Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-08-29
2002-09-17
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S530000, C560S060000, C562S440000, C562S455000, C562S463000, C562S470000, C562S622000, C564S099000
Reexamination Certificate
active
06451859
ABSTRACT:
TECHNICAL FIELD
The subject invention relates to certain novel analogs of the naturally occurring prostaglandins. Specifically, the subject invention relates to novel Prostaglandin F analogs. The subject invention further relates to methods of using said novel Prostaglandin F analogs. Preferred uses include methods of treating bone disorders and glaucoma.
BACKGROUND OF THE INVENTION
Naturally occurring prostaglandins (PGA, PGB. PGE, PGF, and PGI) are C-20 unsaturated fatty acids. PGF
2a
, the naturally occurring Prostaglandin F in humans, is characterized by hydroxyl groups at the C
9
and C
11
positions on the alicyclic 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 formula:
Analogs of naturally occurring Prostaglandin F have been disclosed in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch, Seeger, and Teufel published on July 1, 1976; U.S. Pat. No. 4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8,. 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, “Synthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogs”,
Chem. Rev
. Vol. 93 (1993), pp. 1533-1564; G. L. Bundy and F. H. Lincoln, “Synthesis of 17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG
1
Series”,
Prostaglandins
, Vol. 9 No. 1 (1975), pp. 1-4; W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens, “Luteolytic Prostaglandins: Synthesis and Biological Activity”,
Prostaglandins
, Vol. 17 No. 2 (1979), pp. 301-311; C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, “Derivatives of 17-Phenyl-18,19,20-trinorprostaglandin F
2
&agr; isopropyl Ester: Potential Antiglaucoma Agents”,
Journal of Medicinal Chemistry
, Vol. 38 No. 2 (1995), pp. 289-304.
Naturally occurring prostaglandins are known to possess a wide range of pharmacological properties. For example, prostaglandins have been shown to: relax smooth muscle, which results in vasodilatation and bronchodilatation, to inhibit gastric acid secretion, to inhibit platelet aggregation, to reduce intraocular pressure, and to induce labor. Although naturally occurring prostaglandins are characterized by their activity against a particular prostaglandin receptor, they generally are not specific for any one prostaglandin receptor. Therefore, naturally-occurring prostaglandins are known to cause side effects such as inflammation, as well as surface irritation when administered systemically. It is generally believed that the rapid metabolism of the naturally occurring prostaglandins following their release in the body limits the effects of the prostaglandin to a local area. This effectively prevents the prostaglandin from stimulating prostaglandin receptors throughout the body and causing the effects seen with the systemic administration of naturally occurring prostaglandins.
Prostaglandins, especially prostaglandins of the E series (PGE), are known to be potent stimulators of bone resorption. PGF
2&agr;
has also been shown to be a stimulator of bone resorption but not as potent as PGE
2
. Also, it has been demonstrated the PGF
2&agr;
has little effect on bone formation as compared to PGE
2
. It has been suggested that some of the effects of PGF
2&agr;
on bone resorption, formation and cell replication may be mediated by an increase in endogenous PGE
2
production.
In view of both the wide range of pharmacological properties of naturally occurring prostaglandins and of the side effects seen with the systemic administration of these naturally occurring prostaglandins, attempts have been made to prepare analogs to the naturally occurring prostaglandins that are selective for a specific receptor or receptors. A number of such analogs have been disclosed in the art. Though a variety of prostaglandin analogs have been disclosed, there is a continuing need for potent, selective prostaglandin analogs for the treatment of a variety diseases and conditions.
SUMMARY OF THE INVENTION
The invention provides novel PGF analogs. In particular, the present invention relates to compounds having a structure according to the following formula:
wherein R
1
, X, 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 theses compounds or the compositions containing them.
DETAILED DESCRIPTION OF THE INVENTION
Terms and Definitions
“Alkyl” is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably I 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. Preferred alkyl are saturated. 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 4 substituents. Preferred substituted alkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
“Lower alkyl” is an alkyl chain comprised of 1 to 6, preferably 1 to 3 carbon atoms.
“Aromatic ring” is an aromatic hydrocarbon ring. 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 system. Bicyclic aromatic rings include ring systems wherein one ring in the system is aromatic. Preferred bicyclic aromatic rings are ring systems wherein both rings in the system are aromatic. Aromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred aromatic rings include naphthyl and phenyl. The most preferred aromatic ring is phenyl.
“Carbocyclic aliphatic ring” is a saturated or unsaturated. hydrocarbon ring. Carbocyclic aliphatic rings are not aromatic. Carbocyclic aliphatic rings are monocyclic. Carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Carbocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More preferred carbocyclic aliphatic rings include cyclohexyl, cycloheptyl, and cyclooctyl.
“Halo” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chioro and fluoro, especially fluoro.
“Haloalkyl” is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents; Preferred haloalkyl are C
1
-C
12
; more preferred are
De Biswanath
deLong Mitchell Anthony
Soper David Lindsey
Wos John August
Gerstl Robert
Kellerman James C.
The Procter & Gamble & Company
Upite David V.
LandOfFree
C16 unsaturated FP-selective prostaglandins analogs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with C16 unsaturated FP-selective prostaglandins analogs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and C16 unsaturated FP-selective prostaglandins analogs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2852888