Oxazolone derivatives and uses thereof

Details Oxazolone derivatives and uses thereof Oxazolone derivatives and uses thereof

2000-03-08

2002-03-12

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S254020, C544S328000, C544S331000, C544S364000, C544S369000

Reexamination Certificate

active

06355641

ABSTRACT:

TECHNICAL FIELD
The invention relates generally to oxazolone derivatives, and pharmaceutically acceptable salts or solvates thereof, which exhibit useful pharmacological properties. In particular, the invention relates to compounds, pharmaceutical compositions and methods of using oxazolone derivatives as alpha
1
-adrenergic receptor (alpha
1
-adrenoceptor) modulators, preferably antagonists.
BACKGROUND OF THE INVENTION
Alpha1-adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha
1
-adrenergic receptors are known to exist for which the genes have been cloned: alpha
1A
(previously known as alpha
1C
), alpha
1B
and alpha
1D
. The existence of an additional subtype, the alpha
1L
-adrenergic receptor subtype, has been proposed; however, the gene for the alpha
1L
-adrenergic receptor subtype has yet to be cloned. Although these subtypes can be pharmacologically distinguished, existing subtype-selective compounds are only moderately specific and may interact with more than one alpha
1
-adrenergic receptor subtype. Accordingly, therapeutic use of nonselective alpha
1
-adrenergic receptor antagonists must be carefully monitored as such antagonists can produce significant undesirable side effects such as postural hypotension, sedation or depression, increased gastrointestinal motility and diarrhea, impaired ability to ejaculate, nasal stuffiness, akinesia and the like.
Non-selective alpha
1
-adrenoceptor antagonists have been used to treat lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Further, alpha
1
-adrenoceptor antagonists can be effective in reducing or alleviating urinary tract disorders and/or the symptoms thereof, such as pelvic hypersensitivity, overactive bladder, urinary frequency, nocturia, urinary urgency, detrusor hyperreflexia, outlet obstruction, prostatitis, incontinence, urge incontinence, urethritis, prostatodynia, idiopathic bladder hypersensitivity, and the like.
Compounds that interact more selectively with a particular alpha
1
-adrenergic receptor subtype may prove clinically useful in providing more selective treatment of conditions and diseases, and symptoms thereof, associated with activity at the receptor subtype. For example, alpha
1
-adrenergic receptor antagonists that can selectively reduce or alleviate urinary tract disorders or symptoms, or ameliorate nociceptive and/or neurogenic pain without affecting blood pressure or causing postural hypotension, are desirable. Presently available alpha
1
-adrenergic antagonists are either relatively nonselective with respect to the subtypes with which they interact or generally are not selective for the alpha
1B
-adrenergic receptor subtype.
DESCRIPTION OF THE RELATED ART
U.S. Pat. No. 5,736,412 (Zambias et al.) refers to a method of generating a plurality of certain chemical compounds in a spatially arranged array.
U.S. Pat. No. 5,962,736 ( Zambias et al.) refers to logically ordered arrays of compounds and methods of making and using the same.
U.S. Pat. No. 5,859,014 (Bantle et al.) refers to certain pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives which are disclosed as being useful as alpha
1
adrenergic receptor antagonists.
PCT Published Application WO 95/17903 (assigned to Arqule) refers to a modular design and synthesis of oxazolone-derived molecules.
PCT Published Application WO 95/25726 (assigned to Recordati) refers to certain quinazolyl-amino derivatives which are disclosed as having alpha antagonist activity.
PCT Published Application WO 98/46551 (assigned to Arqule) refers to a synthesis and use of certain biased arrays.
PCT Published Application WO 98/46559 (assigned to Arqule) refers to a synthesis and use of certain alpha-ketoamide derivatives and arrays.
PCT Published Application WO 98/56028 (assigned to Arqule) refers to an automated, highthroughput method for screening a plurality of compounds using mass spectrometry.
PCT Published Application WO 96/16049 (assigned to Glaxo) refers to certain oxazoles as alpha-1C antagonists.
PCT Published Applications WO 99/09979, WO 99/09980, and WO 99/09829 (all assigned to Eli Lilly) refer to certain oxazoles for treating neuropathic pain.
European Patent Application EP 602851 refers to certain quinazoline derivatives.
German Patent Publications No. 117 224, 117 225, 117 228, and DE 2 659 543 refer to synthesis of certain oxazolinones.
Japanese Patent Application No 08-27132 refers to the preparation of certain oxazolones.
Giardina et al., J. Med. Chem. 1996, 39, 4602-4607 refer to the synthesis of cyclazosin enantiomers and their activity as alpha-1B antagonists.
Patane et al., J. Med. Chem 1998, 41, 1206-1208 refer to L-765314 as a potent and selective alpha-1B antagonist.
Xie et al., Soc. for Neuroscience Abstract 24, 2089(1998) refer to certain alpha 1B adrenergic receptor mRNA expression in rat DRG after spinal nerve injury.
Lee et al, J. Neurophysiol. 81, 2226-2233 (1999) refer to certain receptor subtypes mediating the adrenergic sensitivity of pain behaviour.
SUMMARY OF THE INVENTION
The present invention addresses the aforementioned needs in the art by providing oxazolone derivatives, and pharmaceutically acceptable salts or solvates thereof, which exhibit useful pharmacological properties. Particularly, the present invention relates to oxazolone derivatives, pharmaceutical compositions thereof and methods of using such derivatives as alpha
1
-adrenergic receptor (alpha
1
-adrenoceptor) modulators, preferably antagonists.
In one embodiment, the invention relates to a compound comprising the Formula (I):
wherein:
X is Formula (A), (B) or (C);
m is an integer ranging from 1 to 6 inclusive;
n is an integer ranging from 0 to 5 inclusive;
p, q, r and s are each independently integers ranging from 1 to 3
inclusive, with the proviso that when p is greater than one, r is 1 and
when s is greater than one, q is 1;
Y is —(CH
2
)
w
—R
3
, —(CH
2
)
w
—CO—R
4
, —(CH
2
)
w
—CO—NH—R
5
, —(CH
2
)
w
—C(NR
6
)—NH—R
7
, —(CH
2
)
w
—SO
2
—R
8
, —(CH
2
)
w
—NH—R
9
, —(CH
2
)
w
—NH—CO—R
10
, —(CH
2
)
w
—NH—CO—NH—R
11
, or —(CH
2
)
w
—NH—SO
2
—R
12
; wherein w is an integer ranging from 0 to 3 inclusive;
Z is CH or N;
R
1
is cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl;
R
2a
, R
2b
or R
2c
are each independently in each occurrence hydrogen, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl; or R
2a
and R
2b
taken together with the carbons to which they are attached form a 5- to 7-membered ring structure;
R
3
is heterocyclic or heteroaryl;
R
4
, R
5
, R
8
, R
9
, R
10
, R
11
and R
12
are each independently in each occurrence hydrogen, alkyl, alkoxy, hydroxyalkyl, alkylthio, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R
6
and R
7
are each independently in each occurrence hydrogen, alkyl, hydroxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, X is:
or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a more preferred embodiment, X is piperazinyl or piperidinyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. Even more preferably X is piperazinyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, Y is —(CH
2
)
w
—R
3
, —(CH
2
)
w
—CO—R
4
, —(CH
2
)
w
—CO—NH—R
5
, —(CH
2
)
w
—C(NR
6
)—NH—R
7
, —(CH
2
)
w
—SO
2
—R
8
, —(CH
2
)
w
—NH—R
9
, —(CH
2
)
w
—NH—CO—R
10
, —

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