WO2018101762A1 - Pharmaceutical composition for preventing or treating ischemic acute kidney injury, containing tricyclic derivative or pharmaceutically acceptable salt thereof - Google Patents

Abstract

The present invention relates to: a pharmaceutical composition for preventing or treating ischemic acute kidney injury and delayed graft function (DGF), containing a tricyclic derivative or a pharmaceutically acceptable salt thereof; or a method for treating the ischemic acute kidney injury and DGF. The tricyclic derivative of the present invention, preferably, 10-ethoxy-8-(morpholinomethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridin-5(6H)-one dihydrochloride or a pharmaceutically acceptable salt thereof specifically inhibits, as a PARP inhibitor, PARP, thereby enabling the progress of kidney injury caused by the immune inflammatory response promotion of renal tubule cells themselves, which have been damaged by reperfusion injury, to be fundamentally inhibited without direct immunosuppression, having an excellent oral administration absorption rate, and being administrable even when renal function has deteriorated by being mainly metabolized in the liver, and thus can be more clinically useful.

Description

A pharmaceutical composition for preventing or treating ischemic acute renal injury, comprising a tricyclic derivative or a pharmaceutically acceptable salt thereof

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.

Blood carries oxygen or nutrients to each tissue or cell of the body, and blood supply is insufficient due to narrowing or contraction of blood vessels that supply blood to body organs, tissues or parts, or normal blood vessel formation. The lack of oxygen is called ischemia. Ischemia irreversibly damages cells and leads to necrosis of tissues. In particular, the brain or heart are the most sensitive body organs that are sensitive to a lack of blood supply. For example, when ischemia occurs in a tissue due to a stroke or head injury, a series of processes called ischemic cascades are triggered, resulting in a permanent tissue. Is damaged. In order to prevent such tissue damage, the reflow of blood flow after ischemia is called reperfusion.

Conventional treatment for ischemia and thus hypoxia is to restore blood flow and oxygen delivery to normal levels by increasing systemic oxygenation or eliminating the cause of vascular blockage. However, there is a problem that, as blood flow and oxygen delivery are restored, additional cell death or loss of function is caused irrespective of the damage caused by ischemia or hypoxia. Additional damage caused by restoration of blood flow and oxygen delivery is known as reperfusion injury.

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.

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.

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 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). Among these, 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.

Currently known PARP inhibitors are 3-AB (3-aminobenzamide), DPQ, PJ34 and the like. Although 3-AB has been shown to have partial nephroprotective effects in renal perfusion injury experiments in renal tubular cells or in rodents, it is not a selective PARP inhibitor and affects intracellular purine metabolism, such as patients with compromised immunity. In the case of accompanying disorders, it is reported that toxicity can be suppressed by inhibiting the production of DNA purine, which has limitations that cannot be introduced into the current clinical practice. In addition, 3-AB did not report a pronounced dose-response effect. Another PARP inhibitor, DPQ, has been reported to have a very limited effect on cold ischemia-reperfusion injury (IRI), which occurs during storage of kidneys prior to kidney transplantation.

Therefore, it is possible to selectively inhibit PARP, and it is applied to the clinic where the neural tubule cells damaged by reperfusion injury can inhibit the progression of renal damage by promoting the immunological inflammatory response without any direct immunosuppression. There is a need for research on possible PARP inhibitors.

Accordingly, 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.

Accordingly, 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. .

It is also an object of the present invention to provide a food composition for preventing or ameliorating ischemic acute renal injury comprising a tricyclic derivative or a pharmaceutically acceptable salt thereof.

In order to achieve the above object, 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.

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.

In another aspect, 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.

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).

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).

Hereinafter, the present invention will be described in detail.

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:

[Formula 1]

(In Formula 1,

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;

Wherein 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.)

Preferably

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;

Wherein 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.

More preferably

Y ¹ and Y ² are each independently H, methyl, ethyl, hydroxy, methoxy, ethoxy, -COOR ¹ , -NR ² R ^3, or -AB;

Wherein A is 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, 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:

1) 8-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

2) 10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

3) 9-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

4) 9-methyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

5) ethyl 5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridine-9-carboxylate;

6) 9-methoxy-1-propyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

7) 1-methyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

8) 9-methoxy-1-methyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

9) 1-ethyl-9-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

10) 1-methyl-9-hydroxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

11) 9- (1-propylpiperidin-4-yloxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

12) 9- (1-methylpiperidin-4-yloxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

13) 1-methyl-9- (piperidin-4-yloxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

14) 1-methyl-9- (1-methylpiperidin-4-yloxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one ;

15) 5-oxo-N- [2- (piperidin-1-yl) ethyl] -1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridine-9 Carboxamides;

16) 9- [2- (dimethylamino) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

17) 9- [2- (piperidin-1-yl) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

18) 9- (2-methoxyethoxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

19) 9- [2- (piperazin-1-yl) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

20) 9-ethoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

21) 9- [3- (piperidin-1-yl) propoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

22) 9- (2-aminoethoxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

23) 9- [2- (4-phenylpiperidin-1-yl) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H)- On;

24) 9- (2-hydroxyethoxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

25) 9-phenethoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

26) 9- [2- (diethylamino) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

27) 9- (2-morpholinoethoxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

28) 1,1-diethyl-4- [2- (5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-9-yloxy] Ethyl) piperazine-1-yene;

29) 9- [4- (piperidin-1-yl) butoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

30) 1-methyl-9- [2- (piperidin-1-yl) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H) -On;

31) 9- [2- (dimethylamino) ethyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

32) 8- [2- (dimethylamino) ethoxy] -1,2,3,4, -tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

33) 9- [3- (dimethylamino) propyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

34) 8- [2- (dimethylamino) ethoxy] -1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridine-9-carboxamide;

35) 8- [2- (piperidin-1-yl) ethoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

36) 8- [3- (dimethylamino) propoxy] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

37) 8- (dimethylamino) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

38) 8- [1- (dimethylamino) ethyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

39) 8- [1- (methylamino) ethyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

40) 8-ethyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

41) 8-[(dimethylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

42) 8-[(diethylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

43) 8-[(ethylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

44) 8- (pyrrolidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

45) 8-[(isopropylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

46) 8-[(propylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

47) 8-{[ethyl (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

48) 8- (piperidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

49) 8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

50) 9-[(dimethylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

51) 8-{[benzyl (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

52) 8-[(methylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

53) 8-{[(2-hydroxyethyl) (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

54) 8-{[(2- (dimethylaminoethyl) (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one ;

55) 8-[(4-methylpiperazin-1-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1, 6] naphthyridin-5 (6H) -one;

56) 8-[(methyl (propyl) amino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1, 6] naphthyridin-5 (6H) -one;

57) ethyl-3- {methyl [(5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-8-yl) methyl] amino} propano Eight;

58) 3- {methyl [(5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-8-yl) methyl] amino} propanoic acid;

59) 8-{[isopropyl (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

60) 8-{[(2-methoxyethyl) (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

61) ethyl-3-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-8-yl) methylamino] propanoate;

62) 8-[(2,2,2-trifluoroethylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

63) 2-[(5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-8-yl) methylamino] acetonitrile;

64) 8-[(1H-imidazol-1-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

65) 8-[(1H-pyrrol-1-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

66) 8-[(dimethylamino) methyl] -1-methyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

67) 1-methyl-8- (pyrrolidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

68) 8-[(diethylamino) methyl] -1-methyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

69) 1-methyl-8- (piperidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

70) 1-methyl-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

71) 8-{[ethyl (methyl) amino] methyl} -1-methyl-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

72) 8-[(dimethylamino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

73) 10-methoxy-8-[(methylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

74) 10-methoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

75) 8-[(ethylamino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

76) 8-{[ethyl (methyl) amino] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

77) 10-methoxy-8- (pyrrolidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

78) 10-methoxy-8-[(4-oxopiperidin-1-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H )-On;

79) 8-{[4- (hydroxyimino) piperidin-1-yl] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine -5 (6H) -one;

80) 10-methoxy-8-[(4- (methoxyimino) piperidin-1-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine -5 (6H) -one;

81) 10-methoxy-8-{[(2-methoxyethyl) (methyl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 ( 6H) -one;

82) 8-[(2,5-dihydro-1H-pyrrol-1-yl) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine -5 (6H) -one;

83) 8-{[(2-isopropoxyethyl) (methyl) amino] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H) -one;

84) 10-methoxy-8- (piperidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

85) 8-{[(2-chloroethyl) (methyl) amino] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H )-On;

86) 8-[(diethylamino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

87) 8-[(t-butylamino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

88) 8-[(isopropylamino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

89) 8-[(cyclopentylamino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

90) 8-[(2,6-dimethylmorpholino) methyl] -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H)- On;

91) N-[(10-methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-8-yl) methyl] -N, N-dimethylcyclopentanemininium chloride;

92) 8-{[cyclopentyl (methyl) amino] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

93) 8-{[isopropyl (methyl) amino] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

94) 8-{[(2-fluoroethyl) (methyl) amino] methyl} -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 ( 6H) -one;

95) 8-[(1H-tetrazol-5-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

96) 10-methoxy-8-[(morpholinoamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

97) 10-methoxy-8-{[methyl (morpholino) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one ;

98) (E) -10-methoxy-8-[(morpholinoidino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H)- On;

99) 8-[(dimethylamino) methyl] -10-hydroxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5- (6H) -one;

100) 8-[(dimethylamino) methyl] -10-ethoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

101) 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

102) 10-ethoxy-8- (piperidin-1-ylmethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

103) 10-ethoxy-8-[(methylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

104) 10-ethoxy-8-[(ethylamino) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

105) 8- (hydroxymethyl) -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

106) 10-methoxy-8- (thiomorpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

107) 10-methoxy-8-[(2-morpholinoethylamino) methyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one ;

108) 10-methoxy-8-[(4-morpholinopiperidin-1-yl) methyl] -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 ( 6H) -one;

109) 8- (aminomethyl) -10-methoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

110) 8-[(dimethylamino) methyl)]-10-propoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

111) 8- (morpholinomethyl) -10-propoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

112) 8- (aminomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

113) 8- (aminomethyl) -10-ethoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

114) 8- (aminomethyl) -10-propoxy-1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one;

115) 10-methoxy-8-{[methyl (tetrahydro-2H-pyran-4-yl) amino] methyl} -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine -5 (6H) -one;

116) 8-[(dimethylamino) methyl] -10- (2-methoxyethoxy) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H)- On;

117) 10- (2-methoxyethoxy) -8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one ; And

118) 1-[(10-methoxy-5-oxo-1,2,3,4,5,6-hexahydrobenzo [h] [1,6] naphthyridin-8-yl) methylamino] -1H -Pyrrole-2,5-dione.

  For the tricyclic derivatives or pharmaceutically acceptable salts thereof of the present invention, KR 10-0968175 may be incorporated herein by reference.

JPI-289 of the present invention can be represented by the following formula (2).

[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.

The tricyclic derivatives of the present invention, preferably JPI-289 or pharmaceutically acceptable salts thereof, 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.

In addition, the tricyclic derivatives of the present invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof, 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. The tricyclic derivatives of the present invention, preferably JPI-289, 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. Unlike only the effects on ischemic acute renal injury caused by the tricyclic derivative of the present invention, preferably 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.

Also in the present invention, 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. For example, 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.

In addition, 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.

"Delayed graft renal function" of the present invention 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, preferably JPI-289 or a pharmaceutically acceptable salt thereof, 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, preferably JPI-289 or pharmaceutically acceptable salts thereof, can prevent or treat ischemic acute renal injury occurring at any time, but are preferably early, more preferred. Preferably, 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. have. 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.

Thus, the tricyclic derivatives of the present invention, preferably JPI-289 or pharmaceutically acceptable salts thereof, 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.

When treated preoperatively, for example ischemic by ischemia-reperfusion by treating the subject with a tricyclic derivative of the invention, preferably JPI-289 or a pharmaceutically acceptable salt thereof, in advance prior to open heart surgery, aortic surgery and partial resection surgery. 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, preferably JPI-289 or pharmaceutically acceptable salts thereof, may be poly ADP ribose polymerase (PARP) specific inhibitors.

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. In particular 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.

Thus the tricyclic derivatives of the invention, preferably JPI-289 or pharmaceutically acceptable salts thereof, 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.

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.

The tricyclic derivatives of the invention, preferably JPI-289 or pharmaceutically acceptable salts thereof, act as specific inhibitors to PARP, preferably PAPR-1 or PARP-2 to effectively prevent transplant renal intelligence delay, Improve or cure.

The pharmaceutical 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. .

More specifically, 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.

As 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.

The pharmaceutical composition of the present invention can be administered to a subject by various routes. For example, 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.

When the active ingredient of the present invention is 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).

In the case of long-term intake for the purpose of health and hygiene or health control, 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.

There is no particular limitation on the type of dietary supplement. Examples of 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. When formulated as a beverage, 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. Examples of 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. As flavoring agents other than those mentioned above, natural flavoring agents (taumarin, stevia extract) and synthetic flavoring agents (for example, saccharin, aspartame, etc.) can be used.

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. In addition, 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, preferably JPI-289 or pharmaceutically acceptable salts thereof, 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.

If 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.

In the present invention, 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.

Description of other treatment methods follows the description in the pharmaceutical composition and is omitted in order to avoid complexity of excessive description on the specification.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.

Example  1. Ischemic acute Kidney damage  In mouse model JPI Confirmation of Dose of 289

1.1 Ischemic Acute Kidney damage  Establish a mouse model

Ischemic-reperfusion injury surgery (IRI) was performed to establish an ischemic acute renal injury mouse model. Specifically, 7 weeks old B57BL / 6 mice collected one week before surgery were anesthetized by intraperitoneal injection of ketamine and xylazine. After shaving the abdomen of the mouse widely, the abdomen was opened by a central line incision on an operating table where body temperature was kept constant at 37 ° C. The bilateral renal hilum was incised and then clamped with micro vascular clamps. To maintain body temperature and moisture, 1 mL of warm sterile saline solution was administered intraperitoneally, covered with sterile gauze, and observed until a defined ischemia time. After all defined ischemia time had elapsed, the clamps were removed from both sides. To maintain body temperature and moisture, 1 mL of warm sterile saline solution was administered again intraperitoneally and sutured.

The prepared mice were used as a control group (n = 13), and JPI-289 (10-ethoxy-8) of the present invention immediately after starting ischemia induction by blocking renal perfusion during ischemia-reperfusion injury surgery as described above and 24 hours after surgery. 10 mg / kg of-(morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridin-5 (6H) -one dihydrochloride) were administered to mice and It was set as an experimental group (n = 14).

Blood urea nitrogen (BUN) and plasma creatinine, which are major functional indices of renal injury, were measured in the control and experimental mice, and the results are shown in FIG. 1.

The same experiment was performed once more by changing the person in charge of the operation (control n = 4, experimental group n = 5), and the results are shown in FIG. 2.

1 and 2, when JPI-289 was administered, it was confirmed that blood urea nitrogen and plasma creatinine concentrations were significantly lower until the 1 to 3 days after ischemia-reperfusion injury surgery compared to the control group.

Therefore, it was confirmed that JPI-289 has an effect of alleviating early renal injury in an ischemic acute renal injury model.

1.2 JPI -289 Confirmation of the Dosing Effect by Dose

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. In this study, 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. The population used in this experiment is shown in Table 1 below.

	Control	50 mg / kg	100 mg / kg	Sum
1st experiment	4*	3 * †	6	13
2nd experiment	6	7	3	16
Sum	10	10	9	29

* Number except 2 (1 control group, 1 50 mg / kg group)

† Number except one individual infarction

The results of measuring the blood creatinine concentration in each experimental group are shown in FIG. 3 and Table 2. FIG.

Mean ± Standard Deviation	Before dosing (D0)	24h (D1)	48h (D2)	72h (D3)
Control	0.475 ± 0.0815	2.062 ± 0.410	1.852 ± 0.716	1.352 ± 0.460
50 mg / kg	0.525 ± 0.106	1.617 ± 0.371	1.307 ± 0.599	0.974 ± 0.413
100 mg / kg	0.453 ± 0.104	1.172 ± 0.471	0.971 ± 0.497	0.741 ± 0.271

As shown in Figure 3 and Table 2 JPI-289 50 mg / kg or 100 mg / kg treated group was confirmed that the plasma creatinine concentration is significantly lower than the control group. After the statistical analysis of the repeated measurement data using the mixed effect model, Bonferroni correction was performed for comparison between groups, and Dunnett correction was used for comparison between points in time. As a result, the baseline value (D0) was similar, but after 24 hours, the measured values were different among the three experimental groups, and Bonferroni correction showed that the 100 mg / kg and 50 mg / kg groups showed significant differences from the control group. Confirmed. In addition, the 100 mg / kg group was different from the control group at all time points, such as D1, D2, D3, 50 mg / kg group was different from the control group at D2, D3 time points.

These experiments and their results using a warm ischemia-reperfusion injury (IRI) rodent ischemic acute renal injury model showed that JPI-289 had a prophylactic and therapeutic effect of ischemic acute renal injury in both low and high dose regimens. to be. In addition, when the low dose (50 mg / kg) and the high dose (100 mg / kg) administration groups were compared, a clearer improvement in renal function was observed in the high dose group.In the dose range used in the experiment, JPI was used in renal damage caused by ischemic reperfusion injury. It was confirmed that -289 may show a dose dependent protective effect.

Example  2. In human kidney cells JPI Check the effect of -289

Cell proliferation to induce hypoxic damage in HK-2 cells (proximal tubular cell line derived from normal kidney) and to determine the effect of JPI-289 on hypoxic damage. A proliferation assay was performed.

2-1. Cell culture

In order to confirm the effect of JPI-289 on HK-2 cells, 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.

2-2. Cell inoculation

For cell proliferation, 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.

2-3. JPI Preparation of -289

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 μm syringe filter. Dilutions were added to each well to concentrations of 0, 5, 10, 20 μg / mL.

2-4. Experimental group  And hypoxic treatment

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 μg / mL before inducing hypoxia damage for 48 hours, with a 96-well plate at 200 μL / 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 μg / 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 . Immediately after 48 hours of hypoxic treatment, 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.

2-5. Proliferation assay

Immediately before the onset of hypoxic injury, 48 hours immediately after hypoxic injury, the cell proliferation of each group was measured at 24 hours, 48 hours, and 72 hours under normal oxygen.

For cytostatic experiments, media and cell residue in each well of a 96-well plate were removed and fresh DMEM (10% FBS) medium was added at 100 μL / well. 20 μL of Cell Titer 96 solution was added and then incubated in a CO ₂ incubator for 3 hours. Then, 25 μL of 10% SDS solution was added to each well to stop the reaction, and the OD value was read at absorbance at 490 nm.

2-6. Cell counting and cell morphology observation

To determine the cell number, each well of the 6-well plate was washed with PBS and the cells were detached with 1 × Trypsin-EDTA. In a 15 mL conical tube (central tube) was centrifuged at 1500 rpm for 5 minutes, 1 mL of medium was added, and measured using trypan blue dye.

Cell morphology observation was carried out using light microscopy of the cells in each well of the 6-well plate.

As a result, the number of cells in the 10 μg / 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 μg / mL and 10 μg / mL treatment groups. It confirmed that there were more cell numbers. Specifically, normal oxygen control (normoxia) 0.8 × 10 ⁵ ; JPI-289 0 μg / mL (hypoxia control) 0.55 × 10 ⁵ ; JPI-289 5 μg / mL 0.75 x 10 5; JPI-289 10 μg / mL 0.9 × 10 ⁵ ; JPI-289 20 μg / mL 0.55 x 10 ⁵ . This effect, seen on Day 0, showed the same pattern in the cell proliferation experiment.

In addition, after the treatment of DPI (immediately after the end of hypoxia treatment), 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 μg / mL (hypoxia control, hypoxia control) 1.05 × 10 ⁵ ; JPI-289 5 μg / mL 1.30 × 10 ⁵ ; JPI-289 10 μg / mL 1.65 × 10 ⁵ ; JPI-289 20 μg / mL 1.60 x 10 ⁵ .

Claims (20)

1. A pharmaceutical composition for preventing or treating ischemic acute renal injury comprising a tricyclic derivative represented by the following Chemical Formula 1 or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   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;

   Wherein 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 R ⁵ and optionally R ⁶ a N, O or heterocyclic compound containing a C ₅ ~ C ₇ S in the ring one or more heteroatoms selected from the group consisting of which is substituted by a;

   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 compound;

   R ⁶ is H or C ₁ ~ 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 H or C ₁ to C ₁₀ linear or branched alkyl.)
2. The compound of claim 1, wherein the tricyclic derivative is 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1,6] naphthyridine-5 (6H ) -On dihydrochloride, characterized in that the ischemic acute renal injury prevention or treatment pharmaceutical composition.
3. The pharmaceutical composition according to claim 1 or 2, wherein the ischemic acute renal injury is renal injury due to ischemia and reperfusion.
4. The pharmaceutical composition according to claim 1 or 2, wherein the ischemic acute renal injury is caused by cold ischemic or warm ischemic.
5. The pharmaceutical composition according to claim 1 or 2, wherein the ischemic acute renal injury is ischemic acute renal injury of a kidney transplant patient.
6. 6. The pharmaceutical composition of claim 5, wherein the kidney is a brain lion or kidney derived from an aged donor of 60 to 80 years old.
7. The pharmaceutical composition according to claim 1 or 2, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is for preventing or treating delayed graft function (DGF).
8. The pharmaceutical composition of claim 1 or 2, wherein the ischemic acute renal injury is an initial ischemic acute renal injury that occurs within 1 to 10 days of ischemic acute renal injury.
9. The pharmaceutical according to claim 1 or 2, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is for treatment in at least one surgery selected from the group consisting of open heart surgery, aortic surgery and partial nephrectomy surgery. Composition.
10. 10. The pharmaceutical composition of claim 9, wherein the treatment is for preoperative, intraoperative or postoperative treatment.
11. The pharmaceutical composition according to claim 1 or 2, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is a poly ADP ribose polymerase (PARP) specific inhibitor.
12. The pharmaceutical composition of claim 11, wherein the PARP is PARP-1 or PARP-2.
13. A pharmaceutical composition for preventing or treating delayed graft function (DGF) comprising the tricyclic derivative of claim 1 or a pharmaceutically acceptable salt thereof.
14. The method of claim 13, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1, 6] Naphthyridine-5 (6H) -on dihydrochloride pharmaceutical composition for preventing or treating renal transplant delay.
15. A food composition for preventing or ameliorating ischemic acute kidney injury, comprising the tricyclic derivative of claim 1 or a pharmaceutically acceptable salt thereof.
16. The method of claim 15, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1, 6] A food composition for preventing or ameliorating ischemic acute renal injury, which is naphthyridin-5 (6H) -one dihydrochloride.
17. Treating the ischemic acute renal impairment subject with the tricyclic derivative of claim 1 or a pharmaceutically acceptable salt thereof; Ischemic acute renal injury treatment method comprising a.
18. 18. The method of claim 17, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is 10-ethoxy-8- (morpholinomethyl) -1,2,3,4-tetrahydrobenzo [h] [1, 6] A method for treating ischemic acute renal injury, characterized in that it is naphthyridin-5 (6H) -one dihydrochloride.
19. 18. The method of claim 17, wherein the ischemic acute renal injury is caused by one or more operations selected from the group consisting of open heart surgery, aortic surgery and partial nephrectomy surgery.
20. 20. The method of claim 19, wherein the tricyclic derivative or pharmaceutically acceptable salt thereof is administered before, during or after surgery.

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