CN104557862A - Heterocyclic compound having Wnt signal channel inhibitory activity - Google Patents
Heterocyclic compound having Wnt signal channel inhibitory activity Download PDFInfo
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
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- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three 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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Abstract
The invention relates to a heterocyclic compound having the Wnt signal channel inhibitory activity, comprising the compound and pharmaceutically acceptable salts, various isotopes, various isomers or various crystal structures thereof. The heterocyclic compound disclosed by the invention has a structure represented by the general formula I as shown in the specification. The compound and the combined application compositions related by the invention are capable of effectively inhibiting a Wnt signal channel and treating or preventing diseases related to the Wnt signal channel.
Description
Technical field
The invention belongs to medical art, particularly relate to a kind of heterogeneous ring compound with Wnt signal path inhibit activities.
Background technology
The earliest to the discovery of Wnt signal path from the research to oncovirus and fruit bat developmental mechanism.Wnt gene found in nineteen eighty-two, be site as mouse mammary tumor virus preferential incorporation at first and certified, this gene in intercellular trafficking propagation and differentiation information, can be a kind of oncogene, was named as Int gene (mouse Int-1 and Int-3) at that time.Find that the aptery gene (wingless) of it and fruit bat belongs to straight identical sources gene (orthologous gene) subsequently, thus by the two in conjunction with called after Wnt gene (people such as Clevers, Cell.2006127:469-480).So far found and cloned 19 kinds of Wnt gene family members, the signal transduction pathway that Wnt gene mediates is called Wnt signal path by people.Wnt path is a very conservative signal transduction pathway.From unicellular lower eukaryote fruit bat until higher mammal, its member has the homology of height.Wnt signal transduction pathway take part in the regulation and control of regulate several biological processes, comprise maintenance people such as (, Annu Rev Cell Dev Biol.200420:781-810) Logan of the growth of embryo and morphological development, the balance of stable, energy metabolism of tissue and stem cell.People find in the research of stem cell in recent years, Wnt signal path all plays important regulating and controlling effect (people such as Reya, Nature.2005434:843-850) for the maintenance of epidermal stem cells, intestinal stem cell, hemopoietic stem cell, neural stem cell, embryonic stem cell and tumor stem cell.
The conduction of Wnt/ β-catenin signal path is opened after being combined with the Frizzled acceptor of 7 cell transmembrane and complementary acceptor LRP5/6 while that classical Wnt signal path being part Wnts albumen outer by after birth, and activate Dsh albumen in kytoplasm, the Dsh albumen of activation can suppress by APC albumen, GSK-3 β, Axin, the activity of key component GSK-3 β in the degraded complex body that β-catenin etc. are formed, make β-catenin not by GSK-3 β phosphorylation thus avoid Ubiquitin-proteasome to identify and degraded it, and then in kytoplasm, build up (the people such as Boutros, Mech Dev.199983:27-37, Perrimon, Cell.199476:781-784).Just start when β-catenin accumulates to finite concentration in endochylema to shift to nucleus, and the transcription factor TCF/LEFs in karyon is combined and causes the startup factor of the downstream target gene of β-cateninn to come out and the expression that is activated, cause abnormal cell proliferation as activated c-myc, cyclin-D1, survivin, gastrin, VEGF, ASEF etc.And in Normal adult cell, intracytoplasmic β-catenin major part is combined with after birth attachment proteins E-cadherin and α-catenin and forms the adjustment that complex body participates in cytoskeleton, maintain homocellular adhesion, prevent cell from shifting, free β-the catenin of small part to be degraded after complex phosphorylates by Ubiquitin-proteasome identification and to degrade in endochylema, keep β-catenin low-level state in born of the same parents, thus make Wnt signal path be in closing condition.
Research find when Wnt gene itself or other arbitrary member's factors of path change make its abnormal activation time, all likely cause the generation of tumour.Such as, the regulatory factor that extensively there is Wnt path in colorectal cancer patients comprises APC, β-catenin, the isogenic sudden change of Axin, TCF, thus cause and the overexpression growing relevant gene (people such as Klaus, Nat RevCancer.20088:387-398).Lozzo etc. find by normal to more than 100 parts and tumor tissues and 10 human tumour cell lines research the overexpression that all there is Wnt-5a mRNA in mammary cancer, lung cancer, prostate cancer and melanoma, especially the abnormal expression in mammary cancer obviously people such as (, Cancer Research.199555:3495) Lozzo.
The abnormal activation of Wnt approach occurs in cell carcinogenesis, tumour and has vital role in tumor invasiveness process, and the Wnt signal path blocking exception can be bred by inhibition tumor cell, inducing apoptosis of tumour cell.Therefore, Wnt signal path has good antineoplastic target effect.
Research shows that abnormal Wnt signal that in Wnt signal path, LRP5 process LAN causes and certain cancers are associated people such as (, Int.J.Cancer.2004109:106-111) Hoang.As prostate cancer, colorectal carcinoma, ovarian cancer, the esophageal carcinoma and cancer of the stomach.
β-catenin activates circulation and the amplification that Wnt signal path can increase neural progenitor cell, and disappearance can cause disappearance people such as (, Science.2002297:365-369) Chenn at progenitor cell interval.The abnormal activation of Wnt signal is tumorigenesis (people such as Dahmen, Cancer Res.200161:7039-7043) in neural system.Therefore, Wnt antagonist of the present invention can treat neuron proliferation disease to the suppression of Wnt signal, such as brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, primary nervous outer embryoma, pituitary tumor.
Wnt signal path can promote renewal and the maintenance of multipotential hemopoietic stem cell, and the Wnt signal of exception is for the cancer that the various disease caused by multipotential hemopoietic stem cell is relevant with other blood responsible (people such as Reya, Nature.2005434:843-850; The people such as Willert, Nature.2003423; 448-452).Therefore, Wnt antagonist of the present invention can treat the leukemia cancer relevant with various blood to the suppression of Wnt signal, as acute, chronic, lymphocytic and myelogenous leukemia, myelodysplastic syndrome and bone marrow proliferative illness.Comprise myelomatosis, lymphoma, chronic myelomonocytic leukemia, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, myelodysplastic syndrome, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, macroglobulinemia.
The imbalance of Wnt intracellular signaling also can pass through induced retinal inflammation, vascular leakage and neovascularization, causes the development of diabetic retinopathy.
Therefore, improve cause because above-mentioned Wnt signal path is not normal illness, just need to propose effective Wnt signal path conditioning agent.
Summary of the invention
In view of the defect that above-mentioned prior art exists, the object of the invention is to propose a kind of heterogeneous ring compound, as effective antagonist of Wnt signal path, can be used in the illness treating or prevent to cause because Wnt signal path is not normal.
Object of the present invention will be achieved by the following technical programs:
A kind of heterogeneous ring compound with Wnt signal path inhibit activities, comprise this compound and pharmacy acceptable salt, various isotropic substance, various isomer or various crystalline structure, described compound connects three ring skeletons by link group L and replaces structure Q, has the structure shown in general formula I:
Wherein, A1, A2, A3, A4, A5 are separately selected from C or N;
B1, B2, B3 are separately selected from N, O, S, CR1;
C1, C2 are separately selected from B4, B5-B6, B5=B6, and wherein, B4, B5, B6 are separately selected from N, O, S, CR2;
U is selected from D1, D1-D2, D1=D2, D1-D2-D3, and wherein, D1, D2, D3 are separately selected from NR3, O, S, C=O, CR4R5, C=NR4, C=NOR4;
Link group L is selected from E1-E2-E3, and wherein, E1, E2, E3 are separately selected from NR6, O, S, C=O, CR7R8, SO2;
Replacing structure Q is unsubstituted aromatic ring, hetero-aromatic ring, 3-7 unit's saturated rings or 3-7 unit heterocycle, or to be replaced by 1-4 R9 group or the aromatic ring of Cheng Huan, hetero-aromatic ring, 3-7 unit's saturated rings or 3-7 unit heterocycle, wherein said heterocycle and hetero-aromatic ring comprise the heteroatoms that 1-4 is selected from N, O and S independently;
R1, R2, R3, R4, R5, R6, R7, R8, R9 is separately selected from hydrogen atom, low alkyl group, lower alkoxy, alkoxyalkyl, cycloalkyl, oxo, cyano group, halogen, hydroxyl, amino, ester group, amide group, sulfoamido, sulfuryl, urea groups, carbamate groups, amido, aryl amine, low-grade alkenyl, low-grade alkynyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, Heterocyclylalkyl and-C (O)-alkyl, or be that hydrogen atom is by low alkyl group, lower alkoxy, alkoxyalkyl, cycloalkyl, cyano group, halogen, hydroxyl, amino, ester group, amide group, sulfoamido, sulfuryl, urea groups, carbamate groups, amido, aryl amine, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, the low alkyl group that Heterocyclylalkyl replaces with the one or more groups in-C (O)-alkyl, lower alkoxy, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle or Heterocyclylalkyl, wherein, R4, R5 are independently selected from above-mentioned group, or connect into ring, or merging becomes double bond, R7, R8 are independently selected from above-mentioned group, or connect into ring, or merging becomes double bond.
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, described low alkyl group is alkyl or the substituted hydrocarbon radical of saturated straight chain, side chain, ring-type, double-ring or the Spirocyclic of 1-10 carbon atom composition;
Described lower alkoxy is the alkyl of saturated straight chain, side chain, ring-type, double-ring or the Spirocyclic that hydrogen atom is formed by 1-10 carbon atom or the hydroxyl of substituted hydrocarbon radical replacement;
Described low-grade alkenyl is alkyl or the substituted hydrocarbon radical of the straight chain containing at least one carbon-carbon double bond, side chain, ring-type, double-ring or the Spirocyclic that 1-10 carbon atom forms;
Described low-grade alkynyl is alkyl or the substituted hydrocarbon radical of the straight chain containing at least one carbon carbon triple bond, side chain, ring-type, double-ring or the Spirocyclic that 1-10 carbon atom forms;
Described halogen is fluorine, chlorine, bromine and iodine;
Heteroatoms in described assorted alkyl, heteroaryl, heteroaralkyl, heterocycle, Heterocyclylalkyl is nitrogen, oxygen, sulphur, and the quaternary ammonium salt of various oxidation state or nitrogen;
Described aryl is phenyl ring, naphthalene nucleus, cyclohexyl biphenyl and substitutive derivative thereof, or is the derivative cyclic substituents of saturated rings and aromatic ring;
Described heterocycle is the nonaromatic monocycle, dicyclo, three rings or the volution substituting group that comprise the combination of an atom or multiple atom in nitrogen, oxygen and sulphur, and the cyclic substituents of various oxidation state;
Preferably, described heteroaryl is 5-14 former molecular aromatic nucleus of the combination comprising an atom in nitrogen, oxygen and sulphur or multiple atom and the cyclic substituents of various oxidation state thereof, or is the derivative cyclic substituents of saturated rings and hetero-aromatic ring.
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, described three ring skeletons are any one in following skeleton:
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, described link group L is any one in following groups:
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, described replacement structure Q is any one in following groups:
Above-mentioned has in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, it comprises following compounds and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer:
Above-mentioned have in the heterogeneous ring compound of Wnt signal path inhibit activities, and preferably, isotropic substance comprises but is not only limited to
2h,
3h,
11c,
13c,
14c,
15n,
17o,
18o,
18f,
32p,
35s,
36cl etc.
Above-mentioned have in the heterogeneous ring compound of Wnt signal path inhibit activities, preferably, and various isomer, including, but not limited to, steric isomer, cis-trans-isomer, tautomer etc.
The present invention also provides a kind of combined utilization composition with the heterogeneous ring compound of Wnt signal path inhibit activities, and this combined utilization composition is described heterogeneous ring compound and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer and any antitumor drug, the composition that combined utilization obtains is carried out in the combination of one or more in antibacterials, antiviral, medicine for parasitic disease, central nervous system medicine, resisting hyperosteogeny medicine, diabetes medicament.
The present invention also provides the heterogeneous ring compound and pharmacy acceptable salt, various isotropic substance, various crystalline structure or the application of various isomer in the medicine preparing antagonism Wnt signal path with Wnt signal path inhibit activities, or the application of combined utilization composition in the medicine preparing antagonism Wnt signal path of described heterogeneous ring compound.
The heterogeneous ring compound with Wnt signal path inhibit activities that the present invention proposes and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer, or the combined utilization composition of above-mentioned heterogeneous ring compound is used for the treatment of the purposes of the pathology patient's condition or the disease can improved by Wnt signal path antagonistic action.In concrete one, improved disease and illness by the antagonistic action of Wnt signal path, include but not limited to cancer, fibrosis, nervous system disorders, diabetic retinopathy, hematologic disease and myelosis, parasitosis etc.In more specifically, improved disease and illness by the antagonistic action of Wnt signal path, include but not limited to mammary cancer, lung cancer (minicell, non-small cell), bladder cancer, carcinoma of the pancreas, liver cancer, neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, cancer of the stomach, myelomatosis, lymphoma, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis (idiopathic pulmonary fibrosis and radioactive fibrosis), renal fibrosis, hepatic fibrosis comprises liver cirrhosis, diabetic retinopathy, macroglobulinemia, the cancer that leukemia is relevant with various blood, as acute, chronic, lymphocytic and myelogenous leukemia, myelodysplastic syndrome and bone marrow proliferative illness, nervous system disorders is as brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, the outer embryoma of primary nervous, pituitary tumor, and parasitosis, as schistosomicide, malaria etc.
A kind of heterogeneous ring compound that the present invention proposes, as effective antagonist of Wnt signal path, can be used in the illness treating or prevent to cause because Wnt signal path is not normal.
Below just accompanying drawing in conjunction with the embodiments, is described in further detail the specific embodiment of the present invention, is easier to understand, grasp to make technical solution of the present invention.
Accompanying drawing explanation
Fig. 1 is the test result graphic representation of compound A-45;
Fig. 2 is the test result graphic representation of compd A 6.
Embodiment
Below by specific embodiment, method of the present invention is described, but the present invention is not limited thereto.Experimental technique described in following embodiment, if no special instructions, is ordinary method; Described reagent and material, if no special instructions, all can obtain from commercial channels.Solvent for use and medicine are analytical pure or chemical pure; Solvent is before use all through re-distillation; Anhydrous solvent all processes according to standard method or literature method.Column chromatography silica gel (100-200 order) and tlc silica gel (GF254) are Haiyang Chemical Plant, Qingdao and chemical plant, Yantai product; If not otherwise specified, all adopt sherwood oil (60-90 DEG C)/ethyl acetate (v/v) as eluent; The ethanolic soln of developer iodine or phospho-molybdic acid; All extraction solvent unexplained reference all use anhydrous Na
2sO
4dry.1H NMR Bruck-400 type nuclear magnetic resonance analyser record, TMS is interior mark.LC-MS Agilent company 1100 of U.S. type HPLC-ESI-MSn combined instrument (LC-MSD Trap) record, diode-array detector (DAD), determined wavelength 214nm and 254nm, ion trap mass spectrometry (ESI source).HPLC column is Agela Durashell C18 (4.6 × 50mm, 3.5 μm); Moving phase is 0.1%NH
4hCO
3the aqueous solution: acetonitrile (in 5 minutes from 5:95 to 95:5); Flow velocity is 1.8mL/min.
Embodiment 1
The present embodiment provides a kind of heterogeneous ring compound A1, and it synthesizes by the following method:
1) synthesis of intermediate A 1-2:
A1-1 (640mg, 2.63mmol) and 2-methyl-4-pyridine boronic acid pinacol ester (1.1g, 55%, 2.90mmol) are dissolved in tetrahydrofuran (THF) (10mL), add Pd (PPh
3)
4(243mg, 0.21mmol) and cesium carbonate (1.7g, 5.26mmol).Under nitrogen protection, with nitrogen replacement five times, be heated to 75 DEG C, react 12 hours.Filter after being cooled to room temperature, filtrate reduced in volume.Colorless oil (500mg, 75%) is obtained through column chromatography (sherwood oil: ethyl acetate=5:1).
2) synthesis of intermediate A 1-3:
A1-2 (500mg, 0.59mmol) is dissolved in methyl alcohol (6mL), adds the 2N NaOH aqueous solution (2mL).Stirring reaction 15 minutes under normal temperature, after concentrating under reduced pressure, adjusts pH to 7 with the 1N HCl aqueous solution, obtains white solid (600mg, crude product) after concentrating under reduced pressure.Directly can throw next step.
3) synthesis of product A 1:
By A1-3 (86mg, 74%, 0.285mmol) and 3-amino-9-ethyl card azoles (60mg, 0.285mmol) be dissolved in DMF (3mL), add HATU (108mg, 0.285mmol) and DIPEA (184mg, 1.425mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains white solid (36mg, 80%) through column chromatography (methylene dichloride: methyl alcohol=30:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound
Embodiment 2
The present embodiment provides a kind of heterogeneous ring compound A2, and it synthesizes by the following method:
1) synthesis of intermediate A 2-2:
A1-1 (8g, 47.62mmol) is dissolved in trifluoroacetic acid (64mL), under ice bath, slowly adds nitric acid (1.9mL), stir 2 hours under normal temperature, filter and use methyl alcohol diafiltration to obtain yellow solid (7g, 70%).
2) synthesis of intermediate A 2-3:
By A2-2 (6.9g; 32.36mmol) be dissolved in methyl alcohol (50mL) and tetrahydrofuran (THF) (50mL); Pd/C (600mg) is added under nitrogen protection; use hydrogen exchange twice again; react 12 hours under hydrogen shield under normal temperature and pressure; diatomite filtration, filtrate reduced in volume obtains yellow solid (4g, 67%).
3) synthesis of intermediate A 2-4:
By A2-3 (1.2g, 6.56mmol) be dissolved in 18% hydrochloric acid (12mL), 1M sodium nitrite in aqueous solution (9mL) is slowly added under ice bath, stir 1 hour under ice bath, add 2M sodium iodide aqueous solution (6.5mL), stir 4 hours under normal temperature, after adding excessive S-WAT, filter to obtain yellow solid (1.1g, 57%).
4) synthesis of intermediate A 2-5:
By A2-4 (500mg, 1.7mmol) and Zn (CN)
2(117mg, 1.0mmol) is dissolved in DMF (10mL), adds Pd (PPh
3)
4(196mg, 0.17mmol).Under nitrogen protection, with nitrogen replacement five times, be heated to 90 DEG C, react 2 hours.Add water (40mL), extract with ether (40mL*3), merge organic phase, wash with 1N ammoniacal liquor (30mL) saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, white solid (310mg, 85%) is obtained through column chromatography (sherwood oil: ethyl acetate=50:1) after concentrating under reduced pressure.
5) synthesis of intermediate A 2-6:
A2-5 (160mg, 0.83mmol) is dissolved in methyl alcohol (6.5mL) and water (6.5mL), adds KOH (1.4g, 24.8mmol).Heating reflux reaction 6 hours, after concentrating under reduced pressure, adjusts pH to 3 with 10%HCl, and with ethyl acetate (30mL*3) extraction, merges organic phase, anhydrous sodium sulfate drying, obtains white solid (160mg, 91%) after concentrating under reduced pressure.
6) synthesis of product A 2:
A2-6 (50mg, 0.236mmol) and A2-7 (47mg, 0.236mmol) is dissolved in DMF (2mL), adds HATU (90mg, 0.236mmol) and DIPEA (152mg, 1.18mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains light yellow solid (20mg, 22%) through column chromatography (methylene dichloride: methyl alcohol=50:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound
Embodiment 3
The present embodiment provides a kind of heterogeneous ring compound A3, and it synthesizes by the following method:
1) synthesis of product A 3:
A1-3 (111mg, 74%, 0.36mmol) and A2-3 (66mg, 0.36mmol) is dissolved in DMF (3mL), adds HATU (137mg, 0.36mmol) and DIPEA (232mg, 1.80mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains pale solid (85mg, 61%) through column chromatography (methylene dichloride: methyl alcohol=50:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound
Embodiment 4
The present embodiment provides a kind of heterogeneous ring compound A4, and it synthesizes by the following method:
1) synthesis of intermediate A 4-1:
By A2-4 (470mg, 1.60mmol) with methyl aceto acetate (624mg, 4.80mmol) be dissolved in DMSO (5mL), add potassiumphosphate (1.0g, 4.80mmol), ethanol (221mg, 4.80mmol) with cuprous iodide (30mg, 0.16mmol).Under nitrogen protection; with nitrogen replacement five times; be heated to 80 DEG C of reactions 24 hours; add water (40mL), with ethyl acetate (40mL*3) extraction, merge organic phase; wash with saturated aqueous common salt (40mL*2); anhydrous sodium sulfate drying, obtains yellow solid (150mg, 37%) through column chromatography after concentrating under reduced pressure.
1H NMR(400MHz,CDCl
3)δ7.94(d,J＝7.6Hz,1H),7.90(d,J＝8.0Hz,1H),7.59-7.50(m,2H),7.48-7.42(m,1H),7.37-7.31(m,1H),7.28(s,1H),4.18(q,J＝7.2Hz,2H),3.78(s,2H),1.27(t,J＝7.2Hz,3H).
2) synthesis of intermediate A 4-2:
A4-1 (150mg, 0.59mmol) is dissolved in methyl alcohol (2mL), adds the 2N NaOH aqueous solution (0.59mL).Stirring reaction 3 hours under normal temperature, after concentrating under reduced pressure, adjusts pH to 3 with the 1N HCl aqueous solution, and with ethyl acetate (30mL*3) extraction, merges organic phase, anhydrous sodium sulfate drying, obtains white solid (130mg, 97%) after concentrating under reduced pressure.3) synthesis of product A 4:
A4-2 (60mg, 0.265mmol) and A4-3 (46mg, 0.265mmol) is dissolved in DMF (3mL), adds HATU (101mg, 0.26mmol) and DIPEA (172mg, 1.33mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains light yellow solid (20mg, 20%) through column chromatography (methylene dichloride: methyl alcohol=60:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound
Embodiment 5
The present embodiment provides a kind of heterogeneous ring compound A5, and it synthesizes by the following method:
1) synthesis of intermediate A 5-2:
A5-1 (5g, 23.70mmol) is dissolved in acetic acid (125mL), adds chromium trioxide (9.5g, 94.79mmol).Stir 24 hours under normal temperature, filter to obtain yellow solid (3.8g, 71%).
2) synthesis of intermediate A 5-3:
A5-2 (2.6g, 11.56mmol) is dissolved in concentrated hydrochloric acid (67mL) and ethanol (33mL), adds two hydrated stannous chlorides (18g, 80.89mmol).Reflux 5 hours, cooled and filtered obtains red solid, is placed in 10% ammoniacal liquor (80mL) and stirs 0.5 hour, filter to obtain yellow solid (1.8g, 81%).
3) synthesis of product A 5:
A1-3 (110mg, 74%, 0.36mmol) and A5-3 (70mg, 0.36mmol) is dissolved in DMF (3mL), adds HATU (136mg, 0.359mmol) and DIPEA (232mg, 1.8mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains white solid (76mg, 52%) through column chromatography (methylene dichloride: methyl alcohol=60:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound
Embodiment 6
The present embodiment provides a kind of heterogeneous ring compound A6, and it synthesizes by the following method:
1) synthesis of intermediate A 6-1:
By A5-3 (1.5g, 7.69mmol) be dissolved in 18% hydrochloric acid (15mL), 1M sodium nitrite in aqueous solution (11.5mL) is slowly added under ice bath, stir 1 hour under ice bath, add 2M sodium iodide aqueous solution (7.7mL), stir 4 hours under normal temperature, after adding excessive S-WAT, filter to obtain yellow solid (1.2g, 52%).
2) synthesis of intermediate A 6-2:
By A6-1 (1.2g, 3.92mmol) and Zn (CN)
2(275mg, 2.35mmol) is dissolved in DMF (10mL), adds Pd (PPh
3)
4(452mg, 0.392mmol).Under nitrogen protection, with nitrogen replacement five times, be heated to 90 DEG C, react 2 hours.Add water (40mL), extract with ether (40mL*3), merge organic phase, wash with 1N ammoniacal liquor (30mL) saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, yellow solid (800mg, 93%) is obtained through column chromatography (sherwood oil: ethyl acetate=50:1) after concentrating under reduced pressure.
3) synthesis of intermediate A 6-3:
A6-2 (200mg, 0.98mmol) is dissolved in methyl alcohol (7mL) and water (7mL), adds KOH (1.6g, 29.4mmol).Heating reflux reaction 6 hours, after concentrating under reduced pressure, adjusts pH to 3 with 10%HCl, and with ethyl acetate (30mL*3) extraction, merges organic phase, anhydrous sodium sulfate drying, obtains yellow solid (200mg, 91%) after concentrating under reduced pressure.
4) synthesis of A6:
A6-3 (100mg, 0.446mmol) and PP-003-2 (88mg, 0.446mmol) is dissolved in DMF (4mL), adds HATU (169mg, 0.446mmol) and DIPEA (288mg, 2.23mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains light yellow solid (80mg, 44%) through column chromatography (methylene dichloride: methyl alcohol=60:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound
Embodiment 7
The present embodiment provides a kind of heterogeneous ring compound A7, and it synthesizes by the following method:
1) synthesis of intermediate A 7-2:
A7-1 (2g, 8.2mmol) is dissolved in DMF (15mL), adds CuCN (886mg, 9.8mmol).150 DEG C of reactions 24 hours, after being cooled to normal temperature, add water (50mL), extract by ethyl acetate (50mL*3), merge organic phase, wash with saturated aqueous common salt (50mL*2), anhydrous sodium sulfate drying, light yellow solid (780mg, 50%) is obtained through column chromatography (sherwood oil: ethyl acetate=100:1) after concentrating under reduced pressure.
1H NMR(400MHz,CDCl
3)δ7.82-7.76(m,3H),7.65-7.61(m,1H),7.55(d,J＝7.2Hz,1H),7.42-7.33(m,2H),3.91(s,2H).
2) synthesis of intermediate A 7-3:
A7-2 (170mg, 0.89mmol) is dissolved in acetic acid (6mL) and 70%H
2sO
4(6mL), in, 100 DEG C of reactions 12 hours, normal temperature is cooled to, add methylene dichloride (30mL) and water (30mL), add sodium carbonate again, adjust pH to 9, water intaking also adjusts pH to 1 with 1N HCl mutually, extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (50mL*2), anhydrous sodium sulfate drying, white solid (80mg, 43%) is obtained after concentrating under reduced pressure.
3) synthesis of product A 7:
A7-3 (80mg, 0.38mmol) and A2-7 (75mg, 0.38mmol) is dissolved in DMF (3mL), adds HATU (144mg, 0.38mmol) and DIPEA (245mg, 1.90mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains white solid (33mg, 22%) through column chromatography (methylene dichloride: methyl alcohol=60:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compd A 7
Embodiment 8
The present embodiment provides a kind of heterogeneous ring compound A8, and it synthesizes by the following method:
1) synthesis of intermediate A 8-1:
A7-2 (200mg, 1.05mmol) and NFSI (992mg, 3.15mmol) is dissolved in dry THF (5mL), at-78 DEG C, stirs half an hour, slowly drip LiHMDA (3.1mL, 1M in THF).Stir 4 hours at-78 DEG C, add 10% ammoniacal liquor cancellation reaction, extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains faint yellow solid (160mg, 67%) through column chromatography (sherwood oil: ethyl acetate=100:1) after concentrating under reduced pressure.
2) synthesis of intermediate A 8-2:
A8-1 (150mg, 0.59mmol) is dissolved in methyl alcohol (3.5mL) and water (3.5mL), adds KOH (806mg, 14.4mmol).Heating reflux reaction 6 hours, after concentrating under reduced pressure, adjusts pH to 3 with 10%HCl, and with ethyl acetate (30mL*3) extraction, merges organic phase, anhydrous sodium sulfate drying, obtains white solid (105mg, 89%) after concentrating under reduced pressure.
3) synthesis of product A 8:
A8-2 (75mg, 0.30mmol) and PP-003-2 (60mg, 0.30mmol) is dissolved in DMF (3mL), adds HATU (114mg, 0.30mmol) and DIPEA (193mg, 1.50mmol).Stir 12 hours under normal temperature, add water (30mL), extract by ethyl acetate (30mL*3), merge organic phase, wash with saturated aqueous common salt (30mL*2), anhydrous sodium sulfate drying, obtains white solid (50mg, 39%) through column chromatography (methylene dichloride: methyl alcohol=60:1) after concentrating under reduced pressure.Resolve (spectrum data is in table 1) through mass spectrum and nuclear magnetic spectrum, the solid obtained is compound A-28
Table 1 lists analytic structure and the spectral data of the compound that embodiment 1-8 obtains and the compd A 1-A23 obtained according to similar step.
Table 1
Embodiment 9
The rejection ability of compound listed by the present embodiment his-and-hers watches 1 to Wnt signal path measures.
L Wnt3A cell (CRL-2647, ATCC) cultivates in the DMEM substratum (Gibico) containing 10% foetal calf serum (Hyclone).The HEK293STF stable clone cell HEK293 cell of TCF fluorescence report plasmid (transfection has " Super-Top Flash ") is cultivated in perfect medium (the DMEM substratum containing 4mM L-glutaminate, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 6 μ g/mL blasticidins and 10% foetal calf serum).Gather in the crops respectively when L Wnt3A cell and HEK293STF stable clone cell cultures are 90% to degree of converging, and mix with the ratio of 1:1.The mixed cell culture liquid in 100 μ L/ holes joins in 96 orifice plates, makes final cell concn be 12000 cells/well, and then cultivates 24h.Test compound DMSO stepwise dilution, and then be diluted to wanted concentration with DMEM substratum.Get 20 μ L compound solutions to join and be aforesaidly equipped with in 96 orifice plates of cell culture fluid, then in 37 DEG C of hatching 48h.50 μ L luciferase solution (Brigh-Glo, Promega) are added, jolting 5 minutes under normal temperature in last every hole.Luminous signal microplate reader (PHERAstar FS, BMG) measures, and then calculates the IC of compound according to the suppression result of different concns compound to luminous signal
50value (tiring).
The IC of all compounds in the present invention
50numerical value is all less than 5 micromoles per liter.Wherein, 0.1 μM of >IC
50the representation compound of >0.01 μM has: A3, A7, A8,0.01 μM of >IC
50representation compound have: A2, A5, A6, A11.Wherein the graphic representation of representative compound A5 and A6 asks for an interview accompanying drawing.
Therefore the heterogeneous ring compound in the present invention, as effective antagonist of Wnt signal path, can effectively block Wnt signal path, can be used in the illness treating or prevent to cause because Wnt signal path is not normal.
The present invention still has numerous embodiments, all employing equivalents or equivalent transformation and all technical schemes formed, and all drops within protection scope of the present invention.
Claims (9)
1. one kind has the heterogeneous ring compound of Wnt signal path inhibit activities, comprise this compound and pharmacy acceptable salt, various isotropic substance, various isomer or various crystalline structure, described compound connects three ring skeletons by link group L and replaces structure Q, has the structure shown in general formula I:
Wherein, A1, A2, A3, A4, A5 are separately selected from C or N;
B1, B2, B3 are separately selected from N, O, S, CR1;
C1, C2 are separately selected from B4, B5-B6, B5=B6, and wherein, B4, B5, B6 are separately selected from N, O, S, CR2;
U is selected from D1, D1-D2, D1=D2, D1-D2-D3, and wherein, D1, D2, D3 are separately selected from NR3, O, S, C=O, CR4R5, C=NR4, C=NOR4;
Link group L is selected from E1-E2-E3, and wherein, E1, E2, E3 are separately selected from NR6, O, S, C=O, CR7R8, SO2;
Replacing structure Q is unsubstituted aromatic ring, hetero-aromatic ring, 3-7 unit's saturated rings or 3-7 unit heterocycle, or to be replaced by 1-4 R9 group or the aromatic ring of Cheng Huan, hetero-aromatic ring, 3-7 unit's saturated rings or 3-7 unit heterocycle, wherein said heterocycle and hetero-aromatic ring comprise the heteroatoms that 1-4 is selected from N, O and S independently;
R1, R2, R3, R4, R5, R6, R7, R8, R9 is separately selected from hydrogen atom, low alkyl group, lower alkoxy, alkoxyalkyl, cycloalkyl, oxo, cyano group, halogen, hydroxyl, amino, ester group, amide group, sulfoamido, sulfuryl, urea groups, carbamate groups, amido, aryl amine, low-grade alkenyl, low-grade alkynyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, Heterocyclylalkyl and-C (O)-alkyl, or be that hydrogen atom is by low alkyl group, lower alkoxy, alkoxyalkyl, cycloalkyl, cyano group, halogen, hydroxyl, amino, ester group, amide group, sulfoamido, sulfuryl, urea groups, carbamate groups, amido, aryl amine, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle, the low alkyl group that Heterocyclylalkyl replaces with the one or more groups in-C (O)-alkyl, lower alkoxy, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, assorted alkyl, heteroaralkyl, heterocycle or Heterocyclylalkyl, wherein, R4, R5 are independently selected from above-mentioned group, or connect into ring, or merging becomes double bond, R7, R8 are independently selected from above-mentioned group, or connect into ring, or merging becomes double bond.
2. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1, is characterized in that:
Described low alkyl group is alkyl or the substituted hydrocarbon radical of saturated straight chain, side chain, ring-type, double-ring or the Spirocyclic of 1-10 carbon atom composition;
Described lower alkoxy is the alkyl of saturated straight chain, side chain, ring-type, double-ring or the Spirocyclic that hydrogen atom is formed by 1-10 carbon atom or the hydroxyl of substituted hydrocarbon radical replacement;
Described low-grade alkenyl is alkyl or the substituted hydrocarbon radical of the straight chain containing at least one carbon-carbon double bond, side chain, ring-type, double-ring or the Spirocyclic that 1-10 carbon atom forms;
Described low-grade alkynyl is alkyl or the substituted hydrocarbon radical of the straight chain containing at least one carbon carbon triple bond, side chain, ring-type, double-ring or the Spirocyclic that 1-10 carbon atom forms;
Described halogen is fluorine, chlorine, bromine and iodine;
Heteroatoms in described assorted alkyl, heteroaryl, heteroaralkyl, heterocycle, Heterocyclylalkyl is nitrogen, oxygen, sulphur, and the quaternary ammonium salt of various oxidation state or nitrogen;
Described aryl is phenyl ring, naphthalene nucleus, cyclohexyl biphenyl and substitutive derivative thereof, or is the derivative cyclic substituents of saturated rings and aromatic ring;
Described heterocycle is the nonaromatic monocycle, dicyclo, three rings or the volution substituting group that comprise the combination of an atom or multiple atom in nitrogen, oxygen and sulphur, and the cyclic substituents of various oxidation state;
Preferably, described heteroaryl is 5-14 former molecular aromatic nucleus of the combination comprising an atom in nitrogen, oxygen and sulphur or multiple atom and the cyclic substituents of various oxidation state thereof, or is the derivative cyclic substituents of saturated rings and hetero-aromatic ring.
3. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1 and 2, is characterized in that: described three ring skeletons are any one in following skeleton:
4. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1 and 2, is characterized in that: described link group L is any one in following groups:
5. the heterogeneous ring compound with Wnt signal path inhibit activities according to claim 1 and 2, is characterized in that: described replacement structure Q is any one in following groups:
6. the heterogeneous ring compound with Wnt signal path inhibit activities according to any one of claim 1-5, it comprises following compounds and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer:
7. there is a combined utilization composition for the heterogeneous ring compound of Wnt signal path inhibit activities, this combined utilization composition is heterogeneous ring compound described in any one of claim 1-6 and pharmacy acceptable salt, various isotropic substance, various crystalline structure or various isomer and any antitumor drug, the combination of one or more in antibacterials, antiviral, medicine for parasitic disease, central nervous system medicine, resisting hyperosteogeny medicine, diabetes medicament carries out the composition that combined utilization obtains.
8. the heterogeneous ring compound with Wnt signal path inhibit activities according to any one of claim 1-7 and pharmacy acceptable salt, various isotropic substance, various crystalline structure or the application of various isomer in the medicine preparing antagonism Wnt signal path, or the application of combined utilization composition in the medicine preparing antagonism Wnt signal path of described heterogeneous ring compound.
9. application according to claim 8, it is characterized in that: be used for the treatment of mammary cancer, lung cancer, bladder cancer, carcinoma of the pancreas, liver cancer, neck squamous cell carcinoma, thyroid carcinoma, sarcoma, osteosarcoma, fibroma durum, melanoma, prostate cancer, colorectal carcinoma, ovarian cancer, cervical cancer, the esophageal carcinoma, cancer of the stomach, myelomatosis, lymphoma, lymphoma mantle cell, cutaneous T cell lymphoma, chronic and non-Progressive symmetric erythrokeratodermia anaemia, spontaneity or primary thrombocytosis, idiopathic myelofibrosis, pulmonary fibrosis, renal fibrosis, hepatic fibrosis, liver cirrhosis, diabetic retinopathy, macroglobulinemia, the cancer that leukemia is relevant with various blood, as acute, chronic, lymphocytic and myelogenous leukemia, myelodysplastic syndrome and bone marrow proliferative illness, brain tumor, astrocytoma, medulloblastoma, schwann's cell tumor, the outer embryoma of primary nervous, pituitary tumor, and parasitosis, as schistosomicide, malaria etc.
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| US12049466B2 (en) | 2018-05-17 | 2024-07-30 | Forma Therapeutics, Inc. | Fused bicyclic compounds useful as ubiquitin-specific peptidase 30 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US11247987B2 (en) | 2017-10-06 | 2022-02-15 | Forma Therapeutics, Inc. | Inhibiting ubiquitin specific peptidase 30 |
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| CN112375029A (en) * | 2020-11-11 | 2021-02-19 | 湖北省生物农药工程研究中心 | Carbazole alkaloid derivative and preparation method and application thereof |
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