Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-23
2003-11-25
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S187000, C546S199000, C514S326000, C514S322000
Reexamination Certificate
active
06653478
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel substituted benzimidazol-2-ones. More particularly, the compounds of the present invention modulate the binding of the peptide hormone vasopressin and neuropeptide Y to their respective receptors and are therefore useful for treating conditions involving increased vascular resistance, cardiac insufficiency, and disorders of energy metabolism.
BACKGROUND OF THE INVENTION
Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown in the liver; induction of platelet aggregation; release of corticotropin from the anterior pituitary and stimulation of renal water reabsorption. As a neurotransmitter within the central nervous system (CNS), vasopressin can affect aggressive behavior, sexual behavior, the stress response, social behavior and memory. The V-1a receptor mediates central nervous system effects, contraction of smooth muscle and hepatic glycogenolytic effects of vasopressin, while the V-1b receptor mediates anterior pituitary effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase.
Elevated plasma vasopressin levels appear to play a role in the pathogenesis of congestive heart failure (P. A. Van Zwieten,
Progr. Pharmacol. Clin. Pharmacol.
1990, 7, 49). As progress toward the treatment of congestive heart failure, nonpeptide vasopressin V-2 receptor antagonists have induced low osmolality aquaresis and decreased peripheral resistance in conscious dogs with congestive heart failure (H. Ogawa,
J. Med. Chem.
1996, 39, 3547). In certain pathological states, plasma vasopressin levels may be inappropriately elevated for a given osmolality, thereby resulting in renal water retention and hyponatremia. Hyponatremia, associated with edematous conditions (cirrhosis, congestive heart failure, renal failure), can be accompanied by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Treatment of SIADH-compromised rats with a vasopressin V-2 antagonist has corrected their existing hyponatremia (G. Fujisawa,
Kidney Int.
1993, 44(1), 19). Due in part to the contractile actions of vasopressin at its V-1 receptor in the vasculature, vasopressin V-1 antagonists have reduced blood pressure as a potential treatment for hypertension as well. Thus, vasopressin receptor antagonists are useful as therapeutics in the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention.
Several non-peptide arginine vasopressin (AVP) antagonists have been reported. One of the V1a selective antagonists is known as OPC 21268 (see J. Donald Albright and P. S. Chan, Current Pharm. Design, 1997, 3, 615-632),
which is stated to be only active in rat with no activity when tested for binding to human V1a receptor.
U.S. Pat. Nos. 5,849,780 and 5,585,394, both to Malta et. al., show compounds of the following structures, respectively:
Sr-121463A is stated to be a potent selective orally active V2 receptor antagonist.
Neuropeptide Y (NPY) is a 36 residue, amidated polypeptide widely present in both the central and peripheral nervous systems. It is also present in the cardiovascular system, platelets, endothelium, adrenal medulla, pancreas, kidney and other organs. NPY binds to a number of G-protein coupled receptors such as Y1, Y2, and Y3. The Y1 receptor is stimulated by NPY or PYY (Peptide YY) and believed to be the major vascular receptor. The Y2 receptor is stimulated by C-terminal fragments of NPY or PYY and is abundantly expressed both centrally and peripherally. Present in adrenal medulla, heart, and brain stem, Y3 is exclusively responsive to NPY. Other subtypes of this receptor family are also known to exist. NPY has a number of biological effects. Intranasal administration of NPY reduces nasal airway resistance and vascular permeability. NPY also plays an important role in modulating the cardiovascular system, behavior, anxiety and the secretion of certain hormones; it contributes to the central and peripheral control of blood pressure, the regulation of feeding behavior, obesity, diabetes and psychiatric disorders.
It has been reported that Y1 agonists cause an increase in blood pressure as well as feeding behavior. Y2 agonists/antagonists, on the other hand, can modulate neurotransmitter release.
SUMMARY OF THE INVENTION
The present invention is directed to compounds represented by the following Formula I:
wherein
A is aryl or heteroaryl having 0-4 heteroatoms selected from N, O, and S;
X is selected from S, O, NH, and NCN;
Y is S or O;
R
1
is 1-3 groups selected from hydrogen, alkyl, substituted alkyl, halogen, nitro, methylenedioxy, nitrile, —OR
a
, —NHR
a
, —NR
a
R
b
, —S(O)
p
R
a
, —N(R
a
)C(O)R
b
, —C(O)OR
a
, —C(O)NR
a
R
b
, —SO
2
NR
a
R
b
, —N(R
a
)SO
2
R
b
, N(R
a
)C(O)NR
a
, and NHCOOR
a
, wherein R
a
and R
b
are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
R
2
is selected from hydrogen, alkyl, and substituted alkyl;
R
3
is selected from hydrogen, alkyl, substituted alkyl, benzhydryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, —C(O)OR
c
, and —C(O)NR
c
R
d
, wherein R
c
and R
d
are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NR
c
R
d
may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
R
4
and R
5
are independently selected from hydrogen, alkyl, alkyl substituted with aryl or heteroaryl, phenyl, substituted phenyl, or R
4
and R
5
are non-existent when n is 0;
p is from 0 to 2;
n is 0 or 1; and
m is 0 or 1, with the proviso that when m is 0, X is O, and R
3
is selected from heteroaryl, substituted heteroaryl, —C(O)OR
c
, and —C(O)NR
c
R
d
wherein R
c
and R
d
are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NR
c
R
d
may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, then n is 0;
or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are vasopressin receptor antagonists which are useful in disease states of inner ear disorders, aggression, obsessive-compulsive disorders, hypertension, hyperglycemia, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, diabetes, anxiety, depression, stress, and/or Cushing's disease.
The compounds of the present invention are also Neuropeptide Y modulators which are useful in disease states of hypertension, congestive heart failure/cardiac insufficiency, obesity, diabetes, anorexia, hyperglycemia, anxiety, depression, asthma, memory loss, sexual dysfunction, and disorders of sleep and other circadian rhythms.
An embodiment of the invention is a method of treating a condition associated with vasopressin receptor activity or Neuropeptide Y receptor activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions thereof.
An embodiment of the invention
Demarest Keith T.
Gunnet, Jr. Joseph W.
Urbanski Maud J.
Coppins Janet L
Ortho-McNeil Pharmaceutical , Inc.
Rotman Alan L.
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