CN106146504B - A kind of heterocycle and glyoxaline compound, its pharmaceutical composition and its preparation method and application - Google Patents
A kind of heterocycle and glyoxaline compound, its pharmaceutical composition and its preparation method and application Download PDFInfo
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- CN106146504B CN106146504B CN201510189027.4A CN201510189027A CN106146504B CN 106146504 B CN106146504 B CN 106146504B CN 201510189027 A CN201510189027 A CN 201510189027A CN 106146504 B CN106146504 B CN 106146504B
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- 0 COc1ccc(CC(c2ccccc22)=NNC2=O)cc1C(N(CC1)CCN1C1=NC=NC2NC=NC12)=* Chemical compound COc1ccc(CC(c2ccccc22)=NNC2=O)cc1C(N(CC1)CCN1C1=NC=NC2NC=NC12)=* 0.000 description 5
- WCCLFWRMEZTUNL-UHFFFAOYSA-N C=C1NN=C(Cc2cccc(C(N(CC3)CCN3c3ncnc4c3nc[nH]4)=O)c2)c2c1cccc2 Chemical compound C=C1NN=C(Cc2cccc(C(N(CC3)CCN3c3ncnc4c3nc[nH]4)=O)c2)c2c1cccc2 WCCLFWRMEZTUNL-UHFFFAOYSA-N 0.000 description 1
- MDWHGHAVYNPTRF-UHFFFAOYSA-N COc1ccc(CC(c2ccccc22)=NNC2=O)cc1C(N(CC1)CCN1c1ccnc2c1nc[nH]2)=O Chemical compound COc1ccc(CC(c2ccccc22)=NNC2=O)cc1C(N(CC1)CCN1c1ccnc2c1nc[nH]2)=O MDWHGHAVYNPTRF-UHFFFAOYSA-N 0.000 description 1
- JQYSMSLRCZNALG-UHFFFAOYSA-N O=C(c1cc(CC(c2c3cccc2)=NNC3=O)ccc1C(F)(F)F)N(CC1)CCN1c1ccnc2c1nc[nH]2 Chemical compound O=C(c1cc(CC(c2c3cccc2)=NNC3=O)ccc1C(F)(F)F)N(CC1)CCN1c1ccnc2c1nc[nH]2 JQYSMSLRCZNALG-UHFFFAOYSA-N 0.000 description 1
- CYSKEPFCVIQPFK-UHFFFAOYSA-N O=C(c1cccc(CC(c2ccccc22)=NNC2=O)c1)[N-](CC1)CCN1c1c2nc[nH]c2ccn1 Chemical compound O=C(c1cccc(CC(c2ccccc22)=NNC2=O)c1)[N-](CC1)CCN1c1c2nc[nH]c2ccn1 CYSKEPFCVIQPFK-UHFFFAOYSA-N 0.000 description 1
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to heterocycle and imidazole derivative, preparation method and its applications in medicine.Specifically, the present invention relates to heterocycle new shown in a kind of general formula (I) and imidazole derivative, preparation method and pharmaceutical composition containing the derivative as well as therapeutic agents especially as the purposes of poly- (ADP ribose) polymerase (PARP) inhibitor.
Description
Technical field
The present invention relates to heterocycle and imidazole derivative, preparation method and pharmaceutical composition containing the derivative,
As well as therapeutic agent and the purposes as 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 therapies can induce
DNA is single-stranded and/or double-strand break generates cytotoxic effect in turn, and target tumor is since chromosome damage is to dead.
An important results of DNA damage signal are that cell cycle regulating site signal is activated in response, and its object is to protect
Cell is in the case of DNA damage without mitosis to avoid cellular damage.In most cases, tumour cell exists
With very high appreciation rate while showing cell cycle regulating site signal defect.It can therefore be concluded that in tumour cell
There are specific DNA repair mechanisms, with quick response and can repair and be proliferated the relevant chromosome damage of adjusting, to make it certainly
Body survives the cytotoxic effect of some medicines and maintenance survival.
In clinical application, the effective concentration or treatment radiation intensity of chemotherapeutics can fight these DNA repair mechanisms,
Ensure the fragmentation effect to target tumor.However, tumour cell can be to treatment by enhancing its DNA damage repair mechanism
Tolerance effect is generated, is allowed to survive from fatal DNA damage.In order to overcome the tolerance of generation, it usually needs increase
The dosage of medicine improves radiation intensity, this way will have an adverse effect to the normal structure near lesion, to
Make with serious adverse reaction in therapeutic process, and then increases Operative risk.Meanwhile ever-increasing tolerance will drop
Low therapeutic effect, it can therefore be concluded that by the adjusting to DNA damage signal repair mechanism, it can be with tumor cell specific
Mode realize the raising of the cytotoxicity to DNA damage medicament.
PARPs (Poly (ADP-ribose) characterized by poly- adenosine diphosphate-ribosylating activity
Polymerases), the superfamily of 18 kinds of cell ribozyme nucleus matter enzymes is constituted.This poly- adenosine diphosphate-ribosyl is turned into
With the catalytic activity and protein-protein interaction that can adjust destination protein, and many basic bioprocess are adjusted
Control, including DNA are repaired, cell death, and Genome stability is also associated.
PARP-1 activity accounts for about total cell PARP active 80%, it and become jointly with its most similar PARP-2
Has the member of DNA plerosis lesion capability in PARP families.As the inductor and signal protein of DNA damage, PARP-1 can be with
It quickly detects and is bonded directly to DNA damage site, induced aggregation DNA repairs required multiple protein later, and then DNA is made to damage
Wound is repaired.When the PARP-1 in cell lacks, PARP-2 can substitute the reparation that PARP-1 realizes DNA damage.Research
Show compared with normal cell, expression of the PARPs albumen in solid tumor generally enhances.In addition, repairing dependency basis for DNA
Because of the tumour (such as tumor of breast and oophoroma) of missing (such as BRCA-1 or BRCA-2), show to the extreme of PARP-1 inhibitor
Sensitivity, this show PARP inhibitor as single dose treat it is this be known as triple negative breast cancer in terms of potential use.Meanwhile
Since DNA damage repair mechanism is that tumour cell reply chemotherapeutics and ionizing radiation treatment generate resistance to main machine the affected
System, therefore PARP-1 is considered as an Effective target site for exploring new cancer treatment method.
Early development design PARP inhibitor be using as PARP be catalyzed substrate NAD niacinamide as template, open
Send out its analog.Competitive inhibitor of these inhibitor as NAD competes the catalytic site of PARP with NAD, and then prevents poly-
The synthesis of (ADP- ribose) chain.PARP under not poly- (ADP- ribosylation) modification can not be disintegrated down from DNA damage site,
The protein for causing other to participate in repairing be cannot be introduced into injury site, and then repair process cannot be executed.Therefore, in cell toxicant
Property drug or radiation under the action of, the tumour cell that the presence of PARP inhibitor keeps DNA impaired is finally dead.
In addition, be catalyzed substrate and the NAD that is consumed as PARP, be it is essential during cell synthesis ATP, because
This, under high PARP activity levels, intracellular NAD levels can be remarkably decreased, and then the ATP for influencing intracellular is horizontal.Due to thin
The ATP contents of intracellular are insufficient, and cell cannot achieve the programmed cell death process of ATP dependences, and can only turning to necrosis, this special withers
Die process.During necrosis, a large amount of inflammatory factor can be released, to generate toxicity to other organs and tissue
Effect.Therefore, PARP inhibitor can be used for treatment a variety of diseases related with this mechanism, including neurodegenerative disease
(such as senile dementia, Huntington chorea, Parkinson's disease), diabetes, the complication in ischemic or Ischemia-Reperfusion Injury,
Such as myocardial infarction and acute renal failure, circulation system disease, such as infectious shock and diseases associated with inflammation, such as chronic rheumatism.
It is clinical at present to share 14 in the PARP inhibitor one ground, the wherein AZD2281 of Astrazeneca AB's exploitation in
In December, 2014 is ratified to list through U.S. FDA, and treatment indication is the Patients with Advanced Ovarian Carcinoma to platinum class reagent chemosensitivity.Phase
Pass patent application is WO2002036576, WO2006021801.
Although a series of PARP inhibitor has been disclosed at present, there is still a need for exploitation it is new there is more preferable drug effect, more excellent
The compound of pharmacokinetic property and more hypotoxicity.By unremitting effort, present invention design has structure shown in logical formula (I)
Compound, and find have the effect of that the compound of this class formation shows excellent and effect.
Invention content
One of the objects of the present invention is to provide it is a kind of as lead to new heterocycle and glyoxaline compound shown in formula (I) or its
Pharmaceutically acceptable salt.
The second object of the present invention is to provide above-mentioned heterocycle and glyoxaline compound or its pharmaceutically acceptable salt
Preparation method.
The third object of the present invention be to provide it is a kind of preparing above-mentioned heterocycle and glyoxaline compound or its can pharmaceutically connect
The intermediate for the salt received.
The fourth object of the present invention be to provide it is a kind of preparing above-mentioned heterocycle and glyoxaline compound or its can pharmaceutically connect
The preparation method of the intermediate for the salt received.
The fifth object of the present invention be to provide a kind of intermediate be used to prepare the general formula (I) compound or
The application of its pharmaceutically acceptable salt.
The sixth object of the present invention is to provide a kind of with the heterocycle and glyoxaline compound or its is pharmaceutically acceptable
Pharmaceutical composition of the salt as active constituent.
The seventh object of the present invention is to provide a kind of above-mentioned heterocycle and glyoxaline compound or its is pharmaceutically acceptable
Application of the salt in drug.
It is general formula (I) compound represented as the heterocycle and glyoxaline compound of first aspect present invention：
Wherein, in general formula (I)：
R is hydrogen, halogen, C1-C6Alkoxy or C1-C6Halogenated alkyl；
X, Y, Z one of them be nitrogen, remaining for hydrocarbon or X, Y, Z one of them be hydrocarbon, remaining is nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, C1-C6Alkyl or C1-C6Halogenated alkyl.
It is further preferred that structure provided by the invention such as general formula (I) compound represented, wherein：
R is hydrogen, fluorine, methoxyl group or trifluoromethyl；
X, Y, Z one of them be nitrogen, remaining for hydrocarbon 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, a kind of general formula (I) compound represented, wherein R be hydrogen, halogen,
C1-C3Alkoxy or C1-C3Halogenated alkyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R is hydrogen, fluorine, first
Oxygroup or trifluoromethyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein X and Z are nitrogen, and Y is
Hydrocarbon either X is that nitrogen Y and Z are hydrocarbon or Z is nitrogen, and X and Y are hydrocarbon.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R1For hydrogen, oxygen or
C1-C6Alkyl or C1-C6Halogenated alkyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R1For hydrogen, oxygen or
C1-C3Alkyl or C1-C3Halogenated alkyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R1For hydrogen, oxygen or
Methyl or trifluoromethyl.
In a preferred embodiment of the invention, the heterocycle of the general formula (I) and glyoxaline compound are 4- (3- (piperazines
Piperazine -1- carbonyls) benzyl) (2 hydrogen) the -one class compound of dai piperazine -1 and its officinal salt.
Most preferably, general formula (I) compound represented of the present invention includes for one of following compound (1)~(13)：
Described general formula (I) compound is in tautomer, enantiomter, diastereoisomer, rotamer
Any one or both arbitrary or three mixture.
General formula (I) compound is pharmaceutically acceptable derivative.
General formula (I) compound of the present invention can exist as a pharmaceutically acceptable salt form.
The preparation method of general formula (I) compound represented as second aspect of the present invention, reaction equation are as follows：
Wherein, R, X, Y, Z and M are as defined above；R2For hydroxyl, halogen, diimidazole -1- bases；Its specific steps is such as
Under：
With carboxylic acid (VI) derived from dai piperazine condensation reaction occurs for intermediate (V), generates general formula (I) compound represented.
In one embodiment of the invention, intermediate (V) is prepared by following steps：
Step 1)：With the heterocycle halides replaced containing amino, nitro nucleophilic substitution occurs for mono-protected piperazine, obtains
To intermediate (II)；
Step 2)：Catalytic hydrogen reduction nitro occurs for intermediate (II), obtains intermediate (III)；
Step 3)：Intermediate (III) by with acetic anhydride, trifluoroacetic anhydride, trimethyl orthoformate, carbonyl dimidazoles or folded
Ring-closure reaction occurs for nitrogen compound, obtains intermediate (IV)；
Step 4)：Intermediate (IV) removes amido protecting group, obtains intermediate (V)；
Its reaction equation is as follows：
Wherein, lead to formula (I) in, P be amido protecting group, X, Y, Z one of them be nitrogen, remaining for hydrocarbon or X, Y, Z its
In one to be hydrocarbon, remaining is nitrogen；
M is nitrogen or CR1；
R1For hydrogen, oxygen, methyl or trifluoromethyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein X and Z are nitrogen, and Y is
Hydrocarbon either X is that nitrogen Y and Z are hydrocarbon or Z is nitrogen, and X and Y are hydrocarbon.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R1For hydrogen, oxygen or
C1-C6Alkyl or C1-C6Halogenated alkyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R1For hydrogen, oxygen or
C1-C3Alkyl or C1-C3Halogenated alkyl.
In one embodiment of the invention, a kind of general formula (I) compound represented, wherein R1For hydrogen, oxygen or
Methyl or trifluoromethyl.
Preferably, carboxylic acid (VI) compound represented derived from the dai piperazine is as follows：
Preferably, intermediate (V) compound represented is as follows：
In one embodiment of the invention, the condensing agent used in the condensation reaction is selected from 1,1'- carbonyls
Diimidazole, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride, 2- (7- azos benzotriazole)-N, N, N',
N'- tetramethylurea hexafluorophosphoric acids ester, benzotriazole-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester.
In one embodiment of the invention, the solvent used in the condensation reaction is selected from dichloromethane, second
Acetoacetic ester, dimethyl sulfoxide, tetrahydrofuran, dimethylformamide, dimethylacetylamide, N- methylpyrrolines ketone, acetone.In this hair
In a bright specific embodiment, inorganic base or organic base are added in the condensation reaction.
In one embodiment of the invention, the organic base is selected from triethylamine, diethylamine, diisopropyl second
Amine, piperidines.
In one embodiment of the invention, intermediate (III) by with acetic anhydride, trifluoroacetic anhydride, orthoformic acid
Ring-closure reaction occurs for trimethyl or carbonyl dimidazoles, obtains intermediate (IV).
As the intermediate for preparing heterocycle shown in above-mentioned general formula (I) and glyoxaline compound of third aspect present invention,
For structural formula (V) compound represented：
Wherein, in intermediate (V)：
In one embodiment of the invention, X, Y, Z one of them be nitrogen, remaining for hydrocarbon or X, Y, Z its
In one to 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, alkoxy or halogenated alkyl.
In one embodiment of the invention, X and Z are nitrogen, Y be hydrocarbon either X be nitrogen Y and Z be it is hydrocarbon or
Z is nitrogen, and X and Y are hydrocarbon.
In one embodiment of the invention, R1For hydrogen, oxygen, C1-C6Alkyl or C1-C6Halogenated alkyl.
In one embodiment of the invention, R1For hydrogen, oxygen, C1-C3Alkyl or C1-C3Halogenated alkyl.
In one embodiment of the invention, R1For hydrogen, oxygen or trifluoromethyl.
The preparation of the intermediate of heterocycle shown in above structure formula (V) as fourth aspect present invention and glyoxaline compound
Method, wherein intermediate (V) is prepared by following steps：
Step 1)：With the heterocycle halides replaced containing amino, nitro nucleophilic substitution occurs for mono-protected piperazine, obtains
To intermediate (II)；
Step 2)：Catalytic hydrogen reduction nitro occurs for intermediate (II), obtains intermediate (III)；
Step 3)：Intermediate (III) by with acetic anhydride, trifluoroacetic anhydride, trimethyl orthoformate, carbonyl dimidazoles or folded
Ring-closure reaction occurs for nitrogen compound, obtains intermediate (IV)；
Step 4)：Intermediate (IV) removes amido protecting group, obtains intermediate (V)；
Its reaction equation is as follows：
Wherein, lead to formula (I) in, P be amido protecting group, X, Y, Z one of them be nitrogen, remaining for hydrocarbon or X, Y, Z its
In one to be hydrocarbon, remaining is nitrogen；M is nitrogen or CR1；R1For hydrogen, oxygen, methyl or trifluoromethyl.
In one embodiment of the invention, in step 3), intermediate (III) by with acetic anhydride, trifluoro second
Ring-closure reaction occurs for acid anhydrides, trimethyl orthoformate or carbonyl dimidazoles, obtains intermediate (IV).
The intermediate of general formula (V) as fifth aspect present invention is used to prepare answering for the compound of the general formula (I)
With.
As the Pharmaceutical composition of sixth aspect present invention, including constituting the general formula (I) of the therapeutically effective amount of active constituent
Compound or its pharmaceutically acceptable salt and one or more medicinal carrier substances and/or diluent.
The pharmaceutical composition be made tablet, capsule, aqueous suspension, Oil suspensions, dispersible pulvis,
Granula, pastille, emulsion, syrup, cream, ointment, suppository or injection.
In the pharmaceutical composition, general formula (I) compound exists in a free form.
As the application of seventh aspect present invention, wherein being the general formula (I) compound or its pharmaceutically acceptable salt
Application in preparing the disease medicament that treatment improves by PARP activity suppressions.
As the application of seventh aspect present invention, wherein being that described pharmaceutical composition is preparing treatment because of PARP activity suppressions
And the application in improved disease medicament.
The disease improved by PARP activity suppressions is vascular diseases, septic shock, ischemic injuries, Nervous toxicity
Property, hemorrhagic shock, inflammatory disease or multiple sclerosis, neurodegenerative disorders 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) provide the research conditions of relationship between above-mentioned disease and PARP activity.
As the application of seventh aspect present invention, wherein be the general formula (I) compound prepare it is use for cancer treatment
Application in ancillary drug.
As the application of seventh aspect present invention, wherein being the pharmaceutically acceptable derivative of the general formula (I) compound
Application in preparing the ancillary drug for oncotherapy.
As the application of seventh aspect present invention, wherein being that described pharmaceutical composition is preparing auxiliary use for cancer treatment
Application in drug.
As the application of seventh aspect present invention, wherein being that the general formula (I) compound is being prepared for cancer chemotherapy
Application in drug or reinforcing radiotherapeutic drug.
As the application of seventh aspect present invention, wherein being the pharmaceutically acceptable derivative of the general formula (I) compound
Application in preparing the drug for cancer chemotherapy or strengthening radiotherapeutic drug.
As the application of seventh aspect present invention, wherein being that described pharmaceutical composition is preparing the drug for cancer chemotherapy
Or the application in reinforcing radiotherapeutic drug.
As the application of seventh aspect present invention, wherein being that the general formula (I) compound is preparing shortage homologous recombination
(HR) application in the drug for the individuation treatment of cancer that the DNA double chain fracture (DSB) of dependence is repaired.
As the application of seventh aspect present invention, wherein being the pharmaceutically acceptable derivative of the general formula (I) compound
Or salt is in the drug for preparing the individuation treatment of cancer that the DNA double chain fracture (DSB) for lacking homologous recombination (HR) dependence is repaired
In application.
As the application of seventh aspect present invention, wherein be described pharmaceutical composition prepare lack homologous recombination (HR) according to
Rely the application in the drug of the individuation treatment of cancer of DNA double chain fracture (DSB) reparation of property.
Preferably, the DNA double chain fracture restoration approach of homologous recombination (HR) dependence of the cancer is defect
's.
Preferably, the cancer is the ability containing one or more DSB by HR DNA plerosis relative to normal
Cell and the cancer of cancer cell for lowering or losing.
Preferably, the cancer is with BRCA-1 or BRCA-2 defects, the cancer of mutant phenotype.
It is highly preferred that the cancer is BRCA-1 or/and BRCA-2 defects, the cancer of mutation.
Preferably, the cancer be breast cancer, oophoroma, cancer of pancreas or prostate cancer, the carcinoma of the rectum, colon cancer or
Liver cancer.
In order to examine compound provided by the invention for the exposure level of PARP enzymes, tested using biochemistry level enzymatic activity
To determine activity of the various compounds to PARP enzymes of the present invention.
PARP is a kind of posttranscriptional modification enzyme, and DNA damage can activate the enzyme, the catalytic process of PARP to be in vivo mainly
A kind of poly (ADP-ribose) process that NAD is relied on, substrate are mainly some nucleoprotein including PARP,
Histone is one of which, and the present invention is by measuring PARP under NAD effects to being coated in Histone poly in 96 orifice plates
(ADP-ribose) degree, measures PARP activity, PARP activity after the effect of PARP inhibitor is correspondingly measured, to evaluate such
Compound is to the active inhibition levels of PARP.
Specific implementation mode
It is used to further describe the present invention with reference to embodiments, but these embodiments are not to limit the model of the present invention
It encloses.
Test method without specific conditions in the embodiment of the present invention, usually according to normal condition, or according to raw material or
Condition proposed by commodity manufacturer.The reagent in specific source is not specified, for the conventional reagent of market purchase.
Unless stated to the contrary, following that there are following meanings with term in the specification and in the claims.
In the present invention, term " C1-C6Alkyl " refers to having linear chain or branched chain part and containing the saturation of 1 to 6 carbon atom
Monovalent hydrocarbon.The example of such group includes but not limited to methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group and tertiary fourth
Base.
Term " C1-C6Halogenated alkyl " refers to linear chain or branched chain part and containing the saturation monovalent hydrocarbon of 1 to 6 carbon atom
Middle hydrogen moiety is all substituted with halogen atoms the compound to be formed.
Term " C1-C6Alkoxy " refers to the connected linear chain or branched chain part of oxygen atom and full containing 1 to 6 carbon atom
And monovalent hydrocarbon.Including but not limited to methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, isobutoxy, tertiary fourth oxygen
Base.
Term " enantiomter " refers to the stereoisomer of mirror each other.
Term " diastereoisomer ", which refers to molecule, has two or more chiral centres, and intermolecular for non-mirror image pass
The stereoisomer of system.
Term " rotamer " refers to the isomers that organic molecule is generated by singly-bound rotation.
Term " tautomer " refers to that the structure of certain organic compounds generates balance between two kinds of functional isomers
Mutually the phenomenon that conversion, corresponding isomers becomes tautomer.
Term " mesomer " refers to the atom that intramolecular contains asymmetry, but is formed not due to symmetrical factor
Optically active compounds.
Term " racemic modification " refers to a kind of equimolar mixture of tool active chiral molecules and its enantiomer.
Term " metabolite and metabolite precursor or prodrug " refers to the substance for generating or consuming by metabolic process；Before
Medicine refers to the compound that drug is obtained through modifying for chemical structure, and in vitro without activity, original is converted into organism or human body
Come drug and play drug effect.
Term " derivative " refers to atom in compound or group to be replaced and derivative more multiple by other atoms or group
Miscellaneous product.
Term " therapeutically effective amount " refers to any amount for realizing required biological respinse.
Term " halogen " and " halogenated " refer to F, Cl, Br, I.
" pharmaceutical composition " refers to one or more of compound in the present invention and other chemical composition, such as pharmacy
Upper acceptable carrier, mixing.The purpose of pharmaceutical composition is to promote administration to the process of animal.
" pharmaceutical carrier " refers to not causing apparent irritation to organism and does not interfere the biology of given compound
Non-active ingredient in the pharmaceutical composition of activity and property, such as, but not limited to：Calcium carbonate, calcium phosphate, it is various sugar (such as breast
Sugar, mannitol etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylate copolymer or methacrylic polymeric
Object, gel, water, polyethylene glycol, propylene glycol, ethylene glycol, castor oil or rilanit special or more ethoxy aluminium castor oil, sesame
Oil, corn oil, peanut oil etc..
In pharmaceutical composition above-mentioned, other than including pharmaceutically acceptable carrier, medicine (agent) can also be included in
Upper common adjuvant, such as：Antibacterial agent, antifungal agent, antimicrobial, preservative, toner, solubilizer, thickener, table
Face activating agent, complexing agent, protein, amino acid, fat, carbohydrate, vitamin, minerals, trace element, sweetener, pigment, perfume (or spice)
Essence or their combination etc..
A kind of application the invention discloses compound and the compound as poly- (ADP- ribose) polymerase inhibitors, this
Field technology personnel can use for reference present disclosure, be suitably modified technological parameter realization.In particular, it should be pointed out that all similar
Replace and change apparent to those skilled in the art, they are considered as being included in the present invention.The present invention's
Method and application are described by preferred embodiment, and related personnel can obviously not depart from the content of present invention, spirit
Method described herein and application are modified or are suitably changed and combined in range, to realize and apply skill of the present invention
Art.
With reference to embodiment, the present invention is further explained：
Prepare embodiment
The structural formula of compound is by nuclear magnetic resonance (NMR) or/and mass spectrum (MS) come what is determined.NMR displacements (δ) are with 10-6
(ppm) unit provides.Measurement solvent is deuterated methanol, deuterated dimethyl sulfoxide, deuterochloroform, is inside designated as tetramethylsilane.
The measurement of MS is with LC-MS mass spectrograph (manufacturer：Shimadzu, model：LCMS-2020)
The known starting material of the present invention may be used or be synthesized according to methods known in the art, or can be from commercially available
It is directly bought in product.
Embodiment 1
Compound (1)：4- (3- (4- (9 hydrogen-purine -6- bases) piperazine -1- carbonyls) -4- luorobenzyls) dai piperazine -1 (dihydro) -
The preparation of ketone, specific reaction equation are as follows：
Step 1：The preparation of the chloro- 5- nitro-pyrimidines -4- amine of 6-
It will be dissolved with addition ammonia in the tetrahydrofuran (100mL) of bis- chloro- 5- nitro-pyrimidines (9.7g, 50mmol) of compound 4,6-
Water (100mL) and sodium bicarbonate (4.6g, 55mmol), are heated to 55 DEG C and are stirred overnight.Above-mentioned reaction system is cooled to room temperature, and is subtracted
Pressure removes organic solvent, and (dichloromethane is detached through rapid column chromatography after residue filtering：Methanol=100：1) white solid is obtained
Compound a：The chloro- 5- nitro-pyrimidines -4- amine of 6- (8.1g, yield 93%).MS(ESI)m/z:[M+H]+=175.
Step 2：The preparation of 4- (6- amino -5- nitro-pyrimidine -4- bases) piperazine -1- t-butyl carbonates
In the dimethylformamide (10mL) that piperazine (1.86g, 10mmol) will be protected dissolved with compound list tertbutyloxycarbonyl
Compound a (1.91g, 11mmol) and diisopropyl ethyl amine (1.55g, 12mmol) is added, room temperature reaction is depressurized after 8 hours and removed
Solvent, residue is gone to detach (dichloromethane through rapid column chromatography：Methanol=50：1) compound as white solid b is obtained：4- (6- ammonia
Base -5- nitro-pyrimidine -4- bases) piperazine -1- t-butyl carbonates (2.82g, yield 87%).MS(ESI)m/z:[M+H]+=325.
Step 3：The preparation of 4- (5,6- di-amino-pyrimidine -4- bases) piperazine -1- t-butyl carbonates
10% palladium carbon (282mg) is added dissolved in methanol (20mL) solution of compound b (2.82g, 8.7mmol), often
The lower hydrogenation of temperature 7 hours, filtering, residue detaches (dichloromethane through rapid column chromatography：Methanol=10：1) yellow solid is obtained
Close object c：4- (5,6- di-amino-pyrimidine -4- bases) piperazine -1- t-butyl carbonates (2.34g, yield 91%).MS(ESI)m/z:[M+
H]+=295.
Step 4：The preparation of 4- (9 hydrogen-purine -6- bases) piperazine -1- t-butyl carbonates
It is added to toluene sulphur in the trimethyl orthoformate solution (6g) dissolved with compound c (2.34g, 7.9mmol)
Sour (86mg, 0.5mmol) is warming up to reflux, reacts 8 hours postcoolings, solvent is removed under reduced pressure, residue is through rapid column chromatography point
From (dichloromethane：Methanol=10：1) faint yellow solid compound d is obtained：4- (9 hydrogen-purine -6- bases) tertiary fourth of piperazine -1- carbonic acid
Ester (1g, yield 43%).MS(ESI)m/z:[M+H]+=305.
Step 5：The preparation of 6- (piperazine -1- bases) -9 hydrogen-purine
Trifluoroacetic acid is added in a dichloromethane solution (10mL) dissolved with compound d (1g, 3.3mmol)
Solvent is removed under reduced pressure in (2.28g, 20mmol), room temperature reaction after 8 hours, residue is dissolved with dichloromethane (20mL), and carbon is added
For sour hydrogen sodium until pH=8, concentration remove solvent, residue detaches (dichloromethane through rapid column chromatography：Methanol=10：1) it obtains
Faint yellow solid compound e：6- (piperazine -1- bases) -9 hydrogen-purine (0.56g, yield 83%).MS(ESI)m/z:[M+H]+=
205。
Step 6：The preparation of the fluoro- 4- of 2- ((3- oxos isobenzofuran -1 (3 hydrogen)-subunit) methyl) benzene cyanogen
Under ice bath, Asia is slowly added in an absolute methanol solution (1L) dissolved with sodium methoxide (61.8g, 1.14mol)
Dimethyl phosphate (97mL, 1.06mol).It keeps temperature of reaction system to be less than in 5 DEG C, 20 minutes and 2- carboxyl benzaldehydes is slowly added dropwise
(135g, 0.9mol).Above-mentioned reaction system is gradually increased to room temperature, and be gradually added dropwise within half an hour pyrovinic acid (81.6mL,
1.26mol).After solvent is removed under reduced pressure, residue is diluted with water (600mL), and dichloromethane (500mL) extraction is used in combination three times.It closes
And organic phase, it is used in combination water (100mL) to be extracted twice, organic phase is dried with anhydrous magnesium sulfate.Be removed under reduced pressure solvent obtain it is faint yellow
Different furans -1- bases the dimethylphosphite of solid chemical compound 3- oxo -1,3- dihydrobenzos, it is not purified to direct plunge into next step instead
It answers.The not purified different furans -1- bases dimethylphosphite of compound 3- oxo -1,3- dihydrobenzos will be reacted dissolved with upper step
The fluoro- 5- formoxyls benzene cyanogen (20.9g, 0.14mol) of 2-, system are added in the tetrahydrofuran solution (330mL) of (35g, 0.14mol)
15 DEG C are cooled to, triethylamine (19.5mL, 0.14mol) is slowly added dropwise in 30 minutes.Above-mentioned reaction system is gradually increased to room temperature, subtracts
Pressure removes solvent, and residue is beaten with water (250mL), and compound as white solid f is obtained by filtration：The fluoro- 4- of 2- ((the different benzene of 3- oxos
And furans -1 (3 hydrogen)-subunit) methyl) benzene cyanogen (37.2g, yield 96%).
Step 7：The preparation of the fluoro- 5- of 2- ((4- oxo -3,4- dihydro dai piperazine -1- bases) methyl) benzoic acid
13N sodium hydroxide solutions are added in an aqueous solution (200mL) dissolved with compound f (37g, 0.14mol)
(50mL) is warming up to 90 DEG C and stirs 1 hour.Hydrazine hydrate (100mL, 2mol) is added after above-mentioned reaction system is down to 70 DEG C, protects
The temperature is held to stir 18 hours.Reaction solution is cooled to room temperature, and above-mentioned system is adjusted to pH=4, filtering, filter cake using the hydrochloric acid of 8N
It is washed twice successively with water (60mL), ether (50mL) washs three times, and vacuum drying obtains compound as white solid g：The fluoro- 5- of 2-
((4- oxo -3,4- dihydro dai piperazine -1- bases) methyl) benzoic acid (30.1g, yield 77%).MS(ESI)m/z:[M+H]+=
299。
Step 8：4- (3- (4- (9 hydrogen-purine -6- bases) piperazine -1- carbonyls) -4- luorobenzyls) dai piperazine -1 (dihydro) -one
It prepares
Compound e is added in a dimethyl formamide solution (5mL) dissolved with compound g (168mg, 0.56mmol)
(127mg, 0.62mmol), 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester (258mg,
0.68mmol) with triethylamine (234mg, 2.32mmol), it is stirred overnight at room temperature.Concentration removes solvent, and residue is through flash column
Analysis separation (dichloromethane：Methanol=10：1) compound as white solid (1) is obtained：4- (3- (4- (9 hydrogen-purine -6- bases) piperazines -
1- carbonyls) -4- luorobenzyls) dai piperazine -1 (dihydro) -one (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- carbonyls) -4- luorobenzyls) dai
The preparation of piperazine -1 (dihydro) -one, specific reaction equation are as follows：
Step 1：The preparation of 4- (4- amino -3- nitropyridine -2- bases) piperazine -1- t-butyl carbonates
Using the similar methods of 1 step 2 prepare compound b of embodiment, piperazine is protected by compound list tertbutyloxycarbonyl
Nucleophilic substitution occurs with the chloro- 3- nitros of 2- -4-aminopyridine, compound h is made：4- (4- amino -3- nitropyridines -2-
Base) piperazine -1- t-butyl carbonates (0.8g, yield 82%).MS(ESI)m/z:[M+H]+=324.
Step 2：The preparation of 4- (3,4- diamino-pyridine -2- bases) piperazine -1- t-butyl carbonates
Using the similar methods of 1 step 3 prepare compound c of embodiment, catalytic hydrogenation is occurred by compound h and is made
Compound i：4- (3,4- diamino-pyridine -2- bases) piperazine -1- t-butyl carbonates (0.7g, yield 100%).MS(ESI)m/z:
[M+H]+=294.
Step 3：The preparation of 4- (1 hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1- t-butyl carbonates
Using the similar methods of 1 step 4 prepare compound d of embodiment, pass through compound i and trimethyl orthoformate initial ring
Close compound of reaction j：4- (3,4- diamino-pyridine -2- bases) piperazine -1- t-butyl carbonates (0.5g, yield 74%).MS(ESI)
m/z:[M+H]+=304.
Step 4：The preparation of 4- (piperazine -1- bases) -1 hydrogen-imidazo [4,5-c] pyridine
Using the similar methods of 1 step 5 prepare compound e of embodiment, removing is occurred by compound j and trifluoroacetic acid and is protected
It protects base reaction and compound k is made：4- (piperazine -1- bases) -1 hydrogen-imidazo [4,5-c] pyridine (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- carbonyls) -4- luorobenzyls) dai piperazine -1
The preparation of (dihydro) -one
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound g and compound k
Compound (2) is made in reaction：4- (3- (4- (1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine -1- carbonyls) -4- luorobenzyls) dai
Piperazine -1 (dihydro) -one (16mg, yield 20%).MS(ESI)m/z:[M+H]+=484.1H NMR(300MHz,DMSO-d6):δ
12.65 (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- carbonyls) -4- luorobenzyls) dai
The preparation of piperazine -1 (dihydro) -one, specific reaction equation are as follows：
Step 1：The preparation of the chloro- 3- nitros -2-aminopyridine of 4-
Under ice bath, compound 4-chloro -2-aminopyridine (6.4g, 50mmol) is slowly added in fuming nitric aicd (50mL).
Above-mentioned reaction system is gradually increased to room temperature, pours into the water containing trash ice, and (dichloro is detached through rapid column chromatography after residue filtering
Methane：Methanol=100：1) compound as white solid l is obtained：The chloro- 3- nitros -2-aminopyridine (7.4g, yield 85%) of 4-.MS
(ESI)m/z:[M+H]+=174.
Step 2：The preparation of 4- (2- amino -3- nitropyridine -4- bases) piperazine -1- t-butyl carbonates
Using the similar methods of 1 step 2 prepare compound b of embodiment, piperazine is protected by compound list tertbutyloxycarbonyl
Nucleophilic substitution occurs with compound l, compound m is made：4- (2- amino -3- nitropyridine -4- bases) piperazine -1- carbonic acid uncles
Butyl ester (0.8g, yield 88%).MS(ESI)m/z:[M+H]+=324.
Step 3：The preparation of 4- (2,3 diamino pyridine -4- bases) piperazine -1- t-butyl carbonates
Using the similar methods of 1 step 3 prepare compound c of embodiment, catalytic hydrogenation is occurred by compound m and is made
Compound n：4- (2,3- diamino-pyridine -4- bases) piperazine -1- t-butyl carbonates (0.7g, yield 93%).MS(ESI)m/z:[M
+H]+=294.
Step 4：The preparation of 4- (3 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine -1- t-butyl carbonates
Using the similar methods of 1 step 4 prepare compound d of embodiment, pass through compound n and trimethyl orthoformate initial ring
Close compound of reaction o：4- (3 hydrogen-imidazo [4,5-b] pyridin-7-yl) piperazine -1- t-butyl carbonates (0.4g, yield 67%).
MS(ESI)m/z:[M+H]+=304.
Step 5：The preparation of 7- (piperazine -1- bases) -3 hydrogen-imidazo [4,5-b] pyridine
Using the similar methods of 1 step 5 prepare compound e of embodiment, removing is occurred by compound o and trifluoroacetic acid and is protected
It protects base reaction and compound p is made：7- (piperazine -1- bases) -3 hydrogen-imidazo [4,5-b] pyridine (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- carbonyls) -4- luorobenzyls) dai piperazine -1
The preparation of (dihydro) -one
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound g and compound p
Compound (3) is made in reaction：4- (3- (4- (1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine -1- carbonyls) -4- luorobenzyls) dai
Piperazine -1 (dihydro) -one (35mg, yield 16%).MS(ESI)m/z:[M+H]+=484.1H NMR(300MHz,DMSO-d6):δ
12.78 (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-1s hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1- carbonyls
Base) benzyl) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Step 1：The preparation of 4- (- 3 hydrogen of 2- methyl-imidazo [4,5-c] pyridin-4-yl) piperazine -1- t-butyl carbonates
Be added in the acetic acid solution (30mL) dissolved with compound i (1.47g, 5mmol) acetic anhydride (0.56g,
5.5mmol), it is warming up to reflux, reacts 8 hours postcoolings, solvent is removed under reduced pressure, residue detaches (dichloro through rapid column chromatography
Methane：Methanol=10：1) faint yellow solid compound q is obtained：4- (- 3 hydrogen of 2- methyl-imidazo [4,5-c] pyridin-4-yl) piperazine
Piperazine -1- t-butyl carbonates (0.73g, yield 47%).MS(ESI)m/z:[M+H]+=318.
Step 2：The preparation of 2- methyl -4- (piperazine -1- bases) -3 hydrogen-imidazo [4,5-c] pyridine
Using the similar methods of 1 step 5 prepare compound e of embodiment, removing is occurred by compound q and trifluoroacetic acid and is protected
It protects base reaction and compound r is made：2- methyl -4- (piperazine -1- bases) -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-1s hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1- carbonyls) benzyls
Base) dai piperazine -1 (dihydro) -one preparation
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound g and compound r
Compound (4) is made in reaction：4- (the fluoro- 3- of 4- (4- (2- methyl-1s hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1- carbonyls
Base) benzyl) dai piperazine -1 (dihydro) -one (48mg, yield 41%).MS(ESI)m/z:[M+H]+=498.1H NMR(300MHz,
DMSO-d6):δ 12.63 (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-1s hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1-
Carbonyl) benzyl) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Step 1：The system of 4- (- 3 hydrogen of 2- trifluoromethyls-imidazo [4,5-c] pyridin-4-yl) piperazine -1- t-butyl carbonates
It is standby
Trifluoroacetic anhydride is added in a trifluoroacetic acid solution (30mL) dissolved with compound i (1.47g, 5mmol)
(1.16g, 5.5mmol) is warming up to reflux, reacts 8 hours postcoolings, solvent is removed under reduced pressure, residue is through rapid column chromatography point
From (dichloromethane：Methanol=10：1) faint yellow solid compound s is obtained：4- (- 3 hydrogen of 2- trifluoromethyls-imidazo [4,5-c]
Pyridin-4-yl) piperazine -1- t-butyl carbonates (0.58g, yield 34%).MS(ESI)m/z:[M+H]+=372.
Step 2：The preparation of 4- (piperazine -1- bases) -3 hydrogen of -2- trifluoromethyls-imidazo [4,5-c] pyridine
Using the similar methods of 1 step 5 prepare compound e of embodiment, removing is occurred by compound s and trifluoroacetic acid and is protected
It protects base reaction and compound t is made：4- (piperazine -1- bases) -3 hydrogen of -2- trifluoromethyls-imidazo [4,5-c] pyridine (196mg, yield
85%).MS(ESI)m/z:[M+H]+=272.
Step 3：4- (the fluoro- 3- of 4- (4- (2- Trifluoromethyl-1s hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1- carbonyls
Base) benzyl) dai piperazine -1 (dihydro) -one preparation
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound g and compound t
Compound (5) is made in reaction：4- (the fluoro- 3- of 4- (4- (2- Trifluoromethyl-1s hydrogen-imidazo [4,5-c] pyridin-4-yl) piperazine -1-
Carbonyl) benzyl) dai piperazine -1 (dihydro) -one (31mg, yield 44%).MS(ESI)m/z:[M+H]+=552.1H NMR(300MHz,
DMSO-d6):δ 12.71 (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- carbonyls) -4- fluorine
Benzyl) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Step 1：The preparation of 4- (3 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine -1- t-butyl carbonates
Be added in the acetic acid solution (30mL) dissolved with compound i (1.76g, 6mmol) sodium nitrite (0.42g,
6mmol), it is warming up to reflux, reacts 8 hours postcoolings, solvent is removed under reduced pressure, residue detaches (dichloromethane through rapid column chromatography
Alkane：Methanol=10：1) faint yellow solid compound u is obtained：4- (3 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine-
1- t-butyl carbonates (1.3g, yield 83%).MS(ESI)m/z:[M+H]+=305.
Step 2：The preparation of 4- (piperazine -1- bases) -3 hydrogen-[1,2,3] triazole [4,5-c] piperidines
Using the similar methods of 1 step 5 prepare compound e of embodiment, removing is occurred by compound u and trifluoroacetic acid and is protected
It protects base reaction and compound v is made：4- (piperazine -1- bases) -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- carbonyls) -4- luorobenzyls)
The preparation of dai piperazine -1 (dihydro) -one
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound g and compound v
Compound (6) is made in reaction：4- (3- (4- (1 hydrogen-[1,2,3] triazole [4,5-c] pyridin-4-yl) piperazine -1- carbonyls) -4- fluorine
Benzyl) dai piperazine -1 (dihydro) -one (28mg, yield 38%).MS(ESI)m/z:[M+H]+=485.1H NMR(300MHz,DMSO-
d6):δ 12.66 (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- (- 1 hydrogen of 2- oxo -2,3- dihydros-imidazo [4,5-c] pyridin-4-yl) piperazines
Piperazine -1- carbonyls) benzyl) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Step 1：4- (- 1 hydrogen of 2- oxo -2,3- dihydros-imidazo [4,5-c] pyridin-4-yl) piperazine -1- t-butyl carbonates
Preparation
Two miaow of carbonyl is added in an anhydrous tetrahydrofuran solution (20mL) dissolved with compound i (1.47g, 5mmol)
Azoles (1.62g, 10mmol) is warming up to reflux, reacts 8 hours postcoolings, solvent is removed under reduced pressure, residue is through rapid column chromatography point
From (dichloromethane：Methanol=10：1) faint yellow solid compound w is obtained：4- (- 1 hydrogen of 2- oxo -2,3- dihydros-imidazo [4,
5-c] pyridin-4-yl) piperazine -1- t-butyl carbonates (1.3g, yield 86%).MS(ESI)m/z:[M+H]+=320.
Step 2：The preparation of 4- (piperazine -1- bases) -1 hydrogen-imidazo [4,5-c] pyridine -2 (3 hydrogen) -one
Using the similar methods of 1 step 5 prepare compound e of embodiment, removing is occurred by compound w and trifluoroacetic acid and is protected
It protects base reaction and compound x is made：4- (piperazine -1- bases) -1 hydrogen-imidazo [4,5-c] pyridine -2 (3 hydrogen) -one (171mg, yield
69%).MS(ESI)m/z:[M+H]+=220.
Step 3：4- (the fluoro- 3- of 4- (4- (- 1 hydrogen of 2- oxo -2,3- dihydros-imidazo [4,5-c] pyridin-4-yl) piperazines -
1- carbonyls) benzyl) dai piperazine -1 (dihydro) -one preparation
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound g and compound x
Compound (7) is made in reaction：4- (the fluoro- 3- of 4- (4- (- 1 hydrogen of 2- oxo -2,3- dihydros-imidazo [4,5-c] pyridin-4-yl) piperazines
Piperazine -1- carbonyls) benzyl) dai piperazine -1 (dihydro) -one (37mg, yield 49%).MS(ESI)m/z:[M+H]+=500.1H NMR
(300MHz,DMSO-d6):δ 12.63 (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- carbonyls) -4- methoxybenzyls
Base) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Step 1：The preparation of the bromo- 4- methoxyl methyl benzoates of 3-
Slowly add at room temperature in an aqueous solution (10mL) dissolved with 4- methoxyl methyl benzoates (1.5g, 9mol)
Enter potassium bromate (251mg, 1.5mmol) and bromine (722mg, 4.5mmol).Keep less than 30 DEG C stirrings 2.5 of temperature of reaction system
Hour.Methyl tertiary butyl ether(MTBE) (25mL) is added in above-mentioned reaction system, organic phase saturated common salt water washing after extraction is dry dense
Contracting gained residue detaches (petroleum ether through rapid column chromatography：Ethyl acetate=10：1) compound as white solid y is obtained：3- is bromo-
4- methoxyl methyl benzoates (2.1g, yield 95%).
Step 2：The preparation of 3- cyano -4- methoxyl methyl benzoates
Cuprous cyanide is added in a dimethyl formamide solution (10mL) dissolved with compound y (1.1g, 4.4mol)
(1.2g, 13.22mmol).140 DEG C are heated to stir 6 hours.Ethyl acetate (25mL) is added after above-mentioned reaction system is cooled down,
Organic phase saturated common salt water washing after extraction, dry concentration gained residue detach (petroleum ether through rapid column chromatography：Acetic acid second
Ester=10：1) compound as white solid z is obtained：3- cyano -4- methoxyl methyl benzoates (662mg, yield 79%).
Step 3：The preparation of 5- (methylol) -2- methoxybenzene cyanogen
Be added in the tetrahydrofuran solution (25mL) dissolved with compound z (1g, 5.2mol) lithium borohydride (0.45g,
20.7mmol).It is stirred overnight at room temperature.Above-mentioned reaction system is dried and is concentrated, gained residue detaches (stone through rapid column chromatography
Oily ether：Ethyl acetate=2：1) compound as white solid a ' is obtained：5- (methylol) -2- methoxybenzenes cyanogen (845mg, yield
100%).
Step 4：The preparation of 5- formoxyl -2- methoxybenzene cyanogen
At one dissolved with compound a ' (1,1,1- tri- second is added in the dichloromethane solution (50mL) of (845mg, 5.2mol)
Acyl group) -1,1- dihydros -1,2- benzenesulfonyl -3 (1 hydrogen) -one (2.6g, 6.2mmol).It stirs 2 hours at room temperature.By above-mentioned reaction
System drying concentration, gained residue detach (petroleum ether through rapid column chromatography：Ethyl acetate=3：1) white solid chemical combination is obtained
Object b '：5- formoxyl -2- methoxybenzenes cyanogen (845mg, yield 100%).
Step 5：The preparation of 2- methoxyl groups -5- ((3- oxos isobenzofuran -1 (3 hydrogen)-subunit) methyl) benzene cyanogen
Using the similar methods of 1 step 6 prepare compound f of embodiment, pass through compound b ' and 3- oxo -1,3- dihydrobenzenes
And different furans -1- base dimethylphosphites react obtained compound c '：2- methoxyl groups -5- ((3- oxos isobenzofurans -1
(3 hydrogen)-subunit) methyl) benzene cyanogen (795mg, yield 67%).
Step 6：The preparation of 2- methoxyl groups -5- ((4- oxo -3,4- dihydro dai piperazine -1- bases) methyl) benzoic acid
Using the similar methods of 1 step 7 prepare compound g of embodiment, hydrolysis obtainedization is occurred by compound c '
Close object d '：2- methoxyl groups -5- ((4- oxo -3,4- dihydro dai piperazine -1- bases) 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- carbonyls) -4- methoxy-benzyls) dai
The preparation of piperazine -1 (dihydro) -one
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound d ' and compound k
Compound (8) is made in reaction：4- (3- (4- (1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine -1- carbonyls) -4- methoxybenzyls
Base) 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- bases) piperazine -1- carbonyls) -4- methoxy-benzyls) dai piperazine -1 (two
Hydrogen) -one preparation, specific reaction equation is as follows：
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound d ' and compound e
Compound (9) is made in reaction：4- (3- (4- (9 hydrogen-purine -6- bases) piperazine -1- carbonyls) -4- methoxy-benzyls) dai piperazine -1 (two
Hydrogen) -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- carbonyls) benzyl) dai piperazine -1
The preparation of (dihydro) -one, specific reaction equation are as follows：
Step 1：The preparation of 3- (- 1 hydrogen of 1,3- dioxo -2,3- dihydros-indenes -2- bases) benzene cyanogen
Under ice bath, one dissolved with isobenzofuran -1 (3 hydrogen) -one (51g, 0.38mol) and tricyano benzaldehyde (52g,
The methanol solution dissolved with 25% sodium methoxide is slowly added in ethyl propionate solution (200mL) 0.39mol) in 40 minutes
(320mL).Temperature of reaction system is kept to be less than 30 DEG C, above-mentioned reaction system is gradually increased to room temperature and is heated to reflux 1 hour, after
It is continuous that methanol (100mL) is added and stirs 1 hour at reflux.Above-mentioned reaction system is cooled to room temperature, solvent is removed under reduced pressure
Afterwards, residue water (1L) is diluted and is filtered.Filter cake is washed three times with ether (200mL), using acetic acid (110mL) by compound
Acidification.Filtering, filter cake obtain red solid compound e ' after being washed with water (100mL)：3- (1,3- dioxo -2,3- dihydros -1
Hydrogen-indenes -2- bases) benzene cyanogen (69g, yield 94%).
Step 2：The preparation of 3- ((4- oxo -3,4- dihydro dai piperazine -1- bases) methyl) benzoic acid
Using the similar methods of 1 step 7 prepare compound g of embodiment, hydrolysis obtainedization is occurred by compound e '
Close object f '：3- ((4- oxo -3,4- dihydro dai piperazine -1- bases) 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- carbonyls) benzyl) dai piperazine -1 (two
Hydrogen) -one preparation
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound f ' and compound k
Compound (10) is made in reaction：4- (3- (4- (1 hydrogen-imidazoles [4,5-c] pyridin-4-yl) piperazine -1- carbonyls) benzyl) dai piperazine -1
(dihydro) -one (51mg, yield 62%).MS(ESI)m/z:[M+H]+=466.1H NMR(300MHz,DMSO-d6):δ12.57
(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- bases) piperazine -1- carbonyls) benzyl) dai piperazine -1 (dihydro) -one
It prepares, specific reaction equation is as follows：
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound f ' and compound e
Compound (11) is made in reaction：4- (3- (4- (9 hydrogen-purine -6- bases) piperazine -1- carbonyls) 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- carbonyls) -4- methoxybenzyls
Base) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound d ' and compound p
Compound (12) is made in reaction：4- (3- (4- (3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine -1- carbonyls) -4- methoxybenzyls
Base) dai piperazine -1 (dihydro) -one (65mg, yield 41%).MS(ESI)m/z:[M+H]+=496.1H NMR(300MHz,DMSO-
d6):δ 12.80 (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- carbonyls) -4- trifluoromethyls
Benzyl) dai piperazine -1 (dihydro) -one preparation, specific reaction equation is as follows：
Step 1：The preparation of the bromo- 4- trifluoromethyl benzoic acid methyl esters of 3-
One dissolved with the methanol solution (30mL) of the bromo- 4- trifluoromethylbenzoic acids (4.1g, 15.4mol) of 3- in room temperature
Under be slowly added to the concentrated sulfuric acid (1mL).Reaction is heated to 60 DEG C and stirs 6 hours.It is cooled to room temperature, second is added in above-mentioned reaction system
Acetoacetic ester (25mL), organic phase saturated common salt water washing after extraction, dry concentration gained residue are detached through rapid column chromatography
(petroleum ether：Ethyl acetate=10：1) compound as white solid g ' is obtained：(4.2g is received the bromo- 4- trifluoromethyl benzoic acid methyl esters of 3-
Rate 96%).
Step 2：The preparation of 3- cyano -4- trifluoromethyl benzoic acid methyl esters
Using the similar methods of 8 step 2 prepare compound z of embodiment, cyanalation reaction is occurred by compound g ' and is made
Compound h '：3- cyano -4- trifluoromethyl benzoic acid methyl esters (1.6g, yield 64%).MS(ESI)m/z:230[M+1]+。
Step 3：The preparation of 5- (methylol) -2- trifluoromethylbenzene cyanogen
Using the similar methods of 8 step 3 prepare compound a ' of embodiment, reduction reaction obtainedization is occurred by compound h '
Close object i '：5- (methylol) -2- trifluoromethylbenzenes cyanogen (1.2g, yield 87%).MS(ESI)m/z:202[M+1]+。
Step 4：The preparation of 5- formoxyl -2- trifluoromethylbenzene cyanogen
Using the similar methods of 8 step 4 prepare compound b ' of embodiment, reduction reaction obtainedization is occurred by compound i '
Close object j '：5- formoxyl -2- trifluoromethylbenzenes cyanogen (1.3g, yield 96%).MS(ESI)m/z:200[M+1]+。
Step 5：The preparation of 2- trifluoromethyls -5- ((3- oxos isobenzofuran -1 (3 hydrogen)-subunit) methyl) benzene cyanogen
Using the similar methods of 1 step 6 prepare compound f of embodiment, pass through compound j ' and 3- oxo -1,3- dihydrobenzenes
And different furans -1- base dimethylphosphites react obtained compound k '：2- trifluoromethyls -5- ((the different benzo furans of 3- oxos
Mutter -1 (3 hydrogen)-subunit) methyl) benzene cyanogen (721mg, yield 69%).
Step 6：The preparation of 2- trifluoromethyls -5- ((4- oxo -3,4- dihydro dai piperazine -1- bases) methyl) benzoic acid
Using the similar methods of 1 step 7 prepare compound g of embodiment, hydrolysis obtainedization is occurred by compound k '
Close object l '：2- trifluoromethyls -5- ((4- oxo -3,4- dihydro dai piperazine -1- bases) 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- carbonyls) -4- trifluoromethyl benzyls)
The preparation of dai piperazine -1 (dihydro) -one
Using the similar method of 1 step 8 prepare compound (1) of embodiment, it is condensed by compound l ' and compound p
Compound (13) is made in reaction：4- (3- (4- (3 hydrogen-imidazoles [4,5-b] pyridin-7-yl) piperazine -1- carbonyls) -4- trifluoromethyls
Benzyl) dai piperazine -1 (dihydro) -one (54mg, yield 36%).MS(ESI)m/z:[M+H]+=534.1H NMR(300MHz,DMSO-
d6):δ 12.79 (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
Example 1PARP enzyme assays experiment
Experimental principle：
The poly ADP of nucleoprotein is ribosylating be translation when being happened at DNA damage response after.PARP, full name are poly- adenosines
Diphosphonic acid ribose polymerase, in the presence of having NAD, catalysis poly (ADP- ribose) is connected on the nucleoprotein closed on, to draw
Send out the DNA repair mechanisms via base excision repair access.The HT Universal of Trevigen companies production
Chemiluminescent PARP Assay Kit can measure this by the ADP- ribose of biotin labeling and histone
In conjunction with level.
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. plate reader, U.S. Perkin Elmer, EnVision Multilabel Plate Reader.
Solution and buffer solution
1. washing lotion contains the PBS solution of 0.1%Triton X-100.
20X PARP buffer solutions are diluted 20 times and obtain 1X buffer solutions by 2.20X PARP buffer solutions deionized waters, this is slow
Fliud flushing is used to dilution recombination PARP enzymes, PARP Cocktail and tested compound.
3.10X PARP Cocktail prepare 1X PARP Cocktail in accordance with the following methods：10X PARP Cocktail
2.5 μ l/well, 10X activated dna, 2.5 μ l/well, 1X PARP buffer solutions, 20 μ l/well.
4.PARP Enzyme with 1X PARP buffer solutions only before use, carefully dilute recombinase, the enzyme solutions diluted
It to use as early as possible, it is unspent to discard.
5.Strep-HRP only before use, obtain 1X solution again with 1X Strep diluteds Strep-HRP 500.
6. chemiluminescent substrate is only obtained before use, the PeroxyGlow A and B solution of same volume are uniformly mixed
The substrate of horseradish peroxidase.
Experimental method
Compound is prepared
1. each test compound mother liquors of 10mM are diluted to 10 μM, 1 μM with DMSO.
2. only before experiment starts, the gradient concentration solution 1X PARP for being dissolved in each compound in DMSO are slow
Fliud flushing dilutes 20 times, obtains the compound solution of 5X, you can for being detected, positive control (POSITIVE) and negative control
(NEGATIVE) hole is 1X PARP buffer solutions (DMSO contents 5%).Wherein, changed as a contrast using AZD2281 (Olaparib)
Close object.
Operating procedure
1. 50 μ l 1X PARP buffer solutions are added per hole soaks histone, orifice plate is being incubated at room temperature 30 minutes, then by hole
In 1X PARP buffer solutions be sucked out, and residual liquid is patted dry only on paper handkerchief.
2. according to compound (1) to (13) and control compound AZD2281, by the 5X compound solutions diluted addition pair
In the hole answered, per 10 μ l of hole, positive control (POSITIVE) and the hole negative control (NEGATIVE) are 1X PARP buffer solutions
(DMSO contents 5%)
3. PARP enzymes, which are diluted to every 15 μ l solution, with 1X PARP buffer solutions contains 0.5Unit, then in addition to negative right
15 μ l enzyme solutions are added according to other holes other than hole, 1X PARP buffer solutions are only added in negative control hole, and incubation at room temperature orifice plate 10 divides
Clock.
4. in the 1X PARP Cocktail to each hole for continuously adding 25 μ l.
5.27 DEG C are incubated orifice plate 60 minutes.
6. after being incubated, the reaction solution in hole is sucked out, and pat dry residual liquid only on paper handkerchief.Then with containing
The PBS solution of 0.1%Triton X-100 rinses orifice plate 4 times, every time per 200 μ l of hole, and claps residual liquid on paper handkerchief
Totally.
7. next, the 1X Strep-HRP solution diluted is added in every hole, orifice plate 60 is then incubated at 27 DEG C divides
Clock.
8. after being incubated, the reaction solution in hole is sucked out, and pat dry residual liquid only on paper handkerchief.Then with containing
The PBS solution of 0.1%Triton X-100 rinses orifice plate 4 times, every time per 200 μ l of hole, and claps residual liquid on paper handkerchief
Totally.
9. after board-washing, the PeroxyGlow A and B solution of same volume are uniformly mixed, 100 μ l are added per hole, stand
It is put into plate reader record chemiluminescence signal.
Data processing
Reading in per hole needs to be converted into inhibiting rate.The inhibiting rate of compound can be calculated using following equation
Go out：
Note：Positive control wells reading is that the holes positive are read, and meaning is 100% activity of enzyme；Negative control hole is read
The holes negative are read, and meaning is enzyme 0%；Active X is the reading of each concentration of each sample.
Inhibitory activity of 1 compound of table to PARP-1 enzymes
| The number 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 apparent inhibitory activity to the Inhibit proliferaton of PARP-1 enzymes.
Claims (22)
1. heterocycle and glyoxaline compound are I compound represented of general formula or its pharmaceutically acceptable salt：
Wherein, in general formula I：
R is hydrogen, halogen, C1-C6Alkoxy or C1-C6Halogenated alkyl；
X, Y, Z one of them be nitrogen, remaining for hydrocarbon or X, Y, Z one of them be hydrocarbon, remaining is nitrogen；
M is nitrogen or CR1；
R1For hydrogen, C1-C6Alkyl or C1-C6Halogenated alkyl.
2. I compound represented of general formula according to claim 1, wherein：
R is hydrogen, halogen, C1-C3Alkoxy or C1-C3Halogenated alkyl.
3. I compound represented of general formula according to any one of claim 1-2, wherein：
R is hydrogen, fluorine, methoxyl group or trifluoromethyl.
4. I compound represented of general formula according to any one of claim 1-2, wherein：
X and Z is nitrogen, and Y is that hydrocarbon either X is that nitrogen Y and Z are hydrocarbon or Z is nitrogen, and X and Y are hydrocarbon.
5. I compound represented of general formula according to any one of claim 1-2, wherein：
R1For hydrogen, C1-C3Alkyl or C1-C3Halogenated alkyl.
6. I compound represented of general formula according to any one of claim 1-2, wherein：
R1For hydrogen, methyl or trifluoromethyl.
7. I compound represented of general formula according to any one of claim 1-2, wherein chemical combination shown in the general formula I
Object is following compound or its pharmaceutically acceptable salt：
8. a kind of according to any one of claim 1-7 I compounds represented of general formula or its pharmaceutically acceptable salt
Preparation method, reaction equation are as follows：
Wherein, the definition of R, X, Y, Z and M are as described in claim 1；R2 is hydroxyl, halogen, diimidazole -1- bases；Its specific steps
It is as follows：
With dai piperazine class carboxylic acid derivates VI condensation reaction occurs for intermediate V, generates I compound represented of general formula.
9. the preparation method of I compound represented of general formula according to claim 8, wherein the dai piperazine class carboxylic acid derivates
VI compounds represented are as follows：
10. according to the preparation method of any one of claim 8-9 I compounds represented of general formula, wherein the condensation is anti-
The condensing agent used in answering be selected from 1,1'- carbonyl dimidazoles, 1- ethyls-(3- dimethylaminopropyls) carbodiimide hydrochloride,
2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acids ester, benzotriazole-N, N, N', N'- tetramethyl
Urea hexafluorophosphoric acid ester.
11. pharmaceutical composition, wherein described pharmaceutical composition include described in any one of claim 1-7 of therapeutically effective amount
Compound shown in general formula I and one or more pharmaceutically acceptable carrier substances and/or excipient.
12. pharmaceutical composition according to claim 11, wherein tablet, capsule, water is made in the pharmaceutical composition
Property suspension, Oil suspensions, dispersible pulvis, granule, pastille, emulsion, syrup, cream, suppository or injection.
13. pharmaceutical composition according to claim 11, I compound represented of general formula exists in a free form.
14. a kind of I compound represented of general formula as described in any one of claim 1-7 or its pharmaceutically acceptable salt or
Pharmaceutical composition as described in any one of claim 11-13 is preparing the disease medicine treated and improved by PARP activity suppressions
Application in object.
15. being applied according to described in claim 14, the disease improved by PARP activity suppressions is vascular diseases, septic
Shock, ischemia injury, neurotoxicity, hemorrhagic shock, inflammatory disease, multiple sclerosis, neurodegenerative disease or sugar
Urine disease.
16. a kind of I compound represented of general formula as described in any one of claim 1-7 or its pharmaceutically acceptable salt or
Application of the pharmaceutical composition in preparing ancillary drug use for cancer treatment as described in any one of claim 11-13.
17. a kind of I compound represented of general formula as described in any one of claim 1-7 or its pharmaceutically acceptable salt or
Pharmaceutical composition as described in any one of claim 11-13 is preparing chemotherapeutics use for cancer treatment or is strengthening radiotherapy
Application in drug.
18. according to the application described in any one of claim 16-17, wherein the cancer is homologous recombination dependence
The pathway deficiency of DNA double chain fracture restoration.
19. according to the application described in any one of claim 16-17, wherein the cancer include it is one or more relative to
The cancer cell that normal cell is reduced or lost by the ability of the DNA double chain fracture restoration of homologous recombination dependence.
20. according to the application described in any one of claim 16-17, wherein the cancer is to be lacked with BRCA1 or BRCA2
It falls into, the cancer of mutant phenotype.
21. according to the application described in any one of claim 16-17, wherein the cancer lacks for BRCA1 or/and BRCA2
It falls into, the cancer of mutation.
22. according to the application described in any one of claim 16-17, wherein the cancer is breast cancer, oophoroma, pancreas
Gland cancer, prostate cancer, the carcinoma of the rectum, colon cancer or liver cancer.
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| CN104140426A (en) * | 2013-05-07 | 2014-11-12 | 上海汇伦生命科技有限公司 | Pyrimidoimidazole compound and pharmaceutical composition and preparation method and use thereof |
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| CN104003940A (en) * | 2014-06-16 | 2014-08-27 | 华东理工大学 | 2,4-difluoro-5-( phthalazone-1-methyl)-benzoyl piperazine compound and application thereof |
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