Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-09-24
2002-07-23
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S313000, C514S314000
Reexamination Certificate
active
06423724
ABSTRACT:
TECHNICAL FIELD
The subject invention relates to certain substituted 7-(2-imidazolinylamino)quinoline compounds. The compounds have been found to be alpha-2 adrenoceptor agonists and are useful for treatment of disorders modulated by alpha-2 adrenoceptors.
BACKGROUND OF THE INVENTION
Therapeutic indications of alpha-2 adrenoceptor agonists have been discussed in the literature: Ruffolo, R. R., A. J. Nichols, J. M. Stadel, & J. P. Hieble, “Pharmacologic and Therapeutic Applications of Alpha-2 Adrenoceptor Subtypes”,
Annual Review of Pharmacology & Toxicology
. Vol. 32 (1993) pp. 243-279.
Information regarding alpha adrenergic receptors, agonists and antagonists, in general, and regarding compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu & M. J. M. C. Thoolen, “12.1 &agr;-Adrenergic Receptors”,
Comprehensive Medicinal Chemistry
, Vol. 3, Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. & P. A. van Zwieten,“&agr;-Adrenoceptor Agonists and Antagonists”,
Drugs of the Future
, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters & C. J. E. Niemegeers, “Further Validation of in vivo and in vitro Pharmacological Procedures for Assessing the &agr;
1
and &agr;
2
-Selectivity of Test Compounds: (2) &agr;-Adrenoceptor Agonists”,
European Journal of Pharmacology
, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink & P. A. van Zwieten, “Quantitative Relationships between &agr;-Adrenergic Activity and Binding Affinity of &agr;-Adrenoceptor Agonists and Antagonists”,
Journal of Medicinal Chemistry
, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & P. A. van Zwieten, “Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Rat”,
The Journal of Pharmacology and Experimental Therapeutics
, Vol. 219, No. 3 (1981), pp. 760-767;. Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith & M. R. Stillings, “Effect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard &agr;-Adrenoreceptor Agents”,
Eurogean Journal of Medicinal Chemistry
, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings & I. F. Tulloch, “Heteroaromatic Analogues of the &agr;
2
-Adrenoreceptor Partial Agonist Clonidine”,
Journal of Medicinal Chemistry
, Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton & N. T. Thompson, “Effects of &agr;
2
-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets”,
British Journal of Pharmacology
, Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey & Thomas on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992. However, many compounds related in structure to those of this invention do not provide the activity and specificity desirable when treating disorders modulated by alpha-2 adrenoceptors.
For example, many compounds found to be effective nasal decongestants are frequently found to have undesirable side effects, such as causing hypertension and insomnia at systemically effective doses. There is a need for new drugs which provide relief from nasal congestion without causing these undesirable side effects.
OBJECTS OF THE INVENTION
It is an object of the invention to provide compounds and compositions useful in treating disorders modulated by alpha-2 adrenoceptors.
It is an object of this invention to provide novel compounds having substantial activity in preventing or treating nasal congestion, otitis media, and sinusitis, without undesired side effects.
It is also an object of this invention to provide novel compounds for treating cough, chronic obstructive pulmonary disease (COPD) and/or asthma.
It is also an object of this invention to provide novel compounds for treating diseases and disorders associated with sympathetic nervous system activity, including benign prostatic hypertrophy, cardiovascular disorders comprising myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and hypertension.
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 gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, hyperchlorhydria (hyperacidity) and peptic ulcer (ulcer).
It is also an object of this invention to provide novel compounds for treating migraine.
It is also an object of this invention to provide novel compounds for treating pain, substance abuse and/or withdrawal.
It is a still further object of this invention to provide such compounds which have good activity from peroral, parenteral, intranasal and/or topical dosing.
SUMMARY OF THE INVENTION
The subject invention relates to methods of preventing or treating disorders modulated by alpha-2 adrenoceptors, comprising administration, to a mammal in need of such treatment, of a safe and effective amount of a compound having the following structure:
wherein:
(a) R is unsubstituted C
1
-C
3
alkanyl or alkenyl; cycloalkanyl; cycloalkenyl; and
(b) R′ is selected from hydrogen; unsubstituted C
1
-C
3
alkanyl or alkenyl; unsubstituted C
1
-C
3
alkylthio or alkoxy; hydroxy; thiol; cyano; and halo.
The subject invention also relates to novel compounds having the above structure wherein R′ is hydrogen or cyano.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, “alkanyl” means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted.
As used herein, “alkenyl” means a hydrocarbon substituent with one double bond (otherwise saturated), straight or branched chain, unsubstituted or substituted.
As used herein, “alkylthio” means a substituent having the structure Q—S—, where Q is alkanyl or alkenyl.
As used herein, “alkoxy” means a substituent having the structure Q—O—, where Q is alkanyl or alkenyl.
A “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987, incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center, where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts.
The compounds of the invention are sufficiently basic to form acid-addition salts. The compounds are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are in some cases a more convenient form for use. In practice, the use of the salt form inherently amounts to the use of the base form of the active. Acids used to prepare acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts. These salts have anions that are relatively innocuous to the animal organism, such as a mammal, in medicinal doses of the salts so that the beneficial property inherent in the free base are not vitiated by any side effects ascribable to the acid's anions.
Examples of appropriate acid-addition salts include, but at not limited to hydrochloride, hydrobromide, hydroiodiode, sulfate, hydroge
Bogdan Sophie E.
Cupps Thomas Lee
Henry Raymond T.
Sheldon Russell James
Fay Zohreh
Roof Carl J.
The Procter & Gamble & Company
Upite David V.
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