EP1133506A2 - Benzylmaltotriosides inhibiteurs de la prolif ration des cellules des muscles lisses - Google Patents

Benzylmaltotriosides inhibiteurs de la prolif ration des cellules des muscles lisses

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Publication number
EP1133506A2
EP1133506A2 EP99962844A EP99962844A EP1133506A2 EP 1133506 A2 EP1133506 A2 EP 1133506A2 EP 99962844 A EP99962844 A EP 99962844A EP 99962844 A EP99962844 A EP 99962844A EP 1133506 A2 EP1133506 A2 EP 1133506A2
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
hydrogen
independently
alkyl
nitro
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.)
Withdrawn
Application number
EP99962844A
Other languages
German (de)
English (en)
Inventor
Paul Jeffrey Dollings
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth LLC
Original Assignee
American Home Products Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP1133506A2 publication Critical patent/EP1133506A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • C07H15/08—Polyoxyalkylene derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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 benzylmaltotriosides 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 p,articular) 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 moiety is maltotriose and (b) the substituents on the carbohydrate backbone are substantially 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; Stability 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.
  • Gotsberger (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 benzylmaltotriosides which bear no structural resemblance to heparin.
  • sulfated cyclodextrins or to sulfated lactobionic acid dimers, (b) contain no more than three contiguous sugar residues (trisaccharide) and (c) are of a defined structure.
  • This invention provides benzylmaltotriosides of formula I
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 .and R 10 are each, independently, hydrogen, acyl of 2- 7 carbon atoms, perfluoroacyl of 2-10 carbon atoms, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, benzoyl, benzyl or -SO 3 M; M is hydrogen, lithium, sodium, potassium or ammonium;
  • R n is hydrogen, alkyl of 1-6 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, halogen, nitrile, nitro, or alkoxy of 1-6 carbon atoms;
  • R 12 is hydrogen, nitro, amino, acylamino of 2-7 carbon atoms, perfluoroacylamino of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, perfluoroalkylamino of 1- 6 carbon atoms, dialklylamino where each alkyl chain is independently 1-6 carbon atoms, perfluorodialklylamino where each alkyl chain is independently 1-6 carbon atoms alkylsulfonylamino of 1-6 carbon atoms, perfluoroalkylsulfonylamino of 1-6 carbon atoms, arylsulfonylamino of 6-10 carbon atoms or arylsulfonylamino substituted with halo of 6-10 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • Alkyl, alkoxy, alkylsulfonylamino, acylamino and acyl includes both straight chain as well as branched moieties optionally substituted with fluorine.
  • Halogen means bromine, chlorine, fluorine, and iodine.
  • Aryl is defined as a fully unsaturated carbocyclic radical containing one or more rings having 6-10 carbon atoms optionally substituted with fluorine; with phenyl and naphthyl radicals being preferred.
  • 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 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
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each, independently, hydrogen, acyl of 2-
  • M is lithium, sodium, potassium or ammonium
  • R ⁇ is halogen
  • R I2 is nitro, amino, or acylamino of 2-7 carbon atoms; or a pharmaceutically acceptable salt thereof.
  • More preferred compounds of this invention are benzylmaltosides of formula I
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are each, independently, hydrogen, acetyl, or -SO 3 M;
  • M is lithium, sodium, potassium or ammonium
  • R ⁇ is chloro
  • R 12 is hydrogen, nitro, amino, or acetylamino; or a pharmaceutically acceptable salt thereof.
  • 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.
  • R 1 , R 2 , R 3 , R4, R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R" and R 12 are as defined above.
  • maltotriosyl bromide 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.
  • a catalyst such as a mercuric bromide, mercuric cyanide, silver triflate or silver perchlorate
  • an aprotic solvent such as acetonitrile, dichloromethane, ether, toluene or nitromethane at temperatures ranging from -40 °C to reflux to yield glycoside 3.
  • 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 such as ethyl acetate 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 in a polar aprotic solvent such as such as ethyl acetate 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.
  • Coupling of 4 with an acid chloride or a sulfonyl chloride can be completed in the presence of an amine base such as triethylamine, diisopropylethylamine or pyridine in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from - 20°C to ambient temperature gives the amide 5.
  • the acetate groups of 5 can be replaced by hydrolysis with a base such as sodium methoxide in methanol or aqueous sodium hydroxide in methanol at ambient temperature to reflux to yield 6. Sulfation of some or all of the free hydroxyl groups on the sugars with a reagent such as sulfur trioxide-trimethylamine complex or sulfur trioxide-pyridine complex in a polar aprotic solvent such as dimethylformamide or dimethylsulfoxide at temperatures ranging from 0°C to 100°C to give compound 7.
  • a base such as sodium methoxide in methanol or aqueous sodium hydroxide in methanol at ambient temperature to reflux to yield 6.
  • 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.
  • 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 1 5-(Deca-O-acetyl- ⁇ -D-maltotriosyloxymet yI)-2-chIorophenylamine
  • step 2 N-[5-(Deca-O-acetyl- ⁇ -D-maItotriosyloxymethyl)-2-chloro-phenyl]-acetami(le

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Molecular Biology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Epidemiology (AREA)
  • Neurology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Rheumatology (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des inhibiteurs de la prolifération des cellules des muscles lisses représentés par la formule générale (I), ou certains de leurs sels pharmaceutiquement admis. Dans cette formule générale (I), X est tel que représenté par la formule (A). R?1, R2, R3, R4, R5, R6, R7, R8, R9 et R10¿ sont chacun indépendamment C¿2?-C7 acyle, C2-C10 perfluoroacyle, C1-C6 alkyle, C1-C6 perfluoroalkyle, benzoyle, benzyle ou -SO3M; M est hydrogène, lithium, sodium, potassium ou ammonium; R?11¿ est hydrogène, C¿1?-C6 alkyle; R?12¿ est hydrogène, nitro, amino, C¿2?-C7 acylamino, C2-C7 perfluoroacylamino, C1-C6 alkylamino, C1-C6 perfluoroalkylamino, dialklylamino où chaque chaîne alkyle est indépendamment C1-C6 alkyle, perfluorodialklylamino où chaque chaîne alkyle est indépendamment C1-C6 alkyle, C1-C6 alkylsulfonylamino, C1-C6 perfluoroalkylsulfonylamino, C1-C6 arylsulfonylamino ou arylsulfonylamino substitué par C6-C10 halo.
EP99962844A 1998-11-24 1999-11-23 Benzylmaltotriosides inhibiteurs de la prolif ration des cellules des muscles lisses Withdrawn EP1133506A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US19880598A 1998-11-24 1998-11-24
US198805 1998-11-24
PCT/US1999/027775 WO2000031095A2 (fr) 1998-11-24 1999-11-23 Benzylmaltotriosides inhibiteurs de la prolifération des cellules des muscles lisses

Publications (1)

Publication Number Publication Date
EP1133506A2 true EP1133506A2 (fr) 2001-09-19

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Application Number Title Priority Date Filing Date
EP99962844A Withdrawn EP1133506A2 (fr) 1998-11-24 1999-11-23 Benzylmaltotriosides inhibiteurs de la prolif ration des cellules des muscles lisses

Country Status (7)

Country Link
EP (1) EP1133506A2 (fr)
JP (1) JP2002530420A (fr)
CN (1) CN1333778A (fr)
AU (1) AU1919800A (fr)
BR (1) BR9915643A (fr)
CA (1) CA2350759A1 (fr)
WO (1) WO2000031095A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040248945A1 (en) 1999-04-23 2004-12-09 Smithkline Beecham P.L.C. Thiazolidinedione derivative and its use as antidiabetic

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL115745A (en) * 1994-11-07 2000-11-21 American Home Prod Acylated benzylglycosides and pharmaceutical compositions containing them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0031095A2 *

Also Published As

Publication number Publication date
WO2000031095A2 (fr) 2000-06-02
AU1919800A (en) 2000-06-13
BR9915643A (pt) 2001-08-07
WO2000031095A3 (fr) 2001-01-04
CA2350759A1 (fr) 2000-06-02
CN1333778A (zh) 2002-01-30
JP2002530420A (ja) 2002-09-17

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