Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-07-12
2002-05-28
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S649000, C514S652000, C548S135000, C564S306000
Reexamination Certificate
active
06395762
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to phenyl-oxo-tetrahydroquinolin-3-yl &bgr;
3
adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenic inflammation, glaucoma, ocular hypertension, frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
The subdivision of &bgr; adrenergic receptors (&bgr;-AR) into &bgr;
1
- and &bgr;
2
-AR has led to the development of &bgr;
1
- and &bgr;
2
- antagonists and/or agonists which have been used in the treatment of cardiovascular disease and asthma. The recent discovery of “atypical” receptors, later called &bgr;
3
-AR, has led to the development of &bgr;
3
-AR agonists that are potentially useful as antiobesity and antidiabetic agents. For recent reviews on &bgr;
3
-AR agonists, see: 1. Strosberg, A. D.,
Annu. Rev. Pharmacol. Toxicol.,
1997, 37, 421; 2. Weber, A. E.,
Ann. Rep. Med. Chem.,
1998, 33, 193; 3. Kordik, C. P. and Reitz, A. B.,
J. Med. Chem.,
1999, 42, 181; 4. Weyer, C., Gautier, J. F., and Danforth, E.,
Diabetes and Metabolism,
1999, 25, 11.
Compounds that are potent and selective &bgr;
3
agonists, may be potentially useful antiobesity agents. Low levels or lack of &bgr;
1
and &bgr;
2
-agonistic properties will minimize or eliminate the adverse side effects that are associated with &bgr;
1
and &bgr;
2
agonistic activities, i.e. increased heart rate, and muscle tremor, respectively. Early developments in the &bgr;
3
-agonist field are described in European patent 427480, U.S. Pat. Nos. 4,396,627, 4,478,849, 4,999,377, and 5,153,210. These early patents purport to claim compounds with greater selectivity for the &bgr;
3
-AR than for the &bgr;
1
- and &bgr;
2
-AR's. However, clinical trials in humans with such compounds have not been successful to date.
More recently, potent and selective human &bgr;
3
agonists have been described in several patents and published applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549, WO 97/25311, WO 96/16938, and WO 95/29159; European Patents 659737, 801060, 714883, 764640, and 827746; and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in a Chinese hamster ovary (CHO) cell model, an assay that predicts the effects expected in humans. These assays utilize cloned human &bgr;
3
receptors, expressed in CHO cells (see refs. Granneman, et al.,
Mol. Pharmacol,
1992, 42, 964; Emorine, et al.,
Science,
1989, 245, 1118; Liggett,
Mol. Pharmacol,
1992, 42, 634).
&bgr;
3
-AR agonists also are useful in controlling urinary incontinence. It has been shown that relaxation of the bladder detrusor is under beta adrenergic control (Li, J. H., Yasay, G. D. and Kau, S. T., “Beta-adrenoceptor subtypes in the detrusor of guinea-pig urinary bladder”,
Pharmacology,
1992, 44, 13-18). Several laboratories have provided recent experimental evidence that activation of the &bgr;
3
receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder in a number of animal species, including humans (Yamazaki Y., et al., “Species differences in the distribution of the &bgr;-AR subtypes in bladder smooth muscle”,
Br. J. Pharmacol.,
1998, 124, 593-599).
Urge urinary incontinence is characterized by abnormal spontaneous bladder contractions that can be unrelated to bladder urine volume. Urge urinary incontinence is often referred to as hyperactive or unstable bladder. Several etiologies exist and fall into two major categories, myogenic and neurogenic. The myogenic bladder is usually associated with detrusor hypertrophy secondary to bladder outlet obstruction, or with chronic urinary tract infection. The neurogenic bladder is associated with an uninhibited micturition reflex, in which an upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized by abnormal spontaneous contractions that result in an unusual sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder involves the use of antimuscarinic agents to block the action of the excitatory neurotransmitter acetylcholine. While effective in neurogenic bladders, their utility in myogenic bladders is questionable. In addition, due to severe dry mouth side-effects associated with antimuscarinic therapy, the patient compliance with these agents is only approximately 30 percent.
In the bladder, &bgr;
3
-AR agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled &bgr;
3
-AR. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum, thereby decreasing intracellular calcium resulting in an inhibition of bladder smooth muscle contractility.
It is suggested therefore, that activation of the &bgr;
3
-AR in the urinary bladder will inhibit abnormal spontaneous bladder contractions and be useful for the treatment of bladder hyperactivity. Note that unlike the antimuscarinics, &bgr;
3
-AR agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenic inflammation, frequent urination and related diseases. A potent and selective &bgr;
3
-AR agonist is therefore highly desirable for the potential treatment of these disease states.
DESCRIPTION OF THE INVENTION
This invention provides compounds of Formula I having the structure
(a) phenyl optionally substituted with 1-3 Y groups;
(b) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
(d) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
is
X is —OCH
2
— or a bond;
Y is hydroxy, halogen, cyano, —SO
m
R
4
, —SO
n
NR
4
R
5
, —NHSO
2
R
4
, —NR
4
R
5
, alkyl of 1-10 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-10 carbon atoms, arylalkoxy, —COR
4
, or —CO
2
R
4
;
R
1
and R
2
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
R
3
is
(a) alkyl of 1-10 carbon atoms, optionally substituted with 1-5 groups selected from the goup consisting of halogen; hydroxy; spirocycloalkyl of 5-7 carbon atoms, phenyl optionally mono- or di-substituted with Z; oxo; —CO
2
H; —CO
2
R
4
; amino; —NR
4
R
5
; and —NHCOR
4
;
(b) cycloalkyl of 3-8 carbon atoms;
(c) arylalkyl wherein the alkyl moiety contains 1-10 carbon atoms;
(d) heterocycle or heterocyclealkyl, wherein the alkyl moiety contains 1-6 carbon atoms, and the heterocycle is
i) a 5-6 membered heterocyclic ring having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups;
ii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, optionally substituted with 1-2 Y groups; or
iii) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring, optionally substituted with 1-2 Y groups;
R
4
and R
5
are each, independently, hydrogen, alkyl of 1-10 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
Z is halogen, alkyl of 1-10 carbon atoms, —CO
2
R
4
, benzyloxy, —NHC(O)NHR
4
, —NR
4
R
5
, —OR
4
, —COR
4
, —S(O)
m
R
4
; or —S(O)
n
NR
4
R
5
;
m=0-2;
n=1-2;
or a pharmaceutically acceptable salt thereof, which are selective agonists at human &bgr;
3
adrenergic receptors and are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal dis
Fobare William Floyd
Freymuller Jill
American Home Products Corporation
Eck Steven R.
Gerstl Robert
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