Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-12
2003-12-09
Davis, Brian (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S406000, C514S452000, C514S465000, C514S469000, C514S530000, C514S563000, C546S334000, C546S335000, C546S336000, C548S556000, C549S366000, C549S406000, C549S441000, C549S467000, C560S039000, C560S041000, C562S444000, C562S450000
Reexamination Certificate
active
06660756
ABSTRACT:
The invention relates to inhibitors of neutral endopeptidase enzyme (NEP), uses thereof, processes for the preparation thereof, intermediates used in the preparation thereof and compositions containing said inhibitors. These inhibitors have utility in a variety of therapeutic areas including the treatment of male and female sexual dysfunction, particularly female sexual dysfunction (FSD), especially wherein the FSD is female sexual arousal disorder (FSAD).
NEP inhibitors are disclosed in WO 91/07386 and WO 91/10644.
The use of NEP inhibitors for treating FSD is disclosed in EP1 097 719-A1.
According to a first aspect, the invention provides a compound of formula (I), a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof;
wherein
R
1
is C
1-6
alkyl which may be substituted by one or more substituents, which may be the same or different, selected from the list: halo, hydroxy, C
1-6
alkoxy, hydroxyC
1-6
alkoxy, C
1-6
alkoxyC
1-6
alkoxy, carbocyclyl (preferably C
3-7
cycloalkyl, C
3-7
cycloalkenyl or phenyl), carbocyclyloxy (preferably phenoxy), C
1-4
alkoxycarbocyclyloxy (preferably C
1-4
alkoxyphenoxy), heterocyclyl, heterocyclyloxy, —NR
2
R
3
, —NR
4
COR
5
, —NR
4
SO
2
R
5
, —CONR
2
R
3
, —S(O)
p
R
6
, —COR
7
and —CO
2
(C
1-4
alkyl); or R
1
is carbocyclyl (preferably C
3-7
cycloalkyl or phenyl) or heterocyclyl, each of which may be substituted by one or more substituents from said list, which substituents may be the same or different, which list further includes C
1-6
alkyl; or R
1
is hydrogen, C
1-6
alkoxy, —NR
2
R
3
or —NR
4
SO
2
R
5
;
wherein
R
2
and R
3
, which may be the same or different, are carbocyclyl (preferably C
3-7
cycloalkyl or phenyl) or heterocyclyl (each of which may be substituted by C
1-4
alkyl, hydroxy or C
1-4
alkoxy); or are hydrogen or C
1
4alkyl; or R
2
and R
3
together with the nitrogen to which they are attached form a pyrrolidinyl, piperidino, morpholino, piperazinyl or N-(C
1-4
alkyl)piperazinyl group;
R
4
is hydrogen or C
1-4
alkyl;
R
5
is C
1-4
alkyl, CF
3
, carbocyclyl (preferably phenyl), C
1-4
alkylcarbocyclyl (preferably C
1-4
alkylphenyl), C
1-4
alkoxycarbocyclyl (preferably C
1-4
alkoxyphenyl), heterocyclyl, C
1-4
alkoxy or —NR
2
R
3
;
R
6
is C
1-4
alkyl, carbocyclyl (preferably phenyl), heterocyclyl or NR
2
R
3
; and
R
7
is C
1-4
alkyl, carbocyclyl (preferably C
3-7
cycloalkyl or phenyl) or heterocyclyl;
p is 0, 1, 2 or 3;
X is the linkage —(CH
2
)
n
— or —(CH
2
)
q
—O— (wherein Y is attached to the oxygen); wherein one or more hydrogen atoms in linkage X may be replaced independently by C
1-4
alkoxy; hydroxy; hydroxyC
1-3
alkyl; C
3-7
cycloalkyl; carbocyclyl; heterocyclyl; or by C
1-4
alkyl optionally substituted by one or more fluoro or phenyl groups; n is 3, 4, 5, 6 or 7; and q is 2, 3, 4, 5 or 6; and
Y is phenyl or pyridyl, each of which may be substituted by one or more groups R
8
which may be the same or different, wherein R
8
is hydroxy; mercapto; halogen; cyano; acyl; amino; mono(C
1-4
alkyl)amino; di(C
1-4
alkyl)amino; carbocyclyl or heterocyclyl (either of which is optionally substituted by C
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkoxy, haloC
1-6
alkoxy, C
16
alkylthio or halogen); C
16
alkoxy; phenoxy; C
1-6
alkylthio; phenylthio; or alkyl optionally substituted by C
1-6
alkoxy, haloC
1-6
alkoxy, C
1-6
alkylthio, halogen or phenyl; or
two R
8
groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused 5- or 6-membered carbocyclic or heterocyclyic ring, optionally substituted by C
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkoxy, haloC
1-6
alkoxy, C
1-6
alkylthio or halogen.
Preferably R
1
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxyC
1-3
alkyl, C
1-6
alkoxyC
1-6
alkoxyC
1-3
alkyl or C
1-6
alkyl substituted by phenyl.
More preferably R
1
is hydrogen, C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkoxyC
1-3
alkyl (preferably methoxyC
1-3
alkyl) or C
1-6
alkoxyC
1-6
alkoxyC
1-3
alkyl (preferably methoxyethoxymethyl).
More preferably still R
1
is C
1-4
alkyl (preferably propyl) or C
1-6
alkoxyC
1-3
alkyl (preferably methoxyC
1-3
alkyl, more preferably methoxyethyl).
A preferred group of compounds are of formula Ia:
Preferably n is 3 or 4, more preferably 3.
Preferably q is 2 or 3, more preferably 2.
Preferably X is —(CH
2
)
n
— wherein one or more hydrogen atoms in linkage X may be replaced by one or more of the groups defined for X in the first aspect.
Preferably R
8
is C
1-6
alkyl, C
1-6
alkoxy, hydroxy, mercapto, halo, cyano, carbocyclyl or heterocyclyl; or two R
8
groups on adjacent carbon atoms together with the interconnecting carbon atoms may form a fused 5- or 6-membered carbocyclic or heterocyclyic ring, optionally substituted by C
1-6
alkyl, haloC
1-6
alkyl, C
1-6
alkoxy, haloC
1-6
alkoxy, C
1-6
alkylthio or halogen.
When R
8
is carbocyclyl, preferred groups are cyclopentyl, cyclopropyl, cyclohexyl or phenyl.
When R
8
is heterocyclyl, preferred groups are pyridyl, oxadiazolyl, pyrazolyl or triazolyl.
When Y is phenyl and two R
8
groups on adjacent carbon atoms together with the interconnecting carbon atoms form a fused 5- or 6-membered carbocyclic or heterocyclyic ring, preferred fused ring systems are naphthyl, quinolinyl, isoquinolinyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, dihydrobenzofuranyl, benzoxazolyl, indanyl, benzisothiazolyl and benzothiazolyl.
Preferred compounds of the invention are:
(2R)-2-{[1-({[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]methyl}pentanoic acid (Example 16),
3-{[1-({[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]propanoic acid (Example 18),
3-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]propanoic acid (Example 21),
2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 15),
2-{[1-({[3-(4-fluorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 4),
4-methoxy-2-{[1-({[3-(4-methoxyphenyl)propyl]amino}carbonyl)cyclopentyl]-methyl}butanoic acid (Example 1),
2-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]-methyl}-4-methoxybutanoic acid (Example 11),
(2S)-2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 22), and
(2S)-2-{[1-({[3-(2,3-dihydro-1-benzofuran-5-yl)propyl]amino}carbonyl)cyclopentyl]-methyl}-4-methoxybutanoic acid (Example 25).
A particularly preferred compound is (2S)-2-{[1-({[3-(4-chlorophenyl)propyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (Example 22).
Unless otherwise indicated, any alkyl group may be straight or branched and is of 1 to 6 carbon atoms, preferably 1 to 4 and particularly 1 to 3 carbon atoms.
Unless otherwise indicated, any carbocyclyl group contains 3 to 8 ring-atoms, and may be saturated, unsaturated or aromatic. Preferred saturated carbocyclyl groups are cyclopropyl, cyclopentyl or cyclohexyl. Preferred unsaturated carbocyclyl groups contain up to 3 double bonds. A preferred aromatic carbocyclyl group is phenyl. The term carbocylic should be similarly construed. In addition, the term carbocyclyl includes any fused combination of carbocyclyl groups, for example naphthyl, phenanthryl, indanyl and indenyl.
Unless otherwise indicated, any heterocyclyl group contains 5 to 7 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur, and may be saturated, unsaturated or aromatic. Examples of heterocyclyl groups are furyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridyl, p
Challenger Stephen
Cook Andrew Simon
Gillmore Adam Thomas
Middleton Donald Stuart
Pryde David Cameron
Benson Gregg C.
Davis Brian
Olson A. Dean
Pfizer Inc.
Richardson Peter C.
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