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WO2001072297A1 - Methodes d'inhibition de l'angiogenese et de la croissance de tumeurs - Google Patents

Methodes d'inhibition de l'angiogenese et de la croissance de tumeurs Download PDF

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WO2001072297A1
WO2001072297A1 PCT/US2001/009785 US0109785W WO0172297A1 WO 2001072297 A1 WO2001072297 A1 WO 2001072297A1 US 0109785 W US0109785 W US 0109785W WO 0172297 A1 WO0172297 A1 WO 0172297A1
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independently
accordance
covalent bond
cis
cyclohexyl
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Dale L. Boger
David A. Cheresh
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Scripps Research Institute
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Scripps Research Institute
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Priority to JP2001570258A priority Critical patent/JP2003528140A/ja
Priority to EP01922734A priority patent/EP1272173A4/fr
Priority to CA002403630A priority patent/CA2403630C/fr
Priority to US10/240,142 priority patent/US7115660B2/en
Priority to AU2001249499A priority patent/AU2001249499B2/en
Priority to AU4949901A priority patent/AU4949901A/xx
Priority to SK1485-2002A priority patent/SK14852002A3/sk
Priority to MXPA02009510A priority patent/MXPA02009510A/es
Application filed by Scripps Research Institute filed Critical Scripps Research Institute
Priority to HU0301621A priority patent/HUP0301621A3/hu
Publication of WO2001072297A1 publication Critical patent/WO2001072297A1/fr
Priority to NO20024576A priority patent/NO20024576L/no
Anticipated expiration legal-status Critical
Priority to US11/439,918 priority patent/US7368478B2/en
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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • This invention relates to methods for inhibiting angiogenesis and tumor growth. More particularly, the invention relates to methods of inhibiting angiogenesis and tumor growth utilizing a compounds that selectively bind to integrin ⁇ v ⁇ 3 and blocks the interaction of integrin ⁇ v ⁇ 3 with matrix metalloproteinase 2 (MMP2).
  • MMP2 matrix metalloproteinase 2
  • MMP2 and its activator membrane type 1-matrix metalloproteinase (MT1- MMP) are coordinately expressed by mesenchymal cells almost exclusively during embryonic development, indicating specific matrix remodeling constraints in these tissues.
  • angiogenesis and corresponding tumor growth are reduced in MMP2 knockout mice (see Itoh et al., Cancer Res., 58 1048-51
  • MMP2 The negative regulation of MMP2 during vascular invasion and maturation was later shown by Brooks et al. to be dependent upon expression of ⁇ v ⁇ 3 (Cell, 92, 391-400 (1998)). Although inhibition of angiogenesis and concomitant suppression of tumor growth by natural as well as synthetic inhibitors of MMP's, including MMP2, has been documented, the translation of such strategies into clinical modalities has met with limited success, primarily due to the deleterious side effects of such broad spectrum inhibitors. Since MMP function, in general, may be required for many processes in the adult organism, active site inhibition of enzymatic function is likely to have far reaching effects on various biological processes involving tissue remodeling, such as wound healing.
  • the present invention provides a method for the inhibition of the interaction of MMP2 with integrin ⁇ v ⁇ 3 and a method for inhibition of angiogenesis in cells containing integrin v ⁇ 3 . Further, the invention provides a method for inhibition of tumor growth by administration of MMP2- ⁇ v ⁇ 3 interaction inhibitors. Active inhibitor compounds represented by Formula (I), below, are contacted with integrin ⁇ v ⁇ 3 on a cell, which, in turn, inhibits the binding of MMP2 to the v ⁇ 3 .
  • the inhibition of binding of MMPS to ⁇ v ⁇ 3 by the methods of the present invention result in inhibition of angiogenesis and thus tumor growth.
  • ⁇ v ⁇ 3 has been implicated in inflammation, thus compounds of Formula (I), used in accordance with the methods of the present invention can also suppress inflammatory events.
  • G 1 and G 2 are each independently -NH-C(O)-O-R 1 ,
  • Y 1 and Y 2 are each independently -OH, C r C 4 alkyl,
  • R 1 is C r C 4 alkyl
  • X 1 and X 2 are each independently halo or C r C 4 alkoxy
  • X 3 is halo, nitro, C r C 4 alkyl, C 1 - C 4 alkoxy, or C_ - C 4 perfluoroalkyl
  • A is H or a covalent
  • R 2 and R 3 are each independently H, Cj - C 4 alkyl, phenyl or benzyl; X 1 and X 2 are each independently halo or C r C 4 alkoxy; X 4 and X 5 are each independently halo, nitro, Cj - C 4 alkoxy, C t - C 4 alkyl, or C x - C 4 perfluoroalkyl; A is H or a covalent bond; p and r are each independently an integer having a value of 1 or 2; and t is an integer having a value of 0 or 1 with the proviso that when A is H, t is 0 and when A is a covalent bond, t is 1. When A is a covalent bond and t is 1, the iminodiacetamide derivative moieties may be attached to the benzene linking group in the ortho, meta or para position.
  • angiogenesis and tumor growth inhibiting compounds of the present invention are thus useful therapeutic agents for the treatment of patients with tumors or angiogenic disorders. Because the present compounds bind to ⁇ v ⁇ 3 , these compounds can also be used to suppress inflammatory events.
  • the compounds of the present invention may be formulated in suitable pharmaceutically acceptable matrix.
  • the pharmaceutical compositions of the active compounds are administered to a patient with a tumor to reduce or eliminate tumor growth.
  • the active compounds can be administered parenterally by injection or by gradual infusion over time, or by any other method suitable for the particular dosage form.
  • FIG. 1 is a schematic illustration depicting MMP2 interaction with integrin ⁇ v ⁇ 3 and its role in angiogenesis.
  • FIG. 2 depicts the structural subunits A, B and C of a combinatorial library of 600 compounds disclosed in Boger et al. , Bioorg. Med. Chem, 6, 1347-1378 (1998).
  • FIG. 3 graphically illustrates the binding of 60 combinatorial mixtures of compounds with integrin ⁇ v ⁇ 3 in competition with MMP2.
  • FIG. 4 illustrates the binding of mixtures AxBlO with integrin v ⁇ 3 and the binding of the 10 individual components of A6B10C4.
  • FIG. 5 depicts the structures of analogs of A6B10C4.
  • FIG. 6A graphically illustrates the binding of analogs (Compounds 2 - 26) of A6B10C4 (Compound 1) with integrin v ⁇ 3 in competition with MMP2.
  • FIG. 6B graphically illustrates the binding of Compounds 9 and 19 with integrin ⁇ v ⁇ 3 in comparison with MMP2.
  • FIG. 7 illustrates that [ 14 C]-labeled Compound 19 binds specifically to ⁇ v ⁇ 3 and can be competitively displaced from the ⁇ v ⁇ 3 by a 25 fold excess of non-labeled Compound 19, but not by excess Compound 9, a RGD peptide or a c(RGDfV) peptide.
  • FIG. 8 shows that Compound 19 disrupts the binding of MMP2 to integrin ⁇ v ⁇ 3 , but does not interfere with vitronectin binding with integrin ⁇ v ⁇ 3 .
  • FIG. 9 shows that Compound 19 does not directly inhibit purified active MMP2 proteolysis.
  • the binding of MMP2 to integrin ⁇ v ⁇ 3 is an important mechanism in the process of angiogenesis. Specific inhibition of this binding interaction results in a reduction in vascularization in growing tissues such as tumors, and thus retards tumor growth.
  • the interaction of MMP2 with integrin ⁇ v ⁇ 3 is illustrated pictorially in FIG. 1.
  • Certain compounds of this invention may possess one or more asymmetric centers and may exist in optically active forms. Additional asymmetric centers may be present in a substituent group, such as an alkyl group. Pure S-isomers and pure R-isomers, racemic mixtures of the isomers, and mixtures thereof are intended to be within the scope of this invention. Chiral forms of certain compounds of this invention are contemplated and are specifically included within the scope of this invention.
  • alkoxy means an oxygen atom linked by an ether bond to an alkyl group, as defined below, of the size indicated. Examples of alkoxy groups are methoxy, ethoxy, t-butoxy, and the like.
  • alkyl means a straight- or branched-chain carbon radical of the size indicated. Representative of alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2-ethylhexyl, n-octyl, 2,4-dimethylpentyl, and the like.
  • hydroxyalkyl means an alkyl group, as defined above, of the size indicated, attached to a hydroxyl group. Examples include hydroxymethyl, 2-hydroxyethyl, 3-hydroxy-l-propyl, 2-hydroxy-l-propyl, 4-hydroxybutyl, and the like.
  • perfluoroalkyl refers to a alkyl group of the size indicated, as defined below, bearing fluoro substituents in place of each hydrogen, for example trifluorpmethyl and pentafluoroethyl.
  • halo or halogen refer to bromo, chloro, fluoro and iodo.
  • the compounds useful in the methods of the present invention are represented by Formula (I) and include iminodiacetamide derivatives chemically attached to a linking group:
  • R 2 and R 3 are each independently H, C ⁇ - C 4 alkyl, phenyl or benzyl;
  • X 1 and X 2 are each independently halo or C r C 4 alkoxy;
  • X 4 and X 5 are each independently halo, nitro, - C 4 alkoxy, C x - C 4 alkyl, or C x - C 4 perfluoroalkyl;
  • A is H or a covalent bond;
  • p and r are each independently an integer having a value of 1 or 2; and
  • t is an integer having a value of 0 or 1 with the proviso that when A is H, t is 0 and when A is a covalent bond, t is 1.
  • the substituents X 1 and X 2 are attached to the phenyl ring in the 4- position relative to the CH 2 groups (i.e. para substituent).
  • at least one of X 1 and X 2 is fluoro, most preferably X 1 and X 2 are both para-fluoro.
  • r and p are 2.
  • X 4 and X 5 are preferably, to C 4 perfluoroalkyl, most preferably para-trifluoromethyl.
  • the preferred R 2 and R 3 groups are hydrogen and methyl.
  • the substituents X 2 and X 3 may be the same or different, and the substituents R 2 and R 3 may also be the same or different.
  • the compounds of Formulas (I) and (II) are described in detail, along with methods of synthesis thereof, in Boger et al. , Bioorg. Med. Chem, 6, 1347-1378 (1998), incorporated herein by reference.
  • a particularly active member of the family of compounds represented by Formula (II), wherein A is a covalent bond and t is 1, is Compound 19 in Scheme 1, below.
  • Scheme 1 A particularly active member of the family of compounds represented by Formula (II), wherein A is a covalent bond and t is 1, is Compound 19 in Scheme 1, below.
  • Compound 19 is illustrative of a general method of producing compounds of Formulas (I)and (II) described by Boger et al..
  • Compound 19 was synthesized in three steps starting with commercially available N-e-BOC-L-lysine methyl ester. The carbamate was installed in 99% yield by reaction of 4-(trifluoromethyl)benzyl alcohol with N, N-disuccinimidyl carbonate and subsequent addition of the activated product with the free ⁇ -amino group providing intermediate Compound 27.
  • compositions of compounds of Formulas (I) and (II) can be prepared by formulating the compound in a pharmaceutically acceptable carrier matrix.
  • the pharmaceutical compositions comprising the active compounds of Formulas (I) and (II) are administered to a host with a tumor to reduce or eliminate tumor growth.
  • the active compounds can be administered parenterally by injection, or by gradual infusion over time.
  • the tissue to be treated is most often treated by intraperitoneal or subcutaneous administration, the active compounds can also be administered intraocularly, intravenously, intramuscularly, intrasynovially, intracavity, or transdermally, and can be delivered by peristaltic means as well.
  • administration refers to systemic use as when taken orally, parenterally, by inhalation spray, by nasal, rectal or buccal routes, or topically in dosage form unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired.
  • parenteral as used herein includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion techniques.
  • pharmaceutically acceptable it is meant those salts, amides and esters which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio, effective for their intended use in the treatment of tumors and angiogenic-related disorders.
  • Representative acid addition salts include hydrochloride, hydrobromide, sulfate, bisulfate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, methanesulfonate, citrate, maleate, fumarate, succinate, tar tr ate, ascorbate, glucoheptonate, lactobionate, lauryl sulfate salts and the like.
  • Representative alkali or alkaline earth metal salts include sodium, calcium, potassium, magnesium salts and the like.
  • the term "pharmaceutically acceptable carriers” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, saf flower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such, as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl la
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgement of the formulator.
  • antioxidants examples include water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like; oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and the metal chelating agents such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite, sodium sulfite, and the like
  • oil soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propy
  • a “therapeutically effective amount” of the inventive agent or compound is meant a sufficient amount of the compound to treat tumors and angiogenic-related disorders at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidently with the specific compound employed; and like factors well known in the medical arts.
  • compositions in unit dosage forms comprising a therapeutically effective amount of a compound (or compounds) of this invention in combination with a conventional pharmaceutical carrier.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulation can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • the most common way to accomplish this is to inject a suspension of crystalline or amorphous material with poor water solubility
  • the rate of absorption of the drug becomes dependent on the rate of dissolution of the drag which is, in turn, dependent on the physical state of the drug, for example, the crystal size and the crystalline form.
  • Another approach to delaying absorption of a drug is to administer the drug as a solution or suspension in oil.
  • Injectable depot forms can also be made by forming microcapsule matrices of drugs and biodegradable polymers such as polylactide-polyglycolide.
  • the rate of drug release can be controlled.
  • biodegradable polymers include poly-orthoesters and poly anhydrides.
  • the depot injectables can also be made by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders, prills and granules. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings and other release-controlling coatings.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable lo emulsions, microemulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; sweetening, flavoring and perfuming agents. If desired, the compounds of the present invention can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes and microspheres.
  • the active compounds may be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can dissolve in sterile water, or some other sterile injectable medium immediately before use.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions which can be used mclude polymeric substances and waxes. Dosage forms for topical or transdermal administration of a compound of this invention further include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulations, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • compositions containing the active compounds are administered in a manner compatible with the dosage formulation and in a therapeutically effective amount.
  • the quantity to be administered and the timing of administration depend on the host to be treated, capacity of the host's system to utilize the active ingredient, and degree of therapeutic effect desired. Precise amounts of the active ingredient required to be administered depend on the judgment of the practitioner, and are peculiar to each individual.
  • Suitable dosage ranges for systemic application are disclosed herein and depend on the route, of administration. Suitable regimes for administration are also variable, but are typified by an initial administration, followed by repeated doses at one or more predetermined intervals by a subsequent injection or other route of administration.
  • the present invention also provides a pharmaceutical composition useful for practicing the therapeutic methods described herein.
  • the compositions contain an active compound described hereinabove, together with a pharmaceutically acceptable carrier.
  • Preparations for parental administration of the present compounds or compositions include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parental vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases, and the like.
  • Another aspect of the present invention provides a method for inhibiting MMP2 interaction with ⁇ v ⁇ 3 and thus angiogenesis in a tumor tissue.
  • the inhibiting method comprises administering to the host a composition comprising an angiogenesis-inhibiting amount of a compound described hereinabove. MMP2 interaction with ⁇ v ⁇ 3 is inhibited by contacting ⁇ v ⁇ 3 with a compound of the present invention.
  • Angiogenesis is the formation of a neovascular network from preexisting host vessels and is required for tumor growth beyond 1-2 mm 3 .
  • angiogenesis is inhibited as long as angiogenesis and the disease symptoms mediated by angiogenesis are ameliorated.
  • the dosage ranges for the administration to a host of the active compound depend upon the particular active compound and its potency to a particular tumor or integrin. One skilled in the art can readily determine the proper dosage for a particular active compound without undue experimentation.
  • the host can be any mammal.
  • the dosage should be large enough to produce the desired therapeutic effect in which angiogenesis and the disease symptoms mediated by angiogenesis are ameliorated, and is usually an amount sufficient to maintain a plasma level of the active compound in the range of about 0.01 to about 100 micromolar ( ⁇ M), preferably about 0.2 to about 20 ⁇ M, more preferably about 1 to about 10 ⁇ M.
  • the dosage should not be so large as to cause adverse side effects, however.
  • the dosage per kilogram (kg) of body weight can vary from 1 to 20 mg per dose, in one or more dose administrations daily, for one or several days or indefinitely.
  • the therapeutically effective amount is an amount of active compound sufficient to produce a measurable inhibition of angiogenesis in the tissue being treated, i.e., an angiogenesis-inhibiting amount or an MMP2 - v ⁇ 3 interaction inhibiting amount.
  • Inhibition of angiogenesis can be measured in situ by immunohistochemistry, as described herein, or by other methods known to one skilled in the art.
  • the present invention additionally provides pharmaceutical compositions useful for practicing the therapeutic methods described herein.
  • the compositions contain an active compound defined hereinabove together pharmaceutically acceptable carrier.
  • the present invention also provides a method of inducing apoptosis in tumor cells.
  • This method comprises administering to the host a therapeutically effective amount of an active compound sufficient to initiate tumor cell apoptosis.
  • tumor cell apoptosis is induced if an increased tumor cell apoptosis is observed in the target tumor being treated.
  • Tumor cell apoptosis can be measured by methods described herein or commonly known in the art.
  • CS-1 hamster melanoma cells and CS-1 cells transfected with the human ⁇ 3 -integrin subunit ( ⁇ 3 CS-l cells) were described previously (Cell, 85, 683-93 (1996); Cell, 92, 391-400 (1998)).
  • HRP horseradish peroxidase
  • BN-34 and anti-actin mAb AC-40 were obtained from Sigma (St. Louis, MO).
  • Anti-von Willebrand Factor (vWF) polyclonal antibodies (pAb) were obtained from DAKO (Glostrup, Denmark).
  • the cyclic peptides cRGDfV and cRADfV and integrin- ⁇ v ⁇ 3 were provided by Merck KGaA (Darmstadt, Germany).
  • Purified proMMP2 and integrin- ⁇ v ⁇ 3 were provided by Chemicon International (Temecula, CA).
  • Purified active MMP2 was obtained from Calbiochem (La Jolla, CA).
  • Basic fibroblast growth factor (bFGF) was kindly provided by Scios
  • integrins were adsorbed overnight onto microtiter wells (1- 5 ⁇ g/ml, 50 ⁇ g/well) prior to blocking with Caseinblocker (Pierce, Rockford, IL).
  • Biotinylated MMP2 (bMMP2, 3-5 nM) in binding buffer (50 mM Tris, pH 8, 150 mM NaCl, 1 mM MgCl 2 , 0.5 mM MnCl 2 ) was added to the wells in the presence or absence of test compounds, cyclic RGD or RAD peptides, or buffer vehicle alone. Control wells received no integrin.
  • Biotinylated vitronectin (bVN, 1 ⁇ g/ml) was used as a reference.
  • Bound protein was detected with HRP-anti-biotin mAb and quantitated at 450 nm with 3,3',5,5'-tetramethylbenzidine solution (TMB; a substrate for the peroxidase) (BioRad, Hercules, CA).
  • TMB 3,3',5,5'-tetramethylbenzidine solution
  • ⁇ v ⁇ 3 and 5 ⁇ ! (10 ⁇ g/ml, 50 ⁇ l/well) were coated onto Immulon-4 microtiter wells (Dynatech Laboratories, Chantilly, VA), which were substantially blocked and incubated with titration of [ 14 C]-Compound 19 prior to the addition of 150 ⁇ l of binding buffer containing 0.1% Tween-20 and aspiration of all liquid. Dried wells were separated and immersed in BetaMax liquid scintillation cocktail (ICN Biochemicals, Costa Mesa, CA) for quantitation.
  • CS-1 cells or ⁇ 3 CS-l cells were incubated in adhesion buffer fibroblast basal medium (FBM) supplemented with 0.5% bovine serum albumin (BSA), 0.4 mM MnCl 2 and 10 ⁇ g/ml aprotinin) containing either 4 nM purified active MMP2 alone, or in combination with 10 ⁇ M Compound 19 or Compound 9 for 45 minutes at 37 °C prior to washing and addition to the [ 3 H]-collagen IV- coated wells.
  • Wells had been coated overnight with 50 ⁇ l of 0.414 mCi/ml [ 3 H]- collagen IV (ICN Biochemicals, Costa Mesa, CA) and washed extensively until the radioactivity in the recovered wash solution reached background.
  • the individual AB compounds were then coupled to mixtures of ten different C linking groups, to form 60 mixtures of 10 compounds each, designated AxBy wherein the x and y denote the individual A and B subunits, respectively, that were incorporated into the compounds of the mixtures.
  • the A, B and C subunits of the combinatorial library of compounds are shown in FIG. 2.
  • the results of the evaluation assay are presented in FIG. 3.
  • the particularly active mixtures included A1B6, A1B7, A1B8, A4B1, A5B4, A5B5, A5B6, A5B10, and A6B10.
  • the most active mixture was A6B10, therefore, the ten individual compounds of the mixture were synthesized separately and examined in the same assay, the results of which are presented in FIG 4. All of the individual components A6B10C1 through A6B10C10 were active at a 3 ⁇ M concentration in the assay. Analogs Compounds (2 - 26) of A6B10C4 (Compound 1), shown in FIG 5, were also evaluated. The results of the binding assays for Compounds 2 - 26 are presented in FIG. 6A. All of the compounds except Compounds 8, 9 and 23 inhibited MMP2 binding to integrin.
  • the active MMP2 / integrin- ⁇ v - ⁇ 3 binding inhibitors of present invention are encompassed by Formulas (I) and (II).
  • Compound 19 was examined in detail to determine its specific target and to define its biological properties. Benzoyl amide Compound 9 was selected as an appropriate negative control compound for many of these studies since it was found to lack antagonist activity in the binding assay, despite its overall structural similarity and similar physical properties (e.g. solubility and hydrophobicity). Compound 19 exhibited concentration dependent inhibition of binding of MMP2 to integrin as shown in FIG. 6B.
  • a radiolabel ( 14 C) was incorporated into Compound 19 in the ester substituent (relative activity approx. 104 mCi/mmol). After incubation (at 3 ⁇ M) with fixed ⁇ v ⁇ 3 and subsequent washing, this compound was found to adhere to the integrin as demonstrated in FIG 7. Incubation in the presence of a 25-fold molar excess of cold Compound 19 significantly reduced the observed amount of bound agent, whereas incubation in the presence of a 25-fold molar excess of (cold) control Compound 9 did not affect the binding of [ 14 C] -Compound 19. In a similar experiment measuring the interaction of [ 14 C] -Compound 19 to fixed MMP2, no binding was observed.
  • Compound 19 was also studied in a cellular assay, which measures the ability of endothelial cells to utilize MMP2 to degrade a protein matrix, a key step in angiogenesis. It has been shown previously that disrupting the binding of MMP2 to ⁇ v ⁇ 3 inhibits collagen IV degradation. CS-1 melanoma cells transfected with ⁇ v ⁇ 3 were found to degrade immobilized [ 3 H]-collagen IV far above the degradation of ⁇ 3 negative CS-1 cells (which lack ⁇ v ⁇ 3 ). As shown in FIG. 9, treatment of these cells with Compound 19 significantly diminished the increased matrix degradation, consistent with the cells being unable to utilize MMP2, which is not bound to the integrin surface. Compound 19 did not, however, directly inhibit MMP2's proteolytic activity, as purified (active) enzyme in the absence cells was able to degrade [ 3 H] -collagen IV to a similar extent in the presence or absence of the Compound 19.

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Abstract

l'angiogenèse, la croissance des tumeurs et l'interaction de la métalloprotéinase 2 (MMP2) avec l'intégrine-αvβ3 sont inhibées par le composé inhibiteur représenté par la formule (I). Dans cette formule, G1 et G2 sont chacun indépendamment NH-C(O)-O-R1, -NH-C(O)-O-(CH¿2?)v-(C6H4)-X?3¿, -NH-C(O)-NH-(CH¿2?)v-(C6H4)-X?3¿, -O-C(O)-NH-(CH¿2?)v-(C6H4)-X?3¿,-O-C(O)-O-(CH¿2?)v-(C6H4)-X?3¿, ou NH-C(O)-CH¿2?-(C6H4)-X?3; Y1 et Y2¿ sont chacun indépendamment OH, C¿1?-C4 alkyle, C1-C4 hydroxyalkyle, C1-C4 alkoxy, phényle, benzyle, ou NH2; R?1¿ est C¿1?-C4 alkyle; X?1 et X2¿ sont chacun indépendamment halo ou C¿1?-C4 alkoxy; X?3¿ est halo, nitro, C¿1?-C4 alkyle, C1-C4 alkoxy, ou C1-C4 perfluoroalkyle; Z est -C C-, -C6H4-, cis-CH=CH-, trans CH=CH-, cis-CH2-CH=CH-CH2-, trans -CH2-CH=CH-CH2-, 1,4-naphthyle, cis-1, 3-cyclohexyle, trans-1, 3-cyclohexyle, cis-1, 4-cyclohexyle, ou trans-1,4-cyclohexyle; A est H ou une liaison covalente; m et n sont chacun indépendamment un entier de valeur 0 ou 1; t est un entier de valeur 0 ou 1; et p, r, et v sont chacun indépendamment un entier de valeur 1 ou 2; à condition que lorsque A est H, t est O; lorsque A est une liaison covalente, t est 1; lorsque m est 0, Y?1¿ est C¿1?-C4 hydroxyalkyle; et lorsque n est 0, Y?2¿ est C¿1? C4 hydroxyalkyle.
PCT/US2001/009785 2000-03-27 2001-03-27 Methodes d'inhibition de l'angiogenese et de la croissance de tumeurs Ceased WO2001072297A1 (fr)

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SK1485-2002A SK14852002A3 (sk) 2000-03-27 2001-03-27 Spôsoby inhibície angiogenézy a rastu tumoru
CA002403630A CA2403630C (fr) 2000-03-27 2001-03-27 Methodes d'inhibition de l'angiogenese et de la croissance de tumeurs
US10/240,142 US7115660B2 (en) 2001-03-27 2001-03-27 Methods for inhibiting angiogenesis and tumor growth
AU2001249499A AU2001249499B2 (en) 2000-03-27 2001-03-27 Methods for inhibiting angiogenesis and tumor growth
AU4949901A AU4949901A (en) 2000-03-27 2001-03-27 Methods for inhibiting angiogenesis and tumor growth
JP2001570258A JP2003528140A (ja) 2000-03-27 2001-03-27 血管形成と腫瘍成長を阻害する方法
EP01922734A EP1272173A4 (fr) 2000-03-27 2001-03-27 Methodes d'inhibition de l'angiogenese et de la croissance de tumeurs
MXPA02009510A MXPA02009510A (es) 2000-03-27 2001-03-27 Metodos para inhibir angiogenesis y crecimiento de tumor.
HU0301621A HUP0301621A3 (en) 2000-03-27 2001-03-27 Use of integrin inhibitor for inhibiting angiogenesis and tumor growth
NO20024576A NO20024576L (no) 2000-03-27 2002-09-24 Fremgangsmate for a inhibere angiogenese og tumorvekst
US11/439,918 US7368478B2 (en) 2000-03-27 2006-05-24 Methods for inhibiting angiogenesis and tumor growth

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RU2342927C2 (ru) * 2003-10-23 2009-01-10 Оцука Фармасьютикал Ко., Лтд Стерильный состав для инъекций с контролируемым высвобождением, содержащий арипипразол, и способ
US9457026B2 (en) 2007-07-31 2016-10-04 Otsuka Pharmaceutical Co., Ltd. Methods for producing aripiprazole suspension and freeze-dried formulation

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ES2235611B2 (es) * 2003-07-25 2006-07-16 Universidade De Santiago De Compostela Metodo cuantitativo para la deteccion de yesotoxinas en productos pesqueros basado en la activacion que producen en las fosfodiesterasas.
RU2287341C1 (ru) * 2005-03-01 2006-11-20 Автономная некоммерческая организация Научно-технический центр "Фармбиопресс" Ингибитор ангиогенеза, антиангиогенная фармацевтическая композиция на его основе и способ лечения злокачественных новообразований
RU2404794C2 (ru) * 2008-11-27 2010-11-27 Государственное образовательное учреждение высшего профессионального образования Московская медицинская академия им. И.М. Сеченова Федерального агентства по здравоохранению и социальному развитию (ГОУВПО ММА им. И.М. Сеченова Росздрава) Вагинальные суппозитории для лечения рака шейки матки

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Cited By (7)

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RU2342927C2 (ru) * 2003-10-23 2009-01-10 Оцука Фармасьютикал Ко., Лтд Стерильный состав для инъекций с контролируемым высвобождением, содержащий арипипразол, и способ
US7807680B2 (en) 2003-10-23 2010-10-05 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8030313B2 (en) 2003-10-23 2011-10-04 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8722679B2 (en) 2003-10-23 2014-05-13 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US8952013B2 (en) 2003-10-23 2015-02-10 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US9763935B2 (en) 2003-10-23 2017-09-19 Otsuka Pharmaceutical Co., Ltd. Controlled release sterile injectable aripiprazole formulation and method
US9457026B2 (en) 2007-07-31 2016-10-04 Otsuka Pharmaceutical Co., Ltd. Methods for producing aripiprazole suspension and freeze-dried formulation

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