Nothing Special   »   [go: up one dir, main page]

WO2020151623A1 - Composé, procédé de préparation et les applications médicales de son intermédiaire - Google Patents

Composé, procédé de préparation et les applications médicales de son intermédiaire Download PDF

Info

Publication number
WO2020151623A1
WO2020151623A1 PCT/CN2020/073024 CN2020073024W WO2020151623A1 WO 2020151623 A1 WO2020151623 A1 WO 2020151623A1 CN 2020073024 W CN2020073024 W CN 2020073024W WO 2020151623 A1 WO2020151623 A1 WO 2020151623A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
alkyl
alkoxy
hydrogen
Prior art date
Application number
PCT/CN2020/073024
Other languages
English (en)
Chinese (zh)
Inventor
张保献
张宏武
胡杰
康志云
薛春美
李文慧
宋艳威
Original Assignee
北京盈科瑞创新药物研究有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN201910065966.6A external-priority patent/CN111471040B/zh
Priority claimed from CN201910336845.0A external-priority patent/CN111840271B/zh
Application filed by 北京盈科瑞创新药物研究有限公司 filed Critical 北京盈科瑞创新药物研究有限公司
Publication of WO2020151623A1 publication Critical patent/WO2020151623A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • C07D409/10—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 linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07G—COMPOUNDS OF UNKNOWN CONSTITUTION
    • C07G3/00—Glycosides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the invention belongs to the technical field of medicine, and specifically relates to a compound, as well as a method for preparing the compound and its application as a pharmaceutical intermediate.
  • Diabetes is an endocrine and metabolic disease.
  • the cause of diabetes is: insufficient insulin secretion in the body or reduced biological effects, causing metabolic disorders of sugar, fat and protein.
  • the International Diabetes Association (IDF) predicts that by 2035, the number of people with diabetes worldwide will reach 590 million.
  • Type I diabetes is an organ-specific autoimmune disease, which exists for life.
  • the current method of treating type I diabetes is mainly to reduce and stabilize the patient’s blood sugar level. It usually depends on daily insulin injections and long-term diet control. However, the curative effect of this method is slow, and long-term insulin injections can easily cause various complications. Cause a lot of pain.
  • Type II diabetes is a chronic metabolic disease characterized by relatively insufficient insulin and hyperglycemia, which can induce a series of complications.
  • Common drugs for the treatment of type II diabetes include sulfonylurea drugs and ⁇ -carbosidase inhibition Although these drugs can better control blood sugar levels, there are still many adverse reactions in taking these drugs.
  • the purpose of the present invention is to provide a compound, its isomer or its pharmaceutically acceptable salt, as an intermediate for the preparation of drugs for preventing or treating diabetes or as an intermediate for the preparation of drugs for inhibiting and lowering blood sugar.
  • the present invention also provides a method for preparing the compound, its isomer or its pharmaceutically acceptable salt, and its application as a pharmaceutical intermediate.
  • the first aspect of the present invention relates to the compound represented by formula III, its isomers or pharmaceutically acceptable salts thereof,
  • A is selected from -O-, alkylene and imino
  • B is selected from -O- and -S-;
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkoxy, alkyl-C(O)-O-, aryloxy, Heteroaryloxy, heteroaryl, alicyclic, alicyclic, carboxy, arylalkoxy, heteroarylalkoxy, cycloalkyl, aryl, cyano and -NR 7 R 7a , Wherein the alkyl group, alkoxy group, alkyl group-C(O)-O-, aryloxy group, heteroaryloxy group, heteroaryl group, alicyclic group, aliphatic heterocyclic group, arylalkyl group Oxy, heteroarylalkoxy, cycloalkyl, aryl and amine groups are each independently optionally substituted by one or more of the following substituents: alkoxy, alkyl, halogen, hydroxyl, amino, carboxyl , Cy
  • R 7 and R 7a are each independently selected from hydrogen and alkyl
  • R 9 is selected from the group consisting of an alkyl group, a silyl group, an alkyl acyl group and an aliphatic heterocyclic group, wherein the alkyl group, a silyl group, an alkyl acyl group and an aliphatic heterocyclic group are each independently optionally substituted by one or more of the following Group substituted: halogen, hydroxy, amino, carboxy, cyano, alkyl, alkoxy, nitro and aryl.
  • A is selected from -O- and C 1-6 alkylene.
  • A is selected from -O- and C 1-4 alkylene.
  • A is selected from -O- and methylene.
  • A is -O-.
  • A is C 1-6 alkylene, preferably C 1-3 alkylene.
  • A is methylene
  • B is -O-.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl, halogen, alkyl, alkoxy, aryloxy, Heteroaryloxy, heteroaryl, alicyclic, alkyl-C(O)-O-, aliphatic, carboxy, arylalkoxy, heteroarylalkoxy, cycloalkyl, Aryl groups, cyano groups, amino groups and amino groups, wherein the alkyl group, alkoxy group, aryloxy group, heteroaryloxy group, heteroaryl group, aliphatic heterocyclic group, alkyl-C(O)-O- , Alicyclic oxy, arylalkoxy, heteroarylalkoxy, cycloalkyl, aryl, and amine groups are each independently optionally substituted by one or more of the following substituents: alkoxy, Alkyl, halogen, hydroxy, amino
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, C 1-6 Alkoxy, C 5-10 aryloxy, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl, 3-14 membered alicyclic group (e.g. 3-10 membered aliphatic heterocyclic group), C 1-6 alkyl-C(O)-O-, 3-14 membered alicyclic oxy group (e.g.
  • 3-10 membered alicyclic oxy group carboxyl group, C 5-10 aryl group C 1-6 alkoxy Group, 5-10 membered heteroaryl C 1-6 alkoxy group, 3-8 membered cycloalkyl group, C 5-10 aryl group, cyano group, amino group and amino group, wherein the C 1-6 alkyl group , C 1-6 alkoxy, C 5-10 aryloxy, 5-10 heteroaryloxy, 5-10 heteroaryl, 3-14 membered alicyclic group, C 1-6 alkyl-C( O)-O-, 3-14 membered aliphatic heterocyclic oxy group, C 5-10 aryl C 1-6 alkoxy group, 5-10 membered heteroaryl C 1-6 alkoxy group, 3-8 membered ring Alkyl, C 5-10 aryl and amino groups are each independently optionally substituted by one or more of the following substituents: C 1-6 alkoxy, C 1-6 alkyl, halogen, hydroxyl, amino,
  • the number of heteroatoms in the heteroaryloxy group, heteroaryl group, aliphatic heterocyclic group and aliphatic heterocyclic group are each independently selected from 1, 2, 3, and 4.
  • the heteroatoms in the heteroaryloxy group, heteroaryl group, alicyclic group, and aliphatic heterocyclic group are each independently selected from oxygen, sulfur and nitrogen.
  • R 1 is selected from C 1-6 alkoxy, C 1-6 alkyl-C(O)-O-, C 1-6 alkyl, C 5-10 aryl Oxy, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl, C 5-10 aryl, halogen, C 3-8 cycloalkyl, 5-10 membered alicyclic group and 5-10 membered Aliphatic heterocyclic oxy group, wherein the C 1-6 alkoxy group, C 1-6 alkyl-C(O)-O-, C 1-6 alkyl group, C 5-10 aryloxy group, 5- 10-membered heteroaryloxy, 5-10 membered heteroaryl, C 5-10 aryl, C 3-8 cycloalkyl, 5-10 membered aliphatic heterocyclic group and 5-10 membered aliphatic heterocyclic oxy group are each independent Optionally substituted with one or more of the following substituents: C 1-6 alkoxy,
  • R 1 is selected from C 1-6 alkoxy, C 1-6 alkyl-C(O)-O-, C 1-6 alkyl, C 5-10 aryl Oxy, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl, halogen, 5-10 membered alicyclic group and 5-10 membered alicyclic oxy group, wherein the C 1-6 alkane Oxy, C 1-6 alkyl-C(O)-O-, C 1-6 alkyl, C 5-10 aryloxy, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl, The 5-10 membered aliphatic heterocyclic group and the 5-10 membered aliphatic heterocyclic oxy group are each independently optionally substituted by one or more of the following substituents: C 1-6 alkoxy, halogen and C 1-6 alkane base.
  • R 1 is selected from C 1-6 alkoxy, C 1-6 alkyl-C(O)-O-, C 1-6 alkyl, C 5-10 aryl Oxy, 5-10 membered heteroaryloxy, 5-10 membered heteroaryl, halogen, 5-10 membered alicyclic group and 5-10 membered alicyclic oxy group, wherein the C 1-6 alkane Oxy, C 1-6 alkyl, C 5-10 aryloxy and 5-10 membered aliphatic heterocyclic group are each independently optionally substituted by one or more of the following substituents: C 1-6 alkoxy , Halogen, C 1-6 alkyl.
  • R 1 is selected from C 1-6 alkoxy, C 1-6 alkoxy substituted by C 1-6 alkoxy, C 1-6 alkyl-C( O) -O-, halogenated C 1-6 alkyl, halogenated phenoxy, pyrimidinyloxy, thienyl, halogen, piperazinyl substituted by C 1-6 alkyl, tetrahydrofuranyloxy.
  • R 1 is selected from C 1-4 alkoxy, C 1-4 alkoxy substituted by C 1-4 alkoxy, C 1-4 alkyl-C( O)-O-, C 1-4 alkyl substituted by one or more halogens, phenoxy substituted by one or more halogens, 2-pyrimidinyloxy, 2-thienyl, halogen, C 1- 4- alkyl substituted 1-piperazinyl, tetrahydrofuran-3-yloxy.
  • R 1 is selected from ethoxy, Trifluoromethyl, Fluorine, isopropoxy,
  • R 1 is selected from C 1-6 alkoxy, C 1-6 alkyl-C(O)-O-, C 5-10 aryloxy, 5-10 membered Heteroaryloxy, 5-10 membered heteroaryl, halogen, 5-10 membered alicyclic group and 5-10 membered alicyclic oxy group, wherein the C 1-6 alkoxy group, C 1-6 Alkyl-C(O)-O-, C 5-10 aryloxy group, 5-10 membered heteroaryloxy group, 5-10 membered heteroaryl group, 5-10 membered heterocyclic group and 5-10 membered lipid
  • the heterocyclic oxy groups are each independently optionally substituted with one or more of the following substituents: C 1-6 alkoxy, C 1-6 alkyl, and halogen.
  • R 1 is selected from C 1-6 alkoxy, C 1-6 alkyl-C(O)-O-, C 5-10 aryloxy, 5-10 membered Heteroaryloxy, 5-10 membered heteroaryl, halogen, 5-10 membered alicyclic group and 5-10 membered alicyclic oxy group, wherein the C 1-6 alkoxy group, C 5-10 The aryloxy group and the 5-10 membered aliphatic heterocyclic group are each independently optionally substituted with one or more of the following substituents: C 1-6 alkoxy, C 1-6 alkyl and halogen.
  • R 1 is selected from C 1-4 alkoxy, C 1-4 alkoxy substituted by C 1-4 alkoxy, C 1-4 alkyl-C( O) -O-, halogenated phenoxy, pyrimidinyloxy, thienyl, halogen, piperazinyl substituted by C 1-4 alkyl, and tetrahydrofuranyloxy.
  • R 1 is selected from C 1-4 alkoxy, C 1-4 alkoxy substituted by C 1-4 alkoxy, C 1-4 alkyl-C( O)-O-, phenoxy substituted by one or more halogens, 2-pyrimidinyloxy, 2-thienyl, halogen, 1-piperazinyl substituted by C 1-4 alkyl, and tetrahydrofuran-3- ⁇ oxy ⁇
  • R 1 is selected from ethoxy, Fluorine, isopropoxy,
  • R 1 is selected from C 1-6 alkoxy and C 5-10 aryloxy, wherein the C 1-6 alkoxy and C 5-10 aryloxy Each is independently optionally substituted with one or more halogens.
  • R 1 is selected from C 1-6 alkoxy and halogenated C 5-10 aryloxy.
  • R 1 is selected from C 1-4 alkoxy and phenoxy substituted with one or more halogens.
  • R 1 is selected from ethoxy, And isopropoxy.
  • R 1 is selected from ethoxy and
  • R 2 is selected from hydrogen, hydroxy, aryloxy, arylalkoxy, alkoxy, optionally halogenated alkyl, aryl, heteroaryl and halogen.
  • R 2 is selected from hydrogen, hydroxyl, C 5-10 aryloxy, C 5-10 aryl, C 1-6 alkoxy, C 1-6 alkoxy, any Optionally halogenated C 1-6 alkyl, C 5-10 aryl, 5-10 membered heteroaryl and halogen.
  • R 2 is selected from hydrogen and C 1-6 alkoxy.
  • R 2 is selected from hydrogen and C 1-4 alkoxy.
  • R 2 is selected from hydrogen and ethoxy.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, cyano and carboxy, wherein , The alkyl group, alkoxy group and cycloalkyl group are each independently optionally substituted with one or more halogens.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxy, alkyl, alkoxy, cycloalkyl, aryloxy, aryl Alkoxy, aryl, heteroaryl and cyano, wherein the alkyl, alkoxy, cycloalkyl, aryloxy, arylalkoxy, aryl and heteroaryl groups are each independently optionally Replaced by one or more halogens.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, 3- An 8-membered cycloalkyl group and a cyano group, wherein the C 1-6 alkyl group, C 1-6 alkoxy group and 3-8 membered cycloalkyl group are each independently optionally substituted with one or more halogens.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxy and halogenated C 1-6 alkyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, hydroxy, and halogenated C 1-4 alkyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, fluorine, chlorine, hydroxyl, and trifluoromethyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen and hydroxyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, fluorine, chlorine and hydroxyl.
  • R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, fluorine and hydroxyl.
  • R 3 is selected from hydrogen and halogen; preferably, R 3 is selected from hydrogen, fluorine and chlorine; more preferably, R 3 is selected from hydrogen and fluorine.
  • R 4 is selected from hydrogen, halogen, hydroxyl, and halogenated C 1-6 alkyl.
  • R 4 is selected from hydrogen, fluorine, hydroxyl, and trifluoromethyl.
  • R 4 is selected from hydrogen, halogen and hydroxyl.
  • R 4 is selected from hydrogen, fluorine and hydroxyl.
  • R 5 is selected from hydrogen, halogen and hydroxyl; preferably, R 5 is selected from hydrogen, fluorine and hydroxyl.
  • R 6 is hydrogen
  • R 9 is selected from the group consisting of C 1-6 alkyl, silyl, C 1-6 alkyl acyl and 5-10 membered aliphatic heterocyclic group, wherein the C 1-6 The alkyl group and the silyl group are each independently optionally substituted with one or more of the following substituents: C 5-10 aryl, C 1-6 alkyl, and C 1-6 alkoxy.
  • R 9 is selected from C 1-6 alkyl, C 5-10 aryl substituted C 1-6 alkyl, (C 1-6 alkyl) 3 Si-, C 1-6 alkyl acyl group, 5-10 membered aliphatic heterocyclic group and C 1-6 alkoxy substituted C 1-6 alkyl group.
  • R 9 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl Group, isohexyl, benzyl (Bn-), trimethylsilyl (TMS-), formyl, acetyl (Ac-), tetrahydropyranyl (THP-), methoxymethyl (MOM-) And tert-butyldimethylsilyl (TBDMS-).
  • R 9 is selected from methyl, ethyl, benzyl (Bn-), trimethylsilyl (TMS-), formyl, acetyl (Ac-), tetrahydro Pyranyl (THP-), methoxymethyl (MOM-) and tert-butyldimethylsilyl (TBDMS-).
  • R 9 is selected from C 1-6 alkyl and C 5-10 aryl group substituted with C 1-6 alkyl.
  • R 9 is selected from methyl, ethyl and benzyl.
  • R 9 is selected from methyl and benzyl.
  • R 9 is benzyl
  • R 9 is selected from an alkyl group optionally substituted with one or more of the following substituents: aryl.
  • R 9 is selected from alkyl and arylalkyl.
  • R 9 is selected from C 1-6 alkyl optionally substituted with one or more of the following substituents: C 5-10 aryl.
  • R 9 is selected from C 1-6 alkyl and C 5-10 aryl group substituted with C 1-6 alkyl.
  • R 9 is selected from C 1-4 alkyl and C 5-10 aryl group substituted with C 1-4 alkyl.
  • R 9 is selected from methyl, ethyl and benzyl.
  • R 9 is selected from methyl and benzyl.
  • R 9 is arylalkyl.
  • R 9 is C 1-6 alkyl substituted with C 5-10 aryl.
  • R 9 is C 1-4 alkyl substituted with C 5-10 aryl.
  • R 9 is benzyl
  • the compound or isomer thereof is selected from:
  • the second aspect of the present invention relates to a method for preparing the compound according to the first aspect of the present invention, its isomer or pharmaceutically acceptable salt, which comprises the following steps:
  • R 8 is selected from hydrogen, halogen, alkylsulfonyloxy and arylsulfonyloxy, wherein the alkylsulfonyloxy and arylsulfonyloxy are each independently optionally selected by one or more of the following Substituents are substituted: halogen, alkyl and alkoxy.
  • R 8 is selected from hydrogen, halogen, C 1-6 alkylsulfonyloxy and substituted C 5-10 arylsulfonyloxy, wherein said C 1- 6 alkylsulfonyloxy and C 5-10 arylsulfonyloxy are each independently optionally substituted with one or more of the following substituents: halogen, C 1-6 alkyl.
  • R 8 is selected from the group consisting of hydrogen, halogen, C 1-6 alkylsulfonyloxy optionally substituted with C 1-6 alkyl and C 5- 10 Arylsulfonyloxy.
  • R 8 is selected from hydrogen, halogen, C 1-6 alkylsulfonyloxy, benzenesulfonyloxy substituted by C 1-6 alkyl, and halogenated C 1 -6 alkylsulfonyloxy.
  • R 8 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methanesulfonyloxy (-OMs), p-toluenesulfonyloxy (-OTs) and trifluoromethanesulfonate Acyloxy (-OTf).
  • the third aspect of the present invention relates to the use of the compound described in the first aspect of the present invention, its isomer or pharmaceutically acceptable salt in the preparation of the compound represented by formula I;
  • A, B, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described in the first aspect of the present invention.
  • A, B, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as described in the first aspect of the present invention.
  • isomers include, but are not limited to, enantiomers, cis-trans isomers, conformational isomers, mesoisomers, and stereoisomers with a chiral center but not in a mirror image relationship.
  • the present invention also relates to one or more of the following aspects 1 to 13:
  • a method for preparing a glycoside derivative wherein the glycoside derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof, and the compound represented by formula I or a pharmaceutically acceptable salt thereof
  • the salt of is prepared by deprotection reaction of the intermediate compound represented by the following formula II, and the compound represented by formula II is prepared by the compound represented by formula III:
  • A is oxygen, -(CH 2 ) m -or -NH-; m is 1, 2 or 3;
  • B is an oxygen atom or a sulfur atom
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 , -OCHF 2 , -OCF 3 , halogen, -CN, alkoxyalkoxy or -NR 7 R 7a Or a 3-14 membered heterocyclic ring containing 1-4 heteroatoms which are N, O, S, SO and/or SO 2 ;
  • alkyl group, cycloalkyl group, aryl group, and heteroaryl group may be further substituted by one or more substituents, and the substituents include halogen, hydroxy, amino, carboxy, cyano, alkoxy or nitro ;
  • the R 7 and R 7a are independently a hydrogen atom or an alkyl group
  • R 9 is alkyl, TMS-, Bn-, formyl, Ac-, THP-, MOM- or TBDMS-;
  • the alkyl group is preferably C1-C6 chain alkyl; more preferably methyl, ethyl , N-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl.
  • -O-aryl is The -O-heteroaryl group is The -OCH 2 -aryl group is PhCH 2 O-, The -OCH 2 -heteroaryl group is The alkyl group is a C1-C6 chain alkyl group, including linear or branched chain alkyl groups, exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl; the cycloalkyl group is a C3-C6 cycloalkyl group, including a cyclo
  • A, B, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 9 are as defined in aspects 1-5;
  • R 8 is -H, -F, -Cl, -Br, -I, -OMs, -OTs, or -OTf.
  • A is oxygen, -(CH 2 ) m -or -NH-; m is 1, 2 or 3;
  • B is an oxygen atom or a sulfur atom
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, hydroxy, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 , -OCHF 2 , -OCF 3 , halogen, -CN, alkoxyalkoxy or -NR 7 R 7a Or a 3-14 membered heterocyclic ring containing 1-4 heteroatoms which are N, O, S, SO and/or SO 2 ;
  • R 9 is alkyl, TMS-(trimethylsilyl), Bn-(benzyl), formyl, Ac-(acetyl), THP-(tetrahydropyranyl), MOM-(methoxymethyl) ) Or TBDMS-(tert-butyldimethylsilyl);
  • alkyl group, cycloalkyl group, aryl group, and heteroaryl group may be further substituted by one or more substituents, and the substituents include halogen, hydroxy, amino, carboxy, cyano, alkoxy or nitro ;
  • the R 7 and R 7a are independently a hydrogen atom or an alkyl group.
  • R 2 is hydrogen, hydroxyl, -O-aryl, -OCH 2 -aryl, alkoxy, alkyl, aryl, heteroaryl,- CF 3 or halogen.
  • R 4 and R 5 are independently hydrogen, hydroxyl, alkoxy, -O-aryl, -OCH 2 -aryl, alkyl, ring Alkyl, aryl, heteroaryl, -CF 3 , -OCHF 2 , -OCF 3 , halogen or -CN; R 4 , R 5 are the same or different.
  • the -O-aryl group is The -O-heteroaryl group is PhCH 2 O-, The -OCH 2 -heteroaryl group is The alkyl group is a C1-C6 chain alkyl group, including straight chain alkyl group or branched chain alkyl group, exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl, isopentyl, n-hexyl or isohexyl; the cycloalkyl group is a C3-C6 cycloalkyl
  • pharmaceutically acceptable salt refers to (1) a salt formed by an acidic functional group (such as -COOH, -OH or -SO 3 H, etc.) present in a compound and an appropriate inorganic or organic cation (base), such as a compound with Salts formed by alkali metals or alkaline earth metals, ammonium salts of compounds or salts formed with nitrogen-containing organic bases; and (2) Basic functional groups (such as -NH 2 etc.) present in the compounds and appropriate inorganic or organic anions ( Acid), such as a salt formed by a compound with an inorganic acid or organic carboxylic acid.
  • an acidic functional group such as -COOH, -OH or -SO 3 H, etc.
  • base such as a compound with Salts formed by alkali metals or alkaline earth metals, ammonium salts of compounds or salts formed with nitrogen-containing organic bases
  • Basic functional groups such as -NH 2 etc.
  • Acid such as a salt formed by a compound with an inorganic acid
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl refers to a straight or branched alkyl group, such as C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl or C 5 alkyl. Specific examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, or isohexyl.
  • alkoxy refers to alkyl-O-, where "alkyl” is as defined above.
  • alkyl is as defined above.
  • Specific examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 2-butoxy, isobutoxy, tert-butoxy, n-pentoxy Or n-hexyloxy and so on.
  • aryl refers to a monovalent group formed by an aromatic monocyclic or polycyclic compound, such as a C 4-12 aryl group, a C 5-10 aryl group, or a C 6-10 aryl group. Specific examples are Phenyl, p-methylphenyl, p-fluorophenyl, o-chlorophenyl, m-methoxyphenyl or
  • aryloxy refers to aryl-O-, wherein the definition of "aryl” is as described above.
  • aryloxy refers to aryl-O-, wherein the definition of "aryl” is as described above.
  • C 4-12 aryloxy, C 5-10 aryloxy or C 6-10 aryloxy specific examples are
  • heteroaryl refers to a monovalent group formed by an aromatic monocyclic or polycyclic compound containing at least one heteroatom, the heteroatom being selected from N, O and S; for example, 4-12 membered heteroaryl, 5-10 membered heteroaryl group, 6-10 membered heteroaryl group, 4-12 membered (5-10 member, 6-10 member) nitrogen-containing arylhetero group, 4-12 member (5-10 member, 6-10 member) Member) sulfur-containing aromatic heterocyclic group or 4-12 membered (5-10 member, 6-10 member) oxygen-containing aromatic heterocyclic group. Specific examples include but are not limited to
  • heteroaryloxy refers to heteroaryl-O-, wherein the definition of “heteroaryl” is as described above.
  • 4-12 membered (5-10 membered, 6-10 membered) nitrogen-containing heteroaryloxy group or 4-12 membered (5-10 membered, 6-10 membered) sulfur-containing heteroaryloxy group, for example
  • aliphatic heterocyclic group refers to a monovalent group formed by a non-aromatic monocyclic or polycyclic compound containing at least one heteroatom, the heteroatom is selected from N, O and S; for example, 4-12 membered aliphatic hetero Cyclic, 5-10 membered alicyclic group, 5-12 membered alicyclic group, 4-12 membered (5-10 membered, 6-10 membered) nitrogen-containing aliphatic heterocyclic group, 4-12 membered (5- 10-membered, 6-10 membered) oxygen-containing aliphatic heterocyclic group or 4-12 membered (5-10 membered, 6-10 membered) sulfur-containing aliphatic heterocyclic group.
  • specific examples of aliphatic heterocyclic groups include, but are not limited to, 1-pyrrolidinyl, 1-piperazinyl, N-morpholinyl, 1-piperidinyl, or tetrahydrofuranyl.
  • aliphatic heterocyclic oxy group refers to aliphatic heterocyclic group -O-, wherein the definition of "aliphatic heterocyclic group” is as described above.
  • 4-12 membered (5-10 membered, 6-10 membered) aliphatic heterocyclyloxy group
  • 4-12 Member (5-10 member, 6-10 member) sulfur-containing alicyclic oxy group
  • 4-12 member (5-10 member, 6-10 member) oxygen-containing alicyclic oxy group include 1-pyrrolidinyloxy, 1-piperazinyloxy, N-morpholinyloxy, 1-piperidinyloxy, or 3-tetrahydrofuranyloxy.
  • alkylene refers to a divalent group left after one hydrogen atom is removed from an alkyl group, where "alkyl” is defined as described above.
  • alkyl is defined as described above.
  • arylalkoxy can also be referred to as aryl-substituted alkoxy, which refers to aryl-alkylene-O-, where the definitions of "aryl” and “alkylene” are as described above.
  • aryl and “alkylene” are as described above.
  • heteroarylalkoxy can also be referred to as heteroaryl-substituted alkoxy, which refers to heteroaryl-alkylene-O-, where the definitions of "heteroaryl” and “alkylene” are as As mentioned earlier.
  • heteroaryl substituted alkoxy 5-10 membered heteroaryl substituted alkoxy, 5-10 membered nitrogen-containing heteroaryl substituted C 1-6 alkoxy, 5-10 membered sulfur-containing heteroaryl substituted C 1-6 alkoxy Group or 5-10 membered oxygen-containing heteroaryl substituted C 1-6 alkoxy group, specific examples are
  • cycloalkyl refers to a monocyclic saturated alkyl group.
  • a 3-12 membered cycloalkyl group contains 3-12 ring members, such as 2-10 membered cycloalkyl, 3 membered, 4 membered, 5 membered, 6 membered, 7-, 8-, 9- or 10-membered cycloalkyl. Specific examples include but are not limited to: cyclopropyl, cyclobutyl, Cyclopentyl or cyclohexyl.
  • cyano refers to the -CN group.
  • amino refers to the -NH 2 group.
  • amino group refers to a product in which one or more hydrogens in an amino group are substituted by an alkyl group, wherein the definitions of "amino" and “alkyl” are as described above. Specific examples include: methylamino, ethylamino, dimethylamino, or diethylamino.
  • nitro refers to the -NO 2 group.
  • amino refers to a divalent group remaining after removing a hydrogen atom from an amino group.
  • amino refers to a divalent group remaining after removing a hydrogen atom from an amino group.
  • amino refers to a divalent group remaining after removing a hydrogen atom from an amino group.
  • the compound of the present invention can be used as intermediates for the preparation of drugs for the prevention or treatment of diabetes or as intermediates for the preparation of drugs for inhibiting the increase in blood sugar and lowering blood sugar.
  • the present invention provides methods for preparing the above-mentioned compounds, isomers or pharmaceutically acceptable salts thereof.
  • Figure 1 is an H-NMR spectrum of Compound 1 in Example 1 of the present invention.
  • Figure 2 is an H-NMR spectrum of Compound 2 in Example 2 of the present invention.
  • Figure 3 is an H-NMR spectrum of Compound 3 in Example 3 of the present invention.
  • Figure 4 is an H-NMR spectrum of compound 4 in Example 4 of the present invention.
  • Figure 5 is a high performance liquid chromatogram of intermediate compound 4-6 in Example 4 of the present invention.
  • Figure 6 is a high performance liquid chromatogram of intermediate compounds 4-7 in Example 4 of the present invention.
  • the concentrate was extracted with water and petroleum ether.
  • the petroleum ether phase was collected and the crude product was obtained by distillation under reduced pressure.
  • the crude product was passed through a silica gel column with petroleum ether as the mobile phase to obtain 61.6g Compound 1-3 is a colorless oil with a yield of 24.8%.
  • reaction solution was poured into ice water, extracted with dichloromethane, collected the organic phase, and distilled under reduced pressure to obtain a concentrate; the concentrate was subjected to prep-HPLC (preparative HPLC) (column: Phenomenex luna C18, 250mm*50mm, id10 ⁇ m; Mobile phase: 0.1% (W/W) trifluoroacetic acid aqueous solution-acetonitrile, the volume percentage of acetonitrile gradually increased from 30% to 80% within 20 minutes), 0.6 g of compound 1 was obtained as a white solid, and the yield was 32%.
  • prep-HPLC preparative HPLC
  • step (1) Nitrogen and at 0 °C conditions, obtained in step (1) in dichloromethane was added a solution of compound 11-2 ethoxybenzene 16.7g (137mmol, 1.00eq), and then added portionwise AlCl 3 18.3g (137mmol, 1.00eq), then the reaction solution was raised to room temperature for 3h, after the completion, the reaction solution was cooled to 0°C, and then 200mL diluted hydrochloric acid was added, then saturated brine was added, the organic phase was collected, dried with anhydrous Na 2 SO 4 , filtered, The filtrate was concentrated by distillation under reduced pressure to obtain a concentrate.
  • the organic phase was collected and subjected to anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate by distillation under reduced pressure to obtain a concentrate; add 100 mL of MeOH to the concentrate, stir at 20°C for 2 hours, and precipitate a solid.
  • the solid is collected by filtration and dried under reduced pressure to obtain 45.3 g of compound 12-3, which is white Solid, the yield was 85%.
  • prep-HPLC preparative HPLC
  • 7.09 g of compound 18 was obtained as a white solid, and the yield was 32%.
  • prep-HPLC preparative HPLC
  • 3 g of compound 19 was obtained as a white solid, and the yield was 37%.
  • Test Example 1 Evaluation of the therapeutic effect of glycoside derivatives of the present invention on type I diabetes
  • Alloxan was prepared with normal saline to form an ALX solution with a concentration of 7 mg/ml. Healthy ICR mice were adaptively fed for 3 days, fasted for 12 to 16 hours on the third day, and injected with ALX solution (completed within 30 seconds) into the tail vein at a dose of 70.0 mg/kg, induced type I diabetes animal model, after injection After normal feeding for 2 days, the mice were fasted for 12 to 16 hours on the third day. After injection of ALX for 72 hours, blood was taken from the tip of the tail. Pre-blood glucose concentration), the type I diabetic mice with FGB values between 11.1mmol/L and 25.0mmol/L were regarded as successfully modeled for experiments.
  • the successfully modeled type I diabetic mice were selected and randomly divided into 22 groups, each with 4 mice, half male and half, including diabetes model group G2, metformin group G3 (positive control, 200mg/kg) and the present invention
  • the glycoside derivatives were administered in groups G4 to G23.
  • the same batch of 4 healthy, normal blood glucose mice with half male and female were used as blank control group G1.
  • Oral intragastric administration was started on the second day after grouping, once a day for 7 consecutive days. Both the model group and the blank control group were given purified water. On the 7th day after administration for 1 hour, the fasting blood glucose concentration of the mice was measured by a rapid blood glucose meter. (FGB) (ie, blood glucose level after administration), the results are expressed in units of mmol ⁇ L -1 , and the test results are shown in Table 1.
  • Test Example 2 Evaluation of the therapeutic effect of glycoside derivatives of the present invention on type II diabetes
  • the healthy rats were fed with high-fat and high-sugar feed for 4 weeks, and then fasted for 12 hours without water, and injected 2% streptozotocin (STZ) solution intraperitoneally at a dose of 30mg/kg to continue high-fat and high-sugar Feed the feed for 3 days, then fast for 12 hours, use a capillary glass tube to collect 200 ⁇ L of blood from the rat’s internal canthal vein, and use a fast blood glucose meter to measure the rat’s fasting blood glucose (FBG) (ie, the pre-administration blood glucose value).
  • the fasting blood glucose value is 16.7 mmol ⁇ L -1 ⁇ 25mmol ⁇ L -1 are used as the criterion for judging the success of type 2 diabetes model.
  • the glycoside derivatives of the present invention in each administration group T4 ⁇ T30 and dapagliflozin group T3 rats were given corresponding doses of drugs (dissolved in 0.4% sodium carboxymethyl cellulose (CMCNa)) by gavage every day, while blank Control group T1 and type II diabetes model group T2 rats were given the same volume of 0.4% CMCNa by gavage every day, once a day for 2 consecutive weeks, and measured after 1 week of administration and 2 weeks after administration.
  • FBG Fasting blood glucose level
  • the glycoside derivatives of the present invention After 1 week and 2 weeks of administration, compared with the model group G2, the glycoside derivatives of the present invention have the effect of significantly lowering blood sugar in the high, medium and low dose groups; after 1 week of administration, compound 1, compound 2, compound 6. All doses of compound 9, the high dose of compound 3, the high and medium dose of compound 4, the high and medium dose of compound 11, the high and medium dose of compound 12 and the high dose of compound 17 have low blood glucose levels.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention se rapporte au domaine médical et concerne un composé de formule (III), son stéréo-isomère ou son sel pharmaceutiquement acceptable. L'invention concerne aussi un procédé de préparation du composé, de son stéréo-isomère ou de son sel pharmaceutiquement acceptable, ainsi que les applications médicales de son intermédiaire. L'intermédiaire dudit composé, son stéréo-isomère ou son sel pharmaceutiquement acceptable selon l'invention peut être un médicament intermédiaire indiqué pour la prévention ou le traitement du diabète ou comme intermédiaire pour la préparation d'un inhibiteur de l'hyperglycémie et de l'hypoglycémie.
PCT/CN2020/073024 2019-01-24 2020-01-19 Composé, procédé de préparation et les applications médicales de son intermédiaire WO2020151623A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201910065966.6 2019-01-24
CN201910065966.6A CN111471040B (zh) 2019-01-24 2019-01-24 一种糖苷类衍生物的合成方法及其中间体和应用
CN201910336845.0A CN111840271B (zh) 2019-04-25 2019-04-25 一种糖苷类衍生物新用途
CN201910336845.0 2019-04-25

Publications (1)

Publication Number Publication Date
WO2020151623A1 true WO2020151623A1 (fr) 2020-07-30

Family

ID=71736767

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/073024 WO2020151623A1 (fr) 2019-01-24 2020-01-19 Composé, procédé de préparation et les applications médicales de son intermédiaire

Country Status (1)

Country Link
WO (1) WO2020151623A1 (fr)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1047990A (zh) * 1990-08-10 1990-12-26 浙江省乐清铜管件厂 管接头冷挤压成型工艺
CN101103013A (zh) * 2005-01-07 2008-01-09 大正制药株式会社 1-硫代-d-葡萄糖醇衍生物
WO2008013321A1 (fr) * 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Nouveaux inhibiteurs de sglt
JP2008031161A (ja) * 2006-07-06 2008-02-14 Taisho Pharmaceut Co Ltd １−チオ−ｄ−グルシトール誘導体を有効成分として含有する糖尿病の予防又は治療剤
CN101260130A (zh) * 2003-01-03 2008-09-10 布里斯托尔-迈尔斯斯奎布公司 制备c-芳基葡糖苷sglt2抑制剂的方法
CN102656165A (zh) * 2009-10-20 2012-09-05 诺瓦提斯公司 糖苷衍生物及其用途
CN103596564A (zh) * 2011-06-01 2014-02-19 株式会社绿十字 作为sglt2抑制剂的新的二苯基甲烷衍生物
US20140274918A1 (en) * 2013-03-18 2014-09-18 Green Cross Corporation Method for dual inhibition of sglt1 and sglt2 using diphenylmethane derivatives

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1047990A (zh) * 1990-08-10 1990-12-26 浙江省乐清铜管件厂 管接头冷挤压成型工艺
CN101260130A (zh) * 2003-01-03 2008-09-10 布里斯托尔-迈尔斯斯奎布公司 制备c-芳基葡糖苷sglt2抑制剂的方法
CN101103013A (zh) * 2005-01-07 2008-01-09 大正制药株式会社 1-硫代-d-葡萄糖醇衍生物
JP2008031161A (ja) * 2006-07-06 2008-02-14 Taisho Pharmaceut Co Ltd １−チオ−ｄ−グルシトール誘導体を有効成分として含有する糖尿病の予防又は治療剤
WO2008013321A1 (fr) * 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Nouveaux inhibiteurs de sglt
CN102656165A (zh) * 2009-10-20 2012-09-05 诺瓦提斯公司 糖苷衍生物及其用途
CN103596564A (zh) * 2011-06-01 2014-02-19 株式会社绿十字 作为sglt2抑制剂的新的二苯基甲烷衍生物
US20140274918A1 (en) * 2013-03-18 2014-09-18 Green Cross Corporation Method for dual inhibition of sglt1 and sglt2 using diphenylmethane derivatives

Similar Documents

Publication Publication Date Title
KR102057877B1 (ko) 질소함유 헤테로고리 유도체 및 그의 약물에서의 용도
US11731961B2 (en) Phenyl propionic acid derivatives and uses thereof
WO2020011246A1 (fr) Composé contenant un cycle benzénique, son procédé de préparation et son utilisation
WO2020063824A1 (fr) Promédicament de nitroxoline et utilisation associée
WO2021213317A1 (fr) Inhibiteur de hpk1, son procédé de préparation et son utilisation
CN102234287B (zh) 硝基咪唑类化合物、其制备方法和用途
CN102256944A (zh) 鞘氨醇-1-磷酸受体拮抗剂
EP2350039A1 (fr) Inhibiteurs de la polymérase virale
JP2021524439A (ja) 熱ショックタンパク質経路に関連する疾患の治療のための、修飾された糖基を有するビアリールアミド
WO2010102512A1 (fr) Dérivés de c-aryl-glucoside leur procédé de préparation et leur utilisation pharmaceutique
CN102653522B (zh) ω-羧基取代的二苯基硫脲类化合物及其制备方法和用途
EP3228615A1 (fr) Dérivé de dihydronaphtalène
WO2020151623A1 (fr) Composé, procédé de préparation et les applications médicales de son intermédiaire
WO2020151620A1 (fr) Composé, son procédé de préparation et son utilisation en tant qu'intermédiaire de médicament
WO2020151621A1 (fr) Composé, son procédé de préparation et ses applications médicales
RU2194049C2 (ru) Производные тиадиазолил пиридазина, ингибирующие ангиогенез, способ их получения, фармацевтическая композиция и способ ее получения
CN101463031B (zh) 吲唑及四氢吲唑类化合物及其制法和其药物组合物与用途
CN107556276B (zh) C-三芳基葡萄糖苷类化合物及其制备方法和应用
CN113698390B (zh) 用作ret激酶抑制剂的化合物及其应用
WO2022222911A1 (fr) Composé pyrimidone et son utilisation
WO2022161166A1 (fr) Composé chimère de ciblage, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
CN111471032B (zh) 一种糖苷类衍生物的合成方法及其中间体和应用
CN109280068B (zh) 3β-羟基-麦角甾-5-烯甾类化合物的制备方法
CN107614484B (zh) 用于治疗肾脏和/或肝脏疾病的组合物
TW201422611A (zh) □□衍生物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20744278

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20744278

Country of ref document: EP

Kind code of ref document: A1