EP0548226A1 - Monosaccharides presentant une activite anti-proliferative et anti-inflammatoire, compositions et leurs utilisations - Google Patents

Monosaccharides presentant une activite anti-proliferative et anti-inflammatoire, compositions et leurs utilisations

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Publication number
EP0548226A1
EP0548226A1 EP91916966A EP91916966A EP0548226A1 EP 0548226 A1 EP0548226 A1 EP 0548226A1 EP 91916966 A EP91916966 A EP 91916966A EP 91916966 A EP91916966 A EP 91916966A EP 0548226 A1 EP0548226 A1 EP 0548226A1
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EP
European Patent Office
Prior art keywords
isopropylidene
glucofuranose
compound
deoxy
methyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP91916966A
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German (de)
English (en)
Inventor
Sudershan K. Arora
Roy L. Whistler
Albert V. Thomas
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Alseres Pharmaceuticals Inc
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Greenwich Pharmaceuticals Inc
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Publication of EP0548226A1 publication Critical patent/EP0548226A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon 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
    • 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
    • C07H15/10—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical containing unsaturated carbon-to-carbon bonds
    • 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
    • C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
    • 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
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • 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
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • 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
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen

Definitions

  • the compounds of this invention are derivatives of simple monosaccharides which exhibit anti-proliferation and anti-inflammatory activity and are useful for treating mammals having inflammatory disorders and/cr autoimmune disorders.
  • This invention also encompasses pharmaceutical compositions containing these compounds and methods of treating inflammatory and/or autoimmune disorders.
  • monosaccharides and their derivatives are known to have therapeutic value in the treatment of inflammatory and autoimmune disorders.
  • Derivatization of monosaccharides at specific hydroxyl groups may be accomplished by synthetic techniques which are known in the art. For example, it is common to block or protect one or more of the hydroxyl groups leaving one or more hydroxyl groups free to undergo
  • a known derivative of ⁇ -D-giucose having beneficial therapeutic properties is amiprilose, 1,2-O-isopropylidene 3- O-3'-(N,N'-dimethylamino-n-propyl)- ⁇ -D-glucofuranose, and its hydrochloric acid salt, amprilose HCl (THERAFECTIN ® ).
  • amiprilose 1,2-O-isopropylidene 3- O-3'-(N,N'-dimethylamino-n-propyl)- ⁇ -D-glucofuranose
  • amprilose HCl THERAFECTIN ®
  • These two compounds are known to have anti-inflammatory activity and demonstrated utility in managing the signs and symptoms of rheumatoid arthritis. More generally, these compounds have immunomodulatory activity, and therefore have a therapeutic effect on other autoimmune disorders such as psoriasis, eczema or systemic lupus erythematosus.
  • A is H, methyl or ethyl
  • R 1 and R 2 are H, methyl, C 5 -C 10 alkenyl or together form an isopropylidene ring;
  • R 3 is H, C 5 -C 10 alkyl, C 5 -C 10 alkenyl, C 5 -C 10 alkynyl, benzyl, or C 5 -C 10 ester;
  • R 4 is H, C 5 -C 10 alkyl, C 5 -C 10 alkenyl, C 5 -C 10 alkynyl, benzyl, or C 5 -C 10 ester;
  • X 1 is 0
  • Y is selected from cyano, pyrrolyl, pyrrolidinyl,
  • R 5 is C 2 -C 10 alkyl
  • Y is selected from phenyl, cyano, pyrrolyl, methylpyrrolidinyl, pipecolinvl, imidazolyi, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, oxazolidinyl, isooxazolyl, isooxazolidinyl,
  • R 9 and R 10 are hydrogen or form an isopropylidene group; and A compound selected from
  • compositions containing an effective amount of one or more of the above compounds are pharmaceutical compositions containing an effective amount of one or more of the above compounds, and a method of treating an inflammatory disorder and/or an
  • autoimmune disorder comprising administering an effective amount of a compound described above.
  • Monosaccharides are known to exist in an equilibrium between hemiacetal cyclic structures and an open chain sugar.
  • the preferred cyclic structures are furanoses (5-membered ring structures) and pyranoses (6-membered ring structures).
  • Other ring structures may be formed but are not as
  • an acetal is formed.
  • a glycoside can be defined as a cyclized derivative of a monosaccharide having two ether (O-R groups) substituents on the acetal carbon of the sugar.
  • O-R groups ether substituents on the acetal carbon of the sugar.
  • substituents is the carbocylic ring.
  • the second ether substituent is formed by the reaction with the alcohol and is termed the aglycon. Because of the second ether substituent, the resultant glycoside is stable and does not exist in an equilibrium with its open chain structure. Glycosides having a 5-membered ring are known as furanosides, those with 6- membered ring as pyranosides.
  • One embodiment of the present invention relates to derivatives of the simple monosaccharide fructose, in
  • Fructofuranosides can be in an ⁇ -D or ⁇ -D configuration.
  • the fructofuranosides of the present invention shown below in formula I, encompass both ⁇ or ⁇ configurations and are substituted at one or more of the free hydroxyl groups, but, preferably, have at least one free hydroxyl group.
  • the techniques to form these derivatives of the present invention are generally known in carbohydrate chemistry.
  • the fructofuranosides of the present invention are represented by formula (I):
  • aglycon, A is methyl or ethyl, preferably methyl
  • R 1 and R 2 are H, methyl, ethyl, C 5 -C 10 alkenyl or together form an isopropylidene ring;
  • R 3 is H, C 5 -C 10 alkyl, C 5 -C 10 alkenyl, C 5 -C 10 alkynyl, 2-octyne, benzyl, or C 5 -C 10 ester;
  • R 4 is H, C 5 -C 10 alkyl, C 5 -C 10 alkenyl, C 5 -C 10 alkynyl, 2-octyne, benzyl, or C 5 -C 10 ester.
  • the present invention also relates to fructofuranoses. These compounds have the same substituents as defined in formula I where A is hydrogen.
  • a particularly preferred compound is: 2,3-O-isopropylidene-4-O-heptyl- ⁇ -D- fructofuranose (Ik).
  • Examples 1-4 illustrate the preparation of representative compounds of formula I according to this invention. The activity of these compounds is illustrated in Example 5.
  • Step 1 The preparation of Methyl ⁇ -D-fructofuranoside.
  • Step 2 The preparation of Methyl 1,3-O-isopropylidene- ⁇ - D-fructofuranoside.
  • Method two A mixture of methyl ⁇ -D-fructofuranoside (0.8g, 4.1mmole), dimethoxypropane (5g, 49mmole, 6ml) and p-toluenesulfonic acid (0.1g, 0.5mmole) in 20ml of DMF was stirred at 25°C for 24 hours. Sodium bicarbonate was added to neutralize the solution. The solvent was filtered and the filtrate was evaporated to dryness.
  • Step 3 The preparation of Methyl 1,3-O-isopropylidene-6-O- pivaloyl- ⁇ -D-fructofuranoside.
  • Methyl 1,3-O-isopropylidene- ⁇ -D-fructofuranoside (1.3g, 5.55mmole) was dissolved in methylene chloride (10ml; and pyridine (7ml). To this solution, pivaloyl chloride (0.68g, 5.68mmole, 0.7ml) was added at 0°C. The solution was stirred and the temperature rose to 25°C. After 18 hours, another 0.1ml of pivaloyl chloride (0.8mmole) was added and stirring was continued for 24 hours. Water was added to the mixture and solvent was evaporated. The residue was extracted with chloroform, washed with water, brine, dried over sodium sulfate, and concentrated.
  • Step 4 The preparation of Methyl 1,3-O-isopropylidene-4-O- benzyl-6-O-pivaloyl- ⁇ -D-fructofuranoside.
  • Step 5 The preparation of Methyl 1,3-O-isopropylidene-6-O- t-butyldimethylsilyl- ⁇ -D-fructofuranoside.
  • methyl 1,3-O-isopropylidene- ⁇ -D- fructofuranoside (0.25g, 1.07mmole) in DMF (5ml) was added imidazole (0.16g, 2.3mmole) and t-butyldimethylsilyl chloride (0.2g 1.32mmole). The mixture was stirred at 25°C for 48 hours. Water was added and solvent was evaporated under reduced pressure.
  • Methyl 1,3-O-isopropylidene-6-O-t-butyldimethylsilyl-a-D- fructofuranoside [ ⁇ ] n 25 +21.3° (c 1.01, chloroform).
  • Step 6 The preparation of Methyl 1,3-O-isopropylidene-4-O- benzyl-6-O-t-butyldmethylsilyl- ⁇ -D- fructofuranoside.
  • Step 7 The preparation of Methyl 1,3-O-isopropylidene-4-O- benzyl- ⁇ -D-fructofuranoside.
  • Step 9 The preparation of Methyl 1,3-O-isopropylidene-6-O- n-heptyl- ⁇ -D-fructofuranoside.
  • Methyl 1,3-O-isopropylidene- ⁇ -D-fructofuranoside was prepared by the procedure of Cortez-Garcia et al. as
  • Example 1 To a solution of methyl 1,3-O- isopropylidene- ⁇ -D-fructofuranoside (0.3 g, 1.28 mmole) and 1-bromo, 2-octyne (0.73g, 3.85 mmole) in DMF (4 mL) was added 80% NaH (0.12g, 4.0 mmole) slowly and the mixture was stirred at 25° under nitrogen for 40 min. Methancl was added to destroy the excess sodium hydride and solvent was removed. The residue was extracted with methylene chloride and this solution washed with water, brine and sodium bicarbonate.
  • Example 2 The procedure of Example 2 was followed except that 1- bromo-trans-2-octene was substituted for 1-bromo-2-octyne.
  • Methyl 1,3-O-isopropylidene-4,6-di-O-(trans,2-octenyl)- ⁇ -D- fructofuranoside was obtained in 70.0% yield as a colorless oil and identified by its specific rotation, NMR and mass spectral analysis.
  • Step 1 Preparation of 1 ,6-Di-O-trityl-D-fructose.
  • Step 3 Preparation of 2,3-O-Isopropylidene-4-O-heptyl-1,6- di-O-trityl- ⁇ -D-fructofuranose.
  • 1,6-Di-O-trityl-2,3-O-isopropylidene- ⁇ -D- fructosfuranose (0.5 g, 0.71 mmole) was dissolved in DMF (10 mL) and sodium hydride (60%, 0.12 g) was added. The mixture was stirred at 25°C for 20 min. then 1-bromoheptane (0.62 g, 3.5 mmole) was added and stirred for 1 h. Methanol was added to destroy the excess sodium hydride and solvent was
  • Step 4 Preparation of 2,3-O-Isopropylidene-4-O-heptyl- ⁇ - D-fructofuranose.
  • Ammonia (about 100 mL) was passed through a potassium hydroxide tower and cooled into liquid with dry ice to a solution of 2,3-O-Isopropylidene-4-O-heptyl-1,6-di-O-trityl- ⁇ -D-fructofuranose (1.35 g, 1.68 mmole) in dry THF (30 mL) cooled with dry ice. The solution was stirred and pieces of lithium was added until the blue color persisted.
  • THF 2,3-O-Isopropylidene-4-O-heptyl-1,6-di-O-trityl- ⁇ -D-fructofuranose
  • the pharmacologic assays performed to determine the immunomodulatory effects of the experimental compounds in vitro include the Mixed Lymphocyte Reaction (MLR) and the ConA blastogenesis assay. These assays were used to determine the immunomodulatory effects of the experimental compounds in vitro.
  • MLR Mixed Lymphocyte Reaction
  • ConA blastogenesis assay was used to determine the immunomodulatory effects of the experimental compounds in vitro.
  • these assays are appropriate to use as screens for novel compounds having therapeutic potential in the treatment of disorders in which inflammatory mechanisms are involved.
  • the MLR is a classical assay used to measure T ceil function by studying the proliferative response of T cells which are activated in vitro by genetically disparate
  • spleen cells This is accomplished by co-culturing spleen cells from two different strains of mice. Splenic T cell proliferation occurs as a result of cellular activation signals generated by the ongoing cellular interactions.
  • mice were euthanised by cervical dislocation and their spleens removed.
  • Single cell suspensions of the spleens were prepared in culture medium (hepes buffered RPMI- 1640 supplemented with 10% fetal calf serum, 2mM glutamine, 500 units penicillin/streptomycin, and 4 x 10 -5 M 2- mercaptoethanol) using a Teflon pestle.
  • the cells were centrifuged at 1500 rpm and the pellets resuspended in ACT (0.15 M tris, 0.14 M ammonium chloride, pH 7.2 ) in order to lyse the red blood cells. After a 5 minute incubation in a 37 C waterbath, the cells were resuspended in culture medium and counted.
  • C57B1/6 spleen cells which were used as
  • stimulator cells were also prepared by this method.
  • the stimulator cells were treated with 100 ug/ml of mitomycin c f or 1 hour at 37 C ( to inhibit stimulatory cell
  • the proliferative responses were measured by culturing 2.5 x 10 5 responder cells with 5 x 10 5 stimulatory cells in 96 well microtiter plates in the presence or absence of various doses of test compounds or vehicle (DMSO).
  • Solutions of compounds of the present invention in DMSO were prepared at a stock concentration of 120 mM. Dilutions were made in culture medium to the following concentrations: 3, 10, 30, 100, and 300 uM. The vehicle (DMSO) was used as a negative control.
  • the amount of cell proliferation was measured by adding 20 ul of MTT ( 3-[4,5-dimethylthiazol-2-yl]-2,5diphenyl-tetrazolium bromide) (10 mg/ml in phosphate buffered saline) to each well. Plates were incubated for 4 hours at 37 C, after which 180 ul of 10% sodium dodecyl sulphate in phosphate buffered saline was added. After an overnight incubation, the optical density (OD) of each well was read on a Molecular Devices microplate reader at 570 - 650 nm. The results were
  • test articles which were found to inhibit proliferation are those which were found to inhibit proliferation.
  • ConA blastogenesis assay is useful for screening the immunomodulatory and anti- proliferative activities of experimental compounds.
  • mice Six to 8 week old male C57B1/6 mice were purchased from Harlan Sprague Dawley (Indianapolis, IN).
  • Spleens were removed and were homogenized to obtain a single cell suspension. Erythrocytes were lysed by hypotonic shock. Upon determination of the viability and concentration of the lymphoid cells, they were adjusted to 4 x 10 6 cells/ml in culture medium (RPMI-1640) supplemented with 10% fetal bovine serum; 100 ug/ml streptomycin; 100 U/ml penicillin, 0.2 M hepes buffer; 5 x 10 -5 M 2-mercaptoethanol and 2 mM glutamine). Spleen cells were seeded into microtiter plate wells at 2 x 10 5 cells/0.050 ml/well.
  • Control cultures consisted of cells, ConA and culture medium containing the vehicle, DMSO only. In some assays the positive controls cyclosporin A (CSP) and AZT were also run. For the testing of the methyl 1,3-O-isopropylidene-6-O-n-heptyl- ⁇ -D- fructofuranoside compound indomethacin and NDGA were used as controls. All cultures were run in triplicate.
  • Solutions of compounds of the invention in DMSO were prepared and dilutions were made in culture medium. Assay concentrations were either: 1, 2.5, 10, 25, 100, 300 and 750 ug/ml or 0.001, 0.01, 0.1, 1, 2.5, 10, 25 and 100 ug/ml.
  • Interleukin 1 is a potent immunomodulatory cytokine that has a broad range of pro-inflammatory
  • IL-1 is known to be produced by activated accessory cells such as macrophages.
  • accessory cells such as macrophages.
  • mice Six to 8 week old male C57B1/6 mice were purchased from Harlan Sprague Dawley. Peritoneal macrophages were elicited by the administration to mice of a single intraperitoneal injection of 0.2 ml of complete Freund's adjuvant. After 48 hours, elicited macrophages were removed frcm the mice by lavage with the use of Hank's balanced salt solution.
  • Macrophages were washed and seeded into microtiter wells at a density of 2 x 10 5 cells/well in culture medium (as described in the ConA blastogenesis assay).
  • macrophage cultures were added various doses of the compounds of the invention and 10 ug/ml of the macrophage activator lipopolysaccharide (to stimulate IL-1 production).
  • Control cultures consisted of macrophages, lipopolysaccharide and culture medium containing various doses of DMSO only.
  • Cultures were incubated for 24 hours at 37°C in a humidified atmosphere of 5% CO 2 in air.
  • Compounds of the invention were prepared in DMSO and diluted to the following concentrations in culture mediums 0.001, 0.01, 1, 2.5, 10, 25 and 100 ug/ml.
  • the amount of IL-1 produced in the individual wells was determined in a bioassay for IL-1. This involved the removal of thymuses from mice less than 8 weeks of age. Thymocytes were isolated by passing each thymus through a stainless steel mesh screen. Thymocytes were placed in culture at
  • compound (Ik) is inhibitory in a dose dependent manner with significant inhibition of T lymphocyte proliferation observed at concentrations ranging from 1 ug/ml to 100 ug/ml.
  • Table IV demonstrates that compound (Ii) exerts significant, non dose dependent modulation of T lymphocyte proliferation with significant inhibition observed at all dose levels on the 1 ug/ml ConA cultures.
  • the results shown in Table V indicate that methyl 1,3-O-isopropylidene-6-O-n-heptyl- ⁇ -D- fructofuranoside produced a dose-dependent, significant, inhibitory effect upon the ability of normal, splenically- derived, mouse T-cells to proliferate in response to
  • CSP cyclosporin
  • AZT AZT
  • DMSO vehicle
  • Normal spleen cells were cultured with A or 1 ug/ml Con-A together with various doses of experimental compound.
  • the control contained medium with vehicle only. The effect of these compounds on the blastogenic response of spleen cells was determined by pulsing cells with 3 H thymidine after A8 hours of culture and harvesting the cultures 18 hours thereafter.
  • CSP cyclosporin
  • AZT AZT-N-(n-phenyl)-2-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-N-phenyl-N-N-(n-phenyl)-2-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl-N-phenyl
  • compounds of formula I have been found to have immunomodulatory and anti-proliferative effects which predict that these compounds of the present invention have utility, from a therapeutic standpoint, in the treatment of a variety of inflammatory and/or autoimmune diseases.
  • mice spleen cell mixed lymphocyte cultures were suspended in DMSO, diluted in medium and added at the indicated concentrations to mouse spleen cell mixed lymphocyte cultures. Vehicle control cultures contained medium plus the assay concentration of DMSO.
  • T cell prol if erative responses were determined after 5 days of culture by MTT reduction analysis with mean optical density (O.D.) corresponding to the amount of cellular proliferation in triplicate wells.
  • Pesults are expressed as percentage change from the T cell prolifel ive response in vehicle control cultures.
  • a second embodiment of this invention are derivatives of glucose and allose.
  • Glucose and allose are six carbon monosaccharides which differ from each other by the
  • these compounds include mono-substituted ether derivatives of ⁇ -D or ⁇ -O glucofuranoses and ⁇ -D or ⁇ -D allofuranoses as well as analogs thereof.
  • the compounds are substituted at the 3- or 6-position of the monosaccharide.
  • the analogs of these compounds are those where the oxygen at the 3- or 6-positon has been replaced by an amino group or by sulfur.
  • the compounds of this embodiment can be broadly classified into two groups: fully blocked mono-substituted compounds, i.e., those having two isopropylidene protecting groups, and partially blocked mono-substituted compounds, i.e., those having only one isopropylidene protecting group.
  • fully blocked mono-substituted compounds i.e., those having two isopropylidene protecting groups
  • partially blocked mono-substituted compounds i.e., those having only one isopropylidene protecting group.
  • derivatives of glucofuranose and allofuranose are effective in the treatment of autoimmune and/or inflammatory disorders.
  • X 1 is 0
  • cyano selected from cyano, pyrrolyl, pyrrolidinyl, methylpyrrolidinyl, pipecolinvl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,
  • oxazolyl oxazolidinyl, isooxazolyl, isooxazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, O(CH 2 ) 3 N(CH 3 ) 2 , (C 5 - C 10 alkoxy),
  • R 5 is C 2 -C 10 alkyl
  • R 6 and R 7 are hydrogen or form an isopropylidene ring.
  • reaction is monitored by TLC and GC .
  • the normal reaction time varies from 20 minutes to 1 hour. After tne completion of the reaction, it is neutralized with a
  • 1,2:5,6-Di-O-isopropylidene-3-O-3'-propanol- ⁇ -D- glucofuranose was prepared by reacting 1,2:5,6-di-O- isopropylidene- ⁇ -D-glucofuranose with sodium hydroxide
  • Example 6 gave the partially blocked compound 1,2-O-Isopropylidene-3-O-3'-(n- propoxyheptyl)- ⁇ -D-glucofuranose.
  • Step 1 Preparation of 1,2:5,6-di-O-isopropylidene-3-deoxy- 3-azido- ⁇ -D-glucofuranose:
  • Step 2 Preparation of 1,2:5,6-di-O-isopropylidene-3-deoxy- 3-amino- ⁇ -D-glucofuranose.
  • step 1 The azido compound (5g) obtained in step 1 was reduced catalytically using H 2 , Palladium-charcoal (10%, 50 mg) and methanol (100 ml) in a Parr-hydrogenator at a pressure of 35 psi for 6 hours. The reaction mixture was then filtered using Celite, washed with methanol (100 ml) and the solvent removed using a rotary evaporator. The residue obtained showed a single homogenous spot on TLC and complete
  • Example 6 gave the partially blocked compound 1,2-di-O-isopropylidene-3-deoxy-3-amino- ⁇ -D-glucofuranose.
  • Step 4 Preparation of 1,2:5,6-Di-O-isopropylidene-3-deoxy- 3-amino-n-heptyl- ⁇ -D-glucofuranose.
  • 3-Deoxy-3-amino compound obtained in step 3 was heated with 1-bromoheptane at 70-80°C in the ratio of 1:2.2 for 3-4 hours. The progress of the reaction was followed bv TLC and GC. After the completion of the reaction, the product was extracted with ethyl acetate, washed with a saturated solution of sodium bicarbonate, brine and then the organic layer dried over anhydrous MgSO 4 . The removal of the solven: gave the crude compound which was purified by flash
  • Step 5 Hydrolysis according to the general procedure
  • Step 1 1,2:5,6-di-O-isopropylidene- ⁇ ,D-allofuranose was treated with dry powdered sodium hydroxide and a suitable alkyl halide or substituted alkyl halide in the same manner and ratio as described for the glucofuranose derivative in Example 7, step 1.
  • Step 1 Preparation of 1,2:5,6-Di-O-isopropylidene-3-deoxy- 3-amino-n-heptyl ⁇ -D-allofuranose.
  • LTB 4 is the principal biological mediator which is responsible for the promotion of the inflammatory process that exacerbates the disease (Anderson, T.F., "New Reasons for Using Time-Honored Empiric Therapy," Consultant, 1985. In the autoimmune diseases with arthritic components, proliferating synovial fibroblasts are responsible for the production of inflammation mediators .
  • this activity indicates that physiologically acceptable doses of these claimed compounds can be used, either topically or svstemically, to inhibit T-cell and human fibroblast proliferation.
  • the human skin cell fibroblast line, BUD-8 was obtained prior to each assay from the American Type Culture
  • BUD-8 cell cultures were expanded for use in 25 cm 2 flasks at 37°C in an atmosphere of 5% CO 2 in air. At approximately 4-5 five day intervals, or when confluence was reached, the cells were passaged. This was accomplished by detaching the cells with a Teflon scraper, washing and reseeding the cells at a lower density into fresh tissue culture flasks.
  • the effect of the compound of the present invention on the proliferative capacity of human BUD-8 skin fibroblasts was measured with the use of a 3 H-thymidine incorporation assay using culture conditions which were similar to those used for a Con-A blastogenesis assay, described previously.
  • viabilities were determined. These cells were then plated in triplicate at a density of 2X10 3 cells/0.1 ml/microtiter well for the proliferation assay and a density or 1X10 4 cells/
  • NDGA nordihydroguaiaretic. acid
  • samples of the BUD-8 skin cell supernatants were collected from one set of microtiter plates and frozen until assayed for PGE 2 or for LTB 4 content using the radioimmunoassays described below.
  • Group 2 1 ug/ml
  • Group 6 300 ug/ml
  • Group 3 10 ug/ml
  • Group 7 750 ug/ml
  • the incubation medium used for culturing the BUD-8 cells was RPMI-1640 medium containing 10% fetal bovine serum, 100 ug/ml streptomycin, 100 U/ml penicillin, 0.2 M Hepes buffer solution, 5x10 -5 M 2-mercaptoethanol and 2 mM glutamine.
  • Radioimmunoassay Tubes were refrigerated overnight. A charcoal solution (0.5 ml of 0.5% charcoal Norit A) was added and each tube was centrifuged. The radioactivity in the supernatant was then counted in a liquid scintillation counter.
  • CSP cyclosporin
  • AZT AZT
  • DMSO vehicle
  • Normal spleen cells were cultured with 4 or 1 ugg/ml Con-A together with various doses of experimental compound.
  • the control contained medium with vehicle only. The effect of these compounds on the blastogenic response of spleen cells was determined by pulsing the cells with 3 H-thymidine after 48 hours of culture and harvesting the culture 18 hours thereafter.
  • mice spleen cell mixed lymphocyte cultures were suspended in DMSO, diluted in medium and added at the indicated concentrations to mouse spleen cell mixed lymphocyte cultures. Vehicle control cultures contained medium plus the assay concentration of DMSO.
  • T cell prol iferat ive responses were determined after 5 days of culture by MTT reduction analysis with mean optical density (O.D.) corresponding to the amount of cellular proliferation in triplicate wells.
  • Mouse peritoneal macrophage IL-1 production was also found to be inhibited by compounds of the present invention as described in Table XI.
  • Compound (llg) exerted dose dependent inhibition of macrophage IL-1 production with significant decreases in IL-1 activity observed at 10, 25 and 100 ug/ml of compound. Since IL-1 is a potent stimulator of B and T lymphocytes, both of which are active in inflammatory and autoimmune diseases, these data are indicative of the extensive immunomodulatory effects of the compounds of the present invention. Because uncontrolled fibroblast
  • Compound (llg) was observed to exert non dose dependent anti-proliferative effects on Bud-6 skin cell fibroblasts with significant anti-proliferative activity seen at 100, 25 and 10 ug/ml of compound (Table XII).
  • CSP cyclosporin
  • AZT AZT AZT AZT AZT peritoneal exudate cells
  • PEC peritoneal exudate cells
  • thymocytes a peritoneal exudate cells
  • IL-1 IL-1 which selectively stimulates their growth.
  • the effect of these compounds on thymocytes was measured by pulsing the cells with 3 H-thymidine and harvesting the cells 18 hours thereafter. Data shown is menu cpm of triplicates 1 SD. Shown in parenthesis is the percent effect of adding drug to PEC when compared to effect of PEC cultured without drug.
  • glucofuranose and allofuranose are shown by the following general formula III:
  • Y is selected from phenyl, cyano, pyrrolyl, methylpyrrolidinyl, pipecolinyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoozazoiidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, O(CH 2 ) 3 N(CH 3 ) 2 , (C 5 -C 10 alkoxy), NH or
  • R 9 and R 10 are hydrogen or form an isopropylidene group.
  • Step 1 The preparation of 1,2:3,5-di-O-isopropylidene-6- deoxy-6-thio- ⁇ -D-glucofuranose has been described in U.S. Patent No. 4,996,195, the disclosure of which is incorporated by reference.
  • Step 2 The preparation of 1,2:3,5-di-O-isopropylidene-6- deoxy-6-thio-n-heptyl- ⁇ ,D-glucofuranose:
  • Step 1 Preparation of 1,2:3,5-Di-O-isopropylidene-6-deoxy- 6-amino- ⁇ -D-glucofuranose.
  • Example 6 gave the partially blocked compound 1,2-O-isopropylidene-6-deoxy-6-amino- ⁇ -D- glucofuranose.
  • Example 6 gave the partially blocked compound 1,2-O-Isopropylidene-6-deoxy-6-amino-3'- (phenylpropyl)- ⁇ -D-glucofuranose.
  • CSP cyclosporin
  • AZT AZT
  • DMSO vehicle
  • Normal spleen cells were cultured with 4 or 1 ugg/ml Con-A together with various doses of experimental compound.
  • the control contained medium with vehicle only. The effect of these compounds on the blastogenic response of spleen cells was determined by pulsing the cells with 3 H-thymidine after 48 hours of culture and harvesting the culture 18 hours thereafter.
  • mice spleen cells mixed lymphocyte cultures were suspended in DMSO, diluted in medium and added at the indicated concentrations to mouse spleen cells mixed lymphocyte cultures. Vehicle control cultures contained medium plus the assay concentration of DMSO.
  • O.D. mean optical density
  • Results are expressed as percentage change fiom the T cell proliferative response in vehicle control cultures.
  • CSP cyclosporin
  • AZT AZT
  • Thymocytes were collected and added for the subsequent 48 hr. to thymocytes and 1 ug/ml PHA. Thymocytes are used as
  • the compounds of the present invention also include the following monosaccharides:
  • parentheses is the calculated pg PGEo production per 10 5 cells.
  • radioimmunoassay All values are the results of triplicate determinations. Data are expressed as pg LTB 4 in 100 ul supernatant ISD. In parentheses is the calculated pg LTB 4 secretes per 10 5 cells.
  • Step 1 The preparation of 1,2-O-isogropylidene-3-O-3' -
  • Step 2 The preparation of 1,2-O-isopropylidene-6-decxy-3- O-3'-(N',N'-dimethylaminopropyl)- ⁇ a-D- glucofuranose, (2).
  • Step 3 The preparation of 6-Deoxy-3-O-3'-(N',N'-dimethylaminopropyl)-D-glucopyranose, (3).
  • Step 4 The preparation of methyl 3-O-3'-(N',N'- dimethylaminopropyl)-6-deoxy-D-glucopyranoside, (V).
  • Methyl 3-O-3'-(N',N'-dimethylamino-n-propyl)-6-deoxy-D- glucopyranoside of this invention has demonstrated inhibitor effects on the proliferation of GS-109-V-20 human skin cell fibroblasts.
  • a compound that inhibits fibroblast proliferation has the potential to be utilized as a dermatological drug used to treat chronic dermatorse, such as psoriasis and autoimmune disorders which result in joint inflammation, such as
  • rheumatoid arthritis also, an anti-proliferative effect may well be observed with other tissues, such as those that line the blood vessels, or joints, the uncontrolled proliferation of which produce disease, thereby broadening the scope of potential applications.
  • Methyl 3-O-3'-(N',N'-dimethylamino-n-propyl)-6-deoxy-D- glucopyranoside was suspended directly into the medium by extensive sonication, without being filter-sterilized.
  • a range of doses of this compound was used to measure effects of this compound upon GS-109-V-20 cell proliferation. The following doses were used:
  • Group 1 0 ug/ml
  • Group 7 10 ug/ml
  • Group 2 0.001 ug/ml
  • Group 8 25 ug/ml
  • Group 3 0.01 ug/ml
  • Group 9 100 ug/ml
  • the incubation medium used for culturing the GS-109-V-20 cells was RPMI-1640 medium containing 10% fetal bovine serum, 100 ug/ml streptomycin, 100 U/ml penicillin, 0.2 M Hepes buffer solution, 5x10 -5 M 2-mercaptoethanol and 2 mM
  • the human skin cell fibroblast line was obtained from the American Type Culture Collection. This is a fibroblast-like cell line which was originally derived from the skin of an 18 year old Caucasian male with Gardner's syndrome, an autosomal dominant condition which predisposes to carcinoma and multiple polyps of the colon (American Type Culture Collection, Catalogue of Cell Lines and Hybridomas, 6th Ed., 150, 1988). These cells were selected for use because they are considered to exist in an initiated state, as opposed to being normal or transformed, and have a more extensive population doubling time and survival period in culture than do normal fibroblasts.
  • GS-109-V-20 cells were expanded for use in the described assays by culture in 25 cm 2 flasks at 37°C in an atmosphere of 5% CO 2 in air. At approximately 4-5 day intervals, or when confluence was reached, the cells were passaged. This was accomplished by detaching the cells by trypsinization, washing and reseeding the cells at a lower density into fresh tissue culture flasks.
  • the compounds of the present invention as shown by formulae I, II, III, IV and V are useful for treating mammals with inflammatory and/or autoimmune disorders such as psoriasis, atopic dermatitis, rheumatoid, arthritis,
  • the compounds of the present invention or their physiologically acceptable salts are particularly suitable for use as active compounds in pharmaceutical compositions for the treatment of, for example, chronic inflammatory rheumatic disorders.
  • the compounds can either be administered alone in the form of microcapsules, in mixtures with one another or in combination with acceptable pharmaceutical carriers.
  • the invention thus, also relates to pharmaceutical compositions which comprise an effective amount of at least one compound of the present invention with or without a pharmaceutically acceptable carrier.
  • compounds containing an amino functionality may be in the form of an acid-addition salt.
  • Preferred acid addition salts are hydrochloric acid salts.
  • the present invention also encompasses a method of treating animals or humans suffering from inflammatory and/or autoimmune disorders which comprises administering to an animal or person an effective amount of at least one of the compounds of the invention or an acid-addition salt thereof, with or without a pharmaceutically acceptable carrier.
  • the compositions according to the invention can be administered orally, topically, rectally, internally, or, if desired, parenterally. Oral administration is preferred.
  • Suitable solid or liquid galenical formulations for example are granules, powders, coated tablets, microcapsules, suppositories, syrups, elixirs, suspensions, emulsions, drops or injectable solutions. Preparations having a protracted release of the active compound may also be used. These formulations can also contain additives such as excipients, disintegrants, binders, coating agents, swelling agents, glidants, or lubricants, flavors, sweeteners or solubilizers. Frequently used additives are, for example, magnesium
  • compositions are preferably produced and administered in dosage units, each unit containing as active component a certain dose of at least one compound of the present invention and/or at least one of its
  • the dose can range from about 1 to 100 mg per kilogram of body weight per day, preferably 10 - 200 mg.
  • 10 - 200 mg physiologically acceptable acid-addition salts.
  • the effective amount to achieve a 50% inhibition of the cultured cells range from about 1 - 200 ug/ml of culture medium, preferably 10 - 100 ug/ml.

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Abstract

Dérivés de monosaccharides simples présentant une activité anti-proliférative et/ou anti-inflammatoire et utiles dans le traitement de mammifères souffrant d'affections inflammatoires et/ou auto-immunes. Cette invention se rapporte aussi à des compositions pharmaceutiques contenant ces composés et à des méthodes de traitement d'affections inflammatoires et/ou auto-immunes.
EP91916966A 1990-09-12 1991-09-12 Monosaccharides presentant une activite anti-proliferative et anti-inflammatoire, compositions et leurs utilisations Withdrawn EP0548226A1 (fr)

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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
FR2694753B1 (fr) * 1992-07-09 1994-12-23 Picardie Jules Verne Universit Procédés de synthèse spécifique de nouveaux aminothioéthers par substitution des sites hydroxylés sur des molécules mono ou polyhydroxylées, produits obtenus par ces procédés et leurs applications.
US5432163A (en) * 1992-11-13 1995-07-11 Greenwich Pharmaceuticals Incorporated Anti-proliferative and anti-inflammatory compounds: derivatives of pentose monosaccharides
CA2164827A1 (fr) * 1993-06-11 1994-12-22 David S. Thomson Composes immunomodulatoires, anti-inflammatoires et anti-proliferatifs : derives 5,6-didesoxy, 5-amino d'idose et derives 6-desoxy, 6-amino de glucose
US20090048186A1 (en) * 2005-04-19 2009-02-19 Vishwajanani Jitendra Sattigeri Monosaccharide Derivatives as Anti-Inflammatory and/or Anti-Cancer Agents
US20080114031A1 (en) * 2006-03-29 2008-05-15 Sattigeri Viswajanani J Monosaccharide derivatives
US7790689B2 (en) 2006-05-30 2010-09-07 Ranbaxy Laboratories Limited Monosaccharide derivatives
US20080300196A1 (en) * 2006-10-03 2008-12-04 Ashwani Kumar Verma Monosaccharide derivatives

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JPS55154991A (en) * 1979-05-23 1980-12-02 Hisamitsu Pharmaceut Co Inc Beta-d-fructopyranoside derivative
US4735934A (en) * 1981-02-17 1988-04-05 Greenwich Pharmaceuticals Incorporated Method of therapeutically treating a warm blooded animal afflicted with an autoimmune disease
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

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