Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-28
2003-01-28
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S276000, C544S277000, C514S263400, C514S263370
Reexamination Certificate
active
06511984
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
This invention relates to purines, 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.
2. Description of the Related Art
Neuropeptide Y (NPY), a 36 amino acid peptide neurotransmitter, is a member of the pancreatic polypeptide class of neurotransmitters
eurohormones which has been shown to be present in both the periphery and central nervous system. NPY is one of the most potentorexogenic agents known and has been shown to play a major role in the regulation of food intake in animals, including humans. At least 6 NPY receptor subclasses have been identified and cloned to date, with two of these subclasses, NPY-1 and NPY-5, thought to be the most important receptor subtypes for modulation of food intake and energy expenditure. Hence, agents capable of blocking NPY binding at these receptor subtype(s) should have utility in a number of feeding disorders, including obesity, anorexia nervosa, bulimia nervosa; obesity-related disorder including but not limited to insulin resistance, diabetes, hyperlipidemia, and hypertension, as well as other indications for treatment where blockade of NPY activity is beneficial.
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 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 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.
The patent WO 9712615 [Preparation of benzimidazoles as 15-lipoxygenase inhibitors. Trivedi, Bharat Kalidas; Roth, Bruce David; Padia, Janak Khimchand. 78 pp.] covers structures of the type below where W, X, Y, and Z can be independently CR
2
, CR
3
, CR
4
, CR
5
or N where R
2
-R
5
are independently H, C
1-20
alkyl, halogen, CN, nitro, SO
2
H, SO
2
-lower alkyl, SO
2
NR
6
R
7
, alkoxy, SH, (CH2)nNR
6
R
7
, N(R
6
)C(O)NR
7
R
8
, N(R
6
)C(S)NR
7
R
8
, N(R
6
)(CH
2
)
n
NR
6
R
7
, (CH
2
)
n
CONR
6
R
7
, (CH
2
)
n
OR
6
, (CH
2
)
n
CO
2
R
6
, (CH
2
)
n
OC(O)R
6
or CF
3
; n is an integer from 0 to 4; R
1
can be H or lower alkyl and A is a 5 or 6 member heterocyclic ring containing at least one of N, O, or S which is substituted by R and may be substituted by R
12
as described.
JP 62010085 (Trifluoromethyl)purine derivatives as antitumor agents. Obe, Takanori; Sueoka, Hiroyuki; Terasawa, Michio. (Yoshitomi Pharmaceutical Industries, Ltd., Japan). Jpn. Kokai Tokkyo Koho 4 pp.] covers purines of the structure below where R=H, CF
3
, alkyl, etc.; R
1
=H, alkyl; R
2
=alkyl; R
1
R
2
N=heterocyclyl; R
3
=H, alkyl; R
4
=CF
3
, pyridyl, Ph.
SUMMARY OF THE INVENTION
This invention provides a compound of the formula I
Wherein X is NR
4
R
5
where R
4
and R
5
are selected independently from C
1
-C
8
alkyl, C
2
-C
8
alkenyl, C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, C
2
-C
8
alkynyl, C
2
-C
8
alkylalkoxy, alkylaryl, alkylheteroaryl, SO
2
R
7
, or SO
2
NR
7
R
8
; each optionally substituted with 1-2 substituents independently selected from R
6
; or R
4
and R
5
are taken together to be C
3
-C
8
cycloalkyl, optionally substituted with 1-2 substituents independently selected from R
6
; C
5
-C
8
cycloalkenyl, optionally substituted with 1-2 substituents independently selected from R
6
; or a heterocyclic ring containing up to two heteroatoms selected from the group consisting of —O—, —NR
7
—, and —S(O)m— (m=0-2), optionally substituted with 1-3 substituents independently selected from R
6
. Furthermore, when R
4
and R
5
are taken together to be C
3
-C
8
cycloalkyl, C
5
-C
8
cycloalkenyl, or a heterocyclic ring as described above then said ring system may be further substituted to form an additional 3-8 membered ring optionally containing up to two heteroatoms selected from the group consisting of —O—, —NR
7
—, and —S(O)m—(m=0-2). Furthermore, R
5
may be selected from NR
7
R
8
; and
R
6
is selected independently from hydrogen; halogen, nitro, cyano, hydroxy, alkylalkoxy, COOH, C
1
-C
6
alkyl; C
1
-C
6
hydroxyalkyl, C
1
-C
6
aminoalkyl, aryl, heteroaryl, aryloxy, heteroaryloxy, alkoxy; acyloxy, NR
7
R
8
, C
1
-C
4
alkylthio, mono-, di-, or trihaloalkyl; and
R
7
and R
8
are independently selected from H, C
1
-C
6
alkyl; C
2
-C
6
alkenyl, alkylalkoxy, C
2
-C
6
alkynyl, aryl, or heteroaryl; and may be joined to form a carbocyclic or heterocyclic ring; and
Y is selected from C
1
-C
6
alkyl; alkoxyalkyl, C
2
-C
6
alkenyl; C
2
-C
6
alkynyl, alkoxy, aryl, or heteroaryl, or NR
4
R
5
as defined for X; and
R
3
is selected from aryl or heteroaryl, optionally substituted with 1-3 substituents chosen from R
6
.
In another aspect this invention provides a compound of the formula
Wherein R
3
and Y are as defined above.
In another aspect this invention provides a compound of the formula
where R
3
, R
4
, and R
5
are as defined above.
This invention also comprises a compound selected from the group consisting of:
2-Chloro-8-phenyl-6-pyrrolidin-1-yl-7H-purine;
8-Phenyl-2,6-di-pyrrolidin-1-yl-7H-purine;
8-Phenyl-2,6-di-piperidin-1-yl-7H-purine;
8-Phenyl-2-piperidin-1-yl-6-pyrrolidin-1-yl-7H-purine;
N
2
,N
2
,N
6
,N
6
-Tetramethyl-8-phenyl-7H-purine-2,6-diamine;
Benzyl-(8-phenyl-6-pyrrolidin-1-yl-7H-purin-2-yl)-amine; and
Dimethyl-(8-phenyl-6-pyrrolidin-1-yl-7H-purin-2-yl)-amine.
The skilled chemist will be aware that some compounds of formula I may exist in tautomeric forms which are isomers differing in the relative position of a hydrogen atom. All such tautomers and mixtures thereof are included in this invention.
In another aspect, this invention comprises a method of inhibiting or alleviating a pathological condition or physiological disorder in a mammal characterized by an excess of neuropeptide Y which comprises administering to a mammal in need of such treatment a neuropeptide Y inhibiting amount of the compound of Formula I shown above.
In one embodiment, this invention provides a method of inhibiting or alleviating a pathological condition in a mammal characterized by an excess of neuropeptide Y wherein said mammal is a dog or cat.
This invention also comprises a method of treating a pathological condition wherein said pathological condition or
Benson Gregg C.
Berch Mark L.
Habte Kahsay
Musser Arlene K.
Pfizer Inc.
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