Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1997-06-09
2002-08-13
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S179000, C514S182000, C552S530000, C552S553000, C552S555000
Reexamination Certificate
active
06432938
ABSTRACT:
This application is related to U.S. application Ser. No. 08/127,908, filed Sep. 28, 1993 which is a continuation-in-part of U.S. application Ser. No. 07/903,604, filed Jun. 24, 1992, which in turn is a continuation-in-part of U.S. application Ser. No. 07/708,936, filed May 31, 1991, which in turn is a continuation-in-part of U.S. application Ser. No. 07/638,185, filed Jan. 7, 1991, now abandoned.
The application also relates to U.S. application Ser. No. 08/127,980 filed Sep. 28, 1993 which is another continuation-in-part of U.S. patent application Ser. No. 07/903,604, U.S. patent application Ser. No. 08/077,359, filed Jun. 15, 1993, and to commonly assigned, co-pending U.S. patent application Ser. No. 07/903,525, filed Jun. 24, 1992 (a continuation-in-part of U.S. application Ser. No. 07/707,862, filed May 31, 1991, which in turn is a continuation in-part of U.S. application Ser. No. 07/638,743, filed Jan. 7, 1991, now abandoned) entitled “Estrene Steroids as Neurochemical Initiators of Change in Human Hypothalamic Function and Related Pharmaceutical Compositions and Methods”; and to the commonly assigned, co-pending continuation-in-part of 07/903,525, U.S. patent application Ser. No. 08/077,140. The aforementioned U.S. patent applications are each incorporated herein by reference.
Finally, this application may relate to U.S. Patent Application entitled “Fragrance Compositions Containing Human Pheromones, filed Mar. 24, 1992, U.S. Ser. No. 07/856,435.
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-cholane steroids as neurochemical effectuators of physiology and behavior.
DESCRIPTION OF THE RELATED ART
The present invention relates to certain compounds, namely 19-nor-cholane steroids, particularly 19-nor-cholane 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-cholane steroids are characterized by a four ring steroidal structure, methylation at the 13 position and alkylation (C4) at the 17-position. The 19-nor-cholenes 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-16-en-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&agr;-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) 7:207-215, 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-cholane and 19-nor-cholene 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 terminalis 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., supra; 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 hy
Adams Nathan W.
Berliner David L.
Jennings-White Clive L.
Badio Barbara P.
Heller Ehram White & McAuliffe LLP
Pherin Corporation
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