Compounds specific for the human &agr;1d adrenergic receptor...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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Details

C514S253120, C544S360000, C544S365000

Reexamination Certificate

active

06706716

ABSTRACT:

Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains. Full bibliographic citation for these references may be found at the end of this application, preceding the sequence listings and the claims.
BACKGROUND OF THE INVENTION
The designation “&agr;
1d
” is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated “&agr;
1a
” cloned subtype as outlined in the Pharmacological Reviews (Hieble, et al., 1995). The designation “&agr;
1d
” is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated “&agr;
1c
” was renamed “&agr;
1a
”. The new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra). In each case, lowercase letters are used to designate cloned receptors (i.e., &agr;
1a
, &agr;
1b
, &agr;
1d
) and uppercase letters are used to designate pharmacologically defined native receptors (i.e., &agr;
1A
, &agr;
1B
, and &agr;
1D
)
&agr;-Adrenergic receptors (McGrath et al., 1989) are specific neuroreceptor proteins both located in the peripheral and central nervous systems and in tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many &agr;-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension), naphazoline (a nasal decongestant), and apraclonidine (for treatment of glaucoma). &agr;-Adrenergic drugs can be divided functionally into two distinct classes: agonists (e.g., clonidine and naphazoline), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (e.g., phenoxybenzamine and prazosin), which act to block the effects of norepinephrine. Many of these drugs are effective, but also produce unwanted side effects (e.g., clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years, a more precise understanding of &agr;-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one &agr;-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two &agr;-adrenergic receptor types—&agr;
1
and &agr;
2
—existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six &agr;-adrenergic receptors which exist throughout the central and peripheral nervous systems: &agr;
1A
(new nomenclature), &agr;
1B
, &agr;
1D
(new nomenclature), &agr;
2A
, &agr;
2B
and &agr;
2C
(Bylund, D. B., 1992). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current &agr;-adrenergic drugs are not selective for any particular &agr;-adrenergic receptor. Many of these drugs produce untoward side effects that may be attributed to their poor &agr;-adrenergic receptor subtype selectivity.
This invention is directed to compounds which are selective antagonists for cloned human &agr;
1d
receptors. This invention is also related to the use of these compounds as antihypertensive agents (Deng, F. X. et al., 1996). Experimental evidence presented herein indicates that these compounds, while effective at reducing blood pressure in hypertensive individuals, will be devoid of hypotensive actions in normotensive individuals.
This invention is also related to the use of these compounds for the treatment of Raynaud's disease and for treating bladder instability associated with urinary incontinence (Broten, et al., 1998).
SUMMARY OF THE INVENTION
The invention is directed to a method of inhibiting activation of a human &agr;
1d
adrenergic receptor which comprises contacting the receptor with a compound so as to inhibit activation of the receptor, wherein the compound binds to the human &agr;
1d
adrenergic receptor with a binding affinity which is at least ten-fold higher than the binding affinity with which the compound binds to (i) a human &agr;
1a
adrenergic receptor and (ii) a human &agr;
1b
adrenergic receptor, and the compound binds to the human &agr;
1d
adrenergic receptor with a binding affinity which is greater than the binding affinity with which the compound binds to a human 5-HT
1a
receptor.
This invention is additionally directed to a method of inhibiting activation of a human &agr;
1d
adrenergic receptor which comprises contacting the receptor with a compound so as to inhibit activation of the receptor, wherein the compound has the structure:
wherein m is an integer from 0 to 2; wherein n is an integer from 0 to 2;
wherein Y is
wherein Z is
wherein R1 and R2 (i) are independently H, branched or unbranched C
1
-C
6
alkyl or alkoxy, branched or unbranched C
2
-C
6
alkenyl or alkynyl, branched or unbranched C
1
-C
6
hydroxyalkyl, hydroxy, substituted or unsubstituted aryl or aryl-(C
1
-C
6
)-alkyl, or substituted or unsubstituted heteroaryl or heteroaryl-(C
1
-C
6
)-alkyl, wherein the substituent if present is a halogen, CN, nitro, hydroxy, branched or unbranched C
1
-C
6
alkyl or alkoxy group, or branched or unbranched C
2
-C
6
alkenyl or alkynyl group; or (ii) taken together form a substituted or unsubstituted cycloalkyl ring containing 3-10 carbons, wherein the substituent if present is a branched or unbranched C
1
-C
6
alkyl group or branched or unbranched C
2
-C
6
alkenyl or alkynyl group;
wherein R3 is H, branched or unbranched C
1
-C
6
alkyl, branched or unbranched C
2
-C
6
alkenyl or alkynyl, C
3
-C
7
cycloalkyl, C
3
-C
7
cycloalkylalkyl, aryl, heteroaryl, aryl-(C
1
-C
6
)-alkyl, heteroaryl-(C
1
-C
6
-alkyl, substituted C
1
-C
6
alkyl, substituted C
3
-C
7
cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C
1
-C
6
)-alkyl, or substituted heteroaryl-(C
1
-C
6
)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C
1
-C
6
alkyl, OR14, SR14, N(R14)
2
, SO
2
N(R14)
2
, CO
2
R14, SO
3
R14, N(R14)COR14, CON(R14)
2
, or N(R14)CON(R14)
2
;
wherein R4 is H or CH
3
;
wherein R5 is H, branched or unbranched C
1
-C
6
alkyl, branched or unbranched C
2
-C
6
alkenyl or alkynyl, C
3
-C
7
cycloalkyl, C
3
-C
7
cycloalkylalkyl, aryl, heteroaryl, aryl-(C
1
-C
6
)-alkyl, heteroaryl-(C
1
-C
6
)-alkyl, substituted C
1
-C
6
alkyl, substituted C
3
-C
7
cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C
1
-C
6
)-alkyl, or substituted heteroaryl-(C
1
-C
6
)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C
1
-C
6
alkyl, OR14, SR14, N(R14)
2
, SO
2
N(R14)
2
, CO
2
R14, SO
3
R14, N(R14)COR14, CON(R14)
2
, or N(R14)CON(R14)
2
;
wherein R6 is H, branched or unbranched C
1
-C
6
alkyl, branched or unbranched C
2
-C
6
alkenyl or alkynyl, C
3
-C
7
cycloalkyl, C
3
-C
7
cycloalkylalkyl, aryl, heteroaryl, aryl-(C
1
-C
6
)-alkyl, heteroaryl-(C
1
-C
6
)-alkyl, substituted C
1
-C
6
alkyl, substituted C
3
-C
7
cycloalkyl, substituted aryl, substituted heteroaryl, substituted aryl-(C
1
-C
6
)-alkyl, or substituted heteroaryl-(C
3
-C
6
)-alkyl, wherein the substituent if present is a halogen, CN, nitro, C
1
-C
6
alkyl, OR14, SR14, N(R14)
2
, SO
2
N(R14)
2
, C
0
2
R14, SO
3
R14, N(R14)COR14, CON(R14)
2
, or N(R14)CON(R14)
2
;
wherein R7 is H, branched or unbranched C
1
-C
6
alkyl, branched or unbranched C
2
-C
6
alkenyl or alkynyl, C
3
-C
7
cycloalkyl, aryl, aryl-(C
1
-C
6
)-alkyl, CO
2
R14, CON(R14)
2
, substituted C
1
-C
6
alkyl, substituted aryl, wherein the substi

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