Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-04-13
2001-11-06
Vollano, Jean F. (Department: 1621)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S580000, C514S585000
Reexamination Certificate
active
06313172
ABSTRACT:
BACKGROUND OF THE INVENTION
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 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 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 was 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 February 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.
OBJECTS OF THE INVENTION
It is an object of the invention to provide compounds and compositions useful in treating disorders modulated by alpha-2 adrenoreceptors.
It is an object of this invention to provide novel compounds having substantial analgesic activity in the treatment of chronic pain, regardless of origin. Chronic pain may be, without limitation, visceral, inflammatory or neuropathic in origin. Such chronic pain may arise as a result of, or be attendant to, conditions including without limitation: arthritis, (including rheumatoid arthritis), spondylitis, gouty arthritis, osteoarthritis, juvenile arthritis, and autoimmune diseases including, without limitation, lupus erythematosus.
These compositions can also be used within the context of the treatment of chronic gastrointestinal inflammations, Crohn's disease, gastritis, irritable bowel disease (IBD) and ulcerative colitis; and in treatment of visceral pain, including pain caused by cancer or attendant to the treatment of cancer as, for example, by chemotherapy or radiation therapy.
These compositions can be used within the context of the treatment of other chronic pain symptoms, and especially in the treatment of chronic forms of neuropathic pain, in particular, without limitation, neuralgia, herpes, deafferentation pain, and diabetic neuropathies.
It is also an object of this invention to provide novel compounds for treating ocular disorders, such as ocular hypertension, glaucoma, hyperemia, conjunctivitis and uveitis.
It is also an object of this invention to provide novel compounds for treating the pain associated with substance abuse and/or withdrawal.
It is a still further object of this invention to provide such compounds which have good activity when delivered by peroral, parenteral, intranasal, ophthalmic, and/or topical dosing, or injection.
It is also an object of this invention to provide methods of treating pain through the therapeutic administration of the compounds disclosed herein.
It is further an object of the present invention to provide methods of treating conditions known to be susceptible to treatment through alpha 2 adrenergic receptors.
SUMMARY OF THE INVENTION
The present invention is directed to compounds having the formula:
wherein R
1
is F or H, R
2
is Cl or H, and R
3
is F or H; and wherein if R
1
is F then R
2
and R
3
are both H; and if R
1
is H then R
2
is Cl and R
3
is F, and alkyl esters thereof, and pharmaceutically acceptable salts of these compounds.
The invention is also directed to methods of treating pain, particularly chronic pain, through the administration of pharmaceutically effective amounts of compounds of the above structure.
Further, the invention is directed to methods of treating glaucoma through the administration of a pharmaceutically effective amount of these compounds.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention is directed to compounds of Formula 1:
wherein R
1
is F or H, R
2
is Cl or H, and R
3
is F or H; and wherein if R
1
is F then R
2
and R
3
are both H; and if R
1
is H then R
2
is Cl and R
3
is F, and alkyl esters thereof, and pharmaceutically acceptable salts of these compounds.
Preferred compounds corresponding to this structure are the following compound (hereinafter termed Formula 2):
and the following compound (hereinafter termed Formula 3):
and their alkyl esters, and pharmaceutically acceptable derivatives and/or salts of these compounds.
Applicants have discovered that these compounds activate &agr;
2
receptors, particularly &agr;
2B
receptors. Additionally, these compounds act as a highly effective analgesic, particularly in chro
Chow Ken
Fang Wenkui Ken
Garst Michael E.
Gil Daniel W.
Wheeler Larry A.
Allergan Sales Inc.
Baran Robert J.
Fisher Carlos A.
Voet Martin A.
Vollano Jean F.
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