N-phenpropylcyclopentyl-substituted glutaramide derivatives...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

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

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

N-phenpropylcyclopentyl-substituted glutaramide derivatives... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with N-phenpropylcyclopentyl-substituted glutaramide derivatives..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and N-phenpropylcyclopentyl-substituted glutaramide derivatives... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-3134785

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.