CN110256436A - Purine compound as Trk kinase inhibitor - Google Patents
Purine compound as Trk kinase inhibitor Download PDFInfo
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- CN110256436A CN110256436A CN201910566305.1A CN201910566305A CN110256436A CN 110256436 A CN110256436 A CN 110256436A CN 201910566305 A CN201910566305 A CN 201910566305A CN 110256436 A CN110256436 A CN 110256436A
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- A—HUMAN NECESSITIES
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
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Abstract
The invention discloses the purine compounds as Trk kinase inhibitor, belong to chemical medicine.Purine compound of the present invention is as shown in logical formula (I), with good Trk family protein tyrosine-kinase enzyme inhibition activity, cancer, pain, inflammation, neurodegenerative disease, infection by Trypanosoma cruzi or the osteolytic disease that can be used for treating mammal, have a extensive future.
Description
Technical field
The invention belongs to chemical medicines, and in particular to the purine compound as Trk kinase inhibitor.
Background technique
Malignant tumour be it is extremely caused by series of genes, inactivation and proto-oncogene including tumor suppressor gene
Activation.Growth of cancer cells is vigorous, and presentation is grown without end relatively, serious influence not in tune with the metabolism of human normal
The normal function of each organ of human body, destroys the institutional framework of human normal, is the disease for seriously jeopardizing human life and health.
Small molecule kinase inhibitors are as potential cancer therapy at present, its development, which is one, allows the interested field of people, mutation and
The Gene Fusion of certain Trk and the corresponding position that they are controlled occur with uncontrolled tumour and are proliferated related.
Tropomyosin associated kinase (tropomyosin-related kinase, Trk) is a kind of nerve growth factor
Receptor, family have high homology tropomyosin associated kinase A (tropomyosin-related kinase A,
TrkA), tropomyosin associated kinase B (TrkB), tropomyosin associated kinase C (TrkC) form, respectively by NTRK1,
NTRK2 and NTRK3 coding.There is (i) that the nerve growth factor (NGF) of TrkA can be activated in neurotrophic factor, (ii) can be activated
The brain-derived neurotrophic factor (BDNF) and NT-4/5 of TrkB, and (iii) can activate the NT3 of TrkC.Trk finds expression in mind extensively
Through in member tissue and related with the maintenance of neuronal cell, signal transduction and survival.
Trk oncogene is found in colon cancer, and wherein cytoskeletal protein tropomyosin is fused to
One unknown catalytic activity kinase region.Further investigation revealed that the kinases is as a single-pass receptor tyrosine kinase
Expression is in developing central nervous system, so the kinases is referred to as tropomyosin receptor kinase.Trk kinases has one
Homologous conservative structural region, the structural region respectively include 5 extracellular domains, 1 cross-film knot from N-terminal to C-terminal
Structure domain and 1 intracellular kinase domain.In the extracellular regions of Trk, there are a leucine rich regions, two cysteine richnesses
The region of Ji Qu and two similar immunoglobulin structure, these regions are all to all ligand identification and for combining must
It is indispensable.Different from typical RTKs receptor, Trk Intracellular domain is very small, there is about 70 amino acid before kinase domain, is swashing
There are 15 amino acid behind enzyme domain.
The mode that Trks dimer responds ligand binding is similar to RTK superfamily.With after ligand binding, Trks passes through fast
The fast each monomer of phosphorylating kinase activation loop autophosphorylation.These phosphorylation activities enhance the catalytic activity of kinases.For
The binding site for generating adapter protein, NPXY functional domain (TrkA kinases Y490 amino acid sites) in membrane-proximal region and
The YLDIG functional domain (site TrkA kinases Y785) of c-terminus is phosphorylated.These phosphorylation events are 2 (SRC of SRC homeodomain
Homology Domain 2, SH2) and tyrosine binding domain (Phosphotyrosine binding comprising protein
Domain, PTB) creation docking site, such as SHC and phospholipase C gamma1 (PLC- γ 1).In conjunction with rear, SHC and PLC are urged by TRK
Change phosphorylation activation.
SHC is first associated adapter protein of Trk being identified with phosphorylation NPXY functional domain, this cause AKT and
RAS is activated by classical pathway.After SHC is activated, growth factor receptor binding protein precursor 2 (GRB2) can simultaneously and guanine
Nucleotide exchange factor (son of sevenless, SOS), SHC, which are combined, forms SHC-GRB2-SOS compound, SOS and receptor
Or the Tyr phosphorylation site combination on receptor substrate albumen causes cytoplasm protein SOS indexable to film, and the shape near RAS
In conjunction with SOS, SOS and RAS-GDP at highly difficult enrichment, GTP is promoted to replace the GDP on RAS, activates RAS.After RAS is activated
Map kinase series, the activation including RAF, MEK and ERK are had activated in the form of GTP is associated.ERK is once activated, and will continue
Many is located at the target proteins in endochylema and core downstream for activation, participates in cell growth, existence and is proliferated.
AKT is also known as protein kinase B (protein kinase B, PKB), PII structural domain can with lipid products PIP2 and
PIP3 occurs high-affinity and combines, and causes AKT to be transferred to cell membrane from cytoplasm and conformational change occurs, thus in serine/Soviet Union
Propylhomoserin site occurs phosphorylation and is activated.AKT activation leads to cell survival and the proliferation base by the receptor-mediated survival phenotype of Trk
The expression of cause enhances.
The gene mutation of Trk family is reported in many cancers, including colon cancer, thyroid cancer, lung cancer, ovary
Cancer, mastocarcinoma (secretory breast cancer), carcinoma of salivary gland (mammary gland simulation secretion cancer), cancer of pancreas, melanoma, cholangiocarcinoma, mesenchymoma
(congenital sarcoma, soft tissue sarcoma, gastrointestinal stromal tumor, inflammatory myofibroblast tumour, brain tumor (children's glioma,
Astrocytoma and glioma)) and leukaemia.In Trk family, TrkA is the most common cause oncoprotein, in kinds of tumors
Discovery rate is about 7.4% in type.And the discovery rate of TrkC and TrkB is respectively 3.4% and 0.4%.The frequency of TrkB mutation
Less than 0.5%, TrkC mutation frequency less than 1.0%.
When NTRK Gene Fusion occurs, translocation events generate one and are linked to uncorrelated gene by active Trk kinase domain
Or the mixing oncogene that fusion partner generates, trigger the constitutively activated or overexpression of Trk albumen.Resulting exception table
It reaches, in the case where being with or without cross-film field, there may be new oncogenes.Certain mutation in the extracellular field TrkA, i.e.,
P203A and C345S is confirmed to be conversion in laboratory conditions, but the qualification result for the human tumor sample that needs.It is another
Aspect, the in-frame deletion (Δ TrkA) and splicing variants (TrkAIII) of NTRK1 is in human tumor sample by identification of function
And characterization.The Δ TrkA in-frame deletion confirmed in acute myelocytic leukemia (AML), the extracellular domain being truncated comprising one, can
To change epithelium and fibroblast.The TRKAIII splicing variants determined in neuroblastoma are in exon 6,7 and 9
In have missing, this will lead to the forfeiture of Ig-like C2-type I (IG-C2) and glycosylation sites in extracellular domain.TrkA swashs
Mutation living jeopardizes ability to adjusting kinase domain from genome rearrangement, point mutation, gene delection or splicing variants.This shows Trk
A determinant attribute of carciongenic potency be the form of extracellular and/or the missing of function.
Micromolecular inhibitor (the Expert of known several Trk kinases that can be used for cancer or pain
Opin.Ther.Patents,2009,19(3):305-319)。
If international patent application WO2006115452 and WO2006087538 elaborate that Ganlei is stated to be inhibitor or Trk swashs
The small molecule of enzyme can be used for treating pain or cancer.
International patent application WO2007025540 discloses certain imidazo [1,2-b] pyridazines being substituted, and has at 6
There is the piperazinyl of secondary amino group or BOC- protection.These compounds are the inhibitor for being disclosed as protein kinase C (PKC).
International patent application WO2008052734 discloses (R) -4- (6- (2- (3- fluorophenyl) Pyrrolizidine -1- base) imidazoles
And [1,2-b] pyridazine -3- base) benzonitrile, that is, imidazo [1,2b] pyridazine compound, in 6 heterocycles substituted with aryl -
Group and 3 have benzonitrile group.It is said that the compound is receptor-mediated by PI3K receptor, JAK-2 receptor and Trk suitable for treating
Disease.
International patent application WO2007013673 discloses 1- phenyl -3- (6- (1- phenylethylcarbamate) imidazo [1,2-
B] pyridazine -3- base) urea and N- (6- (4- hydroxy-cyclohexyl amino) imidazo [1,2-b] pyridazine -3- base) benzamide, that is, miaow
Azoles simultaneously [1,2b] pyridazine compound has amide or urea part with amino and at 3 at 6.These compounds are stated to be
Trk inhibitor.Novel and significantly more efficient treatment is continuously needed to mitigate pain, especially chronic ache.Due to TrkA and its
Its Trk kinases can be used as the mediator of the biological respinse of NGF driving, therefore the inhibitor of TrkA and other Trk kinases can be chronic pain
Pain state provides effectively treatment.
U.S. Patent Publication No. US20110195948 describes phonetic as the substituted pyrazolo [1,5-a] of Trk inhibitor
Acridine compound.
In recent years, for curative effect more preferably, the Trk inhibitor that less side effects, metabolic stability is high, bioavilability is good deposits
In urgent clinical demand.In order to achieve the purpose that preferably to treat tumour, it is therefore desirable to be able to develop new high-efficiency low-toxicity
Trk inhibitor.The present invention will provide a kind of new structural Trk inhibitor, and find that the compound of such structure is shown
Excellent effect and effect, it is desirable to provide more drugs for treating cancer.
Summary of the invention
Problems to be solved by the invention: the deficiencies of in order to overcome the problems, such as stability of the existing technology, activity, meet day
The clinical demand that benefit increases, the present invention provide a kind of novel substituted purin compound as Trk kinase inhibitor.The structure
Compound pharmacodynamics performance is more preferable, metabolic stability is higher.
Further, the present invention provides a kind of compound with logical formula (I) or its pharmaceutically acceptable salt, medicine group
Close object and purposes.
The first purpose of the invention is to provide a kind of purine compound, the compound is chemical combination described in logical formula (I)
Object or its pharmaceutically acceptable salt,
Wherein: R1Selected from (i) halogen, (1-4C) alkoxy, trifluoromethyl, difluoromethyl, middle one or more substituent groups
Substituted phenyl；Or 5 former or 6 yuan of heteroaromatics that (ii) one or more halogen atoms replace, the heteroaromatic have N and/or
S；
R2Selected from it is following any one: NRaRb, (1-4C) hydroxy alkyl, the heterocyclic aryl that (1-4C alkyl), halogen replace,
Containing heteroatomic naphthenic base；Or one or more substitutions in fluorine-containing, trifluoromethyl, hydroxyl, primary amino group, alkoxy, secondary amino group
(3-6C) naphthenic base that base replaces；
RaIt is H or (1-6C) alkyl；RbIt is (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocyclic aryl is 5 to 6
First hetero-aromatic ring is independently selected from the ring hetero atom of N and O with 1-2, and contains one or more (1-4C) alkyl substituents；Institute
It states heterocyclic aryl or aryl and includes one or more substituent groups in halogen, trifluoromethyl, hydroxyl, cyano；Or NRaRbForm tool
There are 4 circle heterocyclic rings of theheterocyclic nitrogen atom, replaces wherein the heterocycle is optionally independently selected from a kind of or multiple substituent groups below: halogen
Element, hydroxyl, (1-4C) alkyl, (1-4C) alkoxy；Or NRaRb5 to 6 circle heterocyclic rings are formed, the heterocycle has theheterocyclic nitrogen atom and goes back
Comprising optionally from any one hetero atom of N, O, S, the heterocycle includes that one or more substituent groups below replace: hydroxyl, halogen
Element, trifluoromethyl, (1-4C) alkyl, primary amino group, carboxyl；
The heterocyclic aryl in heterocyclic aryl that (the 1-4C alkyl), halogen replace, which is selected from, has 1 to 3 theheterocyclic nitrogen atom
5 yuan of hetero-aromatic rings；Alternatively, at least one nitrogen ring atom and also comprising optionally from N, O, S any one heteroatomic 5 to 6 yuan it is miscellaneous
Aromatic ring；
It is described containing heteroatomic naphthenic base be carbon connection 4 to 6 yuan of azacyclo-s, include (1-4C) alkyl, carboxyl, (1-4C
Alkyl) kind one or more substituent groups；Or (1-4C) alkyl-substituted pyridone or pyridazine ring；
R3Selected from H, C1-C8 linear or branched alkyl group；X is selected from O, NH or NR4；R4Selected from (1-6C) alkyl.
In one embodiment of the invention, R2It is preferred that-NRaRbOr the heterocyclic aryl that halogen replaces；Wherein RaIt is H
Or (1-6C) alkyl；
RaIt is H or (1-6C) alkyl；RbIt is (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocyclic aryl is 5 to 6
First hetero-aromatic ring is independently selected from the ring hetero atom of N and O with 1-2, and contains one or more (1-4C) alkyl substituents；Institute
It states heterocyclic aryl or aryl and includes one or more substituent groups in halogen, trifluoromethyl, hydroxyl, cyano；Or NRaRbForm tool
There are 4 circle heterocyclic rings of theheterocyclic nitrogen atom, replaces wherein the heterocycle is optionally independently selected from a kind of or multiple substituent groups below: halogen
Element, hydroxyl, (1-4C) alkyl, (1-4C) alkoxy；Or NRaRb5 to 6 circle heterocyclic rings are formed, the heterocycle has theheterocyclic nitrogen atom and goes back
Comprising optionally from any one hetero atom of N, O, S, the heterocycle includes that one or more substituent groups below replace: hydroxyl, halogen
Element, trifluoromethyl, (1-4C) alkyl, primary amino group, carboxyl；The heterocyclic aryl that (1-4C alkyl), halogen replace,
The heterocyclic aryl in heterocyclic aryl that (the 1-4C alkyl), halogen replace, which is selected from, has 1 to 3 theheterocyclic nitrogen atom
5 yuan of hetero-aromatic rings；Alternatively, at least one nitrogen ring atom and also comprising optionally from N, O, S any one heteroatomic 5 to 6 yuan it is miscellaneous
Aromatic ring.
In one embodiment of the invention, R2Further preferably-NRaRb；Wherein RaIt is H or (1-6C) alkyl；RbIt is
(1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocyclic aryl is 5 to 6 yuan of hetero-aromatic rings, have 1-2 be independently selected from N and
The ring hetero atom of O, and contain one or more (1-4C) alkyl substituents；The heterocyclic aryl or aryl include halogen, trifluoro
Methyl, hydroxyl, one or more substituent groups in cyano；Or NRaRb4 circle heterocyclic rings with theheterocyclic nitrogen atom are formed, wherein described miscellaneous
Ring is optionally independently selected from a kind of or multiple substituent groups below and is replaced: halogen, hydroxyl, (1-4C) alkyl, (1-4C) alcoxyl
Base；Or-NRaRb5 to 6 circle heterocyclic rings are formed, the heterocycle has theheterocyclic nitrogen atom and also comprising optionally any one miscellaneous original from N, O, S
Son, the heterocycle include that one or more substituent groups below replace: hydroxyl, halogen, trifluoromethyl, (1-4C) alkyl, primaquine
Base, carboxyl.
In one embodiment of the invention, R1It is preferred that substituted-phenyl, the substituted-phenyl includes one or more halogen
Element ,-CF3、-CHF2Substituent group.
In one embodiment of the invention, R1The benzene further preferably replaced containing the fluorine of one or two or chlorine atom
Base, or containing a fluorine atom and-CF3Substituted phenyl.
In one embodiment of the invention, the NRaRbMiddle RaIt is preferred that H；RbIt is preferred that containing halogen, trifluoromethyl, hydroxyl
The phenyl or the-NR of one or more substituent groups in base, cyanoaRb4 circle heterocyclic rings with theheterocyclic nitrogen atom are formed, wherein
The optional ground of the heterocycle is independently selected from a kind of or multiple substituent groups below and is replaced: halogen, hydroxyl, (1-4C) alkyl, (1-
4C) alkoxy or NRaRb5 to 6 circle heterocyclic rings are formed, there is theheterocyclic nitrogen atom and also comprising optionally any one miscellaneous original from N, O, S
Son, the heterocycle include that one or more substituent groups below replace: hydroxyl, halogen, trifluoromethyl, (1-4C) alkyl.
In one embodiment of the invention, by NRaRbIt is preferred that such as flowering structure:
In one embodiment of the invention, R2When for (1-4C) hydroxy alkyl, preferably-C (CH3)2OH and-C (CH3)2CH2OH。
In one embodiment of the invention, R2For (1-4C alkyl) replace heterocyclic aryl when, the heterocyclic aryl
5 yuan of hetero-aromatic rings with 1 to 3 theheterocyclic nitrogen atom, or have at least one theheterocyclic nitrogen atom and 6 yuan of heteroaryls also containing N and/or S
Ring.
In one embodiment of the invention, R21,2, the 4- triazole rings or pyridyl group replaced for (1-4C alkyl)
Ring, pyrimidine-ring, pyrazine basic ring, pyrazoles basic ring, imidazoles basic ring and thiazole basic ring.
In one embodiment of the invention, described (1-4C alkyl) the substituted pyridines basic ring, pyrimidine-ring, pyrazinyl
The R that ring, pyrazoles basic ring, imidazoles basic ring and thiazole basic ring indicate2Specific structure it is as follows:
Preferably, R2For
In one embodiment of the invention, R2It is described to contain heteroatomic naphthenic base when being containing heteroatomic naphthenic base
Azetidinyl, pyrrolidinyl and piperidines basic ring including carbon connection contain one or more containing heteroatomic naphthenic base
Substituent group, the substituent group include methyl, ethyl, propyl, CO2Me、CO2Et and CO2C(CH3)3。
It in one embodiment, include that one or two of above-mentioned substituent group replaces containing heteroatomic naphthenic base.
In some embodiments of the present invention, R2It is described to contain heteroatomic naphthenic base when being containing heteroatomic naphthenic base
The pyridone ring or pyridazinone ring replaced including (1-4C) alkyl substituent.(1-4C) alkyl substituent is methyl or second
Base.
In some embodiments of the present invention, X is selected from O, NH or NCH3、NCH2CH3。
In order to improve compound metabolism stability and activity, it is preferable that X NH.
In one embodiment of the invention, the purine compound includes compound as follows:
In one embodiment of the invention, the pharmaceutically acceptable salt includes inorganic salts or organic salt, described
Inorganic salts include hydrochloride, hydrobromate, hydriodate, sulfate, disulfate, nitrate, phosphate, in acid phosphate
Any one；The organic salt includes acetate, trifluoroacetate, propionate, acetonate, oxyacetate, oxalate, third
Diacid salt, fumarate, maleate, lactate, malate, citrate, tartrate, mesylate, with sulfonate,
Any one in benzene sulfonate, salicylate.
Further, the compound or their salt of formula (I) can be separated in the form of solvate, and therefore any this
Solvate belongs to the scope of the present invention.
The compound of logical formula (I) further includes chemical combination only different in terms of the presence of one or more isotope enrichment atoms
Object.For example, the compound of the present invention includes wherein one or more hydrogen atoms by deuterium or tritium substitution or one or more carbon atoms
The compound replaced by the carbon that 13C- or 14C- is enriched with, within the scope of the invention.
Second object of the present invention is to use purine compound shown in logical formula (I) or its pharmaceutically acceptable salt
In preparation Trk kinase inhibition drug,
Wherein: in logical formula (I), R1Selected from (i) halogen, (1-4C) alkoxy, CF3、CHF2, middle one or more takes
The phenyl replaced for base；Or the 5- or 6-membered heteroaromatic that (ii) one or more halogen atoms replace, wherein heteroaromatic its have
Heteroatom selected from N and/or S includes one or more halogen atom substituents；
R2Selected from once any one: NRaRb, (1-4C) alkyl, (1-4C) fluoroalkyl, (1-4C) hydroxy alkyl, (1-4C)
The heterocyclic aryl that alkyl, halogen replace, contains miscellaneous heteroatomic naphthenic base or halogen, fluorine replace alkyl, hydroxyl, alkoxy, primaquine
(3-6C) naphthenic base that is a kind of or planting a substituent group substitution in base, secondary amine；
RaIt is H or (1-6C) alkyl；RbIt is H, (1-4C) alkyl, (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein
Heterocyclic aryl is 5 to 6 yuan of hetero-aromatic rings, the ring hetero atom of N and O is independently selected from 1-2, and contain one or more (1-4C)
Alkyl substituent；One or more of alkyl, hydroxyl, cyano is replaced to take comprising halogen, fluorine on the heterocyclic aryl or aryl
Dai Ji；Or NRaRbForm 4 circle heterocyclic rings with theheterocyclic nitrogen atom, wherein the heterocycle be optionally independently selected from it is below a kind of or
Multiple substituent groups replace: halogen, hydroxyl, (1-4C) alkyl, (1-4C) alkoxy；Or NRaRb5 or 6 circle heterocyclic rings are formed, wherein institute
Heterocycle is stated with theheterocyclic nitrogen atom and also comprising optionally from any one hetero atom of N, O, S, the heterocycle includes with next or more
A substituent group: hydroxyl, halogen, trifluoromethyl, (1-4C) alkyl, primary amino group, carboxyl；
The heterocyclic aryl in heterocyclic aryl that (the 1-4C alkyl), halogen replace, which is selected from, has 1 to 3 theheterocyclic nitrogen atom
5 yuan of hetero-aromatic rings；Alternatively, at least one nitrogen ring atom and also comprising optionally from N, O, S any one heteroatomic 5 to 6 yuan it is miscellaneous
Aromatic ring；
It is described containing heteroatomic naphthenic base it is miscellaneous be carbon connection 4 to 6 yuan of azacyclo-s, include (1-4C) alkyl, carboxyl, (1-
4C alkyl) kind one or more substituent groups；Or (1-4C) alkyl-substituted pyridone or pyridazine ring；
R3Selected from H, C1-C8 linear or branched alkyl group；
X is selected from O, NH or NR4；R4Selected from (1-6C) alkyl.
Third purpose of the present invention there is provided a kind of pharmaceutical composition, including the above-mentioned general formula compound of the present invention or its
Pharmaceutically acceptable salt and pharmaceutically acceptable carrier, excipient or diluent.
In one embodiment of the invention, described pharmaceutical composition may be formulated for the solid system of oral administration
Agent includes, but are not limited to capsule, tablet, pill, powder, granule etc..
In one embodiment of the invention, the solid pharmaceutical preparation of described pharmaceutical composition can be by the logical formula (I) of the present invention
Compound is mixed as active constituent at least one conventional inert excipients or carrier.
In one embodiment of the invention, the excipient includes sodium citrate or Dicalcium Phosphate.
In one embodiment of the invention, described pharmaceutical composition further includes following ingredient: (1) filler or solubilising
Agent；(2) adhesive；(3) moisturizer；(4) disintegrating agent；(5) retarding solvent；(6) absorbsion accelerator；(7) wetting agent；(8) adsorbent；
(9) lubricant.
In one embodiment of the invention, the filler or solubilizer include starch, it is lactose, sucrose, glucose, sweet
Reveal pure and mild silicic acid.Described adhesive include hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, I
Primary glue.The moisturizer includes glycerol.The disintegrating agent include agar, calcium carbonate, potato starch or tapioca, alginic acid,
It is certain to meet silicate and sodium carbonate.The retarding solvent includes paraffin.The absorbsion accelerator includes quaternary ammonium compound.The profit
Humectant includes cetanol and glycerin monostearate.The adsorbent includes kaolin.The lubricant includes talcum, stearic acid
Or mixtures thereof calcium, solid polyethylene glycol, lauryl sodium sulfate etc.,.
In one embodiment of the invention, the solid pharmaceutical preparation of described pharmaceutical composition can be by the logical formula (I) of the present invention
Compound is mixed as active constituent at least one conventional inert excipients or carrier.Solid dosage forms includes tablet, sugar-pill, glue
Wafer, pill and granule.
In one embodiment of the invention, solid dosage forms is capsule, tablet or pill, also may include delaying in component
Electuary.
In one embodiment of the invention, coating and shell material can be used in the granule, such as enteric coating and other
The coating of material crystal form or microencapsulation well known in the art.The granule may include opacifying agent, also, living in this composition
The release of property ingredient can discharge in certain gastral a part in a delayed fashion.The example of adoptable embedding component is poly-
Close substance and wax material.When necessary, active constituent can also form microcapsules shape with one or more of above-mentioned excipient
Formula.
In one embodiment of the invention, described pharmaceutical composition may be formulated for the liquid agent of oral administration
Type includes, but are not limited to pharmaceutically acceptable lotion, solution, suspension, syrup, tincture etc..
In one embodiment of the invention, in addition to the logical formula (I) chemical combination as active constituent in the liquid dosage form
It may include the inert diluent routinely used in this field, solubilizer and emulsifier outside object or its pharmaceutically acceptable salt.
The inert diluent includes water and other solvents.The solubilizer and emulsifier include ethyl alcohol, isopropanol, carbonic acid
Ethyl ester, ethyl acetate, propylene glycol, 1,3-BDO, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn
Oil, olive oil, castor oil, sesame oil etc. or the mixture of these substances etc..
Other than these inert diluents, fluid present invention dosage form may also comprise conven-tional adjuvants, as wetting agent, emulsifier and
Suspending agent, sweetener, corrigent and fragrance etc..
The suspending agent includes ethoxylated octadecanol, polyoxyethylene sorbitol and anhydro sorbitol, microcrystalline cellulose
Any one or more in element, agar.
In one embodiment of the invention, described pharmaceutical composition is configurable to the agent for parental injection
Type includes, but are not limited to physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, suspension or lotion, and is used for
Re-dissolve into the aseptic powdery of sterile Injectable solution and dispersion liquid.The dosage form of the parental injection includes suitable load
Body, diluent, solvent, excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
In one embodiment of the invention, described pharmaceutical composition is configurable to the dosage form for local administration,
Including such as ointment, powder, suppository, drops, stock solution and inhalant etc..The composition aseptically and physiologically may be used
The carrier of receiving and optional preservative, buffer, and the propellant that may be needed when necessary are mixed together.
In one embodiment of the invention, described pharmaceutical composition includes logical formula (I) compound or it pharmaceutically may be used
The salt of receiving is as active constituent and pharmaceutically acceptable carrier, excipient, diluent.When preparing pharmaceutical composition, lead to
It is often by the logical formula (I) compound of the present invention or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier, excipient or dilution
Agent mixing.The content of its formula of (I) compound or its pharmaceutically acceptable salt can be 0.01-1000mg, such as 0.05-
800mg, 0.1-500mg, 0.01-300mg, 0.01-200mg, 0.05-150mg, 0.05-50mg etc..
4th purpose of the invention is to provide above-mentioned purine compound or its pharmaceutically acceptable salt is used in preparation
In the drug for treating the cancer of mammal, pain, inflammation, neurodegenerative disease, infection by Trypanosoma cruzi or osteolytic disease
Purposes.
Preferably, wherein the cancer includes melanoma, non-small cell lung cancer, thyroid cancer, the white blood of Acute Meyloid
Disease, glioblastoma, astrocytoma and medulloblastoma, colon cancer, neuroblastoma, oophoroma, breast cancer, prostate
Cancer, cancer of pancreas, Huppert's disease and maxicell neuroendocrine tumors.Wherein the pain be related to cancer, surgical operation,
Fracture, the ostalgia as caused by metastases, osteoarthritis, psoriatic arthritis, rheumatoid arthritis, interstitial cystitis,
Chronic pancreatitis, splanchnodynia, inflammatory pain, migraine, chronic low back pain, painful bladder syndrome and neuropathic pain.Wherein institute
The inflammation stated includes asthma, interstitial cystitis, ulcerative colitis, Crohn disease, atopic dermatitis, eczema and chronic eczema.
Logical formula (I) compound or its pharmaceutically acceptable salt are used by inhibiting tropomyosin kinases (Trk) activity
In cancer, pain, inflammation, neurodegenerative disease, infection by Trypanosoma cruzi or osteolytic disease that preparation treatment mammal includes people
The drug of disease.Include the said medicine that people applies therapeutically effective amount to the mammal, reaches therapeutic effect.
" therapeutically effective amount " is effectively to generate biology or medicine response in individual (such as to reduce or inhibit enzyme activity albumen living
Property, either improve symptom, mitigate the patient's condition, slow down or postpone progression of disease or prevention disease) the compound of the present invention amount.
It includes people that drug of the present invention, which can deliver medicine to mammal, can take orally, rectum, it is parenteral (intravenous, intramuscular or
Subcutaneously), it is administered in local administration (pulvis, ointment, drops) or tumor.
Drug of the present invention can be administered alone, or be administered with other pharmaceutically acceptable therapeutic agents, with other
Antitumor combination.This combination therapy can by simultaneously, sequence or be used separately each component for the treatment of and realize.It is described to control
Treating agent includes but is not limited to: acting on the anti-tumor drug of DNA chemical structure, such as cis-platinum, influences the antitumor of nucleotide synthesis
Drug such as methotrexate (MTX), 5 FU 5 fluorouracil etc. influences anti-tumor drug such as adriamycin, Epi-ADM, Accra of transcribed nucleic acid
Mycin etc. acts on the anti-tumor drug such as taxol, vinorelbine etc. of tubulin synthesis, arimedex such as ammonia Shandong
Meter Te, Letrozole, auspicious Ningde etc., cell-signaling pathways inhibitor such as epidermal growth factor receptor inhibitor Imatinib
(Imatinib), Gefitinib (Gefitinib), Tarceva (Erlotinib) etc..Antitumor monoclonal antibody, immunosuppressor PD-
1, PD-L1 etc., each ingredient to be combined can simultaneously or sequentially be given, in the form of single formulation or in the form of different preparations
It gives.The combination not only includes one kind of the compounds of this invention or the combination of other activating agents, but also including the present inventionization
Close the combination of other activating agents of two or more of object.
The one or more other drugs acted on other same or different role mechanisms play are applied in combination.This, which combines, controls
Treat can by simultaneously, sequence or be used separately each component for the treatment of and realize.The therapeutic agent includes but is not limited to: steroid
Dexamethasone, cortisone, fluticasone；Antalgesic, aspirin, brufen, Indomethacin and opioids.
Beneficial effects of the present invention:
The substituted purin compound with structure shown in logical formula (I) provided by the invention, has good Trk inhibitory activity
With excellent pharmacodynamics performance, metabolic stability is higher and production cost is relatively low.
Detailed description of the invention
Fig. 1 embodiment 2 be ((S) -2-'s ((6- (4- fluorobenzoyl) -9- isopropyl -9H- purine -2- alcohol) butanone -1- alcohol)
Nucleus magnetic hydrogen spectrum figure.
Specific embodiment
Technical solution of the present invention is described in detail below in conjunction with embodiment.
" (1-4C) alkyl " refers to the unit price of the linear chain or branched chain of the saturation of respectively 1 to 4 carbon atom in the present invention
Alkyl.Example includes, but are not limited to methyl, ethyl, 1- propyl, 2- propyl, 1- butyl, 2- methyl-1-propyl, 2- butyl and 2-
Methyl-2-propyl.
" (1-4C) alkoxy " refers to the list of the linear chain or branched chain of the saturation of respectively 1 to 4 carbon atom in the present invention
Valence group, wherein the group is on oxygen atom.
" (1-4C) hydroxy alkyl " refers to the linear chain or branched chain of the saturation of respectively 1 to 4 carbon atom in the present invention
Monovalent alkyl group, wherein 1 hydrogen atom is replaced by OH group.
The term " containing fluoroalkyl " being used in the present invention refers to the alkyl that one or more hydrogen atoms are replaced by fluorine atom.
The example of fluoroalkyl includes-CHF2、–CH2CF3Or perfluoroalkyl such as-CF3Or-CF2CF3。
It " is administered " in the present invention or " giving " individual compound is directed to individual in need for the treatment of and provides change of the invention
Close object.
The following example illustrates rather than limit the synthetic method of logical formula (I) compound.Temperature is degree Celsius.If
In addition do not illustrate, all evaporations carry out under reduced pressure.If not stated otherwise, otherwise reagent is from commercial suppliers
It buys and is used without being further purified.The structure of final product, intermediate and raw material is confirmed by standard method of analysis.Such as
NMR, the abbreviation used are this field Conventional abbreviations.
The preparation of 1 intermediate of embodiment:
The preparation of the chloro- N- of 2- (4- luorobenzyl) -9H- purine -6- amine:
Structural formula is as follows:
N-butanol (50mL) and 2 is added in eggplant-shape bottle (250mL), 4- dichloro pyrimidine (5g, 26.7mmol) stirs molten
Solution, then 4-Fluorobenzylamine (3.4g, 27mmol) and triethylamine (3.4g, 33.6mmol) is slowly added dropwise, it is warming up to 110 DEG C of reaction 3h.
TLC detects end of reaction, is cooled to 20 DEG C, there is solid precipitation, filters, is washed with n-butanol (5mL), and drying obtains white solid
Product (5.5g, yield 75%).
The preparation of the chloro- N- of 2- (4- luorobenzyl) -9- isopropyl -9H- purine -6- amine (intermediate A 1):
Structural formula is as follows:
Be added in the eggplant-shape bottle (250mL) DMSO (10mL) and the chloro- N- of 2- (4- luorobenzyl) -9H- purine -6- amine (2g,
7.2mmol), stirring and dissolving, in 18-20 DEG C of addition potassium carbonate (3.5g, 25.3mmol) and 2- N-Propyl Bromide (2g, 16.2mmol),
5h is stirred, TLC detection reaction terminates.5 DEG C of cold water (20mL) are added, are extracted with ethyl acetate (20mL × 3), organic layer salt water
Washing, sodium sulphate is dry, and condensing crystallizing is evaporated under reduced pressure, and 2- propyl alcohol (5mL) is added into residual solution and stirs 10min, filters, obtains
White solid (2g, 86%).
The preparation of the chloro- N- of 2- (3- luorobenzyl) -9H- purine -6- amine:
Structural formula is as follows:
N-butanol (50mL) and 2 is added in eggplant-shape bottle (250mL), 4- dichloro pyrimidine (5g, 26.7mmol) stirs molten
Solution, then 3- fluorin benzyl amine (3.4g, 27mmol) and triethylamine (3.4g, 33.6mmol) is slowly added dropwise, it is warming up to 110 DEG C of reaction 3h.
TLC detects end of reaction, is cooled to 20 DEG C, there is solid precipitation, filters, is washed with n-butanol (5mL), and drying obtains white solid
Product (5.2g, yield 71%).
The preparation of the chloro- N- of 2- (3- luorobenzyl) -9- isopropyl -9H- purine -6- amine (intermediate A 2):
Structural formula is as follows:
Be added in the eggplant-shape bottle (250mL) DMSO (10mL) and the chloro- N- of 2- (3- luorobenzyl) -9H- purine -6- amine (2g,
7.2mmol), stirring and dissolving, in 18-20 DEG C of addition potassium carbonate (3.5g, 25.3mmol) and 2- N-Propyl Bromide (2g, 16.2mmol),
5h is stirred, TLC detection reaction terminates.5 DEG C of cold water (20mL) are added, are extracted with ethyl acetate (20mL × 3), organic layer salt water
Washing, sodium sulphate is dry, and condensing crystallizing is evaporated under reduced pressure, and 2- propyl alcohol (5mL) is added into residual solution and stirs 10min, filters, obtains
White solid (2.1g, 90%).
The preparation of the chloro- N- of 2- (4- (trifluoromethyl) benzyl) -9H- purine -6- amine:
Structural formula is as follows:
N-butanol (50mL) and 2 is added in eggplant-shape bottle (250mL), 4- dichloro pyrimidine (5g, 26.7mmol) stirs molten
Solution, then 4- (trifluoromethyl) benzylamine (4.7g, 27mmol) and triethylamine (3.4g, 33.6mmol) is slowly added dropwise, it is warming up to 110 DEG C
React 3h.TLC detects end of reaction, is cooled to 20 DEG C, there is solid precipitation, filters, is washed with n-butanol (5mL), drying obtains
White solid product (6.2g, yield 71%).
The preparation of the chloro- N- of 2- (4- (trifluoromethyl) benzyl) -9- isopropyl -9H- purine -6- amine (intermediate A 3):
Structural formula is as follows:
DMSO (10mL) and the chloro- N- of 2- (4- (trifluoromethyl) benzyl) -9H- purine -6- is added in eggplant-shape bottle (250mL)
Amine (2.4g, 7.3mmol), stirring and dissolving, 18-20 DEG C of addition potassium carbonate (3.5g, 25.3mmol) and 2- N-Propyl Bromide (2g,
16.2mmol), 5h is stirred, TLC detection reaction terminates.5 DEG C of cold water (20mL) are added, is extracted, is had with ethyl acetate (20mL × 3)
Machine layer is washed with brine, and sodium sulphate is dry, and condensing crystallizing is evaporated under reduced pressure, and 2- propyl alcohol (5mL) stirring is added into residual solution
10min filters, obtains white solid (2g, 74%).
The preparation of the chloro- N- of 2- (3- (trifluoromethyl) benzyl) -9H- purine -6- amine:
Structural formula is as follows:
N-butanol (50mL) and 2 is added in eggplant-shape bottle (250mL), 4- dichloro pyrimidine (5g, 26.7mmol) stirs molten
Solution, then 3- (trifluoromethyl) benzylamine (4.7g, 27mmol) and triethylamine (3.4g, 33.6mmol) is slowly added dropwise, it is warming up to 110 DEG C
React 3h.TLC detects end of reaction, is cooled to 20 DEG C, there is solid precipitation, filters, is washed with n-butanol (5mL), drying obtains
White solid product (5.9g, yield 67%).The chloro- N- of 2- (3- (trifluoromethyl) benzyl) -9- isopropyl -9H- purine -6- amine
The preparation of (intermediate A 4)
The chloro- N- of 2- (3- (trifluoromethyl) benzyl) -9- isopropyl -9H- purine -6- amine
Structural formula is as follows:
DMSO (10mL) and the chloro- N- of 2- (4- (trifluoromethyl) benzyl) -9H- purine -6- is added in eggplant-shape bottle (250mL)
Amine (2.4g, 7.3mmol), stirring and dissolving, 18-20 DEG C of addition potassium carbonate (3.5g, 25.3mmol) and 2- N-Propyl Bromide (2g,
16.2mmol), 5h is stirred, TLC detection reaction terminates.5 DEG C of cold water (20mL) are added, is extracted, is had with ethyl acetate (20mL × 3)
Machine layer is washed with brine, and sodium sulphate is dry, and condensing crystallizing is evaporated under reduced pressure, and 2- propyl alcohol (5mL) stirring is added into residual solution
10min filters, obtains white solid (2.1g, 78%).Structural formula is as follows:
Embodiment 2 (S) -2- (preparation of (6- (4- fluorobenzoyl) -9- isopropyl -9H- purine -2- alcohol) butanone -1- alcohol
To addition intermediate A 1 (1.2g, 3.8mmol) and (R) -2- amino-n-butyl alcohol (3mL), nitrogen in eggplant-shape bottle (25mL)
Gas shielded, being heated to 160 DEG C of reaction 8h, TLC detection reactions terminates, and is cooled to room temperature, is added water (20mL), uses ethyl acetate
(20mL × 4) extraction, organic layer are washed with 50 DEG C of warm water (30mL × 2), and sodium sulphate is dry, remove most of solvent under reduced pressure.To
Ethyl acetate (10mL) is added in residual solution, has crystal precipitation, filters to obtain white crystal (1g, 70%).
1H-NMR(400MHz,CDCl3) δ: 7.48 (d, J=2.0Hz, 1H), 7.36-7.29 (m, 2H), 7.04-6.97 (m,
2H), 6.01 (s, 1H), 5.04 (s, 1H), 4.89 (d, J=6.1Hz, 1H), 4.73 (s, 2H), 4.60 (p, J=6.8Hz, 1H),
3.85-3.93 (m, 1H), 3.82 (dd, J=10.7,2.6Hz, 1H), 3.63 (dd, J=10.7,7.7Hz, 1H), 1.85 (s,
1H), 1.64-1.57 (m, 1H), 1.53 (d, J=6.7Hz, 6H), 0.97-0.08 (m, 3H)
3 2- of embodiment ((6- (4- fluorophenyl) amino) -9- isopropyl -9H- purine -2- base) amino) -2- phenethyl 1-
The preparation of alcohol
Other than using DL- benzene glycinol to replace (R) -2- amino-n-butyl alcohol, with the synthetic method phase with compound 1
Same method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,DMSO-d6) δ: 8.82 (s, 1H), 8.29 (s, 1H), 7.76 (s, 1H), 7.32-7.43 (m,
3H), 7.24 (t, J=7.5Hz, 1H), 7.11-7.19 (m, 2H), 7.05 (s, 1H), 6.61 (d, J=7.5Hz, 0H), 4.71-
4.64 (m, 1H), 4.61 (d, J=6.2Hz, 2H), 4.54-4.40 (m, 1H), 3.69-3.57 (m, 1H), 1.50 (d, J=
6.8Hz, 6H), 1.41 (d, J=6.7Hz, 2H)
Embodiment 41- alcohol 1- (6- (4- fluorophenyl) amino) -9- isopropyl -9H- purine -2- alcohol) piperidines -4- alcohol preparation
Other than using 4- hydroxy piperidine to replace (R) -2- amino-n-butyl alcohol, with identical as the synthetic method of compound 1
Method synthesized.Structural formula is as follows:
1H-NMR (400MHz, CDCl3) δ: 7.47 (s, 1H), 7.37-7.30 (m, 2H), 7.26 (s, 1H) 7.01-6.93
(m, 2H), 6.19 (s, 1H), 4.74 (d, J=5.8Hz, 2H), 4.66 (p, J=6.8Hz, 1H), 4.42-4.52 (m, 2H),
3.83-3.93 (m, 1H), 3.11325 (m, 2H), 2.14 (d, J=50.4Hz, 2H), 1.95-1.85 (m, 2H), 1.54 (d, J=
6.8Hz,6H).
Embodiment 5 (1- (6- ((4- luorobenzyl) amino) -9- isopropyl -9H- purine -2- base) piperidines -3- base) methanol
Preparation
Other than using 3- hydroxymethyl piperidine to replace (R) -2- amino-n-butyl alcohol, with the synthetic method phase with compound 1
Same method is synthesized.Structural formula is as follows:
1H-NMR(300MHz,CDCl3) δ: 7.63 (s, 1H), 7.22 (s, 1H), 7.07-6.88 (m, 1H), 6.69 (s,
1H), 5.37 (s, 2H), 3.72 (q, J=9.3,8.2Hz, 2H), 3.58 (s, 2H), 3.36 (s, 1H), 1.85 (s, 2H), 1.65-
1.54 (m, 6H), 1.46 (d, J=7.0Hz, 3H)
The preparation of 6 N- of embodiment (4- luorobenzyl) -9- isopropyl -2- morpholino -9H- purine -6- amine
Other than using morpholino to replace (R) -2- amino-n-butyl alcohol, in method identical with the synthetic method of compound 1
It is synthesized.Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.47 (s, 1H), 7.35-7.29 (m, 2H), 7.26 (s, 1H), 7.02-6.95
(m, 2H), 6.13 (s, 1H), 4.75 (s, 2H), 4.65 (p, J=6.8Hz, 1H), 3.70-3.84 (m, 8H), 1.54 (d, J=
6.8Hz,6H).
Embodiment 7 (S) -2- ((6- ((3- fluorophenyl) amino) -9- isopropyl -9H- purine -2- base) amino) butyl- 1- alcohol
Preparation
To addition intermediate A 2 (1.2g, 3.8mmol) and (R) -2- amino-n-butyl alcohol (3mL), nitrogen in eggplant-shape bottle (25mL)
Gas shielded, being heated to 160 DEG C of reaction 8h, TLC detection reactions terminates, and is cooled to room temperature, is added water (20mL), uses ethyl acetate
(20mL × 4) extraction, organic layer are washed with 50 DEG C of warm water (30mL × 2), and sodium sulphate is dry, remove most of solvent under reduced pressure.To
Ethyl acetate (10mL) is added in residual solution, has crystal precipitation, filters to obtain white crystal (0.8g, 56%).Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.51 (s, 1H), 7.29 (dd, J=8.0,6.0Hz, 1H), 7.13 (d, J=
7.7Hz, 1H), 7.08 (d, J=9.5Hz, 1H), 7.00-6.91 (m, 1H), 6.08 (s, 1H), 4.88 (d, J=6.0Hz, 1H),
4.77 (s, 2H), 4.61 (p, J=6.8Hz, 1H), 3.88 (t, J=7.0Hz, 1H), 3.82 (dd, J=10.7,2.6Hz, 1H),
3.62 (dd, J=10.7,7.8Hz, 1H), 1.75 (s, 2H), 1.65-1.59 (m, 1H), 1.54 (d, J=6.8Hz, 6H), 1.02
(t, J=7.5Hz, 3H)
8 2- of embodiment (6- (3- fluorophenyl) amino) -9- isopropyl -9H- purine -2- base) amino) -2- phenethyl -1-
The preparation of alcohol
Other than using DL- benzene glycinol to replace (R) -2- amino-n-butyl alcohol, with the synthetic method phase with compound 6
Same method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,DMSO-d6) δ: 7.81 (d, J=24.4Hz, 2H), 7.31 (s, 3H), 7.22 (t, J=
7.4Hz, 2H), 7.14 (t, J=7.3Hz, 2H), 7.07-6.99 (m, 2H), 6.63 (d, J=7.5Hz, 1H), 4.91 (d, J=
6.7Hz, 1H), 4.80 (t, J=5.8Hz, 1H), 4.71-4.59 (m, 1H), 4.55-4.42 (m, 2H), 3.54-3.68 (m,
2H), 1.50 (d, J=6.7Hz, 1H), 1.42 (d, J=6.7Hz, 6H)
Embodiment 91- (6- (3- fluorophenyl) amino) -9- isopropyl -9H- purine -2- alcohol) piperidines -4- alcohol preparation
Other than using 4- hydroxy piperidine to replace (R) -2- amino-n-butyl alcohol, with identical as the synthetic method of compound 1
Method synthesized.Structural formula is as follows:
1H-NMR(400MHz,DMSO-d6) δ: 8.45 (s, 1H), 7.35 (td, J=7.8,5.0Hz, 1H), 7.16 (ddt, J
=16.6,8.0,1.0Hz, 2H), 7.01-6.94 (m, 1H), 6.59 (t, J=5.5Hz, 1H), 4.95-4.81 (m, 3H), 4.03
(ddd, J=12.1,8.0,5.7Hz, 2H), 3.68-3.54 (m, 4H), 1.90-1.70 (m, 4H), 1.47 (d, J=6.3Hz,
6H).
Embodiment 10 (1- (6- ((3- luorobenzyl) amino) -9- isopropyl -9H- purine -2- base) piperidines -3- base) methanol
Preparation
Other than using 3- hydroxymethyl piperidine to replace (R) -2- amino-n-butyl alcohol, with the synthetic method phase with compound 1
Same method is synthesized.Structural formula is as follows:
1H-NMR(300MHz,CDCl3) δ: 9.31 (s, 1H), 8.37 (s, 1H), 7.17 (d, J=9.7Hz, 1H), 6.96
(s, 1H), 5.29 (s, 1H), 4.74 (s, 2H), 3.71 (dt, J=24.5,7.1Hz, 2H), 3.54 (s, 2H), 3.24 (s, 1H),
2.90 (s, 1H), 1.85 (s, 2H), 1.59 (s, 6H), 1.27 (dt, J=7.8,4.3Hz, 3H), 0.96 (t, J=7.4Hz,
1H).
The preparation of embodiment 11N- (3- luorobenzyl) -9- isopropyl -2- morphine -9H- purine -6- amine
Other than using morpholino to replace (R) -2- amino-n-butyl alcohol, in method identical with the synthetic method of compound 1
It is synthesized.Structural formula is as follows:
1H-NMR(400MHz,DMSO-d6) δ: 8.44 (s, 1H), 7.34 (dd, J=7.8,5.0Hz, 1H), 7.21-7.10
(m, 2H), 7.02-6.95 (m, 1H), 6.65 (t, J=5.5Hz, 1H), 4.93-4.82 (m, 3H), 3.76-3.63 (m, 8H),
1.46 (d, J=6.4Hz, 6H)
Embodiment 12 (S) -2- ((9- isopropyl -6- ((4- (trifluoromethyl) benzyl) amino) -9H- purine -2- base) ammonia
Base) butyl- 1- alcohol preparation
To addition intermediate A 3 (1.4g, 3.8mmol) and (R) -2- amino-n-butyl alcohol (3mL), nitrogen in eggplant-shape bottle (25mL)
Gas shielded, being heated to 160 DEG C of reaction 8h, TLC detection reactions terminates, and is cooled to room temperature, is added water (20mL), uses ethyl acetate
(20mL × 4) extraction, organic layer are washed with 50 DEG C of warm water (30mL × 2), and sodium sulphate is dry, remove most of solvent under reduced pressure.To
Ethyl acetate (10mL) is added in residual solution, has crystal precipitation, filters to obtain white crystal (1g, 62%).Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.57 (d, J=8.1Hz, 2H), 7.47 (d, J=9.2Hz, 3H), 7.26 (s,
2H), 6.24 (s, 1H), 4.91-4.82 (m, 2H), 4.65-4.56 (m, 1H), 3.88-3.77 (m, 2H), 3.61 (dd, J=
10.6,7.7Hz, 1H), 1.93 (s, 1H), 1.65-1.56 (m, 1H), 1.53 (d, J=6.8Hz, 6H), 1.00 (t, J=
7.4Hz,3H).
Embodiment 132- (9- isopropyl -6- ((4- (trifluoromethyl) benzyl) amino) -9H- purine -2- base) amino) -2-
The preparation of phenethyl -1- alcohol
Other than using DL- benzene glycinol to replace (R) -2- amino-n-butyl alcohol, with the synthetic method phase with compound 11
Same method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.71 (s, 1H), 7.59 (d, J=8.1Hz, 2H), 7.56-7.43 (m, 3H),
7.40 (d, J=8.0Hz, 1H), 7.37-7.31 (m, 1H), 7.26 (s, 2H), 6.58 (s, 1H), 4.90 (s, 2H), 4.75-
4.76 (m, 1H), 4.01-3.84 (m, 1H), 1.95 (s, 2H), 1.57 (d, J=6.8Hz, 6H), 1.51 (d, J=6.8Hz,
1H).
(1- (9- isopropyl -6- ((4- (trifluoromethyl) benzyl) the amino) -9H- purine -2- base) piperidines -4- of embodiment 14
Base) methanol preparation
Other than using 4- hydroxymethyl piperidine to replace (R) -2- amino-n-butyl alcohol, with the synthetic method with compound 11
Identical method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,DMSO-d6) δ: 9.00 (d, J=39.0Hz, 3H), 8.63 (s, 1H), 7.69 (d, J=
8.0Hz, 2H), 7.59 (d, J=8.0Hz, 2H), 4.73 (d, J=16.2Hz, 3H), 4.59 (d, J=12.9Hz, 2H), 1.77
(d, J=13.9Hz, 2H), 1.65-1.60 (m, 2H), 1.52 (d, J=6.8Hz, 6H), 1.27-1.38 (m, 2H), 0.94 (d, J
=12.1Hz, 1H)
The preparation of embodiment 159- isopropyl -2- morphine-N- (4- (trifluoromethyl) benzyl) -9H- purine -6- amine
Other than using morpholino to replace (R) -2- amino-n-butyl alcohol, with side identical with the synthetic method of compound 11
Method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.55 (d, J=8.1Hz, 2H), 7.47 (d, J=6.9Hz, 2H), 7.26 (s,
1H), 6.38 (s, 1H), 4.84 (d, J=5.8Hz, 2H), 4.58-4.72 (m, 1H), 3.7-3.78 (m, 8H), 1.53 (d, J=
6.8Hz,6H).
Embodiment 16 (S) -2- ((9- isopropyl -6- ((3- (trifluoromethyl) benzyl) amino) -9H- purine -2- base) ammonia
Base) butyl- 1- alcohol preparation
To addition intermediate A 4 (1.4g, 3.8mmol) and (R) -2- amino-n-butyl alcohol (3mL), nitrogen in eggplant-shape bottle (25mL)
Gas shielded, being heated to 160 DEG C of reaction 8h, TLC detection reactions terminates, and is cooled to room temperature, is added water (20mL), uses ethyl acetate
(20mL × 4) extraction, organic layer are washed with 50 DEG C of warm water (30mL × 2), and sodium sulphate is dry, remove most of solvent under reduced pressure.To
Ethyl acetate (10mL) is added in residual solution, has crystal precipitation, filters to obtain white crystal (1.2g, 74%).Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.64 (s, 1H), 7.53 (dd, J=10.4,8.0Hz, 2H), 7.47 (s, 1H),
7.42 (t, J=7.7Hz, 1H), 7.27 (s, 1H), 6.36 (s, 1H), 4.90 (d, J=6.2Hz, 1H), 4.81 (s, 2H),
4.53-4.65 (m, 1H), 3.91-3.78 (m, 2H), 3.62 (dd, J=10.7,7.6Hz, 1H), 2.12 (s, 1H), 1.70-
1.55 (m, 1H), 1.52 (d, J=6.8Hz, 6H), 0.99 (t, J=7.5Hz, 3H)
17 2- of embodiment ((9- isopropyl -6- ((3- (trifluoromethyl) benzyl) amino) -9H- purine -2- base) amino) -
The preparation of 2- phenethyl 1- alcohol
Other than using DL- benzene glycinol to replace (R) -2- amino-n-butyl alcohol, with the synthetic method phase with compound 15
Same method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,DMSO-d6) δ: 7.94 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (d, J=
7.6Hz, 2H), 7.50 (d, J=7.5Hz, 1H), 7.32 (d, J=7.4Hz, 2H), 7.21 (t, J=7.4Hz, 2H), 7.14 (t,
J=7.2Hz, 1H), 6.65 (d, J=7.6Hz, 1H), 4.91 (q, J=6.9Hz, 1H), 4.81 (t, J=5.7Hz, 1H),
4.75-4.63 (m, 1H), 4.48 (dd, J=13.5,6.8Hz, 2H), 3.61 (q, J=6.9,5.9Hz, 2H), 1.50 (d, J=
6.8Hz, 1H), 1.42 (d, J=6.7Hz, 6H)
(1- (9- isopropyl -6- ((3- (trifluoromethyl) benzyl) the amino) -9H- purine -2- base) piperidines -4- of embodiment 18
Base) methanol preparation
Other than using 4- hydroxymethyl piperidine to replace (R) -2- amino-n-butyl alcohol, with the synthetic method with compound 15
Identical method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 8.92 (s, 1H), 8.62 (s, 1H), 7.68 (d, J=19.4Hz, 2H), 7.55-
7.38 (m, 2H), 5.33 (d, J=6.7Hz, 1H), 4.55-4.94 (m, 4H), 3.58-3.44 (m, 2H), 3.07 (t, J=
13.0Hz, 1H), 2.82 (t, J=12.7Hz, 1H), 1.93 (d, J=13.8Hz, 1H), 1.76 (d, J=11.8Hz, 2H),
1.69-1.50 (m, 6H), 1.44-1.27 (m, 1H), 1.11 (d, J=13.2Hz, 1H), 0.94 (t, J=7.3Hz, 1H)
The preparation of embodiment 19 9- isopropyl -2- morphine-N- (3- (trifluoromethyl) benzyl) -9H- purine -6- amine
Other than using morpholino to replace (R) -2- amino-n-butyl alcohol, with side identical with the synthetic method of compound 15
Method is synthesized.Structural formula is as follows:
1H-NMR(400MHz,CDCl3) δ: 7.65 (s, 1H), 7.55 (d, J=7.7Hz, 1H), 7.51 (d, J=7.1Hz,
2H), 7.41 (t, J=7.7Hz, 1H), 6.26 (s, 1H), 4.90-4.73 (m, 2H), 4.66 (p, J=6.8Hz, 1H), 3.70-
3.78 (m, 8H), 1.54 (d, J=6.8Hz, 6H)
Embodiment 20TrkA ELISA measurement
A) experimental material
1) TRKa (Carna, catalog number (Cat.No.): 08-186, lot number: 13CBS-0565G).2) TRKb (Carna, catalog number (Cat.No.): 08-
187, lot number: 12CBS-0461Q).3) TRKc (Carna, catalog number (Cat.No.): 08-197, lot number: 11CBS-0047J).4) polypeptide
Kinase substrate22 (GL Biochem, catalog number (Cat.No.): 112393, lot number: P180803-SL112393).5)DMSO
(Sigma, catalog number (Cat.No.): D8418-1L, lot number: SHBG3288V).6) 384 orifice plates (PerkinElmer, catalog number (Cat.No.): 6007290,
Lot number: 810712).
B) experimental method
(1) 1 × Kinase buffer is prepared.
(2) preparation of compound: test-compound test concentrations are 10000nM, single hole detection.It is diluted in 384 orifice plates
At the 100%DMSO solution of 100 times of final concentrations.It is shifted using dispenser Echo 550 to purpose plate OptiPlate-384F
The compound of 250mL100 times of final concentration.Add the 100%DMSO of 250mL in negative control hole and Positive control wells respectively.
(3) kinase solution of 2.5 times of final concentrations is prepared with 1 × Kinase buffer.
(4) add the kinase solution of 2.5 times of final concentrations of 10 μ L respectively in compound well and Positive control wells；In negative control
1 × Kinase buffer of 10 μ L of Kong Zhongjia.
(5) 1000rpm is centrifuged 30 seconds, and oscillation is incubated at room temperature 10 minutes after mixing.
(6) mixing of the ATP and Kinase substrate18 of 25/15 times of final concentration is prepared with 1 × Kinase buffer
Solution.
(7) ATP of 25/15 times of final concentration of 10 μ L and the mixed solution of substrate, starting reaction is added.
(8) 384 orifice plate 1000rpm are centrifuged 30 seconds, oscillation is incubated at room temperature the corresponding time after mixing.
(9) 30 μ L termination detection liquid are added and stop kinase reaction, 1000rpm is centrifuged 30 seconds, and oscillation mixes.
(10) Caliper EZ Reader reading and converting rate is used.
C) data are analyzed
(1) calculation formula:
Inhibition inhibiting rate %=(Conversion%_max-Conversion%_sample)/
(Conversion%_max-Conversion%_min) * 100%
Wherein: Conversion%_sample is the conversion ratio reading of sample；Conversion%_min: negative control
Hole mean value represents the conversion ratio reading in no enzyme activity hole；Conversion%_max: Positive control wells ratio mean value, representative do not have
There is compound to inhibit the conversion ratio reading in hole.
(2) it is fitted amount effect curve
Using the log value of concentration as X-axis, percent inhibition is Y-axis, using analysis software GraphPad Prism's 5
Log (inhibitor) vs.response-Variable slope is fitted amount effect curve, to obtain each compound to enzyme activity
The IC of property50Value.
(3) fitting formula are as follows: Y=Bottom+ (Top-Bottom)/(1+10^ ((LogIC50-X)*HillSlope
Prepared by resulting purines chemical combination to embodiment 2-19 and carries out above-mentioned TrkA ELISA measurement, the results are shown in Table 1.Table
1 provides inhibiting rate of the purine compound (concentration 500nM) to TrkA of embodiment 2-19 preparation.
The specific IC of the 1 resulting compound of embodiment 2-19 of table50It is worth result
| Embodiment | TrkA ELISA enzyme IC50(nM) |
| 2 | 4 |
| 3 | 5.5 |
| 4 | 3.1 |
| 5 | 26 |
| 6 | 10 |
| 7 | 4.4 |
| 8 | 6 |
| 9 | 3.5 |
| 10 | 48 |
| 11 | 40 |
| 12 | 5 |
| 13 | 20 |
| 14 | 52 |
| 15 | 30 |
| 16 | 4.8 |
| 17 | 17 |
| 18 | 53 |
| 19 | 46 |
By the specific IC of the compound of embodiment 2-1950Value Data connects it is found that for the compound for leading to formula (I) class
Group and substituent group such as X group, R2The selection of group and R1In substituent group and its position for compound pharmacodynamics
Performance and metabolic stability have important influence.Although the specific embodiment before the present invention passes through illustrates, should not be by it
It is construed to be so limited；But the present invention covers disclosed general aspect before.It can be without departing substantially from the spirit and scope of the present invention
It is lower to carry out a variety of modifications and there are multiple embodiments.
Claims (10)
1. a kind of purine compound, which is characterized in that the compound is compound described in logical formula (I) or it can pharmaceutically connect
The salt received,
Wherein: R1Replace selected from (i) halogen, (1-4C) alkoxy, trifluoromethyl, difluoromethyl, middle one or more substituent groups
Phenyl, or 5 former or 6 yuan of heteroaromatics that (ii) one or more halogen atoms replace, the heteroaromatic have N and/or S；
R2Selected from it is following any one: NRaRb, (1-4C) hydroxy alkyl, the heterocyclic aryl that (1-4C) alkyl, halogen replace, containing miscellaneous
The naphthenic base of atom；Or one or more substituent groups take in fluorine-containing, trifluoromethyl, hydroxyl, primary amino group, alkoxy, secondary amino group
(3-6C) naphthenic base in generation；
RaIt is H or (1-6C) alkyl；RbIt is (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocyclic aryl is 5 to 6 yuan miscellaneous
Aromatic ring is independently selected from the ring hetero atom of N and O with 1-2, and contains one or more (1-4C) alkyl substituents；It is described miscellaneous
Cyclophane base or aryl include one or more substituent groups in halogen, trifluoromethyl, hydroxyl, cyano；Or NRaRbBeing formed has ring
4 circle heterocyclic rings of nitrogen-atoms replace wherein the heterocycle is optionally independently selected from a kind of or multiple substituent groups below: halogen,
Hydroxyl, (1-4C) alkyl, (1-4C) alkoxy；Or NRaRb5 to 6 circle heterocyclic rings are formed, the heterocycle has theheterocyclic nitrogen atom and also wraps
Containing optionally from any one hetero atom of N, O, S, the heterocycle includes that one or more substituent groups below replace: hydroxyl, halogen,
Trifluoromethyl, (1-4C) alkyl, primary amino group, carboxyl；
The heterocyclic aryl in heterocyclic aryl that (the 1-4C alkyl), halogen replace is selected from 5 yuan with 1 to 3 theheterocyclic nitrogen atom
Hetero-aromatic ring；Alternatively, at least one nitrogen ring atom and also comprising optional any one heteroatomic 5 to 6 yuan of heteroaryl from N, O, S
Ring；
It is described containing heteroatomic naphthenic base be carbon connection 4 to 6 yuan of azacyclo-s, include (1-4C) alkyl, carboxyl, (1-4C) alkyl
One or more substituent groups of kind；Or (1-4C) alkyl-substituted pyridone or pyridazine ring；
R3Selected from H, C1-C8 linear or branched alkyl group；X is selected from O, NH or NR4；R4Selected from (1-6C) alkyl.
2. purine compound according to claim 1, which is characterized in that R2For-NRaRbOr the heterocycle that halogen replaces
Aryl；Wherein, RaIt is H or (1-6C) alkyl；RbIt is (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocyclic aryl is 5
To 6 yuan of hetero-aromatic rings, it is independently selected from the ring hetero atom of N and O with 1-2, and contains one or more (1-4C) alkyl substituents；
The heterocyclic aryl or aryl include one or more substituent groups in halogen, trifluoromethyl, hydroxyl, cyano；Or NRaRbIt is formed
4 circle heterocyclic rings with theheterocyclic nitrogen atom replace wherein the heterocycle is optionally independently selected from a kind of or multiple substituent groups below:
Halogen, hydroxyl, (1-4C) alkyl, (1-4C) alkoxy；Or NRaRbFormed 5 to 6 circle heterocyclic rings, the heterocycle have theheterocyclic nitrogen atom and
Also comprising optionally from any one hetero atom of N, O, S, the heterocycle includes that one or more substituent groups below replace: hydroxyl,
Halogen, trifluoromethyl, (1-4C) alkyl, primary amino group, carboxyl；The heterocyclic aryl that (1-4C) alkyl, halogen replace,
The heterocyclic aryl in heterocyclic aryl that (the 1-4C alkyl), halogen replace is selected from 5 yuan with 1 to 3 theheterocyclic nitrogen atom
Hetero-aromatic ring；Alternatively, at least one nitrogen ring atom and also comprising optional any one heteroatomic 5 to 6 yuan of heteroaryl from N, O, S
Ring.
3. purine compound according to claim 1 or 2, which is characterized in that R2For-NRaRb；Wherein RaIt is H or (1-
6C) alkyl；RbIt is (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocyclic aryl is 5 to 6 yuan of hetero-aromatic rings, has 1-2
A ring hetero atom for being independently selected from N and O, and contain one or more (1-4C) alkyl substituents；The heterocyclic aryl or aryl
Include one or more substituent groups in halogen, trifluoromethyl, hydroxyl, cyano；Or NRaRb4 yuan with theheterocyclic nitrogen atom of formation miscellaneous
Ring replaces: halogen, hydroxyl, (1-4C) alkane wherein the heterocycle is optionally independently selected from a kind of or multiple substituent groups below
Base, (1-4C) alkoxy；Or-NRaRb5 to 6 circle heterocyclic rings are formed, the heterocycle has theheterocyclic nitrogen atom and also comprising optionally from N, O, S
Any one hetero atom, the heterocycle include that one or more substituent groups below replace: hydroxyl, halogen, trifluoromethyl, (1-
4C) alkyl, primary amino group, carboxyl.
4. purine compound according to claim 1 to 3, which is characterized in that R1For substituted-phenyl, the substituted benzene
Base includes one or more halogen ,-CF3、-CHF2Substituent group.
5. purine compound according to claim 1 to 4, which is characterized in that R1For containing one or two fluorine or
The phenyl that chlorine atom replaces, or containing a fluorine atom and-CF3Substituted phenyl.
6. -5 any purine compound according to claim 1, which is characterized in that R2For NRaRbWhen, including tie as follows
Structure:
7. -6 any purine compound according to claim 1, which is characterized in that X O, NH or NCH3、NCH2CH3。
8. purine compound shown in logical formula (I) or its pharmaceutically acceptable salt are in preparing Trk kinase inhibition drug
Using,
Wherein: in logical formula (I), R1Selected from (i) halogen, (1-4C) alkoxy, CF3、CHF2, middle one or more substituent groups
Substituted phenyl；Or the 5- or 6-membered heteroaromatic that (ii) one or more halogen atoms replace, wherein heteroaromatic its have and be selected from N
And/or the heteroatom of S, include one or more halogen atom substituents；
R2Selected from once any one: NRaRb, (1-4C) alkyl, (1-4C) fluoroalkyl, (1-4C) hydroxy alkyl, (1-4C) alkane
The heterocyclic aryl that base, halogen replace, contains miscellaneous heteroatomic naphthenic base or halogen, fluorine replace alkyl, hydroxyl, alkoxy, primaquine
(3-6C) naphthenic base that is a kind of or planting a substituent group substitution in base, secondary amine；
RaIt is H or (1-6C) alkyl；RbIt is H, (1-4C) alkyl, (1-4C) hydroxy alkyl, heterocyclic aryl or aryl, wherein heterocycle
Aryl is 5 to 6 yuan of hetero-aromatic rings, the ring hetero atom of N and O is independently selected from 1-2, and contain one or more (1-4C) alkyl
Substituent group；Include one or more substituent groups in halogen, fluorine substitution alkyl, hydroxyl, cyano on the heterocyclic aryl or aryl；
Or NRaRb4 circle heterocyclic rings with theheterocyclic nitrogen atom are formed, wherein the heterocycle is optionally independently selected from one kind or multiple below
Substituent group replaces: halogen, hydroxyl, (1-4C) alkyl, (1-4C) alkoxy；Or NRaRb5 or 6 circle heterocyclic rings are formed, wherein described miscellaneous
Ring has theheterocyclic nitrogen atom and also comprising optionally from any one hetero atom of N, O, S, the heterocycle includes that following one or more takes
Dai Ji: hydroxyl, halogen, trifluoromethyl, (1-4C) alkyl, primary amino group, carboxyl；
The heterocyclic aryl in heterocyclic aryl that (the 1-4C alkyl), halogen replace is selected from 5 yuan with 1 to 3 theheterocyclic nitrogen atom
Hetero-aromatic ring；Alternatively, at least one nitrogen ring atom and also comprising optional any one heteroatomic 5 to 6 yuan of heteroaryl from N, O, S
Ring；
It is described containing heteroatomic naphthenic base it is miscellaneous be carbon connection 4 to 6 yuan of azacyclo-s, include (1-4C) alkyl, carboxyl, (1-4C alkane
Base) kind one or more substituent groups；Or (1-4C) alkyl-substituted pyridone or pyridazine ring；
R3Selected from H, C1-C8 linear or branched alkyl group；X is selected from O, NH or NR4；R4Selected from (1-6C) alkyl.
9. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes fast shown in claim 8 formula of (1)
Purine class compound or its pharmaceutically acceptable salt, pharmaceutically acceptable carrier, excipient or diluent.
10. any purine compound of claim 1-6 or its pharmaceutically acceptable salt are in preparation for treating lactation
Application in the cancer of animal, pain, inflammation, neurodegenerative disease, infection by Trypanosoma cruzi or osteolytic disease medicament.
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| CN112979654A (en) * | 2019-12-16 | 2021-06-18 | 成都倍特药业有限公司 | Heteroaryl fused ring compound, preparation method and application thereof |
| WO2021148793A1 (en) * | 2020-01-22 | 2021-07-29 | Cyclacel Limited | Process for the preparation of purine derivatives exhibiting cdk inhibitory activity |
| WO2024014885A1 (en) * | 2022-07-13 | 2024-01-18 | 일동제약(주) | Novel bicyclic heteroaryl compound and use thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112979654A (en) * | 2019-12-16 | 2021-06-18 | 成都倍特药业有限公司 | Heteroaryl fused ring compound, preparation method and application thereof |
| CN112979654B (en) * | 2019-12-16 | 2024-03-19 | 赛诺哈勃药业（成都）有限公司 | Heteroaryl fused ring compounds, preparation method and application thereof |
| WO2021148793A1 (en) * | 2020-01-22 | 2021-07-29 | Cyclacel Limited | Process for the preparation of purine derivatives exhibiting cdk inhibitory activity |
| WO2024014885A1 (en) * | 2022-07-13 | 2024-01-18 | 일동제약(주) | Novel bicyclic heteroaryl compound and use thereof |
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