WO2019120210A1 - 一类苯并呋喃及Coumestans衍生物及其制备方法和应用 - Google Patents
一类苯并呋喃及Coumestans衍生物及其制备方法和应用 Download PDFInfo
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- WO2019120210A1 WO2019120210A1 PCT/CN2018/121968 CN2018121968W WO2019120210A1 WO 2019120210 A1 WO2019120210 A1 WO 2019120210A1 CN 2018121968 W CN2018121968 W CN 2018121968W WO 2019120210 A1 WO2019120210 A1 WO 2019120210A1
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- compound
- benzofuran
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- 238000002360 preparation method Methods 0.000 title claims abstract description 243
- 229930016834 coumestan Natural products 0.000 title claims abstract description 36
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
- C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- 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
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- 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 relates to the field of medicinal chemistry, in particular to a preparation method and application of a class of benzofuran and Coumestans derivatives.
- Tuberculosis is one of the infectious diseases that still maintain high morbidity and mortality worldwide. According to the World Health Organization survey, about 8 million people are infected with tuberculosis each year, and more than 1.6 million people die from this disease. At the same time, due to the widespread use of first-line drugs, such as isoniazid, rifampicin, and ethambutol, the number of drug-resistant and extensively drug-resistant tuberculosis cases is on the rise, and the phenomenon of tuberculosis and AIDS co-infection is also spreading rapidly. New structures and new targets for anti-tuberculosis drugs to curb the spread of tuberculosis.
- first-line drugs such as isoniazid, rifampicin, and ethambutol
- Mycobacterium tuberculosis is the causative agent of tuberculosis and belongs to the genus Mycobacterium. Compared with other pathogens causing major infectious diseases, the most characteristic of Mycobacterium tuberculosis is its unique cellular structure - cell wall, whose cell wall is mainly composed of Peptidoglycan, arabinomannose glycolipid, arabinogalactan, mycolic acid and other lipids. Studies have shown that many pathogenic factors of Mycobacterium tuberculosis have a very close relationship with the structure of the cell wall. This structure not only can resist the attack of the immune system in the human body, but also inhibit the interference of foreign compounds on the cells, and the unique cell wall structure.
- M. tuberculosis It confers resistance to various anti-tuberculosis drugs by M. tuberculosis. Many anti-tuberculosis drugs are not easy to penetrate the cell wall structure, greatly reducing the efficacy of tuberculosis treatment, prolonging the treatment cycle and increasing the burden on patients.
- Mycolic acid is a kind of 2-alkyl, 3-hydroxy long-chain fatty acid, which is closely related to the cell wall formation of Mycobacterium tuberculosis and participates in the cell wall formation of Mycobacterium tuberculosis.
- Pks13 is an important target protein in the mycobacterial acid synthesis pathway. A new target in the development of anti-tuberculosis drugs.
- the invention provides a new chemical entity of benzofuran and a natural product Coumestans derivative, and a preparation method thereof, wherein the benzofuran and the natural product Coumestans derivative are target compounds with stronger anti-tuberculosis activity, and are small at the same time.
- In vivo experiments in mice have shown that these compounds have good bioavailability and antibacterial activity, which lays a foundation for clinical research of such compounds and provides conditions for anti-tuberculosis drug research.
- benzofuran and Coumestans derivatives have the following structural formulas: (I), (II), (III), (IV):
- benzofuran and Coumestans derivatives have the structure shown in the formula (I):
- X is a nitrogen atom, an oxygen atom or a sulfur atom
- R 1 is hydrogen, hydroxy, methoxy, ethoxy, methoxyethyl ether or ester
- R 2 is In the structure, the structure of the benzofuran and Coumestans derivatives is as shown in formula (a):
- R a may be a three- to eight-membered aliphatic ring, a three- to eight-membered aliphatic ring containing a hetero atom in N, O, and S, a substituted three- to eight-membered aliphatic ring such as a C1-C4 alkyl group, and a hydroxyl group.
- R 2 is a C 2 -C 8 cycloalkyl structural group (ie, ), containing a hetero atom C2-C8 cycloalkyl (ie ), substituted C2-C8 cycloalkyl is (ie a primary amine structural group of the chain structure (ie, a N-mono-linear or cycloalkane-substituted secondary amine structural group (ie, a tertiary amine structural group such as an ethylamine group, an propylamino group, a cyclopropylamino group, a cyclopropylene methyleneamino group, a cyclopentylamino group or a cyclohexylamino group, an N,N-bisstrabasic alkane or a cycloalkane (ie, Wherein R a is selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl, and
- R 2 is as follows In the structure, the structure of the benzofuran and Coumestans derivatives is as shown in formula (b):
- R a is a three- to eight-membered aliphatic ring, a three- to eight-membered aliphatic ring structure containing a hetero atom in N, O, and S, a substituted three- to eight-membered aliphatic ring, a C1-C4 alkyl group, and a hydroxy alkane.
- R 3 is a hydroxyl group, a C1 to C8 alkyl group, a C1 to C8 alkoxy group, a C3 to C8 cycloalkyl group, a spiro group, a bridged ring group, an adamantane, an aliphatic amine group or an aromatic amine group; wherein R 3 is an aromatic amine When present, the aromatic ring may each independently be a substituent: a hydroxyl group, a C1-C8 alkyl group, a C1-C8 alkoxy group, a halogen, a nitro group, a trifluoromethyl group, a decyl group or an amine group;
- R 3 is hydroxy, methyl, ethoxy, ethylamino, methylamino, anilino, benzylamino or amantadine;
- R 4 may be a benzene ring, a substituted phenyl group, a methylthio group or various substituted amine groups, wherein:
- R b is selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl
- R c is selected from hydrogen, C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl
- R b , R c may be the same or different
- aromatic amine groups wherein the aromatic ring may be independently the following substituents: hydroxyl group, C1-C8 alkyl group, C1-C8 alkoxy group, halogen, nitro group, trifluoromethyl group
- each substituent on the benzene ring may independently be a substituent: halogen, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, nitro, trifluoromethyl , methoxy, mercapto, amine, cyano, aliphatic amine or methylene piperidinyl; specific preferred groups are shown in Table 1 below.
- R 5 may be halogen, hydroxy, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, nitro, trifluoromethyl, methoxy, decyl, amine, cyano, methylene piperidinyl or cyclohexyl Amide groups; particularly preferred groups are shown in Table 1 below.
- R 6 may be hydrogen, halogen, hydroxy, alkyl, nitro, amino, trifluoromethyl, alkoxy or phenyl;
- benzofuran and Coumestans derivatives have the structure shown in formula (II)
- X is a nitrogen atom, an oxygen atom or a sulfur atom
- R 7 may be a C2-C5 linear alkyl group or a C3-C8 cycloalkyl group
- R 3 may be a hydroxyl group, an alkyl group, an alkoxy group, an aromatic amine group or an aliphatic amine group; wherein, when R 3 is an aromatic amine group, the aromatic ring may each independently be a substituent: a hydroxyl group, an alkyl group, an alkoxy group. , halogen, nitro, trifluoromethyl or methoxy;
- R is an aromatic ring, and each substituent on the aromatic ring may be independently a substituent: hydrogen, halogen, hydroxy, alkyl, nitro, amino, trifluoromethyl, alkoxy, cyano, aliphatic amine or Methylene piperidinyl;
- benzofuran and Coumestans derivatives have the structure shown in formula (III):
- R 7 may be a C2 to C5 linear alkyl group or a C3-C8 cycloalkyl group
- X is a nitrogen atom, an oxygen atom or a sulfur atom
- Y is a nitrogen atom, an oxygen atom or a sulfur atom
- R is an aromatic ring, and each substituent on the aromatic ring may be independently a substituent: hydrogen, halogen, hydroxy, alkyl, nitro, amino, trifluoromethyl, alkoxy, cyano, aliphatic amine or Methylene piperidinyl;
- benzofuran and Coumestans derivatives have the structure shown in the formula (IV):
- X is a nitrogen atom, an oxygen atom or a sulfur atom
- Y is a nitrogen atom, an oxygen atom or a sulfur atom
- R 6 may be hydrogen, halogen, hydroxy, alkyl, nitro, amino, trifluoromethyl, alkoxy or phenyl;
- R 5 may be hydrogen, halogen, hydroxy, alkyl, nitro, amino, trifluoromethyl, alkoxy, N-methylene piperidine or formyl ring C4-C7 amine;
- R 1 may be hydrogen, hydroxy, methoxy, ethoxy, methoxyethyl ether or ester;
- R 2 can be Ra and R b are each independently selected from the group consisting of a hydrogen atom; a chain alkane; a cycloalkane; Wherein Rc is a C2-C8 cycloalkyl group, a hetero atom containing a N, O, S cycloalkyl group, an alkyl substituted cycloalkyl group, or a C3-C8 lactam; Wherein R d is a C2-C8 cycloalkyl group or R f is a C 2 -C 8 cycloalkyl group, and R e is a chain alkane or ether;
- R is an aromatic ring, and each substituent on the aromatic ring may be independently a substituent of hydrogen, halogen, hydroxy, alkyl, nitro, amino, trifluoromethyl, alkoxy or methylene piperidinyl.
- each group used employs its conventional meaning in the art.
- benzofuran and Coumestans derivatives of the formula (I) (II) (III) (IV) of the present invention are represented by the self-designed codes S1 to S132, and specifically include the compounds described in Tables 1-4:
- the invention also provides enantiomers, diastereomers, racemates of the above formula (I), (II), (III), (IV) benzofuran and Coumestans derivatives and a mixture thereof, and its corresponding salt.
- the invention also provides a process for the preparation of the above formula (I), (II), (III), (IV) benzofuran and Coumestans derivatives and intermediates thereof.
- the above compounds of the formula (I), (II), (III) and (IV) can be obtained by the following steps:
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising the compound of the formula (I), (II), (III), (IV) or a pharmaceutically acceptable salt thereof, the pharmaceutical composition further comprising a pharmaceutically acceptable
- the vector or alternatively, also contains other therapeutic ingredients.
- the pharmaceutical composition may comprise a single active ingredient or a mixed active ingredient of the compound of the formula (I), (II), (III), (IV) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical composition may be administered in any form including oral, rectal, nasal, injection (including subcutaneous, intramuscular, intravenous) and the like.
- the pharmaceutical composition is formulated as an injectable fluid, aerosol, cream, gel, pill, capsule, syrup or transdermal patch.
- the pharmaceutically acceptable carrier may be present in any form depending on the actual desired route of administration (e.g., buccal administration, or injection administration, etc.).
- any common chemical medium may be employed in the preparation of the oral dosage form composition.
- liquid oral preparations including suspensions and solutions
- water ethylene glycol, oil, alcohol, Flavoring agents, preservatives, coloring agents, etc.
- solid oral preparations e.g., powders, capsules
- optional carriers such as starch, sugar, microcrystalline cellulose, fillers, granulating agents, lubricants, binders, lysing agents and the like can be employed.
- the invention also provides the use of the compounds of the formula (I), (II), (III), (IV), the pharmaceutical compositions, for the preparation of inhibitors of microorganisms.
- the microorganism includes: bacteria, viruses, fungi, and some small protozoa, microalgae, and the like; wherein the bacteria include Mycobacterium tuberculosis, Staphylococcus aureus, Streptococcus, Pneumococcal, Escherichia coli, Bacillus subtilis , lactic acid bacteria, etc.
- the compounds of the formula (I), (II), (III), (IV) and the pharmaceutical composition are used for inhibiting the growth and reproduction of microorganisms.
- the invention also provides the use of the compounds of the formula (I), (II), (III), (IV), the pharmaceutical composition for the preparation of a Mycobacterium tuberculosis cell wall synthesis inhibitor.
- the present invention also provides the use of the compound of the formula (I), (II), (III), (IV), and the pharmaceutical composition for the preparation of a medicament for inhibiting the growth and reproduction of Mycobacterium tuberculosis.
- the present invention also provides the compound of the above formula (I), (II), (III), (IV), the pharmaceutical composition for treating a disease associated with the polyketide synthase encoded by the pks13 gene fragment as a target The application of the drug.
- the invention also provides the compound of the formula (I), (II), (III), (IV), the pharmaceutical composition for preparing and preventing or treating tuberculosis diseases, anti-cancer, anti-virus, anti-rheumatic , antifungal, anti-oxidant, anti-inflammatory, liver-protecting, hemostasis and blood pressure lowering drugs; preferably used in the treatment of multidrug-resistant tuberculosis diseases.
- the cancer includes breast cancer, colorectal cancer, pancreatic cancer, renal cancer, prostate cancer, urothelial cancer, esophageal cancer, head and neck cancer, liver cancer, mesothelioma, Kaposi's sarcoma, ovarian cancer, Soft tissue sarcoma, glioma, melanoma, small cell-non-small cell lung cancer, endometrial cancer, basal cell carcinoma, urinary tract epithelial transitional cell carcinoma, cervical cancer, endometrial cancer, gastric cancer, bladder cancer, uterus Sarcoma, multiple myeloma, soft tissue, osteosarcoma and cholangiocarcinoma.
- the benzofuran and Coumestans derivatives target a polyketide synthase encoded by a Mycobacterium tuberculosis pks13 gene fragment, inhibiting the synthesis of mycolic acid in the cell wall of Mycobacterium tuberculosis, thereby inhibiting Mycobacterium tuberculosis Growing to achieve the effect of treating tuberculosis.
- the present invention also provides the use of the compound of the formula (I), (II), (III), (IV), the pharmaceutical composition for preventing and/or treating tuberculosis diseases, anti-cancer, anti-viral, anti-intra Rheumatoid, antifungal, antioxidant, anti-inflammatory, liver-protecting, hemostasis and blood pressure lowering methods, comprising administering the compounds of the formula (I), (II), (III), (IV) to an individual in need thereof The pharmaceutical composition.
- the invention has the beneficial effects that the formula (I), (II), (III), (IV) benzofuran and Coumestans derivatives prepared by the invention are novel type of Mycobacterium tuberculosis with novel structure and remarkable bacteriostatic effect. Cell wall inhibitors.
- Figure 1 is a graph showing the relative fluorescence intensity of a serum inhibition titration experiment for oral administration of a compound of the present invention.
- Figure 2 is a graph showing the relative fluorescence intensity of a serum inhibition titration experiment for oral or intraperitoneal administration of a compound of the present invention.
- Figure 3 is a graph showing the relative fluorescence intensity of a serum inhibition titration experiment for oral administration of a compound of the present invention.
- Example 1 Prepared in a manner similar to that of Example 1, except that p-methoxyacetophenone was substituted for acetophenone, piperidine was substituted for N-methylpiperazine, the remaining starting materials, reagents, and preparation method and Example 1 The same, the end product.
- Example 2 Prepared in a manner similar to that of Example 1, except that acetophenone was replaced by p-fluoroacetophenone, and N-methylpiperazine was replaced by piperidine. The remaining starting materials, reagents and preparation methods were the same as in Example 1. The end product.
- Example 2 Prepared in a manner similar to that of Example 1, except that 2,4-dimethoxyacetophenone was substituted for acetophenone, piperidine was substituted for N-methylpiperazine, the remaining starting materials, reagents and preparation methods were prepared. The same as in Example 1, the final product was obtained.
- Example 2 Prepared in a manner similar to that of Example 1, except that 4-bromo-2-methoxyacetophenone was substituted for acetophenone, piperidine was substituted for N-methylpiperazine, and the remaining starting materials, reagents and preparations were prepared. The same procedure as in Example 1 gave the final product.
- Example 2 Prepared in a manner similar to that of Example 1, except that 4-fluoro-2-methoxyacetophenone was substituted for acetophenone, piperidine was substituted for N-methylpiperazine, and the remaining starting materials, reagents and preparations were prepared. The same procedure as in Example 1 gave the final product.
- Example 2 Prepared in a manner similar to that of Example 1, except that 4,5-dimethyl-2-methoxyacetophenone was substituted for acetophenone, and piperidine was used instead of N-methylpiperazine.
- the reagent and the preparation method were the same as in Example 1 to obtain the final product.
- Example 12 Prepared in a manner similar to that of Example 12, except that the propyl propylamine was replaced by piperidine, and the remaining starting materials, reagents and preparations were the same as in Example 12 to give a white solid.
- Example 12 Prepared in a manner similar to that of Example 12, except that benzylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 12 to give the final product.
- Example 12 Prepared in a manner similar to that of Example 12 except that cyclohexylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 12 to give the final product.
- 1 H NMR (400MHz, MeOD) ⁇ 6.98 (s, 1H), 6.81 (s, 1H), 3.81 (br, 1H), 3.71 (s, 2H), 2.58 (br, 4H), 2.39 (s, 3H ), 2.01 (s, 2H), 1.77 (s, 2H), 1.70 - 1.59 (m, 4H), 1.52 (d, J 4.3 Hz, 2H), 1.49 - 1.40 (m, 4H), 1.35 - 1.20 ( m, 2H).
- Example 12 Prepared in a manner similar to that of Example 12, except that dipropylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents, and preparation methods were the same as in Example 12 to give the final product.
- Example 12 Prepared in a manner similar to that of Example 12, except that tetrahydropyrrole was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 12 to give the final product.
- Example 19 Prepared in a manner similar to that of Example 19 except that the remaining starting materials, reagents, and preparations were the same as in Example 19 to give the final product.
- Example 19 Prepared in a manner similar to that of Example 19, except that aniline was used instead of ethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 19 to give the final product.
- Example 58 Prepared in a manner similar to that of Example 58 except that after the compound S58 was formed, 2 mL/mL of BBr 3 ⁇ DCM 2 mL was slowly added dropwise under ice-water bath conditions at 0 ° C, and the mixture was stirred at room temperature for 5 h, and ethanol was quenched.
- Example 25 Prepared in a manner similar to that of Example 25, except that p-methylpiperidine was used in place of piperidine, and the remaining starting materials, reagents, and preparation methods were the same as in Example 25 to give the final product.
- Example 29 Prepared in a manner similar to that of Example 29 except that cyclopropylamine was used in place of ethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 29 to give the final product.
- Example 29 Prepared in a manner similar to that of Example 29 except that ethyl 4-methoxybenzoylacetate was used in place of ethyl 4-fluorobenzoate, the remaining starting materials, reagents and preparation methods and Example 29 The same, the final product.
- Example 29 Prepared in a manner similar to that of Example 29 except that ethyl 4-methoxybenzoate was used in place of ethyl 4-fluorobenzoate, the remaining starting materials, reagents and preparation methods and Example 29 The same, the final product.
- Example 37 Prepared in a manner similar to that of Example 37 except that methyl phenylacetate was used in place of methyl 4-fluorophenylacetate, and the remaining starting materials, reagents and preparations were the same as in Example 37 to give the final product.
- Example 39 Prepared in a manner similar to that of Example 39, except that the ester hydrolysis and acylation were omitted, and the remaining starting materials, reagents and preparation methods were the same as in Example 39 to give the final product.
- Example 39 Prepared in a manner similar to that of Example 39, except that methyl phenylacetate was used in place of methyl 4-fluorophenylacetate, and the remaining starting materials, reagents and preparations were the same as in Example 39 to give the final product.
- Example 39 Prepared in a manner similar to that of Example 39 except that cyclopropylamine was used in place of ethylamine, and the remaining starting materials, reagents and preparations were the same as in Example 39 to give the final product.
- Example 39 Prepared in a manner similar to that of Example 39, except that p-methylpiperidine was used in place of piperidine, and the remaining starting materials, reagents, and preparations were the same as in Example 39 to give the final product.
- the compound S42 is used as a raw material, and the subsequent preparation method is as follows:
- Example 42 Prepared in a manner similar to that of Example 42, the desired starting materials, reagents and preparations were the same as in Example 42 to give the final product.
- Example 42 Prepared in a manner similar to that of Example 42, except that acetophenone was replaced by p-fluoroacetophenone, and the remaining starting materials, reagents and preparation methods were the same as in Example 42 to give the final product.
- Example 42 Prepared in a manner similar to that of Example 42, except that acetophenone was replaced by p-fluoroacetophenone, and the remaining starting materials, reagents and preparation methods were the same as in Example 42 to give the final product.
- Example 2 Prepared in a manner similar to that of Example 1, except that the N-methylpiperazine was replaced by a primary amine cyclopropylmethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 1, to give the final product.
- Example 57 Prepared in a manner similar to that of Example 57 except that acetophenone was replaced by p-methoxyacetophenone, and the remaining starting materials, reagents, and preparations were the same as in Example 57 to give the final product.
- Example 57 Prepared in a manner similar to that of Example 57 except that cyclopropylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 57 to give the final product.
- Example 57 Prepared in a manner similar to that of Example 57 except that p-methylacetophenone was used in place of acetophenone, and the remaining starting materials, reagents and preparation methods were the same as in Example 57 to give the final product.
- Example 57 Prepared in a manner similar to that of Example 57 except that 1-(2-methoxy-5-methylphenyl)ethanone was substituted for acetophenone, the remaining starting materials, reagents, and preparation methods and examples. 57 is the same, the end product.
- Example 19 Prepared in a manner similar to that of Example 19, except that cyclopropylamine was used in place of piperidine, and aniline was used in place of ethylamine. The remaining starting materials, reagents and preparation methods were the same as in Example 19 to give the final product.
- Example 62 Prepared in a manner similar to that of Example 62, except that ethylamine was used instead of ethylamine, and the remaining starting materials, reagents and preparations were the same as in Example 62 to give the final product.
- Example 62 Prepared in a manner similar to that of Example 62, except that p-chloroaniline was used instead of ethylamine, and the remaining starting materials, reagents, and preparations were the same as in Example 62 to give the final product.
- Example 57 Prepared in a manner similar to that of Example 57 except that isoamylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents and preparation methods were the same as in Example 57 to give the final product.
- Example 57 Prepared in a manner similar to that of Example 57 except that cyclopropylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents, and preparations were the same as in Example 57 to give the final product.
- Example 62 Prepared in a manner similar to that of Example 62, except that the aniline was replaced by ethylamine, and the remaining starting materials, reagents, and preparations were the same as in Example 62 to give the final product.
- Example 2 Prepared in a manner similar to that of Example 1, except that 2-methoxy-5-chloroacetophenone was substituted for acetophenone in the first step of synthesis, and 5-hydroxy-2-(2-methoxyl) was synthesized. After ethyl 5-chlorophenyl)benzofuran-3-carboxylate, it was dissolved in DCM, protected with nitrogen, and slowly added dropwise 1 mmol/mL of BBr 3 ⁇ DCM under ice-cold bath at 0 ° C.
- Example 68 Prepared in a manner similar to that of Example 68 except that 2-methoxy-5-bromoacetophenone was substituted for 2-methoxy-5-chloroacetophenone, the remaining starting materials, reagents and preparation methods. The same as in Example 68, the final product was obtained.
- Example 68 Prepared in a manner similar to that of Example 68 except that 2-methoxy-5-fluoroacetophenone was substituted for 2-methoxy-5-chloroacetophenone, the remaining starting materials, reagents and preparation methods. The same as in Example 68, the final product was obtained.
- Example 68 Prepared in a similar manner to Example 68 except that 1-(2-methoxy-5-methylphenyl)ethanone was substituted for 2-methoxy-5-chloroacetophenone.
- the starting materials, reagents and preparation methods were the same as in Example 68 to give the final product.
- Example 68 Prepared in a manner similar to that of Example 68, except that 2,5-dimethoxyacetophenone was substituted for 2-methoxy-5-chloroacetophenone, the remaining starting materials, reagents, and preparation methods were Example 68 was identical to give the final product.
- Example 68 Prepared in a similar manner to Example 68 except that 4,5-dimethyl-2-methoxyacetophenone was substituted for 2-methoxy-5-chloroacetophenone, and the remaining starting materials, The reagent and the preparation method were the same as in Example 68 to give the final product.
- Example 68 Prepared in a similar manner to Example 68 except that 2-methoxy-4,5-dichloroacetophenone was substituted for 2-methoxy-5-chloroacetophenone, the remaining starting materials, reagents The preparation method was the same as in Example 68 to give the final product.
- Example 68 Prepared in a manner similar to that of Example 68 except that 2,4-dimethoxyacetophenone was substituted for 2-methoxy-5-chloroacetophenone, the remaining starting materials, reagents and preparation methods were Example 68 was identical to give the final product.
- Example 78 Prepared in a manner similar to that of Example 78, except that cyclohexylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents, and preparations were the same as in Example 78 to give the final product.
- Example 78 Prepared in a manner similar to that of Example 78, except that cyclopropylamine was used in place of cyclopropylmethylamine, and the remaining starting materials, reagents and preparations were the same as in Example 78 to give the final product.
- Example 68 Prepared in a manner similar to that of Example 68 except that 2-methoxyacetophenone was substituted for 2-methoxy-5-chloroacetophenone, the remaining starting materials, reagents and preparation methods and Example 68. The same, the end product.
- Example 2 Prepared in a manner similar to that of Example 1, except that o-methoxyacetophenone was substituted for acetophenone to synthesize 5-hydroxy-2-(2-methoxyphenyl)benzene.
- the compound was dissolved in DCM, and protected with nitrogen. 1 mmol/mL of BBr 3 ⁇ DCM was slowly added dropwise under ice-cold bath at 0 ° C, and the mixture was stirred at room temperature for 5 h, and then quenched with ethanol.
- Example 79 Prepared in a manner similar to that of Example 79 except that 2-methoxy-4-bromoacetophenone was substituted for o-methoxyacetophenone, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79. , the end product.
- Example 79 Prepared in a manner similar to that of Example 79 except that 2-methoxy-4-fluoroacetophenone was substituted for o-methoxyacetophenone, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79. , to obtain a solid end product.
- Example 79 Prepared in a manner similar to that in Example 79 except that 5-methyl-2-methoxy-acetophenone was substituted for o-methoxyacetophenone, the remaining starting materials, reagents, and preparation methods and examples. The same as 79, the final product was obtained.
- Example 79 Prepared in a manner similar to that of Example 79 except that 2,5-dimethoxy-acetophenone was substituted for o-methoxyacetophenone, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79. , the end product.
- Example 79 Prepared in a manner similar to that of Example 79 except that 2,4-dimethoxy-acetophenone was substituted for o-methoxyacetophenone, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79. , the end product.
- Example 79 Prepared in a similar manner to Example 79 except that 4-hydroxy-3-methylpiperidinyl-2-methoxyacetophenone was substituted for o-methoxyacetophenone, the remaining starting materials, reagents
- the preparation method was the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79, except that bromophenylhydrazine was used in place of phenylhydrazine, and the remaining starting materials, reagents and preparation methods were the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79 except that phenylhydrazine was used in place of phenylhydrazine, and the remaining starting materials, reagents and preparation methods were the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79 except that the phenylhydrazine was used in place of the phenylhydrazine, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79 except that tert-butylphenylhydrazine was used in place of phenylhydrazine, and the remaining starting materials, reagents and preparation methods were the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79 except that phenyl hydrazine was used in place of phenylhydrazine, and the remaining starting materials, reagents and preparation methods were the same as in Example 79 to give the final product.
- Example 25 Prepared in a manner similar to that of Example 25 except that ethyl benzyl benzoylacetate was replaced by ethyl benzoylacetate in 25.1, and the remaining starting materials, reagents and preparation methods were the same as in Example 25. The final product.
- Example 25 Prepared in a manner similar to that of Example 25 except that 2-methoxy-4-methoxyacetophenone was substituted for o-methoxyacetophenone, the remaining starting materials, reagents, and preparation methods and examples. 25 identical, the end product.
- Example 25 Prepared in a manner similar to that of Example 25 except that 2-methoxy-5-methylacetophenone was substituted for o-methoxyacetophenone, the remaining starting materials, reagents, and preparation method and Example 25 The same, the end product.
- Example 25 Prepared in a manner similar to that of Example 25 except that 2-methoxy-4-bromoacetophenone was substituted for o-methoxyacetophenone, and the remaining starting materials, reagents, and preparation methods were the same as in Example 25. , the end product.
- Example 36 Prepared in a manner similar to that of Example 36, except that 2-methoxyphenethylmethyl ester was used in place of phenyl acetyl methyl ester, and the remaining starting materials, reagents and preparation methods were the same as in Example 36 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79, except that pyridine was used in place of piperidine, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79, except that pyrrolidone was used in place of piperidine, and the remaining starting materials, reagents and preparation methods were the same as in Example 79 to give the final product.
- Example 107 The compound of Example 107 was used, dissolved in dichloromethane to give the final product of methylene chloride.
- Example 107 The compound of Example 107 was used, dissolved in dichloromethane to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79, except that cyclohexane lactam was used in place of piperidine, and the remaining starting materials, reagents, and preparation methods were the same as in Example 79 to give the final product.
- Example 79 Prepared in a manner similar to that of Example 79, except that the piperidine was replaced by cycloheptanolacide, and the remaining starting materials, reagents, and preparations were the same as in Example 79 to give the final product.
- Example 112 Prepared in a manner similar to that of Example 112, except that ethyl iodide was used instead of methyl iodide, and the remaining starting materials, reagents and preparations were the same as in Example 112 to give the final product.
- Example 112 Prepared in a manner similar to that of Example 112, except that bromoethyl methyl ether was used instead of methyl iodide, and the remaining starting materials, reagents, and preparations were the same as in Example 112 to give the final product.
- 118-2 Under a nitrogen atmosphere, 118-1, EDC ⁇ HCl, and HOBT were dissolved in DMF, and pyridine and piperidine were added thereto, and the mixture was stirred at room temperature overnight. After TLC detected the reaction was complete, it was quenched with ammonium chloride solution, extracted with ethyl acetate. The organic phase was washed with 5% hydrochloric acid solution, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Concentrated by pressure and purified by TLC to give 118-2.
- Example 118 Prepared in a similar manner to Example 118 except that the cyclopropanylmethyl group was substituted for the piperidine of 118-2, and the remaining starting materials, reagents and preparations were the same as in Example 118 to give the final product.
- Example S122 The compound of Example S122 was used as a starting material to add iodomethane at room temperature overnight to give the final product.
- Example 124 Prepared in a manner similar to that of Example 123, except that bromoethyl methyl ether was used in place of methyl iodide, and the remaining starting materials, reagents and preparations were the same as in Example 124 to give the final product.
- Example 6 Prepared in a manner similar to that of Example 6 and Example 19 except that in Example 6, tert-butylphthalide was substituted for phenylhydrazine to synthesize 7-tert-butyl-5-hydroxy-2-(4-methoxy Ethyl benzofuran-3-carboxylate followed by a procedure similar to that of Example 19 except that methylamine was used in place of ethylamine in Example 19-2, the remaining starting materials, reagents and preparation methods were Examples 6 and 19 were identical to give the final product.
- Example 126 Prepared in a manner similar to that of Example 126 except that ethyl 4-methoxyphenylacetoacetate was used in place of ethyl 4-methoxyphenylacetoacetate, the remaining starting materials, reagents, and preparation methods and examples 126 The same, the end product.
- Example 126 Prepared in a manner similar to that of Example 126, except that ethyl 2-methoxyphenylacetoacetate was used in place of ethyl 4-methoxyphenylacetoacetate, the remaining starting materials, reagents and preparation methods and examples 126 The same, the end product.
- Example 86 Prepared in a manner similar to that of Example 86 except that tert-butylphenylhydrazine was used in place of phenylhydrazine, and the remaining starting materials, reagents, and preparation methods were the same as in Example 86 to give the final product.
- Example 86 Prepared in a manner similar to that of Example 86 except that tert-butylphenylhydrazine was used in place of phenylhydrazine and ethyl 2,5-dimethoxyphenylacetate instead of ethyl 2,4-dimethoxyphenylacetate.
- the remaining starting materials, reagents and preparation methods were the same as in Example 86 to give the final product.
- the present invention provides a MIC 90 test test for a compound of the formula (I) (II) (III) (IV) against Mycobacterium tuberculosis H37Rv.
- Mycobacterium tuberculosis H37Rv strain (cultured in Middlebrook 7H9 broth)
- the present invention provides a serum inhibition titration experiment (hereinafter referred to as SIT experiment) of a partial structural formula (I) (II) (III) (IV) compound for characterizing its oral bioavailability and effectiveness in animals.
- mice 30-week-old female BALB/c mice, 0.5% carboxymethylcellulose, 1 mL syringe, M. tuberculosis H37Rv strain (cultured in Middlebrook 7H9 broth culture), in the present invention
- Some compounds see Table 5 for specific compounds
- isoniazid isoniazid
- alamar Blue reagent isoniazid
- a test compound was prepared as a uniform suspension of 10 mg/mL with 0.5% carboxymethylcellulose (CMC).
- CMC carboxymethylcellulose
- the mice were divided into xx groups, 3 in each group. Each group was fed with different compounds according to the mass of the mice at a dose of 100 mg/kg. Isoniazid was also fed to a group of mice at 100 mg/kg as a positive control. 0.5% carboxymethylcellulose was fed at 100 mg/kg as a blank control. After 60 min, the mice were sacrificed, the heart blood of the mice was collected, and serum was separated for further experiments.
- the blank group and serum were serially diluted from 1:2 to 1:64 in a 96-well plate with Middlebrook 7H9 broth without Tween, and the plate was sealed and incubated at 37 °C for 7 days. Subsequently, 32 ⁇ L of alamar Blue reagent prepared by Tween 80 at a concentration of 0.86% was added to each well, and incubated at 37 ° C. The fluorescence intensity was measured by a BMG microplate reader under 544ex/590em conditions, and the obtained data are the relative fluorescence units (RFUs) in Fig. 1.
- the benzofuran and Coumestans derivatives are targeted by a polyketide synthase encoded by a Mycobacterium tuberculosis pks13 gene fragment, and this assay is used for confirmation of the pks13 target.
- the Coumestans derivatives S79 and S84 are tested for toxicity of human cells MRC-5 cells, HFL-1 cells, QSG-7701 cells, and HEK-293 cells.
- the cytotoxicity of compound S79 and compound S84 on human cells MRC-5 cells, HFL-1 cells, QSG-7701 cells, and HEK-293 cells was found to have an IC50 value of >50 ⁇ g/mL. It is indicated that compound 79 is not toxic to human cells.
- the IC50 values of compound 84 for HFL-1 cells and QSG-7701 cells were 50.2 ⁇ 5.3 and 38.8 ⁇ 2.6, respectively, and the IC50 values for MRC-5 cells and HEK-293 cells were >50 ⁇ g/mL, indicating that compound 84 is the fourth of humans.
- the seed cells are essentially non-toxic.
- the Coumestans derivatives S132, S57, S7, S79, S84, S81, S80, S82, and S77 are comparatively tested for cytotoxicity and activity of Vero cells (African green monkey kidney cells) (see Table 9).
- the SI value is the ratio of IC 50 (Vero) / MIC (Mtb) , and the SI values of the S132, S57, S7, S79, S84, S81, S80, S82 compounds range from 8 to 32, but the IC50 and MIC of the S77 compound are equal.
- the Coumestans derivatives S132, S79, S84, and S86 are tested for stability of human liver microsomes (see Table 10).
- the Coumestans derivatives S86 and S130 are tested for anti-tuberculosis activity of sensitive strains, multidrug resistant strains, and broadly resistant strains (see Table 11).
- Compound MIC 90 ⁇ g/mL Compound MIC 90 : ⁇ g/mL Compound MIC 90 : ⁇ g/mL Compound MIC 90 : ⁇ g/mL S1 ⁇ 64 S2 8 S3 16 S4 - S5 8 S6 16 S7 0.5 S8 16 S9 >64 S10 8 S11 4 S12 - S13 - S14 - S15 - S16 - S17 - S18 - S19 4 S20 8 S21 >64 S22 16 S23 8 S24 2 S25 - S26 - S27 - S28 - S29 4 S30 16 S31 2 S32 64 S33 >64 S34 >64 S35 >64 S36 16 S37 16 S38 64 S39 >64 S40 >64 S41 >64 S42 >64 S43 >64 S44 >64 S45 >64 S46 >64 S47 >64 S48 >64 S49 >64 S50 >64 S51 >64 S52 64 S53 64 S54 >64 S55 64 S56 >64 S
- the compound of the present invention exhibits a good activity against Mycobacterium tuberculosis by exploring the lead compound and modifying the structure-activity relationship, wherein the MIC90 of the S79, S95, S94, and S97 compounds against Mycobacterium tuberculosis H37Rv reaches 0.0625. -0.125 ⁇ g/mL, showing excellent anti-tuberculosis activity, some compounds have a MIC90 value of 0.5-16 ⁇ g/mL for Mycobacterium tuberculosis H37Rv, but some compounds have lost the activity of Mycobacterium tuberculosis MIC90 ⁇ 64 ⁇ g/mL (see Table 5). In short, some of the compounds of the present invention exhibit excellent anti-tuberculosis activity and are expected to develop into a new generation of anti-tuberculosis drugs.
- FIG. 1 shows that the activity of the S7 compound disappeared in the animal, and the S79 and S84 compounds showed good activity in the animal body, showing a high bioavailability (where isoniazid was a positive compound as a control).
- the S132 compound of Figure 2 is inactive in animals either intraperitoneally or orally.
- Table 10 shows the human liver microsome stability data of S132, S79, S84, S86, Testosterone, Diclofenac, and Propafenone.
- the three drugs of Testosterone, Diclofenac, and Propafenone were used as controls for S132, S79, S84, and S86.
- Table 11 shows the anti-tuberculosis activity data of Isoniazid, Rifamplin, Levofloxacin, Oblixacin, Kanamycin, S86, S130 against sensitive strains, multidrug resistant strains, and broadly resistant strains, among which five drugs are Isoniazid, Rifamplin, Levofloxacin, and Ofloxacin Kanamycin was used as a positive control for S86 and S130.
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Abstract
本发明公开了如式(I)、(II)、(III)、(IV)所示的苯并呋喃类及Coumestans衍生物及其制备方法,以及所述苯并呋喃类及Coumestans衍生物化合物在治疗耐多药性肺结核疾病中的应用。本发明所述苯并呋喃类及Coumestans衍生物是一类结构新颖,抑菌效果显著的抗结核杆菌化合物,它是以结核杆菌pks13基因片段编码的聚酮合酶为作用靶点,抑制微生物的生长繁殖,尤其是抑制结核分枝杆菌细胞壁中分枝菌酸的合成,在医药领域具有潜在的应用前景。
Description
本发明涉及药物化学领域,具体涉及一类苯并呋喃及Coumestans衍生物的制备方法和应用。
结核病是一种迄今为止仍在全球范围内维持高发病率和死亡率的传染病之一,根据世界卫生组织的调查报告,每年有约800万人感染肺结核,超过160万人死于此病,同时由于一线药物,如异烟肼、利福平、乙胺丁醇等的广泛使用,使得耐药性、广泛耐药性结核病例呈上升趋势,结核病和艾滋病共同感染现象也迅速蔓延,亟待一种新结构和新靶点的抗结核药物来扼制肺结核病情的扩散。
结核杆菌是导致结核病的病原体,属于结核分枝杆菌(Mycobacterium)属,与其他引起重大传染性疾病的病原体相比,结核杆菌最大的特点在于其具有独特的细胞结构——细胞壁,其细胞壁主要由肽聚糖、阿拉伯甘露糖糖脂、阿拉伯半乳聚糖、分枝菌酸及其它脂类构成。有关研究表明:结核杆菌的很多致病因素与其细胞壁的结构有着十分密切的关系,这种构造不仅能抵御人体内免疫系统的攻击,还可抑制外来化合物对菌体的干扰,同时独特的细胞壁结构赋予了结核分枝杆菌对多种抗结核药物的耐药性。许多抗结核药物不易穿透细胞壁结构,大大削减了结核病治疗过程中的疗效,延长了治疗周期,加重了病患的负担。
分枝菌酸是一类2-烷基,3-羟基长链脂肪酸,它与结核杆菌细胞壁形成密切相关,参与结核杆菌的细胞壁形成,Pks13是分枝菌酸合成途径中重要的靶蛋白,也是抗结核药物研发中的一个新靶点。
发明内容
本发明提供了一种苯并呋喃及天然产物Coumestans衍生物新化学实体,及其制备方法,所述苯并呋喃及天然产物Coumestans衍生物是抗结核活性更强的靶标化合物,同时对其进行小鼠体内试验,实验表明,此类化合物具有良好的生物利用度和抑菌活性,为该类化合物进入临床研究奠定基础,为抗肺结核药物研究提供条件。
根据本发明,所述的苯并呋喃及Coumestans衍生物结构通式如下式(I)、(II)、(III)、(IV)所示:
本发明中,所述苯并呋喃及Coumestans衍生物其结构如式(I)所示:
其中,X为氮原子、氧原子或硫原子;
R
1是氢、羟基、甲氧基、乙氧基、甲氧基乙基醚或酯;
其中,R
a可为三元至八元脂肪环,含N,O,S中杂原子的三元至八元脂肪环,有取代的三元至八元脂肪环如C1-C4烷基、羟基烷基、胺烷基、甲氧基或三元至八元内酰胺,开链结构的伯胺结构基团(即
),N-单直链烷烃或环烷烃取代的仲胺结构基团(即
),N,N-双直链烷烃或环烷烃取代的叔胺结构基团
(其中R
b选自氢、C
1-C
8烷基或C
3-C
8的环烷基,R
c选自氢、C
1-C
8烷基或C
3-C
8的环烷基;其中R
b、R
c可以相同,也可以不同);
优选地,R
2为C2~C8的环烷基结构基团(即
),含杂原子C2-C8环烷基(即
),取代的C2-C8环烷基为(即
),链结构的伯胺结构基团(即
),N-单直链烷烃或环烷烃取代的仲胺结构基团(即
如乙胺基、丙胺基、环丙胺基、环丙烷亚甲胺基、环戊胺基或环己基胺基),N,N-双直链烷烃或环烷烃取代的叔胺结构基团(即
其中R
a选自氢、C
1-C
8烷基或C
3-C
8的环烷基,R
b选自氢、C
1-C
8烷基或C
3-C
8的环烷基(如N,N二丙基胺基);
R
a为三元至八元脂肪环,含N,O,S中杂原子的三元至八元脂肪环结构,有取代的三元至八元脂肪环,有C1-C4烷基、羟基烷基、胺基烷基取代的含N、O、S杂原子的三元至八元脂肪环,开链结构的伯胺结构基团(即
),N-单直链烷烃或环烷烃取代的仲胺结构基团(即
其中R
b为氢、C
1-C
8烷基或C
3-C
8的环烷基),N,N-双直链烷烃或环烷烃取代的叔胺结构基团
(其中R
b选自氢、C
1-C
8烷基或C
3-C
8的环烷基;R
c选自氢、C
1-C
8烷基或C
3-C
8的环烷基;其中R
b、R
c可以相同,也可以不同);
R
3为羟基、C1~C8烷基、C1~C8烷氧基、C3~C8环烷基、螺环基、桥环基、金刚烷、脂肪胺基或芳香胺基;其中R
3为芳香胺基时,芳香环上可各自独立的为以下取代基:羟基、C1~C8烷基、C1~C8烷氧基、卤素、硝基、三氟甲基、巯基或胺基;
进一步优选地,R
3为羟基、甲基、乙氧基、乙胺基、甲胺基、苯胺基、苄胺基或金刚烷胺基;
R
4可为苯环、取代苯基、甲硫基或各种取代胺基,其中:
1.当R
4为取代胺基时,可具体为:C2~C9的环胺基结构基团
其中m=1-8;含氮饱和杂环;开链结构的伯胺结构基团
N-单直链烷烃或环烷烃取代的仲胺结构基团
N,N-双直链烷烃或环烷烃取代的叔胺结构基团
其中R
b选自氢、C
1-C
8烷基或C
3-C
8的环烷基,R
c选自氢、C
1-C
8烷基或C
3-C
8的环烷基,R
b,R
c可以相同也可以不同;芳香胺基,其中芳香环上可各自独立的为以下取代基:羟基、C1~C8烷基、C1~C8烷氧基、卤素、硝基、三氟甲基、巯基或胺基;
2.当R
4为取代苯基时,苯环上各取代基可各自独立的为以下取代基:卤素、羟基、C1~C8烷基、C1~C8烷氧基、硝基、三氟甲基、甲氧基、巯基、胺基、氰基、脂肪胺基或亚甲基哌啶基;具体优选基团参见下表1。
R
5可为卤素、羟基、C1~C8烷基、C1~C8烷氧基、硝基、三氟甲基、甲氧基、巯基、胺基、氰基、亚甲基哌啶基或环己基酰胺基;具体优选基团参见下表1。
R
6可为氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基或苯基;
本发明中,所述苯并呋喃及Coumestans衍生物其结构如式(II)所示
其中,X为氮原子、氧原子或硫原子;
R
7可以是C2-C5的直链烷基或C3-C8环烷基;
R
3可为羟基、烷基、烷氧基、芳香胺基或脂肪胺基;其中R
3为芳香胺基时,芳香环上可各自独立的为以下取代基:羟基、烷基、烷氧基、卤素、硝基、三氟甲基或甲氧基;
R为芳香环,芳香环上各取代基可各自独立的为以下取代基:氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基、氰基、脂肪胺基或亚甲基哌啶基;
本发明中,所述苯并呋喃及Coumestans衍生物其结构如式(III)所示:
其中,R
7可为C2~C5的直链烷基或C3-C8环烷基;
X为氮原子、氧原子或硫原子;
Y为氮原子、氧原子或硫原子;
R为芳香环,芳香环上各取代基可各自独立的为以下取代基:氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基、氰基、脂肪胺基或亚甲基哌啶基;
本发明中,所述苯并呋喃及Coumestans衍生物其结构如式(IV)所示:
其中,X为氮原子、氧原子或硫原子;
Y为氮原子、氧原子或硫原子;
R
6可为氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基或苯基;
R
5可为氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基、N-亚甲基哌啶或甲酰基环C4-C7胺;
R
1可为氢、羟基、甲氧基、乙氧基、甲氧基乙基醚或酯;
R
2可为
Ra和R
b各自独立的选自以下取代基:氢原子;链状烷烃;环烷烃;
其中,Rc为C2-C8环烷基,含杂原子N,O,S环烷基,烷基取代的环烷基,或C3-C8内酰胺;
其中,R
d为C2-C8环烷基或
R
f为C2-C8环烷基,R
e为链状烷烃或醚;
R为芳香环,芳香环上各取代基可各自独立的为以下取代基氢、卤素、羟基、 烷基、硝基、氨基、三氟甲基、烷氧基或亚甲基哌啶基。
本发明中,所使用的各基团采用其在本领域中的常规意义。
本发明所述通式(I)(II)(III)(IV)苯并呋喃及Coumestans衍生物,按自行设计的代号S1~S132表示,具体包括表1~4所述的化合物:
表1
表2
表3
表4
本发明还提供了所述通式(I)、(II)、(III)、(IV)苯并呋喃及Coumestans衍生物的对映异构体、非对映异构体、外消旋体及其混合物,及其对应的盐。
本发明还提供了所述通式(I)、(II)、(III)、(IV)苯并呋喃及Coumestans衍生物及其中间体的制备方法。上述式(I)、(II)、(III)、(IV)化合物可通过以下步骤制得:
路线1
路线2
路线3
路线4
路线5
路线6
路线7
其中,路线1~7中所有基团的定义与所述结构通式(I)、(II)、(III)、(IV)中的定义相同,并优选为表1~4中所表示的优势基团,但不仅限于这些优势基团。
本发明还提供了包括所述通式(I)、(II)、(III)、(IV)化合物或其药学上可接受 的盐的药物组合物,所述药物组合物还包括药物上可接受的载体,或可选地,还包含其它治疗成分。所述药物组合物可包含所述式(I)、(II)、(III)、(IV)化合物或其药学上可接受的盐的单一的活性成分或混合的活性成分。所述药物组合物可以以任何形式给药,包括口服,直肠给药,鼻腔给药,注射给药(包括皮下注射,肌肉注射,静脉注射)等。所述的药物组合物被配置成可注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂或透皮贴剂。
本发明中,所述药学上可接受的载体可以根据实际期望的给药途径(如口腔给药,或注射给药等)以任何形式存在。
本发明中,在制备口服剂型的组合物时,任何常见的化学介质可能被采用,如在制备液体口服制剂(包括悬浮液和溶液)时,可采用水、乙二醇、油、醇类、调味剂、防腐剂和着色剂等。在制备固体口服制剂(如粉剂,胶囊)时,可选用的载体如淀粉、糖、微晶纤维素、填充剂、造粒剂、润滑剂、粘合剂、裂解剂等。
本发明还提供了所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物在制备微生物的抑制剂中的应用。所述微生物包括:细菌、病毒、真菌以及一些小型的原生生物、显微藻类等;其中,所述细菌包括结核分枝杆菌,金黄色葡萄球菌,链球菌,肺炎球菌,大肠杆菌,枯草芽孢杆菌,乳酸菌等。本发明中,所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物用于抑制微生物的生长、繁殖。
本发明还提供了所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物在制备结核分枝杆菌细胞壁合成抑制剂中的应用。
本发明还提供了所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物在制备抑制结核分枝杆菌的生长和繁殖的药物中的应用。
本发明还提供了所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物在制备治疗与pks13基因片段编码的聚酮合酶作为靶点有关的疾病的药物中的应用。
本发明还提供了所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物在制备预防和/或治疗肺结核疾病、抗癌、抗病毒、抗内风湿、抗真菌、抗氧化性、抗炎、护肝、止血及降血压的药物中的应用;优选用于治疗耐多药性肺结核疾病的药物中的应用。
本发明中,所述癌症包括乳腺癌、结肠直肠癌、胰腺癌、肾癌、前列腺癌、尿路上皮癌、食管癌、头颈癌、肝癌、间皮瘤、卡波济氏肉瘤、卵巢癌、软组织 肉瘤、胶质瘤、黑素瘤、小细胞-非小细胞肺癌、子宫内膜癌、基底细胞癌、泌尿道上皮移行细胞癌、子宫颈癌、子宫内膜癌、胃癌、膀胱癌、子宫肉瘤、多发性骨髓瘤、软组织、骨肉瘤和胆管癌等。
本发明中,所述苯并呋喃及Coumestans衍生物以结核杆菌pks13基因片段编码的聚酮合酶为作用靶点,抑制结核分枝杆菌细胞壁中分枝菌酸的合成,从而抑制结核分枝杆菌生长,达到治疗结核病的效果。
本发明还提供了将所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物用于预防和/或治疗肺结核疾病、抗癌、抗病毒、抗内风湿、抗真菌、抗氧化性、抗炎、护肝、止血及降血压的方法,包括向有需要的个体中给予所述通式(I)、(II)、(III)、(IV)化合物、所述药物组合物。
本发明的有益效果在于,本发明制备的式(I)、(II)、(III)、(IV)苯并呋喃类及Coumestans衍生物是一类结构新颖,抑菌效果显著的结核分枝杆菌细胞壁抑制剂。
图1为本发明化合物口服给药血清抑制滴定实验的相对荧光强度。
图2为本发明化合物口服给药或腹腔给药血清抑制滴定实验的相对荧光强度。
图3为本发明化合物口服给药血清抑制滴定实验的相对荧光强度。
结合以下具体实施例和附图,对本发明作进一步的详细说明。实施本发明的过程、条件、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
实施例1 5-羟基-(4-(1-(4-甲基哌嗪基))亚甲基)-2-苯基苯并呋喃-3-羧酸乙酯(化合物S1)的制备
1.1将3.45g碳酸二乙酯,0.87g氢化钠加入到15mL甲苯中,接着在氮气保护下向体系中缓慢滴加2.19g苯乙酮,110℃搅拌30min,反应完毕待冷至室温加入冰水,加入冰醋酸至体系中性,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水100ml洗涤,无水硫酸钠干燥,蒸去溶剂乙酸乙酯后粗品经快速柱层析(石油醚:乙酸乙酯=15:1)得苯甲酰乙酸乙酯(化合物1-1);
1.2将1.38g苯甲酰乙酸乙酯,86.37mg三氟甲磺酸铜溶解于20mL甲苯中,氮 气保护的条件下缓慢滴加1,4-苯醌0.52g,加热回流10h,冷却至室温。NH
4Cl淬灭,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)
得5-羟基-2-苯基苯并呋喃-3-羧酸乙酯(化合物1-2);
1.3将513.3mg化合物1-2,37%aq甲醛,N-甲基哌嗪溶解于10mL无水乙醇中,氮气保护下加热回流16h,乙酸乙酯(20mL×3)萃取,分出有机层,饱和食盐水5ml洗涤,无水硫酸钠干燥,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得最终产物5-羟基-4-(1-亚甲基-N-甲基哌嗪)-2-苯基苯并呋喃-3-羧酸乙酯。
1H NMR(400MHz,MeOD)δ7.82–7.64(m,2H),7.46(d,J=6.1Hz,3H),7.34(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H),4.34(q,J=7.1Hz,2H),3.95(s,2H),2.57(br,8H),2.28(s,3H),1.27(t,J=7.1Hz,3H).
13C NMR(101MHz,MeOD)δ167.6,157.8,155.4,149.7,131.1,130.8,129.6,128.7,127.0,115.8,114.3,111.9,111.8,62.7,56.2,55.8,53.0,45.9,14.3.HRMS(ESI)m/z:Calcd for C23H27N2O4(M+H)
+395.1965;Found 395.1938.
实施例2 4-(二丙基氨基)亚甲基-5-羟基-2-苯基苯并呋喃-3-羧酸乙酯(化合物S2)的制备
采用类似于实施例1的方法制备,不同之处在于以二丙胺代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.78–7.72(m,2H),7.48–7.40(m,3H),7.31(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.35(q,J=7.1Hz,2H),4.06(s,2H),2.54(t,J=7.5Hz,4H),1.70–1.51(m,4H),1.29(t,J=7.2Hz,3H),0.91(t,J=7.4Hz,6H).
13C NMR(101MHz,CDCl
3)δ166.4,156.6,155.6,148.1,130.0,129.5,128.3,127.8,125.3,115.2,112.9,110.6,110.0,61.4,55.7,54.2,19.6,13.9,11.8.HRMS(ESI)m/z:Calcd forC24H30NO4(M+H)
+396.2169;Found 396.2168.
实施例3 5-羟基-(4-(1-(4-(羟甲基)哌啶基))亚甲基)-2-苯基苯并呋喃-3-羧酸乙酯(化合物S3)的制备
采用类似于实施例1的方法制备,不同之处在于以4-羟甲基哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,MeOD)δ7.73–7.67(m,2H),7.51–7.45(m,3H),7.39(d,J=8.9Hz,1H),6.88(d,J=8.9Hz,1H),4.33(q,J=7.1Hz,2H),4.16(s,2H),3.43(d,J=6.3Hz,2H),3.33–3.30(m,1H),3.19(d,J=11.9Hz,2H),2.45(t,J=11.3Hz,2H), 1.84(d,J=13.0Hz,2H),1.70–1.56(m,1H),1.45–1.30(m,2H),1.23(t,J=7.1Hz,3H).
13C NMR(101MHz,MeOD)δ167.6,159.3,156.1,149.7,131.2,130.9,129.5,129.2,127.2,115.8,112.7,112.5,111.4,67.3,64.3,62.7,56.5,53.8,38.9,29.1,14.2.HRMS(ESI)m/z:Calcd for C24H28NO5(M+H)
+410.1962;Found 410.1980.
实施例4 5-羟基-(4-(1-哌啶基)亚甲基)-2-甲硫基苯并呋喃-3-羧酸乙酯(化合物S4)的制备
4.1将4.2mL的10mmol/mL乙酰丙酮,11.04g无水碳酸钾加入到10mLDMF中,N
2保护下室温搅拌30min。冰水浴下滴加2.2mL的20mmol/mL二硫化碳,室温搅拌1h,然后滴加2.28mg/mL碘甲烷2.74mL,过夜反应。冰水浴中析出固体,水洗过滤,得淡粉红色化合物3-[双(甲基磺酰基)亚甲基]-2,4-戊二酮,下称化合物4-1;
4.2将1.624g化合物16-1,1.296g苯醌,46mg溴化铜加入到15mL乙腈中,氮气保护下滴加BF
3·Et
2O,室温反应5h。饱和NaCl溶液洗涤,NaHCO3溶液调节体系呈中性,过滤沉淀,得5-羟基-2-(甲硫基)-3-乙酰基苯并呋喃,下称化合物4-2;
4.3将45mg化合物4-2,0.1mL37%aq甲醛,哌啶加入到2mL乙醇中,氮气保护下加热回流10h,反应毕,得白色固体终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ7.37(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.62(s,2H),4.41(q,J=7.1Hz,2H),3.13(br,4H),2.68(s,3H),1.90–1.76(m,4H),1.75–1.61(m,2H),1.46(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ166.0,165.8,156.2,150.5,127.8,113.2,113.1,109.3,109.2,62.1,55.2,53.9,24.6,23.2,14.7,13.9.
实施例5 5-羟基-(4-(1-哌啶基)亚甲基)-2-(4-(三氟甲基)苯基)苯并呋喃-3-羧酸乙酯(化合物S5)的制备
采用类似于实施例1的方法制备,不同之处在于以对三氟甲基苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,CDCl
3/MeOD=3/1)δ7.87(d,J=8.2Hz,2H),7.73(d,J=8.3Hz,2H),7.33(d,J=8.9Hz,1H),6.84(d,J=8.9Hz,1H),4.37(q,J=7.1Hz,2H),3.95(s,2H),2.58(br,4H),1.70–1.61(m,4H),1.52(br,2H),1.29(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3/MeOD=3/1)δ167.4,156.6,155.9,149.8,134.7,134.7,133.3(q,J
C-F=32.8Hz),129.3,126.5(q,J
C-F=3.8Hz),125.4(q,J
C-F=272.6Hz),117.0,113.7,112.9,112.2,63.1,58.6,55.0,26.9,25.0,14.6.HRMS(ESI)m/z:Calcd for C24H25F3NO4(M+H)
+448.1730;Found 448.1748.
实施例6 5-羟基-2-(4-甲氧基苯基)-(4-(1-哌啶基)亚甲基)苯并呋喃-3-羧酸乙酯(化合物S6)的制备
采用类似于实施例1的方法制备,不同之处在于以对甲氧基苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,MeOD)δ7.62(d,J=8.7Hz,2H),7.25(d,J=8.8Hz,1H),6.95(d,J=8.7Hz,2H),6.75(d,J=8.8Hz,1H),4.31(q,J=7.1Hz,2H),3.91(s,2H),3.80(s,3H),2.53(br,4H),1.67–1.55(m,4H),1.48(br,2H),1.26(t,J=7.1Hz,3H).
13C NMR(101MHz,MeOD)δ167.8,162.3,158.2,156.2,149.2,130.4,126.9,123.4,115.5,114.9,113.3,111.7,110.1,62.6,58.3,55.8,54.8,26.8,24.9,14.4.HRMS(ESI)m/z:Calcd forC24H28NO5(M+H)
+410.1962;Found410.1973.
实施例7 2-(4-氟苯基)-5-羟基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-羧酸乙酯(化合物S7)的制备
采用类似于实施例1的方法制备,不同之处在于以对氟苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,MeOD)δ7.75(dd,J=8.6,5.4Hz,2H),7.33(d,J=8.8Hz,1H),7.19(t,J=8.7Hz,2H),6.83(d,J=8.8Hz,1H),4.35(q,J=7.1Hz,2H),4.02(s,2H),2.64(br,4H),1.73–1.63(m,4H),1.54(br,2H),1.29(t,J=7.2Hz,3H).
13C NMR(101MHz,MeOD)δ167.2,164.7(d,J
C-F=249.8Hz),157.4,156.2,149.3,131.1(d,J
C-F=8.5Hz),127.3(d,J
C-F=3.3Hz),126.5,116.3(d,J
C-F=22.2Hz),116.0,113.0,111.9,111.1,62.6,58.1,54.6,26.5,24.6,14.3.HRMS(ESI)m/z:Calcd for C23H25FNO4(M+H)
+398.1762;Found 398.1778.
实施例8 2-(2,4-二甲氧基苯基)-5-羟基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-羧酸乙酯(化合物S8)的制备
采用类似于实施例1的方法制备,不同之处在于以2,4-二甲氧基苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,MeOD)δ7.47(d,J=9.0Hz,1H),7.28(d,J=8.8Hz,1H),6.76(d,J=8.8Hz,1H),6.66–6.59(m,2H),4.18(q,J=7.1Hz,2H),4.11(s,2H),3.85(s,3H),3.77(s,3H),2.61(br,4H),1.72–1.62(m,4H),1.58–1.49(m,2H),1.12(t,J=7.1Hz,3H).
13C NMR(101MHz,MeOD)δ167.8,164.0,159.6,157.4,156.4,149.5,132.0,126.6,115.2,113.7,113.4,112.6,111.8,106.2,99.3,62.0,58.1,56.0,55.9,54.7,26.8,24.9,14.3.HRMS(ESI)m/z:Calcd forC25H30NO6 (M+H)
+440.2068;Found 440.2079.
实施例9 2-(4-溴-2-甲氧基苯基)-5-羟基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-羧酸乙酯(化合物S9)的制备
采用类似于实施例1的方法制备,不同之处在于以4-溴-2-甲氧基苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ7.46(d,J=8.1Hz,1H),7.31(d,J=8.8Hz,1H),7.28–7.19(m,2H),6.82(d,J=8.8Hz,1H),4.22(q,J=7.1Hz,2H),4.12(s,2H),3.82(s,3H),2.63(br,4H),1.73–1.64(m,4H),1.55(br,2H),1.17(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ166.9,158.2,156.1,155.4,149.4,131.9,125.7,125.5,124.4,119.8,115.6,115.4,113.4,113.3,111.4,61.8,58.3,56.2,54.4,26.5,24.5,14.1.HRMS(ESI)m/z:Calcd forC24H27BrNO5(M+H)
+488.1067;Found 488.1087.
实施例10 2-(4-氟-2-甲氧基苯基)-5-羟基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-羧酸乙酯化合物(S10)的制备
采用类似于实施例1的方法制备,不同之处在于以4-氟-2-甲氧基苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.47(t,J=7.2Hz,1H),7.21(d,J=8.8Hz,1H),6.77(d,J=8.7Hz,1H),6.70(t,J=7.8Hz,1H),6.61(d,J=10.4Hz,1H),4.13(dd,J=13.5,6.6Hz,2H),4.03(s,2H),3.72(s,3H),2.58(br,4H),1.71–1.31(m,6H),1.07(t,J=6.8Hz,3H).
13C NMR(101MHz,CDCl
3)δ165.7,164.5(d,J=250.5Hz),158.3(d,J=10.2Hz),155.7,154.8,148.4,131.6(d,J=10.4Hz),124.8,116.1,114.9,112.6,112.3,110.5,107.3(d,J=21.8Hz),99.2(d,J=26.1Hz),60.7,57.9,55.7,53.8,25.9,23.9,13.9.HRMS(ESI)m/z:Calcd for(M+H)
+428.1868;Found 428.1876.
实施例11 5-羟基-2-(2-甲氧基-4,5-二甲基苯基)-(4-(1-哌啶基)亚甲基)苯并呋喃-3-羧酸乙酯(化合物S11)的制备
采用类似于实施例1的方法制备,不同之处在于以4,5-二甲基-2-甲氧基苯乙酮代替苯乙酮,哌啶代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.36(s,1H),7.28(d,J=8.9Hz,1H),6.82(d,J=8.8Hz,1H),6.74(s,1H),4.22(q,J=7.1Hz,2H),4.09(s,2H),3.76(s,3H),3.03–2.00(m,10H),1.74–1.46(m,6H),1.17(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3)δ166.2,155.5,155.5,154.8,148.3,139.8,131.0,128.5,125.1, 116.9,114.5,112.5,112.4,111.8,110.5,60.7,57.8,55.5,53.8,25.9,24.0,20.3,18.7,13.9.HRMS(ESI)m/z:Calcd forC26H32NO5(M+H)
+438.2275;Found 438.2282.
实施例12 1-(2-((环丙基甲基)氨基)-5-羟基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-(1-乙基)酮(化合物S12)的制备
12.1将4.2mL的10mmol/mL乙酰丙酮,11.04g无水碳酸钾加入到10mLDMF中,N
2保护下室温搅拌30min。冰水浴下滴加2.2mL的20mmol/mL二硫化碳,室温搅拌1h,然后滴加2.28mg/mL碘甲烷2.74mL,过夜反应。冰水浴中析出固体,水洗过滤,得淡粉红色化合物3-[双(甲基磺酰基)亚甲基]-2,4-戊二酮,下称化合物12-1;
12.2将1.624g化合物16-1,1.296g苯醌,46mg溴化铜加入到15mL乙腈中,氮气保护下滴加BF
3·Et
2O,室温反应5h。饱和NaCl溶液洗涤,NaHCO3溶液调节体系呈中性,过滤沉淀,得5-羟基-2-甲硫基-3-乙酰基苯并呋喃,下称化合物12-2;
12.3将50mg化合物16-2与96mg环丙甲基胺加入到5mL乙醇中,氮气保护下加热回流10h,减压浓缩,快速柱纯化,得化合物12-3;
12.4将45mg化合物12-3,0.1mL37%aq甲醛,69.6mg哌啶加入到2mL乙醇中,氮气保护下加热回流10h,反应毕,冷却析出淡黄色固体终产物50mg。
1H NMR(400MHz,MeOD)δ6.99(s,1H),6.83(s,1H),3.69(s,2H),3.40(d,J=7.0Hz,2H),2.53(br,4H),2.43(s,3H),1.65(dd,J=11.0,5.5Hz,4H),1.52(d,J=4.8Hz,2H),1.16(s,1H),0.58(d,J=7.9Hz,2H),0.33(d,J=5.1Hz,2H).
13C NMR(101MHz,MeOD)δ192.9,167.4,156.2,144.6,127.9,116.4,111.2,106.3,95.7,62.2,54.7,47.5,28.7,27.0,25.1,12.2,3.9.
实施例13 1-(5-羟基-2-(哌啶基)-4-(1-哌啶基)亚甲基)苯并呋喃-3-(1-乙基)酮(化合物S13)的制备
采用类似于实施例12的方法制备,不同之处在于以哌啶代替环丙甲基胺,其余所需原料,试剂以及制备方法与实施例12相同,得白色固体终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ7.03(s,1H),6.94(s,1H),3.67(s,2H),3.55(br,4H),2.61–2.42(m,7H),1.71(br,6H),1.67–1.58(m,4H),1.51(br,2H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ192.8,165.9,155.4,143.8,129.1,117.2,110.6,107.4,99.1,62.3,54.5,51.3,30.6,26.8,26.7,24.9,24.9.
实施例14 1-(2-(苄基氨基)-5-羟基-4-(1-哌啶基)亚甲基)苯并呋喃-3-(1-乙基)酮(化合物S14)的制备
采用类似于实施例12的方法制备,不同之处在于以苄胺代替环丙甲基胺,其余所需原料,试剂以及制备方法与实施例12相同,得终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ7.44–7.19(m,5H),6.96(s,1H),6.85(s,1H),4.71(s,2H),3.68(s,2H),2.56(br,4H),2.45(s,3H),1.76–1.60(m,4H),1.52(br,2H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ193.1,166.8,155.9,144.4,139.0,129.6,128.5,128.1,127.7,116.3,111.1,106.2,95.8,62.2,54.6,46.4,28.8,26.8,24.9.
实施例15 1-(5-羟基-2-吗啉基-4-(1-哌啶基)亚甲基)苯并呋喃-3-(1-乙基)酮(化合物S15)的制备
采用类似于实施例12的方法制备,不同之处在于以吗啉代替环丙甲基胺,其余所需原料,试剂以及制备方法与实施例12相同,得终产物。
1H NMR(400MHz,MeOD)δ7.04(d,J=11.5Hz,2H),3.89–3.76(m,4H),3.71(s,2H),3.69–3.59(m,4H),2.62–2.47(m,7H),1.70–1.60(m,4H),1.59–1.50(m,2H).
13C NMR(101MHz,MeOD)δ193.4,165.5,155.9,144.2,129.0,118.1,111.1,107.6,100.2,67.7,62.2,54.7,50.4,30.8,27.0,25.1.
实施例16 1-(2-(环己基氨基)-5-羟基-4-(1-哌啶基)亚甲基)苯并呋喃-3-(1-乙基)酮(化合物S16)的制备
采用类似于实施例12的方法制备,不同之处在于以环己胺代替环丙甲基胺,其余所需原料,试剂以及制备方法与实施例12相同,得终产物。
1H NMR(400MHz,MeOD)δ6.98(s,1H),6.81(s,1H),3.81(br,1H),3.71(s,2H),2.58(br,4H),2.39(s,3H),2.01(s,2H),1.77(s,2H),1.70–1.59(m,4H),1.52(d,J=4.3Hz,2H),1.49–1.40(m,4H),1.35–1.20(m,2H).
13C NMR(101MHz,MeOD)δ192.9,166.5,156.1,144.6,128.1,115.7,111.6,106.3,95.5,61.7,54.6,52.3,34.3,28.7,26.7,26.4,25.5,24.9.
实施例17 (1-(2-(二丙基氨基)-5-羟基-4-(1-哌啶基)亚甲基)苯并呋喃基)-(3-乙基)酮(化合物S17)的制备
采用类似于实施例12的方法制备,不同之处在于以二丙胺代替环丙甲基胺,其余所需原料,试剂以及制备方法与实施例12相同,得终产物。
1H NMR(400MHz,MeOD)δ6.99(d,J=11.5Hz,2H),3.71(s,2H),3.55(t,4H),2.52(m,7H),1.64(dd,J=14.5,7.4Hz,8H),1.52(d,J=4.4Hz,2H),0.89(t,J=7.4Hz,6H).
13C NMR(101MHz,MeOD)δ192.7,165.5,155.6,143.9,129.7,116.9,110.8,107.3,99.2,61.9,54.7,54.2,30.8,26.8,25.0,22.3,11.4.
实施例18 5-羟基-(4-(1-哌啶基)亚甲基)-2-吡咯烷基苯并呋喃-(1-乙基) -3-酮(化合物S18)的制备
采用类似于实施例12的方法制备,不同之处在于以四氢吡咯代替环丙甲基胺,其余所需原料,试剂以及制备方法与实施例12相同,得终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ6.93(s,2H),3.72(s,2H),3.65(t,J=6.4Hz,4H),2.58(br,4H),2.47(s,3H),1.99(t,J=6.6Hz,4H),1.69–1.60(m,4H),1.52(br,2H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ192.2,163.7,155.2,143.9,129.5,115.5,110.7,106.6,97.3,61.8,54.4,51.2,30.7,26.5,26.2,24.6.
实施例19 N-乙基-5-羟基-2-苯基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-甲酰胺(化合物S19)的制备
采用类似于实施例1的方法制备,不同之处在于合成5-羟基-2-苯基苯并呋喃-3-羧酸乙酯后的步骤:
19.1合成5-羟基-2-苯基苯并呋喃-3-羧酸乙酯(后简称化合物19-1)之后,将120mg化合物19-1,24.2mg LiOH·H
2O加入到8mL 1,4-二氧六环,氮气保护室温过夜反应,盐酸调节pH至中性,乙酸乙酯(50mL×3)萃取,饱和NaCl洗,无水Na2SO4干燥,减压浓缩,加入二氯甲烷析出沉淀,过滤白色固体得5-羟基-2-苯基苯并呋喃-3-羧酸(化合物19-2)。
19.2将100mg化合物19-2,21.8mg乙胺,98.0mg EDC·HCl,69.1mg 1-羟基苯并三唑(HOBT)和79.1mg 3-甲基吡啶溶于5mLDMF中,氮气保护下室温反应5h,NH
4Cl淬灭,乙酸乙酯(50mL×3)萃取,5%盐酸溶液洗,饱和NaHCO
3洗,饱和NaCl洗,无水Na
2SO
4干燥,减压浓缩后得粗品N-乙基-5-羟基-2-苯基苯并呋喃-3-甲酰胺(化合物19-3)不经纯化直接进行下一步。
19.3将113.3mg化合物19-3,0.1mL 37%aq甲醛,哌啶溶解于10mL无水乙醇中,氮气保护下加热回流16h,乙酸乙酯(20mL×3)萃取,分出有机层,饱和食盐水5ml洗涤,无水硫酸钠干燥,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得终产物N-乙基-5-羟基-2-苯基-4-(哌啶-1-基甲基)苯并呋喃-3-甲酰胺60.8mg。
1H NMR(400MHz,MeOD)δ7.81(d,J=8.0Hz,2H),7.58–7.29(m,4H),6.86(d,J=8.8Hz,1H),4.10(s,2H),3.42(q,J=7.3Hz,2H),2.83(s,4H),1.83–1.68(m,4H),1.59(s,2H),1.20(t,J=7.3Hz,3H).
13C NMR(101MHz,MeOD)δ168.7,155.7,154.8,149.5,130.8,130.6,129.9,127.9,127.8,115.5,114.4,112.9,111.3,54.8,54.6,36.0,26.1,24.3,14.2.HRMS(ESI)m/z:Calcd for C23H27N2O3(M+H)
+379.2025;Found 379.2016.
实施例20 N-环丙基-5-羟基-2-苯基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-甲酰胺(化合物S20)的制备
采用类似于实施例19的方法制备,不同之处在于以环丙胺代替乙胺,其余所需原料,试剂以及制备方法与实施例19相同,得终产物。
1H NMR(400MHz,MeOD)δ7.79–7.65(m,2H),7.56–7.40(m,4H),6.96(d,J=8.9Hz,1H),4.32(s,2H),3.12(s,4H),3.05–2.89(m,1H),1.91–1.75(m,4H),1.67(s,2H),0.90–0.68(m,2H),0.59–0.45(m,2H).
13C NMR(101MHz,MeOD)δ169.9,156.2,155.5,149.6,131.0,130.5,129.8,128.3,128.3,115.2,114.3,113.9,109.1,54.3,54.1,25.1,24.2,23.4,5.8.HRMS(ESI)m/z:Calcd for C24H27N2O3(M+H)
+391.2016;Found391.2011.
实施例21 N-金刚烷基-5-羟基-2-苯基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-甲酰胺(化合物S21)的制备
采用类似于实施例19的方法制备,不同之处在于以金刚烷胺代替乙胺,得终产物。
1H NMR(400MHz,MeOD)δ7.84(d,J=7.3Hz,2H),7.53–7.44(m,3H),7.40(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),4.20(s,2H),2.88(br,4H),2.13(s,11H),1.66(s,10H).
13C NMR(101MHz,CDCl
3)δ164.4,153.9,151.1,146.9,128.6,128.1,127.6,125.6,125.1,114.0,113.5,111.1,109.5,56.0,53.0,51.7,40.2,35.3,28.4,24.7,22.9.HRMS(ESI)m/z:Calcd for C31H37N2O3(M+H)
+485.2799;Found485.2805.
实施例22 N-苄基-5-羟基-2-苯基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-甲酰胺(化合物S22)的制备
采用类似于实施例19的方法制备,不同之处在于以其余所需原料,试剂以及制备方法与实施例19相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.65(d,J=3.5Hz,2H),7.34–7.10(m,8H),6.71(d,J=8.8Hz,1H),6.26(s,1H),4.51(d,J=5.9Hz,2H),3.75(s,2H),2.92–1.85(br,4H),1.63–1.26(m,6H).
13C NMR(101MHz,CDCl
3)δ165.2,154.1,151.7,146.9,136.3,128.4,128.1,127.8,127.7,127.4,126.7,125.6,124.9,114.0,112.0,111.1,109.5,56.1,52.6,43.3,24.8,22.8.HRMS(ESI)m/z:Calcd forC28H29N2O3(M+H)
+441.2173;Found 441.2188.
实施例23 5-羟基-N,2-二苯基-(4-(1-哌啶基)亚甲基)苯并呋喃-3-甲酰胺(化合物S23)的制备
采用类似于实施例19的方法制备,不同之处在于以苯胺代替乙胺,其余所需原料,试剂以及制备方法与实施例19相同,得终产物。
1H NMR(400MHz,CDCl
3) δ7.91(s,1H),7.73(d,J=6.5Hz,2H),7.49(d,J=7.4Hz,2H),7.33(d,J=8.3Hz,4H),7.19(s,1H),7.13(d,J=6.8Hz,1H),6.78(d,J=8.3Hz,1H),3.89(s,2H),2.79–2.25(br,4H),1.65–1.41(m,6H).
13C NMR(101MHz,CDCl
3)δ164.4,155.2,153.2,148.0,137.7,129.4,129.4,129.2,128.9,126.7,125.9,125.0,120.1,115.3,113.5,111.9,110.8,57.0,53.8,25.6,23.7.HRMS(ESI)m/z:Calcd for C27H27N2O3(M+H)
+427.2016;Found 427.2029.
实施例24 4-(((环丙基甲基)氨基)甲基)-5-羟基-2-(4-甲氧基苯基)苯并呋喃-3-乙酸乙酯(化合物S24)的制备
采用类似于实施例58的方法制备,不同之处在于生成化合物S58后,0℃冰水浴条件下缓慢滴加mL 1mmol/mL的BBr
3·DCM 2mL,滴加完毕室温搅拌5h,乙醇淬灭,减压浓缩除去溶剂,二氯甲烷(50mL×3)萃取,分离有机相减压浓缩,快速柱纯化(石油醚:乙酸乙酯=10:1)得终产物。
1H NMR(400MHz,CDCl
3)δ7.64(d,J=7.4Hz,2H),7.41(d,J=8.6Hz,1H),7.29(d,J=9.0Hz,1H),6.98(d,J=7.4Hz,2H),4.45(s,2H),4.31(q,J=6.8Hz,2H),3.88(s,3H),2.98(d,J=6.9Hz,2H),1.36–1.18(m,5H),0.86(d,J=6.5Hz,1H),0.66(d,J=6.8Hz,2H),0.39(s,2H).
13C NMR(101MHz,CDCl
3)δ167.0,161.4,161.2,154.3,148.9,130.9,126.2,122.1,118.0,113.6,113.5,110.5,108.3,61.9,55.4,52.4,44.0,13.8,8.3,4.2.
实施例25 5-羟基-2-苯基-(4-(1-哌啶基)亚甲基)-1H-吲哚-3-乙酸乙酯(化合物S25)的制备
25.1将原料苯甲酰乙酸乙酯与5.0eq的甲酸铵,5~6粒4A分子筛加入到乙醇中,氮气保护下加热回流10h,反应毕,硅藻土过滤,减压浓缩,乙酸乙酯(50mL×3)萃取,分出有机层,饱和NaCl溶液洗,无水Na
2SO
4干燥,快速柱层析(石油醚:乙酸乙酯=20:1)得乙基(Z)-3-氨基-3-苯基丙烯酸酯,下称化合物25-1;
25.2化合物25-1与1.0eq溴化锌加入到重蒸四氢呋喃溶剂中,滴加1.0eq苯醌的THF溶液,室温反应1h,NH
4Cl淬灭,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,柱纯化(石油醚:乙酸乙酯=10:1)得乙基-5-羟基-2-苯基-1H-吲哚-3-羧酸,下称化合物25-2;
25.3将化合物25-2与5.0eq的CH
2O,5.0eq的哌啶加入到乙醇溶剂中,氮气保护下加热回流3h,反应完毕,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得终产物。
1H NMR(400MHz,MeOD)δ7.48(d,J=6.8Hz,2H),7.40(m,3H),7.22 (d,J=8.6Hz,1H),6.73(d,J=8.6Hz,1H),4.99(br,2H)4.17–4.09(m,4H),2.71–2.49(m,4H),1.69–1.45(m,6H),1.05(t,J=7.1Hz,3H).
13C NMR(101MHz,MeOD)δ169.4,154.7,144.3,134.4,132.1,130.0,129.4,129.1,127.1,114.7,112.6,111.8,106.2,61.4,59.1,54.6,26.8,24.9,14.2.
实施例26 5-羟基-(4–(1-(4-甲基哌啶))亚甲基)-2-苯基-1H-吲哚-3-羧酸乙酯(化合物S26)的制备
采用类似于实施例25的方法制备,不同之处在于以对甲基哌啶代替哌啶,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,MeOD)δ7.52–7.44(m,5H),7.41(d,J=8.7Hz,1H),6.92(d,J=8.7Hz,1H),4.73(s,1H),4.10(q,J=7.1Hz,2H),3.56(d,J=13.7Hz,1H),3.14(t,J=12.0Hz,1H),1.91(d,J=13.2Hz,1H),1.77(s,1H),1.51(s,1H),1.02(d,J=6.4Hz,1H),0.94(t,J=7.1Hz,3H)
实施例27 5-羟基-2-苯基-(4-(1-吡咯烷基)亚甲基)-1H-吲哚-3-羧酸乙酯(化合物S27)的制备
采用类似于实施例25的方法制备,不同之处在于以四氢吡咯代替哌啶,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,MeOD)δ7.51–7.45(m,5H),7.40(d,J=8.7Hz,1H),6.93(d,J=8.7Hz,1H),4.86(s,2H),4.10(q,J=7.1Hz,2H),3.50(t,J=6.8Hz,4H),2.16–2.11(m,4H),1.28(s,1H),0.94(t,J=7.1Hz,3H)
13C NMR(101MHz,MeOD)δ168.93,153.83,147.86,134.85,132.50,130.53,129.82,129.00,128.26,115.77,113.58,108.61,111.08,105.56,61.26,54.65,52.17,24.05,13.96.
实施例28 2-(4-氟苯基)-5-羟基-4-(1-哌啶基)亚甲基)-1H-吲哚-3-羧酸乙酯(化合物S28)的制备
采用类似于实施例25的方法制备,不同之处在于以对氟苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,DMSO)δ12.31(br,1H),7.59–7.52(m,2H),7.42(d,J=8.7Hz,1H),7.34(t,J=8.9Hz,2H),7.03(d,J=8.7Hz,1H),4.69(s,2H),4.05(q,J=7.1Hz,2H),3.15(br,4H),1.73(br,4H),1.54(br,2H),0.94(t,J=7.1Hz,4H).
13C NMR(101MHz,MeOD)δ169.17(s),164.57(d,J=247.2Hz),154.55(s),146.74(s),132.74(d,J=8.4Hz),132.51(s),131.02(d,J=3.4Hz),128.48(s),116.06(s),115.91(d,J=22.0Hz),113.74(s),107.32(s),105.93(s),61.52(s),54.13(s),53.90(s),24.38(s),23.06(s),14.08(s).
实施例29 N-乙基-2-(4-氟苯基)-5-羟基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S29)的制备
29.1将1.5g 4-氟苯甲酰乙酸乙酯,0.1g三氟甲磺酸铜溶于甲苯,0.59g苯醌溶于甲苯,氮气保护下逐滴加入体系,加热回流10h,反应完毕,饱和氯化铵淬灭,乙酸乙酯(50mL×3)萃取,分出有机层,饱和氯化钠溶液洗涤,无水硫酸钠干燥,除去乙酸乙酯后粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得(4-氟苯基)-5-羟基苯并呋喃-3-羧酸乙酯(化合物29-1);
29.2将710mg化合物29-1,265mg氢氧化钾溶入7mL甲醇,加热回流反应5h,反应完毕,2N盐酸洗涤,乙酸乙酯(50mL×3)萃取,分出有机层,饱和氯化钠溶液洗涤,无水硫酸钠干燥,除去乙酸乙酯后用二氯甲烷打浆得粗品(4-氟苯基)-5-羟基苯并呋喃-3-羧酸(化合物29-2);
29.3将386.9mg化合物29-2溶于N,N-二甲基甲酰胺,加入0.4mL三乙胺,657.8mg 2-(7-氧化苯并三氮唑)-N,N,N’,N’,四甲基脲六氟磷酸酯(HATU),搅拌反应20min后,加入78.71mg乙胺,反应30min后,加入饱和氯化钠溶液,乙酸乙酯(30mL×3)萃取,水洗(30mL×3)除去二甲基甲酰胺,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得N-乙基-2-(4-氟苯基)-5-羟基苯并呋喃-3-甲酰胺(化合物S29(化合物29-3);
29.4将23.5mg化合物29-3,31.86mg 37%甲醛,27.92mg哌啶溶于2mL乙醇中加热回流反应8h,反应毕,乙酸乙酯(20mL×3)萃取,无水硫酸钠干燥,除去乙酸乙酯后使用薄层层析硅胶板在石油醚:乙酸乙酯=1:1条件下纯化,得最终产物S29。
1H NMR(400MHz,CDCl
3)δ7.69(dd,J=8.7,5.3Hz,2H),7.20(d,J=8.9Hz,1H),7.04(t,J=8.7Hz,2H),6.72(d,J=8.8Hz,1H),6.01(t,J=5.5Hz,1H),3.79(s,2H),3.46–3.36(m,2H),2.19(m,4H),1.56(m,6H),1.14(t,J=7.2Hz,3H).
13C NMR(101MHz,CDCl
3)δ165.2(s),163.4,160.9(d,J
C-F=248.7Hz),154.0(s),150.6(s),146.9(s),127.5(d,J
C-F=8.3Hz),124.9(s),124.8(d,J
C-F=3.3Hz),115.0,114.8(d,J
C-F=21.8Hz),112.0(s),111.1(s),109.5(s),56.0(s),52.8(s),34.1(s),24.8(s),22.9(s),13.4(s).
实施例30 N-环丙基-2-(4-氟苯基)-5-羟基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S30)的制备
采用类似于实施例29的方法制备,不同之处在于以环丙胺代替乙胺,其余 所需原料,试剂以及制备方法与实施例29相同,得最终产物。
1H NMR(400MHz,MeOD)δ7.80(dd,J=8.7,5.3Hz,2H),7.32(d,J=8.8Hz,1H),7.24(t,J=8.7Hz,2H),6.79(d,J=8.8Hz,1H),3.91(s,2H),2.94(dt,J=11.1,3.7Hz,1H),2.58(m,4H),1.69–1.63(m,4H),1.56(m,2H),0.86–0.81(m,2H),0.57(m,2H).
13C NMR(101MHz,MeOD)δ170.4(s),166.0,162.8(d,J
C-F=242.3Hz),156.0(s),152.9(s),149.3(s),131.0(s),129.6(d,J
C-F=8.4Hz),127.4(d),117.0(d,J
C-F=22.1Hz),115.8(s),114.18(s),113.2(s),111.7(s),57.8(s),54.9(s),27.5(s),24.9(s),24.1(s),6.0(s).
实施例31 N-乙基-5-羟基-2-(4-甲氧基苯基)-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S31)的制备
采用类似于实施例29的方法制备,不同之处在于以4-甲氧基苯甲酰乙酸乙酯代替4-氟苯甲酰乙酸乙酯,其余所需原料,试剂以及制备方法与实施例29相同,得最终产物。
1H NMR(400MHz,MeOD)δ7.74(d,J=8.8Hz,2H),7.30(d,J=8.8Hz,1H),7.02(d,J=8.8Hz,2H),6.75(d,J=8.8Hz,1H),3.92(s,2H),3.85(s,3H),3.43(q,J=7.3Hz,2H),2.58(m,4H),1.66(m,4H),1.54(m,2H),1.23(t,J=7.3Hz,3H).
13C NMR(101MHz,MeOD)δ169.2(s),162.1(s),155.8(s),154.1(s),149.1(s),128.9(s),127.8(s),123.5(s),115.3(s),115.1(s),113.0(s),111.5(s),57.8(s),55.9(s),54.9(s),36.0(s),26.9(s),25.0(s),14.4(s).
实施例32 N-乙基-5-羟基-2-(2-甲氧基苯基)-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S32)的制备
采用类似于实施例29的方法制备,不同之处在于以2-甲氧基苯甲酰乙酸乙酯代替4-氟苯甲酰乙酸乙酯,其余所需原料,试剂以及制备方法与实施例29相同,得最终产物。
1H NMR(400MHz,CDCl
3)δ7.54(dd,J=7.6,1.2Hz,1H),7.41(dd,J=11.4,4.3Hz,1H),7.25(dd,J=8.5,4.4Hz,1H),7.04(t,J=7.5Hz,1H),6.97(d,J=8.3Hz,1H),6.80(d,J=8.8Hz,1H),6.00(s,1H),4.03(s,2H),3.83(s,3H),3.30(dd,J=13.2,7.1Hz,2H),3.02–2.02(m,4H),1.62(s,6H),1.01(t,J=7.2Hz,3H).
13C NMR(101MHz,CDCl
3)δ164.51(s),155.74(s),154.24(s),150.17(s),147.41(s),130.23(s),129.98(s),124.50(s),119.84(s),118.05(s),114.99(s),113.69(s),111.68(s),110.10(s),109.30(s),56.39(s),54.34(s),52.72(s),33.60(s),24.85(s),22.91(s),13.45(s).
实施例33 N-乙基-5-甲氧基-2-苯基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S33)的制备
采用类似于实施例42的方法制备,不同之处在于得到化合物42-1后,将42-1, 哌啶在1.5mL甲醇中搅拌10min后加入硼氢化钠,氯化镁,反应30min后乙酸乙酯(50mL×3)萃取,分出有机层,饱和氯化钠溶液洗涤,无水硫酸钠干燥,除去乙酸乙酯后粗品经硅胶柱层析纯化(石油醚:乙酸乙酯=3:1)得最终产物。
1H NMR(400MHz,CDCl
3)δ7.93(s,1H),7.62(s,1H),7.53(t,J=7.4Hz,1H),7.49(d,J=7.6Hz,1H)7.12(t,J=7.3Hz,1H),7.04(d,J=8.3Hz,1H),5.81(s,1H),4.25(s,2H),3.92(s,3H),3.85(s,3H),3.35(dd,J=7.3,5.8Hz,2H),2.98(m,4H),1.99–1.50(m,6H),1.03(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl
3)δ162.7(s),156.1(s),154.0(s),152.7(s),147.6(s),131.4(s),130.5(s),128.8(s),120.1(s),117.3(s),114.8(s),113.9(s),110.6(s),101.9(s),55.1(s),54.7(s),53.6(s),51.2(s),33.2(s),28.68(s),22.1(s),21.3(s),13.5(s).
实施例34 N-乙基-5-甲氧基-2-苯基-6-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S34)的制备
采用类似于实施例19的方法制备,不同之处在于19-3后的步骤:
34.1化合物19-3,加入氯仿使其溶解,加入二氯甲基甲醚,搅拌,滴加四氯化钛,室温下反应40分钟。反应毕,加水淬灭,用乙酸乙酯萃取,饱和氯化钠溶液洗去水,无水硫酸钠干燥,减压浓缩,抽油泵,得呈淡红色半固体的粗产品N-乙基-5-甲氧基-2-苯基-6-甲酰基苯并呋喃-3-甲酰胺(下称34-1)。
34.2将34-1溶于甲醇中,加入哌啶,醋酸,氰基硼氢化钠,室温下过夜。TLC检测至反应完全后,加乙酸乙酯萃取,饱和氯化钠溶液洗去水,无水硫酸钠干燥,减压浓缩,TLC纯化得最终产物。
1H NMR(400MHz,MeOD)δ7.80–7.72(m,2H),7.65(s,1H),7.47–7.38(m,4H),4.25(s,2H),3.88(s,3H),3.38(q,J=7.3Hz,2H),3.07(s,4H),1.89–1.74(m,4H),1.58(s,2H),1.13(t,J=7.3Hz,3H).
13C NMR(101MHz,MeOD)δ164.20(s),155.99(s),154.89(s),147.74(s),130.16(s),130.02(s),128.69(s),128.61(s),127.61(s),115.08(s),112.75(s),101.73(s).
实施例35 N-乙基-5-甲氧基-2-(2-甲氧基苯基)-6-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S35)的制备
采用类似于实施例19,34的方法制备,不同之处在于以邻甲氧基苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例19,34相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.93(s,1H),7.62(s,1H),7.53(t,J=7.4Hz,1H),7.49(d,J=7.6Hz,1H)7.12(t,J=7.3Hz,1H),7.04(d,J=8.3Hz,1H),5.81(s,1H),4.25(s,2H),3.92(s,3H),3.85(s,3H),3.35(dd,J=7.3,5.8Hz,2H),2.98(m,4H), 1.99–1.50(m,6H),1.03(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl
3)δ162.7(s),156.1(s),154.0(s),152.7(s),147.6(s),131.4(s),130.5(s),128.8(s),120.1(s),117.3(s),114.8(s),113.9(s),110.6(s),101.9(s),55.1(s),54.7(s),53.6(s),51.2(s),33.2(s),28.68(s),22.1(s),21.3(s),13.5(s).
实施例36 5-羟基-2-苯基-4-(哌啶-1-亚甲基)苯并[b]噻吩-3-羧酸乙酯(化合物S36)的制备
采用类似于实施例37的方法制备,不同之处在于苯基乙酸甲酯代替4-氟苯基乙酸甲酯,其余所需原料,试剂以及制备方法与实施例37相同,得最终产物。
1H NMR(400MHz,CDCl
3)δ7.58(d,J=8.7Hz,1H),7.52(d,J=5.5Hz,2H),7.40(d,J=5.6Hz,3H),6.94(d,J=8.7Hz,1H),4.25(q,J=7.1Hz,2H),3.87(s,2H),1.66(m,4H),1.25(m,6H),1.20(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3)δ167.2(s),156.3(s),144.3(s),135.4(s),132.6(s),129.6(s),127.8(s),127.7(s),127.5(s),124.4(s),120.8(s),115.5(s),112.9(s),60.7(s),57.5(s),52.9(s),28.7(s),24.7(s),22.9(s),12.9(s).
实施例37 2-(4-氟苯基)-5-羟基-4-(哌啶-1-亚甲基)苯并[b]噻吩-3-羧酸乙酯(化合物S37)的制备
采用类似于实施例39的方法制备,不同之处在于省略酯水解及酰化反应,其余所需原料,试剂以及制备方法与实施例39相同,得最终产物。
1H NMR(400MHz,CDCl
3)δ7.51(d,J=8.7Hz,1H),7.47–7.40(m,2H),7.03(t,J=8.6Hz,2H),6.87(d,J=8.7Hz,1H),4.18(q,J=7.1Hz,2H),3.79(s,2H),2.9-2.2(m,4H)1.59(m,6H),1.16(t,J=7.2Hz,3H).
13C NMR(101MHz,MeOD)δ168.2(s),163.0(d,J
C-F=249.3Hz),156.7(s),144.2(s),136.1(s),130.7(s),130.6(s),129.4(d,J
C-F=3.4Hz),125.5(s),121.8(s),116.3(s),115.5(d,J
C-F=21.8Hz),113.9(s),61.8(s),58.4(s),53.8(s),25.6(s),23.7(s),13.7(s).
实施例38 N-乙基5-羟基-2-苯基-4-(哌啶-1-亚甲基)苯并[b]噻吩-3-甲酰胺(化合物S38)的制备
采用类似于实施例39的方法制备,不同之处在于苯基乙酸甲酯代替4-氟苯基乙酸甲酯,其余所需原料,试剂以及制备方法与实施例39相同,得最终产物。
1H NMR(400MHz,CDCl
3)δ8.71(s,1H),8.30(s,1H),7.69(d,J=7.5Hz,2H),7.39(s,1H),7.31(t,J=7.4Hz,2H),7.23(d,J=7.3Hz,1H),3.71(s,2H),3.53–3.45(m,2H),2.50(m,4H),1.60(m,4H),1.46(m,2H),1.23(t,J=7.3Hz,3H).
实施例39 N-乙基-2-(4-氟苯基)-5-羟基-6-(哌啶-1-亚甲基)苯并[b]噻吩 -3-甲酰胺(化合物S39)的制备
39.1将8.53g 2-溴-5-甲氧基苯甲醛,5.08g硫单质,10g4-氟苯基乙酸甲酯和16.44g碳酸钾加入到70mL N,N-二甲基甲酰胺中,氮气保护下在110℃持续反应11h,反应完毕旋蒸除去溶剂,二氯甲烷(50mL×3)萃取,分出有机层,饱和食盐水30ml洗涤,无水硫酸钠干燥,蒸去溶剂二氯甲烷后粗品经快速柱层析(石油醚:乙酸乙酯=15:1)得化合物39-1;
39.2将化合物39-1,0.9mL二氯甲基甲醚溶于无水三氯甲烷中,室温滴加1mL四氯化钛,反应30min,反应毕,饱和碳酸氢钠淬灭,硅藻土抽滤除去白色络合物,二氯甲烷(50mL×2)萃取,分出有机层,饱和食盐水30ml洗涤,无水硫酸钠干燥,快速柱层析(石油醚:乙酸乙酯=25:1)得化合物39-2;
39.3将化合物39-2 265mg,251.1mg亚氯酸钠溶入10mL的二氧六环与水7:3的混合体系中,缓慢滴加7滴5%盐酸。反应完毕,饱和氯化铵缓冲pH,饱和亚硫酸钠淬灭,5%盐酸调节体系至弱酸性,二氯甲烷(30mL×3)萃取,分出有机层,饱和食盐水5ml洗涤,无水硫酸钠干燥,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(二氯甲烷:甲醇=50:1)得化合物39-3;
39.4将110mg化合物39-3溶于N,N-二甲基甲酰胺,加入0.08mL三乙胺,130.8mg 2-(7-氧化苯并三氮唑)-N,N,N’,N’,四甲基脲六氟磷酸酯(HATU),搅拌反应20min后,加入15.51mg乙胺,反应30min后,加入饱和氯化钠溶液,乙酸乙酯(30mL×3)萃取,水洗(30mL×3)除去二甲基甲酰胺,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(石油醚:乙酸乙酯=5:1)得化合物39-4;
39.5将化合物39-4 101.4mg溶于5mL无水二氯甲烷,氮气保护下加入0.65mL三溴化硼室温反应,反应完毕,旋蒸除去溶剂,乙酸乙酯(20mL×3)萃取,分出有机层,饱和氯化钠溶液洗涤,无水硫酸钠干燥,蒸去溶剂二氯甲烷后粗品经快速柱层析(石油醚:乙酸乙酯=3:1)得化合物39-5;
39.6将50mg化合物39-5,90.07mg 37%甲醛,56.38mg哌啶于4mL乙醇中加热回流反应8h,反应毕,使用薄层层析硅胶板在石油醚:乙酸乙酯=1:1条件下纯化,得最终产物。
1H NMR(400MHz,CDCl
3)δ8.66(s,1H),8.37(s,1H),7.65(dd,J=8.6Hz,5.3Hz,2H),7.39(s,1H),7.00(t,J=8.6Hz,2H),3.72(s,2H),3.50(dd,J=7.3Hz,2H),2.44(m,4H),1.56(m,6H),1.23(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl
3)δ165.7(s),162.9,160.4(d,J
C-F=246Hz)155.0(s),143.0(s),139.9 (s),130.6(s),129.9(s),127.2(d,J=8.1Hz),123.2(s),121.1(s),119.1(s),114.8,114.6(d,J
C-F=21.62Hz),113.(s),61.2(s),52.4(s),33.3(s),24.5(s),22.7(s),14.0(s).
实施例40 N-环丙基-2-(4-氟苯基)-5-羟基-6-(哌啶-1-亚甲基)苯并[b]噻吩-3-甲酰胺(化合物S40)的制备
采用类似于实施例39的方法制备,不同之处在于以环丙胺代替乙胺,其余所需原料,试剂以及制备方法与实施例39相同,得最终产物。
1H NMR(400MHz,CDCl
3)δ8.80(s,1H),8.63(s,1H),7.72(dd,J=8.6Hz,2H),7.47(s,1H),7.08(t,J=8.6Hz,2H),3.80(s,2H),2.99(dt,J=10.5,3.4Hz,1H),2.91–2.21(m,4H),1.69(m,6H),0.88(dd,J=6.7,12.1Hz,2H),0.66(dd,J=6.7,12.1Hz,2H).
13C NMR(101MHz,CDCl
3)δ167.5(s),162.5,160.4(d,J
C-F=247.1Hz),155.3(s),143.2(s),139.9(s),130.6(s),129.9(s),127.2,127.1(d,J
C-F=8.0Hz),121.2(s),114.9,114.7(d,J
C-F=17.1Hz),61.2(s),52.47(s),28.64(s),24.50(s),22.65(s),21.66(s),5.67(s).
实施例41 N-乙基-2-(4-氟苯基)-5-羟基-6-(4-甲基哌啶-1-亚甲基)苯并[b]噻吩-3-甲酰胺(化合物S41)的制备
采用类似于实施例39的方法制备,不同之处在于以对甲基哌啶代替哌啶,其余所需原料,试剂以及制备方法与实施例39相同,得最终产物。
1H NMR(400MHz,CDCl
3)δ8.72(s,1H),8.42(s,1H),7.72(dd,J=8.5,5.3Hz,2H),7.47(s,1H),7.08(t,J=8.6Hz,2H),3.82(s,2H),3.60–3.51(m,2H),3.02(d,J=11.3Hz,2H),2.19(t,J=11.4Hz,2H),1.73(d,J=12.9Hz,2H),1.48(s,1H),1.30(d,J=7.2Hz,3H),1.25(s,2H),0.98(d,J=6.4Hz,3H).
13C NMR(101MHz,CDCl
3)δ165.7(s),162.9,160.4(d,J
C-F=245.2Hz),154.9(s),143.1(s),139.9(s),130.6(s),129.9(d,J
C-F=3.4Hz),127.16(d,J
C-F=8.1Hz),123.21(s),121.08(s),119.10(s),114.8,114.6(d,J
C-F=21.6Hz),113.03(s),60.87(s),51.93(s),33.33(s),32.81(s),20.52(s),14.01(s).
实施例42 N-乙基-5-甲氧基-2-苯基-4-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S42)的制备
采用34-1中间体,其后续制备方法如下:
42.1将34-1溶于二氧六环中,加入水,亚氯酸钠、氨基磺酸,室温下搅拌半小时。TLC检测至反应完全后,加硫代硫酸钠溶液淬灭,用盐酸溶液调pH为弱酸性,加乙酸乙酯萃取,饱和氯化钠溶液洗去水,无水硫酸钠干燥,减压浓缩,得淡黄色固体42-1。
42.2氮气保护下,将42-1、EDC·HCl、HOBT溶于DMF中,加吡啶、哌啶,室温下搅拌,过夜。TLC检测至反应完全后,加氯化铵溶液淬灭,乙酸乙酯萃取,有机相依次用5%的盐酸溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗,无水硫酸钠干燥,减压浓缩,TLC纯化得最终产物。
1H NMR(400MHz,CDCl
3)δ7.95–7.85(m,1H),7.52–7.34(m,2H),6.96(d,J=9.0Hz,1H),6.24(s,1H),3.98–3.82(m,2H),3.64–3.51(m,1H),3.37–3.27(m,1H),3.26–3.16(m,1H),1.77–1.52(m,4H),1.27–1.20(m,3H).
13C NMR(101MHz,CDCl
3)δ165.38(s),164.05(s),154.85(s),151.93(s),148.90(s),129.67(s),129.45(s),128.79(s),127.21(s),124.91(s),117.75(s),113.44(s),111.68(s),110.02(s),57.18(s),48.15(s),42.47(s),35.19(s),26.17(s),25.55(s),24.77(s),14.39(s).
实施例43 N-乙基-5-羟基-2-苯基-4-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S43)的制备6-47
采用化合物S42作为原料,其后续制备方法如下:
氮气保护,化合物S42加入二氯甲烷使其溶解,加入1M三溴化硼的二氯甲烷溶液,室温下搅拌,过夜。TLC检测反应完全后,加乙醇淬灭,减压浓缩,TLC纯化,得最终产物。
1H NMR(400MHz,MeOD)δ7.77(d,J=7.1Hz,2H),7.43–7.24(m,4H),6.81(d,J=8.8Hz,1H),3.39–3.19(m,6H),1.71–1.47(m,6H),1.13(t,J=7.3Hz,3H).
实施例44 N-乙基-5-甲氧基-2-苯基-6-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S44)的制备
采用类似于实施例42的方法制备,所需原料,试剂以及制备方法与实施例42相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.80(dd,J=7.7,1.6Hz,2H),7.50–7.42(m,3H),7.36(s,1H),7.29(s,1H),6.04(s,1H),3.85(s,3H),3.71(m,2H),3.51–3.35(m,2H),3.23–3.08(m,2H),1.62(br,4H),1.44(br,2H),1.14(t,J=7.2Hz,3H).
13C NMR(101MHz,CDCl
3)δ166.09(s),162.64(s),154.62(s),151.62(s),147.21(s),129.08(s),128.25(s),127.88(s),127.83(s),127.26(s),123.64(s),112.04(s),109.10(s),101.38(s),55.09(s),46.99(s),41.64(s),33.49(s),25.27(s),24.63(s),23.59(s),13.48(s).
实施例45 N-乙基-5-羟基-2-苯基-6-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S45)的制备
采用类似于实施例43的方法制备,所需原料为化合物S44,其制备方法与 实施例43相同,得终产物。
1H NMR(400MHz,CDCl
3)δ9.44(br,1H),7.99–7.81(m,2H),7.51–7.44(m,3H),7.36(s,1H),7.32(s,1H),5.92(br,1H),3.66(t,J=5.2Hz,4H),3.52–3.39(m,2H),1.77–1.63(m,6H),1.19(t,J=7.2Hz,3H).
13C NMR(101MHz,CDCl
3)δ170.62(s),163.50(s),157.43(s),154.77(s),146.93(s),131.05(s),130.38(s),129.27(s),128.89(s),128.33(s),116.34(s),112.97(s),110.43(s),108.16(s),47.09(s),34.82(s),26.26(s),24.68(s),14.80(s).
实施例46 5-羟基-2-苯基-4-(哌啶-1-羰基)苯并呋喃-3-甲酸(化合物S46)的制备
采用化合物S47,用类似于实施例43的方法制备得终产物。
1H NMR(400MHz,MeOD)δ7.88–7.79(m,2H),7.40–7.34(m,3H),7.30(d,J=8.8Hz,1H),6.82(d,J=8.8Hz,1H),3.27(s,4H),1.69-1.46(m,6H).
实施例47 5-甲氧基-2-苯基-4-(哌啶-1-羰基)苯并呋喃-3-羧酸乙酯(化合物S47)的制备
采用中间体19-1,用类似于实施例42的方法制备得终产物。
1H NMR(400MHz,CDCl
3)δ7.84–7.78(m,2H),7.48–7.41(m,4H),6.97(d,J=9.0Hz,1H),4.39–4.21(m,2H),4.05–3.95(m,1H),3.87(s,3H),3.59–3.48(m,1H),3.41–3.28(m,1H),3.23–3.11(m,1H),1.83–1.48(m,6H),1.26(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3)δ165.44(s),163.98(s),158.78(s),152.33(s),149.22(s),130.03(s),129.75(s),128.64(s),128.32(s),125.14(s),118.48(s),111.77(s),110.20(s),110.04(s),61.21(s),57.12(s),48.01(s),42.43(s),26.05(s),25.41(s),24.87(s),14.09(s).
实施例48 5-羟基-2-苯基-6-(哌啶-1-羰基)苯并呋喃-3-甲酸(化合物S48)的制备
采用化合物S49,用类似于实施例43的方法制备得终产物。
1H NMR(400MHz,MeOD)δ7.91(dd,J=6.4,2.9Hz,2H),7.46(s,1H),7.41–7.35(m,3H),7.32(s,1H),3.48(s,4H),1.67–1.44(m,6H).
实施例49 5-甲氧基-2-苯基-6-(哌啶-1-羰基)苯并呋喃-3-羧酸乙酯(化合物S49)的制备
采用中间体19-1,用类似于实施例42的方法制备得终产物。
1H NMR(400MHz,CDCl
3)δ7.98(dd,J=6.3,2.9Hz,2H),7.58(s,1H),7.52–7.45(m,3H),7.40(s,1H),4.40(q,J=7.1Hz,2H),3.92(s,3H),3.77(m,2H),3.21(d,J=4.5Hz,2H),1.67(s,6H),1.39(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3)δ167.18(s), 163.99(s),162.12(s),153.03(s),148.36(s),130.52(s),129.69(s),129.64(s),128.58(s),128.19(s),124.85(s),110.39(s),109.00(s),103.75(s),60.84(s),56.18(s),48.20(s),42.83(s),26.48(s),25.79(s),24.77(s),14.32(s).
实施例50 2-(4-氟苯基)-5-甲氧基-4-(哌啶-1-羰基)苯并呋喃-3-羧酸乙酯(化合物S50)的制备
采用类似于实施例42的方法制备,不同之处在于以对氟苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例42相同,得终产物。1H NMR(400MHz,CDCl3)δ7.81(dd,J=8.7,5.4Hz,2H),7.42(d,J=9.0Hz,1H),7.12(t,J=8.6Hz,2H),6.95(d,J=9.0Hz,1H),4.38–4.20(m,2H),4.06–3.97(m,1H),3.85(s,3H),3.55–3.45(m,1H),3.33(dt,J=9.5,4.5Hz,1H),3.21–3.09(m,1H),1.62(m,6H),1.26(t,J=7.1Hz,3H).13C NMR(101MHz,CDCl3)δ165.35(s),164.92(s),163.72(s),162.42(s),157.92(s),152.36(s),149.07(s),130.81(d,J=8.6Hz),125.91(d,J=3.5Hz),124.98(s),118.51(s),115.54(s),115.32(s),111.69(s),110.02(s),61.16(s),57.00(s),47.94(s),42.35(s),25.97(s),25.35(s),24.80(s),14.08(s).
实施例51 2-(4-氟苯基)-5-羟基-4-(哌啶-1-羰基)苯并呋喃-3-羧酸乙酯(化合物S51)的制备
采用类似于实施例43的方法制备,化合物S50,其余所需原料,试剂以及制备方法与实施例43相同,得终产物。
1H NMR(400MHz,CDCl3)δ7.97(dd,J=8.7,5.4Hz,2H),7.43(d,J=8.9Hz,1H),7.16(t,J=8.6Hz,2H),7.01(d,J=8.9Hz,1H),4.27(q,J=7.1Hz,2H),3.86(s,1H),3.12(dd,J=16.5,6.4Hz,2H),1.66–1.43(m,6H),1.30(d,J=7.1Hz,3H).
实施例52 2-(4-氟苯基)-5-甲氧基-6-(哌啶-1-羰基)苯并呋喃-3-羧酸乙酯(化合物S52)的制备
采用类似于实施例42的方法制备,不同之处在于以对氟苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例42相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.01(dd,J=7.0,5.6Hz,2H),7.56(s,1H),7.39(d,J=0.8Hz,1H),7.16(t,J=8.0Hz,2H),4.43–4.34(m,2H),3.90(s,3H),3.81(d,J=13.2Hz,1H),3.70(d,J=12.9Hz,1H),3.26–3.13(m,2H),1.65(s,4H),1.48(d,J=30.5Hz,2H),1.40(dd,J=7.0,6.2Hz,3H).
13C NMR(101MHz,CDCl
3)δ167.04(s),165.21(s),163.84(s),162.70(s),161.05(s),153.01(s),148.19(s),131.83(d,J=8.7Hz),128.38(s),125.74(d,J=3.2Hz),124.91(s),115.43(s),115.22(s),110.31(s),108.86(s),103.76(s),60.85(s),56.10(s),48.13(s),42.76(s),26.41(s),25.72(s),24.69(s),14.29(s).
实施例53 2-(4-氟苯基)-5-羟基-6-(哌啶-1-羰基)苯并呋喃-3-羧酸乙酯(化合物S53)的制备
采用类似于实施例43的方法制备,化合物S52,其余所需原料,试剂以及制备方法与实施例43相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.08(dd,J=8.8,5.4Hz,2H),7.62(s,1H),7.39(s,1H),7.18(t,J=8.7Hz,2H),4.42(q,J=7.1Hz,2H),3.71(m,4H),1.71(m,6H),1.43(t,J=7.1Hz,3H).
实施例54 N-乙基-2-(4-氟苯基)-5-羟基-4-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S54)的制备
采用类似于实施例42和43的方法制备,不同之处在于以对氟苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例42和43相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.79(dd,J=8.8,5.3Hz,2H),7.28(s,1H),7.05(t,J=8.7Hz,2H),6.80(d,J=8.9Hz,1H),3.30(m,4H),1.59(m,6H),1.13(t,J=7.3Hz,3H).
实施例55 N-乙基-2-(4-氟苯基)-5-羟基-6-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S55)的制备
采用类似于实施例42和43的方法制备,不同之处在于以对氟苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例42和43相同,得终产物。
1H NMR(400MHz,CDCl
3)δ9.49(s,1H),7.97(dd,J=8.8,5.4Hz,2H),7.34(s,1H),7.24(s,1H),7.16(t,J=8.6Hz,2H),5.99(s,1H),3.67(m,4H),3.48(p,J=7.2Hz,2H),1.73–1.65(m,6H),1.22(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl
3)δ170.53(s),163.42(s),156.78(s),154.83(s),146.74(s),130.80(s),130.46(d,J=8.6Hz),125.53(s),116.20(d,J=17.2Hz),115.90(s),112.68(s),110.50(s),107.86(s),34.89(s),29.83(s),26.25(s),24.66(s),14.90(s).
实施例56 N-乙基-5-甲氧基-2-(2-甲氧基苯基)-6-(哌啶-1-羰基)苯并呋喃-3-甲酰胺(化合物S56)的制备
采用类似于实施例42的方法制备,不同之处在于以邻甲氧基苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例42相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.59(s,1H),7.53(t,J=7.6Hz,1H),7.51(d,J=7.5Hz)7.35(s,1H),7.12(t,J=7.6Hz,1H),7.05(d,J=8.4Hz,1H),5.81(s,1H),3.90(s,3H),3.85(s,3H),3.81–3.69(m,2H),3.35(dd,J=18.9,6.3Hz,2H),3.19(dd,J=11.2,6.9Hz,2H),1.69–1.49(m,6H),1.03(t,J=7.3Hz,3H).
13C NMR(101MHz,CDCl
3)δ166.3(s),162.8(s),156.1(s),152.1(s),151.6(s),147.6(s),131.2(s),130.5(s),127.6(s),123.4(s),120.1(s),117.6(s),114.1(s),110.6(s),109.0(s),102.0(s),55.1(s),54.7(s),47.0(s),41.7(s),33.2(s),25.3(s),24.7(s),23.6(s),13.5(s).
实施例57 2-(环丙基甲基)-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸乙酯(化合物S57)的制备
采用类似于实施例1的方法制备,不同之处在于以伯胺环丙基甲胺代替N-甲基哌嗪,其余所需原料,试剂以及制备方法与实施例1相同,得终产物。
1H NMR(400MHz,MeOD)δ7.75–7.70(m,2H),7.49–7.43(m,3H),7.31(d,J=8.9Hz,1H),6.81(d,J=8.9Hz,1H),4.94(s,2H),4.43–4.29(m,4H),2.64(d,J=6.7Hz,2H),1.28(t,J=7.1Hz,3H),1.03–0.92(m,1H),0.60–0.51(m,2H),0.15(q,J=4.7Hz,2H).
13C NMR(101MHz,MeOD)δ166.90(s),159.41(s),151.83(s),150.17(s),131.15(s),131.01(s),129.52(s),129.37(s),125.74(s),116.44(s),113.20(s),111.63(s),111.37(s),82.33(s),62.66(s),57.49(s),50.22(s),14.59(s),10.25(s),4.44(s).
实施例58 2-(环丙基甲基)-8-(4-甲氧基苯基)-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸乙酯(化合物58)的制备
采用类似于实施例57的方法制备,不同之处在于以对甲氧基苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例57相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.74(d,J=8.8Hz,2H),7.26(d,J=8.8Hz,1H),6.97(d,J=8.8Hz,2H),6.77(d,J=8.9Hz,1H),4.99(s,2H),4.51–4.24(m,4H),3.86(s,3H),2.65(d,J=6.7Hz,2H),1.32(t,J=7.1Hz,3H),1.04–0.91(m,1H),0.56–0.51(m,2H),0.15(q,J=5.0Hz,2H).
13C NMR(101MHz,CDCl
3)δ165.4,160.7,158.1,150.5,148.3,129.8,124.7,122.3,114.7,113.7,112.1,110.1,108.9,81.3,61.2,56.2,55.3,49.2,14.0,9.5,3.5.HRMS(ESI)m/z:Calcd for(M+H)
+408.1805;Found408.1808.
实施例59 乙基2-环丙基-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸乙酯(化合物S59)的制备
采用类似于实施例57的方法制备,不同之处在于以环丙胺代替环丙基甲胺,其余所需原料,试剂以及制备方法与实施例57相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.78(dd,J=6.3,1.6Hz,2H),7.50–7.43(m,3H),7.31(d,J=8.9Hz,1H),6.87(d,J=8.9Hz,1H),4.91(s,2H),4.44–4.31(m,4H),2.45–2.38(m,1H),1.31(t,J=7.1Hz,2H),0.58(d,J=4.8Hz,4H).
13C NMR(101MHz,CDCl
3)δ165.3,158.0,150.7,148.7,129.9,129.7,128.3,128.3,124.5,115.4,112.9,110.3,110.2,82.0,61.3,49.8,32.9,13.9,7.0.HRMS(ESI)m/z:Calcd for(M+H)
+364.1543;Found 364.1555.
实施例60 2-(环丙基甲基)-8-(对甲苯基)-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸乙酯(化合物S60)的制备。
采用类似于实施例57的方法制备,不同之处在于以对甲基苯乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例57相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.51(d,J=7.6Hz,1H),7.12(dd,J=19.3,12.3Hz,2H),6.63(d,J=8.8Hz,0H),4.83(s,1H),4.26–4.11(m,2H),2.49(d,J=6.4Hz,1H),2.27(d,J=13.6Hz,2H),1.19–1.10(m,1H),0.82(s,1H),0.38(d,J=7.3Hz,1H).
13C NMR(101MHz,CDCl
3)δ206.88,165.50,158.07,150.61,148.50,139.93,129.02,128.82,128.12,127.03,124.68,114.94,112.26,110.23,109.64,81.46,76.76,61.27,56.31,49.15,30.89,21.45,14.06,9.60,3.56.HRMS(ESI)m/z:Calcd for(M+H)
+392.1856;Found 392.1847.
实施例61 2-(环丙基甲基)-8-(2-甲氧基-5-甲基苯基)-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸乙酯(化合物S61)的制备
采用类似于实施例57的方法制备,不同之处在于以1-(2-甲氧基-5-甲基苯基)乙酮代替苯乙酮,其余所需原料,试剂以及制备方法与实施例57相同,得终产物。
1H NMR(400MHz,CDCl3)δ7.34(s,1H),7.23–7.08(m,2H),6.77(d,1H),6.71(d,1H),4.90(s,2H),4.22–4.08(m,2H),3.68(t,3H),2.58(d,2H),2.27(s,3H),1.08(t,3H),0.96–0.87(m,1H),0.45(d,2H),0.08(d,2H).
13C NMR(101MHz,CDCl3)δ165.25,155.72,154.81,150.56,148.84,131.55,130.62,129.79,124.27,119.33,114.73,112.49,110.89,110.13,81.45,60.69,56.38,55.53,49.44,20.42,13.93,9.63,3.58,1.01,0.86.HRMS(ESI)m/z:Calcd for(M+H)
+422.1962,Found 422.1956.
实施例62 2-(环丙基甲基)-N,8-二苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-甲酰胺(化合物S37)的制备
采用类似于实施例19的方法制备,不同之处在于以环丙基甲胺代替哌啶,以苯胺代替乙胺,其余所需原料,试剂以及制备方法与实施例19相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.84(d,1H),7.51(d,J=7.6Hz,1H),7.48–7.45(m,1H),7.44(d,J=5.1Hz,1H),7.42(d,J=3.3Hz,1H),7.37(t,J=7.9Hz,1H),7.30(d,J=8.9Hz,1H),7.18(t,J=7.4Hz,1H),6.82(d,J=8.9Hz,1H),4.97(s,1H),4.37(s,1H),2.65(d,J=6.7Hz,1H),0.48(dt,J=7.8,5.1Hz,1H),0.12(dt,1H).
13C NMR(101MHz,CDCl
3)δ165.25,155.72,154.81,150.56,148.84,131.55,130.62,129.79,124.27,119.33,114.73,112.49,110.89,110.23,81.45,60.69,48.2, 28.4,15.6,9.5,3.6.HRMS(ESI)m/z:Calcd for(M+H)
+425.1860;Found 425.1861.
实施例63 2-(环丙基甲基)-N-(4-甲基苯基)-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-甲酰胺(化合物S63)的制备
采用类似于实施例62的方法制备,不同之处在于以对乙基苯胺代替乙胺,其余所需原料,试剂以及制备方法与实施例62相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.70(d,J=7.1Hz,2H),7.59(s,1H),7.35–7.25(m,5H),7.15(d,J=8.4Hz,1H),7.08(d,J=7.8Hz,2H),6.67(d,J=8.8Hz,1H),4.81(s,2H),4.22(s,2H),2.66–2.32(m,4H),1.16(m,4H),0.80(d,J=5.8Hz,2H),0.37(d,J=7.4Hz,2H).
13C NMR(101MHz,CDCl
3)δ163.5,153.3,150.4,148.5,141.2,135.1,129.5,129.2,128.9,128.5,126.8,125.1,120.4,115.2,113.7,112.3,110.1,81.7,56.4,48.2,28.4,15.6,9.5,3.6.HRMS(ESI)m/z:Calcd for C29H29N2O3(M+H)
+453.2173;Found 453.2172.
实施例64 N-(4-氯苯基)-2-(环丙基甲基)-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-甲酰胺(化合物S64)的制备
采用类似于实施例62的方法制备,不同之处在于以对氯苯胺代替乙胺,其余所需原料,试剂以及制备方法与实施例62相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.78(s,1H),7.65(s,2H),7.41–7.26(m,4H),7.14(d,J=8.4Hz,1H),6.93(s,2H),6.67(d,J=8.5Hz,1H),4.78(s,2H),4.18(s,2H),2.50(d,J=5.5Hz,2H),1.25–1.10(m,1H),0.80(s,2H),0.37(d,J=5.7Hz,2H).
13C NMR(101MHz,CDCl
3)δ163.25,153.35,150.54,147.78,137.20,129.67,129.24,129.02,126.98,125.07,120.08,115.32,113.85,113.70,112.39,110.23,81.78,56.45,48.26,9.56,3.56,0.94.
实施例65 2-异戊基-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸乙酯(化合物S65)的制备
采用类似于实施例57的方法制备,不同之处在于以异戊胺代替环丙基甲胺,其余所需原料,试剂以及制备方法与实施例57相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.71–7.66(m,2H),7.39–7.32(m,3H),7.20(d,J=8.9Hz,1H),6.74(d,J=8.9Hz,1H),4.80(s,2H),4.27(q,J=7.1Hz,2H),4.19(s,2H),2.68(t,J=7.56Hz,2H),1.56(dt,J=13.2,6.6Hz,1H),1.40(dd,J=14.9,7.1Hz,2H),1.21(t,J=7.1Hz,3H),0.82(d,J=6.6Hz,6H).
13C NMR(101MHz,CDCl
3)δ165.3,157.9,150.7,148.6,129.9,129.6,128.2,128.2,124.5,115.2,112.6,110.2,110.2,81.7,61.2,49.7,49.2,37.1,26.1,22.6,13.9.HRMS(ESI)m/z:Calcd for C24H28NO4(M+H)
+ 394.2013;Found 394.2014.
实施例66 2-环戊基-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-羧酸(化合物S66)的制备
采用类似于实施例57的方法制备,不同之处在于以环戊胺代替环丙基甲胺,其余所需原料,试剂以及制备方法与实施例57相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.84–7.72(m,2H),7.50–7.42(m,3H),7.29(d,J=8.9Hz,1H),6.82(d,J=8.9Hz,1H),4.96(s,2H),4.49–4.22(m,4H),3.37–3.12(m,1H),2.11–1.84(m,2H),1.84–1.69(m,2H),1.65–1.46(m,4H),1.31(t,J=7.2Hz,3H).
13C NMR(101MHz,CDCl
3)δ165.4,157.8,151.2,148.6,129.9,129.7,128.3,128.2,124.4,115.1,112.7,110.2,110.2,81.1,61.3,59.8,48.0,31.5,23.7,14.0.
实施例67 2-环丙基甲基-N-乙基-8-苯基-2,3-二氢-1H-苯并呋喃并[4,5-E][1,3]恶嗪-9-甲酰胺(化合物S67)的制备
采用类似于实施例62的方法制备,不同之处在于以乙胺代替苯胺,其余所需原料,试剂以及制备方法与实施例62相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.70(d,J=7.3Hz,2H),7.39–7.29(m,3H),7.16(d,J=8.8Hz,1H),6.69(d,J=8.8Hz,1H),5.86(s,1H),4.87(s,2H),4.24(s,2H),3.44–3.34(m,2H),2.58(d,J=6.4Hz,2H),1.11(t,J=7.1Hz,3H),0.92–0.86(m,1H),0.46(d,J=7.3Hz,2H),0.08(s,2H).
13C NMR(101MHz,CDCl
3)δ164.5(s),151.9(s),149.3(s),147.5(s),128.4(s),128.3(s),127.8(s),125.8(s),124.1(s),113.9(s),112.6(s),111.3(s),109.1(s),80.7(s),55.5(s),46.9(s),33.9(s),13.3(s),8.6(s),2.6(s).
实施例68 9-氯-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S68)的制备
采用类似于实施例1的方法制备,不同之处在于进行第一步合成时以2-甲氧基-5-氯苯乙酮代替苯乙酮,合成5-羟基-2-(2-甲氧基-5-氯苯基)苯并呋喃-3-羧酸乙酯后,将其溶于DCM中,氮气保护,0℃冰水浴条件下缓慢滴加1mmol/mL的BBr
3·DCM,滴加完毕室温搅拌5h,乙醇淬灭,另加5mL乙醇加热回流5h,减压浓缩除去溶剂,二氯甲烷(50mL×3)萃取,分离有机相减压浓缩,快速柱纯化(石油醚:乙酸乙酯=10:1)得化合物;之后与甲醛,环丙基甲胺在乙醇回流下反应得终产物。
1H NMR(400MHz,CDCl
3)δ7.96(s,1H),7.52(d,J=8.4Hz,1H),7.40(m,2H),6.92(d,J=8.8Hz,1H),5.03(s,2H),4.83(s,2H),2.69(d,J=6.0Hz,2H),1.03 (s,1H),0.56(d,J=6.3Hz,2H),0.15(s,2H).
13C NMR(101MHz,CDCl
3)δ158.0,156.5,151.0,150.7,149.2,130.7,129.1,120.3,120.2,117.6,116.1,113.5,112.6,109.6,106.2,81.0,55.4,48.9,8.5,2.6.HRMS(ESI)m/z:Calcd forC21H17ClNO4(M+H)
+382.0841;Found 382.0862.
实施例69 9-溴-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S69)的制备
采用类似于实施例68的方法制备,不同之处在于以2-甲氧基-5-溴苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.11(s,1H),7.65(d,J=8.3Hz,1H),7.36(dd,J=16.4,8.9Hz,2H),6.91(d,J=8.9Hz,1H),5.02(s,2H),4.82(s,2H),2.69(d,J=6.6Hz,2H),1.02(br,1H),0.56(d,J=7.2Hz,2H),0.15(d,J=4.2Hz,2H).
13C NMR(101MHz,CDCl
3)δ158.9,157.5,152.2,152.1,150.2,134.5,124.3,121.3,118.9,117.4,117.2,114.5,114.1,110.7,107.2,82.0,56.5,49.9,9.6,3.6.HRMS(ESI)m/z:Calcd forC21H17BrNO4(M+H)+426.0335;Found 426.0321.
实施例70 9-氟-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S70)的制备
采用类似于实施例68的方法制备,不同之处在于以2-甲氧基-5-氟苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.57(d,J=7.6Hz,1H),7.36(dd,J=9.0,4.1Hz,1H),7.31(d,J=8.9Hz,1H),7.23(d,J=8.3Hz,1H),6.84(d,J=8.9Hz,1H),4.95(s,2H),4.76(s,2H),2.61(d,J=6.6Hz,2H),1.01–0.91(m,1H),0.48(d,J=7.8Hz,2H),0.08(d,J=4.8Hz,2H).
13C NMR(101MHz,CDCl
3)δ159.1,158.4(d,J
C-F=2.8Hz),156.7(d,J
C-F=3.8Hz),151.0,149.2,148.6,120.4,118.3(d,J
C-F=24.7Hz),117.9(d,J
C-F=8.5Hz),116.1,113.5,112.2(d,J
C-F=9.6Hz),109.6,106.5(d,J
C-F=25.7Hz),106.2,81.0,55.4,48.9,8.5,2.6.HRMS(ESI)m/z:Calcd forC21H17FNO4(M+H)
+366.1136;Found 366.1166.
实施例71 9-甲基-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S71)的制备
采用类似于实施例68的方法制备,不同之处在于以1-(2-甲氧基-5-甲基苯基)乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.76(s,1H),7.42–7.31(m,3H),6.88(d,J=8.9Hz,1H),5.02(s,2H),4.84(s,2H),2.69(d,J=6.6Hz,2H),2.47(s, 3H),1.02(s,1H),0.55(d,J=7.6Hz,2H),0.15(d,J=4.6Hz,2H).
13C NMR(101MHz,CDCl
3)δ159.5,157.3,150.8,150.7,149.0,133.4,131.9,120.7,120.4,115.9,115.4,113.4,111.1,109.4,105.4,80.9,55.4,49.0,19.9,8.6,2.6.HRMS(ESI)m/z:Calcd for C22H19NNaO4(M+Na)
+384.1206;Found 384.1214.
实施例72 9-甲氧基-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S72)的制备
采用类似于实施例68的方法制备,不同之处在于以2,5-二甲氧基苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.37(m,3H),7.13(d,J=9.2Hz,1H),6.89(d,J=8.9Hz,1H),5.02(s,2H),4.84(s,2H),3.92(s,3H),2.69(d,J=6.7Hz,2H),1.13–0.95(m,1H),0.55(d,J=7.6Hz,2H),0.15(d,J=4.5Hz,2H).
13C NMR(101MHz,CDCl
3)δ159.3,157.2,155.2,150.8,149.0,147.1,120.7,119.2,117.4,115.6,113.5,111.7,109.4,105.7,102.2,80.9,55.4,54.9,49.0,8.6,2.6.HRMS(ESI)m/z:Calcd for C21H17BrNO4(M+H)
+426.0335;Found 426.0327.
实施例73 9,10-二甲基-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S73)的制备
采用类似于实施例68的方法制备,不同之处在于以4,5-二甲基-2-甲氧基苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.70(s,1H),7.35(d,J=8.8Hz,1H),7.23(s,1H),6.86(d,J=8.8Hz,1H),5.01(s,2H),4.84(s,2H),2.69(d,J=6.6Hz,2H),2.37(d,J=5.5Hz,6H),1.02(d,J=5.6Hz,1H),0.56(d,J=7.5Hz,2H),0.16(d,J=4.2Hz,2H).
13C NMR(101MHz,CDCl
3)δ159.8,157.5,151.1,150.8,148.8,141.0,132.5,120.8,120.7,116.6,115.1,113.3,109.4,109.0,104.7,80.9,55.4,49.1,19.5,18.3,8.6,2.6.HRMS(ESI)m/z:Calcd for(M+H)
+376.1543;Found 376.1545.
实施例74 9,10-二氯-2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪13-酮(化合物S74)的制备
采用类似于实施例68的方法制备,不同之处在于以2-甲氧基-4,5-二氯苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.06(s,1H),7.59(s,1H),7.39(d,J=9.0Hz,1H),6.93(d,J=8.9Hz,1H),5.02(s,2H),4.81(s,2H),2.68(d,J=6.6Hz,2H),1.07–0.97(m,1H),0.56(d,J=7.6Hz,2H),0.15(d,J=4.6Hz,2H).
13C NMR(101MHz,CDCl
3)δ158.4,157.1,152.2,151.6,150.3,135.9,129.0,122.6,121.3,119.2, 117.4,114.5,112.2,110.7,107.2,82.0,56.5,49.9,9.6,3.6.HRMS(ESI)m/z:Calcd for C21H16Cl2NO4(M+H)
+416.0451;Found 416.0446.
实施例75 2-(环丙基)-10-甲氧基-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪13酮(化合物S75)的制备
采用类似于实施例68的方法制备,不同之处在于以2,4-二甲氧基苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.87(d,J=8.7Hz,1H),7.34(d,J=8.9Hz,1H),7.03–6.91(m,2H),6.85(d,J=8.9Hz,1H),5.02(s,2H),4.84(s,2H),3.91(s,3H),2.69(d,J=6.6Hz,2H),1.11–0.96(m,1H),0.56(d,J=7.5Hz,2H),0.16(d,J=4.7Hz,2H).
13C NMR(101MHz,CDCl
3)δ163.0,161.1,158.4,155.4,151.8,149.7,122.8,121.8,115.8,114.2,113.1,110.3,105.8,104.0,101.0,81.9,56.4,55.8,50.0,9.6,3.6.HRMS(ESI)m/z:Calcd for C22H20NO5(M+H)
+378.1336;Found378.1333.
实施例76 2-环己基-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪13酮(化合物S76)的制备
采用类似于实施例78的方法制备,不同之处在于以环己胺代替环丙基甲胺,其余所需原料,试剂以及制备方法与实施例78相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.99(d,J=7.7Hz,1H),7.58(t,J=7.8Hz,1H),7.46(d,J=8.3Hz,1H),7.38(t,J=8.3Hz,2H),6.88(d,J=8.8Hz,1H),5.04(s,2H),4.84(s,2H),2.75(t,J=10.6Hz,1H),2.01(d,J=11.2Hz,2H),1.76(d,J=12.0Hz,2H),1.43–1.08(m,6H).
13C NMR(101MHz,CDCl
3)δ160.4,158.2,153.5,152.8,150.0,131.8,124.5,121.8,121.2,117.2,116.8,116.0,112.6,110.3,106.6,80.4,59.2,47.1,31.6,25.9,25.6.HRMS(ESI)m/z:Calcd for(M+H)
+376.1543;Found 376.1562.
实施例77 2-环戊基-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪13酮(化合物S77)的制备
采用类似于实施例78的方法制备,不同之处在于以环戊胺代替环丙基甲胺,其余所需原料,试剂以及制备方法与实施例78相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.99(d,J=7.6Hz,1H),7.58(t,J=7.5Hz,1H),7.47(d,J=8.2Hz,1H),7.39(d,J=8.1Hz,2H),6.91(d,J=8.9Hz,1H),4.98(s,2H),4.83(s,2H),3.22(s,1H),1.99(s,2H),1.74(s,2H),1.56(s,4H).
13C NMR(101MHz,CDCl
3)δ160.4,158.1,153.5,152.4,150.1,131.8,124.5,121.8,121.5,117.2,116.5,114.8,112.5,110.4,106.6,81.7,60.1,49.0,31.4,23.7.HRMS(ESI)m/z:Calcd for C22H20NO4 (M+H)
+362.1387;Found 362.1400.
实施例78 2-(环丙基甲基)-2,3-二氢-1H,13H-色烯并[4',3':2,3]苯并呋喃并[4,5-E][1,3]恶嗪-13-酮(化合物S78)的制备
采用类似于实施例68的方法制备,不同之处在于以2-甲氧基苯乙酮代替2-甲氧基-5-氯苯乙酮,其余所需原料,试剂以及制备方法与实施例68相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.00(d,J=7.8Hz,1H),7.59(t,J=7.7Hz,1H),7.47(d,J=8.3Hz,1H),7.43–7.36(m,2H),6.90(d,J=8.9Hz,1H),5.03(s,2H),4.86(s,2H),2.70(d,J=6.6Hz,2H),1.09–0.97(m,1H),0.56(d,J=7.7Hz,2H),0.16(d,J=4.7Hz,2H).
13C NMR(101MHz,CDCl
3)δ160.4,158.0,153.6,151.9,150.1,131.8,124.6,121.8,121.7,117.2,116.6,114.4,112.6,110.6,106.5,82.0,56.5,50.0,9.6,3.6.HRMS(ESI)m/z:Calcd for C21H18NO4(M+H)
+348.1230;Found348.1252.
实施例79 8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S79)的制备
采用类似于实施例1的方法制备,不同之处在于进行第一步合成时以邻甲氧基苯乙酮代替苯乙酮,合成5-羟基-2-(2-甲氧基苯基)苯并呋喃-3-羧酸乙酯后,将化合物溶于DCM中,氮气保护,0℃冰水浴条件下缓慢滴加1mmol/mL的BBr
3·DCM,滴加完毕室温搅拌5h,乙醇淬灭,另加5mL乙醇加热回流5h,减压浓缩除去溶剂,二氯甲烷(50mL×3)萃取,分离有机相减压浓缩,快速柱纯化(石油醚:乙酸乙酯=10:1)得中间体;之后与甲醛,哌啶回流反应,得终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ7.92(d,J=7.6Hz,1H),7.61(t,J=7.7Hz,1H),7.45(d,J=8.9Hz,1H),7.42–7.36(m,2H),6.94(d,J=8.9Hz,1H),4.71(s,2H),2.96(br,4H),1.83–1.70(m,4H),1.61(br,2H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ161.9,159.9,157.5,154.1,150.2,133.2,125.8,124.2,122.6,117.7,116.9,113.5,112.9,112.3,106.6,56.6,54.0,25.1,23.6.HRMS(ESI)m/z:Calcd for C21H20NO4(M+H)
+350.1387;Found 350.1389.
实施例80 3-溴-8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S80)的制备
采用类似于实施例79的方法制备,不同之处在于以2-甲氧基-4-溴苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.87(d,J=8.4Hz,1H),7.66(s,1H),7.52(d,J=8.3 Hz,1H),7.43(d,J=8.9Hz,1H),6.97(d,J=8.9Hz,1H),5.30(br,1H),4.66(s,2H),2.51(br,4H),1.67-1.49(m,6H).
13C NMR(101MHz,CDCl
3)δ160.0,157.7,157.5,153.5,149.5,128.0,125.7,122.8,122.4,120.3,116.8,114.9,111.6,111.1,106.2,58.4,53.6,25.8,23.9.HRMS(ESI)m/z:Calcd for(M+H)
+428.0492;Found 428.0464.
实施例81 3-氟-8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S81)的制备
采用类似于实施例79的方法制备,不同之处在于以2-甲氧基-4-氟苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例79相同,得固体终产物。
1H NMR(400MHz,CDCl
3/MeOD=4/1)δ8.04(dd,J=8.4,6.1Hz,1H),7.44(d,J=8.9Hz,1H),7.25–7.14(m,2H),6.90(d,J=8.9Hz,1H),4.65(d,J=3.8Hz,2H),2.68(br,4H),1.71–1.61(m,4H),1.55(br,2H).
13C NMR(101MHz,CDCl
3/MeOD=4/1)δ165.4(d,J
C-F=253.6Hz),161.3,159.2,158.1,155.2(d,J
C-F=13.0Hz),150.1,124.4(d,J
C-F=10.4Hz),123.1,117.1,114.9,113.7(d,J
C-F=23.3Hz),112.0,110.0,105.5,105.1(d,J
C-F=26.2Hz),58.8,54.1,26.2,24.3.HRMS(ESI)m/z:Calcd for C21H19FNO4(M+H)
+368.1293;Found 368.1307.
实施例82 8-羟基-2-甲基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S82)的制备
采用类似于实施例79的方法制备,不同之处在于以5-甲基-2-甲氧基-苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例79相同,得固体终产物。
1H NMR(400MHz,CDCl
3)δ9.47(br,1H),7.78(s,1H),7.47–7.30(m,3H),6.94(d,J=8.8Hz,1H),4.68(s,2H),3.18–2.29(m,7H),1.90–1.20(m,6H).
13C NMR(101MHz,CDCl
3)δ160.7,158.5,157.3,151.7,149.4,134.4,132.9,122.7,121.5,116.7,116.3,114.9,112.2,110.9,106.0,58.5,53.6,25.9,23.9,21.0.HRMS(ESI)m/z:Calcd for C22H22NO4(M+H)
+364.1543,Found 364.1532.
实施例83 8-羟基-2-甲氧基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S83)的制备
采用类似于实施例79的方法制备,不同之处在于以2,5-二甲氧基-苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.85(br,1H),7.57–7.34(m,3H),7.15(d,J=8.7Hz,1H),6.96(dd,J=8.3,3.4Hz,1H),4.70(d,J=2.8Hz,2H),3.93(d,J=3.0Hz,3H),3.05–2.36(m,4H),1.85–1.42(m,6H).
13C NMR(101MHz,CDCl
3)δ160.6,158.4,157.3,156.3,149.4,148.0,122.7,120.3,118.3,116.4,114.9,112.7,110.9,106.3, 103.2,58.4,55.9,53.6,25.9,23.9.HRMS(ESI)m/z:Calcd for C22H22NO5(M+H)
+380.1492;Found 380.1507.
实施例84 8-羟基-3-甲氧基-(7-(1-哌啶基)亚甲基)-6H-苯并呋喃[3,2h]吡喃-6-酮(化合物S84)的制备
采用类似于实施例79的方法制备,不同之处在于以2,4-二甲氧基-苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ7.86(d,J=8.8Hz,1H),7.45(d,J=8.9Hz,1H),6.98(d,J=8.8Hz,1H),6.93(d,J=8.8Hz,2H),4.75(s,2H),3.90(s,3H),3.00(br,4H),1.81–1.73(m,4H),1.62(s,2H).
13C NMR(101MHz,MeOD)δ164.4,162.7,160.3,157.0,156.0,149.9,124.5,123.7,115.9,114.2,113.4,111.8,106.0,104.0,101.6,56.3,53.9,24.9,23.4.HRMS(ESI)m/z:Calcd for C22H22NO5(M+H)
+380.1492;Found380.1494.
实施例85 3,8-二羟基-4,7-二(1-哌啶基)亚甲基)-6H-苯并呋喃并[3,2-c]苯并吡喃-6-酮(化合物S85)的制备
采用类似于实施例79的方法制备,不同之处在于以4-羟基-3-甲基哌啶基-2-甲氧基苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ7.71(d,J=8.7Hz,1H),7.37(d,J=8.8Hz,1H),6.83(d,J=8.9Hz,1H),6.73(d,J=8.7Hz,1H),4.69(s,2H),4.11(s,2H),3.02–2.65(m,8H),1.76–1.47(m,12H).
实施例86 3,8-二羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S86)的制备
采用S84为原料,在三溴化硼,二氯甲烷做溶剂下,生成最终产物。
1H NMR(400MHz,CDCl3/MeOD=3/1)δ7.77(d,J=8.6Hz,1H),7.45(d,J=8.9Hz,1H),7.02(d,J=8.8Hz,1H),6.89(d,J=8.6Hz,1H),6.82(s,1H),4.85(s,2H),3.15(br,4H),1.82(br,4H),1.62(br,2H).
13C NMR(101MHz,CDCl3/MeOD=3/1)δ163.09(s),162.77(s),160.46(s),155.85(s),155.80(s),149.46(s),124.72(s),123.57(s),115.31(s),114.77(s),113.85(s),109.75(s),104.41(s),103.43(s),102.78(s),54.70(s),53.46(s),23.67(s),22.59(s).
实施例87 2,8-二羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S87)的制备
采用S83为原料,在三溴化硼,二氯甲烷做溶剂下,生成最终产物。
1H NMR(400MHz,CDCl3/MeOD=2/1)δ7.58(d,J=8.9Hz,1H),7.36(d,J=2.5Hz,1H), 7.32(d,J=9.0Hz,1H),7.13(dd,J=9.0,2.6Hz,1H),7.06(d,J=9.0Hz,1H),4.89(s,2H),3.19(br,4H),1.83(br,4H),1.66(br,2H).
实施例88 9-溴-8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S88)的制备
采用S79化合物作为原料,二氯甲烷做溶剂,滴加液溴(1.2eq),室温反应过夜,硫代硫酸钠淬灭,二氯甲烷萃取,无水硫酸钠干燥,减压浓缩,柱纯化,得最终产物。
1H NMR(400MHz,MeOD)δ8.01(dd,J=7.8,1.2Hz,1H),7.79(s,1H),7.67–7.59(m,1H),7.49–7.37(m,3H),4.82(s,2H),2.81(br,4H),1.65(br,6H).
13C NMR(101MHz,MeOD)δ161.35(s),159.03(s),156.59(s),153.62(s),148.28(s),132.60(s),125.24(s),122.58(s),122.25(s),117.30(s),115.40(s),113.43(s),112.51(s),111.94(s),105.82(s),58.56(s),53.35(s),25.23(s),23.56(s).
实施例89 8-羟基-9-甲氧基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S89)的制备
采用S79化合物作为原料,溶于DMF中,加入氯化亚铜,甲醇钠,回流5h,TLC纯化,得最终产物。
1H NMR(400MHz,MeOD)δ7.97(d,J=7.6Hz,1H),7.59(t,J=7.6Hz,1H),7.49–7.37(m,2H),7.24(s,1H),4.86(s,2H),3.96(s,3H),3.07(br,3H),1.80(s,4H),1.62(br,2H).
13C NMR(101MHz,MeOD)δ160.22(s),159.95(s),153.14(s),149.87(s),149.00(s),146.97(s),132.16(s),125.44(s),121.91(s),117.39(s),115.77(s),112.71(s),109.98(s),106.54(s),96.43(s),56.59(s),55.43(s),53.62(s),24.10(s),22.85(s).
实施例90 8-羟基-9-硝基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S90)的制备
采用S79化合物作为原料,溶于醋酸中,滴加硝酸,室温反应1h,反应毕,TLC纯化,得终产物。
1H NMR(400MHz,CDCl
3)δ8.24(s,1H),8.06(d,J=7.8Hz,1H),7.69(t,J=7.7Hz,1H),7.51(d,J=8.4Hz,1H),7.46(t,J=7.6Hz,1H),4.97(s,2H),2.93(br,4H),1.89–1.75(m,4H),1.62(br,2H).
13C NMR(101MHz,CDCl
3)δ165.06(s),162.08(s),159.02(s),154.14(s),143.95(s),136.42(s),133.86(s),129.82(s),125.58(s),122.92(s),117.51(s),114.08(s),112.05(s),110.29(s),104.72(s),57.00(s),52.76(s),23.59(s),22.48(s).
实施例91 8,9-二羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S91)的制备
采用S89化合物作为原料,二氯甲烷做溶剂,滴加BBr3,室温反应过夜, 乙醇淬灭,二氯甲烷萃取,无水硫酸钠干燥,减压浓缩,柱纯化,得最终产物。
1H NMR(400MHz,MeOD)δ8.01(d,J=7.8Hz,1H),7.67(t,J=7.6Hz,1H),7.57–7.42(m,2H),7.25(s,1H),4.91(s,2H),3.64(d,J=12.4Hz,2H),3.20(t,J=11.9Hz,2H),1.98(d,J=14.1Hz,2H),1.86–1.69(m,3H),1.62(t,J=12.8Hz,1H).
13C NMR(101MHz,MeOD)δ161.16(s),160.72(s),154.22(s),151.09(s),147.58(s),146.84(s),133.12(s),126.43(s),122.65(s),118.16(s),116.50(s),113.55(s),109.00(s),107.95(s),100.92(s),54.26(s),53.93(s),23.93(s),22.79(s).
实施例92 10-溴-8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S92)的制备
采用类似于实施例79的方法制备,不同之处在于以溴代苯醌代替苯醌,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ8.08(d,J=7.7Hz,1H),7.64(t,J=7.7Hz,1H),7.51–7.39(m,2H),7.18(s,1H),4.79(s,2H),2.90(br,4H),1.76(s,4H),1.59(br,2H).
13C NMR(101MHz,MeOD)δ161.74(s),159.28(s),157.95(s),153.78(s),146.93(s),133.16(s),125.47(s),124.85(s),122.62(s),119.60(s),117.39(s),112.23(s),111.09(s),106.67(s),105.51(s),55.96(s),53.54(s),24.41(s),23.04(s).
实施例93 10-氯-8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S93)的制备
采用类似于实施例79的方法制备,不同之处在于以氯代苯醌代替苯醌,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ8.06(d,J=7.6Hz,1H),7.62(t,J=7.9Hz,1H),7.50–7.37(m,2H),6.91(s,1H),4.68(s,2H),2.71(br,4H),1.80–1.47(m,6H).HRMS(ESI)m/z:Calcd for C21H19ClNO4(M+H)
+384.0997,Found 384.1014.
实施例94 8-羟基-10-甲基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S94)的制备
采用类似于实施例79的方法制备,不同之处在于以甲基苯醌代替苯醌,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.03(d,J=7.8Hz,1H),7.58(t,J=7.7Hz,1H),7.46(d,J=8.3Hz,1H),7.38(t,J=7.5Hz,1H),6.79(s,1H),4.65(s,2H),3.14–2.20(m,7H),1.86–1.40(br,6H).
13C NMR(101MHz,CDCl
3)δ160.3,158.4,157.0,153.3,148.5,131.6,124.4,122.1,121.8,121.4,117.5,117.0,112.6,112.1,106.3,58.2,53.5,25.8,23.9,14.9.HRMS(ESI)m/z:Calcd for364.1525(M+H)
+C22H22NO4;Found 364.1543.
实施例95 10-叔丁基-8-羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S95)的制备
采用类似于实施例79的方法制备,不同之处在于以叔丁基苯醌代替苯醌,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl3/MeOD=6/1)δ8.06(dd,J=7.8,1.3Hz,1H),7.67–7.60(m,1H),7.51–7.42(m,2H),6.90(s,1H),4.68(s,2H),2.70(br,4H),1.69(br,4H),1.56(s,11H).
13C NMR(101MHz,MeOD)δ160.49(s),159.27(s),156.92(s),153.61(s),148.24(s),135.33(s),132.20(s),125.06(s),123.30(s),122.05(s),117.22(s),114.40(s),112.85(s),112.21(s),106.10(s),58.39(s),53.86(s),34.64(s),30.06(s),26.05(s),24.12(s).
实施例96 8-羟基-9,10-二甲基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S96)的制备
采用类似于实施例79的方法制备,不同之处在于以二甲基苯醌代替苯醌,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ7.97(dd,J=7.8,1.3Hz,1H),7.56–7.49(m,1H),7.39(d,J=8.1Hz,1H),7.34(t,J=7.8Hz,1H),4.56(s,2H),2.49–2.41(m,7H),2.23(s,3H),1.61(br,6H).
13C NMR(101MHz,MeOD)δ159.90(s),159.12(s),155.11(s),153.24(s),149.00(s),131.63(s),124.70(s),124.66(s),121.88(s),120.05(s),119.26(s),116.99(s),112.80(s),111.22(s),106.32(s),58.28(s),53.60(s),25.93(s),24.06(s),12.12(s),11.96(s).
实施例97 8-羟基-7-(哌啶-1-亚甲基)苯并呋喃[3,2-c]喹啉-6(5H)-酮(化合物S97)的制备
97.1以邻溴苯乙酮为原料,甲苯中加入2.5eq的NaH,2.0eq的碳酸二乙酯,氮气保护下70℃加热回流20min,反应毕,待冷至室温加入冰水,加入冰醋酸至体系中性,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,粗品经柱层析(石油醚:乙酸乙酯=40:1)得化合物97-1,邻溴苯甲酰乙酸乙酯;
97.2将邻溴苯甲酰乙酸乙酯,与5%的三氟甲磺酸铜溶解于甲苯中,氮气保护的条件下缓慢滴加0.6eq的1,4-苯醌,加热回流10h,冷却至室温。NH
4Cl淬灭,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,蒸去溶剂乙酸乙酯后所得粗产物用硅胶柱层析纯化(石油醚:乙酸乙酯=20:1) 得化合物97-2;
97.3化合物97-2与Cu
2O溶于NMP中,加入0.6eq的NH
3·H
2O密闭反应,反应7h后EtOH淬灭,并另加适量EtOH回流3h,反应毕,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得得化合物97-3;
97.4将化合物97-3与5.0eq的CH
2O,5.0eq的哌啶加入到乙醇溶剂中,氮气保护下加热回流3h,反应完毕,乙酸乙酯(50mL×3)萃取,分出有机层,饱和食盐水10ml洗涤,无水硫酸钠干燥,硅胶柱层析纯化(石油醚:乙酸乙酯=10:1)得终产物。1H NMR(400MHz,CDCl3/MeOD=10/1)δ7.99(d,J=8.0Hz,1H),7.47–7.40(m,1H),7.37–7.30(m,2H),7.22(t,J=7.2Hz,1H),6.83(dd,J=8.8,3.3Hz,1H),4.78(s,2H),2.52(br,4H),1.57(br,6H).13C NMR(101MHz,CDCl3/MeOD=10/1)δ160.59,159.87,156.37,149.55,137.69,130.66,123.49,122.84,121.76,115.80,115.71,114.87,111.88,111.03,110.87,59.07,53.61,25.81,23.96.
实施例98 8-羟基-7-(哌啶-1-亚甲基)苯并吡喃[4,3-b]吲哚-6(11H)-酮(化合物S98)的制备
采用类似于实施例25的方法制备,不同之处在于25.1中邻甲氧基苯甲酰乙酸乙酯代替苯甲酰乙酸乙酯,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,DMSO)δ8.27(br,1H),8.21(d,J=7.6Hz,1H),7.61(t,J=7.6Hz,1H),7.53–7.41(m,3H),6.93(d,J=8.6Hz,1H),4.79(s,2H),2.75(br,4H),1.61(br,4H),1.49(br,2H).
13C NMR(101MHz,DMSO)δ158.34(s),154.50(s),152.26(s),142.29(s),132.15(s),130.70(s),124.54(s),124.21(s),122.51(s),116.68(s),115.11(s),112.87(s),112.75(s),111.48(s),99.89(s),56.12(s),52.74(s),24.54(s),22.96(s).
实施例99 8-羟基-3-甲氧基-7-(哌啶-1-亚甲基)苯并吡喃[4,3-b]吲哚-6(11H)-酮(化合物S99)的制备
采用类似于实施例25的方法制备,不同之处在于以2-甲氧基-4-甲氧基苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,DMSO)δ13.26(s,1H),8.21(d,J=9.4Hz,1H),7.56(d,J=8.7Hz,1H),7.17–7.05(m,3H),4.95(s,2H),3.90(s,3H),1.86–1.44(m,7H).
13C NMR(101MHz,MeOD)δ124.34,116.02,114.83,113.98,101.94,56.39,53.93, 49.59,49.44,49.23,49.01,48.80,48.59,48.38,23.99,22.94.
实施例100 8-羟基-2-甲基-7-(哌啶-1-亚甲基)苯并吡喃[4,3-b]吲哚-6(11H)-酮(化合物S100)的制备
采用类似于实施例25的方法制备,不同之处在于以2-甲氧基-5-甲基苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,MeOD)δ7.88(s,1H),7.55(d,J=8.8Hz,1H),7.39(dd,J=8.6,1.7Hz,1H),7.34(d,J=8.5Hz,1H),7.06(d,J=8.8Hz,1H),4.99(s,2H),3.61(t,J=6.1Hz,3H),3.12(d,J=13.0Hz,2H),1.98(d,J=17.2Hz,2H),1.80(t,J=16.5Hz,4H),1.56(d,J=8.3Hz,2H).
13C NMR(101MHz,MeOD)δ161.15,152.92,150.10,143.27,134.07,132.28,131.49,124.87,121.44,116.18,114.79,113.68,111.87,105.74,99.83,52.34,51.92,22.20,21.04,19.76.
实施例101 3-溴-8-羟基-7-(哌啶-1-亚甲基)苯并吡喃[4,3-b]吲哚-6(11H)-酮(化合物S101)的制备
采用类似于实施例25的方法制备,不同之处在于以2-甲氧基-4-溴苯乙酮代替邻甲氧基苯乙酮,其余所需原料,试剂以及制备方法与实施例25相同,得终产物。
1H NMR(400MHz,DMSO)δ13.53(s,1H),8.21(d,J=8.4Hz,1H),7.78(d,J=1.8Hz,1H),7.64(dd,J=8.4,1.8Hz,1H),7.57(d,J=8.8Hz,1H),7.11(d,J=8.8Hz,1H),4.90(s,2H),1.79–1.61(m,4H),1.59–1.44(m,2H).
13C NMR(101MHz,MeOD)δ160.04,152.93,151.69,142.09,132.13,127.25,124.41,123.62,123.11,119.28,114.95,114.13,111.08,105.55,99.28,52.41,51.94,22.10,21.02,19.76.
实施例102 8-羟基-7-(哌啶-1-亚甲基)-6H-苯并[4,5]噻吩并[3,2-c]苯并吡喃-6-酮(化合物S102)的制备
采用类似于实施例36的方法制备,不同之处在于以2-甲氧基苯乙酰甲酯代替苯乙酰甲酯,其余所需原料,试剂以及制备方法与实施例36相同,得终产物。
1H NMR(400MHz,MeOD)δ7.80–7.71(m,1H),7.53(t,J=7.8Hz,1H),7.39–7.28(m,1H),7.24(d,J=8.9Hz,1H),4.96(s,1H),3.49(d,J=11.8Hz,1H),3.02(t,J=12.2Hz,1H),1.87(d,J=13.1Hz,1H),1.74(t,J=12.7Hz,1H),1.54–1.37(m,1H).
13C NMR(101MHz,MeOD)δ158.98(s),157.58(s),155.23(s),150.86(s),137.07(s),132.41(s),130.26(s),125.94(s),125.37(s),124.30(s),118.56(s),116.81(s),116.79(s),116.53(s),110.48(s),53.11(s),52.95(s),23.07(s),21.78(s).
实施例103 8-羟基-7-(吡咯烷-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S103)的制备
采用类似于实施例79的方法制备,不同之处在于以吡咯代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ8.02(d,J=7.8Hz,1H),7.65(t,J=7.8Hz,1H),7.58(d,J=8.9Hz,1H),7.50-7.42(m,2H),7.10(d,J=8.9Hz,1H),5.03(s,2H),3.38(s,4H),2.11(s,4H).
13C NMR(101MHz,MeOD)δ162.10(s),159.99(s),155.79(s),153.93(s),150.03(s),133.20(s),125.70(s),124.61(s),122.57(s),117.61(s),116.23(s),114.67(s),112.55(s),110.46(s),106.19(s),54.22(s),52.17(s),23.53(s).
实施例104 8-羟基-7-(4-甲基哌啶-1亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S104)的制备
采用类似于实施例79的方法制备,不同之处在于以对甲基哌啶代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,MeOD)δ7.96(d,J=7.7Hz,1H),7.56(t,J=7.5Hz,1H),7.47–7.28(m,3H),6.89(d,J=8.8Hz,1H),4.01(s,2H),2.98(d,J=10.5Hz,2H),2.29(t,J=10.3Hz,2H),1.66(d,J=13.0Hz,2H),1.44(br,1H),1.25(q,J=11.6Hz,2H),0.91(d,J=6.2Hz,3H).
13C NMR(101MHz,MeOD)δ160.98(s),158.78(s),157.03(s),153.37(s),149.56(s),132.03(s),124.76(s),122.58(s),121.97(s),117.01(s),116.45(s),114.77(s),112.49(s),111.21(s),106.02(s),58.00(s),53.12(s),34.12(s),30.43(s),21.60(s).
实施例105 8-羟基-7-(3-甲基哌啶-1亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S105)的制备
采用类似于实施例79的方法制备,不同之处在于以间甲基哌啶代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,DMSO)δ8.05(d,J=8.0Hz,1H),7.72(t,J=7.3Hz,1H),7.60(dd,J=13.6,8.5Hz,2H),7.49(t,J=7.5Hz,1H),6.92(d,J=8.9Hz,1H),4.58(q,J=14.0Hz,2H),2.89(br,2H),2.14(t,J=11.0Hz,1H),1.87(t,J=10.6Hz,1H),1.68(br,3H),1.49(d,J=11.7Hz,1H),0.97(d,J=9.5Hz,1H),0.85(d,J=6.1Hz,3H).
13C NMR(101MHz,DMSO)δ160.26(s),157.24(s),156.49(s),152.83(s),148.64(s),132.38(s),124.89(s),122.26(s),121.77(s),116.70(s),115.93(s),114.44(s),111.73(s),111.23(s),105.43(s),60.07(s),57.05(s),52.56(s),31.90(s),30.62(s),24.70(s),19.13(s).
实施例106 8-羟基-7-(2-甲基哌啶-1亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S106)的制备
采用类似于实施例79的方法制备,不同之处在于以邻甲基哌啶代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,DMSO)δ8.05(d,J=8.0Hz,1H),7.72(t,J=7.1Hz,1H),7.63–7.56(m,2H),7.50(t,J=7.5Hz,1H),6.88(d,J=8.9Hz,1H),4.71(dd,J=33.3,14.8Hz,2H),2.83(d,J=12.4Hz,1H),2.68(br,1H),2.34(t,J=Hz,1H),1.82–1.28(m,6H),1.16(d,J=6.1Hz,3H).
13C NMR(101MHz,DMSO)δ160.20(s),157.31(s),156.75(s),152.80(s),148.57(s),132.36(s),124.89(s),121.86(s),121.75(s),116.69(s),116.03(s),114.95(s),111.73(s),110.97(s),105.40(s),55.36(s),53.71(s),50.38(s),32.98(s),25.11(s),21.86(s),16.93(s).
实施例107 1-(8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)吡咯烷-2-酮(化合物S107)的制备
采用类似于实施例79的方法制备,不同之处在于以吡咯烷酮代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl
3)δ10.06(s,1H),8.04(d,J=7.7Hz,1H),7.63(t,J=7.8Hz,1H),7.51(dd,J=12.6,8.7Hz,2H),7.43(t,J=7.5Hz,1H),7.14(d,J=8.9Hz,1H),5.44(s,2H),3.65(t,J=7.1Hz,2H),2.45(t,J=8.2Hz,2H),2.07–1.92(m,2H).
13C NMR(101MHz,CDCl
3)δ177.95(s),161.40(s),158.76(s),155.36(s),153.54(s),149.66(s),132.31(s),124.94(s),124.01(s),122.15(s),118.61(s),117.22(s),115.90(s),112.85(s),112.58(s),106.01(s),48.26(s),39.61(s),30.59(s),18.03(s).
实施例108 1-(8-甲氧基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)吡咯烷-2-酮(化合物S108)的制备
采用实施例107的化合物,溶于二氯甲烷中在碘甲烷作用下生成终产物。
1H NMR(400MHz,CDCl
3)δ8.00(d,J=7.2Hz,1H),7.63–7.54(m,2H),7.49–7.35(m,2H),7.05(d,J=9.0Hz,1H),5.40(s,2H),3.88(s,3H),3.16(t,J=7.0Hz,2H),2.37(t,J=8.1Hz,2H),1.90–1.79(m,2H).
13C NMR(101MHz,CDCl
3)δ174.08(s),161.79(s),158.15(s),156.64(s),153.76(s),150.02(s),132.44(s),125.32(s),124.76(s),122.13(s),118.87(s),117.19(s),112.35(s),111.52(s),110.88(s),106.05(s),77.16(s),56.91(s),46.38(s),39.03(s),31.31(s),17.87(s).
实施例109 1-(8-羟基-(2-甲氧基乙氧基)-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)吡咯烷-2-酮(化合物S109)的制备
采用实施例107的化合物,溶于二氯甲烷中在溴乙基甲醚作用下生成终产物。
1H NMR(400MHz,CDCl
3)δ7.95(t,J=7.2Hz,1H),7.62–7.46(m,2H),7.44–7.31(m,2H),7.10–6.98(m,1H),5.43–5.32(m,2H),4.18–3.99(m,2H),3.85–3.69(m,2H),3.51–3.37(m,3H),3.19–3.06(m,2H),2.33(t,J=6.4Hz,2H),1.87–1.76(m,2H).
13C NMR(101MHz,CDCl
3)δ173.84(s),161.62(s),158.00(s),155.92(s),153.62(s),150.07(s),132.36(s),125.16(s),124.70(s),122.04(s),119.28(s),117.05(s),112.27(d,J=13.9Hz),111.50(s),105.94(s),71.20(s),69.33(s),59.21(s),46.22(s),39.03(s),31.16(s),17.76(s).
实施例110 1-(8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)哌啶-2-酮(化合物S110)的制备
采用类似于实施例79的方法制备,不同之处在于以环己内酰胺代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.04(dd,J=7.8,1.0Hz,1H),7.65–7.59(m,1H),7.54-7.47(m,2H),7.42(t,J=7.6Hz,1H),7.10(d,J=8.9Hz,1H),5.62(s,2H),3.47(t,J=5.2Hz,2H),2.46(t,J=6.4Hz,2H),1.81–1.63(m,4H).
13C NMR(101MHz,CDCl
3)δ172.86(s),161.45(s),158.79(s),155.59(s),153.44(s),149.38(s),132.30(s),124.91(s),124.55(s),122.13(s),117.95(s),117.15(s),115.22(s),112.90(s),112.51(s),105.96(s),47.54(s),43.30(s),31.94(s),22.82(s),20.62(s).
实施例111 1-(8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)环己亚胺-2-酮(化合物S111)的制备
采用类似于实施例79的方法制备,不同之处在于以环庚内酰胺代替哌啶,其余所需原料,试剂以及制备方法与实施例79相同,得终产物。
1H NMR(400MHz,CDCl
3)δ10.16(s,1H),8.03(d,J=7.7Hz,1H),7.62(t,J=7.5Hz,1H),7.49(t,J=10.0Hz,2H),7.42(t,J=7.4Hz,1H),7.09(d,J=8.9Hz,1H),5.54(s,2H),3.46(s,2H),2.60(s,2H),1.70(s,4H),1.60(s,2H).
13C NMR(101MHz,CDCl
3)δ178.09(s),160.28(s),157.76(s),154.45(s),152.26(s),148.29(s),131.14(s),123.77(s),122.96(s),120.97(s),116.51(s),116.01(s),114.36(s),111.57(s),111.36(s),104.70(s),47.49(s),42.58(s),35.37(s),28.73(s),26.27(s),22.20(s).
实施例112 1-(8-甲氧基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)哌啶-2-酮(化合物S112)的制备
采用类似于实施例108的方法制备,不同之处在于以S110为原料得终产物。
1H NMR(400MHz,CDCl
3)δ8.02(d,J=7.6Hz,1H),7.65–7.54(m,2H),7.47(d,J=8.3Hz,1H),7.40(t,J=7.5Hz,1H),7.06(d,J=8.9Hz,1H),5.60(s,2H),3.89(s,3H),3.16(t,J=5.3Hz,2H),2.40(t,J=5.9Hz,2H),1.77–1.62(m,4H).
13C NMR(101MHz,CDCl
3)δ169.15(s),161.78(s),158.22(s),156.82(s),153.82(s),150.10(s),132.37(s),125.97(s),124.70(s),122.12(s),120.15(s),117.23(s),112.49(s),111.27(s),111.00(s),106.38(s),56.93(s),46.92(s),42.92(s),32.72(s),23.45(s),21.53(s).
实施例113 1-(8-乙氧基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)哌啶-2-酮(化合物S113)的制备
采用类似于实施例112的方法制备,不同之处在于以碘乙烷代替碘甲烷,其余所需原料,试剂以及制备方法与实施例112相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.01(d,J=7.7Hz,1H),7.60(t,J=7.8Hz,1H),7.53(d,J=8.9Hz,1H),7.46(d,J=8.3Hz,1H),7.39(t,J=7.5Hz,1H),7.03(d,J=9.0Hz,1H),5.60(s,2H),4.07(q,J=6.9Hz,2H),3.15(t,J=5.7Hz,2H),2.40(t,J=6.4Hz,2H),1.76–1.62(m,4H),1.43(t,J=6.9Hz,3H).
13C NMR(101MHz,CDCl
3)δ168.90(s),161.65(s),158.20(s),156.11(s),153.75(s),149.97(s),132.30(s),125.89(s),124.67(s),122.09(s),120.16(s),117.17(s),112.47(s),111.71(s),111.18(s),106.36(s),65.09(s),46.82(s),42.91(s),32.77(s),23.43(s),21.56(s),15.16(s).
实施例114 1-(8-(2-甲氧基乙氧基)-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)哌啶-2-酮(化合物S114)的制备
采用类似于实施例112的方法制备,不同之处在于以溴乙基甲醚代替碘甲烷,其余所需原料,试剂以及制备方法与实施例112相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.99(d,J=7.7Hz,1H),7.58(t,J=7.7Hz,1H),7.52(d,J=8.9Hz,1H),7.44(d,J=8.3Hz,1H),7.37(t,J=7.5Hz,1H),7.05(d,J=8.9Hz,1H),5.59(s,2H),4.13(t,J=4.7Hz,2H),3.78(t,J=4.8Hz,2H),3.44(s,3H),3.14(t,J=5.7Hz,2H),2.38(t,J=6.4Hz,2H),1.77–1.60(m,4H).
13C NMR(101MHz,CDCl
3)δ168.89(s),161.66(s),158.11(s),156.08(s),153.71(s),150.16(s),132.31(s),125.88(s),124.66(s),122.06(s),120.53(s),117.11(s),112.38(s),112.34(s),111.26(s),106.29(s),71.32(s),69.24(s),59.22(s),46.73(s),42.73(s),32.74(s),23.37(s),21.45(s).
实施例115 1-甲基(8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)-1-甲基哌啶-1-季铵盐(化合物S115)的制备
采用S79化合物作为原料,DMF作溶剂在钠氢,碘甲烷的作用下反应30分钟得终产物。
1H NMR(400MHz,CDCl
3)δ8.03(d,J=7.8Hz,1H),7.69(d,J=9.0Hz,1H),7.63(t,J=7.8Hz,1H),7.49(d,J=8.3Hz,1H),7.42(t,J=7.5Hz,1H),7.11(d,J=9.1Hz,1H),5.13(s,2H),4.04(s,3H),3.55(br,2H),2.94(br,2H),2.42(br,2H),1.78(br,4H).
13C NMR(101MHz,CDCl
3)δ161.08(s),158.02(s),155.91(s),152.79(s),148.94(s),131.69(s),125.05(s),123.96(s),121.26(s),116.37(s),113.30(s),111.21(s),109.74(s),109.27(s),105.26(s),55.67(s),52.14(s),51.16(s),21.19(s),20.91(s).
实施例116 1-乙基-1-(8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)-1-甲基哌啶-1-季铵盐(化合物S116)的制备
采用S79化合物作为原料,DMF作溶剂在钠氢,碘乙烷的作用下反应30分钟得终产物。
1H NMR(400MHz,CDCl
3)δ7.99(d,J=7.7Hz,1H),7.68–7.55(m,2H),7.46(d,J=8.4Hz,1H),7.39(t,J=7.4Hz,1H),7.06(d,J=9.1Hz,1H),5.08(s,2H),4.24(q,J=6.7Hz,2H),3.58(br,1H),2.95(br,1H),2.37(br,2H),1.77(br,4H),1.51(t,J=6.8Hz,3H).
13C NMR(101MHz,CDCl
3)δ161.82(s),159.14(s),156.17(s),153.87(s),149.99(s),132.55(s),126.26(s),124.89(s),122.28(s),117.43(s),114.32(s),112.38(s),111.09(s),111.06(s),106.83(s),65.07(s),53.18(s),52.07(s),22.30(s),21.99(s),15.05(s).
实施例117 1-(8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-亚甲基)-1-(2-甲氧基乙基)哌啶-1-季铵盐(化合物S117)的制备
采用S79化合物作为原料,DMF作溶剂在钠氢,溴乙基甲醚的作用下反应30分钟得终产物。
1H NMR(400MHz,CDCl
3)δ11.20(s,1H),8.03(dd,J=7.8,1.1Hz,1H),7.75–7.57(m,2H),7.49(d,J=8.1Hz,1H),7.44–7.37(m,1H),7.13(d,J=9.1Hz,1H),5.14(s,2H),4.40–4.32(m,2H),3.92–3.87(m,2H),3.62(s,2H),3.45(s,4H),2.97(s,2H),2.43(s,2H),1.79(s,6H).
13C NMR(101MHz,CDCl
3)δ162.05(s),159.17(s),156.29(s),153.95(s),150.28(s),132.69(s),126.26(s),125.00(s),122.37(s),117.52(s),114.41(s),112.41(s),111.72(s),111.58(s),106.75(s),71.34(s),68.80(s),59.10(s),53.45(s),52.40(s),22.36(s),22.12(s).
实施例118 8-羟基-7-(哌啶-1-羰基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S118)的制备
采用实施例79中5-羟基-2-(2-甲氧基苯基)苯并呋喃-3-羧酸乙酯中间体,其后续制备方法如下:
118-1.将其溶于二氧六环中,加入水,亚氯酸钠、氨基磺酸,室温下搅拌半小时。TLC检测至反应完全后,加硫代硫酸钠溶液淬灭,用盐酸溶液调pH为弱酸性,加乙酸乙酯萃取,饱和氯化钠溶液洗去水,无水硫酸钠干燥,减压浓缩,得淡黄色固体118-1。
118-2.氮气保护下,将118-1、EDC·HCl、HOBT溶于DMF中,加吡啶、哌啶,室温下搅拌,过夜。TLC检测至反应完全后,加氯化铵溶液淬灭,乙酸乙酯萃取,有机相依次用5%的盐酸溶液、饱和碳酸氢钠溶液、饱和氯化钠溶液洗,无水硫酸钠干燥,减压浓缩,TLC纯化得118-2。
118-3.将化合物118-2溶于DCM中,氮气保护,0℃冰水浴条件下缓慢滴加1mmol/mL的BBr
3·DCM,滴加完毕室温搅拌5h,乙醇淬灭,另加5mL乙醇加热回流5h,减压浓缩除去溶剂,二氯甲烷(50mL×3)萃取,分离有机相减压浓缩,快速柱纯化(石油醚:乙酸乙酯=10:1)得终产物。
1H NMR(400MHz,DMSO)δ9.83(s,1H),8.06(d,J=7.7Hz,1H),7.75–7.70(m,2H),7.57(d,J=8.3Hz,1H),7.50(t,J=7.5Hz,1H),7.07(d,J=9.0Hz,1H),3.77-3.72(m,1H),3.65–3.53(m,1H),3.21–3.02(m,2H),1.84–1.70(m,1H),1.62–1.48(m,3H),1.41–1.31(m,2H).
13C NMR(101MHz,DMSO)δ163.88(s),160.28(s),155.68(s),153.13(s),150.82(s),148.68(s),132.58(s),124.94(s),121.91(s),120.39(s),117.10(s),116.98(s),115.37(s),112.22(s),111.81(s),104.89(s),47.00(s),41.50(s),25.41(s),24.54(s),24.24(s).
实施例119 8-甲氧基-7-(哌啶-1-羰基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S119)的制备
采用S118化合物作为原料,在碘甲烷作用下生成最终产物。
1H NMR(400MHz,CDCl
3)δ8.01(d,J=7.8Hz,1H),7.61(dd,J=8.0,4.4Hz,2H),7.47(d,J=8.4Hz,1H),7.39(t,J=7.6Hz,1H),7.08(d,J=9.1Hz,1H),3.91(s,5H),3.28–3.12(m,2H),2.00–1.89(m,1H),1.73–1.59(m,3H),1.53–1.39(m,2H).
13C NMR(101MHz,CDCl
3)δ165.04(s),161.45(s),156.75(s),154.02(s),153.18(s),150.46(s),132.41(s),124.65(s),122.10(s),121.46(s),119.86(s),117.55(s),112.43(s),111.99(s),110.83(s),105.59(s),56.99(s),48.03(s),42.53(s),26.03(s),25.10(s),24.87(s).
实施例120 N-(环丙基甲基)-8-羟基-6-羰基-6H-苯并呋喃[3,2-c]苯并吡喃-7-甲酰胺(化合物S120)的制备
采用类似于实施例118的方法制备,不同之处在于以环丙烷甲基代替118-2的哌啶,其余所需原料,试剂以及制备方法与实施例118相同,得终产物。
1H NMR(400MHz,CDCl
3)δ13.42(s,1H),8.98(s,1H),8.09(d,J=7.9Hz,1H),7.68(dd,J=14.6,8.1Hz,2H),7.52(d,J=8.4Hz,1H),7.47(t,J=7.6Hz,1H),7.18(d,J=9.1Hz,1H),3.45(dd,J=7.0,5.3Hz,2H),1.21–1.13(m,1H),0.56(q,J=5.7Hz,2H),0.33(q,J=5.1Hz,2H).
13C NMR(101MHz,CDCl
3)δ168.89(s),161.83(s),161.33(s),159.74(s),153.04(s),149.43(s),132.99(s),125.28(s),122.44(s),119.45(s),119.34(s),117.10(s),116.97(s),112.19(s),109.91(s),105.65(s),45.44(s),10.24(s),3.87(s).
实施例121 8-羟基-9-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S121)的制备
采用实施例118-1化合物作为原料加入哌啶,醋酸,氰基硼氢化钠,室温下过夜。TLC检测至反应完全后,加乙酸乙酯萃取,饱和氯化钠溶液洗去水,无水硫酸钠干燥,减压浓缩,TLC纯化,接着溶于DCM中,氮气保护,0℃冰水浴条件下缓慢滴加1mmol/mL的BBr
3·DCM,滴加完毕室温搅拌5h,乙醇淬灭,另加5mL乙醇加热回流5h,减压浓缩除去溶剂,二氯甲烷(50mL×3)萃取,分离有机相减压浓缩,快速柱纯化(石油醚:乙酸乙酯=10:1)得终产物。
1H NMR(400MHz,MeOD)δ8.07(s,1H),8.01(d,J=7.6Hz,1H),7.64(t,J=7.8Hz,1H),7.51–7.40(m,3H),4.39(s,2H),3.49(br,2H),2.94(br,2H),1.93(br,6H).
13C NMR(101MHz,MeOD)δ161.04(s),157.87(s),153.72(s),152.82(s),148.39(s),131.81(s),125.34(s),124.32(s),121.26(s),116.61(s),115.27(s),114.00(s),111.50(s),105.48(s),104.30(s),54.47(s),51.83(s),21.93(s),20.84(s).
实施例122 8-羟基-9-(哌啶-1-羰基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S122)的制备
采用实施例118的方法制备,得终产物。
1H NMR(400MHz,DMSO)δ10.12(s,1H),8.04(d,J=7.7Hz,1H),7.73(t,J=7.8Hz,1H),7.66(s,1H),7.60(d,J=8.3Hz,1H),7.50(t,J=7.5Hz,1H),7.43(s,1H),3.61(br,2H),3.21(br,2H),1.55(br,6H).
13C NMR(101MHz,DMSO)δ165.65(s),160.44(s),157.17(s),153.11(s),151.49(s),148.51(s),132.50(s),125.07(s),124.58(s),123.93(s),121.84(s),117.24(s),112.05(s),110.96(s),105.73(s),104.93(s),47.22(s),41.92(s),25.55(s),24.06(s).
实施例123 8-甲氧基-9-(哌啶-1-羰基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S123)的制备
采用实施例S122化合物作为原料加入碘甲烷室温过夜,得终产物。
1H NMR(400MHz,CDCl
3)δ7.98(dd,J=6.3,2.9Hz,2H),7.58(s,1H),7.52–7.45(m,3H),7.40(s,1H),4.40(q,J=7.1Hz,2H),3.92(s,3H),3.77(m,2H),3.21(d,J=4.5Hz,2H),1.67(s,6H),1.39(t,J=7.1Hz,3H).
13C NMR(101MHz,CDCl
3)δ167.18(s),163.99(s),162.12(s),153.03(s),148.36(s),130.52(s),129.69(s),129.64(s),128.58(s),128.19(s),124.85(s),110.39(s),109.00(s),103.75(s),60.84(s),56.18(s),48.20(s),42.83(s),26.48(s),25.79(s),24.77(s),14.32(s).
实施例124 8-(2-甲氧基乙氧基)-9-(哌啶-1-羰基)-6H-苯并呋喃[3,2-c]苯并吡喃-6-酮(化合物S124)的制备
采用类似于实施例123的方法制备,不同之处在于以溴乙基甲醚代替碘甲烷,其余所需原料,试剂以及制备方法与实施例124相同,得终产物。
1H NMR(400MHz,CDCl
3)δ8.02(d,J=7.8Hz,1H),7.66–7.57(m,2H),7.56(s,1H),7.50(d,J=8.4Hz,1H),7.41(t,J=7.5Hz,1H),4.35–4.14(m,2H),3.88–3.68(m,4H),3.43(s,3H),3.33–3.11(m,2H),1.66(br,6H).
13C NMR(101MHz,CDCl
3)δ166.59(s),161.13(s),158.21(s),153.73(s),152.97(s),150.05(s),132.28(s),126.60(s),124.92(s),124.75(s),122.07(s),117.66(s),112.68(s),111.20(s),105.93(s),104.07(s),70.94(s),68.81(s),59.21(s),48.17(s),42.89(s),26.16(s),25.72(s),24.75(s).
实施例125 7-叔丁基-5-羟基-2-(4-甲氧基)-N-甲基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S125)的制备
采用类似于实施例6和实施例19的方法制备,不同之处在于实施例6中以叔丁基苯醌代替苯醌,合成7-叔丁基-5-羟基-2-(4-甲氧基)苯并呋喃-3-羧酸乙酯后再采用类似于实施例19的方法,不同之处在于实施例19-2中以甲胺代替乙胺,其余所需原料,试剂以及制备方法与实施例6和19相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.71(d,J=8.8Hz,2H),6.97(d,J=8.8Hz,2H),6.73(s,1H),6.01(d,J=4.6Hz,1H),3.85(s,3H),3.79(s,2H),2.99(d,J=4.9Hz,3H),2.48(br,4H),1.62(br,4H),1.51(br,2H),1.49(s,9H).
13C NMR(101MHz,CDCl3)δ167.75(s),160.40(s),154.73(s),152.07(s),146.10(s),134.37(s),128.09(s),126.53(s),122.68(s),114.46(s),112.07(s),111.71(s),109.50(s),56.97(s),55.50(s),53.97(s),34.31(s),29.95(s),27.15(s),26.01(s),24.10(s).
实施例126 7-叔丁基-5-羟基-2-(4-羟基)-N-甲基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S126)的制备
采用S125为原料,在三溴化硼,二氯甲烷做溶剂下,生成最终产物。
1H NMR(400MHz,MeOD)δ7.58(d,J=8.7Hz,2H),6.93(d,J=8.7Hz,2H),6.88(s,1H),4.34(s,2H),3.20(br,4H),2.91(s,3H),1.87(br,4H),1.70(br,2H),1.52(s,9H).
13C NMR(101MHz,MeOD)δ169.60(s),160.63(s),156.37(s),155.17(s),147.50(s),138.88(s),129.89(s),128.95(s),121.64(s),116.87(s),111.82(s),111.64(s),105.57(s),53.96(s),53.18(s),35.42(s),30.09(s),26.95(s),24.85(s),23.14(s).
实施例127 7-叔丁基-5-羟基-2-(3-甲氧基)-N-甲基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S127)的制备
采用类似于实施例126的方法制备,不同之处在于以3-甲氧基苯乙酰乙酸乙酯代替4-甲氧基苯乙酰乙酸乙酯,其余所需原料,试剂以及制备方法与实施例126相同,得终产物。1H NMR(400MHz,CDCl3)δ7.29(t,J=7.9Hz,1H),7.23–7.19(m,2H),7.07(s,1H),6.88(dd,J=8.1,1.6Hz,1H),4.05(s,2H),3.77(s,3H),3.02(br,4H),2.90(d,J=4.8Hz,3H),1.74(br,4H),1.42(br,2H),1.40(s,9H).
13C NMR(101MHz,CDCl3)δ167.72(s),159.87(s),154.38(s),153.43(s),146.66(s),137.29(s),130.62(s),130.05(s),126.98(s),119.60(s),115.30(s),113.76(s),112.83(s),112.65(s),105.57(s),55.45(s),53.04(s),52.89(s),34.55(s),29.87(s),27.18(s),24.01(s),22.54(s).
实施例128 7-叔丁基-5-羟基-2-(3-羟基)-N-甲基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S128)的制备
采用S127为原料,在三溴化硼,二氯甲烷做溶剂下,生成最终产物。
1H NMR(400MHz,MeOD)δ7.27(t,J=7.9Hz,1H),7.19–7.11(m,2H),6.88(s,1H),6.85(dd,J=8.1,1.3Hz,1H),4.26(s,2H),3.10(br,4H),2.88(s,3H),1.80(br,4H),1.63(br,2H),1.47(s,9H).
13C NMR(101MHz,MeOD)δ169.25(s),159.12(s),155.28(s),147.64(s),138.97(s),131.61(s),131.10(s),128.72(s),119.22(s),117.98(s),114.75(s),113.59(s),112.35(s),105.83(s),54.04(s),53.26(s),35.42(s),30.10(s),27.07(s),24.84(s),23.12(s).
实施例129 7-叔丁基-5-羟基-2-(2-甲氧基)-N-甲基-4-(哌啶-1-亚甲基)苯并呋喃-3-甲酰胺(化合物S129)的制备
采用类似于实施例126的方法制备,不同之处在于以2-甲氧基苯乙酰乙酸乙酯代替4-甲氧基苯乙酰乙酸乙酯,其余所需原料,试剂以及制备方法与实施例126相同,得终产物。
1H NMR(400MHz,CDCl
3)δ7.60(d,J=7.6Hz,1H),7.46(t,J=7.9Hz,1H),7.28(s,1H),7.11(t,J=7.5Hz,1H),7.01(d,J=8.4Hz,1H),6.70(s,1H),4.34(s,2H),3.85(s,3H),3.32(m,2H),3.10–2.92(m,2H),2.85(d,J=4.8Hz,3H),2.03–1.57(m,6H),1.44(s,9H).
13C NMR(101MHz,CDCl3)δ167.74(s),156.66(s),154.56(s),152.11(s),147.31(s),137.92(s),131.79(s),131.05(s),126.57(s),121.25(s),118.63(s),114.74(s),114.30(s),111.47(s),104.94(s),55.72(s),52.41(s),52.35(s),34.64(s),29.80(s),27.07(s),23.80(s),22.32(s).
实施例130 10-叔丁基-3,8-二羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯丙吡喃-6-酮(化合物S130)的制备
采用类似于实施例86的方法制备,不同之处在于以叔丁基苯醌代替苯醌,其余所需原料,试剂以及制备方法与实施例86相同,得终产物。
1H NMR(400MHz,MeOD)δ7.88(d,J=8.6Hz,1H),7.00(s,1H),6.95(d,J=8.7Hz,1H),6.90(d,J=1.6Hz,1H),4.90(s,2H),3.53(br,2H),3.04(br,2H),1.86(br,6H),1.53(s,9H).
13C NMR(101MHz,MeOD)δ162.86(s),162.52(s),161.14(s),155.97(s),155.25(s),148.06(s),139.32(s),125.74(s),123.65(s),114.96(s),112.54(s),105.44(s),104.59(s),103.61(s),102.92(s),53.30(s),53.15(s),35.07(s),29.90(s),23.02(s),22.12(s).
实施例131 10-叔丁基-2,8-二羟基-7-(哌啶-1-亚甲基)-6H-苯并呋喃[3,2-c]苯丙吡喃-6-酮(化合物S131)的制备
采用类似于实施例86的方法制备,不同之处在于以叔丁基苯醌代替苯醌和2,5-二甲氧基苯乙酸乙酯替代2,4-二甲氧基苯乙酸乙酯,其余所需原料,试剂以及制备方法与实施例86相同,得终产物。1H NMR(400MHz,MeOD)δ7.41(d,J=2.7Hz,1H),7.34(d,J=9.0Hz,1H),7.15(dd,J=9.0,2.8Hz,1H),7.08(s,1H),4.96(s,2H),3.57(d,J=12.6Hz,2H),3.06(t,J=11.9Hz,2H),1.95(d,J=14.2Hz,2H),1.88–1.76(m,3H),1.52(s,10H).13C NMR(100MHz,MeOD)δ161.32(s),160.74(s),155.26(s),154.91(s),148.37(s),147.47(s),139.44(s),125.36(s), 121.53(s),118.52(s),113.42(s),112.76(s),106.39(s),105.87(s),105.53(s),53.20(s),53.00(s),34.98(s),29.75(s),22.85(s),22.01(s).
试验实施例1
本发明提供结构通式(I)(II)(Ⅲ)(Ⅳ)类化合物对结核杆菌H37Rv的MIC
90测试测试
1.1材料:本发明所述部分化合物
结核分枝杆菌H37Rv菌株(于Middlebrook 7H9肉汤培养液中培养)
1.2实验方法
本实验主要以微孔alamar Blue实验的步骤进行:将H37Rv菌株培养至对数生长期,培养液稀释至OD
600=0.001,将100uL稀释后的培养液(约含104个菌落形成单位)注入单个微孔中,100uL的2倍稀释的化合物也注入对应微孔。96孔平板在37℃下培养7天,随后35uL的Alamar蓝/吐温80(2:1.5,V/V)混合溶液加入到各孔中并培养16小时。以在544ex/590em条件下被酶标仪检测并分析得出数据作为化合物90%抑制结核杆菌H37Rv的最低浓度MIC
90。
试验实施例2
本发明提供部分结构通式(I)(II)(Ⅲ)(Ⅳ)类化合物的血清抑制滴定实验(下称SIT实验),用以表征其口服生物利用度和动物体内有效。
实验材料及试剂:六周大雌性BALB/c小鼠30只,0.5%羧甲基纤维素,1mL注射器若干,结核分枝杆菌H37Rv菌株(于Middlebrook 7H9肉汤培养液中培养),本发明中部分化合物(具体化合物见表5),异烟肼,alamar Blue试剂。
实验方法:将待测化合物用0.5%的羧甲基纤维素(CMC)制备为10mg/mL的均匀悬浮液。将小鼠分为xx组,每组3只,每组依小鼠质量按100mg/kg比例分别喂饲不同化合物,异烟肼同样以100mg/kg对一组小鼠喂饲以作阳性对照,0.5%羧甲基纤维素以100mg/kg喂饲作空白对照。60min后处死小鼠,收集小鼠的心脏血液,分离血清供下一步实验。将空白组及血清用不含吐温的Middlebrook 7H9肉汤培养液在96孔平板从1:2至1:64梯度稀释,将平板密封并于37℃培养7天。随后在每孔中加入32μL由吐温80配制为0.86%浓度的alamar Blue试剂,在37℃培育
后用BMG酶标仪在544ex/590em条件下测定荧光强度,所得数据即为图1中的相对荧光单位(RFUs)。
试验实施例3
本发明中,所述苯并呋喃及Coumestans衍生物以结核杆菌pks13基因片段编码的聚酮合酶为作用靶点,本试验用于对pks13靶点的确认。
本试验采用全基因测序的方法,选取了化合物S7、S79、S84,对上述化合物引起基因突变的结核杆菌进行基因测序(见表6和表7)。
由表6和表7可知,结核杆菌的9个耐药突变体在四个位置上发生了突变(Rv1765c、Rv2015c、Rv3800c、Rv3921c),但6个仅在pks13基因位点发生了突变(A1667V、D1644G、N1640K、N1640S),由此可见,本发明苯并呋喃及Coumestans衍生物以结核杆菌pks13基因片段编码的聚酮合酶为作用靶点。
试验实施例4
本发明中,所述Coumestans衍生物S79和S84对人类细胞MRC-5 cells、HFL-1 cells、QSG-7701 cells、HEK-293 cells毒性的测试。
由表8可知,选取化合物S79和化合物S84分别对人类细胞MRC-5 cells、HFL-1 cells、QSG-7701 cells、HEK-293 cells进行细胞毒性检测发现,化合物79的IC50值>50μg/mL,说明化合物79对人类细胞没有毒性。化合物84对HFL-1 cells、QSG-7701 cells的IC50值分别为50.2±5.3和38.8±2.6,对MRC-5 cells、HEK-293 cells的IC50值>50μg/mL,说明化合物84对人类这四种细胞基本没有毒性。
本发明中,所述Coumestans衍生物S132、S57、S7、S79、S84、S81、S80、S82、S77对Vero细胞(非洲绿猴肾细胞)细胞毒和活性的对比检测(见表9)。SI值为IC
50(Vero)/MIC
(Mtb)的比值,S132、S57、S7、S79、S84、S81、S80、S82化合物SI值范围为8–32,但是S77化合物IC50和MIC是相等的。
试验实施例5
本发明中,所述Coumestans衍生物S132、S79、S84、S86对人肝微粒体稳定性的测试(见表10)。
试验实施例6
本发明中,所述Coumestans衍生物S86、S130对敏感性菌株、耐多药菌株、广泛耐药性菌株抗结核活性的测试(见表11)。
本发明提供的系列化合物对结核杆菌H37Rv MIC
90测试的数据如下表5所 示:
表5
化合物 | MIC 90:μg/mL | 化合物 | MIC 90:μg/mL | 化合物 | MIC 90:μg/mL |
S1 | ≥64 | S2 | 8 | S3 | 16 |
S4 | - | S5 | 8 | S6 | 16 |
S7 | 0.5 | S8 | 16 | S9 | >64 |
S10 | 8 | S11 | 4 | S12 | - |
S13 | - | S14 | - | S15 | - |
S16 | - | S17 | - | S18 | - |
S19 | 4 | S20 | 8 | S21 | >64 |
S22 | 16 | S23 | 8 | S24 | 2 |
S25 | - | S26 | - | S27 | - |
S28 | - | S29 | 4 | S30 | 16 |
S31 | 2 | S32 | 64 | S33 | >64 |
S34 | >64 | S35 | >64 | S36 | 16 |
S37 | 16 | S38 | 64 | S39 | >64 |
S40 | >64 | S41 | >64 | S42 | >64 |
S43 | >64 | S44 | >64 | S45 | >64 |
S46 | >64 | S47 | >64 | S48 | >64 |
S49 | >64 | S50 | >64 | S51 | >64 |
S52 | 64 | S53 | 64 | S54 | >64 |
S55 | 64 | S56 | >64 | S57 | 1 |
S58 | 2 | S59 | 16 | S60 | 4 |
S61 | 8 | S62 | 16 | S63 | 2 |
S64 | 8 | S65 | 4 | S66 | - |
S67 | - | S68 | 16 | S69 | 8 |
S70 | 16 | S71 | 4 | S72 | 16 |
S73 | 8 | S74 | ≥64 | S75 | 2 |
S76 | 16 | S77 | 0.5 | S78 | 2 |
S79 | 0.125 | S80 | 1 | S81 | 1 |
S82 | 0.5 | S83 | 4 | S84 | 2 |
S85 | 4 | S86 | ≤0.0039 | S87 | 0.5 |
S88 | >64 | S89 | 2 | S90 | >64 |
S91 | 4 | S92 | 2 | S93 | 2 |
S94 | 0.125 | S95 | 0.0625 | S96 | >64 |
S97 | 0.125 | S98 | - | S99 | - |
S100 | - | S101 | - | S102 | 1 |
S103 | 0.5 | S104 | 0.5 | S105 | 2 |
S106 | 1 | S107 | >64 | S108 | >64 |
S109 | >64 | S110 | >64 | S111 | >64 |
S112 | >64 | S113 | >64 | S114 | >64 |
S115 | ≥64 | S116 | 32 | S117 | ≥64 |
S118 | >64 | S119 | >64 | S120 | >64 |
S121 | >64 | S122 | >64 | S123 | >64 |
S124 | >64 | S125- | 4 | S126 | 0.5 |
S127 | - | S128 | - | S129 | 16 |
S130 | ≤0.0039 | S131 | 0.125 |
由表5可知,通过对先导化合物的探究,构效关系的改造,本发明的化合物对结核杆菌表现出了很好的活性,其中S79、S95、S94、S97化合物对结核杆菌H37Rv 的MIC90达到0.0625-0.125μg/mL,表现出了优异抗结核活性,部分化合物对结核杆菌H37Rv的MIC90值为0.5-16μg/mL,但也有一些化合物丧失了对结核杆菌的活性MIC90≥64μg/mL(见表5),总之,本发明部分化合物表现出了优异的抗结核活性,有望发展成为新一代的抗结核药物。
本发明提供的部分化合物血清抑制滴定实验的相对荧光强度数据,如图1、2所示。其中,图1显示S7化合物在动物体内活性消失,S79和S84化合物在动物体内显示有很好的活性,表现出了较高的生物利用度(其中异烟肼为阳性化合物作对照)。图2中S132化合物无论是腹腔给药还是口服在动物体内都没有活性。
其中,图2所涉及的化合物S132结构表示如下:
表6
表7
表8
表9
a SI=IC
50(Vero cells)/MIC(H37Rv)
表10
表10表示的是S132、S79、S84、S86、Testosterone、Diclofenac、Propafenone对人肝微粒体稳定性数据,其中Testosterone、Diclofenac、Propafenone三个药物作为S132、S79、S84、S86的对照。
表11
表11表示的是Isoniazid、Rifampin、Levofloxacin、Ofloxacin、Kanamycin、 S86、S130对敏感性菌株、耐多药性菌株、广泛耐药性菌株的抗结核活性数据,其中五个药物Isoniazid、Rifampin、Levofloxacin、Ofloxacin、Kanamycin作为S86、S130阳性对照。
本发明的保护内容不局限于以上实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。
Claims (11)
- 一种苯并呋喃及Coumestans衍生物,其特征在于,其结构如式(I)所示:其中,X为氮原子、氧原子或硫原子;R 1是氢、羟基、甲氧基、乙氧基、甲氧基乙基醚或酯;R 2为 结构时:其中,R a为三元至八元脂肪环;含N,O,S中杂原子的三元至八元脂肪环;有取代的三元至八元脂肪环,选自C1-C4烷基、羟基烷基、胺烷基、甲氧基或三元至八元内酰胺;开链结构的伯胺结构基团 N-单直链烷烃或环烷烃取代的仲胺结构基团 N,N-双直链烷烃或环烷烃取代的叔胺结构基团 其中R b选自氢、C 1-C 8烷基或C 3-C 8的环烷基,R c选自氢、C 1-C 8烷基或C 3-C 8的环烷基,R b、R c可以相同,也可以不同;或,R 2为 结构时,R a为三元至八元脂肪环;含N,O,S中杂原子的三元至八元脂肪环结构;有取代的三元至八元脂肪环;有C1-C4烷基、羟基烷基、胺基烷基取代的含N、O、S杂原子的三元至八元脂肪环;开链结构的伯胺结构基团 N-单直链烷烃或环烷烃取代的仲胺结构基团 其中R b为氢,C 1-C 8烷基或C 3-C 8的环烷基,N,N-双直链烷烃或环烷烃取代的叔胺结构基团 其中R b选自氢、C 1-C 8烷基或C 3-C 8的环烷基,R c选自氢、C 1-C 8烷基或C 3-C 8的环烷基;R 3为羟基、C1~C8烷基、C1~C8烷氧基、C3~C8环烷基、螺环基、桥环基、金刚烷、脂肪胺基或芳香胺基;其中R 3为芳香胺基时,芳香环上各自独立的为以下取代基:羟基、C1~C8烷基、C1~C8烷氧基、卤素、硝基、三氟甲基、巯基或胺基;R 4为苯环、取代苯基、甲硫基或各种取代胺基,其中:当R 4为取代胺基时,为:C2~C9的环胺基结构基团 其中m=1-8;含氮饱 和杂环;开链结构的伯胺结构基团 N-单直链烷烃或环烷烃取代的仲胺结构基团 N,N-双直链烷烃或环烷烃取代的叔胺结构基团 其中R b选自氢、C 1-C 8烷基或C 3-C 8的环烷基,R c选自氢、C 1-C 8烷基或C 3-C 8的环烷基,R b、R c可以相同,也可以不同;芳香胺基,其中芳香环上各自独立的为以下取代基:羟基、C1~C8烷基、C1~C8烷氧基、卤素、硝基、三氟甲基、巯基或胺基;当R 4为取代苯基时,苯环上各取代基各自独立的为以下取代基:卤素、羟基、C1~C8烷基、C1~C8烷氧基、硝基、三氟甲基、甲氧基、巯基、胺基、氰基、脂肪胺基或亚甲基哌啶基;R 5为卤素、羟基、C1~C8烷基、C1~C8烷氧基、硝基、三氟甲基、甲氧基、巯基、胺基、氰基、亚甲基哌啶基或环己基酰胺基;R 6为氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基或苯基。
- 一种苯并呋喃及Coumestans衍生物,其特征在于,其结构如式(IV)所示:其中,X为氮原子、氧原子或硫原子;Y为氮原子、氧原子或硫原子;R 6为氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基或苯基;R 5为氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基、N-亚甲基哌啶或甲酰基环C4-C7胺;R 1为氢、羟基、甲氧基、乙氧基、甲氧基乙基醚或酯;R 2为 Ra和R b各自独立的选自以下取代基:氢原子;链状烷烃;环烷烃; 其中,Rc为C2-C8环烷基,含杂原子N,O,S环烷基,烷基取代的环烷基,或C3-C8内酰胺; 其中,R d为C2-C8环烷基或 R f为C2-C8环烷基,R e为链状烷烃或醚;R为芳香环,芳香环上各取代基各自独立的为以下取代基氢、卤素、羟基、烷基、硝基、氨基、三氟甲基、烷氧基或亚甲基哌啶基。
- 一种药物组合物,其特征在于,所述药物组合物包括如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或其药学上可接受的盐,以及药学上可接受的载体。
- 如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或如权利要求5所述的药物组合物在制备微生物的抑制剂中的应用。
- 如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或如权利要求5所述的药物组合物在制备结核分枝杆菌细胞壁合成抑制剂中的应用。
- 如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或如权利要求5所述的药物组合物在制备治疗与pks13基因片段编码的聚酮合酶作为靶点有关的疾病的药物中的应用。
- 如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或如权利要求5所述的药物组合物在制备预防和/或治疗肺结核疾病、抗癌、抗病毒、抗内风湿、抗真菌、抗氧化性、抗炎、护肝、止血及降血压的药物中的应用。
- 如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或如权利要求5所述的药物组合物在制备治疗耐多药性肺结核疾病的药物中的应用。
- 如权利要求1~4之任一项所述的苯并呋喃及Coumestans衍生物或如权利要求5所述的药物组合物在制备抑制结核分枝杆菌的生长和繁殖的药物中的应用。
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CN114591215B (zh) * | 2022-03-09 | 2023-12-01 | 华东师范大学 | N-取代吲哚化合物及其在治疗结核病中的应用 |
CN118146234A (zh) * | 2022-11-30 | 2024-06-07 | 浙江我武翼方药业有限公司 | 6,5,7,6-四环衍生物、其制备方法和应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2269951A1 (en) * | 1974-05-07 | 1975-12-05 | Delalande Sa | 2H,4H-furo(2',3'-5-6)benzo(1,2-e)-1,3-oxazines - with analgesic, antiinflammatory cardiac analeptic, hypo- or hyper-tensive, and or spasmolytic activity |
CN104829569A (zh) * | 2015-05-12 | 2015-08-12 | 广州中医药大学 | 一种2-苯基-苯骈五元杂环类化合物及其衍生物的应用 |
WO2016112036A1 (en) * | 2015-01-05 | 2016-07-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Myc g-quadruplex stabilizing small molecules and their use |
WO2016172498A1 (en) * | 2015-04-22 | 2016-10-27 | The Texas A&M University System | Substituted benzofuran derivatives as novel antimycobacterial agents |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2219646A4 (en) * | 2007-12-21 | 2010-12-22 | Univ Rochester | METHOD FOR MODIFYING THE LIFETIME OF EUKARYOTIC ORGANISMS |
-
2017
- 2017-12-20 CN CN201711387365.4A patent/CN109942523B/zh active Active
-
2018
- 2018-12-19 WO PCT/CN2018/121968 patent/WO2019120210A1/zh active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2269951A1 (en) * | 1974-05-07 | 1975-12-05 | Delalande Sa | 2H,4H-furo(2',3'-5-6)benzo(1,2-e)-1,3-oxazines - with analgesic, antiinflammatory cardiac analeptic, hypo- or hyper-tensive, and or spasmolytic activity |
WO2016112036A1 (en) * | 2015-01-05 | 2016-07-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Myc g-quadruplex stabilizing small molecules and their use |
WO2016172498A1 (en) * | 2015-04-22 | 2016-10-27 | The Texas A&M University System | Substituted benzofuran derivatives as novel antimycobacterial agents |
CN104829569A (zh) * | 2015-05-12 | 2015-08-12 | 广州中医药大学 | 一种2-苯基-苯骈五元杂环类化合物及其衍生物的应用 |
Non-Patent Citations (5)
Title |
---|
GRINEV, A. N.: "Mannich bases in the series of 5-hydroxybenzofuran de- rivatives", ZHURNAL OBSHCHEI KHIMII, vol. 33, no. 3, 31 December 1963 (1963-12-31), pages 820 - 824 * |
WAN NAMKUNG: "TMEM16A Inhibitors Reveal TMEM16A as a Minor Component of Calcium-activated Chloride Channel Conductance in Airway and Intestinal Epi- thelial Cells", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 286, no. 3, 21 January 2011 (2011-01-21), pages 2365 - 2374, XP002790464 * |
WEI ZHANG ET AL.: "Identification of Novel Coumestan Derivatives as Polyketide Synthase 13 Inhibitors against Mycobacterium tuberculosis", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 3, 2 November 2018 (2018-11-02), pages 791 - 803, XP055514827 * |
ZOTOVA, S. A.: "Synthesis and pharmacological activity of 2-aryl-3-carbe- thoxy-5-oxybenzofuran derivatives", KHIMIKO-FARMATSEVTICHESKII ZHURNAL, vol. 22, 31 December 1988 (1988-12-31), pages 35 - 39 * |
ZOTOVA, S. A.: "Synthesis and some pharmacological properties of indole and benzofuran derivatives containing an imidazole pharmacophore", KHIMIKO-FARMATSEVTICHESKII ZHURNAL, vol. 28, no. 2, 31 December 1994 (1994-12-31), pages 22 - 24 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114456136A (zh) * | 2022-01-27 | 2022-05-10 | 广西中医药大学 | 双靶点非甾体抗炎化合物及其制备方法与用途 |
CN114456136B (zh) * | 2022-01-27 | 2024-06-07 | 广西中医药大学 | 双靶点非甾体抗炎化合物及其制备方法与用途 |
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