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WO2008123756A1 - Compositions pharmaceutiques contenant des dérivés de pyridine de type lactame en tant que principe actif pour la prévention et le traitement de l'ischémie - Google Patents

Compositions pharmaceutiques contenant des dérivés de pyridine de type lactame en tant que principe actif pour la prévention et le traitement de l'ischémie Download PDF

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Publication number
WO2008123756A1
WO2008123756A1 PCT/KR2008/002030 KR2008002030W WO2008123756A1 WO 2008123756 A1 WO2008123756 A1 WO 2008123756A1 KR 2008002030 W KR2008002030 W KR 2008002030W WO 2008123756 A1 WO2008123756 A1 WO 2008123756A1
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WO
WIPO (PCT)
Prior art keywords
compound
dihydro
pyrano
pyridine
ridine
Prior art date
Application number
PCT/KR2008/002030
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English (en)
Inventor
Yong-Baik Cho
Junwon Lee
Jung Bum Yi
Nam Kyu Lee
Bong-Yong Lee
Ki-Chul Hwang
Soyeon Lim
Woochul Chang
Ji Hyung Chung
Byung Ho Lee
Ho Won Seo
Original Assignee
Sk Chemicals Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sk Chemicals Co., Ltd. filed Critical Sk Chemicals Co., Ltd.
Publication of WO2008123756A1 publication Critical patent/WO2008123756A1/fr

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Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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 present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a lactone type pyridine derivative effective in treating ischemic diseases.
  • Ischemic diseases including ischemic stroke and ischemic heart disease are caused by ischemia, which refers to the decrease in blood supply below a threshold value caused by the blocking of the cerebral artery or the coronary artery due to thrombosis or arteriosclerosis.
  • ischemia refers to the decrease in blood supply below a threshold value caused by the blocking of the cerebral artery or the coronary artery due to thrombosis or arteriosclerosis.
  • brain and heart cells are damaged and die, resulting in brain infarction and myocardial infarction.
  • drugs that prevent the damage of cells caused by ischemia or facilitate regeneration thereof can be an ultimate treatment for ischemic brain disease or heart disease.
  • Ischemic heart diseases and cerebrovascular diseases represented by myocardial infarction and stroke, are the first cause of death inside and outside Korea.
  • the drugs currently used for preventing and treating ischemic diseases include beta blockers, nitrates, calcium channel blockers, etc., which prevent the outbreak of ischemic diseases by reducing oxygen demand in the ischemic area or sustain a therapeutic effect after the outbreak, thrombolytic agents, antithrombotic agents, anti-platelet agents, etc., which are used for reperfusion to the ischemic area after the ischemic outbreak, and the like.
  • HSP heat shock proteins
  • adenosine receptor Al adenosine receptor Al
  • the present invention is directed to the control of homeostasis of calcium, which is excessively released from the cytoplasm under ischemic condition and leads to cell death.
  • HSP plays an important role in the control of calcium homeostasis. It is known that calcium is excessively released under ischemic condition. Also, the level of expression of HSP increases under ischemic condition to provide cell-protecting effect. According to a recent report, the excessive release of calcium induces the expression of the HSP27 protein, and the increased expression of HSP70 suppresses the excessive release of calcium. Therefore, it is probable that the exploration of a drug based on the relationship between calcium homeostasis and HSP expression may lead to the development of an ischemic disease treatment of new-concept.
  • an object of the present invention is to provide a new medicinal use of the lactone type pyridine derivatives disclosed in Korean Patent Publication Nos. 2005-69910, 2006-70945 and 2006-110764 and Korean Patent Application No. 2005-127801 and pharmaceutically acceptable salts thereof for preventing and treating ischemic diseases.
  • FIG. 1 shows the confocal microscopic images for evaluating myocardial protecting effect through control of intracellular calcium homeostasis in Example 3;
  • FIG. 2 and FIG. 3 show the photographs illustrating the change of the thickness of ventricular walls in an ischemic animal model in which rats underwent ligation of the distal left anterior descending coronary artery (Example 5) through TTC staining; and FIG. 4 shows the photographs illustrating the change of the thickness of ventricular walls in an ischemic animal model in which rats underwent ligation of the distal left anterior descending coronary artery (Example 5) through H&E staining.
  • the present invention is characterized by a pharmaceutical composition for treating and preventing ischemic disease comprising a lactone type pyridine derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof or a drug prepared therefrom: [Chemical Formula 1 ]
  • miL j mmm represents a single or double bond
  • X is an oxygen or sulfur atom
  • each of R 1 , R 2 , R3, R4 / R5, Re and R7 is independently selected from hydrogen, halo, cyano, nitro, C2-C7 acyl, hydroxy, amino, C 1 -CO alkyl, C3-C9 cycloalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyalkyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 alkoxyalkylamino, Q-C9 cycloalkylamino, C4-C9 heterocycloalkylamino, aryl Ci-C 6 alkylamino, arylamino, heteroaryl Ci-C 6 alkylamino, C2-C7 acylamino, saturated heterocycle, C2-C7 acyloxy
  • X is an oxygen or sulfur atom; and each of Ri, R 2 , R3, R 4 , Rs, R ⁇ , and R7 is independently selected from hydrogen, halo, hydroxy, amino, C 2 -C7 acyl, Q-C7 acyloxy, Ci-C 6 alkyl, C 2 -C 6 alkenyl, Ci-C 6 alkoxy, Ci-C 6 alkoxyalkyl, C3-C9 cycloalkyl, aryl Ci-C 6 alkyl, heteroaryl Ci-C 6 alkyl, saturated heterocyclo Ci-C 6 alkyl, mono(Ci-C 6 alkyl)amino, di(Ci-C 6 alkyl)amino, C 4 -C 9 cycloalkylamino, C 1 -C 6 alkoxyalkylamino, C 4 -C 9 heterocycloalkylamino, aryl Ci-C 6 alkylamino, heteroaryl Ci-C 6 alkylamino, ary
  • Ci-C 6 hydroxyalkyl amino, mono(Ci-C 6 alkyl)amino, di(Ci-Q alkyl)amino and aryl
  • Ci-C 6 alkylamino the aryl is phenyl; and each of the saturated heterocycle and heteroaryl is selected from furan, tetrahydrofuran, pyrrolidine, pyridine, morpholine, oxolane, benzodioxolane, thiophene, thiomorpholine, dioxothiomorpholine, piperidine and piperazine.
  • lactone type pyridine derivative represented by Chemical Formula 1 include:
  • the lactone type pyridine derivative represented by Chemical Formula 1 may form a pharmaceutically acceptable salt with an acid, for example, hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, citric acid, fumaric acid, lactic acid, maleic acid, succinic acid and tartaric acid.
  • the lactone type pyridine derivative represented by Chemical Formula l may form a pharmaceutically acceptable salt by reacting with an alkali metal ion such as sodium, potassium, etc., or an ammonium ion.
  • the pharmaceutical composition of the present invention may comprise, in addition to the lactone type pyridine derivative as an active ingredient, a commonly used nontoxic pharmaceutically acceptable vehicle, adjuvant, excipient, or the like so as to be prepared into preparation forms for oral or parenteral administration common in the pharmaceutical field, for example, tablet, capsule, troche, liquid, suspension, etc.
  • a commonly used nontoxic pharmaceutically acceptable vehicle, adjuvant, excipient, or the like so as to be prepared into preparation forms for oral or parenteral administration common in the pharmaceutical field, for example, tablet, capsule, troche, liquid, suspension, etc.
  • the composition may be prepared into tablet, capsule, solution, syrup, suspension, and the like.
  • parenteral administration it may be prepared into abdominal, subcutaneous, intramuscular or transdermal injection form.
  • the present invention encompasses a method for treating or preventing ischemic diseases comprising administering the compound represented by Chemical Formula 1 to a patient with a therapeutical dose capable of reducing cell death under ischemic condition.
  • the patient refers to a warm-blooded animal or mammal including human suffering from ischemic heart diseases and/ or ischemic cerebrovascular diseases represented by angina pectoris, myocardial infarction, stroke and cerebrovascular dementia.
  • Treatment of a ischemic disease patient means protection of cells and reduction of cell death of the patient.
  • Diagnosis of a patient with an ischemic disease is within the ability and knowledge of those skilled in the art.
  • a clinical doctor skilled in the related art can easily diagnose the disease based on clinical trials, medical checkup, health examination, family history, and the like.
  • the effective dose of the compound represented by Chemical Formula 1 can be easily determined based on the observation of results under similar conditions using common techniques.
  • the effective dose various factors, including but not limited to, constitution, age and general health condition of the patient, degree or severity of the disease, response of the patient, the particular compound to be administered, mode of administration, bioavailability of the administered drug, selected route of administration and presence of jointly administered drug.
  • a general dose for an adult patient whose body weight is 70 kg is 0.01 to 1000 mg/day. Based on the judgment of a doctor or a pharmacist, the dose may be administered once to several times a day at predetermined intervals.
  • the compound represented by Chemical Formula 1 may be administered by any mode or method, including oral and parenteral administration, that makes the compound biologically available at the effective dose.
  • the compound may be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally or rectally.
  • oral administration is preferred.
  • Those skilled in preparing medical preparations can easily select the adequate form and mode of administration, considering the severity of disease or other situations.
  • the compound of the present invention may be administered in the form of a pharmaceutical composition or drug, which is prepared by mixing with a pharmaceutically acceptable vehicle or excipient.
  • a pharmaceutically acceptable vehicle or excipient The mixing ratio and kind of the vehicle or excipient are determined depending on the selected route of administration and in accordance with the general standard pharmaceutical guidance.
  • the pharmaceutical composition or drug is prepared by the methods known to those skilled in the pharmaceutical industry. [Mode for Invention]
  • a 78-mer nucleotide sequence containing three repeating heat shock response elements (HSRE; GAANNTTC), an Nhel site at the 5' end of the DNA sequence and a BgIII site at the 3' end (see the sequence below) and its complementary sequence were prepared.
  • a double helical DNA was prepared by heating at 80 °C for 5 minutes and then annealing at room temperature.
  • the DNA sequence was introduced to a pLUC vector (BD Biosciences, San Jose, CA, USA). After transfection in E. coli DH5 ⁇ and its culture thereof in a liquid medium (LB broth) containing ampicillin, the vector was isolated using a plasmid DNA prep kit (Qiagen, Hilden, Germany). The DNA sequence was identified by sequencing and the resultant vector was named as pHSR3.
  • a 1.5 kb DNA containing neomycin resistance gene ORF, SV40 early promoter, origin and polyA signal was produced by PCR using pcDNA3.1 plasmid (Invitrogen, Carlsbad, CA, USA) as template, and introduced into pHSR3 after BamHI single digestion. After transfection in E. coli DH5 ⁇ and its culture thereof, a new plasmid vector pHSR3-neo was obtained. To prepare an established cell line therefrom, HeLa cells were transfected with lipofectamine (Invitrogen) when they were grown in a Petri dish to 60% to 80% confluent growth.
  • lipofectamine Invitrogen
  • the cells were diluted along with the medium. After transferring to a new Petri dish, the medium was replaced by a medium containing G418. The cells were observed for 3 weeks, while exchanging the medium once in two days. Colonies exhibiting resistance to G418 were observed. The formed colonies were covered with a colony isolator, treated with trypsin and transferred to a 96-well plate, one per each. The cells were cultured using a medium containing G418 for 2 months, gradually transferring to a 24-well plate, to a 6-well plate, and finally to a Petri dish. Each prepared cell line was treated with each compound and was cultured in a CO2 incubator. 24 hours later, luciferase activity was measured using a luciferase activity assay kit (BD Biosciences). The result is given in the following Table 1. [Table 1]
  • cardiac myocytes were isolated from the heart of a newborn rat and then cultured. Experiment was carried out as follows. The ventricular portion was taken from the heart and the red blood cells were removed in PBS (Dulbecco's phosphate-buffered saline solution) (pH 7.4, Gibco BRL). Using micro-dissecting scissors, the heart was minced in 10 mL of collagenase I (0.8 mg/mL, 262 units/ mg, Gibco BRL) solution until the pieces were approximately 1 mm 3 and treated at 37 0 C for 15 minutes.
  • PBS Dulbecco's phosphate-buffered saline solution
  • the supernatant (collagenase I solution) was collected and the remaining tissues were treated with fresh collagenase I solution and left alone at 37 0 C for 15 minutes.
  • the collected supernatant was diluted in ⁇ -MEM (Gibco BRL) containing 10% FBS (fetal bovine serum).
  • FBS fetal bovine serum
  • the diluted supernatant was centrifuged at 1200 rpm, for 4 minutes at room temperature.
  • the precipitated cell pellets were resuspended in ⁇ -MEM medium containing 5 mL of 10% FBS.
  • the above procedure was repeated for about 10 to 15 times until the tissue morphology was changed.
  • the suspended cells were collected and cultured in a 100 mm tissue culture dish for 2 hours at 37 0 C.
  • the cells not adhering to the tissue culture dish were collected again and cultured after being distributed to a 96-well plate at IxIO 4 cells/ well. After culturing for 4 to 6 hours and washing twice with culture medium, 0.1 ⁇ M bromodeoxyuridine (BrdU) was added thereto. The cells were cultured at 37 0 C in a
  • MTT bromide solution 3-(4,5-dimethylthiazol-2- yl)-2,5-diphenyltetrazolium bromide solution (Sigma, St. Louis, MO) was added to each well until the final concentration was 0.5 mg/mL. Then, it was cultured at 37 0 C for 2 hours so as the MTT reaction to occur. The formazan crystal produced in each well was dissolved by adding dimethyl sulfoxide (DMSO) and absorbance was measured at 570 nm using a spectrophotometer. The result is given in the following Table 2. [Table 2]
  • Example 3 Evaluation of effect of myocardial protection through control of calcium homeostasis The level of cytosolic free Ca 2+ was measured by confocal microscopic analysis. Cardiac myocytes of newborn white rats were cultured for 24 hours in a 4- well plate (IxIO 5 cells/ well) coated with 1.5% gelatin, using 10% FBS ⁇ -MEM containing 0.1 ⁇ M BrdU. 24 hours later, the cells were washed twice with serum-free medium, and treated at room temperature with fluo-4 with a final concentration of 2 ⁇ M along with 500 ⁇ L of medium per well. Then, after treating in a 37 0 C incubator for 20 minutes, the cells were washed with PBS and covered with a cover slide after adding PBS to prevent them from drying.
  • Fluorescence images were taken from the light emitted through a 510 to 560 nm bandpass filter, upon activated at 488 nm by argon laser. The relative change of free intracellular Ca 2+ was determined based on the fluorescence intensity. The result is shown in FIG. 1.
  • Example 4 Evaluation of heart protecting effect In order to find out how the test compounds protect the heart from ischemia, anti-ischemic effects were investigated in white rats as follows.
  • mice Male white rats (300 to 450 g, Orient, Seoul, Korea) were anesthetized by injecting sodium pentobarbital (100 mg/kg) intra-abdominally. After intravenous injection of heparin (1000 U/ kg), the heart was collected by ablation. Specifically, a cannula (PE 240) was inserted and artificial respiration was performed using a rodent ventilator. Under that condition, an aortic cannula was inserted in the aorta and the heart was ablated under retrograde perfusion. The extracted heart was hung on Langendorff apparatus quickly and unnecessary tissues on the heart were removed.
  • PE 240 a cannula
  • the left ventricular pressure transmitted through the balloon was transduced by using a pressure transducer, and amplified by using an isovolumetric amplifier (Plugsys bridge amplifier). Then, the pressure was recorded in a recorder (Linearcorder mark 8 WR 3500). Thereafter, the heart was stabilized for 15 minutes. Then, left ventricular end-diastolic pressure (LVEDP) was given by 5 mmHg and such volume of the balloon was kept through the experiments.
  • LVEDP left ventricular end-diastolic pressure
  • LVSP left ventricular peak systolic pressure
  • LVEDP left ventricular end diastolic pressure
  • LVDP left ventricular developed pressure
  • Double product RPP rate-pressure product
  • Total coronary blood flow was measured by the use of a coronary flow probe (diameter: 1.0 mm) installed in the aortic cannula with an electromagnetic flowmeter.
  • Example 5 Activity analysis in an ischemic animal model under ligation of distal left anterior descending coronary artery
  • Myocardial infarction was induced in white rats through ligation of the distal left anterior descending coronary artery.
  • a cannula was inserted into an 8-week-old male Sprague Dawley rat (weighing about 250 g) anesthetized with ketamine (1 mL/rat).
  • Positive pressure circulation 180 mL/min was maintained using a
  • lactone type pyridine derivative represented by Chemical Formula 1 according to the present invention showed excellent HSP expression controlling and cardiac myocyte protecting activities, excellent myocardial protection activity through control of intracellular calcium homeostasis,

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

Composition pharmaceutique contenant un dérivé de pyridine de type lactame pour la prévention et le traitement de pathologies ischémiques, et plus particulièrement une composition pharmaceutique destinée à la prévention et au traitement de pathologies ischémiques contenant comme principe actif un dérivé de pyridine de type lactame ou un sel de qualité pharmaceutique de cette composition, laquelle a un effet cytoprotecteur supérieur, assure une homéostasie du calcium et intervient dans la régulation de l'expression HSP (protéine de choc thermique).
PCT/KR2008/002030 2007-04-10 2008-04-10 Compositions pharmaceutiques contenant des dérivés de pyridine de type lactame en tant que principe actif pour la prévention et le traitement de l'ischémie WO2008123756A1 (fr)

Applications Claiming Priority (2)

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KR10-2007-0035075 2007-04-10
KR1020070035075A KR20080091949A (ko) 2007-04-10 2007-04-10 락톤형 피리딘 화합물을 포함하는 허혈성 질환의 예방 및치료용 약학조성물

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013112788A1 (fr) 2012-01-26 2013-08-01 Ptc Therapeutics, Inc. Composés destinés à traiter l'amyotrophie spinale
WO2018136918A1 (fr) 2017-01-23 2018-07-26 Cadent Therapeutics, Inc. Procédés de traitement de tremblements par modulation positive de canaux sk

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034244A1 (fr) * 1998-12-04 2000-06-15 Bristol-Myers Squibb Company Derives 3-substitues de 4-arylquinolin-2-one utilises comme modulateurs des canaux potassiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000034244A1 (fr) * 1998-12-04 2000-06-15 Bristol-Myers Squibb Company Derives 3-substitues de 4-arylquinolin-2-one utilises comme modulateurs des canaux potassiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
VAN ALLAN J.A. ET AL.: "Reactions of some pyranylideniminium salts with amines II", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 9, no. 6, 1972, pages 1245 - 1249 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013112788A1 (fr) 2012-01-26 2013-08-01 Ptc Therapeutics, Inc. Composés destinés à traiter l'amyotrophie spinale
EP2809322A1 (fr) * 2012-01-26 2014-12-10 PTC Therapeutics, Inc. Composés destinés à traiter l'amyotrophie spinale
JP2015511224A (ja) * 2012-01-26 2015-04-16 ピーティーシー セラピューティクス， インコーポレイテッド 脊髄性筋萎縮症を治療するための化合物
EP2809322A4 (fr) * 2012-01-26 2015-12-23 Ptc Therapeutics Inc Composés destinés à traiter l'amyotrophie spinale
US9399649B2 (en) 2012-01-26 2016-07-26 Ptc Therapeutics, Inc. Compounds for treating spinal muscular atrophy
WO2018136918A1 (fr) 2017-01-23 2018-07-26 Cadent Therapeutics, Inc. Procédés de traitement de tremblements par modulation positive de canaux sk

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