Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-08-28
2004-08-24
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S490000
Reexamination Certificate
active
06780884
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to new compounds which are derivatives of tryptamine and their analogs, pharmaceutical formulations containing them, and use of the compounds in the manufacture of medicaments for treating various diseases.
BACKGROUND OF THE INVENTION
Melatonin is the principal hormone secreted by the pineal gland in all vertebrates. In all mammals studied to date, including humans, a nocturnal rise in the production of melatonin by the pineal gland is evident; melatonin production by the body is acutely suppressed by light. Melatonin is involved in the coordination of photoperiod dependent and physiological processes. The ability of the animals or humans to respond to the melatonin signal may depend upon melatonin receptors. Melatonin acts on the CNS to affect neural mechanisms through receptors located in the brain. Additionally, a number of studies indicate the existence of direct effects of melatonin in peripheral organs via peripheral melatonin receptors. Melatonin receptors are present in the heart, lungs, prostate gland, gonads, white blood cells, retina, pituitary, thyroid, kidney, gut and blood vessels. Retention patterns of radioactive-melatonin injected to rats demonstrate melatonin accumulation in the brain, pituitary, lung, heart, gonads and accessory sex organs (Withyachumnamkul et al., Life Sci 12:1757-65, 1986).
The synthesis and secretion of melatonin exhibit a circadian rhythm that changes with the seasons and with age, e.g., pubescence and senescence. There is very strong evidence that melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhythmicity.
Melatonin has been implicated in many human disorders. Some are known to be linked to chronobiological abnormalities. Melatonin has been administered to re-synchronize circadian rhythms that are out of phase with the local photoperiodical cycle. For example, sleep/wake disorders with rapid crossing of time zones jet lag), or in delayed sleep phase syndrome (DSPS) patients, changes in work shifts, or those experienced by blind people can be treated with melatonin or melatonin analogs (see U.S. Pat. Nos. 4,600,723 and 4,666,086 of Short et al. and U.S. Pat. No. 5,242,941 of Lewy et al.).
However, it appears that melatonin also has direct sedative/hypnotic properties in normal human subjects (e.g., Waldhauser et al., Psychopharmacology, 100: 222-226, 1990; Vollrath et al., Bioscience 29:327-329, 1981: Dollins et al., Proc. Natl. Acad. Sci, 99:1824-1828, 1994, U.S. Pat. No. 5,403,851 of D'Orlando et al). Three melatonin receptor subtypes have been identified so far mt-1, MT-2 and Me11c (Barrett et al., Biol. Signals Recept., 1999, 8: 6-14). MT-2 is localized mainly in the central nervous system and mt-1, localized in the CNS as well as in peripheral organs such as kidney and the urogenital tract (Dubocovich et al., IUPHAR media, London, UK, 187-93, 1998). The presently known subtypes are not sufficient to evaluate the large variety of melatonin effects and additional receptor subtypes await discovery.
Melatonin has been demonstrated in a number of rodent experimental paradigms to have both anxiolytic (Golus and King, Pharmacol. Biochem. Behav., 41:405-408, 1992, Naranjo-Rodriguez et al., Soc. Neurosci. Abst. 18:1167, 1992; Golombek et al., Eur. J. Pharmacol, 237:231-236, 1993) and antiseizure activity (Brallowsky, Electroencephalo. clin. Neurophysiol. 41:314-319, 1976: Farielloet al., Neurology 27:567-570, 1977, Rudeen et al., Epilepsia 21:149-154, 1980; Sugden, J. Pharmacol Exp. Ther. 227:587-591, 1983; Golombek et al., Eur. J. Pharmacol 210:253-258, 1992).
Melatonin is effective in the treatment of cluster headache and migraine (Claustrat et al., Headache, 29:241-4, 1989). Melatonin may play a role in other psychiatric conditions, particularly depression, but also mania and schizophrenia (see Dobocovich “Antidepressant Agents”, U.S. Pat. No. 5,093,352; Miles and Philbrick, Biol. Psychiatry 23:405-425, 1988: Sandyk and Kay, Schizophr. Bull. 16:653-662, 1990). In some instance, psychiatric disorders may have underlying chronobiological etiologies (e.g. seasonal effective disorder) and are definite candidates for melatonin therapy.
Melatonin is involved in the regulation of circadian and circannual changes in body temperature. Administration of exogenous melatonin to humans lowers core body temperature (Strassman et al., J. Appl. Physiol, 71:2178-2182, 1991; Cagnacci et al., J. Clin. Endocrinol. Merab. 75:447-452, 1992). Melatonin may also possess analgesic properties (Sugden, J. Pharmacol. Exp. Ther. 227:587-591, 1983). Therefore, melatonin-like compounds may be useful as an alternative to non-steroidal anti-inflammatory, anti-pyretic drugs, such as aspirin, acetaminophen and ibuprofen.
It is known that melatonin levels decrease with advancing age (Sack et al., J. Pineal Res. 4:379-388, 1986; Waldhauser et al., J. Clin. Endocrinol. Metab., 66:648-652, 1988; Van Coavorden et al., Am. J. Physiol. 260:E651-661, 1991) which may contribute to some disorders, Neurodegenerative diseases often associated with aging, such as Alzheimer's and Parkinson's diseases, may be treated with melatoninergic compounds (Maurizi, Med. Hypotheses 31:233-242, 1990; Sandyk, Int. J. Neurosci. 50:37-53, 1990; Skene et al., Brain Rev. 528:170-174, 1990).
Sleep disorders in the elderly have been shown to respond to melatonin treatment (Garfinkel et al., Lancet, 346:541-543, 1995, U.S. Pat. No. 5,498,423 of Zisapel). Soporific effects of melatonin (0.3-240 mg) have been reported in humans following intravenous, intranasal and oral administration. Apart from its soporific effects, exogenous melatonin may affect sleep via its phase-resetting action on the biological clock. Melatonin administration advanced sleep in delayed sleep syndrome patients, and synchronized sleep to the day-night cycles in blind subjects. The efficacy of melatonin (0.3-5 mg/os) for treatment of insomnia has been demonstrated in studies performed mainly with elderly patients, patients treated with atenolol and chronic heart patients, most of which patients have low or distorted melatonin rhythms. In some of these studies, formulations which release melatonin throughout the night were used, in order to circumvent fast clearance of the hormone and to mimic its endogenous profile (Nutrition, 1998, 14: 1-2; The Aging Male, 1998, 1: 1-8). Melatonin, 3 mg, given to patients with sleep disorders and dementia for 21 days, significantly augmented sleep quality and decreased the number of wakening episodes, while agitated behavior at night (sundowning) decreased significantly (Biol. Signals Recept. 1999, 8(1-2): 126-31).
We have recently found that melatonin treatment may be beneficial not only for improving sleep quality, but may also lead to an improvement in the general state of diabetic patients, as indicated by the decrease in HbA1c levels after long-term treatment.
Daily melatonin supplementation to male Sprague-Dawley rats, starting at middle age (10 months) and continuing into old age (22 months) via the drinking water at a dosage of 4 &mgr;g/ml, restored the age-related elevated levels of relative (% of body weight) retroperitoneal and epididymal fat, as well as plasma insulin and leptin levels to youthful (4 month) levels (Rasmussen et al., Endocrinology, 1999, 140(2): 1009-12).
Even osteoporosis may have a melatoninergic component (Sandyk et al., Int. J. Neurosci. 62:215-225, 1992). In fact, melatonin has been suggested to be an anti-aging, anti-stress hormone (Armstrong and Redman, Med. Hypotheses 34:300-309, 1991; Reiter, Bioassays, 14:169-175, 1992). This may be due to its action as a free radical scavenger (Pooggeler et al., J. Pineal Res. 14:151-168, 1993) or its interaction with the immune system (Maestroni and Conti, J. Neuroimmun. 28:167-176 1990; Fraschini et al., Acta. Oncol. 29:775-776 1990, Guerrero and Reiter, Endocr. Res. 18:91-113, 1992). Melatonin may protect from ischemic stroke (Cho et al., Brain Research 755:335-33
Laudon Moshe
Zisapel Nava
Neurim Pharmaceuticals (1991) Ltd.
Rothwell Figg Ernst & Manbeck
Solola Taofiq
LandOfFree
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