(12) Patent Application Publication (10) Pub. No.: US 2005/0250772 A1 Shelby Et Al
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US 2005O250772A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0250772 A1 Shelby et al. (43) Pub. Date: Nov. 10, 2005 (54) METHODS FOR INDUCING ANTI-ANXIETY (60) Provisional application No. 60/587,167, filed on Jul. AND CALMING EFFECTS IN ANIMALS AND 12, 2004. Provisional application No. 60/196.829, HUMANS filed on Apr. 13, 2000. (76) Inventors: Nancy J. Shelby, Park City, UT (US); Publication Classification Mitchell T. Godfrey, Townsend, MT (US); Mark J. Rosenfeld, Draper, UT (51) Int. Cl." ...................... A61K 31/538; A61K 31/423 (US) (52) U.S. Cl. ......................................... 514/230.5; 514/375 Correspondence Address: (57) ABSTRACT PATE PERCE & BARD Phenolic compounds with a phenolic molecule to which are 215 SOUTH STATE STREET, SUITE 550 covalently linked an oxygen-containing group, a nitrogen or PARKSIDE TOWER another oxygen containing group, and a C-C alkoxy group, SALT LAKE CITY, UT 84111 (US) or their precursor compounds, obtainable from monocoty ledonous plants, or by chemical Synthesis, have been found (21) Appl. No.: 11/178,998 to calm and/or reduce anxiety and related behaviors and (22) Filed: Jul. 11, 2005 States in humans and animals. Additional chemical com pounds of the present invention may include benzoxazi Related U.S. Application Data noids-cyclic hydroxyamic acids, lactams, and corresponding glucosides, which may serve as precursors to phenolic (63) Continuation-in-part of application No. 10/845,388, compounds. The phenolic compounds and precursors of filed on May 13, 2004. phenolic compounds of the present invention, at concentra Continuation-in-part of application No. 10/718,232, tions Suitable for human and animal therapeutic use, may be filed on Nov. 20, 2003, which is a continuation-in-part obtained from monocotyledonous plants Such as corn in of application No. 09/834,592, filed on Apr. 13, 2001, their early growth states which are timely harvested for now Pat. No. 6,667,308. optimum yield. Patent Application Publication Nov. 10, 2005 Sheet 1 of 4 US 2005/0250772 A1 Preservation of immune response to DNFB (ear swelling) in stressed Balb/c mice exposed to novel compounds of the present invention U t E E F.G. 1 Patent Application Publication Nov. 10, 2005 Sheet 2 of 4 US 2005/0250772 A1 Immune response (earswelling) to DNFB in stressed Bab/c mice exposed to novel compounds of the present invention FIG. 2 Patent Application Publication Nov. 10, 2005 Sheet 3 of 4 US 2005/0250772 A1 Immune response (earswelling) to DNFB in stressed calves exposed to novel compounds of the present invention U O 8 9 0.6 E E O. 4 FIG. 3 Patent Application Publication Nov. 10, 2005 Sheet 4 of 4 US 2005/0250772 A1 Immune response (neck swelling) to DNFB in stressed caves exposed to novel compounds of the present invention FIG. 4 US 2005/0250772 A1 Nov. 10, 2005 METHODS FOR INDUCING ANT-ANXIETY AND when treated with antidepressants, many do not respond to CALMING EFFECTS IN ANIMALS AND HUMANS the first antidepressant prescribed. Such individuals or ani mals may eventually benefit from a different antidepressant RELATED APPLICATIONS or, if Sufficiently efficacious, a combination of Suitable antidepressants. 0001) This application claims the benefit of U.S. Patent Application Ser. No. 60/587,167, filed Jul. 12, 2004, and 0007 Sexual dysfunction is another pervasive disorder. entitled “METHODS FOR INDUCING ANTI-ANXIETY In the overall population, it is believed that forty-three AND CALMING EFFECTS IN ANIMALS AND percent (43%) of women and thirty-one percent (31%) of HUMANS,” and is a continuation-in-part of U.S. patent men between the ages of 18 and 59 experience Sexual application Ser. No. 10/845,388, filed May 13, 2004, and dysfunction and Some repeatedly. AS will be appreciated, entitled “METHODS FOR AUGMENTING IMMUNE Sexual dysfunction may include, for example, a lack of DEFENSES CONTEMPLATING THE ADMINISTRA interest in SeX, problems with arousal, not enjoying Sex, and TION OF PHENOLIC AND INDOLEAMINE-LIKE COM anxiety associated with Sexual performance. Indeed, feeling POUNDS FOR USE IN ANIMALS AND HUMANS and good in general has been found to have a significant impact U.S. patent application Ser. No. 10/718,232, filed Nov. 20, on Sexual function. In this regard, those people who are 2003, and entitled “NOVEL COMPOUNDS FOR USE IN unhappy or depressed may be more likely to experience WEIGHT LOSS AND APPETITE SUPPRESSION 1N difficulties associated with Sexual dysfunction. Arousal HUMANS,” which claim the benefit of U.S. patent appli problems affect over 20 million American males (i.e., about cation Ser. No. 09/834,592, filed Apr. 13, 2001, and entitled 2 in 10 adult men), with such difficulties often associated “NOVEL COMPOUNDS FOR USE AS ANTIDEPRES with or accompanied by Some Sort of depression or mood SANTS, APHRODISIACS, AND ADJUNCTIVE THERA disorder. Meanwhile, prescription antidepressants have been PIES 1N HUMANS, now issued as U.S. Pat. No. 6,667, found to actually exacerbate the Situation, Since a frequent 308, which claims the benefit of U.S. provisional application Side effect of their use is Sexual dysfunction. In fact, Sexual Ser. No. 60/196.829, filed Apr. 13, 2000, and entitled response may actually diminish in up to Seventy-five percent “ANTIDEPRESSANT, APHRODISIAC, WEIGHT-LOSS (75%) of prescription antidepressant users for using the AIDE, THERAPY FOR QUITTING NICOTINE OR Same. To this end, there is a need for forms of treatment that ADDICTIVE DRUGS AND TREATMENT OF BETTER reduce depression or otherwise better mood with an accom ING REPRODUCTION 1N HUMANS, all of which are panying enhancement of Sexual response, arousal or desire hereby incorporated herein by reference. or, in the alternative, do not have a negative impact on a perSon's or animal's Sexual function. BACKGROUND 0008 Prior work by those skilled in the art in connection with the compounds of the present invention have been 0002) 1. Field of the Invention primarily focused on 6-methoxy-2,3-benzoxazolinone 0003. This invention relates to compositions for calming (6-MBOA). For example, the role of 6-MBOA in strength and reducing anxiety in humans and animals and, more ening the resistance of monocotyledonous plants against a particularly, to novel compositions of phenolic and wide range of insect pests has been much Studied. It has been indoleamine-like compounds obtainable in concentrations further proven that 6-MBOA and its chemical precursors and amounts Suitable for animal and human use derived, may also have allelopathic properties that may inhibit root isolated, and/or extracted from certain botanicals or from and shoot growth in competing Species. Moreover, it has chemical Synthesis, together with methods for using, pro been found that 6-MBOA may have antimicrobial proper ducing, and harvesting the same for use in calming and/or ties, wherein 6-MBOA appears constitutively during early reducing anxiety in humans and animals Suffering from Stages of growth, localized in those tissues most exposed to anxiety disorders and related behaviors or during periods of microbial and insect attack. StreSS, illness, or injury. 0009. It had been long suspected that compounds in 0004 2. The Background Art plants affect the Seasonal reproductive output of wild 0005. An estimated 35-40 million living Americans will rodents. In 1981, 6-MBOA became the first naturally occur Suffer major depressive episodes, and many more will expe ring compound in a plant that was verified as impacting rience lesser bouts. Of the approximately 17.5 million Seasonal reproductive cycling. AS readily known, 6-MBOA Americans with ongoing depressions, about 9.2 million are may be found in varying concentrations in monocotyledon at a clinically debilitating level. Clinical depression is char ous plants. Since then, a Substantial body of work has acterized by a list of Symptoms that last over a long time accumulated on 6-MBOA as an initiator of seasonal breed Span. AS appreciated by those skilled in the art, depression ing and an effector of population size for many rodents and is a Serious problem that is generally initiated or caused by a few birds. Compounds related to and possibly co-occur outside StreSSors. AS Stresses escalate or persist, a chemical ring with 6-MBOA remain generally unexplored in this imbalance of the body usually results. regard. 0006 Clinical depression can be very debilitating both 0010) 6-MBOA may be passed from adult females to physically and mentally and even lead to death by means of offspring during gestation and lactation, which typically Suicide. Lost productivity and relationship problems may be results in increased growth and larger gonads in the recipient consequences of lesser depressions. Presently, antidepres young. Juveniles rely on the interaction of maternal photo Sant medications are the cornerstones of treating depression, period history and 6-MBOA to time the onset of growth and especially those that are at least moderately Severe. puberty. It has been found that adult animals that are fed a Although depressed individuals and animals tend to improve diet containing 6-MBOA produce more female progeny. US 2005/0250772 A1 Nov. 10, 2005 Similarly, when 6-MBOA is fed to pregnant females, 0015 The inventors of the present invention recognized gonadal development in the male offspring is usually that 6-MBOA and the indoleamine, melatonin, share a enhanced. Structural Similarity. However, melatonin exacerbates Symp 0011. In rodents, it has been found that the inhibitory toms of dysphoria in depressed people. 6-MBOA, as a effects of melatonin on growth and reproduction are blocked melatonin agonist, could prove contrary in this regard and partially by 6-MBOA (Gower et al., “Reproductive actually improve mood. Yet, the inventors are not aware of responses of male Microtus montanus to photo period, any prior art that has explored or Suggested the use of melatonin, and 6-MBOA”, Journal of Pineal Research, 8: 6-MBOA or related compounds as having psychotropic 297-312, 1990).