WO2018141263A1 - Penicilones derivative and application thereof as anti-resistant bacteria drug - Google Patents

Penicilones derivative and application thereof as anti-resistant bacteria drug Download PDF

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Publication number
WO2018141263A1
WO2018141263A1 PCT/CN2018/075069 CN2018075069W WO2018141263A1 WO 2018141263 A1 WO2018141263 A1 WO 2018141263A1 CN 2018075069 W CN2018075069 W CN 2018075069W WO 2018141263 A1 WO2018141263 A1 WO 2018141263A1
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formula
compound
methyl
group
carbon
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PCT/CN2018/075069
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French (fr)
Chinese (zh)
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陈敏
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扬州蓝色生物医药科技有限公司
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Priority to CN201880001533.8A priority Critical patent/CN109071483B/en
Publication of WO2018141263A1 publication Critical patent/WO2018141263A1/en

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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
    • A61K31/352—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 condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention belongs to the field of medicinal chemistry, and particularly relates to a penicilones derivative, a preparation method thereof and application as a drug against drug resistance.
  • the penicilones derivatives of the present invention show good antibacterial activity, especially methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VER).
  • MRSA Methylillin-resistant Staphylococcus aureus
  • MRSA is the main pathogen of clinical infection. It is widely prevalent in the world, with high infection rate, high mortality rate, and the infection rate continues to rise year by year. high. MRSA can cause various infections in the body, and it is extremely difficult for clinical treatment due to its multi-drug resistance and rapid changes in drug resistance. In China, MRSA is one of the main resistant bacteria. Vancomycin has been the last line of defense for the treatment of MRSA infection, but with the large-scale clinical use and misuse, vancomycin-resistant Staphylococcus aureus has begun to appear. Once MRSA is generally resistant to antibiotics, it will seriously threaten the lives of patients. Therefore, the development of new antibacterial drugs for MRSA infection has become a research hotspot at home and abroad, and is of great significance to the sustainable development of human society.
  • Species preservation information of marine fungi Penicillium sp.HK1-6 name of the depository: General Microbiology Center of China Microbial Culture Collection Management Committee; Address of Depository: No. 3, No.1 Beichen West Road, Chaoyang District, Beijing, China Deposit date: July 5, 2016; deposit number: CGMCC No. 12762; classification name: Penicillium sp.
  • the strain collection information can be found in the prior Chinese invention patent application (application number CN201610831163.3 or 201711417393.6).
  • the present invention provides a solvate of a compound of formula I, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a salt thereof, characterized by a compound of formula I Has the following structure:
  • X is selected from O, S, Se or NR 10 ;
  • W is selected from O or S
  • n, m, p are each independently selected from an integer of 0 to 2;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from H, halogen (preferably F, Cl, Br, I), OR 10 , or R 4 together with R 5 O (ie, forming an epoxy, where "---" between R 4 and R 5 is absent), and R 6 and R 7 together are O (ie, forming an epoxy, at this time between R 6 and R 7 "- --" is absent), R 8 and R 9 together are O (ie, forming an epoxy, where "---" between R 8 and R 9 does not exist);
  • the heteroatoms are each independently selected from O, S, N or S e ;
  • R 10 is selected from the group consisting of H, acetyl (Ac), propionyl Bromoacetyl (BrCH 2 CO), n-dodecylthioacetyl (CH 3 (CH 2 ) 11 SCH 2 CO), furan-2-formyl Cyclopentanoyl Thiophene-2-formyl Quinoxaline-2-formyl 6-chloronicotinoyl Monomethyl succinyl Phenylpropionyl When the ring A can only be selected from:
  • Another embodiment of the present invention provides in a further preferred embodiment of the above-described structure of Formula I, wherein the structure of formula I Y 1 and Y 2 together are O or S, Y 3 and Y 4 together are O or S, i.e., having The following structure (Formula I-2):
  • Formula I-7 wherein Y is O or S, and the definitions of the R 1 , R 2 , R 3 , R 6 , R 9 , X, A ring and the like are as defined in the compound of Formula I, with the same preconditions.
  • R 11 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl , n-octyl, 3-methyl-pentyl, 2-methyl-pentyl, 2-methyl-hexyl, 3-methyl-hexyl, 3-ethyl-hexyl, 1-fluoro-3-methyl -pentyl, 1-fluoro-2-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-methyl-hexyl, 1-fluoro-3-ethyl-hexyl,
  • Y 1 of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, and formula I-7 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X , W, A ring, n, m, p are selected from the specific compounds in Tables 1-9 (1001-1091, 1097, 1098, 1201-1297, 1301-1391, 1401-1497, 1501-1671, 1701-1791, 1801-1832) Specific groups at the corresponding positions.
  • the compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 is selected from Table 1 - a compound of 9 (1001-1091, 1097, 1098, 1201-1297, 1301-1391, 1401-1497, 1501-1671, 1701-1791, 1801-1832), a stereoisomer thereof, and a tautomer thereof And a solvate thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof.
  • preferred groups for example, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , in the above preferred embodiments or preferred examples (compounds in Tables 1-9) of the present invention, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, W, A ring, n, m, p, etc. may be combined with each other to form The various preferred compounds of the invention are limited in length and are not described here.
  • the present invention provides a drug against drug resistance, which comprises any of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, and formula I-6.
  • the resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I a compound of -7, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a solvate of a pharmaceutically acceptable salt thereof or a salt thereof, and at least one other antibacterial agent, and pharmaceutically An acceptable carrier, diluent or excipient.
  • the pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like.
  • the pharmaceutical composition is for preventing and/or treating methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC43300, S. aureus ATCC33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E .faecalis ATCC51299) A disease caused
  • the present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof, Use of a tautomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a drug against drug resistance.
  • the resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  • the present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof, Use of a tautomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a medicament for the prophylaxis and/or treatment of S. aureus ATCC43300, Diseases caused by S. aureus ATCC33591, S. aureus ATCC25923, S. aureus ATCC29213, E. faecalis ATCC51299, E. faecium ATCC35667 infection.
  • the present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof,
  • the resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  • the present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof,
  • the resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  • the object of the present invention is to provide an Azaphilones-like compound having strong inhibitory activity against drug-resistant bacteria, MRSA and VER, and the present invention provides Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula a compound of Formula I-4, Formula I-5, Formula I-6, Formula I-7, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or
  • the solvates of the salts have stronger inhibitory activity against MRSA and VER than cohaerins AB, sclerotiorin and compounds 5-9, and their toxic side effects are less than cohaerins AB, sclerotiorin and compounds 5-9.
  • Y is O or S, chemical bond Indicates the key pointing to the paper Or point to a key outside the paper
  • R 3 , R 6 , R 9 , W, A ring, n, m, p are the same as defined in the compound of formula I, provided that the structural compound of formula II does not include compounds 101-183.
  • the intermediate of the above II structure is preferably the following compound:
  • the present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula II-1:
  • Y is O or S, chemical bond Indicates the key pointing to the paper Or point to a key outside the paper
  • R 3 , R 6 , R 9 , W, A ring, n, m, p are the same as defined in the compound of formula I.
  • the intermediate of the above formula II-1 is preferably the following compound:
  • the present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula II-2:
  • Y is O or S, chemical bond Indicates the key pointing to the paper Or point to a key outside the paper
  • R 3 , R 6 , R 9 , R 10 , W, A ring, n, m, p are the same as defined in the compound of formula I.
  • the intermediate of the above formula II-2 is preferably the following compound:
  • Y is O or S, chemical bond Indicates the key pointing to the paper Or point to a key outside the paper
  • R 3 , R 6 , R 9 , and A ring are the same as defined in the compound of formula I, provided that the structural compound of formula III does not include compounds 101-183.
  • the intermediate of the above formula III structure is preferably the following compound:
  • the present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula III-1:
  • Y is O or S, chemical bond Indicates the key pointing to the paper Or point to a key outside the paper
  • R 3 , R 6 , R 9 , and A ring are the same as defined in the compound of formula I.
  • the intermediate of the above formula III-1 is preferably the following compound:
  • the present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula III-2:
  • Y is O or S, chemical bond Indicates the key pointing to the paper Or point to a key outside the paper
  • R 3 , R 6 , R 9 , R 10 , and A ring are the same as defined in the compound of formula I.
  • the intermediate of the above formula III-2 structure is preferably the following compound:
  • the preparation method of the compound of the formula I, I-2, I-4, and I-6 includes the following steps:
  • a compound of formula II can be obtained via Scheme 1. to give the corresponding compound of formula I-6 (X is O); or a compound of formula II can be obtained via Scheme 2. to give the corresponding compound of formula I-6 (X is O); The compound of formula II can be obtained via Scheme 3. to give the corresponding compound of formula I-6 (X is O).
  • the compound of the formula I-6 (X is O) can be obtained via Route 4.
  • a compound of the formula I-4 (X is O) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, which can be subsequently One or more of Routes 1, 2, or 3. provides the corresponding compound of Formula 1-4 (X is O).
  • the compound of the formula I-4 (X is O) may give the corresponding compound of the formula I (X is O) via one or more of the routes 5., 6., 7., 1., 2. or 3.
  • the compound of formula I-2 (X is O) can be obtained by one or more of the routes 4., 7., 1., 2. or 3.
  • the preparation method of the compound of the formula I-1, I-3, I-5, and I-7 includes the following steps:
  • a compound of formula III can be obtained via Scheme 1. to give the corresponding compound of formula I-7 (X is O); or a compound of formula III can be obtained via Scheme 2. to give the corresponding compound of formula I-7 (X is O); Compound III can be obtained via Scheme 3. to give the corresponding compound of formula I-7 (X is O).
  • a compound of formula I-7 (X is O) can be obtained via Route 4.
  • a compound of formula I-5 (X is O) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, which can be subsequently One or more of Routes 1, 2, or 3. provides the corresponding compound of Formula I-5 (X is O).
  • the compound of the formula I-5 (X is O) can be obtained by one or more of the routes 5., 6., 7., 1., 2. or 3.
  • the corresponding compound of the formula I-1 (X is Or a compound of formula I-3 (X is O) may give the corresponding compound of formula I-1 (X is O) via one or more of Routes 4., 7., 1., 2. or 3. .
  • the preparation method of the compound of the formula I, I-2, I-4, and I-6 is similar to the preparation method of the compound of the formula I, I-2, I-4, and I-6 when X is O, only The intermediate of formula II needs to be replaced with the intermediate of formula II-1.
  • the preparation method of the compound of Formula I, I-2, I-4, and I-6 includes the following steps:
  • the compound of the formula II-2 can be obtained by the route 1.
  • the corresponding compound of the formula I-6 (X is NR 10 ); or the compound of the formula II-2 can be obtained by the route 2.
  • the corresponding compound of the formula I-6 (X is NR 10 ); or a compound of formula II-2 can be obtained via Scheme 3. to give the corresponding compound of formula I-6 (X is NR 10 ).
  • a compound of the formula I-6 (X is NR 10 ) can be obtained via Route 4.
  • a compound of the formula I-4 (X is NR 10 ) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, followed by The corresponding compound of formula 1-4 (X is NR 10 ) can be obtained via one or more of Routes 1, 2, or 3.
  • a compound of formula I-6 (X is NR 10) can be obtained by the routes 5-2 I compound portion or all of carbon-carbon double bond reduction of carbon-carbon double bond of formula (X is NR 10); or Formula I-6
  • the compound (X is NR 10 ) can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond (X is NR 10 ) via Route 6.
  • the corresponding horse can be obtained via Route 7.
  • an anti-Martensian compound of formula 1-2 (X is NR 10 ), which can be subsequently subjected to the corresponding hydrocarbylation, acylation or carbonylation via one or more of Routes 1, 2, or 3.
  • Compound I-2 (X is NR 10 ).
  • the compound of the formula I-4 (X is NR 10 ) may give the corresponding compound of the formula I (X is NR) via one or more of the routes 5., 6., 7., 1., 2. or 3. 10);
  • compounds of formula I-2 (X is NR 10) can be 4, 7, 1, 2 or 3. the one or more of the corresponding compound of formula to give I (X is NR 10 via the pathway) .
  • the preparation method of the compound of the formula I-1, I-3, I-5, and I-7 includes the following steps:
  • the compound of the formula III-2 can be obtained by the route 1.
  • the corresponding compound of the formula I-7 (X is NR 10 ); or the compound of the formula III-2 can be obtained by the route 2.
  • the corresponding compound of the formula I-7 (X is NR 10 ); or a compound of formula III-2 can be obtained via Scheme 3. to give the corresponding compound of formula I-7 (X is NR 10 ).
  • a compound of the formula I-7 (X is NR 10 ) can be obtained via Route 4.
  • a compound of the formula I-5 (X is NR 10 ) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, followed by The corresponding compound of formula I-5 (X is NR 10 ) can be obtained via one or more of Routes 1, 2, or 3.
  • a compound of formula I-7 (X is NR 10) can be obtained by the routes 5-3 I compound portion or all of carbon-carbon double bond reduction of carbon-carbon double bond of formula (X is NR 10); or Formula I-7
  • the compound (X is NR 10 ) can be obtained by a route 6 to obtain a compound of the formula I-3 (X is NR 10 ) epoxidized with a partial carbon-carbon double bond or a full carbon-carbon double bond, and then the corresponding horse can be obtained via the route 7.
  • a compound of formula I-3 (X is NR 10 ) which can be followed by one or more of the routes 1, 2. or 3. to give the corresponding hydrocarbylation, acylation or carbonylation.
  • Compound I-3 (X is NR 10 ).
  • the compound of the formula I-5 may give the corresponding compound of the formula I-1 (X) via one or more of the routes 5., 6., 7., 1., 2. or 3. NR 10 ); or a compound of formula I-3 (X is NR 10 ) may give the corresponding compound of formula I-1 (X) via one or more of Routes 4., 7., 1., 2. or 3. For NR 10 ).
  • the route 1. refers to a hydrocarbylation reaction with a halogenated hydrocarbon (R 11 -L, L is a halogen); the route 2. refers to an acid halide (R 11 COL, L is a halogen) or an acid anhydride ((R 11 CO) 2 O) acylation occurs; pathway 3. refers to carbonyl reagents (such as triphosgene, phosgene or phenyl p-nitrochloroformate) and R 11 OH, R 11 SH or R 11 NH 2 reaction; route 4.
  • a carbonyl reducing agent such as NaBH 4 , LiAlH 4 , B 2 H 6 or BH 3 , etc.
  • route 5. refers to a reducing agent (such as Pd-C / H 2 , Pt-C/H 2 , PtO 2 /H 2 , Raney nickel/H 2 , sodium cyanoborohydride) undergo carbon-carbon double bond reduction reaction; pathway 6. refers to peroxides (such as m-chloroperoxybenzene) Ethyl formate mCPBA, hydrogen peroxide H 2 O 2 , peracetic acid CH 3 COOOH or t-butyl hydroperoxide t-BuOOH) epoxidation; pathway 7. refers to epoxy hydrolysis reaction, the required reagent is preferably dilute hydrochloric acid, rare Sulfuric acid, formic acid or acetic acid.
  • the hydrocarbylation reaction conditions of the present invention are conventional in the art: in the case of a base, a halogenated hydrocarbon (R 11 -L, L is a halogen, preferably chlorine, bromine, iodine), the base is preferably an alkali metal carbonate ( Preference is given to Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ), alkali metal hydroxides (preferably LiOH, NaOH, KOH), alkali metal hydrides (preferably NaH, LiH or KH) or alkali metal alkoxides (preferably) CH 3 ONa, EtONa, t-BuOK); acylation conditions are also conventional in the art: in bases, acid halides (R 11 COL, L is halogen, preferably chlorine, bromine, iodine) or anhydrides ((R 11 CO) 2 O) reaction, the base is preferably an alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium
  • the chemical reaction involved in the present invention needs to be carried out in the presence of a solvent selected from the group consisting of dichloromethane, chloroform, methanol, ethanol, ethyl acetate, water, pyridine, acetonitrile, benzene, toluene, THF, diethyl ether and ethylene glycol.
  • a solvent selected from the group consisting of dichloromethane, chloroform, methanol, ethanol, ethyl acetate, water, pyridine, acetonitrile, benzene, toluene, THF, diethyl ether and ethylene glycol.
  • a solvent selected from the group consisting of dichloromethane, chloroform, methanol, ethanol, ethyl acetate, water, pyridine, acetonitrile, benzene, toluene, THF, diethyl ether and ethylene glycol.
  • ether DMF, di
  • C1-C21 hydrocarbyl group refers to a linear, branched or cyclic alkyl group having 1 to 21 carbon atoms, and optionally contains one or more carbon-carbon double or triple bonds; - C21 (linear, branched or cyclic) alkyl, C2-C21 (linear, branched or cyclic) alkenyl, C2-C21 (linear, branched or cyclic) alkynyl.
  • the "saturated or unsaturated 3 to 12 membered ring group optionally containing 0 to 5 hetero atoms" as used in the present invention includes a 3 to 12 membered carbocyclic group (including a saturated carbocyclic ring and an unsaturated carbon ring), and 3 To a 12-membered heterocyclic group (including a saturated heterocyclic group or an unsaturated heterocyclic group), the hetero atom is selected from O, S, N or Se; and the 3- to 12-membered ring group includes a monocyclic ring, a bicyclic ring, a spiro ring or a thick ring.
  • amino acid residue refers to a group remaining after the amino group (NH 2 ) is removed from the amino acid (for example, the amino acid residue of Ala is Preferred amino acid residues are preferred, and amino acids such as Ala, Glu, Leu, Ser, Arg, Gln, Lys, Thr, Asn, Gly, Met, Trp, Asp, His, Phe, Tyr, Cys, Ile, Val, etc. are further preferred. Residues.
  • the silicon group of the present invention is preferably TMS, TBS, TES, TBDPS; the halogen of the present invention is preferably fluorine, chlorine, bromine or iodine.
  • pharmaceutically acceptable salt in the present invention means a non-toxic addition salt of an inorganic or organic acid and/or a base, see “Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201–217. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7. Or separately prepared by reacting a base or an acid functional group with a suitable organic or inorganic acid or base, respectively.
  • Representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyric acid Salt, camphorate, digluconate, cyclopentane propionate, dodecane sulfate, ethanesulfonate, glucoheptonate, glycerol phosphate, hemisulfate, heptanoate, caproic acid Salt, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene Sulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartaric acid Salt, thiocyan
  • the basic nitrogen-containing group may be quaternized by a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfate, For example, dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, dodecyl, tetradecyl, octadecyl chloride, bromide and iodide An aralkyl halide such as benzyl and phenethyl bromide. Water or oil soluble or dispersible products are thus obtained.
  • a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide
  • dialkyl sulfate For example, dimethyl, diethyl, dibutyl and dipentyl sulfate
  • Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, lemon Acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid.
  • inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid
  • organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, lemon Acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid.
  • the basic addition salt can be prepared in situ during the final isolation and purification of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or by reacting a carboxylic acid group with a suitable
  • the base e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation
  • ammonia or an organic primary, secondary or tertiary amine is prepared separately or reacted with ammonia or an organic primary, secondary or tertiary amine.
  • Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
  • solvate in the present invention means a compound of the formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7 of the present invention.
  • the organic solvent is preferably acetone, acetonitrile, methanol or ethanol
  • the solvate is preferably of the formula I, the formula I-1, the formula I-2, the formula I-3 a compound of the formula I-4 or a salt thereof, a monohydrate, a dihydrate, a trihydrate, a monomethanolate, a dimethylformate, an acetonitrile, a diacetonitrile, a monoacetate, a diacetone , semi-fumarate monohydrate, fumarate dihydrate, fumarate monoethanolate, and the like. Further preferred are monohydrate, fumarate dihydrate, fumarate monoethanolate.
  • the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7 of the present invention exist in various tautomeric forms (wherein The protons of one atom of a molecule are transferred to another atom, and the chemical bonds between the atoms of the molecule are subsequently rearranged). See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992).
  • tautomer refers to a compound produced by proton transfer, it being understood that all tautomeric forms (as long as they may be present) are included within the scope of the invention.
  • Compounds of the invention including compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, or stereoisomers thereof, and Any pharmaceutically acceptable salt, ester, metabolite and prodrug thereof may comprise an asymmetrically substituted carbon atom.
  • asymmetrically substituted carbon atoms may allow the compounds of the invention to exist in enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as, for example, (R)- or (based on absolute stereochemistry). S) - configuration.
  • the culture medium used for the culture of the fungus Penicillium sp. (HK1-6) is added per 1000 mL of water: 200 g of potatoes, boiled juice, 20 g of glucose, 30 g of crude sea salt, 15 g of agar; and poured into a glass Petri dish when used. Medium plate.
  • the fungal strain was inoculated into a medium plate and cultured at 20 ° C for 3 days under a shaker.
  • the fermentation medium used for the fermentation of the fungus Penicillium sp. HK1-6 is: per 1000 mL of water: 200 g of potatoes are boiled, 20 g of glucose, 30 g of crude sea salt; and used in an Erlenmeyer flask.
  • the fungal strain was inoculated into a flask flask medium and cultured at 15 to 20 ° C for 28 days.
  • the compound 2 (3.0 mg) was weighed and dissolved in 2.0 mL of methanol, and 320 mg of NaOH was added thereto, and the reaction was stirred at room temperature overnight, and then the pH was adjusted to about 6.0 with 3M HCl.
  • the compound 282 (yellow solid, ESI-MS (m/z): 317.1 [M+H) was obtained by hydrolyzing the compounds 1, 3, and 4, respectively, with methanol as solvent and 4N NaOH, respectively. ] + ), 284 (yellow solid, ESI-MS (m/z): 351.1 [M+H] + , 353.1 [M+2+H] + ), 285 (yellow solid, ESI-MS (m/z) : 333 [M+H] + , 335 [M+2+H] + ).
  • the compound 1 (50 mg, 0.1 mmol) was weighed and dissolved in 10 mL of THF. TBSCl (0.15 mmol) and imidazole (0.2 mmol) were added at room temperature, and the reaction was stirred at 25 ° C overnight. The reaction was stopped by adding an appropriate amount of methanol. After concentration, acetic acid was added.
  • Compound 1 can be obtained in a yield of 89% with Compound 3 (ESI-MS (m/z): 645.3 [M+H] + , 646.3 [M+1+H] + , 647.3 [M+2+H] + ).
  • Compound 10 can be obtained in a yield of 86% with compound 4 (ESI-MS (m/z): 527.2 [M+H] + , 528.2 [M+1+H] + 529.2 [M+2+H] + ).
  • Compound 10 can be obtained in a yield of 91% by compound 4 (ESI-MS (m/z): 555.2 [M+H] + , 556.2 [M+1+H] + , 557.2 [M+2+H] + ).
  • the compound 1 was replaced with the compound 1, 3, respectively, and the compound 1090 (ESI-MS (m/z): 539.3 [M+H] + ) was obtained in a yield of 73% and 77%, respectively.
  • 1091 ESI-MS (m / z): 573.2 [m + H] +, 574.2 [m + 1 + H] +, 575.2 [m + 2 + H] +).
  • an excess of Ac 2 O (6.0 equiv.) and Et 3 N (8.0 equiv.) and a catalytic amount of DMAP can be added in dichloromethane as a solvent, and the yield can be 70% or more.
  • the hydroxy-peracetylated product is obtained, for example, by using compounds 1805, 1807, 1816, 1818, 1826 instead of compound 2 as reactants to obtain peracetylated products 1811, 1812, 1827, 1830, 1832.
  • the compound 1084-1087 was hydrolyzed by 4N NaOH, respectively, and the compound 294-297 and the corresponding fatty acid compound 188 were all obtained in a yield of 80% or more.
  • the compound 101 was replaced with the compound 95-183, 201-297, 301-494, and 501-622, respectively, and the compound 188 was replaced with the following carboxylic acid, and the reaction was carried out at 60 to 80 ° C.
  • the corresponding condensation products can be obtained in a yield of 63% to 87%, such as the compounds 1002-1039, 1081, 1083-1091, 1097, 1098, 1282-1285, 1292-1297 in Table 1, in Table 2 Compounds 1201-1239, 1281, 1286-1291, compounds 1301-1343, 1385-1391 in Table 3, compounds 1401-1443, 1485-1497 in Table 4, compounds 1501-1545, 1587, 1589-1606 in Table 5, Table 6 in the compound 1607-1622, the compound 1701-1706 in Table 7; the above carboxylic acid is selected from the following compounds: (CAS: 1699983-08-8), morpholine propionic acid, cyclopropylacetic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), crotonic acid, 4-bromocrotonic acid, 2-cyano-3-methyl-2-butenoic acid (CAS: 759-21-7), 4,4,4-trifluoro
  • the compound p-nitrophenoxy acylation product can be obtained by substituting the compound 150-183, 201-297, 301-494, and 501-622, respectively, and then with the following alcohol and sulfur.
  • Alcohol or amine (ammonia) reaction MeOH, EtOH, i-PrOH, nC 12 H 25 SH, EtSH, BnOH, PhOH, BnNH 2 ,
  • a series of corresponding carbonylation compounds can be obtained, such as compounds 1041-1064 in Table 1, compounds 1240-1264 in Table 2, compounds 1344-1368 in Table 3, compounds 1444-1468 in Table 4, and compounds 1546-1570 in Table 5.
  • the compound 165 (36 mg, 0.1 mmol) was weighed and dissolved in 5 mL of DMF, and 1.4 equiv. NaH (0.14 mmol) was added in an ice bath. After stirring at room temperature for half an hour, 1.2 equiv. MeI (0.12 mmol) was added at 30 ° C.
  • the compound 165 is replaced with the compound 95-183, 201-297, 301-494, and 501-622, respectively, and a halogenated substance (for example, MeI, EtBr, i-PrBr, CF 3 I, nC 12 H 25 Br, nC 16 H 33 Br, BnBr, diphenylbromomethane (Ph 2 CHBr), Reaction of nC 6 H 13 Br, p-chlorobenzyl bromide, 8-bromoquinoline, 3-bromofuran to give the corresponding hydrocarbylation products, such as compounds 1066-1080, 1082 in Table 1; compounds 1265-1280 in Table 2 ; compounds 1369-1384 in Table 3; compounds 1469-1484 in Table 4; compounds 1571-1586, 1588 in Table 5.
  • a halogenated substance for example, MeI, EtBr, i-PrBr, CF 3 I, nC 12 H 25 Br, nC 16 H 33 Br, BnBr, di
  • methylation method using DMF as a solvent, an excess of NaH (5.0 equiv.) as a base, and MeI (4.5 equiv.) as a methylating agent, a corresponding yield of 75% or more can be obtained.
  • the permethylated product for example, compound 1806, 1808, 1822, 1823, 1825 in place of compound 165 as the reactant, provides the corresponding methylated products 1813, 1814, 1828, 1829, 1831.
  • Compound 1 was replaced with Compounds 1-4, 1001, 1003, and 1084-1091, respectively, with the following amines (or ammonia or amino acid): MeNH 2 , NH 3 ⁇ H 2 O, NH 2 OH , Ala, Glu, Leu, Ser, Arg, Gln, Lys, Thr, Asn, Gly, Met, Trp, Asp, His, Phe, Tyr, Cys, Ile, Val replace 4-aminoacetanilide, all of which can be more than 90% Yield yields the corresponding nitrogen-containing compound, such as compound 1607-1671 in Table 6, (wherein when reacted with the amino acid Arg or Lys, two nitrogen-containing compounds can be produced in close proximity to 1:1, such as compounds 1631 and 1632, 1634 and 1635, 1652 and 1653, 1655 and 1656)
  • methylene chloride or tetrahydrofuran is used as a solvent, and the molar ratio of the reaction substrate (for example, compound 95-183, 201-297) to amine (or ammonia) is 1:1.1, and the reaction is carried out at room temperature. After -30 min, the corresponding nitrogen-containing compound can be obtained in a yield of 90% or more by silica gel column chromatography, for example, the intermediate compound 501-622; the above amine (or ammonia) is selected from the following compounds: NH 3 ⁇ H 2 O, MeNH 2 , Wait.
  • the compound 101-183, 282-285, 294-297, 501-530, 538-622, 1-4, 1084-1091, and the like are used as the reaction substrates, respectively.
  • Xylene, toluene or benzene is used as a solvent, and reacted with 2 times molar equivalent of P 2 S 5 or Lawesson reagent for 1-3 h at room temperature to reflux temperature.
  • the corresponding sulfur can be obtained in a similar yield.
  • Substituting compounds for example, compounds 95-100, 201-281, 286-293, 301-494, 531-537 or compounds 1286-1291 in Table 2, compounds 1386-1391 in Table 3, and compounds 1486-1497 in Table 4.
  • a compound was obtained by reacting Compound 1751 and 1752 with Compound 165 as a reactant, and reacting with 1.4 times molar equivalent of NaH and 1.2 times molar equivalent of MeI, respectively, to obtain a compound.
  • 1753 (89%, ESI-MS (m/z): 417.1 [M+H] + ) and 1754 (93%, ESI-MS (m/z): 417.1 [M+H] + ).
  • the compound 1761 was replaced with the compound 1762 and 1763, respectively, and the compounds 1765 and 1766 were each obtained in a yield of 90% or more.
  • a compound was obtained by reacting compound 1764-1766 with compound 165 as a reactant, and reacting with 1.4 times molar equivalent of NaH and 1.2 times molar equivalent of MeI to obtain a compound. 1767-1769.
  • the compound 1767 (115 mg, 0.2 mmol) was weighed and dissolved in 10 mL of dichloromethane, 3.0 times molar equivalent of m-CPBA was added, and the reaction was carried out for 2 hours at room temperature. The reaction was terminated by adding 1 mL of saturated sodium sulfite, and extracted with dichloromethane.
  • the compound 1767-766, 1768, and 1769 were used instead of the compound 1767, and methylene chloride was used as a solvent to react with 3.0-fold molar equivalent of m-CPBA to obtain a compound 1773-1787.
  • the compound 1771 (61 mg, 0.1 mmol) was dissolved in 4 mL of methanol, and 1 mL of 2.0 N HCl was added. After stirring at room temperature for 0.5 hour, it was diluted with 50 mL of ethyl acetate and washed successively with saturated NaHCO 3 and saturated NaCl. over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by silica gel column chromatography to give compound 1788 (38mg, 63%, ESI -MS (m / z): 611.2 [m + H] +).
  • Compounds 1711-1750 can be prepared by methods such as carbonylation and alkylation.
  • the compound 1 (50 mg, 0.1 mmol) was weighed and dissolved in 10 mL of THF, and NaBH 4 (1.0 mmol) was added at room temperature. After reacting for 5 h at room temperature, the reaction was quenched by adding 2 mL of saturated NH 4 Cl. The organic phase was dried over anhydrous sodium sulfate, and then evaporated tolulululululululululululululululululululululululu MS (m/z): 503.3 [M+H] + ).
  • all ketone carbonyl groups can be reduced at room temperature to obtain corresponding hydroxylated products, for example, compounds 2-4, 1086-1091 , 1607-1614, 1616, 1617, 1620, 1622, instead of compound 1, as a reactant, can obtain a product in which the corresponding ketone carbonyl group is all reduced to a hydroxyl group in a yield of 80% or more, for example, the compounds 1802-1810 and 1815-1826 in Table 9. .
  • Formula I, Formula I-1, Formula I-2, Formula I-3 of the present invention can be prepared according to the methods described in Examples 1-19 or similar reactions in the prior art or on a conventional basis in the art. , the compound of the formula I-4, the formula I-5, the formula I-6, the formula I-7 and the intermediate compound of the formula II, the formula III, the formula II-1, the formula III-1, the formula II-2 and the formula III-2 Any compound within the range.
  • the compounds in Tables 1-9 and the intermediate compounds 201-297, 301-494, and 501-622 all of the above compounds were structurally confirmed by 1 H NMR, ESI-MS, and HPLC purity determination, and some compounds were subjected to CD, 1 H- 1 H COSY, HMQC, HMBC, NOESY were structurally confirmed. Due to space limitations, the present invention lists ESI-MS data only in Tables 1-9.
  • the simple starting materials used in the synthetic methods of the present invention can be prepared by the corresponding hydroxy compounds (or carboxylic acids) with the corresponding anhydrides, acid chlorides, halogenated hydrocarbons and the like according to methods conventional in the art.
  • the antibacterial properties of the compounds of the invention were tested according to the literature method (Pierce CG; Uppuluri P.; Teistan AR; Wormley Jr. FL; Mowat E.; Ramage G.; Lopez-ribot JL Nat. Protoc. 2008, 3, 1494-1500). active.
  • the test strain includes 5 Gram-positive bacteria, of which 2 strains of methicillin-resistant Staphylococcus aureus: S. aureus ATCC43300 and S. aureus ATCC33591, methicillin-sensitive Staphylococcus aureus 2: S. aureus ATCC25923 And S. aureus ATCC29213, vancomycin-resistant Enterococcus faecalis 1 strain: E. faecalis ATCC51299; 1 strain of Gram-negative bacteria: Escherichia coli E. coli ATCC25922.
  • the present invention tested the minimum inhibitory concentration (MIC) of all the compounds against the above 6 strains, and the compound of the present invention has no obvious antibacterial effect on E. coli ATCC25922, but against Gram-positive bacteria, especially Methicillin-resistant Staphylococcus aureus: S. aureus ATCC43300 and S.
  • aureus ATCC29213 (Table 1) -10 is abbreviated as 29213), and the minimum inhibitory concentration (MIC, ⁇ g/mL) of vancomycin-resistant Enterococcus faecalis E.faecalis ATCC51299 (abbreviated as 51199 in Table 1-10) (see Table 1-9) ).
  • the present invention only lists typical compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7. Table 1-9.
  • the present invention lists in Table 10 the activity data of compounds 1-9, cohaerins AB, sclerotiorin and antibacterial agents (vancomycin hydrochloride and oxacillin sodium) which are structurally similar to the compounds of the present invention (see Table 10). ).
  • the compound 5-9 can be produced by the method described in the Journal of Agricultural and Food Chemistry (2012), 60 (18), 4480-4491.
  • aureus ATCC33591 both of which have MIC Less than or equal to 1.56 ⁇ g / mL, far superior to the antibacterial activity of oxacillin sodium (MIC > 100 ⁇ g / mL), comparable to the antibacterial activity of vancomycin hydrochloride; while the compound of the present invention is resistant to vancomycin-resistant feces Coccus E. faecalis ATCC51299 also showed strong antibacterial activity (MIC ⁇ 3.13 ⁇ g / mL), which was superior to the antibacterial activity of vancomycin hydrochloride (6.25 ⁇ g / mL ⁇ MIC ⁇ 12.5 ⁇ g / mL). Moreover, the antibacterial activity (especially resistant bacteria) of the compounds of the present invention is significantly improved (increased 30-60 fold increase in activity) compared to their analogs cohaerins A-B, sclerotiorin and compounds 5-9.
  • the tautomer, a pharmaceutically acceptable salt thereof not only has significant anti-MRSA activity, but also has low toxic side effects.
  • the cytotoxic activity test, Compounds 1–4, and the compounds in Tables 1–9 did not show significant cytotoxic activity at 20 ⁇ M concentration.
  • cohaerins A-B, sclerotiorin and compound 5-9 showed greater cytotoxicity at the same concentration.

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Abstract

A penicilones derivative and an application thereof as an anti-resistant bacteria drug, in particular relating to a compound of formula I, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof or solvates of the salts thereof, characterized in that the compound of formula I has the following structure: formula I. The compound shows strong antibacterial activity against methicillin-resistant Staphylococcus aureus, and the antibacterial activity thereof is superior to that of oxacillin sodium and comparable to that of vancomycin hydrochloride.

Description

Penicilones衍生物及其作为抗耐药菌药物的应用Penicilones derivatives and their use as anti-drug resistant drugs 技术领域Technical field
本发明属于药物化学领域，具体涉及一种penicilones衍生物及其制备方法与作为抗耐药菌药物的应用。本发明penicilones衍生物显示了良好的抗菌活性，尤其是对甲氧西林耐药的金黄色葡萄球菌(MRSA)和万古霉素耐药的粪肠球菌(VER)。The invention belongs to the field of medicinal chemistry, and particularly relates to a penicilones derivative, a preparation method thereof and application as a drug against drug resistance. The penicilones derivatives of the present invention show good antibacterial activity, especially methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VER).
背景技术Background technique
耐甲氧西林金黄色葡萄球菌(methicillin-resistant Staphylococcus aureus,MRSA)是临床感染的首要致病菌，在世界范围内广泛流行，具有高感染率、高致死率等特点，并且感染率逐年持续升高。MRSA可导致机体各种感染，并且由于其表现出的多重耐药性以及耐药性的快速变迁给临床治疗带来了极大困难。在我国，MRSA是主要的耐药菌之一。万古霉素一直作为MRSA感染治疗的最后防线，但是随着临床上大规模的使用和误用，对万古霉素耐药的金黄色葡萄球菌已开始出现。一旦MRSA对抗生素表现出普遍耐药，将严重威胁患者的生命安全。因此，开发针对MRSA感染的新型抗菌药已成为国内外研究热点，对人类社会的可持续发展具有重要意义。Methylillin-resistant Staphylococcus aureus (MRSA) is the main pathogen of clinical infection. It is widely prevalent in the world, with high infection rate, high mortality rate, and the infection rate continues to rise year by year. high. MRSA can cause various infections in the body, and it is extremely difficult for clinical treatment due to its multi-drug resistance and rapid changes in drug resistance. In China, MRSA is one of the main resistant bacteria. Vancomycin has been the last line of defense for the treatment of MRSA infection, but with the large-scale clinical use and misuse, vancomycin-resistant Staphylococcus aureus has begun to appear. Once MRSA is generally resistant to antibiotics, it will seriously threaten the lives of patients. Therefore, the development of new antibacterial drugs for MRSA infection has become a research hotspot at home and abroad, and is of great significance to the sustainable development of human society.
发明内容Summary of the invention
发明人先前从海洋真菌Penicillium sp.HK1-6中分离得到penicilones A-D化合物，其对耐甲氧西林的金黄色葡萄球菌(MRSA)：S.aureus ATCC43300和S.aureus ATCC33591以及耐万古霉素的粪肠球菌(VER)：E.faecalis ATCC51299均显示出很强的抗菌活性(中国发明专利申请号：201611203587.1、201711417393.6)。The inventors previously isolated penicilones AD compounds from the marine fungus Penicillium sp. HK1-6, which are resistant to methicillin-resistant Staphylococcus aureus (MRSA): S. aureus ATCC 43300 and S. aureus ATCC 33591 and vancomycin-resistant feces. Enterococcus (VER): E. faecalis ATCC51299 showed strong antibacterial activity (Chinese Invention Patent Application No.: 201611203587.1, 201711417393.6).
海洋真菌Penicillium sp.HK1-6的菌种保藏信息：保藏单位名称：中国微生物菌种保藏管理委员会普通微生物中心；保藏单位地址：北京市朝阳区北辰西路1号院3号，中国科学院微生物研究所；保藏日期：2016年7月5日；保藏编号：CGMCC No.12762；分类命名：青霉Penicillium sp.。菌株保藏信息可参见，在先中国发明专利申请(申请号CN201610831163.3或201711417393.6)。Species preservation information of marine fungi Penicillium sp.HK1-6: name of the depository: General Microbiology Center of China Microbial Culture Collection Management Committee; Address of Depository: No. 3, No.1 Beichen West Road, Chaoyang District, Beijing, China Deposit date: July 5, 2016; deposit number: CGMCC No. 12762; classification name: Penicillium sp. The strain collection information can be found in the prior Chinese invention patent application (application number CN201610831163.3 or 201711417393.6).
本发明的目的在于提供系列penicilones A-D衍生物及其制备方法与中间体。It is an object of the present invention to provide a series of penicilones A-D derivatives, processes for their preparation and intermediates.
本发明提供一种式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物，其特征在于式I化合物具有如下结构：The present invention provides a solvate of a compound of formula I, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a salt thereof, characterized by a compound of formula I Has the following structure:
Figure PCTCN2018075069-appb-000001
Figure PCTCN2018075069-appb-000001
R 1和R 2各自独立地选自甲基、OR 10，且基团R 1和R 2互不相同，R 10选自H、R 11、C(＝O)-R 11、C(＝O)-OR 11、C(＝O)-SR 11、C(＝O)-NR 11，R 11选自C1-C21烃基、任选含有0至5个杂原子的饱和或不饱和的3至12元环基、或硅基； R 1 and R 2 are each independently selected from methyl group, OR 10 , and the groups R 1 and R 2 are different from each other, and R 10 is selected from H, R 11 , C(=O)-R 11 , C(=O). -OR 11 , C(=O)-SR 11 , C(=O)-NR 11 , R 11 is selected from a C1-C21 hydrocarbyl group, optionally containing 0 to 5 heteroatoms of saturated or unsaturated 3 to 12 a ring group or a silicon group;
R 11任选被羟基、羟甲基、羧基、乙酰氨基、C1-C4烷基(如甲基、乙基、丙基)、三氟甲基、三氟乙酰基、巯基、卤素、硝基、氨基、亚胺基(＝NH)、甲硫基、叠氮基(-N 3)、胍基、氰基、叔丁氧羰基(-Boc)、羰基(-C＝O)、氧代(＝O)、硫代(＝S)、磺酰基、亚磺酰基、C1-C4烷氧基(如甲氧基、乙氧基、叔丁氧基)、苯基、羟基苯基、呋喃基、萘基、苄基、苯乙基咪唑基、吡啶基、噁唑基、异恶唑 基、三氮唑基、四氮唑基、呋喃基、喹啉基、噁嗪基、噻吩基、噻唑基、噻二唑基、吲哚基、咔唑基、咪唑基、异喹啉基、苯并呋喃基、苯并噻唑基、苯并硒二唑基、香豆素基、异香豆素基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、哌啶基、哌嗪基、四氢呋喃基、二氧六环基、噁唑啉、噻唑啉基、四氢吡喃基、二氢香豆素基、二氢异香豆素基、四氢喹啉基、四氢异喹啉基、四氢咔唑基、嘧啶碱基、嘌呤碱基中的一个或多个取代； R 11 is optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (eg methyl, ethyl, propyl), trifluoromethyl, trifluoroacetyl, decyl, halogen, nitro, Amino, imido (=NH), methylthio, azide (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (= O), thio (=S), sulfonyl, sulfinyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), phenyl, hydroxyphenyl, furyl, naphthalene Base, benzyl, phenethyl imidazolyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, quinolyl, oxazinyl, thienyl, thiazolyl, Thiadiazolyl, fluorenyl, carbazolyl, imidazolyl, isoquinolinyl, benzofuranyl, benzothiazolyl, benzoselenadiazole, coumarin, isocoumarin, aza Cyclobutane, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxolyl, oxazoline, thiazolinyl, tetrahydropyranyl, dihydrogen Bean-based, dihydroisocoumarin, tetrahydroquinolyl, tetrahydroisoquinolinyl, tetra One or more substitutions in a hydrocarbazolyl, pyrimidine, or purine base;
Y 1、Y 2、Y 3、Y 4各自独立选自H、OR 10，或者Y 1与Y 2一起为O或S(即Y 1与Y 2一起形成＝O或＝S)，或者Y 3与Y 4一起为O或S(即Y 3与Y 4一起形成＝O或＝S)； Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from H, OR 10 , or Y 1 and Y 2 together are O or S (ie, Y 1 and Y 2 together form =O or =S), or Y 3 Together with Y 4 is O or S (ie, Y 3 and Y 4 together form =O or =S);
X选自O、S、Se或NR 10； X is selected from O, S, Se or NR 10 ;
W选自O或S；W is selected from O or S;
n、m、p各自独立地选自0至2的整数；n, m, p are each independently selected from an integer of 0 to 2;
结构式中3个“---”各自独立地选自单键或不存在，当R 4与R 5间的“---”为单键时，则R 4、R 5不存在，当R 6与R 7间的“---”为单键时，则R 7不存在，当R 8与R 9间的“---”为单键时，则R 8不存在； Wherein three "---" in the formula are each independently selected from a single bond or absent, and when "---" between R 4 and R 5 is a single bond, then R 4 and R 5 are absent, when R 6 When "---" between R and 7 is a single bond, then R 7 does not exist, and when "---" between R 8 and R 9 is a single bond, then R 8 does not exist;
R 3、R 4、R 5、R 6、R 7、R 8、R 9各自独立地选自H、卤素(优选F、Cl、Br、I)、OR 10，或者R 4与R 5一起为O(即形成环氧，此时R 4与R 5间的“---”不存在)、R 6与R 7一起为O(即形成环氧，此时R 6与R 7间的“---”不存在)、R 8与R 9一起为O(即形成环氧，此时R 8与R 9间的“---”不存在)； R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from H, halogen (preferably F, Cl, Br, I), OR 10 , or R 4 together with R 5 O (ie, forming an epoxy, where "---" between R 4 and R 5 is absent), and R 6 and R 7 together are O (ie, forming an epoxy, at this time between R 6 and R 7 "- --" is absent), R 8 and R 9 together are O (ie, forming an epoxy, where "---" between R 8 and R 9 does not exist);
A环为3至12元的饱和或不饱和环，其包含选自碳原子和0至4个杂原子的环成员，且所述环包含0至3个独立选自C(＝O)、C(＝S)、S(＝O)、S(＝O) 2或C(＝NR 10)的环成员，且所述环任选被一个或多个选自R 12的基团取代；R 12选自如下基团：羟基、羟甲基、羧基、乙酰氨基、C1-C4烷基(如甲基、乙基、丙基、叔丁基)、三氟甲基、三氟乙酰基、巯基、卤素、硝基、氨基、叠氮基(-N 3)、胍基、氰基、叔丁氧羰基(-Boc)、羰基(-C＝O)、氧代(＝O)、硫代(＝S)、环氧(环氧可以指向纸面里
Figure PCTCN2018075069-appb-000002
也可以指向纸面外
Figure PCTCN2018075069-appb-000003
)、磺酰基、亚磺酰基、C1-C4烷氧基(如甲氧基、乙氧基、叔丁氧基)、乙酰氧基(AcO)、丙酰氧基、苯甲酰氧基、苯基、叔丁基二甲基硅氧基(TBSO)、三乙基硅氧基(TESO)、三甲基硅氧基(TMSO)、叔丁基二苯基硅氧基(TBDPSO)； The A ring is a 3 to 12 membered saturated or unsaturated ring comprising a ring member selected from the group consisting of a carbon atom and 0 to 4 hetero atoms, and the ring contains 0 to 3 independently selected from C(=O), C. a ring member of (=S), S(=O), S(=O) 2 or C(=NR 10 ), and the ring is optionally substituted by one or more groups selected from R 12 ; R 12 Selected from the group consisting of hydroxyl, hydroxymethyl, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl, tert-butyl), trifluoromethyl, trifluoroacetyl, decyl, Halogen, nitro, amino, azido (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (= S), epoxy (epoxy can point to the paper surface
Figure PCTCN2018075069-appb-000002
Can also point out of the paper
Figure PCTCN2018075069-appb-000003
), sulfonyl, sulfinyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), acetoxy (AcO), propionyloxy, benzoyloxy, benzene Base, tert-butyldimethylsilyloxy (TBSO), triethylsilyloxy (TESO), trimethylsiloxy (TMSO), tert-butyldiphenylsiloxy (TBDPSO);
所述杂原子各自独立地选自O、S、N或S e； The heteroatoms are each independently selected from O, S, N or S e ;
前提条件是当结构中3个“---”均为单键且R 10选自如下基团：H、乙酰基(Ac)、丙酰基
Figure PCTCN2018075069-appb-000004
溴乙酰基(BrCH 2CO)、正十二烷硫基乙酰基(CH 3(CH 2) 11SCH 2CO)、呋喃-2-甲酰基
Figure PCTCN2018075069-appb-000005
环戊甲酰基
Figure PCTCN2018075069-appb-000006
噻吩-2-甲酰基
Figure PCTCN2018075069-appb-000007
喹喔啉-2-甲酰基
Figure PCTCN2018075069-appb-000008
6-氯烟酰基
Figure PCTCN2018075069-appb-000009
单甲酯琥珀酰基
Figure PCTCN2018075069-appb-000010
或苯丙酰基
Figure PCTCN2018075069-appb-000011
时，A环只能选自： The prerequisite is that when the three "---" in the structure are single bonds and R 10 is selected from the group consisting of H, acetyl (Ac), propionyl
Figure PCTCN2018075069-appb-000004
Bromoacetyl (BrCH 2 CO), n-dodecylthioacetyl (CH 3 (CH 2 ) 11 SCH 2 CO), furan-2-formyl
Figure PCTCN2018075069-appb-000005
Cyclopentanoyl
Figure PCTCN2018075069-appb-000006
Thiophene-2-formyl
Figure PCTCN2018075069-appb-000007
Quinoxaline-2-formyl
Figure PCTCN2018075069-appb-000008
6-chloronicotinoyl
Figure PCTCN2018075069-appb-000009
Monomethyl succinyl
Figure PCTCN2018075069-appb-000010
Phenylpropionyl
Figure PCTCN2018075069-appb-000011
When the ring A can only be selected from:
Figure PCTCN2018075069-appb-000012
Figure PCTCN2018075069-appb-000012
其中各个R 13独立地选自H、R 11、C(＝O)-R 11、C(＝O)-OR 11、C(＝O)-SR 11、C(＝O)-NR 11；并且，前提条件是式I结构化合物中不包括如下化合物：
Figure PCTCN2018075069-appb-000013
(CAS登记号：852201-92-4)、
Figure PCTCN2018075069-appb-000014
(CAS登记号：852201-91-3)、
Figure PCTCN2018075069-appb-000015
(CAS登记号：852200-62-5)、
Figure PCTCN2018075069-appb-000016
(CAS 登记号：862390-34-9)、
Figure PCTCN2018075069-appb-000017
(CAS登记号：1199815-43-4)、
Figure PCTCN2018075069-appb-000018
(penicilone A)、
Figure PCTCN2018075069-appb-000019
(penicilone B)、
Figure PCTCN2018075069-appb-000020
(penicilone C)、
Figure PCTCN2018075069-appb-000021
(penicilone D)。 Wherein each R 13 is independently selected from the group consisting of H, R 11 , C(=O)-R 11 , C(=O)-OR 11 , C(=O)-SR 11 , C(=O)-NR 11 ; , provided that the following compounds are not included in the structural compound of formula I:
Figure PCTCN2018075069-appb-000013
(CAS registration number: 852201-92-4),
Figure PCTCN2018075069-appb-000014
(CAS registration number: 852201-91-3),
Figure PCTCN2018075069-appb-000015
(CAS registration number: 852200-62-5),
Figure PCTCN2018075069-appb-000016
(CAS registration number: 862390-34-9),
Figure PCTCN2018075069-appb-000017
(CAS registration number: 1199815-43-4),
Figure PCTCN2018075069-appb-000018
(penicilone A),
Figure PCTCN2018075069-appb-000019
(penicilone B),
Figure PCTCN2018075069-appb-000020
(penicilone C),
Figure PCTCN2018075069-appb-000021
(penicilone D).
本发明的另一实施方案中提供上述式I结构的优选方案，其特征在于式I结构中n、m、p均为0，即具有如下结构(式I-1)：In another embodiment of the present invention, a preferred embodiment of the above formula I is provided, characterized in that in the structure of formula I, n, m, and p are all 0, that is, have the following structure (Formula I-1):
Figure PCTCN2018075069-appb-000022
式I-1，其中Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、X、A环等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000022
Formula I-1, wherein Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, A ring, etc. The definition of a group is the same as defined in the compound of formula I, and the preconditions are unchanged.
本发明的另一实施方案中提供上述式I结构的另一优选方案，其特征在于式I结构中Y 1与Y 2一起为O或S，Y 3与Y 4一起为O或S，即具有如下结构(式I-2)： Another embodiment of the present invention provides in a further preferred embodiment of the above-described structure of Formula I, wherein the structure of formula I Y 1 and Y 2 together are O or S, Y 3 and Y 4 together are O or S, i.e., having The following structure (Formula I-2):
Figure PCTCN2018075069-appb-000023
式I-2，其中Y为O或S，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、X、W、A环、n、m、p等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000023
Formula I-2, wherein Y is O or S, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, W, A ring, n, m, The definition of a group such as p is the same as defined in the compound of formula I, and the preconditions are unchanged.
本发明的另一实施方案中提供上述式I-1结构的另一优选方案，其特征在于式I-1结构中Y 1与Y 2一起为O或S，Y 3与Y 4一起为O或S，即具有如下结构(式I-3)： Another embodiment of the present invention to provide the above formula I-1 further preferred embodiment of the structure, wherein the structure of Formula I 1-Y 1 and Y 2 together are O or S, Y 3 and Y 4 together are O or S, that is, has the following structure (Formula I-3):
Figure PCTCN2018075069-appb-000024
式I-3，其中Y为O或S，R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、X、A环等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000024
Formula I-3, wherein Y is O or S, and the definitions of the groups such as R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, and A ring are the same The definition in the I compound, the preconditions are unchanged.
本发明的另一实施方案中提供上述式I结构的另一优选方案，其特征在于式I结构中的3个“---”均为单键，即具有如下结构(式I-4)：In another embodiment of the present invention, there is provided another preferred embodiment of the above formula I, characterized in that the three "---"s in the structure of the formula I are all single bonds, i.e. have the following structure (formula I-4):
Figure PCTCN2018075069-appb-000025
式I-4，其中Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 6、R 9、X、W、A环、n、m、p等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000025
Formula I-4, wherein Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 6 , R 9 , X, W, A ring, n, m, p, etc. The definition in the compound of the formula I, the preconditions are unchanged.
本发明的另一实施方案中提供上述式I-1结构的另一优选方案，其特征在于式I-1结构中的3个“---”均为单键，即具有如下结构(式I-5)：In another embodiment of the present invention, there is provided another preferred embodiment of the structure of the above formula I-1, characterized in that all three "---" in the structure of the formula I-1 are single bonds, that is, have the following structure (formula I -5):
Figure PCTCN2018075069-appb-000026
式I-5，其中Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 6、R 9、X、A环等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000026
Formula I-5, wherein the definitions of the groups such as Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 6 , R 9 , X, A ring are the same as defined in the compound of formula I, The preconditions remain unchanged.
本发明的另一实施方案中提供上述式I-2结构的另一优选方案，其特征在于式I-2结构中的3个“---”均为单键，即具有如下结构(式I-6)：In another embodiment of the present invention, there is provided another preferred embodiment of the structure of the above formula I-2, characterized in that all three "---" in the structure of the formula I-2 are single bonds, that is, have the following structure (formula I -6):
Figure PCTCN2018075069-appb-000027
式I-6，其中Y为O或S，R 1、R 2、R 3、R 6、R 9、X、W、A环、n、m、p等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000027
Formula I-6, wherein Y is O or S, and R 1 , R 2 , R 3 , R 6 , R 9 , X, W, A ring, n, m, p, etc. are as defined in the compound of formula I Definition, the preconditions are unchanged.
本发明的另一实施方案中提供上述式I-3结构的另一优选方案，其特征在于式I-3结构中的3个“---”均为单键，即具有如下结构(式I-7)：In another embodiment of the present invention, there is provided another preferred embodiment of the structure of the above formula I-3, characterized in that the three "---"s in the structure of the formula I-3 are all single bonds, ie have the following structure (Formula I -7):
Figure PCTCN2018075069-appb-000028
式I-7，其中Y为O或S，R 1、R 2、R 3、R 6、R 9、X、A环等基团的定义同式I化合物中的定义，前提条件不变。
Figure PCTCN2018075069-appb-000028
Formula I-7, wherein Y is O or S, and the definitions of the R 1 , R 2 , R 3 , R 6 , R 9 , X, A ring and the like are as defined in the compound of Formula I, with the same preconditions.
本发明的另一实施方案中提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7结构的另一优选方案，其特征在于结构中X选自O或NR 10，前提条件不变。 In another embodiment of the present invention, there is provided another structure of the above Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 A preferred embodiment is characterized in that X is selected from O or NR 10 in the structure, and the preconditions are unchanged.
本发明的另一实施方案中提供上述式I、式I-1、式I-2、式I-3结构的另一优选方案，其特征在于结构中R 4与R 5、R 6与R 7、R 8与R 9至少有一组一起为O(即形成环氧，形成的环氧结构可以指向纸面里
Figure PCTCN2018075069-appb-000029
也可以指向纸面外
Figure PCTCN2018075069-appb-000030
)，前提条件不变。 In another embodiment of the present invention, there is provided another preferred embodiment of the above formula I, formula I-1, formula I-2, formula I-3, characterized in that R 4 and R 5 , R 6 and R 7 in the structure At least one of R 8 and R 9 is O together (ie, an epoxy is formed, and the formed epoxy structure can be directed to the paper surface)
Figure PCTCN2018075069-appb-000029
Can also point out of the paper
Figure PCTCN2018075069-appb-000030
), the preconditions remain unchanged.
本发明的另一实施方案中提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7结构的另一优选方案，其特征在于A环选自
Figure PCTCN2018075069-appb-000031
Figure PCTCN2018075069-appb-000032
苄基，上述A环任选被一个或多个R 12取代，前提条件不变。A环进一步优选如下基团：
Figure PCTCN2018075069-appb-000033
Figure PCTCN2018075069-appb-000034
In another embodiment of the present invention, there is provided another structure of the above Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 A preferred embodiment characterized in that the ring A is selected from
Figure PCTCN2018075069-appb-000031
Figure PCTCN2018075069-appb-000032
The benzyl group, the above A ring is optionally substituted by one or more R 12 , and the preconditions are unchanged. The A ring is further preferably a group as follows:
Figure PCTCN2018075069-appb-000033
Figure PCTCN2018075069-appb-000034
本发明的另一实施方案中提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7结构的另一优选方案，其特征在于R 11选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、正庚基、正辛基、3-甲基-戊基、2-甲基-戊基、2-甲基-己基、3-甲基-己基、3-乙基-己基、1-氟-3-甲基-戊基、1-氟-2-甲基-戊基、1-氟-2-甲基-己基、1-氟-3-甲基-己基、1-氟-3-乙基-己基、1-氯-3-甲基-戊基、1-氯-2-甲基-戊基、1-氯-2-甲基-己基、1-氯-3-甲基-己基、1-氯-3-乙基-己基、1-溴-3-甲基-戊基、1-溴-2-甲基-戊基、1-溴-2-甲基-己基、1-溴-3-甲基-己基、1-溴-3-乙基-己基、乙烯基、丙烯基、烯丙基、正丁烯基、异丁烯基、丁-2-烯基、丁二烯基、正戊烯基、异戊烯基、戊二烯基、正己烯基、正庚烯基、庚二烯基、庚三烯基、正辛烯基、辛二烯基、辛三烯基、3-甲基-戊-2-烯基、2-甲基-戊-2-烯基、2-甲基-己-2-烯基、3-甲基-己-2-烯基、3-乙基-己-2-烯基、乙炔基、丙炔基、正丁炔基、丁-2-炔基、正戊炔基、异戊炔基、正己炔基、正庚炔基、庚二炔基、正辛炔基、辛二炔基、辛三炔基、2-甲基-戊-2-炔基、2-甲基-己-2-炔基、3-甲基-己-2-炔基、3-乙基-己-2-炔基、苯基、对甲氧基苯基、对氰基苯基、对羟 甲基苯基、苄基、萘-1-基、苯乙基、苯丙基、环戊基、环丙基、环己基、环丁基、氮杂环丁基、呋喃-2-基、噻吩-2-基、卤代甲基(例如BrCH 2、ClCH 2、FCH 2、CF 3)、正十二烷硫代甲基(CH 3(CH 2) 11SCH 2)、6-氯吡啶-3-基、喹喔啉-2-基、
Figure PCTCN2018075069-appb-000035
甲氧亚甲基(MOM)、正壬基(-C 9H 19-n)、正癸基(-C 10H 21-n)、正十一烷基(-C 11H 23-n)、正十二烷基(-C 12H 25-n)、正十三烷基(-C 13H 27-n)、正十四烷基(-C 14H 29-n)、正十五烷基(-C 15H 31-n)、正十六烷基(-C 16H 33-n)、苯乙基咪唑基、吡啶基、噁唑基、异恶唑基、三氮唑基、四氮唑基、喹啉基、噁嗪基、噻吩基、噻唑基、噻二唑基、吲哚基、咔唑基、异喹啉基、苯并呋喃基、苯并噻唑基、苯并硒二唑基、香豆素基、异香豆素基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、哌啶基、哌嗪基、四氢呋喃基、二氧六环基、噁唑啉、噻唑啉基、嘧啶碱基、嘌呤碱基、二苯甲基、氨基酸残基、
Figure PCTCN2018075069-appb-000036
Figure PCTCN2018075069-appb-000037
Figure PCTCN2018075069-appb-000038
TMS、TBS、TES、Ms、Ts。 In another embodiment of the present invention, there is provided another structure of the above Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 A preferred embodiment characterized in that R 11 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl , n-octyl, 3-methyl-pentyl, 2-methyl-pentyl, 2-methyl-hexyl, 3-methyl-hexyl, 3-ethyl-hexyl, 1-fluoro-3-methyl -pentyl, 1-fluoro-2-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-methyl-hexyl, 1-fluoro-3-ethyl-hexyl, 1 -Chloro-3-methyl-pentyl, 1-chloro-2-methyl-pentyl, 1-chloro-2-methyl-hexyl, 1-chloro-3-methyl-hexyl, 1-chloro-3 -ethyl-hexyl, 1-bromo-3-methyl-pentyl, 1-bromo-2-methyl-pentyl, 1-bromo-2-methyl-hexyl, 1-bromo-3-methyl- Hexyl, 1-bromo-3-ethyl-hexyl, vinyl, propenyl, allyl, n-butenyl, isobutenyl, but-2-enyl, butadienyl, n-pentenyl, isuf Alkenyl, pentadienyl, n-hexenyl, n-heptenyl, heptadienyl, heptadienyl, n-octenyl, octadienyl, octatrienyl, 3- Methyl-pent-2-enyl, 2-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, 3-methyl-hex-2-enyl, 3-ethyl -hex-2-enyl, ethynyl, propynyl, n-butynyl, but-2-ynyl, n-pentynyl, isopenynyl, n-hexynyl, n-heptynyl, heptadienyl , n-alkynyl, octadiynyl, octantylene, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2-yne , 3-ethyl-hex-2-ynyl, phenyl, p-methoxyphenyl, p-cyanophenyl, p-hydroxymethylphenyl, benzyl, naphthalen-1-yl, phenethyl, Phenylpropyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, azetidinyl, furan-2-yl, thiophen-2-yl, halomethyl (eg BrCH 2 , ClCH 2 , FCH 2 , CF 3 ), n-dodecylthiomethyl (CH 3 (CH 2 ) 11 SCH 2 ), 6-chloropyridin-3-yl, quinoxalin-2-yl,
Figure PCTCN2018075069-appb-000035
Methoxymethylene (MOM), n-decyl (-C 9 H 19 -n), n-decyl (-C 10 H 21 -n), n-undecyl (-C 11 H 23 -n), n-Dodecyl (-C 12 H 25 -n), n-tridecyl (-C 13 H 27 -n), n-tetradecyl (-C 14 H 29 -n), n-pentadecyl (-C 15 H 31 -n), n-hexadecyl (-C 16 H 33 -n), phenethyl imidazolyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazo Azyl, quinolyl, oxazinyl, thienyl, thiazolyl, thiadiazolyl, fluorenyl, oxazolyl, isoquinolyl, benzofuranyl, benzothiazolyl, benzoselenadiazole Base, coumarin, isocoumarin, azetidinyl, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxolyl, oxazoline , thiazoline group, pyrimidine base, purine base, benzhydryl, amino acid residue,
Figure PCTCN2018075069-appb-000036
Figure PCTCN2018075069-appb-000037
Figure PCTCN2018075069-appb-000038
TMS, TBS, TES, Ms, Ts.
本发明的另一实施方案中上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7结构的Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、X、W、A环、n、m、p选自表1-9中各具体化合物(1001-1091、1097、1098、1201-1297、1301-1391、1401-1497、1501-1671、1701-1791、1801-1832)相应位置的具体基团。 In another embodiment of the present invention, Y 1 of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, and formula I-7 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X , W, A ring, n, m, p are selected from the specific compounds in Tables 1-9 (1001-1091, 1097, 1098, 1201-1297, 1301-1391, 1401-1497, 1501-1671, 1701-1791, 1801-1832) Specific groups at the corresponding positions.
在另一优选例中，式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物选自表1-9中的化合物(1001-1091、1097、1098、1201-1297、1301-1391、1401-1497、1501-1671、1701-1791、1801-1832)、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物。In another preferred embodiment, the compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7 is selected from Table 1 - a compound of 9 (1001-1091, 1097, 1098, 1201-1297, 1301-1391, 1401-1497, 1501-1671, 1701-1791, 1801-1832), a stereoisomer thereof, and a tautomer thereof And a solvate thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof.
应理解，在本发明上述优选实施方案或优选例(表1-9中的化合物)中的优选基团(例如Y 1、Y 2、Y 3、Y 4、R 1、R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9、R 10、R 11、R 12、R 13、X、W、A环、n、m、p等)可相互组合以形成本发明的各种优选化合物，限于篇幅，在此不一一累述。 It is to be understood that preferred groups (for example, Y 1 , Y 2 , Y 3 , Y 4 , R 1 , R 2 , R 3 , in the above preferred embodiments or preferred examples (compounds in Tables 1-9) of the present invention, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , X, W, A ring, n, m, p, etc. may be combined with each other to form The various preferred compounds of the invention are limited in length and are not described here.
本发明的提供一种抗耐药菌药物，其特征在于包含上述任意式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物作为有效成分。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。The present invention provides a drug against drug resistance, which comprises any of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, and formula I-6. A solvate of a compound of the formula I-7, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof as an active ingredient. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
本发明提供一种药物组合物，其特征在于包含上述任意式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物，和至少一种其他抗菌药物，以及药学上可接受的载体、稀释剂或赋形剂。该药物组合物优选注射剂、口服制剂、冻干粉针剂、悬浮剂等。所述药物组合物用于预防和/或治疗由耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)感染引起的疾病。The present invention provides a pharmaceutical composition comprising any of the above Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I a compound of -7, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a solvate of a pharmaceutically acceptable salt thereof or a salt thereof, and at least one other antibacterial agent, and pharmaceutically An acceptable carrier, diluent or excipient. The pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like. The pharmaceutical composition is for preventing and/or treating methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC43300, S. aureus ATCC33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E .faecalis ATCC51299) A disease caused by infection.
本发明提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备抗耐药菌药物中的用途。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。The present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof, Use of a tautomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a drug against drug resistance. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
本发明提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备药物中的用途，所述药物用于预防和/或治疗由S.aureus ATCC43300、S.aureus ATCC33591、S.aureus ATCC25923、S.aureus ATCC29213、E.faecalis ATCC51299、E.faecium ATCC35667感染引起的疾病。The present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof, Use of a tautomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a medicament for the prophylaxis and/or treatment of S. aureus ATCC43300, Diseases caused by S. aureus ATCC33591, S. aureus ATCC25923, S. aureus ATCC29213, E. faecalis ATCC51299, E. faecium ATCC35667 infection.
本发明提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备抗耐药菌药物先导化合物中的应用。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。The present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof, The use of a tautomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a drug-resistant drug lead compound. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
本发明提供上述式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备抗耐药菌候选药物中的应用。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。The present invention provides a compound of the above formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7, a stereoisomer thereof, The use of a tautomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, for the preparation of a drug candidate against drug resistance. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
本发明的目的在于提供一种针对耐药菌——MRSA和VER具有很强抑制活性的Azaphilones类化合物，本发明提供的式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物对MRSA和VER的抑制活性强于cohaerins A-B、sclerotiorin和化合物5-9，同时其毒副作用小于cohaerins A-B、sclerotiorin和化合物5-9。The object of the present invention is to provide an Azaphilones-like compound having strong inhibitory activity against drug-resistant bacteria, MRSA and VER, and the present invention provides Formula I, Formula I-1, Formula I-2, Formula I-3, and Formula a compound of Formula I-4, Formula I-5, Formula I-6, Formula I-7, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or The solvates of the salts have stronger inhibitory activity against MRSA and VER than cohaerins AB, sclerotiorin and compounds 5-9, and their toxic side effects are less than cohaerins AB, sclerotiorin and compounds 5-9.
本发明提供一种中间体，其特征在于所述中间体具有式II所示的结构：The present invention provides an intermediate characterized in that the intermediate has the structure shown in Formula II:
Figure PCTCN2018075069-appb-000039
Figure PCTCN2018075069-appb-000039
Y为O或S，化学键
Figure PCTCN2018075069-appb-000040
表示指向纸面里的键
Figure PCTCN2018075069-appb-000041
或指向纸面外的键
Figure PCTCN2018075069-appb-000042
R 3、R 6、R 9、W、A环、n、m、p的定义与式I化合物中的定义相同，前提条件是式II结构化合物不包括化合物101-183。 Y is O or S, chemical bond
Figure PCTCN2018075069-appb-000040
Indicates the key pointing to the paper
Figure PCTCN2018075069-appb-000041
Or point to a key outside the paper
Figure PCTCN2018075069-appb-000042
The definitions of R 3 , R 6 , R 9 , W, A ring, n, m, p are the same as defined in the compound of formula I, provided that the structural compound of formula II does not include compounds 101-183.
上述II结构的中间体，优选如下化合物：The intermediate of the above II structure is preferably the following compound:
Figure PCTCN2018075069-appb-000043
Figure PCTCN2018075069-appb-000043
本发明提供另一种中间体，其特征在于所述中间体具有式II-1所示的结构：The present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula II-1:
Figure PCTCN2018075069-appb-000044
Figure PCTCN2018075069-appb-000044
Y为O或S，化学键
Figure PCTCN2018075069-appb-000045
表示指向纸面里的键
Figure PCTCN2018075069-appb-000046
或指向纸面外的键
Figure PCTCN2018075069-appb-000047
R 3、R 6、R 9、W、A环、n、m、p的定义与式I化合物中的定义相同。 Y is O or S, chemical bond
Figure PCTCN2018075069-appb-000045
Indicates the key pointing to the paper
Figure PCTCN2018075069-appb-000046
Or point to a key outside the paper
Figure PCTCN2018075069-appb-000047
The definitions of R 3 , R 6 , R 9 , W, A ring, n, m, p are the same as defined in the compound of formula I.
上述式II-1结构的中间体，优选如下化合物：The intermediate of the above formula II-1 is preferably the following compound:
Figure PCTCN2018075069-appb-000048
Figure PCTCN2018075069-appb-000048
Figure PCTCN2018075069-appb-000049
Figure PCTCN2018075069-appb-000049
本发明提供另一种中间体，其特征在于所述中间体具有式II-2所示的结构：The present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula II-2:
Y为O或S，化学键
Figure PCTCN2018075069-appb-000051
表示指向纸面里的键
Figure PCTCN2018075069-appb-000052
或指向纸面外的键
Figure PCTCN2018075069-appb-000053
R 3、R 6、R 9、R 10、W、A环、n、m、p的定义与式I化合物中的定义相同。 Y is O or S, chemical bond
Figure PCTCN2018075069-appb-000051
Indicates the key pointing to the paper
Figure PCTCN2018075069-appb-000052
Or point to a key outside the paper
Figure PCTCN2018075069-appb-000053
The definitions of R 3 , R 6 , R 9 , R 10 , W, A ring, n, m, p are the same as defined in the compound of formula I.
上述式II-2结构的中间体，优选如下化合物：The intermediate of the above formula II-2 is preferably the following compound:
Figure PCTCN2018075069-appb-000054
Figure PCTCN2018075069-appb-000054
Figure PCTCN2018075069-appb-000055
Figure PCTCN2018075069-appb-000055
Figure PCTCN2018075069-appb-000056
Figure PCTCN2018075069-appb-000056
本发明提供另一种中间体，其特征在于所述中间体具有式III所示的结构：The present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula III:
Figure PCTCN2018075069-appb-000057
Figure PCTCN2018075069-appb-000057
Y为O或S，化学键
Figure PCTCN2018075069-appb-000058
表示指向纸面里的键
Figure PCTCN2018075069-appb-000059
或指向纸面外的键
Figure PCTCN2018075069-appb-000060
R 3、R 6、R 9、A环的定义与式I化合物中的定义相同，前提条件是式III结构化合物不包括化合物101-183。 Y is O or S, chemical bond
Figure PCTCN2018075069-appb-000058
Indicates the key pointing to the paper
Figure PCTCN2018075069-appb-000059
Or point to a key outside the paper
Figure PCTCN2018075069-appb-000060
The definitions of R 3 , R 6 , R 9 , and A ring are the same as defined in the compound of formula I, provided that the structural compound of formula III does not include compounds 101-183.
上述式III结构的中间体，优选如下化合物：The intermediate of the above formula III structure is preferably the following compound:
Figure PCTCN2018075069-appb-000061
Figure PCTCN2018075069-appb-000061
Figure PCTCN2018075069-appb-000062
Figure PCTCN2018075069-appb-000062
Figure PCTCN2018075069-appb-000063
Figure PCTCN2018075069-appb-000063
Figure PCTCN2018075069-appb-000064
Figure PCTCN2018075069-appb-000064
本发明提供另一种中间体，其特征在于所述中间体具有式III-1所示的结构：The present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula III-1:
Figure PCTCN2018075069-appb-000065
Figure PCTCN2018075069-appb-000065
Y为O或S，化学键
Figure PCTCN2018075069-appb-000066
表示指向纸面里的键
Figure PCTCN2018075069-appb-000067
或指向纸面外的键
Figure PCTCN2018075069-appb-000068
R 3、R 6、R 9、A环的定义与式I化合物中的定义相同。 Y is O or S, chemical bond
Figure PCTCN2018075069-appb-000066
Indicates the key pointing to the paper
Figure PCTCN2018075069-appb-000067
Or point to a key outside the paper
Figure PCTCN2018075069-appb-000068
The definitions of R 3 , R 6 , R 9 , and A ring are the same as defined in the compound of formula I.
上述式III-1结构的中间体，优选如下化合物：The intermediate of the above formula III-1 is preferably the following compound:
Figure PCTCN2018075069-appb-000069
Figure PCTCN2018075069-appb-000069
Figure PCTCN2018075069-appb-000070
Figure PCTCN2018075069-appb-000070
Figure PCTCN2018075069-appb-000071
Figure PCTCN2018075069-appb-000071
Figure PCTCN2018075069-appb-000072
Figure PCTCN2018075069-appb-000072
Figure PCTCN2018075069-appb-000073
Figure PCTCN2018075069-appb-000073
Figure PCTCN2018075069-appb-000074
Figure PCTCN2018075069-appb-000074
本发明提供另一种中间体，其特征在于所述中间体具有式III-2所示的结构：The present invention provides another intermediate characterized in that the intermediate has the structure shown in Formula III-2:
Figure PCTCN2018075069-appb-000075
Figure PCTCN2018075069-appb-000075
Y为O或S，化学键
Figure PCTCN2018075069-appb-000076
表示指向纸面里的键
Figure PCTCN2018075069-appb-000077
或指向纸面外的键
Figure PCTCN2018075069-appb-000078
R 3、R 6、R 9、R 10、A环的定义与式I化合物中的定义相同。 Y is O or S, chemical bond
Figure PCTCN2018075069-appb-000076
Indicates the key pointing to the paper
Figure PCTCN2018075069-appb-000077
Or point to a key outside the paper
Figure PCTCN2018075069-appb-000078
The definitions of R 3 , R 6 , R 9 , R 10 , and A ring are the same as defined in the compound of formula I.
上述式III-2结构的中间体，优选如下化合物：The intermediate of the above formula III-2 structure is preferably the following compound:
Figure PCTCN2018075069-appb-000079
Figure PCTCN2018075069-appb-000079
Figure PCTCN2018075069-appb-000080
Figure PCTCN2018075069-appb-000080
Figure PCTCN2018075069-appb-000081
Figure PCTCN2018075069-appb-000081
Figure PCTCN2018075069-appb-000082
Figure PCTCN2018075069-appb-000082
按照文献(如WO2015153959A2、Chemical Biology&Drug Design(2012),80(5),682-692、Journal of Agricultural and Food Chemistry(2012),60(18),4480-4491、ACS Combinatorial Science(2012),14(3),236-244、WO 2010151799A2、Natural Product Communications(2007),2(3),287-304、Biological&Pharmaceutical Bulletin(2006),29(1),34-37、JP 2005220040A、Journal of the American Chemical Society(2005),127(26),9342-9343、Phytochemistry(Elsevier)(2005),66(7),797-809、Angewandte Chemie,International Edition(2004),43(10),1239-1243、Organic Letters,2006,8(22),5169-5171、CN201611203587.1、CN201611203588.6等)中记载的方法或者在上述文献记载的方法的基础上，本领域的技术人员进行适当调整，可制备得到式II、式III、式II-1、式III-1、式II-2、式III-2中间体，具体可制备得到如下化合物：According to the literature (eg WO2015153959A2, Chemical Biology & Drug Design (2012), 80 (5), 682-692, Journal of Agricultural and Food Chemistry (2012), 60 (18), 4480-4491, ACS Combinatorial Science (2012), 14 ( 3), 236-244, WO 2010151799A2, Natural Product Communications (2007), 2(3), 287-304, Biological & Pharmaceutical Bulletin (2006), 29(1), 34-37, JP 2005220040A, Journal of the American Chemical Society (2005), 127(26), 9342-9343, Phytochemistry (Elsevier) (2005), 66(7), 797-809, Angewandte Chemie, International Edition (2004), 43(10), 1239-1243, Organic Letters , the methods described in 2006, 8 (22), 5169-5171, CN201611203587.1, CN201611203588.6, etc., or based on the methods described in the above documents, can be prepared by a person skilled in the art by appropriately adjusting the formula II. The intermediates of formula III, formula II-1, formula III-1, formula II-2 and formula III-2, in particular, can be prepared as follows:
Figure PCTCN2018075069-appb-000083
Figure PCTCN2018075069-appb-000083
Figure PCTCN2018075069-appb-000084
Figure PCTCN2018075069-appb-000084
X为O时，式I、I-2、I-4、I-6化合物的制备方法包括如下步骤：When X is O, the preparation method of the compound of the formula I, I-2, I-4, and I-6 includes the following steps:
Figure PCTCN2018075069-appb-000085
Figure PCTCN2018075069-appb-000085
(1)式II化合物可经途径1.得到相应的式I-6化合物(X为O)；或者式II化合物可经途径2.得到相应的式I-6化合物(X为O)；或者式II化合物可经途径3.得到相应的式I-6化合物(X为O)。(1) A compound of formula II can be obtained via Scheme 1. to give the corresponding compound of formula I-6 (X is O); or a compound of formula II can be obtained via Scheme 2. to give the corresponding compound of formula I-6 (X is O); The compound of formula II can be obtained via Scheme 3. to give the corresponding compound of formula I-6 (X is O).
(2)式I-6化合物(X为O)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-4化合物(X为O)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-4化合物(X为O)。 (2) The compound of the formula I-6 (X is O) can be obtained via Route 4. A compound of the formula I-4 (X is O) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, which can be subsequently One or more of Routes 1, 2, or 3. provides the corresponding compound of Formula 1-4 (X is O).
(3)式I-6化合物(X为O)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-2化合物(X为O)；或者式I-6化合物(X为O)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-2化合物(X为O)，随后可经途径7.得到相应的马氏或反马氏的式I-2化合物(X为O)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-2化合物(X为O)。(3) a compound of the formula I-6 (X is O) which can be reduced by a partial carbon-carbon double bond or a full carbon-carbon double bond via a route 5. (X is O); or a compound of the formula I-6 ( X is O) a compound of formula 1-2 (X is O) which can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond via route 6. The corresponding Markov or anti-male can be obtained via Route 7. A compound of formula 1-2 (X is O) which can be subsequently obtained by one or more of Routes 1, 2. or 3. to give the corresponding hydrocarbylation, acylation or carbonylation of a compound of formula 1-2 ( X is O).
(4)式I-4化合物(X为O)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为O)；或者式I-2化合物(X为O)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为O)。(4) The compound of the formula I-4 (X is O) may give the corresponding compound of the formula I (X is O) via one or more of the routes 5., 6., 7., 1., 2. or 3. Or the compound of formula I-2 (X is O) can be obtained by one or more of the routes 4., 7., 1., 2. or 3. The corresponding compound of formula I (X is O).
X为O时，式I-1、I-3、I-5、I-7化合物的制备方法包括如下步骤：When X is O, the preparation method of the compound of the formula I-1, I-3, I-5, and I-7 includes the following steps:
Figure PCTCN2018075069-appb-000086
Figure PCTCN2018075069-appb-000086
(1)式III化合物可经途径1.得到相应的式I-7化合物(X为O)；或者式III化合物可经途径2.得到相应的式I-7化合物(X为O)；或者式III化合物可经途径3.得到相应的式I-7化合物(X为O)。(1) A compound of formula III can be obtained via Scheme 1. to give the corresponding compound of formula I-7 (X is O); or a compound of formula III can be obtained via Scheme 2. to give the corresponding compound of formula I-7 (X is O); Compound III can be obtained via Scheme 3. to give the corresponding compound of formula I-7 (X is O).
(2)式I-7化合物(X为O)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-5化合物(X为O)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-5化合物(X为O)。 (2) A compound of formula I-7 (X is O) can be obtained via Route 4. A compound of formula I-5 (X is O) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, which can be subsequently One or more of Routes 1, 2, or 3. provides the corresponding compound of Formula I-5 (X is O).
(3)式I-7化合物(X为O)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-3化合物(X为O)；或者式I-7化合物(X为O)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-3化合物(X为O)，随后可经途径7.得到相应的马氏或反马氏的式I-3化合物(X为O)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-3化合物(X为O)。(3) a compound of the formula I-7 (X is O) which can be reduced by a partial carbon-carbon double bond or a full carbon-carbon double bond via a route 5. (X is O); or a compound of the formula I-7 ( X is O) a compound of formula I-3 (X is O) which can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond via Route 6. The corresponding Markov or anti-Ma can be obtained via Route 7. A compound of formula 1-3 (X is O) which can be subsequently subjected to the corresponding hydrocarbylation, acylation or carbonylation of a compound of formula 1-3 via one or more of the routes 1., 2. or 3. X is O).
(4)式I-5化合物(X为O)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为O)；或者式I-3化合物(X为O)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为O)。(4) The compound of the formula I-5 (X is O) can be obtained by one or more of the routes 5., 6., 7., 1., 2. or 3. The corresponding compound of the formula I-1 (X is Or a compound of formula I-3 (X is O) may give the corresponding compound of formula I-1 (X is O) via one or more of Routes 4., 7., 1., 2. or 3. .
X为S时，式I、I-2、I-4、I-6化合物的制备方法与X为O时，式I、I-2、I-4、I-6化合物的制备方法类似，只需将式II中间体替换为式II-1中间体。When X is S, the preparation method of the compound of the formula I, I-2, I-4, and I-6 is similar to the preparation method of the compound of the formula I, I-2, I-4, and I-6 when X is O, only The intermediate of formula II needs to be replaced with the intermediate of formula II-1.
X为S时，式I-1、I-3、I-5、I-7化合物的制备方法与X为O时，式I-1、I-3、I-5、I-7化合物的制备方法类似，只需将式III中间体替换为式III-1中间体。When X is S, the preparation method of the compound of the formula I-1, I-3, I-5, I-7 and the preparation of the compound of the formula I-1, I-3, I-5 and I-7 when X is O The procedure is similar, simply replacing the intermediate of formula III with the intermediate of formula III-1.
X为NR 10时，式I、I-2、I-4、I-6化合物的制备方法包括如下步骤： When X is NR 10 , the preparation method of the compound of Formula I, I-2, I-4, and I-6 includes the following steps:
Figure PCTCN2018075069-appb-000087
Figure PCTCN2018075069-appb-000087
(1)式II-2化合物可经途径1.得到相应的式I-6化合物(X为NR 10)；或者式II-2化合物可经途径2.得到相应的式I-6化合物(X为NR 10)；或者式II-2化合物可经途径3.得到相应的式I-6化合物(X为NR 10)。 (1) The compound of the formula II-2 can be obtained by the route 1. The corresponding compound of the formula I-6 (X is NR 10 ); or the compound of the formula II-2 can be obtained by the route 2. The corresponding compound of the formula I-6 (X is NR 10 ); or a compound of formula II-2 can be obtained via Scheme 3. to give the corresponding compound of formula I-6 (X is NR 10 ).
(2)式I-6化合物(X为NR 10)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-4化合物(X为NR 10)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-4化合物(X为NR 10)。 (2) a compound of the formula I-6 (X is NR 10 ) can be obtained via Route 4. A compound of the formula I-4 (X is NR 10 ) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, followed by The corresponding compound of formula 1-4 (X is NR 10 ) can be obtained via one or more of Routes 1, 2, or 3.
(3)式I-6化合物(X为NR 10)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-2化合物(X为NR 10)；或者式I-6化合物(X为NR 10)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-2化合物(X为NR 10)，随后可经途径7.得到相应的马氏或反马氏的式I-2化合物(X为NR 10)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-2化合物(X为NR 10)。 (3) a compound of formula I-6 (X is NR 10) can be obtained by the routes 5-2 I compound portion or all of carbon-carbon double bond reduction of carbon-carbon double bond of formula (X is NR 10); or Formula I-6 The compound (X is NR 10 ) can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond (X is NR 10 ) via Route 6. The corresponding horse can be obtained via Route 7. Or an anti-Martensian compound of formula 1-2 (X is NR 10 ), which can be subsequently subjected to the corresponding hydrocarbylation, acylation or carbonylation via one or more of Routes 1, 2, or 3. Compound I-2 (X is NR 10 ).
(4)式I-4化合物(X为NR 10)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为NR 10)；或者式I-2化合物(X为NR 10)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为NR 10)。 (4) The compound of the formula I-4 (X is NR 10 ) may give the corresponding compound of the formula I (X is NR) via one or more of the routes 5., 6., 7., 1., 2. or 3. 10); Alternatively compounds of formula I-2 (X is NR 10) can be 4, 7, 1, 2 or 3. the one or more of the corresponding compound of formula to give I (X is NR 10 via the pathway) .
X为NR 10时，式I-1、I-3、I-5、I-7化合物的制备方法包括如下步骤： When X is NR 10 , the preparation method of the compound of the formula I-1, I-3, I-5, and I-7 includes the following steps:
Figure PCTCN2018075069-appb-000088
Figure PCTCN2018075069-appb-000088
(1)式III-2化合物可经途径1.得到相应的式I-7化合物(X为NR 10)；或者式III-2化合物可经途径2.得到相应的式I-7化合物(X为NR 10)；或者式III-2化合物可经途径3.得到相应的式I-7化合物(X为NR 10)。 (1) The compound of the formula III-2 can be obtained by the route 1. The corresponding compound of the formula I-7 (X is NR 10 ); or the compound of the formula III-2 can be obtained by the route 2. The corresponding compound of the formula I-7 (X is NR 10 ); or a compound of formula III-2 can be obtained via Scheme 3. to give the corresponding compound of formula I-7 (X is NR 10 ).
(2)式I-7化合物(X为NR 10)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-5化合物(X为NR 10)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-5化合物(X为NR 10)。 (2) A compound of the formula I-7 (X is NR 10 ) can be obtained via Route 4. A compound of the formula I-5 (X is NR 10 ) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, followed by The corresponding compound of formula I-5 (X is NR 10 ) can be obtained via one or more of Routes 1, 2, or 3.
(3)式I-7化合物(X为NR 10)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-3化合物(X为NR 10)；或者式I-7化合物(X为NR 10)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-3化合物(X为NR 10)，随后可经途径7.得到相应的马氏或反马氏的式I-3化合物(X为NR 10)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-3化合物(X为NR 10)。 (3) a compound of formula I-7 (X is NR 10) can be obtained by the routes 5-3 I compound portion or all of carbon-carbon double bond reduction of carbon-carbon double bond of formula (X is NR 10); or Formula I-7 The compound (X is NR 10 ) can be obtained by a route 6 to obtain a compound of the formula I-3 (X is NR 10 ) epoxidized with a partial carbon-carbon double bond or a full carbon-carbon double bond, and then the corresponding horse can be obtained via the route 7. Or a compound of formula I-3 (X is NR 10 ), which can be followed by one or more of the routes 1, 2. or 3. to give the corresponding hydrocarbylation, acylation or carbonylation. Compound I-3 (X is NR 10 ).
(4)式I-5化合物(X为NR 10)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为NR 10)；或者式I-3化合物(X为NR 10)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为NR 10)。 (4) The compound of the formula I-5 (X is NR 10 ) may give the corresponding compound of the formula I-1 (X) via one or more of the routes 5., 6., 7., 1., 2. or 3. NR 10 ); or a compound of formula I-3 (X is NR 10 ) may give the corresponding compound of formula I-1 (X) via one or more of Routes 4., 7., 1., 2. or 3. For NR 10 ).
本发明上述制备方法中，途径1.是指与卤代烃(R 11-L，L为卤素)发生烃基化反应；途径2.是指与酰卤(R 11COL，L为卤素)或酸酐((R 11CO) 2O)发生酰基化反应；途径3.是指与羰基试剂(如三光气、光气或对硝基氯甲酸苯酯)和R 11OH、R 11SH或R 11NH 2反应；途径4.是指与羰基还原剂(如NaBH 4、LiAlH 4、B 2H 6或BH 3等)发生还原反应；途径5.是指与还原剂(如Pd-C/H 2、Pt-C/H 2、PtO 2/H 2、雷尼镍/H 2、氰基硼氢化钠)发生碳碳双键还原反应；途径6.是指与过氧化物(如间氯过氧苯甲酸mCPBA、双氧水H 2O 2、过氧乙酸CH 3COOOH或叔丁基过氧化氢t-BuOOH)发生环氧化反应；途径7.是指环氧水解反应，所需试剂优选稀盐酸、稀硫酸、甲酸或乙酸。 In the above preparation method of the present invention, the route 1. refers to a hydrocarbylation reaction with a halogenated hydrocarbon (R 11 -L, L is a halogen); the route 2. refers to an acid halide (R 11 COL, L is a halogen) or an acid anhydride ((R 11 CO) 2 O) acylation occurs; pathway 3. refers to carbonyl reagents (such as triphosgene, phosgene or phenyl p-nitrochloroformate) and R 11 OH, R 11 SH or R 11 NH 2 reaction; route 4. refers to the reduction reaction with a carbonyl reducing agent (such as NaBH 4 , LiAlH 4 , B 2 H 6 or BH 3 , etc.); route 5. refers to a reducing agent (such as Pd-C / H 2 , Pt-C/H 2 , PtO 2 /H 2 , Raney nickel/H 2 , sodium cyanoborohydride) undergo carbon-carbon double bond reduction reaction; pathway 6. refers to peroxides (such as m-chloroperoxybenzene) Ethyl formate mCPBA, hydrogen peroxide H 2 O 2 , peracetic acid CH 3 COOOH or t-butyl hydroperoxide t-BuOOH) epoxidation; pathway 7. refers to epoxy hydrolysis reaction, the required reagent is preferably dilute hydrochloric acid, rare Sulfuric acid, formic acid or acetic acid.
本发明所述的烃基化反应条件为本领域常规条件：在碱、卤代烃(R 11-L，L为卤素，优选氯、溴、 碘)作用下反应，碱优选碱金属碳酸盐(优选Na 2CO 3、K 2CO 3、Cs 2CO 3)、碱金属氢氧化物(优选LiOH、NaOH、KOH)、碱金属氢化物(优选NaH、LiH或KH)或碱金属醇化物(优选CH 3ONa、EtONa、t-BuOK)；酰基化反应条件也为本领域常规条件：在碱、酰卤(R 11COL，L为卤素，优选氯、溴、碘)或酸酐((R 11CO) 2O)作用下反应，碱优选碱金属氢氧化物(如NaOH、KOH)、三乙胺、吡啶、醋酸钠、喹啉、咪唑、二甲基苯胺、DMAP、2,6-二甲基吡啶等。本发明涉及的化学反应均需在溶剂存在下进行，溶剂选自二氯甲烷、氯仿、甲醇、乙醇、乙酸乙酯、水、吡啶、乙腈、苯、甲苯、THF、乙醚、乙二醇二甲醚、DMF、二氧六环等中的一种或几种。 The hydrocarbylation reaction conditions of the present invention are conventional in the art: in the case of a base, a halogenated hydrocarbon (R 11 -L, L is a halogen, preferably chlorine, bromine, iodine), the base is preferably an alkali metal carbonate ( Preference is given to Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 ), alkali metal hydroxides (preferably LiOH, NaOH, KOH), alkali metal hydrides (preferably NaH, LiH or KH) or alkali metal alkoxides (preferably) CH 3 ONa, EtONa, t-BuOK); acylation conditions are also conventional in the art: in bases, acid halides (R 11 COL, L is halogen, preferably chlorine, bromine, iodine) or anhydrides ((R 11 CO) 2 O) reaction, the base is preferably an alkali metal hydroxide (such as NaOH, KOH), triethylamine, pyridine, sodium acetate, quinoline, imidazole, dimethylaniline, DMAP, 2,6-dimethyl Pyridine, etc. The chemical reaction involved in the present invention needs to be carried out in the presence of a solvent selected from the group consisting of dichloromethane, chloroform, methanol, ethanol, ethyl acetate, water, pyridine, acetonitrile, benzene, toluene, THF, diethyl ether and ethylene glycol. One or more of ether, DMF, dioxane, and the like.
本发明所述的“C1-C21烃基”指含有1-21个碳原子的直链、支链或环状烷基，且任选含有一个或多个碳碳双键或三键；即包括C1-C21(直链、支链或环状)烷基、C2-C21(直链、支链或环状)烯基、C2-C21(直链、支链或环状)炔基。The "C1-C21 hydrocarbyl group" as used in the present invention refers to a linear, branched or cyclic alkyl group having 1 to 21 carbon atoms, and optionally contains one or more carbon-carbon double or triple bonds; - C21 (linear, branched or cyclic) alkyl, C2-C21 (linear, branched or cyclic) alkenyl, C2-C21 (linear, branched or cyclic) alkynyl.
本发明所述的“任选含有0至5个杂原子的饱和或不饱和的3至12元环基”，包括3至12元碳环基(包括饱和碳环和不饱和碳环)、3至12元杂环基(包括饱和杂环基或不饱和杂环基)，所述杂原子选自O、S、N或Se；3至12元环基包括单环、双环、螺环或稠环。The "saturated or unsaturated 3 to 12 membered ring group optionally containing 0 to 5 hetero atoms" as used in the present invention includes a 3 to 12 membered carbocyclic group (including a saturated carbocyclic ring and an unsaturated carbon ring), and 3 To a 12-membered heterocyclic group (including a saturated heterocyclic group or an unsaturated heterocyclic group), the hetero atom is selected from O, S, N or Se; and the 3- to 12-membered ring group includes a monocyclic ring, a bicyclic ring, a spiro ring or a thick ring.
本发明所述的“氨基酸残基”是指氨基酸中去掉氨基(NH 2)后残留的基团(例如Ala的氨基酸残基为
Figure PCTCN2018075069-appb-000089
)，优选常见的氨基酸残基，进一步优选Ala、Glu、Leu、Ser、Arg、Gln、Lys、Thr、Asn、Gly、Met、Trp、Asp、His、Phe、Tyr、Cys、Ile、Val等氨基酸残基。 The "amino acid residue" as used in the present invention refers to a group remaining after the amino group (NH 2 ) is removed from the amino acid (for example, the amino acid residue of Ala is
Figure PCTCN2018075069-appb-000089
Preferred amino acid residues are preferred, and amino acids such as Ala, Glu, Leu, Ser, Arg, Gln, Lys, Thr, Asn, Gly, Met, Trp, Asp, His, Phe, Tyr, Cys, Ile, Val, etc. are further preferred. Residues.
本发明所述硅基优选TMS、TBS、TES、TBDPS；本发明所述卤素优选氟、氯、溴、碘。The silicon group of the present invention is preferably TMS, TBS, TES, TBDPS; the halogen of the present invention is preferably fluorine, chlorine, bromine or iodine.
本发明中各具体取代基中的
Figure PCTCN2018075069-appb-000090
是指该取代基与母核结构的键接位点。 Among the specific substituents in the present invention
Figure PCTCN2018075069-appb-000090
Refers to the bonding site of the substituent to the core structure.
本发明中术语“药学上可接受的盐”是指非毒性的无机或有机酸和/或碱的加成盐，可参见“Salt selection for basic drugs”,Int.J.Pharm.(1986),33,201–217。这些盐可在式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物最后分离和纯化过程中原位制备，或通过使碱或酸官能团分别与适当的有机或无机酸或者碱反应而分别制备。具有代表性的盐包括但不限于下列：乙酸盐、己二酸盐、藻酸盐、柠檬酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、二葡糖酸盐、环戊烷丙酸盐、十二烷硫酸盐、乙磺酸盐、葡庚糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、富马酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对-甲苯磺酸盐和十一酸盐。此外，碱性含氮基团可以被如下试剂季铵盐化：低级烷基卤化物，例如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物；二烷基硫酸酯，例如二甲基、二乙基、二丁基和二戊基硫酸酯；长链卤化物，例如癸基、十二烷基、十四烷基、十八烷基氯化物、溴化物和碘化物；芳烷基卤化物，例如苄基和苯乙基溴化物等。如此可获得水或油溶性或可分散的产物。The term "pharmaceutically acceptable salt" in the present invention means a non-toxic addition salt of an inorganic or organic acid and/or a base, see "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201–217. These salts can be prepared in situ during the final isolation and purification of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7. Or separately prepared by reacting a base or an acid functional group with a suitable organic or inorganic acid or base, respectively. Representative salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyric acid Salt, camphorate, digluconate, cyclopentane propionate, dodecane sulfate, ethanesulfonate, glucoheptonate, glycerol phosphate, hemisulfate, heptanoate, caproic acid Salt, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalene Sulfonate, oxalate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, sulfate, tartaric acid Salt, thiocyanate, p-toluenesulfonate and undecanoate. Further, the basic nitrogen-containing group may be quaternized by a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfate, For example, dimethyl, diethyl, dibutyl and dipentyl sulfate; long chain halides such as decyl, dodecyl, tetradecyl, octadecyl chloride, bromide and iodide An aralkyl halide such as benzyl and phenethyl bromide. Water or oil soluble or dispersible products are thus obtained.
可以用于形成药学上可接受的酸加成盐的酸的实例包括如下的酸：无机酸，例如盐酸、硫酸、磷酸；有机酸，例如草酸、马来酸、甲烷磺酸、琥珀酸、柠檬酸、富马酸、葡萄糖醛酸、甲酸、乙酸、丁二酸。碱性加成盐可以在式I、式I-1、式I-2、式I-3、式I-4化合物的最后分离和纯化过程中原位制备，或通过使羧酸基团与适当的碱(例如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)反应分别制备， 或者与氨或有机伯、仲或叔胺反应制备。药学上可接受的盐包括但不限于：基于碱金属和碱土金属的阳离子，例如钠、锂、钾、钙、镁、铝盐等，以及非毒性铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲基胺、二甲基胺、三甲基胺、三乙胺、乙胺等。用于形成碱加成盐的其它代表性的有机胺包括二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。Examples of the acid which can be used to form a pharmaceutically acceptable acid addition salt include the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid; organic acids such as oxalic acid, maleic acid, methanesulfonic acid, succinic acid, lemon Acid, fumaric acid, glucuronic acid, formic acid, acetic acid, succinic acid. The basic addition salt can be prepared in situ during the final isolation and purification of the compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, or by reacting a carboxylic acid group with a suitable The base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation) is prepared separately or reacted with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, aluminum salts, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, Ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
本发明中术语“溶剂化物”是指本发明式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物或其盐与有机溶剂和/或水形成的溶剂合物，有机溶剂优选丙酮、乙腈、甲醇、乙醇，形成的溶剂化物优选式式I、式I-1、式I-2、式I-3、式I-4化合物或其盐的一水合物、二水合物、三水合物、一甲醇合物、二甲醇合物、一乙腈合物、二乙腈合物、一丙酮合物、二丙酮合物、半富马酸盐一水合物、富马酸盐二水合物、富马酸盐一乙醇合物等。进一步优选一水合物、富马酸盐二水合物、富马酸盐一乙醇合物。The term "solvate" in the present invention means a compound of the formula I, formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, formula I-7 of the present invention. Or a solvate thereof with an organic solvent and/or water, the organic solvent is preferably acetone, acetonitrile, methanol or ethanol, and the solvate is preferably of the formula I, the formula I-1, the formula I-2, the formula I-3 a compound of the formula I-4 or a salt thereof, a monohydrate, a dihydrate, a trihydrate, a monomethanolate, a dimethylformate, an acetonitrile, a diacetonitrile, a monoacetate, a diacetone , semi-fumarate monohydrate, fumarate dihydrate, fumarate monoethanolate, and the like. Further preferred are monohydrate, fumarate dihydrate, fumarate monoethanolate.
本发明式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物存在各种互变异构形式(其中分子的一个原子的质子转移到另一个原子上，分子的原子之间的化学键随后进行重排)。参见，例如，March，高等有机化学：反应、机理及结构(Advanced Organic Chemistry：Reactions，Mechanisms and Structures)，第四版，JohnWiley&Sons，第69-74页(1992)。本文中所使用的术语“互变异构体”是指通过质子转移而产生的化合物，应当理解的是，所有的互变异构形式(只要在它们可能存在)均包括在本发明范围内。例如当式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物中含有酰胺键、烯醇键、咪唑等官能团时存在的一对可以互相转换的一对互变异构体。The compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7 of the present invention exist in various tautomeric forms (wherein The protons of one atom of a molecule are transferred to another atom, and the chemical bonds between the atoms of the molecule are subsequently rearranged). See, for example, March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992). The term "tautomer" as used herein refers to a compound produced by proton transfer, it being understood that all tautomeric forms (as long as they may be present) are included within the scope of the invention. For example, when the compound of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7 contains an amide bond, an enol bond, or an imidazole A pair of tautomers that are interchangeable when functionally equivalent.
本发明化合物，包括式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物或其立体异构体以及其任何药学上可接受的盐、酯、代谢物和前药，可以包含不对称取代的碳原子。此类不对称取代的碳原子可以使得本发明化合物以对映异构体、非对映异构体以及其它立体异构形式存在，它们可以根据绝对立体化学而定义为例如(R)-或(S)-构型。因此，本发明化合物的所有此类可能的异构体、光学纯形式的单一立体异构体、它们的混合物、外消旋混合物(或“外消旋物”)、非对映异构体混合物、单一非对映异构体均包含在本发明中。本文中所使用的术语“S”和“R”构型根据下面定义：IUPAC 1974 Recommendations forSection E，Fundamental Stereochemistry，Pure Appl.Chem.45：13-30(1976)。术语α和β用于环状化合物的环位置。参照平面的α-侧为优选的取代基位于较低编号位置的一侧。位于参照平面相反一侧的那些取代基采用β描述符。需要注意的是，该用法与用于环状立体母核的用法有所区别，在环状母核中“α”是指“平面下面”并代表绝对构型。本文中所使用的术语α和β构型根据Chemical Abstracts Index Guide-Appendix IV(1987)第203段定义。Compounds of the invention, including compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, Formula I-7, or stereoisomers thereof, and Any pharmaceutically acceptable salt, ester, metabolite and prodrug thereof may comprise an asymmetrically substituted carbon atom. Such asymmetrically substituted carbon atoms may allow the compounds of the invention to exist in enantiomers, diastereomers, and other stereoisomeric forms, which may be defined as, for example, (R)- or (based on absolute stereochemistry). S) - configuration. Thus, all such possible isomers, optically pure forms of single stereoisomers, mixtures thereof, racemic mixtures (or "racemates"), diastereomeric mixtures of the compounds of the invention A single diastereomer is included in the present invention. The terms "S" and "R" configurations as used herein are defined according to the following definition: IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. 45: 13-30 (1976). The terms α and β are used for the ring position of the cyclic compound. The α-side of the reference plane is the preferred substituent on one side of the lower numbered position. Those substituents on the opposite side of the reference plane employ a beta descriptor. It should be noted that this usage differs from the usage for the annular stereonuclear, in which "α" means "below the plane" and represents the absolute configuration. The terms alpha and beta configurations as used herein are defined in accordance with paragraph 203 of the Chemical Abstracts Index Guide-Appendix IV (1987).
具体实施方式detailed description
为了便于对本发明的进一步理解，下面提供的实施例对其做了更详细的说明。但是这些实施例仅供更好的理解发明而并非用来限定本发明的范围或实施原则，本发明的实施方式不限于以下内容。In order to facilitate a further understanding of the present invention, the embodiments provided below are described in more detail. However, the examples are only for better understanding of the invention and are not intended to limit the scope or implementation of the invention. The embodiments of the invention are not limited to the following.
实施例1Example 1
(1)海洋真菌Penicillium sp.HK1-6菌种的培养(1) Cultivation of marine fungi Penicillium sp. HK1-6
真菌Penicillium sp.(HK1-6)的菌种培养所用的培养基为每1000mL水中加入：土豆200g煮沸取汁，葡萄糖20g，粗海盐30g，琼脂15g；使用时倒入玻璃培养皿中，制成培养基平板。真菌菌株接种于培养基平板中，在20℃下摇床培养3天。The culture medium used for the culture of the fungus Penicillium sp. (HK1-6) is added per 1000 mL of water: 200 g of potatoes, boiled juice, 20 g of glucose, 30 g of crude sea salt, 15 g of agar; and poured into a glass Petri dish when used. Medium plate. The fungal strain was inoculated into a medium plate and cultured at 20 ° C for 3 days under a shaker.
(2)海洋真菌Penicillium sp.HK1-6的发酵(2) Fermentation of marine fungus Penicillium sp. HK1-6
真菌Penicillium sp.HK1-6的发酵培养所用的发酵培养基为，每1000mL水中加入：土豆200g煮沸 取汁，葡萄糖20g，粗海盐30g；使用时分装于锥形瓶中。真菌菌株接种于锥形瓶的培养基中，于15～20℃静置培养28天。The fermentation medium used for the fermentation of the fungus Penicillium sp. HK1-6 is: per 1000 mL of water: 200 g of potatoes are boiled, 20 g of glucose, 30 g of crude sea salt; and used in an Erlenmeyer flask. The fungal strain was inoculated into a flask flask medium and cultured at 15 to 20 ° C for 28 days.
(3)发酵物中成分的初步分离(3) Preliminary separation of components in the ferment
取步骤(2)所得的发酵物10L，将发酵液和菌体分离后，发酵液用乙酸乙酯萃取3～5次，萃取液减压浓缩得到发酵液浸膏；菌体用甲醇浸提3～5次，减压浓缩得到菌体浸膏；合并发酵液浸膏和菌体浸膏，先进行减压硅胶柱层析，洗脱剂先采用石油醚：乙酸乙酯＝100:0至0:100(体积百分比，下同)梯度洗脱，再采用氯仿：甲醇＝100:0至0:100梯度洗脱，将洗脱得到的成分按照极性大小分成10个组分Fr.1～Fr.10。10 L of the fermented product obtained in the step (2), the fermentation broth and the cells are separated, and the fermentation broth is extracted with ethyl acetate for 3 to 5 times, and the extract is concentrated under reduced pressure to obtain a fermentation broth extract; the cells are extracted with methanol 3 ~5 times, concentrated under reduced pressure to obtain a bacterial extract; combined with fermentation broth extract and bacterial extract, first subjected to vacuum gel column chromatography, the eluent was first petroleum ether: ethyl acetate = 100:0 to 0 : 100 (volume percent, the same below) gradient elution, and then using chloroform: methanol = 100:0 to 0:100 gradient elution, the eluted components are divided into 10 components according to the polarity of the Fr.1 ~ Fr .10.
(4)化合物1–4的分离提取(4) Separation and extraction of compounds 1–4
将步骤(3)得到的组分Fr.4先经Sephadex LH-20凝胶柱层析，洗脱剂为CHCl 3:MeOH＝1:1，再经ODS反相硅胶柱层析，洗脱剂为MeOH:H 2O＝85:15，最后得到化合物4(10.9mg)；组分Fr.5先经正相硅胶柱层析，洗脱剂为乙酸乙酯：石油醚＝1:6至1:3或者甲醇：二氯甲烷＝1:30至1:15，再经高效液相色谱HPLC制备(所用色谱柱为Agilent C18,9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H 2O＝85:15)，最后得到化合物2(30.2mg)；组分Fr.8先经Sephadex LH-20凝胶柱层析，洗脱剂为CHCl 3:MeOH＝1:1，再经ODS反相硅胶柱层析，洗脱剂MeOH:H 2O＝75:25，最后经高效液相色谱HPLC制备(所用色谱柱为Agilent C18,9.4×250mm，7μm，流速为2mL/min，流动相为MeOH:H 2O＝85:15)，分别得到化合物1(23.7mg)和化合物3(8.8mg)。 The component Fr.4 obtained in the step (3) is first subjected to Sephadex LH-20 gel column chromatography, and the eluent is CHCl 3 : MeOH = 1:1, and then subjected to ODS reversed-phase silica gel column chromatography, eluent. MeOH:H 2 O=85:15, finally obtained compound 4 (10.9 mg); component Fr.5 was first subjected to normal phase silica gel column chromatography, eluent was ethyl acetate: petroleum ether = 1:6 to 1 :3 or methanol: dichloromethane = 1:30 to 1:15, and then prepared by high performance liquid chromatography HPLC (using a column of Agilent C18, 9.4 × 250 mm, 7 μm, flow rate of 2 mL / min, mobile phase is MeOH: H 2 O=85:15), finally obtained compound 2 (30.2 mg); component Fr.8 was first subjected to Sephadex LH-20 gel column chromatography, the eluent was CHCl 3 : MeOH = 1:1, and then ODS reversed-phase silica gel column chromatography, eluent MeOH:H 2 O=75:25, and finally purified by HPLC. (The column used was Agilent C18, 9.4×250 mm, 7 μm, flow rate 2 mL/min, flow The phase was MeOH:H 2 O = 85:15), Compound 1 (23.7 mg) and Compound 3 (8.8 mg) were obtained.
Figure PCTCN2018075069-appb-000091
Figure PCTCN2018075069-appb-000091
化合物1:[α] 15 D 156(c 0.3,MeOH)；UV(MeOH)λ max＝332,224nm；CD(0.08mM,MeOH)λ max(Δε)356(7.3),270(–3.3)nm；IR(KBr)ν max 3415,2925,2854,1703,1635,1453,1377,1321,1099,873cm –1； 1H NMR(CDCl 3,600MHz)and  13C NMR(CDCl 3,150MHz),见表1-1；HRESIMS m/z 497.2536(calcd for C 29H 37O 7,497.2534),519.2353(calcd for C 29H 36O 7Na,519.2353). Compound 1: [α] 15 D 156 (c 0.3, MeOH); UV (MeOH) λ max = 332, 224 nm; CD (0.08 mM, MeOH) λ max (Δε) 356 (7.3), 270 (-3.3) nm; IR (KBr) ν max 3415, 2925, 2854, 1703, 1635, 1453, 1377, 1321, 1099, 873 cm -1 ; 1 H NMR (CDCl 3 , 600 MHz) and 13 C NMR (CDCl 3 , 150 MHz), see table 1-1; HRESIMS m/z 497.2536 (calcd for C 29 H 37 O 7 , 497.2534), 519.2353 (calcd for C 29 H 36 O 7 Na, 519.2353).
化合物2:[α] 15 D 136(c 0.4,MeOH)；UV(MeOH)λ max＝336,221nm；CD(0.09mM,MeOH)λ max(Δε)358(9.4),274(–4.8)nm；IR(KBr)ν max 3265,2924,2853,1703,1614,1462,1366,1321,1289,1232,1124,1086,872cm –1； 1H NMR(CDCl 3,600MHz)and  13C NMR(CDCl 3,150MHz),见表1-1；HRESIMS m/z 479.2437(calcd for C 29H 35O 6,479.2428). Compound 2: [α] 15 D 136 (c 0.4, MeOH); UV (MeOH) λ max = 336, 221 nm; CD (0.09 mM, MeOH) λ max (Δε) 358 (9.4), 274 (-4.8) nm; IR (KBr) ν max 3265, 2924, 2853, 1703, 1614, 1462, 1366, 1321, 1289, 1232, 1124, 1086, 872 cm -1 ; 1 H NMR (CDCl 3 , 600 MHz) and 13 C NMR (CDCl 3 , 150MHz), see Table 1-1; HRESIMS m/z 479.2437 (calcd for C 29 H 35 O 6 , 479.2428).
化合物3: 1H NMR(CDCl 3,600MHz)and  13C NMR(CDCl 3,150MHz),见表2-2；HRESIMS m/z 531.2152(calcd for C 29H 36ClO 7,531.2144),553.1973(calcd for C 29H 35ClO 7Na,553.1964). Compound 3: 1 H NMR (CDCl 3 , 600 MHz) and 13 C NMR (CDCl 3 , 150 MHz), see Table 2-2; HRESIMS m/z 531.2152 (calcd for C 29 H 36 ClO 7 , 531.2144), 553.1973 (calcd For C 29 H 35 ClO 7 Na, 553.1964).
化合物4: 1H NMR(CDCl 3,600MHz)and  13C NMR(CDCl 3,150MHz),见表2-2；HRESIMS m/z  513.2057(calcd for C 29H 34ClO 6,513.2038). Compound 4: 1 H NMR (CDCl 3 , 600 MHz) and 13 C NMR (CDCl 3 , 150 MHz), see Table 2-2; HRESIMS m/z 513.2057 (calcd for C 29 H 34 ClO 6 , 513.2038).
表1-1.化合物1和2的 1H(600MHz)and  13C(150MHz)NMR(CDCl 3)数据 Table 1-1. 1 H (600 MHz) and 13 C (150 MHz) NMR (CDCl 3 ) data for Compounds 1 and 2.
Figure PCTCN2018075069-appb-000092
Figure PCTCN2018075069-appb-000092
表2-2.化合物3和4的 1H(600MHz)and  13C(150MHz)NMR(CDCl 3)数据 Table 2-2. 1 H (600 MHz) and 13 C (150 MHz) NMR (CDCl 3 ) data for compounds 3 and 4.
Figure PCTCN2018075069-appb-000093
Figure PCTCN2018075069-appb-000093
Figure PCTCN2018075069-appb-000094
Figure PCTCN2018075069-appb-000094
实施例2Example 2
称取化合物2(3.0mg)溶于2.0mL甲醇中，加入320mg NaOH，于室温下搅拌反应过夜，然后用3M HCl调pH至6.0左右，减压浓缩除去甲醇后，用EtOAc萃取，有机相依次用水、饱和NaCl洗涤，无水Na 2SO 4干燥，过滤，减压浓缩后，经硅胶柱层析(石油醚/乙酸乙酯＝3/1)得化合物283(1.6mg,87.5％)[α] 15 D 134(c 0.15,MeOH)；CD(0.84mM,MeOH)λ max(Δε)368(6.8),280(–6.8)nm； 1H NMR(400MHz,CDCl 3,δ,ppm,J/Hz):8.00(1H,s,H-1),7.21(1H,t,J＝8.0Hz,H-13),6.83(1H,d,J＝8.0Hz,H-12),6.79(1H,d,J＝8.0Hz,H-14),6.43(1H,s,H-4),5.57(1H,s,H-5),2.28(3H,s,H-16),1.59(3H,s,H-9). 13C NMR(CDCl 3,100MHz,δ,ppm):196.3(C-6),195.4(C-8),155.8(C-3),154.2(C-1),153.7(C-15),144.0(C-4a),138.9(C-11),131.8(C-13),122.8(C-12),118.5(C-10),115.6(C-8a),113.9(C-4),113.7(C-14),105.9(C-5),83.6(C-7),28.6(C-9),20.0(C-16).ESI-MS(m/z)：299.1[M+H] +，和化合物188(
Figure PCTCN2018075069-appb-000095
1.1mg， ESI-MS(m/z)：197.2[M-H] -)。 The compound 2 (3.0 mg) was weighed and dissolved in 2.0 mL of methanol, and 320 mg of NaOH was added thereto, and the reaction was stirred at room temperature overnight, and then the pH was adjusted to about 6.0 with 3M HCl. washed with water, saturated NaCl, dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure, purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3/1) to give compound 283 (1.6mg, 87.5%) [ α 15 D 134 (c 0.15, MeOH); CD (0.84 mM, MeOH) λ max (Δε) 368 (6.8), 280 (–6.8) nm; 1 H NMR (400 MHz, CDCl 3 , δ, ppm, J/) Hz): 8.00 (1H, s, H-1), 7.21 (1H, t, J = 8.0 Hz, H-13), 6.83 (1H, d, J = 8.0 Hz, H-12), 6.79 (1H, d, J = 8.0 Hz, H-14), 6.43 (1H, s, H-4), 5.57 (1H, s, H-5), 2.28 (3H, s, H-16), 1.59 (3H, s , H-9). 13 C NMR (CDCl 3 , 100 MHz, δ, ppm): 196.3 (C-6), 195.4 (C-8), 155.8 (C-3), 154.2 (C-1), 153.7 ( C-15), 144.0 (C-4a), 138.9 (C-11), 131.8 (C-13), 122.8 (C-12), 118.5 (C-10), 115.6 (C-8a), 113.9 (C -4), 113.7 (C-14), 105.9 (C-5), 83.6 (C-7), 28.6 (C-9), 20.0 (C-16). ESI-MS (m/z): 299.1 [ M+H] + , and compound 188 (
Figure PCTCN2018075069-appb-000095
1.1 mg, ESI-MS (m/z): 197.2 [MH] - ).
按照上述方法分别以甲醇为溶剂，以4N NaOH分别水解化合物1、3、4均可以80％以上的收率分别得到化合物282(黄色固体，ESI-MS(m/z)：317.1[M+H] +)、284(黄色固体，ESI-MS(m/z)：351.1[M+H] +、353.1[M+2+H] +)、285(黄色固体，ESI-MS(m/z)：333[M+H] +、335[M+2+H] +)。 The compound 282 (yellow solid, ESI-MS (m/z): 317.1 [M+H) was obtained by hydrolyzing the compounds 1, 3, and 4, respectively, with methanol as solvent and 4N NaOH, respectively. ] + ), 284 (yellow solid, ESI-MS (m/z): 351.1 [M+H] + , 353.1 [M+2+H] + ), 285 (yellow solid, ESI-MS (m/z) : 333 [M+H] + , 335 [M+2+H] + ).
实施例3Example 3
称取化合物1(50mg，0.1mmol)溶于10mL THF中，室温下加入TBSCl(0.15mmol)和咪唑(0.2mmol)，于25℃下搅拌反应过夜，加入适量甲醇终止反应，浓缩后、加入乙酸乙酯稀释，依次用1N HCl、饱和NaHCO 3、饱和NaCl洗涤，有机层用无水硫酸钠干燥，过滤，浓缩，经硅胶柱层析(石油醚/EtOAc＝15/1至12/1)，得到化合物1084(56mg，91.7％，ESI-MS(m/z)：611.3[M+H] +)。 The compound 1 (50 mg, 0.1 mmol) was weighed and dissolved in 10 mL of THF. TBSCl (0.15 mmol) and imidazole (0.2 mmol) were added at room temperature, and the reaction was stirred at 25 ° C overnight. The reaction was stopped by adding an appropriate amount of methanol. After concentration, acetic acid was added. diluted with ethyl successively with 1N HCl, saturated NaHCO 3, saturated NaCl, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 15/1 to 12/1), Compound 1084 (56 mg, 91.7%, ESI-MS (m/z): 611.3 [M+H] + ).
按照该实施例记载的方法，以化合物3替换化合物1可以89％的收率得到化合物1085(ESI-MS(m/z)：645.3[M+H] +、646.3[M+1+H] +、647.3[M+2+H] +)。 According to the method described in this example, Compound 1 can be obtained in a yield of 89% with Compound 3 (ESI-MS (m/z): 645.3 [M+H] + , 646.3 [M+1+H] + , 647.3 [M+2+H] + ).
实施例4Example 4
称取化合物2(48mg，0.1mmol)溶于5mL丙酮中，加入K 2CO 3(0.15mmol)，室温下搅拌10min后，加入MeI(0.13mmol)，30℃下反应4h后，TLC检测反应原料几乎完全消失，减压浓缩除去丙酮，加入乙酸乙酯稀释，依次用水、饱和NaCl洗涤，有机层用无水硫酸钠干燥，过滤、浓缩后，经硅胶柱层析(石油醚/EtOAc＝15/1至12/1)，得到化合物1086(41mg，83％，ESI-MS(m/z)：493.2[M+H] +)。 The compound 2 (48 mg, 0.1 mmol) was weighed and dissolved in 5 mL of acetone, and K 2 CO 3 (0.15 mmol) was added thereto. After stirring at room temperature for 10 min, MeI (0.13 mmol) was added, and the reaction was carried out at 30 ° C for 4 h, and the reaction materials were detected by TLC. It is almost completely disappeared, and the acetone is evaporated to dryness. EtOAc (EtOAc) Compounds 1186 (41 mg, 83%, ESI-MS (m/z): 493.2 [M+H] + ).
按照该实施例记载的方法，以化合物4替换化合物2可以86％的收率得到化合物1087(ESI-MS(m/z)：527.2[M+H] +、528.2[M+1+H] +、529.2[M+2+H] +)。 According to the method described in this example, Compound 10 can be obtained in a yield of 86% with compound 4 (ESI-MS (m/z): 527.2 [M+H] + , 528.2 [M+1+H] + 529.2 [M+2+H] + ).
实施例5Example 5
称取化合物2(48mg，0.1mmol)溶于5mL二氯甲烷中，加入Ac 2O(0.12mmol)、Et 3N(0.16mmol)和催化量的DMAP，室温下搅拌30min后，TLC检测反应原料几乎完全消失，加入甲醇终止反应，减压浓缩，经硅胶柱层析(石油醚/EtOAc＝12/1)，得到化合物1088(49mg，94％，ESI-MS(m/z)：521.2[M+H] +)。 Compound 2 (48 mg, 0.1 mmol) was weighed and dissolved in 5 mL of dichloromethane, and Ac 2 O (0.12 mmol), Et 3 N (0.16 mmol) and catalytic amount of DMAP were added, stirred at room temperature for 30 min, and the reaction materials were detected by TLC. Almost completely disappeared, the reaction was quenched with EtOAc EtOAc (EtOAc:EtOAc:EtOAc +H] + ).
按照该实施例记载的方法，以化合物4替换化合物2可以91％的收率得到化合物1089(ESI-MS(m/z)：555.2[M+H] +、556.2[M+1+H] +、557.2[M+2+H] +)。 According to the method described in this example, Compound 10 can be obtained in a yield of 91% by compound 4 (ESI-MS (m/z): 555.2 [M+H] + , 556.2 [M+1+H] + , 557.2 [M+2+H] + ).
按照该实施例记载的方法，分别以化合物1、3替换化合物2可分别以73％和77％的收率得到化合物1090(ESI-MS(m/z)：539.3[M+H] +)和1091(ESI-MS(m/z)：573.2[M+H] +、574.2[M+1+H] +、575.2[M+2+H] +)。 According to the method described in the examples, the compound 1 was replaced with the compound 1, 3, respectively, and the compound 1090 (ESI-MS (m/z): 539.3 [M+H] + ) was obtained in a yield of 73% and 77%, respectively. 1091 (ESI-MS (m / z): 573.2 [m + H] +, 574.2 [m + 1 + H] +, 575.2 [m + 2 + H] +).
按照该实施例记载的乙酰化方法，以二氯甲烷为溶剂，加入过量的Ac 2O(6.0equiv.)和Et 3N(8.0equiv.)以及催化量的DMAP，可以70％以上的收率得到羟基全乙酰化的产物，例如分别采用化合物1805、1807、1816、1818、1826替代化合物2作为反应物，可得到全乙酰化产物1811、1812、1827、1830、1832。 According to the acetylation method described in this example, an excess of Ac 2 O (6.0 equiv.) and Et 3 N (8.0 equiv.) and a catalytic amount of DMAP can be added in dichloromethane as a solvent, and the yield can be 70% or more. The hydroxy-peracetylated product is obtained, for example, by using compounds 1805, 1807, 1816, 1818, 1826 instead of compound 2 as reactants to obtain peracetylated products 1811, 1812, 1827, 1830, 1832.
实施例6Example 6
按照实施例2中记载的水解方法，以4N NaOH分别水解化合物1084-1087，均能以80％以上的收率得到化合物294-297和相应的脂肪酸化合物188。According to the hydrolysis method described in Example 2, the compound 1084-1087 was hydrolyzed by 4N NaOH, respectively, and the compound 294-297 and the corresponding fatty acid compound 188 were all obtained in a yield of 80% or more.
实施例7Example 7
称取化合物188(282mg,1.42mmol)溶于干燥的甲苯(5mL)中，加入DCC(292mg,1.42mmol)、 DMAP(6mg,0.05mmol)，室温下搅拌15分钟，加入化合物101(21mg,0.05mmol)，加热至65℃反应48小时后，过滤、减压浓缩后，经硅胶柱层析(石油醚/EtOAc＝12/1至10/1)，得到化合物1001(24mg；82％)，ESI-MS(m/z):603.1[M+H] +,605.1[M+2+H] +。 Compound 188 (282 mg, 1.42 mmol) was weighed and dissolved in dry toluene (5 mL). DCC (292 mg, 1.42 mmol), DMAP (6 mg, 0.05 mmol) was added and stirred at room temperature for 15 minutes, and compound 101 (21 mg, 0.05) was added. After heating to 65 ° C for 48 hours, the mixture was filtered, EtOAcjjjjjjjjjjjjjjjj - MS (m/z): 603.1 [M+H] + , 605.1 [M+2+H] + .
按照该实施例记载的方法，以甲苯为溶剂，分别以化合物95-183、201-297、301-494、501-622替换化合物101，以下列羧酸替换化合物188，于60至80℃下反应24至48小时，可以63％至87％的收率得到相应的缩合产物，例如表1中化合物1002-1039、1081、1083-1091、1097、1098、1282-1285、1292-1297，表2中化合物1201-1239、1281、1286-1291，表3中化合物1301-1343、1385-1391，表4中化合物1401-1443、1485-1497，表5中化合物1501-1545、1587、1589-1606，表6中化合物1607-1622，表7中化合物1701-1706；上述羧酸选自如下化合物：
Figure PCTCN2018075069-appb-000096
(CAS:1699983-08-8)、吗啉丙酸、环丙基乙酸、二十碳五烯酸(EPA)、二十二碳六烯酸(DHA)、巴豆酸、4-溴巴豆酸、2-氰基-3-甲基-2-丁烯酸(CAS：759-21-7)、4,4,4-三氟-3-甲基-2-丁烯酸(CAS：93404-33-2)、6-庚炔酸、2-丁炔酸、苯甲酸、
Figure PCTCN2018075069-appb-000097
Figure PCTCN2018075069-appb-000098
二十二碳五烯酸(DPA)、
Figure PCTCN2018075069-appb-000099
Figure PCTCN2018075069-appb-000100
(其中含Boc、Ac、Me、炔丙基的羧酸，可由相应羧酸与Boc 2O、Ac 2O、MeI、炔丙基溴等反应制备)。 According to the method described in the examples, the compound 101 was replaced with the compound 95-183, 201-297, 301-494, and 501-622, respectively, and the compound 188 was replaced with the following carboxylic acid, and the reaction was carried out at 60 to 80 ° C. 24 to 48 hours, the corresponding condensation products can be obtained in a yield of 63% to 87%, such as the compounds 1002-1039, 1081, 1083-1091, 1097, 1098, 1282-1285, 1292-1297 in Table 1, in Table 2 Compounds 1201-1239, 1281, 1286-1291, compounds 1301-1343, 1385-1391 in Table 3, compounds 1401-1443, 1485-1497 in Table 4, compounds 1501-1545, 1587, 1589-1606 in Table 5, Table 6 in the compound 1607-1622, the compound 1701-1706 in Table 7; the above carboxylic acid is selected from the following compounds:
Figure PCTCN2018075069-appb-000096
(CAS: 1699983-08-8), morpholine propionic acid, cyclopropylacetic acid, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), crotonic acid, 4-bromocrotonic acid, 2-cyano-3-methyl-2-butenoic acid (CAS: 759-21-7), 4,4,4-trifluoro-3-methyl-2-butenoic acid (CAS: 93404-33 -2), 6-heptynoic acid, 2-butynoic acid, benzoic acid,
Figure PCTCN2018075069-appb-000097
Figure PCTCN2018075069-appb-000098
Docosapentaenoic acid (DPA),
Figure PCTCN2018075069-appb-000099
Figure PCTCN2018075069-appb-000100
(Carboxylic acid containing Boc, Ac, Me, propargyl group, which can be prepared by reacting the corresponding carboxylic acid with Boc 2 O, Ac 2 O, MeI, propargyl bromide or the like).
实施例8Example 8
(1)称取化合物140(41mg,0.1mmol)溶于干燥的CH 2Cl 2(5mL)中，加入对硝基氯甲酸苯酯(0.13mmol)，Et 3N(0.15mmol)和催化量DMAP，室温搅拌反应0.5～1h(直到TLC检测化合物140几乎完全消失)，减压浓缩，经硅胶柱层析(石油醚/EtOAc＝10/1)，得到化合物1040-1(44mg，76％，ESI-MS(m/z)：578.0[M+H] +)。 (1) Compound 140 (41 mg, 0.1 mmol) was weighed and dissolved in dry CH 2 Cl 2 (5 mL), phenyl p-nitrochloroformate (0.13 mmol), Et 3 N (0.15 mmol) and catalytic amount DMAP were added. The reaction was stirred at room temperature for 0.5-1 h (~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ - MS (m/z): 578.0 [M+H] + ).
(2)称取化合物1040-1(58mg，0.1mmol)溶于干燥的CH 2Cl 2(5mL)中，加入正十二醇(0.12mmol)，室温下搅拌反应1.5h后，加入30mL CH 2Cl 2稀释，依次用饱和NaHCO 3、饱和NaCl洗涤，有机相用无水硫酸钠干燥，过滤、浓缩，经硅胶柱层析(石油醚/EtOAc＝15/1)，得到化合物1040(52mg，83％，ESI-MS(m/z)：625.1[M+H] +)。 (2) Weighed compound 1040-1 (58 mg, 0.1 mmol) in dry CH 2 Cl 2 (5 mL), added n-dodecanol (0.12 mmol), stirred at room temperature for 1.5 h, then added 30 mL of CH 2 diluted cl 2, washed with saturated NaHCO 3, washed with saturated NaCl, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 15/1), to give compound 1040 (52mg, 83 %, ESI-MS (m/z): 625.1 [M+H] + ).
按照该实施例记载的方法，分别以化合物95-183、201-297、301-494、501-622替换化合物140可得到相应的对硝基苯氧基酰化产物，然后再与下列醇、硫醇或胺(氨)反应：MeOH、EtOH、i-PrOH、 n-C 12H 25SH、EtSH、BnOH、
Figure PCTCN2018075069-appb-000101
PhOH、BnNH 2、
Figure PCTCN2018075069-appb-000102
Figure PCTCN2018075069-appb-000103
Figure PCTCN2018075069-appb-000104
可得到系列相应的羰基化化合物，例如表1中化合物1041-1064，表2中化合物1240-1264，表3中化合物1344-1368，表4中化合物1444-1468，表5中化合物1546-1570。 According to the method described in this example, the compound p-nitrophenoxy acylation product can be obtained by substituting the compound 150-183, 201-297, 301-494, and 501-622, respectively, and then with the following alcohol and sulfur. Alcohol or amine (ammonia) reaction: MeOH, EtOH, i-PrOH, nC 12 H 25 SH, EtSH, BnOH,
Figure PCTCN2018075069-appb-000101
PhOH, BnNH 2 ,
Figure PCTCN2018075069-appb-000102
Figure PCTCN2018075069-appb-000103
Figure PCTCN2018075069-appb-000104
A series of corresponding carbonylation compounds can be obtained, such as compounds 1041-1064 in Table 1, compounds 1240-1264 in Table 2, compounds 1344-1368 in Table 3, compounds 1444-1468 in Table 4, and compounds 1546-1570 in Table 5.
实施例9Example 9
称取化合物165(36mg，0.1mmol)，溶于5mL DMF中，冰浴下加入1.4equiv.NaH(0.14mmol)，室温下搅拌半小时后，加入1.2equiv.MeI(0.12mmol)，30℃下反应4-6h后，TLC检测反应原料几乎完全消失，加入乙酸乙酯稀释，依次用1N HCl、饱和NaHCO 3、饱和NaCl洗涤，有机层用无水硫酸钠干燥，过滤、浓缩后，经硅胶柱层析(石油醚/EtOAc＝15/1至12/1)，得到化合物1065(32mg，85％，ESI-MS(m/z)：375.0[M+H] +，377.0[M+2+H] +)。 The compound 165 (36 mg, 0.1 mmol) was weighed and dissolved in 5 mL of DMF, and 1.4 equiv. NaH (0.14 mmol) was added in an ice bath. After stirring at room temperature for half an hour, 1.2 equiv. MeI (0.12 mmol) was added at 30 ° C. after the reaction 4-6h, TLC detection reaction starting material disappeared almost completely, diluted with ethyl acetate, washed successively with 1N HCl, saturated NaHCO 3, saturated NaCl, the organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by silica gel column Chromatography (petroleum ether / EtOAc = 15 / 1 to 12 / 1) to afford compound 1065 (32 mg, 85%, ESI-MS (m/z): 375.0 [M+H] + , 377.0 [M+2+H ] + ).
按照该实施例记载的方法，分别以化合物95-183、201-297、301-494、501-622替换化合物165，与卤代物(例如MeI、EtBr、i-PrBr、CF 3I、
Figure PCTCN2018075069-appb-000105
n-C 12H 25Br、n-C 16H 33Br、BnBr、二苯基溴甲烷(Ph 2CHBr)、
Figure PCTCN2018075069-appb-000106
n-C 6H 13Br、对氯苄溴、8-溴喹啉、3-溴呋喃)反应，可得到相应的烃基化产物，例如表1中化合物1066-1080、1082；表2中化合物1265-1280；表3中化合物1369-1384；表4中化合物1469-1484；表5中化合物1571-1586、1588。 According to the method described in the examples, the compound 165 is replaced with the compound 95-183, 201-297, 301-494, and 501-622, respectively, and a halogenated substance (for example, MeI, EtBr, i-PrBr, CF 3 I,
Figure PCTCN2018075069-appb-000105
nC 12 H 25 Br, nC 16 H 33 Br, BnBr, diphenylbromomethane (Ph 2 CHBr),
Figure PCTCN2018075069-appb-000106
Reaction of nC 6 H 13 Br, p-chlorobenzyl bromide, 8-bromoquinoline, 3-bromofuran to give the corresponding hydrocarbylation products, such as compounds 1066-1080, 1082 in Table 1; compounds 1265-1280 in Table 2 ; compounds 1369-1384 in Table 3; compounds 1469-1484 in Table 4; compounds 1571-1586, 1588 in Table 5.
按照该实施例记载的甲基化方法，以DMF为溶剂，以过量的NaH(5.0equiv.)做碱，MeI(4.5equiv.)做甲基化试剂，可以75％以上的收率得到相应的全甲基化产物，例如以化合物1806、1808、1822、1823、1825替代化合物165作为反应物，可得到相应的甲基化产物1813、1814、1828、1829、1831。According to the methylation method described in this example, using DMF as a solvent, an excess of NaH (5.0 equiv.) as a base, and MeI (4.5 equiv.) as a methylating agent, a corresponding yield of 75% or more can be obtained. The permethylated product, for example, compound 1806, 1808, 1822, 1823, 1825 in place of compound 165 as the reactant, provides the corresponding methylated products 1813, 1814, 1828, 1829, 1831.
实施例10Example 10
称取化合物1(50mg，0.1mmol)溶于5mL二氯甲烷中，室温下加入4-氨基乙酰苯胺(0.11mmol)，室温搅拌反应5min后，TLC检测反应原料几乎完全消失，减压浓缩，经硅胶柱层析(石油醚/EtOAc＝5/1至4/1)，得到化合物1607(60mg，95％，ESI-MS(m/z)：629.3[M+H] +)。 Compound 1 (50 mg, 0.1 mmol) was weighed and dissolved in 5 mL of dichloromethane, and 4-aminoacetanilide (0.11 mmol) was added at room temperature. After stirring for 5 min at room temperature, the reaction material was almost completely disappeared by TLC, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether / EtOAc = 5/1 to 4/1) gave Compound 1607 (60 mg, 95%, ESI-MS (m/z): 629.3 [M+H] + ).
按照该实施例记载的方法，分别以化合物1-4、1001、1003、1084-1091替换化合物1，分别以下列胺(或氨水或氨基酸)：MeNH 2、NH 3·H 2O、NH 2OH、
Figure PCTCN2018075069-appb-000107
Figure PCTCN2018075069-appb-000108
Ala、Glu、Leu、Ser、Arg、Gln、Lys、Thr、Asn、Gly、Met、Trp、Asp、His、Phe、Tyr、Cys、Ile、 Val替换4-氨基乙酰苯胺，均可以90％以上的收率得到相应的含氮化合物，例如表6中化合物1607-1671，(其中当与氨基酸Arg或Lys反应时可产生两种比例接近1：1的含氮化合物，例如化合物1631和1632、1634和1635、1652和1653、1655和1656) According to the method described in the examples, Compound 1 was replaced with Compounds 1-4, 1001, 1003, and 1084-1091, respectively, with the following amines (or ammonia or amino acid): MeNH 2 , NH 3 ·H 2 O, NH 2 OH ,
Figure PCTCN2018075069-appb-000107
Figure PCTCN2018075069-appb-000108
Ala, Glu, Leu, Ser, Arg, Gln, Lys, Thr, Asn, Gly, Met, Trp, Asp, His, Phe, Tyr, Cys, Ile, Val replace 4-aminoacetanilide, all of which can be more than 90% Yield yields the corresponding nitrogen-containing compound, such as compound 1607-1671 in Table 6, (wherein when reacted with the amino acid Arg or Lys, two nitrogen-containing compounds can be produced in close proximity to 1:1, such as compounds 1631 and 1632, 1634 and 1635, 1652 and 1653, 1655 and 1656)
按照该实施例记载的方法，以二氯甲烷或四氢呋喃为溶剂，按照反应底物(例如化合物95-183、201-297)与胺(或氨)的摩尔比例为1：1.1，室温下反应2-30min后，经硅胶柱层析，可以90％以上的收率得到相应的含氮化合物，例如中间体化合物501-622；上述胺(或氨)选自如下化合物：NH 3·H 2O、
Figure PCTCN2018075069-appb-000109
MeNH 2、
Figure PCTCN2018075069-appb-000110
Figure PCTCN2018075069-appb-000111
Figure PCTCN2018075069-appb-000112
等。 According to the method described in this example, methylene chloride or tetrahydrofuran is used as a solvent, and the molar ratio of the reaction substrate (for example, compound 95-183, 201-297) to amine (or ammonia) is 1:1.1, and the reaction is carried out at room temperature. After -30 min, the corresponding nitrogen-containing compound can be obtained in a yield of 90% or more by silica gel column chromatography, for example, the intermediate compound 501-622; the above amine (or ammonia) is selected from the following compounds: NH 3 ·H 2 O,
Figure PCTCN2018075069-appb-000109
MeNH 2 ,
Figure PCTCN2018075069-appb-000110
Figure PCTCN2018075069-appb-000111
Figure PCTCN2018075069-appb-000112
Wait.
实施例11Example 11
称取化合物101(42mg，0.1mmol)溶于6mL干燥的甲苯中，加入P 2S 5(0.5mmol)，加热至80-90℃反应1.5小时，趁热过滤，滤液经减压浓缩后，经硅胶柱层析(石油醚/乙酸乙酯＝5/1)依次得化合物201(13.2mg，30％，ESI-MS(m/z)：454.9[M+H] +，456.9[M+2+H] +)、化合物301(14mg，32％，ESI-MS(m/z)：439.0[M+H] +，441.0[M+2+H] +)和化合物315(7.5mg，16％，ESI-MS(m/z)：470.9[M+H] +，472.9[M+2+H] +)。 Compound 101 (42 mg, 0.1 mmol) was weighed and dissolved in 6 mL of dry toluene, P 2 S 5 (0.5 mmol) was added, and the mixture was heated to 80-90 ° C for 1.5 hours, filtered while hot, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) gave compound 201 (13.2 mg, 30%, ESI-MS (m/z): 454.9 [M+H] + , 456.9 [M+2+] H] + ), Compound 301 (14 mg, 32%, ESI-MS (m/z): 439.0 [M+H] + , 441.0 [M+2+H] + ) and Compound 315 (7.5 mg, 16%, ESI-MS (m / z) : 470.9 [m + H] +, 472.9 [m + 2 + H] +).
称取化合物108(76mg，0.2mmol)溶于6mL干燥的二甲苯中，加入劳森试剂(Lawesson reagent，
Figure PCTCN2018075069-appb-000113
0.4mmol)，加热至50-60℃反应2小时后，减压浓缩，经硅胶柱层析(石油醚/乙酸乙酯＝6/1至4/1)依次得化合物208(10mg，12％，ESI-MS(m/z)：415.0[M+H] +)、化合物100(14.6mg，17％，ESI-MS(m/z)：431.0[M+H] +)、化合物98(6.4mg，8％，ESI-MS(m/z)：399.1[M+H] +)、化合物308(7.2mg，9％，ESI-MS(m/z)：399.1[M+H] +)和化合物322(12mg，14％，ESI-MS(m/z)：431.0[M+H] +)、327(18.7mg，21％，ESI-MS(m/z)：447.0[M+H] +)、329(7.4mg，9％，ESI-MS(m/z)：415.0[M+H] +)。 Compound 108 (76 mg, 0.2 mmol) was weighed and dissolved in 6 mL of dry xylene, and Lawesson reagent was added.
Figure PCTCN2018075069-appb-000113
0.4 mmol), heated to 50-60 ° C for 2 hours, concentrated under reduced pressure, EtOAc (EtOAc/EtOAc/EtOAc/EtOAc ESI-MS (m/z): 415.0 [M+H] + ), Compound 100 (14.6 mg, 17%, ESI-MS (m/z): 431.0 [M+H] + ), Compound 98 (6.4 mg , 8%, ESI-MS (m/z): 399.1 [M+H] + ), Compound 308 (7.2 mg, 9%, ESI-MS (m/z): 399.1 [M+H] + ) 322 (12 mg, 14%, ESI-MS (m/z): 431.0 [M+H] + ), 327 (18.7 mg, 21%, ESI-MS (m/z): 447.0 [M+H] + ) 329 (7.4 mg, 9%, ESI-MS (m/z): 415.0 [M+H] + ).
按照该实施例记载的方法，分别以化合物101-183、282-285、294-297、501-530、538-622、1-4、1084-1091等替代化合物101或108作为反应底物，以二甲苯、甲苯或苯为溶剂，于室温至回流温度下，与2倍摩尔当量的P 2S 5或Lawesson reagent反应1-3h后，经硅胶柱层析，可以类似的收率得到相应的硫代化合物，例如化合物95-100、201-281、286-293、301-494、531-537或者表2中化合物1286-1291、表3中化合物1386-1391、表4中化合物1486-1497。 According to the method described in the examples, the compound 101-183, 282-285, 294-297, 501-530, 538-622, 1-4, 1084-1091, and the like are used as the reaction substrates, respectively. Xylene, toluene or benzene is used as a solvent, and reacted with 2 times molar equivalent of P 2 S 5 or Lawesson reagent for 1-3 h at room temperature to reflux temperature. After silica gel column chromatography, the corresponding sulfur can be obtained in a similar yield. Substituting compounds, for example, compounds 95-100, 201-281, 286-293, 301-494, 531-537 or compounds 1286-1291 in Table 2, compounds 1386-1391 in Table 3, and compounds 1486-1497 in Table 4.
实施例12Example 12
按照该实施例5记载的乙酰化方法，分别以化合物282-285为反应物，以二氯甲烷为溶剂，加入1.2倍摩尔当量的Ac 2O和1.6倍摩尔当量的Et 3N及催化量的DMAP，室温下反应1-2小时，可得到相应的乙酰化化合物1707-1710。 According to the acetylation method described in Example 5, compound 282-285 was used as a reactant, and 1.2 times molar equivalent of Ac 2 O and 1.6 times molar equivalent of Et 3 N and a catalytic amount were added as dichloromethane as a solvent. DMAP, reaction at room temperature for 1-2 hours, can give the corresponding acetylated compound 1707-1710.
称取化合物1707(40mg，0.1mmol)溶于8mL THF中，冰盐浴下加入NaBH 4(0.11mmol)，冰盐浴下反应1.0h后，加入1mL饱和NH 4Cl终止反应，蒸除THF后，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，浓缩后，经硅胶柱层析(洗脱剂为EtOAc/石油醚＝1/5至1/4)，分别得到化合物1751(28mg，69.6％，ESI-MS(m/z)：403.1[M+H] +)和1752(8.5mg，21％，ESI-MS(m/z)：403.1[M+H] +)。 The compound 1707 (40 mg, 0.1 mmol) was weighed and dissolved in 8 mL of THF. NaBH 4 (0.11 mmol) was added to the ice salt bath, and the reaction was carried out in an ice salt bath for 1.0 h. Then, 1 mL of saturated NH 4 Cl was added to terminate the reaction, and the THF was evaporated. The mixture was extracted with EtOAc. EtOAc (EtOAc m. 69.6%, ESI-MS (m/z): 403.1 [M+H] + ) and 1752 (8.5 mg, 21%, ESI-MS (m/z): 403.1 [M+H] + ).
按照该实施例9记载的甲基化方法，以丙酮为溶剂，分别以化合物1751和1752替代化合物165作为反应物，与1.4倍摩尔当量的NaH和1.2倍摩尔当量的MeI反应，可分别得到化合物1753(89％，ESI-MS(m/z)：417.1[M+H] +)和1754(93％，ESI-MS(m/z)：417.1[M+H] +)。 According to the methylation method described in Example 9, a compound was obtained by reacting Compound 1751 and 1752 with Compound 165 as a reactant, and reacting with 1.4 times molar equivalent of NaH and 1.2 times molar equivalent of MeI, respectively, to obtain a compound. 1753 (89%, ESI-MS (m/z): 417.1 [M+H] + ) and 1754 (93%, ESI-MS (m/z): 417.1 [M+H] + ).
按照实施例3记载的硅基化方法，以THF为溶剂，分别以化合物1751和1752替代化合物1作为反应物，与1.5倍摩尔当量的TBSCl和2.0倍摩尔当量的咪唑反应，可分别得到化合物1755(92％，ESI-MS(m/z)：517.2[M+H] +)和1756(91％，ESI-MS(m/z)：517.2[M+H] +)。 According to the silylation method described in Example 3, compound 1751 and 1752 were substituted for compound 1 as a reactant, and 1.5 times molar equivalents of TBSCl and 2.0 times molar equivalent of imidazole were respectively reacted to obtain compound 1755. (92%, ESI-MS (m/z): 517.2 [M+H] + ) and 1756 (91%, ESI-MS (m/z): 517.2 [M+H] + ).
实施例13Example 13
称取化合物1755(52mg，0.1mmol)溶于6mL二氯甲烷中，加入1.5倍摩尔当量的m-CPBA，室温下反应2小时，加入1mL饱和亚硫酸钠终止反应，用二氯甲烷萃取，有机相，用无水硫酸钠干燥，过滤、减压浓缩后，经硅胶柱层析，得化合物1757(23mg，43％，ESI-MS(m/z)：533.2[M+H] +)、1758(20mg，38％，ESI-MS(m/z)：533.2[M+H] +)和1759(5mg，9.4％，ESI-MS(m/z)：533.2[M+H] +)。 Compound 1755 (52 mg, 0.1 mmol) was weighed and dissolved in 6 mL of dichloromethane, 1.5 times molar equivalent of m-CPBA was added, and the reaction was carried out for 2 hours at room temperature. The reaction was terminated by adding 1 mL of saturated sodium sulfite, and extracted with dichloromethane. dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by silica gel column chromatography to give compound 1757 (23mg, 43%, ESI -MS (m / z): 533.2 [m + H] +), 1758 (20mg , 38%, ESI-MS (m/z): 533.2 [M+H] + ) and 1759 (5 mg, 9.4%, ESI-MS (m/z): 533.2 [M+H] + ).
称取化合物1755(52mg，0.1mmol)溶于5mLCH 3OH-CH 2Cl 2中(体积比1:1)，加入催化量的Pd-C，室温下于1atm H 2作用下反应过夜，过滤除去Pd-C，浓缩得淡黄色固体49mg，即为化合物1760，产率94％，ESI-MS(m/z):519.2[M+H] +。 Compound 1755 (52 mg, 0.1 mmol) was weighed and dissolved in 5 mL of CH 3 OH-CH 2 Cl 2 (volume ratio 1:1), and a catalytic amount of Pd-C was added thereto, and the reaction was carried out under the action of 1 atm H 2 at room temperature overnight, and removed by filtration. Pd-C, and concentrated to give a light yellow solid 49 mg, 1760 is the compound, yield 94%, ESI-MS (m / z): 519.2 [m + H] +.
将CrO 3(4.0mmol)和3,5-二甲基吡唑(4.0mmol)加入10mL CH 2Cl 2中，于-20℃下快速搅拌15min，待溶于变为淡红色后，加入化合物1755(103mg，0.2mmol)，于-20℃下反应1.5小时后，过滤，滤液经减压浓缩后，经硅胶柱层析(乙酸乙酯/石油醚＝1/10)，得化合物1761(21mg，19.2％，ESI-MS(m/z)：545.2[M+H] +)、1762(34mg，32％，ESI-MS(m/z)：531.2[M+H] +)和1763(31mg，29.2％，ESI-MS(m/z)：531.2[M+H] +)。 CrO 3 (4.0 mmol) and 3,5-dimethylpyrazole (4.0 mmol) were added to 10 mL of CH 2 Cl 2 and stirred rapidly at -20 ° C for 15 min. After dissolved in a reddish color, compound 1755 was added. (103 mg, 0.2 mmol), and the reaction mixture was stirred at -20 ° C for 1.5 hr. 19.2%, ESI-MS (m/z): 545.2 [M+H] + ), 1762 (34 mg, 32%, ESI-MS (m/z): 531.2 [M+H] + ) and 1763 (31 mg, 29.2%, ESI-MS (m/z): 531.2 [M+H] + ).
实施例14Example 14
称取化合物1761(54mg，0.1mmol)溶于10mL THF中，冰盐浴下加入NaBH 4(0.22mmol)，冰盐浴下反应1.5h后，加入1mL饱和NH 4Cl终止反应，蒸除THF后，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，浓缩后，经硅胶柱层析(洗脱剂为EtOAc/石油醚＝1/4至1/3)，分别得到化合物1764(50.5mg，92％，ESI-MS(m/z)：549.2[M+H] +)。 The compound 1761 (54 mg, 0.1 mmol) was weighed and dissolved in 10 mL of THF, and NaBH 4 (0.22 mmol) was added to the ice salt bath. After 1.5 h of ice salt bath, 1 mL of saturated NH 4 Cl was added to terminate the reaction, and the THF was distilled off. The mixture was extracted with EtOAc. EtOAc (EtOAc)EtOAc. , 92%, ESI-MS (m/z): 549.2 [M+H] + ).
按照该实施例记载的方法，分别以化合物1762、1763替换化合物1761，均可以90％以上的收率分别得到化合物1765和1766。According to the method described in the examples, the compound 1761 was replaced with the compound 1762 and 1763, respectively, and the compounds 1765 and 1766 were each obtained in a yield of 90% or more.
按照该实施例9记载的甲基化方法，以丙酮为溶剂，分别以化合物1764-1766替代化合物165作为反应物，与1.4倍摩尔当量的NaH和1.2倍摩尔当量的MeI反应，可分别得到化合物1767-1769。According to the methylation method described in Example 9, a compound was obtained by reacting compound 1764-1766 with compound 165 as a reactant, and reacting with 1.4 times molar equivalent of NaH and 1.2 times molar equivalent of MeI to obtain a compound. 1767-1769.
实施例15Example 15
称取化合物1767(115mg，0.2mmol)溶于10mL二氯甲烷中，加入3.0倍摩尔当量的m-CPBA，室温下反应2小时，加入1mL饱和亚硫酸钠终止反应，用二氯甲烷萃取，有机相，用无水硫酸钠干燥，过滤、减压浓缩后，经硅胶柱层析，得化合物1770(53mg，45％，ESI-MS(m/z)：593.2[M+H] +)、1771(23mg，19％，ESI-MS(m/z)：609.2[M+H] +)、1772(26.8mg，22％，ESI-MS(m/z)：609.2[M+H] +)。 The compound 1767 (115 mg, 0.2 mmol) was weighed and dissolved in 10 mL of dichloromethane, 3.0 times molar equivalent of m-CPBA was added, and the reaction was carried out for 2 hours at room temperature. The reaction was terminated by adding 1 mL of saturated sodium sulfite, and extracted with dichloromethane. dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by silica gel column chromatography to give compound 1770 (53mg, 45%, ESI -MS (m / z): 593.2 [m + H] +), 1771 (23mg , 19%, ESI-MS (m/z): 609.2 [M+H] + ), 1772 (26.8 mg, 22%, ESI-MS (m/z): 609.2 [M+H] + ).
按照该实施例记载的方法，分别以化合物1764-1766、1768、1769替代化合物1767，以二氯甲烷作为溶剂，与3.0倍摩尔当量的m-CPBA反应，可得到化合物1773-1787。According to the method described in the examples, the compound 1767-766, 1768, and 1769 were used instead of the compound 1767, and methylene chloride was used as a solvent to react with 3.0-fold molar equivalent of m-CPBA to obtain a compound 1773-1787.
实施例16Example 16
称取化合物1771(61mg，0.1mmol)溶于4mL甲醇中，加入1mL 2.0N HCl，室温下搅拌0.5小时后，加入50mL乙酸乙酯稀释，依次用饱和NaHCO 3、饱和NaCl洗涤，有机相用无水硫酸钠干燥，过滤、减压浓缩后，经硅胶柱层析，得化合物1788(38mg，63％，ESI-MS(m/z)：611.2[M+H] +)。 The compound 1771 (61 mg, 0.1 mmol) was dissolved in 4 mL of methanol, and 1 mL of 2.0 N HCl was added. After stirring at room temperature for 0.5 hour, it was diluted with 50 mL of ethyl acetate and washed successively with saturated NaHCO 3 and saturated NaCl. over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, purified by silica gel column chromatography to give compound 1788 (38mg, 63%, ESI -MS (m / z): 611.2 [m + H] +).
按照该实施例记载的方法，以化合物1772替代化合物1771，可得到化合物1789(57％，ESI-MS(m/z)：611.2[M+H] +)。 According to the method described in the Example, Compound 1772 was used instead of Compound 1771 to obtain Compound 1789 (57%, ESI-MS (m/z): 611.2 [M+H] + ).
实施例17Example 17
称取化合物1789(61mg，0.1mmol)，溶于THF(5.0mL)中，加入1.5mL新配制的pH 7.0左右的Bu 4NF的THF溶液(用AcOH调pH 7.0,Bu 4NF的浓度为1.0mol/L)，室温反应2h，加水(0.5mL)终止反应，减压蒸除THF，EtOAc(20mL)萃取，有机层用无水Na 2SO 4干燥，过滤、浓缩，经硅胶柱层析得到化合物1790(46mg，93％，ESI-MS(m/z)：497.2[M+H] +)。 Compound 1789 (61 mg, 0.1 mmol) was weighed and dissolved in THF (5.0 mL), and 1.5 mL of a freshly prepared Bu 4 NF solution in pH 7.0 (pH 7.0 was adjusted with AcOH), and the concentration of Bu 4 NF was 1.0. mol / L), the reaction at room temperature 2h, add water (0.5mL) to terminate the reaction, was distilled off under reduced pressure (20mL) and extracted THF, EtOAc, the organic layer was dried over anhydrous Na 2 SO 4, filtered, and concentrated by silica gel column chromatography to give Compound 1790 (46 mg, 93%, ESI-MS (m/z): 497.2 [M+H] + ).
按照该实施例类似的方法，以化合物1788替换化合物1789，可得到化合物1791(91％，ESI-MS(m/z)：497.2[M+H] +)。 Following a procedure analogous to this example, substituting compound 1788 for compound 1789 gave compound 1791 (91%, ESI-MS (m/z): 497.2 [M+H] + ).
实施例18Example 18
按照实施例7记载的方法，以甲苯为溶剂，分别以化合物294替换化合物101，以正十二烷硫基乙酸(n-C 12H 25SCH 2COOH)替代化合物188，于80℃下反应24小时，可得到化合物1711(85％，ESI-MS(m/z)：673.4[M+H] +)。 According to the method described in Example 7, compound 101 was replaced with toluene as a solvent, and compound 188 was replaced with n-dodecylthioacetic acid (nC 12 H 25 SCH 2 COOH), and reacted at 80 ° C for 24 hours. Compound 1711 (85%, ESI-MS (m/z): 673.4 [M+H] + ).
按照1751-1791的制备方法及实施例1-17中记载的甲基化、乙酰化、硅基化、羰基化、碱性酯水解、酸性环氧开环、脱硅基、氧化、酯缩合、羰基化、烷基化等方法，可制备得到化合物1711-1750。According to the preparation method of 1751-1791 and the methylation, acetylation, silylation, carbonylation, alkaline ester hydrolysis, acid epoxy ring opening, desiliconization, oxidation, ester condensation, and the condensation reaction described in Examples 1-17, Compounds 1711-1750 can be prepared by methods such as carbonylation and alkylation.
实施例19Example 19
称取化合物1(50mg，0.1mmol)溶于10mL THF中，室温下加入NaBH 4(1.0mmol)，室温下反应5h后，加入2mL饱和NH 4Cl终止反应，蒸除THF后，用乙酸乙酯萃取，有机相经无水硫酸钠干燥，浓缩后，经硅胶柱层析(洗脱剂为二氯甲烷/甲醇＝15/1至10/1)，得到化合物1801(41mg，82％，ESI-MS(m/z)：503.3[M+H] +)。 The compound 1 (50 mg, 0.1 mmol) was weighed and dissolved in 10 mL of THF, and NaBH 4 (1.0 mmol) was added at room temperature. After reacting for 5 h at room temperature, the reaction was quenched by adding 2 mL of saturated NH 4 Cl. The organic phase was dried over anhydrous sodium sulfate, and then evaporated tolulululululululululululululululululu MS (m/z): 503.3 [M+H] + ).
按照该实施例记载的方法，以THF为溶剂，以过量的NaBH 4作为还原剂，在室温下，可将所有酮羰基还原，得到相应的羟基化产物，例如以化合物2-4、1086-1091、1607-1614、1616、1617、1620、 1622替代化合物1作为反应物，均可以80％以上的收率得到相应酮羰基全部还原为羟基的产物，例如表9中化合物1802-1810、1815-1826。 According to the method described in this example, using THF as a solvent and excess NaBH 4 as a reducing agent, all ketone carbonyl groups can be reduced at room temperature to obtain corresponding hydroxylated products, for example, compounds 2-4, 1086-1091 , 1607-1614, 1616, 1617, 1620, 1622, instead of compound 1, as a reactant, can obtain a product in which the corresponding ketone carbonyl group is all reduced to a hydroxyl group in a yield of 80% or more, for example, the compounds 1802-1810 and 1815-1826 in Table 9. .
实施例20Example 20
按照实施例1-19中记载的方法或现有技术中类似反应或在其基础上进行本领域常规替换，可制备得到本发明式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物及式II、式III、式II-1、式III-1、式II-2、式III-2中间体化合物范围内的任一化合物。例如表1-9中的化合物和中间体化合物201-297、301-494、501-622，以上所有化合物均经 1H NMR、ESI-MS进行结构确证以及HPLC纯度测定，部分化合物经CD、 1H- 1H COSY、HMQC、HMBC、NOESY进行结构确证。限于篇幅，本发明仅在表1-9中列出ESI-MS数据。本发明合成方法中所使用的简单原料，可由相应羟基化合物(或羧酸)与相应的酸酐、酰氯、卤代烃等按照本领域常规的方法进行制备。 Formula I, Formula I-1, Formula I-2, Formula I-3 of the present invention can be prepared according to the methods described in Examples 1-19 or similar reactions in the prior art or on a conventional basis in the art. , the compound of the formula I-4, the formula I-5, the formula I-6, the formula I-7 and the intermediate compound of the formula II, the formula III, the formula II-1, the formula III-1, the formula II-2 and the formula III-2 Any compound within the range. For example, the compounds in Tables 1-9 and the intermediate compounds 201-297, 301-494, and 501-622, all of the above compounds were structurally confirmed by 1 H NMR, ESI-MS, and HPLC purity determination, and some compounds were subjected to CD, 1 H- 1 H COSY, HMQC, HMBC, NOESY were structurally confirmed. Due to space limitations, the present invention lists ESI-MS data only in Tables 1-9. The simple starting materials used in the synthetic methods of the present invention can be prepared by the corresponding hydroxy compounds (or carboxylic acids) with the corresponding anhydrides, acid chlorides, halogenated hydrocarbons and the like according to methods conventional in the art.
实施例21本发明化合物的抗菌活性测试结果Example 21 Test Results of Antibacterial Activity of Compounds of the Invention
按照文献方法(Pierce C.G.；Uppuluri P.；Teistan A.R.；Wormley Jr.F.L.；Mowat E.；Ramage G.；Lopez-ribot J.L.Nat.Protoc.2008,3,1494-1500)测试了本发明化合物的抗菌活性。测试菌株包括5株革兰氏阳性菌，其中耐甲氧西林的金黄色葡萄球菌2株：S.aureus ATCC43300和S.aureus ATCC33591，甲氧西林敏感型金黄色葡萄球菌2株：S.aureus ATCC25923和S.aureus ATCC29213，耐万古霉素的粪肠球菌1株：E.faecalis ATCC51299；1株革兰氏阴性菌：大肠杆菌E.coli ATCC25922。The antibacterial properties of the compounds of the invention were tested according to the literature method (Pierce CG; Uppuluri P.; Teistan AR; Wormley Jr. FL; Mowat E.; Ramage G.; Lopez-ribot JL Nat. Protoc. 2008, 3, 1494-1500). active. The test strain includes 5 Gram-positive bacteria, of which 2 strains of methicillin-resistant Staphylococcus aureus: S. aureus ATCC43300 and S. aureus ATCC33591, methicillin-sensitive Staphylococcus aureus 2: S. aureus ATCC25923 And S. aureus ATCC29213, vancomycin-resistant Enterococcus faecalis 1 strain: E. faecalis ATCC51299; 1 strain of Gram-negative bacteria: Escherichia coli E. coli ATCC25922.
本发明测试了所有化合物对上述6株菌的最小抑菌浓度(minimum inhibitory concentration,MIC)，本发明化合物对大肠杆菌E.coli ATCC25922没有明显抗菌效果，但是对革兰氏阳性菌，尤其是对耐甲氧西林的金黄色葡萄球菌：S.aureus ATCC43300和S.aureus ATCC33591都显示出很强的抗菌活性，其MIC均小于或等于1.56μg/mL，远优于苯唑西林钠的抗菌活性(MIC>100μg/mL)，与万古霉素盐酸盐的抗菌活性相当；同时本发明化合物对耐万古霉素的粪肠球菌E.faecalis ATCC51299也显示出很强的抑菌活性(MIC≤3.13μg/mL)，优于万古霉素的抑菌活性(MIC＝6.25μg/mL)。为了本发明撰写的方便以及便于更加简明直观的理解本发明，以下仅列出本发明化合物的ESI-MS及其对耐甲氧西林的金黄色葡萄球菌S.aureus ATCC43300(表1-10中简写为43300)和S.aureus ATCC33591(表1-10中简写为33591)，甲氧西林敏感型金黄色葡萄球菌S.aureus ATCC25923(表1-10中简写为25923)和S.aureus ATCC29213(表1-10中简写为29213)、以及耐万古霉素的粪肠球菌E.faecalis ATCC51299(表1-10中简写为51299)的最小抑菌浓度(MIC,μg/mL)数据(见表1-9)。The present invention tested the minimum inhibitory concentration (MIC) of all the compounds against the above 6 strains, and the compound of the present invention has no obvious antibacterial effect on E. coli ATCC25922, but against Gram-positive bacteria, especially Methicillin-resistant Staphylococcus aureus: S. aureus ATCC43300 and S. aureus ATCC33591 all showed strong antibacterial activity, and their MICs were all less than or equal to 1.56 μg/mL, far superior to the antibacterial activity of oxacillin sodium ( MIC>100μg/mL), which is equivalent to the antibacterial activity of vancomycin hydrochloride; at the same time, the compound of the present invention also exhibits strong antibacterial activity against vancomycin-resistant Enterococcus faecalis E.faecalis ATCC51299 (MIC≤3.13μg) /mL), superior to the antibacterial activity of vancomycin (MIC = 6.25 μg / mL). For the convenience of the present invention and for a more concise and intuitive understanding of the present invention, only the ESI-MS of the compound of the present invention and its methicillin-resistant Staphylococcus aureus S. aureus ATCC43300 (abbreviated in Table 1-10) are listed below. 43300) and S. aureus ATCC33591 (abbreviated as 33591 in Table 1-10), methicillin-sensitive Staphylococcus aureus S. aureus ATCC25923 (abbreviated as 25923 in Tables 1-10) and S. aureus ATCC29213 (Table 1) -10 is abbreviated as 29213), and the minimum inhibitory concentration (MIC, μg/mL) of vancomycin-resistant Enterococcus faecalis E.faecalis ATCC51299 (abbreviated as 51199 in Table 1-10) (see Table 1-9) ).
限于篇幅，本发明仅列出式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7中的典型化合物于表1-9中。此外，本发明在表10中列出与本发明化合物结构类似的化合物1-9、cohaerins A-B、sclerotiorin及抗菌药物(万古霉素盐酸盐和苯唑西林钠)的相关活性数据(见表10)。Due to space limitations, the present invention only lists typical compounds of Formula I, Formula I-1, Formula I-2, Formula I-3, Formula I-4, Formula I-5, Formula I-6, and Formula I-7. Table 1-9. In addition, the present invention lists in Table 10 the activity data of compounds 1-9, cohaerins AB, sclerotiorin and antibacterial agents (vancomycin hydrochloride and oxacillin sodium) which are structurally similar to the compounds of the present invention (see Table 10). ).
表1Table 1
Figure PCTCN2018075069-appb-000114
Figure PCTCN2018075069-appb-000114
Figure PCTCN2018075069-appb-000115
Figure PCTCN2018075069-appb-000115
Figure PCTCN2018075069-appb-000116
Figure PCTCN2018075069-appb-000116
Figure PCTCN2018075069-appb-000117
Figure PCTCN2018075069-appb-000117
Figure PCTCN2018075069-appb-000118
Figure PCTCN2018075069-appb-000118
Figure PCTCN2018075069-appb-000119
Figure PCTCN2018075069-appb-000119
Figure PCTCN2018075069-appb-000120
Figure PCTCN2018075069-appb-000120
Figure PCTCN2018075069-appb-000121
Figure PCTCN2018075069-appb-000121
Figure PCTCN2018075069-appb-000122
Figure PCTCN2018075069-appb-000122
表2Table 2
Figure PCTCN2018075069-appb-000123
Figure PCTCN2018075069-appb-000123
Figure PCTCN2018075069-appb-000124
Figure PCTCN2018075069-appb-000124
Figure PCTCN2018075069-appb-000125
Figure PCTCN2018075069-appb-000125
Figure PCTCN2018075069-appb-000126
Figure PCTCN2018075069-appb-000126
Figure PCTCN2018075069-appb-000127
Figure PCTCN2018075069-appb-000127
Figure PCTCN2018075069-appb-000128
Figure PCTCN2018075069-appb-000128
Figure PCTCN2018075069-appb-000129
Figure PCTCN2018075069-appb-000129
表3table 3
Figure PCTCN2018075069-appb-000130
Figure PCTCN2018075069-appb-000130
Figure PCTCN2018075069-appb-000131
Figure PCTCN2018075069-appb-000131
Figure PCTCN2018075069-appb-000132
Figure PCTCN2018075069-appb-000132
Figure PCTCN2018075069-appb-000133
Figure PCTCN2018075069-appb-000133
Figure PCTCN2018075069-appb-000134
Figure PCTCN2018075069-appb-000134
Figure PCTCN2018075069-appb-000135
Figure PCTCN2018075069-appb-000135
Figure PCTCN2018075069-appb-000136
Figure PCTCN2018075069-appb-000136
表4Table 4
Figure PCTCN2018075069-appb-000137
Figure PCTCN2018075069-appb-000137
Figure PCTCN2018075069-appb-000138
Figure PCTCN2018075069-appb-000138
Figure PCTCN2018075069-appb-000139
Figure PCTCN2018075069-appb-000139
Figure PCTCN2018075069-appb-000140
Figure PCTCN2018075069-appb-000140
Figure PCTCN2018075069-appb-000141
Figure PCTCN2018075069-appb-000141
Figure PCTCN2018075069-appb-000142
Figure PCTCN2018075069-appb-000142
Figure PCTCN2018075069-appb-000143
Figure PCTCN2018075069-appb-000143
Figure PCTCN2018075069-appb-000144
Figure PCTCN2018075069-appb-000144
表5table 5
Figure PCTCN2018075069-appb-000145
Figure PCTCN2018075069-appb-000145
Figure PCTCN2018075069-appb-000146
Figure PCTCN2018075069-appb-000146
Figure PCTCN2018075069-appb-000147
Figure PCTCN2018075069-appb-000147
Figure PCTCN2018075069-appb-000148
Figure PCTCN2018075069-appb-000148
Figure PCTCN2018075069-appb-000149
Figure PCTCN2018075069-appb-000149
Figure PCTCN2018075069-appb-000150
Figure PCTCN2018075069-appb-000150
Figure PCTCN2018075069-appb-000151
Figure PCTCN2018075069-appb-000151
Figure PCTCN2018075069-appb-000152
Figure PCTCN2018075069-appb-000152
表6Table 6
Figure PCTCN2018075069-appb-000153
Figure PCTCN2018075069-appb-000153
Figure PCTCN2018075069-appb-000154
Figure PCTCN2018075069-appb-000154
Figure PCTCN2018075069-appb-000155
Figure PCTCN2018075069-appb-000155
Figure PCTCN2018075069-appb-000156
Figure PCTCN2018075069-appb-000156
Figure PCTCN2018075069-appb-000157
Figure PCTCN2018075069-appb-000157
Figure PCTCN2018075069-appb-000158
Figure PCTCN2018075069-appb-000158
Figure PCTCN2018075069-appb-000159
Figure PCTCN2018075069-appb-000159
表7Table 7
Figure PCTCN2018075069-appb-000160
Figure PCTCN2018075069-appb-000160
Figure PCTCN2018075069-appb-000161
Figure PCTCN2018075069-appb-000161
表8Table 8
Figure PCTCN2018075069-appb-000162
Figure PCTCN2018075069-appb-000162
Figure PCTCN2018075069-appb-000163
Figure PCTCN2018075069-appb-000163
Figure PCTCN2018075069-appb-000164
Figure PCTCN2018075069-appb-000164
Figure PCTCN2018075069-appb-000165
Figure PCTCN2018075069-appb-000165
Figure PCTCN2018075069-appb-000166
Figure PCTCN2018075069-appb-000166
Figure PCTCN2018075069-appb-000167
Figure PCTCN2018075069-appb-000167
Figure PCTCN2018075069-appb-000168
Figure PCTCN2018075069-appb-000168
Figure PCTCN2018075069-appb-000169
Figure PCTCN2018075069-appb-000169
表9Table 9
Figure PCTCN2018075069-appb-000170
Figure PCTCN2018075069-appb-000170
Figure PCTCN2018075069-appb-000171
Figure PCTCN2018075069-appb-000171
Figure PCTCN2018075069-appb-000172
Figure PCTCN2018075069-appb-000172
表10化合物1-9、282-285、cohaerins A-B、sclerotiorin及苯唑西林钠、万古霉素盐酸盐的抗菌活性测试结果Table 10 Test results of antibacterial activity of compounds 1-9, 282-285, cohaerins A-B, sclerotiorin, oxacillin sodium, vancomycin hydrochloride
Figure PCTCN2018075069-appb-000173
Figure PCTCN2018075069-appb-000173
Figure PCTCN2018075069-appb-000174
Figure PCTCN2018075069-appb-000174
化合物5-9可按文献Journal of Agricultural and Food Chemistry(2012),60(18),4480-4491中记载的方法制备得到。The compound 5-9 can be produced by the method described in the Journal of Agricultural and Food Chemistry (2012), 60 (18), 4480-4491.
表1-10中“A”表示MIC≤1.56μg/mL，“B”表示1.56μg/mL<MIC≤3.13μg/mL，“C”表示6.25μg/mL<MIC≤12.5μg/mL，“D”表示MIC>100μg/mL。In Table 1-10, "A" indicates MIC ≤ 1.56 μg / mL, "B" indicates 1.56 μg / mL < MIC ≤ 3.13 μg / mL, and "C" indicates 6.25 μg / mL < MIC ≤ 12.5 μg / mL, "D "Expression MIC > 100 μg / mL.
上述活性测试结果表明，本发明所有式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其药学上可接受的盐对耐甲氧西林的金黄色葡萄球菌：S.aureus ATCC43300和S.aureus ATCC33591都显示出很强的抗菌活性，其MIC均小于或等于1.56μg/mL，远优于苯唑西林钠的抗菌活性(MIC>100μg/mL)，与万古霉素盐酸盐的抗菌活性相当；同时本发明化合物对耐万古霉素的粪肠球菌E.faecalis ATCC51299也显示出很强的抑菌活性(MIC≤3.13μg/mL)，优于万古霉素盐酸盐的抑菌活性(6.25μg/mL<MIC≤12.5μg/mL)。而且本发明化合物的抗菌活性(尤其是耐药菌)与其类似物cohaerins A-B、sclerotiorin及化合物5-9相比具有显著提高(活性增加30-60倍)。The above activity test results show that all the compounds of the formula I, the formula I-1, the formula I-2, the formula I-3, the formula I-4, the formula I-5, the formula I-6, the formula I-7, and the three-dimensional thereof The isomer, its tautomer, and its pharmaceutically acceptable salt exhibit strong antibacterial activity against methicillin-resistant Staphylococcus aureus: S. aureus ATCC43300 and S. aureus ATCC33591, both of which have MIC Less than or equal to 1.56 μg / mL, far superior to the antibacterial activity of oxacillin sodium (MIC > 100 μg / mL), comparable to the antibacterial activity of vancomycin hydrochloride; while the compound of the present invention is resistant to vancomycin-resistant feces Coccus E. faecalis ATCC51299 also showed strong antibacterial activity (MIC ≤ 3.13 μg / mL), which was superior to the antibacterial activity of vancomycin hydrochloride (6.25 μg / mL < MIC ≤ 12.5 μg / mL). Moreover, the antibacterial activity (especially resistant bacteria) of the compounds of the present invention is significantly improved (increased 30-60 fold increase in activity) compared to their analogs cohaerins A-B, sclerotiorin and compounds 5-9.
此外，本发明式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其药学上可接受的盐不仅具有显著的抗MRSA活性，而且其具有较低的毒副作用。细 胞毒活性测试，化合物1–4、和表1–9中的化合物在20μM浓度时均未显示明显的细胞毒活性。相反cohaerins A-B、sclerotiorin及化合物5-9在相同浓度条件下则显示出较大的细胞毒性。Further, the compound of the formula I, the formula I-1, the formula I-2, the formula I-3, the formula I-4, the formula I-5, the formula I-6, the compound of the formula I-7, the stereoisomer thereof, The tautomer, a pharmaceutically acceptable salt thereof, not only has significant anti-MRSA activity, but also has low toxic side effects. The cytotoxic activity test, Compounds 1–4, and the compounds in Tables 1–9 did not show significant cytotoxic activity at 20 μM concentration. In contrast, cohaerins A-B, sclerotiorin and compound 5-9 showed greater cytotoxicity at the same concentration.
可见本发明式I、式I-1、式I-2、式I-3、式I-4、式I-5、式I-6、式I-7化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物可用于制备预防和/或治疗由耐药菌(尤其是耐甲氧西林的金黄色葡萄球菌和耐万古霉素的粪肠球菌)感染引起的疾病的药物先导化合物、候选药物、药物。The compounds of the formula I, the formula I-1, the formula I-2, the formula I-3, the formula I-4, the formula I-5, the formula I-6, the formula I-7, the stereoisomers thereof, and the mutual a solvate of an isomer, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a salt thereof, for use in the preparation of a prophylactic and/or therapeutic bacterium resistant to methicillin (especially methicillin-resistant Staphylococcus aureus) Drug lead compounds, drug candidates, drugs for diseases caused by vancomycin-resistant Enterococcus faecalis infection.
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(39)中国专利申请号CN201610831163.3、CN201611203587.1(39) Chinese patent application number CN201610831163.3, CN201611203587.1
在本发明提及的所有文献都在本申请中引用作为参考文献，就如同每一篇文献被单独引用作为参考那样。本发明中所使用的中英文简称、代号等均可在参考文献或现有技术的技术手册、教科书、工具书中找到。此外应理解，在阅读了本发明的上述内容之后，本领域的技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present application are hereby incorporated by reference in their entirety as if they are individually incorporated by reference. The Chinese and English abbreviations, codes, and the like used in the present invention can be found in reference documents or prior art technical manuals, textbooks, and reference books. In addition, it should be understood that various modifications and changes may be made to the present invention, and the equivalents of the scope of the present invention.

Claims (36)

  1. 一种式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物，其特征在于式I化合物具有如下结构：A solvate of a compound of the formula I, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof, characterized in that the compound of the formula I has the structure :
    Figure PCTCN2018075069-appb-100001
    Figure PCTCN2018075069-appb-100001
    R 1和R 2各自独立地选自甲基、OR 10，且基团R 1和R 2互不相同，R 10选自H、R 11、C(＝O)-R 11、C(＝O)-OR 11、C(＝O)-SR 11、C(＝O)-NR 11，R 11选自C1-C21烃基、任选含有0至5个杂原子的饱和或不饱和的3至12元环基、或硅基； R 1 and R 2 are each independently selected from methyl group, OR 10 , and the groups R 1 and R 2 are different from each other, and R 10 is selected from H, R 11 , C(=O)-R 11 , C(=O). -OR 11 , C(=O)-SR 11 , C(=O)-NR 11 , R 11 is selected from a C1-C21 hydrocarbyl group, optionally containing 0 to 5 heteroatoms of saturated or unsaturated 3 to 12 a ring group or a silicon group;
    R 11任选被羟基、羟甲基、羧基、乙酰氨基、C1-C4烷基(如甲基、乙基、丙基)、三氟甲基、三氟乙酰基、巯基、卤素、硝基、氨基、亚胺基(＝NH)、甲硫基、叠氮基(-N 3)、胍基、氰基、叔丁氧羰基(-Boc)、羰基(-C＝O)、氧代(＝O)、硫代(＝S)、磺酰基、亚磺酰基、C1-C4烷氧基(如甲氧基、乙氧基、叔丁氧基)、苯基、羟基苯基、呋喃基、萘基、苄基、苯乙基咪唑基、吡啶基、噁唑基、异恶唑基、三氮唑基、四氮唑基、呋喃基、喹啉基、噁嗪基、噻吩基、噻唑基、噻二唑基、吲哚基、咔唑基、咪唑基、异喹啉基、苯并呋喃基、苯并噻唑基、苯并硒二唑基、香豆素基、异香豆素基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、哌啶基、哌嗪基、四氢呋喃基、二氧六环基、噁唑啉、噻唑啉基、四氢吡喃基、二氢香豆素基、二氢异香豆素基、四氢喹啉基、四氢异喹啉基、四氢咔唑基、嘧啶碱基、嘌呤碱基中的一个或多个取代； R 11 is optionally hydroxy, hydroxymethyl, carboxy, acetylamino, C1-C4 alkyl (eg methyl, ethyl, propyl), trifluoromethyl, trifluoroacetyl, decyl, halogen, nitro, Amino, imido (=NH), methylthio, azide (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (= O), thio (=S), sulfonyl, sulfinyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), phenyl, hydroxyphenyl, furyl, naphthalene Base, benzyl, phenethyl imidazolyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, furyl, quinolyl, oxazinyl, thienyl, thiazolyl, Thiadiazolyl, fluorenyl, carbazolyl, imidazolyl, isoquinolinyl, benzofuranyl, benzothiazolyl, benzoselenadiazole, coumarin, isocoumarin, aza Cyclobutane, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxolyl, oxazoline, thiazolinyl, tetrahydropyranyl, dihydrogen Bean-based, dihydroisocoumarin, tetrahydroquinolyl, tetrahydroisoquinolinyl, tetra One or more substitutions in a hydrocarbazolyl, pyrimidine, or purine base;
    Y 1、Y 2、Y 3、Y 4各自独立选自H、OR 10，或者Y 1与Y 2一起为O或S(即Y 1与Y 2一起形成＝O或＝S)，或者Y 3与Y 4一起为O或S(即Y 3与Y 4一起形成＝O或＝S)； Y 1 , Y 2 , Y 3 , Y 4 are each independently selected from H, OR 10 , or Y 1 and Y 2 together are O or S (ie, Y 1 and Y 2 together form =O or =S), or Y 3 Together with Y 4 is O or S (ie, Y 3 and Y 4 together form =O or =S);
    X选自O、S、Se或NR 10； X is selected from O, S, Se or NR 10 ;
    W选自O或S；W is selected from O or S;
    n、m、p各自独立地选自0至2的整数；n, m, p are each independently selected from an integer of 0 to 2;
    结构式中3个“---”各自独立地选自单键或不存在，当R 4与R 5间的“---”为单键时，则R 4、R 5不存在，当R 6与R 7间的“---”为单键时，则R 7不存在，当R 8与R 9间的“---”为单键时，则R 8不存在； Wherein three "---" in the formula are each independently selected from a single bond or absent, and when "---" between R 4 and R 5 is a single bond, then R 4 and R 5 are absent, when R 6 When "---" between R and 7 is a single bond, then R 7 does not exist, and when "---" between R 8 and R 9 is a single bond, then R 8 does not exist;
    R 3、R 4、R 5、R 6、R 7、R 8、R 9各自独立地选自H、卤素(优选F、Cl、Br、I)、OR 10，或者R 4与R 5一起为O(即形成环氧，此时R 4与R 5间的“---”不存在)、R 6与R 7一起为O(即形成环氧，此时R 6与R 7间的“---”不存在)、R 8与R 9一起为O(即形成环氧，此时R 8与R 9间的“---”不存在)； R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from H, halogen (preferably F, Cl, Br, I), OR 10 , or R 4 together with R 5 O (ie, forming an epoxy, where "---" between R 4 and R 5 is absent), and R 6 and R 7 together are O (ie, forming an epoxy, at this time between R 6 and R 7 "- --" is absent), R 8 and R 9 together are O (ie, forming an epoxy, where "---" between R 8 and R 9 does not exist);
    A环为3至12元的饱和或不饱和环，其包含选自碳原子和0至4个杂原子的环成员，且所述环包含0至3个独立选自C(＝O)、C(＝S)、S(＝O)、S(＝O) 2或C(＝NR 10)的环成员，且所述环任选被一个或多个选自R 12的基团取代；R 12选自如下基团：羟基、羟甲基、羧基、乙酰氨基、C1-C4烷基(如甲基、乙基、丙基、叔丁基)、三氟甲基、三氟乙酰基、巯基、卤素、硝基、氨基、叠氮基(-N 3)、胍基、氰基、叔丁氧羰基(-Boc)、羰基(-C＝O)、氧代(＝O)、硫代(＝S)、环氧(环氧可以指向纸 面里
    Figure PCTCN2018075069-appb-100002
    也可以指向纸面外
    Figure PCTCN2018075069-appb-100003
    )、磺酰基、亚磺酰基、C1-C4烷氧基(如甲氧基、乙氧基、叔丁氧基)、乙酰氧基(AcO)、丙酰氧基、苯甲酰氧基、苯基、叔丁基二甲基硅氧基(TBSO)、三乙基硅氧基(TESO)、三甲基硅氧基(TMSO)、叔丁基二苯基硅氧基(TBDPSO)；     The A ring is a 3 to 12 membered saturated or unsaturated ring comprising a ring member selected from the group consisting of a carbon atom and 0 to 4 hetero atoms, and the ring contains 0 to 3 independently selected from C(=O), C. a ring member of (=S), S(=O), S(=O) 2 or C(=NR 10 ), and the ring is optionally substituted by one or more groups selected from R 12 ; R 12 Selected from the group consisting of hydroxyl, hydroxymethyl, carboxyl, acetylamino, C1-C4 alkyl (such as methyl, ethyl, propyl, tert-butyl), trifluoromethyl, trifluoroacetyl, decyl, Halogen, nitro, amino, azido (-N 3 ), fluorenyl, cyano, tert-butoxycarbonyl (-Boc), carbonyl (-C=O), oxo (=O), thio (= S), epoxy (epoxy can point to the paper surface
    Figure PCTCN2018075069-appb-100002
    Can also point out of the paper
    Figure PCTCN2018075069-appb-100003
    ), sulfonyl, sulfinyl, C1-C4 alkoxy (such as methoxy, ethoxy, tert-butoxy), acetoxy (AcO), propionyloxy, benzoyloxy, benzene Base, tert-butyldimethylsilyloxy (TBSO), triethylsilyloxy (TESO), trimethylsiloxy (TMSO), tert-butyldiphenylsiloxy (TBDPSO);
    所述杂原子各自独立地选自O、S、N或Se；The heteroatoms are each independently selected from O, S, N or Se;
    前提条件是当结构中3个“---”均为单键且R 10选自如下基团：H、乙酰基(Ac)、丙酰基
    Figure PCTCN2018075069-appb-100004
    溴乙酰基(BrCH 2CO)、正十二烷硫基乙酰基(CH 3(CH 2) 11SCH 2CO)、呋喃-2-甲酰基
    Figure PCTCN2018075069-appb-100005
    环戊甲酰基
    Figure PCTCN2018075069-appb-100006
    噻吩-2-甲酰基
    Figure PCTCN2018075069-appb-100007
    喹喔啉-2-甲酰基
    Figure PCTCN2018075069-appb-100008
    6-氯烟酰基
    Figure PCTCN2018075069-appb-100009
    单甲酯琥珀酰基
    Figure PCTCN2018075069-appb-100010
    或苯丙酰基
    Figure PCTCN2018075069-appb-100011
    时，A环只能选自：
    Figure PCTCN2018075069-appb-100012
    Figure PCTCN2018075069-appb-100013
    Figure PCTCN2018075069-appb-100014
    其中各个R 13独立地选自H、R 11、C(＝O)-R 11、C(＝O)-OR 11、C(＝O)-SR 11、 C(＝O)-NR 11；并且，式I结构化合物中不包括如下化合物：
    Figure PCTCN2018075069-appb-100015
    (CAS登记号：852201-92-4)、
    Figure PCTCN2018075069-appb-100016
    (CAS登记号：852201-91-3)、
    Figure PCTCN2018075069-appb-100017
    (CAS登记号：852200-62-5)、
    Figure PCTCN2018075069-appb-100018
    (CAS登记号：862390-34-9)、
    Figure PCTCN2018075069-appb-100019
    (CAS登记号：1199815-43-4)、
    Figure PCTCN2018075069-appb-100020
    (penicilone A)、
    Figure PCTCN2018075069-appb-100021
    (penicilone B)、
    Figure PCTCN2018075069-appb-100022
    (penicilone C)、
    Figure PCTCN2018075069-appb-100023
    (penicilone D)。     The prerequisite is that when the three "---" in the structure are single bonds and R 10 is selected from the group consisting of H, acetyl (Ac), propionyl
    Figure PCTCN2018075069-appb-100004
    Bromoacetyl (BrCH 2 CO), n-dodecylthioacetyl (CH 3 (CH 2 ) 11 SCH 2 CO), furan-2-formyl
    Figure PCTCN2018075069-appb-100005
    Cyclopentanoyl
    Figure PCTCN2018075069-appb-100006
    Thiophene-2-formyl
    Figure PCTCN2018075069-appb-100007
    Quinoxaline-2-formyl
    Figure PCTCN2018075069-appb-100008
    6-chloronicotinoyl
    Figure PCTCN2018075069-appb-100009
    Monomethyl succinyl
    Figure PCTCN2018075069-appb-100010
    Phenylpropionyl
    Figure PCTCN2018075069-appb-100011
    When the ring A can only be selected from:
    Figure PCTCN2018075069-appb-100012
    Figure PCTCN2018075069-appb-100013
    Figure PCTCN2018075069-appb-100014
    Wherein each R 13 is independently selected from the group consisting of H, R 11 , C(=O)-R 11 , C(=O)-OR 11 , C(=O)-SR 11 , C(=O)-NR 11 ; The following compounds are not included in the structural formula I:
    Figure PCTCN2018075069-appb-100015
    (CAS registration number: 852201-92-4),
    Figure PCTCN2018075069-appb-100016
    (CAS registration number: 852201-91-3),
    Figure PCTCN2018075069-appb-100017
    (CAS registration number: 852200-62-5),
    Figure PCTCN2018075069-appb-100018
    (CAS registration number: 862390-34-9),
    Figure PCTCN2018075069-appb-100019
    (CAS registration number: 1199815-43-4),
    Figure PCTCN2018075069-appb-100020
    (penicilone A),
    Figure PCTCN2018075069-appb-100021
    (penicilone B),
    Figure PCTCN2018075069-appb-100022
    (penicilone C),
    Figure PCTCN2018075069-appb-100023
    (penicilone D).
  2. 权利要求1所述的式I化合物，其中n、m、p均为0。A compound of formula I according to claim 1 wherein n, m and p are both zero.
  3. 权利要求1所述的式I化合物，其中Y 1与Y 2一起为O或S，Y 3与Y 4一起为O或S。 Compounds of formula I according to claim 1, wherein Y 1 and Y 2 together are O or S, Y 3 and Y 4 together are O or S.
  4. 权利要求2所述的式I化合物，其中Y 1与Y 2一起为O或S，Y 3与Y 4一起为O或S。 Compounds of formula I according to claim 2, wherein Y 1 and Y 2 together are O or S, Y 3 and Y 4 together are O or S.
  5. 权利要求1所述的式I化合物，其中3个“---”均为单键。A compound of formula I as claimed in claim 1, wherein all three "---" are single bonds.
  6. 权利要求2所述的式I化合物，其中3个“---”均为单键。A compound of formula I as claimed in claim 2 wherein all three "---" are single bonds.
  7. 权利要求3所述的式I化合物，其中3个“---”均为单键。A compound of formula I as claimed in claim 3 wherein all three "---" are single bonds.
  8. 权利要求4所述的式I化合物，其中3个“---”均为单键。A compound of formula I as claimed in claim 4 wherein all three "---" are single bonds.
  9. 权利要求1-8任一项所述的式I化合物，其中X选自O或NR 10。 A compound of formula I according to any one of claims 1-8, wherein X is selected from O or NR 10 .
  10. 权利要求1-4任一项所述的式I化合物，其中R 4与R 5、R 6与R 7、R 8与R 9至少有一组一起为O。 A compound of formula I according to any one of claims 1 to 4, wherein R 4 and R 5 , R 6 and R 7 , R 8 and R 9 are at least one group together.
  11. 权利要求1-10任一项所述的式I化合物，其中A环选自
    Figure PCTCN2018075069-appb-100024
    Figure PCTCN2018075069-appb-100025
    Figure PCTCN2018075069-appb-100026
    苄基，上述A环任选被一个或多个R 12取代。A环进一步优选如下基团：
    Figure PCTCN2018075069-appb-100027
    Figure PCTCN2018075069-appb-100028
    A compound of formula I according to any one of claims 1 to 10, wherein ring A is selected from
    Figure PCTCN2018075069-appb-100024
    Figure PCTCN2018075069-appb-100025
    Figure PCTCN2018075069-appb-100026
    Benzyl, the above A ring is optionally substituted by one or more R 12 . The A ring is further preferably a group as follows:
    Figure PCTCN2018075069-appb-100027
    Figure PCTCN2018075069-appb-100028
  12. 权利要求1-11任一项所述的的式I化合物，其中R 11选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、正己基、正庚基、正辛基、3-甲基-戊基、2-甲基-戊基、2-甲基-己基、3-甲基-己基、3-乙基-己基、1-氟-3-甲基-戊基、1-氟-2-甲基-戊基、1-氟-2-甲基-己基、1-氟-3-甲基-己基、1-氟-3-乙基-己基、1-氯-3-甲基-戊基、1-氯-2-甲基-戊基、1-氯-2-甲基-己基、1-氯-3-甲基-己基、1-氯-3-乙基-己基、1-溴-3-甲基-戊基、1-溴-2-甲基-戊基、1-溴-2-甲基-己基、1-溴-3-甲基-己基、1-溴-3-乙基-己基、乙烯基、丙烯基、烯丙基、正丁烯基、异丁烯基、丁-2-烯基、丁二烯基、正戊烯基、异戊烯基、戊二烯基、正己烯基、正庚烯基、庚二烯基、庚三烯基、正辛烯基、辛二烯基、辛三烯基、3-甲基-戊-2-烯基、2-甲基-戊-2-烯基、2-甲基-己-2-烯基、3-甲基-己-2-烯基、3-乙基-己-2-烯基、乙炔基、丙炔基、正丁炔基、丁-2-炔基、正戊炔基、异戊炔基、正己炔基、正庚炔基、庚二炔基、正辛炔基、辛二炔基、辛三炔基、2-甲基-戊-2-炔基、2-甲基-己-2-炔基、3-甲基-己-2-炔基、3-乙基-己-2-炔基、苯基、对甲氧基苯基、对氰基苯基、对羟甲基苯基、苄基、萘-1-基、苯乙基、苯丙基、环戊基、环丙基、环己基、环丁基、氮杂环丁基、呋喃-2-基、噻吩-2-基、卤代甲基(例如BrCH 2、ClCH 2、FCH 2、CF 3)、正十二烷硫代甲基(CH 3(CH 2) 11SCH 2)、6-氯吡啶-3-基、喹喔啉-2- 基、
    Figure PCTCN2018075069-appb-100029
    甲氧亚甲基(MOM)、正壬基(-C 9H 19-n)、正癸基(-C 10H 21-n)、正十一烷基(-C 11H 23-n)、正十二烷基(-C 12H 25-n)、正十三烷基(-C 13H 27-n)、正十四烷基(-C 14H 29-n)、正十五烷基(-C 15H 31-n)、正十六烷基(-C 16H 33-n)、苯乙基咪唑基、吡啶基、噁唑基、异恶唑基、三氮唑基、四氮唑基、喹啉基、噁嗪基、噻吩基、噻唑基、噻二唑基、吲哚基、咔唑基、异喹啉基、苯并呋喃基、苯并噻唑基、苯并硒二唑基、香豆素基、异香豆素基、氮杂环丁烷基、氧杂环丁烷基、吗啉基、哌啶基、哌嗪基、四氢呋喃基、二氧六环基、噁唑啉、噻唑啉基、嘧啶碱基、嘌呤碱基、二苯甲基、氨基酸残基、
    Figure PCTCN2018075069-appb-100030
    Figure PCTCN2018075069-appb-100031
    Figure PCTCN2018075069-appb-100032
    TMS、TBS、TES、Ms、Ts。     A compound of formula I according to any one of claims 1-11, wherein R 11 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, Isoamyl, n-hexyl, n-heptyl, n-octyl, 3-methyl-pentyl, 2-methyl-pentyl, 2-methyl-hexyl, 3-methyl-hexyl, 3-ethyl- Hexyl, 1-fluoro-3-methyl-pentyl, 1-fluoro-2-methyl-pentyl, 1-fluoro-2-methyl-hexyl, 1-fluoro-3-methyl-hexyl, 1- Fluoro-3-ethyl-hexyl, 1-chloro-3-methyl-pentyl, 1-chloro-2-methyl-pentyl, 1-chloro-2-methyl-hexyl, 1-chloro-3- Methyl-hexyl, 1-chloro-3-ethyl-hexyl, 1-bromo-3-methyl-pentyl, 1-bromo-2-methyl-pentyl, 1-bromo-2-methyl-hexyl , 1-bromo-3-methyl-hexyl, 1-bromo-3-ethyl-hexyl, vinyl, propenyl, allyl, n-butenyl, isobutenyl, but-2-enyl, dibutyl Alkenyl, n-pentenyl, isopentenyl, pentadienyl, n-hexenyl, n-heptenyl, heptadienyl, heptadienyl, n-octenyl, octadienyl, octylene , 3-methyl-pent-2-enyl, 2-methyl-pent-2-enyl, 2-methyl-hex-2-enyl, 3-methyl-hex-2-enyl, 3- -hex-2-enyl, ethynyl, propynyl, n-butynyl, but-2-ynyl, n-pentynyl, isopentynyl, n-hexynyl, n-heptynyl, heptadiyne , n-alkynyl, octadiynyl, octantylene, 2-methyl-pent-2-ynyl, 2-methyl-hex-2-ynyl, 3-methyl-hex-2- Alkynyl, 3-ethyl-hex-2-ynyl, phenyl, p-methoxyphenyl, p-cyanophenyl, p-hydroxymethylphenyl, benzyl, naphthalen-1-yl, phenethyl Phenylpropyl, cyclopentyl, cyclopropyl, cyclohexyl, cyclobutyl, azetidinyl, furan-2-yl, thiophen-2-yl, halomethyl (eg BrCH 2 , ClCH 2 , FCH 2 , CF 3 ), n-dodecylthiomethyl (CH 3 (CH 2 ) 11 SCH 2 ), 6-chloropyridin-3-yl, quinoxalin-2-yl,
    Figure PCTCN2018075069-appb-100029
    Methoxymethylene (MOM), n-decyl (-C 9 H 19 -n), n-decyl (-C 10 H 21 -n), n-undecyl (-C 11 H 23 -n), n-Dodecyl (-C 12 H 25 -n), n-tridecyl (-C 13 H 27 -n), n-tetradecyl (-C 14 H 29 -n), n-pentadecyl (-C 15 H 31 -n), n-hexadecyl (-C 16 H 33 -n), phenethyl imidazolyl, pyridyl, oxazolyl, isoxazolyl, triazolyl, tetrazo Azyl, quinolyl, oxazinyl, thienyl, thiazolyl, thiadiazolyl, fluorenyl, oxazolyl, isoquinolyl, benzofuranyl, benzothiazolyl, benzoselenadiazole Base, coumarin, isocoumarin, azetidinyl, oxetanyl, morpholinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dioxolyl, oxazoline , thiazoline group, pyrimidine base, purine base, benzhydryl, amino acid residue,
    Figure PCTCN2018075069-appb-100030
    Figure PCTCN2018075069-appb-100031
    Figure PCTCN2018075069-appb-100032
    TMS, TBS, TES, Ms, Ts.
  13. 权利要求1-12任一项所述的式I化合物，选自说明书表1-9中的化合物1001-1091、1097、1098、1201-1297、1301-1391、1401-1497、1501-1671、1701-1791、1801-1832，其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物。The compound of formula I according to any one of claims 1 to 12, which is selected from the group consisting of the compounds 1001-1091, 1097, 1098, 1201-1297, 1301-1391, 1401-1497, 1501-1671, 1701 in Tables 1-9 of the specification. -1791, 1801-1832, a solvate of a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a salt thereof.
  14. 一种抗耐药菌药物，其特征在于包含权利要求1-13任一项所述的式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物作为有效成分。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。An anti-drug resistant drug characterized by comprising the compound of the formula I according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically thereof thereof A solvate of an acceptable salt or a salt thereof is used as an active ingredient. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  15. 一种药物组合物，其特征在于包含权利要求1-13任一项所述的式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物，和至少一种其他抗菌药物，以及药学上可接受的载体、稀释剂或赋形剂。该药物组合物优选注射剂、口服制剂、冻干粉针剂、悬浮剂等。所述药物组合物用于预防和/或治疗由耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)感染引起的疾病。A pharmaceutical composition comprising a compound of formula I according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable A solvate of a salt or a salt thereof, and at least one other antibacterial agent, and a pharmaceutically acceptable carrier, diluent or excipient. The pharmaceutical composition is preferably an injection, an oral preparation, a lyophilized powder injection, a suspension, or the like. The pharmaceutical composition is for preventing and/or treating methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC43300, S. aureus ATCC33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E .faecalis ATCC51299) A disease caused by infection.
  16. 权利要求1-13任一项所述的式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备抗耐药菌药物中的用途。所述耐药菌选自耐甲氧西林 的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。A solvate of a compound of the formula I according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof Use in the preparation of anti-resistant bacteria drugs. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  17. 权利要求1-13任一项所述的式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备药物中的用途，所述药物用于预防和/或治疗由S.aureus ATCC43300、S.aureus ATCC33591、S.aureus ATCC25923、S.aureus ATCC29213、E.faecalis ATCC51299、E.faecium ATCC35667感染引起的疾病。A solvate of a compound of the formula I according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof Use in the preparation of a medicament for the prevention and/or treatment of a disease caused by infection with S. aureus ATCC43300, S. aureus ATCC33591, S. aureus ATCC25923, S. aureus ATCC29213, E. faecalis ATCC51299, E. faecium ATCC35667 .
  18. 权利要求1-13任一项所述的式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备抗耐药菌药物先导化合物中的应用。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。A solvate of a compound of the formula I according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof The use of a lead compound for the preparation of anti-drug resistant drugs. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  19. 权利要求1-13任一项所述的式I化合物、其立体异构体、其互变异构体、其溶剂化物、其前药、其药学上可接受的盐或其盐的溶剂化物在制备抗耐药菌候选药物中的应用。所述耐药菌选自耐甲氧西林的金黄色葡萄球菌(MRSA，优选S.aureus ATCC43300、S.aureus ATCC33591)和耐万古霉素的粪肠球菌(VER,优选E.faecalis ATCC51299)。A solvate of a compound of the formula I according to any one of claims 1 to 13, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a salt thereof Preparation of anti-resistant bacteria candidate drugs. The resistant bacteria are selected from the group consisting of methicillin-resistant Staphylococcus aureus (MRSA, preferably S. aureus ATCC 43300, S. aureus ATCC 33591) and vancomycin-resistant Enterococcus faecalis (VER, preferably E. faecalis ATCC 51199).
  20. 一种中间体，其特征在于所述中间体具有式II所示的结构：An intermediate characterized by having the structure of formula II:
    Figure PCTCN2018075069-appb-100033
    Figure PCTCN2018075069-appb-100033
    Y为O或S，化学键
    Figure PCTCN2018075069-appb-100034
    表示指向纸面里的键
    Figure PCTCN2018075069-appb-100035
    或指向纸面外的键
    Figure PCTCN2018075069-appb-100036
    R 3、R 6、R 9、W、A环、n、m、p的定义与权利要求1中式I化合物的定义相同，前提条件是式II结构化合物不包括化合物101-183。     Y is O or S, chemical bond
    Figure PCTCN2018075069-appb-100034
    Indicates the key pointing to the paper
    Figure PCTCN2018075069-appb-100035
    Or point to a key outside the paper
    Figure PCTCN2018075069-appb-100036
    The definitions of R 3 , R 6 , R 9 , W, A ring, n, m, p are the same as those defined for the compound of formula I in claim 1, provided that the structural compound of formula II does not include compounds 101-183.
  21. 权利要求20所述的中间体，选自说明书中化合物95-100、201-212。The intermediate of claim 20 selected from the group consisting of compounds 95-100, 201-212.
  22. 一种中间体，其特征在于所述中间体具有式II-1所示的结构：An intermediate characterized by having the structure of the formula II-1:
    Figure PCTCN2018075069-appb-100037
    Figure PCTCN2018075069-appb-100037
    Y为O或S，化学键
    Figure PCTCN2018075069-appb-100038
    表示指向纸面里的键
    Figure PCTCN2018075069-appb-100039
    或指向纸面外的键
    Figure PCTCN2018075069-appb-100040
    R 3、R 6、R 9、W、A环、n、m、p的定义与权利要求1中式I化合物的定义相同。     Y is O or S, chemical bond
    Figure PCTCN2018075069-appb-100038
    Indicates the key pointing to the paper
    Figure PCTCN2018075069-appb-100039
    Or point to a key outside the paper
    Figure PCTCN2018075069-appb-100040
    The definitions of R 3 , R 6 , R 9 , W, A ring, n, m, p are the same as those defined for the compound of formula I in claim 1.
  23. 权利要求22所述的中间体，选自说明书中化合物301-332。The intermediate of claim 22 selected from the group consisting of compounds 301-332.
  24. 一种中间体，其特征在于所述中间体具有式II-2所示的结构：An intermediate characterized by having the structure of the formula II-2:
    Figure PCTCN2018075069-appb-100041
    Figure PCTCN2018075069-appb-100041
    Y为O或S，化学键
    Figure PCTCN2018075069-appb-100042
    表示指向纸面里的键
    Figure PCTCN2018075069-appb-100043
    或指向纸面外的键
    Figure PCTCN2018075069-appb-100044
    R 3、R 6、R 9、R 10、W、A环、n、m、p的定义与权利要求1中式I化合物的定义相同。     Y is O or S, chemical bond
    Figure PCTCN2018075069-appb-100042
    Indicates the key pointing to the paper
    Figure PCTCN2018075069-appb-100043
    Or point to a key outside the paper
    Figure PCTCN2018075069-appb-100044
    The definitions of R 3 , R 6 , R 9 , R 10 , W, A ring, n, m, p are the same as those defined for the compound of formula I in claim 1.
  25. 权利要求24所述的中间体，选自说明书中化合物501-537。The intermediate of claim 24, which is selected from the group consisting of compounds 501-537.
  26. 一种中间体，其特征在于所述中间体具有式III所示的结构：An intermediate characterized by having the structure of formula III:
    Figure PCTCN2018075069-appb-100045
    Figure PCTCN2018075069-appb-100045
    Y为O或S，化学键
    Figure PCTCN2018075069-appb-100046
    表示指向纸面里的键
    Figure PCTCN2018075069-appb-100047
    或指向纸面外的键
    Figure PCTCN2018075069-appb-100048
    R 3、R 6、R 9、A环的定义与权利要求1中式I化合物的定义相同，前提条件是式III结构化合物不包括化合物101-183。     Y is O or S, chemical bond
    Figure PCTCN2018075069-appb-100046
    Indicates the key pointing to the paper
    Figure PCTCN2018075069-appb-100047
    Or point to a key outside the paper
    Figure PCTCN2018075069-appb-100048
    The definition of the R 3 , R 6 , R 9 , A ring is the same as defined in the compound of the formula I in claim 1, provided that the structural compound of the formula III does not include the compound 101-183.
  27. 权利要求26所述的中间体，选自说明书中化合物213-297。The intermediate of claim 26, which is selected from the group consisting of compounds 213-297.
  28. 一种中间体，其特征在于所述中间体具有式III-1所示的结构：An intermediate characterized by having the structure of formula III-1:
    Figure PCTCN2018075069-appb-100049
    Figure PCTCN2018075069-appb-100049
    Y为O或S，化学键
    Figure PCTCN2018075069-appb-100050
    表示指向纸面里的键
    Figure PCTCN2018075069-appb-100051
    或指向纸面外的键
    Figure PCTCN2018075069-appb-100052
    R 3、R 6、R 9、A环的定义与权利要求1中式I化合物的定义相同。     Y is O or S, chemical bond
    Figure PCTCN2018075069-appb-100050
    Indicates the key pointing to the paper
    Figure PCTCN2018075069-appb-100051
    Or point to a key outside the paper
    Figure PCTCN2018075069-appb-100052
    The definition of R 3 , R 6 , R 9 , and A ring is the same as defined in the compound of formula I in claim 1.
  29. 权利要求28所述的中间体，选自说明书中化合物333-494。The intermediate of claim 28, which is selected from the group consisting of compounds 333-494.
  30. 一种中间体，其特征在于所述中间体具有式III-2所示的结构：An intermediate characterized in that the intermediate has the structure shown in formula III-2:
    Figure PCTCN2018075069-appb-100053
    Figure PCTCN2018075069-appb-100053
    Y为O或S，化学键
    Figure PCTCN2018075069-appb-100054
    表示指向纸面里的键
    Figure PCTCN2018075069-appb-100055
    或指向纸面外的键
    Figure PCTCN2018075069-appb-100056
    R 3、R 6、R 9、R 10、A环的定义与权利要求1中式I化合物的定义相同。     Y is O or S, chemical bond
    Figure PCTCN2018075069-appb-100054
    Indicates the key pointing to the paper
    Figure PCTCN2018075069-appb-100055
    Or point to a key outside the paper
    Figure PCTCN2018075069-appb-100056
    The definitions of R 3 , R 6 , R 9 , R 10 , and A ring are the same as those of the compound of formula I in claim 1.
  31. 权利要求30所述的中间体，选自说明书中化合物538-622。The intermediate of claim 30, which is selected from the group consisting of compounds 538-622.
  32. 权利要求1、3、5、7任一项所述的式I化合物(X为O)的制备方法，其特征在于包括如下步骤：A process for the preparation of a compound of formula I (X is O) according to any one of claims 1, 3, 5 or 7, which comprises the steps of:
    Figure PCTCN2018075069-appb-100057
    Figure PCTCN2018075069-appb-100057
    (1)式II化合物可经途径1.得到相应的式I-6化合物(X为O)；或者式II化合物可经途径2.得到相应的式I-6化合物(X为O)；或者式II化合物可经途径3.得到相应的式I-6化合物(X为O)；(1) A compound of formula II can be obtained via Scheme 1. to give the corresponding compound of formula I-6 (X is O); or a compound of formula II can be obtained via Scheme 2. to give the corresponding compound of formula I-6 (X is O); Compounds of formula II can be obtained via Scheme 3. to give the corresponding compound of formula I-6 (X is O);
    (2)式I-6化合物(X为O)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-4化合物(X为O)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-4化合物(X为O)； (2) The compound of the formula I-6 (X is O) can be obtained via Route 4. A compound of the formula I-4 (X is O) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, which can be subsequently Or a compound of formula I-4 (X is O) is obtained from one or more of Routes 1, 2. or 3.
    (3)式I-6化合物(X为O)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-2化合物(X为O)；或者式I-6化合物(X为O)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-2化合物(X为O)，随后可经途径7.得到相应的马氏或反马氏的式I-2化合物(X为O)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-2化合物(X为O)；(3) a compound of the formula I-6 (X is O) which can be reduced by a partial carbon-carbon double bond or a full carbon-carbon double bond via a route 5. (X is O); or a compound of the formula I-6 ( X is O) a compound of formula 1-2 (X is O) which can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond via route 6. The corresponding Markov or anti-male can be obtained via Route 7. A compound of formula 1-2 (X is O) which can be subsequently obtained by one or more of Routes 1, 2. or 3. to give the corresponding hydrocarbylation, acylation or carbonylation of a compound of formula 1-2 ( X is O);
    (4)式I-4化合物(X为O)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为O)；或者式I-2化合物(X为O)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为O)。(4) The compound of the formula I-4 (X is O) may give the corresponding compound of the formula I (X is O) via one or more of the routes 5., 6., 7., 1., 2. or 3. Or the compound of formula I-2 (X is O) can be obtained by one or more of the routes 4., 7., 1., 2. or 3. The corresponding compound of formula I (X is O).
  33. 权利要求2、4、6、8任一项所述的式I化合物(X为O)的制备方法，其特征在于包括如下步骤：A method of preparing a compound of formula I (X is O) according to any one of claims 2, 4, 6, or 8, which comprises the steps of:
    Figure PCTCN2018075069-appb-100058
    Figure PCTCN2018075069-appb-100058
    (1)式III化合物可经途径1.得到相应的式I-7化合物(X为O)；或者式III化合物可经途径2.得到相应的式I-7化合物(X为O)；或者式III化合物可经途径3.得到相应的式I-7化合物(X为O)；(1) A compound of formula III can be obtained via Scheme 1. to give the corresponding compound of formula I-7 (X is O); or a compound of formula III can be obtained via Scheme 2. to give the corresponding compound of formula I-7 (X is O); Compound III can be obtained via Scheme 3. to give the corresponding compound of formula I-7 (X is O);
    (2)式I-7化合物(X为O)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-5化合物(X为O)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-5化合物(X为O)； (2) A compound of formula I-7 (X is O) can be obtained via Route 4. A compound of formula I-5 (X is O) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, which can be subsequently Passing one or more of Routes 1, 2. or 3. to give the corresponding compound of Formula I-5 (X is O);
    (3)式I-7化合物(X为O)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-3化合物(X为O)；或者式I-7化合物(X为O)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-3化合物(X为O)，随后可经途径7.得到相应的马氏或反马氏的式I-3化合物(X为O)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-3化合物(X为O)；(3) a compound of the formula I-7 (X is O) which can be reduced by a partial carbon-carbon double bond or a full carbon-carbon double bond via a route 5. (X is O); or a compound of the formula I-7 ( X is O) a compound of formula I-3 (X is O) which can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond via Route 6. The corresponding Markov or anti-Ma can be obtained via Route 7. A compound of formula 1-3 (X is O) which can be subsequently subjected to the corresponding hydrocarbylation, acylation or carbonylation of a compound of formula 1-3 via one or more of the routes 1., 2. or 3. X is O);
    (4)式I-5化合物(X为O)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为O)；或者式I-3化合物(X为O)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为O)。(4) The compound of the formula I-5 (X is O) can be obtained by one or more of the routes 5., 6., 7., 1., 2. or 3. The corresponding compound of the formula I-1 (X is Or a compound of formula I-3 (X is O) may give the corresponding compound of formula I-1 (X is O) via one or more of Routes 4., 7., 1., 2. or 3. .
  34. 权利要求1、3、5、7任一项所述的式I化合物(X为NR 10)的制备方法，其特征在于包括如下步骤： A process for the preparation of a compound of formula I (X is NR 10 ) according to any one of claims 1, 3, 5 or 7, which comprises the steps of:
    Figure PCTCN2018075069-appb-100059
    Figure PCTCN2018075069-appb-100059
    (1)式II-2化合物可经途径1.得到相应的式I-6化合物(X为NR 10)；或者式II-2化合物可经途径2.得到相应的式I-6化合物(X为NR 10)；或者式II-2化合物可经途径3.得到相应的式I-6化合物(X为NR 10)； (1) The compound of the formula II-2 can be obtained by the route 1. The corresponding compound of the formula I-6 (X is NR 10 ); or the compound of the formula II-2 can be obtained by the route 2. The corresponding compound of the formula I-6 (X is NR 10 ); or a compound of formula II-2 can be obtained via Scheme 3. to give the corresponding compound of formula I-6 (X is NR 10 );
    (2)式I-6化合物(X为NR 10)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-4化合物(X为NR 10)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-4化合物(X为NR 10)； (2) a compound of the formula I-6 (X is NR 10 ) can be obtained via Route 4. A compound of the formula I-4 (X is NR 10 ) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, followed by The corresponding compound of formula I-4 (X is NR 10 ) can be obtained via one or more of Routes 1, 2, or 3.
    (3)式I-6化合物(X为NR 10)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-2化合物(X为NR 10)；或者式I-6化合物(X为NR 10)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-2化合物(X为NR 10)，随后可经途径7.得到相应的马氏或反马氏的式I-2化合物(X为NR 10)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-2化合物(X为NR 10)； (3) a compound of formula I-6 (X is NR 10) can be obtained by the routes 5-2 I compound portion or all of carbon-carbon double bond reduction of carbon-carbon double bond of formula (X is NR 10); or Formula I-6 The compound (X is NR 10 ) can be epoxidized by a partial carbon-carbon double bond or a full carbon-carbon double bond (X is NR 10 ) via Route 6. The corresponding horse can be obtained via Route 7. Or an anti-Martensian compound of formula 1-2 (X is NR 10 ), which can be subsequently subjected to the corresponding hydrocarbylation, acylation or carbonylation via one or more of Routes 1, 2, or 3. Compound I-2 (X is NR 10 );
    (4)式I-4化合物(X为NR 10)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为NR 10)；或者式I-2化合物(X为NR 10)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I化合物(X为NR 10)。 (4) The compound of the formula I-4 (X is NR 10 ) may give the corresponding compound of the formula I (X is NR) via one or more of the routes 5., 6., 7., 1., 2. or 3. 10); Alternatively compounds of formula I-2 (X is NR 10) can be 4, 7, 1, 2 or 3. the one or more of the corresponding compound of formula to give I (X is NR 10 via the pathway) .
  35. 权利要求2、4、6、8任一项所述的式I化合物(X为NR 10)的制备方法，其特征在于包括如下步骤： A method of preparing a compound of formula I (X is NR 10 ) according to any one of claims 2, 4, 6, or 8, which comprises the steps of:
    Figure PCTCN2018075069-appb-100060
    Figure PCTCN2018075069-appb-100060
    (1)式III-2化合物可经途径1.得到相应的式I-7化合物(X为NR 10)；或者式III-2化合物可经途径2.得到相应的式I-7化合物(X为NR 10)；或者式III-2化合物可经途径3.得到相应的式I-7化合物(X为NR 10)； Compound III-2 (1) may be 1 to give I-7 pathway corresponding compound of formula (X is NR 10); III-2, or a compound of formula 2 may be ways to give the corresponding compound of formula I-7 (X is NR 10 ); or a compound of formula III-2 can be obtained via Scheme 3. to give the corresponding compound of formula I-7 (X is NR 10 );
    (2)式I-7化合物(X为NR 10)可经途径4.得到Y 1、Y 2、Y 3或Y 4中至少一个为OH的式I-5化合物(X为NR 10)，随后可经途径1.、2.或3.中的一个或多个得到相应的式I-5化合物(X为NR 10)； (2) A compound of the formula I-7 (X is NR 10 ) can be obtained via Route 4. A compound of the formula I-5 (X is NR 10 ) wherein at least one of Y 1 , Y 2 , Y 3 or Y 4 is OH is obtained, followed by The corresponding compound of formula I-5 (X is NR 10 ) can be obtained via one or more of Routes 1, 2, or 3.
    (3)式I-7化合物(X为NR 10)可经途径5.得到部分碳碳双键或全部碳碳双键还原的式I-3化合物(X为NR 10)；或者式I-7化合物(X为NR 10)可经途径6.得到部分碳碳双键或全部碳碳双键环氧化的式I-3化合物(X为NR 10)，随后可经途径7.得到相应的马氏或反马氏的式I-3化合物(X为NR 10)，接下来可经途径1.、2.或3.中的一个或多个得到相应的烃基化、酰基化或羰基化的式I-3化合物(X为NR 10)； (3) a compound of formula I-7 (X is NR 10) can be obtained by the routes 5-3 I compound portion or all of carbon-carbon double bond reduction of carbon-carbon double bond of formula (X is NR 10); or Formula I-7 The compound (X is NR 10 ) can be obtained by a route 6 to obtain a compound of the formula I-3 (X is NR 10 ) epoxidized with a partial carbon-carbon double bond or a full carbon-carbon double bond, and then the corresponding horse can be obtained via the route 7. Or a compound of formula I-3 (X is NR 10 ), which can be followed by one or more of the routes 1, 2. or 3. to give the corresponding hydrocarbylation, acylation or carbonylation. Compound I-3 (X is NR 10 );
    (4)式I-5化合物(X为NR 10)可经途径5.、6.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为NR 10)；或者式I-3化合物(X为NR 10)可经途径4.、7.、1.、2.或3.中的一个或多个得到相应的式I-1化合物(X为NR 10)。 (4) The compound of the formula I-5 (X is NR 10 ) may give the corresponding compound of the formula I-1 (X) via one or more of the routes 5., 6., 7., 1., 2. or 3. NR 10 ); or a compound of formula I-3 (X is NR 10 ) may give the corresponding compound of formula I-1 (X) via one or more of Routes 4., 7., 1., 2. or 3. For NR 10 ).
  36. 权利要求32-35任一项所述的制备方法，其特征在于途径1.是指与卤代烃(R 11-L，L为卤素)发生烃基化反应；途径2.是指与酰卤(R 11COL，L为卤素)或酸酐((R 11CO) 2O)发生酰基化反应；途径3.是指与羰基试剂(如三光气、光气或对硝基氯甲酸苯酯)和R 11OH、R 11SH或R 11NH 2反应；途径4.是指与羰基还原剂(如NaBH 4、LiAlH 4、B 2H 6或BH 3等)发生还原反应；途径5.是指与还原剂(如Pd-C/H 2、Pt-C/H 2、PtO 2/H 2、雷尼镍/H 2、氰基硼氢化钠)发生碳碳双键还原反应；途径6.是指与过氧化物(如间氯过氧苯甲酸mCPBA、双氧水H 2O 2、过氧乙酸CH 3COOOH或叔丁基过氧化氢t-BuOOH)发生环氧化反应；途径7.是指环氧水解反应，所需试剂优选稀盐酸、稀硫酸、甲酸或乙酸。 The process according to any one of claims 32 to 35, wherein the route 1. means a hydrocarbylation reaction with a halogenated hydrocarbon (R 11 -L, L is a halogen); and the route 2. means an acid halide ( R 11 COL, L is a halogen) or an acid anhydride ((R 11 CO) 2 O) undergoes an acylation reaction; Route 3. refers to a carbonyl reagent (such as triphosgene, phosgene or phenyl p-nitrochloroformate) and R 11 OH, R 11 SH or R 11 NH 2 reaction; route 4. refers to reduction reaction with carbonyl reducing agent (such as NaBH 4 , LiAlH 4 , B 2 H 6 or BH 3 , etc.); pathway 5. refers to and reduction Agents (such as Pd-C/H 2 , Pt-C/H 2 , PtO 2 /H 2 , Raney nickel/H 2 , sodium cyanoborohydride) undergo carbon-carbon double bond reduction reaction; pathway 6. means Oxidation (such as mCPBA, hydrogen peroxide H 2 O 2 , peracetic acid CH 3 COOOH or t-butyl hydroperoxide t-BuOOH) epoxidation; pathway 7. refers to epoxy hydrolysis For the reaction, the desired reagent is preferably dilute hydrochloric acid, dilute sulfuric acid, formic acid or acetic acid.
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