Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-03-25
2003-10-28
Aulakh, Charanjit. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S053000, C546S050000
Reexamination Certificate
active
06638943
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to yohimbine dimer compounds, pharmaceutical compositions containing such compounds, methods of making such compounds, as well as various uses thereof.
BACKGROUND OF THE INVENTION
The initial classification of adrenergic receptors (AR's) into &agr;- and &bgr;-families was first described by Ahlquist in 1948 (Ahlquist RP, “A Study of the Adrenergic Receptors,”
Am. J. Physiol.
153:586-600 (1948)). Functionally, the &agr;-ARs were shown to be associated with most of the excitatory functions (vasoconstriction, stimulation of the uterus and pupil dilation) and inhibition of the intestine. On the other hand, &bgr;-ARs were implicated in vasodilation, bronchodilation and myocardial stimulation (Lands et al., “Differentiation of Receptor Systems Activated by Sympathomimetic amines,”
Nature
214:597-598 (1967)). Since this early work, &agr;-ARs have been subdivided into &agr;
1
- and &agr;
2
-AR. Cloning and expression of &agr;-AR have confirmed the presence of multiple subtypes of both &agr;
1
-(&agr;
1a
, &agr;
1b
, &agr;
1d
) and &agr;
2
-(&agr;
2a
, &agr;
2b
, &agr;
2c
) AR (Michel et al., “Classification of &agr;
1
-Adrenoceptor Subtypes,”
Naunyn
-
Schmiedeberg's Arch. Pharmacol,
352:1-10 (1995); Macdonald et al., “Gene Targeting—Homing in on &agr;
2
-Adrenoceptor-Subtype Function,”
TIPS,
18:211-219 (1997)).
In humans, the three &agr;
2
-AR subtypes are encoded by distinct genes localized in different chromosomes. The &agr;
2a
-AR gene is located in chromosome 10, while the &agr;
2b
-AR gene is found on chromosome 2 and the &agr;
2c
-AR gene on chromosome 4 (Bylund et al., “International Union of Pharmacology Nomenclature of Adrenoceptors,”
Pharmacol. Rev.,
46:121-142 (1994)).
Current therapeutic uses of &agr;
2
-ARs drugs involve the ability of those drugs to mediate many of the physiological actions of the endogenous catecholamines and there are many drugs that act on these receptors to control hypertension, analgesia, anesthesia, and ocular and nasal congestion.
&agr;
2
-ARs are found in the rostral ventrolateral medulla, and are known to respond to the neurotransmitter norepinephrine and the antihypertensive drug clonidine to decrease sympathetic outflow and reduce arterial blood pressure (Bousquet et al., “Role of the Ventral Surface of the Brain Stem in the Hypothesive Action of Clonidine,”
Eur. J. Pharmacol.,
34:151-156 (1975); Bousquet et al., “Imidazoline Receptors: From Basic Concepts to Recent Developments,” 26:S1-S6 (1995)). Clonidine and other imidazolines also bind to imidazoline receptors (formerly called imidazoline-guanidinium receptive sites or IGRS) (Bousquet et al., “Imidazoline Receptors: From Basic Concepts to Recent Developments,” 26:S1-S6 (1995)). Some researchers have speculated that the central and peripheral effects of imidazolines as hypotensive agents may be related to imidazoline receptors (Bousquet et al., “Imidazoline Receptors: From Basic Concepts to Recent Developments,” 26:S1-S6 (1995); Reis et al., “The Imidazoline Receptor: Pharmacology, Functions, Ligands, and Relevance to Biology and Medicine,”
Ann. N.Y. Acad. Sci.,
763:1-703 (1995); Diamant et al., “Imidazoline Binding Sites in Human Placenta: Evidence for Heterogeneity and a Search for Physiological Function,”
Br. J. Pharmacol.,
106:101-108 (1992); Ragunathan et al., “Imidazoline Receptors and Their Endogenous Ligands,”
Annu. Rev. Pharmacol. Toxicol.,
36:511-544 (1996); Miralles et al., “Discrimination and Pharmacological Characterization of I
2
-Imidazoline Sites with [
3
H]idazoxan and Alpha-2-Adrenoceptors [
3
H]RX821002 (2 Methoxy Idazoxan) in Human and Rat Brains,”
J. Pharmacol. Exp. Ther.,
264:1187-1197 (1993)). The pharmacological profiles of drugs acting on imidazoline receptors have resulted in their classification into two main types: I
1
- and I
2
-imidazoline binding sites (Diamant et al., “Imidazoline Binding Sites in Human Placenta: Evidence for Heterogeneity and a Search for Physiological Function,”
Br. J. Pharmacol.,
106:101-108 (1992); Miralles et al., “Discrimination and Pharmacological Characterization of I
2
-Imidazoline Sites with [
3
H]idazoxan and Alpha-2-Adrenoceptors [
3
H]RX821002 (2 Methoxy Idazoxan) in Human and Rat Brains,”
J. Pharmacol. Exp. Ther.,
264:1187-1197 (1993); Olmos et al., “Pharmacological and Molecular Discrimination of Brain I
2
-Imidazoline Receptor Subtypes,”
Naunyn
-
Schmiedberg's Arch. Pharmacol.,
354:709-716 (1996)).
Yohimbine is a known potent and selective &agr;
2
-AR antagonist, and has been used extensively as a pharmacological probe for studying the &agr;
2
-AR (Starke K.,
Rev. Physiol. Biochem. Pharmacol,
88, 199 (1981)). Yohimbine, an indole alkaloid isolated from Pausinystlia yohimbe bark and Rauwolfia roots, is an &agr;
2
-antagonist selective for &agr;
2
over &agr;
1
adrenoreceptors, but is also a serotonic antagonist. It has actions both in the central nervous system and in the periphery inducing hypertension and increases heart rate. Yohimbine has been used to treat male impotence and posturalo hypotension. It has also been used in research to induce anxiety (Foye et al.
Principles of Medicinal Chemistry
, Fourth Edition, Williams & Wilkins (1995), page 359). However, yohimbine does not show selectivity among three &agr;
2
-AR subtypes (Hieble et al.,
J. Med. Chem.,
38, 3415 (1995); Hieble et al.,
Prog. Drug Res.,
47, 81 (1996)).
Although there have been a number of &agr;
2
-AR antagonists identified (Ruffolo et al.,
J. Med. Chem.,
38, 3681 (1995); Clark et al.,
Prog. Med. Chem.,
23, 1 (1986)), only a small set of compounds have been reported that have a varied degree of selectivity among the three subtypes of &agr;
2
-AR. However, these latter compounds suffer from either low subtype selectivity or binding to receptor sites outside the &agr;
2
-AR subfamily (Ruffolo et al.,
J. Med. Chem.,
38, 3681 (1995; Yound et al,
Eur. J. Pharmacol.,
168, 381 (1989); Devedjian et al,
Eur. J. Pharmacol.,
252, 43 (1994); Meana et al.,
Eur. J. Pharmacol.,
312, 385 (1996); Beeley et al.,
Bioorg. Med. Chem.,
3, 1693 (1995); Michel et al.,
Br. J. Pharmacol.,
99, 560 (1990); Uhlen et al.,
Pharmacol. Exp. Ther.,
271, 1558 (1994); Blaxall et al.,
Pharmacol. Exp. Ther.,
259, 353 (1991); Bylund et al.,
Mol. Pharmacol.,
42, 1 (1992); Okumura et al,
Gen. Pharmacol.,
19, 463 (1988)). Thus, a need exists to identify compounds which bind &agr;
2
-AR subtypes with sufficient affinity and selectivity.
The present invention is directed to overcoming these and other problems encountered in the art.
SUMMARY OF THE INVENTION
The present invention relates to a compound according to formula (I):
wherein R is a linker molecule, preferably having a length of about 2.5 Å to about 45 Å.
The present invention also relates to a compound according to formula (I), wherein R (i.e., as a linker molecule) is a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof; wherein R (i.e., as a linker molecule) is a straight or branched chain alkyl, alkenyl, alkynyl comprising at least 2 carbon atoms in a main chain thereof and an X group within the main chain and/or a Y group as a substituent linked to a carbon atom in the main chain with X being —O—, carbonyl, —NR
1
— with R
1
being H or an alkyl, C(O)NHR
1
— with R
1
being an alkyl, —S—, sulfoxide, sulfonyl, or a cyclic or multicyclic ring with or without heteroatoms as ring members and including, optionally, one or more substitutions on the ring structure(s), and with Y being —OH, —NO
2
, —CN, —C(O)H, —SH, or a primary, secondary, or tertiary amine, a carboxylic acid, an ester, a keto group, —SO
2
NH
2
, or —SO
2
NHR
2
with R
2
being an alkyl; or wherein R (i.e., as a linker molecule) is a cyclic or multicyclic ring with or without hetero atoms as ring members and including, optionally, one or more substitutions on the ring structure(s).
The present invention also relates to a pharmaceutical compos
Miller Duane D.
Moore, II Bob M.
Mustafa Suni
Zheng Weiping
Aulakh Charanjit. S.
The University of Tennessee Research Foundation
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