CN102526057B - Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator - Google Patents
Quinazoline derivative as pgk1 (phosphoglycerate kinase 1) activator Download PDFInfo
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- CN102526057B CN102526057B CN2011104139310A CN201110413931A CN102526057B CN 102526057 B CN102526057 B CN 102526057B CN 2011104139310 A CN2011104139310 A CN 2011104139310A CN 201110413931 A CN201110413931 A CN 201110413931A CN 102526057 B CN102526057 B CN 102526057B
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- terazosin
- compound
- thf
- pgk1
- 2mmol
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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 the diseases such as treatment hyperglycemia, cerebral thrombosis.
Background technology
Septicemia (Sepsis) is first cause dead in global intensive care unit.Septicemia it is believed that the abnormal adjusting (Bone et al., 1996) of the inflammation that is a kind of complexity.Yet many clinical trials of cytokine or antiinflammatory specificity medicament fail significantly to improve septicemia patient's survival, rethink that the septicemic cemia strategy for the treatment of is necessary.Although effect is limited, antibiotic therapy is the septicemic cemia important channel for the treatment of.Basic research shows, inhibited apoptosis is the blocking test septicemia effectively.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 for the treatment of (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, multicellular organism, removes in unwanted or abnormal cell and plays a part necessity.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 strict process of controlling of polygenes.These genes are very conservative between kind, as 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 may be direct or indirect with having of numerous disease relation.People understand the brain death that causes due to cerebral thrombosis also with apoptosis-related.In addition, the activation that it is believed that PGK 1 (phosphoglycerate kinase 1, referred to as pgk1) helps for example treatment or the prevention relevant to apoptosis of some diseases.
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 with other antihypertensive drug such as diuretic or Alpha 1 adrenergic blocking agent, share.For existing clinical indication, the daily dose usual range that terazosin is used for the adult is 1～10mg.Terazosin is used for the treatment of benign prostatic hyperplasia (BPH), and after medication, the benign prostate hyperplasia shape alleviates relevant with the caused smooth muscle loosening of alpha 1 adrenergic receptor blocking-up in neck of bladder and prostate with the improvement of urine flow velocity.Because relatively few alpha 1 adrenergic receptor is arranged in body of bladder, so terazosin can alleviate the obstruction of bladder outlet and not affect the contraction of bladder.In addition, thus terazosin makes Blood pressure drop by reducing total peripheral vascular resistance.As if the vasodilation of terazosin, Blood pressure drop effect are mainly caused by the alpha 1 adrenergic receptor blocking-up.
Up to now, still lack clinically effective apoptosis inhibitor, exploitation novel anti--apoptotic compound to be to be 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, a class quinazoline derivant for example clinical for benign prostate hyperplasia and hypertensive medicine terazosin separately or with antibiotic combinations, can effectively treat and/or prevent septicemia and complication thereof.The present invention is based on this discovery and be accomplished.
Summary of the invention
First aspect present invention relates to formula I compound,
Or the acceptable salt of its pharmacy, solvate, ester, prodrug, wherein
R
1aAnd R
1bBe selected from independently of one another H, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, C
1-6Alkyl acyl-, aryl-acyl-, C
6-10Aryl-, C
5-6Cycloalkyl-, perhaps R
1aAnd R
1bForm 5-or 6-ring together with nitrogen-atoms that their connect, wherein said alkyl is optional to be selected from following substituent group by 1-3 and to replace: hydroxyl, halogen;
R
2And R
3Be selected from independently of one another H, halogen, C
1-6Alkyl-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, CN, NO
2, NH
2, OH, C
1-6Alkoxyl-, 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
3Form 5-or 6-unit's carbocyclic ring or heterocycle together with annular atoms that their connect;
R
4And R
5Be selected from independently of one another H, halogen, CN, NO
2, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, 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 compound for example terazosin the preparation as the purposes in the medicine of apoptosis inhibitor, formula I compound for example terazosin in preparation as the purposes in the medicine of pgk1 activator, perhaps formula I compound for example terazosin treat and/or prevent 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 compound for example terazosin or the 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 compound that treats and/or prevents effective dose for example terazosin or the acceptable salt of its pharmacy or solvate, and at least a antimicrobial agents.
Fifth aspect present invention relates to the method for inhibited apoptosis in the experimenter that needs are arranged or biological sample, activate the method for pgk1 in the experimenter that needs are arranged or biological sample, perhaps treat and/or prevent the method for septicemia and complication thereof in the experimenter who needs is arranged.
Sixth aspect present invention relates to as apoptosis inhibitor, as the pgk1 activator or as the formula I 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 represents meansigma methods+SE.Test n=6.
Fig. 2 is the compound list of using in drug screening.These compounds are based on Cmap and select.Divide into groups according to their positive correlation of apoptotic micro-array chip technology or negative correlation.
Fig. 3 has described with apoptosis fruit bat model discrimination medicine.The apoptosis fruit bat represents with average+SE the survival rate of every kind of medicine.Contrast (not giving medicine) shows with white rod.Giving different medicines represents with white or black rod respectively.Test n=5.
Fig. 4 has described terazosin (4 μ g/ml) and can significantly stop due to the apoptosis due to LPS and IFN γ toxicity.By Annexin V dye for apoptotic cell.The statistical result showed terazosin apoptosis capable of inhibiting cell that test obtains.Every group of cell number is counted as 200-250 cell.
In Fig. 5, Fig. 5 a has described the survival rate curve of terazosin (0.4mg/kg) to septicemic cemia LPS modelling effect.Check and carry out the survival rate tracing analysis by Kaplan-Merier with Log Rank algorithm.Number of mice and the p value used are shown in this figure.Fig. 5 b has described agarose gel and has shown LPS treatment DNA break afterwards.Every band represents 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.Check and analyze by Kaplan-Merier with Log Rank algorithm.Number of mice and the p value used are shown in this figure, and in figure, T represents terazosin.
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.Check and analyze by Kaplan-Merier with Log Rank algorithm.Number of mice and the p value used are shown in this figure.
Fig. 8 has described the impact of terazosin on Escherichia coli Growth.After using terazosin 24 hours, by inhibition zone, compare the effect to bacterial growth of it and ampicillin.In figure, result shows, do not add the contrast (control) of medicine and the terazosin of various dose (0.2 μ g T, 2 μ g T, 200 μ g T, 2mg T) and all can not suppress Escherichia coli Growth, and ampicillin (2mg Amp) shows the inhibition Escherichia coli Growth.
Fig. 9 has described the survival rate curve of terazosin to the effect of septicemic cemia CLP model.Passed through twice terazosin of subcutaneous injection in 1.5 and 24 hours with 0.08mg/kg after CLP.Use separately antibiotic Co-Am, to the CLP model, the increase phenomena of mortality are arranged.And the combination of terazosin and antibiotic Co-Am has protective effect to septicemic cemia CLP model.Check and analyze by Kaplan-Merier with the LogRank algorithm.Quantity and the p value of the mice of using are shown in this figure.In figure, T represents terazosin, and Co-Am represents that the weight ratio of amoxicillin and clavulanate potassium is the mixture of 4: 1.
Figure 10 has described the Western blotting of the activity form of caspase-3 3 in Raw 264.7 cells of LPS and IFN γ processing.Albumen applied sample amount in the group of three different disposal is identical.
Figure 11 has described the terazosin chemical modification and has produced the chemical process that Affi-gel connects.
In Figure 12, figure a has described to angle albumen to obtain a protein band that obviously only occurs (using the band of arrow labelling between 43kd to 55kd) in experimental group with the terazosin agarose beads.Be accredited as Pgk1 through protein spectrum.Figure b has described to pass through terazosin agarose beads albumen post with the Pgk1 of vivoexpression, has still obtained the Pkg1 band, illustrates that terazosin and Pgk1 are directly combinations.
Figure 13 has described the impact of the terazosin of variable concentrations on the Pgk1 activity.
But Figure 14 has described to express the Raw 264.7 cell antagonism apoptosis of Pgk1.The cell membrane phospholipid acyl serine of apoptosis by rollover in adipose membrane laterally.Annexin V and phospholipids incorporate, thereby the cell of labelling apoptosis.
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, tested after the 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 compound,
Or the acceptable salt of its pharmacy, solvate, ester, prodrug, wherein
R
1aAnd R
1bBe selected from independently of one another H, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, C
1-6Alkyl acyl-, aryl-acyl-, C
6-10Aryl-, C
5-6Cycloalkyl, perhaps R
1aAnd R
1bForm 5-or 6-ring together with nitrogen-atoms that their connect, wherein said alkyl is optional to be selected from following substituent group by 1-3 and to replace: hydroxyl, halogen;
R
2And R
3Be selected from independently of one another H, halogen, C
1-6Alkyl-, halo C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, CN, NO
2, NH
2, OH, C
1-6Alkoxyl-, 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
3Form 5-or 6-unit's carbocyclic ring or heterocycle together with annular atoms that their connect;
R
4And R
5Be selected from independently of one another H, halogen, CN, NO
2, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, 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 compound of first aspect present invention, wherein R
1aAnd R
1bBe selected from independently of one another H, NH
2, OH, C
1-6Alkyl-, C
1-4Alkoxy-C
1-4Alkyl-, C
2-4Thiazolinyl-, C
2-4Alkynyl-, C
1-4Alkoxyl-, C
1-4Alkyl acyl-, the phenyl acyl group-, phenyl-, C
5-6Cycloalkyl, perhaps R
1aAnd R
1bForm 5-or 6-ring together with nitrogen-atoms that their connect, wherein said alkyl is optional to be selected from following substituent group by 1-3 and to replace: hydroxyl, halogen.In one embodiment, described R
1aAnd R
1bBe selected from independently of one another H ,-NH
2,-OH, CH
3C (O)-,-(CH
2)
2-O-(CH
2)
2-OH ,-CH
2-CH=CH
2,-CH
2-C ≡ CH ,-(CH
2)
5CH
3,-(CH
2)
4-CF
3, cyclohexyl ,-CH
2-(CH
2)
3-CH
2-,-(CH
2)
2O (CH
2)
2-OH ,-Ph, CH
3,-C (O)-CF
3,-C (O)-Ph.
According to the compound of first aspect present invention, wherein R
2And R
3Be selected from independently of one another H, halogen, C
1-6Alkyl-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, 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
3Form 5-or 6-unit's carbocyclic ring or heterocycle together with annular atoms that their connect.In one embodiment, described R
2And R
3Be selected from independently of one another H, CH
3O-,-CH
2-O-CH
2-,-O (CH
2)
2OC
2H
5,-OC (O) CH
3,-F ,-CF
3,
And 1,2-pyridine ring ,-NHCOCH
3,-(CH
2)
2CH
3,-NHCOPh,
According to the compound of first aspect present invention, wherein R
4And R
5Be selected from independently of one another H, halogen, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, 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, described R
4And R
5Be selected from independently of one another H ,-O (CH
2)
2OC
2H
5,-OC (O) CH
3,-OCH
3,
-CF
3,-F ,-NHCOCH
3,-(CH
2)
3CH
3,-NHCOPh,
According to the compound of first aspect present invention, wherein said alkyl, thiazolinyl and alkynyl are straight chain or side chain.In one embodiment, described C
1-6Alkyl is selected from C
1-5Alkyl, C
1-4Alkyl, for example methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, the tert-butyl group.In one embodiment, described C
2-6Thiazolinyl is selected from C
2-5Thiazolinyl, C
2-4Thiazolinyl, for example vinyl, acrylic, pi-allyl.In one embodiment, described C
2-6Alkynyl is selected from C
2-5Alkynyl, C
2-4Alkynyl.
According to the compound of first aspect present invention, wherein said C
5-6Cycloalkyl is selected from cyclopenta and cyclohexyl.
According to the compound of first aspect present invention, wherein said aryl is selected from phenyl, naphthyl, preferred phenyl.
According to the compound of first aspect present invention, wherein said halogen is selected from fluorine, chlorine, bromine and iodine, preferred fluorine and chlorine.
According to the compound of first aspect present invention, it is the compound that is selected from the following Co.1 to Co.33 of being numbered (their structure as compound preparation example part as described in):
Annotate: active * represents that each compound tests under 0.02 μ g/ml concentration, activates the multiple of Pgk1 activity.
Second aspect present invention relate to formula I compound for example terazosin the preparation as the purposes in the medicine of apoptosis inhibitor.
Second aspect present invention also relate to formula I compound for example terazosin the preparation as the purposes in the medicine of pgk1 activator.
Second aspect present invention also relate to formula I compound for example terazosin treat and/or prevent purposes in the medicine of septicemia and complication thereof in preparation.
Second aspect present invention also relate to formula I compound for example terazosin treat and/or prevent 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 and laboratory diagnosis and/or detection of clinical disease.
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 compound for example terazosin every daily dose of being 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 compound is 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 wherein said medicine.
Purposes according to second aspect present invention, also comprise at least a antimicrobial agents in wherein said medicine, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, 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 wherein said medicine, described 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 described medicine, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, also comprise amoxicillin and clavulanate potassium in described medicine.
Third aspect present invention provides a kind of pharmaceutical composition, wherein comprises the formula I compound for example terazosin or the 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, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, 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, described 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 described pharmaceutical composition, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, also comprise amoxicillin and clavulanate potassium in described pharmaceutical composition.
According to the pharmaceutical composition of third aspect present invention, it is for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor is used for treating and/or preventing and laboratory diagnosis and/or detection of clinical disease.
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 and laboratory diagnosis and/or detection of clinical disease.
According to the pharmaceutical composition of third aspect present invention, it is be used for the treatment of and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that 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 be used for the treatment of and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
Pharmaceutical composition according to third aspect present invention, wherein said formula I compound for example terazosin every daily dose of being 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 compound that treats and/or prevents effective dose for example terazosin or the 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 compound for example terazosin or the acceptable salt of its pharmacy or solvate is in same compositions or in the compositions of separating with described at least a antimicrobial agents.
According to the medicine box product of fourth aspect present invention, wherein said formula I compound for example terazosin or the acceptable salt of its pharmacy or solvate is in the compositions of separating with described at least a antimicrobial agents.
Medicine box product according to fourth aspect present invention, comprising the first compositions that is separated from each other and the second compositions, described the first compositions comprises formula I compound for example terazosin or the acceptable salt of its pharmacy or solvate and the optional pharmaceutically acceptable carrier that treats and/or prevents effective dose, and described the second compositions comprises antimicrobial agents and the 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: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, 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, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, described antimicrobial agents comprises amoxicillin and clavulanate potassium.
According to the medicine box product of fourth aspect present invention, it is for apoptosis inhibitor.In one embodiment, wherein said apoptosis inhibitor is used for treating and/or preventing and laboratory diagnosis and/or detection of clinical disease.
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 and laboratory diagnosis and/or detection of clinical disease.
According to the medicine box product of fourth aspect present invention, it is be used for the treatment of and/or prevent septicemia and complication thereof.In one embodiment, wherein said septicemia is the septicemia that 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 be used for the treatment of and/or prevent hyperglycemia, cerebral thrombosis and complication thereof.
Medicine box product according to fourth aspect present invention, wherein said formula I compound for example terazosin every daily dose of being 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 to the method for inhibited apoptosis in the experimenter that needs are arranged or biological sample, and the method comprises the formula I compound terazosin for example of using effective dose to described experimenter or biological sample.
Fifth aspect present invention also relates in the experimenter that needs are arranged or biological sample the method that activates pgk1, and the method comprises the formula I compound terazosin for example of using effective dose to described experimenter or biological sample.
Fifth aspect present invention also relates to the method that treats and/or prevents septicemia and complication thereof in the experimenter of needs is arranged, and the method comprises the formula I compound terazosin for example of using effective dose to described experimenter.
Fifth aspect present invention also relates to the method that treats and/or prevents hyperglycemia, cerebral thrombosis and complication disease thereof in the experimenter of needs is arranged, and the method comprises the formula I compound terazosin for example of using effective dose to described 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 compound for example terazosin every daily dose of being 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 compound is 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 described experimenter or biological sample.
Method according to fifth aspect present invention, wherein also comprise at least a antimicrobial agents of using effective dose to described experimenter or biological sample, described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, 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 described experimenter or biological sample, described 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, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, described antimicrobial is amoxicillin and clavulanate potassium.
Sixth aspect present invention relates to as the formula I compound of apoptosis inhibitor terazosin for example.
Sixth aspect present invention also relates to as the formula I compound of pgk1 activator terazosin for example.
Sixth aspect present invention also relates to as the formula I compound that treats and/or prevents septicemia and complication thereof terazosin for example.
Sixth aspect present invention also relates to as the formula I compound that treats and/or prevents hyperglycemia, cerebral thrombosis and complication thereof terazosin for example.
According to the formula I compound of sixth aspect present invention, wherein said apoptosis inhibitor is used for treating and/or preventing and laboratory diagnosis and/or detection of clinical disease.
According to the formula I compound of sixth aspect present invention, wherein said pgk1 activator is used for treating and/or preventing and laboratory diagnosis and/or detection of clinical disease.
According to the formula I 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 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 compound according to sixth aspect present invention, every daily dose that wherein said formula I 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 compound of sixth aspect present invention, it is terazosin.
According to the formula I compound of sixth aspect present invention, it is the acceptable salt of pharmacy or its solvate of terazosin.
According to the formula I compound of sixth aspect present invention, it is the hydrochlorate of terazosin.
According to the formula I 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 compound of sixth aspect present invention, it also makes up with at least a antimicrobial agents.
Formula I compound according to sixth aspect present invention, it also makes up with at least a antimicrobial agents, and described antimicrobial agents is selected from: Penicillin antibiotics, cephalosporins, beta-lactamase inhibitor, aminoglycoside antibiotics, tetracycline antibiotics, amide alcohols class antibiotic, Macrolide class antibiotic, sulfonamides, trimethoprim class, quinolones.
Formula I compound according to sixth aspect present invention, it also makes up with at least a antimicrobial agents, and described 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, described antimicrobial agents is selected from: amoxicillin, clavulanate potassium.In one embodiment, described antimicrobial agents is amoxicillin and clavulanate potassium.
For example the use amount of terazosin can be with reference to existing clinical medicine dose for the either side according to the present invention, wherein said formula I 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 diseases (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.
The either side 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 diseases (for example infection), preferred 0.02～80 times, preferred 0.05～20 times, preferred 0.1～10 times, preferred 0.2～5 times.
The either side 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 diseases (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 of either side of the present invention, described formula I compound does not comprise the compound of numbering Co.33.
The feature that arbitrary embodiment of either side of the present invention or this either side has is equally applicable to arbitrary embodiment of other either side or this other either side, as long as they can be not conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.
Below be further described with characteristics to various aspects of the present invention.
All documents that the present invention quotes from, their full content is incorporated this paper by reference into, and if when the expressed implication of these documents and the present invention are inconsistent, with statement of the present invention, be as the criterion.In addition, various terms and phrase that the present invention uses have the general sense of well known to a person skilled in the art, nonetheless, the present invention still wishes at this, these terms and phrase to be described in more detail and to explain, the term of mentioning and phrase, if any inconsistent with known implication, are as the criterion with the implication that the present invention was explained.
As described herein, term " septicemia " also is called " septicemia ", it has usually known implication of those skilled in the art, and typically refer to a kind of because antibacterial and/or other microorganism enter 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 gram positive coccus septicemia is easily migrated focus; The easy concurrent infection shock of gram-negative bacteria septicemia.Be called pyaemia septica or be called sepsis during with multiple abscess when septicemia.
As described herein, term " pgk1 activator " refers to PGK 1 (phosphoglycerate kinase 1, referred to as pgk1) activator, its can activate pgk1 and therefore those skilled in the art understand its disease that can be used for being correlated with or disease treatment, prevent, alleviate and/or alleviate.
Term " about " used herein, 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 " refers to realize treating, prevent, alleviate and/or alleviating the dosage of disease of the present invention or disease in the experimenter.
As described herein, term " pharmaceutical composition ", its can with " compositions " Alternate, refer to be used in the experimenter material of realizing treating, prevent, alleviate and/or alleviating disease of the present invention, disease, symptom.
As described herein, term " experimenter " or " patient ", can refer to accept the present composition and extract to treat, to prevent, to alleviate and/or to alleviate the animal of disease of the present invention, disease, symptom, particularly mammal, such as people, Canis familiaris L., monkey, cattle, horse etc.
As described herein, term " disease or symptom " refers to a kind of condition of described experimenter, and this condition is relevant with disease of the present invention or symptom.
As described herein, " % ", as do not specialize, generally refer to the percentage ratio of w/w while for total material, being solid, generally refer to the percentage ratio of weight/volume while for total material, being liquid.Certainly, be liquid and solute while being liquid for total material, the percentage ratio that characterizes this liquid solute generally refers to the percentage ratio of volume/volume.
Terazosin (Terazosin, (4-(4-amido-6,7-dimethoxy quinazoline-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 compound shown in above structure, also comprises the acceptable salt of pharmacy (for example hydrochlorate) of said structure compound, and the solvate of said structure compound and salt thereof hydrate for example.In a preferred embodiment of the invention, described terazosin refers to the terazosin hydrochloride dihydrate.The present invention hereinafter uses the terazosin as formula I compound typical case to carry out large quantity research to show the beat all effect of the present invention; Test hereinafter particularly in biological test, as not indicating in addition, reagent terazosin used refers to the terazosin hydrochloride dihydrate.
The present invention attempts screening apoptosis inhibitor from clinical medicine.At first, the present invention uses the model of cell apoptosis of fruit bat by the gene expression of micro-array chip technical Analysis.Then, the present invention uses contact figure (connectivity map, Cmap) to determine candidate's apoptosis blocker by 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 determined terazosin, and it is for alleviating hypertensive clinical application.In addition, the present invention finds that terazosin can suppress the apoptosis that is mediated by bacterial endotoxin (lipopolysaccharide, LPS, 2 μ g/ml) and interferon gamma (IFN γ, 50U/ml) in macrophage.In addition, the present invention's discovery, in septicemic cemia three test models, terazosin can reduce the mortality rate of mice greatly.What is interesting is, with independent use antibiotic, compare, make terazosin and antibiotic combinations can produce better protective effect.Result of the present invention shows, 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, the apoptosis pathway of caspase-3 (caspase)-mediation is fully conservative between dipteral insect and people.For example Reaper (rpr) brings into play Main Function (White et al., 1994) in the apoptosis of fruit bat.Although, can cause abnormal 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 can screen the apoptosis blocker with the fruit bat Apoptosis Model.HS-Gal4 (a kind of whole body expression and heat activated promoter), can impel 5 ' any genetically modified expression that repeats that contains UAS (upstream activating sequence).(during referred to as HS＞rpr), female descendant is normal development from start to finish when make this HS-Gal4 fruit bat and UAS-Reaper drosophila hybrid under 18 ℃.Yet, give heat shock 2-3 hour under 37 ℃, approximately the offspring of 50-70% after 14-24 hour dead (Fig. 1).The present invention has selected 25 kinds of compounds (Fig. 2) that rank is forward, and their impacts on the fatality rate of HS＞rpr are determined in the pacing of going forward side by side.The present invention finds only have terazosin can improve significantly the survival (Fig. 3) of HS＞rpr fruit bat.
In order to test whether also inhibited apoptosis in the mammalian cell of cultivating of terazosin, the present invention is by LPS and IFN γ cell death inducing in macrophage RAW264.7 cell, and this LPS and IFN γ bring out apoptotic known medicament in cultured cell.The present invention is by dyeing observation of cell apoptosis (Fig. 4) with Annexin V.Inventor's discovery, the cell that LPS (2 μ g/ml) and IFN γ (50U/ml) process causes cell membrane damage, turns up, thereby by Annexin V, is dyeed.This is a kind of apoptosis pattern of classics.And application terazosin (4 μ g/ml) can reduce by 50% apoptosis (Fig. 4).Importantly, the present invention finds unexpectedly effectively inhibited apoptosis and can be further used for treating and/or preventing septicemia and complication thereof of terazosin.
In order further to study the effect of terazosin in septicemic cemia mammal model, the present invention has studied the mice of accepting the LPS treatment.The present invention's discovery, (Fig. 5 a) at injection LPS (13.5mg/kg, i.p.) the 1.5 hours remarkable increase of injection terazosin (0.4mg/kg i.p) meeting mouse survivals afterwards.In order to confirm terazosin to apoptotic effect, the present invention has detected apoptotic label DNA break.As the organ that produces immunocyte, during septicemia, thymus is responsive (Ayala et al., 1998) to apoptosis.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.Result shows, in the mice that LPS processes, obvious DNA ladder type has occurred, but greatly reduces (Fig. 5 b) in the mice with the terazosin treatment.Whether in order to test terazosin, can play a role in the septicemic cemia later stage, the present invention is 12 hours injection terazosins after using LPS.The result demonstration, terazosin still has satisfied effect (Fig. 6).
Then, tested terazosin in the septicemia model of Escherichia Coli Injection.Result shows, the death (Fig. 7) that terazosin can protect mice to be induced by escherichia coli.In order to measure potential antibacterial effect, the inventor has detected the Escherichia coli Growth situation under terazosin exists.The result demonstration, with respect to ampicillin, terazosin can not suppress Escherichia coli Growth (Fig. 8).
Because LPS and escherichia coli model only can be simulated gram-negative bacteria and infected, the present invention has further tested terazosin in caecum ligation and puncture (CLP) model, this model it is believed that it is tentative septicemic cemia 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, not mice faster (data do not show) more dead than matched group of injection terazosin.The present invention infers that this may be because the serious heart dysfunction and the hypotension that are caused by CLP cause.Therefore, the function that reduces blood pressure of medicine may have been covered the effect of its anti-apoptosis.For head it off, the present invention is reduced to 0.08mg/kg with terazosin concentration, and the inventor has measured the impact of this concentration of injected in mice on blood pressure, finds that the mice blood pressure is fully normal.This result is used in rat with it can not reduce blood pressure consistent (Kyncl et al., 1985).What is interesting is, when 1.5 hours and 24 hours were injected 2 times after operation, terazosin had significantly promoted the survival (Fig. 9) of CLP model small mouse.Secondly, the present invention has tested terazosin and antibiotic combinations, in the present invention, antibiotic amoxicillin and clavulanate potassium (Co-Am have been selected, the weight ratio of amoxicillin and clavulanate potassium is 4: 1, when other place of the present invention is mentioned in the mode of concrete example or example, also refer to the proportioning of this 4: 1.Those skilled in the art understand, when making a general reference the combination of amoxicillin and clavulanate potassium, the weight ratio of amoxicillin and clavulanate potassium can be 1: 1 to 10: 1, particularly 1: 1 to 7: 1, for example approximately 1: 1, approximately 4: 1, approximately 7: 1) with the terazosin combination.The present invention's discovery, 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 another kind of α 1-adrenoceptor blocker (Cavero et al., 1977).The present invention finds that septicemia that Minidress causes LPS is without any curative effect.These results show, terazosin can significantly increase the septicemic cemia survival rate that suppresses the LPS-mediation, and its function is likely by apoptotic inhibitory action rather than targeting α 1-adrenoceptor.
In order to study the apoptotic Biological Mechanism of terazosin blocking-up, the present invention has sought its latent effect to inhibited apoptosis protease, realize it being mainly caspase-3 activation (McCall and Steller, 1997) by inherence due to the apoptosis in fruit bat.Yet, western blot analysis demonstration of the present invention, the activity form (homologous genes of Dpc-1 and drICE in fruit bat) of carrying out daughter cell apoptotic proteins enzyme 3 reduces (Figure 10) because of terazosin.The present invention infers, the upstream target of terazosin scalable caspase-3 3.For sldh gene, the present invention links terazosin on agarose beads, and Figure 11 has shown its chemosynthesis approach.Then angle albumen in Raw 264.7 cell extracts, found that (Figure 12 a) to have more a band with respect to blank and medicine competition matched group.Through Mass Spectrometric Identification, this band is Pgk1.In order to determine whether terazosin and the combination of Pgk1 are direct relation, the inventor has expressed also purification in the antibacterial Pgk1 albumen of mice, found that terazosin can be external directly in conjunction with Pgk1 albumen (Figure 12 b).Because cross expression Pgk1 apoptosis capable of inhibiting cell (Mazzoni et al., 2009) in yeast, the inventor guesses that terazosin may activate the enzymatic activity of Pgk1.In order to prove this conjecture, it is active that the inventor has detected the Pgk1 vitro enzyme.Found that, the terazosin of 0.05 μ M can activate nearly 3 times of the enzymatic activity of Pgk1, and increase terazosin concentration, to 0.4 μ M, can reduce activation (Figure 13) to enzymatic activity.If the Pgk1 enzymatic activity is the reason of inhibited apoptosis, crossing expression Pkg1 just should inhibited apoptosis.The inventor's experimental result shows,, with the RAW264.7 cell line of expressing the foundation of Pgk1 slow virus, has significantly reduced the apoptosis after LPS and IFN γ process; (Figure 14) occurs 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, found 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 is not subjected to 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, terazosin can easily be converted in clinical practice, and need not to revise existing antibiotic therapy program.Below biological test of the present invention is elaborated.
Embodiment
A, compound preparation example part
Following preparation example has exemplarily prepared segment bounds I compound of the present invention, and each compound represents with Co.1 to Co.32 respectively, and Co.33 represents terazosin.In the reaction process of following preparation example, " reflux " represents to reflux, " 1-pentanol " expression 1-amylalcohol.
The preparation of preparation example 1:Co.1
Step 1: pass into ammonia in the 200mL tetrahydrofuran solution that is dissolved with compound 1a (50mmol), reaction was carried out 36 hours under 25 ℃.There are a large amount of white solids to separate out in system, filter after the gained white solid washs with oxolane and obtain final products 1f.Productive rate is: 63%.
Step 2: add the 15mL acetic anhydride to compound 1f (10mmol), reaction refluxed 2 hours.Cool to room temperature, have a large amount of white solids to separate out in system, filter after the gained white solid washs with oxolane and obtain final products 1g.Productive rate is: 63%.
Step 3: in the situation that argon atmospher adds 1h (2mmol) in the solution of the 1-amylalcohol that is dissolved with 1g (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 1i after ether/recrystallizing methanol, 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 of preparation example 2:Co.2
Step 1: add compound 1b (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 4 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 1c after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 41%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 1c (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 1e after ether/recrystallizing methanol, 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 of preparation example 3:Co.3
Step 1: add hydrazine hydrate (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 4 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 3a after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 61%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 3a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 3b after ether/recrystallizing methanol, 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 of preparation example 4:Co.4
Step 1: add hydration oxyammonia (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 3 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 4a after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 88%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 4a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 4b after ether/recrystallizing methanol, 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 of preparation example 5:Co.5
Step 1: add allyl amine (22mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 8 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 5a after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 31%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 4a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 5b after ether/recrystallizing methanol, 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 of preparation example 6:Co.6
Step 1: add allyl amine (28mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 10 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 6a after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 44%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 4a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 6b after ether/recrystallizing methanol, 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 of preparation example 7:Co.7
Step 1: add compound 7a (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 3 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 7b after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 61%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 7b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 7c after ether/recrystallizing methanol, 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 of preparation example 8:Co.8
Step 1: add compound 8a (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 1.5 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 8b after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 71%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 8b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 8c after ether/recrystallizing methanol, 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 of preparation example 9:Co.9
Step 1: add compound 9a (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 2.5 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 9b after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 21%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 9b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 9c after ether/recrystallizing methanol, 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 of preparation example 10:Co.10
Step 1: add compound 10a (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 5 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 9b after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 36%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 9b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 10c after ether/recrystallizing methanol, 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 of preparation example 11:Co.11
Step 1: add compound 11b (20mmol) in the 100mL methanol solution that is dissolved with compound 1a (20mmol), reaction was carried out 5 hours under 25 ℃.After thin plate chromatography indication 1a transforms fully, to adding the 100mL ether in system, after mixing, put into-20 ℃ of standing crystallizations of environment.The gained white solid obtains final products 11c after using the petrol ether/ethyl acetate recrystallization.Productive rate is: 41%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 11b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 11c after ether/recrystallizing methanol, 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 of preparation example 12:Co.12
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 12a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 12b after ether/recrystallizing methanol, 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 of preparation example 13:Co.13
Step 1: add 20mL13a to compound 1f (10mmol), reaction refluxed 2 hours.Cool to room temperature, have a large amount of white solids to separate out in system, filter after the gained white solid washs with oxolane and obtain final products 13b.Productive rate is: 82%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 13b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 5.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 13c after ether/recrystallizing methanol, 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 of preparation example 14:Co.14
Step 1: add 22mL14a to compound 1f (10mmol), reaction refluxed 2 hours.Cool to room temperature, have a large amount of white solids to separate out in system, filter after the gained white solid washs with oxolane and obtain final products 14b.Productive rate is: 55%.
Step 2: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 14b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 14c after ether/recrystallizing methanol, 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 of preparation example 15:Co.15
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 15b (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 15c after ether/recrystallizing methanol, 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 of preparation example 16:Co.16
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 16a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 16a after ether/recrystallizing methanol, 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 of preparation example 17:Co.17
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 17a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 17a after ether/recrystallizing methanol, 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 of preparation example 18:Co.18
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 18a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 18b after ether/recrystallizing methanol, 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 of preparation example 19:Co.19
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 19a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 19b after ether/recrystallizing methanol, 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 of preparation example 20:Co.20
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 20a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 20b after ether/recrystallizing methanol, 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 of preparation example 21:Co.21
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 21a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 21b after ether/recrystallizing methanol, 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 of preparation example 22:Co.22
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 22a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 22b after ethyl ketone/recrystallizing methanol, 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 of preparation example 23:Co.23
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 23a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 23b after ether/recrystallizing methanol, 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 of preparation example 24:Co.24
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 25a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 25b after ether/recrystallizing methanol, 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 of preparation example 25:Co.25
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 25a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4.5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 25b after ether/recrystallizing methanol, 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 of preparation example 26:Co.26
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 26a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 26a after ether/recrystallizing methanol, 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 of preparation example 27:Co.27
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 27a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 27b after ether/recrystallizing methanol, 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 of preparation example 28:Co.28
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 28a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 28b after ether/recrystallizing methanol, 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 of preparation example 29:Co.29
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 29a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 3 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 29b after ether/recrystallizing methanol, 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 of preparation example 30:Co.30
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 30a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 5 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 30b after ether/recrystallizing methanol, 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 of preparation example 31:Co.31
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 31a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 31b after ether/recrystallizing methanol, 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 of preparation example 32:Co.32
Step 1: in the situation that argon atmospher adds 1d (2mmol) in the solution of the 1-amylalcohol that is dissolved with 32a (2mmol).Reaction system was placed on standing crystallization in 0-5 ℃ of environment after refluxing 4 hours.With 10mL washing with acetone gained white crystal twice, then with obtaining final products 32b after ether/recrystallizing methanol, 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, the raising of fruit bat and screening compound
UAS-rpr and HS-Gal4 fruit bat store center available from U.S. Bloomington.The F1 filial generation of these two kinds of germline hybridization (HS＞rpr) for screening of medicaments.These filial generation fruit bats are brought up under 18 ℃.Various medicines are dissolved in 5% glucose solution with the concentration of using in the cell culture in cmap.Drug solution (150 μ l) is placed on three layers of filter paper plate in tubule.Then, the adult HS of 20 1-3 ages in days＞rpr fruit bat is placed in this bottle and reaches 1 day., for cell death inducing, make these fruit bats 37 ℃ of lower heat shocks 2 hours.After heat shock 12 hours, calculate survival rate.
2, micro-array chip technical finesse and data analysis
From hs＞rpr and the fruit bat (genetic background mates with control series) for preparing 10 bottles of 1-3 ages in days with the filial generation 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 liquid nitrogen in 1,2,3,4,5,6,7,8 and 12 hours.Prepare total RNA by RNeasy mini test kit (Quiagen, Inc).Be for further processing to remove chromosomal DNA in sample with TURBO DNase test kit (Ambion, Inc).The quality of RNA sample detection and micro-array chip technical finesse step are to carry out according to Affymetrix DNA microarray chip technology standard scheme.Use is from the fruit bat 2.0DNA micro-array chip technology (Affymetrix, Inc) of Affymetrix.Processing simultaneously these arrays affects to reduce between different batches.Use Arrayassist 5.0 (Affymetrix, Inc) software to carry out data analysis.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 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 in transcribing as fruit gene, it can be reflected in adjacent time point.For the functional gene enrichment, usage data of the present invention storehouse instrument (http://david.abcc.ncifcrf.gov/).
3, by contact graph discovery candidate compound
The present invention will be transformed into mammal homologous genes (www.affymetrix.com) by the data base from the upper mediation down-regulated gene 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 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; Escherichia coli O111:B4, Sigma) DMEM (10%FBS) in cultivated 24 hours.
5, Hoechst dyeing
At first use Carnoy fixative (75% ethanol, 25% acetic acid) fixed cell, then use Hoechst 33342 (10 μ g/ml, Sigma) dyeing 10min.After ice-cold PBS washing 3 times, by confocal microscope (TCS SP5, Leica) observation of cell.
6, septicemic cemia mouse model
(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 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.After separating arteria ileocaeca, with No. 22 standard needle to the caecum puncture once, and from 5mm place, caecum top, carrying out ligation.Then make the abdominal part sealing by continous suture.Finally, the normal saline by injecting pre-temperature is (37 ℃; 5ml/100g, s.c.) animal is recovered., for antibiotic therapy, by administration by gavage, give Co-Am (southern Shandong pharmacy group company, Shandong, China) (30mg/kg).Observe the mouse survival rate every 12 hours and reach 7 days.
7, Western blotting
For Western blotting, the antibody test caspase-3 3 of the caspase-3 3 (#9664, Cell Signaling) that activates by identification, the antibody of actin is available from Wuhan doctor's moral company.
8, DNA fragmentation fractional analysis
After lps injection 24 hours, from the mice of accepting different treatments, take out a thymus.Then extract chromosomal DNA by chromosomal DNA purification kit (Biofuture, Beijing, China).Estimate the DNA fragmentation degree by the DNA agarose gel.
9, the analysis of bacteriostatic activity
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 impact on Escherichia coli Growth of terazosin and ampicillin after 24 hours.
10, the analysis of terazosin target
The present invention, by terazosin is connected on Affi-gel, then mixes with the protein extract of RAW 264.7 cells, in connection with the foreign protein on Affi-gel, washes off.With sample-loading buffer in connection with the albumen eluting, run glue (albumin glue of 15% concentration) after 96 degree heating.Special protein band is downcut, carry out Mass Spectrometric Identification.
11, the impact of terazosin on the Pgk1 activity
, at the Pgk1 of expression in escherichia coli mice recombiant protein (His-Pgk1), then use ni-sepharose purification His-Pgk1.Purifying protein is diluted to every milliliter of 0.15 unit, adds the terazosin of gradient concentration, detect the activity of Pgk1.
12, the research of terazosin and Pgk1 affinity
With the His-Pgk1 hatching of the Affi-gel of different disposal and purification, wash away the albumen of non-specific binding after 4 hours, with sample-loading buffer in connection with the albumen eluting, run glue (albumin glue of 15% concentration) after 96 degree heating.
13, statistical analysis
, for survival rate analysis, use the Kaplan-Meier check under Log Rank algorithm.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 for the treatment of and/or prevents 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.Then at reactant liquor (30mM Hepes, 3mM ATP, 0.22mM NADH, 10mM MgSO4,10mM 3-PGA, the GAPDH of 3-4U/ml, pH 7.5) in add certain density formula I compound, detect to absorb with spectrophotometer (340nm) under 25 ℃., according to the variation of absorption value in 1-10 minute, calculate the Pgk1 relative activity.Change sooner, activity is larger.Notice that simultaneously experimental group will deduct with the absorption of isocyatic compound at 340nm.
The activity of formula I compound represents with the multiple that activates Pgk1, and wherein 0.02 μ g/ml terazosin can activate active 2.9 times of Pgk1; O.1, Compound C is tested under 0.02 μ g/ml concentration to Co.32, and the multiple that activates the Pgk1 activity sees above respectively, and for example the multiple of Co.1 and Co.2 activation Pgk1 activity is 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 the (LPS that add 2 μ g/ml; Escherichia coli O111:B4, Sigma-Aldrich) gamma interferon (Peprotech) of 50U/ml is apoptosis-induced.Add simultaneously certain density compound.Assess apoptosis with the method for western blot, antibody is the activity form antibody (#9661, Cell Signaling) of Caspase 3.And take β-Actin as internal reference (Boster).Assess with the value of Caspase 3/ β-Actin the degree that apoptosis occurs.
16, the hypoglycemic activity of terazosin
Give mice shot terazosin (0.4mg/kg i.p.), measure mouse blood sugar after 18 hours, find that blood glucose has reduced nearly 30% left and right (t-check, P＜0.01); And unknown significance difference while giving saline simultaneously.The results are shown in Figure 16.In identical test method, other exemplary compounds of the present invention for example Co.1, Co.3, Co.7, Co.9, Co.13, Co.16, Co.19, Co.24, Co.27, Co.32 all 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, result is presented at brain sheet middle part and presents white (it is the typical phenomenon of brain death); Can obviously reduce thanatogenic tissue's area when shot terazosin (0.4mg/kg i.p.).Result is added up, take % thanatogenic tissue=white portion area/gross area as investigating index, mice quantity=6 under every kind of condition.Through t-check, P＜0.05.The results are shown in Figure 17, as seen, terazosin can obviously reduce the area of brain death tissue to result from figure.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 (20 gram left and right) intraperitoneal injection of LPS (13.5mg/kg), the certain density medicine of injection after an and a half hours, observed the survival of a mice in every 12 hours, observed altogether 7 days, and the statistics survival has there was no significant difference.
Alternate model is caecum puncture and ligation (CLP).After mouse anesthesia, cut off the osculum of 1.5-2 centimetre at its abdominal part, caecum is taken out.Feces is extruded into caecum bottom, be 5 millimeters away from caecum top locate ligation, then with No. 22 syringe needles, wear an aperture, extrude some feces.Caecum is put back to abdominal cavity, with linear slit well and wound closure.The certain density medicine of injection after one and a half hours, observed the survival of a mice in every 12 hours, observed altogether 7 days, and the statistics survival has there was no significant difference.
Result shows, in the test of above two kinds of models, Compound C o.1, Co.4, Co.9, Co.13, Co.18, Co.21, Co.28, Co.29, Co.33 be respectively to inject once a day (0.4mg/kg i.p.) successive administration after 3 days, when 7 day observation period finished, show that these 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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Claims (6)
1. formula I compound or the acceptable salt of its pharmacy treat and/or prevent purposes in the medicine of cerebral thrombosis and complication thereof in preparation,
Wherein
R
1aAnd R
1bBe selected from independently of one another H, NH
2, OH, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkyl-, C
2-6Thiazolinyl-, C
2-6Alkynyl-, C
1-6Alkoxyl-, C
1-6Alkyl acyl-, phenyl-, C
5-6Cycloalkyl, wherein said alkyl is optional is selected from following substituent group replacement by 1-3: hydroxyl, halogen;
R
2And R
3Be selected from independently of one another H, halogen, C
1-6Alkyl-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, C
1-6Alkanoylamino-;
R
4And R
5Be selected from independently of one another H, halogen, C
1-6Alkyl-, C
1-6Alkoxy-C
1-6Alkoxyl-, C
1-6Alkanoyl oxygen base-, halo C
1-6Alkyl-, C
1-6Alkoxyl-, C
1-6Alkanoylamino-.
2. according to claim 1 purposes, wherein 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,-CH
2-(CH
2)
3-CH
2-,-Ph ,-CH
3,-C (O)-CF
3.
3. according to claim 1 purposes, wherein R
2And R
3Be selected from independently of one another H, CH
3O-,-O (CH
2)
2OC
2H
5,-OC (O) CH
3,-F ,-CF
3,-NHCOCH
3,-(CH
2)
2CH
3.
4. according to claim 1 purposes, wherein 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.
5. be selected from the compound of the following Co.1 to Co.33 of being numbered or the acceptable salt of its pharmacy and treat and/or prevent purposes in the medicine of cerebral thrombosis and complication thereof in preparation:
6. according to claim 5 purposes, the compound of the wherein said Co.33 of being numbered is hydrochlorate or its hydrate of terazosin.
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