Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-01-28
2002-06-18
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210010, C514S237800, C514S238200, C514S255020, C514S331000, C514S332000, C514S357000, C514S424000, C514S428000, C514S603000, C514S616000, C514S617000, C544S160000, C544S165000, C544S383000, C546S193000, C546S194000, C546S234000, C546S265000, C546S337000, C548S567000, C548S542000, C548S950000, C564S086000, C564S155000, C564S181000, C564S182000
Reexamination Certificate
active
06407120
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
This invention relates to the use of substituted amides which selectively bind to mammalian Neuropeptide receptors. It further relates to the use of these compounds and compositions containing these compounds 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 an excess of 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.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula I
wherein:
K is phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each ring optionally substituted with one to three substituents selected from halogen, C
1
-C
3
alkyl, C
1
-C
3
perfluoroalkyl, C
1
-C
3
alkoxy and C
1
-C
3
perfluoroalkoxy;
L is H, C
3
-C
8
cycloalkyl,
phenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl;
wherein each phenyl and pyridyl ring may be substituted with one to three substituents selected from C
1
-C
3
alkyl, C
1
-C
3
alkoxy and halogen;
Z is —COR
3
, —CONR
1
R
2
, —NR
1
R
2
and SO
2
R
4
;
X and Y are CH or N, with the proviso that one of X and Y must be CH;
n is an integer from 0 to 3;
m and p are independently selected from the integers 1 to 3;
Q is O, NR, CHR;
R is hydrogen or C
1
-C
6
alkyl;
R
1
and R
2
are independently selected from hydrogen, C
1
-C
6
alkyl, (CH
2
)
m
phenyl, (CH
2
)
m
pyridyl, or R
1
and R
2
may be taken together with the nitrogen to which they are attached to form a 4 to 8 numbered ring optionally containing O, NH or NR;
R
3
is C
1
-C
6
alkyl; R
4
is —NR
1
R
2
,
—NH(CH
2
)
m
phenyl, —N(C
4
-C
8
cycloalkyl)
2
and —NH(C
4
-C
8
cycloalkyl); or a pharmaceutically acceptable salt thereof;
and with the provisio that when n is zero, K and L are phenyl, and both of X and Y are carbon, then Z may not be —N(C
2
H
5
)
2
or
and with the further proviso that if K is phenyl, L may not be hydrogen.
In another aspect, this invention provides a compound of formula I wherein n is zero. This invention also provides a compound of formula I wherein n is zero and L is 2-pyridyl or 4-pyridyl and Z is —N(C
2
H
5
)
2
,
or —SO
2
N(C
2
H
5
)
2
.
This invention further provides a compound formula I wherein n is zero, Y is N and Z
This invention also provides a compound of formula I wherein n is zero, Z is —SO
2
R
4
, wherein R
4
is —N(C
2
H
5
)
2
or N(CH
3
)
2
.
This invention also provides a compound of formula I selected from the group consisting of:
N-(4-Diethylamino-phenyl)-2-phenyl-2-pyridin-4-yl-acetamide;
2-(4-Fluoro-phenyl)-2-pyridin-4-yl-N-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-acetamide;
2-Phenyl-2-pyridin-4-yl-N-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-acetamide;
N-(4-Diethylamino-phenyl)-2-phenyl-2-pyridin-2-yl-acetamide;
N-(4-Diethyl-sulfamoyl-phenyl)-2-phenyl-2-pyridin-4-yl-acetamide;
N-(6-Diethylamino-pyridin-3-yl)-2,2-diphenylacetamide;
2,2-Diphenyl-N-(6-pyrrolidin-1-yl-pyridin-3-yl)-acetamide;
2,2-Diphenyl-N-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-acetamide;
N-[6-(2,5-Dimethyl-pyrrolidin-1-yl)-pyridin-3-yl]-2,2-diphenyl-acetamide;
N-(4-Diethylsulfamoyl-phenyl)-2,2-diphenyl-acetamide; and
N-(4-Dimethylsulfamoyl-phenyl)-2,2-diphenyl-acetamide.
In another aspect, this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by or associated with an excess of neuropeptide Y which accompanies administering to a mammal in need of such treatment a neuropeptide Y inhibiting amount of the compound of Formula I shown above.
This invention also comprises a method of treating a pathological condition wherein said pathological condition or physiological disorder is a feeding disorder such as obesity or bulimia.
In another aspect, this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal wherein said pathological condition or physiological disorder is selected from the group consisting of:
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 surgery 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 hemorrhage, 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 di
Carpino Philip A.
Hammond Marlys
Hank Richard F.
Benson Gregg C.
Huang Evelyn Mei
Kleiman Gabriel L.
Pfizer Inc.
Richardson Peter C.
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