Neuropeptide Y receptor antagonists

Details Neuropeptide Y receptor antagonists Neuropeptide Y receptor antagonists

1999-08-24

2002-01-08

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...

C514S260100, C544S283000, C544S284000, C544S290000, C544S293000

Reexamination Certificate

active

06337332

ABSTRACT:

BACKGROUND OF INVENTION
1. Field of the Invention
This invention relates to the use of certain substituted heterocyclic compounds which selectively bind to mammalian neuropeptide receptors. It further relates to the use of such compounds and compositions in treating conditions related to an excess of neuropeptide Y such as 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 Y1 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 stimulus of food intake, and an inducer of vasoconstriction leading to hypertension. They further point out that low levels of neuropeptide Y (NPY) are 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.
EP0759441 and U.S. Pat. No. 5,576,337 report that physiological disorders related to neuropeptide Y include:
disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure;
conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and sugery in the gastrointestinal tract;
cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemmorrhage, depression, anxiety, schizophrenia, and dementia;
conditions related to pain or nociception;
diseases related to abnormal gastrointenstinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn's disease;
abnormal drink and food intake disorders, such as anorexia and metabolic disorders;
diseases related to sexual dysfunction and reproductive disorders;
conditions or disorders associated with inflammation;
respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin.
WO 96/14307 describes substituted benzylamine derivatives which selectively bind to human neuropeptide Y1 receptors.
The synthesis of certain 4-aminopyrrole (3,2-d) pyridines is described in
Pharm. Chem J
. 22,185 (1988); 8, 14 (1974); and 7, 19 (1973). These compounds were reported to have antibacterial and antitumor activity.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula:
wherein:
R′ is —A—A
1
—(CH
2
)
p
—R
R″ is (CH
2
)
q
—D—(CH
2
)
s
—CX
1
Y
1
—R
2
R
b
is hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
6
alkanoyl, trifluoromethyl, hydroxy, or halo;
R
1
is hydrogen, C
1
-C
6
alkyl, or —(CH
2
)
v
—R
1a
;
where v is 1 to 12, and R
1a
is phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl, any one of which phenyl, naphthyl, hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the groups consisting of C
1
-C
6
alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C
1-C
6
alkyl)amino, C
1
-C
6
alkylamino, C
2
-C
6
alkanoyl, C
2
-C
6
alkanoyloxy, and C
3
-C
8
cycloalkyl,
said phenyl, benzyl, or C
3
-C
8
cycloalkyl, being optionally substituted with one, two or three moieties independently selected from the group consisting of C
1
-C
6
alkyl, halo, or C
1
-C
6
alkoxy;
or R
1a
may be substituted with —(CH
2
)
w
R
1b
, where w is 1 to 12 and R
1b
is piperidinyl, pyrimidyl, pyrrolidinyl, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, di[di(C
1
-C
6
alkyl)amino(C
1
-C
6
alkylenyl)amino, phenyl, C
3
-C
8
cycloalkyl, pyrrolidinyl, and acetamido;
said phenyl, or C
3
-C
8
cycloalkyl, being optionally substituted with one, two, or three moieties independently selected from the group consisting of C
1
-C
6
alkyl, halo, or C
1
-C
6
alkoxy;
A is a bond, —(CH
2
)
m
or —C(O)—;
A
1
is a bond, —NR
a
—, —O—, —(CH
2
)
m
—, or S(O)
n
—;
q is 0 to 6;
p is 0 to 6;
n is 0, 1, or 2;
m is 0 to 6;
s is 0 to 6;
R
a
is hydrogen, C
1
-C
6
alkyl, or C
2
-C
6
alkanoyl;
D is a bond, C
2
-C
4
alkenylenyl, or —C(X)(Y)—,
where one of X and Y is hydroxy and the other is hydrogen, or both X and Y are hydrogen, or X and Y combine to form ═O, or ═NOR
c
;
R
c
is hydrogen, benzyl, acetyl, benzoyl, or C
1
-C
6
alkyl;
one of X
1
and y
1
is hydroxy and the other is hydrogen, or one of X
1
and y
1
is hydroxy and the other is hydrogen, or both X
1
and yl are hydrogen, or X
1
and Y
1
combine to form ═O, or ═NOR
d
;
R
d
is hydrogen or C
1
-C
6
alkyl;
R
2
is hydroxy, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, phenoxy, or a group of the formula
wherein R
4
and R
5
are independently hydrogen, C
1
-C
6
alkyl, phenyl, or phenyl(C
1
-C
6
alkylenyl)-, or R
2
is a heterocyclic ring selected from the group consisting of hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperdinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl;
any one of which hexamethyleneiminyl, piperazinyl, heptamethyleneiminyl, imidazolinyl, piperidinyl, 2-tryptolinyl, pyrrolidinyl, quinuclidinyl, or morpholinyl groups may be substituted with one or more moieties selected from the group consisting of C
1
-C
6
alkyl, halo, trifluoromethyl, benzyl, phenyl, di(C
1
-C
6
alkyl)amino, do(C
1
-C
6
alkyl)amino(C
1
-C
6
alkylenyl)-, C
1
-C
6
alkylamino(C
1
-C
6
alkylenyl)-, C
2
-C
6
alkanoyl, carboxamido, 2-aminoacetyl, C
2
-C
6
alkanoyloxy, C
1
-C
6
alkoxycarbonyl-, C
1
-C
6
alkylamino, C
3
-C
8
cycloalkyl, piperidinyl, pyrrolidinyl, pyrimidyl, phenyl(C
1
-C
6
alkylenyl)-, phenoxy(C
1
-C
6
alkylenyl)-, piperidinyl(C
1
-C
6
alkylenyl)-, pyrrolidinyl(C
1
-C
6
alkylenyl)-, pyrimidyl(C
1
-C
6
alkylenyl)-, C
1
-C
6
alkoxy, C
1
-C
6
alkylthio, di[di(C
1
-C
6
alkyl)amino(C
1
-C
6
alkylenyl)]amino, di(C
1
-C
6
alkyl)amino(C
1
-C
6
alkylenyl)amino, and acetamido,
any one of said benzyl, phenyl, piperidinyl, C
3
-C
8
cycloalkyl, phenyl(C
1
-C
6
alkylenyl)-, phenoxy(C
1
-C
6
alkylenyl)-, pyrrolidinyl, piperidinyl(C
1
-C
6
alkylenyl)-, pyrrolidinyl(C
1
-C
6
alkylenyl)-, pyrrolidinyl(C
1
-C
6
alkylenyl)-, pyrimidyl(C
1
-C
6
alkylenyl)-, or pyrimidyl group may be substituted with one or more moieties selected from the group consisting of C
1
-C
6
alkyl, halo, trifluoromethyl, acetamido, C
2
-C
6
alkanoyl, C
2
-C
7
alkanoyloxy, and C
1
-C
6
alkoxy, or the nitrogen on said piperidinyl, pyrrolidinyl, piperidinyl(C
1
-C
6
alkylenyl)-, pyrrolidinyl(C
1
-C
6
alkylenyl)-, or pyrimidyl may be substituted with an amino-protecting group,
or R
2
is a group of the formula
where R
4a
, R
5a
, and R
6a
are independently hydrogen, C
1
-C
6
alkyl, trifluoromethyl, or C
1
-C
6
alkoxy, or R
4a
is hydrogen, C
1
-C
6
alkyl, trifluoromethyl, or C
1
-C
6
alkoxy and R
5a
and R
6a
combine to form, together with the nitrogen to which they are attached, p

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