CN102532110B - Quinazoline derivative and application of serving as cell apoptosis inhibitor - Google Patents
Quinazoline derivative and application of serving as cell apoptosis inhibitor Download PDFInfo
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- CN102532110B CN102532110B CN201110410902.9A CN201110410902A CN102532110B CN 102532110 B CN102532110 B CN 102532110B CN 201110410902 A CN201110410902 A CN 201110410902A CN 102532110 B CN102532110 B CN 102532110B
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a quinazoline derivative and application of serving as a cell apoptosis inhibitor. In particular, the invention relates to a compound of formula I or pharmaceutically acceptable salt, solvate, ester and prodrug of the compound of formula I, wherein each symbol is as described in specification. The compound of the formula I, disclosed by the invention is an effective cell apoptosis inhibitor and can be used for treating and/or preventing cerebral thrombosis and complications of the cerebral thrombosis.
Description
Technical field
The present invention relates to the pharmaceutic usage of for example terazosin of quinazoline derivant and quinazoline derivant, particularly quinazoline derivant for example terazosin as the purposes in the medicine of apoptosis inhibitor
Background technology
Septicemia (Sepsis) is first cause dead in global intensive care unit.Septicemia it is believed that the abnormal adjusting (Bone et al., 1996) of the inflammation that is a kind of complexity.But many clinical trials of cytokine or anti-inflammatory specificity medicament fail significantly to improve septicemia patient's survival, rethink that the septicemic cemia strategy for the treatment of is necessary.Although effect is limited, antibiotic therapy is the septicemic cemia important channel for the treatment of.Fundamental research shows, inhibited apoptosis is blocking test septicemia effectively.In septicemia patient, the apoptosis of immunocyte can further weaken immunne response.In addition, blocking-up apoptosis has been proved to be a kind of septicemic cemia Critical policies (Braun et al., 1999 of giving treatment to; Hotchkiss et al., 2000; Chung et al., 2001; Weaver et al., 2004; Wesche-Soldato et al., 2005).
Apoptosis is the basic biological phenomena of the one of cell, multicellular organism remove in unwanted or abnormal cell, play a part necessary.It plays an important role in the growth of stable and multiple systems of the evolution of organism, interior environment.Apoptosis is not only a kind of special necrocytosis type, and has important biological significance and complicated the Molecular Biology Mechanism.Apoptosis is the strict process of controlling of polygene.These genes are very conservative between kind, if Bcl-2 family, caspase family, oncogene are as C-myc, cancer suppressor gene P53 etc., along with the development of Protocols in Molecular Biology has had suitable understanding to the process of apoptosis of many kinds, but apoptotic process precise mechanism still imperfectly understands up to now.And the disorder of apoptotic process may be direct or indirect with having of numerous disease relation.People understand the brain death causing due to cerebral thrombosis also with apoptosis-related.In addition the activation that, it is believed that phosphoglycerate kinase 1 (phosphoglycerate kinase 1, referred to as pgk1) contributes to for example treatment or the prevention relevant to apoptosis of some diseases.
Terazosin (Terazosin) is used for clinical conventionally with its hydrochloride, the specification of gone on the market tablet or capsule has 1mg, 2mg and 5mg.Vasocard can be used for treating benign prostate hyperplasia, also can be used for treating hypertension, can be used alone or share as diuretic(s) or Alpha 1 adrenergic blocking agent with other antihypertensive drug.For existing clinical indication, terazosin is 1～10mg for the per daily dose usual range of being grown up.Terazosin is used for the treatment of benign prostatic hyperplasia (BPH), and after medication, benign prostate hyperplasia shape alleviates that to block caused smooth muscle loosening relevant with urine flow velocity improvement and the alpha 1 adrenergic receptor in neck of urinary bladder and prostate gland.Because there is relatively few alpha 1 adrenergic receptor in body of urinary bladder, therefore terazosin can alleviate the obstruction of bladder outlet and not affect the contraction of bladder.In addition, thus terazosin makes Blood pressure drop by reducing total peripheral vascular resistance.It is mainly caused by alpha 1 adrenergic receptor blocking-up that the vasorelaxation of terazosin, Blood pressure drop effect seem.
Up to now, still lack clinically effective apoptosis inhibitor, the novel anti-apoptotic compound of exploitation is for for example treating and/or preventing septicemia and complication thereof, and cerebral apoplexy septicemia and complication thereof are noticeable goals in research.
Summary of the invention
The object of this invention is to provide the novel method and the novel targets that treat and/or prevent septicemia and complication thereof.The inventor is surprisingly found out that, a class quinazoline derivant for example clinical for benign prostate hyperplasia and hypertensive medicine terazosin separately or can effectively treat and/or prevent septicemia and complication thereof with antibiotic combinations.The present invention is based on this discovery and be accomplished.
summary of the invention
First aspect present invention relates to formula I compound,
Or its pharmacologically acceptable salts, solvate, ester, prodrug, wherein
R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl group-, C
1-6alkyl acyl-, aryl-acyl-, C
6-10aryl-, C
5-6cycloalkyl-, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 5-or 6-ring, wherein said alkyl is optionally selected from following substituting group by 1-3 and replaces: hydroxyl, halogen;
R
2and R
3be selected from independently of one another H, halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, CN, NO
2, NH
2, OH, C
1-6alkoxyl group-, C
1-6alkoxy-C
1-6alkoxyl group-, C
1-6alkyloyl oxygen base-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6alkyl acyl-, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit's carbocyclic ring or heterocycle;
R
4and R
5be selected from independently of one another H, halogen, CN, NO
2, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl group-, C
1-6alkyloyl oxygen base-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl group-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclyloxy base-, C
1-6alkyl acyl.
Second aspect present invention relate to formula I compound for example terazosin preparation as the purposes in the medicine of apoptosis inhibitor, for example terazosin is in preparation as the purposes in the medicine of pgk1 activator for formula I compound, or for example terazosin of formula I compound treats and/or prevents the purposes in the medicine of septicemia and complication thereof in preparation.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises for example terazosin of formula I compound or its pharmacologically acceptable salts or the solvate that treat and/or prevent significant quantity, and optional pharmaceutically acceptable carrier.
Fourth aspect present invention provides a kind of medicine box product, comprising for example terazosin of formula I compound or its pharmacologically acceptable salts or the solvate that treat and/or prevent significant quantity, and at least one antimicrobial agents.
Fifth aspect present invention relates in the method that has inhibited apoptosis in the experimenter of needs or biological sample, activate the method for pgk1 having in the experimenter that needs or biological sample, or there being the method that treats and/or prevents septicemia and complication thereof in the experimenter who needs.
Sixth aspect present invention relates to as apoptosis inhibitor, as pgk1 activator or as the such as terazosin of formula I compound that treats and/or prevents septicemia and complication thereof.
Brief description of the drawings
Fig. 1 has described induction HS-Gal4 and has expressed the 1-3 hour survival rate of apoptosis HS > rpr fruit bat afterwards.Each point represents mean value+SE.Test n=6.
Fig. 2 is the compound list using in drug screening.These compounds are selected based on Cmap.Divide into groups according to the positive correlation of their apoptotic micro-array chip technology or negative correlation.
Fig. 3 has described with apoptosis fruit bat model discrimination medicine.Apoptosis fruit bat represents with average+SE the survival rate of every kind of medicine.Contrast (not giving medicine) shows with white rod.Giving different medicines represents with white or black rod respectively.Test n=5.
Fig. 4 has described terazosin (4 μ g/ml) and can significantly stop due to the apoptosis due to LPS and IFN γ toxicity.What dyeed by Annexin V is apoptotic cell.The statistical result showed terazosin apoptosis capable of inhibiting cell that test obtains.Every group of cell number is counted as 200-250 cell.
In Fig. 5, Fig. 5 a has described the survival rate curve of terazosin (0.4mg/kg) to septicemic cemia LPS modelling effect.Check and carry out survival rate tracing analysis by Kaplan-Merier with Log Rank algorithm.The number of mice and the p value that use are shown in this figure.Fig. 5 b has described sepharose and has shown LPS treatment DNA break afterwards.Every band represents the genomic dna from a thymus gland for mouse.The treatment process of each mouse is marked on the top of every band.
Fig. 6 has described mouse and has used the survival rate after terazosin (0.04mg/kg) at lps injection (13.5mg/kg) after 12 hours.Check and analyze by Kaplan-Merier with Log Rank algorithm.The number of mice and the p value that use are shown in this figure, and in figure, T represents terazosin.
Fig. 7 has described the survival rate curve of septicemic cemia intestinal bacteria model.Intestinal bacteria injection was injected terazosin (0.4mg/kg) after 1.5 hours.Check and analyze by Kaplan-Merier with Log Rank algorithm.The number of mice and the p value that use are shown in this figure.
Fig. 8 has described the impact of terazosin on Escherichia coli Growth.After using terazosin 24 hours, compare it and the effect of penbritin to bacterial growth by inhibition zone.In figure, result shows, do not add the contrast (control) of medicine and the terazosin of various dose (0.2 μ g T, 2 μ gT, 200 μ g T, 2mg T) and all can not suppress Escherichia coli Growth, and penbritin (2mg Amp) shows inhibition Escherichia coli Growth.
Fig. 9 has described the survival rate curve of terazosin to the effect of septicemic cemia CLP model.After CLP in 1.5 and 24 hours with 0.08mg/kg by twice terazosin of subcutaneous injection.Use separately microbiotic Co-Am to have the increase phenomena of mortality to CLP model.And the combination of terazosin and microbiotic Co-Am has provide protection to septicemic cemia CLP model.Check and analyze by Kaplan-Merier with LogRank algorithm.Quantity and the p value of the mouse using are shown in this figure.In figure, T represents terazosin, and Co-Am represents the mixture that the weight ratio of amoxycilline Trihydrate bp and Clavulanic Potassium is 4: 1.
Figure 10 has described the western blotting of the activity form of caspase-3 3 in Raw 264.7 cells of LPS and IFN γ processing.Albumen applied sample amount in the group of three different treatment is identical.
Figure 11 has described terazosin chemically modified and has produced the chemical process that Affi-gel connects.
In Figure 12, figure a has described to angle albumen to obtain a protein band obviously only occurring (at the band with arrow mark between 43kd to 55kd) in experimental group by terazosin agarose beads.Be accredited as Pgk1 through protein spectrum.Figure b has described to pass through terazosin agarose beads albumen post with the Pgk1 of vivoexpression, has still obtained Pkg1 band, illustrates that terazosin and Pgk1 are directly combinations.
The impact of the terazosin that Figure 13 has described different concns on Pgk1 activity.
Figure 14 has described to express Raw 264.7 cells of Pgk1 can antagonism apoptosis.There is the cell membrane phospholipid acyl Serine of apoptosis by rollover in adipose membrane laterally.Annexin V and phospholipids incorporate, thereby the cell of mark apoptosis.
Figure 15 has described, after mouse infection Pgk1 slow virus, in CLP model, to show provide protection.Every injected in mice 1x10
7the virus of individual activity unit, tested after one week.
Figure 16 has described the effect of terazosin reduction mouse blood sugar
Figure 17 has described the effect of the anti-cerebral thrombosis of terazosin
Embodiment
First aspect present invention relates to formula I compound,
Or its pharmacologically acceptable salts, solvate, ester, prodrug, wherein
R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl group-, C
1-6alkyl acyl-, aryl-acyl-, C
6-10aryl-, C
5-6cycloalkyl, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 5-or 6-ring, wherein said alkyl is optionally selected from following substituting group by 1-3 and replaces: hydroxyl, halogen;
R
2and R
3be selected from independently of one another H, halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, CN, NO
2, NH
2, OH, C
1-6alkoxyl group-, C
1-6alkoxy-C
1-6alkoxyl group-, C
1-6alkyloyl oxygen base-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6alkyl acyl-, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit's carbocyclic ring or heterocycle;
R
4and R
5be selected from independently of one another H, halogen, CN, NO
2, NH
2, OH, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl group-, C
1-6alkyloyl oxygen base-, halo C
1-6alkyl-, C
2-6thiazolinyl-, C
2-6alkynyl-, C
1-6alkoxyl group-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclyloxy base-, C
1-6alkyl acyl.
According to the compound of first aspect present invention, wherein R
1aand R
1bbe selected from independently of one another H, NH
2, OH, C
1-6alkyl-, C
1-4alkoxy-C
1-4alkyl-, C
2-4thiazolinyl-, C
2-4alkynyl-, C
1-4alkoxyl group-, C
1-4alkyl acyl-, phenyl acyl group-, phenyl-, C
5-6cycloalkyl, or R
1aand R
1btogether with the nitrogen-atoms connecting with them, form 5-or 6-ring, wherein said alkyl is optionally selected from following substituting group by 1-3 and replaces: hydroxyl, halogen.In one embodiment, described R
1aand R
1bbe selected from independently of one another H ,-NH
2,-OH, CH
3c (O)-,-(CH
2)
2-O-(CH
2)
2-OH ,-CH
2-CH=CH
2,-CH
2-C ≡ CH ,-(CH
2)
5cH
3,-(CH
2)
4-CF
3, cyclohexyl ,-CH
2-(CH
2)
3-CH
2-,-(CH
2)
2o (CH
2)
2-OH ,-Ph, CH
3,-C (O)-CF
3,-C (O)-Ph.
According to the compound of first aspect present invention, wherein R
2and R
3be selected from independently of one another H, halogen, C
1-6alkyl-, halo C
1-6alkyl-, C
1-6alkoxyl group-, C
1-6alkoxy-C
1-6alkoxyl group-, C
1-6alkyloyl oxygen base-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, or R
2and R
3together with the annular atoms connecting with them, form 5-or 6-unit's carbocyclic ring or heterocycle.In one embodiment, described R
2and R
3be selected from independently of one another H, CH
3o-,-CH
2-O-CH
2-,-O (CH
2)
2oC
2h
5,-OC (O) CH
3,-F ,-CF
3,
and 1,2-pyridine ring ,-NHCOCH
3,-(CH
2)
2cH
3,-NHCOPh,
According to the compound of first aspect present invention, wherein R
4and R
5be selected from independently of one another H, halogen, C
1-6alkyl-, C
1-6alkoxy-C
1-6alkoxyl group-, C
1-6alkyloyl oxygen base-, halo C
1-6alkyl-, C
1-6alkoxyl group-, C
1-6alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclyloxy base.In one embodiment, described R
4and R
5be selected from independently of one another H ,-O (CH
2)
2oC
2h
5,-OC (O) CH
3,-OCH
3,
-CF
3,-F ,-NHCOCH
3,-(CH
2)
3cH
3,-NHCOPh,
According to the compound of first aspect present invention, wherein said alkyl, thiazolinyl and alkynyl are straight chain or side chain.In one embodiment, described C
1-6alkyl is selected from C
1-5alkyl, C
1-4alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, the tertiary butyl.In one embodiment, described C
2-6thiazolinyl is selected from C
2-5thiazolinyl, C
2-4thiazolinyl, for example vinyl, propenyl, allyl group.In one embodiment, described C
2-6alkynyl is selected from C
2-5alkynyl, C
2-4alkynyl.
According to the compound of first aspect present invention, wherein said C
5-6cycloalkyl is selected from cyclopentyl and cyclohexyl.
According to the compound of first aspect present invention, wherein said aryl is selected from phenyl, naphthyl, preferably phenyl.
According to the compound of first aspect present invention, wherein said halogen is selected from fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
According to the compound of first aspect present invention, it is the compound (their structure is as described in compound preparation example part) that is selected from the following Co.1 to Co.33 of being numbered:
Note: active * represents that each compound tests under 0.02 μ g/ml concentration, activates the multiple of Pgk1 activity.
Second aspect present invention relate to formula I compound for example terazosin preparation as the purposes in the medicine of apoptosis inhibitor.
Second aspect present invention also relate to formula I compound for example terazosin preparation as the purposes in the medicine of pgk1 activator.
Second aspect present invention also relates to for example terazosin of formula I compound and treats and/or prevents the purposes in the medicine of septicemia and complication thereof in preparation.
Second aspect present invention also relates to for example terazosin of formula I compound and treats and/or prevents the purposes in the medicine of hyperglycemia, cerebral thrombosis and complication thereof in preparation.
According to the purposes of second aspect present invention, wherein said apoptosis inhibitor treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the purposes of second aspect present invention, wherein said pgk1 activator treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the purposes of second aspect present invention, wherein said septicemia is the septicemia that bacterium and/or other infected by microbes cause.
According to the purposes of second aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory insufficiency, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathic, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the purposes of second aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every per daily dose of human or animal (Mammals), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
According to the purposes of second aspect present invention, wherein said formula I compound is terazosin.
According to the purposes of second aspect present invention, wherein terazosin is pharmacologically acceptable salts or its solvate of terazosin.
According to the purposes of second aspect present invention, wherein said terazosin is the hydrochloride of terazosin.
According to the purposes of second aspect present invention, wherein said terazosin is the hydrate of terazosin hydrochloride.In one embodiment, terazosin is the dihydrate of terazosin hydrochloride.
According to the purposes of second aspect present invention, in wherein said medicine, also comprise at least one antimicrobial agents.
According to the purposes of second aspect present invention, in wherein said medicine, also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, acid amides alcohols class microbiotic, Macrolide class microbiotic, sulfamido, trimethoprim class, quinolones.
According to the purposes of second aspect present invention, in wherein said medicine, also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, penicillin, penicillin v, Oxazacillin, cloxacillin, Flucloxacillin, Ampicillin Trihydrate, piperacillin, azlocillin, Clavulanic Potassium, Sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, also comprise at least one antimicrobial agents in described medicine, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, Clavulanic Potassium.In one embodiment, in described medicine, also comprise amoxycilline Trihydrate bp and Clavulanic Potassium.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises for example terazosin of formula I compound or its pharmacologically acceptable salts or the solvate that treat and/or prevent significant quantity, and optional pharmaceutically acceptable carrier.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least one antimicrobial agents.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, acid amides alcohols class microbiotic, Macrolide class microbiotic, sulfamido, trimethoprim class, quinolones.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least one antimicrobial agents, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, penicillin, penicillin v, Oxazacillin, cloxacillin, Flucloxacillin, Ampicillin Trihydrate, piperacillin, azlocillin, Clavulanic Potassium, Sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, also comprise at least one antimicrobial agents in described pharmaceutical composition, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, Clavulanic Potassium.In one embodiment, in described pharmaceutical composition, also comprise amoxycilline Trihydrate bp and Clavulanic Potassium.
According to the pharmaceutical composition of third aspect present invention, it is for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the pharmaceutical composition of third aspect present invention, it is as pgk1 activator.In one embodiment, wherein said pgk1 activator treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the pharmaceutical composition of third aspect present invention, it is be used for the treatment of and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that bacterium and/or other infected by microbes cause.In one embodiment, wherein said septicemic cemia complication is selected from: renal failure, respiratory insufficiency, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathic, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the pharmaceutical composition of third aspect present invention, it is be used for the treatment of and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
According to the pharmaceutical composition of third aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every per daily dose of human or animal (Mammals), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
Fourth aspect present invention provides a kind of medicine box product, comprising for example terazosin of formula I compound or its pharmacologically acceptable salts or the solvate that treat and/or prevent significant quantity, and at least one antimicrobial agents.
According to the medicine box product of fourth aspect present invention, for example terazosin of wherein said formula I compound or its pharmacologically acceptable salts or solvate are in same composition or in the composition separating with described at least one antimicrobial agents.
According to the medicine box product of fourth aspect present invention, for example terazosin of wherein said formula I compound or its pharmacologically acceptable salts or solvate are in the composition separating with described at least one antimicrobial agents.
According to the medicine box product of fourth aspect present invention, comprising the first composition being separated from each other and the second composition, described the first composition comprises for example terazosin of formula I compound or its pharmacologically acceptable salts or solvate and the optional pharmaceutically acceptable carrier that treat and/or prevent significant quantity, and described the second composition comprises and treats and/or prevents the antimicrobial agents of significant quantity and optional pharmaceutically acceptable carrier.
According to the medicine box product of fourth aspect present invention, wherein said antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, acid amides alcohols class microbiotic, Macrolide class microbiotic, sulfamido, trimethoprim class, quinolones.
According to the medicine box product of fourth aspect present invention, wherein said antimicrobial agents is selected from: amoxycilline Trihydrate bp, penicillin, penicillin v, Oxazacillin, cloxacillin, Flucloxacillin, Ampicillin Trihydrate, piperacillin, azlocillin, Clavulanic Potassium, Sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, Clavulanic Potassium.In one embodiment, described antimicrobial agents comprises amoxycilline Trihydrate bp and Clavulanic Potassium.
According to the medicine box product of fourth aspect present invention, it is for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the medicine box product of fourth aspect present invention, it is as pgk1 activator.In one embodiment, wherein said pgk1 activator treating and/or preventing and laboratory diagnosis and/or detection for clinical disease.
According to the medicine box product of fourth aspect present invention, it is be used for the treatment of and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that bacterium and/or other infected by microbes cause.In one embodiment, wherein said septicemic cemia complication is selected from: renal failure, respiratory insufficiency, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathic, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the medicine box product of fourth aspect present invention, it is be used for the treatment of and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
According to the medicine box product of fourth aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every per daily dose of human or animal (Mammals), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
Fifth aspect present invention relates in the method that has inhibited apoptosis in the experimenter of needs or biological sample, and the method comprises the such as terazosin of formula I compound of using significant quantity to described experimenter or biological sample.
Fifth aspect present invention also relates to the method that activates pgk1 in the experimenter of needs or biological sample having, and the method comprises the such as terazosin of formula I compound of using significant quantity to described experimenter or biological sample.
Fifth aspect present invention also relates to the method that treats and/or prevents septicemia and complication thereof in the experimenter who has needs, and the method comprises the such as terazosin of formula I compound of using significant quantity to described experimenter.
Fifth aspect present invention also relates to the method that treats and/or prevents hyperglycemia, cerebral thrombosis and complication disease thereof in the experimenter who has needs, and the method comprises the such as terazosin of formula I compound of using significant quantity to described experimenter.
According to the method for fifth aspect present invention, wherein said septicemia is the septicemia that bacterium and/or other infected by microbes cause.
According to the method for fifth aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory insufficiency, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathic, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the method for fifth aspect present invention, for example terazosin of wherein said formula I compound for example, is 0.001～5mg/kg for every per daily dose of human or animal (Mammals), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
According to the method for fifth aspect present invention, wherein said formula I compound is terazosin.
According to the method for fifth aspect present invention, wherein terazosin is pharmacologically acceptable salts or its solvate of terazosin.
According to the method for fifth aspect present invention, wherein said terazosin is the hydrochloride of terazosin.
According to the method for fifth aspect present invention, wherein said terazosin is the hydrate of terazosin hydrochloride.In one embodiment, terazosin is the dihydrate of terazosin hydrochloride.
According to the method for fifth aspect present invention, wherein also comprise at least one antimicrobial agents of using significant quantity to described experimenter or biological sample.
According to the method for fifth aspect present invention, wherein also comprise at least one antimicrobial agents of using significant quantity to described experimenter or biological sample, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, acid amides alcohols class microbiotic, Macrolide class microbiotic, sulfamido, trimethoprim class, quinolones.
According to the method for fifth aspect present invention, wherein also comprise at least one antimicrobial agents of using significant quantity to described experimenter or biological sample, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, penicillin, penicillin v, Oxazacillin, cloxacillin, Flucloxacillin, Ampicillin Trihydrate, piperacillin, azlocillin, Clavulanic Potassium, Sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, Clavulanic Potassium.In one embodiment, described antimicrobial be amoxycilline Trihydrate bp and Clavulanic Potassium.
Sixth aspect present invention relates to the such as terazosin of formula I compound as apoptosis inhibitor.
Sixth aspect present invention also relates to the such as terazosin of formula I compound as pgk1 activator.
Sixth aspect present invention also relates to as the such as terazosin of formula I compound that treats and/or prevents septicemia and complication thereof.
Sixth aspect present invention also relates to as the such as terazosin of formula I compound that treats and/or prevents hyperglycemia, cerebral thrombosis and complication thereof.
According to the formula I compound of sixth aspect present invention, wherein said apoptosis inhibitor treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the formula I compound of sixth aspect present invention, wherein said pgk1 activator treats and/or prevents and laboratory diagnosis and/or detection for clinical disease.
According to the formula I compound of sixth aspect present invention, wherein said septicemia is the septicemia that bacterium and/or other infected by microbes cause.
According to the formula I compound of sixth aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory insufficiency, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathic, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
According to the formula I compound of sixth aspect present invention, wherein said formula I compound for example, is 0.001～5mg/kg for every per daily dose of human or animal (Mammals), preferably 0.002～4mg/kg, preferably 0.003～3mg/kg, preferably 0.005～2.5mg/kg, preferably 0.0075～2mg/kg, preferably 0.01～2mg/kg, preferably 0.01～1mg/kg.
According to the formula I compound of sixth aspect present invention, it is terazosin.
According to the formula I compound of sixth aspect present invention, it is pharmacologically acceptable salts or its solvate of terazosin.
According to the formula I compound of sixth aspect present invention, it is the hydrochloride of terazosin.
According to the formula I compound of sixth aspect present invention, it is the hydrate of terazosin hydrochloride, for example the dihydrate of terazosin hydrochloride.
According to the formula I compound of sixth aspect present invention, it also combines with at least one antimicrobial agents.
According to the formula I compound of sixth aspect present invention, it also combines with at least one antimicrobial agents, and described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, acid amides alcohols class microbiotic, Macrolide class microbiotic, sulfamido, trimethoprim class, quinolones.
According to the formula I compound of sixth aspect present invention, it also combines with at least one antimicrobial agents, and described antimicrobial agents is selected from: amoxycilline Trihydrate bp, penicillin, penicillin v, Oxazacillin, cloxacillin, Flucloxacillin, Ampicillin Trihydrate, piperacillin, azlocillin, Clavulanic Potassium, Sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, described antimicrobial agents is selected from: amoxycilline Trihydrate bp, Clavulanic Potassium.In one embodiment, described antimicrobial agents is amoxycilline Trihydrate bp and Clavulanic Potassium.
The either side according to the present invention, the usage quantity of wherein said for example terazosin of formula I compound can be with reference to existing clinical medicine dose.For example, when for human therapy and/or prevention septicemia and complication thereof, the using dosage of terazosin can be at present clinically this medicine for example, for 0.01～100 times of the dosage of Other diseases (hypertension), preferably 0.02～80 times, preferably 0.05～20 times, preferably 0.1～10 times, preferably 0.1～5 times, preferably 0.2～5 times, preferably 0.2～2 times.
The either side according to the present invention, the usage quantity of wherein said antimicrobial agents can be with reference to existing clinical medicine dose.For example, when for human therapy and/or prevention septicemia and complication thereof, its using dosage can be at present clinically this antimicrobial agents for example, for 0.01～100 times of the dosage of Other diseases (anti-infective), preferably 0.02～80 times, preferably 0.05～20 times, preferably 0.1～10 times, preferably 0.2～5 times.
The either side according to the present invention, wherein said amoxycilline Trihydrate bp and/or the usage quantity of Clavulanic Potassium can be with reference to existing clinical medicine doses.For example, when for human therapy and/or prevention septicemia and complication thereof, its using dosage can be at present clinically this amoxycilline Trihydrate bp and/or Clavulanic Potassium for example, for 0.01～100 times of the dosage of Other diseases (anti-infective), preferably 0.02～80 times, preferably 0.05～20 times, preferably 0.1～10 times, preferably 0.2～5 times.
In some embodiments of either side of the present invention, described formula I compound does not comprise the compound of numbering Co.33.
The feature that arbitrary embodiment of either side of the present invention or this either side has is equally applicable to arbitrary embodiment of other either side or this other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.
Be further described with feature to various aspects of the present invention below.
All documents that the present invention quotes from, their full content is incorporated to herein by reference, and if when the expressed implication of these documents and the present invention are inconsistent, be as the criterion with statement of the present invention.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to be explained, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
As described herein, term " septicemia " is also called " septicemia ", it has conventionally known implication of those skilled in the art, and typically refer to a kind of because bacterium and/or other microorganism enter circulation of blood, and therein growth and breeding, produce toxin and the general severe infections that causes.Clinical manifestation is increased etc. for heating, serious toxemic symptoms, fash petechia, hepatosplenomegaly and leukocyte count.Gram positive coccus septicemia is easily migrated focus; The easy concurrent infection shock of gram-negative bacteria septicemia.When septicemia is called pyaemia septica or is called Sepsis during with multiple abscess.
As described herein, term " pgk1 activator " refers to phosphoglycerate kinase 1 (phosphoglycerate kinase 1, referred to as pgk1) activator, its can activate pgk1 and therefore those skilled in the art understand its treatment that can be used for relevant disease or illness, prevent, alleviate and/or alleviate.
Term " about " used herein, it typically refers to the limit of error that comprises that this area allows, for example ± 10%, for example ± 5%, for example ± 2%.
As described herein, term " significant quantity " refers to the dosage that can realize treatment in experimenter, prevent, alleviate and/or alleviate disease of the present invention or illness.
As described herein, term " pharmaceutical composition ", it can exchange and use with " composition ", refers to be used in experimenter to realize the material for the treatment of, prevent, alleviate and/or alleviate disease of the present invention, illness, symptom.
As described herein, term " experimenter " or " patient ", can refer to accept the present composition and extract to treat, to prevent, to alleviate and/or to alleviate the animal of disease of the present invention, illness, symptom, particularly Mammals, such as people, dog, monkey, ox, horse etc.
As described herein, term " disease or symptom " refers to a kind of physical state of described experimenter, and this physical state is relevant with disease of the present invention or symptom.
As described herein, " % ", as do not specialize, while being solid for total material, generally refer to the per-cent of w/w, while being liquid for total material, generally refer to the per-cent of weight/volume.Certainly, be liquid and solute while being liquid for total material, the per-cent that characterizes this liquid solute generally refers to the per-cent of volume/volume.
Terazosin (Terazosin, (4-(4-amino-6,7--dimethoxyquinazoline-2-yl) piperazine-1-yl) (tetrahydrofuran (THF)-2-yl) ketone, C
19h
25n
5o
4), it has following chemical structural formula:
In the present invention, in the time mentioning terazosin, it not only comprises the compound shown in above structure, also comprises the pharmacologically acceptable salts (for example hydrochloride) of said structure compound, and such as hydrate of the solvate of said structure compound and salt thereof.In a preferred embodiment of the invention, described terazosin refers to Vasocard dihydrate.The present invention is below used as the terazosin of formula I compound typical case to carry out large quantity research to show the beat all effect of the present invention; Below testing particularly in biological test, as do not indicated in addition, reagent terazosin used refers to Vasocard dihydrate.
The present invention attempts screening apoptosis inhibitor from clinical medicine.First, the present invention uses the model of cell apoptosis of fruit bat by the genetic expression of micro-array chip technical Analysis.Then, the present invention uses contact figure (connectivity map, Cmap) to determine candidate's apoptosis blocker by bioinformatic analysis decision.Then, the present invention has screened the apoptotic drug candidate of inhibition dipteral insect fruit bat (Drosophila).As a result, the present invention has determined terazosin, and it is for alleviating hypertensive clinical application.In addition, the present invention finds that terazosin can suppress the apoptosis being mediated by bacterial endotoxin (lipopolysaccharides, LPS, 2 μ g/ml) and interferon-gamma (IFN γ, 50U/ml) in scavenger cell.In addition, the present invention's discovery, in septicemic cemia three trial models, terazosin can reduce the mortality ratio of mouse greatly.What is interesting is, compared with independent use microbiotic, make terazosin and antibiotic combinations can produce better provide protection.Result of the present invention shows, terazosin is a kind of new apoptosis inhibitor.It can be used for combining with antibiotic therapy.
Fruit bat is the important animal model system of screening of medicaments.The apoptosis pathway of caspase-3 (caspase) in addition ,-mediation is fully conservative between dipteral insect and people.For example Reaper (rpr) brings into play Main Function (White et al., 1994) in the apoptosis of fruit bat.Although, can cause abnormal cells apoptosis and the organic death (White et al., 1996) of extensive distribution from the rpr expression of heat shock promoter.Whether the present invention has studied the present invention program can screen apoptosis blocker with fruit bat Apoptosis Model.HS-Gal4 (a kind of whole body expression and heat activated promotor), can impel 5 ' any genetically modified expression repeating that contains UAS (upstream activating sequence).When make this HS-Gal4 fruit bat and UAS-Reaper drosophila hybrid (referred to as HS > rpr) at 18 DEG C time, female offspring is normal development from start to finish.But, at 37 DEG C, give heat-shocked 2-3 hour, approximately the offspring of 50-70% after 14-24 hour dead (Fig. 1).The present invention has selected 25 kinds of compounds (Fig. 2) that rank is forward, and the impact of their lethality rates on HS > rpr is determined in the pacing of going forward side by side.The present invention finds only have terazosin can improve significantly the survival (Fig. 3) of HS > rpr fruit bat.
In order to test whether also inhibited apoptosis in the mammalian cell of cultivating of terazosin, the present invention is by LPS and IFN γ cell death inducing in scavenger cell RAW264.7 cell, and this LPS and IFN γ bring out apoptotic known medicament in culturing cell.The present invention is by the observation of cell apoptosis (Fig. 4) that dyes with Annexin V.Inventor's discovery, the cell that LPS (2 μ g/ml) and IFN γ (50U/ml) process causes cell membrane damage, turns up, thereby is dyeed by Annexin V.This is a kind of apoptosis pattern of classics.And application terazosin (4 μ g/ml) can reduce by 50% apoptosis (Fig. 4).Importantly, the present invention finds unexpectedly effectively inhibited apoptosis and can be further used for treating and/or preventing septicemia and complication thereof of terazosin.
In order further to study the effect of terazosin in septicemic cemia Mammals model, the present invention has studied the mouse of accepting LPS treatment.The present invention's discovery, at injection LPS (13.5mg/kg, i.p.) the 1.5 hours remarkable increase of injection terazosin (0.4mg/kg i.p) meeting mouse survivals afterwards, (Fig. 5 a).In order to confirm that terazosin is to apoptotic effect, the present invention has detected apoptotic marker DNA break.As the organ that produces immunocyte, during septicemia, thymus gland is responsive (Ayala et al., 1998) to apoptosis.Therefore, the present invention has compared the genomic dna and the genomic dna of mouse thymus that adds terazosin treatment with LPS of the mouse thymus of the LPS treatment of using by oneself.Result shows, in the mouse of processing at LPS, obvious DNA ladder type has occurred, but in the mouse with terazosin treatment, greatly reduces that (Fig. 5 b).Whether can play a role in the septicemic cemia later stage in order to test terazosin, the present invention is 12 hours injection terazosins after using LPS.Result demonstration, terazosin still has satisfied effect (Fig. 6).
Then, in the septicemia model of Escherichia Coli Injection, tested terazosin.Result shows, the death (Fig. 7) that terazosin can protect mouse to be induced by intestinal bacteria.In order to measure potential antibacterial effect, the inventor has detected the Escherichia coli Growth situation under terazosin exists.Result demonstration, with respect to penbritin, terazosin can not suppress Escherichia coli Growth (Fig. 8).
Because LPS and intestinal bacteria model only can be simulated gram-negative bacteria and infected, the present invention has further tested terazosin in caecum ligation and puncture (CLP) model, this model it is believed that it is tentative septicemic cemia gold standard model (Parker and Watkins, 2001; Wichterman et al., 1980).First, bolt of the present invention is surveyed the terazosin (for the identical concentration of LPS model) of 0.4mg/kg.But, at initial 5 days, not faster (data do not show) that the mouse of injection terazosin is more dead than control group.The present invention infers that this may be because the serious heart dysfunction and the ypotension that are caused by CLP cause.Therefore the function that, medicine reduces blood pressure may have been covered the effect of its anti-apoptosis.For head it off, terazosin concentration is reduced to 0.08mg/kg by the present invention, and the inventor has measured the impact of this concentration of injected in mice on blood pressure, finds that mouse blood pressure is completely normal.This result is used in it in rat, can not reduce blood pressure consistent (Kyncl et al., 1985).What is interesting is, in the time within 1.5 hours and 24 hours after operation, injecting 2 times, terazosin has significantly promoted the survival (Fig. 9) of CLP model small mouse.Secondly, the present invention has tested terazosin and antibiotic combinations, in the present invention, microbiotic amoxycilline Trihydrate bp and Clavulanic Potassium (Co-Am are selected, the weight ratio of amoxycilline Trihydrate bp and Clavulanic Potassium is 4: 1, in the time that other place of the present invention is mentioned in the mode of concrete example or example, also refer to the proportioning of this 4: 1.Those skilled in the art understand, in the time making a general reference the combination of amoxicillin and clavulanate potassium, the weight ratio of amoxycilline Trihydrate bp and Clavulanic Potassium can be 1: 1 to 10: 1, particularly 1: 1 to 7: 1, for example approximately 1: 1, approximately 4: 1, approximately 7: 1) with terazosin combination.The present invention's discovery, terazosin combines with Co-Am the Co-Am in independent comparing and demonstrates stronger provide protection (Fig. 9).In addition, this combination therapy has still proved the result for the treatment of of CLP administration in 6 hours afterwards.
Whether relevant with its function as α 1-adrenoceptor inhibitor in order to test the protection effect of terazosin; the present invention has checked Minidress (0.4mg/kg; i.p.), it is another kind of α 1-adrenoceptor retarding agent (Cavero et al., 1977).The present invention finds that septicemia that Minidress causes LPS is without any curative effect.These results show, terazosin can significantly increase the septicemic cemia survival rate that suppresses LPS-mediation, and its function is likely by apoptotic restraining effect instead of target α 1-adrenoceptor.
Block apoptotic Biological Mechanism in order to study terazosin, the present invention has sought its latent effect to inhibited apoptosis proteolytic enzyme, realizing due to the apoptosis in fruit bat is mainly the caspase-3 activation (McCall and Steller, 1997) by inherent.But western blot analysis of the present invention shows, the activity form (homologous gene of Dpc-1 and drICE in fruit bat) of carrying out daughter cell apoptotic proteins enzyme 3 reduces (Figure 10) because of terazosin.The present invention infers, the upstream target of the adjustable caspase-3 3 of terazosin.For sldh gene, the present invention links terazosin in agarose beads, and Figure 11 has shown its chemosynthesis approach.Then in Raw 264.7 cell extracts, angle albumen, found that (Figure 12 a) to have more a band with respect to blank and medicine competition control group.Through Mass Spectrometric Identification, this band is Pgk1.For whether the combination of determining terazosin and Pgk1 is direct relation, the inventor has expressed also purifying in the bacterium Pgk1 albumen of mouse, found that terazosin can be external directly in conjunction with Pgk1 albumen, (Figure 12 b).Because cross expression Pgk1 apoptosis capable of inhibiting cell (Mazzoni et al., 2009) in yeast, the inventor guesses that terazosin may activate the enzymic activity of Pgk1.In order to prove this conjecture, the inventor has detected Pgk1 vitro enzyme activity.Found that, the terazosin of 0.05 μ M can activate nearly 3 times of the enzymic activity of Pgk1, can reduce the activation (Figure 13) to enzymic activity and increase terazosin concentration to 0.4 μ M.If Pgk1 enzymic activity is the reason of inhibited apoptosis, crossing expression Pkg1 just should inhibited apoptosis.The inventor's experimental result shows, by the RAW264.7 clone of expressing the foundation of Pgk1 slow virus, has significantly reduced LPS and IFN γ apoptosis after treatment; And there is not change (Figure 14) in the apoptosis of excessively expressing EGFP.Further, the inventor has expressed Pgk1 with subcutaneous injection slow virus or EGFP contrasts in mouse.After one week, do CLP operation, found that, with respect to the one group of mouse that infects green fluorescent protein, the mouse of injection Pgk1 virus has significantly been improved survival rate (Figure 15).The present invention is not subject to the constraint of any particular theory, and the inventor thinks that Pgk1 is the target spot that terazosin is new.
Research of the present invention shows, terazosin can easily be converted in clinical application, and without the existing antibiotic therapy program of amendment.Below biological test of the present invention is elaborated.
embodiment
a, compound preparation example part
Following preparation example has exemplarily been prepared segment bounds I compound of the present invention, and each compound represents with Co.1 to Co.32 respectively, and Co.33 represents terazosin.In the reaction process of following preparation example, " reflux " represents to reflux, " 1-pentanol " ' expression 1-amylalcohol.
the preparation of preparation example 1:Co.1
Step 1: pass into ammonia to being dissolved with in the 200mL tetrahydrofuran solution of compound 1a (50mmol), reaction is carried out 36 hours at 25 DEG C.In system, there are a large amount of white solids to separate out, filter after gained white solid tetrahydrofuran (THF) washs and obtain the finished product 1f.Productive rate is: 63%.
Step 2: add 15mL acetic anhydride to compound 1f (10mmol), reaction refluxes 2 hours.Cool to room temperature, has a large amount of white solids to separate out in system, filter after gained white solid tetrahydrofuran (THF) washs and obtain the finished product 1g.Productive rate is: 63%.
Step 3: the in the situation that of argon atmospher, add 1h (2mmol) to being dissolved with in the solution of 1-amylalcohol of 1g (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.1 with obtaining the finished product 1i after ether/recrystallizing methanol.Productive rate is: 60%.
1H NMR (300MHz, CDCl
3): 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), d 2.61 (s, 3H, CH
3), 3.47-4.07 (m, 11H, thf-H, pip-H and CH2CH2O), 3.93 (s, 3H, OCH
3), 3.97 (s, 3H, OCH3), 4.82 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 430.20928 (M+H) (calculated value: 430.20904); Ultimate analysis: (C, 58.74; H, 6.34; N, 16.30; O, 18.63); Calculated value: (C, 58.73; H, 6.34; N, 16.31; O, 18.63).
the preparation of preparation example 2:Co.2
Step 1: add compound 1b (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 4 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 1c after petrol ether/ethyl acetate recrystallization.Productive rate is: 41%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 1c (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.2 with obtaining the finished product 1e after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 14H, thf-H, pip-H and CH
2cH
2o), 3.84 (s, 3H, OCH
3), 3.87 (s, 3H, OCH
3), 4.73 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); 13C NMR (DMSO-d6): d 25.2,27.9,40.9,44.1,44.6,55.8,56.2,60.1,68.1,68.2,72.1,74.9,102.4,104.4,106.9,146.2,154.4,154.2,158.6,169.6; HR-MS (ESI-positivity): 476.25120 (M+H) (calculated value: 476.25091); Ultimate analysis: C, 58.08; H, 7.00; N, 14.73; O, 20.19; Calculated value: (C, 58.09; H, 6.99; N, 14.73; O, 20.19).
the preparation of preparation example 3:Co.3
Step 1: add hydrazine hydrate (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 4 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 3a after petrol ether/ethyl acetate recrystallization.Productive rate is: 61%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 3a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.3 with obtaining the finished product 3b after ether/recrystallizing methanol.Productive rate is: 31%.
1H NMR (300MHz, DMSO-d6): d 1.87 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.43-4.07 (m, 6H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.63 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 403.20938 (M+H) (calculated value: 403.20946).
the preparation of preparation example 4:Co.4
Step 1: add hydration oxyammonia (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 3 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 4a after petrol ether/ethyl acetate recrystallization.Productive rate is: 88%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 4a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.4 with obtaining the finished product 4b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, DMSO-d6): 1.81 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 6H, thf-H, pip-H), 3.87 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.43 (m, 1H, thf-2H), 7.26 (s, 1H, Ar-5H), 7.74 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 404.19339 (M+H) (calculated value: 404.19341).
the preparation of preparation example 5:Co.5
Step 1: add allyl amine (22mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 8 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 5a after petrol ether/ethyl acetate recrystallization.Productive rate is: 31%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 4a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.5 with obtaining the finished product 5b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, DMSO-d6): 1.82 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 6H, thf-H, pip-H), 3.87 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.04 (d, 2H), 4.43 (m, 1H, thf-2H), 5.19-5.23 (m, 2H), 5.82-5.88 (m, 1H), 7.26 (s, 1H, Ar-5H), 7.74 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 428.22978 (M+H) (calculated value: 428.22986).
the preparation of preparation example 6:Co.6
Step 1: add allyl amine (28mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 10 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 6a after petrol ether/ethyl acetate recrystallization.Productive rate is: 44%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 4a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.6 with obtaining the finished product 6b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, DMSO-d6): 1.82 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 6H, thf-H, pip-H), 3.80 (s, 2H), 3.87 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.04 (d, 2H), 4.43 (m, 1H, thf-2H), 7.26 (s, 1H, Ar-5H), 7.74 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 426.21413 (M+H) (calculated value: 426.21408).
the preparation of preparation example 7:Co.7
Step 1: add compound 7a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 3 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 7b after petrol ether/ethyl acetate recrystallization.Productive rate is: 61%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 7b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.7 with obtaining the finished product 7c after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 0.86-1.62 (m, 11H), 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.46-4.07 (m, 8H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.83 (s, 3H, OCH
3), 4.75 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 472.29238 (M+H) (calculated value: 472.29229).
the preparation of preparation example 8:Co.8
Step 1: add compound 8a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 1.5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 8b after petrol ether/ethyl acetate recrystallization.Productive rate is: 71%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 8b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.8 with obtaining the finished product 8c after ether/recrystallizing methanol.Productive rate is: 42%.
1H NMR (300MHz, DMSO-d6): 1.22-1.72 (m, 11H), 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.05 (m, 8H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.73 (s, 3H, OCH
3), 4.43 (m, 1H, thf-2H), 7.54 (s, 1H, Ar-5H), 7.86 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 512.24846 (M+H) (calculated value: 512.24859).
the preparation of preparation example 9:Co.9
Step 1: add compound 9a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 2.5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 9b after petrol ether/ethyl acetate recrystallization.Productive rate is: 21%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 9b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.9 with obtaining the finished product 9c after ether/recrystallizing methanol.Productive rate is: 43%.
1H NMR (300MHz, DMSO-d6): 1.32-1.52 (m, 10H), 1.86 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.47-4.07 (m, 9H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.79 (s, 3H, OCH
3), 4.46 (m, 1H, thf-2H), 7.33 (s, 1H, Ar-5H), 7.78 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 470.27673 (M+H) (calculated value: 470.27658).
the preparation of preparation example 10:Co.10
Step 1: add compound 10a (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 9b after petrol ether/ethyl acetate recrystallization.Productive rate is: 36%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 9b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.10 with obtaining the finished product 10c after ether/recrystallizing methanol.Productive rate is: 43%.
1H NMR (300MHz, DMSO-d6): 1.33-1.47 (m, 6H), 1.86 (m, 2H, thf-H), 2.04 (m, 2H, thf-H), 3.57-4.09 (m, 12H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.77 (s, 3H, OCH
3), 4.48 (m, 1H, thf-2H), 7.37 (s, 1H, Ar-5H), 7.79 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 456.26108 (M+H) (calculated value: 456.26119).
the preparation of preparation example 11:Co.11
Step 1: add compound 11b (20mmol) to being dissolved with in the 100mL methanol solution of compound 1a (20mmol), reaction is carried out 5 hours at 25 DEG C.After thin plate chromatography instruction 1a transforms completely, put into-20 DEG C of environment to adding 100mL ether in system, after mixing and leave standstill crystallization.Gained white solid is with obtaining the finished product 11c after petrol ether/ethyl acetate recrystallization.Productive rate is: 41%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 11b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.11 with obtaining the finished product 11c after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 1.79 (m, 2H, thf-H), 2.06 (m, 2H, thf-H), 3.27-4.08 (m, 17H, thf-H, pip-H and CH
2cH
2o), 3.85 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.73 (m, 1H, thf-2H), 7.26 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 490.26656 (M+H) (calculated value: 490.26658).
the preparation of preparation example 12:Co.12
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 12a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.12 with obtaining the finished product 12b after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, DMSO-d6): 1.79 (m, 2H, thf-H), 2.06 (m, 2H, thf-H), 3.47-4.08 (m, 11H, thf-H, pip-H), 3.85 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.73 (m, 1H, thf-2H), 6.86-7-62 (m, 7H, Ar-H); HR-MS (ESI-positivity): 464.22978 (M+H) (calculated value: 464.22996).
the preparation of preparation example 13:Co.13
Step 1: add 20mL13a to compound 1f (10mmol), reaction refluxes 2 hours.Cool to room temperature, has a large amount of white solids to separate out in system, filter after gained white solid tetrahydrofuran (THF) washs and obtain the finished product 13b.Productive rate is: 82%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 13b (2mmol).After reaction system refluxes 5.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.13 with obtaining the finished product 13c after ether/recrystallizing methanol.Productive rate is: 62%.
1H NMR (300MHz, CDCl
3): 1.80 (m, 2H, thf-H), 2.06 (m, 2H, thf-H), 3.47-4.07 (m, 13H, thf-H, pip-H), 3.93 (s, 3H, OCH
3), 3.97 (s, 3H, OCH3), 4.82 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 484.18078 (M+H) (calculated value: 484.18084).
the preparation of preparation example 14:Co.14
Step 1: add 22mL14a to compound 1f (10mmol), reaction refluxes 2 hours.Cool to room temperature, has a large amount of white solids to separate out in system, filter after gained white solid tetrahydrofuran (THF) washs and obtain the finished product 14b.Productive rate is: 55%.
Step 2: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 14b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.14 with obtaining the finished product 14c after ether/recrystallizing methanol.Productive rate is: 48%.
1H NMR (300MHz, CDCl
3): d 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.45-4.47 (m, 13H, thf-H, pip-H), 3.93 (s, 3H, OCH
3), 3.97 (s, 3H, OCH
3), 4.82 (m, 1H, thf-2H), 6.89-7.72 (m, 7H, Ar-H); HR-MS (ESI-positivity): 492.22469 (M+H) (calculated value: 492.22478).
the preparation of preparation example 15:Co.15
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 15b (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.15 with obtaining the finished product 15c after ether/recrystallizing methanol.Productive rate is: 55%.
1H NMR (300MHz, CDCl
3): 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.49-4.27 (m, 13H, thf-H, pip-H), 4.82 (m, 1H, thf-2H), 6.07 (s, 2H, CH
2oCH
2) 7.27 (s, 1H, Ar-5H), 7.68 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 372.16718 (M+H) (calculated value: 372.16726).
the preparation of preparation example 16:Co.16
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 16a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.16 with obtaining the finished product 16a after ether/recrystallizing methanol.Productive rate is: 45%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (t, 6H, CH
3-H) 1.87 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.45-4.17 (m, 25H, thf-H, pip-H), 4.79 (m, 1H, thf-2H), 7.27 (s, 1H, Ar-5H), 7.68 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 504.28215 (M+H) (calculated value: 504.28221).
the preparation of preparation example 17:Co.17
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 17a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.17 with obtaining the finished product 17a after ether/recrystallizing methanol.Productive rate is: 55%.
1H NMR (300MHz, CDCl
3): 1.83 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), d 2.61 (s, 3H, CH
3), 3.47-4.07 (m, 11H, thf-H, pip-H and CH2CH2O), 3.94 (s, 3H, OCH
3), 4.82 (m, 1H, thf-2H), 7.18 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 416.19344 (M+H) (calculated value: 416.19339).
the preparation of preparation example 18:Co.18
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 18a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.18 with obtaining the finished product 18b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, CDCl
3): 1.80 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.80 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 376.17853 (M+H) (calculated value: 376.17849).
the preparation of preparation example 19:Co.19
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 19a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.19 with obtaining the finished product 19b after ether/recrystallizing methanol.Productive rate is: 54%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (m, 6H), 1.89 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.07-4.07 (m, 15H, thf-H, pip-H), (4.85 m, 1H, thf-2H), (7.63 s, 1H, Ar-5H), (7.89 s, 1H, Ar-8H); HR-MS (ESI-positivity): 479.23836 (M+H) (calculated value: 479.23823).
the preparation of preparation example 20:Co.20
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 20a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.20 with obtaining the finished product 20b after ether/recrystallizing methanol.Productive rate is: 54%.
1H NMR (300MHz, CDCl
3): 1.83 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.07-4.07 (m, 11H, thf-H, pip-H), 4.88 (m, 1H, thf-2H), 7.58 (m, 1H, Ar-H), 7.63 (s, 1H, Ar-H), 7.89 (s, 1H, Ar-H), 8.38 (d, 1H, Ar-H) 8.83 (d, 1H, Ar-H); HR-MS (ESI-positivity): 379.18833 (M+H) (calculated value: 379.18825).
the preparation of preparation example 21:Co.21
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 21a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.21 with obtaining the finished product 21b after ether/recrystallizing methanol.Productive rate is: 54%.
1H NMR (300MHz, CDCl
3): 1.86 (m, 2H, thf-H), 2.01 (m, 2H, thf-H), 2.62 (s, 3H, CH
3), 3.17-4.07 (m, 11H, thf-H, pip-H), 3.97 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.89 (s, 1H, Ar-H), 8.83 (d, 1H, Ar-H); HR-MS (ESI-positivity): 379.18833 (M+H) (calculated value: 379.18825).
the preparation of preparation example 22:Co.22
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 22a (2mmol).After reaction system refluxes 5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.22 with obtaining the finished product 22b after ethyl ketone/recrystallizing methanol.Productive rate is: 61%.
1H NMR (300MHz, CDCl
3): 0.88-0.93 (t, 3H), 1.62 (m, 2H), 1.88 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 2.64 (t, 2H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 400.23464 (M+H) (calculated value: 400.23486).
the preparation of preparation example 23:Co.23
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 23a (2mmol).After reaction system refluxes 5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.23 with obtaining the finished product 23b after ether/recrystallizing methanol.Productive rate is: 48%.
1H NMR (300MHz, CDCl
3): 1.87 (m, 2H, thf-H), 2.01 (m, 2H, thf-H), 3.17-4.07 (m, 11H, thf-H, pip-H), 3.97 (s, 3H, OCH
3), 4.87 (m, 1H, thf-2H), 6.86-7.62 (m, 7H, Ar-H); HR-MS (ESI-positivity): 477.22497 (M+H) (calculated value: 477.22503).
the preparation of preparation example 24:Co.24
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 25a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.25 with obtaining the finished product 25b after ether/recrystallizing methanol.Productive rate is: 24%.
1H NMR (300MHz, CDCl
3): 1.86 (m, 2H, thf-H), 1.94-2.58 (m, 8H), 3.17-4.07 (m, 12H, thf-H, pip-H), 3.97 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 5.56 (m, 2H), 7.15 (s, 1H, Ar-5H), 7.71 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 454.24499 (M+H) (calculated value: 454.24543).
the preparation of preparation example 25:Co.25
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 25a (2mmol).After reaction system refluxes 4.5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.25 with obtaining the finished product 25b after ether/recrystallizing methanol.Productive rate is: 45%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (t, 6H, CH
3-H) 1.88 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.44-4.17 (m, 25H, thf-H, pip-H), 3.85 (s, 3H, OCH
3), 3.87 (s, 3H, OCH
3), 4.87 (m, 1H, thf-2H), 7.27 (s, 1H, Ar-5H), 7.68 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 564.30330 (M+H) (calculated value: 564.30334).
the preparation of preparation example 26:Co.26
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 26a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.17 with obtaining the finished product 26a after ether/recrystallizing methanol.Productive rate is: 55%.
1H NMR (300MHz, CDCl
3): 1.86 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), d 2.61 (s, 3H, CH
3), 3.47-4.07 (m, 11H, thf-H, pip-H and CH2CH2O), 3.91 (s, 3H, OCH
3), 3.95 (s, 3H, OCH
3), 3.99 (s, 3H, OCH
3), 4.82 (m, 1H, thf-2H), 7.16 (s, 1H, Ar-5H), 7.72 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 476.21445 (M+H) (calculated value: 476.21452).
the preparation of preparation example 27:Co.27
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 27a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.27 with obtaining the finished product 27b after ether/recrystallizing methanol.Productive rate is: 53%.
1H NMR (300MHz, CDCl
3): 1.15-1.26 (m, 6H), 1.88 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.07-4.07 (m, 15H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.63 (s, 1H, Ar-5H), 7.89 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 539.25942 (M+H) (calculated value: 539.25936).
the preparation of preparation example 28:Co.28
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 28a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.28 with obtaining the finished product 28b after ether/recrystallizing methanol.Productive rate is: 75%.
1H NMR (300MHz, CDCl
3): 1.78 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.86 (s, 3H, OCH
3), 3.88 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 436.19955 (M+H) (calculated value: 436.19962).
the preparation of preparation example 29:Co.29
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 29a (2mmol).After reaction system refluxes 3 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.29 with obtaining the finished product 29b after ether/recrystallizing methanol.Productive rate is: 44%.
1H NMR (300MHz, CDCl
3): 1.84 (m, 2H, thf-H), 2.01 (m, 2H, thf-H), 2.62 (s, 3H, CH
3), 3.17-4.07 (m, 11H, thf-H, pip-H), 3.82 (s, 3H, OCH
3), 3.85 (s, 3H, OCH
3), 3.97 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.89 (s, 1H, Ar-H), 8.83 (d, 1H, Ar-H); HR-MS (ESI-positivity): 475.23050 (M+H) (calculated value: 475.23051).
the preparation of preparation example 30:Co.30
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 30a (2mmol).After reaction system refluxes 5 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.30 with obtaining the finished product 30b after ether/recrystallizing methanol.Productive rate is: 65%.
1H NMR (300MHz, CDCl
3): 0.88-0.93 (t, 3H), 1.62 (m, 2H), 1.84 (m, 2H, thf-H), 2.03 (m, 2H, thf-H), 2.64 (t, 2H), 3.57-4.07 (m, 11H, thf-H, pip-H), 3.71 (s, 3H, OCH
3), 3.76 (s, 3H, OCH
3), 3.91 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 7.23 (s, 1H, Ar-5H), 7.82 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 400.23464 (M+H) (calculated value: 474.27164).
the preparation of preparation example 31:Co.31
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 31a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.31 with obtaining the finished product 31b after ether/recrystallizing methanol.Productive rate is: 24%.
1H NMR (300MHz, CDCl
3): 1.864 (m, 2H, thf-H), 1.93-2.58 (m, 8H), 3.17-4.07 (m, 12H, thf-H, pip-H), 3.80 (s, 3H, OCH
3), 3.83 (s, 3H, OCH
3), 3.94 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 5.56 (m, 2H), 7.15 (s, 1H, Ar-5H), 7.71 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 536.25085 (M+H) (calculated value: 536.25091).
the preparation of preparation example 32:Co.32
Step 1: the in the situation that of argon atmospher, add 1d (2mmol) to being dissolved with in the solution of 1-amylalcohol of 32a (2mmol).After reaction system refluxes 4 hours, be placed on standing crystallization in 0-5 DEG C of environment.With 10mL washing with acetone gained white crystal twice, then be Compound C o.32 with obtaining the finished product 32b after ether/recrystallizing methanol.Productive rate is: 45%.
1H NMR (300MHz, CDCl
3): 1.860 (m, 2H, thf-H), 1.95-2.58 (m, 8H), 3.17-4.07 (m, 12H, thf-H, pip-H), 3.80 (s, 3H, OCH
3), 3.86 (s, 3H, OCH
3), 3.93 (s, 3H, OCH
3), 4.85 (m, 1H, thf-2H), 5.56 (m, 2H), 7.15 (s, 1H, Ar-5H), 7.71 (s, 1H, Ar-8H); HR-MS (ESI-positivity): 514.26655 (M+H) (calculated value: 514.26656).
B, biological test example part
1, the raising of fruit bat and screening compound
UAS-rpr and HS-Gal4 fruit bat are purchased from U.S. Bloomington storage center.The F1 filial generation (HS > rpr) of these two kinds of germline hybridization is for screening of medicaments.These filial generation fruit bats are brought up at 18 DEG C.Various medicines are dissolved in 5% glucose solution with the concentration using in the cell culture in cmap.By drug solution, (150 μ l) are placed on three layers of filter paper plate in tubule.Then, adult 20 1-3 ages in days HS > rpr fruit bat is placed in this bottle and reaches 1 day.For cell death inducing, make these fruit bats heat-shocked 2 hours at 37 DEG C.After heat-shocked 12 hours, calculate survival rate.
2, micro-array chip technical finesse and data analysis
The fruit bat (genetic background mates with control series) that 10 bottles of 1-3 ages in days are prepared in the filial generation of the hs-Gal4 of hybridizing from hs > rpr with yw67c23.In every bottle, contain 35 female fruit bats.This fruit bat (time is 0 hour) and heat-shocked before heat-shocked are refrigerated in liquid nitrogen for 1,2,3,4,5,6,7,8 and 12 hours.Prepare total RNA by RNeasy mini test kit (Quiagen, Inc).Be for further processing to remove the chromosomal DNA in sample with TURBO DNase test kit (Ambion, Inc).The quality of RNA sample detection and micro-array chip technical finesse step are to carry out according to Affymetrix DNA microarray chip technology standard scheme.Use the fruit bat 2.0DNA micro-array chip technology (Affymetrix, Inc) from Affymetrix.Process these arrays affects to reduce between different batches simultaneously.Use Arrayassist 5.0 (Affymetrix, Inc) software to carry out data analysis.The algorithm of " RMA " is for analytical data.Because each time point is only collected an experimental data point, three adjacent time points are analyzed jointly, and the intermediate value of this each time point is regarded as the data of this group.The for example time 0,1 and 2 is called " time 1 " in result.The present invention has designed micro-array chip technical data to increase the instantaneous resolving power of changes in gene expression in this process.The present invention infers and in transcribing, shown variation as fruit gene, and it can be reflected in adjacent time point.For functional gene enrichment, usage data of the present invention storehouse instrument (http://david.abcc.ncifcrf.gov/).
3, by contact graph discovery candidate compound
The present invention is transformed into Mammals homologous gene (www.affymetrix.com) by the upper mediation down-regulated gene from fruit bat micro-array chip technology by database.Then the scheme, providing based on cmap generates signal file (Lamb et al., 2006).After this, obtain the compound of positive correlation and negative correlation.These medicines are purchased from Sigma-Aldrich.
4, cell cultures and apoptosis induction
RAW 264.7 cells are cultivated in DMEM substratum (Gibco), in this substratum, be supplemented with 10%FBS (Gibco), 0.1g/L Streptomycin sulphate and 0.06g/L penicillin (Amresco).For cell death inducing, the RAW of 90% fusion 264.7 cells are being contained to 2 μ g/ml lipopolysaccharides (LPS; Escherichia coli O111:B4, Sigma) DMEM (10%FBS) in cultivate 24 hours.
5, Hoechst dyeing
First use Carnoy stationary liquid (75% ethanol, 25% acetic acid) fixed cell, then use Hoechst 33342 (10 μ g/ml, Sigma) dyeing 10min.After ice-cold PBS washing 3 times, by confocal microscope (TCS SP5, Leica) observation of cell.
6, septicemic cemia mouse model
Male BALB/C (20 ± 3g) mouse purchased from Vital River (Beijing company of dimension tonneau China, China) is raised the animal center in Peking University.All tests are by Peking University's animal maintenance and the use council (Peking University Institutional Animal Care and Use Committee) approval.For septicemic cemia LPS model, by injected in mice LPS (13.5mg/kg, i.p.) once.For septicemic cemia intestinal bacteria model, each injected in mice (i.p.) 1x10
8the bacterium of CFU.For drug test, 1.5 hours injection (i.p.) terazosins (0.4mg/kg or 0.04mg/kg) or solvent damping fluids after giving LPS.Every 12 hour record mouse lethality rate 7 days.
For septicemic cemia caecum ligation and puncture (CLP) model, with Chloral Hydrate (300mg/kg, i.p.) anesthetized mice.Ventrimeson cuts 1.5-2.0cm, exposes caecum.Separate after arteria ileocaeca, caecum is punctured once by No. 22 standard needle, and carrying out ligation from 5mm place, caecum top.Then make belly sealing by continous suture.Finally, by injecting (37 DEG C, the physiological saline of pre-temperature; 5ml/100g, s.c.) animal is recovered.For antibiotic therapy, give Co-Am (southern Shandong pharmacy group company, Shandong, China) (30mg/kg) by administration by gavage.Observe mouse survival rate every 12 hours and reach 7 days.
7, western blotting
For western blotting, the antibody test caspase-3 3 of the caspase-3 3 (#9664, Cell Signaling) activating by identification, the antibody of actin is purchased from Wuhan doctor's moral company.
8, DNA fragmentation fractional analysis
After lps injection 24 hours, take out a thymus gland from the mouse of accepting different treatments.Then extract chromosomal DNA by chromosomal DNA purification kit (Biofuture, Beijing, China).Evaluate DNA fragmentation degree by DNA agarose gel.
9, the analysis of bacteriostatic activity
Utilize Oxford cup to analyze the potential antibiotic activity of terazosin.The terazosin of different mass is added in the cup of Oxford, put into the LB culture dish that is paved with intestinal bacteria (Escherichia coli O111:B4), after 24 hours, observe terazosin and the impact of penbritin on Escherichia coli Growth.
10, the analysis of terazosin target
The present invention is upper by terazosin being connected to Affi-gel, then mixes with the protein extract of RAW 264.7 cells, washes off in connection with the foreign protein on Affi-gel.With the combining albumen wash-out of sample-loading buffer, after 96 degree heating, run glue (albumin glue of 15% concentration).Special protein band is cut, carry out Mass Spectrometric Identification.
11, the impact of terazosin on Pgk1 activity
At the Pgk1 of expression in escherichia coli mouse recombinant protein (His-Pgk1), then use ni-sepharose purification His-Pgk1.Purifying protein is diluted to every milliliter of 0.15 unit, adds the terazosin of gradient concentration, detect the activity of Pgk1.
12, the research of terazosin and Pgk1 avidity
With the Affi-gel of different treatment and the His-Pgk1 of purifying hatching, after 4 hours, wash away the albumen of non-specific binding, with the combining albumen wash-out of sample-loading buffer, after 96 degree heating, run glue (albumin glue of 15% concentration).
13, statistical study
For survival rate analysis, under Log Rank algorithm, use Kaplan-Meier inspection.For group relatively, use one-sided ANOVA inspection.In order to compare two data sets, the present invention uses student-t inspection.
According to the present invention, have been found that the new performance of terazosin, particularly it can be used as apoptosis inhibitor, and is used for the treatment of and/or prevents septicemia and complication thereof.
14, Pgk1 is active detects
Utilize the composition of Colorimetric GAPDHAssay Kit (ScienCell), and the GAPDH solution of buying and preparing, HEPES solution, MgSO4 solution.Then at reaction solution (30mM Hepes, 3mM ATP, 0.22mMNADH, 10mM MgSO4,10mM 3-PGA, the GAPDH of 3-4U/ml, pH 7.5) in add certain density formula I compound, at 25 DEG C with spectrophotometer (340nm) detect absorb.According to the variation of absorption value in 1-10 minute, calculate Pgk1 relative reactivity.Change sooner, activity is larger.Notice that experimental group will deduct the absorption at 340nm with isocyatic compound simultaneously.
The activity of formula I compound represents to activate the multiple of Pgk1, and wherein 0.02 μ g/ml terazosin can activate active 2.9 times of Pgk1; O.1, Compound C is tested under 0.02 μ g/ml concentration to Co.32, and the multiple that activates Pgk1 activity sees above respectively, and the multiple that for example Co.1 and Co.2 activate Pgk1 activity is respectively 2.9 and 2.3.
15, apoptosis-inducing and detection
By RAW 264.7 cell cultures (Gibco) in DMEM substratum, add 5% foetal calf serum and dual anti-(Streptomycin sulphate of 0.1mg/ml and the penicillin of 0.06mg/ml).Add lipopolysaccharides and the (LPS of 2 μ g/ml; Escherichia coli O111:B4, Sigma-Aldrich) gamma interferon (Peprotech) of 50U/ml is apoptosis-induced.Add certain density compound simultaneously.Assess apoptosis by the method for western blot, antibody is the activity form antibody (#9661, Cell Signaling) of Caspase 3.And taking β-Actin as internal reference (Boster).Assess with the value of Caspase 3/ β-Actin the degree that apoptosis occurs.
16, the hypoglycemic activity of terazosin
Give mouse shot terazosin (0.4mg/kg i.p.), after 18 hours, measure mouse blood sugar, find that blood sugar has reduced nearly 30% left and right (t-inspection, P < 0.01); And unknown significance difference while simultaneously giving salt solution.The results are shown in Figure 16.In identical test method, other exemplary compounds of the present invention for example Co.1, Co.3, Co.7, Co.9, Co.13, Co.16, Co.19, Co.24, Co.27, Co.32 all show can make blood sugar reduce by 20% to 50%.
17, the effect of the anti-cerebral thrombosis of terazosin
Make mouse brain thrombus model, after mouse is because of thrombus death, cerebral tissue is dyeed, result is presented at brain sheet middle part and presents white (it is the typical phenomenon of brain death); When shot terazosin (0.4mg/kg i.p.), can obviously reduce thanatogenic tissue's area.Result is added up, taking % thanatogenic tissue=white portion area/total area as investigating index, mouse quantity=6 under every kind of condition.Through t-inspection, P < 0.05.The results are shown in Figure 17, result from figure, terazosin can obviously reduce the area of brain death tissue.In identical test method, other exemplary compounds of the present invention for example Co.1, Co.4, Co.7, Co.8, Co.13-14, Co.16, Co.19, Co.24-27, Co.29, Co.31-32 all show can obviously reduce thanatogenic tissue's area, P < 0.05.
18, anti-septicemia effect
BALB/C mice (20 grams of left and right) intraperitoneal injection of LPS (13.5mg/kg), injects certain density medicine after one and a half hours, within every 12 hours, observe the survival of a mouse, observes altogether 7 days, and statistics survival has there was no significant difference.
Alternate model is caecum puncture and ligation (CLP).After mouse anesthesia, cut off the osculum of 1.5-2 centimetre at its belly, caecum is taken out.Ight soil is extruded into caecum bottom, be 5 millimeters away from caecum top locate ligation, then wear an aperture with No. 22 syringe needles, extrude some ight soil.Caecum is put back to abdominal cavity, with linear slit well and wound closure.After one and a half hours, inject certain density medicine, within every 12 hours, observe the survival of a mouse, observe altogether 7 days, statistics survival has there was no significant difference.
Result shows, in the test of above two kinds of models, Compound C o.1, Co.4, Co.9, Co.13, Co.18, Co.21, Co.28, Co.29, Co.33 be respectively to inject once a day (0.4mg/kg i.p.) successive administration after 3 days, in the time that within 7 day, the observation period finishes, show that these compounds all can significantly improve the survival rate of mouse (P < 0.05, with the control group comparison of not giving medicine).
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