Strategic Medical Research Corporation

Other

Greenwich Pharmaceuticals Incorporated

Newport Pharmaceuticals International, Inc.

Paul Gordon

Edward P Gamson

Bruce Ronsen

Shrikant V Kulkarni

A glucofuranose derivative substituted at the 3,5,6- or 3,6-positions with a radical that provides an anionic charge at physiological pH values is disclosed, as are pharmaceutical compositions, and methods of making and using the same. The compounds are useful in treating inflammation, and particularly conditions that involve neutrophil influx; they are also useful in inhibiting gastric ulcer formation.

Anionic furanose derivatives, methods of making and using the same

In one variant, the invention provides a method of enhancing the activity of phagocytes including macrophages, and in a further variant, a method of modulating the cellular or humoral immune response to warm blooded animals. The invention also provides a method of reducing the adverse effects of stress in warm blooded animals. This is accomplished by administering an ethereally monosubstituted monosaccharide having the general formula M.sub.1 --O--Y, an ethereal monosubstitution of monosaccharide derivatives having the general formula M.sub.2 --O--Y, or pharmaceutically acceptable organic acid and inorganic acid salts thereof as defined hereinafter. In the first variant, the above substances are administered in an amount effective to enhance the microbicidal activity of phagocytes, including macrophages in a normal to depressed state of activation or macrophages already activated in response to infection. In the second variant, the above substances are administered in an amount to enhance the cellular or humoral immune response when the warm blooded animal has a normal or depressed cellular or humoral immune response system, or in an amount effective to reduce the cellular or humoral immune response when the warm blooded animal has a hypersensitive cellular or humoral immune response system. In the third variant, the above substances are administered in an amount effective to reduce the adverse effects of stress on the aforementioned defense mechanisms of warm blooded animals subjected to stress.

Method of enhancing the activity of phagocytes including macrophages,

A glucofuranose derivative substituted at the 3,5,6- or 3,6-positions with a radical that provides an anionic charge at physiological pH values is disclosed, as are pharmaceutical compositions, and methods of making and using the same. The compounds are useful in treating inflammation, and particularly conditions that involve neutrophil influx; they are also useful in inhibiting peptic ulcer formation.

Anionic glucofuranose derivatives, methods of making and using the same

The invention provides a method of therapeutically treating a warm blooded animal afflicted with an autoimmune disease such as rheumatoid arthritis. In one variant, this is accomplished by administering an ethereally monosubstituted monosaccharide having the general formula M.sub.1 -O--Y, and/or an ethereal monosubstitution of monosaccharide derivatives having the general formula M.sub.2 -O--Y, and/or pharmaceutically acceptable organic acid and inorganic acid salts thereof as defined hereinafter. In a preferred variant, a synergistic mixture is used containing one or more of the foregoing compounds as a first ingredient and an additional compatible substance as a second ingredient which is effective to therapeutically treat autoimmune diseases in warm blooded animals. The invention further provides a novel synergistic composition for therapeutically treating warm blooded animals afflicted with an autoimmune disease which consists essentially of the aforementioned first and second ingredients.

Method of therapeutically treating a warm blooded animal afflicted with

The invention provides a method of therapeutically treating a warm blooded animal afflicted with an autoimmune disease such as rheumatoid arthritis. In one variant, this is accomplished by administering an ethereally monosubstituted monosaccharide having the general formula M.sub.1 --O--Y, and/or an ethereal monosubstitution of monosaccharide derivatives having the general formula M.sub.2 --O--Y, and/or pharmaceutically acceptable organic acid and inorganic acid salts thereof as defined hereinafter. In a preferred variant, a synergistic mixture is used containing one or more of the foregoing compounds as a first ingredient and an additional compatible substance as a second ingredient which is effective to therapeutically treat autoimmune diseases in warm blooded animals. The invention further provides a novel synergistic composition for therapeutically treating warm blooded animals afflicted with an autoimmune disease which consists essentially of the aforementioned first and second ingredients.

Inosiplex has been found to be useful as an anti-inflammatory agent, e.g., to treat rheumatoid arthritis. There is no need to employ known anti-inflammatory agents, e.g., indomethacin or aspirin, with it and, in fact, the anti-inflammatory action of inosiplex is reduced if either of these two drugs are present.

Method of treating inflammation using inosiplex

Ethereally substituted monosaccharides are prepared from certain selectively derivatized monosaccharides. In practicing the method: 1. a monosaccharide derivative having the general formula A.sub.1 -O-H, wherein O is oxygen, H is hydrogen and A.sub.1 is the residue of a monosaccharide selected from the group consisting of pentoses, hexoses and heptoses which has been derivatized with at least one substance selected from the group consisting of (1-a) at least one aliphatic alcohol containing 1-18 carbon atoms to produce an hydrolyzable acetal group at the site of at least one available hydroxyl residue, (1-b) at least one aldehyde containing 1-18 carbon atoms to produce at least one hydrolyzable acetal group at the site of at least one available hydroxyl residue, (1-c) at least one ketone containing 1-18 carbon atoms to produce at least one hydrolyzable ketal group at the site of at least one available hydroxyl residue, and (1-d) at least one organic acid residue containing 1-18 carbon atoms to produce an hydrolyzable ester group at the site of at least one available hydroxyl residue; is reacted with 2. an organic halide having the general formula Y - X, wherein X is selected from the group consisting of chlorine, bromine and iodine and Y is selected from the group consisting of (2-a) cyclic monovalent nitrogen containing organic radicals and residua, and (2-b) monovalent organic radicals and residue having the general formula -R.sub.1 B wherein B is selected from the group consisting of ##STR1## --O--R.sub.4 and --S--R.sub.4, R.sub.1 is a divalent organic radical having a linear carbon chain length of about 1-7 carbon atoms, R.sub.2 and R.sub.3 are selected from the group consisting of --H,--OH, --SH, halogen and monovalent organic radicals and residua having a linear carbon chain length of about 1-7 carbon atoms, R.sub.4 is selected from the group consisting of --H and monovalent organic radicals and residua having a linear carbon chain length of about 1-7 carbon atoms, N is nitrogen, O is oxygen, S is sulfur and H is hydrogen; To produce an ethereally substituted monosaccharide derivative having the general formula A-O-Y wherein A, Y and O are as above defined. The monosaccharide derivative (1) and the organic halide (2) are reacted at an elevated reaction temperature while dissolved in a substantially anhydrous organic solvent in the presence of a solid substantially anhydrous strong inorganic base of a metal selected from the group consisting of the alkali metals and the alkaline earth metals. The resultant ethereally substituted monosaccharides may be partially or fully hydrolyzed in an aqueous acidic medium. In one preferred variant, 1,2:5,6-di-O-isopropylidene 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose is prepared and, when desired, thereafter partially or fully hydrolyzed to produce 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose or 3-O-3'-(N'-N'-dimethylamino-n-propyl-D-glucose in the free amine and/or salt forms. The method is capable of preparing the ethereally substituted monosaccharides in high yield and purity with a minimum of side products. The resultant compounds exhibit striking antiviral activity and/or have other therapeutically valuable properties and are useful in the treatment of warm-blooded animals.

Preparation of ethers of monosaccharides

The invention provides a novel therapeutic composition comprising a pharmaceutically acceptable carrier containing a therapeutically effective amount of an ethereal monosubstitution of a monosaccharide derivative having the general formula S-O-Y, wherein S is the residue of the monosaccharide derivative selected from the group consisting of pentoses, hexoses and heptoses as single or polysubstituted acetals, ketals or esters and Y is selected from the group consisting of cyclic monovalent nitrogen-containing organic radicals and residua and monovalent organic radicals and residua having the general formula ##STR1## wherein R.sub.1 is a divalent organic radical having a linear carbon chain length of about 1-7 carbon atoms and R.sub.2 and R.sub.3 are selected from the group consisting of --H, --OH, --SH; halogen and monovalent organic radicals and residua having a linear carbon chain length of about 1-7 carbon atoms. The invention also provides certain novel ethereal monosubstitutions of monosaccharide derivatives, of which 3-O-3'-(N',N'-dimethylamino-n-propyl)-1,2-O-isopropylidene-D-glucofuranose is an example. The novel monosaccharide derivatives show striking antiviral activity or other therapeutically valuable properties and are useful as active ingredients in the above therapeutic composition. The invention further provides a method of therapeutically treating warm-blooded animals with the aforementioned therapeutic composition and novel monosubstituted monosaccharide derivatives.

Therapeutic composition and method of therapeutically treating warm

The invention provides a novel therapeutic composition comprising a pharmaceutically acceptable carrier containing a therapeutically effective amount of an ethereally monosubstituted monosaccharide having the general formula S--O--Y, wherein S is the residue of a monosaccharide selected from the group consisting of pentoses, hexoses and heptoses and Y is selected from the group consisting of cyclic monovalent nitrogen containing organic radicals and residua and monovalent organic radicals and residua having the general formula ##STR1## wherein R.sub.1 is a divalent organic radical having a linear carbon chain length of about 1-7 carbon atoms and R.sub.2 and R.sub.3 are selected from the group consisting of --H, --OH, --SH, halogen and monovalent organic radicals and residua having a linear carbon chain length of about 1-7 carbon atoms. The invention also provides certain novel ethereally monosubstituted monosaccharides, of which 3--O--3'-(N',N'-dimethylamino-n-propyl)-D-glucose is an example. The novel monosaccharides show striking antiviral activity or other therapeutically valuable properties and are useful as an active ingredient in the above therapeutic composition. The invention further provides a method of therapeutically treating warm blooded animals with the aforementioned therapeutic composition and novel monosubstituted monosaccharides.

The present invention provides a novel method of enhancing learning and/or memory in warm blooded animals. This is accomplished by administering an effective amount to enhance the ability of the animal to learn tasks, or to enhance the ability of the animal to memorize information of at least one ethereally monosubstituted monosaccharide having the general formula S.sub.1 --O--Y, and/or at least one ethereal monosubstitution of monosaccharide derivatives having the general formula S.sub.2 -- O--Y, and/or organic acid and inorganic acid salts thereof as defined hereinafter. The warm blooded animal is subjected to an environment wherein it is required to learn tasks and/or memorize information and it is capable of learning tasks and memorizing informaton at markedly increased rates.

Method of enhancing learning and/or memory in warm blooded animals

The invention provides a novel therapeutic composition comprising a pharmaceutically acceptable carrier containing a therapeutically effective amount of an ethereal monosubstitution of a monosaccharide derivative having the general formula S--O--Y, wherein S is the residue of the monosaccharide derivative selected from the group consisting of pentoses, hexoses and heptoses as single or polysubstituted acetals, ketals or esters and Y is selected from the group consisting of cyclic monovalent nitrogen-containing organic radicals and residua and monovalent organic radicals and residua having the general formula ##EQU1## wherein R.sub.1 is a divalent organic radical having a linear carbon chain length of about 1-7 carbon atoms and R.sub.2 and R.sub.3 are selected from the group consisting of --H, --OH, --SH, halogen and monovalent organic radicals and residua having a linear carbon chain length of about 1-7 carbon atoms. The invention also provides certain novel ethereal monosubstitutions of monosaccharide derivatives, of which 3-O-3'-(N',N'-dimethylamino-n-propyl)-1,2-O-isopropylidene-D-glucofuranose is an example. The novel monosaccharide derivatives show striking antiviral activity or other therapeutically valuable properties and are useful as active ingredients in the above therapeutic composition. The invention further provides a method of therapeutically treating warm-blooded animals with the aforementioned therapeutic composition and novel monosubstituted monosaccharide derivatives.

Novel ethereal monosubstitutions of monosaccharide derivatives

The invention provides a novel therapeutic composition comprising a pharmaceutically acceptable carrier containing a therapeutically effective amount of an ethereally monosubstituted monosaccharide having the general formula S-O-Y, wherein S is the residue of a monosaccharide selected from the group consisting of pentoses, hexoses and heptoses and Y is selected from the group consisting of cyclic monovalent nitrogen containing organic radicals and residua and monovalent organic radicals and residua having the general formula ##EQU1## wherein R.sub.1 is a divalent organic radical having a linear carbon chain length of about 1-7 carbon atoms and R.sub.2 and R.sub.3 are selected from the group consisting of --H, --OH, --SH, halogen and monovalent organic radicals and residua having a linear carbon chain length of about 1-7 carbon atoms. The invention also provides certain novel ethereally monosubstituted monosaccharides, of which 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose is an example. The novel monosaccharides show striking antiviral activity or other therapeutically valuable properties and are useful as an active ingredient in the above therapeutic composition. The invention further provides a method of therapeutically treating warm blooded animals with the aforementioned therapeutic composition and novel monosubstituted monosaccharides.

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Chicago, IL, United States of America

Paul Gordon