WO2016200183A1 - Composition pour la prévention ou le traitement de myome utérin comprenant le 2-([1,1'-biphényl]-4-yl)-n-(5-(1,1-dioxidoisothiazolidin-2-yl)-1h-indazol-3-yl)acétamide en tant que substance active - Google Patents

Composition pour la prévention ou le traitement de myome utérin comprenant le 2-([1,1'-biphényl]-4-yl)-n-(5-(1,1-dioxidoisothiazolidin-2-yl)-1h-indazol-3-yl)acétamide en tant que substance active Download PDF

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WO2016200183A1
WO2016200183A1 PCT/KR2016/006137 KR2016006137W WO2016200183A1 WO 2016200183 A1 WO2016200183 A1 WO 2016200183A1 KR 2016006137 W KR2016006137 W KR 2016006137W WO 2016200183 A1 WO2016200183 A1 WO 2016200183A1
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Prior art keywords
bai
acetamide
indazol
biphenyl
dioxidoisothiazolidin
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PCT/KR2016/006137
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English (en)
Korean (ko)
Inventor
김신
이진호
박종욱
조치흠
김기석
이향애
김재곤
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계명대학교 산학협력단
한국화학연구원
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Publication of WO2016200183A1 publication Critical patent/WO2016200183A1/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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/425—Thiazoles
    • 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
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings

Definitions

  • the present invention is 2 - ([1,1'-biphenyl] -4-yl) - N - (5- (1,1- FIG isothiazol between Jolly dioxane-2-yl) -1 H-indazol- 3- yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazol-3-yl) It relates to a technique of using acetamide (BAI) as a composition for treating myoma.
  • BAI acetamide
  • Myoma of the uterus is a solid benign tumor of fibrous tissue of the smooth muscles that make up most of the uterus, also called fibroid. Clinically, about 20% of females are of childbearing age. Uterine fibroids vary widely in size and number of tumors, and most of them are tumors that grow slowly without any symptoms.
  • the treatment of fibroids is divided into pharmacologic and surgical treatments.
  • the treatment method is selected according to the patient's age, menopause, symptoms, and preference. Most asymptomatic myomas only observe their progress. If the myoma is large or causes symptoms, treatment should be done. If you want to preserve the uterus for future pregnancy, you can use hormone injections (gonadotropin-releasing hormone agonists). In the case of hormonal injections, the action is temporary, so after completion of treatment, the size of the fibroid may increase and there may be side effects due to the decrease in female hormones.
  • Surgical methods include hysterectomy and myomectomy can be performed to preserve the uterus.
  • the recurrence rate is about 50% in the case of myoma extraction.
  • One third of these may require reoperation.
  • the pharmacological treatment of uterine leiomyoma is to lower blood levels of ovarian hormones by using gonadotropin-releasing hormone analogs such as goserelin or leuprorelin acetate.
  • an object of the present invention is to provide a composition for preventing or treating uterine myoma without side effects.
  • the present invention is 2 - ([1,1'-biphenyl] -4-yl) - N - (5- (1,1- dioctyl between FIG iso thiazolidin-2-yl) -1 H - indazol-3-yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazol-3-yl) acetamide, BAI) provides a composition for the prevention or treatment of uterine myoma, comprising as an active ingredient.
  • the present invention is 2 - ([1,1'-biphenyl] -4-yl) - N - (5- (1,1-dioxane also between iso-thiazolidin-2-yl) -1 H-indazol -3-yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazol-3- yl) acetamide, BAI) provides a health food for preventing or improving uterine fibroids as an active ingredient.
  • FIGS. 6 and 7 show the results of left ventricular heart rate, left ventricular systolic, diastolic pressure and left ventricular contractile force of rats treated with BAI.
  • the inventors of the present invention 2 represented by the following formula (1) while trying to study the effective fibroids treatment without side effects - ([1,1'-biphenyl] -4-yl) - N - (5- (1, between 1 dioxane FIG iso thiazolidin-2-yl) -1 H - indazol-3-yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- Treatment of (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazol-3-yl) acetamide, BAI) with uterine myoma cells inhibits cell proliferation and poly (ADP-ribose) polymerase (poly ( Induces fragmentation of ADP-ribose) polymerase (PARP), but inhibits uterine myoma cell proliferation and fragmentation of PARP at the human Ether-a-go-go-Related Gene (hER
  • BAI has been developed as a Cyclin-dependent kinase (CDK) inhibitor, and it is a head and neck cancer cell (AMC-HN-4 and AMC-HN-6), lung cancer cell line (A549), kidney cancer cell line (Caki), colon cancer cell Anticancer effects have been observed in various cancer cell lines including HCT-116.
  • intercellular junction molecule-1 intercellular
  • NF- ⁇ B nuclear factor kappa-light-chain-enhancer of activated B cells
  • Cell adhesion was inhibited by inhibiting adhesion molecule-1, ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression.
  • Bcl-2 B-cell lymphoma-2
  • c-FLIP cellular FLICE-like inhibitory protein (L) when mixed with farnesyltransferase inhibitors Apoptosis was induced through down regulation of
  • the invention is 2 - ([1,1'-biphenyl] -4-yl) - N - (5- (1,1-dioxane also between iso-thiazolidin-2-yl) -1 H-indazol -3-yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazol-3- It provides a pharmaceutical composition for preventing or treating uterine myoma, comprising yl) acetamide, BAI) as an active ingredient.
  • the BAI may be included in an amount of 0.1 to 50 parts by weight based on 100 parts by weight of the pharmaceutical composition.
  • composition induces fragmentation of poly (ADP-ribose) polymerase (PARP) and inhibits proliferation of myoma cells.
  • PARP ADP-ribose polymerase
  • the effective concentration at which the composition inhibits proliferation of uterine myoma cells or induces fragmentation of PARP does not induce cardiac toxicity by not inhibiting the human Ether-a-go-go-Related Gene (hERG) ion channel.
  • hERG human Ether-a-go-go-Related Gene
  • the pharmaceutical composition may further include a suitable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition.
  • Carriers, excipients or diluents usable in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
  • compositions according to the present invention may be used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods.
  • sterile injectable solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and the solid preparations may include at least one excipient, for example, starch, calcium carbonate, sucrose ( sucrose, lactose, gelatin and the like can be mixed and prepared.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the amount of BAI used as an active ingredient of the pharmaceutical composition according to the present invention may vary depending on the age, sex, weight, and disease of the patient, but is 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg once or several times daily. May be administered.
  • the dosage of the pharmaceutical composition comprising the BAI according to the present invention can be increased or decreased depending on the route of administration, degree of disease, sex, weight, age and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
  • the pharmaceutical composition may be administered to mammals such as mice, mice, livestock, humans, and the like by various routes. All modes of administration can be expected, for example oral, rectal or intravenous injection, intramuscular injection, subcutaneous injection, intrabronchial inhalation, intrauterine, subdural injection, intrauterine myoma injection or intracerebroventricular injection. It can be administered by.
  • the present invention is 2-([1,1'-biphenyl] -4-yl) -N (-5- (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazole 3-yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- (1,1-dioxidoisothiazolidin-2-yl) -1 H -indazol-3-yl ) acetamide, BAI) provides a health food for preventing or improving uterine fibroids as an active ingredient.
  • the health food may be provided in the form of powder, granules, tablets, capsules, syrups or beverages, and the health food may be used with other foods or food additives in addition to the active ingredient BAI, and may be appropriately used according to conventional methods. have.
  • the mixed amount of the active ingredient can be suitably determined depending on the purpose of use thereof, for example, prophylactic, health or therapeutic treatment.
  • the effective dose of BAI contained in the health food may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range in the case of long-term intake for health and hygiene purposes or health control purposes, It is evident that the active ingredient can be used in an amount above the above range because there is no problem in terms of safety.
  • BAI a drug used in this study - ([1,1'-biphenyl] -4-yl) - N - (5- (1,1- dioctyl between FIG iso thiazolidin-2-yl) -1H- indazol-3-yl) acetamide (2 - ([1,1'-biphenyl ] -4-yl) - N - (5- (1,1 dioxidoisothiazolidin-2-yl) -1 H -indazol-3- yl) acetamide (BAI) was provided by Professor Jin Ho Lee, Department of Chemistry, Keimyung University. The synthesis method of the BAI is as follows.
  • PARP antibody was purchased from Santa Cruz Biotechnology (Santa Cruz Biotechnology, CA, USA) and ⁇ -actin antibody was purchased from Sigma (Sigma, St. Louis, MO, USA), respectively.
  • Uterine myoma tissues from Uterine myoma patients were washed twice with cold phosphate buffered saline (PBS) and cut into 5 mm. The cut pieces are placed in a 50 ml conical tube containing Hanks' balanced salts (Sigma-Aldrich, St Louis, MO, USA) and then 25 mM (4- (2-hydroxyethyl).
  • PBS cold phosphate buffered saline
  • -Piperazineethanesulfonic acid (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES), 100 units / mL antibiotics, 1.5 mg / mL collagenase IV, Sigma- Aldrich) and 0.2 mg / mL of dienase hydrolase I (DNase I, Roche Diagnostics, Mannheim, Germany) were filled in. A tube containing tissue was placed in a 37 ° C. water bath and stirred for 3 hours.
  • the tissues were filtered and centrifuged for 5 minutes at a speed of 1000 rpm
  • the washed tissue was washed once with Hanks' stabilized salts followed by 10% fetal bovine serum (FBS), 1% penicillin / streptomycin ( inoculated in DMEM / F12 cell culture medium containing penicillin / streptomycin. It was.
  • FBS fetal bovine serum
  • penicillin / streptomycin inoculated in DMEM / F12 cell culture medium containing penicillin / streptomycin. It was.
  • Cell viability was determined by 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide , MTT) using MTT analysis.
  • MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide , MTT) using MTT analysis.
  • MTT 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide , MTT) using MTT analysis.
  • the intensity of purple is proportional to the number of viable cells.
  • the optical density (OD) value was measured at 540 nM using a spectrophotometer. Cell survival was determined by subtracting the background OD value containing only the culture medium, and then the control (untreated) wells as the OD value of each experimental group well. It was calculated by dividing by the OD value of. Mean and standard deviation were calculated from three independent experiments.
  • lysis buffer 137 mM NaCl, 15 mM EGTA, 0.1 mM Na 3 VO 4 , 15 mM MgCl 2 , 0.1% Triton X-100, 25 mM OPS, 100 mM phenyl methyl sulfonyl fluoride (PMSF) and 20 mM leupeptin ), pH7.2
  • PMSF phenyl methyl sulfonyl fluoride
  • leupeptin pH7.2
  • Proteins of the samples were quantified by measuring absorbance at 562 nm, and proteins were separated using 10% sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The separated protein was transferred to an immobilon membrane (Milipore, USA). The membrane was blocked for 1 hour at TBST (20 mM Tris-HCL, 137 mM NaCl, 0.1% Tween 20, pH 7.4) at room temperature with 5% skim milk, followed by PARP (Santa Cruz, USA) antibody and actin (actin, Sigma, USA) was reacted with TBST containing 5% skim milk diluted with antibody at room temperature for 12 hours.
  • SDS-PAGE sodium dodecylsulfate-polyacrylamide gel electrophoresis
  • hERG channel analysis used a Chinese hamster ovary (CHO) cell line that permanently contains the hERG gene and expresses IKr ion channels in the cell membrane.
  • Patch clamp technology was used to quantitatively measure the flow of ions through the ion channels of the cell membrane.
  • the microelectrode having an inner diameter of 0.5 to 3 ⁇ m was adhered to the cell membrane by using a slight negative pressure, and then the cell membrane was burst, and the activity of the hERG channel was measured through the whole cell membrane.
  • An amplifier was used to amplify and digitize the current, and the data obtained using a specific storage media software program was stored and analyzed.
  • Electrocardiograms were measured using rat Sprague-dawley (SD) (Orientbio Inc., Seoul, Korea), 200-250 g of rats. At fixed temperature (23 ⁇ 3 ° C.) until the experiment was started, Breeding in relative humidity (50 ⁇ 3%) and illumination (12-hour day / night cycle) All rats were fed daily standard animal food and drinking water (ad libitum) Animals were randomly divided into groups All animals following the procedures were performed as directed by the Institutional Animal Care and Use Committee of our institute (IACUC).
  • SD rat Sprague-dawley
  • IACUC Institutional Animal Care and Use Committee of our institute
  • Isoflurane was anesthetized by breathing 2 to 3 cc / min in each mouse.
  • BIA was then administered intravenously at the following dosage concentrations: 300 nM (130 ug / kg), 500 nM (220 ug / kg), 1 ⁇ M (450 ug / kg), 30 ⁇ M (13.40 mg / kg), 50 ⁇ M (22.33 mg / kg). For convenience, it is expressed in Mole concentration.
  • the electrode is attached to the left and right upper limbs through the limb-induced platinum ECG needle electrode, grounded to the right and tongue of the lower extremity, and connected to an AC signal amplifier (AC amplifier, AM-system AC amplifier model 1700, USA). Heart rate, PR-interval, QT-interval and Tpe-interval were measured using ponemah, DSI, USA 4.83 software.
  • Isoflurane Isoflurane was anesthetized by respiratory administration to each mouse in an amount of 2-3 cc per minute, and the ventilation was maintained after maintaining positive pressure with a ventilator (Harvard, USA) through a tracheal cannulation. After depilating the right neck of the rat with a depilatory agent, the right carotid artery is peeled off and the upper and lower ligatures are ligated with a blood vessel clamp. Three traps are made using 4-0 silk. Was completely ligated and the two remained loose.
  • LVESP left ventricular diastolic pressure
  • LVEDP left ventricular diastolic pressure
  • dP / dt max and min maximum and minimum left ventricular contractile force
  • the activity of hERG channels was measured in the voltage clamp mode of the whole-cell patch clamp.
  • the maximum tail current peaked at +20 mV.
  • the leak current was checked before the test pulse, and the magnitude of the leak current was combined with the magnitude of the measured hERG current to determine the total hERG current. As a result, it was confirmed that the current usually represents about 500 to 2000 pA.
  • the ratio of the current magnitude (% inhibition) after the BAI administration to the control group was analyzed, in which the average value of the data obtained for 1 minute was used.
  • the degree of inhibition of hERG current with a 0.3, 1, 30 or 50 ⁇ M BAI concentration was shown graphically, and the IC50 value, which is the concentration causing 50% of the maximum inhibition of hERG current, was obtained.
  • Left ventricular pressure was measured 40 minutes after BAI administration, and the measurement parameters were heart rate, left ventricular systolic and diastolic pressure, and left ventricular contractile force.
  • There was a significant decrease in all dose groups except 300 nM of (274 ⁇ 14 **, n 4) (* P ⁇ 0.05, ** P ⁇ 0.01) compared to control.
  • the left ventricular end systolic pressure showed a significant change of 1 ⁇ M (105 ⁇ 1.9 *), 30 ⁇ M (99 ⁇ 3.7 **), 50 ⁇ M (97 ⁇ 4.1 **) compared to the control, and 30 ⁇ M (108 ⁇ ) at the maximum systolic pressure. 1.5 *), only 50 ⁇ M (103 ⁇ 3.4 *) showed a significant decrease (* P ⁇ 0.05, ** P ⁇ 0.01 compared to control). As shown in FIG.
  • the left ventricular diastolic pressure was not significantly changed compared to the control group, and the maximum left ventricular contraction force was significantly 1 ⁇ M (6924 ⁇ 144 *), 30 ⁇ M (6182 ⁇ 450 *), and 50 ⁇ M (5939 ⁇ 466 *).
  • the minimum left ventricular contraction force was significantly increased to 30 ⁇ M (-4515 ⁇ 400 *) and 50 ⁇ M ( ⁇ 4631 ⁇ 277 *) (P ⁇ 0.05 compared to the control).

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Abstract

Une composition pour la prévention ou le traitement du myome utérin comprenant le (2-([1,1'-biphényl]-4-yl)-N-(5-(1,1-dioxidoisothiazolidin-2-yl)-1H-indazol-3-yl)acétamide, BAI) en tant que substance active de la présente invention inhibe la prolifération des cellules du myome de l'utérus et induit la fragmentation de PARP. Cependant, la composition peut être efficacement utilisée en tant que composition pour la prévention ou le traitement de myome utérin étant donné que la composition n'induit pas de toxicité dans le système cardiovasculaire à une concentration efficace de BAI capable d'induire une inhibition de la prolifération de cellules de myome utérin et la fragmentation de PARP.
PCT/KR2016/006137 2015-06-09 2016-06-09 Composition pour la prévention ou le traitement de myome utérin comprenant le 2-([1,1'-biphényl]-4-yl)-n-(5-(1,1-dioxidoisothiazolidin-2-yl)-1h-indazol-3-yl)acétamide en tant que substance active WO2016200183A1 (fr)

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KR1020150081386A KR101661723B1 (ko) 2015-06-09 2015-06-09 2-([1,1''-바이페닐]-4-일)-ｎ-(5-(1,1-다이옥사이도아이소티아졸리딘-2-일)-1ｈ-인다졸-3-일)아세트아마이드를 유효성분으로 포함하는 자궁근종 예방 또는 치료용 조성물
KR10-2015-0081386 2015-06-09

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Citations (1)

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KR20010103618A (ko) * 2000-05-10 2001-11-23 성재갑 세포 증식 억제제로 유용한 1,1-디옥소이소티아졸리딘을갖는 인다졸

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KR101103481B1 (ko) 2009-05-21 2012-01-10 영남대학교 산학협력단 한약재 추출물을 유효성분으로 함유하는 자궁근종 치료용 약학조성물

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KR20010103618A (ko) * 2000-05-10 2001-11-23 성재갑 세포 증식 억제제로 유용한 1,1-디옥소이소티아졸리딘을갖는 인다졸

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Title
HONG, H. ET AL.: "BAI, A 3-Amino Indazole Derivative, inhibits Interleukin-1beta-Induced Expression of Cyclooxygenase-2 in A549 Human Airway Cells", INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol. 29, no. 3, 2012, pages 454 - 460, XP055335514 *
JANG, J. H. ET AL.: "BAI, A Novel Cdk Inhibitor, enhances Farnesyltransferase Inhibitor LB42708-mediated Apoptosis in Renal Carcinoma Cells through the Downregulation of Bcl-2 and c-FLIP (L", INTERNATIONAL JOURNAL OF ONCOLOGY, vol. 45, no. 4, 2014, pages 1680 - 1690, XP055335511 *
KIM, S. ET AL.: "BAI, A Novel Cyclin-dependent Kinase Inhibitor induces Apoptosis in A549 Cells through Activation of Caspases and Inactivation of Akt", JOURNAL OF CELLULAR BIOCHEMISTRY, vol. 114, no. 2, 2013, pages 282 - 293, XP055335512 *
LEE, J. ET AL.: "Synthesis and Biological Evaluation of 3,5-Diaminoindazoles as Cyclin-dependent Kinase Inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 18, no. 7, 2008, pages 2292 - 2295, XP022574948 *

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