Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2000-08-03
2002-04-16
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C558S207000
Reexamination Certificate
active
06372730
ABSTRACT:
BACKGROUND OF THE INVENTION
The naturally occurring prostaglandin, PGF
2a
, is a twenty-carbon (C-20) unsaturated fatty acid derived from arachidonic acid. Using standard prostaglandin nomenclature, PGF
2a
possesses alpha-hydroxyl groups at both C
9
and at C
11
on the cyclopentane ring, a cis double bond between C
5
and C
6
, and a trans double bond between C
13
and C
14
. Thus PGF
2a
has the following structure:
Analogs of PGF
2a
are useful for the treatment of several medical conditions including, for example: ocular disorders, such as glaucoma; circulatory disorders, gastrointestinal disorders; fertility control; and bone disorders, such as osteoporosis. Information regarding the biological effects of Prostaglandin F analogs is disclosed in the following references: PCT Publication No. WO 99/12895, 1999; PCT Publication No. WO 99/12896, 1999; PCT Publication No. WO 99/12898;
Chem. Abstr.
1999, 194116 “Molecular mechanisms of diverse actions of prostanoid receptors”,
Biochimica et Biophysica Acta,
1259 (1995) 109-120; U.S. Pat. No. 3,776,938 issued to Bergstrom, S., and Sjovall, J., Dec. 4, 1973; U.S. Pat. No. 3,882,241 issued to Pharriss, G., May 6, 1975; G.B. Patent No. 1,456,512 (1976) issued to Pfizer Inc., Bundy, G. L.; Lincoln, F. H., “Synthesis of 17-Phenyl-18,19,20-trinor prostaglandins I. The PGI Series”,
Prostaglandins
Vol. 9 (1975) pp. 1-4.; CRC Handbook of Eicosanoids: Prostaglandins and Related Lipids Vol. 1, Chemical and Biochemical Aspects, Parts A & B, A. L. Willis, eds., CRC Press (1987); Liljebris, C.; et. al. “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2
a
Isopropyl Ester: Potential Antiglaucoma Agents”,
Journal of Medicinal Chemistry
Vol. 38, (1995), pp. 289-304; Collins, P. W.; Djuric, S. W. “Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs”,
Chemical Reviews
93 (1993), pp. 1533-1564.
All naturally occurring prostaglandins, including PGF
2a
, possess a carboxylic acid moiety at the C
1
position. The carboxylic acid moiety is a site for metabolic degradation by beta oxidation, which contributes to the rapid metabolism of the naturally occurring prostaglandins. Attempts to prevent beta oxidation by modifying the carboxylic acid moiety at the 1 position as an ester moiety, an amide moiety, a sulfonamide moiety, and as a tetrazole moiety are known in the art (See e.g. PCT Publication No. WO 99/12895, 1999; PCT Publication No. WO 99/12896, 1999; PCT Publication No. WO 99/12898).
However, such modifications have either resulted in only modest increases in half-life (such as the esters) or resulted in compounds with diminished potency.
Prostaglandin F analogs wherein C
1
, itself is replaced with a heteroatom have also been described in the art. For example, PGF analogs containing a sulfonic acid moiety at C
1
, (The chemistry of prostaglandins containing the sulfo group. Iguchi, Y.; Kori, S.;
Hayashi, M. J
Org. Chem.,
40, pp. 521-523 1975) and PGF analogs containing a phosphonic acid moiety at C, (The Synthesis of dimethylphosphonoprostaglandin analogs, Kluender, H. C. & Woessner, W.
Prostaglandins and Medicine,
2: pp.441-444, 1979) have been disclosed. However, such compounds suffer from significantly diminished potency.
Further research in the area of heteroatom—containing C
1
, replacements has been hampered by the lack of a general synthetic route to advanced or key intermediates that would allow for the rapid preparation of a multitude of variants to replace C
1
. The Corey route to prostaglandins was specifically designed for a carboxcyclic acid moiety, and modifications which create reagents with relatively acidic protons are either incompatible with this route or cause significant optimization of this difficult step for each new C
1
replacement. Syntheses of Prostaglandin F analogs via the Corey route are described in the following references: Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W J
Am. Chem. Soc.,
1969, 91, 5675 and Corey, E. J.; Schaaf, T. K.; Huber, W; Koelliker, U.; Weinshenker, N. M.; J.
Am. Chem. Soc.,
1970, 92, 397.
Thus, while a few Prostaglandin F analogs wherein C
1
has been replaced with a heteroatom—containing moiety have been disclosed, there is a continuing need for suitable C
1
replacements that result in potent, selective Prostaglandin F analogs for the treatment of a variety diseases and conditions.
SUMMARY OF THE INVENTION
The invention provides novel Prostaglandin F analogs. In particular, the present invention is directed to compounds having a structure according to the following formula:
wherein R
1
, R
2
, X, Y, V, a, b, W, and Z are defined below.
This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically—acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using these compounds or compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
The invention is directed to novel 2-decarboxy-2-phosphinico Prostaglandin F analogs, pharmaceutical compositions comprising these compounds, and methods of treating a variety of disorders by administering these compounds.
Definitions and Usage of Terms
“Alkyl” is a saturated or unsaturated hydrocarbon chain. Unless otherwise specified (e.g. see “C
4
alkyl”, “C
1,
alkyl”, “C
m
alkyl” and “C
p
alkyl” below), alkyl chains have 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches, preferably one branch. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Alkyl chains may be unsubstituted or substituted with from 1 to about 4 substituents unless otherwise specified. Preferred substituted alkyl are mono-, di-, or trisubstituted. Preferred alkyl substituents include cyano, halo, hydroxy, aryl (e.g., phenyl, tolyl, alkyloxphenyl, alkyloxycarbonylphenyl, halophenyl), heterocyclyl, and heteroaryl.
“Aromatic ring” is an aromatic hydrocarbon ring system. Aromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring. Aromatic rings may be unsubstituted or substituted with from 1 to about 4 substituents on the ring. Preferred aromatic ring substituents include: halo, cyano, lower alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. More preferred substituents include lower alkyl, cyano, halo and haloalkyl.
“Biohydrolyzable amide” is an amide moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
“Biohydrolyzable ester” is an ester moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
“Biohydrolyzable imide” is an imide moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal.
“C
4
alkyl” is an alkyl chain having 4 carbon member atoms. C
4
alkyl may be staurated or unsaturated with one or two double bonds (cis or trans), one triple bond, or one double bond (cis or trans) and one triple bond. Preferred unsaturated C
4
alkyl have one double bond. C
4
alkyl may be unsubstituted or substituted with one or two substituents. Preferred substituents include lower alkyl, lower heteroalkyl, cyano, hal
De Biswanath
deLong Mitchell Anthony
Ebetino Frank Hallock
Wos John August
Lambkin Deborah C.
McMahon Mary Pat
Roof Carl J.
The Procter & Gamble & Company
Upite David V.
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