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United States Patent (19) 11 Patent Number: 6,117,871 Maurer Et Al

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United States Patent (19) 11 Patent Number: 6,117,871 Maurer Et Al USOO611 7871A United States Patent (19) 11 Patent Number: 6,117,871 Maurer et al. (45) Date of Patent: Sep. 12, 2000 54 6-(2-IMIDAZOLINYLAMINO)QUINOXALINE Attorney, Agent, or Firm-Cynthia M. Bott; James C. COMPOUNDS USEFUL AS ALPHA-2 Kellerman; David L. Suter ADRENOCEPTORAGONSTS 57 ABSTRACT 75 Inventors: Peter J. Maurer, Cincinnati; Raymond The Subject invention relates to methods of treating alpha-2 T. Henry, Pleasant Plain; Russell ade no receptor modulated disorders, comprising James Sheldon, Fairfield, all of Ohio administration, to a mammal in need of Such treatment, of a 73 Assignee: The Procter & Gamble Company, Safe and effective amount of a compound having the fol Cincinnati, Ohio lowing Structure: 21 Appl. No.: 08/755,941 22 Filed: Nov. 25, 1996 Related U.S. Application Data 63 Continuation-in-part of application No. 08/496,707, Jun. 29, 1995, abandoned, which is a continuation-in-part of appli R cation No. 08/169,785, Dec. 17, 1993, abandoned. (51) Int. Cl." ..................................................... A61K 31/50 wherein: 52 U.S. Cl. .............................................................. 514/249 (a) R is unsubstituted C-C alkanyl or alkenyl; and 58 Field of Search ............................................... 514/249 (b) R' is selected from hydrogen; unsubstituted C-C, alkanyl or alkenyl; unsubstituted C-C alkylthio or 56) References Cited alkoxy; hydroxy; thiol, and halo. PUBLICATIONS The Subject invention also relates compounds and compo Sitions for preventing or treating of disorderS modulated by Chemical Abstracts 119 (23):249974X (1992). Gluchowski alpha-2 adrenoreceptors. et al. Primary Examiner Zohreh Fay 18 Claims, No Drawings 6,117,871 1 2 6-(2-IMIDAZOLINYLAMINO)QUINOXALINE related in structure to those of this invention do not provide COMPOUNDS USEFULAS ALPHA-2 the activity and Specificity desirable when treating disorders ADRENOCEPTORAGONSTS modulated by alpha-2 adrenoreceptors. For example, many compounds found to be effective nasal This is a continuation-in-part of application Ser. No. 5 decongestants are frequently found to have undesirable side 08/496,707, filed on Jun. 29, 1995, now abandoned which is effects, Such as causing hypertension and insomnia at effec a continuation-in-part of application Ser. No. 08/169,785, tive doses, particularly when administered Systemically. filed on Dec. 3, 1993 now abandoned. There is a need for new drugs which provide relief from nasal congestion without causing these undesirable side TECHNICAL FIELD 1O effects. The subject invention relates to certain substituted 6-(2- imidazolinylamino)quinoxaline compounds. The com OBJECTS OF THE INVENTION pounds have been found to be alpha-2 adrenoceptor agonists It is an object of the invention to provide compounds and and are useful for treatment of disorders modulated by compositions useful in treating disorderS modulated by alpha-2 adrenoreceptors. 15 alpha-2 adrenoreceptors. It is an object of this invention to provide novel com BACKGROUND OF THE INVENTION pounds having Substantial activity in preventing or treating Therapeutic indications of alpha-2 adrenoreceptor ago nasal congestion, without undesired Side effects. nists have been discussed in the literature: Ruffolo, R. R., A. It is also an object of this invention to provide novel J. Nichols, J. M. Stadel, & J. P. Hieble, “Pharmacologic and compounds for treating cough, chronic obstructive pulmo Therapeutic Applications of Alpha-2. Adrenoceptor nary disease (COPD) and/or asthma. Subtypes”, Annual Review of Pharmacology & Toxicology It is also an object of this invention to provide novel (1993) Vol. 32 pp. 243–279". compounds for treating diseases and disorders associated Information regarding alpha adrenergic receptors, ago 25 with Sympathetic nervous System activity, including benign nists and antagonists, in general, and regarding compounds prostatic hypertrophy, cardiovascular disorders comprising related in Structure to those of this invention are disclosed in myocardial ischemia, cardiac reperfusion injury, angina, the following references: Timmermans, P. B. M. W. M., A. cardiac arrhythmia, heart failure and hypertension. T. Chiu & M. J. M. C. Thoolen, “12.1 O-Adrenergic It is also an object of this invention to provide novel Receptors”, Comprehensive Medicinal Chemistry, Vol. 3, compounds for treating ocular disorders, Such as ocular Membranes & Receptors, P. G. Sammes & J. B. Taylor, eds., hypertension, glaucoma, hyperemia, conjunctivitis and uvei Pergamon Press (1990), pp. 133–185; Timmermans, P. B. M. tis. W. M. & P. A. Van Zwieten, "O-Adrenoceptor Agonists and It is also an object of this invention to provide novel Antagonists”, Drugs of the Future, Vol. 9, No. 1, (January, compounds for treating gastrointestinal disorders, Such as 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. 35 diarrhea, irritable bowel Syndrome, hyperchlorhydria and L. Awouters & C. J. E. Niemegeers, “Further Validation of peptic ulcer, by antimotility and antisecretory actions on the in vivo and in vitro Pharmacological Procedures for Assess gastrointestinal tract. ing the C. and C-Selectivity of Test Compounds: (2) It is also an object of this invention to provide novel C.-Adrenoceptor Agonists”, European Journal Of compounds for treating migraine. Pharmacology, Vol. 129 (1986), pp. 57–64; Timmermans, P. 40 B. M. W. M., A. de Jonge, M.J. M. C. Thoolen, B. Wilffert, It is also an object of this invention to provide novel H. Batink & P. A. van Zwieten, “Quantitative Relationships compounds for treating pain, Substance abuse and/or with between C.-Adrenergic Activity and Binding Affinity of drawal. It is a still further object of this invention to provide C-Adrenoceptor Agonists and Antagonists”, Journal of Such compounds which have good activity from peroral, Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van 45 parenteral and/or topical dosing. Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans & SUMMARY OF THE INVENTION P. A. van Zwieten, “Selectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2. Adrenoceptors The Subject invention relates to methods of treating nasal in the Normotensive Rat', The Journal of Pharmacology or preventive alpha-2 modulated disorders, comprising and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 50 administration, to a mammal in need of Such treatment, of a 760–767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Safe and effective amount of a compound having the fol Myers, C. F. C. Smith & M. R. Stillings, “Effect of 1,4- lowing Structure: Dioxanyl Substitution on the Adrenergic Activity of Some Standard C-Adrenoreceptor Agents”, European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619–622; Chapleo, 55 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 C-Adrenoreceptor Par tial Agonist Clonidine”, Journal of Medicinal Chemistry, Vol. 32 (1989), pp. 1627–1630; Clare, K. A., M. C. Scrutton 60 R & N. T. Thompson, “Effects of O-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Platelets”, British wherein: Journal of Pharmacology, Vol. 82 (1984), pp. 467-476; U.S. (a) R is unsubstituted C-C alkanyl or alkenyl; and Pat. No. 3,890,319 issued to Danielewicz, Snarey & Thomas 65 (b) R' is selected from hydrogen; unsubstituted C-C, on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to alkanyl or alkenyl; unsubstituted C-C alkylthio or Gluchowski on Feb. 25, 1992. However, many compounds alkoxy; hydroxy; thiol, and halo. 6,117,871 3 4 DETAILED DESCRIPTION OF THE Compounds INVENTION The Subject invention involves compounds having the AS used herein, "alkanyl' means a Saturated hydrocarbon following Structures: Substituent, Straight or branched chain, unsubstituted or Substituted. AS used herein, “alkenyl' means a hydrocarbon Substitu ent with one double bond, 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 15 In the above structure, R is unsubstituted alkanyl or known in the art, as described in World Patent Publication alkenyl having from 1 to about 3 carbon atoms. R is 87/05297, Johnston et al., published Sep. 11, 1987 preferably alkanyl. R is more preferably methyl or ethyl, (incorporated by reference herein). Preferred cationic Salts most preferably methyl. include the alkali metal Salts (such as Sodium and In the above Structure, R is Selected from hydrogen; potassium), and alkaline earth metal Salts (Such as magne unsubstituted alkanyl or alkenyl having from 1 to about 3 sium and calcium) and organic salts. Preferred anionic Salts carbon atoms, unsubstituted alkylthio or alkoxy having from include the halides (Such as chloride Salts). “Biohydrolyzable amide” refers to an amide of the com 1 to about 3 carbon atoms; hydroxy; thiol; and halo. R' is pound of the invention that is readily converted in vivo by preferably hydrogen. R' is also preferably alkanyl, more a mammal Subject to yield an active compound of the preferably methyl or ethyl, most preferably methyl. R' which invention. 25 is alkylthio or alkoxy is preferably Saturated, also preferably A “biohydrolyzable ester” refers to an ester of the com C or C, more preferably methylthio or methoxy. R' which pound of the invention that is readily converted by an animal is halo is preferably chloro or bromo, more preferably to yield an active compound of the invention. chloro. “Optical isomer”, “stereoisomer”, “enantiomer,” Preferred compounds of the Subject invention are com "diastereomer,” as referred to herein have the standard art pounds having the following Structure: recognized meanings (Cf., Hawley's Condensed Chemical Dictionary, 11th Ed.).
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