Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-02-08
2002-05-28
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S622000, C564S171000, C564S189000
Reexamination Certificate
active
06395787
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to ocular hypotensive lipids. More particularly the present invention relates to PGF
2&agr;
1-ethanolamide and related compounds, and to pharmaceutical compositions containing these compounds, as well as methods for using the compounds to lower intraocular pressure in a mammal.
2. Brief Description of the Prior Art
The prior art is well aware of numerous ocular hypotensive agents which are used to treat various ocular hypertensive conditions, including primary and secondary glaucoma which represent a serious human health problem. Drugs used for treating ocular hypertension (glaucoma) include &bgr;-adrenoreceptor antagonists, and various prostaglandins. There is a substantial volume of scientific and patent literature pertaining to prostaglandins and to their use in the treatment of ocular hypertension. See for example Bito L. Z.
Biological Protection with Prostaglandins
Cohen, M. M., ed., Boca Raton. Fla., CRC Press Inc., 1985, pp. 231-252; and Bito, L. Z.,
Applied Pharmacology in the Medical Treatment of Glaucomas
Drance, S. M. and Neufeld, A. H. eds., New York, Grune & Stratton, 1984, pp. 477-505.
U.S. Pat. No. 5,288,754 includes further citations to specific prior art directed to prostaglandins and related derivatives which are active as agents for reducing intraocular pressure in a mammal. U.S. Pat. No. 5,288,754 itself, describes “Polar C-1 Esters of Prostaglandins”, including C-1 amides and C-1 substituted amides of the carboxylic acid compound known as PGF
2&agr;
. Additional prostaglandin derivatives related to PGF
2&agr;
which have emerged in prior art research conducted in the research facilities of the corporate assignee of the present application and which show strong intraocular hypotensive activity, are shown below by formula and are identified by arbitrary numbers as “prior art compound no. 1” and “prior art compound no. 2”. Prior art compound no. 1 is described in U.S. Pat. Nos. 5,352,708; 5,607,978 and 5,688,819, and prior art compound no. 2 is described in U.S. Pat. No. 5,545,665.
The vast majority of ocular hypotensive agents which have a prostaglandin (or closely) related structure act through known “prostglandin” receptors. Particularly, the compound PGF
2&agr;
is known to exert its ocular hypotensive action through the receptor known as FP. By “FP receptor” is meant a human prostaglandin receptor as disclosed in Abramovitz et al.,
J. Biol. Chem.
269:2632 (1994), hereby incorporated by reference herein. The structure of PGF
2&agr;
, including the numbering customarily used in the nomenclature of prostaglandin and related compounds, is shown below.
The present invention is directed to a class of compounds related to PGF
2&agr;
1-ethanolamide, which suprisingly have been discovered, together with the prior art compound nos. 1 and 2, as agents having strong ocular hypotensive activity, but which do no exert their ocular hypotensive effects through the FP receptor, nor through any hitherto recognized prostaglandin receptor, such as DP, EP, EP
2
, EP
3
, EP
4
, FP, IP and TP.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula 1 wherein the dashed lines represent absence of a bond, or a bond with the proviso that there are no two adjacent double bonds in the formula;
the wavy line attachments represent either alpha (&agr;, down) or beta (&bgr;, up) configuration, where the wavy lines are attached to a double bond they represent either Z (cis) or E (trans) configuration;
the hatched lines indicate alpha (&agr;) configuration and solid triangles indicate beta (&bgr;) configuration;
m is an integer having the values of 0 to 5;
n is an integer having the values 1-6, with the proviso that the compound represented by the formula is not PGF
2&agr;
1-ethanolamide;
q and r each independently are integers having the value of 0 to 6;
X is CH
2
, O or S with the proviso that when X is O or S then the dashed line adjacent to X represents absence of a bond;
R is CH
3
, phenyl, furyl, thienyl, cycloalkyl of 3 to 8 carbons, or phenyl furyl or thienyl itself substituted with one or two substituents selected from the group consisting of F, Cl, Br, alkyl of 1 to 6 carbons, NO
2
, CN, COOH and COOalkyl where alkyl has 1 to 6 carbons;
R
1
, R
2
, R
3
, and R
4
each independently represent H, a straight or branch-chained alkanoyl group having 1 to 6 carbons, benzoyl or lower alkyl of 1 to 6 carbons;
R
5
is H or straight or branch-chained alkyl group having 1 to 6 carbons, and
R
6
is H or straight or branch-chained alkyl of 1 to 4 carbons or a pharmaceutically acceptable salt of said compound, and said compounds being active to lower intraocular pressure in the eye of a mammal but do not exert their ocular hypotensive activity through the FP prostaglandin receptor, nor through any hitherto recognized prostaglandin receptor.
The present invention is also directed to isolated substantially pure PGF
2&agr;
1-ethanolamide, which has surprisingly been discovered to be present in certain biological systems as a naturally occurring substance. Further, the present invention is directed to pharmaceutical compositions containing as an active ingredient PGF
2&agr;
1-ethanolamide and/or one or more of the compounds in accordance with Formula 1, and to the process of treating a mammal, including a human, in need of such treatment with an effective amount of a pharmaceutical composition containing as active ingredient PGF
2&agr;
1-ethanolamide and/or one or more of the compounds in accordance with Formula 1, for the purpose of lowering intraocular pressure.
REFERENCES:
patent: 5288754 (1994-02-01), Woodward et al.
patent: 5353708 (1994-10-01), Woodward et al.
patent: 5545665 (1996-08-01), Burk
patent: 5607978 (1997-03-01), Woodward et al.
patent: 5688819 (1997-11-01), Woodward et al.
patent: 5834498 (1998-11-01), Burk
patent: 2258372 (1975-08-01), None
patent: 1439511 (1976-06-01), None
patent: 50-71650 (1975-06-01), None
patent: WO 96/36599 (1996-11-01), None
patent: WO 99/25358 (1999-05-01), None
Yu, et al., Synthesis of Prostaglandin E2Ethanolamide from Anandamide by Cyclooxygenase-2,Journal of Biological Chem.,vol. 272, No. 34, pp. 21181-21186 (1975).
Woodward, D. F. et al.: “Neutral Replacement of the Carboxylic Acid Group of Prostaglandin F2alpha Provides A Novel Series of Ocular Hypotensive Lipids with Pharmacological Activity Distinct Prostanoids.” IOVS, (Mar. 15, 1998) vol. 39, No. 4, pp. S420. Meeting Info: Annual Meeting of the Association for Research In Vision and Opthamolgy, Fort Lauderdale, Florida, USA May 10-15, 1998 Association for Research In Vision and Opthamology, XP00104773;
Schaaf, Thomas K., et al.: “Synthesis and Biological Activity of Carboxyl-Terminus Modified Prostaglandin Analogs” J. Med. Chem. (1979), 22(11), 1340-6, XP002184770.
Bito L. Z., Biological Protection with Prostaglandins, M.M., et., Boca Raton, Fla., CRC Press Inc., 1985, pp. 231-252.
Bito L. Z., Applied Pharmacology in the Medical Treatment of Glaucomas, Drance, S.M. and Neufeld, A.H. eds., New York, Grune & Stratton, 1984, pp. 477-505.
Abramovitz et al.,J. Biol. Chem.,269:2632 (1994).
Meade et al.,J. Biol. Chem.,268: 6610-6614 (1993).
Ogletree et al.,J. Pharmacol Exp. Ther.,234: 435-441 (1985).
Chen et al.,Br. J. Pharmacol,116: 3035-3041 (1995).
Andrews Steven W.
Burk Robert M.
Chen June
Krauss Achim H-P.
Madhu Cherukury
Allergan Sales Inc.
Fisher Carlos A.
Gerstl Robert
Szekeres Gabor L.
Voet Martin A.
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