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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]
  • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
• • 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
  • A61P9/10—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
• • 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
  • 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

Definitions

• This invention relates to the use of substituted benzylglycosylamides 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; Karnovs y, 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 (a) the carbohydrate posesses an anomeric amide, (b) the substituents on the carbohydrate backbone are substantually different and, (c) the activity against smooth muscle cell proliferation is greater.
• 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 benzylglosylamides of formula I
• Y is C or N; where n is 0 - 3; X is
• R 1 , and R 2 are each independently, hydrogen, alkyl of 1 to 6 carbon atoms, halo, acetyl, phenyl, CF 3 , CN, OH, NO 2 , NH 2 , alkoxy of 1 to 6 carbon atoms, or cyanoalkoxy of 2 to 7 carbon atoms;
• R 3 is hydrogen, acylamide of 2 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms;
• R 4 , R 5 , R 6 , R 7 , and R 8 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, benzyl substituted with R 1 , and R 2 ; or benzoyl substituted with R 1 and R 2 ;
• R 9 and R 10 are each, independently, acyl of 1 to 6 carbon atoms, or the R 9 and
• R 10 groups on the 4' and 6' positions of the maltose may be taken together to form a cyclic acetal which may be substituted with alkyl of 1 to 6 carbon atoms, two alkyl groups each having 1 to 6 carbon atoms, pyridine substituted with R 1 , phenyl substituted with R 1 , benzyl substituted with R 1 , 2-phenylethyl substituted with R 1 , or 3-phenylpropyl substituted with R 1 ; with the proviso that when R 1 or R 2 are cyanoalkoxy of 2-7 carbon atoms, R 3 is not acylamide, and further provided that when R 1 , R 2 , or R 3 are alkoxy of 1-6 carbon atoms, at least one of R 1 , R 2 , R 3 , or R 4 are not hydrogen; or a pharmaceutically acceptable salt thereof.
• Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and
• 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 formula I of this invention are those in which n is 0 - 1 ; R 1 , and R 2 are each independently, hydrogen, halogen, CF 3 , OH, NO 2 , NH 2 , methoxy, butoxy, or butoxynitrile; R 3 is hydrogen, acetamide, or methoxy; R 4 , R 5 , R 6 , R 7 , and R 8 are each, independently, hydrogen, an acyl of 1-6 carbon atoms, or benzoyl; R 9 and R 10 are each, independently, acyl of 1-6 carbon atoms, or the R 9 and R 10 groups on the 4' and 6 ' positions of the maltose are taken together form a benzylidene ring; or a pharmaceutically acceptable salt thereof, with all other substituents as defined above. More preferred compounds of formula I are those in which n is O;
• R 1 , and R 2 are each independently, hydrogen or halogen; R 3 is hydrogen;
• R 4 , R 5 , R 6 , R 7 , and R 8 are each, independently, hydrogen, acyl of 1 to 6 carbon atoms, or benzoyl;
• R 9 and R 10 are each, independently, acyl of 1-6 carbon atoms, or the R 9 and R 10 groups on the 4 * and 6' positions of the maltose are taken together form a benzylidene ring; or a pharmaceutically acceptable salt thereof, with all other substituents as defined above.
• Specifically preferred compounds of this invention are: N-(Hepta-0-acetyl-l-deoxy- ⁇ -D-maltosyl)-4-chloro-3-nitro-benzamide;
• Y, n. and R 1U are as defined above.
• the maltosyl amine 1 is coupled with a benzoic acid derivative 2 in the presence of a coupling reagent such as EEDQ, DEC/HOBT, or DCC/HOBT in a suitable solvent system such as benzene, ethanol, dichloromethane, triethyl amine at room temperatures to yield glycoside 3.
• a coupling reagent such as EEDQ, DEC/HOBT, or DCC/HOBT
• a suitable solvent system such as benzene, ethanol, dichloromethane, triethyl amine at room temperatures
• the glycoside can also be prepared by coupling the amine 1 to a substituted acid chloride 2 in the presense of triethyl amine in a suitable solvent system such as tetrahydofuran, dichloromethane, acetonitrile, and ethyl acetate to yield glycoside 3.
• R 3 a nitro group reduction of the nitro group of 3 can be accomplished with a reducing agent such as stannous chloride or iron metal in a polar aprotic solvent such as ethyl acetate or a polar protic solvent such as ethanol or methanol at ambient temperature to reflux, or by catalytic hydrogenation in the presence of a catalyst such as palladium on carbon gives an anilino compound 4.
• a reducing agent such as stannous chloride or iron metal in a polar aprotic solvent such as ethyl acetate or a polar protic solvent such as ethanol or methanol
• Coupling of 4 with an acid chloride or sulfonyl chloride in the presence of an amine base such as triethylamine or diisopropulethylamine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from -20 °C to ambient temperature yields the target compounds 5.
• an amine base such as triethylamine or diisopropulethylamine in an aprotic solvent such as dichloromethane or tetrahydrofuran
• the acetate groups of 3 or 5 can be removed by hydrolysis with a base such as catalytic sodium methoxide in methanol or aqueous sodium hydroxide in methanol at ambient temperature to reflux to yield 6.
• a base such as catalytic sodium methoxide in methanol or aqueous sodium hydroxide in methanol at ambient temperature to reflux to yield 6.
• the 4' and 6' hydroxy groups of maltose can be reacted with benzaldehyde diemthyl acetal in the presence of an acid catalyst such as camphorsulfonic acid or toluene sulfonic acid in a polar aprotic solvent such as acetonitrile or dimethyl formamide at ambient temperature to 70 °C to yield a benzylidene derivative.
• the 6 hydroxyl group can be selectively benzoylated in a collidine / tetrahydofuran mixture at -78 °C to ambient temperature to yield 7.
• 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 Thvmidine Incorporation
• 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.
• Hepta-( -acetyl- l- ⁇ -maltosylamine was obtained by the platinum oxide reduction of the azide prepared by the method of A. Bertho, Justus Liebigs Ann. Chem., 562, 229 (1949).
• Step 2 (R)-4-chIoro-3-nitro-N-[4-0-[4,6- O -(phenylmethyIene)- ⁇ -D-gIucopyranosyl]- ⁇ - D-gIucopyranosyl]-benzamide
• the aqueous layer was seperated and extracted with ethyl acetate (3 x 30 ml).
• the organic layers were washed with IN hydrogen chloride (50 ml) then water (50 ml) and dried (MgSO 4 ) and concentrated.
• Step 1 affording 100 % as a white solid, mp decomposition at 210; ⁇ NMR (DMSO- d 6 ) 0.91 (t, 7.5 Hz, 3H), 1.41 - 1.50 (m, 2 H), 1.70 - 1.77 (m, 2 H), 3.06 (bt, IH), 3.22
• Step 2 4-butoxy-3-chloro-N-[(4', 6'-0-benzylidene)- ⁇ -D-maltosyl]-5-methoxy- benzamide Hydrate
• Example 2 The title compound was prepared according to the procedure of Example 2 as a white solid (86 %), mp 185 - 187 °C; 'H NMR (CDCL , ) ⁇ 2.00 (s, 3 H), 2.01 (s, 3 H), 2.03 (s, 3 H). 2.05 (s, 3 H), 2.08 (s, 3 H), 2.10 (s. 3 H), 2.13 (s, 3 H), 2.19 - 2.24 (m, 2 H), 2.59 (t.
• Step 2 affording a white solid, mp 115 °C; ⁇ NMR (CDCL , ) ⁇ 2.01 (s, 6 H), 2.03 (s,
• Step 3 affording a white solid, mp 106 °C; ⁇ NMR (CDC1 3 ) ⁇ 1.93 (s, 3 H), 2.00 (s,

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• 1999
  • 1999-11-23 CN CN99815705A patent/CN1333780A/zh active Pending
  • 1999-11-23 AU AU18293/00A patent/AU1829300A/en not_active Abandoned
  • 1999-11-23 JP JP2000583922A patent/JP2002530419A/ja active Pending
  • 1999-11-23 WO PCT/US1999/027823 patent/WO2000031094A2/en not_active Application Discontinuation
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