Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-23
2003-05-27
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S342000, C514S376000, C514S377000, C546S270700, C546S271400, C546S274400, C546S274700, C548S226000, C548S233000, C548S234000
Reexamination Certificate
active
06569873
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to azolidine derivatives which are &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 frequent urination; and are particularly useful in the treatment 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 agonists 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,
R
1
, R
2
, R
3
are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6 to 10 carbon atoms, aryloxy of 6-10 carbon atoms, halogen, trifluoromethyl of atoms, alkoxy of 1-6 carbon atoms, hydroxy, nitro, amino, aminocarbonyl, alkylamino of 1-6 carbon atoms, dialkyl amino of 1-6 carbon atoms per alkyl group, formamido, ureido, acyl of 2-7 carbon atoms, acylamino of 2-7 carbon atoms, amino, alkylsulfonylamino of 1-6 carbon atoms, or arylsulfonylamino of 6 to 10 carbon atoms; or two of R
1
, R
2
, and R
3
are taken together to form a phenyl ring or a heterocyclic ring which is fused to the ring which contains the R
1
, R
2
, or R
3
substituents, wherein the heterocyclic ring contains 1-3 heteroatoms selected from N, O, or S;
R
4
is hydrogen or alkyl of 1-6 carbon atoms;
R
5
is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-14 carbon atoms, halogen substituted arylalkyl of 7-14 carbon atoms, arylalkene of 8-16 carbon atoms, arylalkyne of 8-16 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, aryloxycarbonyl of 7-11 carbon atoms, alkylsulfonyl of 1-6 carbon atoms, or arylsulfonyl of 1-6 carbon atoms;
R
6
is hydrogen, alkyl of 1-6 carbon atoms, aryl or arylalkyl of 7-14 carbon atoms;
A is phenyl, naphthyl, benzofuryl, or benzothienyl;
X is bond, —OCH
2
—, or —SCH
2
—;
Y is alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms;
Z is carbon, sulfur, oxygen, or nitrogen;
W is carbon or nitrogen;
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 disorders, neurogenetic inflammation, glaucoma, ocular hypertension, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes.
Pharmaceutically acceptable salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable aids when a compound of this invention contains a basic moiety. Salts
Gunawan Iwan
Largis Elwood Eugene
Li Zenan
Malamas Michael Sotirios
Hild Kimberly R.
McKane Joseph K.
Saeed Kamal
Wyeth
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