Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-11-25
2003-12-16
Aulakh, Charanjit S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S217000, C546S229000, C546S224000, C546S214000, C546S213000, C546S208000, C546S112000, C514S331000, C514S329000, C514S326000, C514S299000
Reexamination Certificate
active
06664273
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to antagonists of melanin-concentrating hormone (MCH) and their use in the treatment of obesity, eating disorders and diabetes, pharmaceutical compositions containing the compounds, and methods of treatment using the compounds.
BACKGROUND OF THE INVENTION
MCH, a cyclic peptide, was first identified over a decade ago in teleost fish where it appears to regulate color change. More recently, MCH has been the subject of investigation for its possible role as a regulator of eating behavior in mammals. As reported by Shimada et al.,
Nature
, Vol. 396 (Dec. 17 1998), pp. 670-673, MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding). In view of their findings, it was suggested that antagonists of MCH may be effective for the treatment of obesity. U.S. Pat. No. 5,908,830 discloses a combination therapy for the treatment of diabetes or obesity involving the administration of a metabolic rate increasing agent and a feeding behavior modifying agent, an example of the latter being an MCH antagonist. Further, MCH receptor antagonists may also be useful in the treatment of depression and/or anxiety. Borowksy et al.,
Nature Medicine
, 8, pp. 825-830 (Aug. 1, 2002).
SUMMARY OF THE INVENTION
The present invention relates to the compound represented by structural formula I:
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
Ar
1
is aryl, heteroaryl, (R
7
)
p
-substituted aryl or (R
7
)
p
-substituted heteroaryl, wherein p is a number from 1 to 5 and when p is more than 1, each R
7
can be the, same or different and each R
7
is hydrogen or independently selected from the group consisting of OH, alkoxy, CN, halogen, NR
8
R
9
, C(O)NR
8
R
9
, N(R
8
)C(O)R
5
, N(R
8
)S(O
2
)R
5
, S(O
2
)NR
8
R
9
, C(O)OR
8
, OCF
3
, CF
3
, S(O
2
)R
5
and C(O)R
5
, or two adjacent R
7
can be joined together to form an alkylenedioxy selected from
or when Ar
1
is an (R
7
)
p
-substituted aryl, where R
7
and the phenyl ring to which it is shown attached in Formula I can be bridged by Y as shown by
R
1
is H, alkyl, aryl, aralkyl, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heteroaryl, (styrenyl)methyl, heteroaralkyl, cycloalkylalkyl, heterocyclyl, cycloalkyl, wherein each of said alkyl, aralkyl, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heteroaralkyl, cycloalkylalkyl, heterocyclyl and cycloalkyl can be unsubstituted or optionally substituted with one or more R
7
moieties which can be the same or different, —S(O
2
)NR
8
R
9
, S(O
2
)R
5
, C(O)OR
8
, C(O)R
5
, C(O)NR
8
R
9
, (R
7
)
p
-substituted aryl or (R
7
)
p
-substituted heteroaryl, wherein p is a number from 1 to 5 and when p is more than 1, each R
7
can be the same or different and each R
7
is hydrogen or independently selected from the group consisting of alkyl, cycloalkyl, OH, alkoxy, CN, halogen, heteroaryl, OC(O)OH; aryloxy, NR
8
R
9
, C(O)NR
8
R
9
, N(R
8
)C(O)R
5
, N(R
8
)S(O
2
)R
5
, S(O
2
)NR
8
R
9
, C(O)OR
8
, OCF
3
, CF
3
, SR
5
, S(O
2
)R
5
and C(O)R
5
,
or two adjacent R
7
can be joined together to form an alkylenedioxy selected from
R
2
, R
3
, R
8
and R
9
can each be the same or different and each independently H or alkyl;
or R
2
and R
3
together are alkylene and with the carbon to which they are attached form a 3 to 7 membered ring;
R
4
is H, alkyl, aralkyl, R
5
C(O), R
5
S(O
2
) or
R
5
is alkyl or aryl;
R
6
is alkyl, aralkyl or (R
7
)
p
-substituted aralkyl, wherein p is a number from 1 to 5 and when p is more than 1, each R
7
can be the same or different and each R
7
is hydrogen or independently selected from the group consisting of OH, alkoxy, CN, halogen, NR
8
R
9
, C(O)NR
8
R
9
, N(R
8
)C(O)R
5
, N(R
8
)S(O
2
)R
5
, —S(O
2
)NR
8
R
9
, C(O)OR
8
, OCF
3
, CF
3
, S(O
2
)R
5
and C(O)R
5
,
R
10
is aryl, heteroaryl, (R
7
)
p
-substituted aryl or (R
7
)
p
-substituted heteroaryl, wherein p is a number from 1 to 5 and when p is more than 1, each R
7
can be the same or different and each R
7
is hydrogen or independently selected from the group consisting of OH, alkoxy, CN, halogen, NR
8
R
9
, C(O)NR
8
R
9
, N(R
8
)C(O)R
5
, N(R
8
)S(O
2
)R
5
, S(O
2
)NR
8
R
9
, C(O)OR
8
, OCF
3
, CF
3
, S(O
2
)R
5
, C(O)R
5
and heterocycloalkyl or R
10
is an alkylene or heteroalkylene where said alkylene or heteroalkylene is attached to the N of NR
10
to form a heterocyclyl ring selected from the group consisting of
X is N(R
4
), O, S, S→O, S(O
2
), C(O) or CH
2
;
Y is O, CH
2
, C(O), N(H), N(R
6
) or S;
k is 0, 1 or 2;
m is 0, 1 or 2;
n is 0 or 2; and
wherein each of said alkyl, alkylene, heteroalkylene, aryl, aralkyl, alkoxy, arylyoxy, aryloxyalkyl, hydroxyalkyl, alkoxyalkyl, heterocyclyl, heterocycloalkyl, heteroaryl, heteroaralkyl, cycloalkylalkyl, heterocyclyl and cycloalkyl can be unsubstituted or optionally substituted with one or more R
7
moieties which can be the same or different.
This invention is also directed to pharmaceutical compositions for the treatment of metabolic disorders such as obesity, and eating disorders such as hyperphagia. In one aspect, this invention is also directed to pharmaceutical compositions for the treatment of obesity which comprise an obesity treating amount of a compound of formula I, or a pharmaceutically acceptable salt or solvate of said compound and a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
The present invention relates to compounds that are represented by structural formula I, or a pharmaceutically acceptable salt or solvate, wherein the various moieties are as described above.
The compounds of formula I can be administered as racemic mixtures or enantiomerically pure compounds.
A preferred group of compounds are compounds of formula Ia
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
R
1
is H, alkyl or cycloalkyl;
R
4
is H or alkyl; and
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF
3
and OCF
3
.
Another preferred embodiment is a compound of formula Ib:
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF
3
and OCF
3
.
A further preferred embodiment is a compound of formula Ic:
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
R is H, alkyl or cycloalkyl; and
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF
3
and OCF
3
.
A further preferred embodiment is a compound of formula Id:
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
R
1
is independently selected from the group consisting of H, alkyl and cycloalkyl; and
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of halogen, CF
3
and OCF
3
.
A further preferred embodiment is a compound of formula Ie:
or a pharmaceutically acceptable salt or solvate of said compound, wherein:
q is 1 or 2;
Z is 1 or 2 substituents which can be the same or different and independently selected from the group consisting of Cl, CF
3
and F.
A further preferred embodiment is a compound of formula If
or a pharmaceutically acceptable salt or solvate of said compound, wherein
R is selected from the group consisting of CH
3
C(O), CH
3
S(O
2
), CH
3
CH
2
OC(O), (CH
3
CH
2
)
2
NC(O), (CH
3
)
2
NS(O
2
), CH
3
CH
2
NHS(O
2
) and cyclopropylmethyl.
A set of preferred compounds are listed below in Table 1.
Except where stated otherwise, the following definitions apply throughout the present specification and claims. These definitions apply regardless of whether a term is used by itself or in combination with other terms. Hence the definition of “alkyl” applies to “alkyl” as well as to the “alkyl” portions of “alkoxy”, “alkylamino” etc.
As used above, and throughout the specification, the following terms, unless otherwise indicated, shal
Burnett Duane A.
Wu Wen-Lian
Aulakh Charanjit S.
Lee William Y.
Schering Corporation
LandOfFree
Piperidine based MCH antagonists for treatment of obesity... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Piperidine based MCH antagonists for treatment of obesity..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Piperidine based MCH antagonists for treatment of obesity... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3131653