CN111233695A - Niclosamide cyclopropyl derivative, preparation method and application thereof - Google Patents
Niclosamide cyclopropyl derivative, preparation method and application thereof Download PDFInfo
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- 229960001920 niclosamide Drugs 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 claims abstract description 41
- 230000002300 anti-fibrosis Effects 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 210000002950 fibroblast Anatomy 0.000 claims description 26
- 210000004881 tumor cell Anatomy 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 13
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 12
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- 229940079593 drug Drugs 0.000 claims description 9
- 150000003839 salts Chemical group 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000013078 crystal Chemical group 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 230000004663 cell proliferation Effects 0.000 claims description 7
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 210000004072 lung Anatomy 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 230000003510 anti-fibrotic effect Effects 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 230000035755 proliferation Effects 0.000 claims description 3
- 206010061968 Gastric neoplasm Diseases 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 210000004204 blood vessel Anatomy 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000037841 lung tumor Diseases 0.000 claims description 2
- 208000019420 lymphoid neoplasm Diseases 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 15
- 206010016654 Fibrosis Diseases 0.000 abstract description 14
- 230000004761 fibrosis Effects 0.000 abstract description 14
- 230000000259 anti-tumor effect Effects 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 5
- 238000006243 chemical reaction Methods 0.000 description 16
- 230000005764 inhibitory process Effects 0.000 description 11
- 208000005069 pulmonary fibrosis Diseases 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FKWORQBQNPAITE-UHFFFAOYSA-N 4-bromobutanoyl bromide Chemical compound BrCCCC(Br)=O FKWORQBQNPAITE-UHFFFAOYSA-N 0.000 description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 229940125890 compound Ia Drugs 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 206010009944 Colon cancer Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 201000001155 extrinsic allergic alveolitis Diseases 0.000 description 2
- 230000003176 fibrotic effect Effects 0.000 description 2
- 208000022098 hypersensitivity pneumonitis Diseases 0.000 description 2
- 230000031700 light absorption Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 230000030248 negative regulation of fibroblast proliferation Effects 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001717 pathogenic effect Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 210000005084 renal tissue Anatomy 0.000 description 2
- 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 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 1
- LSTRKXWIZZZYAS-UHFFFAOYSA-N 2-bromoacetyl bromide Chemical compound BrCC(Br)=O LSTRKXWIZZZYAS-UHFFFAOYSA-N 0.000 description 1
- UCLPNTKRPMTACI-UHFFFAOYSA-N 2-chloro-n-[2-(5-methoxy-1h-indol-3-yl)ethyl]acetamide Chemical compound COC1=CC=C2NC=C(CCNC(=O)CCl)C2=C1 UCLPNTKRPMTACI-UHFFFAOYSA-N 0.000 description 1
- FRXLFVNGTPQFEJ-UHFFFAOYSA-N 3-bromopropanoyl bromide Chemical compound BrCCC(Br)=O FRXLFVNGTPQFEJ-UHFFFAOYSA-N 0.000 description 1
- IIFKIZQRIBFNIN-UHFFFAOYSA-N 5-bromopentanoyl bromide Chemical compound BrCCCCC(Br)=O IIFKIZQRIBFNIN-UHFFFAOYSA-N 0.000 description 1
- NOPKNBDBHMWPEF-UHFFFAOYSA-N 6-bromohexanoyl bromide Chemical compound BrCCCCCC(Br)=O NOPKNBDBHMWPEF-UHFFFAOYSA-N 0.000 description 1
- AINBSIBVRCPNQC-UHFFFAOYSA-N 7-bromoheptanoyl bromide Chemical compound BrCCCCCCC(=O)Br AINBSIBVRCPNQC-UHFFFAOYSA-N 0.000 description 1
- 206010001889 Alveolitis Diseases 0.000 description 1
- 208000029147 Collagen-vascular disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000030852 Parasitic disease Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 150000001262 acyl bromides Chemical group 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000009787 cardiac fibrosis Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000374 effect on fibrosis Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 210000000630 fibrocyte Anatomy 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005918 in vitro anti-tumor Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 206010035653 pneumoconiosis Diseases 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 201000002793 renal fibrosis Diseases 0.000 description 1
- 201000000306 sarcoidosis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention provides a niclosamide cyclopropyl derivative shown in a formula I, which has better anti-fibrosis activity than niclosamide, has good anti-tumor activity, and can be better used for patients with fibrosis and tumor diseases. The invention also provides a preparation method of the niclosamide cyclopropyl derivative, and the niclosamide cyclopropyl derivative can be safely and conveniently prepared.
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a niclosamide cyclopropyl derivative, and a preparation method and application thereof.
Background
Fibrosis refers to a pathological process of decrease or necrosis of parenchymal cells of organs, increase of extracellular matrix in tissues and diffuse excessive deposition of tissues caused by various pathogenic factors, and the continuous progress can lead to the destruction of organ structures and the hypofunction until the failure. Fibrosis can occur in a variety of organs, with the most common clinically occurring fibrosis being mainly: (1) pulmonary fibrosis; (2) liver fibrosis; (3) cardiac fibrosis; (4) renal fibrosis and (5) pancreatic fibrosis; in addition, fibrosis may also occur in the eye, blood vessels, nervous system.
Pulmonary Fibrosis (PF) is a common outcome of various Pulmonary diseases of different etiologies, such as SARS, idiopathic Pulmonary fibrosis, sarcoidosis, pneumoconiosis, hypersensitivity pneumonitis, drug and radiation induced Pulmonary fibrosis, and fibrotic alveolitis associated with collagen vascular disease. It has a potentially large pathogenic base, and many common basic diseases are likely to cause pulmonary fibrosis, which should be of greater concern in the medical and pharmaceutical fields.
Niclosamide is an FDA approved small molecule preparation, and is mainly used for resisting intestinal parasitic infection in the past clinic. In recent years, researches show that the small molecular compound has a good anti-fibrosis effect, and an invention patent with the application number of CN201210158802.6 and the patent name of 'application of niclosamide or salt thereof in preparing a medicament for preventing and treating pulmonary fibrosis' discloses the curative effect of niclosamide on inhibiting pulmonary fibrosis, and provides a good direction for treating pulmonary fibrosis.
In addition, niclosamide or a drug taking niclosamide as an active center has a certain research on other common fibrosis, for example, the invention patent with the application number of CN201810496062.4, namely the patent name of the application of niclosamide and a structure modifier thereof in heart protection, pulmonary hypertension resistance and tumor resistance, discloses that niclosamide has a good curative effect on resisting heart fibrosis; the invention patent with the application number of CN201510916996.5 and the patent name of the application of niclosamide phosphate in preparing the medicine for inhibiting the kidney tissue fibrosis discloses the function of niclosamide in inhibiting the kidney tissue fibrosis.
The disclosures in the above patents show that niclosamide has a certain therapeutic effect in inhibiting fibrosis, but the effect thereof has a great space for improvement, and in order to better serve patients with fibrotic diseases, it is necessary to further improve niclosamide and develop a new compound having better anti-fibrotic activity.
Disclosure of Invention
One of the purposes of the invention is to provide a niclosamide cyclopropyl derivative which has better anti-fibrosis activity than niclosamide, has better anti-tumor activity and can better serve patients with fibrosis and tumor diseases.
Another object of the present invention is to provide a method for preparing the niclosamide cyclopropyl derivative, which can safely and conveniently prepare the niclosamide cyclopropyl derivative of the present invention.
Other objects of the present invention are to provide a pharmaceutical composition comprising the above niclosamide cyclopropyl derivative as an active ingredient and use of the niclosamide cyclopropyl derivative of the present invention.
Therefore, the inventor provides the following technical scheme:
firstly, the inventor provides niclosamide cyclopropyl derivatives shown as a formula I or pharmaceutically acceptable salts, crystal forms, hydrates or solvates thereof,
in the formula: m is 1-6; preferably, m is 1 to 5, more preferably, m is 1, 2, 3 or, 4; even more preferably: m is 1, 2 or 3; most preferably, m is 1 or 2.
When m is 1, the structural formula of the compound I is as follows:
the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof is a compound which is researched and developed on the basis of understanding of the application of niclosamide in anti-fibrosis effect, has good synergistic effect on the anti-fibrosis of niclosamide, is formed by creatively introducing cyclopropyl into niclosamide molecules to form a niclosamide cyclopropyl derivative, and has anti-fibrosis activity obviously superior to that of niclosamide under the synergistic effect of cyclopropyl, thereby bringing good treatment effect on fibrosis patients, particularly patients with pulmonary fibrosis; in addition, the compound shown in the formula I has an anti-tumor effect equivalent to that of niclosamide.
The invention also provides a preparation method of the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof, which comprises the following steps:
step 1: under the action of alkali, cyclopropylamine reacts with bromoyl bromide IV in a solvent to obtain a compound III;
step 2: and adding alkali into the compound III and niclosamide in a solvent to react to obtain a compound I.
In the formula: m is 1 to 6.
In the reactions in the step 1 and the step 2, the alkali is one or more selected from potassium carbonate, sodium carbonate and triethylamine; the solvent is selected from one or more of dichloromethane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and 1, 4-dioxane.
Step 2, which is a key step in the preparation method of compound I of the present application, is to react compound III with niclosamide to load cyclopropyl groups on the niclosamide molecule and introduce an acyl bromide group, thereby forming a new compound: the niclosamide cyclopropyl derivative is simple and safe in reaction process and easy to realize industrialization; in addition, the reaction between bromoyl bromide and cyclopropyl is a conventional chemical combination reaction, and can produce the compound III in high yield, so as to provide a simple and easily available raw material for the reaction of step 2.
On the basis of the content of the invention, the invention also provides a pharmaceutical composition, which is a preparation prepared by taking the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
Specifically, the pharmaceutical composition can be tablets, capsules, granules, injections, suspensions and the like; the above adjuvants can be one or more selected from excipient (including solid carrier, pasty carrier, or liquid solvent), antiseptic, lubricant, antioxidant, emulsifier, suspending agent, binder, stabilizer, cosolvent, dispersant, buffer, pH regulator, antifreezing agent, correctant, disintegrating agent, filler, and colorant.
The invention also provides application of the compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof in preparing anti-fibrosis drugs and/or anti-tumor drugs.
Specifically, the anti-fibrosis drug is a drug for inhibiting fibroblast proliferation; more specifically, the fibroblast is any one or more of embryonic fibroblast, lung fibroblast, liver fibroblast, heart fibroblast, kidney fibroblast, pancreas fibroblast, eye fibroblast and vascular fibroblast; more particularly, the fibroblast is a lung fibroblast.
The anti-tumor medicament is a medicament for inhibiting tumor cell proliferation; specifically, the tumor cells are any one or more of breast tumor cells, colorectal tumor cells, lung tumor cells, gastric tumor cells and lymphoid tumor cells; more specifically, the tumor cell is a breast tumor cell or a colorectal tumor cell.
The invention has the beneficial effects that:
1. the niclosamide cyclopropyl derivative has better anti-fibrosis activity than niclosamide and better treatment effect than niclosamide on fibrosis diseases; experiments prove that the inhibition rate of the compound on the proliferation of the lung fibrocyte can reach more than 85 percent, and the inhibition rate of the compound has obvious synergy relative to 77 percent of inhibition rate of niclosamide, so that the niclosamide cyclopropyl derivative has good industrialization prospect.
2. The niclosamide cyclopropyl derivative has good anti-tumor activity.
3. The preparation method of the niclosamide cyclopropyl derivative has simple and safe reaction process and is easy to realize industrialization.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following examples are presented to enable those skilled in the art to more fully understand the present invention and are not intended to limit the invention in any way.
Example 1
This example provides compound IIIa and a method for its preparation:
the specific preparation process of the compound IIIa comprises the following steps:
under ice-water bath conditions, cyclopropylamine (1.47mmol) was dissolved in dichloromethane (2mL) and triethylenetetramine was added0.21mL (1.47mmol) of amine was added dropwise slowly, compound Iva bromoacetyl bromide (1.47mmol) was stirred for 15min, the reaction was terminated, water (6mL) was added to the reaction solution, dichloromethane (3X 3mL) was extracted, the organic phases were combined, washed with saturated brine (1X 3mL), dried over anhydrous sodium sulfate, the solvent was evaporated off, and the residue was chromatographed on a silica gel column to give compound IIIa. Of compound IIIa1H NMR(300MHz,CDCl3)δ:6.66(s,1H),3.83(d,J＝2.2Hz,2H),2.71(tq,J＝7.2,3.8Hz,1H),0.91～0.67(m,2H),0.55(ddd,J＝6.9,5.3,3.8Hz,2H)。
Example 2
The embodiment provides a niclosamide cyclopropyl derivative Ia and a preparation method thereof:
the specific preparation process of the compound Ia comprises the following steps:
the compound IIIa (0.85mmol) obtained in example 1 was dissolved in acetonitrile (15mL), and potassium carbonate 235mg (1.70mmol) and niclosamide 277mg (0.85mmol) were added to react for 3 hours, after completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product Ia. Of compounds Ia1H NMR(300MHz,DMSO-d6)δ:10.86(s,1H),8.63(d,J＝9.2Hz,1H),8.43(d,J＝2.6Hz,1H),8.37(s,1H),8.29(dd,J＝9.2,2.6Hz,1H),7.93(d,J＝2.8Hz,1H),7.66(dd,J＝9.0,2.8Hz,1H),7.19(d,J＝9.0Hz,1H),4.88(s,2H),2.63(dq,J＝7.1,3.5Hz,1H),0.61(dd,J＝7.1,2.3Hz,2H),0.47～0.24(m,2H).HR-MS(ESI)m/z:Calcdfor C18H15Cl2N3O5Na{[M+Na]+}446.0286,found 446.0278。
Example 3
The embodiment provides a niclosamide cyclopropyl derivative Ia and a preparation method thereof:
the specific preparation process of the compound Ia comprises the following steps:
the compound IIIa (0.85mmol) obtained in example 1 was dissolved in dichloromethane (15mL), 172mg of triethylamine (1.70mmol) and 277mg of niclosamide (0.85mmol) were added, the reaction was carried out for 3 hours, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product Ia.
Example 4
The embodiment provides a niclosamide cyclopropyl derivative Ia and a preparation method thereof:
the specific preparation process of the compound Ia comprises the following steps:
the compound IIIa (0.85mmol) obtained in example 1 was dissolved in tetrahydrofuran (15mL), and 180mg (1.70mmol) of sodium carbonate and 277mg (0.85mmol) of niclosamide were added to react for 3 hours, after completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give product Ia.
Example 5
This example provides compound IIIb and a method for its preparation:
the specific preparation process of the compound IIIb comprises the following steps:
under the condition of ice-water bath, dissolving cyclopropylamine (1.47mmol) in dichloromethane (2mL), adding triethylamine 0.21mL (1.47mmol), slowly dropwise adding compound IVb bromopropionyl bromide (1.47mmol), stirring for 15min, finishing the reaction, adding water (6mL) into the reaction solution, extracting with dichloromethane (3X 3mL), combining organic phases, washing with saturated saline (1X 3mL), drying with anhydrous sodium sulfate, evaporating to remove the solvent, and carrying out silica gel column chromatography on the residue to obtain compound IIIb and compound IIIb1H NMR(300MHz,CDCl3)δ:6.68(s,1H),3.59(t,J＝2.2Hz,2H),2.71(m,1H),2.68(t,J＝2.2Hz,2H),0.91～0.67(m,2H),0.55(m,2H)。
Example 6
The embodiment provides a niclosamide cyclopropyl derivative Ib and a preparation method thereof:
the specific preparation process of the compound Ib is as follows:
dissolving the compound IIIb (0.85mmol) prepared in example 5 in acetonitrile (15mL), adding potassium carbonate 235mg (1.70mmol), niclosamide 277mg (0.85mmol), reacting for 3h, concentrating under reduced pressure, and purifying the residue by silica gel column chromatography to obtain product Ib, compound Ib1H NMR(300MHz,DMSO-d6)δ:10.88(s,1H),8.64(d,J＝9.2Hz,1H),8.45(d,J＝2.6Hz,1H),8.37(s,1H),8.29(m,1H),7.93(d,J＝2.8Hz,1H),7.66(m,1H),7.19(d,J＝9.0Hz,1H),4.86(t,J＝2.5Hz,2H),2.68(t,J＝2.5Hz,2H),2.63(m,1H),0.61(m,2H),0.47～0.24(m,2H).
Example 7
This example provides compound IIIc and a method for its preparation:
the specific preparation process of the compound IIIc comprises the following steps:
under the condition of an ice-water bath, cyclopropylamine (1.47mmol) is dissolved in dichloromethane (2mL), triethylamine 0.21mL (1.47mmol) is added, the compound IVc bromobutyryl bromide (1.47mmol) is slowly added dropwise, stirring is carried out for 15min, the reaction is finished, water (6mL) is added to the reaction solution, dichloromethane (3X 3mL) is used for extraction, organic phases are combined, the mixture is washed with saturated saline (1X 3mL), dried over anhydrous sodium sulfate, the solvent is evaporated, and the residue is subjected to silica gel column chromatography to obtain the compound IIIc.1H NMR(300MHz,CDCl3)δ:6.68(s,1H),3.51(t,J＝2.3Hz,2H),2.71(m,1H),2.34(m,2H),2.07(t,J＝2.5Hz,2H),0.91～0.67(m,2H),0.55(m,2H)。
Example 8
The embodiment provides a niclosamide cyclopropyl derivative Ic and a preparation method thereof:
the specific preparation process of the compound Ic is as follows:
the compound IIIc (0.85mmol) obtained in example 7 was dissolved in acetonitrile (15mL), potassium carbonate 235mg (1.70mmol) and niclosamide 277mg (0.85mmol) were added, the reaction was carried out for 3h, concentration under reduced pressure was carried out, and the residue was purified by silica gel column chromatography to give product Ic, compound Ic of formula Ic1H NMR(300MHz,DMSO-d6)δ:10.87(s,1H),8.64(d,J＝9.2Hz,1H),8.46(d,J＝2.6Hz,1H),8.37(s,1H),8.29(m,1H),7.94(d,J＝2.8Hz,1H),7.66(m,1H),7.19(d,J＝9.0Hz,1H),4.84(t,J＝2.7Hz,2H),2.63(m,3.5Hz,1H),2.34(m,2H),2.09(t,J＝2.5Hz,2H),0.63(m,2H),0.47～0.24(m,2H).
Example 9
This example provides a niclosamide cyclopropyl derivative Id (m ═ 4) and a preparation method thereof, including the following steps:
step 1:
step 2:
the above-mentioned compound IIId can be prepared by a method different from that of example 7 in that compound IVc (bromobutyryl bromide) is replaced with compound IVd (bromovaleryl bromide);
the above-mentioned production method of the compound Id is different from that of example 8 in that the compound IIIc is replaced with the compound IIId.
Example 10
This example provides a niclosamide cyclopropyl derivative Ie (m ═ 5) and a preparation method thereof, including the following steps:
step 1:
step 2:
the above-mentioned compound IIIe can be prepared by a process which differs from that of example 7 in that compound IVc (bromobutyryl bromide) is replaced by compound IVe (bromohexanoyl bromide);
the above-mentioned process for the preparation of compound Ie differs from example 8 in that compound IIIc is replaced by compound IIIe.
Example 11
This example provides a niclosamide cyclopropyl derivative If (m ═ 6) and a preparation method thereof, including the following steps:
step 1:
step 2:
the above-mentioned compound IIIf can be prepared by a method different from that of example 7 in that compound IVc (bromobutyryl bromide) is replaced with compound IVf (bromoheptanoyl bromide);
the above-mentioned compound If was prepared in a manner different from that of example 8 in that compound IIIc was replaced with compound IIIf.
Experimental example 1
In vitro anti-fibrotic Activity Studies
This experimental example demonstrates the inhibitory effect of the niclosamide derivative Ia prepared in example 2 on fibroblasts, and compares it with the inhibitory effect of niclosamide on fibroblasts. The specific experimental process is as follows:
inoculating 3T3 cells in logarithmic growth phase into 96-well culture plate with 1300 cells per well and 100 μ L/well, standing at 37 deg.C and 5% CO2Incubate in incubator for 24 hours. Setting blank control group (culture medium without medicine) and positive medicine group, compound concentration is 10 μmol/L, setting 5 multiple wells, and adding CO2Incubator (37 ℃, 5% CO)2) Middle cultureAnd 72 h. Adding 20 mu L of 5mg/mL MTT solution into each hole, continuously culturing for 3h, discarding the supernatant, adding 150 mu L DMSO into each hole, shaking for 5min to dissolve formazan particles, measuring the light absorption value at 492nm wavelength by using an enzyme labeling instrument, and calculating the inhibition rate of the control group and the experimental group on the fibroblasts according to the OD value of absorbance.
The inhibition ratio%.
After 48h and 72h, the MTT method detects the evaluation results of the inhibition rate of the compound of the invention on the cell proliferation of the mouse 3T3 at two concentrations of 10 and 30 mu M, and the results are shown in Table 1.
TABLE 1 results of inhibition of fibroblast proliferation by Compounds of the invention
Description of the drawings: the higher the inhibition rate, the better the anti-fibrosis activity of the compound is; the inhibition activity of the blank control was 0 and niclosamide was used as a positive control.
The above results show that: compared with niclosamide, the compound provided by the invention has a relatively obvious improvement on both the 48h inhibition rate and the 72h inhibition rate of mouse 3T3 cell proliferation, which indicates that the compound provided by the invention has an obvious synergistic effect on inhibition of fibroblast proliferation compared with niclosamide.
Experimental example 2
In vitro antitumor Activity Studies
This experimental example demonstrates the tumor-inhibiting effect of the niclosamide derivative Ia prepared in example 2, and compares it with the tumor-cell-inhibiting effect of niclosamide. The specific experimental process is as follows:
inoculating the tumor cells in logarithmic growth phase to 96-well culture plate with 1300 cells per well and 100 μ L/well, standing at 37 deg.C and 5% CO2Incubate in incubator for 24 hours. Setting blank control group (culture medium without medicine) and positive medicine group (culture medium containing niclosamide), the compound concentration is 10 μmol/L, setting 5 multiple wells, and adding CO2Incubator (37 ℃, 5% CO)2) And culturing for 72 h. Adding 20 μ L of 5mg/mL MTT solution into each well, culturing for 3 hr, and discardingRemoving supernatant, adding 150 μ L DMSO into each well, shaking for 5min to dissolve formazan particles, measuring light absorption value at 492nm wavelength with microplate reader, and calculating IC of control group and experimental group according to OD value50And (6) obtaining the result.
The test results are shown in table 2:
TABLE 2 IC of compounds of the invention on tumor cell proliferation50Results (in. mu.M)
Description of the drawings: IC (integrated circuit)50The half inhibition concentration is shown, the smaller the numerical value is, the better the anti-tumor activity is, and niclosamide is used as a positive control. 4T1 is mouse breast cancer cell, MDA-MB-231, MCF-7 is human breast cancer cell, CT26 is mouse colorectal cancer cell, HCT116 is human colorectal cancer cell.
The above results show that: compared with niclosamide, the compound of the invention has basically equivalent IC50 for 72h of tumor cell proliferation, and has good anti-tumor cell proliferation effect.
In conclusion, the niclosamide cyclopropyl derivative has better effect of resisting fibroblast growth than niclosamide, has excellent effect of resisting tumor cell proliferation, and can be well used for patients with fibrosis and tumor diseases.
The above is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and various modifications and changes will occur to those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A compound shown in formula I or a pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof,
in the formula: m is 1 to 6.
2. A method for preparing a compound represented by formula III, comprising the steps of:
step 1: under the action of alkali, cyclopropylamine reacts with bromoyl bromide IV in a solvent to obtain a compound III;
in the formula: m is 1 to 6.
3. The preparation method according to claim 2, wherein the base in step 1 is one or more selected from potassium carbonate, sodium carbonate and triethylamine; the solvent in the step 1 is one or more selected from dichloromethane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and 1, 4-dioxane.
4. A process for the preparation of a compound of formula i, comprising the steps of:
step 2: reacting the compound III as claimed in any one of claims 2 or 3 with niclosamide in a solvent with the addition of a base to obtain a compound I;
in the formula: m is 1 to 6.
5. The preparation method according to claim 4, wherein the base in the step 2 is selected from one or more of potassium carbonate, sodium carbonate and triethylamine; the solvent in the step 2 is selected from one or more of dichloromethane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, N, N-dimethylacetamide and 1, 4-dioxane.
6. A pharmaceutical composition is characterized in that the pharmaceutical composition is a preparation prepared by taking a compound shown as a formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
7. The compound shown in the formula I or pharmaceutically acceptable salt, crystal form, hydrate or solvate thereof is applied to the preparation of anti-fibrosis drugs and/or anti-tumor drugs.
8. The use of claim 7, wherein the anti-fibrotic drug is a drug that inhibits fibroblast proliferation; the anti-tumor drug is a drug for inhibiting tumor cell proliferation.
9. The use of claim 8, wherein the fibroblast is any one or more of embryonic fibroblast, lung fibroblast, liver fibroblast, heart fibroblast, kidney fibroblast, pancreas fibroblast, eye fibroblast, and blood vessel fibroblast.
10. The use of claim 8, wherein the tumor cells are any one or more of breast tumor cells, colorectal tumor cells, lung tumor cells, gastric tumor cells, and lymphoid tumor cells.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254183A (en) * | 2008-03-19 | 2008-09-03 | 中国科学院广州生物医药与健康研究院 | Novel use of niclosamide and pharmaceutically acceptable salt thereof |
| CN102697760A (en) * | 2012-05-21 | 2012-10-03 | 南京大学 | Application of niclosamide and salts of niclosamide in preparation of drugs for preventing and treating pulmonary fibrosis |
| WO2014113467A1 (en) * | 2013-01-15 | 2014-07-24 | Board Of Regents, The University Of Texas System | Stat3 inhibitor |
| CN105362280A (en) * | 2015-12-11 | 2016-03-02 | 南方医科大学南方医院 | Application of niclosamide phosphate to preparation of medicine for inhibiting kidney tissue fibrosis |
| CN106038527A (en) * | 2016-06-24 | 2016-10-26 | 南京海澳斯生物医药科技有限公司 | Application of composition of derivatives of Artalbic acid in preparation of anti-liver fibrosis medicine |
| KR101910078B1 (en) * | 2017-09-08 | 2018-10-19 | 한국원자력의학원 | Composition for inhibiting CIP2A comprising niclosamide |
| CN108815148A (en) * | 2018-05-22 | 2018-11-16 | 哈尔滨医科大学 | Niclosamidum and its structural modification object Cardioprotective, anti-pulmonary hypertension and it is antitumor in application |
-
2020
- 2020-03-13 CN CN202010176865.9A patent/CN111233695B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101254183A (en) * | 2008-03-19 | 2008-09-03 | 中国科学院广州生物医药与健康研究院 | Novel use of niclosamide and pharmaceutically acceptable salt thereof |
| CN102697760A (en) * | 2012-05-21 | 2012-10-03 | 南京大学 | Application of niclosamide and salts of niclosamide in preparation of drugs for preventing and treating pulmonary fibrosis |
| WO2014113467A1 (en) * | 2013-01-15 | 2014-07-24 | Board Of Regents, The University Of Texas System | Stat3 inhibitor |
| US20150361031A1 (en) * | 2013-01-15 | 2015-12-17 | Board Of Regents, The University Of Texas System | Stat3 inhibitor |
| CN105362280A (en) * | 2015-12-11 | 2016-03-02 | 南方医科大学南方医院 | Application of niclosamide phosphate to preparation of medicine for inhibiting kidney tissue fibrosis |
| CN106038527A (en) * | 2016-06-24 | 2016-10-26 | 南京海澳斯生物医药科技有限公司 | Application of composition of derivatives of Artalbic acid in preparation of anti-liver fibrosis medicine |
| KR101910078B1 (en) * | 2017-09-08 | 2018-10-19 | 한국원자력의학원 | Composition for inhibiting CIP2A comprising niclosamide |
| CN108815148A (en) * | 2018-05-22 | 2018-11-16 | 哈尔滨医科大学 | Niclosamidum and its structural modification object Cardioprotective, anti-pulmonary hypertension and it is antitumor in application |
Non-Patent Citations (4)
| Title |
|---|
| ，SIMON J. SHAW等: "Structure-Activity Relationships of 9-Substituted-9-Dihydroerythromycin-Based Motilin Agonists: Optimizing for Potency and Safety", 《J. MED. CHEM.》, vol. 52, pages 6851 - 6859 * |
| 刘会财，等: "氯硝柳胺衍生物的合成及抗肿瘤活性研究", 《化学研究与应用》, vol. 27, no. 6, pages 886 - 890 * |
| 刘大伟: "第一部分： ６ － （α 乙基鹅去氧胆酸及其衍生物的设计与合成 第二部分： 氯硝柳胺衍生物的设计与合成与生物活性评价", 《广西医科大学硕士学位论文》 * |
| 常晓燕，等: "氯硝柳胺磷酸酯通过抑制Wnt /β - catenin 通路 抑制肾脏组织纤维化", 《安徽医科大学学报》, vol. 43, no. 10, pages 1538 - 1543 * |
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