Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-01
2001-04-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S087000, C544S106000, C544S362000, C544S405000, C514S231500, C514S252130
Reexamination Certificate
active
06221875
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to certain substituted 9H-pyridino[2,3-b]indole and 9H-pyrimidino[4,5-b]indole derivatives which selectively bind mammalian neuropeptide Y (NPY) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating physiological disorders associated with an excess of neuropeptide Y, especially feeding disorders and certain cardiovascular diseases.
2. Description of the Related Art
Neuropeptide Y, a peptide first isolated in 1982, is widely distributed in the central and peripheral neurons and is responsible for a multitude of biological effects in the brain and the periphery. Various animal studies have shown that activation of neuropeptide NPY
1
receptors is related to vasoconstriction, Wahlestedt et al., Regul. Peptides, 13: 307-318 (1986), McCauley and Westfall, J. Pharmacol. Exp. Ther. 261: 863-868 (1992), and Grundemar et al., Br. J. Pharmacol. 105: 45-50 (1992); and to stimulation of consummatory behavior, Flood and Morley, Peptides, 10: 963-966 (1989), Leibowitz and Alexander, Peptides, 12: 1251-1260 (1991), and Stanley et al., Peptides, 13: 581-587 (1992).
Grundemar and Hakanson, TiPS, May 1994 [Vol. 15 ], 153-159, state that, in animals, neuropeptide Y is a powerful stimuli of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y is associated with loss of appetite. These reports clearly indicate that compounds that inhibit the activity of this protein will reduce hypertension and appetite in animals.
SUMMARY OF THE INVENTION
Compounds that interact with NPY
1
receptors and inhibit the activity of neuropeptide Y at those receptors are useful in treating physiological disorders associated with an excess of neuropeptide Y, including eating disorders, such as, for example, obesity and bulimia, and certain cardiovascular diseases, for example, hypertension.
This invention provides novel compounds of Formula I which selectively bind to neuropeptide Y (NPY) receptors. Such compounds are useful in treating feeding disorders such as obesity and bulimia as well as certain cardiovascular diseases such as essential hypertension.
The novel compounds encompassed by the instant invention have general Formula I:
wherein:
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4-or 5-pyrimidinyl, each of which is optionally mono-, di-, or trisubstituted with halogen, trifluoromethyl, hydroxy, amino, C
1
-C
6
alkylamino, C
1
-C
6
dialkylamino, C
3
-C
7
cycloalkylamino, carboxamido, C
1
-C
6
alkylcarboxamido, C
3
-C
7
cycloalkylcarboxamido, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
alkoxy, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkoxy, C
3
-C
7
cycloalkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R
1
is hydrogen, halogen, trifluoromethyl, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, or (C
1
-C
6
alkylene)—G
1
—R
2
wherein G
1
is oxygen or sulfur and R
2
is hydrogen, C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl;
W is N or C-R
3
, wherein R
3
is hydrogen or C
1
-C
6
alkyl;
X is
wherein
A
1
is NR
4
R
5
wherein R
4
and R
5
are independently hydrogen, a C
1
-C
6
alkyl group which optionally forms a heterocycloalkyl group with Y, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl;
C
1
-C
6
alkanoyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkanoyl, C
3
-C
7
cycloalkanoyl, C
1
-C
6
alkylsulfonyl, or C
3
-C
7
cycloalkylsulfonyl with the proviso that R
4
and R
5
may not both be alkanoyl or alkylsulfonyl;
C
1
-C
6
heterocycloalkyl, wherein heterocycloalkyl is morpholinyl, piperazinyl, piperidinyl, or pyrrolidinyl;
C
1
-C
6
arylalkyl or C
1
-C
6
heteroarylalkyl, where aryl is phenyl, and heteroaryl is 2-,3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 2-, 4-, or 5-thiazolyl,1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono-, di-, or tri-substituted with halogen, trifluoromethyl, hydroxy, amino, C
1
-C
6
alkylamino, C
1
-C
6
dialkylamino, C
3
-C
7
cycloalkylamino, C
1
-C
6
alkylcarboxamido, C
3
-C
7
cycloalkylcarboxamido, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
alkoxy, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkoxy, or C
3
-C
7
cycloalkoxy, where any 2 adjacent substituents may together form a 5-7 fused cycloalkyl or heterocycloalkyl ring;
NR
4
R
5
taken together form a C
3
-C
6
heterocycloalkyl, or a group of the formula:
wherein e and f are independently 1, 2, or 3 and the sum of e and f is at least 3; and
G
2
is
(i) NR
6
wherein R
6
is hydrogen, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl; or
(ii) CH(C
0
-C
6
alkyl)—G
3
—R
7
wherein G
3
is —CONH—, —CONH(C
1
—C
6
alkyl)—, —NH—, —NH(C
1
-C
6
alkyl)—, —NH(C
3
-C
7
cycloalkyl)—, where R
7
is hydrogen, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl; or
(iii) —CONH
2
—, or —CO[N(C
1
-C
6
alkylene)R
8
]— wherein R
8
is hydrogen, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl;
A
2
is NH, SO
2
, oxygen or sulfur;
V is CH
2
, CO, CS, SO
2
, CH(C
1
-C
6
alkyl), CH(C
3
-C
7
cycloalkyl), with the proviso that V may not be CO, CS or SO
2
when A
2
is SO
2
, oxygen or sulfur; and
Y is a bond or C
1
-C
6
alkylene; or
X is
heteroaryl is 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, 1-, 3- , or 5-thiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-pyrazinyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally mono- or di-substituted with halogen, trifluoromethyl, amino, C
1
-C
6
alkylamino, C
1
-C
6
dialkylamino, C
3
-C
7
cycloalkylamino, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
alkoxy, C
3
-C
7
cycloalkoxy, with the proviso that tetrazolyl may have at most one substituent;
Z is C
1
-C
6
alkylene; and
A
2
is NH, SO
2
, oxygen or sulfur.
As the compounds of Formula I are effective neuropeptide Y1 receptor antagonists, these compounds are useful in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.
DETAILED DESCRIPTION OF THE INVENTION
The novel compounds encompassed by the instant invention can be described by general Formula I:
wherein:
Ar is phenyl, 1- or 2-naphthyl, 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, each of which is optionally mono-, di-, or trisubstituted with halogen, trifluoromethyl, hydroxy, amino, C
1
-C
6
alkylamino, C
1
-C
6
dialkylamino, C
3
-C
7
cycloalkylamino, carboxamido, C
1
-C
6
alkylcarboxamido, C
3
-C
7
cycloalkylcarboxamido, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, C
1
-C
6
alkoxy, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkoxy, C
3
-C
7
cycloalkoxy, with the proviso that at least one of the positions ortho or para to the point of attachment of Ar to the tricyclic ring system is substituted;
R
1
is hydrogen, halogen, trifluoromethyl, C
1
-C
6
alkyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, C
3
-C
7
cycloalkyl, or (C
1
-C
6
alkylene)—G
1
—R
2
wherein G
1
is oxygen or sulfur and R
2
is hydrogen, C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl;
W is N or C—R
3
, wherein R
3
is hydrogen or C
1
-C
6
alkyl;
X is
wherein
A
1
is NR
4
R
5
wherein R
4
and R
5
are independently hydrogen, a C
1
-C
6
alkyl group which optionally forms a heterocycloalkyl group with Y, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkyl, or C
3
-C
7
cycloalkyl;
C
1
-C
6
alkanoyl, (C
3
-C
7
cycloalkyl) C
1
-C
6
alkanoyl, C
3
-C
7
cycloalkanoyl, C
1
-C
6
alkylsulfonyl, or C
3
-C
7
cycloalkylsulfonyl with the proviso that R
4
and R
5
may not both be alkanoyl or alkylsulfonyl;
Darrow James W.
De Lombaert Stephane
Horvath Raymond F.
Maynard George D.
Tran Jennifer
Balasubramanian Venkataraman
McDonnell & Boehnen Hulbert & Berghoff
Neurogen Corporation
Sarussi Steven J.
Shah Mukund J.
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