Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1996-06-06
1999-07-20
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
552638, 552639, 552640, 552641, 552647, 552648, 552649, A61K 3156, C07J 100
Patent
active
059256303
ABSTRACT:
The invention relates to 3.alpha.-hydroxy, 17-(un)substituted derivatives of the androstane series and 3.alpha.-hydroxy, 21-substituted derivatives of the pregnane series. These derivatives are capable of acting at a recently identified site on the GRC, thereby modulating brain excitability in a manner that will alleviate stress, anxiety, insomnia, mood disorders that are amenable to GRC-active agents (such as depression) and seizure activity. The steroid derivatives of this invention are those having the general structural Formula: ##STR1## wherein R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are further defined herein and the dotted lines are single or double bonds. The structure includes androstanes, pregnanes (R.sub.4 =methyl), 19-norandrostanes, and norpregnanes (R.sub.4 =H).
REFERENCES:
patent: 3135744 (1964-06-01), Ercoli et al.
patent: 3316146 (1967-04-01), Wechter
patent: 3822298 (1974-07-01), Clayton et al.
patent: 3882151 (1975-05-01), Phillips et al.
patent: 3943124 (1976-03-01), Phillipps et al.
patent: 3953429 (1976-04-01), Cook et al.
patent: 3959260 (1976-05-01), Phillips et al.
patent: 3969345 (1976-07-01), Phillips et al.
patent: 3998829 (1976-12-01), Phillips et al.
patent: 4192871 (1980-03-01), Phillips et al.
patent: 4197296 (1980-04-01), Phillips et al.
patent: 4297350 (1981-10-01), Babcock et al.
patent: 5120723 (1992-06-01), Gee et al.
patent: 5208227 (1993-05-01), Gee et al.
patent: 5232917 (1993-08-01), Bolger et al.
patent: 5319115 (1994-06-01), Tahir et al.
patent: 5591733 (1997-01-01), Bolger et al.
Im et al., "Studies on the mechanism or interactions between anesthetic steroids and gamma-aminobutyric acid receptors". Mol. Pharm. vol. 37(3), 429-434, 1990.
Cross et al., "Steroids CCLXXII. Biologically-active labile ethers III. A new class of potent estrogens". Steroids vol. (3), 557-583, 1965.
Neef et al., "Reaction of unsaturated sulfoxides with alkyllithiums". Tetrahedron Letters vol. 21, 903-906, 1980.
Cross, A.D. et al., "Steroids CCLXXII. Biologically-Active Labile Ethers III. A New Class of Potent Estrogens," Steroids 5(3):557-583 (1965).
Hu, Y. et al., "Neurosteroid Analogues: Structure-Activity Studies of 6-Methyl Substitution on the Electrophysiological Activity of 36(24):3956-3967 (1993).
Im, W.B. et al., "Studies on the Mechanism of Interactions between Anesthetic Steroids and .gamma.-Aminobutyric Acid-A Receptors," Mol. Pharmacol. 37(3):429-434 (1990).
Communication Relating to the Results of the Partial International Search issued by ISA/EPO for PCT/US96/10115, filed Jun. 6, 1996.
Hu et al., "Neurosteroid Analogues: Structure-Activity Studies of 6-Methyl Substitution on the Electrophysical Activity 7-Substituted
Lawrence and Gill, "Structurally specific effects of some steroid anesthetics on spin labeled liposomes," Chem. Abs. 84(9):54385g, pp. 85-86 (1976).
International Search Report issued by PCT International Searching Authority for Patent Application No. PCT/US96/10115 (Mailed Feb. 17, 1997).
Atkinson, R.M. et al., "Action of Some Steroids on the Central Nervous System of the Mouse. II Pharmacology," J. Med. Chem. 8:426-432 (1965).
Atwal, K.S. et al., "On Carcioactive Steroids. VI. The Synthesis of 17.alpha.-Methyl Cardenolides," Heterocycles 19(4): 641-646 (1982).
Bauer, P.E. et al., "A Synthesis of 3.beta.-Hydroxy-5.beta., 14.alpha.-bufa-20, 22-dienolide From Deoxycorticosterone," J. Org. Chem. 48:34-39 (1983).
Buckett, W.R. et al., "Pancuronium Bromide and Other Steroidal Neuromuscular Blocking Agents Containing Acetylcholine Fragments," J. Med. Chem. 16(10):1116-1142 (1973).
Bull, J.R. and Hoadley, C., "Cycloaddition-Oxidative Cleavage Pathways to 14.beta.-Formyl-19-norsteroids," Tetrahedron Lett. 35(33):6171-6174 (Aug., 1994).
Chanoine, F. et al., "Isolation and Identification of Major Metabolites of Tixocortol Pivalate in Human Urine," Drug Metab. Disp. 15(6):868-876 (1987).
Cocker, J.D. et al.,"Action of Some Steroids on the Central Nervous System of the Mouse," Chem. Abstr. 63: 4361f (1965).
Cocker, J.D. et al., "Action of Some Steroids on the Central Nervous System of the Mouse. I. Synthetic Methods," J. Med. Chem. 8:417-425 (1965).
Drasar, P. et al., "Alternative Synthesis of Steroidal Maleimides," Collection Czechoslovak Chem. Comm. 48: 1224-1232 (1983).
Engel, Ch.R. et al., "Favorsky Rearrangements of .alpha.-Halogenated Acetylcycloalkanes," J. Org. Chem. 47:4485-4491 (1982).
Ercoli, A. and Gardi, R., "17.beta.-Alkenyloxyandrostanes," Chem. Abstr. 66: 3656, Abstract No. 38147d (1967).
Falconi, G., "Steroid-17.beta.-yl Acetals and Enol Ethers: Neew Orally Active, C-17.alpha. Not Alkylated, Anabolic Compounds," Chem. Abstr. 64:17971f (1966).
Farmaceutici Italia Soc. Anon., "21-Triphenylmethyl Ethers of Corticosteroids," Chem. Abstr. 58:530h (1962).
Gee, K.W. and Yamamura, H.I., "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia, and Seizuire Disorders," in: Drugs in Central Nervous System Disorders, D.C Horwell (Ed.), New York: Marcel Dekker, pp. 123-147 (1985).
Gee, K.W. et al., GABA-Dependent Modulation of the Cl-Ionophore by Steroids in Rat Brain, J. Pharmacol. 136:419-423 (1987).
Gee, K.W. et al., "Steroid Modulation of the Chloride Ionophore in Rat Brain: Structure-Activity Requirements, Regional Dependence and Mechanism of Action," J. Pharmacol. Exp. Ther. 246(2):803-821 (Aug., 1988).
Grieco, P.A. and Stuk, T.L., "Remote Oxidation of Unactiviated C-H Bonds in Steroids via Oxometalloporphinates," J. Am. Chem. Soc. 112:7799-7801 (1990).
Harrison, N.L. et al., "Structure-Activity Relationships for Steroid Interaction with the .gamma.-Aminobutyric Acid.sub.A Receptor Complex," J. Pharmacol. Exp. Ther. 241(1):346-353 (Apr., 1987).
Hawkinson, J.E. et al., "Correlation of Neuroactive Steroid Modulation of Flunitrazepam Binding and .gamma.-Aminobutyric Acid.sub.A Receptor Function," Molec. Pharmacol. 46(5):977-985 (Nov., 1994).
Ihara, M. et al., "Stereoselective Total Synthesis of Testosterone and Androsterone via A/B-Ring Construction of the Steroidal Ring System by Intramolecular Diels-Alder Reaction," J. Chem. Soc. Perkin Trans. I:117-123 (1986).
Kirk, D.N. and Yeoh, B.L., "New Synthesis of 19,21-Dihydroxypregn-4-ene-3, 20-dione, 21-Hydroxy-19-norpregn-4-ene-3, 20-dione, and 11.beta.,19,21-Trihydroxypregn-4-ene-3,20-dione," J. Chem. Soc. Perkin Trans. I:2945-2951 (1983).
Laboratoires Francais de Chimiotherapie, "Derivatives of Etiocholane," Chem. Abstr. 55:619d (1960).
Lambert et al., "Actions of Synthetic and Endogenous Steroids on the GABA.sub.A Receptor," Trends Pharmacol. Sci. 8:224-227 (Jun., 1987).
Lan, N.C. et al., "Identification and Characterization of a Pregnane Steroid Recognition Site That is Functionally Coupled to an Expressed GABA.sub.A Receptor," Neurochem. Res. 16(3):347-356 (Mar., 1991).
Lalievre, V. et al., "Correlation Between Binding Activity, Inhibition of Lymphoblastic Transformation and Metabolism of Tixocortol 21 Pivalate in Mouse Thymocytes," Agents and Actions 21(3/4):262-265 (1987).
Lewbart, M.L. and Mattox, V.R., "Oxidation of Steroidal .alpha.-Ketols to Glyoxals with Cupric Acetate," Chem. Abstr. 59:6474c (1963).
Lewbart, M.L. and Mattox, V.R., "Oxidation of Steroidal .alpha.-Ketols to Glyoxals with Cupric Acetate," J. Org. Chem. 28:2001-2006 (1963).
Lloyd, K.G. and Morselli, P.L., "Psychopharmacology of GABAergic Drugs," in: Psychopharmacology: The Third Generation of Progress, H.Y. Meltzer (Ed.), New York: Raven Press, pp. 183-195 (1987).
Majewska, M.D. et al., "Steroid Hormone Metabolites are Barbiturate-Like Modulators of the GABA Receptor," Science 232 (4753):1004-1007 (May 1986).
Neef, G. et al., "Reaction of Unsaturated Sulfoxides with Alkyllithiums," Tetrahedron Lett. 21:903-906 (1980).
Phillips, G.H., "Structure-Activity Relationships in Steroidal Anaesthetics," J. Steroid Biochem. 6:607-613 (1975).
Philips, G.H., "Structure-Activity Relationships in Steroidal Anaesthetics," in: Molecular Mechanisms in General Anesthesia, Halsey, M.J. et al. (Eds.) Glaxo Symposium, pp. 32-47 (1975).
Purdy et al., "Synt
Fick David B.
Hogenkamp Derk J.
Lan Nancy C.
Upasani Ravindra B.
Badio Barbara
Cocensys Inc.
Dees Jos,e G.
LandOfFree
Neuroactive steroids of the androstane and pregnane series does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Neuroactive steroids of the androstane and pregnane series, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Neuroactive steroids of the androstane and pregnane series will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1321974