Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-05
2001-12-11
Higel, Floyd D. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S249000, C514S255030, C514S370000, C514S377000, C514S392000, C514S397000, C514S401000, C514S413000, C514S415000, C514S816000, C514S913000, C514S230800
Reexamination Certificate
active
06329369
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method of treating glaucoma or elevated intraocular pressure and other diseases with substantially reduced cardiovascular or sedative side effects by administering to mammals including humans, compounds which are selective agonists of the &agr;2B alone or &agr;2B and &agr;2C adrenergic receptor subtypes and which lack substantial activity at the &agr;2A receptor subtype. The present invention is also directed to novel compounds and pharmaceutical compositions adapted for administering said compounds to mammals, including humans.
BRIEF DESCRIPTION OF THE PRIOR ART
Compounds which have adrenergic activity are well known in the art, and are described innumerous United States and foreign patents and in scientific publications. It is generally known and accepted in the art that adrenergic activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having an adrenergic compound or compounds as the active ingredient are useful for treating glaucoma, chronic pain, nasal congestion, high blood pressure, congestive heart failure and inducing anesthesia.
The two main families of adrenergic receptor are termed alpha adrenergic receptors and beta adrenergic receptors in the art, and each of these two families is known to have subtypes, which are designated by letters of the alphabet, such as &agr;2A, &agr;2B. See the article by Bylund et al,
Pharmacol Rev.
46, pp. 121-136(1994).
SUMMARY OF THE INVENTION
It has been discovered in accordance with the present invention that adrenergic compounds which act selectively, and preferably even specifically as agonists of the &agr;2B or &agr;2B/&agr;2C (hereinafter referred to as &agr;2B or &agr;2B/2C) receptor subtypes in preference over the &agr;2A receptor subtype, possess desirable therapeutic properties associated with adrenergics but without having one or more undesirable side effects such as changes in blood pressure or sedation. For the purposes of the present invention, a compound is defined to be a specific or at least selective agonist of the &agr;2B or &agr;2B/2C receptor subtype(s) if the compound is at least approximately ten times more potent as an agonist at either the &agr;2B and &agr;2C or both receptor subtypes than at the &agr;2A receptor subtype, or if the difference in the compound's efficacy at the &agr;2B and &agr;2B/2C receptor relative to the &agr;2A receptor is greater than 0.3 and its efficacy at the &agr;2A receptor is ≦0.4.
Accordingly, the present invention relates to methods of treating animals of the mammalian species, including humans, with a pharmaceutical composition comprising one or more specific or selective &agr;2B or &agr;2B/2C adrenergic agonist compounds as the active ingredient, for treatment of the many diseases or conditions against which alpha adrenergic compounds are useful, including without limitation glaucoma, reducing elevated intraocular pressure, chronic pain, diarrhea, and nasal congestion. In addition, the compounds of this invention are useful for treating muscle spasticity including hyperactive micturition, diarrhea, diuresis, withdrawal syndromes, pain including neuropathic pain, neurodegenerative diseases including optic neuropathy, spinal ischemia and stroke, memory and cognition deficits, attention deficit disorder, psychoses including manic disorders, anxiety, depression, hypertension, congestive heart failure, cardiac ischemia and nasal congestion.
The present invention is also directed to the pharmaceutical compositions used in the above-noted methods of treatment.
The present invention particularly covers methods for treating diseases and conditions where adrenergic compounds are effective for treatment, but their use is limited because of their generally known side effects.
DETAILED DESCRIPTION OF THE INVENTION
Compounds which are used in the pharmaceutical compositions and methods of treatment of the present invention are selective or specific agonists of the &agr;2B or &agr;2B/2C adrenergic receptor subtypes, in preference over the &agr;2A receptor subtype. In accordance with the present invention, a compound is considered a selective &agr;2B or &agr;2B/2C agonist if that compound's difference in efficacy as an agonist of the &agr;2B or &agr;2B/2C receptor subtype(s) compared to the &agr;2A receptor subtype is greater than 0.3 and its efficacy at the &agr;2A receptor subtype is ≦0.4 and/or it is at least approximately 10 times more potent. Preferably, the compounds utilized in accordance with the present invention are specific agonists of the &agr;2B or &agr;2B/2C receptor subtypes. Specifically, in this regard, a specific agonist is defined in the sense that a specific a adrenergic agonist does not act as an agonist of the &agr;2A receptor subtype to any measurable or biologically significant extent.
A set of agents has been discovered that are functionally selective for the &agr;2B or &agr;2B/2C—subtypes of said adrenergic receptors. This preferential activity can be determined in a variety of functional assays such as Cyclic AMP Production, Shimizu et al,
J. Neurochem.
16, pp. 1609-1619 (1969); R-SAT (Receptor Selection and Amplification Technology), Messier et al,
Pharmacol. Toxicol.
76, pp. 308-311(1995) and the Cytosensor microphysiometer, Neve et al,
J. Biol. Chem.
267, pp. 25748-25753, (1992) using cells that naturally express individual subtypes or have had one of the subtypes introduced. The cells or recombinant receptors used should be human or from a species that has been shown to have a similar pharmacology. In the study below, the RSAT assay on cells that have been transiently transfected with the human &agr;2A (c10 gene), rat &agr;2B (RNG gene) and human &agr;2C (c4 gene) receptors was used. The rat &agr;2B receptor has been shown to have a pharmacology that corresponds to the human &agr;2B receptor (see, for example, Bylund et al.,
Pharmocol, Rev.
46, pp. 127-129(1994)).
In the treatment of glaucoma, particularly, topical administration may be used. Any common topical formulation such as a solution, suspension, gel, ointment, or salve and the like may be applied to the eye in glaucoma and dermally to treat other indications. Preparation of such topical formulations are well described in the art of pharmaceutical formulations as exemplified, for example, by Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa.
If the drug is to be administered systemically, it may be confected as a powder, pill, tablet or the like or as a syrup or elixir for oral administration. For intravenous, intraperitoneal, intrathecal or epidural administration, the compound will be prepared as a solution or suspension capable of being administered by injection. In certain cases, it may be useful to formulate these compounds in suppository or as an extended release formulation, including the dermal patch form, for deposit on or under the skin or for intramuscular injection.
Treatment of glaucoma or any other indications known or discovered to be susceptible to treatment by adrenergic compounds will be effected by administration of therapeutically effective dose of one or more compounds in accordance with the instant invention. A therapeutic concentration will be that concentration which effects reduction of the particular condition, or retards its expansion. In certain instances, the drug potentially could be used in a prophylactic manner to prevent onset of a particular condition. A given therapeutic concentration will vary from condition to condition and in certain instances may vary with the severity of the condition being treated and the patient's susceptibility to treatment. Accordingly, a given therapeutic concentration will be best determined at the time and place through routine experimentation. However, it is anticipated that in the treatment of, for example, gla
Burke James A.
Chow Ken
Garst Michael E.
Gil Daniel W.
Harcourt Dale A.
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Higel Floyd D.
Voet Martin A.
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