Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-02-19
2001-06-12
Spivack, Phyllis G. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S178000, C514S179000, C514S182000
Reexamination Certificate
active
06245756
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a method of treating estrogen deficiency in the central nervous system without influencing other organs or systems by administration of a pharmaceutical preparation of selected steroids and to the pharmaceutical composition used in that method.
These steroids are characterized by a selective neurotropic, estrogen-like transcription action in contrast to the systematically acting natural and synthetic estrogens, including 17&agr;-estradiol. These steroids are compounds of the general formula I:
wherein R
1
represents a hydrogen atom, a hydroxy group or an alkoxy group having 1 to 5 carbon atoms; R
2
represents a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an acyl group having 1 to 5 carbon atoms or a group of the formula SO
2
NR
10
R
11
, wherein R
10
and R
11
represent, independently of each other, a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, or together with nitrogen, a pyrrolidino group, a piperidino group or a morpholino group; R
3
represents a hydrogen atom or a hydroxy group; R
4
represents a hydrogen atom, a hydroxy group or an alkyl group with 1 to 5 carbon atoms; R
5
and R
6
each represent, independently of each other, a hydrogen atom or a halogen atom; R
7
represents hydrogen or a methyl group; R
8a
represents a hydrogen and R
8b
represents a hydroxy group or R
8a
represents a hydroxy group and R
8b
represents a hydrogen or both together represent an oxo group or a group of formula CR
12
R
13
, in which R
12
and R
13
each represent, independently of each other, a hydrogen atom or a halogen atom; R
9
represent a methyl or an ethyl group; Z either represents a double bond or a substituted or unsubstituted cyclopropane ring; and >CR
5
R
6
is an a group or a &bgr; group and R
7
is a &bgr; group when >CR
5
R
6
is an &agr; group and vice versa.
An abrupt or gradual decrease of the estrogen concentrations in organisms can occur both in women and in men in various physiological conditions (increasing age, menopause) and pathological conditions (gonadectomy, use of GnRH analogs in supplemental cancer therapy). Troublesome thermoregulation in the form of hot flashes, osteoporosis and an increased predisposition to heart and circulatory illness are part of the best known clinical symptoms of estrogen deficiency (A. Netter, “The menopause”, in C. Thibault, M. C. Levasseur, R. H. F. Hunter (eds.), Reproduction in Mammals and Man, Ellipses, Paris, 1993, pp. 627 to 643). The latest clinical studies (A. W. van den Beld, et al, “The Role of Estrogens in Physical and Psycho-social Well-being in Elderly Men”, The Aging Male 1 (Suppl. 1), 54, 1998) definitely prove the connection between decreased serum estrogen levels and increasing aging in man. Because of that the presence and patho-physiological relevance of an “estrogen deficiency syndrome” in aging men is underscored.
The brain is a very important target organ for estrogen action. Estrogens have a decisive physiological effect on numerous neurobiological processes. Their action may be classified generally into two broad classes, organizing action and activating action (B. S. McEwen, et al, “Steroid Hormones as Mediators of Neural Plasticity”, J. Steroid Biochem. Mol. Biol., 39, 223 to 232, 1991).
The first group relate primarily to the gender-specific organization of neural substrates during early ontogenesis.
The second group include specific changes in the function of neural regulatory cycles that are influenced by estrogen concentrations, which result from physiological secretion of the gonads after gender maturation. The activating effect of estrogens in the central nervous system has been reported in the following physiological processes, among others:
Gender-specific regulation of gonadotropin secretion (G. Fink, “Gonadotropin Secretion and its Control”, in E. Knobil and J. D. Neil(eds.), The Physiology of Reproduction, Raven Press, New York, 1348 to 1376, 1998);
Control of Sexual Behavior (M. J. Baum, et al, “Hormonal Basis of Proceptivity and Receptivity in Female Primates”, Arch. Sex. Behav. 6, 173 to 192, 1977);
Regulation of Neuroendocrine Reactions during Stress (V. Viau and M. J. Meaney, “Variations in Hypothalamic-pituitary-adrenal Response to Stress during the Estrous Cycle in the Rat”, Endrocrinology 129, 2503 to 2511, 1991);
Learning and Retention of Behavioral Patterns in Adaptive Relevance (M. F. O'Neal, et al, “Estrogen Affects Performance of Ovariectomized Rats in a Two-choice Water-escape Working Memory Task”, Psychoneuroendorcrinology 21, 51 to 65, 1996);
Maintenance of Reactivity of Neurochemical Mechanisms that are Indispensible for Guaranteeing Alterness and Adequate Information Processing (G. Fink, et al, “Estrogen Control of Central Neurotransmission: Effects on Mood, Mental State and Memory”, Cell. Mol. Neurobiol. 16, 325 to 344, 1996);
Brain structure with Decisive Roles for Cognitive Performance and Emotional States (C. S. Wooley, B. S. McEwen, “Estradiol Mediates Fluctuations in Hippocampal Synapse Density During the Estrous Cycle in the Adult Rat”, J. Neurosci. 12, 2549 to 2554, 1992);
The great neurotropic potential of estrogens finds its expression in their ability:
to induce expression of a series of central nervous system specific genes, whose products are of critical significance for the survival of nerve cells (R. C. Miranda, F. Sohrabji, C. D. Toran-Allerand, “Presumptive Estrogen Target Neurons Express mRNA for both the Neurotrophins and Neurotrophin Receptors: A Basis for Potential Development Interactions of Estrogen with the Neurotrophins”, Mol. Cell. Neurosci. 4, 510 to 525, 1993);
to guarantee the variety and quality of the signal transmission in the central nervous system (V. N. Luine, “Estradiol Increases Choline Acetyltransferase Activity in Specific Basal Forebrain Nuclei and Projection Areas of Female Rates”, Exp. Neurol. 89, 489 to 490, 1985); (N. Weiland, “Glutamic Acid Decarboxylase Messenger Ribonucleic Acid is Regulated by Estradiol and Progesterone in the Hippocampus”, Endocrinology 131, 2697 to 2702, 1992); (R. Bossé, T. DiPaolo, “The Modulation of Brain Dopamine and GABA
A
Receptors by Estradiol: A Clue for CNS Changes occuring at Menopause”, Cell Mol. Neurobiol. 16, 199 to 212, 1996); and
to increase the resistance of nerve cells against pathological action (Y. Goodman, et al, “Estrogens Attenuate and Corticosterone Exacerbates Excitotoxicity, Oxidative Injury, and Amyloid b-peptide Toxicity in Hippocampal Neurons”, J. Neurochem. 66, 1836 to 1844, 1996).
Clinical findings implicate estrogen deficiency as a causal factor in Morbus Alzheimer's pathogenicity, which maintains the clinical manifestation or progression of this disease, and point to the possiblity of estrogen replacement (V. W. Henderson, et al, “Estrogen Replacement Therapy in Older Women: Comparisons Between Alzheimer's Disease Cases and Controls”, Arch. Neurol. 51, 896 to 900, 1994); (A. Paganini-Hill, V. W. Henderson,“Estrogen Deficiency and Risk of Alzheimer's Disease”, Am. J. Epidemiol. 140, 256 to 261, 1994). A series of neuropeptides, whose gene transcription is influenced by physiological estrogen amounts (e.g. oxytocin and arginine vasopressin) play an important role in the control of emotional behavior components (R. A. Adan, J. P. Burbach, “Regulation of Vasopressin and Oxytocin Gene Expression by Estrogen and Thyroid Hormone”, Progr. Brain Res. 92, 127 to 136, 1992).
Reports in the literature point out that estrogen deficiency is accompanied by a definite weakening of the organism's ability to eliminate reactive oxygen species and free radicals (E. Niki, M. Nakano, “Estrogens as Antioxidants”, Methods Enzymol. 186, 330 to 333, 1990); (M. Lacort, et al,“Protective Effects of Estrogens and Catecholestrogens against Peroxidative Membrane Damage In Vitro”, Lipids 30, 141 to 146, 1995). The excess of free radicals is implicated in mechanisms of cellular damage in many organs and systems and is connected with pathogenesis of neurodegenerative illnesses (C. D. Smith,
Oettel Michael
Patchev Vladimir
Roemer Wolfgang
Schwarz Sigfrid
Thieme Ina
JENAPHARM GmbH & Co. KG
Spivack Phyllis G.
Striker Michael J.
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