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WO2024169790A1 - Composé sulfoxyde et son utilisation - Google Patents

Composé sulfoxyde et son utilisation Download PDF

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Publication number
WO2024169790A1
WO2024169790A1 PCT/CN2024/076356 CN2024076356W WO2024169790A1 WO 2024169790 A1 WO2024169790 A1 WO 2024169790A1 CN 2024076356 W CN2024076356 W CN 2024076356W WO 2024169790 A1 WO2024169790 A1 WO 2024169790A1
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alkyl
alkylene
membered
pharmaceutically acceptable
solvate
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Chinese (zh)
Inventor
张学军
臧杨
李群
周圆
尹珊珊
王猛
钱丽娜
李莉娥
杨俊�
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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Wuhan Humanwell Innovative Drug Research and Development Center Ltd Co
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    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4436—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention belongs to the field of medicine, and in particular, relates to a sulfoxide compound and a use thereof.
  • the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) gene is located on chromosome 4, 4q34-q35, with a span of approximately 31kb, a total of 7 exons, and a molecular weight of 29kD.
  • 15-PGDH is composed of 266 amino acids and belongs to the short-chain dehydrogenase (SDR) family. It is a dimer composed of two identical subunits, but some people believe that it is only enzymatically active when it exists as a monomer.
  • 15-PGDH is a key enzyme for the degradation and inactivation of prostaglandins (PGs) and related eicosane bioactive substances.
  • the object of the present invention is to provide a novel compound useful as a 15-PGDH inhibitor.
  • a sulfoxide compound as shown in Formula I a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof:
  • Ra is H, halogen, hydroxy, amino, nitro, cyano, carbonyl, oxo, carboxyl, C 1 -C 6 alkyl, -NH(C 1 - C 1 -C 6 alkyl), C 1 -C 6 deuterated alkyl, C 2 -C 6 alkynyl, halogenated C 1 -C 6 alkyl, hydroxy C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 8 cycloalkyl), 6-20 membered aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, 6-20 membered aryl
  • R b is H, halogen, CN, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
  • R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11-membered heterocycloalkyl, or -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different;
  • Each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, deuterated C 1 -C 6 alkoxy;
  • R 2 is amino, CN, or -NHC(O)(C 1 -C 6 alkyl);
  • R 3-1-2 is H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, which optionally contains an additional heteroatom selected from O, S(O) r , or N;
  • X is N or CH
  • n, p, and r are 0, 1, or 2 respectively.
  • Ra is H, halogen, hydroxy, amino, nitro, cyano, -carbonyl- R1-1 , oxo, carboxyl, C1 - C6 alkyl, -NH( C1 - C6 alkyl), C1 - C6 deuterated alkyl, C2 - C6 alkynyl, halogenated C1-C6 alkyl, hydroxyC1 - C6 alkyl, C1 - C6 alkylcarbonyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), 6-20 membered aryl, 3-11 membered heterocycloalkyl or 5-11 membered heteroaryl; wherein the C1 - C6 alkyl, C3- C6 alkyl 8
  • R b is H, halogen, CN, C 1 -C 6 alkyl or halogenated C 1 -C 6 alkyl;
  • R1 is C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, C3 -C8 cycloalkyl , -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy, -( C1 - C6 alkylene)-( C1 - C6 alkoxy), 3-11-membered heterocycloalkyl or -( C1 - C6 alkylene)-(3-11-membered heterocycloalkyl); and, said R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, said substituents are the same or different;
  • Each R 1-1 is independently H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 6 alkyl), -O-alkylene-OH, C 1 -C 6 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or deuterated C 1 -C 6 alkoxy;
  • R 2 is amino, CN or -NHC(O)(C 1 -C 6 alkyl);
  • Each R 3-1-2 is independently H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, which optionally contains a heteroatom selected from O, S(O) r or N;
  • X is N or CH
  • n, p, and r are 0, 1, or 2 respectively;
  • the heteroatom of the 5-11 membered heteroaryl group is O, S(O) r or N, and the number of heteroatoms is 1, 2, 3 or 4;
  • heteroatom of the 3-11 membered heterocycloalkyl is O, S(O) r or N, and the number of heteroatoms is 1, 2, 3 or 4;
  • heteroatom of the 3-11 membered heterocycloalkenyl group is O, S(O) r or N, and the number of heteroatoms is 1, 2, 3 or 4;
  • the heteroatom of the 4-7 membered heterocyclic ring is O, S(O) r or N, and the number of heteroatoms is 1, 2, 3 or 4.
  • the Ra is H, halogen, C1 - C6 alkyl, C1 - C6 deuterated alkyl, halogenated C1 - C6 alkyl, hydroxy C1- C6 alkyl, C1 - C6 alkoxy, halogenated C1-C6 alkoxy , C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), 6-20-membered aryl, 3-11-membered heterocycloalkyl or 5-11-membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, 6-20-membered aryl, 3-11-membered heterocycloalkyl and the 5-11-membered heteroaryl are each optionally substituted by R1-1 ; when the Ra is a plurality of substituents, the substituents are the
  • the Ra is H, C1 - C6 alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, 6-20 membered aryl or 5-11 membered heteroaryl; wherein the 6-20 membered aryl and the 5-11 membered heteroaryl are each Optionally substituted by R 1-1 ; when the Ra is a plurality of substituents, the substituents are the same or different.
  • said Ra is methyl
  • the Ra is a C1 - C6 alkyl group, for example
  • said R b is halogen or CN.
  • said R b is F or CN.
  • R b is halogen, such as F.
  • R 1 is C 1 -C 4 alkyl, C 1 -C 4 deuterated alkyl, halogenated C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), C 1 -C 4 alkoxy, -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy), 3-6 membered heterocycloalkyl or -(C 1 -C 4 alkylene)-(3-6 membered heterocycloalkyl); and R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, the substituents are the same or different; the definition of R 1-1 is as described in the first aspect of the present invention.
  • R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl), C1 - C6 alkoxy or -( C1 - C6 alkylene)-( C1 - C6 alkoxy); and, R1 is optionally substituted by one or more R1-1 ; when there are multiple substituents, the substituents are the same or different.
  • R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 8 cycloalkyl) or -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy).
  • R 1 is butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH 2 ) x -cyclopropyl , -(CH 2 ) x -cyclobutyl, -(CH 2 ) x -cyclopentyl, -(CH 2 ) x -cyclohexyl or -(C 1 -C 4 alkylene)-(C 1 -C 4 alkoxy); wherein x is 1, 2, or 3.
  • R 1 is -CH 2 CH 2 -O-CH 3 , butyl, cyclobutyl, or -CH 2 -cyclopropyl.
  • R 1 is -CH 2 CH 2 -O-CH 3 , n-butyl, cyclobutyl or -CH 2 -cyclopropyl.
  • R 1 is -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), for example -CH 2 CH 2 -O-CH 3 .
  • R 1-1 is H, halogen, hydroxyl, nitro, cyano, carbonyl, oxo, carboxyl, -NH(C 1 -C 3 alkyl), -O-alkylene-OH, C 1 -C 3 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or deuterated C 1 -C 3 alkoxy.
  • each R 1-1 is independently H, halogen, C 1 -C 3 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy or deuterated C 1 -C 3 alkoxy.
  • each R 1-1 is independently H, halogen or C 1 -C 3 alkyl.
  • said R 1-1 is H, F or methyl.
  • each R 1-1 is independently H.
  • said R 2 is -NH 2 , CN or -NH-C(O)-CH 3 .
  • said R 2 is -NH 2 .
  • R 3 is a 6-10 membered aryl group, a 5-6 membered heterocycloalkyl group, a 3-6 membered heterocycloalkenyl group or a 5-10 membered heteroaryl group, which is optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • R 3 is a 5-6 membered heteroaryl group optionally substituted by one or more R 3-1 , or an 8-10 membered bicyclic heteroaryl group optionally substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • R 3 is a 3-11 membered heterocycloalkenyl group; which is optionally substituted by one or more R 3-1 ; the heteroatom of the 3-11 membered heterocycloalkenyl group is N, and the number of heteroatoms is 1 or 2; the number of unsaturated bonds of the 3-11 membered heterocycloalkenyl group is 1 or 2.
  • R 3 is a 5-6 membered heterocycloalkenyl group; which is optionally substituted by one or more R 3-1 ; the heteroatom of the 5-6 membered heterocycloalkenyl group is N, and the number of heteroatoms is 1 or 2; the unsaturated bond of the 5-6 membered heterocycloalkenyl group is 1 or 2; for example, R 3 is
  • Each R 3-1-2 is independently H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring optionally containing a heteroatom selected from O, S(O) r or N.
  • the R 3-1 is oxo or C 1 -C 6 alkyl; the C 1 -C 6 alkyl is preferably methyl.
  • R 3 is pyrimidine, 2H-pyrimidine, 4H-pyrimidine, 4-hydroxy-pyrimidine, pyrazolopyridine, triazolopyridine, pyridine or thiazole, which is substituted by one or more R 3-1 , and the definition of R 3-1 is as described in the first aspect of the present invention.
  • said R 3 is
  • X is CH.
  • said m is 1.
  • n 1
  • the sulfoxide compound as shown in formula I is a compound of formula IA or a compound of formula IB:
  • Ra , Rb , R1 , R2 , R3 , X and M are as defined in any one of the schemes of the first aspect of the present invention.
  • the sulfoxide compound structure as shown in Formula I is a compound of Formula I-1:
  • Ra , Rb , R1 and R3 are defined as described in any one of the schemes of the first aspect of the present invention.
  • the sulfoxide compound as shown in formula I is a compound of formula I-2:
  • Ra , R1 and R3 are defined as described in any one of the schemes of the first aspect of the present invention.
  • the sulfoxide compound as shown in formula I is a compound of formula I-3:
  • Ra and R1 are defined as described in any one of the schemes of the first aspect of the present invention.
  • the C1 - C6 alkyl in Ra , R1 , R1-1 , R3-1 , R3-1-1 and R3-1-2 , the C1 - C6 alkyl, -NH( C1 - C6 alkyl), hydroxy C1- C6 alkyl, C1 - C6 alkylcarbonyl and halogenated C1 - C6 alkyl, the C1-C6 alkyl is methyl,
  • the C3 - C8 cycloalkyl and the C3 -C8 cycloalkyl in -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) are C3 - C5 cycloalkyl , for example
  • the halogen atom in the halogenated C1 - C6 alkyl and halogen is F, Cl, Br or I, preferably F.
  • the C1 - C6 alkylene in the -(C1-C6 alkylene)-( C3 - C8 cycloalkyl), -( C1 - C6 alkylene)-(C1- C6 alkoxy), C1 - C6 alkylene- OH, -C1-C6 alkylene-NH2, -C1-C6 alkylene - N ( R3-1-2 ) 2 , -C1 - C6 alkylene - OC1 - C6 alkylene-OH, -C1 - C6 alkylene- OC1 - C6 alkylene-NH2 and -C1 - C6 alkylene-COOH is C1 - C3 alkylene , such as methylene or ethylene.
  • the C 1 -C 6 alkoxy group in the -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy) group is a C 1 -C 3 alkoxy group, such as -OMe.
  • the 6-20 membered aryl group is a 6-10 membered aryl group, such as phenyl.
  • the 5-11 membered heteroaryl is a 5-6 membered heteroaryl
  • the heteroatom of the 5-6 membered heteroaryl is preferably N; the number of the heteroatom is preferably 1 or 2; for example
  • the 5-11 membered heteroaryl group may be a 5-6 membered heteroaryl group or a 8-10
  • the 5-6 membered heteroaryl group is preferably a 5-6 membered heteroaryl group having 1 or 2 heteroatoms, such as pyrimidine, 2H-pyrimidine, 4H-pyrimidine, thiazole or pyridine;
  • the 8-10 membered bicyclic heteroaryl group is preferably a bicyclic heteroaryl group with N as the heteroatom and 2, 3 or 4 heteroatoms, such as pyrazolopyridine or triazolopyridine.
  • R 3 the 5-11 membered heteroaryl group optionally substituted by one or more R 3-1 is
  • Ra is H, halogen, C1 - C6 alkyl, C1 - C6 deuterated alkyl , halogenated C1 - C6 alkyl, hydroxy C1- C6 alkyl, C1 - C6 alkoxy, halogenated C1 - C6 alkoxy, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-(C3- C8 cycloalkyl), 6-20-membered aryl, 3-11-membered heterocycloalkyl or 5-11-membered heteroaryl; wherein the C1 - C6 alkyl, C3 - C8 cycloalkyl, 6-20-membered aryl, 3-11-membered heterocycloalkyl and the 5-11-membered heteroaryl are each optionally substituted by R1-1 ; when the Ra is a plurality of substituents, the substituents are the same or different;
  • R b is halogen or CN
  • R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, -(C 1 -C 6 alkylene)-(C 3 -C 8 cycloalkyl), C 1 -C 6 alkoxy or -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy); and, said R 1 is optionally substituted by one or more R 1-1 ; when there are multiple substituents, said substituents are the same or different;
  • Each R 1-1 is independently H, halogen, C 1 -C 3 alkyl, deuterated C 1 -C 6 alkyl, halogenated C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or deuterated C 1 -C 3 alkoxy;
  • R 2 is -NH 2 , CN or -NH-C(O)-CH 3 ;
  • R3 is a 3-11-membered heterocycloalkenyl group; which is optionally substituted by one or more R3-1 ; the heteroatom of the 3-11-membered heterocycloalkenyl group is N, and the number of heteroatoms is 1 or 2; the unsaturated bonds of the 3-11-membered heterocycloalkenyl group are 1 or 2;
  • Each R 3-1-2 is independently H or C 1 -C 6 alkyl, or two R 3-1-2 together with the N atom to which they are attached can form a 4-7 membered heterocyclic ring, which optionally contains a heteroatom selected from O, S(O) r or N;
  • X is N or CH
  • n, p, and r are 0, 1, or 2 respectively.
  • Ra is H, C1 - C6 alkyl, halogenated C1 - C6 alkyl, C3 - C8 cycloalkyl, 6-20-membered aryl or 5-11-membered heteroaryl; wherein the 6-20-membered aryl and the 5-11-membered heteroaryl are each optionally substituted by R1-1 ; when Ra is a plurality of substituents, the substituents are the same or different;
  • R b is F or CN
  • R1 is C1 - C6 alkyl, C3 - C8 cycloalkyl, -( C1 - C6 alkylene)-( C3 - C8 cycloalkyl) or -( C1 - C6 alkylene)-( C1 - C6 alkoxy);
  • Each R 1-1 is independently H, halogen or C 1 -C 3 alkyl
  • R 2 is -NH 2 , CN or -NH-C(O)-CH 3 ;
  • R3 is a 3-11-membered heterocycloalkenyl group; which is optionally substituted by one or more R3-1 ; the heteroatom of the 3-11-membered heterocycloalkenyl group is N, and the number of heteroatoms is 1 or 2; the unsaturated bonds of the 3-11-membered heterocycloalkenyl group are 1 or 2;
  • X is N or CH
  • n 0, 1 or 2 respectively.
  • Ra is a C1 - C6 alkyl group, for example
  • R b is halogen, such as F
  • R 1 is -(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), for example -CH 2 CH 2 -O-CH 3 ;
  • R2 is -NH2 ;
  • R3 is a 5-6 membered heterocycloalkenyl group; which is optionally substituted by one or more R3-1 ; the heteroatom of the 5-6 membered heterocycloalkenyl group is N, and the number of heteroatoms is 1 or 2; the unsaturated bond of the 5-6 membered heterocycloalkenyl group is 1 or 2; for example, the R3 is
  • R 3-1 is oxo or C 1 -C 6 alkyl; the C 1 -C 6 alkyl is preferably methyl;
  • X is CH
  • n 1;
  • n 1.
  • the sulfoxide compound as shown in formula I is selected from any one of the following compounds:
  • the compound 1 is the compound that elutes first under chiral chromatography conditions; the elution time of the "first elution" of the compound 1 is preferably 2.3 min; the chiral chromatography conditions are preferably chromatographic column: Chiralpak AD-350 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: mobile phase A: CO2 , mobile phase B: ethanol solution containing 0.05 volume % diethylamine; gradient elution: the volume of ethanol (0.05 volume % diethylamine) solution in CO2 is eluted from 5% to 40% in sequence; flow rate: 3mL/min; detector: PDA, column temperature: 35°C; column pressure: 100Bar.
  • the sulfoxide compound as shown in formula I is selected from any one of the following compounds:
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises: a sulfoxide compound as shown in Formula I as described in the first aspect of the present invention, a solvate thereof, a pharmaceutically acceptable salt thereof, a solvate of a pharmaceutically acceptable salt thereof, or a prodrug thereof; and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the use of the sulfoxide compound of formula I as described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt or its prodrug, or the use of the pharmaceutical composition described in the second aspect of the present invention, the uses including: inhibiting 15-PGDH; and/or, preventing and/or treating 15-PGDH-related diseases; and/or, as a 15-PGDH inhibitor, and/or preparing drugs, pharmaceutical compositions or preparations for preventing and/or treating 15-PGDH-related diseases.
  • the 15-PGDH-related diseases include, but are not limited to, one, two or more of: fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and neuronal cell death, blood cell reconstitution, tissue damage, cervical disease and kidney disease.
  • the 15-PGDH-related diseases include, but are not limited to, one, two or more of fibrotic diseases, inflammatory diseases, cardiovascular diseases, trauma, autoimmune diseases, graft-versus-host disease, hair growth, osteoporosis, ear diseases, eye diseases, neutropenia, diabetes, underactive bladder, implant promotion in stem cell or bone marrow transplantation or organ transplantation, neurogenesis and nerve cell death, blood cell reconstruction, tissue damage, cervical disease and kidney disease.
  • the 15-PGDH-related diseases include, but are not limited to, fibrotic diseases (such as pulmonary fibrosis, including idiopathic pulmonary fibrosis, etc., liver fibrosis, kidney fibrosis, myocardial fibrosis, scleroderma and myelofibrosis inflammatory diseases (e.g., chronic obstructive pulmonary disease (COPD), acute lung injury, sepsis, asthma and exacerbations of lung disease, inflammatory bowel disease (IBD) (e.g., ulcerative colitis and Crohn's disease), peptic ulcers (e.g., NSAID-induced ulcers), autoinflammatory diseases (e.g., Behcet's disease), vasculitic syndromes, acute liver injury, acute kidney injury, nonalcoholic fatty liver disease (NASH), atopic dermatitis, psoriasis, interstitial cystitis, prostatitis syndromes (e.g., chronic prostatitis/
  • the tissue damage is liver damage and/or muscle damage (such as muscle atrophy and muscular dystrophy).
  • the 15-PGDH-related diseases include but are not limited to idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the 15-PGDH-related diseases include but are not limited to: liver damage.
  • the 15-PGDH-related diseases include but are not limited to: IBD.
  • the prevention and/or treatment of 15-PGDH related diseases includes but is not limited to: liver regeneration.
  • the use is for preparing a medicament for preventing and/or treating the following diseases; the diseases are one or more of fibrotic diseases, inflammatory diseases or tissue damage.
  • the fibrotic disease, the inflammatory disease and the tissue damage may all be the same as described above.
  • a method for inhibiting 15-PGDH, or preventing and/or treating 15-PGDH-related diseases comprising the steps of administering to a subject in need thereof the sulfoxide compound of formula I described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt solvate, its prodrug or the pharmaceutical composition described in the second aspect of the present invention.
  • a method for preventing or treating the following diseases comprising the steps of: administering the sulfoxide compound of formula I described in the first aspect of the present invention, its solvate, its pharmaceutically acceptable salt, its solvate of a pharmaceutically acceptable salt, its prodrug or the pharmaceutical composition described in the second aspect of the present invention to a subject in need; the disease is a fibrotic disease and/or an inflammatory disease.
  • the fibrotic disease and the inflammatory disease may be the same as described above.
  • the manufacturer's instructions for the use of the kit can be used, or the reactions and purifications can be carried out in a manner known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various general and more specific references cited and discussed in this specification.
  • groups and substituents thereof can be selected by those skilled in the art to provide stable structural parts and compounds.
  • substituents When substituents are described by conventional chemical formulas written from left to right, the substituents also include chemically equivalent substituents that would result if the formula were written from right to left. For example, CH 2 O is equivalent to OCH 2 .
  • substituents or Indicates the attachment site of a group.
  • R 1 ", “R1” and “R 1 " have the same meaning and can be replaced with each other. For other symbols such as R 2 , similar definitions have the same meaning.
  • a number from 1 to 10 should be understood as not only recording each integer of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10, but also at least recording the sum of each integer therein and 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 respectively; for example, 1 to 3 should be understood as 1, 2 and 3.
  • C 3 -C 20 alicyclic hydrocarbon group refers to a cyclic hydrocarbon group with aliphatic properties, containing a closed carbon ring in the molecule, which can represent a saturated or partially unsaturated monovalent monocyclic, bicyclic or polycyclic hydrocarbon ring, and also includes a bridged ring or a spirocyclic ring.
  • the alicyclic hydrocarbon group when the alicyclic hydrocarbon group contains two or more carbon rings, they can be connected in a variety of ways: two rings in the molecule can share a carbon atom, and this system is called a spirocyclic ring; two carbon atoms on the ring can be connected by a carbon bridge to form a bicyclic or polycyclic system, which is called a bridged ring; several rings can also be connected to each other to form a cage-like structure.
  • the alicyclic hydrocarbon group can have 3 to 20 carbon atoms, preferably "C 3 -C 12 alicyclic hydrocarbon group", and can also be "C 3 -C 7 alicyclic hydrocarbon group", which can have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 carbon atoms.
  • the alicyclic hydrocarbon group may be a "cycloalkyl", “cycloalkenyl”, “cycloalkynyl” or the like (the carbon number may be selected from any integer between 3 and 20 as mentioned above), and the alicyclic hydrocarbon group may be a monocyclic hydrocarbon group, such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • C 3 -C 7 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which may be a spirocyclic or bridged ring, having 3, 4, 5, 6 or 7 carbon atoms.
  • the C 3 -C 7 cycloalkyl group may be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.0]butyl, spiropentyl, spiro[2.3]hexyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.0]pentyl, bicyclo[2.1.1]hexyl or bicyclo[3.1.0]hexyl.
  • halogen alone or as part of another substituent refers to fluorine, chlorine, bromine, iodine; preferably fluorine or chlorine.
  • alkyl when alone or as part of another substituent, means a straight or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, free of unsaturated bonds, having, for example, 1 to 6 carbon atoms and connected to the rest of the molecule by a single bond.
  • C 1 -C 6 alkyl when alone or as part of another substituent, is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • the alkyl radical is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl
  • the group has 1, 2 or 3 carbon atoms ("C 1 -C 3 alkyl"), for example methyl, ethyl, n-propyl or isopropyl.
  • cycloalkyl refers to a cyclic alkyl group when used alone or as part of another substituent.
  • mn-membered cycloalkyl or "C m -C n cycloalkyl” should be understood to mean a saturated carbocyclic ring having m to n ring atoms.
  • 3-15-membered cycloalkyl or "C 3 -C 15 cycloalkyl” refers to a cyclic alkyl group containing 3 to 15, 3 to 9, 3 to 6 or 3 to 5 carbon atoms, which may contain 1 to 4 rings.
  • 3-10-membered cycloalkyl contains 3-10 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl, or a bicyclic hydrocarbon group such as a decalin ring.
  • cycloalkyl can be used interchangeably with the term "carbocyclic group”.
  • heterocycloalkyl when used alone or as part of another substituent refers to a cycloalkyl group in which one or more (in some embodiments, 1 to 3) carbon atoms are replaced by heteroatoms, such as, but not limited to, N, O, S, and P.
  • heteroatoms such as, but not limited to, N, O, S, and P.
  • mn-membered heterocycloalkyl or Cm - Cn heterocycloalkyl is understood to mean a saturated ring having m to n ring atoms, wherein the heteroatoms are selected from N, O, S, P, preferably N, O or S.
  • the term "4-8 membered heterocycloalkyl” or " C4 - C8 heterocycloalkyl” is understood to mean a saturated ring having 4 to 8 ring atoms, wherein 1, 2, 3, or 4 ring atoms are selected from N, O, S, P, preferably N, O or S.
  • "4-10 membered heterocycloalkyl” then means a saturated ring having 4 to 10 ring atoms.
  • the number of carbons is also meant to include the heteroatoms. Including monocyclic, bicyclic, tricyclic, spirocyclic or bridged ring.
  • heterocycloalkyl examples include: pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrrolyl, azetidinyl, thiazolidinyl, oxazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl, diazepanyl, oxazepanyl, etc.
  • heterocycloalkyl can be used interchangeably with the term “heteroalkyl ring”.
  • heterocycloalkenyl when used alone or as part of another substituent refers to a monocyclic or bicyclic ring system containing a partially unsaturated alkenyl group, wherein the ring contains 3-10 carbon atoms and at least one ring atom selected from nitrogen, sulfur and oxygen atoms ("C3- C11 heterocycloalkenyl”); wherein the heterocycloalkenyl group is non-aromatic and does not contain any aromatic rings.
  • the sulfur atom of the ring can be optionally oxidized to an S-oxide.
  • the heterocycloalkenyl group is preferably a C 3 -C 6 heterocycloalkenyl group; examples of C 3 -C 6 heterocycloalkenyl groups include, but are not limited to, dihydrofuranyl, dihydrothiophenyl, dihydropyrrolyl, dioxolyl, dihydroimidazolyl, dihydropyrazolyl, dihydrothiazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrothiadiazolyl, dihydrotriazolyl, dihydrotetrazolyl, tetrahydropyridinyl, 3,4-dihydro-2H-pyran, pyranyl, thiopyranyl, dihydropyridinyl, dihydropyrazinyl, dihydropyrimidinyl, oxazinyl and
  • exemplary C 3 -C 11 heterocycloalkenyl groups include, but are not limited to, the above-mentioned C 3 -C 6 heterocycloalkenyl groups together with octahydroisoquinolyl, 3H-indolyl, dihydroisoquinolyl, dihydroquinolyl or 4H-quinolizinyl, or isomers and stereoisomers thereof.
  • alkynyl by itself or as part of another substituent refers to a dialkyl radical having at least one carbon-carbon sp triple bond.
  • a linear or branched monovalent hydrocarbon group of from 40 to 50 carbon atoms eg, C 2 -C 6 alkynyl, and also C 2 -C 4 alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl and propynyl.
  • alkoxy by itself or as part of another substituent refers to the group -ORX , wherein RX is "alkyl” as defined above.
  • oxo when used alone or as part of another substituent refers to the replacement of two hydrogen atoms on a methylene group by oxygen, ie, the methylene group is replaced by a carbonyl group.
  • aryl when used alone or as part of another substituent refers to a monocyclic or polycyclic carbon ring having from 6 to 20 carbon atoms, wherein at least one ring is aromatic. When one of the rings is non-aromatic, the group may be attached via the aromatic ring or via the non-aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthrenyl, anthracenyl, and acenaphthenyl.
  • heteromatic ring refers to a monocyclic or polycyclic carbocyclic ring in which at least one ring atom is a heteroatom independently selected from oxygen, sulfur and nitrogen, and the remaining ring atoms are C, wherein at least one ring is an aromatic ring.
  • the group may be a carbon group or a heteroatom group (i.e., it may be C-connected or N-connected, as long as it is possible).
  • the group may be connected through an aromatic ring or through a non-aromatic ring.
  • heteroaryl examples include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, N-methylpyrrolyl and tetrahydroquinoline.
  • heteroaryl examples include, but are not limited to, imidazolyl, acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,
  • haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl.
  • Deuterated alkyl by itself or as part of another substituent refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
  • Deuterated alkoxy when used alone or as part of another substituent refers to an alkoxy group ( -ORX ) wherein the RX portion is substituted with one or more deuterium atoms, wherein RX is an "alkyl" group as defined above.
  • salt or “pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are suitable for use in contact with human and animal tissues within the scope of sound medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and are comparable to a reasonable benefit/risk ratio. say.
  • “Pharmaceutically acceptable acid addition salts” refer to salts formed with inorganic or organic acids that retain the biological effectiveness of the free base without other side effects.
  • “Pharmaceutically acceptable base addition salts” refer to salts formed with inorganic or organic bases that retain the biological effectiveness of the free acid without other side effects.
  • other salts are contemplated by the present invention. They can serve as intermediates in the purification of compounds or in the preparation of other pharmaceutically acceptable salts or can be used for the identification, characterization or purification of the compounds of the present invention.
  • amine salt refers to the product obtained by neutralizing an alkyl primary amine, secondary amine or tertiary amine with an acid.
  • the acid includes the inorganic acid or organic acid described in the present application.
  • solvate means that the compound of the present invention or a salt thereof includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent forces between molecules.
  • solvent is water, it is a hydrate.
  • pharmaceutically acceptable solvate of a salt refers to a substance formed by the combination of a compound with a pharmaceutically acceptable acid or base and a solvent (including but not limited to water, methanol, ethanol, etc.). The amount of the solvent may be stoichiometric or non-stoichiometric. Pharmaceutically acceptable solvates of salts include but are not limited to monohydrochloride monohydrate.
  • prodrug refers to a compound of the present invention that can be converted into a biologically active compound under physiological conditions or by solvolysis.
  • the prodrug of the present invention is prepared by modifying the functional groups in the compound, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug includes a compound formed by connecting a hydroxyl or amino group in the compound of the present invention to any group.
  • pharmaceutical composition refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering the biologically active compound to a mammal (e.g., a human).
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote administration of the organism, facilitate the absorption of the active ingredient, and thus exert biological activity.
  • pharmaceutically acceptable carrier includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the relevant governmental regulatory authorities as acceptable for human or livestock use.
  • excipient refers to a pharmaceutically acceptable inert ingredient.
  • excipient include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients can enhance the handling characteristics of a pharmaceutical formulation, i.e., make the formulation more suitable for direct compression by increasing fluidity and/or adhesion.
  • treatment refers to therapeutic treatment.
  • treatment means: (1) ameliorating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more biological manifestations of the condition, (3) improving one or more symptoms, effects, or side effects associated with the condition or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slowing down the condition or one or more of the symptoms, effects, or side effects of the condition. Multiple biological manifestations develop.
  • prevent refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • patient refers to any animal, preferably a mammal, that is about to or has been administered the compound or composition according to embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., preferably humans.
  • terapéuticaally effective amount refers to an amount of a compound that is effective in treating a disease or condition described herein when administered to a patient.”
  • Therapeutically effective amount will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as needed by those skilled in the art.
  • IBD inflammatory bowel disease
  • Ulcerative colitis causes inflammation and ulcers in the superficial lining of the large intestine (colon) and rectum.
  • Crohn's disease is characterized by inflammation of the lining of the digestive tract, which often affects deeper layers of the digestive tract.
  • the reaction temperature of each step can be appropriately selected according to the solvent, starting materials, reagents, etc., and the reaction time can also be appropriately selected according to the reaction temperature, solvent, starting materials, reagents, etc.
  • the target compound can be separated and purified from the reaction system by common methods, such as filtration, extraction, recrystallization, washing, silica gel column chromatography, etc. In the case of not affecting the next step reaction, the target compound can also be directly used in the next step reaction without separation and purification.
  • the present inventors have unexpectedly developed a heterocyclic compound or a pharmaceutically acceptable salt thereof, a preparation method and a use thereof through extensive and in-depth research.
  • the present invention provides a compound, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug of a compound of formula I, wherein the compound of formula I has a significant inhibitory effect on 15-PGDH.
  • the production of PGE2 can be significantly increased in a dose-dependent manner, and has a significant effect on IPF and liver regeneration. Combined with the pharmacokinetic data of mice, it can be seen that the compounds of the present invention exhibit excellent pharmacokinetic properties in mice, and have high safety and drug properties.
  • the present invention provides a method for preparing the compound shown in I, a solvate, a pharmaceutically acceptable salt, a solvate of a pharmaceutically acceptable salt or a prodrug and an intermediate.
  • the method is simple to operate, has a high yield and high purity, and can be used for industrial production of medicines.
  • IC 50 Half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved
  • n-butyllithium 14.56 mL, 29.1 mmol, 2.5 M n-hexane solution
  • n-butyllithium n-hexane solution means a n-butyllithium n-hexane solution with a molar concentration of 2.5 mol/L
  • N equivalent concentration, for example, 2N hydrochloric acid means 2 mol/L hydrochloric acid solution
  • PE Petroleum ether
  • the synthetic route of target compound 1 is as follows:
  • 6-Bromo-2,3-difluoro-4-methoxybenzonitrile (1-3) (1.0 g, 4.0 mmol), 4,4,5,5-tetramethyl-2-(2-methylpropyl-1-enyl)-1,3,2-boronate (1.34 g, 8.0 mmol), sodium carbonate (1.06 g, 10 mmol) were dissolved in 1,4-dioxane (20 mL) and water (4 mL), 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (290 mg, 0.4 mmol) was added thereto, argon was replaced three times, and the reaction was carried out at 80°C for 16 h.
  • 2,3-difluoro-4-methoxy-6-(prop-1-en-2-yl)benzonitrile (1-4) (1.4 g, 6.69 mmol) was dissolved in methanol (15 mL), replaced with nitrogen three times, wet palladium carbon (0.5 g, 10% w/w) was added, and then replaced with hydrogen balloon (15 psi) three times and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered and concentrated to obtain the target compound 2,3-difluoro-6-isopropyl-4-methoxybenzonitrile (1-5) (1.2 g, yield 85.1%).
  • 2,3-Difluoro-4-hydroxy-6-isopropylbenzonitrile (1-3 mg, 1.5 mmol) was dissolved in dichloromethane (10 mL), N,N-diisopropylethylamine (581.6 mg, 4.5 mmol) was added, trifluoromethanesulfonic anhydride (846.4 mg, 3.0 mmol) was added at 0°C, and the mixture was reacted at room temperature for 3 hours.
  • Step 7 Synthesis of 2,3-difluoro-6-isopropyl-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (1-9)
  • Step 8 Synthesis of 3-fluoro-6-isopropyl-2-mercapto-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (1-10)
  • aqueous phase was extracted with ethyl acetate (20 mL ⁇ 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound 3-fluoro-6-isopropyl-2-mercapto-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (1-10) (300 mg, yield 95.4%).
  • Step 9 Synthesis of 3-fluoro-6-isopropyl-2-((((2-methoxyethyl)thio)methyl)thio)-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (1-11)
  • Step 10 Synthesis of 3-fluoro-6-isopropyl-2-((((2-methoxyethyl)sulfinyl)methyl)thio)-4-(1-methyl-6-oxo-1,6-dihydropyrimidin-4-yl)benzonitrile (1-12)
  • the mixture was diluted with water (10 mL), quenched with saturated sodium sulfite aqueous solution (10 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate aqueous solution.
  • the reaction mixture was extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 11 Synthesis of 6-(3-amino-7-fluoro-4-isopropyl-2-((2-methoxyethyl)sulfinyl)benzo[b]thiophen-6-yl)-3-methylpyrimidin-4(3H)-one (Compound 1)
  • Step 12 Synthesis of (R)-6-(3-amino-7-fluoro-4-isopropyl-2-((2-methoxyethyl)sulfinyl)benzo[b]thiophen-6-yl)-3-methylpyrimidin-4(3H)-one (Compound 1-A) and (S)-6-(3-amino-7-fluoro-4-isopropyl-2-((2-methoxyethyl)sulfinyl)benzo[b]thiophen-6-yl)-3-methylpyrimidin-4(3H)-one (Compound 1-B)
  • Test Example 1 Compound Inhibition Test on 15-PGDH Enzyme
  • 15-PGDH (R&D Systems, catalog number 5660-DH-010) was prepared with Assay Buffer (50mM Tris-HCl, pH 7.5, 0.01% Tween 20 by volume) to twice the final concentration, i.e. 30nM. Then, it was added to a 384 white plate (Cisbio Bioassays, catalog number 66PL384025) at 8 ⁇ l/well. A negative control well was set up, with only Assay Buffer added without enzyme. Then, the compound was prepared with Assay Buffer to 4 times the final concentration, i.e. 4000nM starting, 3-fold dilution, and 10 concentrations.
  • Assay Buffer 50mM Tris-HCl, pH 7.5, 0.01% Tween 20 by volume
  • Test Example 2 Effect of Compounds on PGE2 Levels in A549 Cell Supernatant
  • A549 cells (Wuhan Punosai) were cultured in F12K + 10% FBS. Cells in good logarithmic phase were used for the experiment. The cells were digested and counted, and the cells were inoculated into 24-well plates, 8000 cells/well. The cells were cultured in a 37°C, 5% CO2 incubator overnight. After the cells adhered to the wall, the culture medium containing 0.5% FBS was changed for about 10 hours, and IL-1 ⁇ (final concentration 20ng/mL, 1mL/well) was added to each well. At the same time, a control group was set up (the control group did not add IL-1 ⁇ ).
  • mice Male mice were adaptively fed for 1-2 weeks and after reaching the target weight (25g), an IPF model (idiopathic pulmonary fibrosis model) was induced with a certain dose of bleomycin. On the day of modeling, the mice were randomly divided into a model group and a treatment group according to their weight, and oral gavage was started every day. The vehicle control group was given a blank vehicle for 21 consecutive days. During the drug administration period, the body weight was weighed every 3 days.
  • IPF model idiopathic pulmonary fibrosis model
  • the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), 10% formalin was slowly perfused into the lungs until both lungs were filled, the main trachea was ligated and fixed in 10% formalin with a volume of 5-10 times the tissue volume, paraffin tissue sections were made for the left lung, HE staining, Masson Trichrome staining, and the slices were panoramically scanned using a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner for pathological analysis.
  • S210 Hamamatsu NanoZoomer Digital Pathology
  • the experimental results show that the compounds of the present invention can significantly reduce the degree of fibrosis in the IPF prevention model of mice.
  • Test Example 4 Efficacy experiment on mouse IPF treatment model
  • mice Male mice were adaptively fed for 1-2 weeks and after reaching the target weight (25g), an IPF model (idiopathic pulmonary fibrosis model) was induced with a certain dose of bleomycin. On the day of modeling, the mice were randomly divided into a model group and a treatment group according to their weight. Oral gavage was started every day on Day 7, and the vehicle control group was given a blank vehicle for 14 consecutive days. During the drug administration period, the body weight was weighed twice a week.
  • IPF model idiopathic pulmonary fibrosis model
  • the animals were euthanized, the lungs were removed from the thyroid cartilage (no perfusion was required), 10% formalin was slowly perfused into the lungs until both lungs were filled, the main trachea was ligated and fixed in 10% formalin with a volume of 5-10 times the tissue volume, paraffin tissue sections were made for the left lung, HE staining, Masson Trichrome staining, and the slices were panoramically scanned using a Hamamatsu NanoZoomer Digital Pathology (S210) slice scanner for pathological analysis.
  • S210 Hamamatsu NanoZoomer Digital Pathology
  • the experimental results show that the compounds of the present invention can significantly reduce the degree of fibrosis in the IPF treatment model of mice.
  • Test Example 5 Mouse liver resection and regeneration efficacy experiment
  • mice The pharmacokinetic properties of the compounds of the present invention in mice were determined according to the following experimental methods.
  • mice Male CD-1 mice were used, with a dose of 10 mg/kg, and the administration route was oral gavage.
  • the solvent was 5% DMSO + 10% Solutol + 85% Saline.
  • the mice were fasted overnight, and blood was collected before administration and 15, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours after administration.
  • the blood samples were centrifuged at 6800g for 6 minutes at 2-8°C, and the plasma was collected and stored at -80°C.
  • 10 ⁇ L of plasma at each time point was added to 200 ⁇ L of methanol containing 100ng/mL internal standard, vortexed and mixed, and centrifuged at 18000g for 7 minutes at 2-8°C. 200 ⁇ L was transferred to a 96-well sample plate for LC-MS/MS quantitative analysis.
  • the main pharmacokinetic parameters were analyzed by non-compartmental model using WinNonlin 7.0 software.
  • mice The experimental results show that the compound of the present invention exhibits excellent pharmacokinetic properties in mice.

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Abstract

La présente invention concerne un composé sulfoxyde et son utilisation. La présente invention concerne un composé sulfoxyde tel que représenté dans la formule (I), un solvate, un sel pharmaceutiquement acceptable, un solvate du sel pharmaceutiquement acceptable, ou un promédicament. Le composé a un meilleur effet inhibiteur de 15-PGDH.
PCT/CN2024/076356 2023-02-17 2024-02-06 Composé sulfoxyde et son utilisation Ceased WO2024169790A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106916091A (zh) * 2015-12-24 2017-07-04 广东东阳光药业有限公司 组织蛋白酶k抑制剂及其用途
CN107921025A (zh) * 2015-03-08 2018-04-17 卡斯西部储备大学 用于治疗纤维症的短链脱氢酶活性的抑制剂
WO2020160151A1 (fr) * 2019-01-31 2020-08-06 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de 15-pgdh
CN113507931A (zh) * 2018-11-21 2021-10-15 卡斯西部储备大学 调节短链脱氢酶活性的组合物和方法
WO2021236779A1 (fr) * 2020-05-20 2021-11-25 Rodeo Therapeutics Corporation Compositions et procédés pour moduler l'activité de la déshydrogénase à chaîne courte

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107921025A (zh) * 2015-03-08 2018-04-17 卡斯西部储备大学 用于治疗纤维症的短链脱氢酶活性的抑制剂
CN106916091A (zh) * 2015-12-24 2017-07-04 广东东阳光药业有限公司 组织蛋白酶k抑制剂及其用途
CN113507931A (zh) * 2018-11-21 2021-10-15 卡斯西部储备大学 调节短链脱氢酶活性的组合物和方法
WO2020160151A1 (fr) * 2019-01-31 2020-08-06 Kyorin Pharmaceutical Co., Ltd. Inhibiteurs de 15-pgdh
WO2021236779A1 (fr) * 2020-05-20 2021-11-25 Rodeo Therapeutics Corporation Compositions et procédés pour moduler l'activité de la déshydrogénase à chaîne courte

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