USRE32268E - Therapeutic composition and method of therapeutically treating warm blooded animals therewith - Google Patents

Therapeutic composition and method of therapeutically treating warm blooded animals therewith Download PDF

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USRE32268E
USRE32268E US06/474,734 US47473483A USRE32268E US RE32268 E USRE32268 E US RE32268E US 47473483 A US47473483 A US 47473483A US RE32268 E USRE32268 E US RE32268E
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acid
propyl
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dimethylamino
iaddend
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Paul Gordon
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Alseres Pharmaceuticals Inc
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Strategic Medial Research Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical

Definitions

  • the present invention is concerned with a novel therapeutic composition and a method of therapeutically treating warm blooded animals therewith.
  • the invention further relates to certain novel ethereally monosubstituted monosaccharides which are especially useful as ingredients in the aforementioned composition and in practicing the aforementioned method.
  • 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.
  • 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 can not be safely administered to patients, and still other antiviral drugs have undesirable side effects.
  • 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.
  • compositions of the invention overcome the disadvantages of the prior art antiviral agents noted above, and also produce other unusual and unexpected results.
  • the ethereally monosubstituted monosaccharides described hereinafter are therapeutically effective at very low concentrations while at the same time they exhibit no side effects and are very non-toxic.
  • the ratio of the minimum toxic to therapeutic dose is greater than 50 in both tissue culture and animals.
  • the novel therapeutic composition of the invention comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of an ethereally monosubstituted monosaccharide having the general formula S--O--Y and organic acid and inorganic acid salts thereof, 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 ##STR2## wherein R 1 is a divalent organic radical having a .[.linear.].
  • R 2 and R 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 halogen may be F, Cl, Br or I, of which Cl or Br is usually preferred.
  • the organic radical R 1 , and R 2 and R 3 when they are organic radicals, may be branched or unbranched .[.linear.]. carbon chains and may be saturated or unsaturated and, when saturated, the .[.linear.].
  • .Iadd.unbranched .Iaddend.and/or branched carbon chains may contain one or more double or triple carbon-to-carbon bonds.
  • the .[.linear.]. .Iadd.unbranched .Iaddend.and/or branched carbon chains of R 1 , R 2 and R 3 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, --OR 4 and/or --SR 4 radicals wherein R 4 is a branched or unbranched and saturated or unsaturated hydrocarbon radical containing 1-7 and preferably 1-3 carbon atoms, carboxylic acid residues containing 1-7 and preferably 1-3 carbon atoms, and amino groups and aminohydrocarbon radicals containing 1-7 and preferably 1-3 carbon atoms.
  • R 1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 or 1-4 carbon atoms and R 2 and R 3 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, --OR 5 and/or --SR 5 radicals wherein R 5 is a branched or unbranched and saturated or unsaturated hydrocarbon radical containing 1-7 and preferably 1-3 carbon atoms, carbocyclic acid residues containing 1-7 and
  • the monosaccharide residue S may exist in an open chain or cyclic form. However, it is usually preferred that the ethereally monosubstituted monosaccharide have the following general formula: ##STR3## wherein X and Z are H, OH and/or hydroxyalkyl groups containing up to 2 carbon atoms and Y represents the same organic radicals and residua as aforementioned for the general formula S--O--Y.
  • the above general formula illustrates the hexacyclic form of 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 group of the hemiacetal or hemiketal linkage may assume an ⁇ or a ⁇ configuration.
  • the compounds of the invention may be in the form of anomers or mixtures of anomers.
  • One half of the aforementioned isomers have the property, when in aqueous solution, of causing a plane of polarized light to rotate to the right and thus are referred to as dextrorotatory compounds and are given the prefix D- or (+) to distinguish them from their levorotatory counterparts, which are given the prefix L- or (-).
  • dextrorotatory compounds are given the prefix D- or (+) to distinguish them from their levorotatory counterparts, which are given the prefix L- or (-).
  • 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. Nevertheless, it is understood that substitution of certain positions of specific monosaccharides results in more therapeutically active or less toxic compounds. For instance, substitution of the 1-O- and 3-O- positions of glucose and the 6-O-position of galactose results in especially valuable compounds.
  • --(N',N'-dimetylamino-n-propyl) is presently preferred and especially when substituted in the 1-O- or 3-O- position of glucose or in the 6-O- position of galactose.
  • 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose is presently preferred.
  • 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:
  • the present invention also provides certain novel compounds which have wide spectrum antiviral activity.
  • the novel compounds may be defined generically as follows:
  • 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, such as at position 1-O- or 3-O- of D-glucose, position 6-O- or D-galactose, and position 3-O- of D-frustose.
  • the condensation of the substituent substrate with the monosaccharide 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 tetrahydrofuran, dioxane and benzene.
  • the improved method involves the reaction of a monosaccharide which has been 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.
  • the resulting intermediate products are blocked derivatives of the compounds of the invention.
  • the blocking groups may be removed by hydrolysis and the resulting free amine may be purified to arrive at the final product, which may be in the form of a salt. Further details of this preferred method are set out in the Examples appearing hereinafter.
  • the above mentioned blocked intermediate product may be used as an ingredient in the therapeutic composition and method of the invention. This will be described more fully below.
  • 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.
  • Suitable acids include HCl, HBr, H 2 SO 4 , HNO 3 , benzoic acid, p-aminobenzoic acid, p-acetamidobenzoic 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 .[.salt.]. .Iadd.salts .Iaddend. 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.
  • the compounds of the invention possess strong hydrophilic properties due to the presence of a plurality of free hydroxyl groups. In some instances, it is desirable to decrease the hydrophilic properties and thereby increase the solubility of the compound in the fatty tissues of a warm blooded animal to be therapeutically treated therewith. This technique also aids in the transportation of the drug to a desired tissue or the concentration thereof in a desired tissue.
  • a labile organic substituent is selected which temporarily blocks at least one free monosaccharide hydroxyl group and thereby decreases the hydrophilic properties temporarily, and allows the compound to be transported or concentrated in fatty tissues. The labile organic substituent is removed in vivo during treatment of the warm blooded animal and the hydroxyl group is unblocked. The initial hydrophilic properties of the compound are thus restored thereby assuring its effectiveness as a drug.
  • 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.
  • 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.
  • 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.
  • 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.
  • alpha or beta alkyl derivatives of monosaccharides such as glucose 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 and reacted with the compound in the presence of a catalyst such as hydrogen chloride. 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.
  • the compounds may also include monosubstituted monosaccharides in which the substrate ##STR5## may be replaced by a substituent R 7 , where R 7 is a deoxymonosaccahride derivative of halogen, keto, amino, lower alkyl, mercapto, alkenyl, alkynyl, aromatic, heterocyclic or alkylcarboxylic acid and its derivatives. R 7 may also represent the same groups as the above substrate of the monosaccharide ethers.
  • Still other antiviral agents have a general formula S--O--Y wherein Y is --R 8 --S--R 9 where R 8 is a saturated or unsaturated hydrocarbon radical containing 1-7 carbon atoms and R 9 is a monovalent saturated or unsaturated hydrocarbon radical containing 1-7 carbon atoms or 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, which is highly unusual and unexpected in view of the very limited and specific antiviral activity of 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 and mumps. In tests in the whole animal, the compounds can reduce mortality and morbidity manifestations of influenza infections 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.
  • the therapeutic composition 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.
  • a water solution or suspension of the therapeutic composition may be admixed with a flavored syrup such as cherry syrup and administered orally.
  • the compound 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.
  • the salt form in aqueous solution may also be administered by nasopharyngeal spray. 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 non-toxic 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.
  • 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 milligrams per kilogram per day, over the period required for treatment of the viral infection.
  • 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 are photosensitive and may be used in photographic applications.
  • the oil was diluted 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-dimethylamino propane.
  • An elemental analysis showed C, H, N and O contents of 59.13%, 8.99%, 4.12% and 27.70% respectively.
  • the yield was 80% of the novel compound 1,2:5,6-di-O-isopropylidene-3-O-3'-(N',N'-dimethylamino-n-propyl
  • the gas-liquid chromatograms for the above intermediate and final novel compounds were run on a Beckman G.C. Model 72-5 with a hydrogen flame detector.
  • the column used for the intermediate novel compound was a commercially available SE-52 column, wherein methylphenyl 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.
  • 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 THF.
  • the reaction mixture was fractionally distilled under reduced pressure to obtain a yellow viscous oil (b.p. 142°-145° C./0.07 mm Hg) in 81% yield.
  • ⁇ -N,N-dimethylaminopropyl-D-glucoside was prepared by starting with 0.1 mole of anhydrous D-glucose in 300 ml of THF and adding 0.3 mole of N,N-dimethylamino-2-propanol along with 95 g of dry Dowex 50-X cation exchange resin in H - form.
  • the reaction mixture was refluxed for 18 hours and then 70 ml of 5 N ammonium hydroxide was added.
  • the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a brown viscous oil.
  • the oil was dissolved in hot ethanol, decolorized with charcoal, dried with anhydrous MgSO 4 , and acidified with dry HCl gas.
  • the ethanol solution was concentrated from 500 ml to approximately 100 ml and allowed to cool under running tap water.
  • the ⁇ -N,N-dimethylaminopropyl-D-glucoside product crystallized from the concentrated solution upon scratching the container.
  • Example 2 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.
  • This example illustrates the preparation of 6-O-2'-(N',N'-dimethylaminopropyl)-D-galactose.
  • Example 2 The general procedure of Example 2 was followed with the exception of using 2-chloro-N,N-dimethylaminopropane hydrochloride as a starting material rather than the corresponding 3-chloro derivative.
  • the virus inoculum of day 0 was always 100 times that amount required to kill 50% of the tissue culture cells (100 TCD 50 ). These results indicate that different derivatives suppress viral growth by from 3 to 10,000 fold, the most potent effect being exerted by 3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose.
  • mice were infected by a sublethal, disease-producing dose of mouse-adapted human influenza virus and were treated either with distilled water (control) or with 40 mg/Kg compound.
  • the above medication was also examined for its capacity to prevent death in mice ill with a lethal influenza A/PR/8 infection.
  • the drug was given subcutaneously at 3 dose levels, once 90 minutes before infection. The results illustrate a significant dose-dependent protection against death and are shown in Table 3, part B.

Abstract

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 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. 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.

Description

.Iadd.This application is a continuation of application Ser. No. 224,438, filed Jan. 12, 1981, now abandoned which is a reissue of U.S. Pat. No. 4,016,261, which is a continuation of Ser. No. 029,040 filed Apr. 11, 1979, now abandoned, which is a division of Ser. No. 337,134, filed Mar. 1, 1973 now U.S. Pat. No. 3,939,145..Iaddend.
BACKGROUND OF THE INVENTION
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 ethereally monosubstituted monosaccharides 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 can not 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 ethereally monosubstituted monosaccharides 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 ethereally monosubstituted monosaccharides described hereinafter are therapeutically effective at very low concentrations while at the same time they exhibit no side effects and are very non-toxic. The ratio of the minimum toxic to therapeutic dose is greater than 50 in both tissue culture and animals.
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 ethereally monosubstituted monosaccharides to be described more fully hereinafter.
It is a further object to provide certain novel compounds to be described more fully hereinafter, which are ethereally monosubstituted monosaccharides 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 monosaccharides 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 monosaccharides 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.
DETAILED DESCRIPTION OF THE INVENTION INCLUDING PREFERRED VARIANTS THEREOF
The novel therapeutic composition of the invention comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of an ethereally monosubstituted monosaccharide having the general formula S--O--Y and organic acid and inorganic acid salts thereof, 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 ##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.]. .Iadd.unbranched .Iaddend.and/or branched carbon chains may contain one or more double or triple carbon-to-carbon bonds. The .[.linear.]. .Iadd.unbranched .Iaddend.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 residues 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 residues 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 monosaccharide residue S may exist in an open chain or cyclic form. However, it is usually preferred that the ethereally monosubstituted monosaccharide have the following general formula: ##STR3## wherein X and Z are H, OH and/or hydroxyalkyl groups containing up to 2 carbon atoms and Y represents the same organic radicals and residua as aforementioned for the general formula S--O--Y. The above general formula illustrates the hexacyclic form of 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 group 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 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); Advanced Organic Chemistry, by Fieser and Fieser (1961); and Organic Chemistry, by Paul Karrer (1947). The prior art discloses, for example, a total of eight open chain isomers for the reducing pentoses, 16 open chain isomers for the reducing hexoses, and an even larger number of open chain isomers for the reducing heptoses. One half of the aforementioned isomers have the property, when in aqueous solution, of causing a plane of polarized light to rotate to the right and thus are referred to as dextrorotatory compounds and are given the prefix D- or (+) to distinguish them from their levorotatory counterparts, which are given the prefix L- or (-). 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. Nevertheless, it is understood that substitution of certain positions of specific monosaccharides results in more therapeutically active or less toxic compounds. For instance, substitution of the 1-O- and 3-O- positions of glucose and the 6-O-position of galactose 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:
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylaminoisopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl).
Of the foregoing substituents, --(N',N'-dimetylamino-n-propyl) is presently preferred and especially when substituted in the 1-O- or 3-O- position of glucose or in the 6-O- position of galactose.
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:
3-O-3'-(n-propylamino)-D-glucose,
3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose,
3-O-4'-(N-methyl piperidyl)-D-glucose,
3-O-2'-(N',N'-dimethylaminoethyl)-D-glucose,
3-O-2'-(N',N'-diethylaminoethyl)-D-glucose,
3-O-3'-(2',N',N'-trimethylamino-n-propyl)-D-glucose,
α-N,N-dimethylaminoisopropyl-D-glucoside,
6-O-3'-(N',N'-dimethylamino-n-propyl)-D-galactose,
3-O-2'-(N',N'-dimethylaminopropyl)-D-glucose,
6-O-2'-(N',N',-dimethylaminopropyl)-D-galactose, and organic acid and inorganic acid salts thereof.
Of the foregoing compounds, 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose 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:
______________________________________                                    
Monosaccharide                                                            
              Substituent (Y)                                             
Residue (S)   R.sub.1      R.sub.2  R.sub.3                               
______________________________________                                    
3-O--D-Glucose                                                            
              3'-n-propyl  H        methyl                                
  "             "          ethyl     "                                    
  "             "          H        ethyl                                 
  "           2'-n-propyl  methyl   methyl                                
  "           3'-1,2-propenyl                                             
                            "        "                                    
  "           sec-butyl     "        "                                    
  "           3'-butyl      "        "                                    
3-O--D-Glucose                                                            
              2'-ethyl     H        H                                     
  "           methyl       H        H                                     
6-O--D-Galactose                                                          
              3'-n-propyl  H        methyl                                
  "             "          ethyl     "                                    
  "             "          H        ethyl                                 
  "           3'-1,2-propenyl                                             
                           methyl   methyl                                
  "           sec-butyl     "        "                                    
  "           3'-butyl      "        "                                    
______________________________________
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)                                               
Monosaccharide             Substituent on the                             
Residue (S)   Cyclic Radical                                              
                           Cyclic Radical                                 
______________________________________                                    
3-O--D-Glucose 4'-piperidyl                                               
                           H                                              
  "            3'-piperidyl                                               
                           methyl, H                                      
  "            2'-piperidyl                                               
                            "                                             
  "            3'-pyrrolidyl                                              
                            "                                             
  "            2'-pyrrolidyl                                              
                            "                                             
6-O--D-Galactose                                                          
               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:
3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose,
3-O-4'-(N-methyl piperidyl)-glucose,
3-O-2'-(N',N'-dimethylaminoethyl)-glucose
3-O-3'-(2',N',N'-trimethylamino-n-propyl)-glucose,
α-N,N-dimethylaminoisopropyl-glucoside,
6-O-3'-(N',N'-dimethylamino-n-propyl)-galactose,
3-O-2'-(N',N'-dimethylaminopropyl)-glucose,
6-O-2'-(N',N'-dimethylaminopropyl)-galactose, and organic acid and inorganic acid salts thereof.
Species of the foregoing novel compounds which possess striking wide spectrum antiviral activity are as follows:
3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucopyranose,
3-O-4'N-methyl piperidyl)-D-glucopyranose,
3-O-2'-(N',N'-dimethylaminoethyl)-D-glucopyranose,
3-O-3'-(2',N',N'-trimethylamino-n-propyl)-D-glucopyranose,
α-N,N-dimethylaminoisopropyl-D-glucoside,
6-O-3'-(N',N'-dimethylamino-n-propyl)-D-galactopyranose,
3-O-2'(N',N'-dimethylaminopropyl)-D-glucopyranose,
6-O-2'-(N',N'-dimethylaminopropyl)-D-galactopyranose, and
organic acid 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, such as at position 1-O- or 3-O- of D-glucose, position 6-O- or D-galactose, and position 3-O- of D-frustose. The condensation of the substituent substrate with the monosaccharide 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 tetrahydrofuran, dioxane and benzene. Briefly, the improved method involves the reaction of a monosaccharide which has been 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. The resulting intermediate products are blocked derivatives of the compounds of the invention. The blocking groups may be removed by hydrolysis and the resulting free amine may be purified to arrive at the final product, which may be in the form of a salt. Further details of this preferred method are set out in the Examples appearing hereinafter. In practicing one variant of the invention, the above mentioned blocked intermediate product may be used as an ingredient in the therapeutic composition and method of the invention. This will be described more fully below.
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-acetamidobenzoic 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 .[.salt.]. .Iadd.salts .Iaddend.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.
The compounds of the invention possess strong hydrophilic properties due to the presence of a plurality of free hydroxyl groups. In some instances, it is desirable to decrease the hydrophilic properties and thereby increase the solubility of the compound in the fatty tissues of a warm blooded animal to be therapeutically treated therewith. This technique also aids in the transportation of the drug to a desired tissue or the concentration thereof in a desired tissue. In practicing one variant of the invention, a labile organic substituent is selected which temporarily blocks at least one free monosaccharide hydroxyl group and thereby decreases the hydrophilic properties temporarily, and allows the compound to be transported or concentrated in fatty tissues. The labile organic substituent is removed in vivo during treatment of the warm blooded animal and the hydroxyl group is unblocked. The initial hydrophilic properties of the compound are thus restored thereby assuring its effectiveness as a drug.
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.
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 alpha or beta alkyl derivatives of monosaccharides such as glucose 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 and reacted with the compound in the presence of a catalyst such as hydrogen chloride. 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 monosubstituted monosaccharides in which the substrate ##STR5## may be replaced by a substituent R7, where R7 is a deoxymonosaccahride 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 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 or 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, which is highly unusual and unexpected in view of the very limited and specific antiviral activity of 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 and mumps. In tests in the whole animal, the compounds can reduce mortality and morbidity manifestations of influenza infections 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 or 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 spray. 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 non-toxic 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 milligrams 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 are photosensitive and may be used in photographic applications.
The following specific Examples further illustrate the present invention.
EXAMPLE 1
To a solution of 104 g (0.4 mole) of 1,2:5,6-di-O-isopropylidene-D-glucofuranose in 550 ml of tetrahydrofuran (THF) 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 THF, and the washings were combined with the filtered liquid. The THF was removed under reduced pressure and an amber-colored viscous oil was obtained.
The oil was diluted 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-dimethylamino propane. The high boiling fraction had a boiling point of 139°-143° C. at 0.07 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 nd 26 =1.4576. Gas chromatography showed a purity greater than 99%. An elemental analysis showed C, H, N and O contents of 59.13%, 8.99%, 4.12% and 27.70% respectively. 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 60:30:10 respectively, was Rf =0.356.
The gas-liquid chromatograms for the above intermediate and final novel compounds were run on a Beckman G.C. Model 72-5 with a hydrogen flame detector. The column used for the intermediate novel compound was a commercially available SE-52 column, wherein methylphenyl 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.
EXAMPLE 2
A solution of 26.0 g of 1,2:3,4-di-O-isopropylidene-D-galactopyranose in 50 ml of anhydrous THF was mixed with a suspension of 0.3 mole of 3-chloro-N,N-dimethylamino propane hydrochloride and 36 g of sodium hydroxide in 100 ml THF. The mixture was stirred vigorously and refluxed for three hours. The resulting brownish solution was cooled, filtered and most of the solvent was evaporated leaving a brown oil. The remaining solvent and unreacted 3-chloro-N,N-dimethylamino propane were removed by fractional distillation under reduced pressure. The residual oil was extracted with chloroform, decolorized with activated charcoal and dried over anhydrous magnesium sulfate. Removal of the chloroform solvent yielded 13.4 g of yellow oil, which was identified as 1,2:3,4-di-O-isopropylidene-6-O-3'-(N',N'-dimethylamino-n-propyl)-D-galactopyranose. Infrared and gas chromatography in accordance with Example 1 indicated the presence of one major component having a refractive index of nD 28 =1.461 and an optical rotation of [α]D 25 =-49.4° in chloroform.
The oil was refluxed with 50 ml of 0.5N sulfuric acid for 18 hours. The resulting solution was washed with chloroform and the pH value was adjusted to 4.2. On lyophillization, the aqueous solution yielded 4.67 g of white crystalline solid 6-O3'-(N',N'-dimethylamino-n-propyl)-D-galactopyranose having an optical rotation of [α]D 25 =+77.2° in H2 O. A gas chromatography analysis in accordance with Example 1 indicated that the purity of the product was in excess of 95%.
EXAMPLE 3
Starting with 51 g (0.3 mole) of 4-chloro-N-methylpiperidine hydrochloride, 26 g (0.1 mole) of 1,2:5,6-di-O-isopropylidene-D-glucofuranose and 36 g of NaOH in 150 ml THF, 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.
EXAMPLE 4
A solution of 0.1 mole of 1,2:5,6-O-isopropylidene-D-glucofuranose in 50 ml of THF was added to a suspension of 0.3 mole of 2-chloro-N,N-dimethylaminoethane hydrochloride and 36 of sodium hydroxide in 100 ml of THF. 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 (b.p. 144°-150° C./0.15 mm Hg) having an optical rotation of [α]D 28 =-20.6° neat and a refractive index of nD 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 a 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'-dimethylaminoethyl)-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 THF was added dropwise over one hour 0.3 mole of 3-bromopropionitrile in 50 ml of THF. The reaction mixture was refluxed for an additional six hours and then filtered. The solids were washed with THF and the washings were combined with the filtrate. The solvent was removed under reduced pressure and solid 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 were 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 HCl 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 IR 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.
EXAMPLE 6
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 THF. The reaction mixture was fractionally distilled under reduced pressure to obtain a yellow viscous oil (b.p. 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 nD 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 sulfuric 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 =+37.86°. Gas chromatography in accordance with Example 1 indicated a purity in excess of 82%.
EXAMPLE 7
α-N,N-dimethylaminopropyl-D-glucoside was prepared by starting with 0.1 mole of anhydrous D-glucose in 300 ml of THF and adding 0.3 mole of N,N-dimethylamino-2-propanol along with 95 g of dry Dowex 50-X cation exchange resin in H- form. The reaction mixture was refluxed for 18 hours and then 70 ml of 5 N ammonium hydroxide was added. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a brown viscous oil. The oil was dissolved in hot ethanol, decolorized with charcoal, dried with anhydrous MgSO4, and acidified with dry HCl gas. The ethanol solution was concentrated from 500 ml to approximately 100 ml and allowed to cool under running tap water. The α-N,N-dimethylaminopropyl-D-glucoside product crystallized from the concentrated solution upon scratching the container. Thin layer chromatography in accordance with Example 1 indicated a flow rate on silica gel of Rf =0.34.
EXAMPLE 8
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°.
EXAMPLE 9
This example illustrates the preparation of 6-O-2'-(N',N'-dimethylaminopropyl)-D-galactose.
The general procedure of Example 2 was followed with the exception of using 2-chloro-N,N-dimethylaminopropane hydrochloride as a starting material rather than the corresponding 3-chloro derivative. The intermediate product had an optical rotation in water of [α]D 24 =-54.5°, and a refractive index of nD 24 =1.4552. The final product had a rate of flow value on thin layer chromatography analysis in accordance with Example 1 of Rf =0.376.
EXAMPLE 10
Well established methodology of the prior art was employed to determine the antiviral potency of compounds against influenza A2 virus, Hong Kong strain, in tissue cultures, employing the baby hamster kidney cell line (see R. L. Muldoon, L. Mezny and G. G. Jackson in Antimicrobial Agents and Chemotherapy 2:224-228, 1972). Virus infectivity was evaluated by both hemagglutination techniques and cytopathogenic effects, with identical results for each method. In Table 1 below, the virus-inhibiting effects of two low drug concentrations, 3 and 10 μg/ml, are depicted. Results are given as the log decrease in infectivity of the virus inoculum. A log decrease of 4.0 is the maximum obtainable, representing complete suppression of virus growth in the system. The virus inoculum of day 0 was always 100 times that amount required to kill 50% of the tissue culture cells (100 TCD50). These results indicate that different derivatives suppress viral growth by from 3 to 10,000 fold, the most potent effect being exerted by 3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose.
              TABLE 1                                                     
______________________________________                                    
                   Log Decrease                                           
                   in Infectivity of                                      
                   Vitrus Inoculum at                                     
                   Concentration of                                       
Compound             3 μg/ml                                           
                               10 μg/ml                                
______________________________________                                    
3-O--3'-(N',N'--dimethylamino-p-                                          
                     3.2       4.0 (max)                                  
propyl)-D-glucose                                                         
3-O--4'-(N--methylpuperidyl)-D-                                           
                     2.5       3.5                                        
glucose                                                                   
3-O--2'-(N',N'--dimethylaminoethyl)-                                      
                     2.5       3.5                                        
D-glucose                                                                 
3-O--3'-(2'N',N'--trimethylamino-                                         
                     2.4       3.0                                        
n-propyl)-D-glucose                                                       
α-N,N--dimethylaminoisopropyl                                       
                     1.5       2.5                                        
glucoside                                                                 
6-O--3'-(N',N'--dimethylamino-n-                                          
                     1.0       2.0                                        
propyl)-D-galactose                                                       
3-O--2'-(N',N'--dimethylaminopropyl)-                                     
                     1.0       2.0                                        
D-glucose                                                                 
3-O--2'-(N',N'--diethylaminoethyl)-                                       
                     0.5       1.0                                        
D-glucose                                                                 
6-O--2'-(N',N'--dimethylaminopropyl)-                                     
                     0.1       0.5                                        
D-galactose                                                               
______________________________________
EXAMPLE 11
Using well established methodology of the prior art, derivatives were examined for their capacity to inhibit the multiplication of herpes simplex virus in tissue culture. Therapeutic effects were evaluated by the plaque formation technic of Rapp (see Fred Rapp in Journal of Immunology 93:643, 1964). The concentrations of the drug required to reduce plaque formation by 50% and by 100% respectively were determined. In Table 2 below, the results given illustrate the effectiveness of a number of derivatives and high dependence of potency on drug structure. As in the influenza study, the most potent derivative is 3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose. Identical anti-herpes results as given above were obtained with study of cytopathogenic effects, whether in primary rabbit kidney or human embryo cell tissue culture lines. In other studies, a similar array of antiviral effects against mumps virus in tissue cultures were also found.
EXAMPLE 12
The most potent of the above derivatives, 3-O-3'-(N',N'-dimethylamino-n-propyl)-glucose, was examined for its capacity to suppress influenza A2 /Hong Kong disease in mice. In this study, mice were infected by a sublethal, disease-producing dose of mouse-adapted human influenza virus and were treated either with distilled water (control) or with 40 mg/Kg compound.
                                  TABLE 2                                 
__________________________________________________________________________
                          Concentration required                          
                                      Concentration required              
                          to exert 50% inhibition                         
                                      to exert 100% inhibition            
                          of herpes-induced                               
                                      of herpes-induced                   
                          plaque formation                                
                                      plaque formation                    
Compound                  (μg/ml)  (μg/ml)                          
__________________________________________________________________________
3-O--3'-(N',N'--dimethylamino-n-propyl)-D-glucose                         
                          0.3         1                                   
3-O--4'-(N--methylpiperidyl)-D-glucose                                    
                          0.7         6                                   
6-O--3'-(N',N'--dimethylamino-n-propyl)-D-galactose                       
                          2           >10                                 
3-O--3'-(2',N',N'--trimethylamino-n-propyl)-D-glucose                     
                          2           7                                   
3-O--2'-(N',N'--diethylaminoethyl)-D-glucose                              
                          2           20                                  
1,2,5,6-di-O--isopropylidene-3-O--3'-(N',N'--                             
                          <3          --                                  
dimethylamino-n-propyl)-D-glucofuranose                                   
1,2,5,6-di-O--isopropylidene-3-O--4'-(N--methyl-                          
                          <3          --                                  
piperidyl)-D-glucofuranose                                                
3-O--2'-(N',N'--dimethylaminopropyl)-D-glucose                            
                          3           >20                                 
3-O--3'-n-propylamino-D-glucose                                           
                          3           20                                  
1,2,5,6-di-O--isopropylidene-3-O--2'-(N'N'--                              
                          6           30                                  
diethylaminoethyl)-D-glucofuranose                                        
α-N,N--dimethylaminoisopropylglucoside                              
                          10          >50                                 
__________________________________________________________________________
 Fifty percent of the administered drug was in a form reduced in
 hydrophilicity by addition of a labile organic group, i.e., acetone, to
 the 1,2-positions to promote absorption into the cells and slow release
 from body fat. Medication was administered orally, beginning 24 hours
 post-infection. Disease progression and drug effect were evaluated at 8
 days by examination of the lung for pneumonic consolidation using the
 method T. W. Chang and L. Weinstein (Am. J. Med. Sci., 1973, in press) and
 by the objective technic of weighing the lungs. Note that lung weight
 increase during influenza infection reflects edema, hemorrhage and virus
 content (see P. Gordon and E. R. Brown, Canad. J. Micro. 18:1463, 1972).
 Below in Table 3, part A, objective data are presented for lung weights
 illustrating an 82% suppression of disease by the derivative.
The above medication was also examined for its capacity to prevent death in mice ill with a lethal influenza A/PR/8 infection. The drug was given subcutaneously at 3 dose levels, once 90 minutes before infection. The results illustrate a significant dose-dependent protection against death and are shown in Table 3, part B.
              TABLE 3                                                     
______________________________________                                    
A. ACTION IN MICE ILL WITH INFLUENZA                                      
A.sub.2 /HONG KONG DISEASE                                                
                                 Frequency of                             
          Average Lung                                                    
                      % Disease  Normal Lungs                             
Group     Weight (mg) Suppression                                         
                                 (<170 mg)                                
______________________________________                                    
Normal    160                    12/21                                    
Infected control                                                          
          258                     1/21                                    
Infected treated                                                          
          177         82         13/21                                    
______________________________________                                    
B. ACTION IN MICE ILL WITH A LETHAL                                       
INFLUENZA A/PR/8 INFECTION                                                
          Mortality              %                                        
          Frequency at           of Population                            
Drug      8 Days      % Mortality                                         
                                 Protected                                
______________________________________                                    
0    (Control)                                                            
              42/44       95                                              
10   mg/Kg    18/22       81       14                                     
40   mg/Kg    16/22       72       23                                     
160  mg/Kg    10/22       45       50                                     
______________________________________

Claims (42)

I claim:
1. A .[.novel.]. therapeutic composition comprising a pharmaceutically acceptable carrier containing a therapeutically effective amount .Iadd.for treating a warm blooded animal .Iaddend.of at least one .[.substance.]. .Iadd.compound .Iaddend.selected from the group consisting of ethereally monosubstituted monosaccharides having the formula S-O-Y, and therapeutically effective and pharmaceutically acceptable organic acid and .[.inoragnic.]. .Iadd.inorganic .Iaddend.acid salts thereof, wherein S is the residue of a .[.monosaccharide selected from the group consisting of pentoses, hexoses and heptoses.]. .Iadd.hexose .Iaddend.and Y is selected from the group consisting of .[.cyclic monovalent nitrogen containing organic radicals.]. .Iadd.piperidyl and pyrrolidyl radicals .Iaddend.and monovalent organic radicals having the general formula ##STR6## wherein R1 is a divalent organic radical having a .[.linear.]. carbon chain length of about .[.1-7.]. .Iadd.1-4 .Iaddend.carbon atoms and R2 and R3 are selected from the group consisting of .[.--H, --OH, --SH, halogen.]. .Iadd.hydrogen .Iaddend.and monovalent organic radicals having a .[.linear.]. carbon chain length of about .[.1-7.]. .Iadd.1-4 .Iaddend.carbon atoms.
2. A .[.novel.]. therapeutic composition in accordance with claim 1 wherein Y is ##STR7## R1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 carbon atoms, and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon radicals having a .[.linear.]. carbon chain length of 1-3 carbon atoms.
3. A .[.novel.]. therapeutic composition in accordance with claim 1 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylaminoisopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl).
4. A .[.novel.]. therapeutic composition in accordance with claim 1 wherein Y is -(N',N'-dimethylamino-n-propyl).
5. A .[.novel.]. therapeutic composition in accordance with claim 1 wherein the monosubstituted monosaccharide has the formula ##STR8## wherein X and Z are selected from the group consisting of H, OH and hydroxyalkyl groups containing .[.up to 2.]. .Iadd.1 .Iaddend.carbon .[.atoms.]. .Iadd.atom.Iaddend., Y represents the same organic radicals and residua as set out in claim .[.2.]. 1, and one of the OH groups, X or Z in said formula is replaced by .[.-o-Y..]. -.Iadd.O-Y..Iaddend.
6. A .[.novel.]. therapeutic composition in accordance with claim 5 wherein Y is ##STR9## R1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 carbon atoms, and R2 and R3 ae selected from the group consisting of hydrogen and hydrocarbon radicals having a .[.linear.]. carbon chain length of 1-3 carbon atoms.
7. A .[.novel.]. therapeutic composition in accordance with claim 5 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
.[.(N',N'-dimethylaminolso-propyl),.]. (.Iadd.N',N'-dimethylaminopropyl).Iaddend.
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl).
8. A .[.novel.]. therapeutic composition in accordance with claim 5 wherein Y is -(N',N'-dimethylamino-n-propyl). .[.9. A novel therapeutic composition in accordance with claim 5 wherein the monosaccharide in a hexose..]. .[.10. A novel therapeutic composition in accordance with claim 9 wherein Y is ##STR10## R1 is a hydrocarbon radical having a linear carbon chain length of 1-3 carbon atoms, and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon radicals having a linear carbon
chain length of 1-3 carbon atoms..]. .[.11. A novel therapeutic composition in accordance with claim 9 wherein Y is selected from the group consisting of
(n-propylamino).
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylaminoisopropyl,
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl)..]. .[.12. A novel therapeutic composition in accordance with claim 9 wherein Y is
-(N',N'-dimethylamino-n-propyl)..]. 13. A .[.novel.]. therapeutic composition in accordance with claim 5 wherein the monosaccharide is
selected from the group consisting of glucose and galactose. 14. A .[.novel.]. therapeutic composition in accordance with claim 13 wherein the glucose is monosubstituted in the 1-O- or 3-O- position and the
galactose is monosubstituted in the 6-O- position. 15. A .[.novel.]. therapeutic composition in accordance with claim 14 wherein Y is ##STR11## R1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 carbon atoms, and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon radicals having a .[.linear.].
carbon chain length of 1-3 carbon atoms. 16. A .[.novel.]. therapeutic composition in accordance with claim 14 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylaminoisopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl). 17. A .[.novel.]. therapeutic composition in accordance with claim 14 wherein Y is
-(N',N'-dimethylamino-n-propyl). 18. A .[.novel.]. therapeutic composition in accordance with claim 13 wherein the monosubstituted monosaccharide is selected from the group consisting of
3-O-3'-(n-propylamino)-D-glucose,
3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose,
3-O-4'-(N-methyl piperidyl)-D-glucose,
3-O-2'-(N',N'-dimethylaminoethyl)-D-glucose,
3-O-2'-(N',N'-diethylaminoethyl)-D-glucose,
3-O-3'-(2',N'-trimethylamino-n-propyl)-D-glucose, ,N'
α-N,N-dimethylaminoisopropyl-D-glucoside,
6-O-3'-N',N'-dimethylamino-n-propyl)=D-galactose,
3-O-2'-(N',N'-dimethylaminopropyl)-D-glucose, and
6-O-2'-(N',N'-dimethylaminopropyl)-D-galactose. 19. A .[.novel.]. therapeutic composition in accordance with claim 13 wherein the monosubstituted monosaccharide is
3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose. 20. A method of therapeutically treating .Iadd.a viral infection in .Iaddend.a warm blooded animal comprising therapeutically administering thereto .[.a therapeutically effective amount of.]. at least one .[.substance.]. .Iadd.compound .Iaddend.selected from the group consisting of ethereally monosubstituted monosaccharides having the formula S-O-Y and therapeutically effective and pharmaceutically acceptable organic acid and inorganic acid salts thereof, wherein S is the residue of a .[.monosaccharide selected from the group consisting of pentoses, hexoses and heptoses.]. .Iadd.hexose .Iaddend.and Y is selected from the group consisting of .[.cyclic monovalent nitrogen containing organic.]. .Iadd.piperidyl and pyrrolidyl .Iaddend.radicals and monovalent organic radicals having the formula ##STR12## wherein R1 is a divalent organic radical having a .[.linear.]. carbon chain length of about .[.1-7.]. .Iadd.1-4 .Iaddend.carbon atoms and R2 and R3 are selected from the group consisting of .[.--H, --OH, --SH, halogen.]..Iadd., hydrogen .Iaddend.and monovalent organic radicals having a .[.linear.]. carbon chain length of about .[.1-7.]. .Iadd.1-4 .Iaddend.carbon atoms, said .[.substance.]. .Iadd.compound being administered in an amount which is therapeutically effective to treat such
viral infection. .Iaddend. 21. The method of claim 20 wherein Y is ##STR13## R1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 carbon atoms, and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon having a .[.linear.]. carbon chain
length of 1-3 carbon atoms. 22. The method of claim 20 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylaminoisopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl). 23. The method of claim 20 wherein Y is
-(N',N'-dimethylamino-n-propyl). 24. The method of claim 20 wherein the monosubstituted monoaccharide has the formula ##STR14## wherein X and Z are selected from the group consisting of H, OH and hydroxyalkyl groups containing .[.up to 2.]. .Iadd.1 .Iaddend.carbon .[.atoms.]. .Iadd.atom.Iaddend., Y represents the same organic radicals and residua as set out in claim 20, and one of the OH groups, X or Z in
said formula is replaced by --O--Y. 25. The method of claim 24 wherein Y is ##STR15## R1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 carbon atoms, and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon radicals having a .[.linear.].
carbon chain length of 1-3 carbon atoms. 26. The method of claim 24 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
N',N'-dimethylaminoisopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
N',N'-diethylaminoethyl), and
(2', N',N'-trimethylamino-n-propyl). 27. The method of claim 24 wherein Y is -(N',N'-dimethylamino-n-propyl). .[.28. The method of claim 24 wherein
the monosaccharide is hexose..]. .[.29. The method of claim 28 wherein Y is ##STR16## R1 is a hydrocarbon radical having a linear carbon chain length of 1-3 carbon atoms, and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon radicals having a linear carbon
chain length of 1-3 carbon atoms..]. .[.30. The method of claim 28 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylaminoisopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2',N',N'-trimethylamino-n-propyl)..]. .[.31. The method of claim 28
wherein Y is -(N',N'-dimethylamino-n-propyl)..]. 32. The method of claim 24 wherein the monosaccharide is selected from the group consisting of
glucose and galactose. 33. The method of claim 32 wherein the glucose is monosubstituted in the 1-O- or 3-O- position and the galactose is
monosubstituted in the 6-O- position. 34. The method of claim 33 wherein Y is ##STR17## R1 is a hydrocarbon radical having a .[.linear.]. carbon chain length of 1-3 carbon atoms and R2 and R3 are selected from the group consisting of hydrogen and hydrocarbon radicals having a .[.linear.].
carbon chain length of 1-3 carbon atoms. 35. The method of claim 33 wherein Y is selected from the group consisting of
(n-propylamino),
(N',N'-dimethylamino-n-propyl),
(N',N'-dimethylamino-isopropyl),
(N-methyl piperidyl),
(N',N'-dimethylaminoethyl),
(N',N'-diethylaminoethyl), and
(2°,N',N'-trimethylamino-n-propyl). 36. The method of claim 33
wherein Y is -(N',N'-dimethylamino-n-propyl). 37. The method of claim 32 wherein the monosubstituted monosaccharide is selected from the group consisting of
3-O-3'-(n-propylamino)-D-glucose,
3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose,
3-O-4'-(N-methyl piperidyl)-D-glucose,
3-O-2'-(N',N'-dimethylaminoethyl)-D-glucose,
3-O-2'-N',N'-diethylaminoethyl)-D-glucose,
3-O-3'-(2',N',N'-dimethylamino-n-propyl)-D-glucose
α-N,N-dimethylaminoisopropyl-D-glucoside,
6-O-3'-(N',N'-dimethylamino-n-propyl)-D-galactose,
3-O-2'-(N',N'-dimethylaminopropyl)-D-glucose, and
6-O-2'-(N',N'-dimethylaminopropyl)-D-galactose. 38. The method of claim 32 wherein the monosubstituted monosaccharide is
3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose. 39. A .[.novel.]. therapeutic composition in accordance with claim 1 wherein the said substance is in the form of a salt of an acid selected from the group consisting of HCl, HBr, H2 SO4, HNO3, benzoic acid, p-amino-benzoic acid, p-acetamidobenzoic acid p-hydroxybenzoic acid, alkane sulfonic acids, p-toluene sulfonic acid, lower alkyl monocarboxylic acids, oxalic acid, tartaric acid, lactric acid, pyruvic acid, malic acid,
succinic acid, gluconic acid and glucuronic acid. 40. The .[.novel.]. therapeutic composition in accordance with claim 39 wherein the said acid
is HCl. 41. The .[.novel.]. therapeutic composition in accordance with claim 19 wherein the said 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose is in the form of a salt of an acid selected from the group consisting of HCl, HBr, H2 SO4, HNO3, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoic acid, p-hydroxybenzoic acid, alkane sulfonic acids, p-toluene sulfonic acid, lower alkyl monocarboxylic acids, oxalic acid, tartaric acid, lactic acid, pyruvic acid, malic acid, succine acid,
gluconic acid and glucuronic acid. 42. The .[.novel.]. therapeutic
composition in accordance with claim 41 wherein the said acid is HCl. 43. The method of claim 20 wherein the said substance is in the form of a salt of an acid selected from the group consisting of HCl, HBr, H2 SO4, HNO3, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoic acid, p-hydroxybenzoic acid, alkane sulfonic acids, p-toluene sulfonic acid, lower alklyl monocarboxylic acids, oxalic acid, tartaric acid, lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid and
glucuronic acid. 44. The method of claim 43 wherein the said acid is HCl.
5. The method of claim 38 wherein the said 3-O-3'-(N',N'-dimethylamino-n-propyl)-D-glucose is in the form of a salt of an acid selected from the group consisting of HCl, HBr, H2 SO4, HNO3, benzoic acid, p-aminobenzoic acid, p-acetamidobenzoic acid, p-hydroxybenzoic acid, alkane sulfonic acids, p-toluene sulfonic acid, lower alkyl monocarboxylic acids, oxalic acid, tartaric acid, lactic acid, pyruvic acid, malic acid, succinic acid, gluconic acid and
glucuronic acid. 46. The method of claim 45 wherein the said acid is HCl.
.Iadd.47. The method of claim 20 wherein said viral infection is an influenza, a mumps, or a herpes infection and wherein said compound is administered in an amount which is therapeutically effective to treat said influenza, mumps, or herpes infection. .Iaddend. .Iadd.48. The method of claim 21 wherein said viral infection is an influenza, a mumps, or a herpes infection and wherein said compound is administered in an amount which is therapeutically effective to treat said influenza, mumps, or herpes infection. .Iaddend. .Iadd.49. The method of claim 22 wherein said viral infection is an influenza, a mumps, or a herpes infection and wherein said compound is administered in an amount which is therapeutically effective to treat said influenza, mumps, or herpes infection..Iaddend. .Iadd.50. The method of claim 32 wherein said viral infection is an influenza, a mumps, or a herpes infection and wherein said compound is administered in an amount which is therapeutically effective to treat said influenza, mumps, or herpes infection. .Iaddend. .Iadd.51. The method of claim 38 wherein said viral infection is an influenza, a mumps or a herpes infection and wherein said compound is administered in an amount which is therapeutically effective to treat said influenza, mumps, or herpes infection. .Iaddend.
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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4996195A (en) * 1989-01-09 1991-02-26 Greenwich Pharmaceuticals Inc. Derivatives of α,D-glucofuranose or α,D-allofuranose and intermediates for preparing these derivatives
US5010058A (en) * 1989-06-22 1991-04-23 501 Greenwich Pharmaceuticals Incorporated 3,5,6-substituted derivatives of 1,2-O-isopropylidene-α,D-glucofuranose and intermediates for preparing these derivatives
US5298494A (en) * 1989-01-09 1994-03-29 Greenwich Pharmaceuticals Incorporated Monosaccharides having anti-proliferation and anti-inflammatory activity, compositions and uses thereof
US5344924A (en) * 1991-02-20 1994-09-06 Greenwich Pharmaceuticals, Incorporated Solvent-free synthesis of ethereally substituted blocked monosaccharides and the selective hydrolysis thereof
US5360792A (en) * 1991-12-20 1994-11-01 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
US5432163A (en) * 1992-11-13 1995-07-11 Greenwich Pharmaceuticals Incorporated Anti-proliferative and anti-inflammatory compounds: derivatives of pentose monosaccharides
US6060453A (en) 1993-06-11 2000-05-09 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
US6509323B1 (en) * 1998-07-01 2003-01-21 California Institute Of Technology Linear cyclodextrin copolymers
US6884789B2 (en) * 1998-07-01 2005-04-26 California Institute Of Technology Linear cyclodextrin copolymers
US20080058427A1 (en) * 2002-09-06 2008-03-06 Insert Therapeutics, Inc. Cyclodextrin-based polymers for therapeutics delivery
US7375096B1 (en) * 1998-12-04 2008-05-20 California Institute Of Technology Method of preparing a supramolecular complex containing a therapeutic agent and a multi-dimensional polymer network
US20110237540A1 (en) * 2009-11-23 2011-09-29 Crawford Thomas C Cyclodextrin-based polymers for therapeutic delivery
US8497365B2 (en) 2007-01-24 2013-07-30 Mark E. Davis Cyclodextrin-based polymers for therapeutics delivery
US9218453B2 (en) 2009-06-29 2015-12-22 Roche Diabetes Care, Inc. Blood glucose management and interface systems and methods
US11464871B2 (en) 2012-10-02 2022-10-11 Novartis Ag Methods and systems for polymer precipitation and generation of particles

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3016372A (en) * 1956-12-13 1962-01-09 Searle & Co Glycosides of the pyridone series
US3781267A (en) * 1969-07-03 1973-12-25 Ciba Geigy Corp O-esters of monosaccharides having ether groupings
US4016261A (en) * 1973-03-01 1977-04-05 Strategic Medical Research Corporation Therapeutic composition and method of therapeutically treating warm blooded animals therewith

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3016372A (en) * 1956-12-13 1962-01-09 Searle & Co Glycosides of the pyridone series
US3781267A (en) * 1969-07-03 1973-12-25 Ciba Geigy Corp O-esters of monosaccharides having ether groupings
US4016261A (en) * 1973-03-01 1977-04-05 Strategic Medical Research Corporation Therapeutic composition and method of therapeutically treating warm blooded animals therewith

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Derwent Abstract of Japanese Patent, JA 72 25 057, 1972. *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4996195A (en) * 1989-01-09 1991-02-26 Greenwich Pharmaceuticals Inc. Derivatives of α,D-glucofuranose or α,D-allofuranose and intermediates for preparing these derivatives
US5298494A (en) * 1989-01-09 1994-03-29 Greenwich Pharmaceuticals Incorporated Monosaccharides having anti-proliferation and anti-inflammatory activity, compositions and uses thereof
US5010058A (en) * 1989-06-22 1991-04-23 501 Greenwich Pharmaceuticals Incorporated 3,5,6-substituted derivatives of 1,2-O-isopropylidene-α,D-glucofuranose and intermediates for preparing these derivatives
US5344924A (en) * 1991-02-20 1994-09-06 Greenwich Pharmaceuticals, Incorporated Solvent-free synthesis of ethereally substituted blocked monosaccharides and the selective hydrolysis thereof
US5360792A (en) * 1991-12-20 1994-11-01 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
US5432163A (en) * 1992-11-13 1995-07-11 Greenwich Pharmaceuticals Incorporated Anti-proliferative and anti-inflammatory compounds: derivatives of pentose monosaccharides
US6060453A (en) 1993-06-11 2000-05-09 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
US6509323B1 (en) * 1998-07-01 2003-01-21 California Institute Of Technology Linear cyclodextrin copolymers
US6884789B2 (en) * 1998-07-01 2005-04-26 California Institute Of Technology Linear cyclodextrin copolymers
US7091192B1 (en) * 1998-07-01 2006-08-15 California Institute Of Technology Linear cyclodextrin copolymers
US20070025952A1 (en) * 1998-07-01 2007-02-01 California Institute Of Technology Linear cyclodextrin copolymers
US20110143944A1 (en) * 1998-07-01 2011-06-16 California Institute Of Technology Linear cyclodextrin copolymers
US7375096B1 (en) * 1998-12-04 2008-05-20 California Institute Of Technology Method of preparing a supramolecular complex containing a therapeutic agent and a multi-dimensional polymer network
US20080279954A1 (en) * 1998-12-04 2008-11-13 California Institute Of Technology Method of preparing a supramolecular complex containing a therapeutic agent and a multi-dimensional polymer network
US20110144190A1 (en) * 1998-12-04 2011-06-16 California Institute Of Technology Method of preparing a supramolecular complex containing a therapeutic agent and a multi-dimensional polymer network
US8252276B2 (en) 2002-09-06 2012-08-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8580244B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8110179B2 (en) 2002-09-06 2012-02-07 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US20080058427A1 (en) * 2002-09-06 2008-03-06 Insert Therapeutics, Inc. Cyclodextrin-based polymers for therapeutics delivery
US8314230B2 (en) 2002-09-06 2012-11-20 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8389499B2 (en) 2002-09-06 2013-03-05 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8399431B2 (en) 2002-09-06 2013-03-19 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8404662B2 (en) 2002-09-06 2013-03-26 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8475781B2 (en) 2002-09-06 2013-07-02 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US9550860B2 (en) 2002-09-06 2017-01-24 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8518388B2 (en) 2002-09-06 2013-08-27 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8680202B2 (en) 2002-09-06 2014-03-25 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8580243B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8580242B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8603454B2 (en) 2002-09-06 2013-12-10 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8609081B2 (en) 2002-09-06 2013-12-17 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8497365B2 (en) 2007-01-24 2013-07-30 Mark E. Davis Cyclodextrin-based polymers for therapeutics delivery
US9610360B2 (en) 2007-01-24 2017-04-04 Ceruliean Pharma Inc. Polymer drug conjugates with tether groups for controlled drug delivery
US9218453B2 (en) 2009-06-29 2015-12-22 Roche Diabetes Care, Inc. Blood glucose management and interface systems and methods
US20110237540A1 (en) * 2009-11-23 2011-09-29 Crawford Thomas C Cyclodextrin-based polymers for therapeutic delivery
US11464871B2 (en) 2012-10-02 2022-10-11 Novartis Ag Methods and systems for polymer precipitation and generation of particles

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