CN115716822A - Application of benzimidazolyl isoxazole compound in preparation of medicines related to multiple myeloma - Google Patents
Application of benzimidazolyl isoxazole compound in preparation of medicines related to multiple myeloma Download PDFInfo
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- CN115716822A CN115716822A CN202211419132.9A CN202211419132A CN115716822A CN 115716822 A CN115716822 A CN 115716822A CN 202211419132 A CN202211419132 A CN 202211419132A CN 115716822 A CN115716822 A CN 115716822A
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- Prior art keywords
- compound
- ethyl
- isoxazole
- myc
- acid
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- -1 benzimidazolyl isoxazole compound Chemical class 0.000 title claims abstract description 74
- 206010035226 Plasma cell myeloma Diseases 0.000 title claims abstract description 31
- 208000034578 Multiple myelomas Diseases 0.000 title claims abstract description 24
- 239000003814 drug Substances 0.000 title claims abstract description 17
- 229940079593 drug Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title abstract description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 71
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 239000007787 solid Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 6
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
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- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- JVJQPDTXIALXOG-UHFFFAOYSA-N nitryl fluoride Chemical compound [O-][N+](F)=O JVJQPDTXIALXOG-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 abstract description 31
- 101710150448 Transcriptional regulator Myc Proteins 0.000 abstract description 31
- 102100038895 Myc proto-oncogene protein Human genes 0.000 abstract description 27
- 102000009092 Proto-Oncogene Proteins c-myc Human genes 0.000 abstract description 14
- 108010087705 Proto-Oncogene Proteins c-myc Proteins 0.000 abstract description 14
- 230000006907 apoptotic process Effects 0.000 abstract description 8
- 108091028690 C-myc mRNA Proteins 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 6
- 238000000978 circular dichroism spectroscopy Methods 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 230000000079 pharmacotherapeutic effect Effects 0.000 abstract description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 39
- 125000000217 alkyl group Chemical group 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 239000000243 solution Substances 0.000 description 17
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 238000002983 circular dichroism Methods 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
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- 230000000694 effects Effects 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 8
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- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 5
- OFWUBERMKPVMCT-UHFFFAOYSA-N 5-(4-fluorophenyl)-1,2-oxazole-3-carboxylic acid Chemical compound O1N=C(C(=O)O)C=C1C1=CC=C(F)C=C1 OFWUBERMKPVMCT-UHFFFAOYSA-N 0.000 description 5
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108091081406 G-quadruplex Proteins 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 3
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
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- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 3
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Abstract
The invention relates to application of a benzimidazolyl isoxazole compound in preparation of medicines related to multiple myeloma, belongs to the field of pharmaceutical chemistry and pharmacotherapeutics, and shows good RPMI-8226 cell inhibitory activity. In addition, the compound EP12 induces apoptosis and inhibits the expression of c-Myc mRNA and c-Myc protein, and circular dichroism spectroscopy experimental research shows that the compound EP12 can stabilize c-Myc G4. The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof can be applied to the preparation of medicines related to multiple myeloma.
Description
Technical Field
The invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to a benzimidazolyl isoxazole compound and application of the compound in the preparation of medicines related to multiple myeloma, especially application of the compound in the preparation of medicines related to a c-Myc G-quadruplex (c-Myc G4) stabilizer.
Background
Multiple Myeloma (MM) is a common plasma cell malignancy in the blood system, and is frequently found in middle-aged and elderly people, accounting for about 13% of tumors in the blood system. In recent years, with the maturation of hematopoietic stem cell transplantation technology, the emergence of first-line therapeutic drugs such as immunomodulators and proteasome inhibitors has led to an increase in the survival of patients with multiple myeloma, but the patients have not yet been completely cured. During the clonal evolution of MM, one of the key molecular events is the activation of the c-My c gene; in addition, inhibition of c-Myc protein activity reduces the occurrence of multiple myeloma. Therefore, the reasonable design of the c-Myc targeted drug is expected to effectively and safely treat multiple myeloma and related diseases thereof.
The c-Myc protein belongs to the basic helix-loop-helix leucine zipper (b-HLH-LZ) DNA binding protein superfamily, the half-life of the c-Myc protein is only 20-30 minutes, and a clear molecule binding site is lacked, so that the design of a medicine for directly targeting the c-Myc protein is difficult. The c-Myc protein and molecular chaperone Max usually form heterodimers to play a role in transcriptional regulation, and a compound 25 reported in earlier patents (application of pyrrolidine-2-ketone compounds in preparation of medicines related to multiple myeloma, application number: 202011215542.2) is an inhibitor targeting c-Myc/Max heterodimers, can inhibit the expression of the c-Myc protein, and shows a good effect of inhibiting multiple myeloma. Bortezomib is a proteasome inhibitor and a first-line drug for treating multiple myeloma, but bortezomib has drug resistance and more adverse reactions.
In addition to direct inhibition of the c-Myc protein or its post-translational regulation, another strategy is to regulate the expression of the c-Myc protein from upstream. Transcriptional regulation of c-Myc protein expression is complex, involving multiple promoters and transcription initiation sites. A large number of studies have shown that nuclease hypersensitivity element III is located near the P1 promoter 1 (NHE III 1 ) Controls 80-95% of the transcription activity of the c-Myc gene. NHE III 1 Is a DNA single-strand sequence consisting of bases rich in guanine (G), under normal physiological conditions, a transcription active double-strand form, a transient single-strand DNA and a silent G-quadruplex (G4) form exist, and the three are in dynamic balance to play physiological roles. When NHE III 1 When the sequence is in a single-stranded state, the transcription activating factors CNB P and hnRNP K are combined with the single-stranded DNA, so that the c-Myc transcription can be promoted; when the sequence is K + Or Na + When stable, G4 formation blocks CNBP and hnRNP K and NHE III 1 In combination, transcription of the c-Myc gene is inhibited. If a small molecule compound can be designed to target and stabilize c-Myc G4, the inhibition of the expression of c-Myc protein from the upstream can be realized.
At present, various types of c-Myc G4 stabilizers have been reported, including natural products such as flavonoids, ellipticine, cryptolepine and berberine and their derivatives. However, the affinity and specificity of these natural products are much lower than those of their structurally modified derivatives. The c-Myc G4 stabilizer obtained by a chemical synthesis method is a hotspot of current research, and although some small molecular compounds such as BMVC, IZCZ-3 and QN-1 belong to better c-Myc G4 stabilizers, the structural characteristics of the compounds are conjugated plane regions with multiple aromatic rings, and related symptoms of tumors can be remarkably relieved on a cellular or animal level, but most compounds are still in an early development stage, and the stabilizing activity of the compounds needs to be further improved. Therefore, the development of more structurally novel high-activity c-Myc G4 stabilizers is urgently needed.
Disclosure of Invention
The invention aims to modify the structure of a compound 25 (with the patent number of 202011215542.2) in the earlier patent by combining the aromatic conjugated structure characteristic of a stabilizer of c-Myc G4, and provides a benzimidazolyl isoxazole compound, and application of the compound, an isomer or a pharmaceutically acceptable salt thereof in the preparation of medicines related to multiple myeloma. In order to increase the aromatic conjugation, a series of benzimidazolyl isoxazole compounds are designed and synthesized by changing a pyrrolidine-2-ketone ring into an isoxazole ring. This class of compounds also has cellular activity in inhibiting multiple myeloma, but it inhibits c-Myc protein expression in a different manner than compound 25. The benzimidazolyl isoxazole compound can obviously inhibit the expression of c-Myc mRNA, but the compound 25 can not inhibit the expression of the c-Myc mRNA. In addition, circular dichroism spectroscopy (CD) studies have shown that compound EP12 stabilizes c-Myc G4. Therefore, the benzimidazolyl isoxazole compound is expected to be developed into a stabilizing agent targeting the G-quadruplex of the promoter region of the c-Myc gene so as to better treat multiple myeloma.
The benzimidazolyl isoxazole compound provided by the invention has good c-Myc G4 stable activity and can be used for preparing medicines related to multiple myeloma.
Another object of the present invention is to provide a pharmaceutical composition for treating multiple myeloma, which comprises the above mentioned compound, isomer or pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, together with a pharmaceutically acceptable carrier.
The technical scheme of the invention is as follows:
the compound, the isomer or the pharmaceutically acceptable salt thereof shown in the formula I, and the application of the compound, the isomer or the pharmaceutically acceptable salt thereof in the preparation of medicines related to multiple myeloma,
wherein,
R 1 represents hydrogen, hydroxy, nitro, carboxy, cyano, amino, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or C 1 -C 4 An alkoxycarbonyl group;
m represents an integer of 1 to 3;
R 2 represents hydrogen, hydroxy, nitro, carboxy, cyano, amino, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or C 1 -C 4 An alkoxycarbonyl group;
n represents an integer of 1 to 3.
In a preferred embodiment, R 1 Represents fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl.
In a more preferred embodiment, R 1 Represents fluorine or methoxy.
m represents 1 or 2; preferably, m represents 1.
In a preferred embodiment, R 2 Represents hydrogen, nitro, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl.
In a more preferred embodiment, R 2 Represents hydrogen, nitro, fluoro, methyl, ethyl, methoxy, ethoxy or methoxycarbonyl.
Further, n represents 1 or 2.
Further, in the compound, isomer, or pharmaceutically acceptable salt thereof represented by formula I, the compound is selected from the group consisting of:
the nomenclature of the above compounds provided by the present invention is as follows:
the EP1 compound is named 5- (4-methoxyphenyl) -3- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
the EP2 compound is named 3- (1- (2- (3, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole;
the EP3 compound is named 3- (1- (2- (4-ethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole;
the EP4 compound is named 3- (1- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole;
the EP5 compound is named 5- (4-methoxyphenyl) -3- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
the EP6 compound is named 5- (4-methoxyphenyl) -3- (1- (2- (4-nitrophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
the EP7 compound is named 3- (1- (2- (2-ethoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole;
naming of the EP8 compounds: 3- (1- (2- (4-methoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole;
EP9 compound nomenclature: 4- (2- (2- (5- (4-methoxyphenyl) isoxazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethoxy) benzoic acid methyl ester;
EP10 compound nomenclature: 3- (1- (2- (4-fluorophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole;
EP11 compound nomenclature: 5- (4-fluorophenyl) -3- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
EP12 compound nomenclature: 3- (1- (2- (3, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole;
EP13 compound nomenclature: 3- (1- (2- (4-ethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole;
EP14 compound nomenclature: 5- (4-fluorophenyl) -3- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
EP15 compound nomenclature: 5- (4-fluorophenyl) -3- (1- (2- (4-nitrophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
EP16 compound nomenclature: 3- (1- (2- (2-ethoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole;
EP17 compound nomenclature: 5- (4-fluorophenyl) -3- (1- (2- (4-methoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole;
EP18 compound nomenclature: 4- (2- (2- (5- (4-fluorophenyl) isoxazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethoxy) benzoic acid methyl ester;
EP19 compound nomenclature: 3- (1- (2- (4-fluorophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole.
In particular, the compounds of formula I are further preferably selected from the following compounds:
more specifically, the compounds of formula I are even more preferably selected from the following compounds:
the invention discloses a synthesis of EP1-EP19 compounds, and the synthetic route of the compounds shown in the general formula I is as follows:
taking the preparation method of the compound EP11 as an example, the specific preparation method of the synthetic route of the compound comprises the following steps:
performing claisen condensation reaction on 1- (4-fluorophenyl) ethyl-1-ketone (1) and diethyl oxalate (2) to obtain 4- (4-fluorophenyl) -2-hydroxy-4-oxobutyl-2-ethyl enoate (3), and reacting the compound (3) with hydroxylamine hydrochloride in an ethanol solvent for 4h to obtain 5- (4-fluorophenyl) isoxazole-3-ethyl carboxylate (4). After hydrolysis of the compound (4), the corresponding 5- (4-fluorophenyl) isoxazole-3-carboxylic acid (5) is first amidated with o-phenylenediamine (6) at room temperature, followed by dehydrative ring closure by heating to give 3- (1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (7). Finally, through the nucleophilic substitution reaction of the intermediate (7) and (2-bromoethoxy) benzene (8), the target compound EP11 shown in the general formula I is generated, and the specific synthetic route is as follows:
the invention provides application of the compound, the isomer or the pharmaceutically acceptable salt thereof in preparing medicines related to multiple myeloma.
In a preferred embodiment, the present invention provides a pharmaceutical composition for treating multiple myeloma, which comprises the compound, isomer or pharmaceutically acceptable salt thereof of the present invention as an active ingredient or a main active ingredient, together with a pharmaceutically acceptable carrier. Further, the pharmaceutical composition can be prepared into a liquid preparation or a solid preparation. Furthermore, the pharmaceutical composition can be prepared into injection, oral liquid, granules, tablets, powder or capsules.
Unless otherwise indicated, the following terms used in the specification and claims have the meanings discussed below:
"alkyl" means a saturated aliphatic group of 1 to 20 carbon atoms, including straight and branched chain groups (a numerical range referred to in this application, e.g., "1 to 20", refers to the group, in this case alkyl, which may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms). Alkyl groups having 1 to 4 carbon atoms are referred to as lower alkyl groups. When a lower alkyl group has no substituent, it is referred to as unsubstituted lower alkyl. More preferably, the alkyl group is a medium size alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, and the like. Preferably, the alkyl group is a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, or the like. Alkyl groups may be substituted or unsubstituted. When substituted alkyl, the substituent is preferably one or more, more preferably 1 to 3, most preferably 1 or 2 substituents.
"haloalkyl" denotes halogen-substituted alkyl, preferably halogen-substituted lower alkyl as defined above, which is substituted by one or more identical or different halogen atoms, e.g. -CH 2 Cl、-CF 3 、-CH 2 CF 3 、-CH 2 CCl 3 And the like.
"halogen" means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
"hydroxy" means an-OH group.
"cyano" means a-CN group.
"nitro" means-NO 2 A group.
"amino" means-NH 2 A group.
"carboxyl" means a-COOH group.
"alkoxy" means-O- (unsubstituted alkyl) and-O- (unsubstituted cycloalkyl). Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
"hydroxyalkyl" denotes hydroxy-substituted alkyl, preferably hydroxy-substituted lower alkyl as defined above, which is substituted by one or more identical or different hydroxy groups, e.g. -CH 2 CH 2 -OH、-CH 2 CH 2 CH 2 -OH and the like.
"aminoalkyl" means an amino-substituted alkyl group, preferably an amino-substituted lower alkyl group as defined above, which is substituted by one or more amino groups, which may be the same or different, e.g., -CH 2 NH 2 、-CH 2 NH 2 、-CH 2 C H 2 NH 2 And so on.
"Alkylalkoxy" refers to a group in which at least one hydrogen on the alkyl group is replaced with an alkoxy group, such as 2-methylaminoethyl, 2-ethoxyethyl, 3-methoxypropyl, and the like.
“C 1 -C 4 Alkoxycarbonyl "denotes a group R-O-CO-R ', wherein R or R' is a group selected from: hydrogen, unsubstituted lower alkyl, trihalomethyl, unsubstituted cycloalkyl or phenyl, optionally substituted by one or more, preferably 1,2 or 3 groups selected from unsubstituted lower alkyl, trihalomethyl, unsubstituted lower alkoxy.
“C 1 -C 4 Alkoxycarbonyl "represents an R-CO group, wherein R represents methoxy, ethoxy, propoxy, or the like.
"pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the parent compound. Such salts include:
(1) Salts with acids are obtained by reaction of the free base of the parent compound with inorganic acids including hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid and the like, or with organic acids including acetic acid, trifluoroacetic acid, propionic acid, acrylic acid, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, benzoic acid, hydroxybenzoic acid, γ -hydroxybutyric acid, methoxybenzoic acid, phthalic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, cinnamic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, aspartic acid, stearic acid, mandelic acid, succinic acid or malonic acid and the like.
(2) The acidic protons present in the parent compound are replaced with metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or are complexed with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, quinine, and the like.
"pharmaceutical composition" refers to the combination of one or more of the compounds of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof with another chemical ingredient, such as a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration process to the animal.
By adopting the technical scheme of the invention, the advantages are as follows:
the benzimidazolyl isoxazole compound provided by the invention is applied to the preparation of medicines related to multiple myeloma, shows good RPMI-8226 cell inhibitory activity, and can be used for preparing medicines related to multiple myeloma. In addition, the compound EP12 induces apoptosis and inhibits the expression of c-Myc mRNA and c-Myc protein, and circular dichroism spectroscopy experimental research shows that the compound EP12 can stabilize c-Myc G4.
Drawings
FIG. 1 (a) shows Q-PCR detection of c-Myc mRNA expression in myeloma cells treated with different active compounds (EP 8, EP9, EP12, EP 18); FIG. 1 (b) is a graph in which the effect of compounds (EP 8, EP9, EP12 and EP 18) on c-Myc expression was examined by Western blotting; error bars: mean ± standard error of mean from at least three independent experiments; * P <0.05.
FIG. 2 is a flow cytometry experiment analyzing the effect of EP12 on the apoptosis rate of RPMI-8226 cells; all cells were treated with 5 μ M compound for 48h using RPMI-8226 cells; error bars: mean ± standard error of mean from at least three independent experiments; * P <0.01.
The left panel in FIG. 3 is the normal temperature CD spectrum of the studied c-Myc G4 with or without EP 12; the right panel in FIG. 3 is the CD melting curve of c-Myc G4 in the presence or absence of EP 12.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only, and should not be understood as limiting the invention.
Example 1
5- (4-methoxyphenyl) -3- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 1)
7.19g (133.18mmol, 2e.q) of sodium methoxide was charged into a 500-ml round-bottomed flask at 0 ℃ and 300ml of anhydrous ethanol was added thereto, followed by stirring until dissolved, 1- (4-methoxyphenyl) ethan-1-one (10g, 66.59mmol, 1e.q) was added thereto, followed by further stirring for 30min, and then diethyl oxalate (6.125ml, 45.5mmol, 1.1e.q) was added to the mixture. After stirring at room temperature for 6 to 8 hours, 6N diluted hydrochloric acid solution was added to the solution, and dropwise added with stirring until the pH was adjusted to 5. The residue was poured into excess ice water, more solid precipitated, filtered and dried in a vacuum oven to give 2-hydroxy-4- (4-methoxyphenyl) -4-oxobut-2-enoic acid ethyl ester (15.04g, 90.2%) as a yellow solid.
Ethyl 2-hydroxy-4- (4-methoxyphenyl) -4-oxobut-2-enoate (16.165g, 64.60mmol, 1e.q) was dissolved in an appropriate amount of anhydrous ethanol, and hydroxylamine hydrochloride (5.39g, 77.51mmol, 1.1e.q) was added thereto, followed by heating and refluxing for 6 hours. The reaction mixture was cooled to room temperature, washed with copious amounts of ice water and dried with suction filtration to give a yellow crude product which was purified by column chromatography (PE/EA =10 (V/V)) to give ethyl 5- (4-methoxyphenyl) isoxazole-3-carboxylate as a white solid (13.45g, 84.2%).
Ethyl 5- (4-methoxyphenyl) isoxazole-3-carboxylate (13.45g, 54.4 mmol) was weighed out and dissolved in 100ml of absolute ethanol, followed by addition of 5% NaOH (100 ml). After refluxing for 3 hours, it was cooled to room temperature. The pH of the solution was adjusted to 3 by slowly adding 1N aqueous HCl. The resulting precipitate was filtered and dried under vacuum to give the intermediate 5- (4-methoxyphenyl) isoxazole-3-carboxylic acid (11.4 g, 95.6%) as a white solid.
5- (4-methoxyphenyl) isoxazole-3-carboxylic acid (462mg, 2.12mmol, 1e.q) was dissolved in DMF (2 ml) and DIEPA (418. Mu.L, 2.53mmol, 1.2e.q) and HATU (962mg, 2.53mmol, 1.2e.q) were added in that order. After stirring for 30 minutes, benzene-1, 2-diamine (251mg, 2.32mmol,1.1 e.q) was added and stirred at room temperature for 3 hours. Ice water was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate. With 1N hydrochloric acid, saturated NaHCO 3 The organic layer was washed with an aqueous solution and distilled water, and Na was added 2 SO 4 And (5) drying. After concentration in vacuo, the residue was directly dissolved by addition of an appropriate amount of acetic acid and refluxed overnight. After cooling to room temperature, the solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/EA = 12 (V/V)) to give 3- (1H-benzo [ d]Imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (240mg, 38.9%).
Reacting 3- (1H-benzo [ d ]]Imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (200mg, 0.69mmol, 1e.q) was dissolved in DMF solution and potassium carbonate (250mg, 1.8mmol, 2.61e.q) was added and stirred for 30 minutes. (2-Bromoethoxy) benzene (277mg, 1.38mmol, 2e.q) was then added and stirring continued at 90 ℃ for 2 hours. The reaction was then quenched with distilled water and extracted with ethyl acetate. The combined organic extracts were washed with brine, na 2 SO 4 Dried and evaporated to afford the crude product, which was purified by column chromatography (PE/EA =2 (V/V)) to give finally a yellow solid (125mg, 44.2%).
1 H NMR(400MHz,DMSO-d 6 ):δ7.94-7.92(m,2H,2×Ar-H),7.80-7.77(m,1H,Ar-H),7.74-7.72(m,1H,Ar-H),δ7.58(s,H,Ar-H),δ7.39-7.35(m,H,Ar-H),δ7.31-7.27(m,H,Ar-H),7.18-7.08(m,4H,4×Ar-H),δ6.85-6.81(m,H,Ar-H),δ6.76-6.73(m,2H,2×Ar-H),5.06(t,J＝5.2Hz,2H,CH 2 ),4.37(t,J＝5.3Hz,2H,CH 2 ),3.81(s,3H,OCH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.11,161.73,158.40,157.34,143.08,142.93,136.95,130.00(2C),128.19(2C),124.47,123.28,121.36,120.20,119.46,115.33(2C),114.78(2C),112.33,100.32,67.03,55.98,44.91；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 21 N 3 O 3 ,412.1656,found 412.1656,found 412.1629.Purity:95.1％.
Example 2
3- (1- (2- (3, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (EP 2)
In a similar manner to example 1, a white powder, 42.4%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.94-7.91(m,2H,2×Ar-H),δ7.78-7.72(m,2H,2×Ar-H),δ7.55(s,1H,Ar-H),δ7.40-7.35(m,1H,Ar-H),δ7.31-7.27(m,1H,Ar-H),7.11-7.08(m,2H,2×Ar-H),6.45(s,1H,Ar-H),6.34(s,2H,2×Ar-H),5.03(t,J＝6.2Hz,2H,CH 2 ),4.32(t,J＝6.6Hz,2H,CH 2 ),3.81(br,3H,OCH 3 ),2.08(s,6H,2×CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.08,161.72,158.41,157.32,143.08,142.96,139.11(2C),136.91,128.15(2C),124.46,123.26,122.94,120.20,119.47,115.30(2C),112.49(2C),112.27,100.32,66.83,55.96,44.91,21.45(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 25 N 3 O 3 ,440.1969,found 440.1943.Purity:98.1％.
Example 3
3- (1- (2- (4-ethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (EP 3)
In a similar manner to example 1, a pale yellow solid, 36.5%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.94-7.91(m,2H,2×Ar-H),7.78-7.72(m,2H,2×Ar-H),7.56(s,1H,Ar-H),δ7.39-7.35(m,1H,Ar-H),δ7.31-7.26(m,1H,Ar-H),7.11-7.07(m,2H,2×Ar-H),6.98-6.95(m,2H,2×Ar-H),6.66-6.63(m,2H,2×Ar-H),5.04(t,J＝5.2Hz,2H,CH 2 ),4.33(t,J＝5.4Hz,2H,CH 2 ),3.81(br,3H,OCH 3 ),2.41(q,J＝7.5Hz,2H,CH 2 ),1.03(t,J＝7.6Hz,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.08,161.71,157.32,156.48,143.08,142.94,136.93,136.57,129.12(2C),128.16(2C),124.45,123.26,120.20,119.46,115.29(2C),114.63(2C),112.31,100.31,67.10,55.96,44.92,27.75,16.39；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 25 N 3 O 3 ,440.1969,found 440.1941.Purity:95.0％.
Example 4
3- (1- (2, 4-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (EP 4)
In a similar manner to example 1, a white solid, 45.3%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.94-7.91(m,2H,2×Ar-H),7.79-7.77(m,1H,Ar-H),7.75-7.72(m,1H,Ar-H),δ7.57(s,1H,Ar-H),δ7.37-7.33(m,1H,Ar-H),δ7.30-7.26(m,1H,Ar-H),7.11-7.08(m,2H,2×Ar-H),6.82-6.79(m,1H,Ar-H),6.74-6.69(m,2H,2×Ar-H),5.12(t,J＝5.1Hz,2H,CH 2 ),4.31(t,J＝4.9Hz,2H,CH 2 ),3.81(br,3H,OCH 3 ),2.06(s,3H,CH 3 ),1.65(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.02,161.73,157.39,154.47,143.13,142.96,136.91,131.62,129.55,128.17(2C),127.50,125.73,124.35,123.25,120.20,119.49,115.33(2C),112.37,111.37,100.34,67.06,55.99,44.94,20.50,16.19；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 25 N 3 O 3 ,440.1969,found 440.1938.Purity:99.0％.
Example 5
5- (4-methoxyphenyl) -3- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 5)
In a similar manner to example 1, a white solid, 50.4%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.96-7.92(m,2H,2×Ar-H),7.79(d,J＝8.1Hz,1H,Ar-H),7.74(d,J＝8.0Hz,1H,Ar-H),δ7.58(s,H,Ar-H),δ7.38-7.34(m,H,Ar-H),δ7.30-7.27(m,H,Ar-H),7.11-7.09(m,2H,2×Ar-H),δ7.04-7.00(m,H,Ar-H),δ6.94-6.93(m,H,Ar-H),δ6.83-6.81(m,H,Ar-H),δ6.73-6.69(m,H,Ar-H),5.15(t,J＝5.1Hz,2H,CH 2 ),4.36(t,J＝5.1Hz,2H,CH 2 ),3.81(s,3H,OCH 3 ),1.96(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.02,161.73,157.42,156.55,143.12,142.94,136.91,130.89,128.18(2C),127.45,125.96,124.37,123.28,121.01,120.20,119.47,115.33(2C),112.39,111.41,100.37,66.99,55.98,44.92,16.27；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 23 N 3 O 3 ,426.1812,found 426.1785.Purity:95.4％.
Example 6
5- (4-methoxyphenyl) -3- (1- (2- (4-nitrophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 6)
In a similar manner to example 1, a yellow solid, 49.5%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.08-8.04(m,2H,2×Ar-H),7.92-7.88(m,2H,2×Ar-H),7.80(d,J＝8.2Hz,1H,Ar-H),7.72(d,J＝8.0Hz,1H,Ar-H),δ7.56(s,1H,Ar-H),δ7.40-7.36(m,1H,Ar-H),δ7.31-7.27(m,1H,Ar-H),7.11-7.07(m,2H,2×Ar-H),6.98-6.94(m,2H,2×Ar-H),5.11(t,J＝5.1Hz,2H,CH 2 ),4.55(t,J＝5.2Hz,2H,CH 2 ),3.81(br,3H,OCH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.14,163.60,161.74,157.24,143.08,142.95,141.51,136.83,128.15(2C),126.31(2C),124.57,123.34,120.26,119.42,115.47(2C),115.31(2C),112.22,100.29,68.12,55.98,44.55；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 20 N 4 O 5 ,457.1506,found 457.1477.Purity:97.9％.
Example 7
3- (1- (2- (2-ethoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (EP 7)
In a similar manner to example 1, a white solid, 60.8%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.95-7.89(m,2H,2×Ar-H),7.81(d,J＝8.1Hz,1H,Ar-H),7.73(d,J＝7.9Hz,1H,Ar-H),δ7.58(s,H,Ar-H),7.36-7.26(m,2H,2×Ar-H),δ7.11-7.06(m,2H,2×Ar-H),δ6.87-6.83(m,1H,Ar-H),δ6.80-6.71(m,3H,3×Ar-H),5.06(t,J＝5.1Hz,2H,CH 2 ),4.37(t,J＝5.1Hz,2H,CH 2 ),3.80(br,3H,OCH 3 ),3.76(q,J＝7.1Hz,2H,CH 2 ),1.10(t,J＝7.0Hz,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.99,161.70,157.36,148.62,148.20,143.04,142.94,137.09,128.15(2C),124.39,123.19,121.89,121.12,120.04,119.50,115.32(2C),113.88,113.76,112.67,100.35,68.01,63.95,55.97,45.27,15.13；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 25 N 3 O 4 ,456.1918,found 456.1888.Purity:97.1％.
Example 8
3- (1- (2- (4-methoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (EP 8)
In a similar manner to example 1, a white solid, 39.8%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.96-7.90(m,2H,2×Ar-H),7.78-7.72(m,2H,2×Ar-H),δ7.58(s,H,Ar-H),7.39-7.35(m,H,Ar-H),7.31-7.27(m,H,Ar-H),δ7.12-7.08(m,2H,2×Ar-H),δ6.74-6.64(m,4H,4×Ar-H),5.03(t,J＝5.2Hz,2H,CH 2 ),4.30(t,J＝5.3Hz,2H,CH 2 ),3.81(br,3H,OCH 3 ),3.58(br,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.11,161.74,157.32,154.02,152.44,143.09,142.94,136.93,128.19(2C),124.45,123.26,120.20,119.47,115.68(2C),115.32(2C),115.06(2C),112.31,100.31,67.58,55.99,55.80,44.97；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 23 N 3 O 4 ,442.1761,found 442.1732.Purity:97.7％.
Example 9
4- (2- (2- (5- (4-methoxyphenyl) isoxazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethoxy) benzoic acid methyl ester (EP 9)
In a similar manner to example 1, a white solid, 53.4%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.92-7.90(m,2H,2×Ar-H),7.80-7.72(m,4H,4×Ar-H),δ7.54(br,H,Ar-H),7.40-7.36(m,H,Ar-H),7.31-7.27(m,H,Ar-H),δ7.11-7.08(m,2H,2×Ar-H),δ6.87-6.84(m,2H,2×Ar-H),5.09(t,J＝5.8Hz,2H,CH 2 ),4.48(t,J＝5.4Hz,2H,CH 2 ),3.81(br,3H,OCH 3 ),3.72(br,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.12,166.28,162.17,161.72,157.26,143.09,142.94,136.87,131.69(2C),128.17(2C),124.53,123.31,122.63,120.23,119.44,115.30(2C),114.87(2C),112.25,100.29,67.42,55.98,52.32,44.65；ESI-HRMS(TOF):m/z[M+H] + calcd for C 27 H 23 N 3 O 5 ,470.1710,found 470.1684.Purity:98.1％.
Example 10
3- (1- (2- (4-fluorophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-methoxyphenyl) isoxazole (EP 10)
In a similar manner to example 1, a white solid, 67.8%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ7.95-7.90(m,2H,2×Ar-H),7.78-7.72(m,2H,2×Ar-H),δ7.57(s,H,Ar-H),δ7.39-7.35(m,H,Ar-H),δ7.31-7.27(m,H,Ar-H),7.12-7.07(m,2H,2×Ar-H),δ7.02-6.94(m,2H,2×Ar-H),δ6.78-6.72(m,2H,2×Ar-H),5.05(t,J＝5.3Hz,2H,CH 2 ),4.35(t,J＝5.3Hz,2H,CH 2 ),3.81(s,3H,OCH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:170.10,161.71,157.31,157.28(d, 1 J CF ＝234.8Hz),154.72,143.06,142.92,136.91,128.17(2C),124.48,123.29,120.21,119.44,116.33(2C,d, 2 J CF ＝23.4Hz),116.04(2C,d, 3 J CF ＝8.0Hz),115.30(2C),112.30,100.30,67.65,55.97,44.84；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 20 FN 3 O 3 ,430.1561,found 430.1534.Purity:98.7％.
Example 11
5- (4-fluorophenyl) -3- (1- (2-phenoxyethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 11)
1- (4-fluorophenyl) ethan-1-one (5ml, 41.4mmol, 1e.q) was added to anhydrous ethanol (200 ml) containing sodium methoxide (4.47g, 82.8mmol, 2e.q) at 0 ℃ and then diethyl oxalate (6.125ml, 45.5mmol, 1.1e.q) was added to the solution. After stirring at room temperature for 6 hours, 6N aqueous HCl was added to the solution, and the reaction was terminated by stirring for 30 minutes. The residue was poured into an excess of ice water, and the precipitate was filtered and dried in a vacuum oven to give ethyl 2-hydroxy-4- (4-fluorophenyl) -4-oxobut-2-enoate (8.614g, 87.4%) as a yellow solid.
Ethyl 2-hydroxy-4- (4-fluorophenyl) -4-oxobut-2-enoate (8g, 33.6mmol, 1e.q) and hydroxylamine hydrochloride (2.567g, 36.9mmol, 1.1e.q) were added to absolute ethanol (100 ml) and heated under reflux for 4h. The reaction mixture was cooled to room temperature, washed with ice water, and dried by suction filtration to give a crude product, which was purified by column chromatography (PE/EA =10 (1 (V/V)) to give ethyl 5- (4-fluorophenyl) isoxazole-3-carboxylate (6.795g, 86.0%) as a white solid.
Ethyl 5- (4-fluorophenyl) isoxazole-3-carboxylate (5.5g, 22.5mmol) was dissolved in 50ml of anhydrous ethanol, followed by addition of a 5% NaOH (50 ml) solution. After refluxing for 3 hours, it was cooled to room temperature. The pH of the solution was adjusted to 3 by slowly adding 1N aqueous HCl. The resulting precipitate was filtered and dried under vacuum to give the intermediate 5- (4-fluorophenyl) isoxazole-3-carboxylic acid (4.3g, 92.2%) as a white powder.
5- (4-fluorophenyl) isoxazole-3-carboxylic acid (2g, 9.6mmol, 1e.q) was dissolved in DMF (30 ml) and DIEPA (1.9ml, 11.5mmol, 1.2e.q) and HATU (4.37g, 11.5mmol, 1.2e.q) were added in that order. After stirring for 30 minutes, benzene-1, 2-diamine (1.15g, 10.6mmol, 1.1e.q) was added and stirred at room temperature for 6 hours. Ice water was added to terminate the reaction, and the reaction solution was extracted with ethyl acetate. With 1N hydrochloric acid, saturated NaHCO 3 The organic layer was washed with aqueous and distilled water and Na 2 SO 4 And (5) drying. After concentration in vacuo, the residue is directly dissolved by addition of an appropriate amount of acetic acid and taken backThe flow was overnight. After cooling to room temperature, the solution was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (PE/EA = 12 (V/V)) to give 3- (1H-benzo [ d]Imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (1.35g, 50.4%).
Reacting 3- (1H-benzo [ d ]]Imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (200mg, 0.7mmol, 1e.q) was dissolved in DMF solution and potassium carbonate (250mg, 1.8mmol, 2.57e.q) was added and stirred for 30 minutes. (2-Bromoethoxy) benzene (281mg, 1.4mmol, 2e.q) was then added and stirring continued for 2 hours at 100 ℃. The reaction was quenched with distilled water and extracted with ethyl acetate. The combined organic extracts were washed with brine, na 2 SO 4 Dried and evaporated to afford the crude product, which was purified by column chromatography (PE/EA =5 (V/V)) to afford a white solid (89mg, 31.9%).
1 H NMR(400MHz,DMSO-d 6 ):δ8.07-8.03(m,2H,2×Ar-H),δ7.79-7.72(m,3H,3×Ar-H),δ7.42-7.35(m,3H,3×Ar-H),δ7.31-7.27(m,1H,Ar-H),δ7.17-7.13(m,2H,2×Ar-H),δ6.84-6.81(m,H,Ar-H),δ6.75-6.72(m,2H,2×Ar-H),5.06(t,J＝5.2Hz,2H,CH 2 ),4.37(t,J＝5.4Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.11,163.95(d, 1 J CF ＝247.9Hz),158.37,157.46,142.92,142.86,136.94,129.99(2C),128.97(2C,d, 3 J CF ＝8.8Hz),124.54,123.51(d, 4 J CF ＝3.0Hz),123.32,121.35,120.23,117.06(2C,d, 2 J CF ＝22.1Hz),114.75(2C),112.33,101.78,66.98,44.90；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 18 FN 3 O 2 ,400.1456,found 400.1454.Purity:99.1％.
Example 12
3- (1- (2- (3, 5-dimethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (EP 12)
In a similar manner to example 11, a white solid, 45.2%;
1 H NMR(400MHz,DMSO-d 6 ):δ8.08-8.03(m,2H,2×Ar-H),δ7.79-7.73(m,2H,2×Ar-H),7.70(s,1H,Ar-H),δ7.43-7.36(m,3H,3×Ar-H),δ7.31-7.27(m,1H,Ar-H),6.44(s,1H,Ar-H),6.34(s,2H,2×Ar-H),5.04(t,J＝5.4Hz,2H,CH 2 ),4.32(t,J＝5.2Hz,2H,CH 2 ),2.08(s,6H,2×CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.10,163.96(d, 1 J CF ＝248.2Hz),158.39,157.46,142.96,142.91,139.10(2C),136.89,128.97(2C,d, 3 J CF ＝8.8Hz),124.55,123.55(d, 4 J CF ＝3.4Hz),123.31,122.94,120.24,117.07(2C,d, 2 J CF ＝22.0Hz),112.49(2C),112.31,101.83,66.78,44.91,21.45(2C)；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 22 FN 3 O 2 ,428.1769,found 428.1742.Purity:98.2％.
example 13
3- (1- (2- (4-ethylphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (EP 13)
In a similar manner to example 11, a white solid, 29.4%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.07-8.04(m,2H,2×Ar-H),δ7.79-7.72(m,3H,3×Ar-H),δ7.43-7.35(m,3H,3×Ar-H),δ7.31-7.27(m,1H,Ar-H),6.98-6.96(m,2H,2×Ar-H),6.65-6.63(m,2H,2×Ar-H),5.05(t,J＝5.3Hz,2H,CH 2 ),4.33(t,J＝5.3Hz,2H,CH 2 ),2.41(q,J＝7.6Hz,2H,CH 2 ),1.03(t,J＝7.6Hz,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.11,163.96(d, 1 J CF ＝247.8Hz),157.46,156.46,142.95,142.91,136.92,136.58,129.10(2C),128.98(2C,d, 3 J CF ＝8.9Hz),124.52,123.54(d, 4 J CF ＝3.3Hz),123.30,120.23,117.06(2C,d, 2 J CF ＝22.1Hz),114.64(2C),112.32,101.80,67.06,44.92,27.73,16.35；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 22 FN 3 O 2 ,428.1769,found 428.1747.Purity:95.0％.
Example 14
5- (4-fluorophenyl) -3- (1- (2- (o-tolyloxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 14)
In a similar manner to example 11, a yellow solid, 36.0%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.07-8.04(m,2H,2×Ar-H),δ7.81-7.71(m,3H,3×Ar-H),δ7.43-7.34(m,3H,3×Ar-H),δ7.31-7.27(m,1H,Ar-H),7.04-7.00(m,1H,Ar-H),6.94-6.92(m,1H,Ar-H),6.83-6.81(m,1H,Ar-H),6.73-6.69(m,1H,Ar-H),5.15(t,J＝5.0Hz,2H,CH 2 ),4.36(t,J＝4.7Hz,2H,CH 2 ),1.68(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.03,163.95(d, 1 J CF ＝248.0Hz),157.55,156.53,142.94,142.91,136.90,130.88,128.97(2C,d, 3 J CF ＝8.7Hz),127.43,125.95,124.44,123.53(d, 4 J CF ＝3.2Hz),123.32,121.00,120.23,117.06(2C,d, 2 J CF ＝22.1Hz),112.39,111.39,101.83,66.94,44.92,16.25；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 20 FN 3 O 2 ,414.1612,found 414.1589.Purity:97.5％.
Example 15
5- (4-fluorophenyl) -3- (1- (2- (4-nitrophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 15)
In a similar manner to example 11, a pale yellow solid, 32.6%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.06-8.02(m,4H,4×Ar-H),7.81(d,J＝8.1Hz,1H,Ar-H),7.74(d,J＝8.1Hz,1H,Ar-H),7.70(s,1H,Ar-H),δ7.43-7.37(m,3H,3×Ar-H),δ7.32-7.28(m,1H,Ar-H),6.98-6.94(m,2H,2×Ar-H),5.12(t,J＝5.1Hz,2H,CH 2 ),4.56(t,J＝5.2Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.13,163.71(d, 1 J CF ＝247.9Hz),163.55,157.36,142.92,142.87,141.46,136.81,128.94(2C,d, 3 J CF ＝8.8Hz),126.30(2C),124.65,123.45(d, 4 J CF ＝3.1Hz),123.39,120.28,117.06(2C,d, 2 J CF ＝22.1Hz),115.45(2C),112.25,101.77,68.05,44.52；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 17 FN 4 O 4 ,445.1307,found 445.1278.Purity:95.4％.
Example 16
3- (1- (2- (2-ethoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (EP 16)
In a similar manner to example 11, a white solid, 44.1%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.08-8.04(m,2H,2×Ar-H),7.83(d,J＝8.1Hz,1H,Ar-H),δ7.77-7.69(m,2H,2×Ar-H),δ7.43-7.27(m,4H,4×Ar-H),δ6.86-6.84(m,1H,Ar-H),6.80-6.72(m,3H,3×Ar-H),5.07(t,J＝5.1Hz,2H,CH 2 ),4.37(t,J＝5.1Hz,2H,CH 2 ),3.76(q,J＝7.0Hz,2H,CH 2 ),1.10(t,J＝7.0Hz,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.01,163.99(d, 1 J CF ＝250.2Hz),157.51,148.64,148.21,142.96,142.86,137.08,128.97(2C,d, 3 J CF ＝8.8Hz),124.46,123.59,123.23,121.91,121.13,120.09,117.08(2C,d, 2 J CF ＝21.9Hz),113.95,113.81,112.68,101.86,67.99,63.97,45.28,15.12；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 22 FN 3 O 3 ,444.1718,found 444.1691.Purity:98.3％.
Example 17
5- (4-fluorophenyl) -3- (1- (2- (4-methoxyphenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) isoxazole (EP 17)
In a similar manner to example 11, a yellow solid, 52.0%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.07-8.04(m,2H,2×Ar-H),δ7.78-7.72(m,3H,3×Ar-H),δ7.43-7.35(m,3H,3×Ar-H),δ7.31-7.27(m,1H,Ar-H),6.72-6.65(m,4H,4×Ar-H),5.04(t,J＝5.3Hz,2H,CH 2 ),4.30(t,J＝5.2Hz,2H,CH 2 ),3.58(s,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.13,163.97(d, 1 J CF ＝247.5Hz),157.46,154.01,152.41,142.94,142.92,136.92,129.00(2C,d, 3 J CF ＝8.8Hz),124.54,123.54(d, 4 J CF ＝3.1Hz),123.32,120.24,117.08(2C,d, 2 J CF ＝22.0Hz),115.67(2C),115.04(2C),112.34,101.81,67.51,55.79,44.96；ESI-HRMS(TOF):m/z[M+H] + calcd for C 25 H 20 FN 3 O 3 ,430.1561,found 430.1533.Purity:96.7％.
Example 18
4- (2- (2- (5- (4-fluorophenyl) isoxazol-3-yl) -1H-benzo [ d ] imidazol-1-yl) ethoxy) benzoic acid methyl ester (EP 18)
In a similar manner to example 11, a white solid, 47.4%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.06-8.01(m,2H,2×Ar-H),7.81-7.79(m,H,Ar-H),δ7.77-7.73(m,3H,3×Ar-H),7.70(br,H,Ar-H),δ7.43-7.36(m,3H,3×Ar-H),δ7.32-7.27(m,1H,Ar-H),6.86-6.84(m,2H,2×Ar-H),5.10(t,J＝5.2Hz,2H,CH 2 ),4.48(t,J＝5.2Hz,2H,CH 2 ),3.72(br,3H,CH 3 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.13,166.26,163.96(d, 1 J CF ＝247.8Hz),162.13,157.38,142.95,142.91,136.85,131.67(2C),128.97(2C,d, 3 J CF ＝8.8Hz),124.60,123.50(d, 4 J CF ＝3.3Hz),123.35,122.63,120.27,117.04(2C,d, 2 J CF ＝22.1Hz),114.87(2C),112.27,101.79,67.35,52.30,44.63；ESI-HRMS(TOF):m/z[M+H] + calcd for C 26 H 20 FN 3 O 4 ,458.1511,found 458.1483.Purity:96.4％.
Example 19
3- (1- (2- (4-fluorophenoxy) ethyl) -1H-benzo [ d ] imidazol-2-yl) -5- (4-fluorophenyl) isoxazole (EP 19)
In a similar manner to example 11, a white solid, 43.5%, was obtained.
1 H NMR(400MHz,DMSO-d 6 ):δ8.08-8.04(m,2H,2×Ar-H),δ7.80-7.73(m,3H,3×Ar-H),δ7.44-7.36(m,3H,3×Ar-H),δ7.31-7.27(m,1H,Ar-H),7.01-6.95(m,2H,2×Ar-H),6.76-6.73(m,2H,2×Ar-H),5.06(t,J＝5.3Hz,2H,CH 2 ),4.36(t,J＝5.3Hz,2H,CH 2 )； 13 C NMR(100MHz,DMSO-d 6 )δppm:169.14,163.97(d, 1 J CF ＝247.9Hz),157.45,157.32(d, 1 J CF ＝234.9Hz),154.72,142.94,142.89,136.91,129.00(2C,d, 3 J CF ＝8.9Hz),124.56,123.51,123.33,120.25,117.07(2C,d, 2 J CF ＝22.2Hz),116.31(2C,d, 2 J CF ＝22.9Hz),116.08(2C,d, 3 J CF ＝8.0Hz),112.31,101.80,67.63,44.85；ESI-HRMS(TOF):m/z[M+H] + calcd for C 24 H 17 F 2 N 3 O 2 ,418.1362,found 418.1337.Purity:96.1％.
Experimental methods and results
1. Cell viability assay
The experimental principle is as follows: the reagent contains WST-8, which is reduced by dehydrogenase in cells to yellow formazan product (Formazan dye) with high water solubility under the action of electron carrier 1-Methoxy-5-methylphenazinium dimethyl sulfate (1-Methoxy PMS). The amount of formazan produced was proportional to the number of living cells. Therefore, the cell proliferation and toxicity analysis can be directly carried out by utilizing the characteristic.
The experimental steps are as follows:
1. plate paving: taking RPMI-8226 humanized myeloma cells in logarithmic growth phase, inoculating the RPMI-8226 humanized myeloma cells into a 96-well plate, wherein each well has 100 mu L of cell suspension, and the cell number is 5 multiplied by 10 3 Per well, only 100. Mu.L of 10% FBS-containing complete medium RPM I-1640 was added to the blank control group, and 3 to 5 duplicate wells were set for each group.
2. The RPMI-8226 treated by small molecule compounds with different concentration gradients is placed in a cell culture box (37 ℃, 5% CO) 2 ) Culturing for 24h, adding 5 microliter CCK-8 solution into each hole, and continuously culturing for 3 h and detecting by an enzyme-labeling instrument;
3. and (3) detection: zeroing blank control group, detecting absorbance (OD value) at 450nm wavelength, repeating for 2-3 times, averaging, and calculating IC of administered compound 50 The value is obtained.
The experimental results are as follows: as shown in the following Table 1, the compounds EP8, EP9, EP12 and EP18 in the present invention have significantly better ability to inhibit the proliferation of humanized myeloma cells RPMI-8226 than the compound 25 of the prior patent (patent No. 202011215542.2), and are better than the positive control 10074-G5.
TABLE 1 Effect of 19 Compounds of the invention on cell viability of human myeloma RPMI-8226
1 IC 50 Mean of three measurements ± standard error of mean.
2. Biological experiments
1. Q-PCR assay
Q-PCR was carried out to determine the effect of structurally modified active compounds (EP 8, EP9, EP12 and EP 18) on the transcription of the c-Myc gene in RPMI-8226 cells. Total RNA was extracted and reverse transcribed into cDNA. The cDNA was then used as a template for quantitative PCR amplification of the c-Myc sequence. After 48 hours of treatment with 5. Mu.M ligand, the target cells were collected, total RNA was extracted, and cDNA was synthesized using M-MLV reverse transcriptase synthesis cDNA kit (Promega). Q-PCR experiments were then carried out by SYBR Green reaction mix (Roche) and 2 was used -ΔΔCt The method analyzes the data.
The experimental results are as follows: as shown in FIG. 1 (a), compound EP12 reduced c-Myc mRNA levels at 5. Mu.M, whereas other compounds had no effect. EP12 can reduce the expression level of c-Myc mRNA.
2. Western Blot (WB)
RPMI-8226 cells were treated with 5. Mu.M EP12 for 48 hours, and then the cells were collected and completely lysed with RIPA lysis buffer (Beyotime Biotechnology, shanghai, china). Thereafter, all the extracted proteins were mixed with the loading buffer for subsequent SDS-PAGE. The protein was then transferred to a PVDF membrane, which was incubated with primary β -actin and c-Myc (Proteintech) antibodies.
The experimental results are as follows: as shown in FIG. 1 (b), the expression level of c-Myc was also decreased after treatment with EP12, and it was revealed that EP12 has an inhibitory activity of c-Myc protein.
3. Cell viability and flow cytometry analysis
1X 104 RPMI-8226 cells were seeded in 96-well plates. Cell viability was measured by CCK8 kit (KeyGEN BioTECH, china) after 48 hours incubation with different doses of compound. The rate of apoptosis was determined using Annexin V-APC/7-AAD apoptosis kit (KeygEN BioTECH, china) according to the manufacturer's protocol and analyzed by flow cytometry (BD Biosciences).
The experimental results are as follows: as shown in figure 2, EP12 significantly affected RPMI-8226 apoptosis. The apoptosis rate of EP12 at 5. Mu.M is 21.9%, which induces better apoptosis of RPMI-8226 cells, and proves that EP12 has excellent inhibitory effect on c-Myc in proliferating cells.
3. Circular dichroism spectrum experiment
Circular dichroism experiments were recorded with a J-815CD spectrometer (Jasco) at 25 ℃ in a cuvette with a 1mm optical path. To anneal the oligonucleotides, the samples were heated to 95 ℃, stabilized for 5 minutes, then cooled to room temperature for 30 minutes, and then placed in a 4 ℃ freezer overnight. The oligonucleotide was then diluted to 5M in 10mM Tris buffer (pH 6.8, containing 50mM KCl) and 4 equivalents of compound were added to give 20M compound in 1% DMSO. The CD signal was scanned from 230 nm to 320 nm at a scan speed of 200 nm/min and a bandwidth of 2 nm. CD melting was performed at a heating rate of 1 deg.C/min over a temperature range of 25-95 deg.C by tracking the change in CD signal at the wavelength of maximum CD intensity (264 nm). The melting temperature (Tm) was determined from curve fitting using Origin 9.0 software. The Δ Tm value was determined as the difference in melting temperature between the DNA with and without ligand. All experiments were repeated three times and the values reported are the average of three measurements.
The experimental results are as follows: as shown in fig. 3, circular Dichroism (CD) spectroscopy is commonly used to determine the secondary structure of proteins or nucleic acids. When c-Myc G4 contains K + It will have a positive peak around 264nm and a negative peak at 240nm (FIG. 3, left), indicating the formation of a parallel conformation of c-Myc G4. When EP12 was added, the peak shape changed slightly, indicating that the binding of compound EP12 to c-Myc G4 did not change its conformation. To investigate the stability of this compound to c-Myc G4, a CD melting experiment was performed. As shown on the right of FIG. 3, EP12 tends to stabilize c-Myc G4.
The above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: modifications may be made to the technical solutions described in the foregoing embodiments, or equivalents may be substituted for some of the technical features; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. The application of the compound shown in the formula I, isomers or pharmaceutically acceptable salts thereof in preparing medicines related to multiple myeloma,
wherein,
R 1 represents hydrogen, hydroxy, nitro, carboxy, cyano, amino, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or C 1 -C 4 An alkoxycarbonyl group;
m represents an integer of 1 to 3;
R 2 represents hydrogen, hydroxy, nitro, carboxy, cyano, amino, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or C 1 -C 4 An alkoxycarbonyl group;
n represents an integer of 1 to 3.
2. Use according to claim 1, wherein R 1 Represents fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl; preferably, R 1 Represents fluorine or methoxy; r 2 Represents hydrogen, nitro, fluorine, chlorine, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl or ethoxycarbonyl; preferably, R 2 Represents hydrogen, nitro, fluoro, methyl, ethyl, methoxy, ethoxy or methoxycarbonyl.
3. Use according to claim 1, wherein m represents 1 or 2; preferably, m represents 1; n represents 1 or 2.
4. Use according to claim 1, wherein the compound is selected from:
5. the use according to claim 1, wherein the compound of formula I is prepared by the following synthetic route:
6. a compound, isomer, or pharmaceutically acceptable salt thereof, represented by formula I,
wherein,
R 1 represents hydrogen, hydroxy, nitro, carboxy, cyano, amino, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or C 1 -C 4 An alkoxycarbonyl group;
m represents an integer of 1 to 3;
R 2 represents hydrogen, hydroxy, nitro, carboxy, cyano, amino, halogen, C 1 -C 4 Alkyl radical, C 1 -C 4 Alkoxy or C 1 -C 4 An alkoxycarbonyl group;
n represents an integer of 1 to 3.
7. The compound of claim 6, selected from the group consisting of:
8. a pharmaceutical composition for treating multiple myeloma, which comprises the compound shown as the formula I in claim 6, an isomer, or a pharmaceutically acceptable salt thereof as an active ingredient or a main active ingredient, and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition is formulated as a liquid or solid formulation.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition is formulated as an injection, an oral liquid, a granule, a powder, a tablet, or a capsule.
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| CN115844884A (en) * | 2022-11-29 | 2023-03-28 | 徐州医科大学 | Application of compound EP9 in preparation of drugs for resisting diabetic nephropathy and renal fibrosis |
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| CN115844884A (en) * | 2022-11-29 | 2023-03-28 | 徐州医科大学 | Application of compound EP9 in preparation of drugs for resisting diabetic nephropathy and renal fibrosis |
| CN115844884B (en) * | 2022-11-29 | 2024-03-05 | 徐州医科大学 | Application of compound EP9 in preparation of medicines for resisting renal fibrosis of diabetic nephropathy |
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