WO2011046239A1 - Nouvelle utilisation d'un composé imidazole - Google Patents

Nouvelle utilisation d'un composé imidazole Download PDF

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Publication number
WO2011046239A1
WO2011046239A1 PCT/KR2009/005984 KR2009005984W WO2011046239A1 WO 2011046239 A1 WO2011046239 A1 WO 2011046239A1 KR 2009005984 W KR2009005984 W KR 2009005984W WO 2011046239 A1 WO2011046239 A1 WO 2011046239A1
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WO
WIPO (PCT)
Prior art keywords
angiogenesis
present
eye
dihydroxyphenyl
dimethylamino
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PCT/KR2009/005984
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English (en)
Korean (ko)
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김태윤
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주식회사 바이오씨에스
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Publication of WO2011046239A1 publication Critical patent/WO2011046239A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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

Definitions

  • the present invention relates to a new use of the imidazole compound represented by formula (I), and more particularly to (E) -2- (2-((3,4-dihydroxyphenyl) (4-) represented by formula (I).
  • the present invention relates to a composition for preventing and treating angiogenesis-related diseases of the eye, which comprises the same, a method for treating and preventing the same, and an active ingredient thereof.
  • Angiogenesis refers to the process of forming new capillaries from existing microvascular vessels. Angiogenesis normally occurs when embryo development, tissue regeneration, organ growth, wound healing, and the corpus luteum, a cyclical change in a woman's genital system, are developed. In this case, angiogenesis is strictly controlled (Folkman and Cotran, Int. Rev. Exp. Patho., 16: 207-248, 1976). Angiogenesis generally involves the breakdown of the vascular basement membrane by proteolytic enzymes, migration of vascular endothelial cells, formation of lumen by proliferation and differentiation of vascular endothelial cells, and thereby reconstitution of blood vessels.
  • Eruptive angiogenesis begins with the degradation of the basal membrane and interstitial membranes of blood vessels.
  • Angiogenesis factors promote the proliferation and migration of vascular endothelial cells, and when tubules form, thin blood vessels and confluent vasculatures are formed. The new blood vessels then undergo differentiation and maturation with supplementation of perivascular cells. The neovascularization process is terminated by the accumulation of termination carriers in the basement membrane.
  • Non-eruptive angiogenesis is a case where endothelial cell differentiation is induced in existing blood vessels to form lumen and is mainly observed in lungs of tumors or embryos.
  • angiogenesis stage appropriate steps can be taken to prevent new angiogenesis and, conversely, to promote angiogenesis.
  • Normal balance between endogenous stimulants and inhibitors leads to mature angiogenesis leading to normal blood vessel formation. However, if this balance is broken, abnormal neovascularization will occur.
  • Angiogenesis is not autonomously regulated, and abnormal development causes various diseases.
  • Diseases related to angiogenesis in pathological conditions include various cancers (tumors), vascular diseases such as angioplasty, arteriosclerosis, angiogenesis, edema sclerosis, corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, neovascularization
  • Vascular diseases such as corneal disease, spot degeneration, pterygium, retinal degeneration, posterior capsular fibrosis, granuloconjunctivitis, inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroiditis, psoriasis, capillary dilatation, purulent granulomas , Dermatological diseases such as seborrheic dermatitis, acne, and the like (US Patent No.
  • intraocular angiogenesis that occurs in adults is primarily a pathological condition and provides a major cause leading to multiple blindness.
  • the eye consists of tissues with immune privileges, and the cornea is devoid of blood vessels.
  • Neovascularization in the cornea inhibits transparency and results in decreased visual acuity, and neovascularization after corneal transplantation causes graft rejection.
  • Neovascularization in the retina produces abnormal blood vessels, leading to blood exudation, leading to degeneration of retinal nerve cells.
  • Age-related macular degeneration, diabetic retinopathy, neovascular glaucoma, corneal neovascularization, prematurity retinopathy and intraocular tumors are such circumstances, and these diseases are one of the most common causes of blindness. Therefore, clarifying the mechanism by which angiogenesis occurs may reveal ways to prevent blindness.
  • studies on the inhibition of angiogenesis include a method of administering a competitive substance to inhibit the action of VEGF and basic fibroblast growth factor (bFGF), which are known as potent inducers in the process of angiogenesis, and inhibiting metastasis of cancer cells.
  • VEGF vascular endothelial growth factor
  • bFGF basic fibroblast growth factor
  • integrin integrin
  • the present inventors have studied to develop a new method for effectively preventing / inhibiting / treating ocular diseases caused by angiogenesis.
  • the compound of the present invention represented by the formula (I) has an excellent antiangiogenic effect in the eye, particularly the cornea and the retina. Confirmed that the present invention was completed.
  • an object of the present invention is to provide a composition for the prevention and treatment of diseases related to angiogenesis of the eye, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a prophylactic and therapeutic agent for angiogenic diseases of the eye.
  • Another object of the present invention is to provide a method for preventing and treating ocular angiogenesis-related diseases, characterized in that the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to an individual in need thereof in an effective amount.
  • the present invention provides a composition for the prevention and treatment of eye diseases related to angiogenesis, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a preventive and therapeutic agent for angiogenesis-related diseases of the eye.
  • the present invention is a method for preventing and treating ocular angiogenesis-related diseases, characterized in that the compound of the present invention or a pharmaceutically acceptable salt thereof is administered to an individual in need thereof in an effective amount.
  • composition of the present invention is (E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazole-1 represented by formula (I) -Yl) methyl) benzo [d] [1,3] dioxol-5-yl) vinyl sulfate ((E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazol-1-yl) methyl) benzo [d] [1,3] dioxol-5-yl) vinyl sulfate) or a pharmaceutically acceptable salt thereof as an active ingredient, and angiogenesis of the eye It can be used for the purpose of preventing and treating related diseases.
  • the compounds of the present invention can be used on their own or in the form of salts, preferably in the form of pharmaceutically acceptable salts.
  • the salt an acid addition salt formed by a pharmaceutically acceptable free acid is preferable.
  • the compounds of the present invention may be extracted and separated according to methods known in the art, and may also be chemically synthesized according to chemical methods known in the art.
  • the compound of the present invention inhibits angiogenesis occurring in the eye, and therefore, has the effect of preventing or treating a disease associated with it.
  • the eye may be cornea or retina, preferably human eye.
  • the disease namely ocular angiogenesis-related diseases, may be keratitis, hyperemia, diabetic retinopathy, macular degeneration, choroidal neovascularization, neovascular glaucoma, corneal angiogenesis, prematurity retinopathy, and ocular tumor.
  • 5 ⁇ g and 50 ⁇ g of sodium salt of the compound of the present invention were injected subconjunctivally in the corneal neovascularization-induced corneal neovascularization model, and the effects on the angiogenesis were observed.
  • the angiogenesis inhibitory effect was not large in the 5 ⁇ g administration group of the compound of the present invention, whereas the angiogenesis was inhibited in the cornea in the 50 ⁇ g administration group of the compound of the present invention.
  • the effect of the compound of the present invention on angiogenesis in the retina was observed in a model following laser injury. As a result, it was confirmed that the area of the damaged laser was reduced when the compound of the present invention is administered.
  • VEGF and VEGF receptor 2 FLK-1
  • the expression of VEGF A and FLK-1 was strongly observed in the neovascularized cornea, whereas the expression of VEGF A and FLK-1 was significantly reduced in the cornea to which the compound of the present invention was administered.
  • the present invention provides (E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazole-1- represented by the formula (I).
  • I) methyl) benzo [d] [1, 3] diosol-5-yl) vinyl sulfate or a pharmaceutically acceptable salt thereof as an active ingredient provides a composition for the prevention and treatment of eye diseases related to angiogenesis. .
  • composition of the present invention is represented by formula (E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazole-1- 1) methyl) benzo [d] [1,3] dioxol-5-yl) vinyl sulfate or a pharmaceutically acceptable salt thereof, and a balance comprising 0.001 to 99.999% by weight and the balance of the carrier.
  • the compounds of the present invention can be used on their own or in the form of pharmaceutically acceptable salts.
  • pharmaceutically acceptable refers to a physiologically acceptable and, when administered to a human, usually does not cause an allergic reaction or the like, and may be used in the form of the above or pharmaceutically acceptable salts.
  • physiological form of the term 'pharmaceutically acceptable' may be used an organic acid and an inorganic acid.
  • the physiological acid is not limited to this, but citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, triple
  • the inorganic acids including but not limited to uroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, glutane and aspartic acid, include, but are not limited to, acids, bromic acid, sulfuric acid and Contains phosphoric acid.
  • the pharmaceutical composition according to the present invention may contain a pharmaceutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof alone or further include one or more pharmaceutically acceptable carriers.
  • pharmaceutically effective amount refers to an amount that exhibits a higher response than a negative control, and preferably an amount sufficient to treat or prevent obesity.
  • Pharmaceutically effective amounts of the compounds of the invention according to the invention are from 0.00001 to 100 mg / day / kg body weight. However, the pharmaceutically effective amount may be appropriately changed depending on various factors such as the disease and its severity, the patient's age, weight, health condition, sex, route of administration and duration of treatment.
  • composition of the present invention may be formulated in various ways according to the route of administration by a method known in the art together with the pharmaceutically acceptable carrier. Routes of administration may be administered orally or parenterally, but not limited to these. Parenteral routes of administration include, for example, several routes including transdermal, nasal, abdominal, muscle, subcutaneous, intravenous or intravitreal injection of the eye.
  • the pharmaceutical composition of the present invention is prepared in powder, granule, tablet, pill, dragee, capsule, liquid, gel according to a method known in the art together with a suitable oral carrier. , Syrups, suspensions, wafers, eye drops and the like.
  • suitable carriers include sugars, including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol and starch, cellulose, starch including corn starch, wheat starch, rice starch and potato starch, and the like.
  • Fillers such as cellulose, gelatin, polyvinylpyrrolidone, and the like, including methyl cellulose, sodium carboxymethylcellulose, hydroxypropylmethyl-cellulose, and the like.
  • crosslinked polyvinylpyrrolidone, agar, alginic acid or sodium alginate and the like may optionally be added as a disintegrant.
  • the pharmaceutical composition may further include an anticoagulant, a lubricant, a humectant, a perfume, an emulsifier, and a preservative.
  • compositions of the present invention may be formulated according to methods known in the art in the form of injections, transdermal and nasal inhalants together with suitable parenteral carriers.
  • suitable parenteral carriers include, but are not limited to, solvents or dispersion media comprising water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycols, etc.), mixtures thereof and / or vegetable oils Can be.
  • suitable carriers include Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanol amine or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose Etc. can be used.
  • PBS phosphate buffered saline
  • various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like may be further included.
  • the injection may in most cases further comprise an isotonic agent such as sugar or sodium chloride.
  • transdermal administration means the topical administration of the pharmaceutical composition to the skin to deliver an effective amount of the active ingredient contained in the pharmaceutical composition into the skin.
  • the present invention provides (E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazol-1-yl) represented by the formula (I).
  • Methyl) benzo [d] [1,3] dioxol-5-yl) vinyl sulfate
  • the present invention provides (E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazol-1-yl represented by the formula (I). ) Methyl) benzo [d] [1,3] dioxol-5-yl) vinylsulfate and its pharmaceutically acceptable salts are administered in an effective amount to an individual in need thereof. It provides a prevention and treatment method.
  • (E) -2- (2-((3,4-dihydroxyphenyl) (4- (2- (dimethylamino) ethyl) -1H-imidazol-1-yl) methyl) benzo [d of the present invention ] [1,3] dioxol-5-yl) vinyl sulfate and its pharmaceutically acceptable salts can be administered in an effective amount via several routes including oral, transdermal, subcutaneous, intravenous or intramuscular.
  • the term 'effective amount' refers to an amount that shows a therapeutic effect of an eye disease related to angiogenesis of the eye.
  • the term 'subject' refers to an animal, preferably a mammal, particularly an animal including a human. It may be a cell, tissue, organ, etc. derived from the animal. The subject may be a patient in need of treatment.
  • orally or parenterally such as oral, intramuscular, intravenous, intradermal, intraarterial, intramedullary, intradural, intraperitoneal, intranasal, intravaginal, intrarectal, sublingual or subcutaneous, May be administered.
  • a method of directly applying the compound of the present invention and a pharmaceutically acceptable salt thereof to the skin, or preparing the polypeptide in an injectable formulation and injecting a predetermined amount into the lower layer of the skin with a 30 gauge thin needle or It can be administered by lightly pricking the skin. Preferably it can be applied directly to the skin.
  • the compounds of the present invention and pharmaceutically acceptable salts thereof may also be administered in a form that is bound to or encapsulated within a molecule that induces high affinity binding to a target cell or tissue (eg, skin cells or skin tissue).
  • a target cell or tissue eg, skin cells or skin tissue.
  • Compounds of the invention and their pharmaceutically acceptable salts can be prepared using techniques known in the art, such as sterols (e.g. cholesterol), lipids (e.g. cationic lipids, virosomes or liposomes) or target cell specific binding agents (e.g. Ligands recognized by target cell specific receptors).
  • Suitable coupling or crosslinking agents can include, for example, Protein A, carbodiimide, N-succinimidyl-3- (2-pyridyldithio) propiotate (SPDP) and the like.
  • the compounds used according to the invention can be prepared by pressurized packs or by means of It can be delivered conveniently from the nebulizer in the form of an aerosol spray.
  • the dosage unit can be determined by providing a valve to deliver a metered amount.
  • capsules and cartridges for use in inhalers or blowers may be formulated to contain a powder mixture of suitable powder bases.
  • composition of the present invention can be administered in parallel with known compounds having the effect of preventing and treating angiogenesis-related diseases of the eye.
  • the compounds of the present invention exhibit the effect of inhibiting angiogenesis by inhibiting the expression of VEGF A and FLK-1 in the eye. Therefore, the pharmaceutical composition of the present invention can be usefully used to prevent and treat diseases related to angiogenesis of the eye.
  • Figure 1 confirms the effect of the compound of the present invention 1 week after the induction of corneal injury in corneal neovascular model (A: negative control group, B: positive control group, C: 5 ⁇ g compound of the present invention, D: the present invention 50 ⁇ g compound of the group, E is a close-up of A, F is a close-up of D)
  • Figure 2 confirms the effect of the compound (BAZ) of the present invention 2 weeks after corneal injury induction in corneal neovascularization model (A: control, B: 50 ⁇ g compound of the present invention, C: Avastin administration group, D : Numerical result of A ⁇ C result)
  • Figure 3 confirms the effect of the compound of the present invention in retinal angiogenesis model.
  • A normal, B: control, C: 50 ⁇ g administered group of the compound of the present invention, D: numerical results of B ⁇ C results
  • Figure 4 confirms the effect of inhibiting the expression of VEGF-A and the expression of FLK-1 by the compound of the present invention (N: negative control group, NON: positive control group, IZ: compound administration group of the present invention).
  • VEGF and VEGF receptor 2 FLK-1 in the cornea was confirmed.
  • VEGF A primers of SEQ ID NO: 1 (forward; 5′-CTTGCCTTGCTGCTCTACC-3 ′) and SEQ ID NO: 2 (reverse; 5′-CACACAGGATGGCTTGAAG-3 ′) were used.
  • SEQ ID NO: 3 forward; 5'-AAAATGGGCGATGTTAGTGC-3 '
  • SEQ ID NO: 4 reverse; 5'-AGAGCAAGCAACCTTCCAAA-3'
  • VEGF A and FLK-1 were strongly observed in the neovascularized cornea (NON), whereas the expression of VEGF A and FLK-1 in the cornea to which the compound of the present invention was administered. This marked reduction was noted (WON).
  • Normal band showed no band in normal cornea (N).
  • Two bands appearing in VEGF A of FIG. 4 are 189 bp and 165 bp, respectively, while VEGF A is expressed and spliced to these sizes to express proteins, and 165 bp is known to be involved in angiogenesis.
  • the compound of the present invention exhibits the effect of inhibiting angiogenesis by inhibiting expression of VEGF A and FLK-1 in the eye. Therefore, the composition of the present invention can be usefully used to prevent and treat diseases related to angiogenesis of the eye.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Ophthalmology & Optometry (AREA)
  • Engineering & Computer Science (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

La présente invention concerne une nouvelle utilisation d'un composé imidazole représenté par la formule chimique I, et plus particulièrement, un composé représenté par la formule chimique I, qui comprend du sulfate de (E)-2-(2-((3,4-dihydroxyphényl)(4-(2-(diméthylamino)éthyl)-1H-imidazole-1-yl)méthyl)benzo[d][1,3]dioxole-5-yl)vinyle en tant que principe actif, pour la prévention et le traitement de troubles oculaires angiogéniques. Le composé de la présente invention présente les effets de prévenir l'expression du VEGF A et de FLK-1 dans la rétine et de prévenir l'angiogenèse. Ainsi, une composition pharmaceutique de la présente invention peut s'avérer avantageuse pour la prévention et le traitement de troubles oculaires angiogéniques.
PCT/KR2009/005984 2009-10-12 2009-10-16 Nouvelle utilisation d'un composé imidazole WO2011046239A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020090096866A KR20110039842A (ko) 2009-10-12 2009-10-12 이미다졸 화합물을 유효성분으로 포함하는 안구의 혈관 신생 관련 질환의 예방 및 치료용 조성물
KR10-2009-0096866 2009-10-12

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WO2019022444A1 (fr) * 2017-07-25 2019-01-31 서울대학교산학협력단 Dérivé d'alcaloïde ayant un effet inhibiteur de l'angiogenèse, et composition pharmaceutique le contenant
KR20210091865A (ko) * 2020-01-14 2021-07-23 서울대학교산학협력단 혈관생성 저해 효과를 가지는 n-페닐벤조티아졸-2-아민 화합물 및 그를 포함하는 약제학적 조성물

Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1996033714A1 (fr) * 1995-04-24 1996-10-31 President And Fellows Of Harvard College Traitement de la keratose actinique, des naevi dysplasiques et d'autres troubles cutanes proliferatifs au moyen de clotrimazole topique
WO1996040098A2 (fr) * 1995-06-07 1996-12-19 Neorx Corporation Prevention et traitement de pathologies cardio-vasculaires au moyen d'analogues de tamoxifene
US5698586A (en) * 1988-09-01 1997-12-16 Takeda Chemical Industries, Ltd Angiogenesis inhibitory agent

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US5698586A (en) * 1988-09-01 1997-12-16 Takeda Chemical Industries, Ltd Angiogenesis inhibitory agent
WO1996033714A1 (fr) * 1995-04-24 1996-10-31 President And Fellows Of Harvard College Traitement de la keratose actinique, des naevi dysplasiques et d'autres troubles cutanes proliferatifs au moyen de clotrimazole topique
WO1996040098A2 (fr) * 1995-06-07 1996-12-19 Neorx Corporation Prevention et traitement de pathologies cardio-vasculaires au moyen d'analogues de tamoxifene

Non-Patent Citations (1)

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Title
C. -K. JOO ET AL.: "The effect of wondonin on corneal neovascularization", ARVO 2009 ANNUAL MEETING, REDUCING DISPARITIES IN EYE DISEASE AND TREATMENT, 3 May 2009 (2009-05-03) *

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