Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1997-10-17
2001-09-25
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S025000, C514S825000, C514S885000, C536S004100, C536S117000, C536S120000, C536S123130
Reexamination Certificate
active
06294521
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel phosphosugars and novel phosphosugar containing compounds that possess anti-inflammatory properties, and in particular it relates to the use of these compounds in the treatment of cell-mediated inflammatory diseases in animals and man.
BACKGROUND OF THE INVENTION
International Patent PCT/AU89/00350 (WO 90/01938) incorporated herein by reference, discloses certain phosphosugars and phosphosugar containing compounds as potent anti-inflammatory agents, and the use of these compounds as anti-inflammatory agents in animals and man. In particular, mannose-6-phosphate was shown to have anti-inflammatory activity against cell-mediated inflammatory diseases such as experimental autoimmune encephalomyelitis, adjuvant-induced artries and delayed type hypersensitivity in experimental animals.
In the work leading to the present invention, the inventors have found novel derivatives of mannose-6-phosphate and other phosphosugars which have more potent anti-inflammatory activity than phosphosugar compounds previously identified, and many of these novel compounds have pharmacological and physicochemical properties that are superior to those of the simple phosphosugars. These agents function by binding to certain receptor molecules (for example the mannose-6-phosphate receptor(s) or tile insulin-like growth factor II receptor), on the surface and/or inside cells, for which mannose-6-phosphate is an integral part of a natural ligand. These agents, when present, can effectively inhibit the ability of inflammatory leukocytic cells to cause inflammation and can inhibit the pathological sequence associated with inflammation.
The mannose-6-phosphate receptor is a multifunctional receptor and, in addition to binding degradative enzymes to the cell surface (1), it can also bind certain cytokines and growth factors, such as transforming growth factor-beta (TGF-beta) (2) and insulin-like growth factor II (1,3), which may have roles in inflammation and its sequels TOF-beta is one of a superfamily of signaling molecules which play important roles in modulating cell growth (4). TGF-beta, is a potent fibrogenic cytokine, and thus is probably important in scar tissue formation (5) as an integral part of the inflammatory response. Thus, another part of the anti-inflammatory effect of mannose-6-phosphate-containing compounds is their potential to block the effects of cytokine and/or growth factors in inflammation by blocking their binding to the mannose-6-phosphate receptor. While it is not intended that the present invention should be restricted in any way by a theoretical explanation of the mode of action of the novel phosphosugars in accordance with the invention, it is presently believed that these active compounds may exert their anti-inflammatory effect by acting as antagonists or competitive inhibitors of the natural ligands of mannose phosphate receptors on and/or in cells.
Accordingly, the active novel phosphosugars and novel phosphosugar containing compounds include compounds which are effective as competitive inhibitors or antagonists of the cellular receptors for which mannose-6-phosphate is wholly or an integral part of the natural ligand.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides novel derivatives of naturally occurring phosphosugars which have been found to be effective inhibitors of inflammation in experimental animals. These derivatives include
D
-mannose-6-phosphate derivatives of the general Formula I:
wherein the mannose-6-phosphate residue as shown in Formula I can be in either the &agr; configuration or the &bgr; configuration. Formula I thus may represent a 1—O—X-substituted &agr;- or &bgr;-
D
-mannose-6-phosphate or a mixture of these and, where X is not hydrogen, such compounds are known as mannoside 6-phosphates. When R
1
, R
2
, R
3
and X all represent hydrogen atoms, Formula I represents the chemical structure of
D
-mannose-6-phosphate.
Referring to Formula I, X may be selected from among the following functional groups, which may optionally be substituted: aliphatic hydrocarbon, saturated or unsaturated, branched or straight chain; cyclic aliphatic hydrocarbons, saturated or unsaturated; aryl; heteroaryl; aralkyl; heteroaralkyl; polyether; and monosaccharide, disaccharide or trisaccharide. R
1
, R
2
and R
3
, which may be the same or different, may be selected from hydrogen or an ester group, particularly an ester group such as acetyl, which may optionally be substituted.
Where X in Formula I is straight chain or branched alkyl, the alkyl chain may be from 1 to 20 carbon atoms inclusive. Where X is alkenyl or alkynyl, the carbon chain may be straight or branched and may be from 2 to 20 carbon atoms inclusive. The optional substituents for these aliphatic chains may be selected from among the following functional groups: trichloromethyl; trifluoromehyl; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl; methoxy; ethoxy; propoxy; iso-propoxy; butoxy; sec-butoxy; isobutoxy; phenoxy; benzyloxy; oxo; hydroxy; thio; methythio; fluoro; chloro or bromo. Where X is cycloalkyl, it may be selected from among the following: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl and cycloheptyl. Where X is aryl, it may be selected from among the following: phenyl or naphthyl, and this group may be variously substituted with from among the following moieties: hydrogen, methyl, ethyl, 2-propyl, methylenedioxy, fluoro, chloro, bromo, iodo, trichworomethyl; tritluoromethyl, methoxy; ethoxy; propoxy; iso-propoxy; butoxy,; sec-butoxy; isobutoxy; phenoxy; benzyloxy; hydroxy; thio; methylthio; carboxy; carboxymethyl and carboxyethyl. Where X is heteroaryl, it may be selected from among the following: pyridyl; thiophenyl; furyl; pyrimidinyl; benzimidazolyl; sym-triazinyl, asym-triazinyl; thiazolyl and thiadiazolyl, and these groups may be variously substituted with from among the following moieties; hydrogen, methyl, ethyl, 2-propyl, methylenedioxy, fluoro, chloro, bromo, iodo, trichloromethyl; trifluoromethyl, methoxy; ethoxy; propoxy; iso-propoxy; butoxy; sec-butoxy; isobutoxy; phenoxy; benzyloxy; hydroxy; thio; methylthio; carboxy; carboxymethyl and carboxyethyl. Where X is aralkyl, it may be selected from among the following: methylaryl; ethylaryl; 2- or 3-propylaryl; 2-, 3- or 4-butylaryl or 2-, 3-, 4- or 5-pentylaryl wherein the aryl group may be selected from among the following: phenyl; naphthyl; phenanthrenyl and anthracenyl, and these aryl groups may be variously substituted with from among the following moieties hydrogen, methyl, ethyl, 2-propyl, methylenedioxy, fluoro, chloro, bromo, iodo, trichloromethyl; trifluoromethyl, methoxy; ethoxy; propoxy; iso-propoxy; butoxy; sec-butoxy; isobutoxy; phenoxy; benzyloxy; hydroxy; thio; methylthio; carboxy; carboxymethyl and carboxyethyl. Where X is heteroaralkyl, it may be selected from among the following: methylheteroaryl; ethylheteroaryl; 2- or 3-propylheteroaryl; 2-, 3- or 4-butylheteroaryl or 2-, 3-, 4-, or 5-pentylheteroayl wherein the heteroaryl group may be selected from among the following: pyridyl; thiophenyl; furyl; pyrimidinyl; benzimidazolyl; sym-triazinyl; asym-triazinyl; thiazolyl and thiadiazolyl, and these heteroaryl groups may be variously substituted with from among the following moieties: hydrogen, methyl, ethyl, 2-propyl, methylenedioxy, fluoro, chloro, bromo, iodo, trichloromethyl; trifluoromethyl, methoxy; ethoxy; propoxy; iso-propoxy; butoxy; sec-butoxy; isobutoxy; phenoxy; benzyloxy; hydroxy; thio; methylthio; carboxy; carboxymethyl and carboxyethyl. Where X is polyether, it may be selected from among the following: polyethylene glycol up to 400 molecular weight (MW); methoxypolyethylene glycol up to 400 MW; polypropylene glycol up to 425 MW and methoxypolypropylene glycol up to 425 MW. Where X is a monosaccharide, disaccharide or trisaccharide it can be any such sugar group where the chemical link, as illustrated in Formula I, is through an oxygen atom.
As described above, in Formula I, R
1
, R
2
and R
3
may represent eithe
Australian National University
Fulwider Patton Lee & Utecht LLP
Geist Gary
Owens, Jr. Howard V.
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