Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
1998-08-11
2001-06-05
Cook, Rebecca (Department: 1614)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
C552S530000
Reexamination Certificate
active
06242619
ABSTRACT:
TECHNICAL FIELD
This invention relates generally to pharmaceutical compositions and methods for effectuating change in human hypothalamic function, thereby altering certain behavior and physiology mediated by the hypothalamus of individuals. More particularly, the invention relates to the use of 19-nor-pregnane steroids as neurochemical effectuators of physiology and behavior.
DESCRIPTION OF THE RELATED ART
The present invention relates to certain compounds, namely 19-norpregnane steroids, particularly 19-norpregnane steroids and related compounds as will be described herein, and methods of using these compounds as human vomeropherins in order to alter hypothalamic function, thereby affecting certain consequent behavior and physiology, e.g., the reduction of anxiety. The 19-nor-pregnane steroids are characterized by a four ring steroidal structure, methylation at the 13 position and ethylation at the 17-position. The 19-nor-pregnenes are a subset which have at least one double bond.
Ohloff, G. et al. (
Helv. Chim. Acta
(1983) 66:192-217), which is incorporated herein by reference, have shown that several steroids (androstenes) have an odor which varies with different isomeric, diastereomeric, and enantiomeric forms. Some members of this group have been reported to act as a pheromone in some mammalian species for instance, 5&agr;-androst-16-en-3-one and 5&agr;-androst-16en-3&agr;-ol in pigs (Melrose, D. R., et al.,
Br. vet. J
. (1971) 127:497-502). These 16-androstenes produced by the boar induce mating behavior in estrus sows (Claus, et al., Experimentia (1979) 35:1674-1675).
In some studies it has been noted that, in some species, various characteristics of certain 16-androstenes (including 5&agr;-Androst-16-en-3&agr;-ol and 5 a -Androst-16-en-3-one), such as concentration, metabolism, and localization, are sexually dimorphic (Brooksbank et al., J. Endocr. (1972) 52:239-251; Claus, et al., J. Endocr. (1976) 68:483-484; Rwan, et al., Med. Sci. Res. (1987) 15:1443-1444). For instance, 5&agr;-Androst-16-en-3&agr;-ol and 5&agr;-Androst-16-en-3-one, as well as Androsta-4,16-dien-3-one, have been found at different concentrations in the peripheral blood, saliva and axillary secretions of men and of women (Kwan, T. X., et al.,
Med. Sci. Res
. (1987) 15:1443-1444), and their function as a human pheromone, to the extent of affecting choice and judgement, has been suggested (Id.; see also Gower, et al., “The Significance of Odorous Steroids in Axillary Odour”, In,
Perfumery
, pp. 68-72, Van Toller and Dodd, Eds., Chapman and Hall, 1988); Kirk-Smith, D. A., et al.,
Res. Comm. Psychol. Psychiat
. Behav. (1978) 3:379). Androstenol (5&agr;-androst-16-en-3&agr;-ol) has been claimed to exhibit a pheromone-like activity in a commercial men's cologne and women's perfume (Andron for men and Andron for women by Jovan). Japanese Kokai No. 2295916, refers to perfume compositions containing androstenol and/or its analogues. 5&agr;-Androstadien-3&bgr;-ol (and perhaps the 3&agr;-ol) has also been identified in human axillary secretion (Gower, et al., Supra at 57-60. On the other hand, there is little agreement in the literature as to whether or not any putative pheromone actually plays any role in the sexual or reproductive behavior of mammals, particularly of humans. See: Beauchamp, G. X., et al., “The Pheromone Concept in Mammalian Chemical Communication: A Critique”, In:
Mammalian Olfaction. Reproductive Processes and Behavior
, Doty R. L., Ed., Academic Press, 1976). See also: Gower, et al., supra at 68-73.
The pheromone properties of some estrene steroids for some mammalian species have been described. Michael, R. P. et al.,
Nature
(1968) 218:746 refers to Estrogens (particularly Estradiol) as a pheromonal attractant of male rhesus monkeys. Parrot, R. F., Hormones and Behavior (1976) 7:207-21S, reports Estradiol benzoate injection induces mating behavior in ovariectomized rats; and the role of the blood level of Estradiol in make sexual response (Phoenix, C. H., Physiol. and Behavior (1976) 16:305-310) and female sexual response (Phoenix, C. H., Hormones and Behavior (1977) 8:356-362) in Rhesus monkeys has been described. On the other hand, there is little agreement in the literature as to whether or not pheromones as such play any role in the reproductive behavior and interpersonal communication of mammals (Beuchamp, G. K., et al., “The Pheromone Concept in Mammalian Chemical Communication: A Critique”, In:
Mammalian Olfaction Reproductive Processes. and Behavior
, Doty, R. L., Ed., Academic Press, 1976).
An embodiment of the subject invention concerns the non-systemic, nasal administration of certain 19-nor-pregnane and 19-nor-pregnene steroids to affect a specific behavioral or physiological response in human subjects, e.g., a reduction of negative affect, mood, and character traits. In particular, nasal administration provides for contacting neurochemical receptors of a heretofore poorly understood neuroendocrine structure, commonly known as the vomeronasal organ (“VNO); also known as “Jacobson's organ”), with one or more steroid(s) or with compositions containing the steroid(s). This organ is accessed through the nostrils of most higher animals—from snakes to humans, and has been associated, inter alia, with pheromone reception in certain species (see generally Muller-Schwarze & Silverstein,
Chemical Signals
, Plenum Press, New York (1980)). The axons of the neuroepithelia of the vomeronasal organ, located supra palatinal, form the vomeronasal nerve and have direct synaptic connection to the accessory olfactory bulb and indirect input from there to the cortico-medial amygdaloid basal forebrain and hypothalamic nuclei of the brain. The distal axons of terminals nerve neurons may also serve as neurochemical receptors in the VNO. Stensaas, L. J., et al.,
J. Steroid Biochem. and Molec. Biol
. (1991) 39:553. This nerve has direct synaptic connection with the hypothalamus.
Johnson, A. et al. (J. Otolarynaoloav (1985) 14:71-79) report evidence for the presence of the vomeronasal organ in most adult humans, but conclude that the organ is probably non-functional. Contravening results which suggest that the VNO is a functional chemosensory receptor are reported by Stensaas, L., et al., surra; and by Moran, D. T., et al., Garcia-Velasco, J. and M. Mondragon; MontiBloch, L. and B. Grosser all in
J. Steroid Biochem. and Molec. Biol
. (1991) 39.
It is apparent that it would be desirable to identify and synthesize human vomeropherins and pheromones and to develop pharmaceutical compositions and methods of use to influence hypothalamic function. This invention relates to the unexpected discovery that, when nasally administered to human subjects, certain neurochemical ligands, particularly 19-nor-pregnane steroids, 19-nor-pregnene steroids and related compounds, or pharmaceutical compositions containing 19-nor-pregnanes, 19-nor-pregnenes or related compounds, specifically bind to chemoreceptors of certain nasal neuroepithelial cells and this binding generates a series of neurophysiological responses resulting in an alteration of hypothalamic function of an individual. When properly administered, the effect of certain of these compounds on the hypothalamus affects the function of the autonomic nervous system and a variety of behavioral-or physiological phenomena which include, but are not limited to the following: anxiety, premenstrual stress, fear, aggression, hunger, blood pressure, and other behavioral and physiological functions normally regulated by the hypothalamus. See Otto Appenzeller,
The Autonomic Nervous System. An Introduction of Basic and Clinical Concepts
(1990); Rorner, P. I.
Central nervous control of autonomic cardiovascular function
, and Levy N. M. and Martin, P. J.
Neural control of the heart
, both in
Handbook of Physiology: Section
2
: Cardiovascular System—the heart
, Vol. I, Washington, D.C, 1979, American Physiological society; Fishman, A. P., et al. editors,
Handbook of Physiology: Section
3
: Respiratory System. Vol. II. Control of Breathing
, Be
Adams Nathan W.
Berliner David L.
Jennings-White Clive L.
Cook Rebecca
Heller Ehrman White & McAuliffe LLP
Pherin Pharmaceuticals, Inc.
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