CN109730996A - Quinoline structure type androgen receptor antagonists and its application - Google Patents

Quinoline structure type androgen receptor antagonists and its application Download PDF

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CN109730996A
CN109730996A CN201910136005.XA CN201910136005A CN109730996A CN 109730996 A CN109730996 A CN 109730996A CN 201910136005 A CN201910136005 A CN 201910136005A CN 109730996 A CN109730996 A CN 109730996A
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compound
androgen receptor
antagonist
pharmaceutical composition
application
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CN109730996B (en
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侯廷军
李丹
周文方
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Zhejiang University ZJU
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine

Abstract

This divisional application discloses quinoline structure type androgen receptor antagonists and its application, belongs to technological field of biochemistry.Compound provided by the invention has apparent antagonistic activity to androgen receptor, therefore above compound can be applied in the preparation of androgen receptor antagonists, prostate gland cancer cell antiblastic and anti-prostate tumor drug.Pharmaceutical composition the present invention also provides above compound as effective component, the drug research for treatment prostate cancer at present provide new selection.

Description

Quinoline structure type androgen receptor antagonists and its application
The application is application number 201710117698.9, on March 2017 applying date 1, " androgen receptor is short of money for denomination of invention The divisional application of anti-agent and its application ".
Technical field
The present invention relates to technological field of biochemistry, and in particular to androgen receptor antagonists and its application.
Background technique
Prostate cancer is the second largest fatal tumor of male in western countries, and recently as our people's living standard Raising and dietary structure variation, the trend obviously increased is presented in the disease incidence of domestic prostate cancer.It is (early for Limited-stage Phase) patients with prostate cancer, Prostate Cancer after Radical, radiotherapy can reach good therapeutic effect.But due to prostate cancer early clinic symptom The concealment of the unobvious, state of an illness, in addition screening is not popularized, when many patient assessments, has been in the advanced stage that tumour has shifted, at this time Prostate Cancer after Radical and chemotherapy are difficult to obtain ideal effect, it is necessary in addition use endocrine therapy.For hormone-sensitive type evening Phase patients with prostate cancer, endocrine therapy are essential therapeutic arsenals, including operation castration, medical castration and use are with androgen receptor Antiandrogen drug based on body (AndrogenReceptor, AR) antagonist；For having progressed to the prostate of repellence Cancer (Castration-resistant Prostate Cancer, CRPC) patient, AR antagonist be important treatment means it One.
AR antagonist (antiandrogen) in the treatment of prostate cancer application have the long period history, initially with change It is similar to learn castration drug gonadotropin-releasing hormone (GRH) (Luteinizing Hormone Releasing Hormone, LHRH) Internet of Things are used, as one of Androgen deprivation therapy (Androgen Deprivation Therapy, the ADT) means of supplementing out economy, Its main function is that disease symptoms aggravate caused by blocking medicine castration initial stage patient's body testosterone levels increase in short term.
AR antagonist can be divided into steroid and nonsteroidal by structure type；Steroid antagonist due to there are hepatotoxicity wind agitation, Interfere sexual desire, cardiovascular side effects and it is inefficient the defects of, clinical use is limited；And the clinical use of nonsteroidal antagonist is from upper Since century the eighties, there is first generation antagonist Flutamide, alpha..alpha..alpha.-Trifluoro-2-methyl-4'-nitro-m-lactotoluidide, Bicalutamide, Nilutamide and The two miscellaneous Shandong amine of generation antagonist grace.Studies have shown that AR and its leading signal transduction pathway are sent out in the progression of prostate cancer Critical effect is waved, the endocrine therapy of advanced prostate cancer is also primarily directed in this.Castration can be as far as possible The main source for cutting off patient's body androgen makes AR lack the combination of native ligand to inhibit the access；AR antagonist then may be used Acted on to reduce the Pathway Activation of androgen in other sources of patient's body by competitively being combined AR with androgen, from And reach complete hormone ablative effect.Just because of this, AR antagonist was also approved as single medication later makes in ADT With.
First generation nonsteroidal antagonists are derivative by Flutamide and go out, therefore have similar structural framework；Bicalutamide Outstanding person best as wherein tolerance, most stable and the most widely used, in addition to can competitive binding AR be at it is short of money Anti- state and be difficult to assemble the co-activation factor, in conjunction with DNA outside, moreover it is possible to play cancer resistant effect by reducing the stability of AR.Such as Fruit says that first generation AR antagonist only plays limited secondary utility in the treatment of prostate cancer, then second generation antagonist grace is miscellaneous AR antagonist has then been shifted onto the new critical role of CRPC standard care by the appearance of Shandong amine.Compared with Bicalutamide, the miscellaneous Shandong of grace Amine has higher affinity to AR, to bring stronger drug effect；It is removed on mechanism of action and has first generation nonsteroidal antagonists Except characteristic, it can also inhibit the nuclear transfer of AR, be allowed to that the effect that core plays transcription factor cannot be entered.The miscellaneous Shandong amine of grace initially in It is approved within 2012 the treatment for the CRPC patient that cancer has been spread after endocrinotherapy and chemotherapy, further in 2014 It is approved for ADT treatment failure but does not receive the treatment of asymptomatic or light symptoms the metastatic CRPC of chemotherapy；As it can be seen that Advanced metastatic CRPC available for rare drug, the miscellaneous Shandong amine of AR antagonist grace of new generation of energy independent medication, which has, lifts foot The heavy pound medicine status of weight；And with further clinical research, therapeutic domain continues to expand in prostate cancer.
However, as the progress of disease always generates drug resistance, AR antagonist produces after each prostate cancer drug use The concrete reason of raw drug resistance not yet illustrates completely at present, and a large amount of research observes that the mutation of AR albumen is wherein very crucial A bit.The point mutation of AR albumen can not only make antagonist fail, but also will lead to the small molecule function for once playing antagonism Can reverse and generate agonist effect, have even if in curative effect two generation antagonists of unique advantage after a period of use can not keep away The meeting exempted from takes a turn for the worse effect.Therefore, of new generation, to AR high-affinity, have AR antagonist skeleton knot different from the past The Novel antagonists molecule of structure is still the emphasis direction of prostate cancer drug research, and there is also urgent clinical demands.
Clinic mainly has ARN-509, ODM-201 and AZD3514 in the AR antagonist pharmaceuticals of new generation ground, the above two are respectively For receiving different therapy and prostate patient in different phase is at present respectively to the phase iii clinical trial stage, It is expected to very much granted in the near future and treatment ranks is added.ARN-509 has the structure closely similar with the miscellaneous Shandong amine of grace, mesh Preceding result of study shows that compared with the miscellaneous Shandong amine of grace, it has a stronger receptor binding capacity, the dosage for needing to take relatively compared with It is low, and have lower central nervous system infiltration with cause epilepsy side effect, but just because of structure excessive similarity, for grace There is miscellaneous Shandong amine the F876L mutation of drug resistance equally can generate drug resistance to ARN-509.ODM-201 and its cylinder metabolism-ure ORM-15341 has more novel chemical structure, its mechanism of action is similar to two generation antagonists, but very to the affinity of AR To more than ARN-509 and the miscellaneous Shandong amine of grace.
The research situation of domestic and international AR antagonist is summarized it can be found that exploitation targets the site HBP and has novel framework knot Structure, high-affinity and highly selective antagonist of new generation are still the emphasis of research, with the aggravation of the problem of an aging population, There is huge clinical demands.The non-HBP antagonist for targeting other regions of AR albumen, can overcome traditional antagonist drug resistance Defect, there are still very big clinical blank for this aspect research；The drug development of new A R antagonist shoulders heavy responsibilities.
Summary of the invention
The object of the present invention is to provide with the active compound of androgen receptor antagonist, androgen receptor is applied it to Antagonist, anti-prostate tumor drug preparation in.
The present invention is achieved through the following technical solutions above-mentioned purpose:
The present invention has found guide's chemical combination of targeting androgen receptor using the means of Computeraided drug design Object, then the virtual screening based on molecular docking is carried out to multiple small molecule compound three-dimensional structure databases, it is forward to obtain score 1000 compounds (energy is lower, and score is more forward).Pass through the MTT cell of prostate cancer classics cell strain LNCaP later Proliferation experiment, the Inhibition test of AR transcription factor activity and use kit PolarScreenTM AR Competitor Assay, Green (Thermo Fisher Scientific) investigate the combination situation of compound and the ligand binding domain LBP of AR, Finishing screen obtains 1 representative reactive compound: the chloro- 4- of ethyl 7- ((3- hydroxy phenyl) amino) -8- methylquinoline -3- Carboxylic acid, shown in structural formula such as formula (1)；
The present invention carries out further Determination of biological activity to the above-mentioned compound screened, finds above compound to hero Hormone receptor has apparent antagonistic activity, and therefore, it is male sharp in preparation that the present invention provides above compounds or its officinal salt Application in hormone receptor antagonists.
The research of the invention finds that: above compound shows in the experiment of the anti-prostate tumor of protein level and cellular level Good effect, therefore, the present invention provides above compounds or its officinal salt to prepare prostate gland cancer cell Proliferation Ability Application in agent.
The present invention also provides above compounds or its officinal salt to prepare the application in anti-prostate tumor drug.
The present invention also provides a kind of pharmaceutical compositions, include the compound or pharmaceutically acceptable salt thereof as effective component.
Compound as effective component is androgen receptor antagonists, and therefore, pharmaceutical composition of the invention can be used as There is the therapeutic agent of related disorders with androgen receptor.
The officinal salt be hydrochloride, phosphate, sulfate, acetate, maleate, citrate, benzene sulfonate, Toluenesulfonate, fumarate or tartrate.
Described pharmaceutical composition further includes pharmaceutically acceptable excipient, diluent or carrier.It is specific as syrup, I Primary glue and starch etc..The pharmaceutical composition can by vein, it is oral, sublingual, given through muscle or subcutaneous, skin and mucosa approach Medicine.
The dosage form of described pharmaceutical composition is liquid preparation or solid pharmaceutical preparation.Specific such as tablet, capsule and injection Agent etc..Each dosage form can be prepared with pharmacy conventional method.
It is that the present invention has the utility model has the advantages that
The present invention is based on the virtual screening method of molecular docking and Determination of biological activity to find compound ethyl for the first time The chloro- 4- of 7- ((3- hydroxy phenyl) amino) -8- methylquinoline -3- carboxylic acid has apparent antagonistic activity to androgen receptor, can It is applied in disease treatment related with androgen receptor as androgen receptor antagonists, for treatment prostate at present The drug research of cancer provides new selection.
Detailed description of the invention
Fig. 1 be 13 compounds of the invention under the conditions of concentration is 10 μM to AR binding ability experimental result.
Fig. 2 is for compound 1 to AR binding ability experimental result under a series of concentration gradients.
Fig. 3 is for compound 3 to AR binding ability experimental result under a series of concentration gradients.
Fig. 4 is for compound 4 to AR binding ability experimental result under a series of concentration gradients.
Fig. 5 is that antagonist is mutual between combination conformation and antagonist in AR active pocket and AR active pocket residue Binding mode, wherein (a) is that (albumen uses beam shapes to combination conformation of the antagonist in AR active pocket, and antagonist uses Stick-like model is shown)；(b) Interactions Mode between antagonist and AR active pocket residue.
Fig. 6 be 13 compounds under the conditions of concentration is 10 μM to the antagonistic activity experimental result of AR.
Fig. 7 is for compound 5-7 to AR antagonistic ability experimental result under a series of concentration gradients.
Fig. 8 is for compound 8-10 to AR antagonistic ability experimental result under a series of concentration gradients.
Fig. 9 is for compound 11-13 to AR antagonistic ability experimental result under a series of concentration gradients.
Figure 10 is the rejection ability result that compound 1-8 is proliferated prostate gland cancer cell under the conditions of concentration is 10 μM.
Figure 11 is the rejection ability result that compound 9-13 is proliferated prostate gland cancer cell.
Specific embodiment
The present invention is further explained in the light of specific embodiments.
Embodiment 1
(1) based on the virtual screening of molecular docking
Experimental principle: molecular docking method is utilized, to the interaction between the compound and AR in compound database It predicted, analyzed and is assessed, so that it is determined that the antagonist molecules that can be combined with AR.
Experimental method: forming the crystal structure (PDB number: 2PNU, 2Q7I and 3V49) of compound based on AR and androgen, The research of virtual screening based on molecular docking has been carried out using the Glide module in Schrodinger molecular simulation software.Virtually Compound library used by screening includes Chembridge, ChemDiv of latest edition and the packet of applicant seminar exploitation Chinese herbal medicine effective ingredients three-dimensional structure database containing more than 60,000 a compounds.We are to optimal 2000 of virtual screening marking Compound is evaluated using Reos rule, eliminates the molecule comprising reactive group.
Experimental result: molecular docking, which can be determined relatively accurately, can form organic small point compared with strong interaction with AR Son.Prediction result based on molecular docking, we have purchased a compound more than 200 from commercial compound library, and after having carried out It is continuous based on molecular level Binding experiment (PolarScreenTMAR Competitor Assay, Green, Thermo Fisher Scientific active testing) therefrom has found that a batch has the small molecule compound of obvious AR antagonistic activity, is specifically shown in Table 1。
Table 1
The structural formula of above compound is as follows:
(2) AR competitive binding experiment
Experimental principle: the measurement of compound AR binding ability uses Invitrogen company (Thermo Fisher Under Scientific) fluorescence polarization experiment.Androgen receptor { AR-LBD (His-GST) } and a kind of hero with fluorescence swash Plain ligand (FluormoneTMAL Green) combines and forms binary complex (AR-LBD (His-GST)/FluormoneTMAL Green), compound fluorescence polarization value with higher.This compound is added in the microwell plate containing test compound, Tested compound replaces the fluorescent ligand (FluormoneTMAL in binary complex as a kind of competitiveness with cognition Green), decline fluorescence polarization value.If what is be added is the noncompetitive ligand for not having replacement fluorescent chemicals ability, Polarization value can still maintain high level.Therefore, after tested compound is added, the change of fluorescence polarization value can be used to quantitative survey Tested compound is measured to the relative affinity of AR-LBD (His-GST).
Experimental method: after AR LBD albumen and high-affinity fluorescent ligand are mixed in buffer, various concentration is added Test compound (virtual screening compound) using androgen dihydrotestosterone (DHT) as positive control).If testing compound pair AR LBD has higher affinity, as a kind of competitiveness with the fluorescent ligand replaced in binary complex is known from experience, makes system The decline of fluorescence polarization value；If the test compound being added is not bound with ability, the fluorescence polarization of system to AR LBD substantially Value can still maintain high value, we can quantitative measurment using the variation of the fluorescence polarization value of multi-function microplate reader measurement system Binding ability (binding affinity) of the virtual screening compound to AR.
Experimental result: as shown in Figure 1, the AR Percentage bound of 1-13 compound is more than 30%.We test various concentration Compound and AR binding ability, discovery series compound has a good binding ability, the fluorescent ligand of AR inhibited to combine 503nhibiting concentration IC50To be micromole's rank, as shown in Figure 2,3, 4, wherein the IC of 1,3, No. 4 compound50Value is respectively 33 μM, 50-100 μM and 2.6 μM.
(3) between antagonist and AR Interactions Mode evaluation
Experimental principle: being based on molecular docking and molecular dynamics simulation, predicted from atomic scale AR antagonist and AR it Between Interactions Mode.
Experimental procedure: based on molecular docking predict as a result, carrying out the molecular dynamics mould of 50ns to antagonist/AR Quasi-, simulation uses AMBER14.
Experimental result: the phase interaction between antagonist and AR obtained by molecular docking prediction and molecular dynamics simulation With as shown in Figure 5.Pre- geodesic structure shows that the molecular recognition between antagonist and AR mainly passes through Van der Waals and hydrogen bond phase interaction With.Hydroxyl on antagonist can form stable hydrogen bond with Ser110；Two phenyl ring can be produced with multiple hydrophobic residues of surrounding Raw strong Van der Waals interaction.
(4) AR antagonistic ability evaluation experimental
Experimental principle: AR as transcription factor, need with specific sequence, i.e. ARE response element, in conjunction with competence exertion turn Record activity；Therefore it is enhanced green the reporter gene that ARR2PB promoter controls to be imported to the prostate gland cancer cell LNCaP of the AR positive Color fluorescin EGFP, after various concentration tests compound drug treatment, the height for measuring the expression quantity of EGPF in cell is Compound can be obtained to the power of AR antagonistic ability.
Experimental procedure: we with it is building in advance, containing there is the ARR that responds by force to AR2The EGFP of PB promoter control (enhanced green fluorescence protein) reporter plasmid is obtained using the method for slow virus stable transfection LNCaP cell by AR tune Expression EGFP prostate cancer cell line (LN-ARR is stablized in control2PB-EGFP)。LN-ARR2PB-EGFP cell first swashs without male It is cultivated several days in the complete medium of element, so that background fluorescence activity is down to reduced levels, then by it with the density in 40000/hole It is seeded in 96 saturating orifice plates of black bottom, after cytotostatic is adherent, while giving androgen and various concentration test compound (virtual screening compound has listed the miscellaneous Shandong amine of antagonist pharmaceuticals grace), after being incubated for 24-48h, with multi-function microplate reader in wavelength 530nm wavelength fluorescence intensity level nearby is detected under 485nm exciting light, can quantitatively calculate test compound antagonism AR albumen Inhibiting rate.
Experimental result:
As shown in fig. 6,1-13 compound can reach 30% or more inhibiting rate.
As Figure 7-9, after various concentration compound handles LN-ARR2PB-EGFP cell 36h, compound is to report The expression of gene EGFP generates apparent downward effect, and dose-dependence is presented, this illustrates the compound cited by us It is all active good potential AR antagonist.
(5) mtt assay detection compound anti-prostate tumor cell-proliferation activity
Experimental principle: the succinate dehydrogenase in living cells mitochondria can make exogenous MTT ((3- (4,5- dimethyl thiophenes Azoles -2) -2,5- diphenyltetrazolium bromide bromide)) be reduced to bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) of water-insoluble and be deposited on In cell, and the first a ceremonial jade-ladle, used in libation formed in buffer solution cell is added without this function in dead cell, is existed with enzyme-linked immunosorbent assay instrument Its absorbance value is measured at 490nm wavelength, can reflect living cells quantity indirectly.
Experimental procedure: with being free of, androgen complete medium is thin in 96 orifice plate inoculated and cultured cancers with the density in 3000/hole Born of the same parents, after cytotostatic is adherent, while give 1nM DHT and various concentration test compound (virtual screening compound has listed Antagonist pharmaceuticals or DMSO), 10 μ L 5mg/ml MTT are added in every hole after being incubated for 4days, continue to be incubated in incubator 3hours, then 100 μ L SDS-HCl-PBS, tri- buffer is added in every hole, after 37 degree are incubated overnight, detects under microplate reader Each hole absorbance value, is scaled survival rate at 570nM, can be obtained to the IC of drug compound50Value.
Experimental result: as shown in Figure 10,11, the compound on prostate cancer cell LNCaP in the present invention has apparent increasing Rejection ability is grown, IC is inhibited50It can reach and the miscellaneous Shandong amine similar level of marketed drug grace.

Claims (7)

1. structural formula such as formula (1) compound represented or its officinal salt are preparing the application in androgen receptor antagonists,
2. compound or pharmaceutically acceptable salt thereof as described in claim 1 is preparing answering in prostate gland cancer cell antiblastic With.
3. compound or pharmaceutically acceptable salt thereof as described in claim 1 is preparing the application in anti-prostate tumor drug.
4. a kind of pharmaceutical composition, which is characterized in that comprising as the compound as described in claim 1 of effective component or its Officinal salt.
5. pharmaceutical composition as claimed in claim 4, which is characterized in that the officinal salt is hydrochloride, phosphate, sulfuric acid Salt, acetate, maleate, citrate, benzene sulfonate, toluenesulfonate, fumarate or tartrate.
6. pharmaceutical composition as claimed in claim 4, which is characterized in that further include pharmaceutically acceptable excipient, dilution Agent or carrier.
7. pharmaceutical composition as claimed in claim 4, which is characterized in that the dosage form of pharmaceutical composition be liquid preparation or Solid pharmaceutical preparation.
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