NPY Y5 receptor antagonists

Details NPY Y5 receptor antagonists NPY Y5 receptor antagonists

2001-06-29

2002-12-17

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S330000, C544S405000, C546S018000

Reexamination Certificate

active

06495559

ABSTRACT:

SUMMARY OF THE INVENTION
This invention is concerned with compounds which are spiro-indolines of general structure:
The invention is also concerned with the use of these novel compounds to selectively antagonize the Y5 receptors and thereby inhibit obsessive food intake and the resulting obesity and complications associated therewith.
The invention is also concerned with pharmaceutical formulations comprising one of the compounds as active ingredient.
The invention is further concerned with processes for preparing the compounds of this invention.
BACKGROUND OF THE INVENTION
Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system. NPY and its relatives elicit a broad range of physiological effects through activation of at least six G protein-coupled receptor subtypes known as Y1, Y2, Y3, Y4, Y5 and Y6. The Y5 subtype was isolated, characterized and reported recently in U.S. Pat. No. 5,602,024 (WO 96/16542).
The cited WO 96/16542 also reports the discovery of chemical compounds which bind selectively to the Y5 receptor and which act as antagonists of the Y5 receptor, several of which were shown to inhibit food intake in rats.
Now with the present invention there is provided a class of compounds characterized as spiro-indolines, which are useful in the treatment, control or prevention of diseases, disorders or conditions mediated by activation of the Y5 receptor. These compounds are, thus, useful in the treatment of obesity in man or animals and in conditions caused by or exacerbated by obesity.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of this invention are represented by the compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein;
V, W, X and Z are independently selected from CH and N;
R
1
is H, C
1-3
alkyl, C
1-3
alkoxy, F, or Cl;
R
2
is S(O)
n
R
6
, COR
6
or CHO, wherein
n is 0, 1 or2; and
R
6
is N(R
3
)
2
or C
1-3
alkyl;
R
3
is independently H or C
1-3
alkyl;
Ar is aryl or heteroaryl;
R
4
and R
5
are independently selected from:
(1) hydrogen,
(2) aryl, either unsubstituted or substituted with
(a) halo
(b) C
1-3
alkoxy,
(c) —N(C
1-3
alkyl)
2
,
(d) C
2-4
alkanoyl, or
(e) aryl,
(3) nitro,
(4) C
1-5
alkyl,
(5) C
1-5
alkoxy,
(6) hydroxy-C
1-3
alkyl,
(7) carboxy,
(8) halo,
(9) C
1-5
alkylthio,
(10) C
1-5
alkoxycarbonyl,
(11) pyridylcarbonyl,
(12) benzoyl,
(13) phenyl-C
1-3
alkoxy,
(14) pyridyl, either unsubstituted or substituted with C
1-3
alkyl or C
1-3
alkoxy,
(15) C
3-6
cycloalkyl,
(16) oxazolyl,
(17) thiazolyl,
(18) triazolyl,
(19) phenoxy or
(20) C
2-6
alkanoyl.
The term “alkyl” means linear and branched structures and combinations thereof, containing the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl and the like.
“Cycloalkyl” means a hydrocarbon having the indicated number of carbon atoms, containing one or more rings. Examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
“Halogen” or “halo” includes F, Cl, Br, and I unless otherwise specified.
“Heteroaryl” is a 5- or 6-membered aromatic heterocycle, or a benzo- or pyrido-fused version thereof, all having, besides carbon atoms, 1 to 3 hetero atoms selected from N, O, and S as atom(s) constituting the ring. Examples thereof include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, benzothienyl, benzofuranyl, indolyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiadiazolyl, benzoxazolyl, benzothiazolyl, benzopyrazolyl, benzimidazolyl, pyridothiazolyl, quinolyl, isoquinolyl or triazolyl.
“Aryl” is phenyl or naphthyl.
“Alkoxy” means linear and branched structures and combinations thereof, containing the indictaed number of carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, s- and t-butoxy, pentoxy, and the like.
“Alkanoyl” means linear and branched structures and combinations thereof, containing the indicated number of carbon atoms. Examples of alkanoyl groups include, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like.
One embodiment of the novel compounds of this invention is that wherein Ar is phenyl of structural formula I(a)
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment is that wherein X and Z are both nitrogen, and V and W are both —CH═.
A sub-class is that wherein R
2
is —SO
2
(C
1-3
alkyl) or —SO
2
NH
2
.
A sub-sub-class of the compounds of this embodiment is that wherein R
4
and R
5
are independently selected from: phenyl, pyridyl, benzoyl, halophenyl, phenoxy, C
1-5
alkylpyridyl, benzhydryl, phenyl-C
1-3
alkoxy, NO
2
, C
2-4
alkanoyl, halo, C
1-5
alkoxy, C
1-3
alkoxycarbonyl, C
1-5
alkylthio, triazolyl, carboxy, hydrogen, C
1-5
alkyl, pyridylcarbonyl, and C
1-3
alkoxyphenyl.
Typical of the compounds of this sub-sub-class are those wherein R
2
and phenyl(R
4
)(R
5
) are as shown in the following TABLE I:
TABLE I

R
2
—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
C
2
H
5

—SO
2
CH
3

—SO
2
CH
3

—SO
2
NH
2

—SO
2
NH
2

—SO
2
NH
2

—SO
2
NH
2

—SO
2
NH
2

—SO
2
NH
2

—SO
2
C
2
H
5

—SO
2
CH(CH
3
)
2

—SO
2
CH(CH
3
)
2
A second embodiment of the compounds of this invention is that wherein Ar is a 5- or 6-membered heteroaryl having, besides carbon atoms, 1 to 3 hetero atoms selected from N, O and S as atoms constituting the ring, or benzo- or pyrido-fused versions thereof, of structural formula I(b);
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment, is that wherein X and Z are both nitrogen, and V and W are both —CH═.
A sub-class is that wherein R
2
is —SO
2
(C
1-3
alkyl) or —SO
2
N(C
1-3
alkyl)
2
.
A sub-sub-class of compounds within this embodiment is that wherein the heteroaryl group, Ar, is selected from: thiazolyl, thiadiazolyl, pyrazolyl, pyridyl, benzothiazolyl, oxazolyl, pyridothiazolyl, benzoxazolyl, quinolyl, pyrazinyl, thienyl, isoxazolyl, pyrimidinyl, benzimidazolyl, oxadiazolyl and imidazolyl.
Typical of the compounds of this sub-sub-class are those wherein R
2
and Ar(R
4
)(R
5
) are as shown in TABLE II.
TABLE II

R
2
—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
NH
2

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
N(CH
3
)
2

—SO
2
NH
2

—SO
2
CH
3

—SO
2
C
2
H
5

—SO
2
C
2
H
5

—SO
2
CH
3

—SO
2
CH
3

—SO
2
C
2
H
5

—SO
2
C
2
H
5
A third embodiment of the compounds of this invention is that wherein one of X and Z is N and the other is —CH═ of structural formula 1(c):
or a pharmaceutically acceptable salt thereof.
A class of compounds within this embodiment is that wherein X is N, Z is —CH═ and V and W are both —CH═
Typical of the compounds within this class are those shown in TABLE III:
TABLE III

R
2
—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3
A second class of compounds within this embodiment is that wherein X is —CH═, Z is N and V and W are both —CH═.
Typical of the compounds within this second class are those shown in TABLE IV:
TABLE IV

R
2
X
—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3

—SO
2
CH
3




A fourth embodiment of the compounds of this invention is that wherein R
2
is —COR
6
of structural formula I(d):
or a pharmaceutically acceptabl

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