Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-04-13
2003-12-23
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S375000
Reexamination Certificate
active
06667308
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field
The invention is in the field of treating depression, sexual dysfunction, substance abuse or addiction, and in inducing weight loss, compounds used in such treatments, and the making of such compounds.
2. State of the Art
An estimated 35-40 million living Americans will suffer major depressive episodes, and many more will experience lesser bouts. Of the approximately 17.5 million Americans with ongoing depressions, about 9.2 million are at a clinically debilitating level. Clinical depression is characterized by a list of symptoms that last over a long time span. It is a serious problem that is usually or initially caused by outside stressors. As stresses escalate or persist, a chemical imbalance can result. Clinical depression can be very debilitating both physically and mentally and even lead to death by means of suicide. However, lost productivity and relationship problems are also consequences of lesser depressions. At present, antidepressant medications are the cornerstones of treating depression, especially those that are at least moderately severe. Although depressed people tend to improve when treated with antidepressants, many do not respond to the first one. Such individuals may eventually benefit from a different antidepressant or a combination of antidepressants.
Sexual dysfunction is a pervasive disorder. In the overall population, 43 percent of women and 31 percent of men between the ages of 18 and 59 repeatedly experience it. Sexual dysfunction includes lacking interest in sex, problems with arousal, not enjoying sex, and anxiety about sexual performance. Indeed, feeling good in general has significant impact on sexual function, with those people unhappy or depressed more likely to experience difficulties. Arousal problems affect over 20 million American males, about two in 10 adult men, with such difficulties often associated with or accompanied by some sort of depression. Meanwhile, prescription antidepressants actually exacerbate the situation, since a frequent side effect of their use is sexual dysfunction. In fact, sexual response diminishes in up to 75% of prescription antidepressant users.
There is a need for treatments to reduce depression or otherwise better mood with an accompanying enhancement of sexual response or desire, or at least no sexual dysfunction.
Prior work on the compounds of the invention has solely been on 6-methoxy-2,3-benzoxazolinone (6-MBOA). Its role in strengthening the resistance of monocotyledonous plants against a wide range of insect pests has been much studied. 6-MBOA and its chemical precursors also have allelopathic properties that inhibit root and shoot growth in competing species. Furthermore, it has antimicrobial properties. 6-MBOA appears constitutively during early stages of growth, localized in those tissues most exposed to microbial and insect attack.
It had been long suspected that compounds in plants affect the seasonal reproductive output of wild rodents. In 1981, 6-MBOA became the first naturally occurring compound in a plant verified as impacting seasonal reproductive cycling. Since then, a substantial body of work has accumulated on 6-MBOA as an initiator of seasonal breeding and an effector of population size for many rodents and a few birds. Compounds related to and possibly co-occurring with 6-MBOA remain unexplored in this regard.
6-MBOA is passed from adult females to offspring during gestation and lactation, with increased growth and greater gonadal size in the recipient young. Juveniles rely on the interaction of maternal photoperiod history and 6-MBOA to time the onset of growth and puberty. Adults fed a diet containing 6-MBOA produce more female progeny. When 6-MBOA is fed to pregnant females, gonadal development in the male offspring is enhanced.
For rodents, the inhibitory effects of melatonin on growth and reproduction are blocked partially by 6-MBOA (Gower et al., “Reproductive responses of male
Microtus montanus
to photoperiod, melatonin, and 6-MBOA”,
Journal of Pineal Research,
8:297-312, 1990). 6-MBOA may obstruct melatonin at the melatonin receptors or act independently to check melatonin action (Sweat et al., “Uterotropic 6-methoxybenzoxazolinone is an adrenergic agonist and melatonin analog,
Molecular and Cellular Endocrinology,
57:131-138, 1988). The high melatonin levels that accumulate in the presence of 6-MBOA may cause desensitization of melatonin receptors (Daya et al., “Effect of 6-methoxy-2-benzoxazolinone on the activities of rat pineal N-acetyltransferase and hydroxyindole-O-methyltransferase and on melatonin production”,
Journal of Pineal Research,
8:57-66, 1990), but not in all rodents (Anderson et al., “Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodic control of testis size in adult male golden hamsters”,
Journal of Pineal Research,
5:351-65, 1988). This compound stimulates rather than inhibits melatonin biosynthesis and does not prevent stimulation of melatonin synthesis by norepinephrine (Yuwiler et al., “Effects of 6-methoxy-2-benzoxazolinone on the pineal melatonin generating system.
J. Pharmacol. Exp. Ther.
233:45-50, 1985). 6-MBOA acts at both the a- and b-adrenergic receptors (Daya et al., “Effect of 6-methoxy-2-benzoxazolinone on the activities of rat pineal N-acetyltransferase and hydroxyindole-O-methyltransferase and on melatonin production”,
Journal of Pineal Research,
8:57-66, 1990), and stimulates adenylcyclase activity in the pineal, hypothalamus and pituitary glands (Sweat et al., “Uterotropic 6-methoxybenzoxazolinone is an adrenergic agonist and melatonin analog,
Molecular and Cellular Endocrinology,
57:131-138, 1988). Certain responses to 6-MBOA, like uterine hypertrophy, can be duplicated with estrogen, but 6-MBOA is not an estrogenic compound (Gower, “Endocrine effects of the naturally occurring reproductive stimulant, 6-methoxybenzoxazolinone”, Ph.D. Thesis, University of Utah, Salt Lake City, Utah, 116p., 1990). Also, 6-MBOA increases the rate of synthesis of follicle stimulating hormone (Butterstein et al., “The plant metabolite 6-methoxybenzoxazolinone interacts with follicle-stimulating hormone to enhance ovarian growth”,
Biology of Reproduction,
39:465-71, 1988) and pituitary prolactin (Vaughan et al., “Hormonal consequences of subcutaneous 6-methoxy-2-benzoxazolinone pellets or injections in prepubertal male and female rats”,
Journal of Reproduction and Fertility,
83:859-66, 1988). Hypothalamic luteinizing hormone-releasing hormone contents and pituitary gland weights are greater for at least one rodent species implanted with capsules containing 6-MBOA (Urbanski et al., “Influence of photoperiod and 6-methoxybenzoxazolinone on the reproductive axis of inbred LSH/Ss Lak male hamsters.
Journal of Reproduction and Fertility,
90:157-163, 1990). The above studies cumulatively point to 6-MBOA acting in the pineal-hypothalami-pituitary axis, possibly as a melatonin agonist and at the a- and b-adrenergic receptors in its own right.
The inventors recognized that 6-MBOA and the indoleamine, melatonin, share a structural similarity. However, melatonin exacerbates symptoms of dysphoria in depressed people. 6-MBOA, as a melatonin agonist, could prove contrary in this regard and actually improve mood. Yet, the inventors are not aware of any prior art that has explored or suggested the use of 6-MBOA and related compounds as having psychotropic effects in humans, particularly with respect to depression or mood.
An object of the invention is to develop therapies for depression and sexual dysfunction entailing use of compounds belonging to related chemical families, of which 6-MBOA is a member. Pursuant to this end, a further object is to develop methods for getting said compounds from plant and animal sources in amounts suitable for human therapeutic use.
SUMMARY OF THE INVENTION
According to the invention, it has been found that certain phenolic compounds, related to each other by shared structural similarities and having structural similarities with melatonin, are effective in bettering mood, im
Berger Patricia J.
Negus Norman C.
Rosenfeld Mark J.
Ford John M.
Pate & Pierce & Baird
Seroctin Research & Technology, Inc.
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