CN107286169B - Tankyrase inhibitors - Google Patents
Tankyrase inhibitors Download PDFInfo
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- CN107286169B CN107286169B CN201610206972.5A CN201610206972A CN107286169B CN 107286169 B CN107286169 B CN 107286169B CN 201610206972 A CN201610206972 A CN 201610206972A CN 107286169 B CN107286169 B CN 107286169B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to the technical field of medicines, and particularly relates to a tankyrase inhibitor shown in a general formula (I), and pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof, wherein R is1、R2、R3、R4、R5M, n, p, Z, L, X and Y are as defined in the specification. The invention also relates to a preparation method of the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the compounds, pharmaceutically acceptable salts, esters, solvates or stereoisomers thereof in preparing medicaments for treating and/or preventing cancer and related diseases mediated by tankyrase.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a tankyrase inhibitor, or pharmaceutically acceptable salts, esters, solvates and stereoisomers thereof, a preparation method of the compounds, a pharmaceutical preparation and a pharmaceutical composition containing the compounds, and application of the compounds in preparing medicines for treating and/or preventing cancers, Alzheimer's disease, osteoporosis, skin diseases, cardiovascular diseases and type II diabetes.
Background
It is well known that cancer has become one of the most serious diseases threatening human life and health, and about nine million people worldwide each year suffer from malignant tumors. Therefore, finding effective drugs and methods for preventing and treating cancer is an irresistible task in today's society. Cancer is a disease characterized by the loss of proper control of cell growth. The classical wnt signaling pathway, β -Catenin mediated wnt signaling pathway, has been reported to be associated with a number of biological processes, such as cell fate, cell proliferation, maintenance of stem cells, and the like. Aberrant activation of the Wnt signaling pathway can lead to a variety of cancers, and thus this signaling pathway becomes a hot pathway for anti-tumor therapy.
The beta-Catenin and Axin proteins are important components of the classical wnt signaling pathway. Excessive β -Catenin leads to increased wnt signaling and activation of the associated nuclear transcription factors, while excessive Axin leads to intracellular β -Catenin degradation and reduced signaling. Thus, wnt signaling is controlled by the relative stability of these two proteins. When the cells are not stimulated by wnt signaling, most of the β -Catenin in the cytoplasm is degraded by proteasome in the form of a degradation complex. When the wnt signal path is abnormally activated, the beta-Catenin is greatly liberated by a degradation complex, and the free beta-Catenin increased in cytoplasm enters a cell nucleus to interact with a lymphoenhancer binding factor 1 to regulate the expression of downstream genes. These downstream genes have been implicated in many cancers.
The degradation complex formed in the degradation process of the beta-Catenin mainly comprises the beta-Catenin, APC, Axin, CK1 and GSK3 beta. Wherein Axin is a scaffold protein, has a site for acting with other proteins, and can combine beta-Catenin, APC, CK1 and GSK3 beta together. CK1 is a tyrosine kinase that phosphorylates Ser45 of β -Catenin, and then GSK3 β phosphorylates Thr41, Ser37, and Ser33 of β -Catenin, and the phosphorylated β -Catenin is recombined onto β -TRCP protein, covalently modified by ubiquitin, and thereby degraded by proteasome. The role of the APC protein is to enhance the affinity of the degraded complex to β -Catenin. When the wnt signaling pathway is activated, activated DVL proteins can disrupt the degradation complex, allowing β -Catenin to be released in large amounts, leading to free β -Catenin accumulation. The literature reports that the concentration of degraded complex can be effectively increased by stabilizing Axin protein in cells, so as to promote the degradation of beta-Catenin.
Tankyrases belongs to the ADP-ribose polymerase (PARP) protein family, and human Tankyrases 1(TNKS1) and 2(TNKS2) are also known as PARP-5a and PARP-5b, respectively. The tankyrase can lead the Axin protein to generate poly ADP ribosylation and mark the subsequent ubiquitination and proteasome degradation, so that the concentration of the Axin protein can be increased by inhibiting the activity of the tankyrase, thereby leading the concentration of a beta-Catenin degradation complex to be increased, and promoting the degradation of the beta-Catenin and the reduction of wnt signal transduction. The documents report that XAV939 and IWR-1-endo both belong to small molecule tankyrase inhibitors, can stabilize the Axin protein level and inhibit the wnt signaling pathway. Therefore, inhibition of tankyrase has great significance in the study of cancer therapy. Furthermore, the wnt signaling pathway may be applied to other disease areas, such as alzheimer's disease, osteoporosis, skin disorders, cardiovascular disease, type II diabetes, in addition to cancer-related, directed to correcting wnt signaling abnormalities. Although the focus is on the wnt pathway's relationship to cancer, this pathway has potential utility in other diseases as well. At the same time, inhibition of tankyrase can also have an effect on other biological functions, such as chromosome end protection (telomeres), spindle assembly during mitosis, and glucose transport by adipocytes. Thus, it is envisioned that tankyrase inhibitors may also be useful in the treatment of diseases mediated by such inhibition.
At present, no small molecule inhibitor aiming at tankyrase enters clinical research, so that the application of the target in the field of cancer treatment is greatly needed. Therefore, the development of new-structure anti-tumor drugs aiming at the target of tankyrase with high efficiency and low toxicity is hoped for. The invention provides a tankyrase inhibitor with a novel structure, and the compound with the structure has higher inhibition effect on TNKS1 and TNKS2, has better selectivity on PARP1 and PARP2 in a PARP protein family, and shows better anti-tumor effect.
Disclosure of Invention
The invention aims at developing a small molecule inhibitor aiming at tankyrase, and provides a tankyrase inhibitor which has a good effect on treating and/or preventing tankyrase-mediated cancers and related diseases. The specific technical scheme is as follows:
scheme 1. compounds of general formula (i), pharmaceutically acceptable salts, esters, solvates, or stereoisomers thereof:
wherein X, Y are each independently selected from CH, N atom;
z is selected from CRbRcNH or N atom;
l is selected from O, S, CRbRc、NRd、C(O)；
Rb、RcEach independently selected from the group consisting of absent, hydrogen atom, hydroxyl group, amino group, carboxyl group, nitro group, cyano group, halogen atom, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkoxy radical C1-6Alkyl, halo C1-6Alkyl, halo C1-6Alkoxy radical, C1-6Alkylcarbonyl group, C1-6Alkylthio radical, C1-6Alkoxycarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylsulfonyl radical, C1-6Alkylamido or C1-6An alkylsulfonylamino group;
Rdselected from hydrogen atoms, C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkylcarbonyl or C1-6An alkylsulfonyl group;
R1、R2、R3、R4、R5each independently selected from hydrogen atom, halogen atom, cyano, hydroxyl, amino, carboxyl, nitro and C1-6Alkyl, halo C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkoxy, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl radical, C1-6Alkylthio radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylcarbonyl group, C1-6Alkylsulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylamido radical, C1-6Alkoxy radical C1-6Alkyl, aminosulfonyl C1-6Alkyl, ammoniaRadical sulfonylamino C1-6An alkyl group;
m is selected from 0, 1,2 or 3;
n is selected from 0, 1,2, 3 or 4;
p is selected from 0, 1,2 or 3.
Scheme 2. the compound of scheme 1, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof,
wherein X, Y are each independently selected from CH, N atom;
z is selected from CRbRcNH or N atom;
l is selected from O, S, CRbRc、NRd；
Rb、RcEach independently selected from the group consisting of absent, hydrogen atom, hydroxyl group, amino group, carboxyl group, nitro group, cyano group, halogen atom, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl, halo C1-4Alkoxy radical, C1-4Alkylcarbonyl group, C1-4Alkylamino or di (C)1-4Alkyl) amino;
Rdselected from hydrogen atoms, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkylcarbonyl or C1-4An alkylsulfonyl group;
R1、R2、R3、R4、R5each independently selected from hydrogen atom, halogen atom, cyano, hydroxyl, amino, carboxyl, nitro and C1‐4Alkyl, halo C1‐4Alkyl radical, C1‐4Alkoxy, halo C1‐4Alkoxy, hydroxy C1‐4Alkyl, amino C1‐4Alkyl or carboxyl C1‐4An alkyl group;
m is selected from 0, 1 or 2;
n is selected from 0, 1,2 or 3;
p is selected from 0, 1,2 or 3.
Scheme 3. the compound of scheme 2, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof, having the structure of formula (ii),
scheme 4. the compound of scheme 3, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof,
wherein Z is selected from CRbRcNH or N atom;
l is independently selected from O, S, CRbRc、NRd；
Rb、RcEach independently selected from the group consisting of absent, hydrogen atom, hydroxyl group, amino group, carboxyl group, nitro group, cyano group, fluorine atom, chlorine atom, bromine atom, iodine atom, methyl group, ethyl group, propyl group, butyl group, methoxy group, ethoxy group, trifluoromethyl group, trifluoromethoxy group, formyl group, acetyl group, methylamino group and dimethylamino group;
Rdselected from hydrogen atom, methyl, ethyl, propyl, trifluoromethyl, formyl, acetyl or methylsulfonyl;
m is selected from 0 or 1;
p is selected from 0, 1 or 2.
Scheme 5. the compound of scheme 4, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof,
wherein the content of the first and second substances,
selected from the group consisting of,
scheme 6. the compound of scheme 5, a pharmaceutically acceptable salt, ester, solvate, or stereoisomer thereof,
wherein the content of the first and second substances,
selected from the following groups:
R2、R3、R4each independently selected from a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a carboxyl group, a nitro group, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a hydroxymethyl group, an aminomethyl group or a carboxymethyl group.
The technical features of the above-mentioned aspects can be combined arbitrarily, and the obtained aspects are all described in the present invention.
Part of the Compounds of the invention
Detailed Description
In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula or chemical reaction formula is the standard.
The "halogen atom" in the present invention includes fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
"C" according to the invention1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C1-4Alkyl group "," C1-3Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, 1-dimethylethyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentylCyclopentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like.
"C" according to the invention2-8Alkenyl "means a straight or branched chain or cyclic alkenyl group of 2 to 8 carbon atoms containing at least one double bond, including, for example," C2-6Alkenyl group "," C2-4Alkenyl group "," C2-3Alkenyl groups "and the like, specific examples include, but are not limited to: vinyl group, 1-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 1-methyl-2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-dimethyl-2-propenyl group, 1-ethyl-2-propenyl group, 2-hexenyl group, 3-hexenyl group, 2-methyl-1-pentenyl group, 3-methyl-1-pentenyl group, 1-methyl-2-pentenyl group, 3-methyl-2-pentenyl group, 2-methyl-3-pentenyl, 1-methyl-4-pentenyl, 3-methyl-4-pentenyl, 1-dimethyl-3-butenyl, 1, 2-dimethyl-3-butenyl, 1, 3-dimethyl-2-butenyl, 2-dimethyl-3-butenyl, 2, 3-dimethyl-2-butenyl, 2, 3-dimethyl-1-butenyl, 2-ethyl-3-butenyl, and the like.
"C" according to the invention2-8Alkynyl refers to a straight or branched chain alkynyl group of 2-8 carbon atoms containing a triple bond, including, for example, "C2-6Alkynyl group "," C2-4Alkynyl group "," C2-3Alkynyl "and the like, specific examples include, but are not limited to: ethynyl, 1-propynyl, 2-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 1-methyl-2-butynyl, 2-methyl-3-butynyl, 1-dimethyl-2-propynyl, 1-ethyl-2-propynyl, 2-hexynyl, 3-hexynyl, 1-methyl-2-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 1-dimethyl-3-butynyl, 2-ethyl-3-butynyl, 2-heptynyl, 3-heptynyl and the like.
"C" according to the invention1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkylthio radical, C1-6Alkylcarbonyl group, C1-6Alkoxycarbonyl group, C1-6Alkylcarbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfonylamino group, C1-6Alkylaminosulfonyl, di (C)1-6Alkyl) aminosulfonyl "means with C1-6alkyl-O-, C1-6alkyl-NH-, (C)1-6Alkyl radical)2-N-、C1-6alkyl-S-, C1-6alkyl-C (O) -, C1-6alkyl-O-C (O) -, C1-6alkyl-C (O) -O-, C1-6alkyl-C (O) -NH-, C1-6alkyl-SO2-、C1-6alkyl-SO2-NH-、C1-6alkyl-NH-SO2-、(C1-6Alkyl radical)2-NH-SO2A group formed in the formula (I) wherein "C1-6Alkyl "is as defined above.
"C" according to the invention1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkylthio radical, C1-4Alkylcarbonyl group, C1-4Alkoxycarbonyl group, C1-4Alkylcarbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfonylamino group, C1-4Alkylaminosulfonyl, di (C)1-4Alkyl) aminosulfonyl "means with C1-4alkyl-O-, C1-4alkyl-NH-, (C)1-4Alkyl radical)2-N-、C1-4alkyl-S-, C1-4alkyl-C (O) -, C1-4alkyl-O-C (O) -, C1-4alkyl-C (O) -O-, C1-4alkyl-C (O) -NH-, C1-4alkyl-SO2-、C1-4alkyl-SO2-NH-、C1-4alkyl-NH-SO2-、(C1-4Alkyl radical)2-NH-SO2A group formed in the formula (I) wherein "C1-4Alkyl "is as defined above.
The "halo C" of the present invention1-6Alkyl, hydroxy C1-6Alkyl, amino C1-6Alkyl, carboxyl C1-6Alkyl, aminosulfonyl C1-6Alkyl, aminosulfonylamino C1-6Alkyl radical, C1-6Alkoxy radical C1-6Alkyl, halo C1-6The "alkoxy group" means one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl group, amino group, carboxyl group, aminosulfonyl group, aminosulfonylamino group, C1-6Alkoxy radicals each being substituted for C1-6Alkyl radical, C1-6A group formed by a hydrogen atom in an alkoxy group.
The "halo C" of the present invention1-4Alkyl, hydroxy C1-4Alkyl, amino C1-4Alkyl, carboxyl C1-4Alkyl, aminosulfonyl C1-4Alkyl, aminosulfonylamino C1-4Alkyl radical, C1-4Alkoxy radical C1-4Alkyl, halo C1-4Alkoxy, hydroxy C1-4The "alkoxy group" means one or more, for example, 1 to 4, 1 to 3, 1 to 2 halogen atoms, hydroxyl group, amino group, carboxyl group, aminosulfonyl group, aminosulfonylamino group, C1-4Alkoxy radicals each being substituted for C1-4Alkyl radical, C1-4A group formed by a hydrogen atom in an alkoxy group.
Described in the invention "
"means a single or double bond.
The invention also provides a preparation method of the compound, but not limited to the following method, and the reaction equation is as follows:
the reaction steps are as follows:
step 1 preparation of intermediate 1
Adding the raw material 1, the raw material 2 and N, N-diisopropylethylamine into an organic solvent (such as dimethyl sulfoxide), reacting at 90-110 ℃ for 10-20h, adding the organic solvent (such as ethyl acetate) and water, separating, drying the organic phase, and concentrating to obtain an intermediate 1.
Step 2 preparation of intermediate 2
Intermediate 2 was obtained either by purchase or by self-preparation.
Step 3 preparation of intermediate 3
Dissolving the intermediate 2 and the pinacol diboron in a proper solvent (such as 1, 4-dioxane), adding potassium acetate and tetrakis (triphenylphosphine) palladium under the protection of nitrogen, heating (such as 100 ℃ F. and 120 ℃ C.) for reaction for 6h, completely reacting, concentrating, and purifying (such as silica gel column chromatography) to obtain an intermediate 3.
Step 4 preparation of Compounds of formula (I)
Dissolving the intermediate 1, the intermediate 3 and sodium carbonate in a proper solvent (such as 1, 4-dioxane and water), adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex under the protection of nitrogen, reacting at 90-110 ℃ (such as 4-8h), concentrating the reaction solution, and purifying (such as silica gel column chromatography) to obtain the compound of the general formula (I).
In the reaction equation, R1、R2、R3、R4、R5M, n, p, Z, L, X and Y are as defined above, and Q represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.
"stereoisomers" of the compounds of formula (I) according to the present invention means that enantiomers are produced when asymmetric carbon atoms are present in the compounds of formula (I), cis-trans isomers are produced when carbon-carbon double bonds or cyclic structures are present in the compounds, tautomers are produced when ketones or oximes are present in the compounds, and all enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds of formula (I) are included in the scope of the present invention.
When any compound shown in the general formula (I) of the invention is synthesized as a racemate, the required enantiomerically pure compound can be obtained by a conventional chiral resolution method, which includes but is not limited to: chromatography (such as high pressure preparative liquid chromatography, supercritical fluid chromatography), chemical resolution, membrane resolution, and capillary electrophoresis resolution.
The pharmaceutically acceptable salt of any compound shown in the general formula (I) refers to a salt prepared from pharmaceutically acceptable and nontoxic alkali or acid, and comprises organic acid salt, inorganic acid salt, organic alkali salt and inorganic alkali salt.
The organic acid salts include salts of formic acid, acetic acid, trifluoroacetate, benzenesulfonic acid, benzoic acid, p-toluenesulfonic acid, camphorsulfonic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid, and the like.
The inorganic acid salt includes salts of hydrobromic acid, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
Organic base salts include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines and basic ion exchange resins selected from the group consisting of betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, meglumine, glucosamine, hydrabamine, isopropylamine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Natural amino acid salts such as glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, and the like.
Inorganic base salts include ammonium and salts of lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminum, iron, ketone, ferrous, manganese, manganous, and the like.
The "ester" of the compound of formula (I) of the present invention means an ester which can be formed by esterification with an alcohol when a carboxyl group is present in the compound of formula (I), or an ester which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when a hydroxyl group is present in the compound of formula (I). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.
The compound represented by the general formula (I), a pharmaceutically acceptable salt, an ester or a stereoisomer thereof may be in the form of a solvate. Where the solvate is a hydrate, the hydration may be accomplished during the manufacturing process or may be gradual, taking advantage of the hygroscopic properties of the original anhydrous product.
The invention further claims a pharmaceutical composition comprising any compound shown in the formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof and one or more pharmaceutically acceptable carriers and/or diluents, and the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. Such as tablets, capsules, pills, granules, oral solutions, oral suspensions, syrups, injections, sterile powders for injections, concentrated solutions for injections, suppositories, inhalants or sprays and the like.
The "carrier" of the present invention includes, but is not limited to, fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, and solubilizers.
The present invention further claims pharmaceutical compositions comprising a compound of any of the above-described formula (I), pharmaceutically acceptable salts, esters, solvates, or stereoisomers thereof, in combination with one or more other antineoplastic agents and/or immunosuppressive agents. The antineoplastic agent and/or immunosuppressant is antimetabolite, including but not limited to capecitabine, gemcitabine, pemetrexed disodium; are growth factor inhibitors including, but not limited to, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib; antibodies including but not limited to herceptin, bevacizumab; is mitotic inhibitor selected from paclitaxel, vinorelbine, docetaxel, and doxorubicin; are anti-tumor hormones including, but not limited to, letrozole, tamoxifen, fulvestrant, flutamide, triptorelin; are alkylating agents including, but not limited to, cyclophosphamide, mechlorethamine, melphalan, cinchonine, carmustine; is a metal platinum group, including but not limited to carboplatin, cisplatin, oxaliplatin; are topoisomerase inhibitors including, but not limited to, topotecan, irinotecan; are immunosuppressive, including but not limited to everolimus, sirolimus, and temazepride; are purine analogs including, but not limited to, 6-mercaptopurine, 6-thioguanine, azathioprine; antibiotics, including but not limited to, rhzomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin; are adrenocortical suppressants including, but not limited to, aminoglutethimide, dexamethasone; is a histone deacetylase inhibitor, including but not limited to vorinostat.
The invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of tankyrase-mediated cancer or a related disease, including, but not limited to, brain cancer, lung cancer, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumors, prostate cancer, thyroid cancer, cancer of the female reproductive tract, carcinoma in situ, lymphoma, neurofibroma, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, small cell lung cancer, gastrointestinal stromal tumor, prostate tumor, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma, glioblastoma, astrocytoma, neuroblastoma, non-hodgkin lymphoma, brain tumor, central nervous system tumor, glioma, glioblastoma multiforme, gliosarcoma, histiocytic lymphoma; the related diseases include but are not limited to Alzheimer's disease, osteoporosis, skin diseases, cardiovascular diseases and type II diabetes.
The compound of the invention has the following advantages:
(1) the compound of formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof has excellent tankyrase inhibitory activity;
(2) the compound of formula (I), pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof shows good biological stability, longer action and high bioavailability;
(3) the compound of the invention has simple preparation process, high medicine purity, stable quality and easy large-scale industrial production.
The beneficial effects of the compounds of the present invention are further illustrated below by biological experiments, but this should not be understood as the only beneficial effects of the compounds of the present invention.
The abbreviations used in the following experiments have the following meanings:
ADP: adenosine diphosphate; PARP: poly ADP-ribose polymerase
TNKS: a tankyrase; DMSO, DMSO: dimethyl sulfoxide
Tween-20: tween-20; FBS: fetal bovine serum
P/S: penicillin-streptomycin; CCK-8: cell proliferation-toxicity detection kit
1X, 5X wherein "X": multiple times
Experimental example 1 in vitro enzymatic Activity test of the Compound of the present invention
And (3) testing the sample: the chemical names and preparation methods of the trifluoroacetate of the compound 1 and the compound 2 of the invention are shown in preparation examples of the compounds.
Preparation of test article
Preparation of compound 10mM stock: respectively weighing appropriate amount of the test sample (see the following table), adding appropriate amount of DMSO for dissolving, and mixing.
Stock solutions of 10mM were each diluted with DMSO to a concentration of 1mM as stock solutions. Diluting the above mother liquor 10 times step by step with DMSO to obtain a series of solutions with a series of concentrations, and diluting with water 10 times respectively to obtain a solution containing DMSO and DMSO
10% DMSO, concentrations were: 100. mu.M, 10. mu.M, 1. mu.M, 0.1. mu.M.
(II) Experimental method
1.1 XPBS (pH7.4) was prepared
2. Preparation of PBST (1 XPBS with 0.05% Tween-20)
Adding about 200mL of 1 XPBS (pH7.4) into the beaker, then adding 100. mu.L of Tween-20, and uniformly mixing to obtain PBST.
3. Kinase reaction
3.1 coating histidine to 96-well plates
3.1.1 dilution of 5 × histidine mix 1:5 with 1 × PBS, 50 μ L of 1 × histidine per well, overnight at 4 deg.C;
3.1.2 Wash 3 times with 200 μ L PBST per well, each time blotted with a clean paper towel;
3.1.3 adding 150 mul of confining liquid into each hole, and incubating for 60-90min at room temperature;
3.1.4 Wash 3 times with 200. mu.L PBST per well, blotted with clean paper towels each time.
3.2 Ribosylation
3.2.1. The kinase is thawed on ice, and before use, the kinase is diluted by 1 XPARP analysis buffer solution to the concentration recommended by the instruction, and is always placed on ice, and can not be reused after dilution;
3.2.2 adding each reaction solution and the compound in turn according to the instruction, and incubating for 1h at room temperature;
3.2.3 remove the reaction solution, wash three times with 200. mu. LPBST, and blot clean with a clean paper towel each time.
3.3 detection
3.3.1Streptavidin-HRP diluted 50 times with blocking solution;
3.3.2 Add 50. mu.L of diluted Streptavidin-HRP per well and incubate for 30min at room temperature;
3.3.3 Wash three times with 200 μ L PBST per well, blotted with clean paper towels each time;
3.3.4 HRP chemiluminescent substrates A and B were mixed well on 50. mu.L ice before use, 100. mu.L was added to each well;
3.3.5 microplate reader readings.
4. Formula for calculation
Inhibition [% 1- (T-P)/(P-B) ]. 100%
Where P refers to the chemiluminescent reading of the positive control well and B refers to the chemiluminescent reading of the blank well. T is the chemiluminescent reading of the test compound well.
(III) results and conclusions:
TABLE 1 results of enzymatic evaluation of respective kinases
As can be seen from table 1: the compound of the invention has higher inhibitory activity to TNKS1/2, and the IC of the compound 150Less than 10nM, IC of Compound 250Less than 100nM, and simultaneous detection of the inhibitory effect of the compounds of the invention on PARP1/2, indicating IC50Are all greater than 1000 nM. The compounds of the invention are shown to have higher selectivity against TNKS 1/2.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Example 12- (4- (6- (3, 5-dimethylpiperazin-1-yl) -4-methylpyridin-3-yl) phenyl) -3,5,7, 8-tetra
Hydrogen-4H-pyrano [4,3-d ]]Preparation of pyrimidin-4-one (Compound 1)
(1) Preparation of methyl 4-oxotetrahydro-2H-pyran-3-carboxylate
Sodium hydride (60% by mass, 10.0g,250mmol) was slowly added to tetrahydrofuran (300mL) at 25 deg.C, and after the addition was complete, tetrahydro-4H-pyran-4-one (10.0g,100mmol) and dimethyl carbonate (21mL,250mmol) were added. The reaction was stirred for 16 hours while warming to 45 ℃. LC-MS detects the reaction was complete, suction filtered, the filtrate was adjusted to pH7 with 1mol/L hydrochloric acid and extracted with ether (500mL), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 50:1) to give the title compound (3.0g, 19.0% yield).
(2) Preparation of 2- (4-bromophenyl) -3,5,7, 8-tetrahydro-4H-pyrano [4,3-d ] pyrimidin-4-one
Methyl 4-oxotetrahydro-2H-pyran-3-carboxylate (564mg,3.57mmol), 4-bromobenzamidine hydrochloride (1.01g,4.28mmol) and potassium carbonate (985.3mg,7.14mmol) were added to methanol (40mL), the temperature was raised to 85 ℃ under nitrogen protection for 4 hours, the reaction was complete by TLC, the temperature was reduced to 0 ℃ and a white solid precipitated, which was filtered off with suction and the filter cake was dried in vacuo to give the title compound (700mg, 63.6% yield).
(3) Preparation of 2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -3,5,7, 8-tetrahydro-4H-pyrano [4,3-d ] pyrimidin-4-one
2- (4-bromophenyl) -3,5,7, 8-tetrahydro-4H-pyrano [4,3-d ] pyrimidin-4-one (307.2mg,1.0mmol) and pinacol diboron (254mg,1.0mmol) were added to 1, 4-dioxane (30mL), potassium acetate (196mg,2.0mmol) and tetrakis (triphenylphosphine) palladium (115.5mg,0.1mmol) were added under nitrogen, and after addition, the temperature was raised to 110 ℃ for 6 hours. The reaction was complete by LC-MS detection, the reaction was concentrated directly in vacuo and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (181mg, 51.1% yield).
(4) Preparation of 1- (5-bromo-4-methylpyridin-2-yl) -3, 5-dimethylpiperazine
5-bromo-2-chloro-4-methylpyridine (10.0g,48.4mmol), 2, 6-dimethylpiperazine (16.6g,145.6mmol) and N, N-diisopropylethylamine (6.24g,48.4mmol) were added to dimethyl sulfoxide (100mL) and reacted at 100 ℃ for 16 hours. Ethyl acetate (200mL) and water (100mL) were added to the system, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (12.0g, 87.3% yield).
(5) Preparation of 2- (4- (6- (3, 5-dimethylpiperazin-1-yl) -4-methylpyridin-3-yl) phenyl) -3,5,7, 8-tetrahydro-4H-pyrano [4,3-d ] pyrimidin-4-one
2- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -3,5,7, 8-tetrahydro-4H-pyrano [4,3-d ] pyrimidin-4-one (181mg,0.51mmol), 1- (5-bromo-4-methylpyridin-2-yl) -3, 5-dimethylpiperazine (145mg,0.51mmol) and sodium carbonate (108mg,1.02mmol) were added to a mixed solvent of 1, 4-dioxane (10mL) and water (2mL), and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (42mg,0.05mmol) was added under nitrogen protection, and the mixture was heated to 100 ℃ for 6 hours. The reaction was concentrated directly, and the crude product was subjected to silica gel column chromatography (dichloromethane: methanol ═ 15:1) to give the title compound (25mg, yield 11.4%).
The molecular formula is as follows: c25H29N5O2Molecular weight: 431.54LC-MS (m/z): 432.3(M + H)+)
1H-NMR(400MHz,DMSO-d6):8.15(s,2H),8.00(s,1H),7.49(s,2H),6.94(s,1H),4.51-4.00(m,4H),3.95-3.85(m,2H),2.83-2.72(m,2H),2.69-2.62(m,2H),2.25(s,3H),2.03-1.94(m,1H),1.32-1.18(m,9H).
Example 25- (4- (6- (3, 5-dimethylpiperazin-1-yl) -4-methylpyridin-3-yl) phenyl) -1, 6-dihydro-
7H-pyrazolo [4,3-d]Preparation of pyrimidin-7-one (compound 2) trifluoroacetate salt
(1) Preparation of 1- (5-bromo-4-methylpyridin-2-yl) -3, 5-dimethylpiperazine
5-bromo-2-chloro-4-methylpyridine (10.0g,48.4mmol), 2, 6-dimethylpiperazine (16.6g,145.6mmol) and N, N-diisopropylethylamine (6.24g,48.4mmol) were added to dimethyl sulfoxide (100mL) and reacted at 100 ℃ for 16 hours. Ethyl acetate (200mL) and water (100mL) were added to the system, the layers were separated, the organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound (12.0g, 87.3% yield).
(2) Preparation of methyl 4-nitro-1H-pyrazole-3-carboxylate
4-Nitro-1H-pyrazole-3-carboxylic acid (20.0g,0.127mmol) was dissolved in methanol (100mL), thionyl chloride (18.1g,0.152mmol) was added thereto, and the mixture was reacted at 25 ℃ for 2 hours, heated to 60 ℃ and reacted for 2 hours. The reaction was concentrated in vacuo, methyl tert-butyl ether (80mL) was added, filtered to give a white solid, and dried in vacuo to give the product (20.0g, 92.1% yield).
(3) Preparation of methyl 1- (4-methoxybenzyl) -4-nitro-1H-pyrazole-5-carboxylate
Methyl 4-nitro-1H-pyrazole-3-carboxylate (20.0g,0.117mmol) and potassium carbonate (32.3g,0.234mmol) were added to acetonitrile (200mL), 4-methoxybenzyl chloride (21.9g,0.14mmol) was added dropwise at 0 deg.C, and reaction was carried out at 25 deg.C for 16 hours. The reaction was concentrated in vacuo and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 10:1) to give the title compound (20.5g, 60.2% yield).
(4) Preparation of methyl 4-amino-1- (4-methoxybenzyl) -1H-pyrazole-5-carboxylate
Methyl 1- (4-methoxybenzyl) -4-nitro-1H-pyrazole-5-carboxylate (20.5g,70.4mmol), ammonium chloride (5.65g,105.6mmol) and iron powder (19.7g,352mmol) were added to a mixed solution of ethanol (300mL) and water (100mL), and heated to 85 ℃ for reaction for 3 hours. After cooling, filtration and concentration of the filtrate to about 200mL, water (200mL), ethyl acetate (500 mL. times.2) was added and extracted, the organic phases were combined, washed with saturated brine (300mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound (17.5g, 95.2% yield).
(5) Preparation of 5- (4-bromophenyl) -1- (4-methoxybenzyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
Methyl 4-amino-1- (4-methoxybenzyl) -1H-pyrazole-5-carboxylate (6.0g,23.0mmol) and 4-bromoxynil (12.8g,69.0mmol) were dissolved in a solution of hydrogen chloride in 1, 4-dioxane (4mol/L,100mL) and reacted at 110 ℃ for 24 hours. Concentration in vacuo and purification of the crude product by silica gel column chromatography (petroleum ether: ethyl acetate 1:1) afforded the product (1.5g, 15.9% yield).
(6) Preparation of 1- (4-methoxybenzyl) -5- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
5- (4-bromophenyl) -1- (4-methoxybenzyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (1.0g,2.4mmol), pinacol diboron (742mg,2.9mmol), potassium acetate (470mg,4.8mmol) and tetrakis (triphenylphosphine) palladium (139mg,0.12mmol) were added to 1, 4-dioxane (50mL) and reacted under nitrogen at 100 ℃ for 14 hours. The system was concentrated in vacuo and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the title compound (600mg, 54.6% yield).
(7) Preparation of 5- (4- (6- (3, 5-dimethylpiperazin-1-yl) -4-methylpyridin-3-yl) phenyl) -1- (4-methoxybenzyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one
1- (4-methoxybenzyl) -5- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (400mg,0.87mmol), 1- (5-bromo-4-methylpyridin-2-yl) -3, 5-dimethylpiperazine (258mg,0.91mmol), sodium carbonate (184mg,1.74mmol) and [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (73mg,0.09mmol) were added to 1, 4-dioxane (40mL) and water (4mL) and reacted under nitrogen at 90 ℃ for 12 hours. The system was concentrated in vacuo and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give the product (300mg, 64.3% yield).
(8) Preparation of 5- (4- (6- (3, 5-dimethylpiperazin-1-yl) -4-methylpyridin-3-yl) phenyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one trifluoroacetate
5- (4- (6- (3, 5-dimethylpiperazin-1-yl) -4-methylpyridin-3-yl) phenyl) -1- (4-methoxybenzyl) -1, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one (300mg,0.56mmol) was dissolved in trifluoroacetic acid (20mL), and a catalytic amount of anisole was added to react at 90 ℃ for 12 hours. The system was concentrated in vacuo and the crude product was chromatographed on silica gel column (dichloromethane: methanol ═ 20:1) to give the final product (200mg, 55.5% yield).
The molecular formula is as follows: c23H25N7O molecular weight: 415.5LC-MS (m/z): 416.2(M + H)+)
1H-NMR(400MHz,DMSO-d6):9.06-9.02(m,1H),8.51-8.42(m,1H),8.21-8.12(m,3H),8.02(s,1H),7.48-7.46(m,2H),6.97(s,2H),4.53-4.45(m,2H),3.37-3.28(m,2H),2.80-2.72(m,2H),2.26(s,3H),1.28-1.21(m,6H)。
Claims (6)
1. A compound represented by the general formula (II), a pharmaceutically acceptable salt thereof or a stereoisomer thereof:
wherein the content of the first and second substances,
selected from the following groups:
R2、R3、R4each independently selected from a hydrogen atom, a halogen atom, a cyano group, a hydroxyl group, an amino group, a carboxyl group, a nitro group, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, a hydroxymethyl group, an aminomethyl group or a carboxymethyl group.
2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:
3. a pharmaceutical composition comprising a compound of claim 1 or 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, characterized by one or more pharmaceutically acceptable carriers.
4. The pharmaceutical composition of claim 3, further comprising one or more antineoplastic and/or immunosuppressive agents, wherein said antineoplastic and/or immunosuppressive agents are
(1) An antimetabolite selected from capecitabine, gemcitabine, pemetrexed disodium;
(2) a growth factor inhibitor selected from the group consisting of pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib;
(3) an antibody selected from herceptin, bevacizumab;
(4) mitotic inhibitors selected from paclitaxel, vinorelbine, docetaxel, doxorubicin;
(5) antineoplastic hormones selected from letrozole, tamoxifen, fulvestrant, flutamide, triptorelin;
(6) alkylating agents selected from cyclophosphamide, mechlorethamine, melphalan, cremastrin, carmustine;
(7) metallic platins selected from carboplatin, cisplatin, oxaliplatin;
(8) a topoisomerase inhibitor selected from topotecan camptothecin, topotecan, irinotecan;
(9) immunosuppressants selected from everolimus, sirolimus, and anticancer drugs;
(10) purine analogs selected from the group consisting of 6-mercaptopurine, 6-thioguanine, azathioprine;
(11) antibiotics selected from the group consisting of rhzomycin D, daunorubicin, doxorubicin, mitoxantrone, bleomycin, and plicamycin;
(12) adrenocortical hormone inhibitors selected from aminoglutethimide, dexamethasone;
(13) a histone deacetylase inhibitor selected from vorinostat.
5. Use of a compound of claim 1 or 2, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, in the manufacture of a medicament for the treatment and/or prevention of tankyrase-mediated cancer and related diseases selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, rectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, prostate cancer, thyroid cancer, carcinoma in situ, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer; the related diseases are selected from Alzheimer's disease, osteoporosis, skin diseases, cardiovascular diseases and type II diabetes.
6. The use according to claim 5, wherein the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
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