Substituted...

Details Substituted... Substituted...

2001-07-12

2003-01-14

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S327000

Reexamination Certificate

active

06506901

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to substituted 2-(S)-hydroxy-3-(piperidin-4-yl-methylamino)-propyl ethers and substituted 2-aryl-2-(R)-hydroxy-1-(piperidin-4-yl-methyl)-ethylamine &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, neurogenetic inflammation, glaucoma, ocular hypertension, and and 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 useful for 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 agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on &bgr;
3
-AR agnoists, see: 1. A. D. Strosberg, Annu. Rev.
Pharmacol. Toxicol
. 1997, 37, 421; 2. A. E. Weber,
Ann. Rep. Med. Chem
. 1998, 33, 193; 3. C. P. Kordik and A. B. Reitz,
J. Med. Chem
. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth,
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, 5,153,210. Although the early developments purport to claim compounds with greater &bgr;
3
-AR selectivity over the &bgr;
1
- and &bgr;
2
-AR. However, clinical trials in humans with those early developed &bgr;
3
-agonists have, so far, not been successful.
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, WO 95/29159, European Patents 659737, 801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142, 5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated in Chinese hamster ovary (CHO) cells test procedures, expressing cloned human &bgr;
3
receptors, which predict the effects that can be expected in humans (Granneman et al.,
Mol Pharmacol
., 1992, 42, 964; Emorine et al.,
Science
, 1989, 245, 1118; Liggett
Mol. Pharmacol
., 1992, 42, 634).
&bgr;
3
-Adrenergic agonists also are useful in controlling the frequent urge of urination. It has been known that relaxation of the bladder detrusor is under beta adrenergic control (Li J H, Yasay G D and Kau S T
Pharmacology
1992; 44: 13-18). Beta-adrenoceptor subtypes are in the detrusor of guinea-pig urinary bladder. Recently, a number of laboratories have provided experimental evidence of &bgr;
3
adrenergic receptors in a number of animal species including human (Yamazaki Y, Takeda H, Akahane M, Igawa Y, et al.
Br. J. Pharmacol
. 1998; 124: 593-599), and that activation of the &bgr;
3
receptor subtype by norepinephrine is responsible for relaxation of the urinary bladder.
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 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. Neurogenic bladders are associated with an uninhibited micturition reflex. An upper motor neuron disease is usually the underlying cause. In either case, the disease is characterized my abnormal spontaneous contractions that result in an abnormal sense of urinary urgency and involuntary urine loss. At present, the most common therapy for hyperactive bladder includes 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%.
In the bladder, &bgr;
3
adrenergic receptor agonists activate adenylyl cyclase and generate cAMP through the G-protein coupled &bgr;
3
receptor. The resulting phosphorylation of phospholamban/calcium ATPase enhances uptake of calcium into the sarcoplasmic reticulum. The decrease in intracellular calcium inhibits bladder smooth muscle contractility.
It is suggested therefore, that activation of the &bgr;
3
adrenergic receptor 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
adrenergic receptor agonists would be expected to be active against both neurogenic and myogenic etiologies.
Despite all these recent developments there is still no single therapy available for the treatment of type II diabetes (NIDDM), obesity, atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, frequent urination and related diseases. A potent and selective &bgr;
3
adrenergic receptor agonist is therefore highly desirable for the potential treatment of such disease states.
DESCRIPTION OF THE INVENTION
This invention provides compounds of Formula I having the structure
wherein,
A is —OCH
2
— or a bond;
R is
(a) aryl optionally substituted with R
2
, R
3
, R
4
, R
5
, or R
6
; or
(b) Het optionally substituted with R
2
, R
3
, or R
4
;
R
1
is:
(a) alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, or cycloalkylamino of 3-8 carbon atoms;
(b) aryl optionally substituted with R
9
, R
10
, or R
11
;
(c) arylamino optionally substituted with R
9
, R
10
, or R
11
;
(d) arylalkyl having 1-6 carbon atoms in the alkyl moiety, and which the aryl moiety may be optionally substituted with R
9
, R
10
, or R
11
;
(e) Het optionally substituted with R
9
or R
10
R
2
, R
3
, R
4
, R
5
, and R
6
are each, independently, alkyl of 1-6 carbon atoms, hydroxy, alkoxy of 1-6 carbon atoms, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, halogen, —NHSO
2
R
7
, —CO
2
R
8
, or —CONH
2
;
R
7
and R
8
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or arylalkyl having 1-6 carbon atoms in the alkyl moiety;
Z is a bond, —SO
2
— or —CO—;
Het is
(a) a 5-6 membered heterocycle having 1-4 heteroatoms selected from O, N, and S;
(b) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S;
(c) a phenyl fused heterocycle having 1-4 heteroatoms selected from O, N, and S, having a second phenyl ring fused to the heterocyclic ring;
R
9
, R
10
, and R
11
are each, independently:
(a) alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, arylalkyl having 1-6 carbon atoms in the alkyl moiety, alkoxy of 1-6 carbon atoms, aryloxy, arylalkoxy having 1-6 carbon atoms in the alkyl moiety, hydroxy, alkylamino of 1-6 carbon atoms, dialkylamino of 1-6 carbon atoms per alkyl moiety, arylamino, halogen, alkylthio of 1-6 carbon atoms, trifluoromethyl, trifluoromethylalkyl of 2-7 carbon atoms, trifluoromethoxy, —(CH
2
)
n
—NHR
14
, —OCH
2
(CH
2
)
n
CO
2
R
7
, —(CH
2
)
n
—CO
2
R
7
, —COR
7
, —SO
2
R
13
, —(CH
2
)
n
NHCOR
14
, —CN, or NO
2
;
(b) Het optionally substituted with R
15
; or
R
12
is hydrogen, alkyl of 1-6 carbon atoms, aryl optionally substituted with R
15
, arylalkyl having 1-6 carbon atoms in the alkyl moiety and the aryl moiety optionally substituted with R
15
, Het optionally substituted with R
15
, Hetalkyl having 1-6

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