CN106146504A - A kind of heterocycle glyoxaline compound, its pharmaceutical composition and its production and use - Google Patents
A kind of heterocycle glyoxaline compound, its pharmaceutical composition and its production and use Download PDFInfo
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- CN106146504A CN106146504A CN201510189027.4A CN201510189027A CN106146504A CN 106146504 A CN106146504 A CN 106146504A CN 201510189027 A CN201510189027 A CN 201510189027A CN 106146504 A CN106146504 A CN 106146504A
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- 0 C*(*=C(Cc1cc(C(*(CC2)CC*2/C2=*\CC/C=N/C3=C2*=C*3(C)*)=O)c(*)cc1)c1ccccc11)C1=* Chemical compound C*(*=C(Cc1cc(C(*(CC2)CC*2/C2=*\CC/C=N/C3=C2*=C*3(C)*)=O)c(*)cc1)c1ccccc11)C1=* 0.000 description 5
- LERGGOZDLSQPGC-UHFFFAOYSA-N C(C1N2CCNCCCC2)C=NC2=C1N=CNC2 Chemical compound C(C1N2CCNCCCC2)C=NC2=C1N=CNC2 LERGGOZDLSQPGC-UHFFFAOYSA-N 0.000 description 1
- PFZKRYJPOMLSIJ-UHFFFAOYSA-N CC(C=CCN=C1CN)C=C1[N+]([O-])=O Chemical compound CC(C=CCN=C1CN)C=C1[N+]([O-])=O PFZKRYJPOMLSIJ-UHFFFAOYSA-N 0.000 description 1
- QFVUNKLEZXXYAI-UHFFFAOYSA-N CC1C=CN=C(CN)C1 Chemical compound CC1C=CN=C(CN)C1 QFVUNKLEZXXYAI-UHFFFAOYSA-N 0.000 description 1
- VHPJFLXMJXYNIZ-UHFFFAOYSA-N CC1Nc(c(N2CCNCC2)ncc2)c2N1 Chemical compound CC1Nc(c(N2CCNCC2)ncc2)c2N1 VHPJFLXMJXYNIZ-UHFFFAOYSA-N 0.000 description 1
- ZGBLLDHNEDAENS-UHFFFAOYSA-N Cc1nc2c(N(CC3)CCN3C(c3cc(CC(c4ccccc44)=NNC4=O)ccc3F)=O)nccc2[nH]1 Chemical compound Cc1nc2c(N(CC3)CCN3C(c3cc(CC(c4ccccc44)=NNC4=O)ccc3F)=O)nccc2[nH]1 ZGBLLDHNEDAENS-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- 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 present invention relates to heterocycle imidazole derivative, its preparation method and in application pharmaceutically.Concrete, the present invention relates to the new heterocycle shown in a kind of logical formula I imidazole derivative, its preparation method and the pharmaceutical composition containing this derivant and its as therapeutic agent especially as the purposes of poly-(ADP-ribose) polymerase (PARP) inhibitor.
Description
Technical field
The present invention relates to heterocycle imidazole derivative, its preparation method and the drug regimen containing this derivant
Thing and it is as therapeutic agent with as the purposes of poly-(ADP-ribose) polymerase (PARP) inhibitor.
Background technology
Chemotherapeutics and ionizing radiation treatment are two kinds of common methods for the treatment of cancer.Both Therapeutic Method all can
Inducing DNA strand and/or double-strand break and then produce cytotoxic effect, target tumor is due to chromosome
Damage thus dead.An important results as response DNA damage signal is cell cycle regulating site letter
Number it is activated, its object is to protect cell not carry out mitosis in the case of DNA damage thus avoid
Cell injury.In most of the cases, tumor cell is showing the same of cell cycle regulating site signal defect
Time there is the highest appreciation rate.It can therefore be concluded that tumor cell exists specific DNA repair mechanism,
Can quickly responding and repair the chromosome damage relevant to breeding regulation, controlling so that himself surviving some
Treat cytotoxic effect the maintenance survival of medicine.
In clinical practice, valid density or the treatment radiant intensity of chemotherapeutics can be resisted these DNA and repair
The system of answering a pager's call, it is ensured that the fragmentation effect to target tumor.But, tumor cell damages by strengthening its DNA
Hinder repair mechanism and treatment can be produced tolerance effect, be allowed to survive from fatal DNA damage.For
Overcome the toleration of generation, it usually needs increase the dosage of medicine or improve radiant intensity, this way
Normal structure near focus will be had a negative impact, so that with serious untoward reaction in therapeutic process,
And then increase Operative risk.Meanwhile, ever-increasing toleration will reduce therapeutic effect, therefore can push away
Disconnected, by the regulation to DNA damage signal repair mechanism, it is possible to realize in the way of tumor cell specific
Cytotoxic raising to DNA damage medicament.
PARPs (the Poly (ADP-ribose) being characterized with poly-adenosine diphosphate-ribosylating activity
Polymerases), the superfamily of 18 kinds of cell ribozyme nucleus matter enzymes is constituted.This poly-adenosine diphosphate-
Ribosylation can regulate catalysis activity and the protein-protein interaction of destination protein, and to many bases
This bioprocess regulates and controls, and repairs including DNA, and cell death, Genome stability is the most associated.
PARP-1 activity accounts for the 80% of total cell PARP activity, it and the PARP-2 the most close with it
Jointly become the member possessing DNA plerosis lesion capability in PARP family.Sensing as DNA damage
Device and signal protein, PARP-1 can quickly detect and be bonded directly to DNA damage site, inducing afterwards
Assemble the multiple protein needed for DNA repairs, and then make DNA damage be repaired.As the PARP-1 in cell
During shortage, PARP-2 can substitute PARP-1 and realize the reparation of DNA damage.Research shows, thin with normal
Born of the same parents compare, and the expression in solid tumor of the PARPs albumen generally strengthens.Additionally, repair dependency basis for DNA
Because lacking the tumor (such as breast tumor and ovarian cancer) of (such as BRCA-1 or BRCA-2), show PARP-1
The extreme sensitivity of inhibitor, this shows that PARP inhibitor this is known as three negative breast as single dose in treatment
Potential use in terms of cancer.Simultaneously as DNA damage repair mechanism be tumor cell reply chemotherapeutics and
Ionizing radiation treatment produces resistance to main mechanism the affected, and therefore PARP-1 is considered as to explore new cancer to control
One Effective target site for the treatment of method.
The PARP inhibitor of early development design is the nicotiamide work using the NAD as PARP catalytic substrate
For template, develop its analog.These inhibitor, as the competitive inhibitor of NAD, are competed with NAD
The catalytic site of PARP, and then stop the synthesis of poly-(ADP-ribose) chain.There is no poly-(ADP-ribosyl
Change) modify lower PARP and cannot disintegrate down from DNA damage site, other will be caused to participate in the egg of reparations
White matter cannot be introduced into injury site, and then can not perform repair process.Therefore, in cytotoxic drug or radiation
Effect under, the tumor cell that the existence of PARP inhibitor makes DNA impaired is the most dead.
Additionally, the NAD being consumed as PARP catalytic substrate, it is must not during cell synthesizes ATP
Can lack, therefore, under high PARP activity level, intracellular NAD level can be remarkably decreased, and then
Affect the ATP level of intracellular.Owing to intracellular ATP content is not enough, cell cannot realize what ATP relied on
Programmed cell death process, can only turn to this special apoptotic process downright bad.During necrosis, substantial amounts of inflammation
Inflammation factor can be released, thus other organs and tissue are produced toxic action.Therefore, PARP suppression
Agent can be used for treating the multiple disease relevant with this mechanism, including neurodegenerative diseases (as old age is crazy about
Slow-witted disease, Huntington chorea, parkinson disease), diabetes, the concurrent disease in ischemia or Ischemia-Reperfusion Injury
Disease, such as myocardial infarction and acute renal failure, blood circulation diseases, such as septic shock, and diseases associated with inflammation,
Such as chronic rheumatism etc..
Clinic has 14 at the PARP inhibitor one ground at present, and wherein Astrazeneca AB develops
AZD2281 lists through U.S. FDA approval in December, 2014, and treatment indication is to platinum class reagent
Treat sensitive Patients with Advanced Ovarian Carcinoma.Related application is WO2002036576, WO2006021801.
Although a series of PARP inhibitor is had been disclosed at present, but remain a need for developing new have more preferable drug effect,
More excellent pharmacokinetic property and more hypotoxic compound.Through unremitting effort, present invention design has formula
(I) compound of the structure shown in, and find to have the compound of this class formation show excellence effect and
Effect.
Summary of the invention
An object of the present invention is to provide a kind of new heterocycle as shown in logical formula (I) imidazoles chemical combination
Thing or its pharmaceutically acceptable salt.
The two of the purpose of the present invention are to provide above-mentioned heterocycle glyoxaline compound or it is pharmaceutically acceptable
The preparation method of salt.
The three of the purpose of the present invention be provide one prepare above-mentioned heterocycle glyoxaline compound or its pharmaceutically
The intermediate of acceptable salt.
The four of the purpose of the present invention be provide one prepare above-mentioned heterocycle glyoxaline compound or its pharmaceutically
The preparation method of the intermediate of acceptable salt.
The five of the purpose of the present invention are the change providing a kind of described intermediate for preparing described logical formula I
Compound or the application of its pharmaceutically acceptable salt.
The six of the purpose of the present invention be to provide a kind of with described heterocycle glyoxaline compound or its pharmaceutically may be used
The salt accepted is as the pharmaceutical composition of active component.
The seven of the purpose of the present invention be to provide a kind of above-mentioned heterocycle glyoxaline compound or its pharmaceutically can connect
The salt being subject to application in medicine.
As heterocycle the glyoxaline compound of first aspect present invention, it is the compound shown in logical formula I:
Wherein, in logical formula I:
R is hydrogen, halogen, C1-C6Alkoxyl or C1-C6Haloalkyl；
X, Y, Z one of them be nitrogen, remaining be hydrocarbon or X, Y, Z one of them for hydrocarbon, remaining
For nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, C1-C6Alkyl or C1-C6Haloalkyl.
It is further preferred that the compound that the structure of present invention offer is as shown in logical formula I, wherein:
R is hydrogen, fluorine, methoxyl group or trifluoromethyl；
X, Y, Z one of them be nitrogen, remaining be hydrocarbon or X, Y, Z one of them for hydrocarbon, remaining
For nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, methyl or trifluoromethyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R
For hydrogen, halogen, C1-C3Alkoxyl or C1-C3Haloalkyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R
For hydrogen, fluorine, methoxyl group or trifluoromethyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein X
Being nitrogen with Z, Y is hydrocarbon or X is nitrogen, Y and Z is hydrocarbon or Z is nitrogen, X and Y is hydrocarbon.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R1
For hydrogen, oxygen or C1-C6Alkyl or C1-C6Haloalkyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R1
For hydrogen, oxygen or C1-C3Alkyl or C1-C3Haloalkyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R1
For hydrogen, oxygen or methyl or trifluoromethyl.
In a preferred embodiment of the invention, heterocycle the glyoxaline compound of described logical formula I is
4-(3-(piperazine-1-carbonyl) benzyl) dai piperazine-1 (2 hydrogen)-one compounds and its officinal salt.
Most preferably, the present invention is led to the compound shown in formula I and is included for following compound (1)～(13)
One of:
Described logical formula I compound is tautomer, enantiomer, diastereomer, conformation
Any one or arbitrarily both or the mixture of three in isomer.
Described logical formula I compound is pharmaceutically acceptable derivant.
Logical formula I compound of the present invention can exist as a pharmaceutically acceptable salt form.
As the preparation method of the compound shown in the logical formula I of second aspect present invention, its reaction equation is as follows:
Wherein, R, X, Y, Z and M are as defined above；R2For hydroxyl, halogen, diimidazole 1
Base；It specifically comprises the following steps that
Carboxylic acid (VI) the generation condensation reaction that intermediate (V) is derivative with dai piperazine, generates shown in logical formula I
Compound.
In one embodiment of the invention, intermediate (V) is prepared by following steps:
Step 1): mono-protected piperazine with containing amino, nitro substituted heterocycle halides generation nucleophilic displacement of fluorine
Reaction, obtains intermediate (II)；
Step 2): there is catalytic hydrogen reduction nitro in intermediate (II), obtains intermediate (III)；
Step 3): intermediate (III) by with acetic anhydride, trifluoroacetic anhydride, trimethyl orthoformate, carbonyl
Diimidazole or azido compound generation ring-closure reaction, obtain intermediate (IV)；
Step 4): intermediate (IV) removing amido protection group, obtain intermediate (V)；
Its reaction equation is as follows:
Wherein, in logical formula (I), P is amido protection group, X, Y, Z one of them be nitrogen, remaining is carbon
Hydrogen or X, Y, Z one of them be hydrocarbon, remaining is nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, methyl or trifluoromethyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein X
Being nitrogen with Z, Y is hydrocarbon or X is nitrogen, Y and Z is hydrocarbon or Z is nitrogen, X and Y is hydrocarbon.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R1
For hydrogen, oxygen or C1-C6Alkyl or C1-C6Haloalkyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R1
For hydrogen, oxygen or C1-C3Alkyl or C1-C3Haloalkyl.
In one embodiment of the invention, the compound shown in a kind of logical formula I, wherein R1
For hydrogen, oxygen or methyl or trifluoromethyl.
Preferably, the compound shown in carboxylic acid (VI) that described dai piperazine is derivative is as follows:
Preferably, the compound shown in described intermediate (V) is as follows:
In one embodiment of the invention, the condensing agent used in described condensation reaction is selected from 1,1'-
Carbonyl dimidazoles, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride, 2-(7-azo benzo three nitrogen
Azoles)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, BTA-N, N, N', N'-tetramethylurea hexafluoro phosphorus
Acid esters.
In one embodiment of the invention, in described condensation reaction use solvent selected from dichloromethane,
Ethyl acetate, dimethyl sulfoxide, oxolane, dimethylformamide, dimethyl acetylamide, N-methylpyrroline
Ketone, acetone.In one embodiment of the invention, described condensation reaction adds inorganic base or organic
Alkali.
In one embodiment of the invention, described organic base is selected from triethylamine, diethylamine, diisopropyl
Base ethamine, piperidines.
In one embodiment of the invention, intermediate (III) by with acetic anhydride, trifluoroacetic anhydride,
Trimethyl orthoformate or carbonyl dimidazoles generation ring-closure reaction, obtain intermediate (IV).
Heterocycle the centre of glyoxaline compound shown in above-mentioned logical formula I is prepared as third aspect present invention
Body, it is the compound shown in structural formula (V):
Wherein, in intermediate (V):
In one embodiment of the invention, X, Y, Z one of them be nitrogen, remaining be hydrocarbon or
X, Y, Z one of them be hydrocarbon, remaining is nitrogen；
In one embodiment of the invention, M is nitrogen or CR1；
In one embodiment of the invention, R1For hydrogen, oxygen, alkyl, alkoxyl or haloalkyl.
In one embodiment of the invention, X and Z is nitrogen, and Y is hydrocarbon or X is nitrogen, Y and Z
Being nitrogen for hydrocarbon or Z, X and Y is hydrocarbon.
In one embodiment of the invention, R1For hydrogen, oxygen, C1-C6Alkyl or C1-C6Haloalkyl.
In one embodiment of the invention, R1For hydrogen, oxygen, C1-C3Alkyl or C1-C3Haloalkyl.
In one embodiment of the invention, R1For hydrogen, oxygen or trifluoromethyl.
As heterocycle shown in the said structure formula V of fourth aspect present invention the intermediate of glyoxaline compound
Preparation method, wherein, intermediate (V) is prepared by following steps:
Step 1): mono-protected piperazine with containing amino, nitro substituted heterocycle halides generation nucleophilic displacement of fluorine
Reaction, obtains intermediate (II)；
Step 2): there is catalytic hydrogen reduction nitro in intermediate (II), obtains intermediate (III)；
Step 3): intermediate (III) by with acetic anhydride, trifluoroacetic anhydride, trimethyl orthoformate, carbonyl
Diimidazole or azido compound generation ring-closure reaction, obtain intermediate (IV)；
Step 4): intermediate (IV) removing amido protection group, obtain intermediate (V)；
Its reaction equation is as follows:
Wherein, in logical formula (I), P is amido protection group, X, Y, Z one of them be nitrogen, remaining is carbon
Hydrogen or X, Y, Z one of them be hydrocarbon, remaining is nitrogen；M is nitrogen or CR1；R1For hydrogen, oxygen, first
Base or trifluoromethyl.
In one embodiment of the invention, in step 3) in, intermediate (III) by with acetic acid
Acid anhydride, trifluoroacetic anhydride, trimethyl orthoformate or carbonyl dimidazoles generation ring-closure reaction, obtain intermediate (IV).
Intermediate as the formula (V) of fifth aspect present invention is used for preparing the change of described logical formula I
The application of compound.
As the Pharmaceutical composition of sixth aspect present invention, comprise the formula of the therapeutically effective amount constituting active component
(I) compound or its pharmaceutically acceptable salt and one or more medicinal carrier substances and/or diluent.
Described pharmaceutical composition makes tablet, capsule, aqueous suspension, Oil suspensions, dispersible
Powder, granule, lozenge, Emulsion, syrup, ointment, ointment, suppository or injection.
In described pharmaceutical composition, described logical formula I compound exists in a free form.
As the application of seventh aspect present invention, be wherein described logical formula I compound or its pharmaceutically can connect
The salt being subject to application in the disease medicament that preparation treatment improves because of the suppression of PARP activity.
As the application of seventh aspect present invention, it is wherein that described pharmaceutical composition is treated because PARP lives in preparation
Property suppression and application in the disease medicament that improves.
Described because the suppression of PARP activity the disease improved be angiopathy, septic shock, ischemic injuries,
Neurotoxicity, hemorrhagic shock, inflammatory diseases or multiple sclerosis, neurodegenerative disease or diabetes.
Document (Cantoni etc., Biochim.Biophys.Acta, 1989,1014:1-7；Liaudet etc., Proc.
Natl.Acad.Sci.U.S.A., 97 (3), 2000,97 (3): 10203-10208) above-mentioned disease and PARP are provided
The research conditions of relation between activity.
As the application of seventh aspect present invention, it is wherein that described logical formula I compound is being prepared for cancer
Application in the ancillary drug for the treatment of.
As the application of seventh aspect present invention, it is wherein the pharmaceutically acceptable of described logical formula I compound
Derivant application in preparation is used for the ancillary drug of oncotherapy.
As the application of seventh aspect present invention, it is wherein that described pharmaceutical composition is being prepared for treatment of cancer
Application in ancillary drug.
As the application of seventh aspect present invention, it is wherein that described logical formula I compound is being prepared for cancer
Application in the medicine of chemotherapy or strengthening radiotherapeutic drug.
As the application of seventh aspect present invention, it is wherein the pharmaceutically acceptable of described logical formula I compound
Derivant for the medicine of cancer chemotherapy or strengthens the application in radiotherapeutic drug in preparation.
As the application of seventh aspect present invention, it is wherein that described pharmaceutical composition is being prepared for cancer chemotherapy
Application in medicine or strengthening radiotherapeutic drug.
As the application of seventh aspect present invention, it is wherein that described logical formula I compound lacks homology in preparation
In the medicine of the individuation treatment of cancer that restructuring (HR) dependent DNA double chain interruption (DSB) is repaired
Application.
As the application of seventh aspect present invention, it is wherein the pharmaceutically acceptable of described logical formula I compound
Derivant or salt lack what homologous recombination (HR) dependent DNA double chain interruption (DSB) was repaired in preparation
Application in the medicine of individuation treatment of cancer.
As the application of seventh aspect present invention, it is wherein that described pharmaceutical composition lacks homologous recombination in preparation
(HR) application in the medicine of the individuation treatment of cancer that dependent DNA double chain interruption (DSB) is repaired.
As preferably, way is repaired in homologous recombination (HR) the dependent DNA double chain interruption of described cancer
Footpath is defect.
As preferably, described cancer is by the ability of the DSB of HR DNA plerosis containing one or more
The cancer of the cancerous cell lowered relative to normal cell or lose.
As preferably, described cancer is the cancer with BRCA-1 or BRCA-2 defect, mutant phenotype.
It is highly preferred that described cancer is BRCA-1 or/and BRCA-2 defect, the cancer of sudden change.
As preferably, described cancer be breast carcinoma, ovarian cancer, cancer of pancreas or carcinoma of prostate, rectal cancer,
Colon cancer or hepatocarcinoma.
In order to check compound that the present invention provides for the exposure level of PARP enzyme, biochemistry level enzyme is used to live
Property test determine the various compounds of the present invention activity to PARP enzyme.
PARP is a kind of posttranscriptional modification enzyme, and DNA damage can activate this enzyme, PARP catalysis in vivo
Process is mainly poly (ADP-ribose) process that a kind of NAD relies on, and its substrate mainly includes PARP
At some interior nucleoprotein, histone is one of which, and the present invention is by measuring PARP under NAD effect
To being coated in Histone poly (ADP-ribose) degree in 96 orifice plates, measure PARP activity, correspondingly
Measure PARP activity after PARP inhibitor effect, thus evaluate the suppression to PARP activity of this compounds
Degree.
Detailed description of the invention
It is used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit the present invention's
Scope.
The experimental technique of unreceipted actual conditions in the embodiment of the present invention, generally according to normal condition, or according to former
Condition proposed by material or commodity manufacturer.The reagent in unreceipted concrete source, the conventional examination bought for market
Agent.
Unless stated to the contrary, following have following implication with term in the specification and in the claims.
In the present invention, term " C1-C6Alkyl " refer to have straight or branched part former containing 1 to 6 carbon
The saturated monovalent hydrocarbon of son.The example of this type of group include but not limited to methyl, ethyl, propyl group, isopropyl,
Normal-butyl, isobutyl group and the tert-butyl group.
Term " C1-C6Haloalkyl " refer to straight or branched part and contain saturated the one of 1 to 6 carbon atom
Hydrogen moiety or be all substituted with halogen atoms the compound of formation in valency alkyl.
Term " C1-C6Alkoxyl " refer to oxygen atom be connected straight or branched part and contain 1 to 6 carbon former
The saturated monovalent hydrocarbon of son.Include but not limited to methoxyl group, ethyoxyl, propoxyl group, isopropoxy, positive fourth oxygen
Base, isobutoxy, tert-butoxy.
Term " enantiomer " refers to the stereoisomer of mirror image relationship each other.
Term " diastereomer " refers to that molecule has two or more chiral centre, and intermolecular for non-
The stereoisomer of mirror image relationship.
Term " conformer " refers to that organic molecule is rotated by singly-bound and the isomer that produces.
Term " tautomer " refers to that the structure of some organic compound produces between two kinds of functional isomers
Balancing the phenomenon of mutual phase transformation, corresponding isomer becomes tautomer.
Term " mesomer " refers to the atom that intramolecular contains unsymmetry, but because there is symmetry factor and shape
The inactivity compound become.
Term " racemic modification " refers to a kind of have active chiral molecule and mix with the equimolar of its enantiomer
Thing.
Term " metabolite and metabolite precursor or prodrug " refers to the thing being produced by metabolic process or consuming
Matter；Prodrug refers to the compound that medicine obtains through modifying for chemical structure, does not has activity in vitro, at organism or
It is converted into original medicine in human body and plays drug effect.
Term " derivant " refers to what the atom in compound or group were replaced by other atoms or group and derive
More complicated product.
Term " therapeutically effective amount " refers to realize any amount of required biological respinse.
Term " halogen " and " halo " refer to F, Cl, Br, I.
" pharmaceutical composition " refers to the one or more and other chemical composition in the compound in the present invention, such as
Pharmaceutically acceptable carrier, mixing.The purpose of pharmaceutical composition is to promote to be administered to the process of animal.
" pharmaceutical carrier " refers to organism does not cause obvious zest and does not disturb given compound
Non-active ingredient in the pharmaceutical composition of biological activity and character, such as but not limited to: calcium carbonate, calcium phosphate,
Various sugar (such as lactose, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate,
Acrylate copolymer or methacrylate polymer, gel, water, Polyethylene Glycol, propylene glycol, ethylene glycol, castor
Oleum Sesami or castor oil hydrogenated or many ethoxy aluminium Oleum Ricini, Oleum sesami, Semen Maydis oil, Oleum Arachidis hypogaeae semen etc..
In aforesaid pharmaceutical composition, in addition to including pharmaceutically acceptable carrier, it is also possible to be included in medicine (agent)
Adjuvant conventional on, such as: antibacterial agent, antifungal, antimicrobial, preservative, toner,
Solubilizing agent, thickening agent, surfactant, chelating agent, protein, aminoacid, fat, saccharide, vitamin,
Mineral, trace element, sweeting agent, pigment, essence or their combination etc..
The invention discloses a kind of compound and this compound as poly-(ADP-ribose) AG14361
Application, those skilled in the art can use for reference present disclosure, is suitably modified technological parameter and realizes.Need especially to refer to
Go out, all similar replacements and change apparent to those skilled in the art, they all by
It is considered as being included in the present invention.Method and the application of the present invention are described by preferred embodiment, relevant
Method described herein and application substantially can be changed in without departing from present invention, spirit and scope by personnel
Dynamic or suitable change and combination, realize and apply the technology of the present invention.
Below in conjunction with embodiment, the present invention it is expanded on further:
Preparation embodiment
The structural formula of compound by nuclear magnetic resonance, NMR (NMR) or/and what mass spectrum (MS) determined.NMR
Displacement (δ) is with 10-6(ppm) unit is given.Mensuration solvent be deuterated methanol, deuterated dimethyl sulfoxide,
Deuterochloroform, is inside designated as tetramethylsilane.
The mensuration of MS is with LC-MS mass spectrograph (manufacturer: Shimadzu, model: LCMS-2020)
The known initiation material of the present invention can use or synthesize according to methods known in the art, or can be from
Commercially available prod is directly buied.
Embodiment 1
Compound (1): 4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine-1 (dihydro)
The preparation of-one, concrete reaction equation is as follows:
The preparation of step 1:6-chloro-5-nitro-pyrimidine-4-amine
Will be dissolved with the oxolane (100mL) of compound 4,6-bis-chloro-5-nitro-pyrimidine (9.7g, 50mmol)
Middle addition ammonia (100mL) and sodium bicarbonate (4.6g, 55mmol), be heated to 55 DEG C and be stirred overnight.On
Stating reaction system and be cooled to room temperature, decompression removes organic solvent, and residue separates (two through rapid column chromatography after filtering
Chloromethanes: methanol=100:1) obtain compound as white solid a:6-chloro-5-nitro-pyrimidine-4-amine (8.1g,
Yield 93%).MS(ESI)m/z:[M+H]+=175.
The preparation of step 2:4-(6-amino-5-nitro-pyrimidine-4-base) piperazine-1-t-butyl carbonate
Will be dissolved with the dimethylformamide of compound list tertbutyloxycarbonyl protection piperazine (1.86g, 10mmol)
(10mL) compound a (1.91g, 11mmol) and diisopropyl ethyl amine (1.55g, 12mmol) are added in,
Room temperature reaction is removal of solvent under reduced pressure after 8 hours, residue through rapid column chromatography separate (dichloromethane: methanol=50:
1) obtain compound as white solid b:4-(6-amino-5-nitro-pyrimidine-4-base) piperazine-1-t-butyl carbonate (2.82g,
Yield 87%).MS(ESI)m/z:[M+H]+=325.
The preparation of step 3:4-(5,6-di-amino-pyrimidine-4-base) piperazine-1-t-butyl carbonate
10% palladium carbon (282mg) is added the methanol (20mL) dissolved with compound b (2.82g, 8.7mmol)
In solution, hydrogenating 7 hours under room temperature, filter, residue separates (dichloromethane: methanol through rapid column chromatography
=10:1) obtain yellow solid compound c:4-(5,6-di-amino-pyrimidine-4-base) piperazine-1-t-butyl carbonate (2.34g,
Yield 91%).MS(ESI)m/z:[M+H]+=295.
The preparation of step 4:4-(9 hydrogen-purine-6-base) piperazine-1-t-butyl carbonate
It is right to add in the trimethyl orthoformate solution (6g) dissolved with compound c (2.34g, 7.9mmol)
Toluenesulfonic acid (86mg, 0.5mmol), is warming up to backflow, cools down, removal of solvent under reduced pressure after reacting 8 hours,
Residue separates (dichloromethane: methanol=10:1) through rapid column chromatography and obtains faint yellow solid compound d:
4-(9 hydrogen-purine-6-base) piperazine-1-t-butyl carbonate (1g, yield 43%).MS(ESI)m/z:[M+H]+=
305。
The preparation of step 5:6-(piperazine-1-base)-9 hydrogen-purine
Trifluoro is added in a dichloromethane solution dissolved with compound d (1g, 3.3mmol) (10mL)
Acetic acid (2.28g, 20mmol), room temperature reaction is removal of solvent under reduced pressure, residue from dichloromethane after 8 hours
(20mL) dissolving, add sodium bicarbonate until pH=8, concentrate and remove solvent, residue is through rapid column chromatography
Separate (dichloromethane: methanol=10:1) obtain faint yellow solid compound e:6-(piperazine-1-base)-9 hydrogen-
Purine (0.56g, yield 83%).MS(ESI)m/z:[M+H]+=205.
The preparation of the fluoro-4-of step 6:2-((3-oxo isobenzofuran-1 (3 hydrogen)-subunit) methyl) benzene cyanogen
Under ice bath, slow in an absolute methanol solution dissolved with Feldalat NM (61.8g, 1.14mol) (1L)
Slowly dimethylphosphite (97mL, 1.06mol) is added.Temperature of reaction system is kept to be less than 5 DEG C, 20 minutes
Inside it is slowly added dropwise 2-carboxyl benzaldehyde (135g, 0.9mol).Above-mentioned reaction system is gradually increased to room temperature, and
Pyrovinic acid (81.6mL, 1.26mol) is gradually dripped in half an hour.After removal of solvent under reduced pressure, residue with water
(600mL) dilution, and extract three times with dichloromethane (500mL).Merge organic facies, and with water (100mL)
Being extracted twice, organic facies anhydrous magnesium sulfate is dried.Removal of solvent under reduced pressure obtains faint yellow solid compound 3-
Oxo-1,3-dihydrobenzo different furan-1-base dimethylphosphite, the most purified direct plunge into next step reaction.Will
Dissolved with the compound 3-oxo-1,3-dihydrobenzo different furan-1-base dimethylphosphite that the reaction of upper step is the most purified
The tetrahydrofuran solution (330mL) of (35g, 0.14mol) middle addition 2-fluoro-5-formoxyl benzene cyanogen (20.9g,
0.14mol), system is cooled to 15 DEG C, is slowly added dropwise triethylamine (19.5mL, 0.14mol) in 30 minutes.
Above-mentioned reaction system is gradually increased to room temperature, removal of solvent under reduced pressure, and residue with water (250mL) is pulled an oar, and filters
Obtain the fluoro-4-of compound as white solid f:2-((3-oxo isobenzofuran-1 (3 hydrogen)-subunit) methyl) benzene cyanogen (37.2g,
Yield 96%).
The fluoro-5-of step 7:2-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic preparation
13N hydrogen-oxygen is added in an aqueous solution dissolved with compound f (37g, 0.14mol) (200mL)
Change sodium solution (50mL), be warming up to 90 DEG C and stir 1 hour.Add after above-mentioned reaction system is down to 70 DEG C
Hydrazine hydrate (100mL, 2mol), keeps this temperature to stir 18 hours.Reactant liquor is cooled to room temperature, uses
The hydrochloric acid above-mentioned system of regulation of 8N, to pH=4, filters, and filter cake washes twice with water (60mL) successively, second
Ether (50mL) washs three times, and vacuum drying obtains the fluoro-5-of compound as white solid g:2-((4-oxo-3,4-bis-
Hydrogen dai piperazine-1-base) methyl) benzoic acid (30.1g, yield 77%).MS(ESI)m/z:[M+H]+=299.
Step 8:4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine-1 (dihydro)-one
Preparation
In a dimethyl formamide solution dissolved with compound g (168mg, 0.56mmol) (5mL)
Add compound e (127mg, 0.62mmol), 2-(7-azo BTA)-N, N, N', N'-tetramethylurea six
Fluorophosphoric acid ester (258mg, 0.68mmol) and triethylamine (234mg, 2.32mmol), stirred overnight at room temperature.
Concentrating and remove solvent, residue separates (dichloromethane: methanol=10:1) through rapid column chromatography and obtains white admittedly
Body compound (1): 4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine-1 (dihydro)-
Ketone (10mg, yield 4%).MS(ESI)m/z:[M+H]+=485.1H NMR(300MHz,DMSO-d6):
δ12.62(br,2H),8.27-8.22(m,2H),8.14(s,1H),8.00-7.82(m,3H),7.47-7.40(m,
2H),7.27-7.21(m,1H),4.34(s,2H),4.17-4.10(m,1H),3.78-3.74(m,1H),3.36(br,
6H)。
Embodiment 2
Compound (2): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine
The preparation of-1 (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:4-(4-amino-3-nitropyridine-2-base) piperazine-1-t-butyl carbonate
Use embodiment 1 step 2 to prepare the similar method of compound b, protected by compound list tertbutyloxycarbonyl
Protect piperazine and prepare compound h:4-(4-amino-3-with 2-chloro-3-nitro-4-aminopyridine generation nucleophilic substitution
Nitropyridine-2-base) piperazine-1-t-butyl carbonate (0.8g, yield 82%).MS(ESI)m/z:[M+H]+=324.
The preparation of step 2:4-(3,4-diamino-pyridine-2-base) piperazine-1-t-butyl carbonate
Use embodiment 1 step 3 to prepare the similar method of compound c, by compound h, catalytic hydrogenation occurs
Reaction prepares compound i:4-(3,4-diamino-pyridine-2-base) piperazine-1-t-butyl carbonate (0.7g, yield 100%).
MS(ESI)m/z:[M+H]+=294.
The preparation of step 3:4-(1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate
Embodiment 1 step 4 is used to prepare the similar method of compound d, by compound i and orthoformic acid front three
(0.5g receives ester generation cyclization compound of reaction j:4-(3,4-diamino-pyridine-2-base) piperazine-1-t-butyl carbonate
Rate 74%).MS(ESI)m/z:[M+H]+=304.
The preparation of step 4:4-(piperazine-1-base)-1 hydrogen-imidazo [4,5-c] pyridine
Use embodiment 1 step 5 to prepare the similar method of compound e, sent out with trifluoroacetic acid by compound j
Raw prepared compound k:4-(piperazine-1-base)-1 hydrogen-imidazo [4, the 5-c] pyridine of deprotection base reaction (261mg,
Yield 71%).MS(ESI)m/z:[M+H]+=204.
Step 5:4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine-1 (two
Hydrogen) preparation of-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound g and compound
K occurs condensation reaction to prepare compound (2): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl
Base)-4-luorobenzyl) dai piperazine-1 (dihydro)-one (16mg, yield 20%).MS(ESI)m/z:[M+H]+=484.1H NMR(300MHz,DMSO-d6):δ12.65(br,1H),12.56(s,1H),8.22(d,1H,
J=8.0Hz), 8.12 (s, 1H), 7.96-7.94 (m, 1H), 7.89-7.85 (m, 1H), 7.82-7.76 (m, 2H),
7.41-7.37 (m, 2H), 7.23-7.18 (m, 1H), 6.90 (d, 1H, J=4.8Hz), 4.31 (s, 2H), 4.14 (br,
2H),3.95(br,2H),3.74(br,2H),3.29(br,2H)。
Embodiment 3
Compound (3): 4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine
The preparation of-1 (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:4-chloro-3-nitro-PA
Under ice bath, compound 4-chloro-PA (6.4g, 50mmol) is slowly added to fuming nitric aicd (50mL)
In.Above-mentioned reaction system is gradually increased to room temperature, pours in the water containing trash ice, through quick post after residue filtration
Chromatography (dichloromethane: methanol=100:1) obtains compound as white solid l:4-chloro-3-nitro-2-ammonia
Yl pyridines (7.4g, yield 85%).MS(ESI)m/z:[M+H]+=174.
The preparation of step 2:4-(2-amino-3-nitropyridine-4-base) piperazine-1-t-butyl carbonate
Use embodiment 1 step 2 to prepare the similar method of compound b, protected by compound list tertbutyloxycarbonyl
Protecting piperazine occurs nucleophilic substitution to prepare compound m:4-(2-amino-3-nitropyridine-4-base) with compound l
Piperazine-1-t-butyl carbonate (0.8g, yield 88%).MS(ESI)m/z:[M+H]+=324.
The preparation of step 3:4-(2,3 diamino pyridine-4-base) piperazine-1-t-butyl carbonate
Use embodiment 1 step 3 to prepare the similar method of compound c, by compound m, catalysis hydrogen occurs
Change reaction and prepare compound n:4-(2,3-diamino-pyridine-4-base) piperazine-1-t-butyl carbonate (0.7g, yield
93%).MS(ESI)m/z:[M+H]+=294.
The preparation of step 4:4-(3 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-t-butyl carbonate
Embodiment 1 step 4 is used to prepare the similar method of compound d, by compound n and orthoformic acid three
Methyl ester generation cyclization compound of reaction o:4-(3 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine-1-t-butyl carbonate
(0.4g, yield 67%).MS(ESI)m/z:[M+H]+=304.
The preparation of step 5:7-(piperazine-1-base)-3 hydrogen-imidazo [4,5-b] pyridine
Use embodiment 1 step 5 to prepare the similar method of compound e, sent out with trifluoroacetic acid by compound o
Raw prepared compound p:7-(piperazine-1-base)-3 hydrogen-imidazo [4, the 5-b] pyridine of deprotection base reaction (223mg,
Yield 84%).MS(ESI)m/z:[M+H]+=204.
Step 6:4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl)-4-luorobenzyl) dai piperazine-1 (two
Hydrogen) preparation of-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound g and compound
P occurs condensation reaction to prepare compound (3): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl
Base)-4-luorobenzyl) dai piperazine-1 (dihydro)-one (35mg, yield 16%).MS(ESI)m/z:[M+H]+=484.1H NMR(300MHz,DMSO-d6):δ12.78(br,1H),12.57(s,1H),8.24(d,1H,
J=7.6Hz), 8.11 (s, 1H), 7.98-7.95 (m, 2H), 7.90-7.86 (m, 1H), 7.83-7.79 (m, 1H),
7.45-7.37 (m, 2H), 7.25-7.21 (m, 1H), 6.48 (d, 1H, J=6.4Hz), 4.32 (s, 2H), 4.00 (br,
2H),3.77-3.73(m,4H),3.32(br,2H)。
Embodiment 4
Compound (4): 4-(the fluoro-3-of 4-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)
Benzyl) preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:4-(2-methyl-3 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate
An acetic acid solution dissolved with compound i (1.47g, 5mmol) (30mL) adds acetic anhydride (0.56g,
5.5mmol), being warming up to backflow, cool down after reacting 8 hours, removal of solvent under reduced pressure, residue is through flash column
Analysis separates (dichloromethane: methanol=10:1) and obtains faint yellow solid compound q:4-(2-methyl-3 hydrogen-miaow
Azoles also [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate (0.73g, yield 47%).MS(ESI)m/z:
[M+H]+=318.
The preparation of step 2:2-methyl-4-(piperazine-1-base)-3 hydrogen-imidazo [4,5-c] pyridine
Use embodiment 1 step 5 to prepare the similar method of compound e, sent out with trifluoroacetic acid by compound q
Raw deprotection base reaction prepares compound r:2-methyl-4-(piperazine-1-base)-3 hydrogen-imidazo [4,5-c] pyridine
(261mg, yield 81%).MS(ESI)m/z:[M+H]+=218.
Step 3:4-(the fluoro-3-of 4-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-carbonyl) benzyl)
The preparation of dai piperazine-1 (dihydro)-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound g and compound
R occurs condensation reaction to prepare compound (4): 4-(the fluoro-3-of 4-(4-(2-methyl isophthalic acid hydrogen-imidazo [4,5-c] pyridine-4-
Base) piperazine-1-carbonyl) benzyl) dai piperazine-1 (dihydro)-one (48mg, yield 41%).MS(ESI)m/z:[M+H]+
=498.1H NMR(300MHz,DMSO-d6):δ12.63(br,1H),12.54(s,1H),8.21(d,1H,
J=8.0Hz), 8.13 (s, 1H), 7.97-7.94 (m, 1H), 7.89-7.86 (m, 1H), 7.83-7.75 (m, 2H),
7.42-7.38 (m, 2H), 7.21-7.17 (m, 1H), 6.91 (d, 1H, J=5.2Hz), 4.32 (s, 2H), 4.15 (br,
2H),3.96(br,2H),3.73(br,2H),3.25(br,2H),2.61(s,3H)。
Embodiment 5
Compound (5): 4-(the fluoro-3-of 4-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-
Carbonyl) benzyl) preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
The system of step 1:4-(2-trifluoromethyl-3 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate
Standby
Trifluoro is added in a trifluoroacetic acid solution dissolved with compound i (1.47g, 5mmol) (30mL)
Acetic anhydride (1.16g, 5.5mmol), is warming up to backflow, cools down, removal of solvent under reduced pressure after reacting 8 hours, residual
Excess separates (dichloromethane: methanol=10:1) through rapid column chromatography and obtains faint yellow solid compound s:4-(2-
Trifluoromethyl-3 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate (0.58g, yield 34%).
MS(ESI)m/z:[M+H]+=372.
The preparation of step 2:4-(piperazine-1-base)-2-trifluoromethyl-3 hydrogen-imidazo [4,5-c] pyridine
Use embodiment 1 step 5 to prepare the similar method of compound e, sent out with trifluoroacetic acid by compound s
Raw deprotection base reaction prepares compound t:4-(piperazine-1-base)-2-trifluoromethyl-3 hydrogen-imidazo [4,5-c] pyrrole
Pyridine (196mg, yield 85%).MS(ESI)m/z:[M+H]+=272.
Step 3:4-(the fluoro-3-of 4-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)
Benzyl) preparation of dai piperazine-1 (dihydro)-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound g and compound
T occurs condensation reaction to prepare compound (5): 4-(the fluoro-3-of 4-(4-(2-Trifluoromethyl-1 hydrogen-imidazo [4,5-c] pyrrole
Pyridine-4-base) piperazine-1-carbonyl) benzyl) dai piperazine-1 (dihydro)-one (31mg, yield 44%).MS(ESI)m/z:
[M+H]+=552.1H NMR(300MHz,DMSO-d6):δ12.71(br,1H),12.59(s,1H),8.25
(d, 1H, J=7.6Hz), 8.13 (s, 1H), 7.99-7.96 (m, 1H), 7.89-7.83 (m, 1H), 7.85-7.79 (m,
2H), 7.44-7.39 (m, 2H), 7.24-7.18 (m, 1H), 6.96 (d, 1H, J=4.4Hz), 4.32 (s, 2H), 4.15
(br,2H),3.97(br,2H),3.77(br,2H),3.29(br,2H)。
Embodiment 6
Compound (6): 4-(3-(4-(1 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)-4-fluorine benzyl
Base) preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:4-(3 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate
Sodium nitrite is added in an acetic acid solution dissolved with compound i (1.76g, 6mmol) (30mL)
(0.42g, 6mmol), is warming up to backflow, cools down, removal of solvent under reduced pressure after reacting 8 hours, and residue is through fast
Speed column chromatography for separation (dichloromethane: methanol=10:1) obtains faint yellow solid compound u:4-(3 hydrogen-[1,2,3]
Triazole [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate (1.3g, yield 83%).MS(ESI)m/z:[M+H]+
=305.
The preparation of step 2:4-(piperazine-1-base)-3 hydrogen-[1,2,3] triazole [4,5-c] piperidines
Use embodiment 1 step 5 to prepare the similar method of compound e, sent out with trifluoroacetic acid by compound u
Raw deprotection base reaction prepares compound v:4-(piperazine-1-base)-3 hydrogen-[1,2,3] triazole [4,5-c] piperidines
(257mg, yield 88%).MS(ESI)m/z:[M+H]+=205.
Step 3:4-(3-(4-(1 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)-4-luorobenzyl) dai
The preparation of piperazine-1 (dihydro)-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound g and compound
V occurs condensation reaction to prepare compound (6): 4-(3-(4-(1 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine-1-
Carbonyl)-4-luorobenzyl) dai piperazine-1 (dihydro)-one (28mg, yield 38%).MS(ESI)m/z:[M+H]+=485.1H NMR(300MHz,DMSO-d6):δ12.66(br,1H),12.58(s,1H),8.21(d,1H,
J=7.6Hz), 8.13 (s, 1H), 7.95-7.93 (m, 1H), 7.87-7.84 (m, 1H), 7.81-7.75 (m, 2H),
7.42-7.35 (m, 2H), 7.22-7.16 (m, 1H), 6.91 (d, 1H, J=4.8Hz), 4.30 (s, 2H), 4.12 (br,
2H),3.91(br,2H),3.72(br,2H),3.24(br,2H)。
Embodiment 7
Compound (7): 4-(the fluoro-3-of 4-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine
-1-carbonyl) benzyl) preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
Step 1:4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate
Preparation
An anhydrous tetrahydrofuran solution dissolved with compound i (1.47g, 5mmol) (20mL) adds
Carbonyl dimidazoles (1.62g, 10mmol), is warming up to backflow, cools down, removal of solvent under reduced pressure after reacting 8 hours,
Residue separates (dichloromethane: methanol=10:1) through rapid column chromatography and obtains faint yellow solid compound w:
4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-t-butyl carbonate (1.3g, yield
86%).MS(ESI)m/z:[M+H]+=320.
The preparation of step 2:4-(piperazine-1-base)-1 hydrogen-imidazo [4,5-c] pyridine-2 (3 hydrogen)-one
Embodiment 1 step 5 is used to prepare the similar method of compound e, by compound w and trifluoroacetic acid
Prepared compound x:4-(piperazine-1-base)-1 hydrogen-imidazo [4,5-c] pyridine-2 (3 hydrogen) of generation deprotection base reaction-
Ketone (171mg, yield 69%).MS(ESI)m/z:[M+H]+=220.
Step 3:4-(the fluoro-3-of 4-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine-1-
Carbonyl) benzyl) preparation of dai piperazine-1 (dihydro)-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound g and compound
X occurs condensation reaction to prepare compound (7): 4-(the fluoro-3-of 4-(4-(2-oxo-2,3-dihydro-1 hydrogen-imidazo [4,5-c]
Pyridin-4-yl) piperazine-1-carbonyl) benzyl) dai piperazine-1 (dihydro)-one (37mg, yield 49%).MS(ESI)m/z:
[M+H]+=500.1H NMR(300MHz,DMSO-d6):δ12.63(br,1H),10.96(br,1H),
10.35 (br, 1H), 8.20 (d, 1H, J=8.0Hz), 7.95-7.93 (m, 1H), 7.87-7.83 (m, 1H),
7.82-7.74 (m, 2H), 7.43-7.38 (m, 2H), 7.24-7.19 (m, 1H), 6.91 (d, 1H, J=4.4Hz), 4.32
(s,2H),4.15(br,2H),3.92(br,2H),3.77(br,2H),3.26(br,2H)。
Embodiment 8
Compound (8): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)-4-methoxy-benzyl)
The preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:3-bromo-4-methoxyl methyl benzoate
In room in an aqueous solution dissolved with 4-methoxyl methyl benzoate (1.5g, 9mol) (10mL)
Potassium bromate. (251mg, 1.5mmol) and bromine (722mg, 4.5mmol) it is slowly added under temperature.Keep anti-
Answer system temperature to be less than 30 DEG C to stir 2.5 hours.Above-mentioned reaction system is added methyl tertiary butyl ether(MTBE) (25mL),
After extraction, organic facies saturated aqueous common salt washs, and is dried and concentrates gained residue through rapid column chromatography separation (oil
Ether: ethyl acetate=10:1) obtain compound as white solid y:3-bromo-4-methoxyl methyl benzoate (2.1g,
Yield 95%).
The preparation of step 2:3-cyano group-4-methoxyl methyl benzoate
A dimethyl formamide solution dissolved with compound y (1.1g, 4.4mol) (10mL) adds
Cupricin. (1.2g, 13.22mmol).It is heated to 140 DEG C to stir 6 hours.By cold for above-mentioned reaction system
Adding ethyl acetate (25mL) the most afterwards, after extraction, organic facies saturated aqueous common salt washs, and is dried concentration gained residual
Excess separates (petroleum ether: ethyl acetate=10:1) through rapid column chromatography and obtains compound as white solid z:3-
Cyano group-4-methoxyl methyl benzoate (662mg, yield 79%).
The preparation of step 3:5-(methylol)-2-methoxybenzene cyanogen
Hydroboration is added in a tetrahydrofuran solution dissolved with compound z (1g, 5.2mol) (25mL)
Lithium (0.45g, 20.7mmol).It is stirred overnight under room temperature.Above-mentioned reaction system is dried concentration, and gained is remaining
Thing separates (petroleum ether: ethyl acetate=2:1) through rapid column chromatography and obtains compound as white solid a ': 5-(hydroxyl
Methyl)-2-methoxybenzene cyanogen (845mg, yield 100%).
The preparation of step 4:5-formoxyl-2-methoxybenzene cyanogen
At one dissolved with compound a ' dichloromethane solution (50mL) of (845mg, 5.2mol) adds (1,1,1-
Triacetyl)-1,1-dihydro-1,2-benzenesulfonyl-3 (1 hydrogen)-one (2.6g, 6.2mmol).Stir 2 hours under room temperature.
Above-mentioned reaction system is dried concentration, gained residue through rapid column chromatography separate (petroleum ether: ethyl acetate=3:
1) compound as white solid b ': 5-formoxyl-2-methoxybenzene cyanogen (845mg, yield 100%) is obtained.
The preparation of step 5:2-methoxyl group-5-((3-oxo isobenzofuran-1 (3 hydrogen)-subunit) methyl) benzene cyanogen
Embodiment 1 step 6 is used to prepare the similar method of compound f, by compound b ' and 3-oxo-1,3-
Dihydrobenzo different furan-1-base dimethylphosphite reacts prepared compound c ': 2-methoxyl group-5-((3-oxygen
For isobenzofuran-1 (3 hydrogen)-subunit) methyl) benzene cyanogen (795mg, yield 67%).
Step 6:2-methoxyl group-5-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic preparation
Use embodiment 1 step 7 to prepare the similar method of compound g, by compound c ', hydrolysis occurs
Prepared compound d ': 2-methoxyl group-5-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic acid (318mg,
Yield 63%).MS(ESI)m/z:311[M+1]+。
Step 7:4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)-4-methoxy-benzyl) dai piperazine
The preparation of-1 (dihydro)-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound d ' and compound
K occurs condensation reaction to prepare compound (8): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl
Base)-4-methoxy-benzyl) dai piperazine-1 (dihydro)-one (39mg, yield 42%).MS(ESI)m/z:[M+H]+
=496.1H NMR(300MHz,DMSO-d6):δ12.92(br,1H),12.56(s,1H),8.24-8.22(m,
2H),7.96-7.75(m,4H),7.34-7.32(m,1H),7.18(s,1H),7.02-6.98(m,2H),4.25(s,
2H),4.19-4.18(m,2H),3.99(br,2H),3.74(s,3H),3.73(br,2H),3.26-3.24(m,2H)。
Embodiment 9
Compound (9): 4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl)-4-methoxy-benzyl) dai piperazine-1 (two
Hydrogen) preparation of-one, concrete reaction equation is as follows:
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound d ' and compound
E occurs condensation reaction to prepare compound (9): 4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl)-4-methoxyl group
Benzyl) dai piperazine-1 (dihydro)-one (128mg, yield 69%).MS(ESI)m/z:[M+H]+=497.1H
NMR(300MHz,DMSO-d6):δ13.06(br,1H),12.55(s,1H),8.24-8.22(m,1H),8.21
(s,1H),8.13(s,1H),7.96-7.94(m,1H),7.89-7.87(m,1H),7.82-7.80(m,1H),
7.34-7.31 (m, 1H), 7.18 (s, 1H), 7.00 (d, 1H, J=8.8Hz), 4.26 (br, 2H), 4.24 (s, 2H),
4.02(br,2H),3.74(s,3H),3.72-3.70(m,2H),3.21-3.19(m,2H)。
Embodiment 10
Compound (10): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl) benzyl) dai piperazine-1
The preparation of (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:3-(1,3-dioxo-2,3-dihydro-1 hydrogen-indenes-2-base) benzene cyanogen
Under ice bath, at one dissolved with isobenzofuran-1 (3 hydrogen)-one (51g, 0.38mol) and tricyano benzene first
The ethyl propionate solution (200mL) of aldehyde (52g, 0.39mol) was slowly added to dissolved with 25% in 40 minutes
The methanol solution (320mL) of Feldalat NM.Keeping temperature of reaction system less than 30 DEG C, above-mentioned reaction system is gradually
It is warmed to room temperature and is heated to reflux 1 hour, continuously add methanol (100mL) and stir 1 at reflux
Hour.After above-mentioned reaction system is cooled to reduced pressure at room temperature removing solvent, residue with water (1L) dilutes also
Filter.Filter cake ether (200mL) washs three times, uses acetic acid (110mL) to be acidified by compound.Cross
Filter, obtains red solid compound e ': 3-(1,3-dioxo-2,3-dihydro after filter cake water (100mL) washing
-1 hydrogen-indenes-2-base) benzene cyanogen (69g, yield 94%).
Step 2:3-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic preparation
Use embodiment 1 step 7 to prepare the similar method of compound g, by compound e ', hydrolysis occurs
Prepare compound f ': 3-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic acid (28g, yield 55%).
MS(ESI)m/z:281[M+1]+。
Step 3:4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl) benzyl) dai piperazine-1 (dihydro)
The preparation of-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound f ' and compound k
Condensation reaction is occurred to prepare compound (10): 4-(3-(4-(1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine-1-carbonyl)
Benzyl) dai piperazine-1 (dihydro)-one (51mg, yield 62%).MS(ESI)m/z:[M+H]+=466.1H NMR
(300MHz, DMSO-d6): δ 12.57 (br, 1H), 12.51 (br, 1H), 8.22 (d, 1H, J=7.6Hz), 8.00 (s,
1H),7.96-7.92(m,1H),7.86-7.72(m,3H),7.41-7.34(m,3H),7.25-7.24(m,1H),
6.90 (d, 1H, J=7.6Hz), 4.33 (s, 2H), 4.13 (br, 2H), 3.93 (br, 2H), 3.73 (br, 2H), 3.27
(br,2H)。
Embodiment 11
Compound (11): 4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl) benzyl) dai piperazine-1 (dihydro)-one
Preparation, concrete reaction equation is as follows:
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound f ' and compound e
Condensation reaction is occurred to prepare compound (11): 4-(3-(4-(9 hydrogen-purine-6-base) piperazine-1-carbonyl) benzyl) dai piperazine
-1 (dihydro)-one (36mg, yield 58%).MS(ESI)m/z:[M+H]+=467.1H NMR(300MHz,
DMSO-d6):δ12.53(br,1H),12.50(br,1H),8.23(s,1H),8.20(s,1H),7.94-7.91(m,
1H),7.83-7.72(m,3H),7.41-7.38(m,3H),7.25-7.22(m,1H),4.31(s,2H),4.11(br,
2H),3.92(br,2H),3.75(br,2H),3.26(br,2H)。
Embodiment 12
Compound (12): 4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl)-4-methoxy-benzyl)
The preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound d ' and compound
P occurs condensation reaction to prepare compound (12): 4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl
Base)-4-methoxy-benzyl) dai piperazine-1 (dihydro)-one (65mg, yield 41%).MS(ESI)m/z:[M+H]+
=496.1H NMR(300MHz,DMSO-d6):δ12.80(br,1H),12.55(s,1H),8.22(d,1H,
J=6.8Hz), 8.09 (s, 1H), 7.96-7.92 (m, 2H), 7.87-7.77 (m, 2H), 7.31 (d, 1H, J=8.0Hz),
7.16 (s, 1H), 6.99 (d, 1H, J=8.0Hz), 6.47 (d, 1H, J=6.8Hz), 4.23 (br, 2H), 3.95 (br,
2H),3.72(br,5H),3.30(br,2H),3.22(br,2H)。
Embodiment 13
Compound (13): 4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl)-4-trifluoromethyl benzyl
Base) preparation of dai piperazine-1 (dihydro)-one, concrete reaction equation is as follows:
The preparation of step 1:3-bromo-4-trifluoromethyl benzoic acid methyl ester
At a methanol solution (30mL) dissolved with 3-bromo-4-(Trifluoromethyl)benzoic acid. (4.1g, 15.4mol)
In be slowly added to concentrated sulphuric acid (1mL) at room temperature.Reaction is heated to 60 DEG C and stirs 6 hours.It is cooled to room
Temperature, adds ethyl acetate (25mL) by above-mentioned reaction system, and after extraction, organic facies saturated aqueous common salt washs,
It is dried concentration gained residue and obtains white admittedly through rapid column chromatography separation (petroleum ether: ethyl acetate=10:1)
Body compound g ': 3-bromo-4-trifluoromethyl benzoic acid methyl ester (4.2g, yield 96%).
The preparation of step 2:3-cyano group-4-trifluoromethyl benzoic acid methyl ester
Use embodiment 8 step 2 to prepare the similar method of compound z, by compound g ' occur cyanalation instead
Compound h ': 3-cyano group-4-trifluoromethyl benzoic acid methyl ester (1.6g, yield 64%) should be prepared.MS(ESI)m/z:
230[M+1]+。
The preparation of step 3:5-(methylol)-2-trifluoromethylbenzene cyanogen
Embodiment 8 step 3 is used to prepare compound a ' similar method, there is reduction reaction by compound h '
Prepare compound i ': 5-(methylol)-2-trifluoromethylbenzene cyanogen (1.2g, yield 87%).MS(ESI)m/z:202
[M+1]+。
The preparation of step 4:5-formoxyl-2-trifluoromethylbenzene cyanogen
Use embodiment 8 step 4 to prepare the similar method of compound b ', by compound i ', reduction reaction occurs
Prepare compound j ': 5-formoxyl-2-trifluoromethylbenzene cyanogen (1.3g, yield 96%).MS(ESI)m/z:200
[M+1]+。
The preparation of step 5:2-trifluoromethyl-5-((3-oxo isobenzofuran-1 (3 hydrogen)-subunit) methyl) benzene cyanogen
Embodiment 1 step 6 is used to prepare the similar method of compound f, by compound j ' and 3-oxo-1,3-
Dihydrobenzo different furan-1-base dimethylphosphite reacts prepared compound k ': 2-trifluoromethyl-5-((3-oxygen
For isobenzofuran-1 (3 hydrogen)-subunit) methyl) benzene cyanogen (721mg, yield 69%).
Step 6:2-trifluoromethyl-5-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic preparation
Use embodiment 1 step 7 to prepare the similar method of compound g, by compound k ', hydrolysis occurs
Prepared compound l ': 2-trifluoromethyl-5-((4-oxo-3,4-dihydro dai piperazine-1-base) methyl) benzoic acid (678mg,
Yield 86%).MS(ESI)m/z:349[M+1]+。
Step 7:4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl)-4-trifluoromethyl benzyl) dai
The preparation of piperazine-1 (dihydro)-one
Embodiment 1 step 8 is used to prepare the method that compound (1) is similar, by compound l ' and compound p
Condensation reaction is occurred to prepare compound (13): 4-(3-(4-(3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine-1-carbonyl
Base)-4-trifluoromethyl benzyl) dai piperazine-1 (dihydro)-one (54mg, yield 36%).MS(ESI)m/z:[M+H]+
=534.1H NMR(300MHz,DMSO-d6):δ12.79(br,1H),12.58(br,1H),8.23(d,1H,
J=8.0Hz), 8.10 (s, 1H), 7.97-7.72 (m, 5H), 7.55 (d, 1H, J=8.0Hz), 7.51 (s, 1H), 6.47 (d,
1H, J=5.6Hz), 4.42 (s, 2H), 4.03-3.95 (m, 1H), 3.85-3.82 (m, 1H), 3.68-3.63 (m, 4H),
3.19(br,2H)。
Biological assessment
The enzyme assay of example 1PARP is tested
Experimental principle:
After the translation that the poly ADP of nucleoprotein is ribosylating when being to occur at DNA damage response.PARP, entirely
Title is Poly adenosine diphosphate-ribose polymerase-1, and in the presence of having NAD, catalysis poly (ADP-ribose) connects
On the nucleoprotein closed on, thus cause the DNA repair mechanism via base excision repair path.Trevigen
The HT Universal Chemiluminescent PARP Assay Kit that company produces can measure this being given birth to
The ADP-ribose of thing element labelling and the combination level of histone.
Reagent and consumptive material
1.HT Universal Chemiluminescent PARP Assay Kit with Histone-coated Strip
Wells, U.S. Trevigen, article No.: 4676-096-K.
2. read plate instrument, U.S. Perkin Elmer, EnVision Multilabel Plate Reader.
Solution and buffer
1. washing liquid contains the PBS solution of 0.1%Triton X-100.
20X PARP buffer dilution 20 times is i.e. obtained 1X by 2.20X PARP buffer deionized water
Buffer, this buffer is used to dilution restructuring PARP enzyme, PARP Cocktail and tested compound.
3.10X PARP Cocktail prepares 1X PARP Cocktail:10X PARP in accordance with the following methods
Cocktail 2.5 μ l/well, 10X activated dna 2.5 μ l/well, 1X PARP buffer 20 μ l/well.
4.PARP Enzyme the most before use, carefully dilutes recombinase with 1X PARP buffer, dilutes
Enzymatic solution to use as early as possible, unspent to discard.
5.Strep-HRP the most before use, obtains 1X again by 1X Strep diluted Strep-HRP 500
Solution.
6. chemical luminous substrate is the most before use, by equal to PeroxyGlow A and the B solution mixing of same volume
The even substrate obtaining horseradish peroxidase.
Experimental technique
Compound is prepared
1. with DMSO, each for 10mM test compound mother solution is diluted to 10 μMs, 1 μM.
The most only before experiment starts, the gradient concentration solution 1X of each compound being dissolved in DMSO
PARP buffer dilutes 20 times, obtains the compound solution of 5X, i.e. can be utilized for detection, positive control
And negative control (NEGATIVE) hole is 1X PARP buffer (DMSO content 5%) (POSITIVE).
Wherein, use AZD2281 (Olaparib) as control compound.
Operating procedure
1. every hole adds 50 μ l 1X PARP buffer moistening histones, incubated at room orifice plate 30 minutes,
Then by the 1X PARP buffer sucking-off in hole, and on napkin, residual liquid is patted dry only.
2. according to compound (1) to (13) and control compound AZD2281, the 5X chemical combination that will have diluted
Thing solution adds in corresponding hole, every hole 10 μ l, positive control (POSITIVE) and negative control (NEGATIVE)
Hole is 1X PARP buffer (DMSO content 5%)
3. with 1X PARP buffer, PARP enzyme is diluted to every 15 μ l solution and contains 0.5Unit, then exist
Other holes in addition to negative control hole add 15 μ l enzymatic solution, and negative control hole only adds 1X PARP and delays
Rush liquid, incubated at room orifice plate 10 minutes.
4. continuously add the 1X PARP Cocktail of 25 μ l in each hole.
Hatch orifice plate 60 minutes for 5.27 DEG C.
6., after hatching end, by the reactant liquor sucking-off in hole, and on napkin, residual liquid is patted dry only.Connect
And rinse orifice plate 4 times by the PBS solution containing 0.1%Triton X-100, the most every hole with 200 μ l, and
On napkin, residual liquid is patted dry only.
7., it follows that add the 1X Strep-HRP solution diluted in every hole, then hatch at 27 DEG C
Orifice plate 60 minutes.
8., after hatching end, by the reactant liquor sucking-off in hole, and on napkin, residual liquid is patted dry only.Connect
And rinse orifice plate 4 times by the PBS solution containing 0.1%Triton X-100, the most every hole with 200 μ l, and
On napkin, residual liquid is patted dry only.
9., after washing the bundle that hardens, by PeroxyGlow A and the B solution mix homogeneously of same volume, every hole adds
100 μ l, are immediately placed in reading plate instrument record chemiluminescence signal.
Data process
Reading in every hole needs to be converted into suppression ratio.The suppression ratio of compound can use following equation to calculate
Draw:
Note: Positive control wells reading is positive hole reading, meaning is enzyme 100% activity；Negative control hole
Reading is negative hole reading, and meaning is enzyme 0%；Activity X is the reading of each each concentration of sample.
Table 1 compound inhibitory activity to PARP-1 enzyme
| The numbering of embodiment compound | IC50(PARP)/nM |
| (1) | 4 |
| (2) | 2 |
| (3) | 5 |
| (4) | 2 |
| (5) | 7 |
| (6) | 4 |
| (7) | 6 |
| (8) | 9 |
| (9) | 2 |
| (10) | 3 |
| (11) | 4 |
| (12) | 8 |
| (13) | 5 |
| Control compound AZD2281 | 8 |
Conclusion: preferred compound of the present invention has obvious inhibitory activity to the Inhibit proliferaton of PARP-1 enzyme.
Claims (26)
1. heterocycle glyoxaline compound, it is the compound shown in formula I or its pharmaceutically acceptable salt:
Wherein, in formula I:
R is hydrogen, halogen, C1-C6Alkoxyl or C1-C6Haloalkyl；
X, Y, Z one of them be nitrogen, remaining be hydrocarbon or X, Y, Z one of them for hydrocarbon, remaining
For nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, alkyl, alkoxyl or haloalkyl.
Compound shown in formula I the most according to claim 1, wherein:
R is hydrogen, halogen, C1-C3Alkoxyl or C1-C3Haloalkyl.
3. according to the compound shown in the formula I according to any one of claim 1-2, wherein:
R is hydrogen, fluorine, methoxyl group or trifluoromethyl.
4. according to the compound shown in the formula I according to any one of claim 1-3, wherein:
X and Z is nitrogen, and Y is hydrocarbon or X is nitrogen, Y and Z is hydrocarbon or Z is nitrogen, X and Y is
Hydrocarbon.
5. according to the compound shown in the formula I according to any one of claim 1-4, wherein:
R1For hydrogen, oxygen or C1-C6Alkyl or C1-C6Haloalkyl.
6. according to the compound shown in the formula I according to any one of claim 1-5, wherein:
R1For hydrogen, oxygen or C1-C3Alkyl or C1-C3Haloalkyl.
7. according to the compound shown in the formula I according to any one of claim 1-6, wherein:
R1For hydrogen, oxygen, methyl or trifluoromethyl.
8. according to the compound shown in the formula I according to any one of claim 1-7, wherein, described formula
Compound shown in I is following compound 1～13 or its pharmaceutically acceptable salt:
9. one kind according to the compound shown in formula I according to any one of claim 18 or its pharmaceutically may be used
The preparation method of the salt accepted, its reaction equation is as follows:
Wherein, the definition of R, X, Y, Z and M is as claimed in claim 1；R2 be hydroxyl, halogen,
Diimidazole 1 base；It specifically comprises the following steps that
There is condensation reaction in intermediate V and dai piperazine class carboxylic acid derivates VI, generates the compound shown in formula I.
The preparation method of the compound shown in formula I the most according to claim 9, wherein, described dai piperazine
Compound shown in class carboxylic acid derivates VI is as follows:
11. according to the preparation method of the compound shown in formula I according to any one of claim 9-10, wherein,
The condensing agent used in described condensation reaction is selected from 1,1'-carbonyl dimidazoles, 1-ethyl-(3-dimethylaminopropyl)
Carbodiimide hydrochloride, 2-(7-azo BTA)-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester, benzo three
Nitrogen azoles-N, N, N', N'-tetramethylurea hexafluorophosphoric acid ester.
Compound shown in 12. 1 kinds of formula I prepared as according to any one of claim 18 or its pharmacy
The intermediate of upper acceptable salt, described intermediate structure formula is as follows:
Wherein, in intermediate V:
X, Y, Z one of them be nitrogen, remaining be hydrocarbon or X, Y, Z one of them for hydrocarbon, remaining
For nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, alkyl, alkoxyl or haloalkyl.
13. intermediate according to claim 12, wherein, in intermediate V:
X and Z is nitrogen, and Y is hydrocarbon or X is nitrogen, Y and Z is hydrocarbon or Z is nitrogen, X and Y is
Hydrocarbon；
R1For hydrogen, oxygen, methyl or trifluoromethyl.
14. according to the intermediate according to any one of claim 12-13, wherein, shown in described intermediate V
Compound as follows:
15. pharmaceutical compositions, appoint in the claim 18 that wherein said pharmaceutical composition comprises therapeutically effective amount
Compound shown in one described formula I and one or more pharmaceutically acceptable carrier material and/or excipient.
16. pharmaceutical compositions according to claim 15, wherein said pharmaceutical composition make tablet,
Capsule, aqueous suspension, Oil suspensions, dispersible powder, granule, lozenge, Emulsion, syrup
Agent, ointment, suppository or injection.
17. pharmaceutical compositions according to claim 15, the described compound shown in formula I is with trip
Exist from form.
Compound shown in 18. 1 kinds of formula I as according to any one of claim 18 or its pharmaceutically may be used
The salt accepted or the pharmaceutical composition as according to any one of claim 15 17 are lived because of PARP in preparation treatment
Property suppression and application in the disease medicament that improves.
19. apply according to described in claim 18, and the described disease improved because of the suppression of PARP activity is blood vessel
Disease, septic shock, ischemia injury, neurotoxicity, hemorrhagic shock, inflammatory diseases, multiple firmly
Change disease, neurodegenerative diseases or diabetes.
Compound shown in 20. 1 kinds of formula I as according to any one of claim 18 or its pharmaceutically may be used
The salt accepted or the pharmaceutical composition as according to any one of claim 15 17 are used for treatment of cancer in preparation
Application in ancillary drug.
Compound shown in 21. 1 kinds of formula I as according to any one of claim 18 or its pharmaceutically may be used
The salt accepted or the pharmaceutical composition as according to any one of claim 15 17 are used for treatment of cancer in preparation
Application in chemotherapeutics or strengthening radiotherapeutic drug.
22. is homologous recombination according to the application according to any one of claim 20 21, wherein said cancer
The pathway deficiency that dependent DNA double chain interruption is repaired.
23. according to the application according to any one of claim 20 21, wherein said cancer comprise one or
Multiple reduced by the ability of homologous recombination dependent DNA double chain interruption reparation relative to normal cell or
The cancerous cell lost.
24. according to the application according to any one of claim 20 21, and wherein said cancer is for having
BRCA1 or BRCA2 defect, the cancer of mutant phenotype.
25. according to the application according to any one of claim 20 21, wherein said cancer be BRCA1 or
/ and BRCA2 defect, the cancer of sudden change.
26. according to the application according to any one of claim 20 21, wherein, described cancer be breast carcinoma,
Ovarian cancer, cancer of pancreas, carcinoma of prostate, rectal cancer, colon cancer or hepatocarcinoma.
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| CN108558773A (en) * | 2018-05-17 | 2018-09-21 | 苏州莱克施德药业有限公司 | A kind of preparation method of olaparib pharmaceutical intermediate |
| US20210323946A1 (en) * | 2020-04-21 | 2021-10-21 | Idience Co., Ltd. | Process for preparing a phthalazinone derivative and intermediates thereof |
| CN114174294A (en) * | 2019-05-28 | 2022-03-11 | 人类制药有限公司 | Novel compounds for inhibiting JANUS kinase 1 |
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| WO2018068715A1 (en) * | 2016-10-14 | 2018-04-19 | 上海汇伦生命科技有限公司 | Pharmaceutical salt of antitumor heterocyclic imidazole compound |
| US10874667B2 (en) | 2016-10-14 | 2020-12-29 | Shanghai Huilin Life Scinece & Technology Co., Ltd. | Pharmaceutical salt of antitumor heterocyclic imidazole compound |
| CN108558773A (en) * | 2018-05-17 | 2018-09-21 | 苏州莱克施德药业有限公司 | A kind of preparation method of olaparib pharmaceutical intermediate |
| CN114174294A (en) * | 2019-05-28 | 2022-03-11 | 人类制药有限公司 | Novel compounds for inhibiting JANUS kinase 1 |
| EP3976612A4 (en) * | 2019-05-28 | 2023-04-26 | Mankind Pharma Ltd | Novel compounds for inhibition of janus kinase 1 |
| US20210323946A1 (en) * | 2020-04-21 | 2021-10-21 | Idience Co., Ltd. | Process for preparing a phthalazinone derivative and intermediates thereof |
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