WO2018141263A1 - Dérivé de pénicilones et son application en tant que médicament anti-bactéries résistantes - Google Patents

Dérivé de pénicilones et son application en tant que médicament anti-bactéries résistantes Download PDF

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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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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/zh
Publication of WO2018141263A1 publication Critical patent/WO2018141263A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—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

L'invention concerne un dérivé de pénicilones et une application de celui-ci en tant que médicament contre les bactéries résistantes. La présente invention concerne particulièrement, un composé de formule I, des stéréoisomères, des tautomères, des solvates, des promédicaments, et des sels pharmaceutiquement acceptables de celui-ci, ou des solvates de leurs sels, ayant la caractéristique en ce que le composé de formule I possède la structure suivante : formule I. Le composé de l'invention présente une forte activité antibactérienne contre Staphylococcus aureus résistant à la méthicilline, et son activité antibactérienne est supérieure à celle de l'oxacilline sodique et comparable à celle du chlorhydrate de vancomycine.
PCT/CN2018/075069 2017-02-04 2018-02-02 Dérivé de pénicilones et son application en tant que médicament anti-bactéries résistantes WO2018141263A1 (fr)

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