WO2000034338A2 - Benzylmaltosides acetiques, inhibiteurs de proliferation des cellules des muscles lisses - Google Patents

Benzylmaltosides acetiques, inhibiteurs de proliferation des cellules des muscles lisses Download PDF

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WO2000034338A2
WO2000034338A2 PCT/US1999/027781 US9927781W WO0034338A2 WO 2000034338 A2 WO2000034338 A2 WO 2000034338A2 US 9927781 W US9927781 W US 9927781W WO 0034338 A2 WO0034338 A2 WO 0034338A2
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carbon atoms
phenyl
substituted
alkyl
perfluoroalkyl
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PCT/US1999/027781
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WO2000034338A3 (fr
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Paul Jeffrey Dollings
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American Home Products Corporation
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Priority to BR9915622-9A priority Critical patent/BR9915622A/pt
Priority to JP2000586780A priority patent/JP2002531579A/ja
Priority to AU17438/00A priority patent/AU1743800A/en
Priority to CA002351060A priority patent/CA2351060A1/fr
Priority to EP99960571A priority patent/EP1133303A2/fr
Publication of WO2000034338A2 publication Critical patent/WO2000034338A2/fr
Publication of WO2000034338A3 publication Critical patent/WO2000034338A3/fr

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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
    • C07H15/20—Carbocyclic rings
    • C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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

Definitions

  • This invention relates to the use of substituted 4',6'-acetal benzylmaltosides as smooth muscle cell proliferation inhibitors and as therapeutic compositions for treating diseases and conditions which are characterized by excessive smooth muscle proliferation such as restenosis.
  • 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).
  • WO 96/14325 discloses acylated benzylglycosides as smooth muscle cell proliferation inhibitors.
  • the compounds of the present invention differ in that the substituents on the carbohydrate backbone are different.
  • 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. L; 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 antiproliferative 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 4',6'-acetal 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 4',6'-acetal benzylmaltosides of formula I
  • W is S, SO, SO 2 , NR;
  • Y is O, S, NR, or CH 2 ;
  • R is hydrogen or alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, perfluoroacyl of 2-7 carbon atoms;
  • R 1 and R 7 are each, independently, alkyl of 1-6 carbon atoms, perfluoroalkyl 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, nitriloalkyl of 1-6 carbon atoms, phenyl mono-, di-, or tri-substituted with R 8 , phenylalkyl of 7-10 carbon atoms, wherein the phenyl ring is mono-, di-, or tri-substituted with R 8 , pyridyl substituted with R 8 , furyl substituted with R 8 , thienyl substituted with R 8 , and thiazolyl substituted with R 8 ;
  • R 2 is hydrogen
  • R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, acyl of 2-7 carbon atoms, perfluoroacyl of 2-7 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, benzyl, wherein the phenyl moiety is mono-, di-, or tri- substituted with R 8 , benzoyl, wherein the phenyl moiety is mono-, di-, or tri- substituted with R 8 ;
  • R 8 is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, phenyl, - CN, -NO 2 , halogen, or -CF 3 ;
  • R 9 is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, phenyl, - CN, -NO 2 , halogen, -NHCO 2 R 13 , -NHSO 2 R 13 , -NR 14 R 15 ,
  • R 10 , R 11 , and R 12 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, phenyl, -CN, -NO 2 , halogen, acyl of 2-7 carbon atoms, perfluoroacyl of 2-7 carbon atoms, or benzoyl, wherein the phenyl moiety of the benzoyl group is optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, -CN, -NO 2 , halogen, or -CF 3 ;
  • R 13 is alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, phenyl or phenyl substituted with halogen;
  • R 14 and R 15 are each,
  • Alkyl, alkoxy and acyl includes both straight chain as well as branched moieties optionally substituted with fluorine.
  • Halogen means bromine, chlorine, fluorine, and iodine.
  • 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, napthalenesulfonic, 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 is 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 4',6'-acetal benzylmaltosides of formula I
  • W is S, SO, SO 2 , NR;
  • Y is O
  • R is hydrogen or alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms, perfluoroacyl of 2-7 carbon atoms;
  • R 1 is alkyl of 1-6 carbon atoms, perfluoroalkyl 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, nitriloalkyl of 1-6 carbon atoms, phenyl mono-, di-, or tri-substituted with R 8 , phenylalkyl of 7-10 carbon atoms, wherein the phenyl ring is mono-, di-, or tri-substituted with R 8 , pyridyl substituted with R 8 , furyl substituted with R 8 , thienyl substituted with R 8 , and thiazolyl substituted with R 8 ;
  • R 2 is hydrogen
  • R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, acyl of 2-7 carbon atoms or perfluoroacyl of 2-7 carbon atoms;
  • R 7 is hydrogen, methyl, or phenyl;
  • R 8 is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, phenyl, - CN. -NO 2 , halogen, or -CF :
  • R 9 is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, perfluoroalkoxy of 1-6 carbon atoms, phenyl, -
  • R 10 , R 11 , and R 12 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, -CN, -NO 2 , halogen, -CF 3 , acyl of 2-7 carbon atoms, or benzoyl, wherein the phenyl moiety of the benzoyl group is optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms. -CN, -NO 2 , halogen, or -CF 3 ;
  • R 13 is alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, phenyl or phenyl substituted with halogen;
  • W is S, SO, SO 2 , NR;
  • Y is O
  • R is hydrogen or alkyl of 1-6 carbon atoms
  • R 1 is phenyl mono-, di-, or tri-substituted with R 8 ;
  • R 2 is hydrogen
  • R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, or acyl of 2-7 carbon atoms;
  • R 7 is hydrogen, methyl, or phenyl;
  • R 8 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, -CN, -NO 2 , halogen, or -CF 3 ;
  • R 9 is hydrogen, -NO 2 , halogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, -NHCO 2 R 13 , -NR 14 R 15 , 0
  • R 10 , R ⁇ , and R 12 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, -CN, -NO 2 , halogen, -CF 3 , acyl of 2-7 carbon atoms, or benzoyl, wherein the phenyl moiety of the benzoyl group is optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, -CN, -NO 2 , halogen, or -CF 3 ;
  • R 13 is alkyl of 1-6 carbon atoms
  • 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. This scheme shows 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 the anilino compound 4.
  • Coupling of 4 with an acid chloride or a sulfonyl 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 4' and 6' groups of 6 can be reacted with an acetal in the presence of an acid catalyst such as camphorsulfonic acid or p-toluene sulfonic acid in a polar aprotic solvent such as N,N-dimethylformamide at temperatures ranging from 25 °C to reflux to give the acetal derivative 7.
  • an acid catalyst such as camphorsulfonic acid or p-toluene sulfonic acid
  • a polar aprotic solvent such as N,N-dimethylformamide
  • Acetal 7 can be converted to the 6-tosylate 10 using tosyl chloride and pyridine in a solvent such as dichloromethane (Scheme 3); the resulting intermediate is then peracylated with an acid chloride or an acid anhydride in the presence of an amine base such as triethylamine or diisopropylethylamine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0 °C to ambient temperature to generate compound 11.
  • a solvent such as dichloromethane 3
  • the tosylate intermediate 11 can be converted to a thioether via direct displacement with a sulfide nucleophile generated from a base such as sodium hydride and an appropriate thiol in a polar solvent such as N,N-dimefhylformamide.
  • the C-6 position can also be converted to an amine or amide linkage by first converting the tosylate 11 to an azide (Scheme 5); this reaction can be accomplished using sodium azide in a polar solvent such as NN-dimethylformamide at 50 °C.
  • the intermediate can be reduced to a primary amine with triphenylphosphine and 5% water in tetrahydrofuran.
  • the amine can be coupled to an appropriate acid chloride in the presence of a base such as pyridine in an aprotic solvent such as tetrahydrofuran or dichloromethane followed by the standard hydrolysis conditions to afford compound 14.
  • the intermediate amine or amide 14 can be alkylated with an alkyl halide in the presence of a base such as sodium hydride (for sterically hindered systems) in a polar solvent such as N,N-dimethylformamide at temperatures ranging from 0 °C to reflux.
  • a base such as sodium hydride (for sterically hindered systems)
  • a polar solvent such as N,N-dimethylformamide
  • the free hydroxyl groups of compounds 10, 13 and 14 can be derivatized.
  • the free hydroxyl groups of compounds 10, 13 and 14 can be acylated with an acid chloride or an acid anhydride in the presence of an amine base such as triethylamine or diisopropylethylamine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0 °C to ambient temperature.
  • the free hydroxyl groups of compounds 10, 13 and 14 can be alkylated with an appropriate alkyl halide in the presence of a base such as sodium hydride or potassium hydroxide in a polar solvent such as N,N-dimethylformamide or DMSO at temperatures ranging from 0 °C to reflux.
  • a base such as sodium hydride or potassium hydroxide
  • a polar solvent such as N,N-dimethylformamide or DMSO
  • W S, SO, or SO ⁇
  • 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
  • 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. Although compounds were found to be more effective with longer pre-incubations, in general, the procedures were initiated with the addition of compound, 3 H thymidine and serum / growth factor to serum deprived synchronized cells and results are reported accordingly.
  • 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 process by which new capillaries are formed, is of principal importance for a number of pathological events including chronic inflammation and malignant processes.
  • 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 absorption 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 2 2-ChIoro-5-(hepta-O-acetyl- ⁇ -D-maltosyl-oxymethyl)-phenylamine
  • step 3 N-[2-Chloro-5-(hepta-O-acetyl- ⁇ -D-maltosyl-oxymethyl)-phenyl]-acetamide
  • step 4 N-[2-Chloro-5-( ⁇ -D-maltosyl-oxymethyl)-phenyI]-acetamide
  • step 5 N- ⁇ 5-[(4',6'-0-Benzylidene- ⁇ -D-maltosyloxy)-methyl]-2-chloro-phenyl ⁇ - acetamide
  • reaction was diluted with diethyl ether (100 mL), washed successively with H 2 O (2x), with sat. aq. NaHCO 3 (2x), with sat. aq. CuSO 4 (2x), with brine (2x), dried (Na 2 SO 4 ) and concentrated.
  • Example 6 (racemate); Example 7 (diastereomer #1); Example 8 (diastereomer
  • the title compound was prepared as a 1:1 mixture of diastereomers, white solid (0.335 g, 69%) from N- ⁇ 5-[(2,2',3,3'-tetra-( -acetyl-4',6'-O-benzylidene-6- deoxy-6-phenylsulfanyl- ⁇ -D-maltosyl)-oxy-methyl]-2-chloro-phenyl ⁇ -acetamide using a procedure similar to Example 5, mp 160-187 °C; ⁇ NMR (DMSO-d 6 ) ⁇ 1.91, 1.92, 1.93, 1.95, 1.96, 1.97.
  • step 2 N-(5- ⁇ [4',6'-O-Benzylidene-6-(phenyl-ethyl-sulfinyl)- ⁇ -D-maltosyl]-oxy-methyl ⁇ - 2-chloro-phenyl)-acetamide
  • step 2 N- ⁇ 5-[(2,2',3,3'-Tetra-O-acetyI-4',6'-0-benzylidene-6-deoxy-6-benzoylamino- ⁇ - D-maltosyl)-oxy-methyl]-2-chloro-phenyl ⁇ -acetamide
  • step 3 N- ⁇ 5-[(4',6'-O-Benzylidene-6-deoxy-6-benzolyamino- ⁇ -D-maltosyl)-oxy-methyl]- 2-chloro-phenyl ⁇ -acetamide
  • the title compound was prepared as a white solid (0. 812 g, 99%) from N-(5- ⁇ [4',6'-O-benzylidene-6-O-(4-toluenesulfonyl)- ⁇ -D-maltosyl]-oxy-methyl ⁇ -2-chloro- phenyl)-carbamic acid methyl ester using a procedure similar to step 7 of Example 1; 'H ⁇ MR DMSO-d 6 ) ⁇ 1.92 (s, 3H), 1.93 (s, 3H), 1.97 (s, 3H), 2.01 (s, 3H), 2.30 (s, 3H), 3.66 (s. 3H), 3.69-4.04 (m, 5H).

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Abstract

Cette invention concerne des inhibiteurs de prolifération des cellules des muscles lisses de la formule (I), ou des sels pharmaceutiquement acceptables desdits inhibiteurs.
PCT/US1999/027781 1998-11-24 1999-11-23 Benzylmaltosides acetiques, inhibiteurs de proliferation des cellules des muscles lisses WO2000034338A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
BR9915622-9A BR9915622A (pt) 1998-11-24 1999-11-23 Acetal benzilmaltosìdeos como inibidores de proliferação de células de músculo liso
JP2000586780A JP2002531579A (ja) 1998-11-24 1999-11-23 平滑筋細胞増殖の阻害薬としてのアセチルベンジルマルトシド
AU17438/00A AU1743800A (en) 1998-11-24 1999-11-23 Acetal benzylmaltosides as inhibitors of smooth muscle cell proliferation
CA002351060A CA2351060A1 (fr) 1998-11-24 1999-11-23 Benzylmaltosides acetiques, inhibiteurs de proliferation des cellules des muscles lisses
EP99960571A EP1133303A2 (fr) 1998-11-24 1999-11-23 Benzylmaltosides acetiques, inhibiteurs de proliferation des cellules des muscles lisses

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US19898498A 1998-11-24 1998-11-24
US09/198,984 1998-11-24

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WO2000034338A2 true WO2000034338A2 (fr) 2000-06-15
WO2000034338A3 WO2000034338A3 (fr) 2000-11-30

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JP (1) JP2002531579A (fr)
CN (1) CN1348460A (fr)
AU (1) AU1743800A (fr)
BR (1) BR9915622A (fr)
CA (1) CA2351060A1 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000031100A2 (fr) * 1998-11-24 2000-06-02 American Home Products Corporation Benzylmaltosides utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses
WO2000034295A2 (fr) * 1998-11-24 2000-06-15 American Home Products Corporation Benzylmaltosides acyles, inhibiteurs de proliferation des cellules des muscles lisses
CN1310795C (zh) * 2003-02-07 2007-04-18 本田技研工业株式会社 车辆用锁装置

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014325A1 (fr) * 1994-11-07 1996-05-17 American Home Products Corporation Benzylglycosides acyles en tant qu'inhibiteurs de la proliferation cellulaire du muscle lisse

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996014325A1 (fr) * 1994-11-07 1996-05-17 American Home Products Corporation Benzylglycosides acyles en tant qu'inhibiteurs de la proliferation cellulaire du muscle lisse

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000031100A2 (fr) * 1998-11-24 2000-06-02 American Home Products Corporation Benzylmaltosides utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses
WO2000034295A2 (fr) * 1998-11-24 2000-06-15 American Home Products Corporation Benzylmaltosides acyles, inhibiteurs de proliferation des cellules des muscles lisses
WO2000034295A3 (fr) * 1998-11-24 2000-11-23 American Home Prod Benzylmaltosides acyles, inhibiteurs de proliferation des cellules des muscles lisses
WO2000031100A3 (fr) * 1998-11-24 2000-11-23 American Home Prod Benzylmaltosides utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses
CN1310795C (zh) * 2003-02-07 2007-04-18 本田技研工业株式会社 车辆用锁装置

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AU1743800A (en) 2000-06-26
JP2002531579A (ja) 2002-09-24
EP1133303A2 (fr) 2001-09-19
BR9915622A (pt) 2001-08-14
WO2000034338A3 (fr) 2000-11-30
CN1348460A (zh) 2002-05-08
CA2351060A1 (fr) 2000-06-15

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