Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-05-18
2002-11-26
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S306100
Reexamination Certificate
active
06486190
ABSTRACT:
TECHNICAL FIELD
The subject invention is directed to certain substituted benzimidazole compounds that have improved resistance to metabolism in primates. The subject compounds are alpha adrenoceptor agonists and are useful in treating alpha agonist associated disorders.
BACKGROUND OF THE INVENTION
Alpha adrenergic receptors, agonists, antagonists, and 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”,
European 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”,
J. Med. Chem.,
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”,
Br. J. Pharmac.,
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.
Alpha-2 adrenergic agonists are useful for treating a variety of disorders including: respiratory disorders (e.g., asthma, nasal congestion, COPD, cough, cystic fibrosis), gastrointestinal disorders (e.g., diahrrea, irritable bowel syndrome), ocular disorders (e.g., glaucoma), cardiovascular disorders (e.g., myocardial ischemia, shock, arrhythmias, angina, congestive heart failure), benign prostatic hypertrophy and migraine. However, many compounds disclosed in the art and related in structure to those of this invention are not alpha-2 adrenoceptor selective (e.g., they interact with other alpha receptors such as alpha-1 adrenoceptors). Alpha-2 adrenoceptor selectivity is desirable when treating alpha-2 associated or alpha-2 mediated disorders. For example, alpha-2 adrenergic agonists that possess significant alpha-1 adrenergic effects are known to cause cardiovascular side effects such as hypertension. In addition, many compounds disclosed in the art and related in structure to those of this invention possess significant central nervous system (CNS) activity which may lead to undesirable side effects such as severe sedation.
It has also been observed that some alpha adrenergic agonists are subject to extensive metabolic transformation in primates. Such metabolic transformation results in inactivation of the parent compound or in the formation of an active metabolite with a different pharmacological profile from the parent compound. Of particular importance to the present invention is the metabolic transformation that occurs to some alpha adrenergic benzimidazoles that are peripherally acting alpha-2-adrenoceptor selective agonists. Metabolic N-methylation at the benzimidazole ring may result in compounds that (1) are inactive; (2) are alpha-2 adrenoceptor antagonists; (3) possess enhanced activity at other undesired receptors, such as at alpha-1 adrenoceptors; and/or (4) have an increased potential for CNS activity. Thus, there is a continuing need for peripherally acting selective alpha-2 adrenergic compounds that have lower CNS activity and that resist metabolic transformation into undesirable compounds.
SUMMARY OF THE INVENTION
The present invention is directed to compounds having a structure according to the following formula:
wherein:
(a) R1 is alkyl;
(b) R2 is selected from the group consisting of: hydrogen, alkyl, methoxy, cyano, and halo;
(c) R3 is selected from the group consisting of: hydrogen, methyl, hydroxy, cyano and halo;
(d) R4 is selected from the group consisting of: hydrogen, methyl, ethyl and isopropyl;
(e) R5 is selected from the group consisting of: hydrogen, methyl, amino, methoxy, hydroxy, cyano and halo;
(f) provided that at least one of R2, R3, R4 or R5 is other than hydrogen or fluorine;
(g) provided that when R1 is methyl and both R2 and R5 are hydrogen, R3 is other than methyl or halo;
(h) provided that when R3 is cyano, R1 is methyl; and
any tautomer of the above structure or a pharmaceutically acceptable salt, or biohydrolyzable ester, amide, or imide thereof.
The compounds of the present invention are useful in treating many medical disorders, including for example, respiratory disorders, ocular disorders, gastrointestinal disorders, disorders associated with sympathetic nervous system activity, migraine, peripheral pain, and disorders where vasoconstriction would provide a benefit. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment using these compounds or the compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
Terms and Definitions
“Alkyl” is an unsubstituted saturated or unsaturated hydrocarbon chain having 1 to 3 carbon atoms. Alkyl chains may be straight, branched or cyclized. Preferred alkyl groups are methyl, ethyl, and cyclopropyl.
“Biohydrolyzable amide” refers to an amide of a compound of the invention that is readily converted in vivo by a subject to yield an active compound of the invention.
“Biohydrolyzable ester” refers to an ester of a compound of the invention that is readily converted by a subject to yield an active compound of the invention.
“Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodo. Preferred halo are chloro, bromo, and iodo. More preferred halo are chloro and bromo.
“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.
“Primate” includes humans.
Compounds
The present invention involves compounds having the following structure:
In the above structure, R1 is alkyl. Preferred R1 is methyl, ethyl or cyclopropyl.
In the above structure, R2 is hydrogen, alkyl, methoxy, cyano, or halo. Pre
Bogdan Sophie Eva
Cruze Charles Andrew III
Cupps Thomas Lee
Dobson Roy Lee
Gazda Michael
Kellerman James C.
Stockton Laura L.
The Procter & Gamble & Company
Upite David V.
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