substituted by C
1-4
alkyl, e.g., N-methyl imidazole, N-methyl piperazine, or pyrrolidine, C(═O)OR
a
, e.g., CO
2
H or CO
2
Me, C
1-4
alkyleneHet, wherein Het optionally is substituted with C
1-4
alkyl, e.g., a pyrrolidinylmethyl or piperazinylmethyl group, C
2-4
alkyleneNR
a
R
b
, e.g., O(CH
2
)
2
NMe
2
, or NR
a
R
b
, e.g., NH
2
, NHMe and NMe
2
. Most preferably, when A represents a pyridine group, R
1
represents O(CH
2
)
2
NMe
2
.
R
3
and R
4
can be taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring containing at least one heteroatom. Preferably, R
3
and R
4
are taken together, and with the phenyl ring to which they are attached form:
In an especially preferred subclass of compounds within the general scope of formulae (I) and (II), R
2
is hydrogen, n and m are the integer 1, and is represented by compounds of formula (III),
wherein
R
1
is selected from the group consisting of hydrogen, a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, and sulphur, C(═O)OR
a
, OC
2-4
alkylene-NR
1
R
b
, and NR
a
R
b
;
R
3
and R
4
are taken together to form a 3- or 4-membered alkylene or alkenylene chain component of a 5- or 6-membered ring, optionally containing at least one oxygen atom;
R
a
and R
b
can be the same or different and are independently selected from hydrogen and C
1-6
alkyl;
and pharmaceutically acceptable salts and solvates (e.g., hydrates) thereof.
The compounds of formula (I) can contain one asymmetric center and thus can exist as enantiomers. The present invention includes both mixtures and separate individual isomers of the compounds of formula (I).
Pharmaceutically acceptable salts of the compounds of formula (I) that contain a ba

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