text:
|Publication number
|Publication type
|Application number
|Publication date
|Apr 12, 1977
|Filing date
|Sep 2, 1975
|Priority date
|Dec 14, 1973
|Publication number
|Paul Gordon
|Original Assignee
|Strategic Medical Research Corporation
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (1), Referenced by (28), Classifications (8), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a division of application Ser. No. 424,786 filed Dec. 14, 1973, and now U.S. Pat. No. 3,939,146, is a continuation in part of application Ser. No. 424,786, in turn, my copending application Ser. No. 337,134, filed on Mar. 1, 1973 and now U.S. Pat. No. 3,939,145, for Therapeutic Composition, Novel Compounds Useful Therein and Method of Using the Same.
The present invention is concerned with a novel therapeutic composition and a method of therapeutically treating warm-blooded animals therewith. In one of its more specific variants, the invention further relates to certain novel ethereal monosubstitutions of monosaccharide derivatives which are especially useful as ingredients in the aforementioned composition and in practicing the aforementioned method.
Many diseases caused by certain living microorganisms may be treated very effectively by administering a therapeutically effective amount of an antibiotic. However, antibiotics are not effective in the treatment of virus infections insofar as suppressing the proliferation of the virus particles and reducing cell damage are concerned.
A number of substances other than antibiotics have been proposed heretofore for use in treating virus infections, but they have not been used extensively for a number of reasons. For instance, the previously proposed antiviral agents usually exhibit very low antiviral activity and have little positive effect on the course of the viral infection. The previously proposed antiviral drugs also have not been effective in the treatment of a wide spectrum of virus infections and this has been a major disadvantage. The therapeutic treatment of a large number of patients having undetermined viral infections of widely differing types is impractical with the narrow spectrum prior art antiviral drugs, as it is too difficult to determine the exact virus causing the infection and then select an effective drug. Many potentially effective antiviral drugs are toxic and cannot be safely administered to patients, and still other antiviral drugs have undesirable side effects. As a result of the foregoing and other deficiencies, it is apparent that an entirely satisfactory wide spectrum nontoxic antiviral drug has not been available heretofore for routinely administering to patients having a viral infection caused by many of the common viruses.
It has been discovered that certain ethereal monosubstitutions of monosaccharide derivatives provide important biological signals which allow living cells to resist virus infections. As will be described in greater detail hereinafter, the signals also provide other types of control in cell chemistry.
The therapeutic compositions of the invention overcome the disadvantages of the prior art antiviral agents noted above, and also produce other unusual and unexpected results. For example, the ethereal monosubstitutions of monosaccharide derivatives described hereinafter are therapeutically effective at very low concentrations, while at the same time they exhibit no side effects and are very nontoxic. The ratio of the minimum toxic to therapeutic dose is greater than 50 in both tissue culture and animals.
The antiviral compounds and the therapeutic compositions containing the same disclosed and claimed in my earlier filed copending application Ser. No. 337,134 and now U.S. Pat. No. 3,939,145 possess striking antiviral properties and are highly effective in the treatment of a wide variety of viral infections in warm blooded animals. Nevertheless, the earlier described antiviral compounds and therapeutic compositions do have certain limitations and disadvantages which are over come by the present invention. For example, the earlier described compounds possess strong hydrophilic properties due to the presence of a plurality of free hydroxyl groups which result in several limitations on the effective use thereof in situ including short shelf life, variability of the stability in solution as a function of temperature, and extreme hygroscopicity.
The compounds of the present invention have been found to be more desirable with respect to the properties listed above. This is presently believed to be the direct result of a decrease in the hydrophilic properties and, thereby, an increase in the solubility of the compounds in the fatty tissues of a warm-blooded animal which has been therapeutically treated therewith. This technique also aids in the transportation of the drug to a desired tissue or the concentration thereof on a desired tissue. In the practice of one variant of the invention, an organic substituent is selected which blocks at least one free monosaccharide hydroxyl group and thereby decreases the hydrophilic properties and allows the compound to be transported or concentrated in fatty tissues. In a further variant, a labile organic substituent is selected which may be removed in vivo during treatment of the warm-blooded animal after it has served its purpose, thereby unblocking the hydroxyl group(s).
It is an object of the present invention to provide a therapeutic composition including a pharmaceutically acceptable carrier and a therapeutically effective amount of certain ethereal monosubstitutions of monosaccharide derivatives to be described more fully hereinafter.
It is a further object to provide certain novel compounds to be described more fully hereinafter, which are ethereal monosubstitutions of monosaccharide derivatives exhibiting striking antiviral activity and/or other therapeutically valuable properties.
It is still a further object to provide a therapeutic composition containing one or more of the novel monosaccharide derivatives of the invention.
It is still a further object to provide a method of therapeutically treating a warm-blooded animal wherein the above described therapeutic composition and/or novel monosaccharide derivatives are administered thereto in a therapeutically effective amount.
Still other objects and advantages of the invention will be apparent to those skilled in the art upon reference to the following detailed description.
The novel therapeutic composition of the invention comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of an ethereal monosubstitution of a monosaccharide derivative having the general formula S-O-Y and organic and inorganic acid salts thereof, wherein S is the residue of a monosaccharide selected from the group consisting of pentoses, hexoses and heptoses which has been derivatized with (a) one or more aliphatic alcohols containing 1-18 carbon atoms and preferably 1-4 carbon atoms to produce an acetal group at one or more available hydroxyl residua, (b) one or more aldehydes containing 1-18 carbon atoms and preferably 1-4 carbon atoms to produce single or multiple acetal groups at one or more available hydroxyl residua, (c) one or more ketones containing 1-18 carbon atoms and preferably 1-4 carbon atoms to produce single or multiple ketal groups at one or more available hydroxyl residua, or (d) one or more organic acid residua containing 1-18 carbon atoms and preferably 1-4 carbon atoms to produce ester groups at one or more available hydroxyl residua, 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 ##STR2## wherein R1 is a divalent organic radical having a linear carbon chain length of about 1-7 carbon atoms and R2 and R3 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. When R2 or R3 is halogen, the halogen may be F, Cl, Br or I, of which Cl or Br is usually preferred. The organic radical R1, and R2 and R3 when they are organic radicals, may be branched or unbranched linear carbon chains and may be saturated or unsaturated, and, when saturated, the linear and/or branched carbon chains may contain one or more double or triple carbon-to-carbon bonds. The linear and/or branched carbon chains of R1, R2 and R3 may be substituted or unsubstituted and, when substituted, one or more substituents may be present, such as --OH, --SH, halogen (F, Cl, Br and/or I), branched or unbranched and saturated or unsaturated hydrocarbon radicals containing 1-7 and preferably 1-3 carbon atoms, --OR4 and/or --SR4 radicals wherein R4 is a branched or unbranched and saturated or unsaturated hydrocarbon radical containing 1-7 and preferably 1-3 carbon atoms, carboxylic acid residua containing 1-7 and preferably 1-3 carbon atoms, and amino groups and aminohydrocarbon radicals containing 1-7 and preferably 1-3 carbon atoms. Preferably R1 is a hydrocarbon radical having a linear carbon chain length of 1-3 or 1-4 carbon atoms and R2 and R3 are individually selected from the group consisting of hydrogen and/or hydrocarbon radicals having linear carbon chain lengths of 1-3 or 1-4 carbon atoms.
Examples of compounds from which cyclic organic radicals and residua are derived include (a) monovalent nitrogen containing saturated, unsaturated or aromatic carbocyclic compounds containing about 4-8 carbon atoms in the ring and preferably about 5-6 carbon atoms in the ring and at least one nitrogen atom attached thereto or to an organo substituent thereon, (b) heterocyclic organic compounds containing about 3-8 carbon atoms in the ring and at least one ring nitrogen atom and (c) derivatives of the foregoing compounds wherein at least one substituent is present, such as --OH, --SH, halogen (F, Cl, Br and/or I), branched or unbranched and saturated or unsaturated hydrocarbon radicals containing 1-7 and preferably 1-3 carbon atoms, --OR5 and/or --SR5 radicals wherein R5 is a branched or unbranched and saturated or unsaturated hydrocarbon radical containing 1-7 and preferably 1-3 carbon atoms, carbocyclic acid residua containing 1-7 and preferably 1-3 carbon atoms, and amino groups and aminohydrocarbon radicals containing 1-7 and preferably 1-3 carbon atoms.
The derivatized monosaccharide residue S may exist in an open chain or cyclic form having the general formulae: ##STR3## wherein X and Z are H, OH, hydroxyalkyl, alkoxyl and/or alkoxyalkyl containing up to 3 carbon atoms, W is H, alkyl, alkenyl, cyclic alkane or cyclic aromatic containing 1-18 and preferably 1-6 carbon atoms or acyl containing 1-18 and preferably 1-4 carbon atoms, and Y represents the same organic radicals and residua as aforementioned for the general formula S-O-Y. The above general formulae illustrate the various isomers of the pentoses, hexoses and heptoses, the relative spatial configuration of the --H and --OH groups about the ring, and the monosubstitution thereof in accordance with one presently preferred variant of the invention. The hydroxyl or alkoxyl residue of the hemiacetal or hemiketal linkage may assume an α or a β configuration. The compounds of the invention may be in the form of anomers or mixtures of anomers.
The configurations of the various derivatives of isomers of the pentoses, hexoses and heptoses are well known to those skilled in this art and numerous reference books are available on the subject, the teachings of which are incorporated herein by reference. For example, see Textbook of Biochemistry, 4th Edition, by West et al (1966) and The Monosaccharides by Stanek, Cerny, Kocourek and Pacak (1963). The prior art discloses, for example, a total of eight open chain isomers for the reducing hexoses, and an even larger number of open chain isomers for the reducing heptoses. Either the D-series or the L-series of the pentoses, hexoses and heptoses may be used in practicing the invention, but it is usually preferred to use the D-series. The hexoses often give the best results and especially D-talose, D-galactose, L-galactose, D-idose, D-gulose, D-mannose, D-glucose, L-glucose, D-altrose and D-allose. The aforementioned pentoses, hexoses and heptoses may be ethereally monosubstituted in any available position and derivatized at one or more of the remaining hydroxyl groups. Nevertheless, it is understood that substitution of certain positions of specific monosaccharide derivatives results in more therapeutically active or less toxic compounds. For instance, substitution of the 3-O- position of 1,2-O-isopropylidene-D-glucofuranose or 1,2:5,6-di-O-isopropylidene-D-glucofuranose and the 6-O- position of 1,2-O-isopropylidene-D-galactopyranose or 1,2:3,4-di-O-isopropylidene-D-galactopyranose results in especially valuable compounds.
The following substituents may be ethereally substituted on any of the available positions of the various isomers of the pentoses, hexoses and heptoses to produce nontoxic compounds having exceptional therapeutic activity:
Of the foregoing substituents, -(N',N'-dimethylamino-n-propyl) is presently preferred and especially when substituted in the 3-O- position of 1,2-O-isopropylidene-D-glucofuranose or 1,2:5,6-di-O-isopropylidene-D-glucofuranose or the 6-O- position of 1,2-O-isopropylidene-D-galactopyranose or 1,2:3,4-di-O-isopropylidene-D-galactopyranose.
The following compounds have been found to have exceptional wide spectrum antiviral activity and other therapeutically valuable properties and are presently preferred for use in the composition and method of the invention:
and organic and inorganic acid salts thereof.
Of the foregoing compounds, 3-O-3'-(N',N'-dimethylamino-n-propyl)-1,2-O-isopropylidene-D-glucofuranose is presently preferred.
Additional compounds of the general formula S-O-Y, wherein Y is ##STR4## which may be used in practicing the invention are listed below:
______________________________________ SubstituentMonosaccharide Residue (Y)(S) R1 R2 R3______________________________________3-O-1,2-O-isopropylideneD-glucofuranose 3'-n-propyl H methyl " " ethyl " " " H ethyl " 2'-iso-propyl methyl methyl " 3'-1,2-propenyl " " " sec-butyl " " " 3'-butyl " " " 2'-ethyl H H " methyl H H6-O-1,2-O-isopropylideneD-galactopyranose 3'-n-propyl H methyl " " ethyl " " " H ethyl " 3'-1,2-propenyl methyl methyl " 2'-iso-propyl " " " sec-butyl " " " 3'-butyl " " " 2'-ethyl H H " methyl H H3-O-1,2:5,6-di-O-iso-propylidene-D-gluco-furanose 3'-n-propyl H methyl " " ethyl " " " H ethyl " 2'-iso-propyl methyl methyl " 3'-1,2-propenyl " " " sec-butyl " " " 3'-butyl " " " 2'-ethyl H H " methyl H H6-O-1,3:3,4-di-O-iso-propylidene-D-galactopyranose 3'-n-propyl H methyl " " ethyl " " " H ethyl " 3'-1,2-propenyl methyl methyl " 2'-iso-propyl " " " sec-butyl " " " 3'-butyl " " " 2'-ethyl H H " methyl H H______________________________________
Still other compounds of the general formula S-O-Y, wherein Y is a cyclic monovalent nitrogen-containing organic radical or residue, which may be used in practicing the invention, are as follows:
______________________________________ Substituent (Y)______________________________________ SubstituentMonosaccharide Residue on the(S) Cyclic Radical Cyclic Radical______________________________________3-O-1,2-O-isopropylidene-D-glucofuranose 4'-piperidyl H " 3'-piperidyl methyl, H " 2'-piperidyl " " 3'-pyrrolidyl " " 2'-pyrrolidyl "6-O-1,2-O-isopropylidene-D-galactopyranose 4'-piperidyl H " 3'-piperidyl methyl, H " 2'-piperidyl " " 3'-pyrrolidyl " " 2'-pyrrolidyl "3-O-1,2:5,6-di-O-iso-propylidene-D-glucofuranose 4'-piperidyl H " 3'-piperidyl methyl, H " 2'-piperidyl " " 3':pyrrolidyl " " 2'-pyrrolidyl 10 "6-O-1,2:3,4-di-O-isopropylidene-D-galactopyranose 4'-piperidyl H " 3'-piperidyl methyl, H " 2'-piperidyl " " 3'-pyrrolidyl " " 2'-pyrrolidyl "______________________________________
The present invention also provides certain novel compounds which have wide spectrum antiviral activity. The novel compounds may be defined generically as follows:
and organic and inorganic acid salts thereof.
Species of the foregoing novel compounds which possess striking wide spectrum antiviral activity are as follows:
3-O-2'-(N',N'-dimethylaminopropyl)-1,2:5,6 -di-O-isopropylidene-D-glucofuranose,
and organic and inorganic acid salts thereof.
In general, the preparation of the monosubstituted compounds described herein involves the formation of alkyl ethers or substituted alkyl ethers at selected positions on the desired monosaccharide derivative, such as at position 3-O- of 1,2-O-isopropylidene-D-glucofuranose or 1,2:5,6-di-D-glucofuranose, position 6-O- of 1,2-O-isopropylidene-D-galactopyranose or 1,2:3,4-di-O-isopropylidene-D-galactopyranose, and position 3-O- of 1,2-O-isopropylidene-D-fructopyranose or 1,2:5,6-di-O-isopropylidene-D-fructopyranose. The condensation of the substituent substrate with the monosaccharide derivative at the desired position may be achieved by various prior art techniques. One method is described in U.S. Pat. No. 2,715,121, issued Aug. 9, 1955, to GLEN et al., the disclosure of which is incorporated herein by reference. The method described in this patent requires extreme reaction conditions and often gives low yields. The product purity is also less than satisfactory.
The preferred method of preparation involves much milder reaction conditions than employed in U.S. Pat. No. 2,715,121. The side reactions are minimized, the purity of the final product is greatly improved and the method may be adapted to a series of solvents having varying properties such as dioxane, tetrahydrofuran and benzene. Briefly, the improved method involves the reaction of a monosaccharide derivative which is blocked with one or more organo groups in the hydroxyl group positions adjacent the desired position to be substituted. The blocked monosaccharide is dissolved in one of the foregoing solvents and is reacted with a halogenated organo amino compound having the desired carbon chain length and configuration in the presence of a base such as sodium hydroxide. Selective removal of one or more blocking groups may be accomplished by hydrolysis under specific conditions resulting in a new product which is to be considered a compound of this invention. The reaction of either the blocked compound or the hydrolyzed compound with any organic or inorganic acid to form a salt thereof or with any organic or inorganic base to form a salt thereof results in a compound of this invention.
It is understood that simple derivatives of the compounds described herein are embraced by the invention. Such derivatives may be prepared by prior art techniques and procedures and used as an ingredient in the therapeutic composition and method of the invention.
For example, the free amine compounds are basic and form organic acid salts and inorganic acid salts, and the resulting salts are useful in the therapeutic composition and method of the invention. The salts may be prepared by the usual prior art techniques, such as by adding the free amine compound to water and then adding the desired organic acid or mineral acid thereto in an amount sufficient to neutralize the free amine. Examples of suitable acids include HCl, HBr, H2 SO4, HNO3, benzoic acid, p-aminobenzoic acid, p-acetamido-benzoic acid, p-hydroxybenzoic acid, alkane sulfonic acid, p-toluene sulfonic acid, acetic acid, alkylcarboxylic acids, oxalic acid, tartaric acid, lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid and glucuronic acid. The aqueous solution of the resulting salt is evaporated to the volume necessary to assure precipitation of the salt upon cooling. The precipitated salt is recovered by filtration, washed and dried to obtain a final amine salt product. The amine salts are often preferred for use in formulating the therapeutic compositions of the invention as they are crystalline and relatively nonhygroscopic. The amine salts are also better adapted for intramuscular injection than are the free amines.
Prior art blocking techniques may be employed such as acetonization and acetylation. Suitable prior art blocking methods are described in the aforementioned U.S. Pat. No. 2,715,121 and are described in the specific examples appearing hereinafter. In instances where an aldehyde or ketone is reacted with hydroxyl groups on adjacent carbon atoms, the initial compound may be dissolved in the desired aldehyde or ketone under anhydrous conditions and a Lewis acid catalyst is added in a catalytic quantity, such as 1% zinc chloride or anhydrous phosphoric acid. Often acetone is the preferred blocking agent, but aldehydes or ketones of much higher molecular weight may be used when desired such as those containing up to 25 carbon atoms. The reaction mixture is agitated at room temperature for a prolonged reaction period, such as 24-48 hours. The compound may be blocked in a plurality of positions, such as the 1,2- and 5,6- positions. It is usually preferred to block positions such as the 1,2- positions as the resulting partially blocked compound is much less toxic than compounds blocked in all available hydroxyl groups.
It is also possible to block one or more free hydroxyl positions of the compound with an ester group, wherein the carboxylic acid residue contains 1-18 and preferably 1-3 carbon atoms. The ester derivatives likewise may be prepared following prior art techniques such as by reacting a carboxylic acid anhydride with the compound following prior art practices. Additionally, the α or β alkyl derivatives of monosaccharide derivatives such as 2,3:5,6-di-O-isopropylidene-D-glucofuranoside may be prepared following prior art techniques. In this latter instance, the compound is dissolved in a dry alcohol having the desired carbon chain length with aformentioned residua and reacted with the compound in the presence of a catalyst such as hydrogen chloride of Dowex 50 H+ resin. While the above discussed derivatives are presently preferred, it is understood that still other simple derivatives may be prepared following prior art techniques and then used in practicing the present invention. In addition to the foregoing, the compounds may also include monosubstitutions of monosaccharide derivatives in which the substrate ##STR5## may be replaced by a substituent R7, where R7 is a deoxymonosaccharide derivative of halogen, keto, amino, lower alkyl, mercapto, alkenyl, alkynyl, aromatic, heterocyclic or alkylcarboxylic acid and its derivatives. R7 may also represent the same groups as the above substrate of the monosaccharide derivative ethers. Still other antiviral agents have a general formula S--O--Y wherein Y is --R8 --S--R9, where R8 is a saturated or unsaturated hydrocarbon radical containing 1-7 carbon atoms and R9 is a monovalent saturated or unsaturated hydrocarbon radical containing 1-7 carbon atoms and hydrogen.
The compounds of the invention are especially useful as wide spectrum antiviral agents for the therapeutic treatment of warm-blooded animals. They exhibit potent antiviral activity against both RNA and DNA viruses, contrary to the prior art antiviral agents. The compounds of the present invention exhibit marked suppression of virus particle multiplication and virus-induced cell injury in animal and human cell tissue culture systems against such widely varying viruses as herpes simplex, influenza A, mumps, poliovirus and rhinovirus. In tests in the whole animal, the compounds can reduce mortality and morbidity manifestations of influenza A infection by from 50 to 85%.
The compounds of the present invention may be administered to human patient or animal to be treated either orally or by parenteral administration. When the therapeutic composition is to be administered orally, the compound may be admixed with a prior art filler and/or binder such as starch and a disintegrator, and the admixture is pressed into a tablet of a size convenient for oral administration. Capsules also may be filled with the powdered therapeutic composition and administered orally. Alternatively, a water solution por suspension of the therapeutic composition may be admixed with a flavored syrup such as cherry syrup and administered orally. When the therapeutic composition is administered by intramuscular injection, the compound is usually dissolved in a physiological saline solution which contains sodium chloride in sufficient concentration to make the overall solution to be injected isotonic to body fluids. A salt of the free amine compound is usually preferred in instances where the compound is administered by intramuscular injection. In treating upper respiratory viral infections, the salt form in aqueous solution may also be administered by nasopharyngeal spary. Administration also may be by means of a suppository in patients unable to retain medication administered by mouth.
The dosage may be varied over extremely wide limits, as the compounds are effective at low dosage levels and are relatively free of toxicity and adverse side effects. The compounds may be administered in the minimum quantity which is therapeutically effective, and the dosage may be increased as desired up to the maximum dosage tolerated by the patient. Animal toxicity data indicate that the limiting nontoxic dosage may be up to 100-200 times the minimum effective dosage. Also, it is not necessary to carefully control the dosage for patients sensitive to the prior art antiviral drugs. As a general rule, the compound may be administered in an amount of about 1-40 milligrams per kilogram of body weight per day, and preferably in an amount of about 2-20 miligrams per kilogram per day, over the period required for treatment of the viral infection.
Surprisingly, the compounds described herein have still other unusual and unexpected therapeutically valuable properties. The learning of new tasks is enhanced. The therapeutic composition also protects against death due to water deprivation. The buffer capacity of the compounds over a pH range of approximately 7-9.8 is very good and they may be used for this purpose. Certain compounds also exhibit lubricative properties and may be used as a specialized lubricant. Compounds such as 3-O-D-glucopropionitrile and its derivatives are photosensitive and may be used in photographic applications.
It has been further discovered that the normal life span of tissue culture cells being grown in a prior art tissue culture medium may be extended very substantially and often by several fold by growing the cells in a tissue culture medium which contains an effective amount of one or more of the antiviral compounds described herein. This variant of the present invention is especially useful in the growing of human embryo cells and it has been observed that such cells survive for a significantly longer period of time in a tissue culture medium in the presence of as little as 2 micrograms per milliliter of one or more of the antiviral compounds described herein. However, much larger quantities of the compound may be present, such as the quantity described herein in the treatment of tissue culture cells infected with a virus, or in amounts up to the tolerance level of the cells. Preferably, the compound is 3-O-3'(N',N'-dimethylamino-n-propyl)-1:2-O-isopropylidene glucofuranose. This variant of the invention reduces research costs due to the longer life span of the tissue culture cells. It also has other positive effects as the surviving cells tend to be more vigorous and in a better state of preservation and more consistent research results are obtained.
It has also been discovered that the antiviral compounds disclosed herein the pharmaceutical compositions containing the same, and the method of the invention are effective in the treatment of metastatic cancer in warm blooded animals. In practicing this variant of the invention, a warm blooded animals having a metastatic cancer, as carcinoma, is treated by administering thereto a therapeutically effective amount of at least one anti-viral compound disclosed herein. The compound may be administered at the dosage level described herein for common viral infections such as influenza. Often much larger quantities are more effective such as 10-50 times this amount, or quantities within the tolerance level of the warm blooded animal regardless of the amount. Death from cancer in warm blooded animals is caused by metastatic spread of the tumor cells, which in turn results from a greater freedom to translocate that individual cells develop when they become cancerous (Leighton, J., The Spread of Cancer. Academic Press, New York and London, 1967). The compounds used in the treatment of cancers specifically prevent this tendency to metastasis, thereby rendering the cancer non-malignant and allowing the warm blooded animal to live.
The compounds used in the treatment of metastatic cancer and/or in the tissue culture medium in the growing of tissue culture cells are preferably the antiviral compounds disclosed herein. However, it is understood that the antiviral compounds disclosed in my earlier filed application Ser. No 337,134 also are useful for this purpose and may be substituted in equal quantities. The teachings of application Ser. No. 337,134 are therefore incorporated herein by reference.
The following specific examples further illustrate the present invention.
To a solution of 104 g (0.4 mole) of 1,2:5,6-di-O-isopropylidene-D-glucofuranose in 550 ml of 1,4-dioxane was added 189.7 g (1.2 mole) of 3-chloro-N,N-dimethylamino propane in the form of the hydrochloride salt and 144 g (3.6 mole) of sodium hydroxide. The suspension was mechanically stirred and heated to reflux for 18 hours. The reaction mixture thus prepared was filtered, the solids were washed with 1,4-dioxane and the washings were combined with the filtered liquid. The solvent was removed under reduced pressure and an amber-colored viscous oil was obtained.
The oil was distilled under high vacuum (less than 1 mm Hg) while using a very slight dry nitrogen purge to obtain high and low boiling fractions. The low boiling fraction was identified as unreacted 3-chloro-N,N-di-methylamino propane. The high boiling fraction had a boiling point of 148�-154� C at 2.5 mm Hg and was a clear viscous oil with an optical rotation of {α}D 25 = -19.3� neat (100 mm) and a density of 0.95 g/cc. The refractive index was ηD 21 = 1.4576. Gas chromatography showed a purity greater than 99%. An elemental analysis showed: C, 59.13; H, 8.99; N, 4.12; O, 27.7. The yield was 80% of the novel compound 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose.
A portion of the above oil (10 g) was hydrolyzed in aqueous sulfuric acid at a pH value of 1.9-2.1 for 10 hours with refluxing. The resulting solution was adjusted to a pH value of 4.5 with saturated Ba(OH)2 solution, centrifuged, and filtered through an ultrafine filter. The filtrate was lyophillized to a white-to-slightly yellow solid having a melting point of 78�-80� C. Gas chromatography data indicated above 99% purity of the novel compound 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucopyranose. In thin-layer chromatography, the flow rate on silica gel with a solvent mixture composed of n-propanol, ethyl acetate, H2 O and NH3 in the ratio by volume of 60:10:30:10, respectively, was Rf = 0.356.
A portion of the oil is partially hydrolyzed to 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose by dissolving it in distilled water and adjusting the pH of the approximately 1M solution to 3.0 � 0.2 with 6N HCl. The solution is extracted twice with chloroform and the clear aqueous solution is refluxed for about two hours. Completion of partial hydrolysis reaction was monitored by gas chromatography from disappearance of the peak of parent compound and appearance of a new peak with larger retention time. The solution is then cooled, made alkaline with 30% sodium hydroxide to pH 10.5 and then extracted with chloroform. The chloroform phase is separated, dried over anhydrous magnesium sulfate and vacuum distilled to remove the solvent. The resulting colorless viscous oil has optical rotation of αneat � = -12� and refractive index of 1.4687 at 25� C. Alternatively, the compound can be obtained as the hydrochloride salt by lyophillizing the aqueous solution after partial hydrolysis at pH 4.0-4.5. a white crystalline material is obtained which is recrystallized from methanol. The crystalline hydrochloride of 1,2-O-ispropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose has a melting point of 181�-183� C and purity as indicated by gas chromatography is 98+%. Infrared spectrophotometry indicates the presence of strong --OH band which is not present in the parent oil. The elemental analysis for the hydrochloride salt in a typical batch showed: C, 49.09; H, 8.40; N, 4.14; Cl, 10.32; O, 28.12. Theoretical values are as follows: C, 49.19; H, 8.19; N, 4.09; Cl, 10.39; O, 28.11.
The gas-liquid chromatograms for the above intermediate and final novel compounds were run on a Beckman GC, Model 72-5 with a hydrogen flame detector. The column used for the intermediate novel compound was a commercially available SE-52 column, wherein methyl phenyl resins act as stationary phases supported on Chromosorb W (H.P.) which is made by Johns-Manville Corporation. The final novel compound was chromatographed on a Chromosorb 103 glass column, which is packed with porous resins. The foregoing materials are commercially available.
Starting with 51 g (0.3 mole) of 4-chloro-N-methylpiperidine hydrochloride and 26 g (0.1 mole) of 1,2:5,6-di-O-isopropylidene-D-glucofuranose and 36 g of NaOH in 150 ml 1,4-dioxane, condensation was accomplished using the general procedure outlined in Example 1. The residue remaining following vacuum distillation was dissolved and recrystallized from hot methanol. The melting point was 106�-107.5� C (sharp).
Hydrolysis of the above product in H2 SO4 at a pH value of 2.1 yielded 3-O-4'-(N'-methylpiperidyl)-D-glucopyranose having an optical rotation of {α}D 25 = + 38.42� in H2 O. A gas chromatography analysis in accordance with Example 1 indicated that the purity of the product was in excess of 96%. The melting point was 62�-65� C.
A solution of 0.1 mole of 1,2:5,6-di-O-isopropylidene-D-glucofuranose in 50 ml of tetrahydrofuran was added to a suspension of 0.3 mole of 2-chloro-N,N-diethylaminoethane hydrochloride and 36 g of sodium hydroxide in 100 ml of tetrahydrofuran. The suspension was mechanically stirred and refluxed overnight and the reaction mixture was treated as set out in Example 1. The desired product, 1,2:5,6-di-O-isopropylidene-3-O-2'-(N',N'-diethylaminoethyl)-D-glucofuranose was obtained as a clear yellow liquid (boiling point 144�-150�C/0.15 mm Hg) having an optical rotation of {α}D 28 = -20.6� neat and a refractive index of ηD 25 = 1.4532. The liquid solidified on exposure to air, probably due to formation of the carbonate salt. The yield was 85%.
Ten grams of the above product were hydrolyzed with aqueous sulfuric acid at pH value of 1.9-2.1 for ten hours under reflux. The resulting solution was adjusted to a pH value of 4-5 with saturated barium hydroxide solution and then centrifuged and filtered. Lyophillization of the filtrate yielded 6.55 g of light brown crystalline 3-O-2'-(N',N'-diethylaminoethyl)-D-glucopyranose. The optical rotation in water was {α}D 25 = +36.33�. A gas chromatography analysis in accordance with Example 1 indicated that the purity was in excess of 99%.
To 26 g (0.1 mole) of 1,2:5,6-di-O-isopropylidene-D-glucofuranose and 36 g (0.9 mole) of sodium hydroxide in 150 ml of refluxing tetrahydrofuran was added dropwise over one hour 0.3 mole of 3-bromopropionitrile in 50 ml of tetrahydrofuran. The reaction mixture was refluxed for an additional six hours and then filtered. The solids were washed with tetrahydrofuran and the washings were combined with the filtrate. The solvent was removed under reduced pressure and solid 1,2:5,6-di-O-isopropylidene-3-O-3'-propionitrile-D-glucofuranose was obtained. The decomposition point was 165� C and it was light sensitive indicating utility in photographic applications.
Five grams (0.016 mole) of the above product was dissolved in anhydrous ether and added dropwise to a suspension of 0.76 g (0.02 mole) of lithium aluminum hydride in ether. The resulting complex was dissolved in cold hydrochloric acid and neutralized rapidly with sodium bicarbonate, The suspension thus produced was extracted with chloroform and the solvent was removed to obtain a yellow oil in a yield of 250 mg. Gas chromatography in accordance with Example 1 indicated a purity of 98% and there was a sharp infrared band at 3400 cm- 1. The oil was hydrolyzed at a pH value of 2.1 in sulfuric acid and lyophillized to dryness. The yield was 85 mg of 3-O-3'-(n-propylamino)-D-glucopyranose.
The 3-O-2'-(N',N'-dimethylaminopropyl) derivative of 1,2:5,6-di-O-isopropylidene-D-glucofuranose was prepared by condensing 0.1 mole of 1,2:5,6 -di-O-isopropylidene-D-glucofuranose with 0.3 mole of 2-chloro-N,N-dimethylamino propane hydrochloride in the presence of 0.9 mole of sodium hydroxide in 150 ml of 1,4-dioxane. The reaction mixture was fractionally distilled under reduced pressure to obtain a yellow viscous oil (boiling point 142�-145� C/0.07 mm Hg) in 81% yield. The optical rotation was {α}D 25 = -21.5� neat and the refractive index was ηD 25 = 1.4549. Gas chromatography in accordance with Example 1 indicated only one component.
The above prepared yellow viscous oil (10 g) was hydrolyzed with aqueous sufuric acid at a pH value of 2.0 by refluxing for 10 hours. The pH value of the hydrolysate was adjusted to 4-5 with saturated barium hydroxide solution, filtered and lyophillized to obtain 10.5 g of light yellow crystals of 3-O-2'-(N',N'-dimethylaminopropyl)-D-glucopyranose. The optical rotation in water was {α}D 25 = + 37.85�. Gas chromatography in accordance with Example 1 indicated a purity in excess of 82%.
A portion of the oil, 1,2:5,6-di-O-isopropylidene-3-O-2'-(N',N'-dimethylaminopropyl)-D-glucofuranose, is partially hydrolyzed at pH 3.0 � 0.2 as indicated in Example 1. A white crystalline hydrochloride salt is obtained on lyophillization. The salt obtained is highly hygroscopic, with gas chromatographic purity being of the order of 80%.
To 0.1 mole of 1,2:5,6-di-O-isopropylidene-D-glucofuranose was added 0.3 mole of 2,N,N-trimethylaminopropyl chloride hydrochloride along with 36 g of sodium hydroxide. The general reaction procedure was in accordance with Example 1. The oil resulting from the reaction had a boiling point of 144�-146� C at 0.6 mm Hg and an optical rotation of {α}D 20 = -20.05� neat.
The above product was hydrolyzed according to the general method outlined in Example 1 to obtain the desired 3-O-3'-(2',N',N'-trimethylamino-n-propyl)-D-glucopyranose. The optical rotation of the product in water was {α}D 20 = +38.0�.
A portion of the oil, 1,2:5,6 -di-O-isopropylidene-3-O-3'-(2',N',N'-trimethylamino-n-propyl)-D-glucofuranose, is partially hydrolyzed at pH 3.0 � 0.2 according to the procedure mentioned in Example 1. A white crystalline 1,2-O-isopropylidene-3-O-3'-(2',N',N'-trimethylamino-n-propyl)-D-glucofuranose hydrochloride was obtained which is highly hygroscopic in nature. Optical rotation of the hydrochloride salt at pH 7.0 and 25� C is -21.33�. Gas chromatography analysis indicated better than 99% pure major component.
Using the general method outlined in Example 1, 0.02 mole of 1,2:5,6-di-O-isopropylidene-D-glucofuranose in 1,4-dioxane was reacted with 0.0225 mole of 2-(2-chloroethyl)-N-methylpyrrolidine hydrochloride and 0.0675 mole of sodium hydroxide. After 18 hours, the solvent was removed and the resulting orange oil was vacuum distilled under nitrogen. The residue consisted of the desired product, 1,2:5,6-di-O-isopropylidene-3-O-2'-{2"-(N"-methyl)-pyrrolidyl}-ethyl-D-glucofuranose having an optical rotation of {α}D 25 = -22.95� in chloroform.
1,2:5,6-di-O-isopropylidene-D-glucofuranose (0.1 mole) and N-(2-chloroethyl)-pyrrolidine hydrochloride (0.15 mole) are mechanically stirred and refluxed with 0.45 mole of sodium hydroxide in 150 ml of etrahydrofuran for 18 hours. The tetrahydrofuran is removed from the reaction products and the resulting oil is vacuum distilled under nitrogen. The 3-O-2'-{N'-pyrrolidyl)-ethyl}-1,2:5,6-di-O-isopropylidene-D-glucofuranose derivative has aboiling point of 165�-171� C/0.15 mm Hg. Gas chromatography indicates a purity of 99%. Using the hydrolysis procedure outlined in Example 1, 10 g of the blocked oil was hydrolyzed and lyophillized giving a white hygroscopic crystalline solid.
The N',N'-dimethylamino-n-pentyl derivative of 1,2:5,6-di-O-isopropylidene-D-glucofuranose is made by condensing N,N-dimethylamino-n-pentyl-5-chloride hydrochloride with 1,2:5,6-di-O-isopropylidene-D-glucofuranose in the presence of pulverized sodium hydroxide in freshly purified, dry 1,4-dioxane as described in the procedure in Example 1. The product was confirmed by gas chromatography and infrared spectra.
N,N-dimethylamino-n-pentyl chloride hydrochloride is made from a commercially available sample of N,N-dimethylamino-n-pentyl alcohol by treatment with thionyl chloride (SOCl2). Specifically, 10.7 g of thionyl chloride in a 250 ml three neck round bottom flask is cooled in a salt-ice water bath and stirred vigorously. To the cooled solution is added, dropwise, 10 g of N,N-dimethylamino-n-pentyl alcohol. The reaction is exothermic and the temperature is carefully controlled. The mixture is stirred for one hour after the evolution of SO2 and HCl subsides. The mixture is brought to room temperature and allowed to stir overnight. Absolute alcohol is added to destroy excess thionyl chloride. Ten grams of crude N,N-dimethylamino-n-pentyl chloride hydrochloride is obtained as a white solid. This is used directly for the condensation reaction with 1,2:5,6-di-O-isopropylidene-D-glucofuranose without further purification. The alcohol and chloride can be resolved on a Chromosorb 103 gas chromatographyl column.
Bromine (9.8 g) was added slowly and dropwise to a mechanically stirred mixture of 50 g of cracked ice and a chilled aqueous sodium hydroxide solution (7 g/20 ml water). After the addition of bromine is complete, 15 g of 1,2:5,6-di-O-isopropylidene-3-O-acetamido-D-glucofuranose (prepared by the general procedure outlined in Example 1 by the condensation of 1,2:5,6-di-O-isopropylidene-D-glucofuranose with 2-chloroacetamide in the presence of sodium hydroxide) is added in four portions 15 minutes apart. The reaction mixture is heated for one hour in a water bath. After this time, an additional portion of the aqueous solution of sodium hydroxide (20 g/20 ml) is added and heating is continued for another hour. The mixture is cooled and extracted three times with ether. The ether extract is dried over anhydrous magnesium sulfate. The yellow hygroscopic solid remaining after evaporating off the ether is the desired 1,2:5,6-di-O-isopropylidene-3-O-aminomethyl-D-glucofuranose derivative. The product was identified by the disappearance of the carbonyl stretching at 1670 cm- 1 found in the parent acetamido compound.
Well established methodology of the prior art was empolyed to determine the antiviral potency of derivatives of 1,2-O-isopropylidene-D-glucofuranose.sup.. HCl against poliovirus, type 1, and rhinovirus, type 1A, in tissue cultures at 37� C, employing HeLa cells with an agar overlay and WI-38 cells respectively. (See Wallis, C., F. Morales, J. Powell, and J. L. Melnick, Plaque enhancement of enteroviruses by magnesium chloride, cysteine, and pancreatin. J. Bacteriol. 91:1932-1935, 1966.) Poliovirus cell injury was determined by the study of plaque formation and rhinovirus was examined for cytopathic effect. In Table I, the virus inhibiting effects of three concentrations of the 3-O-3'-(N',N'-dimethylamino-n-propyl) derivative are depicted. The results are given as the degree of inhibition of infectivity, identified as plaque formation in the poliovirus system and as cytopathic effect in the system studying rhinovirus. The results indicate that, at the appropriate dose, the drug can completely inhibit 1000 plaque forming units (PFU) of poliovirus and a 1000 TCID50 dose of rhinovirus 1A, which is a virus dose 1000 times that amount required to kill 50% of the tissue cultured cells.
TABLE I__________________________________________________________________________DERIVATIVES OF 1,2-O-ISOPROPYLIDENE-D-GLUCOFURANOSE . HClSUMMARY OF ANTIVIRAL ACTIONS IN TISSUE CULTURE__________________________________________________________________________ VirusDerivative Dose System Type Titer Determination Drug Effect__________________________________________________________________________3-O-3'(N',N'- 1 μg/ml HeLa cells in Poliovirus 50 PFU1 Plaque number Total inhibitiondimethylamino- vitro with type 1n-propyl) agar overlay " 20 μg/ml " " 250 PFU " " " 40 μg/ml " " 1000 PFU " "3-O-3'-(N',N'- 2μg/ml WI-38 cells Rhinovirus 100 TCID50 2 Cytopathic "dimethylamino- type 1A effectn-propyl) " 20 μg/ml " " 1000 TCID50 " " " 40 μg/ml " ' 1000 TCID50 " "__________________________________________________________________________ 1 plaque-forming units. 2 tissue culture infectious dose involving 50% of cells.
Derivatives of 1,2-O-isopropylidene-D-glucofuranose hydrochloride were examined for their capacity to suppress influenza A2 disease in mice and for their capacity to suppress death and nonlethal nervous system disease produced by the encephalomyocarditis virus in mice. In these studies, drug effect on lung pathology produced by a 15 ID50 dose of influenza virus was examined. This dose is 15 times the dose that produces disease in 50% of the animals. Disease and drug effect on disease were determined by lung weight increase and reduction thereof. In the encephalomyocarditis study, 10 times the dose capable of killing 50% of the animals was given, and the degree of nonlethal disease and death were determined, as well as drug inhibition of both of these parameters. The results for these experiments are summarized in Table II, and indicate the production of significant reduction in lung weight increased by drug, as well as a significant inhibition of death and nonlethal disease produced by encephalomyocarditis virus. These effects were more potent for the 3-O-3'-(N',N'-dimethylamino-n-propyl) derivative than for the other two derivatives studied.
TABLE II__________________________________________________________________________DERIVATIVES OF 1,3-O-ISOPROPYLIDENE-D-GLUCOFURANOSE . HClSUMMARY OF ANTIVIRAL ACTIONS IN VIVO IN MICE__________________________________________________________________________ VirusDerivative Dose System Type Titer Determination Drug Effect__________________________________________________________________________3-O-3'-(N',N'- 20 mg/Kg Mouse in vivo Influenza 15 ID50 1 Lung weight Significant re-dimethylamino- type increase duction in lungn-propyl) weight increase3-O-3'-(N',N'- 80 mg/Kg Mouse in vivo Encephalo- 10 LD50 2 Involvement Significant in-dimethylamino- myocarditis of CNS3 and hibition of deathn-propyl) death and nonlethal disease " 160 mg/Kg " " " " "3-O-2'-(N',N'- 80 mg/Kg " " " " Inhibition sig-dimethylamino- nificant, but lessiso-propyl) than n-propyl derivative " 160 mg/Kg " " " " "3-O-3'-(2',N', 80 mg/Kg " " " " "N'-trimethyl-amino-n-propyl) " 160 mg/Kg " " " " "__________________________________________________________________________ 1 infectious dose involving 50% of animals. 2 lethal dose killing 50% of animals. 3 central nervous system.
Human embryonic fibroblast cells, WI-38 type, were obtained from Microbiological Associates and grown in maintenance medium 199 with 1% fetal calf serum in the presence and absence of either 2, 20, or 40 μg/ml of 1,2-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucofuranose.sup..HCl at 37� C and 34� C. For cells grown at 37� C, survival of tissue cultured cells in the absence of drug diminished progressively through day 15, at which time 95% of cells failed to metabolize and no longer formed a monolayer. At 34� C, by 72 hours 95% of cells without drug were no longer actively metabolizing as determined by pH and a monolayer was no longer evident under microscopic examination. Addition of drug in the concentrations described above reduced this loss of viability by 75% at 15 days and 72 hours at 37� C and 34� C respectively.
C57Bl/6J mice bearing transplanted melanoma B-16 were obtained from The Jackson Laboratories. This tumor was transplanted into recipient C57BL/6J mice at 10 days and the behavior of tumor growth in recipient mice was observed over two months. During this period, 90% of control animals died manifesting metastatic spread to the liver, bowel and kidney. Animals treated with 80 mg/Kg per day 1, 2-O-isopropylidene-3-O-3"-(N',N'-dimethylamino-n-propyl)-D-glucofuranose.sup.. HCl, injected subcutaneously, exhibited significant central necrosis of primary tumors and only 15% succumbed to such cancer metastasis.
|Cited Patent
|Filing date
|Publication date
|Dec 31, 1968
|Mar 27, 1973
|Smith Kline French Lab
|Anti-inflammatory compositions containing acylated-{62 -d-glucopyranosides and methods of using them
|Citing Patent
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|Publication date
|Jul 10, 1978
|Oct 14, 1980
|Merck & Co., Inc.
|1-Substituted glycopyranosides
|Jun 27, 1979
|Feb 17, 1981
|Ciba-Geigy Corporation
|Unsaturated or substituted methyl ethers having antibiotic activity
|Dec 2, 1982
|Oct 7, 1986
|Asahi Kasei Kogyo Kabushiki Kaisha
|Method for the cultivation of normal diploid cells and cultivation medium used therefor
|Mar 14, 1983
|Apr 19, 1988
|Greenwich Pharmaceuticals Incorporated
|Method of therapeutically treating a warm blooded animal afflicted with an autoimmune disease and a synergistic composition therefor
|Jan 13, 1989
|Sep 19, 1989
|Regents Of The University Of Minnesota
|Method for elevating glutathione levels
|Jan 13, 1986
|Sep 19, 1989
|Symbicom Aktiebolag
|Glycosidic derivatives
|Jan 9, 1989
|Feb 26, 1991
|Greenwich Pharmaceuticals Inc.
|Derivatives of α,D-glucofuranose or α,D-allofuranose and intermediates for preparing these derivatives
|Jun 22, 1989
|Apr 23, 1991
|501 Greenwich Pharmaceuticals Incorporated
|3,5,6-substituted derivatives of 1,2-O-isopropylidene-α,D-glucofuranose and intermediates for preparing these derivatives
|Aug 3, 1990
|Mar 10, 1992
|Paul Gordon
|Anionic glucofuranose derivatives, methods of making and using the same
|Feb 19, 1988
|Oct 20, 1992
|Strategic Medical Research Corporation
|Method of enhancing the activity of phagocytes including macrophages, modulating the cellular or humoral immune response, and reducing the adverse effects of stress in warm blooded animals
|Jun 30, 1993
|Mar 29, 1994
|Greenwich Pharmaceuticals Incorporated
|Monosaccharides having anti-proliferation and anti-inflammatory activity, compositions and uses thereof
|Apr 6, 1993
|Sep 6, 1994
|Greenwich Pharmaceuticals, Incorporated
|Solvent-free synthesis of ethereally substituted blocked monosaccharides and the selective hydrolysis thereof
|Jul 31, 1991
|Oct 25, 1994
|Paul Gordon
|Anionic furanose derivatives, methods of making and using the same
|Jun 29, 1992
|Nov 1, 1994
|Greenwich Pharmaceuticals Incorporated
|Anti-proliferative and anti-inflammatory compounds: 5- or 6-deoxy hexose monosaccharides having a saturated nitrogen-containing heterocycle at the 5- or 6-position bound through the nitrogen atom
|Aug 21, 1992
|Nov 22, 1994
|Medicarb Inc.
|Disubstituted and deoxydisubstituted derivatives of α-d-lyxofuranosides having anti-inflammatory and anti-proliferative activity
|Nov 13, 1992
|Jul 11, 1995
|Greenwich Pharmaceuticals Incorporated
|Anti-proliferative and anti-inflammatory compounds: derivatives of pentose monosaccharides
|May 26, 1992
|Aug 15, 1995
|University Of British Columbia
|Factors which regulate macrophage antibacterial activity
|Aug 30, 1995
|Jan 21, 1997
|Adir Et Compagnie
|Tetrahydropyran compounds
|Sep 13, 1999
|May 9, 2000
|Greenwich Pharmaceuticals Incorporated
|Immunomodulatory, anti-inflammatory, and anti-proliferative compounds: 5,6-dideoxy, 5-amino derivatives of idose and 6-deoxy, 6-amino derivatives of glucose
|May 30, 2007
|Sep 7, 2010
|Ranbaxy Laboratories Limited
|Monosaccharide derivatives
|May 30, 2007
|Dec 13, 2007
|Verma Ashwani K
|Monosaccharide derivatives
|Mar 28, 2007
|May 15, 2008
|Sattigeri Viswajanani J
|Monosaccharide derivatives
|Apr 19, 2005
|Feb 19, 2009
|Vishwajanani Jitendra Sattigeri
|Monosaccharide Derivatives as Anti-Inflammatory and/or Anti-Cancer Agents
|Jun 24, 2005
|May 5, 2011
|Nicholas Valiante
|Small molecule immunopotentiators and assays for their detection
|Mar 18, 1983
|Jul 25, 1989
|Greenwich Pharmaceuticals, Incorporated
|Therapeutic composition and method of treating viruses
|Aug 1, 1991
|Feb 20, 1992
|Paul Gordon
|Anionic furanose derivatives, methods of making and using the same
|Jun 24, 2005
|Nov 2, 2006
|Novartis Vaccines And Diagnostics Inc.
|Small molecule immunopotentiators and assays for their detection
|Jun 24, 2005
|Aug 16, 2007
|Novartis Vaccines & Diagnostic
|Small molecule immunopotentiators and assays for their detection
|U.S. Classification
|514/25, 536/17.9, 536/17.6, 536/120, 536/17.4
|International Classification
|Cooperative Classification
|European Classification
|Mar 9, 1982
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Experience The Advanced Actions Against The Signs Of Skin Aging. This Product Will Increase Cell Turnover, Reduce Wrinkles, Firm The Skin And Provide 24-Hour Moisturization. Multi-Action Technology Advanced Anti-Wrinkle Action: Encapsulated...
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Elastin fibers are essential for skin's elasticity. With age, there are less elastin fibers and the network connecting them begins to deteriorate. The thin and delicate eye area is particularly susceptible to signs of aging: lines and wrinkles, dark...
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VenEffectAnti-Aging Eye Treatment, .5 oz.Highlights This highly effective eye treatment with advanced phytoestrogen technology immediately improves elasticity around the delicate eye area, reducing the appearance of fine lines and wrinkles for a...
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Obagi Elastiderm Eye Cream -- 0.5 oz. Obagi Elastiderm Eye Cream is a smooth, rich cream for normal to dry skin. Elastiderm Eye Cream is ideal if you live in a cooler or more arid climate. Obagi Elastiderm Eye products are one-of-a-kind eye...
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Clinically proven to help visibly repair 4 major signs of eye aging. Although it s not the same as a prescription and doesn t operate anything like surgery, this cutting edge eye treatment with Anogeissus does visibly help repair crow s feet, under...
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Find facial skin care at Target.com! Reduce the signs of aging and moisturize your skin with the atopalm moisturizing eye repair serum. Original formula is perfect for use on dry and sensitive skin types. The serum helps to restore the protective...
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Helps Lighten Severe Dark Circles Also Helps Reduce The Appearance Of Under-Eye Inflammation And Puffiness Helps Diminish Fine Lines And Wrinkles Helps Restore The Appearance Of Firmness Results Guaranteed Nothing Makes A Woman Look Older Than Her Age...
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An ultra-rich cream, fortified with antioxidant Vitamin C and phytonutrient Wild Yam, helps repair prematurely-aging skin and smooth fine dehydration lines.
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EB5 Moisturizing Eye Treatment. Powered to achieve 5 different results. This age-defying gel-cream helps to diminish puffiness and reduce appearance of the finer lines.
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Cane + Austin Corrective Treatment Eye Cream. Reverse and repair signs of aging and fatigue around the delicate eye area. Reduces fine lines and wrinkles - all in one advanced treatment eye cream. Arnica and cucumber extract and green tea reduce...
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New With Hibiscus and Apple Rejuvenating Complex Clinically Shown to Help Improve Firmness 1 Clinically Shown to Help Reduce the Look of Wrinkles Dark Circles 3 99.0% Natural 5 Dermatologist Tested 4 Ophthalmologist Tested Help restore the smooth,...
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Instantly bright ens under eyes. Formulated with Haloxyl to reduce the appearance of dark circles. Helps reduce puffiness and firms skin. For over 40 years, its innovative blend of the highest quality Ingredients has delivered proven results for...
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Intense Rehydration Anti-puffiness 2 Paraben free 3 Fragrance free 4 Cellular junctions within the skin ensure cohesion of the epidermis, essential for correct hydration levels within the skin. 5 Intensely re-hydrating anti under-eye bag doubled...
Vichy Laboratoires Idea lia Eyes Eye Contour Idealizer, .5 fl oz
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Helps Instantly, Visibly Correct Skin Tone Texture Helps Reduce: Dark Circles Shadows 5 Signs of Fatigue 6 Fine Lines Innovation Sensitive Skin Allergy Tested Vichy Thermal Spa Water Paraben Free Dual-Action Blur Care Beyond eyecare, beyond concealer,...
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Replenish undereye hollows. Reduces dark circles. Smoothes lines and wrinkles. Inspired by skin volume research, Revitalift Volume Filler Eye Treatment works to replenish the skin around the eyes and reduce dark circles. This anti wrinkle eye cream...
La Roche-Posay Substiane [+] Eyes, .5 fl oz
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La Roche-Posay Substiane [+] Eyes restores and tightens the sagging skin around the delicate eye area and helps to corrects under-eye bags. Skin regains intense comfort, is firmer, more toned and radiant. Acts against skin sagging so that day after...
Lancôme BIENFAIT MULTI-VITAL EYE SPF 28 24-hour Moisturizing Eye Treatment Antioxidant and Vitamin Enriched Broad Spectrum SPF 28 Sunscreen, .5 oz
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Lancôme 24-hour Moisturizing Eye Treatment Antioxidant and Vitamin Enriched Broad Spectrum SPF 28 Sunscreen 0.5 oz. Dehydration lines around the eyes are visibly reduced. Enriched with caffeine, this formula helps to reduce the appearance of...
Ingenue Eye Gel - Multi-Action Renewal - .5 oz - Pack of 3
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Multi-Action Renewal Eye Gel targets the 5 specific signs of aging around the eyes with clinically proven and dermatologist tested ingredients. Benefits: Reduce Fine Lines and Wrinkles Firms & Tones Softens & Moisturizes Antioxidant Renewal ...
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PREVAGE .5 fl. oz. Anti-aging Eye Serum
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PREVAGE® .5 fl. oz. Anti-aging Eye Serum Tired of looking tired? This intensive age-defying serum helps transform the look of your eyes. It helps reduce the appearance of fine lines, wrinkles and crow's feet for a younger, more...
Intensive Infusion Eye Treatment - 15ml/0. 5oz
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Tom Ford Intensive Infusion eye treatment is a revitalizing, balmy cream formulated to increase natural cellular energy and repair around the eyes. It nouri shes and hydrates while firming the look of your skin and softening fine lines. Your eyes...
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L'Oreal Paris Age Perfect Eye Renewal Cream, 0.5 fl oz
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As we age, cell renewal can slow down, causing a decrease in overall vitality, even around the eye area. Inspired by 20 years of skin cell biology research, L'Oreal introduces Eye Renewal, a brilliant eye cream with 5 beautifying actions on signs of...
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Dark circles and puffiness around the eyes and fine lines around the lips will be a thing of the past in just 4 weeks with this luxurious serum. Containing Japanese pagoda and horsechestnut extract, it reduces the appearance of wrinkles and targets...
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PREVAGE® .5 oz. Anti-aging + Intensive Eye Serum Tired of looking tired? This intensive age-defying serum helps transform the look of your eyes. It helps reduce the appearance of fine lines, wrinkles and crow's feet for a...
Perricone MD Acyl-Glutathione Eye Lid Serum, .5 oz
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Scientifically formulated to tighten and firm the upper eye lid area, while smoothing crea ses and improving the appearance of redness and dark circles. It also works on the 360-degree orbital rim by tightening loose, sagging skin and tackling dark...
Orlane Extreme Line Reducing Night Care Eye Care Contour, .5 oz
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The first nighttime care specially dedicated to the eye contour for the moisture lost at night. A combination of exceptional and specific active ingredients for the night in order to repair and reduce lines. When you are lying down, toxins and...
Olay Age Defying Anti-Wrinkle Eye Cream 0.5 oz.
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Proven to reduce the appearance of fine lines and wrinkles around the eye. Visible Results: Visibly reduces the appearance of fine lines and wrinkles - around the delicate eye area where signs of aging are most likely to appear. Hydrates to leave...
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Protect, prevent and correct with this eye wrinkle cream.Free radicals, UV rays and harsh environments all cause damage to the complexion, especially the delicate area around the eyes. Replenix Eye Repair Cream combats these issues to restore a...
Priori Idebenone Complex Eye Serum, .5 fl oz
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Idebenone is the bio engineered cousin of the vital human antioxidant enzyme - CoEnzyme Q10 - but its 60% smaller (so it penetrates the skin) and up to 1000x more effective, simply put its Super CoQ10 . Unlike vitamin and botanical antioxidants,...
Yes To BPC1025314 Yes To Blueberries, Eye Firming Treatment - 1x.5 OZ
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Enjoy Yes To Blueberries, Eye Firming Treatment. Yes to Blueberries Eye Firming Treatment is a powerful way to say Yes to gorgeous, youthful peepers, and can be used in the morning (along with Daily Repairing Moisturizer), or before...
OBAGI Medical Professional-C Eye Brightener Serum, .5 oz
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Feed the delicate skin around the eyes with the vitamin C in Obagi Professional-C Eye Brightener. This serum delivers essential nutrients to help strengthen skin and defend against signs of aging such as fine lines, wrinkles and dark circles. The...
Erno Laszlo Firmarine Eye Serum, .5 oz
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Refresh and visibly firm the delicate skin around your eyes with a gentle, weightless preparation that protects against environmental damage.Features and benefits:- Spirulina maxima feeds collagen growth and revitalizes the skin's natural firmness.-...
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Targets key signs of ageing for younger looking eyes in 4 weeks. 2 The first clinically proven Eye Serum from No7. Our advanced formula with a blend of Hyaluronic Acid, Vitamin C and soft focus spheres instantly smoothes, revitalises and bright ens...
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Daily Eye Repair Emulsion by MDSolarSciences helps define your eye contours by repairing the appearance of past sun damage in addition to reducing the appearance of fine lines and wrinkles. Its soothing 24-hour time-released moisturizers, humectants,...
Dr. Scheller Anti-Aging De-Pigment Eye Care, Organic Wild Rose, .5 oz
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Clean & Clear Blackhead Eraser Scrub, Oil Free, 5 oz (141 g) - JOHNSON & JOHNSON/HEALTH/BABY
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Salicylic Acid Acne Medication. Gently exfoliates to lift away dirt & oil. Now see fewer black heads in just 2 days! Gently massage product all over face for 20-30 seconds, avoiding eye area. When using this product and other topical acne...
Garnier U-SC-1305 Nutritioniste Ultra Lift Anti Wrinkle Firming Eye Cream by Garnier for Unisex - 0.5 oz Creme
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Anti-wrinkle firming eye cream continuously delivers a powerful wrinkle repair action. Garnier Ultra-Lift Anti-Wrinkle Firming Eye Cream with Pro-Retinol from nature works to firm wrinkles and fine lines around the eyes, while being gentle on skin....
Clinique 'Repairwear Laser Focus' Wrinkle Correcting Eye Cream No Color
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Now for eyes, a three-dimensional improvement that visibly smoothes lines and plumps and ref ines the entire eye area with notice able results in four weeks. Keep smiling, you'll see a 54% younger look in 12 weeks. Another chance to forgive.How to...
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This concentrated serum helps diminish the look of dark circles and expression lines around the eyes with Anti-Aging Marine Blend and Triple Tea Complex Prevent photo-aging, environmental damage and dehydration around the eyes with a potent...
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Yes To Blueberries Eye Firming Treatment is a natural way to get gorgeous, youthful eyes. Best if used in the morning or before you go to bed, this formula blends paracress flower to reduce fine lines, antioxidant-rich blueberries, and skin-softening...
Giorgio Armani 12665031001 Regenessence [3. R] Eye Rejuvenating Serum - 15ml-0. 5oz
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An innovative weapon for the eyes with an ultra-fresh beveled applicator to eliminate puffiness, reduce lines and wrinkles and transform the eye contour. With Giorgio Armani's exclusive 3.R technology plus yeast extract, caffeine and tensor agents...
Radha Beauty Eye Gel for Dark Circles, Puffiness, Bags & Wrinkles, .5oz
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Are you TIRED of Eye bags, Dark Circles, Puffiness and Tired Looking Eyes? *Discover the new INTENSIVE YOUTH EYE GEL by RADHA BEAUTY* Our new and innovative mix of the perfect ingredients will give you Dramatically Radiant & Youthful Eyes by:
Nourish Organic - Eye Treatment, Avocado + Argan Oil
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Deeply hydrates the delicate skin around the eye while unique cooling applicator reduces puffiness. USDA organic. 100% natural. Nourish organic renewing & cooling eye treatment provides rich hydration to the delicate skin around the eyes. Its...
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Discover the new force in wrinkle repair. This advanced formula has the power to defy eye wrinkles by significantly improving texture and elasticity. Made in USA. 0.5 oz.
Olay Total Effects Eye Transforming Cream, 7-in-1 Anti-Aging Booster, 0.5 oz (14 g)
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Eye cream with vitamins bright ens the eye area and fights 7 signs of aging around your eyes. This daily all-in-one treatment with a proven vitamin-rich complex fights 7 signs of aging around the eyes for a youthful vibrancy. For a complete...
NUXE Eye and Lip Global Anti-Aging Cream, Green, 1 ea
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A non-greasy, non-sticky fluid emulsion that provides a comprehensive anti-aging action, targeting the 5 visible signs of aging around the eyes and lips. It reduces wrinkles, lifts the skin, minimizes dark circles, reduces under-eye bags and light...


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Looking back at Dennis Green's memorable Stanford tenureESPN BlogsJul 22 12:22 PM
Looking back at Dennis Green's memorable Stanford tenure
Irish A-to-Z: Jonathan JonesNBC Sports: Inside the IrishJul 11 05:03 AM
Notre Dame's coaching staff landed a linebacker they have high hopes for when Jonathan Jones picked the Irish on Signing Day. A battle with Michigan and several other heavy-hitting programs, the Florida native is a middle linebacker who'll step into an unknown depth chart behind Nyles Morgan, and the staff believes he's capable of contributing […]
Recruiting trail keeps rolling with Louisiana WR Michael YoungNBC Sports: Inside the IrishJul 21 11:03 AM
It may still only be mid-July, but Notre Dame's recruiting class looks in midseason form. Wednesday, Louisiana wide receiver Michael Young became the latest 2017 target to jump on board, picking the Irish over finalists Oregon and Texas A&M. Young is the 17th member of an Irish class that doesn't have much room left. He's a […]
Irish A-to-Z: Tyler LuatuaNBC Sports: Inside the IrishJul 18 10:48 AM
With a change of heart, Tyler Luatua decided to stay at Notre Dame after announcing his intention to transfer to BYU before spring practice. Accepted back onto the team after a meeting with Brian Kelly, Luatua now needs to find his place back into a stacked tight end depth chart. Luatua's got a unique skill-set […]
Irish land IMG Academy OL Robert HainseyNBC Sports: Inside the IrishJul 10 07:18 PM
Notre Dame landed their second commitment at The Opening, with IMG Academy's Robert Hainsey picking the Irish. The offensive lineman chose the Irish over national offers from Michigan, Florida, Georgia, LSU, Penn State and plenty of others, with Harry Hiestand once again landing one of his priority targets, snapping up a player who profiles as a Top 100 prospect. Hainsey […]
M. Basketball. Irish Events Rank Among Most-Watched So Far in 2016Notre Dame AthleticsJul 18 08:05 AM
Three University of Notre Dame games ranked among the 50 most-watched sporting events in the first half of 2016-and no college placed more events on that list than the Irish did.
Irish A-to-Z: Mike McGlincheyNBC Sports: Inside the IrishJul 21 12:33 PM
Notre Dame has another star at left tackle, with Mike McGlinchey following in the footsteps of first rounders Zack Martin and Ronnie Stanley. With the nasty disposition of Martin and the athletic traits of Stanley, McGlinchey has the promise to be the best one yet for Harry Hiestand—and that's saying something. Of course, doing it is […]
Irish A-to-Z: Nicco FertittaNBC Sports: Inside the IrishJun 27 07:04 AM
As Notre Dame searches for answers at safety, one under-discussed option is sophomore Nicco Fertitta. The Las Vegas native, best known through his recruitment as the high school teammate of Alizé Jones (and outside the football world for his father Lorenzo, the Chairman & CEO of the UFC), has been overlooked before. That comes with the […]
Irish A-to-Z: Tristen HogeNBC Sports: Inside the IrishJul 02 01:33 PM
Notre Dame's center of the future is fighting to be the right guard of today. Tristen Hoge was one of the few offensive linemen that Harry Hiestand and Brian Kelly have recruited with positional specificity. A multi-year high school center, that still didn't stop him from cross-training, with his best chance at a starting job in […]
Dennis Green dies; former 49ers assistant, Stanford coachSan Jose Mercury NewsJul 22 10:18 AM
Dennis Green was first African-American head coach in the then Pac-10 and spent two stints as a 49ers assistant under Bill Walsh.
Former Tennessee coach Summitt honored at public... - Everett Herald
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Switching the crop orientation
Switching the crop orientation
Here, we are going to look at two more shortcuts that we can use when working with the Crop tool. In particular, we'll look at how we can crop from the center of the image. We'll also look at how we can switch our Crop Orientation from Portrait to Landscape, or from vertical to horizontal. Let's go ahead and access the Crop tool by pressing the R key. Next, if we want to crop from the center of our image, what you can do is hold down the Option key on a Mac, or Alt key on Windows, and then just click and drag. By doing that, you can see that this crop area is anchored off of the center of where I clicked.
Now, if we don't like the crop, we can go ahead and press the Escape key to exit out of that. Press the R key again to access the Crop tool. Again, if you want to choose that starting point, just hold down the Option key on a Mac, or Alt key on Windows, and then click and drag from that point, and here you can see I can create this crop. Well, next let's say that we wa...
Switching the crop orientation provides you with in-depth training on Photography. Taught by Chris Orwig as part of the Lightroom Power Shortcuts
- Subject:
- Photography
- Software:
- Lightroom
- Author:
- Chris Orwig
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Look how she's grown! Steve Irwin's daughter Bindi blows out the candles on her 15th birthday cake at family zoo in Australia
She is familiar to many as the gap-toothed, pig-tailed young star of Bindi the Jungle Girl.
But these pictures reveal just how much the daughter of the late Steve Irwin has grown up, as she celebrated her 15th birthday at her family's Australia Zoo in Queensland.
With her blonde hair in a neat ponytail, and sporting the same khaki shirt and shorts combo favoured by her famous father, the actress and conservationist beamed for the cameras at the bash.
Happy birthday Bindi! The now 15-year-old daughter of the late Steve Irwin celebrated at Australia Zoo with her mother Terri and brother Bob
Growing up fast: The teenager cuts into her impressive cake, which resembles a tropical island surrounded by wildlife
The teenage animal-lover, who celebrated with her mother Terri and younger brother Bob at the tourist-packed park, is well on her way to becoming as well-known as her father, who died in 2006 after being pierced by a stingray barb while filming an underwater documentary.
Bindi - who has vowed to continue his legacy -was just eight-years-old at the time of the tragedy.
Already an accomplished wildlife conservationist, the 15-year-old has been appearing on television screens since the age of two.
Legacy: Already an enthusiastic wildlife conservationist, Bindi is following in the footsteps of her father; 'Crocodile Hunter' Steve Irwin
Celebrations: The theme of Bindi's birthday bash was Return to Nim's Island - the adventure film the teenager stars in
After appearing alongside her father on his series The Crocodile Hunter Diaries, Bindi went on to front her own show; Bindi the Jungle Girl.
The popular teen, who has also appeared on the big screen in Free Willy: Escape from Pirate's Cove, and Return to Nim's Island, received birthday wishes from the likes of Russell Crowe on her big day yesterday.
The New Zealand-born actor posted the message: 'Happy Birthday Bindi!!!' on the teenager's Twitter page.
Memories: Bindi's father Steve Irwin died in 2006 after being pierced by a stingray barb while filming an underwater documentary
Family time: A four-year-old Bindi enjoys a playful moment with her parents, Steve and Terri
Australian comedian and presenter Adam Hills also tweeted: 'Happy birthday buddy! Hope it's a great one'.
It seems the birthday girl, who blew out the candles on her huge cake in front of an audience of tourists at the wildlife park, enjoyed every moment of her special day.
'So happy to be 15 today. I'm feeling blessed to be spending my birthday with my wonderful friends and family,' she told her Twitter followers.
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Crazy Substitute Teachers
Enjoy, NG4.03 / 5.00 1,288 Views
Vacuum Salesman
This dude and his Megazord vacuum cleaner3.97 / 5.00 2,362 Views
Markiplier Animated | Mark Of The Survey Corps
This took far too long to make...3.88 / 5.00 3,314 Views
Art always wins. XD
Yeah, and nobody can deny that here, cuz everyone here in NG love art, it's part of Flash & animation! :p
nice style
The animation was very good, and your graphical style is great. This was really original because you fit everything in your idea of Chemistry vs biology.
Thx & thx.
Great new concept, humorous fighting powers and techniques. Animation was a little off, but not so much that it took away from the movie. Overall, nice work.
Alright, thx & IU'll try to improve the animation next time! :D
You've come a long way in your flashes. I remember voice acting for your Grand Theft Semi Auto. I've improved since then though ^_^ anywho, this flash is great! I'm voting 5 on it
Wow, thx.
Respect that u've seen GTSA & also watched this one too... thx
wow this ownz


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Our son Scott and his wife Lilla have created a nook in their home to display Scott's books and other Sherlock Holmes memorabilia.
sherlock holmes books violin ohio
Well good for them after all he was the greatest detective in history. Cheers.Tony.
Ah, now you'll start a firestorm with that one, Tony! But I agree!
Thanks very much, Katarina!
Congratulations on your wonderful feature.excellent work!
Thanks very much, Ana!
Congratulations – 31st March, 2014 – Shirley & Jean
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Fantastic! Thanks, Shirley and Jean!
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