CN110922368B - Chloro-phenyl-isoxazole aminobenzoic acid derivative and preparation method and application thereof - Google Patents
Chloro-phenyl-isoxazole aminobenzoic acid derivative and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- -1 Chloro-phenyl-isoxazole aminobenzoic acid derivative Chemical class 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 229910001923 silver oxide Inorganic materials 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 150000008316 benzisoxazoles Chemical class 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 6
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 description 5
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 102000003746 Insulin Receptor Human genes 0.000 description 2
- 108010001127 Insulin Receptor Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- FBKJXTWVDQJDDU-UHFFFAOYSA-N NC(C(C1=NOC=C1)=C(C1=CC=CC=C1)C(Cl)=C1)=C1C(O)=O Chemical class NC(C(C1=NOC=C1)=C(C1=CC=CC=C1)C(Cl)=C1)=C1C(O)=O FBKJXTWVDQJDDU-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- CMZUMMUJMWNLFH-UHFFFAOYSA-N sodium metavanadate Chemical compound [Na+].[O-][V](=O)=O CMZUMMUJMWNLFH-UHFFFAOYSA-N 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910000166 zirconium phosphate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a chloro-benzisoxazole aminobenzoic acid derivative, a preparation method and application thereof, wherein the halogenated benzisoxazole derivative has a structure shown in a formula I:
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a chloro-phenyl isoxazole aminobenzoic acid derivative, and a preparation method and application thereof.
Background
Diabetes is a metabolic disease, and patients usually have hyperglycemia, so that the diabetes causes functional disorders of tissues and organs such as eyes, hearts, kidneys and nerves. Protein tyrosine enzyme 1B (PTP1B) regulates the phosphorylation level of tyrosine in cells by interacting with protein tyrosine phosphokinases to accomplish intracellular signal transduction. Overexpression of PTP1B can lead to over-dephosphorylation of insulin and insulin receptor, thus further hindering the binding process of insulin and insulin receptor and further leading to insulin resistance in organisms. Therefore, the development of a novel PTP1B inhibitor is expected to be useful for the treatment of diabetes. The applicant recently discovered that a halogenated benzisoxazole derivative has strong PTP1B inhibitory activity, and in order to further study the influence of the position of an amino group in a group cyclohexane amine on the structure-activity relationship, the applicant carried out the design of a series of compounds.
Disclosure of Invention
The invention provides a chloro-benzisoxazole aminobenzoic acid derivative with a structure shown in formula I or a pharmaceutically acceptable salt thereof, which is characterized in that the structure shown in formula I is as follows:
another embodiment of the present invention provides a method for preparing a chloro-benzisoxazole aminobenzoic acid derivative having the structure of formula I above, which is characterized by comprising the steps of:
(1) in an organic solvent, reacting a compound shown in a formula II with a compound shown in a formula III under the action of silver oxide to obtain a compound shown in a formula IV;
(2) the compound of formula IV is demethylated under alkaline conditions and the pH is adjusted to 5-6 to obtain the compound of formula I.
In the step (1), the organic solvent is preferably one or more of acetonitrile, toluene and dioxane. A compound of formula II: the compound of formula III is 1:3.0-4.0 (molar ratio), the molar amount of silver oxide and the compound of formula III is the same, and the reaction temperature is preferably 70 ℃ to reflux temperature; AgOTf is preferably added to the reaction in a molar amount of from 10% to 15% of the compound of formula III.
The alkaline condition in step (2) is preferably NaOH/MeOH or KOH/MeOH, and the pH is 9-10.
Another embodiment of the present invention provides an intermediate of formula V for the preparation of a compound of formula I, characterized in that formula V has the following structure:
Another embodiment of the present invention provides the use of an intermediate of formula V, as described above, preferably formula IV, in the preparation of a compound of formula I.
Another embodiment of the present invention provides a process for the preparation of an intermediate of formula IV, characterized by the steps of:
and (3) in an organic solvent, reacting the compound of the formula II with the compound of the formula III under the action of silver oxide to obtain the compound of the formula IV.
In the step (1), the organic solvent is preferably one or more of acetonitrile, toluene and dioxane. A compound of formula II: the compound of formula III is 1:3.0-4.0 (molar ratio), the molar amount of silver oxide and the compound of formula III is the same, and the reaction temperature is preferably 70 ℃ to reflux temperature; AgOTf is preferably added to the reaction in a molar amount of from 10% to 15% of the compound of formula III.
In another embodiment, the present invention provides the use of a chlorobenzoisoxazole aminobenzoic acid derivative of the structure of formula I above or a pharmaceutically acceptable salt thereof in the preparation of PTP1B inhibitors.
In another embodiment of the invention, the application of the chloro-phenyl isoxazolyl aminobenzoic acid derivative with the structure shown in the formula I or the pharmaceutically acceptable salt thereof in preparing the medicine for treating diabetes is provided.
Another embodiment of the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition comprises a chloro-benzisoxazole aminobenzoic acid derivative having the structure of formula I or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition may also comprise other drugs for treating diabetes. The pharmaceutical composition may further comprise pharmaceutically acceptable excipients. The dosage form of the pharmaceutical composition is selected from solid preparation, liquid preparation or semisolid preparation. Preferably tablets, capsules or injections.
The compounds of formula II, the compounds of formula III for use in the present invention are commercially available (and can be prepared by one skilled in the art on their own). For example, the compounds of the formula II can be prepared from
(wherein P is a hydroxyl protecting group and X is a leaving group) with
The preparation method comprises the following steps of.
Detailed Description
To facilitate a further understanding of the invention, the following examples are provided to illustrate it in more detail. However, these examples are only for better understanding of the present invention and are not intended to limit the scope or the principle of the present invention, and the embodiments of the present invention are not limited to the following.
Example 1
Taking the compound of formula II (1.0mmol) and the compound of formula III(4.0mmol), dissolved in 25mL of toluene, and Ag added 2 O (4.0mmol), heating to reflux temperature for 15 hours, TLC detecting the disappearance of the compound of formula II, stopping heating and returning to room temperature, filtering, concentrating the filtrate, and silica gel column chromatography (ethyl acetate/petroleum ether: 1/10-1/5) to obtain 38.8mg of a white solid, i.e., the compound of formula IV, with a yield of about 7.3%. Structure confirmation data: mp: 109 ℃ and 111 ℃ ESI-MS M/z 531.2[ M + H ]] + 。
Dissolving the compound of formula IV (30mg) in NaOH/MeOH solution (6mL, pH 9-10), reacting at room temperature for 3 hours, adding diluted hydrochloric acid (1mol/L) to adjust pH to 5-6, concentrating under reduced pressure, extracting with ethyl acetate, washing with water, concentrating the organic phase, and performing silica gel column chromatography (ethyl acetate/petroleum ether: 1/5-1/3) to obtain 21.6mg of white solid, i.e., the compound of formula I, with a yield of about 74.0%, as structural confirmation data: mp: 114 ℃ and 116 ℃ ESI-MS M/z 515.2[ M-H ]] - ， 1 H NMR(DMSO-d 6 ,400MHz)δ:7.66(d,1H),7.64(s，1H),7.56(dd，1H),7.10-7.05(m，3H),6.67(d,1H),5.74-5.72(m,1H),4.22(s,2H),3.38-3.36(m,1H),3.02-2.99(m,1H),2.82(t,2H),2.04-1.94(m,1H),1.75-1.70(m,4H),1.32(d,6H),0.94-0.81(m,4H).
Example 2
Dissolving the compound of formula II (1.0mmol) and the compound of formula III (3.0mmol) in 25mL acetonitrile, adding Ag 2 O (3.0mmol) and AgOTf (0.3mmol, about 77.1mg) were heated to 70 ℃ to react overnight, the disappearance of the compound of formula II was detected by TLC, after returning to room temperature by stopping heating, the filtrate was concentrated and subjected to silica gel column chromatography (ethyl acetate/petroleum ether 1/10-1/5) to give 152.0mg of a white solid, which was the same as the compound of formula IV prepared in example 1 by TLC comparison, yield was about 28.6%, ESI-MS M/z 531.2[ M + H + 531.2 ]] + ，533.2[M+2+H] + 。
Example 3
Compounds of the present invention were tested for inhibitory activity against tyrosine phosphatase 1B (PTP1B) according to routine procedures in the art. Enzyme activity buffer solution of the reaction system: glycerol 10%, HEPES 50mM pH7.2, NaCl 10mM, BSA 0.10%; the reaction was performed in 96-well plates, with a total reaction system of 100 μ L, divided into three groups, an experimental group, a negative control group and a positive control group. Each well of the experimental group was sequentially addedmu.L 100nM PTP1B (obtained by artificial purification), 2. mu.L 50mM compound of formula I (dissolved in DMSO), mixed well with shaking for 30s, incubated for 10min at 32 ℃ and then 50. mu.L 50mM pNPP was added, mixed well with shaking for 30s, OD was measured at 405nM and the inhibition was calculated, i.e. [1- (OD sample-OD blank)/(OD negative-OD blank)]X 100%. Using software and calculating to obtain IC 50 The results are shown in the following table. The negative control group replaced "2. mu.L of 50mM compound of formula I (dissolved in DMSO)" in the experimental group with 2. mu.L DMSO; the positive control group used 2. mu.L of 50mM sodium vanadate instead of "2. mu.L of 50mM compound of formula I (dissolved in DMSO)" in the experimental group.
| Group of | IC 50 (μM) |
| Experimental group | 5.61±0.33 |
| Positive control group | 7.92±0.65 |
Claims (10)
1. A chloro-benzisoxazole aminobenzoic acid derivative of formula I or a pharmaceutically acceptable salt thereof as a PTP1B inhibitor, characterized in that formula I has the following structure:
2. the preparation method of the chloro-benzisoxazole aminobenzoic acid derivative with the structure of formula I as claimed in claim 1, is characterized by comprising the following steps:
(1) in an organic solvent, reacting a compound shown in a formula II with a compound shown in a formula III under the action of silver oxide to obtain a compound shown in a formula IV;
(2) after removing methyl from the compound of the formula IV under alkaline conditions, adjusting the pH value to 5-6 to obtain a compound of a formula I;
in the step (1), the organic solvent is selected from one or more of acetonitrile, toluene and dioxane; the molar ratio of the compound of the formula II to the compound of the formula III is 1:3.0-4.0, the molar amount of the silver oxide is the same as that of the compound of the formula III, and the reaction temperature is 70 ℃ to the reflux temperature.
3. The process according to claim 2, wherein AgOTf is added to the reaction of step (1) in a molar amount of from 10% to 15% of the compound of formula III.
4. The process of claim 2, wherein in step (2), the basic conditions are selected from KOH/MeOH or NaOH/MeOH, and the pH is 9-10.
5. An intermediate of formula V for the preparation of a compound of formula I according to claim 1, characterized in that formula V has the following structure:
6. A process for the preparation of an intermediate of formula IV, comprising the steps of:
and (3) in an organic solvent, reacting the compound of the formula II with the compound of the formula III under the action of silver oxide to obtain the compound of the formula IV.
7. Use of a chloro-benzisoxazole aminobenzoic acid derivative of formula I according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a PTP1B inhibitor.
8. A pharmaceutical composition, characterized in that it comprises the chloro-benzisoxazole aminobenzoic acid derivative of formula I as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition further comprises other agents for treating diabetes.
10. The pharmaceutical composition of claim 9, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
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| CN201911211205.3A CN110922368B (en) | 2019-11-29 | 2019-11-29 | Chloro-phenyl-isoxazole aminobenzoic acid derivative and preparation method and application thereof |
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|---|---|---|---|
| CN201911211205.3A CN110922368B (en) | 2019-11-29 | 2019-11-29 | Chloro-phenyl-isoxazole aminobenzoic acid derivative and preparation method and application thereof |
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| CN110922368A CN110922368A (en) | 2020-03-27 |
| CN110922368B true CN110922368B (en) | 2022-08-16 |
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| CN101977505A (en) * | 2007-06-13 | 2011-02-16 | 葛兰素史密丝克莱恩有限责任公司 | Farnesoid x receptor agonists |
| WO2017201152A1 (en) * | 2016-05-18 | 2017-11-23 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as fxr agonists and methods of use thereof |
| WO2019089667A1 (en) * | 2017-11-01 | 2019-05-09 | Bristol-Myers Squibb Company | Bridged bicyclic compounds as farnesoid x receptor modulators |
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2019
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101977505A (en) * | 2007-06-13 | 2011-02-16 | 葛兰素史密丝克莱恩有限责任公司 | Farnesoid x receptor agonists |
| CN101877966A (en) * | 2007-07-02 | 2010-11-03 | 葛兰素史密丝克莱恩有限责任公司 | Farnesoid X receptor agonists |
| WO2017201152A1 (en) * | 2016-05-18 | 2017-11-23 | Enanta Pharmaceuticals, Inc. | Isoxazole derivatives as fxr agonists and methods of use thereof |
| WO2019089667A1 (en) * | 2017-11-01 | 2019-05-09 | Bristol-Myers Squibb Company | Bridged bicyclic compounds as farnesoid x receptor modulators |
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