CN109485691A - Tanshinone compound and its for treating angiomatous purposes - Google Patents
Tanshinone compound and its for treating angiomatous purposes Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/003—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by oxygen as hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C50/00—Quinones
- C07C50/16—Quinones the quinoid structure being part of a condensed ring system containing three rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/537—Salvia (sage)
Abstract
The present invention provides class I tanshinone class compound and its for treating angiomatous purposes, specifically, the present invention provides a kind of such as following formula I compounds represented or the purposes of its pharmaceutically acceptable salt, wherein the definition of each group is as noted in the discussion.Tanshinone compound of the invention has hemangioma cell inhibitory activity, can be used for preparing the angiomatous pharmaceutical composition for the treatment of.
Description
Technical field
The present invention relates to drug fields, specifically, the present invention provides class I tanshinone class compound and its for treating
Angiomatous purposes.
Background technique
Hemangioma (infantile hemangiomas, IH), is the most common benign tumour of infant, is blood vessel endothelium
Abnormal cell proliferation and the true property hemangioma generated.Its disease incidence about 5%-10%, male to female ratio are mostly 1:3-5.The disease is going out
Be difficult to be found when raw, recent cohort study prompt, the summit of growth phase multidigit of infant hemangioma in 5.5-7.5 weeks,
4 weeks or so average, subsequent lesion is faded in, and into the rapid growth phase, is subsided slowly, the few then several months, and more then 70 to ten years.It is a small number of
The signs such as the hemangioma area of infant is larger, leaves pigmentation, while with shallow scar, and atrophoderma is sagging, more have even
It is not cured all the life.
The pathogenesis of IH obscures so far.Early stage theory thinks that the behavior of mother leads to hemangioma or blood vessel during gestation
The generation of deformity, strawberry hemangioma had even once been considered mother and were taking caused by red fruit.Currently, angiomatous generation machine
System is mainly the following theory: embryonic period, embryonic phase angiodysplasia, vascularization disease, influence of estrogen etc..Hemangioma
Current research focus mostly on the recruitment in progenitor cells, mesenchymal neoplasm cell, extracellular matrix exception, promote blood vessel hyperplasia the factor
Deng.
IH is more than half voluntarily to subside, it is general advocate to hold in hemangioma early stage look around and permissive attitude, but it is angiomatous
Occurrence and development may will affect the life of infant, and with advancing age, autopsychic promotion, infant often shows to lack certainly
Letter, anxiety and sense of guilt etc. should treat in time when especially angiomatous growth jeopardizes infant life or organ function.It controls at present
Treatment means include: oral or external medication, operation excision, cold therapy, radio nuclide therapy and laser therapy etc..Swash
Element and Propranolol are the primary selections of current oral medication IH, and Propranolol has become the first-line drug for the treatment of IH.General naphthalene
The mechanism of action of IH is still not clear in Luo Er and hormone, while significant in efficacy, also faces many side effects.Such as Propranolol
Bradycardia, different degrees of atrioventricular block, low blood pressure, cardiogenic shock, bronchial spasm, asthma and edema with the lung involved can be induced
It swells；Hormone can cause fungal infection, hypertension, Cushing syndrome and upset,gastro-intestinal etc..Other angiomatous external drugs are still
Belong to trial state, such as imiquimod, by generating a large amount of cell factor, induction of vascular tumor subsides, but actual efficacy also needs to see
Examine summary.Therefore, it is extremely urgent that novel anti-angiogenic tumor medicine, the task of the more effectively treatment means of exploitation are researched and developed.
Summary of the invention
The object of the present invention is to provide a kind of novel having, and blood vessel oncocyte to be inhibited to generate active medical compounds, and
It is used to treat angiomatous purposes.
The first aspect of the present invention provides one kind such as following formula I compound represented or its pharmaceutically acceptable salt
Purposes:
Wherein, A ring is selected from the group: substituted or unsubstituted 3-10 member carbocyclic ring, takes substituted or unsubstituted 3-10 circle heterocyclic ring
Generation or unsubstituted C6-C10Aromatic ring, substituted or unsubstituted 5-12 member hetero-aromatic ring；
R1It is selected from the group: H, oxygen atom (=O), O-R '；
R2It is selected from the group: H, oxygen atom, O-R '；
The R' is selected from the group: H, substituted or unsubstituted C2-C10Acyl group, fluorenes methoxy carbonyl acyl group (Fmoc) or take
Generation or unsubstituted C1-C10Alkyl；Preferably, R' is H；
R3It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkoxy, C1-C4Alkyl, C1-C4
Halogenated alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted C2-C10Ester group ,-OC (O)-R ,-NH-
R；Wherein, R is selected from the group: H, C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
R4It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkoxy, C1-C4Alkyl, C1-C4
Halogenated alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted C2-C10Ester group ,-OC (O)-R ,-NH-
R；Wherein, R is selected from the group: H, C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R1、R2、R3And R4In any two and adjacent carbon atom collectively form group selected from the group below: replace or
Unsubstituted C3-C10First carbocyclic ring, substituted or unsubstituted 3-10 circle heterocyclic ring, substituted or unsubstituted C6-C10Aromatic ring, substitution or not
Substituted 5-12 member hetero-aromatic ring；
R5It is selected from the group: H, halogen, cyano, hydroxyl, C1-C4Alkoxy ,-COOR, C substituted or unsubstituted1-C10Alkyl,
Substituted or unsubstituted C1-C10Halogenated alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted C2-C10Ester
Base；Wherein, R is selected from the group: H, C2-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
R6It is selected from the group: H, halogen, oxygen atom, cyano, carboxyl, hydroxyl, C1-C4Alkoxy ,-COOR, replace or do not take
For C1-C10Alkyl, substituted or unsubstituted C1-C10Halogenated alkyl, substituted or unsubstituted C2-C10Acyl group, replace or do not take
The C in generation2-C10Ester group；Wherein, R is selected from the group: H, C2-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R5And R6Collectively form-R "-O-R "-, wherein the R " is nothing or substituted or unsubstituted C1-C4Asia
Alkyl；
R7For the group selected from the group below on A ring: H, hydroxyl, amino, substituted or unsubstituted C1-C10Alcoxyl
Base ,-COOR, substituted or unsubstituted C2-C10Acyl group, C substituted or unsubstituted1-C10Alkyl, substituted or unsubstituted C2-C10
Ester group；Wherein, R is selected from the group: H, C2-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
N=1,2,3,4,5,6,7,8,9 or 10；
In the above formulas, substitution refers to one or more hydrogen atoms on group replaced substituent group selected from the group below: carboxylic
Base, phenyl, C3-C6Naphthenic base, C2-C10Ester group, halogen, C1-C10Alkyl-oxygroup, C2-C10Acyl group, hydroxyl, hydroxyl-C1-
C10Alkylidene；
" " is double bond or singly-bound；
It is characterized in that, being used to prepare:
(a) angiomatous pharmaceutical composition is treated；
(b) inhibit the pharmaceutical composition of the proliferation activity of blood vessel oncocyte；
(c) promote the pharmaceutical composition of blood vessel apoptosis of tumor；
(d) inhibit cell at the pharmaceutical composition of pipe.
In another preferred example, the R3It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkane
Base, C1-C4Halogenated alkyl；
R4It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkyl, C1-C4Halogenated alkyl；
Or R3And R4Collectively form group selected from the group below: substituted or unsubstituted 3-8 circle heterocyclic ring, substituted or unsubstituted
5-7 member hetero-aromatic ring.
In another preferred example, the A ring is selected from the group: substituted or unsubstituted 5-7 member carbocyclic ring, substituted or unsubstituted
5-7 circle heterocyclic ring, substituted or unsubstituted 6 yuan of aromatic rings, substituted or unsubstituted 5-7 member hetero-aromatic ring.
In another preferred example, R7For one or more groups selected from the group below: H, hydroxyl, amino, C1-C4Alkyl,
C1-C4Halogenated alkyl, C1-C4Alkoxy ,-COOR；Wherein, R is selected from the group: H, C1-C4Acyl group, substituted or unsubstituted
C1-C4Alkyl.
In another preferred example, R1For=O.
In another preferred example, the R3For C1-C4Alkyl or C1-C4Halogenated alkyl；
R4It is selected from the group: H, oxygen atom；
Or R3And R4Collectively form group selected from the group below: substituted or unsubstituted furan nucleus, substituted or unsubstituted dihydro
Furan nucleus, substituted or unsubstituted tetrahydrofuran ring.
In another preferred example, the Formulas I compound represented is selected from the group:
In another preferred example, in the pharmaceutical composition, the effective dose of the compound of formula I is 0.1-50mg/
Kg weight, preferably 1-20mg/kg weight.
In another preferred example, the pharmaceutical composition is dosage form selected from the group below: peroral dosage form, injection type.
In another preferred example, the pharmaceutical composition is also used to inhibit the angiogenesis of endothelial cells in infant hemangioma.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1-Fig. 3: dihydrotanshinone I and Propranolol are in corresponding drug concentration (3uM, 50uM) and set time
Under (48h), Apoptosis is at time and concentration dependent；
Fig. 4: the albumen result figure of dihydrotanshinone I and Propranolol to Apoptosis；
Fig. 5: dihydrotanshinone I and Propranolol are to cell at the influence result figure of pipe；
Fig. 6: dihydrotanshinone I and Propranolol are on influence result figure angiomatous in Mice Body.
Specific embodiment
The present inventor's in-depth study by long-term, it has unexpectedly been found that, tanshinone compound has good blood vessel
Oncocyte inhibitory activity, and activity is better than existing general drug Propranolol.The compound can with time dependence and
Dose-dependently inhibit the proliferation of blood vessel oncocyte in vivo or in vitro.Based on above-mentioned discovery, inventor completes the present invention.
Term
As used herein, term " C1-C4Alkyl " or " C1-C10Alkyl " refers to straight with 1~4 or 1-10 carbon atom
Chain or branched alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, or similar group.
Term " C3-C6Naphthenic base " refers to the naphthenic base with 3~6 carbon atoms, such as cyclopropyl, cyclobutyl, methyl ring fourth
Base, cyclopenta, or similar group.
As used herein, term " C1-C10Acyl group " or " C1-C4Acyl group " finger-type such as " has 0~9 or 0-3 carbon atom
Linear or branched alkyl group/naphthenic base/aryl-carbonyl " structure substituent group, such as acetyl group, propiono, bytyry or similar
Group.
Term " C2-C10Ester group " finger-type such as " linear or branched alkyl group/naphthenic base/aryl-carbonyl with 1~9 carbon atom
The substituent group of base-oxygen atom " structure, such as acetyl group, propiono, bytyry, or similar group.
Term " C1-C4Alkylidene " refers to that C1~C4 alkyl as described above loses the group that a hydrogen atom is formed later,
Such as-CH2-、-CH2-CH2, or similar group.
Term " halogen " refers to F, Cl, Br and I.
Term " C6-C10Aryl " refers to aryl with 6-10 carbon atom, such as phenyl, naphthalene etc..
Term " C1-C10Heteroaryl " refers to 1-10 carbon atom and one or more hetero atoms for being selected from O, S and/or N
Heteroaryl.
In the present invention, term " containing ", "comprising" or " comprising " indicate that various composition can be applied to of the invention mix together
It closes in object or composition.Therefore, term " mainly by ... form " and " consist of " were included in term " containing ".
In the present invention, term " pharmaceutically acceptable " ingredient refers to suitable for people and/or animal and without excessive bad pair
It reacts (such as toxicity, stimulation and allergy), that is, has the substance of reasonable benefit/risk ratio.
In the present invention, amount or table that term " effective quantity " refers to therapeutic agent treatment, alleviates or prevent target disease or situation
Reveal the detectable amount for treating or preventing effect.The figure of the object is depended on for the accurate effective quantity of certain an object and is good for
The combination of therapeutic agent and/or therapeutic agent that health situation, the property and degree of illness and selection are given.Therefore, standard is preassigned
True effective quantity is useless.However, can determine the effective quantity with routine experiment for the situation that Mr. Yu gives, face
Bed doctor can judge.
Herein, except place is illustrated, term " substitution " refers to that one or more hydrogen atoms on group are selected from down
The substituent group of group replaces: halogen, unsubstituted or halogenated C1-C6 alkyl, unsubstituted or halogenated C2-C6Acyl group, unsubstituted or halogen
The C1-C6 alkyl-hydroxyl in generation.
Unless stated otherwise, in the present invention, the compound occurred is intended to including all possible optical isomer,
Such as the compound of single chiral or the mixture (i.e. racemic modification) of various different chipal compounds.All chemical combination of the invention
Among object, each asymmetric carbon atom can be optionally the mixture of R configuration or S configuration or R configuration and S configuration.
As used herein, term " the compounds of this invention " refers to Formulas I compound represented.The term further includes and Formulas I chemical combination
Various crystalline forms, pharmaceutically acceptable salt, hydrate or the solvate of object.
As used herein, term " pharmaceutically acceptable salt " refers to that the compounds of this invention and acid or alkali are formed by suitable use
Make the salt of drug.Pharmaceutically acceptable salt includes inorganic salts and organic salt.A kind of preferred salt is the compounds of this invention and acid
The salt of formation.The acid for suitably forming salt includes but is not limited to: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid etc. are inorganic
Acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,
Picric acid, methanesulfonic acid, benzene methanesulfonic acid, the organic acids such as benzene sulfonic acid；And the acidic amino acids such as aspartic acid, glutamic acid.
Tanshinone compound and its application
Belong to surgery its " blood tumor " in infant hemangioma traditional medicine.Blood tumor is longer than between skin boundary between muscles, mostly because of warp
Network blocks, and caused by disharmony between ying and wei, qi and blood stagnation, therefore channels and collaterals can not be obstructed.Traditional medicine principle-method-recipe-medicines are mutually integrated, and hemangioma is more
It is sent out because qi and blood blocks in channels and collaterals, when based on activating microcirculation and removing stasis medicinal.
Radix Salviae Miltiorrhizae is that the root ingredient of Lamiaceae plant first recorded in Shennong's Herbal is commonly to activate blood circulation and disperse blood clots, dispel simply
Become silted up raw new Chinese medicine.A series of isolated tanshinone compounds in Radix Salviae Miltiorrhizae fat-soluble extract (tanshinone extract),
External activity screening discovery, tanshinone compound significantly inhibit (positive control: general to blood vessel tumor cell proliferation
Naphthalene Luo Er (Propranolol)), wherein before the effect most of dihydrotanshinone I (Dihydrotanshinone I, DHTS), hence it is evident that
Better than Propranolol to the inhibiting effect of blood vessel oncocyte.Study on mechanism shows that DHTS and Propranolol all can
The apoptosis of blood vessel oncocyte is remarkably promoted, respectively under corresponding drug concentration (3uM, 50uM) and set time (48h), cell
Apoptosis is at time and concentration dependent.Western Blot and tube formation are the results show that DHTS passes through FAS/ simultaneously
FASL and mitochondria pathway vasoactive oncocyte generate apoptosis effect, while to the angiogenesis of endothelial cells in infant hemangioma
Generate inhibiting effect.
Tanshinone compound of the invention has the structure being shown below:
Wherein, A, R1, R2, R3, R4, R5, R6, R7 are group corresponding in particular compound of the invention.
Preferred tanshinone compound of the present invention includes compound selected from the group below:
Pharmaceutical composition and method of administration
Due to the compounds of this invention have the excellent inhibitory activity to blood vessel oncocyte, the compounds of this invention and its
Various crystal forms, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and contain based on the compounds of this invention
Wanting the pharmaceutical composition of active constituent can be used for treating, prevents and alleviate since blood vessel oncocyte generates caused disease, such as
Fatty liver etc..
Pharmaceutical composition of the invention include safe and effective amount within the scope of the compounds of this invention or its be pharmacologically subjected to
Salt and pharmacologically acceptable excipient or carrier.Wherein " safe and effective amount " refers to: the amount of compound is enough obviously
Improve the state of an illness, and is unlikely to generate serious side effect.In general, pharmaceutical composition contains 1-3000mg (active dose range 3-
30mg/kg) the compounds of this invention/agent more preferably contains 10-2000mg the compounds of this invention/agent.Preferably, described " one
Agent " is a capsule or tablet.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or jello
Matter, they are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as combines
In object each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Medicine
Acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fibre on
Tie up plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame
Sesame oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as tween)、
Wetting agent (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to): in oral, tumor, rectum, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mixing: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerol；(d) disintegrating agent, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Pure and mild glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Coating and shell material preparation can be used in solid dosage forms such as tablet, sugar-pill, capsule, pill and granule, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain a part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound can also be with one of above-mentioned excipient or a variety of formation microencapsulation forms.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
Sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or the mixture of these substances etc..
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, stock solution and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
The compounds of this invention can be administered alone, or be administered in combination with other pharmaceutically acceptable compounds.
It is the mammal that the compounds of this invention of safe and effective amount is applicable to treatment when using pharmaceutical composition
(such as people), wherein dosage is the effective dosage pharmaceutically thought when application, for the people of 60kg weight, day is to medicament
Amount is usually 1~2000mg, preferably 6~600mg.Certainly, specific dosage be also contemplated that administration route, patient health situation etc. because
Element, within the scope of these are all skilled practitioners technical ability.
Compared with prior art, main advantages of the present invention include:
1. discovery tanshinone compound has good hemangioma cell inhibitory activity for the first time, external activity is better than existing
Known drug Propranolol in technology；
2. tanshinone compound of the invention can effectively inhibit blood vessel oncocyte to promote its apoptosis, blood can also be inhibited
The angiogenesis of tuberculation endothelial cell；
3. the external of the compounds of this invention, activity in vivo are effective, active dose is low, can be in the agent down to 10mg/kg
Tumor killing effect is just shown under amount, far below the drug effect dosage of Propranolol.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
1, instrument and equipment
This external spectrum UV:SHIMADIU UV-2550 and Beckman DU-7 UV-Visible spectrophotometer；
577 type infrared spectrophotometer of infrared spectroscopy IR:Perkin-Elmer；
Low Resolution Mass Spectra LR-EIMS:Finnigan MAT-95；
High resolution mass spectrum HR-EIMS:Kratos 1H spectrometer；
Nuclear magnetic resoance spectrum: 600 type Nuclear Magnetic Resonance of Varian INOVA, Bruker AM-500, AM-400, AM-300 type
Nuclear Magnetic Resonance, δ (ppm), using TMS as internal standard；
1100 liquid phase lotus root of LC-MS:Agilent joins Bruker esquire mass spectrograph；
2690 Separate Model, Waters PDA of analytic type HPLC:Waters, 996 detector lotus root joins Alltch
2000 detector of ELSD, 2000 operating system of Millennium, Waters RP18 column (5.0 × 125mm, 5 μm,
Waters), flow velocity 1.0ml/min, CH3CN (Merck, Germany), H2O (Robust)；Jasco HPLC(Chiralcel
IA column, 5 μm, 150 × 4.6mm), flow velocity 0.6ml/min, hexane/ethanol (7:3)
2998 detector lotus root of HPLC-MS:Waters 2695Separate Model, Waters PDA joins Alltch
2424 detector of ELSD, 3100Ms detector, SunFireTM C-18column (4.6 × 100mm, 3.5 μm,
Waters), flow velocity 1.0ml/min, CH3CN (Merck, Germany), H2O (Robust)；Jasco HPLC(Chiralcel
IA column, 5 μm, 150 × 4.6mm), flow velocity 0.6ml/min, hexane/ethanol (7:3)
Preparative HPLC: 320 Single wavelength detector of Varian SD1 instrument, Varians, C18 column
(220 × 25nm, 10 μm, Waters), flow velocity 15ml/min, CH3CN (Merck, Germany), H2O (Robust)；
Biological experiment capital equipment: carbon dioxide cell incubator, microplate reader, centrifuge, clean work station and chemistry
Light-emitting appearance (Thermo Scientific, USA)；Optical microscopy and photomicrographic system Leica DM 4000B microscope
(Lecia,Germany)；Inverted fluorescence microscope (OLYMPUS, Japan)；Flow cytometer (Beckman Coulter)；Water
Yawing bed (Beijing DingGuo ChangSheng Biology Technology Co., Ltd)；Electrophoresis apparatus (Bio-Rad, USA)；Full-automatic high-pressure autoclave
(Tomy digital biology,Japan)；Pvdf membrane (Millipore, USA)；
2, reagent and material
Column chromatography silica gel: 100-200 mesh, 200-300 mesh silica gel and silica gel H are Haiyang Chemical Plant, Qingdao's production；
TLC thin layer prepares plate: HSGF254 is the production of Yantai chemical plant；
MCI resin: (75-150 μm) of CHP20P produces for Mitsubishi；
Sephadex Sephadex LH-20:Pharmacia Biotech AB, Uppsala, Sweden.
Color developing agent: 10% sulfuric acid -4-hydroxyl-3-methoxylbenxaldehyde solution, potassium permanganate solution；
Vegetable material: Radix Salviae Miltiorrhizae is purchased from Bozhou medicinal material market, is acquired by Shanghai institute of materia medica Specimen Room associate professor Shen Jingui
And identify, Saving specimen is in this institute Specimen Room.
Biology main agents: 1640 culture mediums, fetal calf serum (Gibco, USA)；Dual anti-(Sigma, USA)；Antibody:
Caspase 3, Caspase 8, Caspase 9, AIF, PARP, Bax, FADD, Cyst3 (Abclonal/ China)；Cyclodextrin
(Medchem,USA)；Streaming apoptosis fluorescent reagent (FITC-Annexin, PI) (BD, USA)；Matrigel (Corning, USA)；
Western Blot with glue reagent, secondary antibody, CCK8 reagent, enhanced chemiluminescence agent, Tween-20 and crystal violet (assist is holy/in
State)；Protease inhibitors (Roche, Switzerland)；Experimental animal is nude mice, and 20 ± 5g of weight is big purchased from Shanghai traffic
Attached Xinhua Hospital is learned, animal deposits in Xinhua Hospital SPF animal house.
Embodiment 1: the separation and identification of tanshinone compound
After crushing 95% industrial alcohol (50L) is added soaking at room temperature 5 days, altogether 3 times in 30kg Radix Salviae Miltiorrhizae.Ethanol extract merges
After liquid extract is concentrated under reduced pressure to obtain.Liquid extract is extracted 3 times after adding 10L to distill aqueous suspension with 8L ethyl acetate, acetic acid ethyl acetate extract
Merge tanshinone total extract after being concentrated under reduced pressure.
Tanshinone total extract 200g is taken, sample is mixed in methylene chloride dissolution, through silicagel column (2kg, 200-300 mesh, Qingdao Haiyang
Work production) purifying, with petroleum ether-ethyl acetate 100:2,100::3,100:5,100:10,100:20,100:50, ethyl acetate
The low elution of elution, merges after TLC detection and obtains 18 fractions.Fraction S3 (5.46g) is recrystallized by petroleum ether-ethyl acetate
It obtains tanshinone IIA (3.2g).Fraction S6 (4.32g) obtains 5 after silica gel column chromatography (petroleum ether: ethyl acetate 100:3~10:1)
A fraction S6A-S6E；Fraction S6A (152mg) is after Sephadex LH-20 gel filtration chromatography (chloroform: methanol 1:1) again through making
Compound miltionone (5mg) is obtained after standby type silica gel plate purifying (methylene chloride)；Fraction S6C (311mg) chromatographs (first through ODS column
Alcohol-water, 65%-95%) purify to obtain compound Veronica sibirica paraquinones A (10mg).Take the fraction S10 (6.5g) of 800mg through ODS
Gained fraction S10C must change after preparative silica gel plate purifies (methylene chloride) after column chromatography (methanol-water, 65%-95%) separation
It closes object isopropyl ortho position phenanthrenequione (10mg).Fraction S13 (10.89g) obtains Tanshinone I after petroleum ether-ethyl acetate recrystallizes
(3.2g).Fraction S14 (17.72g) recrystallizes to obtain Cryptotanshinone (1.5g) through petroleum ether-ethyl acetate.Fraction S15 (3.61g)
5 fraction S15A-S15E are obtained after silica gel column chromatography (petroleum ether: acetone 30:1~0:1) separation；The S15D of 25mg is taken to pass through
Compound tanshinone methyl ester (15mg) is obtained after Sephadex LH-20 (chloroform: methanol 1:1) column gel chromatography.Fraction S16 (20g)
Through silicagel column (petroleum ether: acetone 100:3~100:10) after purification gained fraction using MCI column chromatography (alcohol-water 80%~
95%), compound dihydrotanshinone I (1.2g) is obtained after Sephadex LH-20 (chloroform: methanol 1:1) column gel chromatography.Fraction
S18 (950mg) after Sephadex LH-20 gel filtration chromatography (chloroform: methanol 1:1) gained fraction S18C using ODS column layer
Analyse (methanol-water, 65%-95%), preparative silica gel plate purifying (methylene chloride) obtains compound Tanshinol B (3mg) and tanshinone
IIB(5mg)。
Tanshinone IIA, Tanshinone IIA, cherry red acicular crystal.EI MS m/z 284[M]+；1H NMR
(500MHz,CDCl3) δ 7.59 (d, J=8.0Hz, 1H, H-6), 7.10 (d, J=8.0Hz, 1H, H-7), 7.07 (d, J=
1.0Hz, 1H, H-14), 3.17 (t, J=6.4Hz, 1H, H-1), 3.02 (m, 1H, H-15), 1.79 (m, 2H, H-3), 1.65 (m,
2H, H-2), 1.29 (s, 3H, H-18,19), 1.16 (d, J=6.19Hz, 3H, H-16,17)13C NMR(125MHz,CDCl3)δ
183.6,175.8,161.7,150.2,144.3,141.3,133.6,127.4,126.6,121.1,120.2,38.0,34.7,
31.9,29.8,19.1,8.7.
Miltionone, Rosmariquinone, cherry red solid.EI MS m/z 284[M]+；1H NMR(500MHz,
CDCl3) δ 7.59 (d, J=8.0Hz, 1H, H-6), 7.10 (d, J=8.0Hz, 1H, H-7), 7.07 (d, J=1.0Hz, 1H, H-
14), 3.17 (t, J=6.4Hz, 1H, H-1), 3.02 (m, 1H, H-15), 1.79 (m, 2H, H-3), 1.65 (m, 2H, H-2),
1.29 (s, 3H, H-18,19), 1.16 (d, J=6.19Hz, 3H, H-16,17)13C NMR(125MHz,CDCl3)δ182.6,
181.7,149.9,145.2,144.7,140.1,134.6,134.0,128.4,128.1,38.0,34.7,32.0,30.1,
27.1,21.7,19.3.
Veronica sibirica paraquinones A, Sibiriquinone, cherry red solid；EI MS m/z 284[M]+；1H NMR
(400MHz, CDCl3) δ 7.86 (d, J=9.8Hz, 1H, H-1), 7.50 (d, J=7.8Hz, 1H, H-6), 7.11 (d, J=
7.9Hz, 1H, H-7), 7.08 (s, 1H), 6.33 (dt, J=9.7,4.6Hz, 1H, H-2), 3.02 (p, J=6.9Hz, 1H, H-
15), 2.27 (dd, J=4.6,1.9Hz, 2H, H-3), 1.28 (s, 6H, H-18, H-19), 1.16 (d, J=6.9Hz, 6H, H-
16,H-17).13C NMR(126MHz,CDCl3)δ183.38,181.71,148.15,145.13,140.09,137.42,
134.61,134.41,130.74,129.37,124.86,124.84,38.16,34.22,28.52,27.06,21.68.
Isopropyl ortho position phenanthrenequione, Ro 09-0680, cherry red solid；EI MS m/z 264[M]+；1H NMR(500MHz,
CDCl3) δ 9.26 (d, J=9.0Hz, 1H, H-6), 8.30 (d, J=9.0Hz, 1H, H-7), 7.00-7.70 (overlap, 3H,
), H-1,2,3 7.14 (s, 1H, H-14), 7.10 (d, J=8.0Hz, 1H, H-7), 7.07 (d, J=1.0Hz, 1H, H-14),
3.07 (m, 1H, H-15), 2.70 (s, 3H, H-18), 1.23 (d, J=6.0Hz, 6H, H-16,17)13C NMR(125MHz,
CDCl3)δ182.5,181.7,139.6,136.9,136.7,135.1,132.9,132.9,130.9,128.5,126.7,
125.4,125.4,125.0,27.3,21.7,21.7,19.9.
Tanshinone I, Tanshinone I, cherry red solid, EI MS m/z 264 [M]+；1H NMR(500MHz,CDCl3)
δ 9.20 (d, J=9.0Hz, 1H, H-6), 8.23 (d, J=8.0Hz, 1H, H-7), 7.74 (d, J=9Hz, 1H, H-1), 7.51-
7.54 (m, 1H, H-2), 7.32 (d, J=9.0Hz, 1H, H-3), 7.27 (d, J=1.5Hz, 1H, H-17), 2.66 (s, 3H, H-
18), 2.27 (d, J=1.5Hz, 1H, H-16)13C NMR(125MHz,CDCl3)δ183.4,175.6,161.1,142.0,
135.2,133.6,132.7,130.6,129.6,128.3,124.7,123.1,121.7,123.1,121.7,120.5,
118.7,19.8,8.8.
Cryptotanshinone, Cryptotanshinone, cherry red acicular crystal, EI MS m/z 296 [M]+；1H NMR
(500MHz,CDCl3) δ 7.64 (d, J=8.0Hz, 1H, H-6), 7.51 (d, J=8.0Hz, 1H, H-7), 4.90and 4.37
(dd, J=6.0,9.6Hz, 2H, 17), 3.59-3.65 (m, 1H), 3.22 (m, 2H), 1.77-1.83 (m, 2H), 1.65-1.69
(m, 2H), 1.36 (d, J=6.0Hz, 3H, H-16), 1.32 (s, 6H, H-18/19)13C NMR(125MHz,CDCl3)δ
184.0,175.5,170.8,152.3,143.6,132.5,128.8,126.1,122.5,118.2,81.5,38.7,34.7,
34.6,31.7,29.6,19.3,18.7.
Tanshinone methyl ester, Methyl tanshinonate, red solid, EI MS m/z 338 [M]+.1H NMR
(500MHz,CDCl3) δ 7.56 (d, J=8.3Hz, 1H, H-6), 7.48 (d, J=8.3Hz, 1H, H-7), 7.23 (d, J=
1.4Hz,H-17),3.67(s,3H,-OCH3), 3.24 (m, 2H, H-1), 2.27 (d, J=1.4Hz, 3H, H-16), 2.26and
1.75(m,each 1H,H-3),1.82(m,2H,H-2),1.58(s,3H,H-18).13C NMR(125MHz,CDCl3)δ
183.6,177.3,175.8,161.5,144.6,143.3,141.8,135.2,128.6,126.7,121.5,120.5,52.8,
47.4,34.2,29.2,27.8,19.4,9.0.
15,16- dihydrotanshinone Is, 15,16-Dihydrotanshinone I, cherry red needle-like solid, EI MS m/z
278[M]+.1H NMR(500MHz,CDCl3) δ 9.28 (d, J=9.0Hz, 1H, H-6), 8.30 (d, J=9.0Hz, 1H, H-7),
7.76 (d, J=9.2Hz, H-1), 7.57 (m, 1H, H-2), 7.40 (d, J=7.0Hz, 1H, H-3), 4.97and 4.43 (t, J
=6.3,9.5Hz, each 1H, H-17), 3.66 (m, 1H, H-17), 2.70 (s, 3H, H-18), 1.41 (d, J=6.5Hz, 1H,
H-16).13C NMR(125MHz,CDCl3)δ184.3,175.8,170.6,135.0,134.6,132.2,131.9,130.4,
128.9,128.2,126.2,125.0,120.5,118.3,81.6,34.7,19.8,18.8.
Tanshinol B, Tanshinol B, cherry red solid, EI MS m/z 296 [M]+.1H NMR(500MHz,CDCl3)δ
7.95 (d, J=8.1Hz, 1H, H-6), 7.61 (d, J=8.3Hz, 1H, H-15), 7.25 (m, H-7), 3.28 (m, 1H, H-1),
3.16 (m, 1H, H-1), 2.27 (d, J=1.3Hz, 3H, H-17), 2.00 (overlap, 2H), 1.83 (m, 1H), 1.56 (s,
3H,H-18).13C NMR(126MHz,CDCl3)δ183.35,175.60,161.39,147.29,143.95,141.74,
133.68,129.04,126.09,121.46,120.80,120.49,71.03,38.75,31.18,29.14,20.17,8.94.
Tanshinone II B, Tanshinone IIB, cherry red solid, EI MS m/z 310 [M]+.1H NMR(600MHz,
CDCl3) δ 7.65 (d, J=8.1Hz, 1H, H-6), 7.52 (d, J=8.1Hz, 1H, H-6), 7.21 (s, 1H, H-16), 3.79
(d, J=11.1Hz, 1H, H-18b), 3.62 (d, J=11.3Hz, 1H, H-18a), 3.18 (m, 2H, H-1), 2.28 (s, 3H, H-
17),1.98(m,1H,H-3b),1.88(m,1H,H-2b),1.75(m,1H,H-2a),1.58(m,1H,H-3a),1.29(s,
3H,H-19).13C NMR(126MHz,CDCl3)δ183.38,175.57,161.55,146.31,146.08,141.59,
133.87,127.94,126.67,121.31,120.36,120.24,71.66,40.09,32.38,29.85,26.81,
18.91,8.94.
Embodiment 2: cell inhibitory effect activity of the tanshinone compound to blood vessel oncocyte
1) cell culture: the blood vessel oncocyte of lotus mouse spontaneity of the EOMA cell line originating from 129/J system.Cell culture
Using 1640 culture mediums containing 10% fetal calf serum, and it is mixed with the penicillin of 100mg/l and the streptomysin of 100ug/l.Carefully
Born of the same parents are placed in 37 DEG C, cultivate in the incubator containing 5%CO2.It replaces culture medium every other day, is passed when cell density is up to 80%
Generation.
2) dissolution of drug: drug powder is dissolved in DMSO, and storage concentration is 10uM, and -20 degree of packing saves.
3) .CCK8 detects IC50: before agent-feeding treatment, cell bed board in 96 orifice plates carries out cell count, so that each hole
Cell concentration reach 2000-3000/ul, after cell is adherent, draw culture medium, be added various concentration gradient dihydrotanshinone
I.After 72h, the culture medium containing drug is exhausted, cck8 is added, while three blank control wells are set, 2h or so surveys 450 wavelength
The light absorption value at place.According to: it calculates under various concentration, the percentage of cell Proliferation [(dosing group-blank control group) * 100%/
(control group-blank control group)], nonlinear regression is carried out by Graphpad Prim software, cell proliferation rate is measured and reduces one
Corresponding drug concentration-IC when half50。
Tanshinone compound is as shown in table 1 below to the cell inhibitory effect activity to blood vessel oncocyte.Active testing knot
Fruit shows that tanshinone compound can significantly inhibit the proliferation of blood vessel oncocyte.
Table 1: tanshinone compound is to hemangioma cell inhibitory effect activity
| Compound name | IC50(μM) |
| Dihydrotanshinone I | 2.63 |
| Miltionone | 3.17 |
| Veronica sibirica paraquinones A | 3.19 |
| Tanshinone methyl ester | 4.33 |
| Tanshinol B | 5.32 |
| Isopropyl ortho position phenanthrenequione | 7.83 |
| Cryptotanshinone | 10.48 |
| Positive control (Propranolol) | 53.67 |
Embodiment 3: influence of the dihydrotanshinone I to blood vessel apoptosis of tumor
1) cell clonal formation test: in six orifice plates be added 1000/2ml cell, after cell is adherent, respectively plus
Enter different drug concentrations to be handled, blank group adds DMSO (solvent) to be compareed, after condition satisfaction to be processed (for 24 hours,
48h), fresh culture medium is changed, carries out crystallizing sub- dyeing after ten days or so, take pictures.
2) flow cytometer and hochest33342 detect apoptotic cell percentage and form respectively: preparing cell, six
Bed board in orifice plate carries out drug-treated, meets after condition (different concentration, different time-triggered protocols) after cell is adherent, receives
Collect cell, be added in centrifuge tube, be centrifuged 800rmp, 5min, eppendorf pre-cooling then carry out pbs and clean cell, is being pre-chilled
Centrifuge in continue to be centrifuged, 800rmp, 5min, draw pbs after, sample be added 200ul binding buffer, add
5ul FITC-Annexin V is resuspended, and is protected from light 10min, and the PI of 5ul is then added, and moves into streaming pipe, 4 degrees Celsius, is protected from light, Yu Yi
Upper machine after hour.
3) Hochest33258 is dyed: plating cells are carried out in 12 orifice plates, after cell is adherent, carry out drug-treated,
After meeting corresponding condition, cell is fixed, and then washes away fixer, be added hochest33258 under 37 degrees Celsius into
Row dyeing 30min.Observe the karyon of dense pyknosis.
Test result is shown shown in following Fig. 1-3: dihydrotanshinone I and Propranolol corresponding drug concentration (3uM,
50uM) and under set time (48h), Apoptosis has system at time and concentration dependent, the results of analysis of variance prompt, difference
Meter learns meaning.
4) western blot detects apoptotic proteins: different protein expression levels can be detected by wb in cell.
Cell carries out pbs cleaning, collects, then use on ice after drug (dihydrotanshinone I and Propranolol) and solvent processing
RIPA lytic cell 30min after cracking, under conditions of 4 degrees Celsius, with the speed centrifuge cell 10min of 12000g, takes cell
Supernatant.Using BCA Quantitative Western concentration, albumen is adjusted to same concentration.The loading in enough electrophoresis liquids, it is ensured that loading
Amount goes to the albumen on SDS-PAG glue on pvdf membrane in 20-30ug under the electric current of 300Ma, and 5% BSA closes 1h, presses
Primary antibody is added in 1:1000, and 4 spend night, and TBST washes film three times, each 10min, and secondary antibody, room temperature then is added with the concentration of 1:3000
Lower 1h is incubated for, and TBST washes film three times, each 10min, and luminescent solution is added, develops.
Western Blot result is as shown in Figure 4: DHTS can act on blood by FAS/FASL and mitochondria pathway simultaneously
Tuberculation cell, in low concentration based on the mitochondrial pathways, when high concentration based on FASL access；PropranololZ is then low
When concentration based on FASL access, when high concentration based on the mitochondrial pathways.
Embodiment 4:Tube formation observes drug to cell into the influence of pipe:
Not solidified Matrigel is layered on 96 orifice plates with the amount of every hole 10ul, 96 orifice plates is placed in incubator 1h, makes
Colloid solidifies completely, and 96 orifice plates are added in EOMA cell (3 × 104/ every hole), while will be laid on or without the culture medium of drug
The surface of colloid and cell continues to be placed in incubator, after 2h, observes under the microscope, retention of taking pictures.
At the angiogenesis of pipe experiment reacting cells in vivo, process includes the work of vascular endothelial growth factor (VEGF)
With, the degradation of intercellular matrix (mmp9), the migration of endothelial cell.
The result of Tube formation and Western blot as shown in figure 5, drug after function cells, endothelial growth
The factor is reduced, and the synthesis of metal matrix enzyme is reduced, and endothelial cell can not migrate, and causes cell that can not carry out angiogenesis, it is sufficient to
Illustrate the ability of Drug inhibition blood vessel.
Embodiment 5: animal experiment in vivo desk study drug is to angiomatous curative effect
The mouse type that experiment in vivo uses is 6 weeks female mices for BALB/c nude mice, and totally 15.Collect about 1 ×
It after 107 cell, is suspended into the pbs of 200ul, is inoculated in the oxter of nude mice, two weeks or so, is reached in knurl mean size
100mm3 (volume=length × wide2/ 2) it is grouped at random afterwards.It is prompted according to document, dihydrotanshinone I is injected in abdominal cavity
(10mg/kg), Propranolol (40mg/kg) and solvent (beta cyclodextrin+20%DMSO), are detected weekly the change of knurl three times
Change and the weight of nude mice put to death nude mice after 4 weeks, knurl is cut and measures, while portion of tissue carries out immunohistochemistry, inspection
Survey the variation of the observation index such as CD31, CD34, vWF, Glut1, Caspase3, MMP9 and VEGFR2.
Test results are shown in figure 6: dihydrotanshinone I and Propranolol can be under corresponding concentration to hemangioma
Inhibiting effect, the results of analysis of variance prompt are generated, the effect that drug generates has significant statistical significance (p=0.0008),
And the result of DHTS and Propranolol is prompted without significant difference (P=0.097).
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of such as following formula I compound represented or the purposes of its pharmaceutically acceptable salt:
Wherein, A ring is selected from the group: substituted or unsubstituted 3-10 member carbocyclic ring, substituted or unsubstituted 3-10 circle heterocyclic ring, replace or
Unsubstituted C6-C10Aromatic ring, substituted or unsubstituted 5-12 member hetero-aromatic ring；
R1It is selected from the group: H, oxygen atom (=O), O-R '；
R2It is selected from the group: H, oxygen atom, O-R '；
The R' is selected from the group: H, substituted or unsubstituted C2-C10Acyl group, fluorenes methoxy carbonyl acyl group (Fmoc) or replace or
Unsubstituted C1-C10Alkyl；Preferably, R' is H；
R3It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkoxy, C1-C4Alkyl, C1-C4Halogen
Substituted alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted C2-C10Ester group ,-OC (O)-R ,-NH-R；Its
In, R is selected from the group: H, C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
R4It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkoxy, C1-C4Alkyl, C1-C4Halogen
Substituted alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted C2-C10Ester group ,-OC (O)-R ,-NH-R；Its
In, R is selected from the group: H, C1-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R1、R2、R3And R4In any two and adjacent carbon atom collectively form group selected from the group below: it is substituted or unsubstituted
C3-C10First carbocyclic ring, substituted or unsubstituted 3-10 circle heterocyclic ring, substituted or unsubstituted C6-C10It is aromatic ring, substituted or unsubstituted
5-12 member hetero-aromatic ring；
R5It is selected from the group: H, halogen, cyano, hydroxyl, C1-C4Alkoxy ,-COOR, C substituted or unsubstituted1-C10Alkyl, substitution
Or unsubstituted C1-C10Halogenated alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted C2-C10Ester group；
Wherein, R is selected from the group: H, C2-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
R6It is selected from the group: H, halogen, oxygen atom, cyano, carboxyl, hydroxyl, C1-C4Alkoxy ,-COOR, C substituted or unsubstituted1-
C10Alkyl, substituted or unsubstituted C1-C10Halogenated alkyl, substituted or unsubstituted C2-C10Acyl group, substituted or unsubstituted
C2-C10Ester group；Wherein, R is selected from the group: H, C2-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
Or R5And R6Collectively form-R "-O-R "-, wherein the R " is nothing or substituted or unsubstituted C1-C4Alkylidene；
R7For the group selected from the group below on A ring: H, hydroxyl, amino, substituted or unsubstituted C1-C10Alkoxy ,-
COOR, substituted or unsubstituted C2-C10Acyl group, C substituted or unsubstituted1-C10Alkyl, substituted or unsubstituted C2-C10Ester
Base；Wherein, R is selected from the group: H, C2-C4Acyl group, substituted or unsubstituted C1-C4Alkyl；
N=1,2,3,4,5,6,7,8,9 or 10；
In the above formulas, substitution refers to one or more hydrogen atoms on group replaced substituent group selected from the group below: carboxyl, benzene
Base, C3-C6Naphthenic base, C2-C10Ester group, halogen, C1-C10Alkyl-oxygroup, C2-C10Acyl group, hydroxyl, hydroxyl-C1-C10Asia
Alkyl；
DescribedFor double bond or singly-bound；
It is characterized in that, being used to prepare:
(a) angiomatous pharmaceutical composition is treated；
(b) inhibit the pharmaceutical composition of the proliferation activity of blood vessel oncocyte；
(c) promote the pharmaceutical composition of blood vessel apoptosis of tumor；
(d) inhibit cell at the pharmaceutical composition of pipe.
2. purposes as described in claim 1, which is characterized in that the R3It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl
Base, carboxyl, C1-C4Alkyl, C1-C4Halogenated alkyl；
R4It is selected from the group: H, halogen, oxygen atom, cyano, hydroxyl, carboxyl, C1-C4Alkyl, C1-C4Halogenated alkyl；
Or R3And R4Collectively form group selected from the group below: substituted or unsubstituted 3-8 circle heterocyclic ring, substituted or unsubstituted 5-7 member
Hetero-aromatic ring.
3. purposes as described in claim 1, which is characterized in that the A ring is selected from the group: substituted or unsubstituted 5-7 member
Carbocyclic ring, substituted or unsubstituted 5-7 circle heterocyclic ring, substituted or unsubstituted 6 yuan of aromatic rings, substituted or unsubstituted 5-7 member hetero-aromatic ring.
4. purposes as described in claim 1, which is characterized in that R7For one or more groups selected from the group below: H, hydroxyl, ammonia
Base, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy ,-COOR；Wherein, R is selected from the group: H, C1-C4Acyl group,
Substituted or unsubstituted C1-C4Alkyl.
5. purposes as described in claim 1, which is characterized in that R1For=O.
6. purposes as described in claim 1, which is characterized in that the R3For C1-C4Alkyl or C1-C4Halogenated alkyl；
R4It is selected from the group: H, oxygen atom；
Or R3And R4Collectively form group selected from the group below: substituted or unsubstituted furan nucleus, substituted or unsubstituted dihydrofuran
Ring, substituted or unsubstituted tetrahydrofuran ring.
7. purposes as described in claim 1, which is characterized in that the Formulas I compound represented is selected from the group:
8. purposes as described in claim 1, which is characterized in that in the pharmaceutical composition, the compound of formula I it is effective
Dosage is 0.1-50mg/kg weight, preferably 1-20mg/kg weight.
9. purposes as described in claim 1, which is characterized in that the pharmaceutical composition is dosage form selected from the group below: oral
Dosage form, injection type.
10. purposes as described in claim 1, which is characterized in that the pharmaceutical composition is also used to inhibit hemangioma endothelium
The angiogenesis of cell.
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| CN201710819070.3A CN109485691B (en) | 2017-09-12 | 2017-09-12 | Tanshinone compound and application thereof in treating hemangioma |
| PCT/CN2018/105278 WO2019052477A1 (en) | 2017-09-12 | 2018-09-12 | Tanshinone compound and use thereof for treating hemangioma |
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| CN201710819070.3A CN109485691B (en) | 2017-09-12 | 2017-09-12 | Tanshinone compound and application thereof in treating hemangioma |
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| CN116514896A (en) * | 2023-03-27 | 2023-08-01 | 浙江大学 | Synthesis method of dihydrotanshinone I |
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| CN109485691B (en) | 2023-04-11 |
| WO2019052477A1 (en) | 2019-03-21 |
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