Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-03-19
2004-03-16
Coleman, Brenda (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S377000, C548S190000, C548S193000, C548S234000
Reexamination Certificate
active
06706747
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to aliphatic bridged-cyclic compounds with 2-amino-imidazoline, 2-amino-oxazoline or 2-amino-thiazoline substituents. More particularly, the invention relates to such compounds which are selective in blocking the &agr;
2
adrenoreceptor. These compounds find use in the treatment of conditions which are responsive to regulation of &agr;
2
-receptor responses, such activities include, for example, treatment of depression, palliation of non insulin-dependent diabetes, alleviation of male impotence, lowering of intraocular pressure (which is useful in treating e.g. glaucoma) and stimulation of weight loss.
BACKGROUND OF THE INVENTION
Adrenergic agents, and particularly agents affective on &agr;
2
adrenergic receptors are known in the art. For example, U.S. Pat. No. 5,091,528 describes 6- or 7-(2-imino-2-imidazoline)-1,2-benzoxazine as a adrenergic agent. Published European patent application 0 251 453 describes certain cyclohexyl substituted amino-dihydro-oxazoles, -thiazoles and -imidazoles as &agr;
2
agents. U.S. Pat. No. 3,598,833 describes 2-cycloalkylamino oxazolines having local anesthetic, sedative, vasoconstrictor, mucous membrane de-swelling, blood pressure depressant and gastric fluid secretory inhibition effects. Further United States and foreign patents and scientific publications which pertain to substituted amino-oxazoline, imidazolines and thiazolines are as follows:
U.S. Pat. No. 4,587,257 [2-trisubstituted phenylimino) imidazoline compounds capable of controlling ocular bleeding];
U.S. Pat. No. 3,636,219 [2-(substituted-phenylamino)-thiazolines and imidazolines having anticholinergic activity];
U.S. Pat. No. 3,453,284 [2-substituted anilino)-2-oxazolines;
U.S. Pat. No. 3,432,600 [partially reduced 2-(naphthylamino) oxazolines and 2-(indanylamino) oxazolines;
U.S. Pat. No. 3,679,798 [compositions comprising arylaminooxazolines and an anticholinergic agent];
U.S. Pat. No. 3,624,092 [amino-oxazolines useful as central nervous system depressants];
U.S. Pat. No. 2,876,232 [2-(9-fluorenylamino)-oxazolines), and German Patent nos. 1,191,381 and 1,195,323 and European Patent Application no 87304019.0;
U.S. Pat. No. 4,515,800 [2-(trisubstituted phenylimino) imidazoline compounds, also known as 2-(trisubstituted-anilino)-1,3-diazacyclopentene-(2) compounds, for treatment of glaucoma];
U.S. Pat. No. 5,066,664 [2-(hydroxy-2-alkylphenylamino)-oxazolines and thiazolines as anti-glaucoma and vasoconstrictive agents].
Chapleo et al. journal of Medicinal Chemistry 1989, 32, 1627-30] describe heteroaromatic analogs of clonidine as partial agonists of &agr;
2
adrenoceptors.
Poos, et al. [Journal of Organic Chemistry, 1961, 26, 4898-904.] reported the syntheses of isomeric forms of 2-amino-3-phenylnorbornanes, and that the endo-phenyl-exo-amino compounds demonstrated a biphasic effect on blood pressure. U.S. Pat. No. 3,514,486 to Hartzler discloses making 3-isopropyl-2-norbornanamine and reports that they have useful antihypertensive activity.
Additionally, commonly assigned co-pending application Ser. Nos. 08/186,406 and 08/185,653 disclose alpha-substituted derivatives of aromatic 2-amino-imidazoles and methods of using the same as &agr;
2A
selective agonists.
The background of the division of adrenoceptors into differing categories can be briefly described as follows. Historically, adrenoceptors were first divided into &agr; and &bgr; subtypes by Ahlquist in 1948. This division was based on pharmacological characteristics. Later, &bgr;-adrenoceptors were subdivided into &bgr;
1
and &bgr;
2
subtypes, again based on a pharmacological definition by comparison of the relative potencies of 12 agonists. The &agr;-adrenoceptors were also subdivided into &agr;
1
and &agr;
2
subtypes, initially based on a presumed localization of &agr;
1
receptors postsynaptically and &agr;
2
presynaptically. Now, however, this physiologic division is no longer used and it is generally accepted that the most useful way to subdivide the a-adrenoceptors is based on pharmacology, using affinities for the a-antagonists yohimbine and prazosin. At &agr;
1
receptors, prazosin is more potent than yohimbine, whereas at &agr;
2
receptors, yohimbine is more potent than prazosin. More recently the &agr;
1
and &agr;
2
receptors have been further subdivided into subtypes such as &agr;
1A
, &agr;
1B
, &agr;
1C
, &agr;
2A
, &agr;
2B
and &agr;
2C
.
The term agonist refers to a class of compounds which bind with some affinity to and activate a particular type of receptor. Activation refers to what could be considered analogous to flipping on a switch, i.e. the receptor is induced to initiate some kind of action like a physiologic response or a chain of biochemical events. The term antagonist (or receptor blocker) refers to a class of compounds which bind to a receptor with some affinity, but are unable to activate the receptor to provide an effect. The antagonist can be compared to a key which is able to slide into a lock, but is unable to turn in the lock to open it.
Some examples of alpha
2
(&agr;
2
) adrenergic receptor blocking compounds known in the art are:
Idazoxan is classified as a selective &agr;
2
antagonist, and has been studied in combination with, tyrosine as an antidepressant and in combination with D
2
dopamine receptor antagonists as an antipsychotic agent. 1,2,3,4-tetrahydro-6-hydroxy-1-((N-methyl-amino)-methyl-N-phenylethyl)naphthalene hydrochloride (A-75169) lowers intraocular pressure in mammals.
The receptor affinity of candidate compounds can be determined by radioligand binding competition studies. Radioligand binding competition studies assess the affinity of a compound by measuring its ability to displace a radioligand of known affinity.
As described above, an agonist is defined as a compound that binds to and activates a receptor response. An antagonist binds to, but does not activate; a response by, the receptor. The measure of activation caused by a bound molecule is said to be its efficacy. Functional experiments are designed to determine whether, after binding, a test compound elicits a biochemical effect, or rather binds without causing the receptor to respond. An antagonist, if of sufficient binding affinity, can be used to block the binding of endogenous molecules in the body which activate a receptor, and thereby prevent its activation. Antagonists can find therapeutic use by blocking the binding of an oversupply of an endogenous receptor activator or the over expression of a receptor effect. Owing to the intricacy of the interactions between a given binding molecule and the conformation and function of the receptor itself, partial agonists and partial antagonists are also known in receptor pharmacology.
SUMMARY OF THE INVENTION
The present invention concerns novel compounds of the formula I,
in which: ring A is any of the five alternative multi-cyclic rings shown, X is nitrogen, oxygen or sulfur and R is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, or straight or branched chain alkenyl of 2 to 6 carbon atoms, a cycloaliphatic ring of 3 to 6 carbon atoms, phenyl optionally mono- or di-substituted with hydroxy, halogen, alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 2 carbon atoms, or methylenedioxyphenyl. In the drawing of chemical structures as shown above, the intersection of two or more lines indicates a carbon atom, a single line indicates a single bond, and a double line a double bond, and a dotted line adjacent a single line indicates either a single or double bond. The chemical nomenclature for the rings shown above from left to right in descending order is norbornane (or bicyclo[2.2.1]heptane); bornane (or 1,7,7-trimethyl-bicyclo[2.2.1]heptane); 7-oxa-bicyclo[2.2.1]heptane; bicyclo[2.2.2]octane and adamantane (or tricyclo[3.3.1.13,7]decane). The wavy lines across a bond indicate that the bond attaches to either the R or 2-amino-heterocyclic moieties.
Burke James A.
Garst Michael E.
Munk Stephen A.
Allergan Inc.
Baran Robert J.
Coleman Brenda
Fisher Carlos A.
Voet Martin A.
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