WO2024141925A1 - Compositions for preventing and treating renal failure (rf) - Google Patents

Compositions for preventing and treating renal failure (rf) Download PDF

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Publication number
WO2024141925A1
WO2024141925A1 PCT/IB2023/063232 IB2023063232W WO2024141925A1 WO 2024141925 A1 WO2024141925 A1 WO 2024141925A1 IB 2023063232 W IB2023063232 W IB 2023063232W WO 2024141925 A1 WO2024141925 A1 WO 2024141925A1
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Prior art keywords
alkyl
aryl
renal failure
heteroaryl
compound
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PCT/IB2023/063232
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French (fr)
Inventor
Ju Hee Lee
Beom Seob Lee
Yeong Su Jang
Seo-Yeon KO
Jiyeon KANG
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Chong Kun Dang Pharmaceutical Corp.
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Abstract

The present invention relates to a pharmaceutical composition for preventing and treating renal failure, including a compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient, a method for preventing and treating renal failure using the compound, a use of the compound for preventing and treating renal failure, and a use of the compound in preparing a medicament for preventing and treating renal failure.

Description

Specification
Title
COMPOSITIONS FOR PREVENTING AND TREATING RENAL FAILURE (RF)
Technical Field
The present disclosure relates to a pharmaceutical composition for preventing and treating renal failure, including a compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient, a method for preventing and treating renal failure using the compound, a use of the compound for preventing and treating renal failure, and a use of the compound in preparing a medicament for preventing and treating renal failure.
Background
Renal failure (RF) may be classified into acute renal failure (also called acute kidney injury) and chronic renal failure (also called chronic kidney disease) in a state in which the function of the kidney is not properly performed.
Acute renal failure has many causes, which may be divided into three types. First, there is no problem with the kidney itself, but there are cases where the blood supply to the kidneys is reduced due to the overall body function decline. Second, there are cases in which urine cannot be produced due to abnormalities in the kidney itself, and finally urinary tract and bladder, from which urine is excreted, are blocked. Chronic renal failure is caused by polycystic kidney disease, glomerulonephritis, diabetes, high blood pressure, etc., and refers to a continuous decline in kidney function for at least three months. Chronic renal failure is divided into five stages depending on the degree of kidney damage and functional decline. If not managed properly, chronic renal failure deteriorates to end-stage renal failure. The treatment of renal failure is to prevent renal diseases which cause continuous deterioration in renal function and to reduce an incidence rate of end-stage renal failure by lowering a rate of disease progression, if there is the onset of chronic deterioration in renal function. To treat causative diseases of renal failure, therapeutic agents for high blood pressure or diabetes are used, but there are many cases in which an original disease cannot be identified because the disease has already been severely progressed a lot (Lancet 2012; 379: 165-180, Kidney Int 2012; 81 : 351-362).
Therefore, there is no appropriate treatment for renal failure. Since steroids and immunosuppressive drugs may cause decrease in the function of the renal, there are high unmet medical needs, for the development of novel drugs which are capable of preventing and treating renal failure.
Prior Art Reference
Patent Documents
(Patent Document 1) Korean Unexamined Patent Publication No. 10-2017-0017792 Non-Patent Documents
(Non-Patent Document 1) Qing Hou et al., Front Pharmacol. 2022 Jull4; 13:938391 (Non-Patent Document 2) Seung Seob Son et al., Sci Rep. 2021 Jan 26; 11(1):2191 (Non-Patent Document 3) Xingying Chen et al., Am J PhysiolRenal Physiol. 2020 Dec Description of the Invention Technical Problem
The present disclosure may provide a pharmaceutical composition for preventing and treating renal failure, containing a compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient. The present disclosure may provide a method for preventing and treating renal failure, including administering the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual.
The present disclosure may provide a use of the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing and treating renal failure.
The present disclosure may provide a use of the compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating renal failure.
Technical Solution
This is described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be also applied to other descriptions and embodiments thereof, respectively. In other words, every combination of various elements disclosed in the present invention falls within the scope of the present invention. Also, it cannot be seen that the scope of the present invention is limited to the specific description described below.
The present disclosure may provide a pharmaceutical composition for preventing and treating renal failure (RF), containing a compound represented by formula I below, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.
[Formula
Figure imgf000005_0001
In Formula I, wherein Li, L2 or L3 are each independently a bond or -(C1-C2 alkylene)-;
Ri is -CX2H or -CX3;
Figure imgf000006_0001
substituted with -X, -OH, -O(Ci-C4 alkyl), -NRDRE, -(C1-C4 alkyl), -CF3, -CF2H, -CN, -aryl, - heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl, [wherein at least one H of the -aryl, - heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl may be substituted with -X, -OH, -CF3 or -CF2H]};
R3 is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl,
Figure imgf000006_0002
{wherein, at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, at least one H of -aryl or -heteroaryl each independently may be substituted with -X, - OH, -O(Ci-C4 alkyl), -OCF3, -O-aryl, -NRDRE, -(C1-C4 alkyl), -CF3, -CF2H, -C(=O)-(Ci-C4 alkyl), alkyl), aryl, heteroaryl,
Figure imgf000006_0003
Figure imgf000006_0004
[wherein, at least one H of
Figure imgf000007_0003
,
(C1-C4 alkyl)};
Yi, Y2 and Y4 are each independently -CH2-, -NRF-, -O-, -C(=O)- or -S(=O)2-;
Y3 is -CH- or -N-;
Zi to Z4 are each independently N or CRZ, {wherein at least three of Zi to Z4 may not be simultaneously N, and Rz is -H, -X or -O(Ci-C4 alkyl)};
Z5 and Ze are each independently -CH2- or -O-;
Z7 and Zx are each independently =CH- or =N-;
Z9 is -NRG- or -S-;
RA and RB are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NRDRE, -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl)
Figure imgf000007_0001
least one H of the -(C1-C4 alkyl), -(C1-C4 alkyl)-OH or -(C1-C4 alkyl)-NRDRE may be substituted with -X, at least one H of the -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, - (C3-C7 cycloalkyl) or -(C2-C6 heterocycloalkyl) may be substituted with -X, -OH, -O(Ci-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H or -CN, at least one
Figure imgf000007_0002
may be substituted with -X, -OH, -O(Ci-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H, -CN, -(C2-C6 heterocycloalkyl), -aryl, -(C1-C4 alkyl)-aryl, - heteroaryl or -heteroaryl-(Ci-C4 alkyl)}; Rc is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl {wherein, at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, at least one H of - aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl may be substituted with -X, -OH, -CF3 or -CF2H};
RD and RE are each independently -H, -(C1-C4 alkyl), -aryl or -(C1-C4 alkyl)-aryl {wherein, at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, at least one H of - aryl or -(C1-C4 alkyl)-aryl may be substituted with -X, -OH, -CF3 or -CF2H};
RF is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(Ci-C4 alkyl), -C(=O)-(Ci- C4 alkyl), -C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-NRDRE, - S(=O)2-(Ci-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)- heteroaryl, -C(=O)-(C3-C? cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-Ce heterocycloalkyl)
{wherein, at least one H of -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(Ci-C4 alkyl), -C(=O)-(Ci-C4 alkyl), -C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4 alkyl), -(Ci- C4 alkyl)-NRDRE or -S(=O)2-(Ci-C4 alkyl) may be substituted with -X, at least one H of -aryl, -(Ci-C4alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C? cycloalkyl), -C2-C6 heterocycloalkyl or -(Ci-C4alkyl)-C(=O)- (C2-C6heterocycloalkyl) may be substituted with -X, -OH, -CF3 or -CF2H};
RG is -H or -(C1-C4 alkyl);
Q is -O- or a bond;
Figure imgf000008_0001
is a single bond or double bond {provided that, is a double bond, Yi is =CH-{; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that, a and b may not be simultaneously 0, and c and d may not be simultaneously 0};
X is each independently F, Cl, Br or I.
In the pharmaceutical composition according to the present disclosure, the compound represented by formula I may be below:
Li, L2 or L3 are each independently a bond or -(Ci-C2alkylene)-;
Ri is -CX2H or -CX3;
Figure imgf000009_0001
may be substituted with -X, -OH, -NRDRE, -(C1-C4 alkyl)};
R3 is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl,
Figure imgf000009_0002
Figure imgf000009_0003
{wherein at least one H of -aryl or -heteroaryl may be each independently substituted with -X, -O(Ci-C4alkyl), -OCF3, -O-aryl, -NRDRE, -(C1-C4 alkyl), -CF3, -S(=O)2-(Ci-C4alkyl), -
Figure imgf000009_0004
Figure imgf000009_0005
maybe each independently substituted with -(C1-C4 alkyl)};
Yi, Y2 and Y4 are each independently -CH2-, -NRF-, -O-, -C(=O)- or -S(=O)2-;
Y3 is -CH- or -N-;
Zi to Z4 is each independently N or CRZ {wherein at least three of Zi to Z4 may not be simultaneously N, and Rz is -H, -X or -O(Ci-C4 alkyl)}; Ls and Ze are each independently -CH2- or -O-;
Z7 and Zx are each independently =CH- or =N-;
Z9 is -NRG- or -S-;
RA and RB are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-NRDRE, -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl)
Figure imgf000010_0001
{wherein at least one
Figure imgf000010_0002
may be substituted with -X, -(Ci-
C4alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl or heteroaryl-(Ci-C4 alkyl)};
Rc is -(C1-C4 alkyl) or -aryl;
RD and RE are each independently -H, -(Ci-C4alkyl) or -(C1-C4 alkyl)-aryl;
RF is -H, -(Ci-Cealkyl), -(Ci-C4alkyl)-OH, -(C1-C4 alkyl)-O-(Ci-C4 alkyl), -C(=O)-(Ci- C4alkyl), -C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4alkyl), -(Ci-C4alkyl)-NRDRE, - S(=O)2-(Ci-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)- heteroaryl, -C(=O)-(C3-C? cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-Ce heterocycloalkyl)
{wherein at least one H of -(Ci-C4alkyl) or -C(=O)-O(Ci-C4alkyl) may be substituted with -X, at least one H of -aryl may be substituted with -X};
RG is -(C1-C4 alkyl);
Q is -O- or a bond; is a single bond or a double bond {provided that is a double bond, Yi is -CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b may not be simultaneously 0, and c and d may not be simultaneously 0};
X is each independently F, Cl, Br or I. In the pharmaceutical composition according to the present disclosure, the compound represented by the formula I may be the compound represented by formula la:
[Formula la]
Figure imgf000011_0001
R3 is -aryl {wherein at least one H of -aryl may be each independently substituted with -X};
Yi is -O- or -S(=O)2-;
Zi is N or CRZ {wherein Rzis -X}; a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein a and b may not be simultaneously 0};
X is each independently F, Cl, Br or I.
In the pharmaceutical composition according to the present disclosure, the compound represented by formula la may be below:
Figure imgf000011_0002
R3 is -phenyl {wherein at least one H of -phenyl each independently may be substituted with -F or -Cl};
Yi is -O- or -S(=O)2-;
Zi is N or CF.
In the pharmaceutical composition according to the present disclosure, the compounds represented by formula I may be shown in Table A below:
[Table A]
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
According to the present disclosure, a pharmaceutical composition containing a compound in the above Table A (compound 1 to 450), optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient may prevent and treat renal failure.
In the pharmaceutical composition according to the disclosure, the compounds represented by formula I may be shown in Table B below:
[Table B]
Figure imgf000041_0001
According to the present disclosure, a pharmaceutical composition containing a compound in the above Table B (compounds 40, 43, 239, 285, 295, and/or 296), optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient may prevent and treat renal failure.
In the present disclosure, the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may be prepared by a method disclosed in Korean Unexamined Patent Application Publication No. 10-2017-0017792, but is not limited thereto.
In the pharmaceutical composition according to the present disclosure, the compound represented by the above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may contain at least one asymmetric carbon, and thus may be present as a racemic mixture, a single enantiomer (optical isomer), a mixture of diastereomers, and a single diastereomer. Such isomer may be separated by being split according to the prior art, for example, column chromatography, HPLC or the like. Alternatively, the isomer may be stereospecifically synthesized with a known array of optically pure starting materials and/or reagents. Particularly, said isomer may be an optical isomer (enantiomer).
In the present disclosure, the term “pharmaceutically acceptable” may refer to the one which is physiologically acceptable and does not conventionally cause gastrointestinal disturbance, an allergic response such as dizziness or other responses similar thereto, when being administered to an individual.
The pharmaceutically acceptable salts according to the embodiments of the present invention may be prepared by a conventional method known to those skilled in the art.
The pharmaceutically acceptable salts according to the embodiment of the present invention may include, for example, inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, etc.; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene sulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but are not limited thereto. In the embodiments of the present invention, salts may include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, tartaric acid or a mixture thereof.
As used herein, "renal failure (RF)" refers to a state in which the function of the kidneys to filter unnecessary waste products from the blood and to properly maintain the concentration of water and electrolyte levels in the body are reduced or lost.
Renal failure may be divided into two categories: acute renal failure and chronic renal failure. Acute renal failure refers to a disease condition which has problem in excreting waste products out of the body due to a rapid decline in kidney function, resulting in the accumulation of uremic toxins and an imbalance of water and electrolytes. Chronic renal failure refers to a disease condition which has damage in renal tissue and decreased renal function for at least three months.
The causes of acute renal failure may include low blood pressure, urethral obstruction, specific drugs, muscle degradation, hemolytic uremic syndrome, etc., while the causes of chronic renal failure may include diabetes, high blood pressure, nephrotic syndrome, polycystic kidney disease, etc.
In the embodiments of the present invention, renal failure may be caused by various causes and thus is not limited thereto.
In the embodiments of the present invention, in order to evaluate the effects of the compound according to the present disclosure on preventing and treating renal failure, a chronic renal failure model, in which metabolic products accumulate in the kidney through adenine diet so as to cause a malfunction in the function thereof, was used, but the renal failure of the present invention is not limited thereto.
In embodiments of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure on preventing and treating renal failure, a relative fibrosis region and a tubulointerstitial fibrosis score for evaluating renal fibrosis were selected, but the evaluation of renal fibrosis is not limited thereto.
In embodiments of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure on preventing and treating renal failure, a glomerulosclerosis (GS) index for evaluating kidney diseases was selected, but the evaluation of kidney diseases is not limited thereto.
In the embodiments of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure on preventing and treating renal failure, an increase in the acetylation of the tubulin protein has been confirmed, but is not limited thereto.
In the embodiments of the present invention, in order to confirm the effect of the compound of formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure on preventing and treating renal failure, change in the expression of collagen type I alpha 1 (COL1A1) for evaluating the fibrosis of the kidney were selected, but are not limited thereto.
In the embodiments of the present invention, in order to confirm the effects of the compound of formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure on preventing and treating renal failure, change in concentration of blood urea nitrogen (BUN) were selected for renal function but kidney function evaluation is not limited thereto.
As used herein, the term “prevention” may refer to all the acts, which inhibit or delay the occurrence of a renal failure disease by administering the compound of formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure.
As used herein, the term “treatment” may refer to all the acts, by which a symptom of an individual having a suspected renal failure disease and having the disease developed gets better or takes a favorable turn by administering the compound of formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof to the present disclosure; all the acts, by which a symptom of an individual having a suspected renal failure disease and having the disease developed does not further deteriorate; and all the acts capable of stopping or delaying the progression of renal failure.
In the present disclosure, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may have an effect on preventing and treating renal failure.
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may have an effect on preventing and treating acute renal failure and/or chronic renal failure.
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may have an effect on preventing and treating a decreased or impaired kidney function due to chronic renal failure.
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may delay or inhibit the progression of renal failure. For example, the pharmaceutical composition according to an embodiment of the present invention may inhibit or delay renal failure from progressing to end-stage renal failure as much as possible, may prevent a patient from undergoing dialysis or renal transplantation, or may delay the rate, at which renal failure reaches such a state.
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may have an effect on preventing and treating renal fibrosis due to chronic renal failure.
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may ameliorate renal fibrosis, may delay or inhibit the progression of renal fibrosis, and may slow down the rate of renal fibrosis.
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may exhibit a pharmacological effect due to the TGF- p/SMAD mechanism in relation to chronic renal failure, but is not limited thereto.
In embodiments of the present invention, a pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may ameliorate renal fibrosis, or delay or inhibit a progress of renal fibrosis, and slow down a rate of progress of renal fibrosis with regard to renal failure (acute renal failure and chronic renal failure). For example, the pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may slow down a rate of progress of renal fibrosis in an animal model with adenine-induced chronic renal failure induced by adenine diet (FIG. 1).
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may ameliorate glomerulosclerosis, or delay or inhibit a progress of glomerulosclerosis, and slow down a rate of progress of glomerulosclerosis with regard to renal failure (acute renal failure and chronic renal failure). For example, the pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may slow down a rate of progress of glomerulosclerosis in an animal model with adenine-induced chronic renal failure induced by adenine diet (FIG. 2). In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may increase the acetylation of tubulin protein in chronic renal failure. For example, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may increase the acetylation of tubulin protein in an animal model with adenine-induced chronic renal failure (FIG. 3).
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may inhibit the increase of collagen type I alpha 1 (COL1A1) in chronic renal failure. For example, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may inhibit the increase of collagen type I alpha 1 in an animal model with adenine-induced chronic renal failure (FIGS. 4).
In embodiments of the present invention, the pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may decrease blood urea nitrogen (BUN) in chronic renal failure to improve a kidney function, or delay or inhibit a decrease in the kidney function, and delay a rate at which the kidney function decreases (FIG. 5). For example, the pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may decrease blood urea nitrogen (BUN) in an animal model with adenine-induced chronic renal failure.
In embodiments of the present invention, the pharmaceutical composition may be administered to a subject having renal failure, and the renal failure in the subject may be caused by other diseases. Diseases, which may cause the renal failure, may include at least one selected from the group consisting of hypotension, urethral obstruction, acute renal failure, acute pyelitis, chronic pyelitis, IgA nephropathy, muscle degradation, hemolytic uremic syndrome, glomerular disease (e.g., nephritis syndrome, acute advanced glomerulonephritis, chronic glomerulonephritis, nephrotic syndrome, etc.), hereditary kidney disease (e.g., polycystic kidney disease), diabetes, hypertension, heart disease, and liver disease.
In embodiments of the present invention, the pharmaceutical composition may be administered to a subject having chronic renal failure, and the chronic renal failure in the subject may be caused by other diseases. Diseases, which may cause the renal failure, may include at least one selected from the group consisting of diabetes, hypertension, nephrotic syndrome, nephritic syndrome, hereditary kidney disease (e.g., polycystic kidney disease), heart disease, and liver disease. The compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure may exhibit an effect on preventing and treating renal failure at a level which is similar to or substantially the same as or superior to a conventionally known drug for preventing and treating renal failure.
The pharmaceutical composition of the present disclosure may further include at least one pharmaceutically acceptable carrier, in addition to the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof. The pharmaceutically acceptable carrier may be the one which is conventionally used in the art, specifically including, but not limited thereto, lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidine, cellulose, water, syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral, or oil. The pharmaceutical composition of the present invention may further include lubricants, humectants, sweetening agents, flavoring agents, emulsifiers, suspending agents, preservatives, dispersing agents, stabilizing agents, etc., in addition to the above ingredients. In addition, the pharmaceutical composition of the present disclosure may be formulated into an oral dosage form such as a tablet, powder, granule, pill, capsule, suspension, emulsion, liquid for internal use, oiling agent, syrup, etc., as well as a form of external application, suppository or sterile solution for injection, by using pharmaceutically acceptable carriers and excipients and thus may be prepared in a unit dose form or prepared by being inserted into a multi-dose container. Such preparations may be prepared according to a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science (19th ed., 1995), and may be formulated into various preparations depending on each disease or ingredient.
A non-limiting example of preparations for oral administration using the pharmaceutical composition of the present disclosure may include tablets, troches, lozenges, water-soluble suspensions, oil suspensions, prepared powders, granules, emulsions, hard capsules, soft capsules, syrups, elixirs or the like. To formulate the pharmaceutical composition according to the embodiments of the present invention into preparation for oral administration, the followings may be used: binders such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose, gelatin or the like; excipients such as dicalcium phosphate, etc.; disintegrants such as maize starch, sweet potato starch or the like; lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate, polyethylene glycol wax, or the like; etc., in which sweetening agents, flavoring agents, syrups, etc. may also be used. Furthermore, in the case of the capsules, liquid carriers such as fatty oil, etc. may be further used in addition to the above-mentioned materials.
A non-limiting example of parenteral preparations using the pharmaceutical composition according to the embodiments of the present invention may include injectable solutions, suppositories, powders for respiratory inhalation, aerosols for spray, ointments, powders for application, oils, creams, etc. To formulate the pharmaceutical composition according to the embodiments of the present invention into preparation for parenteral administration, the following may be used: sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze- dried preparations, external preparations, etc. As said non-aqueous solvents and suspensions, the following may be used, but without limitation thereto: propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, etc.
The pharmaceutical composition according to the embodiments of the present invention may be subjected to oral administration or parenteral administration according to a targeted method, for example, intravenous, subcutaneous, intraperitoneal or local administration, particularly oral administration, but is not limited thereto.
A daily dosage of the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure may be particularly about 0.1 to about 10,000 mg/kg, about 1 to about 8,000 mg/kg, about 5 to about 6,000 mg/kg, or about 10 to about 4,000 mg/kg, and more particularly about 50 to about 2,000 mg/kg, but is not limited thereto and may be also administered once a day or several times a day by dividing the daily dosage of the compound.
A pharmaceutically effective dose and an effective dosage of the pharmaceutical composition according to the embodiments of the present invention may vary depending on a method for formulating the pharmaceutical composition, an administration mode, an administration time, an administration route, and/or the like, and may be diversified according to various factors including a type and degree of reaction to be achieved by administration of the pharmaceutical composition, a type of an individual for administration, the individual’s age, weight, general health condition, disease symptom or severity, gender, diet and excretion, ingredients of other drug compositions to be used for the corresponding individual at the same time or different times, etc., as well as other similar factors well known in a pharmaceutical field, and those skilled in the art may easily determine and prescribe an effective dosage for the intended treatment.
The pharmaceutical composition according to the embodiments of the present invention may be administered once a day or several times a day by dividing the daily dosage of the composition. The pharmaceutical composition of the present disclosure may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with a conventional therapeutic agent. Considering all the above factors, the pharmaceutical composition of the present disclosure may be administered in such an amount that a maximum effect may be achieved by a minimum amount without a side effect, and such amount may be easily determined by those skilled in the art to which the present invention pertains.
The pharmaceutical composition according to the embodiments of the present invention may show an excellent effect even when solely used, but may be further used in combination with various methods such as hormone therapy, drug treatment, etc. to increase therapeutic efficiency.
The present disclosure may provide a method for preventing and treating renal failure, including administering the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual. The present disclosure may provide a method for preventing and treating renal failure, including administering the above compound 40, 43, 239, 285, 295, and/or 296, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual.
In the prevention and treatment method of the present disclosure, above terms "renal failure," "prevention" and "treatment" may be the same as described above.
As used herein, the term “administration” may refer to introducing a predetermined substance into an individual by an appropriate method.
As used herein, the term “individual” may refer to all the animals such as rats, mice, livestock, etc., including humans, who are likely to develop or have already developed renal failure, and specifically refer to mammals including humans, but is not limited thereto.
The method for preventing and treating renal failure of the present disclosure may include administering a therapeutically effective amount of the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof.
As used herein, the term “therapeutically effective amount” may refer to an amount enough to treat a disease at a reasonable risk/benefit ratio applicable to medical treatment and not to cause a side effect, and may be determined by those skilled in the art according to factors including a patient’s gender, age, weight and health condition, a type of disease, severity, activity of a drug, sensitivity to a drug, an administration method, an administration time, an administration route, an excretion rate, a treatment period, a drug combined or concurrently used, as well as other factors well known in a medical field. It may be preferable to differently apply a specific therapeutically effective amount for a certain patient depending on various factors including a type and degree of reaction to be achieved therefrom, a specific composition including a presence of other preparations used in some cases, a patient’s age, weight, general health condition, gender and diet, an administration time, an administration route, a secretion rate of the composition, a treatment period and a drug used together with the specific composition or simultaneously therewith, as well as other similar factors well known in a pharmaceutical field.
The method for preventing and treating renal failure of the present disclosure may include not only dealing with the disease per se before expression of its symptoms, but also inhibiting or avoiding such symptoms by administering the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof. In managing the disease, a preventive or therapeutic dose of a certain active ingredient may vary depending on properties and severity of the disease or condition, and a route in which the active ingredient is administered. A dose and a frequency thereof may vary depending on an individual patient’s age, weight and reactions. A suitable dose and usage may be easily selected by those skilled in the art, naturally considering such factors.
In addition, the method for preventing and treating renal failure of the present disclosure may further include administering a therapeutically effective amount of an additional active agent, which is helpful in preventing and treating the disease, along with the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof, and the additional active agent may show a synergy effect or an additive effect together with the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof.
Matters mentioned in the pharmaceutical composition of the present disclosure are also applied to the prevention and treatment method, if not contradictory to each other.
The present disclosure may provide a use of the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing and treating renal failure.
The present disclosure may provide a use of the above compound 40, 43, 239, 285, 295 and/or 296, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing and treating renal failure.
The present disclosure may provide a use of the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating renal failure.
The present disclosure may provide a use of the compound represented by the above compound 40, 43, 239, 285, 295 and/or 296, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating renal failure.
In the prevention and treatment use of the present disclosure, above terms "renal failure," "prevention" and "treatment" may be the same as described above.
For the preparation of the medicament, the compound represented by above formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may be mixed with pharmaceutically acceptable adjuvants, diluents, carriers, etc., and may be prepared into a complex preparation together with other active agents, thus providing a synergy action.
Matters mentioned in the pharmaceutical composition, prevention and treatment method and use of the present disclosure may be applied the same, if not contradictory to each other.
Advantageous Effects
The compound represented by formula I of the present disclosure, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof and the pharmaceutical composition including the same as an active ingredient may be advantageously used in preventing and treating renal failure. Brief Description of the Drawings
FIG. 1 shows the results of measuring a degree of fibrosis in the kidney obtained by collecting the kidney of mice after 14 days of adenine diet in an animal model with adenine- induced chronic renal failure. The pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may decrease fibrosis which occurs in an animal model with renal failure.
FIG. 2 shows the results of measuring a degree of glomerulosclerosis in the kidney obtained by collecting the kidney of mice after 14 days of adenine diet in an animal model with adenine-induced chronic renal failure. The pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may decrease glomerulosclerosis which occurs in an animal model with renal failure.
FIG. 3 shows the results of measuring the levels of tubulin acetylation in mouse kidney tissues after 14 days of adenine diet in an animal model with adenine-induced chronic renal failure. The pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may increase tubulin acetylation of the kidney in an animal model with renal failure.
FIG. 4 shows the results of measuring the levels of expression of COL1A1 in mouse kidney tissues after 14 days of adenine diet in an animal model with adenine-induced chronic renal failure. The pharmaceutical composition including the compound represented by formula I, compound 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may decrease the expression of COL1A1, which increases in an animal model with renal failure.
FIG. 5 shows the results of measuring concentration of blood urea nitrogen (BUN) in blood obtained by collecting blood of mice after 14 days of adenine diet in an animal model with adenine-induced chronic renal failure. The pharmaceutical composition including the compound represented by formula I, compounds 1 to 450, optical isomers thereof or pharmaceutically acceptable salts thereof may decrease a level of blood urea nitrogen (BUN) which increases in an animal model with renal failure.
Detailed description of exemplary embodiments
The present disclosure will be described in detail with reference to Examples hereinafter. However, the Examples are only for the purpose of illustrating the present invention and it is obvious to those skilled in the art that the scope of the present invention is not limited to the Examples disclosed hereinafter.
Preparation Example 1. Synthesis of compound 43, N- ((5-(5-(difluoromethyl)- l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide _ 1,1- dioxide
Figure imgf000057_0001
To a solution of aniline (3.000 g, 32,213 mmol) and N,N-diisopropylethylamine (33.439 mL, 193.278 mmol) in dichloromethane (100 mL) was added at 0 °C triphosgene (4.780 g, 16.107 mmol) and was stirred at the same temperature. Thiomorpholine 1,1-dioxide (4.790 g, 35.434 mmol) was added to the reaction mixture and stirred for an additional 16 hr at room temperature. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSCU), filtered, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (SiC>2, 40 g cartridge; methanol / dichloromethane = 2 %) to give the title compound as yellow solid (1.325 g, 16.2 %).
[Step 2] Synthesis of Methyl 6-((l,l-dioxido-N-phenylthiomorpholine-4- carb oxami do)methy 1 )ni cotinate
Figure imgf000058_0001
A solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) prepared in Step 1 and sodium hydride (60.00 %, 0.157 g, 3.932 mmol) inN,N-dimethylformamide (10 mL) was stirred at 0 °C for 1 hr, and mixed with methyl 4-(bromomethyl)-3 -fluorobenzoate (0.905 g, 3.932 mmol). The reaction mixture was stirred at room temperature for an additional 2 hr. The reaction mixture was concentrated under the reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSC ), filtered, and concentrated under the reduced pressure. The crude product was crystallized at room temperature using methanol (20 mL). The resulting precipitates obtained by filtration were washed by methanol, and dried to give the title compound as brown solid (0.816 g. 51.4 %).
[Step 3] Synthesis of N- ((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N- phenylthiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000058_0002
Methyl 6-((l,l-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinate (0.816 g, 2.023 mmol) prepared in Step 2 and hydrazine monohydrate (1.910 mL, 40.451 mmol) was mixed in ethanol (10 mL) at the room temperature and then heated at 100 °C under the microwaves for 1 hr, and cooled down to the room temperature to terminate the reaction. The reaction mixture was concentrated under the reduced pressure to remove the solvent. The crude product was crystallized at room temperature using dichloromethane (20 mL). The resulting precipitates obtained by filtration were washed by dichloromethane, and dried to give the title compound as light brown solid (0.560 g, 68.6 %).
[Step 4] Synthesis of N- ((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2- yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000059_0001
A solution of N- ((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)-N- phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.260 g, 0.644 mmol) prepared in Step 3 and triethylamine (0.178 mL, 1.289 mmol) in dichloromethane (2 mL) was mixed with Difluoroacetic Anhydride (0.087 mL, 0.580 mmol) at the room temperature. The reaction mixture was stirred at the same temperature for 16 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The mixture was passed through a plastic frit to remove solid residues and an aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (SiCb, 4 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give the title compound as white foam (0.156 g, 50.3 %).
[Step 5] Synthesis of compound 43
Figure imgf000059_0002
A mixture of N- ((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2-yl)methyl)- N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.156 g, 0.324 mmol) prepared in Step 4 and 1 -methoxy -N-triethylammoniosulfonyl-methanimidate (Burgess reagent, 0.116 g, 0.486 mmol) in tetrahydrofuran (2 mL) was heated at 150 °C for 30 min under the microwaves, and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and an aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (SiCh, 4 g cartridge; methanol / dichloromethane = 3 %) to give the title compound as colorless oil (0.078 g, 51.9 %).
'H NMR (400 MHz, CDCh) 6 9.23 (d, 1H, J= 22 Hz), 8.38 (dd, 1H, J= 8.2, 2.2 Hz), 7.54 (d, 1H, J= 8.2 Hz), 7.41 - 7.31 (m, 2H), 7.19 (ddd, 3H, J = 6.4, 3.0, 1.6 Hz), 6.94 (m, 1H), 5.10 (s, 2H), 3.72 (dd, 4H, J= 6.9, 3.7 Hz), 2.97 - 2.90 (m, 4H); LRMS (ES) m/z 464.2 (M++ 1).
Synthesis Example 2. Synthesis of compound 40, N-(4-(5-(difluoromethyl)-l,3,4- oxadiazol-2-yl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide
[Step 1] Methyl 4-((l,l-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)-3- fluorobenzoate
Figure imgf000060_0001
A solution of N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1.000 g, 3.932 mmol) and sodium hydride (60.00 %, 0.189 g, 4.719 mmol) in N,N-dimethylformamide (30 mL) was mixed at 0 °C with methyl 4-(bromomethyl)-3-fluorobenzoate (1.020 g, 4.129 mmol), and stirred at the room temperature for 18 hr. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSCU), filtered, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (SiCb, 40 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give the title compound methyl 4-((l, 1-dioxido- N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate as white solid (1.240 g, 75.0 %).
[Step 2] N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4- carboxamide 1,1-dioxide
Figure imgf000061_0001
A solution of methyl 4-((l,l-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)- 3 -fluorobenzoate (1.240 g, 2.949 mmol) prepared in Step 1 and hydrazine monohydrate (2.786 mL, 58.983 mmol) in ethanol (15 mL) was stirred at 120 °C for 1 hr, and cooled down to the room temperature to terminate the reaction. The reaction mixture was concentrated under the reduced pressure to remove the solvent, and saturated aqueous sodium bicarbonate solution was added to the concentrate, followed by extraction with di chloromethane. The bi-phasic mixture was passed through a plastic frit to remove solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The crude title compound N-(2-fluoro-4- (hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4-carboxamide 1,1 -di oxide was used without further purification (1.240 g, 100.0 %, white solid).
[Step 3] N-(4-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)-2-fluorobenzyl)-N- phenylthiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000061_0002
A solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-phenylthiomorpholine-4- carboxamide 1,1-dioxide (0.615 g, 1.463 mmol) prepared in Step 2, triethylamine (0.304 mL, 2.194 mmol) and difluoroacetic anhydride (0.164 mL, 1.316 mmol) in dichloromethane (10 mL) was stirred at the room temperature for 18 hr. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgSCU), filtered, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (SiCb, 24 g cartridge; methanol / dichloromethane = 0 % to 3 %) to give the title compound N-(4-(2-(2,2- difluoroacetyl)hydrazine-l-carbonyl)-2-fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide as white solid (0.462 g, 63.4 %).
[Step 4] Synthesis of compound 40
Figure imgf000062_0001
A mixture of N-(4-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)-2-fluorobenzyl)-N- phenylthiomorpholine-4-carboxamide 1,1-dioxide (0.462 g, 0.927 mmol) prepared in Step 3 and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (burgess reagent, 0.331 g, 1.390 mmol) in tetrahydrofuran (10 mL) was heated at 150 °C for 30 min under the microwaves, and cooled down to the room temperature to terminate the reaction. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (SiCb, 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give the title compound N-(4-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)-2- fluorobenzyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide as white solid (0.337 g, 75.7 %).
'H NMR (400 MHz, CDCh) 6 7.87 - 7.85 (m, 1H), 7.75 - 7.72 (m, 1H), 7.67 - 7.64 (m, 1H), 7.38 - 7.34 (m, 2H), 7.25 - 7.20 (m, 1H), 7.13 - 7.10 (m, 2H), 7.03 - 6.77 (m, 1H), 4.92 (s, 2H), 3.71 - 3.67 (m, 4H), 2.77 - 2.74 (m, 4H); LRMS (ES) m/z 481.1 (M++ 1).
Synthesis Example 3. Synthesis of the compound 239, N-(3-chlorophenyl)-N-((5-(5-
(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide
[Step 1] Synthesis of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide
Figure imgf000062_0002
A solution of l-chloro-3-isocyanatobenzene (1.000 g, 6.512 mmol) and thiomorpholine 1,1-dioxide (0.871 g, 6.447 mmol) in diethyl ether (20 mL) was stirred at the room temperature for 18 hr. The precipitates were filtered, washed by diethyl ether, and dried to give the title compound as white solid (1.811 g, 96.3 %).
[Step 2] Synthesis of Methyl 6-((N-(3 -chlorophenyl)- 1,1 -di oxidothiom orpholine-4- carb oxami do)methy 1 )ni cotinate
Figure imgf000063_0001
To a solution of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.200 g, 0.693 mmol) prepared in Step 1 in N,N-dimethylformamide (5 mL) was added at 0 °C sodium hydride (60.00 %, 0.028 g, 0.693 mmol). The reaction mixture was stirred at the same temperature for 1 hr, added at the same temperature with methyl 6-(bromomethyl)nicotinate (0.159 g, 0.693 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgSCU), filtered, and concentrated under the reduced pressure. The residue was purified and concentrated by chromatography (SiCh, 12 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give the title compound as brown oil (0.261 g, 86.0 %).
[Step 3] Synthesis of N- (3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2- yl)methyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000063_0002
6-((N-(3 -chlorophenyl)- 1 , 1 -di oxidothiom orpholine-4- carboxamido)methyl)nicotinate (0.261 g, 0.596 mmol) prepared in Step 2 and hydrazine monohydrate (0.290 mL, 5.958 mmol) were mixed at the room temperature in ethanol (2 mL) and then stirred at 110 °C for 18 hr and cooled down to the room temperature to terminate the reaction. The reaction mixture was concentrated under the reduced pressure to remove the solvent. Then, water was added to the obtained concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The residue was purified and concentrated by chromatography (SiCb, 4 g cartridge; methanol / dichloromethane = 5 % to 15 %) to give the title compound as brown oil (0.261 g, 100.0 %).
[Step 4] Synthesis of compound 239
Figure imgf000064_0001
N-(3-chlorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4 - carboxamide 1,1-dioxide (0.261 g, 0.596 mmol) prepared in Step 3, triethylamine (0.415 mL, 2.980 mmol) and 2,2-difluoroacetic anhydride (0.195 mL, 1.788 mmol) were mixed at the room temperature in tetrahydrofuran (2 mL) and then the obtained solution was stirred at 80 °C for 18 hr and cooled down to the room temperature to terminate the reaction. The reaction mixture was concentrated under the reduced pressure to remove the solvent. Then, water was added to the obtained concentrate, followed by extraction with dichloromethane. The biphasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The residue was purified and concentrated by chromatography (SiCh, 4 g cartridge; methanol / dichloromethane = 0 % to 3 %) to give the title compound as yellow foam (0.087 g, 29.3 %).
'H NMR (400 MHz, CDCh) 6 9.27 (dd, 1H, J= 2.2, 0.8 Hz), 8.43 (dd, 1H, J= 8.2, 2.2 Hz), 7.55 (dd, 1H, J = 8.2, 0.9 Hz), 7.31 (t, 1H, J = 8.0 Hz), 7.23 (t, 1H, J= 2.1 Hz), 7.21 - 7.10 (m, 2H), 7.10 (t, 1H), 5.12 (s, 2H), 3.75 (t, 4H, J= 5.3 Hz), 3.06 - 2.99 (m, 4H); LRMS (ES) m/z 498.3 (M++ 1).
Synthesis Example 4. Synthesis of the compound 285: N-(4-(5-(difluoromethyl)- l,3.,4-oxadiazol-2-yl)-2-fluorobenzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide
[Step 1] N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000064_0002
A solution of l-fluoro-4-isocyanatobenzene (0.500 g, 3.647 mmol) in diethylether (10 mL) was mixed at 0 °C with thiomorpholine 1,1 -di oxide (0.493 g, 3.647 mmol), and stirred at the same temperature for 1 hr. The reaction mixture was stirred at the room temperature for additional 4 hr. The precipitates were collected by filtration, washed by diethylether, and dried to give N-(4- fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as white solid (0.920 g, 92.7 %).
[Step 2] Methyl 3-fluoro-4-((N-(4-fluorophenyl)-l,l-dioxidothiomorpholine-4- carb oxami do)methy l)b enzoate
Figure imgf000065_0001
A solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.300 g, 1.102 mmol) prepared in Step 1 and sodium hydride (60.00 %, 0.048 g, 1.212 mmol) in N,N- dimethylformamide (5 mL) was stirred at 0 °C for 2 hr, and mixed with methyl 4-(bromomethyl)- 3 -fluorob enzoate (0.299 g, 1.212 mmol). The reaction mixture was stirred at the room temperature for additional 17 hr, quenched at the room temperature by the addition of water (2 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The crude product was crystallized at the room temperature using dichloromethane (3 mL). The resulting precipitates were filtered, washed by dichloromethane, and dried to give methyl
3-fluoro-4-((N-(4-fluorophenyl)-l,l-dioxidothiomorpholine-4-carboxamido)methyl)benzoate as white solid (0.212 g, 43.9 %).
[Step 3] N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine-
4-carboxamide 1 , 1 -dioxide
Figure imgf000065_0002
Methyl 3 -fluoro-4-((N-(4-fluorophenyl)- 1 , 1 -dioxidothiomorpholine-4- carboxamido)methyl)benzoate (0.212 g, 0.484 mmol) prepared in Step 2 and hydrazine monohydrate (0.470 mL, 9.670 mmol) in ethanol (4 mL) was mixed at the room temperature and then heated at 120 °C under the microwaves for 1 hr and cooled down to the room temperature to terminate the reaction. The reaction mixture was concentrated under the reduced pressure to remove the solvent. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The residue was diluted with di ethylether (5 mL) and ethyl acetate (1 mL) and stirred at the ambient temperature. The resulting precipitates were collected by filtration, washed by hexane, and dried to give N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4-fluorophenyl)thiomorpholine- 4-carboxamide 1,1-dioxide as white solid (0.179 g, 84.4 %).
[Step 4] Synthesis of compound 285
Figure imgf000066_0001
A solution of N-(2-fluoro-4-(hydrazinecarbonyl)benzyl)-N-(4- fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.100 g, 0.228 mmol) prepared in Step 3 and triethylamine (0.095 mL, 0.684 mmol) in dichloromethane (4 mL) was mixed at the room temperature with 2,2-difluoroacetic anhydride (0.028 mL, 0.228 mmol), and stirred at the same temperature for 17 hr. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The residue was chromatographed (SiCh, 4 g cartridge; ethyl acetate / hexane = 20 % to 50 %) to giveN-(4-(5-(difluoromethyl)-l,3,4-oxadiazol- 2-yl)-2-fluorobenzyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as white solid (0.053 g, 46.6 %).
'H NMR (400 MHz, CDCh) 6 7.90 (dd, 1H, J= 8.0, 1.6 Hz), 7.77 (dd, 1H, J= 10.1, 1.6 Hz), 7.69 (t, 1H, J= 7.6 Hz), 7.14 - 6.81 (m, 5H), 4.90 (s, 2H), 3.74 - 3.71 (m, 4H), 2.85 - 2.82 (m, 4H); LRMS (ES) m/z 499.3 (M+ + 1). Synthesis Example 5. Synthesis of the compound 295, N-((5-(5-(difluoromethyl)- l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4- carboxamide 1,1-dioxide
[Step 1] Methyl 6-((N-(4-fluorophenyl)-l,l-dioxidothiomorpholine-4- carb oxami do)methy 1 )ni cotinate
Figure imgf000067_0001
A solution of N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) prepared in Step 1 of Synthesis Example 4(Compound 285) and sodium hydride (60.00 %, 0.081 g, 2.020 mmol) in N,N-dimethylformamide (10 mL) was stirred at 0 °C for 30 min, and mixed with methyl 6-(bromomethyl)nicotinate (0.465 g, 2.020 mmol). The reaction mixture was stirred at the room temperature for additional 5 hr, quenched at the room temperature by the addition of water (5 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgSCU), filtered, and concentrated under the reduced pressure. methyl 6-((N-(4-fluorophenyl)- 1 , 1 -dioxidothiomorpholine-4- carboxamido)methyl)nicotinate was used without further purification (0.450 g, 58.1 %, brown solid).
[Step 2] N-(4-fhiorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2- yl)methyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000067_0002
Methyl 6-((N-(4-fluorophenyl)- 1 , 1 -dioxidothiomorpholine-4- carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were mixed at the room temperature in ethanol (5 mL) and then stirred at 100 °C for 17 hr, cooled down to the room temperature. The precipitates were collected by filtration, washed by ethanol, and dried to give N-(4-fluorophenyl)-N-((5-
(hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide as pale yellow solid (0.111 g, 74.0 %).
[Step 3] N-((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2-yl)methyl)-N-(4- fluorophenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000068_0001
A solution of N-(4-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2- yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.111 g, 0.263 mmol) prepared in Step 2 and triethylamine (0.110 mL, 0.790 mmol) in dichloromethane (5 mL) was mixed at the room temperature with 2,2-difluoroacetic anhydride (0.065 mL, 0.527 mmol), and stirred at the same temperature for 1 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. The crude product was used without further purification (0.082 g, 62.3 %, yellow solid).
[Step 4] Synthesis of compound 295
Figure imgf000068_0002
N-((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2-yl)methyl)-N-(4- fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.082 g, 0.164 mmol) prepared in Step 3 and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent, 0.117 g, 0.493 mmol) were mixed at the room temperature in tetrahydrofuran (5 mL) and then stirred at 70 °C for 5 hr, cooled down to the room temperature, filtered to remove solids, and concentrated under the reduced pressure. The residue was chromatographed (SiCh, 4 g cartridge; methanol / dichloromethane = 0 % to 10 %) to give N-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-N-(4-fluorophenyl)thiomorpholine-4-carboxamide 1,1 -di oxi de as white solid (0.015 g, 19.0 %).
'H NMR (400 MHz, CDCh) 6 9.27 (d, 1H, J= 1.6 Hz), 8.43 (dd, 1H, J= 8.2, 2.2 Hz), 7.58 (d, 2H, J= 8.2 Hz), 7.25 - 7.21 (m, 2H), 7.10 - 6.84 (m, 3H), 5.08 (s, 2H), 3.73 (t, 4H, J= 5.1 Hz), 2.98 (t, 4H, J= 5.2 Hz); LRMS (ES) m/z 482.1 (M+ + 1).
Synthesis Example 6. Synthesis of the compound 296, N-((5-(5-(difluoromethyl)- l,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4- carboxamide 1,1-dioxide
[Step 1] Methyl 6-((N-(3 -fluorophenyl)- 1,1 -di oxidothiom orpholine-4- carb oxami do)methy 1 )ni cotinate
Figure imgf000069_0001
A solution of l-fluoro-3-isocyanatobenzene (0.500 g, 3.647 mmol) in diethylether (10 mL) was mixed at 0 °C with thiomorpholine 1,1 -di oxide (0.493 g, 3.647 mmol), and stirred at the same temperature for 1 hr. The reaction mixture was stirred at the room temperature for additional 4 hr. The precipitates were collected by filtration, washed by di ethylether, and dried to give N-(3- fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as white solid (0.870 g, 87.6 %).
A solution of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.500 g, 1.836 mmol) prepared above and sodium hydride (60.00 %, 0.081 g, 2.020 mmol) in N,N- dimethylformamide (10 mL) was stirred at 0 °C for 30 min, and mixed with methyl 6- (bromomethyl)nicotinate (0.465 g, 2.020 mmol). The reaction mixture was stirred at the room temperature for additional 5 hr, quenched at the room temperature by the addition of water (5 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgSCU), filtered, and concentrated under the reduced pressure. Methyl 6-((N-(3- fluorophenyl)-l,l-dioxidothiomorpholine-4-carboxamido)methyl)nicotinate was used without further purification (0.450 g, 58.1 %, brown solid). [Step 2] N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2- yl)methyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000070_0001
Methyl 6-((N-(3 -fluorophenyl)- 1 , 1 -dioxidothiomorpholine-4- carboxamido)methyl)nicotinate (0.150 g, 0.356 mmol) prepared in Step 1 and hydrazine monohydrate (0.346 mL, 7.118 mmol) were mixed at the room temperature in ethanol (5 mL) and then stirred at 100 °C for 17 hr, cooled down to the room temperature. The precipitates were collected by filtration, washed by ethanol, and dried to give N-(3-fluorophenyl)-N-((5- (hydrazinecarbonyl)pyridin-2-yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide as pale yellow solid (0.113 g, 75.3 %).
[Step 3] N-((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2-yl)methyl)-N-(3- fluorophenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide
Figure imgf000070_0002
solution of N-(3-fluorophenyl)-N-((5-(hydrazinecarbonyl)pyridin-2- yl)methyl)thiomorpholine-4-carboxamide 1,1-dioxide (0.113 g, 0.268 mmol) prepared in Step 2 and triethylamine (0.112 mL, 0.804 mmol) in dichloromethane (5 mL) was mixed at the room temperature with 2,2-difluoroacetic anhydride (0.067 mL, 0.536 mmol), and stirred at the same temperature for 1 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated under the reduced pressure. N-((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2-yl)methyl)-N-(3- fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide was used without further purification
(0.090 g, 67.2 %, yellow solid).
[Step 4] Synthesis of Compound 296
Figure imgf000071_0001
N-((5-(2-(2,2-difluoroacetyl)hydrazine-l-carbonyl)pyridin-2-yl)methyl)-N-(3- fluorophenyl)thiomorpholine-4-carboxamide 1,1 -di oxide (0.090 g, 0.180 mmol) prepared in Step 3 and 1-methoxy-N-triethylammoniosulfonyl-methanimidate (Burgess reagent, 0.129 g, 0.541 mmol) were mixed at the room temperature in tetrahydrofuran (5 mL) and then stirred at 70 °C for 5 hr, cooled down to the room temperature, filtered to remove solids, and concentrated under the reduced pressure. The residue was chromatographed (SiCh, 4 g cartridge; methanol / dichloromethane = 0 % to 10 %) to give N-((5-(5-(difluoromethyl)-l,3,4-oxadiazol-2-yl)pyridin- 2-yl)methyl)-N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide as white solid (0.044 g, 50.7 %).
'H NMR (400 MHz, CDCh) 6 9.28 (d, 1H, J= 1.6 Hz), 8.46 (dd, 1H, J= 8.2, 2.2 Hz), 7.58 (d,
1H, J= 8.2 Hz), 7.37 - 7.32 (m, 1H), 7.10 - 6.92 (m, 4H), 5.14 (s, 2H), 3.76 (t, 4H, J= 5.1 Hz), 3.03 (t, 4H, J= 5.2 Hz); LRMS (ES) m/z 482.3 (M+ + 1).
<Example 1> Confirmation of Prevention or Treatment Effect on Renal Failure 1
Through this experiment, an attempt was made to confirm the effect of the compound of the present disclosure on kidney functions with regard to renal fibrosis and glomerulosclerosis.
Six-week-old C57BL/6J mice were subjected to 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. Mice with adenine-induced chronic renal failure were orally dosed with Preparation Example 1 (compound 43) twice a day for two weeks (experimental group, compound 43). Meanwhile, in case of an induced group (vehicle), a vehicle was orally administered into mice with adenine-induced chronic renal failure twice a day, and the vehicle was orally administered into normal mice (Ctrl) twice a day. Animals were provided with a standard diet (Central Lab Animal, Inc.), 0.2% adenine diet (ENVIGO) and water ad libitum and were housed in a controlled environment with a temperature (22 ± 2°C), humidity (44-56%) and a 12-hour light-dark cycle. All experimental procedures were approved and performed according to the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (with the IACUC animal study protocol approval number: S-21-037).
Each group was classified as shown in table 1 below.
[Table 1]
Figure imgf000072_0001
In an animal model with adenine-induced chronic renal failure, a compound of formula I (compound 43 of Preparation Example 1) was repeatedly administered into an experimental group twice a day for two weeks together with administration of 0.2% adenine diet. Two weeks after administration, the kidney was obtained by sacrificing the mouse.
In order to measure a degree of fibrosis in the kidney, the kidney of the mouse was fixed to a 10% neutral buffered formalin (NBF) to infiltrate paraffin into the kidney tissue of the mouse, followed by embedding, and then a corresponding block was subjected to a sagittal section to a thickness of 4 pm, thereby performing Masson's trichrome staining, and then capturing an image using an image analyzer (NIS-Elements BR 5.11.01 (Nikon)). With regard to a relative fibrotic area, an average value was calculated by measuring a positive area compared to a total area, and the evaluation was performed by assuming that a tubulointerstitial fibrosis score was 0 point if tubulointerstitial fibrosis was normal, 1 point if it was 10% or less, 2 points if it was more than 10% to 25% or less, 3 points if it was more than 25% to 75% or less, and 4 points if it was 75% or more.
In order to measure a glomerulosclerosis of the kidney, the kidney of the mouse was fixed to a 10% neutral buffered formalin (NBF) to infiltrate paraffin into the kidney tissue of the mouse, followed by embedding, and then a corresponding block was subjected to a sagittal section to a thickness of 4 pm, thereby performing periodic acid Schiff (PAS) staining, and then capturing an image using an image analyzer (NIS-Elements BR 5.11.01 (Nikon)). With regard to the glomerulosclerosis (GS) index, depending on the number of glomerulus in which a corresponding lesion occurred, the evaluation was performed with 0 point if it was normal, 1 point if it was less than 25%, 2 points if it was 25% or more but less than 50%, 3 points if it was 50% or more but less than 75%, and 4 points if the lesion was seen in the entire body.
All results were presented as mean±SEM and analyzed using GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed by one-way ANOVA (multiple comparison).
The results of analyzing the relative fibrotic area, tubulointerstitial fibrosis score, and glomerulosclerosis score are shown in FIGS. 1 and 2. In above FIGS. 1 and 2, an error bar may refer to ±SEM (standard error of the mean) (vehicle vs. each group), ** p<0.01, **** p<0.0001).
As confirmed from above FIGS. 1 and 2, it could be seen that compound 43 (preparation example 1) reduces renal fibrosis in an animal model with kidney failure and alleviates kidney sclerosis. Thus, it could be seen that the compound of the present disclosure may be advantageously used for preventing and treating renal failure disease.
<Example 2> Confirmation of Prevention or Treatment Effect on Renal Failure 2
Through this experiment, a change in the level of acetylated-alpha tubulin (Ace-tub) according to the administration of the compound of the present disclosure was measured to confirm the effect of the compound of the present disclosure on preventing and treating renal failure.
Six-week-old C57BL/6J mice were subjected to 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. Mice with adenine-induced chronic renal failure were orally dosed with Preparation Example 1 (compound 43) twice a day for two weeks (experimental group, compound 43). Meanwhile, in case of an induced group (Vehicle), a vehicle was orally administered into mice with adenine-induced chronic renal failure twice a day, and the vehicle was orally administered into the mice of the normal group (Ctrl) twice a day.
Animals were provided with a standard diet (Central Lab Animal, Inc.), 0.2% adenine diet (ENVIGO) and water ad libitum and were housed in a controlled environment with a temperature (22 ± 2°C), humidity (44-56%) and a 12-hour light-dark cycle. All experimental procedures were approved and performed according to the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (with the IACUC animal study protocol approval number: S-21-037).
Each group was classified as shown in table 2 below.
[Table 2]
Figure imgf000074_0001
Figure imgf000075_0001
In order to confirm the effect of the compound of formula I according to the present disclosure on preventing and treating renal failure disease, the expression of acetyl-alpha tubulin was analyzed in the mouse with adenine-induced chronic renal failure, and the results thereof were shown in FIG. 3.
In an animal model with adenine-induced chronic renal failure, a compound of formula I (compound 43 of Preparation Example 1) was repeatedly administered into an experimental group once a day for two weeks together with administration of 0.2% adenine diet. After administration for two weeks, the kidney of the mice was homogenized using a RIPA buffer, and then centrifuged at 13,000 rpm at 4°C for 20 minutes. After centrifugation, the supernatant was transferred to a new tube and the concentration of proteins was measured using a BCA protein assay kit (PIERCE). 20 pg of protein was loaded on a NuPAGE Bis-Tris gel (Invitrogen), after which the protein in the gel was transferred to a nitrocellulose membrane using a iBlot 2 Gel Transfer. After that, the acetylated alpha-tubulin (Ace-tub) and alpha tubulin (a-tub) antibodies were added to 3% bovine serum albumin (BSA) solution and incubated at 4 °C together with a nitrocellulose membrane. After incubation, the expression of proteins was measured using detection reagent (Thermo Scientific) and ChemiDocTM MP (BIO-RAD, 12003154) equipment, and analyzed using Image Lab Software (version 5.0) of BIO-RAD. All the results were expressed as mean±SEM and analyzed with GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed with one-way ANOVA (multiple comparison).
The results of the Ace-tub and a-tub analysis were shown in FIG. 3. In FIG. 3, Error bar means + SEM (standard error of the mean) (Vehicle vs. Each group, ** p<0.05, **** p<0.0001).
As shown in above FIG. 3, it was confirmed that compound 43 (Preparation Example 1) increases the acetylation of tubulin in an animal model with renal failure.
Thus, it could be seen that the compound of the present disclosure may be advantageously used for preventing and treating renal failure disease.
<Example 3> Confirmation of Prevention or Treatment Effect on Renal Failure 3
Through this experiment, a degree of change in the expression of collagen type I alpha I (COL1A1), which was associated with fibrosis according to the administration of the compound of the present disclosure, was identified to confirm the effect of the compound of the present disclosure on preventing and treating renal failure.
Six-week-old C57BL/6J mice were subjected to 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. Mice with adenine-induced chronic renal failure were orally dosed with Preparation Example 1 (compound 43) twice a day for two weeks (experimental group, compound 43). Meanwhile, in case of an induced group, a vehicle was orally administered into mice with adenine-induced chronic renal failure twice a day, and the vehicle was orally administered into the mice of the normal group (Ctrl) twice a day.
Animals were provided with a standard diet (Central Lab Animal, Inc.), 0.2% adenine diet (ENVIGO) and water ad libitum and were housed in a controlled environment with a temperature (22 ± 2°C), humidity (44-56%) and a 12-hour light-dark cycle. All experimental procedures were approved and performed according to the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (with the IACUC animal study protocol approval number: S-21-037).
Each group was classified as shown in table 3 below.
[Table 3]
Figure imgf000077_0001
The expression of collagen type I alpha I (COL1 Al), which was associated with fibrosis in the kidney, was analyzed to confirm the effect of the compound of formula I according to the present disclosure on preventing and treating renal failure disease.
In an animal model with adenine-induced chronic renal failure, a compound of formula I (compound 43 of Preparation Example 1) was repeatedly administered into an experimental group once a day for two weeks together with administration of 0.2% adenine diet. After administration for two weeks, the kidney of the mice was homogenized using a RIPA buffer, and then centrifuged at 13,000 rpm at 4°C for 20 minutes. After centrifugation, the supernatant was transferred to a new tube and the concentration of proteins was measured using a BCA protein assay kit (PIERCE). 20 pg of protein was loaded on a NuPAGE Bis-Tris gel (Invitrogen), after which the protein in the gel was transferred to a nitrocellulose membrane using a iBlot 2 Gel Transfer. After that, COL1 Al and GAPDH antibodies were added to 3% bovine serum albumin (BSA) solution and incubated at 4°C together with a nitrocellulose membrane. After incubation, the expression of proteins was measured using detection reagent (Thermo Scientific) and ChemiDocTM MP (BIO-RAD, 12003154) equipment, and analyzed using Image Lab Software (version 5.0) of BIO-RAD.
All the results were expressed as mean±SEM and analyzed with GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed with one-way ANOVA (multiple comparison).
The expression of COL1A1 was analyzed to compare a degree of kidney fibrosis in each group, and the results thereof were shown in FIG. 4 below. In FIG. 4, Error bar means ± SEM (standard error of the mean) (Vehicle vs. Each group, ** p<0.01, **** p<0.0001).
As shown in FIG. 4, it was observed that compound 43 (Preparation Example 1) reduces the expression of COL1A1 in a mouse with chronic renal failure.
Thus, it could be seen that the compound according to the present disclosure has an effect on inhibiting kidney fibrosis in a patient with renal failure, and thus is advantageously used in preventing or treating renal failure disease.
<Example 4> Confirmation of Prevention or Treatment Effect on Renal Failure 4
Through this experiment, an attempt was made to confirm the effect of the compound of the present disclosure on kidney functions with regard to renal failure.
Six-week-old C57BL/6J mice were subjected to 0.2% adenine diet for two weeks to prepare an animal model with chronic renal failure. Mice with adenine-induced chronic renal failure were orally dosed with Preparation Example 1 (compound 43) twice a day for two weeks (experimental group, compound 43). Meanwhile, in case of an induced group (Vehicle), a vehicle was orally administered into mice with adenine-induced chronic renal failure twice a day, and the vehicle was orally administered into the mice of the normal group (Ctrl) twice a day.
Animals were provided with a standard diet (Central Lab Animal, Inc.), 0.2% adenine diet (ENVIGO) and water ad libitum and were housed in a controlled environment with a temperature (22 ± 2°C), humidity (44-56%) and a 12-hour light-dark cycle. All experimental procedures were approved and performed according to the Institutional Animal Care and Use Committee (IACUC) of the Korea CKD Laboratory Animal Center (with the IACUC animal study protocol approval number: S-21-037).
Each group was classified as shown in table 4 below.
[Table 4]
Figure imgf000079_0001
In an animal model with adenine-induced chronic renal failure, the compound of formula I (compound 43 of preparation example 1) was repeatedly administered into an experimental group twice a day for two weeks together with administration of 0.2% adenine diet. Two weeks after administration, the blood of the mouse was placed in a tube treated with EDTA and centrifuged to measure a concentration of blood urea nitrogen (BUN). Plasma, which was the supernatant, was transferred to a new tube. Plasma was added into a sample cup using a biochemical analyzer (HITACHI-7020), and a BUN concentration was measured using a blood urea nitrogen (BUN) reagent (WAKO, 416-55192, 416-55292).
All the results were presented as mean±SEM and analyzed with GraphPad Prism 5 (GraphPad Software, Inc., USA), and statistical analysis was performed with one-way ANOVA (multiple comparison).
The results of measure in the concentration of blood urea nitrogen(BUN) were shown in FIG. 5 below. In FIG. 5, Error bar means ± SEM (standard error of the mean) (Vehicle vs. Each group, **** p<0.0001).
As confirmed from above FIG. 5, it could be seen that compound 43 (preparation example 1) reduces a concentration of the BUN in a mouse with chronic kidney failure.
Thus, it could be seen that the compound according to the present disclosure has an effect of improving kidney functions in a patient with kidney failure, and thus may be advantageously used for preventing or treating kidney failure disease.
The present disclosure provides a pharmaceutical composition, a prevention and treatment method, and a prevention and treatment use as follow:
Item 1. A pharmaceutical composition for preventing and treating renal failure, comprising a compound represented by above formula I, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient.
Item 2. The pharmaceutical composition of item 1, wherein the compound represented by above formula I is at least one selected from the group consisting of the compound 1 to 450 which is described in the above-mentioned Table A.
Item 3. The pharmaceutical composition of item 1 or 2, wherein the compound represented by above formula I is at least one selected from the group consisting of compound 40, compound 43, compound 239, compound 285, compound 295, and compound 296 which is described in the above-mentioned Table B.
Item 4. A method for preventing and treating renal failure, including administering the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof described in any one of items 1 to 3 into an individual.
Item 5. A use of the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof described in any one of items 1 to 3 for preventing and treating renal failure.
Item 6. A use of the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof described in any one of items 1 to 3 in preparing a medicament for preventing and treating renal failure.
Item 7. The pharmaceutical composition according to any one of items 1 to 3, the method according to item 4, or the use according to item 5 or 6, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.
Item 8. The pharmaceutical composition according to any one of items 1 to 3, wherein the pharmaceutical composition is orally administered.
Item 9. The method according to item 4, or the use according to item 5 or 6, wherein the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof described in any one of items 1 to 3 is orally administered.
While specific portions of the present invention have been described in detail above, it is apparent to those skilled in the art that such detailed descriptions are set forth to illustrate exemplary embodiments only, but are not construed to limit the scope of the present invention. Thus, it should be understood that the substantial scope of the present invention is defined by the accompanying claims and equivalents thereto.

Claims

1. A pharmaceutical composition for preventing and treating renal failure, comprising a compound represented by formula I below, optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient:
[Formula I]
Figure imgf000083_0001
in formula I, wherein Li, L2 or L3 are each independently a bond or -(C1-C2 alkylene)-;
Ri is -CX2H or -CX3;
Figure imgf000083_0002
least one
Figure imgf000083_0004
may be substituted with -X, -OH, -
O(Ci-C4 alkyl), -NRDRE, -(C1-C4 alkyl), -CF3, -CF2H, -CN, -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl, [wherein at least one H of the -aryl, -heteroaryl, -(C1-C4 alkyl)-aryl or -(C1-C4 alkyl)-heteroaryl may be substituted with -X, -OH, -CF3 or -CF2H]};
R3 is -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4 alkyl), -(C3-C7 cycloalkyl), -(C2-C6 cycloheteroalkyl), -aryl, -heteroaryl, -adamantyl,
Figure imgf000083_0003
{wherein, at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, at least one H of -aryl or -heteroaryl each independently may be substituted with -X, - OH, -O(Ci-C4 alkyl), -OCF3, -O-aryl, -NRDRE, -(Ci-C4 alkyl), -CF3, -CF2H, -C(=O)-(Ci-C4 alkyl), 4 alkyl), aryl, heteroaryl,
Figure imgf000084_0001
Figure imgf000084_0002
[wherein, at least one H of
Figure imgf000084_0004
,
(Ci-C4 alkyl)};
Yi, Y2 and Y4 are each independently -CH2-, -NRF-, -O-, -C(=O)- or -S(=O)2-;
Y3 is -CH- or -N-;
Zi to Z4 are each independently N or CRZ, {wherein at least three of Zi to Z4 may not be simultaneously N, and Rz is -H, -X or -O(Ci-C4 alkyl)};
Z5 and Ze are each independently -CH2- or -O-;
Z7 and Zx are each independently =CH- or =N-;
Z9 is -NRG- or -S-;
RA and RB are each independently -H, -(Ci-C4 alkyl), -(Ci-C4 alkyl)-OH, -(Ci-C4 alkyl)- NRDRE, -aryl, -(Ci-C4 alkyl)-aryl, -heteroaryl, -(Ci-C4 alkyl)-heteroaryl, -(C3-C7 cycloalkyl), -(C2-
Ce heterocycloalkyl)
Figure imgf000084_0003
{wherein, at least one H of the -(Ci-C4 alkyl), -(Ci-C4 alkyl)-OH or -(Ci-C4 alkyl)- NRDRE may be substituted with -X, at least one H of the -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, - (C3-C7 cycloalkyl) or -(C2-C6 heterocycloalkyl) may be substituted with -X, -OH, -O(Ci-C4 alkyl), -(C1-C4 alkyl), -CF3, -CF2H or -CN, at least one
Figure imgf000085_0001
may be substituted with -X, -OH, -O(Ci-C4 alkyl),
-(C1-C4 alkyl), -CF3, -CF2H, -CN, -(C2-C6 heterocycloalkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -heteroaryl-(Ci-C4 alkyl)};
Rc is -(C1-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl, {wherein, at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, at least one H of - aryl, -(C1-C4 alkyl)-aryl, -heteroaryl or -(C1-C4 alkyl)-heteroaryl may be substituted with -X, -OH, -CF3 or -CF2H};
RD and RE are each independently -H, -(C1-C4 alkyl), -aryl or -(C1-C4 alkyl)-aryl, {wherein, at least one H of -(C1-C4 alkyl) may be substituted with -X or -OH, at least one H of - aryl or -(C1-C4 alkyl)-aryl may be substituted with -X, -OH, -CF3 or -CF2H};
RF is -H, -(C1-C6 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(Ci-C4 alkyl), -C(=O)-(Ci- C4 alkyl), -C(=O)-0(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-NRDRE, - S(=O)2-(Ci-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)- heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-Ce heterocycloalkyl)
{wherein at least one H of -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-O-(Ci-C4 alkyl), -C(=O)-(Ci-C4 alkyl), -C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4 alkyl), -(Ci- C4 alkyl)-NRDRE or -S(=O)2-(Ci-C4 alkyl) may be substituted with -X, at least one H of -aryl, -(Ci-C4alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)-heteroaryl, -C(=O)-(C3-C7 cycloalkyl), -C2-C6 heterocycloalkyl or -(Ci-C4alkyl)-C(=O)- (C2-C6heterocycloalkyl) may be substituted with -X, -OH, -CF3 or -CF2H};
RG is -H or -(C1-C4 alkyl);
Q is -O- or a bond; is a single bond or double bond, {provided that, is a double bond, Yi is =CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that, a and b may not be simultaneously 0, and c and d may not be simultaneously 0};
X is each independently F, Cl, Br or I.
2. The pharmaceutical composition of claim 1, wherein in the compound represented by formula I,
Li, L2 or L3 are each independently a bond or -(Ci-C2alkylene)-;
Ri is -CX2H or -CX3;
Figure imgf000086_0001
substituted with -X, -OH, -NRDRE, -(C1-C4 alkyl)};
Ra is -(C1-C4 alkyl), -(C3-C7 cycloalkyl), -aryl, -heteroaryl, -adamantyl,
Figure imgf000086_0002
Figure imgf000086_0003
{wherein at least one H of -aryl or -heteroaryl may be each independently substituted with -X, -O(Ci-C4alkyl), -OCF3, -O-aryl, -NRDRE, -(C1-C4 alkyl), -CF3, -S(=O)2-(Ci-C4alkyl), - aryl, -heteroaryl,
Figure imgf000086_0004
least one
Figure imgf000087_0001
substituted with -NRDRE or -(C1-C4 alkyl)],
Figure imgf000087_0002
maybe each independently substituted with -(C1-C4 alkyl)};
Yi, Y2 and Y4 are each independently -CH2-, -NRF-, -O-, -C(=O)- or -S(=O)2-;
Y3 is -CH- or -N-;
Zi to Z4 is each independently N or CRZ {wherein at least three of Zi to Z4 may not be simultaneously N, and Rz is -H, -X or -O(Ci-C4 alkyl)};
Z5 and Ze are each independently -CH2- or -O-;
Z7 and Zx are each independently =CH- or =N-;
Z9 is -NRG- or -S-;
RA and RB are each independently -H, -(C1-C4 alkyl), -(C1-C4 alkyl)-OH, -(C1-C4 alkyl)-
NRDRE, -aryl, -(C1-C4 alkyl)-aryl, -(C3-C7 cycloalkyl)
Figure imgf000087_0003
{wherein, at least one
Figure imgf000087_0004
may be substituted with -X, -(Ci-
C4alkyl), -CF3, -(C2-C6 heterocycloalkyl), -(C1-C4 alkyl)-aryl, -heteroaryl or heteroaryl-(Ci-C4 alkyl)};
Rc is -(C1-C4 alkyl) or -aryl;
RD and RE are each independently -H, -(Ci-C4alkyl) or -(C1-C4 alkyl)-aryl;
RF is -H, -(Ci-Cealkyl), -(Ci-C4alkyl)-OH, -(C1-C4 alkyl)-O-(Ci-C4 alkyl), -C(=O)-(Ci- C4alkyl), -C(=O)-O(Ci-C4 alkyl), -(C1-C4 alkyl)-C(=O)-O(Ci-C4alkyl), -(Ci-C4alkyl)-NRDRE, - S(=O)2-(Ci-C4 alkyl), -aryl, -(C1-C4 alkyl)-aryl, -(C2-C4 alkenyl)-aryl, -heteroaryl, -(C1-C4 alkyl)- heteroaryl, -C(=O)-(C3-C? cycloalkyl), -(C2-C6 heterocycloalkyl) or -(C1-C4 alkyl)-C(=O)-(C2-Ce heterocycloalkyl)
{wherein at least one H of -(Ci-C4alkyl) or -C(=O)-O(Ci-C4alkyl) may be substituted with -X, at least one H of -aryl may be substituted with -X};
RG is -(C1-C4 alkyl);
Q is -O- or a bond; is a single bond or a double bond {provided that is a double bond, Yi is -CH-}; a to e are each independently an integer of 0, 1, 2, 3 or 4 {provided that a and b may not be simultaneously 0, and c and d may not be simultaneously 0};
X is each independently F, Cl, Br or I.
3. The pharmaceutical composition of claim 1 , wherein the compound represented by formula
I is the compound represented by formula la:
[Formula la]
Figure imgf000088_0001
R3 is -aryl {wherein, at least one H of -aryl may be each independently substituted with -X};
Yi is -O- or -S(=O)2-;
Zi is N or CRZ {wherein, Rz is -X}; a and b are each independently an integer of 0, 1, 2, 3 or 4 {wherein, a and b may not be simultaneously 0}; X is each independently F, Cl, Br or I.
4. The pharmaceutical composition of claim 1, wherein in the compound represented by formula la,
Figure imgf000089_0001
R3 is -phenyl {wherein, at least one H of -phenyl each independently is substituted with -F or -Cl};
Yi is -O- or -S(=O)2-;
Zi is N or CF.
5. A pharmaceutical composition for preventing and treating renal failure, comprising a compound having a following structure of [Table A], optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient:
[Table A]
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
6. A pharmaceutical composition for preventing and treating renal failure, comprising a compound having a following structure of [Table B], optical isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient:
[Table B]
Figure imgf000119_0001
7. The pharmaceutical composition of claim 6, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.
8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is orally administered.
9. A method for preventing and treating renal failure, including administering the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual, wherein the compound represented by above formula I is the same as in claim 1.
10. A method for preventing and treating renal failure, including administering a compound having a structure of [Table A] in claim 5, optical isomers thereof or pharmaceutically acceptable salts thereof into an individual:
11. A method for preventing and treating renal failure, including administering a compound having a following structure of [Table B], optical isomers thereof or pharmaceutically acceptable salts thereof into an individual:
[Table B]
Figure imgf000121_0001
12. The method of claim 11, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.
13. A use of the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing and treating renal failure, wherein the compound represented by above formula I is the same as in claim 1.
14. A use of a compound having a structure of [Table A] in claim 5, optical isomers thereof or pharmaceutically acceptable salts thereof for preventing and treating renal failure.
15. A use of a compound having a following structure of [Table B], optical isomers thereof or pharmaceutically acceptable salts thereof for preventing and treating renal failure:
[Table B]
Figure imgf000123_0001
16. The use of claim 15, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.
17. A use of the compound represented by formula I, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating renal failure, wherein the compound represented by above formula I is the same as in claim 1.
18. A use of a compound having a structure of [Table A] in claim 5, optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating renal failure.
19. A use of a compound having a following structure of [Table B], optical isomers thereof or pharmaceutically acceptable salts thereof in preparing a medicament for preventing and treating renal failure:
[Table B]
Figure imgf000125_0001
20. The use of claim 19, wherein the renal failure is at least one selected from the group consisting of acute renal failure and chronic renal failure.
PCT/IB2023/063232 2022-12-27 2023-12-26 Compositions for preventing and treating renal failure (rf) WO2024141925A1 (en)

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