CN102526057A - Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator - Google Patents
Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator Download PDFInfo
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- CN102526057A CN102526057A CN2011104139310A CN201110413931A CN102526057A CN 102526057 A CN102526057 A CN 102526057A CN 2011104139310 A CN2011104139310 A CN 2011104139310A CN 201110413931 A CN201110413931 A CN 201110413931A CN 102526057 A CN102526057 A CN 102526057A
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- Prior art keywords
- alkyl
- terazosin
- chemical compound
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Images
Abstract
The invention relates to a quinazoline derivative as a pgk1 (phosphoglycerate kinase 1) activator. Specially, the invention relates to application of the compound shown in formula I or pharmaceutically-acceptable salts, solvates, esters and prodrugs thereof in preparing medicines as pgk1 activators, or in preparing medicines for treating and/or preventing hyperglycemia, cerebral thrombosis and complications thereof, wherein the substituents are indicated as in the specification.
Description
Technical field
The present invention relates to as the quinazoline derivant of pgk1 activator terazosin for example, and their purposes in diseases such as treatment hyperglycemia, cerebral thrombosis.
Background technology
Septicemia (Sepsis) is a first cause dead in the global intensive care unit.Septicemia is according to the unusual adjusting (Bone et al., 1996) of thinking a kind of inflammation of complicacy.Yet many clinical trials of cytokine or antiinflammatory specificity medicament fail significantly to improve septicemia patient's survival, rethink that the septicemic cemia strategy of treatment is necessary.Although effect is limited, antibiotic therapy is the septicemic cemia important channel of treatment.Basic research shows, suppresses effectively blocking test property septicemia of apoptosis.In the septicemia patient, the apoptosis of immunocyte can further weaken immunne response.In addition, the blocking-up apoptosis has been proved to be the septicemic cemia Critical policies of a kind of treatment (Braun et al., 1999; Hotchkiss et al., 2000; Chung et al., 2001; Weaver et al., 2004; Wesche-Soldato et al., 2005).
Apoptosis is a kind of basic biological phenomena of cell, removes multicellular organism to play a part necessity in the unwanted or unusual cell.It plays an important role in the growth of stable and a plurality of systems of the evolution of organism, interior environment.Apoptosis is not only a kind of special cell death type, and has important biological significance and complicated The Molecular Biology Mechanism.Apoptosis is the process of the strict control of polygenes.These genes are very conservative between kind; Like Bcl-2 family, caspase family, oncogene such as C-myc, antioncogene P53 etc.; Along with the development of Protocols in Molecular Biology has had suitable understanding to the process of apoptosis of many kinds, but the apoptotic process precise mechanism still imperfectly understands up to now.And the disorder of apoptotic process maybe with the direct or indirect relation of having of numerous disease.People understand since the brain death that cerebral thrombosis causes also with apoptosis-related.In addition, the activation that it is believed that PGK 1 (phosphoglycerate kinase 1 abbreviates pgk1 as) helps some diseases for example relevant with apoptosis treatment or prevention.
Terazosin (Terazosin) is used for clinical usually with its hydrochlorate, the specification of gone on the market tablet or capsule has 1mg, 2mg and 5mg.Terazosin hydrochloride can be used for treating benign prostate hyperplasia, also can be used for treating hypertension, can use separately or share with other antihypertensive drug such as diuretic or Alpha 1 adrenergic blocking agent.To existing clinical indication, the daily dose usual range that terazosin is used to be grown up is 1～10mg.Terazosin is used to treat benign prostatic hyperplasia (BPH), and the 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 bladder and the prostate after the medication.Because few relatively alpha 1 adrenergic receptor is arranged in body of bladder, so terazosin can alleviate the obstruction of bladder outlet and not influence the contraction of bladder.In addition, thus terazosin reduces blood pressure through reducing total peripheral vascular resistance.As if the vasodilation of terazosin, blood pressure reduction effect mainly are caused by the alpha 1 adrenergic receptor blocking-up.
Up to now; Still lack effective apoptosis inhibitor clinically; Novel anti--apoptotic the chemical compound of exploitation to be being used for for example treating and/or preventing septicemia and complication thereof, and apoplexy septicemia and complication thereof are noticeable goals in research.
Summary of the invention
The purpose of this invention is to provide the new method and the novel targets that treat and/or prevent septicemia and complication thereof.The inventor is surprisingly found out that, one type of quinazoline derivant is for example clinical to be used for benign prostate hyperplasia and hypertensive medicine terazosin can effectively treat and/or prevent septicemia and complication thereof separately or with the antibiotic combination.The present invention is based on this discovery and be accomplished.
Summary of the invention
First aspect present invention relates to formula I chemical compound,
Or the acceptable salt of its pharmacy, solvate, ester, prodrug, wherein
R
1aAnd R
1bBe selected from H, NH independently of one another
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, C
1-6Alkyl acyl-, aryl-acyl-, C
6-10Aryl-, C
5-6Cycloalkyl-, perhaps R
1aAnd R
1bNitrogen-atoms with their connections forms 5-or 6-unit ring, and wherein said alkyl is optional to be selected from following substituent group replacement by 1-3: hydroxyl, halogen;
R
2And R
3Be selected from H, halogen, C independently of one another
1-6Alkyl-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, CN, NO
2, NH
2, OH, C
1-6Alkoxyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, C
1-6Alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6Alkyl acyl-, perhaps R
2And R
3The annular atoms that connects with them forms 5-or 6-unit's carbocyclic ring or heterocycle;
R
4And R
5Be selected from H, halogen, CN, NO independently of one another
2, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, 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 chemical compound for example terazosin the preparation as the purposes in the medicine of apoptosis inhibitor; Formula I chemical compound for example terazosin in preparation as the purposes in the medicine of pgk1 activator, perhaps formula I chemical compound for example terazosin treat and/or prevent the purposes in the medicine of septicemia and complication thereof in preparation.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises the formula I chemical compound for example terazosin or acceptable salt of its pharmacy or the solvate that treat and/or prevent effective dose, and optional pharmaceutically acceptable carrier.
Fourth aspect present invention provides a kind of medicine box product, comprising the formula I chemical compound that treats and/or prevents effective dose for example terazosin or acceptable salt of its pharmacy or solvate, and at least a antimicrobial agents.
Fifth aspect present invention relates to and in experimenter that needs are arranged or biological sample, suppresses apoptotic method; In experimenter that needs are arranged or biological sample, activate the method for pgk1, perhaps in the experimenter who needs is arranged, treat and/or prevent the method for septicemia and complication thereof.
Sixth aspect present invention relates to as apoptosis inhibitor, as the pgk1 activator, or as the formula I chemical compound that treats and/or prevents septicemia and complication thereof terazosin for example.
Description of drawings
Fig. 1 has described and has induced HS-Gal4 to express the 1-3 hour survival rate of apoptosis HS＞rpr fruit bat afterwards.Each point is represented meansigma methods+SE.Test n=6.
Fig. 2 is the chemical compound tabulation of using in the drug screening.These chemical compounds are based on the Cmap selection.Divide into groups according to their positive correlation or the negative correlation of apoptotic micro-array chip technology.
Fig. 3 has described with apoptosis fruit bat model discrimination medicine.The apoptosis fruit bat is represented with average+SE the survival rate of every kind of medicine.Contrast (not giving medicine) shows with white rod.Giving different drug representes with white or black rod respectively.Test n=5.
Fig. 4 has described that terazosin (4 μ g/ml) can significantly stop because the apoptosis due to LPS and the IFN γ toxicity.By Annexin V painted be apoptotic cell.The statistical result showed terazosin apoptosis capable of inhibiting cell that test obtains.Every group of cell number counting is 200-250 cell.
Among Fig. 5, Fig. 5 a has described the survival rate curve of terazosin (0.4mg/kg) to septicemic cemia LPS modelling effect.Carry out the survival rate tracing analysis with Log Rank algorithm through Kaplan-Merier check.Number of mice and the p value used are shown among this figure.Fig. 5 b has described agarose gel and has shown LPS treatment dna break afterwards.Every band is represented the genomic DNA from the thymus of mice.The processing method of each mice is marked on the top of every band.
Fig. 6 has described the survival rate of mice after lps injection (13.5mg/kg) uses terazosin (0.04mg/kg) after 12 hours.Analyze through the Kaplan-Merier check with Log Rank algorithm.Number of mice and the p value used are shown among this figure, and T representes terazosin among the figure.
Fig. 7 has described the survival rate curve of septicemic cemia escherichia coli model.The escherichia coli injection was injected terazosin (0.4mg/kg) after 1.5 hours.Analyze through the Kaplan-Merier check with Log Rank algorithm.Number of mice and the p value used are shown among this figure.
Fig. 8 has described the influence of terazosin to the escherichia coli growth.Use after the terazosin 24 hours, through inhibition zone relatively it and ampicillin to the effect of bacterial growth.The result shows among the figure, do not add the contrast (control) of medicine and the terazosin of various dose (0.2 μ g T, 2 μ g T, 200 μ g T, 2mg T) and all can not suppress the escherichia coli growth, and ampicillin (2mg Amp) shows that suppressing escherichia coli grows.
Fig. 9 has described the survival rate curve of terazosin to the effect of septicemic cemia CLP model.After CLP, passed through twice terazosin of subcutaneous injection with 0.08mg/kg in 1.5 and 24 hours.Use antibiotic Co-Am that the CLP model is had the increase phenomena of mortality separately.And the combination of terazosin and antibiotic Co-Am has protective effect to septicemic cemia CLP model.Analyze through the Kaplan-Merier check with the LogRank algorithm.Quantity and the p value of the mice of using are shown among this figure.T representes terazosin among the figure, and Co-Am representes that the weight ratio of amoxicillin and clavulanate potassium is 4: 1 a mixture.
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 disposal is identical.
Figure 11 has described the terazosin chemical modification and has produced the chemical process that Affi-gel connects.
Among Figure 12, figure a described with the terazosin agarose beads angle albumen obtained one obviously a protein band that in experimental group, occurs (between the 43kd to 55kd with the band of arrow labeled).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 the Pkg1 band, explains that terazosin and Pgk1 can directly combine.
Figure 13 has described the terazosin of variable concentrations to the active influence of Pgk1.
But Figure 14 has described to express the Raw 264.7 cell antagonism apoptosis of Pgk1.Apoptotic cells membrane phospholipid acyl serine takes place by rollover in the adipose membrane laterally.Annexin V and phospholipids incorporate, thereby labelling apoptotic cells.
Figure 15 shows protective effect after having described mouse infection Pgk1 slow virus in the CLP model.Every injected in mice 1x10
7The virus of individual active unit experimentized 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
The specific embodiment
First aspect present invention relates to formula I chemical compound,
Or the acceptable salt of its pharmacy, solvate, ester, prodrug, wherein
R
1aAnd R
1bBe selected from H, NH independently of one another
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, C
1-6Alkyl acyl-, aryl-acyl-, C
6-10Aryl-, C
5-6Cycloalkyl, perhaps R
1aAnd R
1bNitrogen-atoms with their connections forms 5-or 6-unit ring, and wherein said alkyl is optional to be selected from following substituent group replacement by 1-3: hydroxyl, halogen;
R
2And R
3Be selected from H, halogen, C independently of one another
1-6Alkyl-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, CN, NO
2, NH
2, OH, C
1-6Alkoxyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, C
1-6Alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6Alkyl acyl-, perhaps R
2And R
3The annular atoms that connects with them forms 5-or 6-unit's carbocyclic ring or heterocycle;
R
4And R
5Be selected from H, halogen, CN, NO independently of one another
2, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, 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 chemical compound of first aspect present invention, wherein R
1aAnd R
1bBe selected from H, NH independently of one another
2, OH, C
1-6Alkyl-, C
1-4Alkoxy-C
1-4Alkyl-, C
2-4Thiazolinyl-, C
2-4Alkynyl-, C
1-4Alkoxyl-, C
1-4Alkyl acyl-, the phenyl acyl group-, phenyl-, C
5-6Cycloalkyl, perhaps R
1aAnd R
1bNitrogen-atoms with their connections forms 5-or 6-unit ring, and wherein said alkyl is optional to be selected from following substituent group replacement by 1-3: hydroxyl, halogen.In one embodiment, said 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 chemical compound of first aspect present invention, wherein R
2And R
3Be selected from H, halogen, C independently of one another
1-6Alkyl-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, C
1-6Alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, perhaps R
2And R
3The annular atoms that connects with them forms 5-or 6-unit's carbocyclic ring or heterocycle.In one embodiment, said R
2And R
3Be selected from H, CH independently of one another
3O-,-CH
2-O-CH
2-,-O (CH
2)
2OC
2H
5,-OC (O) CH
3,-F ,-CF
3,
And 1, the 2-pyridine ring ,-NHCOCH
3,-(CH
2)
2CH
3,-NHCOPh,
According to the chemical compound of first aspect present invention, wherein R
4And R
5Be selected from H, halogen, C independently of one another
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, 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, said 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 chemical compound of first aspect present invention, wherein said alkyl, thiazolinyl and alkynyl are straight chain or side chain.In one embodiment, said C
1-6Alkyl is selected from C
1-5Alkyl, C
1-4Alkyl, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group.In one embodiment, said C
2-6Thiazolinyl is selected from C
2-5Thiazolinyl, C
2-4Thiazolinyl, for example vinyl, acrylic, pi-allyl.In one embodiment, said C
2-6Alkynyl is selected from C
2-5Alkynyl, C
2-4Alkynyl.
According to the chemical compound of first aspect present invention, wherein said C
5-6Cycloalkyl is selected from cyclopenta and cyclohexyl.
According to the chemical compound of first aspect present invention, wherein said aryl is selected from phenyl, naphthyl, preferred phenyl.
According to the chemical compound of first aspect present invention, wherein said halogen is selected from fluorine, chlorine, bromine and iodine, preferred fluorine and chlorine.
According to the chemical compound of first aspect present invention, it is the chemical compound (their structure such as compound example part are said) that is selected from the following Co.1 to Co.33 of being numbered:
Annotate: active * representes that each chemical compound tests under 0.02 μ g/ml concentration, activate the active multiple of Pgk1.
Second aspect present invention relate to formula I chemical compound for example terazosin the preparation as the purposes in the medicine of apoptosis inhibitor.
Second aspect present invention also relate to formula I chemical compound for example terazosin the preparation as the purposes in the medicine of pgk1 activator.
Second aspect present invention also relate to formula I chemical compound for example terazosin treat and/or prevent the purposes in the medicine of septicemia and complication thereof in preparation.
Second aspect present invention also relate to formula I chemical compound for example terazosin treat and/or prevent 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 is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the purposes of second aspect present invention, wherein said pgk1 activator is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detects.
According to the purposes of second aspect present invention, wherein said septicemia is the septicemia that antibacterial 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 failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
Purposes according to second aspect present invention; Wherein said formula I chemical compound for example terazosin dosage every day that is used for human or animal (for example mammal) is 0.001～5mg/kg, preferred 0.002～4mg/kg, preferred 0.003～3mg/kg; Preferred 0.005～2.5mg/kg; Preferred 0.0075～2mg/kg, preferred 0.01～2mg/kg, preferred 0.01～1mg/kg.
According to the purposes of second aspect present invention, wherein said formula I chemical compound is a terazosin.
According to the purposes of second aspect present invention, wherein terazosin is the acceptable salt of pharmacy or its solvate of terazosin.
According to the purposes of second aspect present invention, wherein said terazosin is the hydrochlorate of terazosin.
According to the purposes of second aspect present invention, wherein said terazosin is the hydrate of terazosin hydrochlorate.In one embodiment, terazosin is the dihydrate of terazosin hydrochlorate.
According to the purposes of second aspect present invention, also comprise at least a antimicrobial agents in the wherein said medicine.
Purposes according to second aspect present invention; Also comprise at least a antimicrobial agents in the wherein said medicine, said antimicrobial agents is selected from: PCs, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, TCs, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
Purposes according to second aspect present invention; Also comprise at least a antimicrobial agents in the wherein said medicine, said antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, also comprise at least a antimicrobial agents in the said medicine, said antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, also comprise amoxicillin and clavulanate potassium in the said medicine.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises the formula I chemical compound for example terazosin or acceptable salt of its pharmacy or the solvate that treat and/or prevent effective dose, and optional pharmaceutically acceptable carrier.
According to the pharmaceutical composition of third aspect present invention, wherein also comprise at least a antimicrobial agents.
Pharmaceutical composition according to third aspect present invention; Wherein also comprise at least a antimicrobial agents, said antimicrobial agents is selected from: PCs, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, TCs, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
Pharmaceutical composition according to third aspect present invention; Wherein also comprise at least a antimicrobial agents, said antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, also comprise at least a antimicrobial agents in the said pharmaceutical composition, said antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, also comprise amoxicillin and clavulanate potassium in the said pharmaceutical composition.
According to the pharmaceutical composition of third aspect present invention, it is to be used for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the pharmaceutical composition of third aspect present invention, it is as the pgk1 activator.In one embodiment, wherein said pgk1 activator is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the pharmaceutical composition of third aspect present invention, it is to be used to treat and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.In one embodiment, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, 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 to be used to treat and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
Pharmaceutical composition according to third aspect present invention; Wherein said formula I chemical compound for example terazosin dosage every day that is used for human or animal (for example mammal) is 0.001～5mg/kg, preferred 0.002～4mg/kg, preferred 0.003～3mg/kg; Preferred 0.005～2.5mg/kg; Preferred 0.0075～2mg/kg, preferred 0.01～2mg/kg, preferred 0.01～1mg/kg.
Fourth aspect present invention provides a kind of medicine box product, comprising the formula I chemical compound that treats and/or prevents effective dose for example terazosin or acceptable salt of its pharmacy or solvate, and at least a antimicrobial agents.
According to the medicine box product of fourth aspect present invention, wherein said formula I chemical compound for example terazosin or the acceptable salt of its pharmacy or solvate and said at least a antimicrobial agents is in same compositions or in composition isolated.
According to the medicine box product of fourth aspect present invention, wherein said formula I chemical compound for example terazosin or the acceptable salt of its pharmacy or solvate and said at least a antimicrobial agents is in composition isolated.
Medicine box product according to fourth aspect present invention; Comprising first compositions that is separated from each other and second compositions; Said first compositions comprises formula I chemical compound for example terazosin or the acceptable salt of its pharmacy or the solvate and optional pharmaceutically acceptable carrier that treats and/or prevents effective dose, and said second compositions comprises the antimicrobial agents and optional pharmaceutically acceptable carrier that treats and/or prevents effective dose.
According to the medicine box product of fourth aspect present invention, wherein said antimicrobial agents is selected from: PCs, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, TCs, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
According to the medicine box product of fourth aspect present invention, wherein said antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, said antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, said antimicrobial agents comprises amoxicillin and clavulanate potassium.
According to the medicine box product of fourth aspect present invention, it is to be used for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the medicine box product of fourth aspect present invention, it is as the pgk1 activator.In one embodiment, wherein said pgk1 activator is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the medicine box product of fourth aspect present invention, it is to be used to treat and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.In one embodiment, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, 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 to be used to treat and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
Medicine box product according to fourth aspect present invention; Wherein said formula I chemical compound for example terazosin dosage every day that is used for human or animal (for example mammal) is 0.001～5mg/kg, preferred 0.002～4mg/kg, preferred 0.003～3mg/kg; Preferred 0.005～2.5mg/kg; Preferred 0.0075～2mg/kg, preferred 0.01～2mg/kg, preferred 0.01～1mg/kg.
Fifth aspect present invention relates in experimenter that needs are arranged or biological sample and to suppress apoptotic method, and this method comprises the formula I chemical compound terazosin for example of using effective dose to said experimenter or biological sample.
Fifth aspect present invention also relates in experimenter that needs are arranged or biological sample the method that activates pgk1, and this method comprises the formula I chemical compound terazosin for example of using effective dose to said experimenter or biological sample.
Fifth aspect present invention also relates to the method that in the experimenter of needs is arranged, treats and/or prevents septicemia and complication thereof, and this method comprises the formula I chemical compound terazosin for example of using effective dose to said experimenter.
Fifth aspect present invention also relates to the method that in the experimenter of needs is arranged, treats and/or prevents hyperglycemia, cerebral thrombosis and complication disease thereof, and this method comprises the formula I chemical compound terazosin for example of using effective dose to said experimenter.
According to the method for fifth aspect present invention, wherein said septicemia is the septicemia that antibacterial 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 failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
Method according to fifth aspect present invention; Wherein said formula I chemical compound for example terazosin dosage every day that is used for human or animal (for example mammal) is 0.001～5mg/kg, preferred 0.002～4mg/kg, preferred 0.003～3mg/kg; Preferred 0.005～2.5mg/kg; Preferred 0.0075～2mg/kg, preferred 0.01～2mg/kg, preferred 0.01～1mg/kg.
According to the method for fifth aspect present invention, wherein said formula I chemical compound is a terazosin.
According to the method for fifth aspect present invention, wherein terazosin is the acceptable salt of pharmacy or its solvate of terazosin.
According to the method for fifth aspect present invention, wherein said terazosin is the hydrochlorate of terazosin.
According to the method for fifth aspect present invention, wherein said terazosin is the hydrate of terazosin hydrochlorate.In one embodiment, terazosin is the dihydrate of terazosin hydrochlorate.
According to the method for fifth aspect present invention, wherein also comprise at least a antimicrobial agents of using effective dose to said experimenter or biological sample.
Method according to fifth aspect present invention; Wherein also comprise at least a antimicrobial agents of using effective dose to said experimenter or biological sample, said antimicrobial agents is selected from: PCs, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, TCs, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
Method according to fifth aspect present invention; Wherein also comprise at least a antimicrobial agents of using effective dose to said experimenter or biological sample, said antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, said antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, said antimicrobial is amoxicillin and clavulanate potassium.
Sixth aspect present invention relates to as the formula I chemical compound of apoptosis inhibitor terazosin for example.
Sixth aspect present invention also relates to as the formula I chemical compound of pgk1 activator terazosin for example.
Sixth aspect present invention also relates to as the formula I chemical compound that treats and/or prevents septicemia and complication thereof terazosin for example.
Sixth aspect present invention also relates to as the formula I chemical compound that treats and/or prevents hyperglycemia, cerebral thrombosis and complication thereof terazosin for example.
According to the formula I chemical compound of sixth aspect present invention, wherein said apoptosis inhibitor is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the formula I chemical compound of sixth aspect present invention, wherein said pgk1 activator is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
According to the formula I chemical compound of sixth aspect present invention, wherein said septicemia is the septicemia that antibacterial and/or other infected by microbes cause.
According to the formula I chemical compound of sixth aspect present invention, wherein said septicemic cemia complication is selected from: renal failure, respiratory failure, blood coagulation disorders, organ injury (including but not limited to toxic myocardosis change, encephalopathy, hepatopathy and toxical paralytic ileus etc.), purulent meningitis, pneumonia, pulmonary abscess, cellulitis, osteomyelitis, pyelonephritis.
Formula I chemical compound according to sixth aspect present invention; Dosage every day that wherein said formula I chemical compound is used for human or animal (for example mammal) is 0.001～5mg/kg, preferred 0.002～4mg/kg, preferred 0.003～3mg/kg; Preferred 0.005～2.5mg/kg; Preferred 0.0075～2mg/kg, preferred 0.01～2mg/kg, preferred 0.01～1mg/kg.
According to the formula I chemical compound of sixth aspect present invention, it is a terazosin.
According to the formula I chemical compound of sixth aspect present invention, it is the acceptable salt of pharmacy or its solvate of terazosin.
According to the formula I chemical compound of sixth aspect present invention, it is the hydrochlorate of terazosin.
According to the formula I chemical compound of sixth aspect present invention, it is the hydrate of terazosin hydrochlorate, for example the dihydrate of terazosin hydrochlorate.
According to the formula I chemical compound of sixth aspect present invention, it also makes up with at least a antimicrobial agents.
Formula I chemical compound according to sixth aspect present invention; It also makes up with at least a antimicrobial agents, and said antimicrobial agents is selected from: PCs, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, TCs, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
Formula I chemical compound according to sixth aspect present invention; It also makes up with at least a antimicrobial agents, and said antimicrobial agents is selected from: amoxicillin, penicillin, penicillin V, oxazacillin, cloxacillin, flucloxacillin, ampicillin, piperacillin, azlocillin, clavulanate potassium, sulbactam, sultamicillin, tazobactam, aztreonam, meropenem.In one embodiment, said antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, said antimicrobial agents is amoxicillin and clavulanate potassium.
For example the use amount of terazosin can be with reference to existing clinical medicine dose for arbitrary aspect according to the present invention, wherein said formula I chemical compound.For example when being used for human therapy and/or prevention septicemia and complication thereof; The using dosage of terazosin can be at present clinically this medicine be used for 0.01～100 times of dosage of other disease (for example hypertension), preferred 0.02～80 times, preferred 0.05～20 times; Preferred 0.1～10 times; Preferred 0.1～5 times, preferred 0.2～5 times, preferred 0.2～2 times.
Arbitrary aspect according to the present invention, the use amount of wherein said antimicrobial agents can be with reference to existing clinical medicine dose.For example when being used for human therapy and/or prevention septicemia and complication thereof; Its using dosage can be at present clinically this antimicrobial agents be used for 0.01～100 times of dosage of other disease (for example infection); Preferred 0.02～80 times; Preferred 0.05～20 times, preferred 0.1～10 times, preferred 0.2～5 times.
Arbitrary aspect according to the present invention, the use amount of wherein said amoxicillin and/or clavulanate potassium can be with reference to existing clinical medicine dose.For example when being used for human therapy and/or prevention septicemia and complication thereof; Its using dosage can be that this amoxicillin and/or clavulanate potassium are used for 0.01～100 times of dosage of other disease (for example infection) clinically at present; Preferred 0.02～80 times; Preferred 0.05～20 times, preferred 0.1～10 times, preferred 0.2～5 times.
In some embodiments aspect the present invention is arbitrary, said formula I chemical compound does not comprise the chemical compound of numbering Co.33.
The characteristic that arbitrary embodiment had of the arbitrary aspect of the present invention or this arbitrary aspect is equally applicable to arbitrary embodiment of other arbitrary aspect or this other arbitrary aspect; 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.
Do further to describe with characteristics to various aspects of the present invention below.
All documents that the present invention quoted from, their full content is incorporated this paper by reference into, and if the expressed implication of these documents and the present invention when 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 hopes at this more detailed explanation and explanation to be done in these terms and phrase, and term of mentioning and phrase are as the criterion with the implication that the present invention was explained if any inconsistent with known implication.
As described herein; Term " septicemia " also is called " septicemia "; It has the common known implication of those skilled in the art, and typically refers to a kind of because antibacterial and/or other microorganism gets into blood circulation, and therein growth and breeding, produce toxin and the general severe infections that causes.Clinical manifestation is increased etc. for heating, serious toxemic symptoms, erythra petechia, hepatosplenomegaly and leukocyte count.The GPC septicemia is prone to migrate focus; Gram-negative bacteria septicemia is prone to concurrent infection property shock.When septicemia is called pyaemia septica or is called sepsis during with multiple abscess.
As described herein; Term " pgk1 activator " is meant PGK 1 (phosphoglycerate kinase 1; Abbreviate pgk1 as) activator, therefore it can activate pgk1 and it will be apparent to those skilled in the art that disease or treatment of conditions that it can be used for being correlated with, prevents, alleviates and/or alleviate.
The term " about " of using among this paper, it typically refers to the range of error that comprises that this area allows, for example ± 10%, for example ± 5%, for example ± 2%.
As described herein, term " effective dose " is meant the dosage that can in the experimenter, realize treating, prevent, alleviate and/or alleviating disease according to the invention or disease.
As described herein, term " pharmaceutical composition ", it can exchange with " compositions " and use, and is meant to be used in the material of realizing treating, prevent, alleviate and/or alleviating disease according to the invention, disease, symptom among the experimenter.
As described herein; Term " experimenter " or " patient "; Can receive the present composition and extract to treat, to prevent, to alleviate and/or to alleviate the animal of disease according to the invention, disease, symptom, particularly mammal by finger, for example people, Canis familiaris L., monkey, cattle, horse etc.
As described herein, term " disease or symptom " is meant a kind of condition of said experimenter, this condition is relevant with disease according to the invention or symptom.
As described herein, " % ", as do not specialize, generally be meant the percentage ratio of w/w when being solid for total material, generally be meant the percentage ratio of weight/volume when being liquid for total material.Certainly, be liquid and solute when being liquid for total material, the percentage ratio that characterizes this liquid solute generally is meant the percentage ratio of volume.
Terazosin (Terazosin, (4-(4-amino-6,7-dimethoxyquinazoline-2-yl) piperazine-1-yl) (oxolane-2-yl) ketone, C
19H
25N
5O
4), it has following chemical structural formula:
In the present invention, when mentioning terazosin, it not only comprises the chemical compound shown in the above structure, also comprises the acceptable salt of pharmacy (for example hydrochlorate) of said structure chemical compound, and the solvate of said structure chemical compound and salt thereof hydrate for example.In a preferred embodiment of the invention, said terazosin is meant the terazosin hydrochloride dihydrate.Hereinafter of the present invention uses the terazosin as formula I chemical compound typical case to carry out big quantity research to show the beat all effect of the present invention; Test hereinafter particularly in the biological test, as not indicating in addition, used reagent terazosin is meant the terazosin hydrochloride dihydrate.
The present invention attempts from clinical medicine, screening apoptosis inhibitor.At first, the present invention uses the model of cell apoptosis of fruit bat to pass through the gene expression of micro-array chip technical Analysis.Then, the present invention uses contact figure (connectivity map Cmap) decides candidate's apoptosis blocker through the 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 confirmed terazosin, and it is for alleviating hypertensive clinical application.In addition, the present invention finds that terazosin can suppress in the macrophage by bacterial endotoxin (lipopolysaccharide, LPS, 2 μ g/ml) and interferon gamma (IFN γ, 50U/ml) apoptosis of mediation.In addition, the present invention finds that in septicemic cemia three test models, terazosin can reduce mortality of mice greatly.What is interesting is, compare, make terazosin and antibiotic combination can produce the better protection effect with independent use antibiotic.Result of the present invention shows that terazosin is a kind of new apoptosis inhibitor.It can be used for making up with antibiotic therapy.
Fruit bat is the important animal model system of screening of medicaments.In addition, caspase-3 (caspase)-mediated Apoptosis approach is fully conservative between dipteral insect and people.For example Reaper (rpr) brings into play main effect (White et al., 1994) in the apoptosis of fruit bat.Though, can cause the abnormal cell 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 and can use fruit bat apoptosis model to screen the apoptosis blocker.HS-Gal4 (a kind of whole body expression and heat activated promoter) can impel 5 ' the multiple any genetically modified expression that contains UAS (upstream activating sequence).(when abbreviating HS＞rpr) as, female descendant is normal development from start to finish when under 18 ℃, making this HS-Gal4 fruit bat and UAS-Reaper drosophila hybrid.Yet, under 37 ℃, give heat shock 2-3 hour, approximately the offspring of 50-70% after 14-24 hour dead (Fig. 1).The present invention has selected 25 kinds of chemical compounds (Fig. 2) that rank is forward, and their influences to the fatality rate of HS＞rpr are decided in the pacing of going forward side by side.The present invention finds only have terazosin can improve the survival (Fig. 3) of HS＞rpr fruit bat significantly.
Whether also in the mammalian cell of cultivating, suppress apoptosis in order to test terazosin; Through LPS and IFN γ cell death inducing, this LPS and IFN γ bring out apoptotic known medicament in cultured cell in macrophage RAW264.7 cell in the present invention.The present invention is through dyeing observation of cell apoptosis (Fig. 4) with Annexin V.The inventor finds that the cell that LPS (2 μ g/ml) and IFN γ (50U/ml) handle causes cell membrane damage, turns up, thereby is dyeed by Annexin V.This is a kind of apoptosis pattern of classics.Can reduce by 50% apoptosis (Fig. 4) and use terazosin (4 μ g/ml).Importantly, the present invention finds that unexpectedly terazosin can effectively suppress apoptosis and can be further used for treating and/or preventing septicemia and complication thereof.
In order further in septicemic cemia mammal model, to study the effect of terazosin, the present invention has studied the mice of accepting the LPS treatment.The present invention finds, injection LPS (13.5mg/kg, i.p.) afterwards 1.5 hours the injection terazosin (0.4mg/kg i.p) can significantly increase the mice survival (Fig. 5 a).In order to confirm the effect of terazosin pair cell apoptosis, the present invention has detected apoptotic label dna break.As the organ that produces immunocyte, thymus pair cell apoptosis is responsive (Ayala et al., 1998) during the septicemia.Therefore, the present invention has compared the genomic DNA of genomic DNA and the mouse thymus that adds the terazosin treatment with LPS of the mouse thymus of the LPS treatment of using by oneself.The result shows, in the mice that LPS handles, obvious dna ladder type has taken place, but in the mice with the terazosin treatment, reduces (Fig. 5 b) greatly.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.The result shows that terazosin still has satisfied effect (Fig. 6).
Then, in the colibacillary septicemia model of injection, tested terazosin.The result shows that terazosin can protect mice by the inductive death of escherichia coli (Fig. 7).In order to measure potential antibacterial effect, the inventor has detected the escherichia coli growing state in the presence of terazosin.The result shows that with respect to ampicillin, terazosin can not suppress escherichia coli growths (Fig. 8).
Because only simulating gram-negative bacteria, LPS and escherichia coli model infect; The present invention has further tested terazosin in caecum ligation and puncture (CLP) model; This model is according to thinking tentative septicemic cemia goldstandard model (Parker and Watkins, 2001; Wichterman et al., 1980).At first, the present invention detects the terazosin (being used for the identical concentration of LPS model) of 0.4mg/kg.Yet, at initial 5 days, faster (data not shown) that the mice of injection terazosin is more dead than matched group.The present invention infers that this possibly be because the serious heart dysfunction and the hypotension that are caused by CLP cause.Therefore, the function that brings high blood pressure down of medicine possibly covered its anti-effect of apoptosis.For head it off, the present invention is reduced to 0.08mg/kg with terazosin concentration, and the inventor has measured the influence of this concentration of injected in mice to blood pressure, finds that the mice blood pressure is normal fully.This result is used in can not bring high blood pressure down in the rat consistent (Kyncl et al., 1985) with it.What is interesting is that when 1.5 hours and 24 hours were injected 2 times after operation, terazosin had significantly promoted the survival (Fig. 9) of mice in the CLP model.Secondly; The present invention has tested terazosin and antibiotic combination; In the present invention, selected antibiotic amoxicillin and clavulanate potassium (Co-Am, the weight ratio of amoxicillin and clavulanate potassium is 4: 1; When other place of the present invention is mentioned with the mode of concrete example or instance, also be meant this 4: 1 proportioning.It will be appreciated by those skilled in the art that the weight ratio of amoxicillin and clavulanate potassium can be 1: 1 to 10: 1 when making a general reference the combination of amoxicillin and clavulanate potassium, particularly 1: 1 to 7: 1, for example about 1: 1, about 4: 1, about 7: 1) make up with terazosin.The present invention finds that terazosin demonstrates stronger protective effect (Fig. 9) with the Co-Am in independent that the Co-Am combination is compared.In addition, this combination therapy has still proved the therapeutic effect of CLP administration in 6 hours afterwards.
For the protection effect of testing terazosin whether relevant with its function as α 1-adrenoceptor inhibitor; The present invention has checked Minidress (0.4mg/kg; I.p.), it is an another kind of α 1-adrenoceptor blocker (Cavero et al., 1977).The present invention finds that the septicemia that Minidress causes LPS do not have any curative effect.These results show that terazosin can significantly increase the septicemic cemia survival rate that suppresses the LPS-mediation, and its function is might be through apoptotic inhibitory action rather than targeting α 1-adrenoceptor.
Block apoptotic biology of mechanism in order to study terazosin; The present invention has sought it to suppressing the latent effect of caspase-3; Because it mainly is through intrinsic caspase-3 activation (McCall and Steller, 1997) that the apoptosis in the fruit bat is realized.Yet western blot analysis of the present invention shows that the activity form (homologous genes of Dpc-1 and drICE in the fruit bat) of carrying out daughter cell apoptotic proteins enzyme 3 reduces (Figure 10) because of terazosin.The present invention infers, the upper reaches target of terazosin scalable caspase-3 3.For sldh gene, the present invention links terazosin on the agarose beads, and Figure 11 has shown its chemosynthesis approach.In Raw 264.7 cell extracts, angle albumen then, the result finds that (Figure 12 a) to have more a band with respect to blank and medicine competition matched group.Identify that through mass spectrum this band is Pgk1.For confirm terazosin and Pgk1 whether combine be direct relation, the inventor has expressed also purification in the antibacterial Pgk1 albumen of mice, the result finds that terazosin can external direct combination Pgk1 albumen (Figure 12 b).Because in yeast, cross expression Pgk1 apoptosis capable of inhibiting cell (Mazzoni et al., 2009), the inventor guesses that terazosin possibly activate the enzymatic activity of Pgk1.In order to prove this conjecture, it is active that the inventor has detected the Pgk1 vitro enzyme.The result finds, the terazosin of 0.05 μ M can activate nearly 3 times of the enzymatic activity of Pgk1, can reduce the activation (Figure 13) to enzymatic activity and increase terazosin concentration to 0.4 μ M.If the Pgk1 enzymatic activity is to suppress apoptotic reason, crosses expression Pkg1 and just should suppress apoptosis.The inventor's experimental result shows, with expressing the RAW264.7 cell line that the Pgk1 slow virus is set up, has significantly reduced the apoptosis after LPS and IFN γ handle; (Figure 14) takes place not change and cross the apoptosis of expressing EGFP.Further, the inventor has expressed Pgk1 with the subcutaneous injection slow virus or EGFP does contrast in mice.Do the CLP operation after one week, the result finds that with respect to the one group of mice that infects green fluorescent protein, the mice of injection Pgk1 virus has significantly been improved survival rate (Figure 15).The present invention does not receive the constraint of any particular theory, and the inventor thinks that Pgk1 is the new target spot of terazosin.
Research of the present invention shows that terazosin can easily be converted in the clinical practice, and need not to revise existing antibiotic therapy program.Be elaborated in the face of biological test of the present invention down.
Embodiment
A, compound example part
Below the preparation example has exemplarily prepared segment bounds I chemical compound of the present invention, and each chemical compound is represented with Co.1 to Co.32 respectively, and Co.33 representes terazosin.In the reaction process of below preparation example, " reflux " representes to reflux, " 1-pentanol " expression 1-amylalcohol.
The preparation for preparing routine 1:Co.1
Step 1: in the 200mL tetrahydrofuran solution that is dissolved with chemical compound 1a (50mmol), feed ammonia, be reflected at and carried out under 25 ℃ 36 hours.There are a large amount of white solids to separate out in the system, filter and get final products 1f after the gained white solid washs with oxolane.Productive rate is: 63%.
Step 2: add the 15mL acetic anhydride to chemical compound 1f (10mmol), reaction refluxed 2 hours.Cool to room temperature has a large amount of white solids to separate out in the system, filter to get final products 1g after the gained white solid washs with oxolane.Productive rate is: 63%.
Step 3: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 1g (2mmol), add 1h (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 1i after reuse ether/recrystallizing methanol and be Compound C o.1.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) (value of calculation: 430.20904); Elementary analysis: (C, 58.74; H, 6.34; N, 16.30; O, 18.63); Value of calculation: (C, 58.73; H, 6.34; N, 16.31; O, 18.63).
The preparation for preparing routine 2:Co.2
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add chemical compound 1b (20mmol), be reflected at and carried out under 25 ℃ 4 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 1c.Productive rate is: 41%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 1c (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 1e after reuse ether/recrystallizing methanol and be Compound C o.2.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, and 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) (value of calculation: 476.25091); Elementary analysis: C, 58.08; H, 7.00; N, 14.73; O, 20.19; Value of calculation: (C, 58.09; H, 6.99; N, 14.73; O, 20.19).
The preparation for preparing routine 3:Co.3
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add hydrazine hydrate (20mmol), be reflected at and carried out under 25 ℃ 4 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 3a.Productive rate is: 61%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 3a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 3b after reuse ether/recrystallizing methanol and be Compound C o.3.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) (value of calculation: 403.20946).
The preparation for preparing routine 4:Co.4
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add hydration oxyammonia (20mmol), be reflected at and carried out under 25 ℃ 3 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 4a.Productive rate is: 88%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 4a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 4b after reuse ether/recrystallizing methanol and be Compound C o.4.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) (value of calculation: 404.19341).
The preparation for preparing routine 5:Co.5
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add allyl amine (22mmol), be reflected at and carried out under 25 ℃ 8 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 5a.Productive rate is: 31%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 4a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 5b after reuse ether/recrystallizing methanol and be Compound C o.5.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) (value of calculation: 428.22986).
The preparation for preparing routine 6:Co.6
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add allyl amine (28mmol), be reflected at and carried out under 25 ℃ 10 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 6a.Productive rate is: 44%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 4a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 6b after reuse ether/recrystallizing methanol and be Compound C o.6.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) (value of calculation: 426.21408).
The preparation for preparing routine 7:Co.7
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add chemical compound 7a (20mmol), be reflected at and carried out under 25 ℃ 3 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 7b.Productive rate is: 61%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 7b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 7c after reuse ether/recrystallizing methanol and be Compound C o.7.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) (value of calculation: 472.29229).
The preparation for preparing routine 8:Co.8
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add chemical compound 8a (20mmol), be reflected at and carried out under 25 ℃ 1.5 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 8b.Productive rate is: 71%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 8b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 8c after reuse ether/recrystallizing methanol and be Compound C o.8.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) (value of calculation: 512.24859).
The preparation for preparing routine 9:Co.9
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add chemical compound 9a (20mmol), be reflected at and carried out under 25 ℃ 2.5 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 9b.Productive rate is: 21%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 9b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 9c after reuse ether/recrystallizing methanol and be Compound C o.9.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) (value of calculation: 470.27658).
The preparation for preparing routine 10:Co.10
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add chemical compound 10a (20mmol), be reflected at and carried out under 25 ℃ 5 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 9b.Productive rate is: 36%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 9b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 10c after reuse ether/recrystallizing methanol and be Compound C o.10.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) (value of calculation: 456.26119).
The preparation for preparing routine 11:Co.11
Step 1: in the 100mL methanol solution that is dissolved with chemical compound 1a (20mmol), add chemical compound 11b (20mmol), be reflected at and carried out under 25 ℃ 5 hours.After thin plate chromatography indication 1a transforms fully, in system, put into-20 ℃ of environment behind adding 100mL ether, the mixing and leave standstill crystallization.The gained white solid after with the petrol ether/ethyl acetate recrystallization final products 11c.Productive rate is: 41%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 11b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 11c after reuse ether/recrystallizing methanol and be Compound C o.11.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) (value of calculation: 490.26658).
The preparation for preparing routine 12:Co.12
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 12a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 12b after reuse ether/recrystallizing methanol and be Compound C o.12.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) (value of calculation: 464.22996).
The preparation for preparing routine 13:Co.13
Step 1: add 20mL13a to chemical compound 1f (10mmol), reaction refluxed 2 hours.Cool to room temperature has a large amount of white solids to separate out in the system, filter to get final products 13b after the gained white solid washs with oxolane.Productive rate is: 82%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 13b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 5.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 13c after reuse ether/recrystallizing methanol and be Compound C o.13.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) (value of calculation: 484.18084).
The preparation for preparing routine 14:Co.14
Step 1: add 22mL14a to chemical compound 1f (10mmol), reaction refluxed 2 hours.Cool to room temperature has a large amount of white solids to separate out in the system, filter to get final products 14b after the gained white solid washs with oxolane.Productive rate is: 55%.
Step 2: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 14b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 14c after reuse ether/recrystallizing methanol and be Compound C o.14.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) (value of calculation: 492.22478).
The preparation for preparing routine 15:Co.15
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 15b (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 15c after reuse ether/recrystallizing methanol and be Compound C o.15.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) (value of calculation: 372.16726).
The preparation for preparing routine 16:Co.16
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 16a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 16a after reuse ether/recrystallizing methanol and be Compound C o.16.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) (value of calculation: 504.28221).
The preparation for preparing routine 17:Co.17
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 17a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, get final products 17a after reuse ether/recrystallizing methanol and be Compound C o.17.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) (value of calculation: 416.19339).
The preparation for preparing routine 18:Co.18
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 18a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, get final products 18b after reuse ether/recrystallizing methanol and be Compound C o.18.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) (value of calculation: 376.17849).
The preparation for preparing routine 19:Co.19
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 19a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, get final products 19b after reuse ether/recrystallizing methanol and be Compound C o.19.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) (value of calculation: 479.23823).
The preparation for preparing routine 20:Co.20
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 20a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, get final products 20b after reuse ether/recrystallizing methanol and be Compound C o.20.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) (value of calculation: 379.18825).
The preparation for preparing routine 21:Co.21
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 21a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, get final products 21b after reuse ether/recrystallizing methanol and be Compound C o.21.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) (value of calculation: 379.18825).
The preparation for preparing routine 22:Co.22
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 22a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 5 hours.With 10mL washing with acetone gained white crystal twice, get final products 22b after reuse ethyl ketone/recrystallizing methanol and be Compound C o.22.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) (value of calculation: 400.23486).
The preparation for preparing routine 23:Co.23
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 23a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 5 hours.With 10mL washing with acetone gained white crystal twice, get final products 23b after reuse ether/recrystallizing methanol and be Compound C o.23.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) (value of calculation: 477.22503).
The preparation for preparing routine 24:Co.24
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 25a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, get final products 25b after reuse ether/recrystallizing methanol and be Compound C o.25.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) (value of calculation: 454.24543).
The preparation for preparing routine 25:Co.25
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 25a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, get final products 25b after reuse ether/recrystallizing methanol and be Compound C o.25.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) (value of calculation: 564.30334).
The preparation for preparing routine 26:Co.26
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 26a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, get final products 26a after reuse ether/recrystallizing methanol and be Compound C o.17.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) (value of calculation: 476.21452).
The preparation for preparing routine 27:Co.27
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 27a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, get final products 27b after reuse ether/recrystallizing methanol and be Compound C o.27.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) (value of calculation: 539.25936).
The preparation for preparing routine 28:Co.28
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 28a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, get final products 28b after reuse ether/recrystallizing methanol and be Compound C o.28.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) (value of calculation: 436.19962).
The preparation for preparing routine 29:Co.29
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 29a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, get final products 29b after reuse ether/recrystallizing methanol and be Compound C o.29.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) (value of calculation: 475.23051).
The preparation for preparing routine 30:Co.30
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 30a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 5 hours.With 10mL washing with acetone gained white crystal twice, get final products 30b after reuse ether/recrystallizing methanol and be Compound C o.30.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) (value of calculation: 474.27164).
The preparation for preparing routine 31:Co.31
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 31a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, get final products 31b after reuse ether/recrystallizing methanol and be Compound C o.31.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) (value of calculation: 536.25091).
The preparation for preparing routine 32:Co.32
Step 1: under the situation of argon atmospher, in the solution of the 1-amylalcohol that is dissolved with 32a (2mmol), add 1d (2mmol).Reaction system was placed in the 0-5 ℃ of environment and leaves standstill crystallization after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, get final products 32b after reuse ether/recrystallizing methanol and be Compound C o.32.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) (value of calculation: 514.26656).
B, biological test example part
1, raising of fruit bat and screening compound
UAS-rpr and HS-Gal4 fruit bat store the center available from U.S. Bloomington.(HS＞rpr) is used for screening of medicaments in the F1 filial generation of this two all systems hybridization.These filial generation fruit bats are brought up down at 18 ℃.Various medicines are dissolved in 5% glucose solution with the concentration of using in the cell culture among the cmap.Drug solution (150 μ l) is placed on three layers of filter paper plate in the tubule.Then, the adult HS of 20 1-3 ages in days＞rpr fruit bat is placed on and reaches 1 day in this bottle.For cell death inducing, make these fruit bats 37 ℃ of following heat shocks 2 hours.After the heat shock 12 hours, calculate survival rate.
2, micro-array chip technical finesse and data analysis
From hs＞rpr and with the fruit bat (genetic background matees with control series) of 10 bottles of 1-3 ages in days of filial generation preparation of the hs-Gal4 of yw67c23 hybridization.Contain 35 female fruit bats in every bottle.This fruit bat (time is 0 hour) and heat shock before heat shock were refrigerated in the liquid nitrogen in 1,2,3,4,5,6,7,8 and 12 hours.(Quiagen Inc) prepares total RNA through RNeasy mini test kit.(Ambion Inc) is for further processing to remove the chromosomal DNA in the sample with TURBO DNase test kit.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 from the fruit bat 2.0DNA micro-array chip of Affymetrix technology (Affymetrix, Inc).Handling these arrays simultaneously influences to reduce between different batches.(Affymetrix, Inc) software carries out data analysis to use Arrayassist 5.0.The algorithm of " RMA " is used 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.For example the time 0,1 and 2 is called " time 1 " in the result.The present invention has designed the micro-array chip technical data to increase the instantaneous resolution of changes in gene expression in this process.The present invention's deduction has shown variation like fruit gene in transcribing, it can be reflected in the adjacent time point.For the functional gene enrichment, the present invention uses data base tool (http://david.abcc.ncifcrf.gov/).
3, through contact graph discovery candidate compound
The present invention will be transformed into mammal homologous genes (www.affymetrix.com) through the data base from the mediation down-regulated gene of going up of fruit bat micro-array chip technology.Then, the scheme that provides based on cmap generates signal file (Lamb et al., 2006).After this, obtain the chemical compound of positive correlation and negative correlation.These medicines are available from Sigma-Aldrich.
4, cell culture and apoptosis induction
RAW 264.7 cells are cultivated in DMEM culture medium (Gibco), be supplemented with 10%FBS (Gibco), 0.1g/L streptomycin and 0.06g/L penicillin (Amresco) in this culture medium.For cell death inducing, 90% RAW 264.7 cells that merge are being contained 2 μ g/ml lipopolysaccharide (LPS; Cultivated 24 hours among the Escherichia coli O111:B4, DMEM Sigma) (10%FBS).
5, Hoechst dyeing
At first use Carnoy fixative (75% ethanol, 25% acetic acid) fixed cell, use Hoechst 33342 (10 μ g/ml, Sigma) dyeing 10min then.After ice-cold PBS washing 3 times, through confocal microscope (TCS SP5, Leica) observation of cell.
6, septicemic cemia mouse model
(20 ± 3g) mices are raised the animal center in Peking University available from the male BALB/C of Vital River (Beijing dimension tonneau China company, China).All tests are by Peking University's animal maintenance and use committee (Peking University Institutional Animal Care and Use Committee) approval.For septicemic cemia LPS model, with injected in mice LPS (13.5mg/kg, i.p.) once.For septicemic cemia escherichia coli model, each injected in mice (i.p.) 1x10
8The antibacterial of CFU.For drug test, 1.5 hours injections (i.p.) terazosin (0.4mg/kg or 0.04mg/kg) or solvent buffer after giving LPS.Every at a distance from 12 hour record mice fatality 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 the arteria ileocaeca, with No. 22 standard needle once, and carrying out ligation from 5mm place, caecum top to the caecum puncture.Make the abdominal part sealing through continous suture then.At last, the normal saline through injecting preparatory temperature is (37 ℃; 5ml/100g s.c.) makes the animal recovery.For antibiotic therapy, give Co-Am (southern Shandong pharmacy group company, Shandong, China) (30mg/kg) through administration by gavage.Whenever reach 7 days at a distance from 12 h observation mice survival rates.
7, Western blotting
For Western blotting, through discerning the antibody test caspase-3 3 of activated caspase-3 3 (#9664, Cell Signaling), the antibody of actin is available from Wuhan doctor's moral company.
8, dna fragmentation fractional analysis
After lps injection 24 hours, take out a thymus from the mice of accepting different treatments.Extract chromosomal DNA through chromosomal DNA purification kit (Biofuture, Beijing, China) then.Estimate the dna fragmentation degree through the DNA agarose gel.
9, the active analysis of bacteriostatic
Utilize the Oxford cup to analyze the potential antibiotic activity of terazosin.The terazosin of different quality is added in the cup of Oxford, put into the LB culture dish that is paved with escherichia coli (Escherichia coli O111:B4), observe the influence of terazosin and ampicillin after 24 hours the escherichia coli growth.
10, the analysis of terazosin target
The present invention is through being connected to terazosin on the Affi-gel, and the protein extract with RAW 264.7 cells mixes then, and the foreign protein that is combined on the Affi-gel is washed off.With bonded albumen eluting, glue (albumin glue of 15% concentration) is run in 96 degree heating backs with sample-loading buffer.Special protein band is downcut, carry out mass spectrum and identify.
11, terazosin is to the active influence of Pgk1
At the Pgk1 of expression in escherichia coli mice recombiant protein (His-Pgk1), use ni-sepharose purification His-Pgk1 then.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 affinity
Hatch with the Affi-gel of different disposal and the His-Pgk1 of purification, the albumen of the non-specific bond of flush away after 4 hours, with bonded albumen eluting, glue (albumin glue of 15% concentration) are run in 96 degree heating backs with sample-loading buffer.
13, statistical analysis
For survival rate analysis, under Log Rank algorithm, use the Kaplan-Meier check.For group relatively, use one-sided ANOVA check.In order to compare two data sets, the present invention uses the student-t check.
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 to treat and/or prevent septicemia and complication thereof.
14, Pgk1 is active detects
Utilize the composition of Colorimetric GAPDH Assay Kit (ScienCell), and the GAPDH solution of buying and preparing, HEPES solution, MgSO4 solution.In reactant liquor (0.22mM NADH, 10mM MgSO4,10mM 3-PGA, the GAPDH of 3-4U/ml, pH 7.5 for 30mM Hepes, 3mM ATP), add certain density formula I chemical compound then, detect absorption with spectrophotometer (340nm) down at 25 ℃.According to the variation of absorption value in 1-10 minute, calculate the Pgk1 relative activity.Change soon more, activity is big more.Notice that simultaneously experimental group will deduct with the absorption at 340nm of the chemical compound of isoconcentration.
The activity of formula I chemical compound representes that with the multiple that activates Pgk1 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, activates the active multiple of Pgk1 and sees above respectively, and for example Co.1 and Co.2 activate the active multiple of Pgk1 and be respectively 2.9 and 2.3.
15, apoptosis-inducing and detection
With RAW 264.7 cell culture (Gibco) in the DMEM culture medium, add 5% hyclone and two anti-(streptomycin of 0.1mg/ml and the penicillins of 0.06mg/ml).The lipopolysaccharide and (LPS that add 2 μ g/ml; Escherichia coli O111:B4, Sigma-Aldrich) gamma interferon of 50U/ml (Peprotech) is apoptosis-induced.Add certain density chemical compound simultaneously.Method with western blot is assessed apoptosis, and antibody is the activity form antibody (#9661, Cell Signaling) of Caspase 3.And be confidential reference items (Boster) with β-Actin.Assess the degree that apoptosis takes place with the value of Caspase 3/ β-Actin.
16, the hypoglycemic activity of terazosin
Give mice shot terazosin (0.4mg/kg i.p.), measure mouse blood sugar after 18 hours, find that blood glucose has reduced nearly about 30% (t-check, P＜0.01); And unknown significance difference when giving saline simultaneously.The result sees 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 shows and can make blood glucose reduce by 20% to 50%.
17, the effect of the anti-cerebral thrombosis of terazosin
Make the mouse brain thrombus model, after mice is because of thrombosis death, cerebral tissue is dyeed, the 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.The result is added up, and serves as to investigate index, mice quantity=6 under every kind of condition with % thanatogenic tissue=white portion area/gross area.Through t-check, P＜0.05.The result sees Figure 17, and the result is visible from figure, and 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 shows and can obviously reduce thanatogenic tissue's area, P＜0.05.
18, anti-septicemia effect
BALB/C mice (about 20 grams) lumbar injection lipopolysaccharide (13.5mg/kg) was injected two fun gi polysaccharides after one and a half hours, and the survival of a mice of per 12 h observation was observed 7 days altogether, and the statistics survival has there was no significant difference.
Alternate model is caecum puncture and ligation (CLP).Behind the mouse anesthesia, cut off 1.5-2 centimetre osculum, caecum is taken out at its abdominal part.Feces 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 feces.Caecum is put back to the abdominal cavity, well and wound closure with linear slit.Inject two fun gi polysaccharides after one and a half hours, the survival of a mice of per 12 h observation was observed 7 days altogether, and the statistics survival has there was no significant difference.
The 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 with injection (0.4mg/kg i.p.) successive administration once a day after 3 days; When 7 day observation period finished, show that these chemical compounds all can significantly improve the survival rate of mice (compare with the matched group of not giving medicine P＜0.05).
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16.Lamb，J.et?al.The?Connectivity?Map：using?gene-expression?signatures?to?connect?small?molecules，genes，and?disease.Science?313，1929-1935(2006).
Claims (11)
1. formula I chemical compound or the acceptable salt of its pharmacy, solvate, ester, prodrug as the purposes in the medicine of pgk1 activator, perhaps treat and/or prevent the purposes in the medicine of hyperglycemia, cerebral thrombosis and complication thereof in preparation in preparation,
Wherein
R
1aAnd R
1bBe selected from H, NH independently of one another
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, C
1-6Alkyl acyl-, aryl-acyl-, C
6-10Aryl-, C
5-6Cycloalkyl, perhaps R
1aAnd R
1bNitrogen-atoms with their connections forms 5-or 6-unit ring, and wherein said alkyl is optional to be selected from following substituent group replacement by 1-3: hydroxyl, halogen;
R
2And R
3Be selected from H, halogen, C independently of one another
1-6Alkyl-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, CN, NO
2, NH
2, OH, C
1-6Alkoxyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, C
1-6Alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, C
1-6Alkyl acyl-, perhaps R
2And R
3The annular atoms that connects with them forms 5-or 6-unit's carbocyclic ring or heterocycle;
R
4And R
5Be selected from H, halogen, CN, NO independently of one another
2, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, 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.
2. according to the purposes of claim 1, R wherein
1aAnd R
1bBe selected from H, NH independently of one another
2, OH, C
1-6Alkyl-, C
1-4Alkoxy-C
1-4Alkyl-, C
2-4Thiazolinyl-, C
2-4Alkynyl-, C
1-4Alkoxyl-, C
1-4Alkyl acyl-, the phenyl acyl group-, phenyl-, C
5-6Cycloalkyl, perhaps R
1aAnd R
1bNitrogen-atoms with their connections forms 5-or 6-unit ring, and wherein said alkyl is optional to be selected from following substituent group replacement by 1-3: hydroxyl, halogen.
3. according to the purposes of claim 1, R wherein
2And R
3Be selected from H, halogen, C independently of one another
1-6Alkyl-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, C
1-6Alkanoylamino-, aroylamino-, saturated or undersaturated 5-or 6-unit's carbocyclic ring or heterocyclic radical, perhaps R
2And R
3The annular atoms that connects with them forms 5-or 6-unit's carbocyclic ring or heterocycle.
4. according to the purposes of claim 1, R wherein
4And R
5Be selected from H, halogen, C independently of one another
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, 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.
5. according to the purposes of claim 1, wherein said formula I chemical compound is the chemical compound that is selected from the following Co.1 to Co.33 of being numbered:
6. the formula I chemical compound in each said purposes of claim 1-5 is preparing as the purposes in the medicine of apoptosis inhibitor; Perhaps treat and/or prevent the purposes in the thing of septicemia and complication thereof, perhaps treat and/or prevent the purposes in the medicine of hyperglycemia, cerebral thrombosis and complication thereof in preparation in preparation.
7. according to each purposes of claim 1-5, wherein said pgk1 activator is used for treating and/or preventing of clinical disease and laboratory diagnosis and/or detection.
8. according to each purposes of claim 1-5, wherein said formula I chemical compound is terazosin or the acceptable salt of its pharmacy or its solvate.
9. the pharmaceutical composition as the pgk1 activator wherein comprises the formula I chemical compound in each the said purposes of claim 1-5 that treats and/or prevents effective dose, and optional pharmaceutically acceptable carrier.
10. a pharmaceutical composition that is used to treat and/or prevent hyperglycemia and complication thereof wherein comprises the formula I chemical compound in each the said purposes of claim 1-5 that treats and/or prevents effective dose, and optional pharmaceutically acceptable carrier.
11. a pharmaceutical composition that is used to treat and/or prevent cerebral thrombosis and complication thereof wherein comprises the formula I chemical compound in each the said purposes of claim 1-5 that treats and/or prevents effective dose, and optional pharmaceutically acceptable carrier.
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| CN201110173409.X | 2011-06-27 | ||
| CN201110173409 | 2011-06-27 | ||
| CN2011104139310A CN102526057B (en) | 2010-12-22 | 2011-12-12 | Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102908352A (en) * | 2012-09-12 | 2013-02-06 | 北京英科博雅科技有限公司 | Application of terazosin or its salt in preparing drug for treating septicemia/stroke |
| WO2013138951A1 (en) * | 2012-03-23 | 2013-09-26 | 无锡新融合药业有限公司 | Quinazoline derivate and use thereof as apoptosis inhibitor |
| WO2015085968A1 (en) * | 2013-12-10 | 2015-06-18 | 北京融鑫创业投资中心（有限合伙） | Quinazoline derivative used for cardiovascular and cerebrovascular diseases |
| CN104887682A (en) * | 2015-06-18 | 2015-09-09 | 刘磊 | Application of terazosin type medicines |
| CN113403387A (en) * | 2021-07-16 | 2021-09-17 | 兰州大学 | Pgk1 application of target in preparing or screening medicine for treating gastrointestinal tract diseases |
| CN117430614A (en) * | 2023-12-20 | 2024-01-23 | 首都医科大学 | Isoquinoline derivative and synthetic method and application thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927166A (en) * | 2006-09-29 | 2007-03-14 | 何岩 | Terazosin slowly releasing preparation |
| CN101444512A (en) * | 2008-12-29 | 2009-06-03 | 孙少芳 | Application of terazosin for preparing medicines for treating postpartum urinary retention |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101134023A (en) * | 2006-08-31 | 2008-03-05 | 海南海灵制药厂有限公司 | Hydrochloric acid terazosin oral cavity disintegrating lyophilized tablets and method for preparing the same |
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2011
- 2011-12-12 CN CN201110412182.XA patent/CN102552272B/en active Active
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1927166A (en) * | 2006-09-29 | 2007-03-14 | 何岩 | Terazosin slowly releasing preparation |
| CN101444512A (en) * | 2008-12-29 | 2009-06-03 | 孙少芳 | Application of terazosin for preparing medicines for treating postpartum urinary retention |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013138951A1 (en) * | 2012-03-23 | 2013-09-26 | 无锡新融合药业有限公司 | Quinazoline derivate and use thereof as apoptosis inhibitor |
| CN102908352A (en) * | 2012-09-12 | 2013-02-06 | 北京英科博雅科技有限公司 | Application of terazosin or its salt in preparing drug for treating septicemia/stroke |
| WO2015085968A1 (en) * | 2013-12-10 | 2015-06-18 | 北京融鑫创业投资中心（有限合伙） | Quinazoline derivative used for cardiovascular and cerebrovascular diseases |
| CN104887682A (en) * | 2015-06-18 | 2015-09-09 | 刘磊 | Application of terazosin type medicines |
| CN113403387A (en) * | 2021-07-16 | 2021-09-17 | 兰州大学 | Pgk1 application of target in preparing or screening medicine for treating gastrointestinal tract diseases |
| CN113403387B (en) * | 2021-07-16 | 2022-09-30 | 兰州大学 | Pgk1 application of target in preparing or screening medicine for treating gastrointestinal tract diseases |
| CN117430614A (en) * | 2023-12-20 | 2024-01-23 | 首都医科大学 | Isoquinoline derivative and synthetic method and application thereof |
| CN117430614B (en) * | 2023-12-20 | 2024-03-08 | 首都医科大学 | Isoquinoline derivative and synthetic method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102532110B (en) | 2014-12-03 |
| CN102552272A (en) | 2012-07-11 |
| CN102526057B (en) | 2013-11-13 |
| CN102532110A (en) | 2012-07-04 |
| CN102552272B (en) | 2014-11-12 |
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