WO2020151621A1 - Composé, son procédé de préparation et ses applications médicales - Google Patents

Composé, son procédé de préparation et ses applications médicales Download PDF

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WO2020151621A1
WO2020151621A1 PCT/CN2020/073014 CN2020073014W WO2020151621A1 WO 2020151621 A1 WO2020151621 A1 WO 2020151621A1 CN 2020073014 W CN2020073014 W CN 2020073014W WO 2020151621 A1 WO2020151621 A1 WO 2020151621A1
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compound
group
alkyl
alkoxy
hydrogen
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Chinese (zh)
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张保献
张宏武
胡杰
康志云
薛春美
李文慧
宋艳威
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Beijing Increase Innovative Drug Co Ltd
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Beijing Increase Innovative Drug Co Ltd
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Priority claimed from CN201910065981.0A external-priority patent/CN111471031B/zh
Priority claimed from CN201910336845.0A external-priority patent/CN111840271B/zh
Application filed by Beijing Increase Innovative Drug Co Ltd filed Critical Beijing Increase Innovative Drug Co Ltd
Publication of WO2020151621A1 publication Critical patent/WO2020151621A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/382—Heterocyclic compounds having sulfur as a ring hetero atom having six-membered rings, e.g. thioxanthenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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

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 medical use.
  • 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, which can be used to prevent or treat diabetes and has the effects of inhibiting the increase in blood sugar and lowering the blood sugar level.
  • the present invention also provides a preparation method and medical use of the compound, its isomer or its pharmaceutically acceptable salt.
  • the first aspect of the present invention relates to the compound represented by formula I, its isomer or pharmaceutically acceptable salt,
  • 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.
  • 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 C1-6 alkyl -C (O) -O-, 3-14 membered aliphatic heterocyclic oxy group (e.g., 3-10 membered aliphatic heterocyclic group), a carboxyl group, C 5-10 aryl 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 Al
  • 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 and 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, 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, 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, hydroxyl, 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
  • the compound or isomer thereof is selected from:
  • the second aspect of the present invention relates to a composition
  • a composition comprising the compound according to the first aspect of the present invention, an isomer or a pharmaceutically acceptable salt thereof.
  • the composition is a pharmaceutical composition.
  • the composition further comprises pharmaceutical excipients.
  • the pharmaceutical composition may be, but not limited to, tablets, pills, capsules, lozenges, hard candy, powders, sprays, creams, ointments, suppositories, gels Dosage forms such as gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs or syrups.
  • the pharmaceutical composition can be administered parenterally, locally, intravenously, oral, subcutaneous, intraarterial, intradermal, transdermal (transdermal), rectal, intracranial, peritoneal Intranasal, intramuscular route or as an inhalant for administration, and can also be administered by all use forms well known to those skilled in the medical field.
  • pharmaceutical excipients include but are not limited to diluents, lubricants, binders, disintegrants, absorbents, coloring agents, flavoring agents, sweeteners, emulsifiers, and dispersants , Reagents and fillers to enhance the absorption of compounds.
  • diluents include, but are not limited to, water, triglycerides such as hydrogenated or partially hydrogenated vegetable oils or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils such as docosahexaenoic acid or its esters Or triglycerides or mixtures, omega-3 fatty acids or their derivatives, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, glucose and/or glycine; lubricants include but are not limited to dioxide Silicon, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and/or polyethylene glycol; binders include but Not limited to magnesium aluminum silicate, starch paste, gelatin, methyl cellulose, sodium carboxymethyl cellulose, magnesium carbonate, natural sugars such as glucose or ⁇ -lactose,
  • the third aspect of the present invention relates to a method for preparing the compound, its isomer or pharmaceutically acceptable salt according to the first aspect of the present invention, which comprises the following steps:
  • the compound represented by formula II is subjected to a deprotection reaction to obtain the compound, its isomer or pharmaceutically acceptable salt according to the first aspect of the present invention
  • 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.
  • R 9 is selected from 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
  • the compound represented by formula II is prepared by the following steps:
  • R 9 is as described in the compound represented by formula II;
  • 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 C 5-10 arylsulfonyloxy, wherein the C 1-6 alkane
  • the sulfonyloxy group and the C 5-10 arylsulfonyloxy group 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 with 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 fourth aspect of the present invention relates to the compound described in the first aspect of the present invention, its isomers or pharmaceutically acceptable salts, or the composition described in the second aspect of the present invention is used in the preparation of drugs for preventing or treating diabetes or in the preparation of drugs for inhibiting blood sugar. Use in drugs that raise or lower blood sugar.
  • the diabetes is type I diabetes and/or type II diabetes.
  • type I diabetes is type I diabetes induced by injection of alloxan.
  • type 2 diabetes is type 2 diabetes induced by a high-fat and high-sugar diet.
  • the fifth aspect of the present invention relates to a method for preventing or treating diabetes or a method for inhibiting the increase in blood sugar or reducing blood sugar, including the following steps:
  • a subject in need is administered an effective amount of the compound described in the first aspect of the present invention, its isomer or pharmaceutically acceptable salt, or the composition described in the second aspect of the present invention.
  • the diabetes is type I diabetes and/or type II diabetes.
  • type I diabetes is type I diabetes induced by injection of alloxan.
  • type 2 diabetes is type 2 diabetes induced by a high-fat and high-sugar diet.
  • the compound according to the first aspect of the present invention, its isomers or pharmaceutically acceptable salts, or the composition according to the second aspect of the present invention, are used for preventing or treating diabetes or for inhibiting or reducing blood glucose;
  • the diabetes is type I diabetes and/or type II diabetes.
  • type I diabetes is type I diabetes induced by injection of alloxan.
  • type 2 diabetes is type 2 diabetes induced by a high-fat and high-sugar diet.
  • isomers include, but are not limited to, enantiomers, cis-trans isomers, conformational isomers, mesoisomers, and stereoisomers that have a chiral center but are not in a mirror image relationship. .
  • the present invention also relates to one or more of the following 1 to 14:
  • glycoside derivative wherein the glycoside derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof:
  • 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, hydroxyl, carboxy, alkoxy, -O-aryl, -O-heteroaryl, -OCH 2 -aryl, -OCH 2 -Heteroaryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 , -OCHF 2 , -OCF 3 , halogen (fluorine, chlorine, bromine or iodine), -CN, alkoxy Alkoxy 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 (fluorine, chlorine, bromine or iodine), hydroxyl, amino, carboxy, Cyano, alkoxy or nitro;
  • the R 7 and R 7a are independently a hydrogen atom or an alkyl group.
  • R 4 and R 5 are independently hydrogen, hydroxy, alkoxy, -O -Aryl, -OCH 2 -aryl, alkyl, cycloalkyl, aryl, heteroaryl, -CF 3 , -OCHF 2 , -OCF 3 , halogen (fluorine, chlorine, bromine or iodine) or -CN ; R 4 , R 5 are the same or different.
  • the -O-aryl group 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 straight chain alkyl group or branched chain alkyl group, exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, is
  • 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 (fluorine, chlorine, bromine or iodine), -CN, alkoxy Alkoxy 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 TMS-, Bn-, Ac-, THP-, MOM- or TBDMS-;
  • alkyl group, cycloalkyl group, aryl group, and heteroaryl group may be further substituted by one or more substituents, and the substituents include halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, carboxy, Cyano, alkoxy or nitro;
  • the R 7 and R 7a are independently a hydrogen atom or an alkyl group.
  • 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 (fluorine, chlorine, bromine or iodine), -CN, alkoxy Alkoxy 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 TMS-, Bn-, Ac-, THP-, MOM- or TBDMS-;
  • alkyl group, cycloalkyl group, aryl group, and heteroaryl group may be further substituted by one or more substituents, and the substituents include halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, carboxy, Cyano, alkoxy or nitro;
  • the R 7 and R 7a are independently a hydrogen atom or an alkyl group.
  • 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 (fluorine, chlorine, bromine or iodine), -CN, alkoxy Alkoxy 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 8 is -H, -F, -Cl, -Br, -I, -OMs, -Ots or -OTf;
  • R 9 is TMS-, Bn-, Ac-, THP-, MOM- or TBDMS-;
  • alkyl group, cycloalkyl group, aryl group, and heteroaryl group may be further substituted by one or more substituents, and the substituents include halogen (fluorine, chlorine, bromine or iodine), hydroxyl, amino, carboxy, Cyano, alkoxy or nitro;
  • the R 7 and R 7a are independently a hydrogen atom or an alkyl group.
  • glycoside derivatives of any one of aspects 1 to 6 in the prevention and/or treatment of type II diabetes drugs induced by high-fat and high-sugar foods.
  • 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: Salts formed with 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)
  • 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.
  • C 4-12 aryl group substituted with a C 1-6 alkoxy C 5-10 aryl group substituted with a C 1-6 alkoxy or C 6-10 aryl group substituted with a C 1-6 alkoxy group, particularly Such as PhCH 2 O-,
  • 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 to prevent or treat diabetes and have the effects of inhibiting the increase in blood sugar and lowering the blood sugar level.
  • 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%.
  • prep-HPLC preparative HPLC
  • column is Phenomenex Luna C18, 250mm*100mm, id10 ⁇ m; mobile phase: 0.1% (W/W) Trifluoroacetic acid aqueous solution-acetonitrile, the volume percentage of acetonitrile gradually increased from 25% to 53% within 30 minutes), 15 g of compound 2 was obtained as a white solid, and the yield was 41.5%.
  • 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 prep-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.

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Abstract

L'invention se rapporte au domaine médical et concerne particulièrement un composé de formule (I), son isomère et son sel pharmaceutiquement acceptable. L'invention concerne plus particulièrement un composé, son stéréo-isomère ou son procédé de préparation de son sel pharmaceutiquement acceptable et ses applications médicales. Le composé, son stéréo-isomère ou son sel pharmaceutiquement acceptable selon la présente invention peuvent être utilisé pour prévenir ou traiter le diabète et pour inhiber l'hyperglycémie ou l'hypoglycémie.
PCT/CN2020/073014 2019-01-24 2020-01-19 Composé, son procédé de préparation et ses applications médicales Ceased WO2020151621A1 (fr)

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CN201910336845.0A CN111840271B (zh) 2019-04-25 2019-04-25 一种糖苷类衍生物新用途
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