EP1133509A1 - Benzylmaltosides acetal utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses - Google Patents

Benzylmaltosides acetal utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses

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Publication number
EP1133509A1
EP1133509A1 EP99959083A EP99959083A EP1133509A1 EP 1133509 A1 EP1133509 A1 EP 1133509A1 EP 99959083 A EP99959083 A EP 99959083A EP 99959083 A EP99959083 A EP 99959083A EP 1133509 A1 EP1133509 A1 EP 1133509A1
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EP
European Patent Office
Prior art keywords
carbon atoms
phenyl
chloro
methyl
pharmaceutically acceptable
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
EP99959083A
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German (de)
English (en)
Inventor
Scott Christian Mayer
Paul Jeffrey Dollings
Robert Emmett Mcdevitt
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Wyeth LLC
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American Home Products Corp
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Publication of EP1133509A1 publication Critical patent/EP1133509A1/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
    • 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
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

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. 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 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 benzylglycosylamides 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
  • X is O or S
  • R 1 is 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, 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, acyl of 2-6 carbon atoms, haloacyl of 2-6 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-7 carbon atoms, or trifluoromethylacyl of 3-
  • R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, acyl of 2-7 carbon atoms, benzoyl. wherein the phenyl moiety is mono-, di-, or tri-substituted with R 8 , haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 2-
  • 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, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, phenyl, -CN, -NO 2 , halogen, -CF 3 , -NHR 3 , -NR 3 R 3 , -NR 3 R 14 , -NHCO 2 R 14 , -NHSO 2 R 14 ,
  • 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 group or 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 hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, -CN, -NO 2 , halogen. -CF 3 , or phenyl group, wherein the phenyl moiety is optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen;
  • R 14 is alkyl of 1-6 carbon atoms;
  • R 15 is hydrogen, acyl of 2-7 carbon atoms, benzoyl, or -CO 2 R 16 ;
  • Nlkyl includes both straight chain as well as branched moieties.
  • Halogen means bromine, chlorine, fluorine, and iodine.
  • R 9 is - ⁇ R 3 R 3
  • each of the moieties may be the same or different.
  • 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 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
  • X is O or S
  • R 1 is 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, phenyl mono-, di-, or tri-substituted with R 8 , phenylaikyl 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, acyl of 2-6 carbon atoms, carboalkoxyacyl of 4-12 carbon atoms,
  • 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. -CF 3 , -NHR 3 , -NR R 3 , -NR R 14 , -NHCO 2 R 14 , -NHSO 2 R 14 ,
  • 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 group or 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 hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, -CN, -NO 2 , halogen* -CF 3 , or phenyl group, wherein the phenyl moiety is optionally mono-, di-. or tri-substituted with alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen;
  • R 14 is alkyl of 1-6 carbon atoms;
  • R 15 is hydrogen, acyl of 2-7 carbon atoms, benzoyl, or -CO 2 R 16 ;
  • R 1 is 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, 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 , or pyridyl substituted with R 8 ;
  • R 2 is hydrogen, acyl of 2-6 carbon atoms, carboalkoxyacyl of 4-12 carbon atoms,
  • R 3 , R 4 , R 5 , and R 6 are each, independently, hydrogen, or acyl of 2-7 carbon atoms; R 7 is hydrogen;
  • R 8 is hydrogen, alkyl of 1-6 carbon atoms, -CN, or halogen;
  • R 9 is hydrogen, -NO 2 , halogen, -CF 3 , -NHR 3 , -NR R 3 , -NR R 14 , -NHCO 2 R 14 ,
  • 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 group or 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 , halogen, or -CF 3 ;
  • R 13 is hydrogen, alkyl of 1-6 carbon atoms, halogen, or phenyl group, wherein the phenyl moiety is optionally mono-, di-, or tri-substituted with alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or halogen;
  • R 14 is alkyl of 1-6 carbon atoms
  • R 15 is hydrogen, acyl of 2-7 carbon atoms, benzoyl, or -CO 2 R 16 ;
  • Specifically preferred compounds of this invention are: N- ⁇ 2-Chloro-5-[(4',6'-O-ethylidene)- ⁇ -D-maltosyloxymethyl]-phenyl ⁇ -acetamide or a pharmaceutically acceptable salt thereof; (R)-N-[5-[[[6-O-Benzoyl-4-O-(4,6-O-ethylidene- ⁇ -D-glucopyranosyl)- ⁇ -D- glucopyranosyl]oxy]methyl]-2-chlorophenyl]acetamide or a pharmaceutically acceptable salt thereof;
  • Nicotinic acid 4.5-diacetoxy-6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-diacetoxy- 2-phenyl-hexahydro-pyrano[3,2-d][l,3]dioxin-6-yloxy)-tetrahydro-pyran-2-ylmethyl ester or a pharmaceutically acceptable salt thereof;
  • 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.
  • Ncetobromomaltose 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.
  • 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.
  • an acetal (7) was formed at the C-4', 6' positions of the disaccharide of heptahydroxy compound 6 using an appropriate aldehyde dimethyl or diethyl acetal and an acid source such as /?-toluenesulfonic acid monohydrate or camphorsulfonic acid in a polar solvent such as N,N- dimethylformamide at 60 °C.
  • an aldehyde and sulfuric acid can be used in DMF at higher temperatures to obtain the product acetal.
  • the 6- position primary alcohol was selectively acylated using an 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 to generate compound 8.
  • the remaining four secondary alcohols of the disaccharide can then be protected with acetic anhydride and triethylamine in a solvent such as dichloromethane to afford the peracetylated compound 9.
  • acetal 7 can first be converted to a tosylate using tosyl chloride and pyridine in a solvent such as dichloromethane (Scheme 3); the resulting intermediate is then peracetylated as mentioned above to generate compound 10.
  • a solvent such as dichloromethane
  • the 6- ⁇ osition tosylate alcohol formation with sodium formate followed by ether formation with benzyl 2,2,2-trichloroacetimidate
  • an ether linkage is incorporated at this site on the molecule.
  • the benzylidene acetal is then removed under strongly acidic conditions such as 1M ethereal HC1 to afford compound 11.
  • N new acetal is then formed at the C-4', 6' positions using the conditions mentioned previously or just an aldehyde and the acid source in benzene at elevated temperature (60 °C). Finally, the four secondary acetates are removed with catalytic sodium methoxide in methanol or aqueous sodium hydroxide in methanol at temperatures ranging from ambient temperature to reflux to obtain the hydroxy compound 12.
  • 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.
  • 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 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. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.1 to 10 mg/kg administered parenterally (intravenous preferred), with projected daily oral dosage being approximately ten-fold higher. Anticipated intravenous administration would last for approximately 5-30 days following acute vascular injury (i.e., balloon angioplasty or transplantation) and for a longer duration for the treatment of chronic disorders. Treatment will generally be initiated with small dosages less than the optimum dose of the compound.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • 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. The following provides the preparation of representative compounds of this invention.
  • step 2 2-Chloro-5-(hepta-0-acetyl- ⁇ -D-maltosyl-oxymethyI)-phenylamine
  • step 4 N-[2-Chloro-5-( ⁇ -D-maltosyI-oxymethyl)-phenyI]-acetamide
  • step 5 N- ⁇ 2-ChIoro-5-[(4',6'-O-ethylidene)- ⁇ -D-maltosyIoxymethyl]-phenyI ⁇ -acetamide
  • N- ⁇ 5-[(4',6'-O-benzylidene- ⁇ -D- maltosyloxy)-methyl]-2-chloro-phenyl ⁇ -acetamide (1.81 g, 2.96 mmol) in pyridine (6.0 mL) was added a solution of / toluenesulf onyl chloride (0.686 g, 3.60 mmol) in CH 2 C1 2 (3.75 mL).
  • the title compound was prepared as a white foam (0.149 g, 50%) from N- ⁇ 5- [(4',6'-O-benzylidene- ⁇ -D-maltosyloxy)-methyl]-2-chloro-phenyl ⁇ -acetamide using methyl-4-(chloroformyl)-butyrate as the acid chloride and a procedure similar to Example 2, mp 79-81 °C; ⁇ ⁇ MR (CDC1 3 ) ⁇ 1.90-1.98 (m, 2H), 2.13 (s.
  • the title compound was prepared as a yellow powder (1.04 g, 97%) from 4- chloro-3-nitro-benzyl- ⁇ -D-maltoside heptaacetate using a procedure similar to step 4 of Example 1, mp 168-169 °C; ⁇ NMR (DMSO-J 6 ) ⁇ 3.03-3.13 (m, 2H), 3.20-3.38 (m, 4H), 3.41-3.49 (m, 3H), 3.55-3.64 (m, 2H), 3.68-3.75 (m, IH), 4.00-5.50 (bs. 7H), 4.31 (d.
  • step 2 4-ChIoro-3-nitro-benzyl-4',6'-O-benyzlidene- ⁇ -D-maltoside
  • the title compound was prepared as a white foam (0.211 g, 45%) from 4- chloro-3-nitro-benzyl-4',6'-O-benyzlidene- ⁇ -D-maltoside using nicotinoyl chloride hydrochloride and a procedure similar to Example 2 (except compound purified directly with flash chromatography), mp >105 °C (decomp.); ⁇ NMR (DMSO-J 6 ) ⁇ 3.21-3.28 (m, IH), 3.32-3.42 (m, 2H), 3.51-3.60 (m, 3H), 3.65 (t, J
  • the title compound was prepared as a white foam (0.284 g, 47%) from N- ⁇ 5- [(4',6'-O-benzylidene- ⁇ -D-maltosyloxy)-methyl]-2-chloro-phenyl ⁇ -acetamide using
  • the title compound was prepared as a white foam (0.142 g, 81%) from 4- methoxy-benzoic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-dihydroxy-2- phenyl-hexahydro-pyrano[3,2-d][l,3]dioxin-6-yloxy)-4,5-dihydroxy-tetrahydro- pyran-2-ylmethyl ester using a procedure similar to Example 25, mp >110 °C (decomp.); ⁇ NMR (DMSO--i 6 ) ⁇ 1.94 (s, 3H), 1.95 (s, 3H), 1.98 (s, 3H), 1.
  • the title compound was prepared as a white foam (0.225 g, 72%) from 4- chloro-benzoic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8-dihydroxy-2- phenyl-hexahydro-pyrano[3,2-d][l,3]dioxin-6-yloxy)-4,5-dihydroxy-tetrahydro- pyran-2-ylmethyl ester using a procedure similar to Example 25, mp 114-115 °C; ⁇
  • Example 53 (3.4-Dimethoxy-phenvI)-acetic acid 4.5-diacetoxy-6-(3-acetylamino-4-chloro- benzyloxy)-3-(7.8-diacetoxy-2-phenyl-hexahvdro-pyranor3.2-diri,3]dioxin-6-yloxy)- tetrahvdro-pyran-2-ylmethyl ester
  • the title compound was prepared as a white foam (0.105 g, 89%) from (3,4- dimethoxy-phenyl)-acetic acid 6-(3-acetylamino-4-chloro-benzyloxy)-3-(7,8- dihydroxy-2-phenyl-hexahydro-pyrano[3,2-d][l,3]dioxin-6-yloxy)-4,5-dihydroxy- tetrahydro-pyran-2-ylmethyl ester using a procedure similar to Example 25, mp >98 °C (decomp.): ⁇ NMR (DMSO-J 6 ) ⁇ 1.92 (s, 3H), 1.94 (s, 3H), 1.97 (s, 3H), 1.99 (s, 3H), 2.07 (s, 3H).
  • Nicotinic acid 4.5-diacetoxy-6-(3-acetylamino-4-chloro-benzyloxy)-3-(7.8-diacetoxy- 2-phenyl-hexahvdro-pyranor3.2-diri.31dioxin-6-yloxy)-tetrahydro-pyran-2-ylmethyl ester
  • the title compound was prepared as a white powder (0.347 g, 52%) from N- ⁇ 5-[(4',6'-O-benzylidene- ⁇ -D-maltosyloxy)-methyl]-2-chloro-phenyl ⁇ -acetamide using -benzoylbenzoyl chloride (prepared from / benzoylbenzoic acid and oxalyl chloride) and a procedure similar to Example 2, mp >117 °C (decomp.); 'H ⁇ MR DUSO-d 6 ) ⁇ 2.03 (s, 3H), 3.17-3.23 (m, IH), 3.27-3.43 (m, 2H), 3.49-3.66 (m, 4H), 3.70-3.82 (m, 2H), 4.08 (4.8, 10.1 Hz, IH), 4.39-4.44 (m, 2H), 4.64 (d.
  • the title compound was prepared as a colorless solid (8.02 g, 53%) from 4- methyl-3-nitrobenzyl alcohol and acetobromomaltose using a procedure similar to step 1 of Example 1, mp 68-74 °C; ⁇ ⁇ MR (OMSO-d 6 ) ⁇ 1.93 (s, 3 H), 1.94 (s, 3 H), 1.95 (s, 3 H), 1.96 (s, 3 H), 1.97 (s, 3 H), 2.012 (s, 3 H), 2.07 (s, 3 H), 3.93 - 4.01 (m, 4 H), 4.13 - 4.21 (m, 2 H), 4.37 (d, 2 H), 4.64 - 4.90 (m, 5 H), 4.97 (t, 1 H), 5.20 (dd, 1 H), 5.27 - 5.33 (m, 2 H), 7.48 (d, 1 H), 7.52 (d, IH), 7.88 (s, 1 H).
  • the title compound was prepared as a white foam (5.39 g, 79%) from 5- (hepta-O-acetyl- ⁇ -D-maltosyloxymethyl)-2-methyl-l -nitrobenzene using a procedure similar to step 2 of Example 1; ⁇ NMR (OMSO-d 6 ) ⁇ 1.93 (s, 3 H), 1.94 (s, 3 H), 1.95 (s, 3 H), 1.97 (s, 3 H), 1.98 (s, 3 H), 2.03 (s.
  • the title compound was prepared as a white foam (6.60 g, 91%) from 5-
  • step 4 N-[5-( ⁇ -D-MaltosyIoxy-methyI)-2-methyl-phenyl]-acetamide
  • step 2 N-[2-chloro-5-[[(4- 9- ⁇ -D-glucopyranosyI- ⁇ -D-glucopyranosyl)oxy]methyl] phenyl]-3-pyridinecarboxamide
  • Furan-2-carboxylic acid ( 5-1(4'.6'-0-benzylidene- ⁇ -D-maltosyl)-oxy-methyll-2- chloro-phenyl ⁇ -amide step 1
  • Furan-2-carboxyIic acid ⁇ 5-[(2,2',3,3',4',6,6'-hepta-O-acetyl- ⁇ -D-maltosyl)- oxymethyl]-2-chloro-phenyl ⁇ -amide
  • Furan-2-carboxylic acid ⁇ 2-chloro-5-[( ⁇ -D-maltosyI)-oxy-methyl]-phenyl ⁇ -amide A solution containing furan-2-carboxylic acid ⁇ 5-[(2,2'33 ⁇ 4',6,6'-hepta-O- acetyl- ⁇ -D-maltosyl)-oxymethyl]-2-chloro-phenyl ⁇ -amide (136 g, 1.56 mmol) and 25 weight % NaOMe in MeOH (26.8 ⁇ L, 0.468 mmol) in MeOH (41 ml) was stirred at rt for 18 h.
  • the title compound was prepared as a white solid (0.352 g, 63%) from furan-
  • step 2 N- ⁇ 2-Chloro-5-[( ⁇ -D-maltosyl)-oxy-methyl]-phenyl ⁇ -pent-4-enyIamide
  • step 2 (4-Chloro-benzyl)- ⁇ -D-maltoside
  • step 3 (4-Chloro)-benzyl-4',6'-O-benzylidene- ⁇ -D-maltoside
  • the title compound was prepared as a white foam (1.20 g, 65%) from (4- chloro-benzyl)- ⁇ -D-maltoside using a procedure similar to Example 24, mp 187-
  • the title compound was prepared as a white solid (0.378 g, 59%) from 4- benzoyl-N- ⁇ 5-[(4',6'-O-benzylidene- ⁇ -D-maltosyl)-oxy-methyl]-2-chloro-phenyl ⁇ - benzamide using -iodobenzoyl chloride and a procedure similar to Example 2, mp >151 °C (decomp.); ⁇ ⁇ MR (DMSO-J 6 ) ⁇ 3.18-3.24 (m. IH), 332-3.42 (m, 2H), 3.49-3.63 (m. 4H).
  • the title compound was prepared as a white foam (2.50 g, 36%) from 2- chloro-5-(hepta-O-acetyl- ⁇ -D-maltosyl-oxymethyl)-phenylamine using N-(9H- fluoren-9-ylmethyoxycarbonylamino)-L-alanine and a procedure similar to step 1 of Example 65, mp >96 °C (decomp.); !
  • step 3 (l- ⁇ 5-[(4',6'-O-Benzylidene- ⁇ -D-maltosyl)-oxy-methyl]-2-chloro-phenyl- carbamoyl ⁇ ethyl)-carbamic acid 9H-fluoren-9ylmethyl ester
  • N-(9H-fluoren-9ylmethoxycarbonyl)-N'- ⁇ 5-[(6-O-benzoyl-4',6'- O-benzylidene- ⁇ -D-maltosyl)-oxy-methyl]-2-chloro-phenyl ⁇ -L-alaninamide (0.300 g, 0.256 mmol).
  • step 2 N- ⁇ 5-[( ⁇ -D-MaItosyl)-oxy-methyl]-2-chloro-phenyl ⁇ -methanesulfonamide sodium salt
  • the title compound was prepared as a white solid (0310 g, 71%) from N- ⁇ 5- [(2,2'3,3',4',6,6'-hepta-O-acetyl- ⁇ -D-maltosyl)-oxy-methyl]-2-chloro-phenyl ⁇ - methanesulfonamide using 1.3 eq.
  • step 2 ⁇ -Hydroxy-2-nitro- ?-tolunitrile
  • ⁇ -bromo-2-nitro-/?-tolunitrile 1.228 g, 5.095 mmol
  • sodium formate 0.8664 g, 12.74 mmol
  • ethano water 4:1, 25 mL
  • the reaction was cooled to room temperature, diluted with 20% CH 2 CL/EtOAc. washed with H2O (3x), dried (MgSO 4 ) and concentrated. Purification by flash chromatography (1,2 and 3% MeOH/CHCl 3 gradient) gave 0.695 g (77%) of the title compound as a white solid.
  • step 3 5-[(Hepta-0-acetyl- ⁇ -D-maltosyl)-oxy-methyl]-2-cyano-l-nitrobenzene
  • acetobromomaltose (2.39 g
  • step 6 N- ⁇ 5-[( ⁇ -D-Maltosyl)-oxy-methyI]-2-cyano-phenyl ⁇ -acetamide

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Abstract

La présente invention concerne des inhibiteurs de la prolifération cellulaire des muscles lisses représentés par la formule (I), dans laquelle X, R?1, R2, R3, R4, R5 R6, R7¿, sont tels que décrits dans le descriptif et les revendications.
EP99959083A 1998-11-24 1999-11-23 Benzylmaltosides acetal utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses Withdrawn EP1133509A1 (fr)

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US198803 1994-02-17
US19880398A 1998-11-24 1998-11-24
PCT/US1999/027828 WO2000031096A1 (fr) 1998-11-24 1999-11-23 Benzylmaltosides acetal utilises comme inhibiteurs de la proliferation cellulaire des muscles lisses

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EP1133509A1 true EP1133509A1 (fr) 2001-09-19

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EP (1) EP1133509A1 (fr)
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CN (1) CN1328566A (fr)
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BR (1) BR9915965A (fr)
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EP1133510A2 (fr) * 1998-11-24 2001-09-19 American Home Products Corporation Benzylmaltosides acyles, inhibiteurs de proliferation des cellules des muscles lisses
CN103360437B (zh) * 2013-04-27 2015-10-21 江苏教育学院 一种硫辛酸糖类衍生物及其制备方法和在制备抗肿瘤药物中的应用

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IL115745A (en) * 1994-11-07 2000-11-21 American Home Prod Acylated benzylglycosides and pharmaceutical compositions containing them

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JP2002530421A (ja) 2002-09-17
AU1633000A (en) 2000-06-13

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