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EP1737452A1 - Composes agissant sur l'angiogenese et procedes d'utilisation de ceux-ci - Google Patents

Composes agissant sur l'angiogenese et procedes d'utilisation de ceux-ci

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Publication number
EP1737452A1
EP1737452A1 EP05730890A EP05730890A EP1737452A1 EP 1737452 A1 EP1737452 A1 EP 1737452A1 EP 05730890 A EP05730890 A EP 05730890A EP 05730890 A EP05730890 A EP 05730890A EP 1737452 A1 EP1737452 A1 EP 1737452A1
Authority
EP
European Patent Office
Prior art keywords
group
angiogenesis
organism
cells
tissue
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.)
Ceased
Application number
EP05730890A
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German (de)
English (en)
Inventor
Helmut Tumor Biology Center Freiburg AUGUSTIN
Mats c/o AngioGenetics Sweden AB HELLSTRÖM
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.)
Angiogenetics Sweden AB
Original Assignee
Angiogenetics Sweden AB
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Filing date
Publication date
Application filed by Angiogenetics Sweden AB filed Critical Angiogenetics Sweden AB
Publication of EP1737452A1 publication Critical patent/EP1737452A1/fr
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • 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
    • A61P9/10—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

  • the invention relates to compounds useful for promoting or inhibiting angiogenesis and to pharmaceutical compositions containing a compound that affects angiogenesis, which are useful in a number of angiogenesis-related conditions. Further, the invention relates to methods of using such angiogenesis-affecting compounds.
  • Angiogenesis is the fundamental process by which new blood vessels are formed. The process involves the migration of vascular endothelial cells into tissue, followed by the condensation of such endothelial cells into vessels.
  • Angiogenesis may be induced by an angiogenic agent or be the result of a natural condition.
  • Angiogenesis or its absence, plays an important role in the maintenance of a variety of pathological states. Some of these states are characterized by neovascularization, e.g., cancer, diabetic retinopathy, glaucoma, and age related macular degeneration. Others, e.g., stroke, infertility, heart disease, ulcers, and scleroderma, are diseases of angiogenic insufficiency.
  • Angiogenesis has a number of stages (see, e.g., Zhu and Witte, Invest New Drags 17: 195-212, 1999).
  • the early stages of angiogenesis include endothelial cell protease production, migration of cells, and proliferation. The early stages also appear to require some growth factors.
  • Later stages of angiogenesis include population of the vessels with mural cells, basement membrane production, and the induction of vessel bed specializations.
  • the final stages of vessel formation include remodelling, wherein a forming vasculature becomes a stable, mature vessel bed. Thus, the process is highly dynamic, often requiring coordinated spatial and temporal waves of gene expression.
  • the complex angiogenesis process is subject to disruption through interference with one or more critical steps, and numerous disease states can result from or be exacerbated by the disruption.
  • Unregulated angiogenesis can cause or worsen disease, for example, ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases.
  • ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases.
  • ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases.
  • ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases.
  • ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology of approximately 20 eye diseases.
  • ocular neovascularization has been implicated as the most common cause of blindness and underlies the pathology
  • Perhexiline was initially used for management of angina pectoris. Despite some positive effects, adverse hepatic and neurological effects were also associated with Perhexiline administration. The original classification as a coronary vasodilator was revised to a calcium channel antagonist, but recent data suggest it may be a cardiac metabolic agent acting through the inhibition of the enzyme carnitine palmitoyltransferase-1 (CPT-1). Killalea S.M. and Krum H. describe an evaluation of Perhexiline for managing severe myocardial ischemia in Am. J. Cardiocasc. Drugs, 2001; l(3): 193-204.
  • CPT-1 carnitine palmitoyltransferase-1
  • Erythromycin is produced by a strain of Streptomyces erythraeus belonging to the macrolide group of antibiotics. It is basic and readily forms salts with acids, however, it is the base which is microbiologically active. It is primarily given topically or orally to treat bacterial infections. Given the substantial history for use of this drug in humans, it would be desirable to elucidate any further applications for which it would be a candidate. Some recent research has indicated that erythromycin may have new applications, see, for example, Yatsunami J, et al., Inhibitory effects of roxithromycin on tumor angiogenesis, growth and metastasis of mouse B16 melanoma cells, Clin Exp Metastasis.
  • Dopamine regulators are known and many have been effectively used in patients.
  • Bromocriptine mesylate (Bromocriptine) is an ergot derivative with potent dopamine receptor antagonist activity. It can be used in various other applications, such as infertility, but its full range of potential uses has not yet been elucidated.
  • Eticlopride and Lisuride are described in the relevant literature for their ability to regulate dopamine.
  • Dopamine and Dopamine receptor-2 selective agonists such as Bromocriptine have been shown to prevent angiogenesis in Basu S et al., The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor, Nat Med. 2001 May;7(5):569-74. Eticlopride was shown to have not effect on angiogenesis.
  • anti-androgens have been provided, examples of which include flutamide and danazol.
  • Flutamide has been successfully used to inhibit androgen, however, there is a serious and substantial risk of hepatic injury in conjunction with its use. Liver failure and death have been reported, typically within the initial few months of flutamide use. Despite this, determining any other potentially beneficial uses of flutamide is warranted.
  • the synthetic hormone danazol derived from ethisterone, could be a desirable medicament due to its rapid and extensive metabolization following oral administration. Unlike flutamide which is primarily used in male patients, danazol also offers the advantage of having clinical data in both male and female subjects.
  • an object of the present invention to provide compounds that affect angiogenesis. It is a further object of the invention to provide methods of using angiogenesis-affecting compounds. Yet another object of the invention is to elucidate new uses for known compounds.
  • a method of inhibiting angiogenesis in a group of cells, a tissue or an organism comprises administering a therapeutically effective amount of perhexiline or a combination of erythroniycin and at least one anti- VEGF treatment or pharmaceutically acceptable prodrags, salts, solvates, hydrates, active metabolites, or combinations thereof to the group of cells, tissue or organism.
  • the organism can be a mammal, and the mammal can have a condition selected from the group consisting of cancer, sarcomas, retinopathy, macular degeneration, corneal ulceration, scleroderma, Berger's disease, proliferative vitreoretinopathy, chronic inflammation, inflammatory bowel disease, psoriasis, sarcoidosis, and rheumatoid arthritis.
  • the compound can be administered locally.
  • a method of inhibiting angiogenesis in a group of cells, a tissue or an organism comprises administering a therapeutically effective amount of a pharmaceutical composition comprising perhexiline or a combination of erythromycin and at least one anti-VEGF treatment or pharmaceutically acceptable prodrags, salts, solvates, hydrates, active metabolites, or combinations thereof to the group of cells, tissue or organism.
  • the organism can be a mammal, and the mammal can have a condition selected from the group consisting of cancer, sarcomas, retinopathy, macular degeneration, corneal ulceration, scleroderma, Berger's disease, proliferative vitreoretinopathy, chronic inflammation, inflammatory bowel disease, psoriasis, sarcoidosis, and rheumatoid arthritis.
  • the compound can be administered locally.
  • the pharmaceutical composition can be formulated as a salve, gel, ointment, patch, injection, oral solution or suspension and can be in a controlled release matrix.
  • the pharmaceutical composition can further comprise a pharmaceutically acceptable carrier, diluent, vehicle, or excipient. Where the pharmaceutical composition comprises perhexiine the method can further comprise administering at least one anti-VEGF treatment to the group of cells, tissue, or organism.
  • An anti-VEGF treatment can be AVASTLN or MACUGEN.
  • a method of stimulating angiogenesis in a group of cells, a tissue or an organism comprises administering a therapeutically effective amount of a compound selected from the group consisting of Bromocriptine, Eticlopride, Lisuride (S)(-), Miconazole, Sulconazole, Econazole, Flutamide and Danazol or pharmaceutically acceptable prodrags, salts, solvates, hydrates, active metabolites, or combinations thereof to the group of cells, tissue or organism.
  • the organism can be a mammal.
  • the mammal can have a condition selected from the group consisting of stroke, ischemic heart disease, wound healing, ischemia, myocardial infarction, myocardosis, angina pectoris, unstable angina, coronary arteriosclerosis, arteriosclerosis obliterans, and cerebral infarction.
  • the compound may be administered locally .
  • a method of stimulating angiogenesis in a group of cells, a tissue or an organism comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a compound selected from the group consisting of Bromocriptine, Eticlopride, Lisuride (S)(-), Miconazole, Sulconazole, Econazole, Flutamide and Danazol or pharmaceutically acceptable prodrags, salts, solvates, hydrates, active metabolites, or combinations thereof to the group of cells, tissue or organism.
  • the organism can be a mammal.
  • the mammal can have a condition selected from the group consisting of stroke, ischemic heart disease, wound healing, ischemia, myocardial infarction, myocardosis, angina pectoris, unstable angina, coronary arteriosclerosis, arteriosclerosis obliterans, and cerebral infarction.
  • a method of increasing blood flow to a tissue comprises administering a pharmaceutical composition comprising a compound selected from the group consisting of Bromocriptine, Eticlopride, Lisuride (S)(-), Miconazole, Sulconazole, Econazole, Flutamide and Danazol to the tissue in an amount effective to promote angiogenesis.
  • a pharmaceutical composition comprising a compound selected from the group consisting of Bromocriptine, Eticlopride, Lisuride (S)(-), Miconazole, Sulconazole, Econazole, Flutamide and Danazol
  • patient refers to the subject of the novel treatment disclosed herein.
  • tissue refers to a group of living cells.
  • the term should be read to encompass single cells and groups of cells where appropriate.
  • the term can also be read to include organs.
  • the term refers not only to living material in situ but also to living material that has been cultured in vitro or extracted from an organism.
  • animal or "organism” refers to mammals, preferably humans.
  • angiogenesis means the process by which living cells, tissues, or organisms form new blood ⁇ vessels.
  • angiogenesis-affecting means a compound or process which influences angiogenesis in a treated tissue or organism.
  • the effect could be, for example, inhibition or promotion of angiogenesis.
  • angiogenesis-related condition refers to any one of the medical conditions or disease states recognized to be influenced by angiogenesis or by an increase/decrease in angiogenesis of by the lack thereof, including conditions which may be linked to angiogenesis in the future.
  • Such conditions include cancer, sarcoma, retinopathy, macular degeneration, corneal ulceration, stroke, ischemic heart disease, infertility, ulcers, scleradoma, wound nealing, ischemia, ischemic heart disease, myocardial infarction, myocardosis, angina pectoris, unstable angina, coronary arteriosclerosis, arteriosclerosis obliterans, Berger's disease, arterial embolism, arterial thrombosis, cerebro vascular occlusion, cerebral infarction, cerebral thrombosis, cerebral embolism, rabeosis proliferative vitreoretinopathy, chronic inflammation, inflammatory bowel disease, psoriasis, sarcoidosis, and rheumatoid arthritis.
  • stimulation refers to molecules or compounds which initiate, promote, or increase in speed, duration, or degree the natural or typical (i.e., unaffected) angiogenesis in the treated tissue or patient.
  • inhibitor refers to molecules or compounds which stop, prevent, reduce, hinder, or delay the natural or typical (i.e., unaffected) angiogenesis in the treated tissue or patient.
  • pharmaceutical refers to any medicinal substance used in living cells, tissues, humans or other animals. Encompassed within this definition are compound analogs, naturally occurring and synthetic compounds.
  • phrases “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a patient.
  • terapéuticaally effective amount is used herein to mean an amount which, when applied as part of a desired dosage regimen, is sufficient to affect angiogenesis to an extent that results in some clinically significant change.
  • the term means an amount which will prevent, or preferably reduce by at least about 30 percent, more preferably by at least about 50 percent, most preferably by at least about 90 percent, angiogenesis in the tissue or patient treated.
  • the term means an amount which will start, or preferably increase by at least about 30 percent, more preferably by at least about 50 percent, most preferably by at least about 90 percent, angiogenesis in the tissue or patient treated.
  • the amount of a given compound described herein that will correspond to a "therapeutically effective amount” will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the identity of the mammal in need thereof, but it can nevertheless be readily determined by one of skill in the art.
  • Treating is intended to mean at least the mitigation of a disease condition in a mammal, such as a human, that is alleviated by affecting angiogenesis, and includes: (a) prophylactic treatment in a mammal, particularly when the mammal is found to be predisposed to having the disease condition but not yet diagnosed as having it; (b) inhibiting the disease condition; and/or (c) alleviating, in whole or in part, the disease condition.
  • a “pharmaceutically acceptable prodmg” means a compound that may be converted under physiological conditions or by solvolysis to a compound of one of the formulas disclosed herein.
  • a "pharmaceutically acceptable active metabolite” means a pharmacologically active product produced through biological metabolism, such as in the body of a patient, of a compound of one of the formulas disclosed herein.
  • a "pharmaceutically acceptable solvate” means a solvate that retains the biological effectiveness and properties of the biologically active compounds of one of the formulas disclosed herein.
  • pharmaceutically acceptable solvates include, but are not limited to, one or more of the compounds disclosed herein in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic axid, or ethanolamine.
  • a "pharmaceutically acceptable salt” means a salt that retains the biological effectiveness and properties of the free acids and bases of compounds disclosed herein and that is not biologically or otherwise undesirable.
  • pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free base -with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p- toluenesulfonic acid or ethanesulfonic acid; or the like.
  • an inorganic acid such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric
  • the desired salt may oe prepared by any suitable method known to the art, including treatment of the free acid vith an inorganic or organic base, such as an amine (primary, secondary or tertiary); an alkali metal or alkaline earth metal hydroxide; or the like.
  • suitabLe salts include organic salts derived from amino acids such as glycine and arginine; ammonia; prima-ry, secondary and tertiary amines; and cyclic amines such as piperidine, morpholine, aird piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium-, manganese, iron, copper, zinc, aluminum, and lithium.
  • inventive compounds may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. Preferably, the inventive compounds are used in optically pure form.
  • an optically pure co ⁇ rpound is one that is enantiomerically pure.
  • the term “optically pure” is intended to mean a compound which comprises at least a sufficient amount of a single esnantiomer to yield a compound having the desired pharmacological activity.
  • “optically pure” means a compound that comprises at least 90% of a single isomer, preferably at least 95%, more preferably 97.5%, and most preferably 99%.
  • the present invention is also directed to methods of affecting angiogenesis and methods of treating or preventing angiogenesis-related conditions, which methods or treatments comprise the use of a compound disclosed herein or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof.
  • the activity of the inventive compounds as angiogenesis-effectors may be measured by any of the methods available to those skilled in the art, including in vivo and in vitro assays.
  • Administration of the compounds disclosed herein, or their pharmaceutically acceptable prodrags, salts, active metabolites, and solvates, may be performed according to any of the accepted modes of administration available to those skilled in the art.
  • suitable modes of administration include, but are not limited to, oral, nasal, parenteral, topical, and transdermal.
  • the compounds disclosed herein may be administered as a pharmaceutical composition in any suitable pharmaceutical form recognizable to the skilled artisan.
  • suitable pharmaceutical forms include, but are not limited to, solid, semisoli ., liquid, or lyopholized formulations, such as tablets, powders, capsules, suspensions, and aerosols.
  • the pharmaceutical composition may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use.
  • ph-armaceutical preparations may be prepared following conventional techniques of the ph-armaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for, for example, oral, parenteral, topical, intranasal, intrabronchial and/or intraocular administration.
  • Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions.
  • Illustrative solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid.
  • Illustrative liquid carriers may include alcohol, oil, saline, and water.
  • the carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g. solution), or a nonaqueous or aqueous liquid suspension.
  • a dose of the phannaceutical composition contains at least a therapeutically effective amount of the active compound (i.e., a compound described herein or a pharmaceutically acceptable prodrug, salt, active metabolite, or solvate thereof) and preferably is made up of one or more pharmaceutical dosage units.
  • the selected dose may be administered to a mammal, for example, a human patient, in need of angiogenesis-effecting treatment, by any known method of administering the dose including topical, for example, as an ointment or cream; orally; parenterally by injection; or continuously by intranasal, intrabronchial, intraaural, or intraocular infusion.
  • Figure 1 shows exemplary results of primary angiogenesis screening assays
  • Figure 2 shows the chemical structure of perhexiline maleate
  • Figure 3 shows the chemical structure of erythromycin
  • Figures 4A, 4B, and 4C depict cell proliferation data for perhexiline
  • Figures 5A, 5B, and 5C depict cell proliferation data for erythromycin
  • Figures 6A, 6B, and 6C show cytoviability assay results for perhexiline
  • Figures 7A, 7B, and 7C show cytoviability assay results for erythromycin
  • Figure 8 depicts cell viability data for B16F10 cells treated with perhexiline
  • Figure 9 depicts cell viability data for B 16F10 cells treated with erythromycin
  • Figure 10 shows IC 50 values for two VEGFR-1 inhibitors
  • FIGS 11 A and 1 IB show IC 50 values for perhexiline alone and in conjunction with
  • VEGFR-1 inhibitors are VEGFR-1 inhibitors, respectively;
  • Figures 12 A and 12B show IC 50 values for erythromycin alone and in conjunction with VEGFR-1 inhibitors, respectively;
  • Figure 13 shows the chemical structure of lisuride (S)(-);
  • Figure 14 shows the chemical structure of miconazole
  • Figure 15 shows the chemical structure of sulconazole
  • Figure 16 shows the chemical structure of flutamide
  • Figure 17 shows the chemical structure of danazol
  • Figure 18 shows cell proliferation data for lisuride
  • Figure 19 shows cell proliferation data for miconazole
  • Figure 20 shows cell proliferation data for flutamide
  • Figure 21 shows cell proliferation data for danazol
  • Figure 22 quantifies measured HUVEC sprouting after treatment with select compounds
  • Figure 23 quantifies measured HUVEC sprouting after treatment with select compounds in conjunction with VEGF
  • Figure 24 quantifies measured HUVEC sprouting after treatment with select compounds and a VEGFR-1 inhibitor.
  • the compounds of the present invention may have chemical and structural properties which are different from those specified hereinafter at some point during their manufacture and use.
  • the compounds may undergo a series of metabolic changes that result in intermediaries with properties outside of the ranges set forth hereinafter for certain parameters.
  • intermediates and metabolic end products are nevertheless still within the scope of this invention if they at one time before, during, or after administration have the requisite values specified hereinafter.
  • compounds of the present invention can be used to affect angiogenesis. Such uses could be confined to cell or tissue culture application, as well as administration to a patient. In order to ensure the invention is fully disclosed to skilled workers, details related to the identification of the claimed compounds are provided by way of introduction herein. Where a description provides the purpose of a particular step or material, such purpose is based on the current understanding of the mechanism of action. Such description is provided in the interest of full disclosure; however, the invention is not bound to the theories described herein.
  • test substance was selected for evaluation in angiogenesis screens.
  • the test substance was synthesized or obtained as appropriate and stored at -20 °C in DMSO. Prior to use, the test substance was thawed and 5 mM of the substance was diluted to a 10 fold concentrated working solution (100 ⁇ M) in endothelial cell basal medium. The basal medium fraction was supplemented with 25 ng VEGF/ 100 ⁇ l for the stimulation of HUVEC sprouting.
  • spheroids were prepared by pipetting 400 human umbilical vein endothelial cells (HUVEC) into each well of nonadhesive 96-well plates. Prior to use the HUVEC were cultured according to the supplier's instructions (PromoCell, Heidelberg, Germany). The cells were allowed to aggregate overnight into spheroids (Korff and Augustin: J Cell Biol 143: 1341-52, 1998). After aggregation, 48 HUVEC spheriods were harvested. Each harvested spheroid was seeded in 900 ⁇ l of methocel-collagen solution and pipetted into an individual well of a 24-well plate to allow collagen gel polymerization.
  • HUVEC human umbilical vein endothelial cells
  • test substance was added.
  • the working dilution (10 fold concentration) was utilized, 100 ⁇ l was pipetted on top of the polymerized collagen gel in each well.
  • the plates were then incubated at 37°C for 24 hours. At the end of the incubation period the plates were fixed by adding 1 ml paraformaldehyde (10 %) to each well.
  • the HUVEC spheriods were microscopically assayed for endothelial cell (EC) sprouting intensity.
  • the degree of EC sprouting was classified into one of four groups by comparing the degree of sprouting to that observed in VEGF control cells.
  • the groups were: strong inhibition of sprouting (indicating the test compound is a strong angiogenesis inhibitor), sprouting inhibited to basal sprouting (indicating that the test compound is an angiogenesis inhibitor), excessively above the VEGF control sprouting (indicating the test compound is an angiogenesis stimulator) or indistinguishable to the VEGF control sprouting (where the test compound appears to have no effect).
  • strong inhibition of sprouting indicating the test compound is a strong angiogenesis inhibitor
  • sprouting inhibited to basal sprouting indicating that the test compound is an angiogenesis inhibitor
  • excessively above the VEGF control sprouting indicating the test compound is an angiogenesis stimulator
  • indistinguishable to the VEGF control sprouting where the test compound appears to
  • test compound was classified as an inhibitor or stimulator
  • a second screening process was performed.
  • the test substance was thawed and 5 mM of the substance was diluted to a 10 fold concentrated working solution (100 ⁇ M) in endothelial cell basal medium. No supplements were used in the basal medium.
  • spheroids were prepared by pipetting 400 human dermal fibroblasts (NHDF) into each well of nonadhesive 96-well plates. Prior to use the NHDF were cultured according to the supplier's instructions (PromoCell, Heidelberg, Germany). The cells were allowed to aggregate overnight into spheroids (Korff and Augustin: J Cell Biol 143: 1341-52, 1998). After aggregation, 48 NHDF spheroids were harvested. Each of the harvested spheroids was seeded in 900 ⁇ l of methocel-collagen solution and pipetted into an individual well of a 24-well plate to allow collagen gel polymerization.
  • NHDF human dermal fibroblasts
  • test substance was added.
  • the working dilution (10 fold concentration) was utilized, 100 ⁇ l was pipetted on top of the polymerized collagen gel in each well.
  • the plates were then incubated at 37°C for 24 hours. At the end of the incubation period the plates were fixed by adding 1 ml paraformaldehyde (10 %) to each well.
  • the NHDF spheroids were microscopically assayed for fibroblast scattering intensity.
  • the degree of fibroblast scattering intensity was classified into one of four groups: strong inhibition of scattering (indicating the test compound is a non-specific inhibitor), scattering inhibited or only mildly inhibited (indicating the test compound is an EC specific inhibitor), scattering unaffected (indicating the test compound is an EC specific stimulator) or scattering increased (indicating the test compound is a non-specific stimulator).
  • strong inhibition of scattering indicating the test compound is a non-specific inhibitor
  • scattering inhibited or only mildly inhibited indicating the test compound is an EC specific inhibitor
  • scattering unaffected indicating the test compound is an EC specific stimulator
  • scattering increased indicating the test compound is a non-specific stimulator.
  • test compound reduced HUVEC sprouting to basal sprouting or there was no sprouting at all, and where NHDF scattering was not affected or mildly affected, the compound was deemed an inhibitor of angiogenesis.
  • Perhexiline maleate is one such inhibitor. Its' chemical structure is shown in Figure 2.
  • Erythromycin is one such inhibitor. Its' chemical structure is shown in Figure 3. Its' CAS
  • Erythromycin exhibited sprouting inhibition but no fibroblast invasion effect, making it a specific angiogenesis inhibitor. This finding is surprising in light of the historical uses of erythromycin and even in light of more recent work with alternative applications of the compound.
  • angiogenesis inhibitors By identifying the above-noted compounds as angiogenesis inhibitors, the present inventors make available new compounds that will inhibit or prevent angiogenesis. It may be desirable to prevent, decrease, or stop angiogenesis in a patient with certain disease states, such as cancer. Alternatively, it may be desirable to prevent angiogenesis in an otherwise healthy animal or cell/tissue culture model to further study the mechanisms of angiogenesis.
  • the OD-value of the plated cells before addition of the compounds was subtracted from all OD-values obtained after treatment. The percentage in relation to control proliferation was then calculated. Negative values therefore represent a count of fewer cells than were plated.
  • the IC 50 is given below in Table 1. Results are shown as a percentage in relation to the control proliferation. The IC 50 were calculated using GraphPad Prism software (GraphPad Software, Inc.). Perhexiline results are depicted graphically in Figures 4A - 4C and Erythromycin results in Figures 5 A - 5C.
  • Table 1 Summary of the IC 50 obtained in the proliferation assay.
  • Cytoviability Assay A cell viability assay based on cellular reduction of resazurin to the fluorescent product resorafm was performed. Viable cells can metabolize and reduce the dye, whereas dead cells rapidly lose the capacity to do so, making the increase in fluorescence directly proportional to the number of viable cells. The tested compounds were added in a log 2 titration and viable cells were analyzed 24 hours after treatment. The fluorescence was determined at an excitation wavelength of 560 nm and an emission wavelength of 590 nm. The percentage of viable cells in relation to the untreated control proliferation was calculated. Table 2 shows the IC 50 values obtained in the cell viability assay. Perhexiline results are depicted graphically in Figures 6A - 6C and Erythromycin results in Figures 7A - 7C.
  • the B16F10 tumor model like the RENCA model, is an orthotopic tumor model.
  • the IC 50 after 24 and 48 hours incubation for Perhexiline- and Erythromycin-treated B16F10 cells was determined at 1.0 x 10 "5 M; results are given in Figures 8 and 9. Evaluation of synergistic effects in combination with VEGF inhibitors
  • the 3D angiogenesis assay is suitable for IC 50 determinations with a narrow variation.
  • the assay was applied to test compounds alone or in combination with a VEGFR-2 inhibitor to address changes in IC 50 .
  • the inhibitors tested were SU5614 and PTK787/ZK222584.
  • the IC 50 value of the VEGFR-2 inhibitors was determined in the spheroid-based 3D assay, see Figure 10.
  • the perhexiline or erythromycin was added on top of the gel where tested in combination with AGl or directly in the gel when tested in combination with SU5614, at the concentration shown in Figures 11A and B and 12A and B, respectively. Data are summarized in Table 3.
  • Table 3 Summary of the IC 50 obtained in the synergistic 3D angiogenesis assay
  • the Spherogenex angiogenesis assay can be used to elucidate the effects of specific enantiomers of the test compounds.
  • angiogenesis is known to be driven at times by VEGF
  • the assay can also be employed to ascertain bFGF-driven angiogenesis, thereby allowing determination of the effects of the compounds on non- VEGF-driven angiogenesis.
  • mRNA expression profiling of the Spherogenex angiogenesis assay comparing treatment with the angiogenesis modulating compounds and nontreated controls could be used to determine which signalling pathways are affected by the test compounds.
  • HCC Hepato-Cellular Carcinoma Model
  • Alexander cells are available from, e.g. American Type Culture Collection (Manassas, Virginia, USA). Monolayers of Alexander cells can be grown in 85% Dulbecco s Modified Eagle t s Medium (DMEM), 15% Fetal Bovine Serum (FBS), 4mM L-glutamine, 100 units penicillinG/ml, and lOO ⁇ g of streptomycin-sulfate/ml. The cells can be cultured in a humidified atmosphere of 90% air and 10% carbon dioxide at 37°C. Media may preferably be changed every 4 days.
  • DMEM Dulbecco s Modified Eagle t s Medium
  • FBS Fetal Bovine Serum
  • 4mM L-glutamine 100 units penicillinG/ml
  • penicillinG/ml 100 units penicillinG/ml
  • lOO ⁇ g of streptomycin-sulfate/ml 100 units penicillinG/ml
  • streptomycin-sulfate/ml 100 units penicillinG/m
  • the Alexander cells can be implanted in the left flank region of the mice, for example, by injecting 4x10 cells in 0.2 ml aliquots into the subcutaneous space of the left flank using a 29G needle syringe. After inoculation the appearing subcutaneous tumours can be measured by callipering and multiplying the distances of all three dimensions.
  • Group 1 would serve as control, where the animals would receive no further treatment after injection of Alexander cells.
  • Group 2 could evaluate perhexiline' s effects on the tumor through daily doses of 40 mg/kg via oral gavage.
  • Group 3 could receive erythromycin once daily in standard dose levels, such as 10 mg/kg i.p., preferably given in conjunction with a low dose of PTK787/ZK222584.
  • Group 4 could be administered PTK787/ZK222584 orally at doses of 50 mg/kg twice daily, optionally a sub-group of Group 4 or a separate Group 5 could receive a low dose of PTK787/ZK222584.
  • mice After approximately 21 days of treatment, mice could be sacrificed and tumors collected and optionally stored appropriately at -80°C.
  • cryosections of the tissues For histological examination of the tumor vasculature, cryosections of the tissues (thickness of 5-10 ⁇ m) can be taken.
  • immunohistochemical staining for CD 31 PECAM-1
  • vessels counted microscopically using a defined magnification (x200). Examinations of all tissue sections at low magnification and can be carried out, including photography if desired.
  • the proliferation index of the tumor tissue could be examined by BrdU labeling of cryosections. If that is the case, BrdU (500mg/kg) should be administered to the animals 12 hours before sacrifice.
  • a TUNEL staining could be performed on cryosections.
  • tumors in animals receiving these compounds would be considerably smaller than those observed in control animals. Tumor apoptosis could be increased and a decrease in microvascular density could be observed for the Group 2 and 3 animals.
  • test compound stimulated HUVEC sprouting excessively above the VEGF control and where NHDF scattering was unaffected or only mildly increased, the compound was deemed a stimulator of angiogenesis.
  • Bromocriptine is an angiogenesis stimulator with the molecular formula C 32 H 4 oBrN 5 ⁇ 5 'CH 4 S ⁇ 3 and a molecular weight of 750.70.
  • Eticlopride is also known as a dopamine receptor blocker, as is Lisuride (S)(-).
  • Lisuride' s chemical structure is shown in Figure 13. Its' CAS No. is 18016-80-3, formulaic structure is C 2 oH 26 N 4 O, and molecular weight is 338.5.
  • Lisuride (S)(-) exhibited increased sprouting stimulation but no fibroblast invasion effect, making it a specific angiogenesis stimulator. This is in surprising contrast to that described previously and noted above, where research indicated that certain of these dopamine regulators had no effect on angiogenesis or actually works to prevent angiogenesis.
  • Miconazole is one such stimulator. Its' chemical structure is shown in Figure 14. Its' CAS No. is 22916-47-8, formulaic structure is C ⁇ 8 Hi 4 C ⁇ 4 N 2 O, and molecular weight is 416.1. Miconazole exhibited increased sprouting stimulation but no fibroblast invasion effect, making it a specific angiogenesis stimulator. Sulconazole, whose chemical structure is shown in Figure 15, is (+)-l-[2.4-dichloro-b -[(p-chlorobenzyl)-thio]- phenethyljimidazole mononitrate.
  • Econazole is l-[2- ⁇ (4-chloro-phenyl)methoxy ⁇ -2-(2,4- dichlorophenyl)ethyl]-lH-imidazole mononitrate, both are known anti-mycotics and have su ⁇ risingly been shown to be angiogenesis stimulators as well
  • Flutamide is one such stimulator. Its' chemical structure is shown in Figure 16. Its' CAS No. is 13311-84-7, formulaic structure is C ⁇ HnF 3 N 2 O 3 , and molecular weight is 276.2. Flutamide exhibited increased sprouting stimulation but no fibroblast invasion effect, making it a specific angiogenesis stimulator. Danazol is also an anti-androgen that has su ⁇ risingly been shown to be an angiogenesis stimulator. Its' chemical structure is shown in Figure 17. Its' CAS No. is 17230-88-5, formulaic structure is C 22 H 27 NO 2 , and molecular weight is 337.5. Danazol exhibited increased sprouting stimulation but no fibroblast invasion effect, making it a specific angiogenesis stimulator.
  • angiogenesis stimulators By identifying the above-noted compounds as angiogenesis stimulators, the present inventors make possible the possibility of new compounds that will stimulate or begin angiogenesis. It may be desirable to stimulate angiogenesis in a patient with certain disease states, such as ischemia. Alternatively, it may be desirable to stimulate angiogenesis in an animal or cell/tissue culture model to further study the mechanisms of angiogenesis. For example, by administering a compound of the present invention, angiogenesis could be stimulated in an animal model expressing a tumor, providing additional research opportunities into the growth of the tumor and possibly improved animal models for studying tumor treatments.
  • the compounds were tested in a cell proliferation assay.
  • the assay was performed as described, above.
  • the OD value at day 0 was subtracted from the OD value after 72 hours of treatment. Negative values therefore represent observation of fewer cells than originally plated and further indicate cytotoxic effects of the compound on HUVEC.
  • the compounds inhibit proliferation, results are shown in Figures 18-21.
  • HUVEC Spheroid Results As described above with regard to angiogenesis inhibitors, the compounds newly found to be angiogenesis stimulators were also evaluated in a 3D angiogenesis assay. They were all consistently found to independently stimulate EC sprouting or further increase VEGF-induced sprouting.
  • the HUVEC monolayer was treated for 6 hours with the compounds then the induced transcriptional changes, when compared to untreated HUVEC, were determined.
  • the compounds were tested according to their ability to induce sprouting without addition of VEGF, in combination with VEGF and together with the VEGFR-2 inhibitor PTK787/ZK222584 (1 ⁇ M).
  • the VEGFR-2 inhibitor completely prevents VEGF-induced sprouting at a concentration of 1 ⁇ M.
  • Figure 22 shows the effects of the compounds alone on HUVEC sprouting, after 24 hours of treatment the basal sprouting was subtracted and the resultant sprouting compared to VEGF-induced sprouting. Both bromocriptine and eticlopride stimulated sprouting in excess of the VEGF-induced sprouting.
  • the compounds given in combination with VEGF were also evaluated, data shown in Figure 23.
  • the compounds can enhance VEGF-driven angiogenesis even further.
  • Results from the evaluation of the compounds administered in conjunction with PTK787/ZK222584 are shown in Figure 24, where the percentage is given as compared to untreated control. The results show that the sprouting is not VEGF-dependent since it can not be inhibited by VEGFR inhibitor.
  • test compounds could be evaluated in conjunction with or without angiogenic stimulators (for example, growth factors such as VEGF or bFGF) in a matrigel angiogenesis assay as described in Passaniti, A., et al Lab Invest. 1992 Oct;67(4):519-28.
  • angiogenic stimulators for example, growth factors such as VEGF or bFGF
  • the modified matrigel angiogenesis procedure as in Guedez, L., et al., American Journal of Pathology, 2003, vol. 162, no. 5, 1431-39 could be used.
  • a further in vitro evaluation that could be performed would be to evaluate the retinal vascularization and vessel density in mice treated with the compounds as described in WO 05/008250.
  • the compounds described herein can be used to affect angiogenesis.
  • the amount of compound, route of administration and other related factors could well be based on the regimen advised for the compound's original indication. Such information is available to the skilled worker; see, for example, Goodman & Gilman, The Pharamacological Basis of Therapeutics. Dosing and delivery could be modified based on the needs of the patient and the availability of improved dosing techniques as they develop in the art.
  • the preferred method of treatment may further include a step of detecting angiogenesis in the affected tissue or organism following treatment.
  • Methods of detecting angiogenesis are known in the art, see for example, U.S. Patent No. 6,689,807.
  • a compound of the present invention could be metabolised by enzymes in the body of the organism such as a human being to generate a metabolite that can affect angiogenesis. Such metabolites are within the scope of the present invention. It is also contemplated that precursor compounds could be administered which, after undergoing processing such as enzyme metabolism, would result in the compound of the present invention.
  • a skilled worker may choose to employ one or more of the compounds discussed above in conjunction with another active compound.
  • two or more of the compounds disclosed herein may be administered in conjunction to affect angiogenesis to a different degree.
  • the compounds may be administered at the same time or in a sequential fashion.
  • One way to determine whether particular combinations of compounds interact in a preferred fashion is by preparing a linear isobologram (Tallarida RJ., et al, Statistical analysis of drug-drug and site-site interactions with isobolograms, Life Sciences. 45(11):947-61, 1989). Such a diagram helps elucidate where the additional compound(s) have merely an additive effect, or where they have a synergistic effect.
  • At least nine experimental groups are evaluated; three groups define the dose-response of a first compound, three groups define the dose-response for a second compound, and three groups define the dose-response for a fixed ratio combination of those two compounds.
  • the selected dose response values, ED 50 values, for the single dose groups are plotted as a line which assumes an addititive effect. This line is based on the compound ratio tested; a 1 :2 ratio of first test compound to second test compound is shown.
  • an observed dose response which lies to the left (i.e., below) of the additive line represents a synergistic effect of the compounds used together, whereas a observed dose response to the right (i.e., above) of the additive line represents an antagonistic effect of the compounds in combination.
  • the compounds disclosed herein may be particularly effective when combined with treatments which block VEGF activity or signalling.
  • anti-VEGF treatments include inhibitory anti-VEGF receptor antibodies, soluble receptor constracts, antisense strategies, RNA aptamers against VEGF and low molecular weight VEGF receptor tyrosine kinase (RTK) inhibitors.
  • RTK low molecular weight VEGF receptor tyrosine kinase
  • AVASTIN bevacizumab
  • MACUGEN pegaptanib sodium
  • the effective dosage amount will vary with the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy (if any), the specific route of administration and factors within the knowledge and expertise of a health care practitioner.
  • an effective amount is that amount which engenders sufficient angiogenesis so as to provide an increase in blood flow in the ischemic region.

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Abstract

L'invention concerne un composé agissant sur l'angiogenèse lorsqu'il est administré à un groupe de cellules, à un tissu ou à un organisme. Cette action inhibe ou stimule l'angiogenèse. Ces composés peuvent servir à traiter des états pathologiques liés à une angiogenèse insuffisante ou excessive.
EP05730890A 2004-04-06 2005-04-06 Composes agissant sur l'angiogenese et procedes d'utilisation de ceux-ci Ceased EP1737452A1 (fr)

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