Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-12-17
2002-10-29
Rao, Deepak R. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S266220, C514S314000, C514S321000, C514S322000, C514S330000, C514S331000, C544S283000, C544S353000, C546S168000, C546S175000, C546S197000, C546S198000, C546S199000, C546S225000, C546S233000, C546S234000
Reexamination Certificate
active
06472394
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to amide derivatives of 1,4-di-substituted piperidine antagonists for melanin-concentrating hormone (MCH) and their use in the treatment of obesity and diabetes.
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, the authors have suggested that antagonists of MCH action 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.
Piperidine-derivative muscarinic antagonists useful in the treatment of cognitive disorders such as Alzheimer's disease are disclosed in U.S. Pat. No. 6,037,352. In particular, U.S. Pat. No. 6,037,352 discloses compounds of the generic formula
wherein, inter alia, Y is CH; Z is N; X is —NHCO—; R is substituted benzyl or cycloalkylalkyl; R
1
, R
21
, R
3
, R
4
, R
27
and R
28
are each hydrogen; and R
2
is optionally substituted cycloalkyl or arylalkyl. U.S. Pat. No. 6,037,352 does not disclose the use of the compounds for treating obesity or diabetes.
SUMMARY OF THE INVENTION
The present invention relates to compounds represented by structural formula I:
or a pharmaceutically acceptable salt, ester or solvate thereof, wherein
W is R
1
—CR
3
R
12
NR
4
C(O)— or R
11
C(O)NR
4
—;
the dotted line is an optional double bond;
X is —CHR
8
—, —C(O)—, —C(═NOR
9
)—, or, when the double bond is present, —CR
8
═;
Y is
or, when the double bond is present,
R
1
is R
5
—(C
3
-C
8
)cycloalkyl, R
5
—(C
3
-C
8
)cycloalkyl(C
1
-C
6
)alkyl, R
5
-aryl, R
5
-aryl-(C
1
-C
6
)alkyl, R
5
-heteroaryl, R
5
-heteroaryl(C
1
-C
6
)alkyl, R
5
-heterocycloalkyl or R
5
-heterocycloalkyl(C
1
-C
6
)alkyl;
R
2
is R
6
-aryl or R
6
-heteroaryl;
n is 1, 2 or 3;
R
3
is C
1
-C
6
alkyl, aryl or heteroaryl;
R
4
is H or C
1
-C
6
alkyl;
R
5
is 1-4 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, C
1
-C
6
alkoxy, —CF
3
, (C
1
-C
6
)-alkoxycarbonyl, —SO
2
NHR
4
, —C(O)NHR
4
, —NR
4
C(O)NHR
4
, —NR
4
C(O)R
4
, —NR
4
SO
2
R
4
, R
13
-phenyl and naphthyl;
R
6
is 1-4 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, —SH, —S(C
1
-C
6
alkyl), —CN, C
1
-C
6
alkoxy, C
1
-C
6
alkylcarboxy, CF
3
, —NO
2
, —NH
2
, (C
1
-C
6
)alkylamino, phenyl, (C
1
-C
6
)-alkoxycarbonyl and R
7
-phenoxy, or adjacent ring carbon atoms form a ring with the group —O(CH
2
)
1-2
O—, —O(CH
2
)
2-3
— or —O(CF
2
)O—;
R
7
is 1-3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, C
1
-C
6
alkoxy and CF
3
;
R
8
is H, C
1
-C
6
alkyl or (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl;
R
9
is H, C
1
-C
6
alkyl or aryl-(C
1
-C
4
)alkyl;
R
10
is independently selected from the group consisting of H, C
1
-C
6
alkyl and aryl;
R
11
is
or, when R
2
is R
6
-heteroaryl or R
10
is not H, R
11
can also be R
5
-phenyl(C
0
-C
2
)alkyl;
m is 1, 2, 3, 4 or 5;
R
12
is H or C
1
-C
6
alkyl;
R
13
is 1 to 3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, C
1
-C
6
alkoxy, —CF
3
, —OCF
3
, —NO
2
and —C(O)CH
3
; and
R
14
is 1-3 substituents independently selected from the group consisting of H, C
1
-C
6
alkyl, halogen, —OH, C
1
-C
6
alkoxy and CF
3
.
The present invention also relates to a method of treating eating disorders, such as obesity and hyperphagia, and diabetes comprising administering to a mammal in need of such treatment an effective amount of a compound of formula I.
Another aspect of the invention is a pharmaceutical composition for treating eating disorders and diabetes which comprises a compound of formula I in combination with a pharmaceutically acceptable carrier.
DETAILED DESCRIPTION
Referring to formula I, above, one group of preferred compounds is that wherein W is R
1
—CR
3
R
12
NR
4
C(O)—.
R
1
is preferably R
5
-phenyl, R
5
is preferably H, halogen, C
1
-C
6
alkyl or phenyl, more preferably halogen or phenyl.
Another group of preferred compounds is that wherein R
2
is R
6
-aryl, especially when n is 1. More preferred is R
6
-aryl wherein “aryl” is phenyl and R
6
is 1-2 substituents.
X is preferably —CHR
8
wherein R
8
is H and Y is CH, or X and Y form a double bond.
R
3
is preferably ethyl or methyl, and R
4
and R
12
are each preferably H.
R
10
is preferably H or —CH
3
; when n is 2-5, preferably only one R
10
is alkyl and the rest are hydrogen.
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”, etc.
“Alkyl” represents a straight or branched saturated hydrocarbon chain having the designated number of carbon atoms. Where the number of carbon atoms is not specified, 1 to 6 carbons are intended.
“Cycloalkyl” represents a saturated carbocyclic ring having 3 to 8 carbon atoms.
The term “heterocycloalkyl” refers to 4- to 7-membered saturated rings comprising 1 to 3 heteroatoms independently selected from the group consisting of —O—, —S— and —NR
7
—, wherein R
7
is H or C
1
-C
6
alkyl, and wherein the remaining ring members are carbon. Where a heterocyclic ring comprises more than one heteroatom, no rings are formed where there are adjacent oxygen atoms, adjacent sulfur atoms, or three consecutive heteroatoms. Examples of heterocyclic rings are tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.
Halogen represents fluoro, chloro, bromo or iodo.
Aryl represents a monoaromatic ring or a bicyclic fused ring system of 6- to 10 carbon atoms, possessing one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and the like.
Heteroaryl means a 5- to 10-membered single or benzofused aromatic ring comprising 1 to 3 heteroatoms independently selected from the group consisting of —O—, —S— and —N═, provided that the rings do not include adjacent oxygen and/or sulfur atoms. Examples of single ring heteroaryl groups are pyridyl, isoxazolyl, oxadiazolyl, furanyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazolyl. Examples of benzofused rings are indolyl, benzofuranyl, quinolyl, quinazolinyl, quinoxalinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, thianaphthenyl, and benzofurazanyl. N-oxides are also included. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl.
When a variable appears more than once in the structural formula, for example R
5
, the identity of each variable appearing more than once may be independently selected from the definition for that variable.
N-oxides can form on a tertiary nitrogen present in an R
1
or R
2
substituent, or on ═N— in a heteroaryl ring substituent and are included in the compounds of formula I.
For compounds of the invention having at least one asymmetrical carbon atom, all isomers, including diastereomers, enantiomers and rotational isomers are contemplated as being part of this invention. The invention includes d and l isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using conventional techniques, either by reacting optically pure or optically enriched starting materials or by separating isomers of a compound of formula I. The preferred stereochemistry for c
Clader John W.
Guo Guihau
Li Shengjian
McKittrick Brian A.
Su Jing
Magatti Anita W.
Rao Deepak R.
Schering Corporation
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