Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-02-27
2003-03-18
O'Sullivan, Peter (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S548000, C514S580000, C560S193000, C560S251000, C564S017000
Reexamination Certificate
active
06534542
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to cycloalkyl, cycloalkenyl, cycloalkylmethyl and cycloalkenylmethyl (2-hydroxy)ethylthioureas and their use as specific or selective agonists of &agr;
2B
adrenergic receptors. More specifically the present invention relates to the above-noted compounds, pharmaceutical compositions containing these compounds as active ingredient for modulating the &agr;
2B
adrenergic receptors, and even more specifically for utilizing these compounds and pharmaceutical compositions to alleviate chronic pain and allodynia.
2. Background Art
Human adrenergic receptors are integral membrane proteins which have been classified into two broad classes, the alpha and the beta adrenergic receptors. Both types mediate the action of the peripheral sympathetic nervous system upon binding of catecholamines, norepinephrine and epinephrine.
Norepinephrine is produced by adrenergic nerve endings, while epinephrine is produced by the adrenal medulla. The binding affinity of adrenergic receptors for these compounds forms one basis of the classification: alpha receptors tend to bind norepinephrine more strongly than epinephrine and much more strongly than the synthetic compound isoproterenol. The preferred binding affinity of these hormones is reversed for the beta receptors. In many tissues, the functional responses, such as smooth muscle contraction, induced by alpha receptor activation are opposed to responses induced by beta receptor binding.
Subsequently, the functional distinction between alpha and beta receptors was further highlighted and refined by the pharmacological characterization of these receptors from various animal and tissue sources. As a result, alpha and beta adrenergic receptors were further subdivided into &agr;
1
, &agr;
2
, &bgr;
1
, and &bgr;
2
subtypes. Functional differences between &agr;
1
and &agr;
2
receptors have been recognized, and compounds which exhibit selective binding between these two subtypes have been developed. Thus, in published international patent application WO 92/0073, the selective ability of the R(+) enantiomer of terazosin to selectively bind to adrenergic receptors of the &agr;
1
subtype was reported. The &agr;
1
/&agr;
2
selectivity of this compound was disclosed as being significant because agonist stimulation of the &agr;
2
receptors was said to inhibit secretion of epinephrine and norepinephrine, while antagonism of the &agr;
2
receptor was said to increase secretion of these hormones. Thus, the use of non-selective alpha-adrenergic blockers, such as phenoxybenzamine and phentolamine, was said to be limited by their &agr;
2
adrenergic receptor mediated induction of increased plasma catecholamine concentration and the attendant physiological sequelae (increased heart rate and smooth muscle contraction). For a further general background on the &agr;-adrenergic receptors, the reader's attention is directed to Robert R. Ruffolo, Jr., &agr;-Adrenoreceptors: Molecular Biology, Biochemistry and Pharmacology., (Progress in Basic and Clinical Pharmacology series, Karger, 1991), wherein the basis of &agr;
1
/&agr;
2
subclassification, the molecular biology, signal transduction, agonist structure-activity relationships, receptor functions, and therapeutic applications for compounds exhibiting &agr;-adrenergic receptor affinity is explored.
The cloning, sequencing and expression of alpha receptor subtypes from animal tissues has led to the subclassification of the &agr;
1
adrenoreceptors into (&agr;
1A
, &agr;
1B
, and &agr;
1D
. Similarly, the &agr;
2
adrenoreceptors have also been classified &agr;
2A
, &agr;
2B
, and &agr;
2C
receptors. Each &agr;
2
receptor subtype appears to exhibit its own pharmacological and tissue specificities. Compounds having a degree of specificity for one or more of these subtypes may be more specific therapeutic agents for a given indication than an &agr;
2
receptor pan-agonist (such as the drug clonidine) or a pan-antagonist.
Among other indications, such as the treatment of glaucoma, hypertension, sexual dysfunction, and depression, certain compounds having alpha 2 adrenergic receptor agonist activity are known analgesics. However, many compounds having such activity do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoreceptors. For example, many compounds found to be effective agents in the treatment of pain are frequently found to have undesirable side effects, such as causing hypotension and sedation at systemically effective doses. There is a need for new drugs that provide relief from pain without causing these undesirable side effects. Additionally, there is a need for agents which display activity against pain, particularly chronic pain, such as chronic neuropathic and visceral pain.
British Patent 1 499 485, published Feb. 1, 1978 describes certain thiocarbamide derivatives; some of these are said to be useful in the treatment of conditions such as hypertension, depression or pain.
Certain presently pending applications for patent owned by the the assignee as the present application describe phenylmethyl-(2hydroxy)ethylthioureas which have no significant cardiovascular or sedative effects and are useful for alleviating chronic pain and allodynia.
SUMMARY OF THE INVENTION
The present invention is directed to compounds having formula (i) and formula (ii)
wherein the dotted line represents a bond, or absence of a bond with the provisos that only one dotted line represents a bond in the ring of formula (i) or of formula (ii);
R
1
is H, or is absent when the carbon bearing the R
1
is double bonded;
R
2
is H, alkyl of 1 to 4 carbons, alkenyl of 2 to 4 carbons, alkynyl of 2 to 4 carbons; OH, O-alkyl where the alkyl group has 1 to 4 carbons, OCOR
4
where R
4
is alkyl of 1 to 4 carbons, F, Cl, Br or I;
m is an integer having the values of 1,2 or 3 with the proviso that when the compound is in accordance with formula (i) and m is 2 then the dotted line designated &ggr; represents absence of a bond, and
R
3
is H, or R
4
CO, with the further provisos that when the compound is in accordance with formula (ii) then R
2
is not OH, and when the compound is in accordance with formula (ii) and m is 1 then at least one R
2
of the five-membered ring is not H.
In a second aspect the present invention is directed to pharmaceutical compositions containing as the active ingredient one or more compounds of formula (i) or of formula (ii), the compositions being utilized as medicaments in mammals, including humans, for treatment of diseases and or alleviations of conditions which are responsive to treatment by agonists of &agr;
2B
adrenergic receptors. The compositions containing the compounds of the invention are primarily, but not exclusively, used for alleviation of chronic pain and/or allodynia. The compounds have the advantageous property that they are specific or selective to &agr;
2B
and/or &agr;
2C
adrenergic receptors in preference over &agr;
2A
adrenergic receptors, and as such have no or only minimal cardivascular and/or sedatory activity.
REFERENCES:
patent: 2161772 (1939-06-01), Carswell
patent: 3686303 (1972-08-01), Knowles
patent: 6313172 (2001-11-01), Chow et al.
patent: 1499485 (1978-02-01), None
patent: 92/0073 (1992-01-01), None
patent: WO-01-00586 (2001-01-01), None
L'abbe et al., Tetrahedron (1992), 48, pp. 7505-7518.
Messier et al., Pharmacol. Toxicol.(1995), 76, pp. 308-311.
Conklin et al., Nature (1993), 363, pp. 274-276.
Dirig, D.M. et al., J. Neurosci. Methods (1997), 76, pp. 183-191.
Hargreaves, K. et al., Pain (1988), 32, pp. 77-88.
Dixon, W.J., Ann. Rev. Pharmacol. Toxicol. (1980), 20, pp. 441-462.
Reiter, J. et al., Eur. J. Med. Chem.—Chimica Therapeutica, (Jan.-Feb. 1980), 15, pp. 41-53.
Chow Ken
Fang Wenkui Ken
Garst Michael E.
Gil Daniel W.
Allergen Sales, Inc.
Fisher Carlos A.
O'Sullivan Peter
Szekeres Gabor L.
Voet Martin A.
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