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• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • 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
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H11/00—Compounds containing saccharide radicals esterified by inorganic acids; Metal salts thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms

Definitions

• glycosaminoglycans heparin and heparan sulfate are endogenous inhibitors of SMC proliferation, yet are able to promote endothelial cell growth (Castellot, J.J. Jr.; Wright, T. C; Karnovsky, M.J. Seminars in Thrombosis and Hemostasis 1987, 13, 489).
• heparin, heparin fragments, chemically modified heparin, low molecular weight heparins, and other heparin mimicking anionic polysaccharides may be compromised due to other pharmacological liabilities (excessive bleeding arising from anticoagulation effects, in particular) coupled with heterogeneity of the various preparations (Borman, S. Chemical and Engineering News, 1993, June 28, 27).
• Patent numbers US 5,498,775, WO96/14324, and US 5,464,827 describe polyanionic benzylglycosides or cyclodextrins as smooth muscle cell proliferation inhibitors for treating diseases and conditions which are characterized by excessive smooth muscle proliferation, ⁇ -cyclodextrin tetradecasulfate has been described as a smooth muscle cell proliferation inhibitor and as an effective inhibitor of restenosis (Reilly, C.F.; Fujita, T.; McFall, R. C; Stabilito, I. I.; Wai-se E.; Johnson, R. G. Drug Development Research 1993, 29, 137).
• US 5019562 discloses anionic derivatives of cyclodextrins for treating pathological conditions associated with undesirable cell or tissue growth.
• WO 93/09790 discloses antiproliterative polyanionic derivatives of cyclodextrins bearing at least 2 anionic residues per carbohydrate residues.
• Wetsberger (EP 312087 A2 and EP 312086 A2) describes the antithrombotic and anticoagulant properties of sulfated bis-aldonic acid amides.
• US 4431637 discloses polysulfated phenolic glycosides as modulators of the complement system.
• the compounds of the present invention differ from all of the prior art in that the compounds (a) are benzylmaltosides which bear no structural resemblance to heparin, sulfated cyclodextrins, or to sulfated lactobionic acid dimers, (b) contain no more than two contiguous sugar residues (disaccharide), (c) are of a defined structure, (d) and are not sulfated. DESCRIPTION OF THE INVENTION
• This invention provides benzylmaltosides of formula I
• R 1 , R 2 , R 3 , R 4 , and R 5 are each, independently, hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2- 7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R 8 ;
• R 6 and R 7 are each, independently, -OH, -OR 9 , O-tert-butyldimethylsilyl, O- trialkylsilyl of 1-6 carbon atoms per alkyl moiety, O-triphenylsilyl,
• R 8 , R 10 , R 11 , and R 12 are each, independently, hydrogen, -CN, -NO 2 , halogen, CF 3 , alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy of 1-6 carbon atoms;
• R 9 is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R 8 ;
• Y is O, S, NH, NMe, or CH 2 ;
• W is halogen, -CN, CF 3 , alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon atoms, or phenyl mono-, di-, or tri-substituted with R 8 ;
• Z is -NO 2 , -NH 2 , -NHR 13 , or -NHCO-Het;
• R 13 is acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, benzoyl in which the phenyl moiety is substituted
• n 0-3; with the proviso that when Z is -NHR 13 and Y is O, at least one of R 1 , R 2 , R 3 , R 4 , and R 5 is hydrogen, or at least one of R 6 and R 7 is OH, or a pharmaceutically acceptable salt thereof.
• Alkyl includes both straight chain as well as branched moieties.
• Halogen means bromine, chlorine, fluorine, and iodine.
• R 13 is an ⁇ -amino acid
• the carboxyl moiety exists as an amide with the amide nitrogen being bonded to the phenyl ring of the compound of formula I. The following exemplifies the resulting structure when R 13 is alanine:
• the amino acid contains a second carboxyl moiety
• the moiety is an alkyl ester of the free acid.
• the following example shows aspartic acid methyl ester.
• Preferred amino acids include alanine, arginine, aspartic acid, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
• the amino acids defined by R 13 include both the D and L amino acids.
• salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, na thalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
• Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium.
• Acid addition salts can be prepared when Y contains a nitrogen or the compound of formula I contains a basic nitrogen, and base addition salts can typically be prepared when the compound of formula I contains a hydroxyl group.
• the compounds of this invention may contain an asymmetric carbon atom or sulfoxide moiety and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
• Preferred compounds of this invention are benzylmaltosides of formula I
• R 1 , R 2 , R 3 , R 4 , and R 5 are each, independently, hydrogen or acyl of 2-7 carbon;
• R 6 and R 7 are each, independently, -OH, -OR 9 , O-tert-butyldimethylsilyl,
• R 8 , R 10 , R 11 , and R 12 are each, independently, hydrogen, -CN, -NO 2 , halogen, CF 3 , alkyl of 1-6 carbon atoms, acetyl, benzoyl, or alkoxy of 1-6 carbon atoms;
• R 9 is acyl of 2-7 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R 8 ;
• Y is O or S
• W is halogen, or alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, nitroalkyl of 1-6 carbon atoms, cyanoalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkoxy of 1-6 carbon atoms, or phenyl mono-, di-, or tri- substituted with R 8 ;
• Z is -NO 2 , -NH 2 , -NHR 13 , or -NHCO-Het;
• R 13 is acyl of 2-7 carbon atoms, or benzoyl in which the phenyl moiety is substituted with R 8 , or R 13 is an ⁇ -amino acid in which the ⁇ carboxyl group forms an amide with the nitrogen of Z, wherein if said amino acid is glutamic acid or aspartic acid, the non- ⁇ carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms; Het is pyridyl substituted with R 8 , thienyl substituted with R 8 , furyl substituted with R 8 , oxazolyl substituted with R 8 , pyrazinyl substituted with R 8 , pyrimidinyl substituted with R 8 , or thiazolyl substituted with R 8 ;
• Specifically preferred compounds of this invention are:
• the compounds of this invention were be prepared according to the following schemes from commercially available starting materials or starting materials which can be prepared using literature procedures. These schemes show the preparation of representative compounds of this invention.
• Acetobromomaltose 1 is coupled with a benzyl alcohol 2 in the presence of a catalyst such as a mercuric bromide, mercuric cyanide, silver triflate, or silver perchlorate in an aprotic solvent such as acetonitrile, dichloromethane, ether, toluene or nitromethane at temperatures ranging from -40 °C to reflux to yield glycoside 3 (Scheme 1).
• This glycosidation can also be accomplished using Schmidt's trichloroacetimidate coupling with zinc bromide in a solvent such as dichloromethane.
• Reduction of the nitro group of 3 can be accomplished with a reducing agent such as stannous chloride in a polar aprotic solvent such as ethyl acetate at ambient temperature to reflux to afford an anilino compound 4.
• Coupling of 4 with an acid chloride can be completed in the presence of an amine base such as triethylamine or diisopropylethylamine or using a stronger base such as sodium hydride (for sterically hindered systems) in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0 °C to ambient temperature to yield the target compound 5.
• the peracetylated compound 5 can be converted to the heptahydroxy compound 6 with catalytic sodium methoxide in methanol or aqueous sodium hydroxide in methanol at temperatures ranging from ambient temperature to reflux.
• the C-6 and C-6' positions can be selectively protected as a silyl ether (7) using t-butyldimethylchlorosilane, a tertiary base such as triethylamine, and a catalytic amount of 4-dimethylaminopyridine.
• the 6- and o p position primary alcohols can be selectively acylated (Scheme 3) using an appropriate acid chloride in a 1:1 mixture of tetrahydrofuran and the hindered base 2,4,6-collidine at -40 °C initially to ambient temperature overnight.
• the compounds of this invention are useful as antiproliferative agents.
• the following procedures show the evaluation of representative compounds of this invention in standard pharmacological test procedure which measured ability of the evaluated compound to inhibit smooth muscle cell proliferation Effects of Compounds on Cell Proliferation Using 3 H Thymidine Incorporation
• Human and porcine smooth muscle cells were tested in early passage (generally passage 3 - 7) at sub-confluent conditions. Cultures were grown in 16 mm (24 well) multi-well culture dishes in medium 199 supplemented with 10% fetal bovine serum and 2% antibiotic / antimycotic. At sub-confluence, the cells were placed in a defined serum free medium (AIM-V; Gibco) for 24 - 48 h prior to initiating the experimental protocol.
• AIM-V defined serum free medium
• the compounds of this invention are useful in treating or inhibiting diseases which are characterized by excessive smooth muscle cell proliferation (smooth muscle cell hyperproliferation).
• the compounds are particularly useful in treating hyperproliferative vascular diseases which are characterized by smooth muscle cell hyperproliferation, such as restenosis, which most frequently arises from vascular reconstructive surgery and transplantation, for example, balloon angioplasty, vascular graft surgery, coronary artery bypass surgery, and heart transplantation.
• Other disease states in which there is unwanted "cellular" vascular proliferation include hypertension, asthma, and congestive heart failure.
• the compounds of this invention are also useful as inhibitors of angiogenesis.
• Angiogenesis neovascularization
• the compounds of this invention are therefore useful as antineoplastic agents.
• the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
• the pharmaceutical carrier may be solid or liquid.
• a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
• the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
• the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
• Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
• Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
• the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
• the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
• suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g.
• cellulose derivatives preferably sodium carboxymethyl cellulose solution
• alcohols including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
• the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
• Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
• the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
• Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
• the compounds of this invention can also be administered orally either in liquid or solid composition form.
• the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
• the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
• the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic abso ⁇ tion into the blood stream via the skin.
• the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
• the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
• Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
• a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
• the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated.
• the pharmaceutical composition is in unit dosage form, e.g.
• the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
• the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids.
• the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
• step 3 5-[(Hepta-0-acetyl- ⁇ -D-maltosyl)-oxy-methyI]-2-cyano-l-nitrobenzene
• step 2 N-[2-Chloro-5-( ⁇ -D-maltosyl-oxymethyl)-phenyl]-acetamide
• step 2 N-[2-Chloro-5-[[(4-- - ⁇ -D-glucopyranosyl- ⁇ -D-gIucopyranosyl)oxy]methyl] phenyl]-3-pyridinecarboxamide

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• 1999
  • 1999-11-23 WO PCT/US1999/027777 patent/WO2000034295A2/en not_active Application Discontinuation
  • 1999-11-23 CA CA002351059A patent/CA2351059A1/en not_active Abandoned
  • 1999-11-23 AU AU37912/00A patent/AU3791200A/en not_active Abandoned
  • 1999-11-23 EP EP99973295A patent/EP1133510A2/en not_active Withdrawn
  • 1999-11-23 BR BR9915632-6A patent/BR9915632A/pt not_active Application Discontinuation
  • 1999-11-23 CN CN99813623A patent/CN1329616A/zh active Pending
  • 1999-11-23 JP JP2000586738A patent/JP2003521460A/ja active Pending

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