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WO2018101762A1 - Composition pharmaceutique de prévention ou de traitement d'une lésion rénale aiguë ischémique, comprenant un dérivé tricyclique ou un sel pharmaceutiquement acceptable de ce dernier - Google Patents

Composition pharmaceutique de prévention ou de traitement d'une lésion rénale aiguë ischémique, comprenant un dérivé tricyclique ou un sel pharmaceutiquement acceptable de ce dernier Download PDF

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Publication number
WO2018101762A1
WO2018101762A1 PCT/KR2017/013891 KR2017013891W WO2018101762A1 WO 2018101762 A1 WO2018101762 A1 WO 2018101762A1 KR 2017013891 W KR2017013891 W KR 2017013891W WO 2018101762 A1 WO2018101762 A1 WO 2018101762A1
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Prior art keywords
ischemic acute
pharmaceutically acceptable
tetrahydrobenzo
acute renal
acceptable salt
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English (en)
Korean (ko)
Inventor
허우성
장혜련
고재욱
김정렬
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Samsung Life Public Welfare Foundation
Jeil Pharmaceutical Co Ltd
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Samsung Life Public Welfare Foundation
Jeil Pharmaceutical Co Ltd
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Priority to KR1020197015719A priority Critical patent/KR102450649B1/ko
Publication of WO2018101762A1 publication Critical patent/WO2018101762A1/fr
Anticipated expiration legal-status Critical
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
    • 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
    • A61K31/4375—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 nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to a pharmaceutical composition for treating or preventing ischemic acute renal injury, delayed graft function (DGF), or a method for treating the ischemic acute renal injury, including a tricyclic derivative or a pharmaceutically acceptable salt thereof.
  • DGF delayed graft function
  • the lack of oxygen is called ischemia.
  • Ischemia irreversibly damages cells and leads to necrosis of tissues.
  • the brain or heart are the most sensitive body organs that are sensitive to a lack of blood supply.
  • ischemic cascades are triggered, resulting in a permanent tissue. Is damaged.
  • reperfusion the reflow of blood flow after ischemia is called reperfusion.
  • Ischemic acute renal injury is a result of sustained decline in renal perfusion to the kidney resulting in ischemic damage to the renal tubule, which is the most important and common type of acute renal injury.
  • Ischemic acute renal injury is not only the most common type of acute renal injury occurring in normal kidneys, but also causes delayed graft function (DGF) in recipients of kidney transplantation and It is known to decrease the long-term survival rate of the transplant graft by increasing the risk of development.
  • DGF delayed graft function
  • ischemic acute renal injury After finding that the main mechanism of ischemic acute renal injury is an immunological inflammatory response, there are a number of treatments that either deplete or inhibit the function of major immune cells or inhibit the infiltration of major immune cells into the kidney after ischemia. Attempts have been made, but no clinical effects have been found. In the early stage of renal impairment of ischemic acute renal impairment, the damaged tubules themselves in the renal tissue after ischemia stimulate the immune system to promote the inflammatory response, thus initially suppressing the immune system stimulation by damaged tubule cells If so, it is possible to effectively suppress the progression of renal injury by the subsequent immunological inflammatory response.
  • ischemic acute renal injury Although much research has been done on the mechanism of the development of ischemic acute renal injury, the treatment of ischemic acute renal injury relies on conservative treatment and dialysis treatment since there are no specific therapeutic agents that can be used clinically in both normal kidney and transplant. Considering that the immunological inflammatory response is the main pathophysiology of developing and progressing ischemic acute renal injury, it is necessary to develop therapeutics that can block this inflammatory response. It is known that the expression of PARP (poly ADP ribose polymerase) is increased by ischemia and inflammation in renal tissues. Thus, a specific substance that can reduce PARP's stimulation of the immune system and subsequent inflammatory response is a treatment for ischemic acute renal injury. Can be used.
  • PARP poly ADP ribose polymerase
  • PARP promotes the production of poly (ADP-ribose) polymers from the substrate NAD + (nicotinamide adenine dinucleotide) and is activated by DNA damage. Overactivation of PARP following severe DNA damage results in a decrease in the amount of NAD + in the cell, depletion of ATP due to NAD + resynthesis, and as a result of this process necrosis of the cell.
  • PARP is a large family of 18 proteins encoded by different genes. The well-known members are PARP-1, PARP-2, PARP-3, vPARP (PARP-4) and tankyrase 1 (PARP- 5a) and tankyrase 2 (PARP-5b).
  • PARP-1 is an enzyme in the nucleus, which accounts for more than 85% of the maximum activated PARP activity, and accounts for 97% of the brain's poly (ADP-ribose) production. Its activity is reported to increase up to 500-fold. Depending on the type of cell and the extent of DNA damage, PARP-1 is involved in DNA repair, and overexpression of PARP-1 leads to NAD + and ATP depletion, promoting cell death.
  • the present inventors have been studying the prevention and treatment of ischemic acute renal injury, and tricyclic derivatives or pharmaceutically acceptable salts thereof can selectively inhibit PARP, thereby improving blood creatinine level that is increased during ischemic acute renal injury. It was confirmed that the present invention was completed.
  • an object of the present invention is to provide a pharmaceutical composition for preventing or treating ischemic acute renal injury, and thus induced retardation of transplant renal function, including a tricyclic derivative or a pharmaceutically acceptable salt thereof, and a method of treating the same. .
  • the present invention provides a pharmaceutical composition for preventing or treating ischemic acute renal injury, including a tricyclic derivative or a pharmaceutically acceptable salt thereof.
  • the present invention also provides 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one dihydrochloride or It provides a pharmaceutical composition for preventing or treating ischemic acute renal injury, including a pharmaceutically acceptable salt thereof.
  • the present invention also provides a pharmaceutical composition for preventing or treating delayed graft function (DGF) comprising a tricyclic derivative or a pharmaceutically acceptable salt thereof.
  • DGF delayed graft function
  • the present invention also provides 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one dihydrochloride or Provided is a pharmaceutical composition for preventing or treating delayed graft function (DGF) including a pharmaceutically acceptable salt thereof.
  • DGF delayed graft function
  • the present invention provides a food composition for preventing or ameliorating ischemic acute renal injury comprising a tricyclic derivative or a pharmaceutically acceptable salt thereof.
  • the present invention also provides 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one dihydrochloride or It provides a food composition for preventing or ameliorating ischemic acute renal injury, including a pharmaceutically acceptable salt thereof.
  • the present invention also provides a method for treating ischemic acute renal injury individuals comprising treating a tricyclic derivative or a pharmaceutically acceptable salt thereof; It provides a method for treating ischemic acute kidney injury comprising a.
  • the present invention also provides 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one dihydrochloride or Treating the ischemic acute renal impairment subject thereof with a pharmaceutically acceptable salt thereof; It provides a method for treating ischemic acute kidney injury comprising a.
  • Tricyclic derivatives of the invention preferably 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H) -On dihydrochloride or a pharmaceutically acceptable salt thereof specifically inhibits PARP with an inhibitor of PARP, thereby directly causing the autotubule cells damaged by reperfusion injury to promote the immunological inflammatory response and thereby advance renal damage. It can be suppressed at the source without immunosuppression, and the absorption rate of oral administration is not only good, but also can be administered even in a state in which the renal function is mainly metabolized to the liver, and thus can be more useful in clinical use.
  • FIG. 1 is a diagram showing the results obtained by measuring blood urea nitrogen and plasma creatinine in the ischemic acute renal injury mouse model (* P ⁇ 0.05).
  • FIG. 2 is a diagram showing the results obtained by measuring blood urea nitrogen and plasma creatinine in the ischemic acute renal injury mouse model (* P ⁇ 0.05, ** P ⁇ 0.01, *** P ⁇ 0.001) ).
  • Figure 3 is a diagram showing the results confirmed by measuring the blood creatinine JPI-289 50mg / kg, 100mg / kg administration effect in the ischemic acute renal injury mouse model (* P ⁇ 0.05).
  • the present invention provides a pharmaceutical composition for preventing or treating ischemic acute renal injury, which comprises a tricyclic derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof:
  • Y 1 , Y 2 and Y 3 are each independently H, C 1 -C 10 straight or branched chain alkyl, hydroxy, C 1 -C 10 alkoxy, -COOR 1 , -NR 2 R 3 or -AB;
  • A is —O—, —CH 2 —, —CH (CH 3 ) —, —CH ⁇ N— or —CONH—;
  • B is-(CH 2 ) n 1 -Z,-(CH 2 ) n 2 -NR 2 R 3 or-(CH 2 ) n 3 -OR 1 ;
  • Z is unsubstituted, or R 5 and optionally R a by a 6-substituted C 5 ⁇ aryl of C 7, unsubstituted or R 5 and optionally substituted C of 3 ⁇ C 10 cycloalkyl by R 6, or unsubstituted Or a C 5 to C 7 heterocyclic compound comprising at least one heteroatom selected from the group consisting of R 5 and optionally N, O and S substituted by R 6 in the ring;
  • R 1 is H or C 1 to C 10 straight or branched alkyl
  • R 2 and R 3 are each independently H, C 1 to C 10 straight or branched chain alkyl, or — (CH 2 ) n 4 R 7 ;
  • R 5 is a H, C 1 ⁇ C 10 straight-chain or branched alkyl, C 5 ⁇ C 7 aryl, or N, O and C 5 ⁇ including my S ring one or more heteroatoms selected from the group consisting of C 7 of the Heterocyclic compounds;
  • R 6 is H or C 1 to C 10 straight or branched alkyl
  • R 7 is —NR 8 R 9 , —COOR 1 , —OR 1 , —CF 3 , —CN, halogen or Z;
  • R 8 and R 9 are each independently H or C 1 to C 10 straight or branched alkyl
  • n 1 to n 4 are each an integer of 0 to 15;
  • Y 4 is a straight or branched chain alkyl of H or C 1 ⁇ C 10.
  • Y 1 and Y 2 are each independently H, C 1 -C 5 straight or branched alkyl, hydroxy, C 1 -C 5 alkoxy, -COOR 1 , -NR 2 R 3 or -AB;
  • A is —O—, —CH 2 —, —CH (CH 3 ) —, —CH ⁇ N— or —CONH—;
  • B is-(CH 2 ) n 1 -Z,-(CH 2 ) n 2 -NR 2 R 3 or-(CH 2 ) n 3 -OR 1 ;
  • Z is one group selected from the group consisting of the following structural formulas
  • R 1 is H or C 1 to C 5 straight or branched alkyl
  • R 2 and R 3 are each independently H, C 1 to C 5 straight or branched chain alkyl, or — (CH 2 ) n 4 R 7 ;
  • R 5 is H, C 1 to C 5 straight or branched alkyl, phenyl or morpholino
  • R 6 is H or C 1 to C 5 straight or branched alkyl
  • R 7 is —NR 8 R 9 , -COOR 1 , -OR 1 , -CF 3 , -CN, F, Cl or Z;
  • R 8 and R 9 are each independently H or C 1 to C 5 linear or branched alkyl
  • n 1 to n 4 are each an integer of 0 to 10;
  • Y 3 is H, hydroxy, C 1 -C 5 alkoxy or —O (CH 2 ) n 3 —OR 1 ;
  • Y 4 is H or C 1 to C 5 straight or branched alkyl.
  • Y 1 and Y 2 are each independently H, methyl, ethyl, hydroxy, methoxy, ethoxy, -COOR 1 , -NR 2 R 3, or -AB;
  • B is-(CH 2 ) n 1 -Z,-(CH 2 ) n 2 -NR 2 R 3 or-(CH 2 ) n 3 -OR 1 ;
  • Z is one group selected from the group consisting of the following structural formulas
  • R 1 is H, methyl, ethyl or isopropyl
  • R 2 and R 3 are each independently H, methyl, ethyl, propyl, isopropyl, t-butyl or-(CH 2 ) n 4 R 7 ;
  • R 5 is H, methyl, ethyl, propyl, phenyl or morpholino
  • R 6 is H, methyl or ethyl
  • R 7 is —NR 8 R 9 , -COOR 1 , -OR 1 , -CF 3 , -CN, F, Cl or Z;
  • R 8 and R 9 are each independently H or methyl
  • n 1 to n 4 are each an integer of 0 to 5;
  • Y 3 is H, hydroxy, methoxy, ethoxy, propoxy or methoxyethoxy
  • Y 4 is H, methyl, ethyl or propyl.
  • Preferred compounds among the tricyclic derivatives of the general formula (I) of the present invention are specifically as follows:
  • KR 10-0968175 may be incorporated herein by reference.
  • JPI-289 of the present invention can be represented by the following formula (2).
  • the tricyclic derivatives or pharmaceutically acceptable salts thereof of the present invention specifically inhibit PARP, thereby directly immunosuppressing autologous tubule cells damaged by reperfusion injury to promote an immunological inflammatory response and progress renal damage. Since it is inherently suppressed without immunosuppression, it is possible to effectively suppress ischemic acute renal injury and graft rejection.
  • the "ischemic acute renal injury" of the present invention is caused by a sustained decrease in renal perfusion to the kidney, resulting in ischemic injury of the renal tubule, which is the most important cause and type of acute renal injury.
  • Ischemic acute renal injury is not only the most common type of acute renal injury in the native kidney, but also causes delayed graft function (DGF) in recipients undergoing kidney transplantation. Increased risk of graft rejection may eventually reduce long-term survival of the graft.
  • DGF delayed graft function
  • the tricyclic derivatives of the present invention can exert unlimited effects on a variety of ischemic acute renal injury, but in particular prevent or prevent ischemic acute renal injury by ischemia and reperfusion. It can be cured.
  • the tricyclic derivatives of the present invention can prevent or treat ischemic acute renal injury due to cold ischemic or warm ischemic.
  • ischemic acute renal injury due to cold ischemia means ischemic acute renal injury caused by the storage of kidneys taken from a donor during renal transplantation in storage, and "ischemic acute renal injury due to warm ischemia”. Ischemic acute renal injury that occurs in the process of anastomosis and reperfusion of blood vessels. Such ischemia-reperfusion injury may result in delayed graft function (DGF) of the renal allograft and may increase the risk of acute and chronic rejection.
  • DGF delayed graft function
  • the tricyclic derivatives of the present invention can inhibit such acute renal injury due to cold ischemia or warm ischemia without limitation, and in particular, DPQ, previously reported as a therapeutic agent for ischemic renal injury, is exclusively used for cold ischemia.
  • DPQ previously reported as a therapeutic agent for ischemic renal injury
  • JPI-289 or a pharmaceutically acceptable salt thereof may exhibit a therapeutic effect on ischemic acute renal injury caused by warm ischemia. It can be used for more ischemic acute renal injury.
  • the ischemic acute renal injury may be an ischemic acute renal injury of a kidney transplant patient.
  • the ischemic acute renal injury of a kidney transplant patient of the present invention may be an ischemic acute renal injury, particularly in the case of transplantation of a brain-derived or kidney-derived kidney from a donor that causes higher ischemia-reperfusion injury during renal transplantation.
  • Donors with any brain death that are not limited to the cause of brain death may include, but are not limited to, for example, donors with brain death due to traumatic injuries, strokes, cerebrovascular causes, more preferably between 55 and 59 years old with high blood pressure, Brain death may include patients with cerebrovascular disease or the last creatinine of 1.5 mg / dL or more prior to extraction.
  • the older donor may be at least 60 years old, preferably 60 to 80 years old, more preferably 60 to 70 years old.
  • a donor providing a graft for use in the renal transplantation of the present invention may be an extended category donor, which is a donor whose age is 60 years or older or 55 to 59 years old and is associated with cerebral vascular disease or excision before the cause of hypertension, brain death. It is the case that two or more of the patients with last creatinine 1.5 mg / dL or more.
  • the tricyclic derivatives of the present invention preferably JPI-289 or pharmaceutically acceptable salts thereof, prevent or treat ischemic acute renal injury, thereby preventing or treating delayed graft function (DGF). It can be used for the purpose.
  • DGF delayed graft function
  • Delayed graft renal function refers to a phenomenon caused by a recipient who has received a kidney transplant, which means that the transplanted kidney does not function or is delayed after renal transplantation, and may be used interchangeably with transplant renal failure.
  • Delayed graft renal function may typically include symptoms such as acute graft necrosis of the graft. Transplant renal acute tubular necrosis may occur because graft renal function may be stopped or reduced, the urine volume is reduced, blood creatinine levels are increased, electrolyte failure, pulmonary edema, anemia and systemic edema may be caused. This delay in graft renal function adversely affects both the long-term and short-term prognosis of the graft and can lead to a decrease in the long-term renal survival of allografts.
  • the tricyclic derivatives of the present invention can significantly reduce blood urea nitrogen and plasma creatinine concentrations in an ischemic acute renal injury model that occurs at the time of transplantation. It can be seen that effective delay can be treated.
  • the tricyclic derivatives of the present invention can prevent or treat ischemic acute renal injury occurring at any time, but are preferably early, more preferred.
  • ischemic acute renal injury can be rapidly restored by acting on an ischemic acute renal injury that occurs very early from immediately after the ischemic acute renal injury to 10 days, preferably immediately after the occurrence of about 7 days.
  • the tricyclic derivative of the present invention preferably JPI-289 or a pharmaceutically acceptable salt thereof, can act very effectively on early ischemic acute renal injury, and thus can be used as a surgical aid for surgery that can cause ischemic acute renal injury.
  • Surgery that can cause ischemic acute renal injury may be, but is not limited to, surgery for severe cardiovascular disease, more preferably open heart surgery or aortic surgery or surgery, or kidney tissue. It may be partial nephrectomy or nephron saving surgery.
  • the tricyclic derivatives of the present invention are preferably used as surgical aids for one or more surgical treatments selected from the group consisting of open heart surgery, aortic surgery and partial nephrectomy surgery. It may be utilized and may be used for preoperative, intraoperative, or postoperative treatment.
  • Ischemic acute renal injury can be prepared for acute renal injury, and if treated during surgery, ischemic acute renal injury, which may occur during the procedure at the same time as the surgery, and if treated after surgery, ischemic acute renal disease that may occur after surgery is completed. Damage, more preferably early ischemic acute renal injury.
  • the tricyclic derivatives of the invention may be poly ADP ribose polymerase (PARP) specific inhibitors.
  • PARP poly ADP ribose polymerase
  • PARP may be overexpressed in ischemic acute renal injury due to ischemia-reperfusion injury, and tricyclic derivatives of the present invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof, inhibit PARP overexpression by inhibiting such overexpression of PARP. It can effectively alleviate the stimulation of the immune system and thereby the inflammatory response.
  • the tricyclic derivatives of the invention preferably JPI-289 or pharmaceutically acceptable salts thereof, can selectively inhibit PARP and in particular have good enzyme inhibitory capacity against PAPR-1 or PARP-2.
  • the tricyclic derivatives of the invention are neural tubules impaired by ischemia-reperfusion injury as specific inhibitors to PARP, preferably PAPR-1 or PARP-2. Since the cells themselves inhibit the progression of renal damage by promoting an immunological inflammatory response, without direct immunosuppression, there is a preventive or therapeutic effect of ischemic acute renal injury. In addition, there is no genetic toxicity, can be repeated long-term administration, oral administration absorption is good and can be administered even in a state where the renal function is mainly metabolized by the liver, it can be effectively used for the prevention or treatment of ischemic acute renal injury. In particular, by preventing and treating graft delay caused by ischemic acute renal injury in the graft, the risk of graft rejection can be lowered to increase the long-term survival of the graft.
  • PARP preferably PAPR-1 or PARP-2.
  • the present invention also provides a pharmaceutical composition for preventing or treating delayed graft function (DGF) comprising the tricyclic derivative of the present invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof.
  • DGF delayed graft function
  • the tricyclic derivatives of the invention act as specific inhibitors to PARP, preferably PAPR-1 or PARP-2 to effectively prevent transplant renal intelligence delay, Improve or cure.
  • composition according to the present invention may further include additional ingredients, ie, pharmaceutically acceptable or nutritionally acceptable carriers, excipients, diluents or subcomponents depending on the dosage form, the method of use and the purpose of use, in addition to the active ingredient. .
  • the composition may be added to the active ingredient in addition to nutrients, vitamins, electrolytes, flavors, coloring agents, fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH regulators, stabilizers, It may further contain a preservative, glycerin, alcohol, carbonation agent used in the carbonated beverage.
  • the carrier excipient and diluent
  • all conventional ones can be used, for example, 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, calcium carbonate, dextrin, propylene glycol, liquid Paraffin may be one or more selected from the group consisting of saline, but is not limited thereto. Said components may be added independently or in combination to the active ingredient, ie the tricyclic derivative of the invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention is selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories It can have any one formulation.
  • composition of the present invention can be administered to a subject by various routes.
  • the composition of the present invention can be administered intravenously, intraperitoneally, intramuscularly, intraarterally, orally, intracardiac, intramedullary, intradural, transdermal, enteric, subcutaneous, sublingual or topical, but is not limited thereto.
  • JPI-289 has a good oral absorption absorption, so it can be preferably administered orally or directly to the surgical site.
  • Therapeutically effective dosages of the pharmaceutical compositions of the invention will vary depending on the species, weight, age and individual condition of the subject, the disorder or disease being treated, or their severity.
  • the daily dosage of the composition of the present invention is 35 to 1800 mg, preferably 450 to 900 mg, based on the amount of the tricyclic derivative of the present invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof, per day It may be administered 1-2 times, the dosage does not in any way limit the scope of the invention.
  • the present invention also provides a food composition for preventing or ameliorating ischemic acute renal injury, including the tricyclic derivative of the present invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof.
  • the term food composition of the present invention may be used interchangeably with health functional food, and may be provided as a health functional food composition by mixing with a foodstuff acceptable carrier.
  • the tricyclic derivative, preferably JPI-289 or a pharmaceutically acceptable salt thereof is preferably included in a weight ratio of 0.01 to 99.99% with respect to the whole nutraceutical composition, but is not limited thereto.
  • the active ingredient of the present invention When used as a food or beverage additive, the active ingredient may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method.
  • the mixed amount of the active ingredient can be determined by appropriately adjusting the purpose of use (prevention, health or therapeutic treatment).
  • the health functional food composition of the present invention can be taken for a long time because there is no problem in terms of safety.
  • the type of dietary supplement There is no particular limitation on the type of dietary supplement.
  • foods to which the substance may be added include beverages, vitamin complexes, health supplement powders, granules, tablets, capsules, pills, suspensions, emulsions, syrups, tea bags, leach teas, and health beverages.
  • the liquid component added in addition to the nutraceutical composition is not limited, but may include various flavors or natural carbohydrates, etc. as additional ingredients, as in general beverages.
  • the above-mentioned natural carbohydrates include conventional monosaccharides (e.g. glucose, fructose, etc.), disaccharides (e.g.
  • maltose, sucrose, etc. and polysaccharides (e.g., dextrins, cyclodextrins, etc.).
  • Phosphorous sugar and sugar alcohols such as xylitol, sorbitol, and erythritol.
  • the proportion of such natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the composition of the present invention.
  • natural flavoring agents taumarin, stevia extract
  • synthetic flavoring agents for example, saccharin, aspartame, etc.
  • the health functional food composition of the present invention is a variety of nutrients, vitamins, minerals (electrolytes), flavors such as synthetic and natural flavors, colorants and enhancers (such as cheese, chocolate), pectic acid and salts thereof, organic acids, protection Sex colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks and the like.
  • the health functional food composition of the present invention may contain a pulp for the production of fruit and vegetable drinks. These components may be used alone or in combination, and the proportion of such additives is generally selected in the range of 0.001 to 50 parts by weight per total weight of the composition.
  • the present invention also provides a method for treating ischemic acute renal injury individuals comprising treating a tricyclic derivative of the present invention or a pharmaceutically acceptable salt thereof; It provides a method for treating ischemic acute kidney injury comprising a.
  • the tricyclic derivative or pharmaceutically acceptable salt thereof may preferably be JPI-289 or a pharmaceutically acceptable salt thereof.
  • the tricyclic derivatives of the present invention can be used as an adjuvant in various surgeries causing ischemic acute renal injury, for example consisting of open heart surgery, aortic surgery and partial nephrectomy surgery. It can be used for the prevention or treatment of ischemic acute renal injury caused by one or more surgery selected from the group.
  • tricyclic derivatives of the invention preferably JPI-289 or a pharmaceutically acceptable salt thereof, are to be treated for ischemic acute renal injury caused by surgery, they may be administered without limitation before, during or after surgery. Can be.
  • the subject to be administered is preferably a mammal including a human, and any potential patient group suffering from, suffering from, or potentially suffering from ischemic acute renal injury may be included.
  • the tricyclic derivative, preferably JPI-289 or a pharmaceutically acceptable salt thereof, may be delivered in a pharmaceutically effective amount to the subject to be administered.
  • IRI Ischemic-reperfusion injury surgery
  • BUN Blood urea nitrogen
  • plasma creatinine which are major functional indices of renal injury
  • JPI-289 has an effect of alleviating early renal injury in an ischemic acute renal injury model.
  • the rodent efficacy test was further performed to confirm the ischemic acute renal injury alleviation effect of JPI-289 identified in Example 1.1 according to the dose. Similar to Example 1.1, the mouse (C57BL / 6 9-week-old male) was ligated on both sides of the newspaper for 29 minutes to induce ischemia / reperfusion injury (IRI), immediately before reperfusion (D0) and 24 hours (D1), 48 hours (D2). ), Test substance (JPI-289) or saline IP was administered at 72 hours (D3) and plasma creatinine was measured over 72 hours.
  • IRI ischemia / reperfusion injury
  • D0 immediately before reperfusion
  • D1 24 hours
  • D2 48 hours
  • Test substance JPI-289
  • saline IP was administered at 72 hours (D3) and plasma creatinine was measured over 72 hours.
  • the warm IRI rodent model was used to determine whether JPI-289 has a direct protective effect on ischemic acute renal injury during ischemia-reperfusion surgery.
  • FIG. 3 The results of measuring the blood creatinine concentration in each experimental group are shown in FIG. 3 and Table 2.
  • FIG. 3 The results of measuring the blood creatinine concentration in each experimental group are shown in FIG. 3 and Table 2.
  • HK-2 cells proximal tubular cell line derived from normal kidney
  • HK-2 cells were distributed from ATCC and used. HK-2 cells distributed from ATCC were cultured using serum free keratinocyte medium (GIBCO # 17005-042) according to the ATCC manual, and replaced with DMEM (10% FBS) medium at the time of the present experiment. Cells were used for passages 5-6, when passaged 70-80% confluence, it was passaged using 1x Trypsin-EDTA in PBS.
  • HK-2 cells were seeded at 1.5 ⁇ 10 3 cells / well in 96-well plates, 1.5 in 6-well plates for cell counting, cell morphology and Ki-67 immunofluorescence staining. It was inoculated with x10 4 cells / well. Cell inoculation and this experiment were performed using DMEM (10% FBS) medium.
  • JPI-289 was dissolved in PBS to make a 1 mg / mL stock, diluted with a concentration of 0.1 mg / mL using DMEM (10% FBS) medium, filtered and sterilized with a 0.22 ⁇ m syringe filter. Dilutions were added to each well to concentrations of 0, 5, 10, 20 ⁇ g / mL.
  • the experimental group was divided into a pre-treatment group and a post-treatment group.
  • Prior treatment group added JPI-289 to a dilution of 0, 5, 10, 20 ⁇ g / mL before inducing hypoxia damage for 48 hours, with a 96-well plate at 200 ⁇ L / Wells and 6-well plates were added at 2 mL / well.
  • the later treatment group added a small amount of 0.1 mg / mL JPI-289 stock to each well to a final concentration of 0, 5, 10, 20 ⁇ g / mL immediately after inducing hypoxic damage for 48 hours.
  • Hypoxia treatment was performed in a multi-gas incubator for 48 hours at 37 ° C., 5% CO 2 , 1% O 2 .
  • the cells were transferred to a CO 2 cell incubator (37 ° C., 5% CO 2 ) and cultured from day 1 to day 3 (24h, 48h, 72h) under normal oxygen (normoxia) and observed for cell changes. It was.
  • each well of the 6-well plate was washed with PBS and the cells were detached with 1 ⁇ Trypsin-EDTA.
  • a 15 mL conical tube central tube
  • 1 mL of medium was added, and measured using trypan blue dye.
  • the number of cells in the 10 ⁇ g / mL JPI-289 treatment group was slightly higher than that in the normal oxygen control group at day 0 (immediately after the cells were removed from the incubator), and the hypoxic control group in the 5 ⁇ g / mL and 10 ⁇ g / mL treatment groups. It confirmed that there were more cell numbers.
  • normal oxygen control 0.8 ⁇ 10 5 ; JPI-289 0 ⁇ g / mL (hypoxia control) 0.55 ⁇ 10 5 ; JPI-289 5 ⁇ g / mL 0.75 x 10 5; JPI-289 10 ⁇ g / mL 0.9 ⁇ 10 5 ; JPI-289 20 ⁇ g / mL 0.55 x 10 5 .
  • This effect seen on Day 0, showed the same pattern in the cell proliferation experiment.
  • JPI-289 was administered in the late treatment group, and all of the groups treated with JPI-289 on day 1 had higher cell proliferation and increased the number of cells compared to the hypoxic control group. It was confirmed. Specifically, normal oxygen control (normoxia) 1.40 x 10 5 ; JPI-289 0 ⁇ g / mL (hypoxia control, hypoxia control) 1.05 ⁇ 10 5 ; JPI-289 5 ⁇ g / mL 1.30 ⁇ 10 5 ; JPI-289 10 ⁇ g / mL 1.65 ⁇ 10 5 ; JPI-289 20 ⁇ g / mL 1.60 x 10 5 .

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Abstract

La présente invention concerne : une composition pharmaceutique de prévention ou de traitement d'une lésion rénale aiguë ischémique et d'une fonction de greffe retardée (DGF), comprenant un dérivé tricyclique ou un sel pharmaceutiquement acceptable de ce dernier ; ou un procédé de traitement de la lésion rénale aiguë ischémique et du DGF. Le dérivé tricyclique de la présente invention, de préférence un dichlorhydrate de 10-éthoxy-8-(morpholinométhyl)-1,2,3,4-tétrahydrobenzo[h][1,6]naphtyridin-5(6H)-one ou un sel pharmaceutiquement acceptable de ce dernier, inhibe plus particulièrement, en tant qu'inhibiteur de PARP, la PARP, permettant ainsi l'inhibition essentielle, sans immunosuppression directe, de la progression d'une lésion rénale provoquée par la promotion de réponse inflammatoire immunitaire de cellules tubulaires rénales elles-mêmes, qui ont été endommagées par une lésion de reperfusion, possédant un excellent taux d'absorption d'administration orale, et étant apte à être administré même en cas de détérioration de la fonction rénale du fait qu'il est principalement métabolisé dans le foie, et peut donc être cliniquement avantageux.
PCT/KR2017/013891 2016-12-01 2017-11-30 Composition pharmaceutique de prévention ou de traitement d'une lésion rénale aiguë ischémique, comprenant un dérivé tricyclique ou un sel pharmaceutiquement acceptable de ce dernier Ceased WO2018101762A1 (fr)

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WO2021020612A1 (fr) * 2019-07-29 2021-02-04 제일약품주식회사 Méthode de traitement d'accident vasculaire cérébral à l'aide d'un dérivé tricyclique
KR20220149268A (ko) * 2021-04-30 2022-11-08 주식회사 온코크로스 트리사이클로 유도체 화합물을 포함하는 대사질환 예방 또는 치료용 조성물

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