CN106008256A - Deferoxamine derivative compound with bone affinity, preparation method and application thereof - Google Patents
Deferoxamine derivative compound with bone affinity, preparation method and application thereof Download PDFInfo
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- CN106008256A CN106008256A CN201610380476.1A CN201610380476A CN106008256A CN 106008256 A CN106008256 A CN 106008256A CN 201610380476 A CN201610380476 A CN 201610380476A CN 106008256 A CN106008256 A CN 106008256A
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- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
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- C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C243/26—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C243/28—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of a saturated carbon skeleton
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Abstract
The invention develops a deferoxamine derivative with bone affinity, a preparation method and application thereof. More specifically, the invention provides a compound with a structure shown as formula (1) and its pharmaceutically acceptable salt, ester, amide, acyl halide, hydrate or solvate. The invention also provides a preparation method of the compound shown as formula (1) and application thereof in preparation of drugs for treatment of osteoporosis, osteonecrosis, delayed union or nonunion and bone defect. (formula I).
Description
Technical field
The present invention relates to one desferrioxamine derivative compound, by carrying out structurally-modified to this compound so that this chemical combination
Thing has excellent ferrum complexing power and bone affinity simultaneously.Present invention also offers the preparation side of this derivative compound of desferrioxamining
Method and preparation for treat osteoporosis, osteonecrosis, delayed fracture healing or disunion and Cranial defect medicine in
Application.
Background technology
Osteoporosis (osteoporosis, OP) is to increase with the reduction of bone amount Progressive symmetric erythrokeratodermia, bone micro-structure destruction, bone fragility
For the bone metabolic disease of major pathologic features, easily sending out fracture is one of serious consequence that osteoporosis causes.Osteoporosis
It is not only harm old people especially postmenopausal women health and affects the medical problem of its quality of life, and having become current
The serious problem of society today of aging society, to this end, substantial amounts of human and material resources are all poured in countries in the world, to illustrating its generation machine
On the basis of reason, reasonable, potent control strategy is proposed.
Osteoporotic Drug therapy, in addition to the basis of application calcium preparation and promotion calcium absorption is intervened, also includes estrogen
Class, selective estrogen receptor modulators, calcitonin class, diphosphonic acid salt, parathyroid hormone, strontium salt etc..At present, turn for bone
During changing, " couple " factor between osteoblastic bone formation and osteoclastic bone resorption function, develop or enter
Row clinical trial RANKL albumen and osteosclerosis albumen soluble antibody etc. treat osteoporotic biological preparation.
Ischemic osteonecrosis especially ischemia femur head necrosis (Osteonecrosis of the femoral head,
ONFH), point traumatic and atraumatic two class, all with bone necrosis progrediens, bone resorption as major pathologic features.At joint part
(such as ONFH), because of subchondral osteonecrosis, absorption, can cause articular cartilage to subside, and disability rate is high.Senile osteoporosis hip
Fracture, is the Etiological of traumatic ONFH.So far, the pathogenesis about ischemic osteonecrosis is unclear, and it is effectively treated
Medicine lacks, and the effectiveness of the Drug therapy such as current tentative application Low molecular heparin, diphosphate, pravastatin has to be determined
Or it is difficult to gather effect.
Although the relatedness between osteoporosis and osteonecrosis waits to illustrate, but increasing research shows, osteoporosis
Generation and development is transshipped with internal ferrum and osseous tissue blood supply insufficiency (especially old people) is closely related, and have been considered as
The generation of osteoporosis and the independent factor of development；Osseous tissue blood supply obstacle caused by unknown cause is that osteonecrosis occurs development
Initiating agent, is also the viewpoint of common recognition now.Therefore, improve and recover osseous tissue blood supply, not only have protection osseous tissue construct,
Prevent and treat effect of osteoporosis and osteonecrosis, and because of the minimizing of osteoporotic fracture, the sickness rate making osteonecrosis is lowered.
Desferrioxamining, have another name called deferoxamine (deferoxamine, DFO), have the structure shown in formula (3), it can be with 1:1 ratio
With Fe3+In conjunction with.
DFO, as iron ion chelating agent, starts to be applied to clinic in the 1970's, is mainly used in treating hemochromatosis
With thalassemia, sicklemia etc. due to the disease of transfusional chronic iron overloading.Applicant in recent years
Research finds, the characteristic of DFO chelated iron ion can activate osteoblast cells hypoxia/hypoxia inducible factor (HIF)-α path,
And stimulating osseous tissue angiogenesis, and then promoting bone growing and Bone Defect Repari, DFO activates that hypoxia/HIF-α path can promoting bone growing
Beneficial effect, guiding the preventing and treating that the research and development of medicinal hypoxia-mimicking compound and osteopathia are damaged, and in hot research content
Development trend.Therefore, DFO can be at least through transshipping iron ion and the two of indirect induced bone tissue blood vessel in direct complexation osseous tissue
The approach of kind, and play bone protective effect.Although, DFO uses comparatively safe, but the half-life is short, needs the most subcutaneous or venoclysis,
And because of the water miscible feature of DFO and Blood flow, metabolism relatively low under feature, make DFO distributive law in osseous tissue relatively low；
Strengthen DFO dosage and administration time, the untoward reaction such as audition or visual disorder, growth retardation, textured bone can be caused, from
And limit the bone action effect of DFO, the most also it is difficult to be applicable to the systemic drug treatment of Progressive symmetric erythrokeratodermia bone loss diseases.
In order to solve problem above, it was found by the inventors of the present invention that special structurally-modified by DFO is carried out, permissible
Make it present the feature to osseous tissue with affinity, do not affect the activity of DFO chelated iron ion simultaneously, thus obtain having
The DFO derivative compound of bone, uses this compound to be capable of DFO and imports and be concentrated in osseous tissue, to specificity
Ground increases DFO concentration in osseous tissue, improves it and prevents and treats the bone metabolic disease drug effect such as osteoporosis, osteonecrosis, reduces medicine
Thing systematicness ill effect.
Summary of the invention
The first aspect of the invention provides the compound shown in a kind of formula (1), and pharmaceutically acceptable salt,
Ester, amide, carboxylic acid halides, hydrate or solvate:
Wherein R1Selected from following group: substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Thiazolinyl, take
Generation or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R2-R4It is each independently selected from following group: hydroxyl, substituted or unsubstituted C1-C10Alkyl, take
Generation or unsubstituted C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine,
Chlorine, bromine and iodine；
R5-R7It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or do not take
The C in generation1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and
Iodine；
R8-R45It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or not
Substituted C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine
And iodine；
M is selected from following integer: 1,2,3,4,5,6,7,8,9,10,11 and 12；
A is derived from the group of the organic multicomponent acid comprising 1-8 nitrogen-atoms and 2-6 carboxyl, by one of them nitrogen
Atom is connected with the other parts of compound shown in formula (1).
According to an embodiment of the invention, described A group is selected from following group, by the list of shown nitrogen-atoms
Key is connected with the other parts of compound shown in formula (1):
In above group, n is selected from following integer: 1,2,3,4,5 and 6.
One according to the present invention is preferred embodiment, in the compound shown in formula (1), and R1Selected from following group:
Substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, replacement
Or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R2-R4It is each independently selected from following group: hydroxyl, substituted or unsubstituted C1-C4Alkyl, replacement or unsubstituted
C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R5-R7It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, replacement or do not take
The C in generation1-C4Thiazolinyl, substituted or unsubstituted C1-C4 alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R8-R45It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, replacement or do not take
The C in generation1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine.
The second aspect of the invention provides a kind of for the method preparing the compound of described formula (1), the method bag
Include following steps:
I () makes the organic multicomponent comprising 1-8 nitrogen-atoms and 2-6 carboxyl acid react with alcohol, with to described organic many
The sour all of carboxyl of unit is protected；
(ii) carboxyl making step (i) prepared receives organic multicomponent acid and the C of protection3-C14The anhydride reaction of diacid；
(iii) make the product of step (ii) and there is the derivatives reaction of desferrioxamining or desferrioxamine of formula (2)；
(iv) carboxyl being protected of the product prepared to step (iii) carries out deprotection, obtains the chemical combination of formula (1)
Thing:
Wherein in the structure shown in formula (2), R1Selected from following group: substituted or unsubstituted C1-C10Alkyl, replacement or
Unsubstituted C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine,
Bromine and iodine；The most substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4
Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R2-R4It is each independently selected from following group: hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or unsubstituted
C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；
Preferably hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkane
Epoxide, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R5-R7It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or do not take
The C in generation1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and
Iodine；Preferably hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted
C1-C4 alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R8-R45It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or not
Substituted C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine
And iodine；Hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-
C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine.
According to an embodiment of the invention, in the method for the compound for formula (1), described in comprise 1-8
The organic multicomponent acid of individual nitrogen-atoms and 2-6 carboxyl one or more shown nitrogenous organic multicomponents in following structural formula
Acid:
According to an embodiment of the invention, in a solvent, there is the situation of catalyst in the reaction of described step (i)
Under carry out,
Described alcohol is selected from: C1-C10Alkylol and C7-C16Aryl alcohol；Preferably benzyl alcohol；
Described solvent is selected from: benzene, toluene, hexamethylene, acetone, ether, dimethyl ether, dipropyl ether and they in the middle of arbitrarily
The mixture of two or more；
Described catalyst is selected from following acid catalyst: sulphuric acid, hydrochloric acid, phosphoric acid, nitric acid, C1-C6Alkyl sulfonic acid, benzene sulphur
Acid, toluenesulfonic acid；Preferably p-methyl benzenesulfonic acid.
According to another implementation of the invention, described step (ii) is being carried out in following solvent: comprise one
Individual or the liquid alkane of multiple halogen atom, described halogen atom is selected from fluorine, chlorine, bromine, iodine；Preferably, the solvent that step (ii) uses
Selected from monochloro methane, dichloromethane, chloroform, carbon tetrachloride and any mixture thereof.
According to another implementation of the invention, described step (iii) in a solvent, using under conditions of catalyst
Carry out,
Described solvent is selected from: benzene, toluene, hexamethylene, acetone, ether, dimethyl ether, dipropyl ether, N,N-dimethylformamide
And any two or more mixture in the middle of them；
Described catalyst is selected from: hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus (PyBOP), 1H-benzo
Triazol-1-yl oxo three (dimethylamino) phosphorus hexafluorophosphate (BOP), 1-hydroxy benzo triazole (HOBT) and N, N'-bis-
Carbodicyclo hexylimide (DCC), preferably hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus (PyBOP).
According to another implementation of the invention, the carboxyl deprotection reaction of described step (iv) is to exist at catalyst
In the case of carried out by hydrogenation,
Described catalyst is selected from loaded noble metal catalyst, preferably load type palladium, platinum, rhodium catalyst, more preferably
Palladium carbon.
According to a preferred embodiment of the present invention, the substituent R in the above formula (1) and formula (2)1To R45It is
The when of substituted group, represent that any one or more hydrogen atoms on these groups are selected from one or more following bases
Group replaces: C1-C10Alkyl, C1-C4Alkyl, C1-C10Thiazolinyl, C1-C4Thiazolinyl, C1-C10Alkoxyl, C1-C4Alkoxyl, cyano group, fluorine,
Chlorine, bromine, iodine, hydroxyl, ester group, ether, amide groups, sub-amide groups.
The third aspect of the invention provides a kind of pharmaceutical composition, and this pharmaceutical composition comprises:
The compound of the above formula (1) and pharmaceutically acceptable salt, ester, amide, carboxylic acid halides, hydrate or solvent close
Thing；
(ii) one or more in pharmaceutically acceptable optional excipient, filler, carrier and diluent；And
(iii) the optional pharmaceutical active being different from component (i), described pharmaceutical active is selected from: alendronic Acid
Sodium sheet, zolendronate sodium, Pamidronate Disodium, vitamin D, risedronate sodium, teriparatide, Strontium Ranelate, raloxifene, fall
Calcium element, estrogen, nilestriol, female pregnant sharp, tamoxifen, ipriflavone, clodronate disodium sheet, GUSONGBAO KELI, again U.S.
Power, Tibolone Tablets, solid Su An, etidronate disodium sheet, Bang Telin, tridin, calcium gluconate tablet, calcium-zinc gluconate are administered orally
The strange carbonic acid of solution, Premelle Cycle, ribavirin tablet, elcatonin, Yi Weite, Bei Bang, Calcitonin Salmon, kidney osteocomma, calcareacarbonica, calcium that
Calcium D3 sheet, vitamin D 2 and calcium colloid injection, Gai Ruining, clodronate disodium capsule, Alfacalcidol, injection bone peptide, deer melon are many
Peptide injection, DANHONG ZHUSHEYE, Flos Carthami injection, cefradine, clindamycin, vancomycin, low molecular dextran amino
Acid, hydroxyethyl starch injection liquid, Low molecular heparin sodium injection, sodium lactate ringer's injection, Mannitol sodium chloride injection.
The fourth aspect of the invention provides compound and pharmaceutically acceptable salt, ester, the acyl of shown formula (1)
Amine, carboxylic acid halides, hydrate or solvate are used for treating osteoporosis, osteonecrosis, delayed fracture healing or disunion in preparation
With the application in the medicine of Cranial defect.
Accompanying drawing explanation
Combine accompanying drawing in the present invention principle and the embodiment of the present invention are described.
Fig. 1 is the flow chart of the method for the compound of the synthesis type (1) according to one embodiment of the present invention；
Fig. 2 is according to one embodiment of the present invention compound characterization result to ferric ion complexing power；
Fig. 3 shows that the compound stimulating osteoblast according to one embodiment of the present invention expresses the table of HIF-1 α albumen
Levy result；
Fig. 4 shows the compound stimulating osteoblast VEGF expression according to one embodiment of the present invention, HO-1mRNA
Characterization result (in real time-PCR)；
Fig. 5 shows the characterization result of the compound parent's bone performance according to one embodiment of the present invention.
Detailed description of the invention
The present invention will be further described in detail by herein below.It should be noted however that following
Detailed description of the invention provides the concrete operations example of the present invention the most in an exemplary fashion, but protection scope of the present invention is not
It is only limitted to this.Protection scope of the present invention is only limited only by the claims that follow.Those skilled in the art can be apparently
Expect, within the protection domain that claims of the present invention limits embodiment of the present invention can be carried out various its
Its improvement and replacement, and remain able to realize identical technique effect, reach the final technical purpose of the present invention.
In the present invention, unless indicated to the contrary, all of ratio is weight ratio, and all of percent is weight
Percent, the unit of temperature is DEG C, and pressure unit of force is handkerchief.The ambient temperature that room temperature is conventional in referring to laboratory, with season and position
Put change, usually 25 DEG C.It addition, all numerical rangies that the present invention describes all include end value and can include disclosed
The new numerical range that the mutual combination in any of upper and lower bound of scope obtains.Such as, if disclosing the weight of certain component
Percentage composition is 10～30 weight %, preferably 15～25 weight %, and more preferably 20～23 weight % are then equivalent to also disclose
Following numerical range: 10～15 weight %, 10～25 weight %, 10～20 weight %, 10～23 weight %, 15～30 weights
Amount %, 15～20 weight %, 15～23 weight %, 20～25 weight %, 23～25 weight %.
The compound of the formula (1) of the present invention is by desferrioxamining (DFO) or the de-iron shown in formula (2) shown in formula (3)
Quick derivative compound carries out the most structurally-modified and prepared.It will be seen that the structure of desferrioxamining shown in formula (3) is actually wrapped
Include within the scope of structure shown in formula (2).The derivatization of desferrioxamining shown in formula (2) used in the synthesis step of the present invention
Desferrioxamining shown in compound and formula (3) belongs to commercial product well known in the art, be all purchased from Sigma, traditional Chinese medicines group and
Aladdin company.Specifically used in the experiment of the present invention desferrioxamine, the derivative compound a that desferrioxamines, derivative compounds of desferrioxamining
Thing b, the derivative compound c that desferrioxamines are purchased from Sigma company.It addition, those skilled in the art can also be according to required final
The structure of product, replaces arbitrarily on the molecule desferrioxamined and modifies.
In order to prepare the compound shown in formula (1), inventor uses and comprises 3-14 carbon, preferred 3-8 carbon, more
The diacyl linkages of preferably 3-6 carbon by modified group A with desferrioxamine in end nitrogen-atoms covalently bound.According to this
A bright embodiment, described group A is by comprising at least one nitrogen-atoms and the organic polycarboxylic acid of at least two carboxyl
Slough on its nitrogen-atoms hydrogen atom and obtain.Structurally-modified by this kind so that the compound table generally of formula (1)
Revealing splendid bone affinity, ferrum complexing power is essentially unaffected simultaneously.
Fig. 1 shows and describes the present invention's as a example by desferrioxamining shown in formula (3), succinic anhydride and iminodiacetic acid
The synthesis course of bone affinity compound (DFO-SF).It should be noted however that protection scope of the present invention is not limited to that,
According to the concrete structure of target product, raw materials used kind, reaction condition and operating procedure can be adjusted.
As it is shown in figure 1, the structure of the iminodiacetic acid used is as follows:
In first shown in Fig. 1 step, use benzyl alcohol is as protective agent, under the catalytic action of p-methyl benzenesulfonic acid
React so that two carboxyls of iminodiacetic acid are all protected with benzyl alcohol generation esterification.
In the second step shown in Fig. 1 so that the product of first step and succinic acid anhydride are in chloroform solvent
Reaction, thus generate amide structure.
In the 3rd shown in Fig. 1 step so that the product of second step desferrioxamines (DFO) at solvent N, N-diformazan
In base Methanamide, react under conditions of there is PyBOP catalyst, thus by the iminodiacetic acid of esterification by fourth two
Acyl group is connected with the nitrogen-atoms of end of desferrioxamining.
In the 4th shown in Fig. 1 step, use palladium-carbon catalyst that the product of the 3rd step carries out de-benzyl (remove-insurance
Protect reaction), prepare final target compound.
The compound of the present invention may be used for pharmaceutical composition, and this pharmaceutical composition comprises of the present inventionization of therapeutically effective amount
Compound and pharmaceutical excipient.
Described " therapeutically effective amount " refers to that the content of the compounds of this invention should be enough to provide required bone for its lower limit
Sick therapeutic effect, meanwhile, is still unlikely to cause serious adverse side effect for its upper limit, is i.e. widely recognized as in this area
Within the scope of effective hazard ratio.This effective dose depends on many factors, such as but not limited to: the indication treated, the order of severity, with
Public's factors such as the phase treats, the course for the treatment of and patient age, health status, medical history.Based on selected osteopathia medicine the most above-mentioned because of
Element, those skilled in the art are not difficult to determine or take the most described effective dose by routine test.
The dosage form of pharmaceutical composition of the present invention can be at least solid formulation, such as tablet；Or liquid agent, such as injection, mainly
It it is the i.e. systematicness medication of whole body.For example, it is possible to oral, injection, including intramuscular injection and intravenous administration etc..
Described pharmaceutical excipient is known in the art.According to active component, dosage form, required formulation properties, not
On the premise of affecting the compounds of this invention curative effect, those skilled in the art are not difficult to make suitably choosing directly or by routine test
Select.Described excipients is such as, but not limited to: diluent, filler, disintegrating agent, binding agent, thickening agent, correctives, antimicrobial
Agent, antioxidant, lubricant etc..
Present invention also offers the compounds of this invention at preparation treatment osteoporosis, osteonecrosis and the medicine of relevant disease thereof
In purposes.
Technical scheme is specifically described below in conjunction with embodiment.
Embodiment
What following synthetic example 1-4 was used desferrioxamine, the derivative compound a that desferrioxamines, the derivative compound b that desferrioxamines,
The derivative compound c that desferrioxamines is purchased from Sigma company；Iminodiacetic acid and 2,2'-hydrazine-1,2-diyl oxalic acid, 2,2'-is sub-
Methyl-allophanamide diyl oxalic acid, 2,2'-propyl group-1,3-allophanamide diyl oxalic acid is purchased from Aladdin company；Succinic anhydride is with own
Dicarboxylic anhydride is respectively purchased from traditional Chinese medicines group and Aladdin company；PyBOP is purchased from Sigma company；Pd/C is purchased from Sigma company, its Pd
Doping is 10%；Remaining chemical reagent is the analytical grade reagent purchased from Sigma company；The water used is that deionization is double
Distilled water.Reaction is carried out under normal temperature and pressure conditions.Melting point compound Fisher-John melting point apparatus measures.Nuclear magnetic resoance spectrum
By Bruker AM-400 type spectrophotometer.Mass spectrum VG-707E mass spectrograph measures.Elementary analysis Carlo Erba1106
Type elemental analyser measures.
Synthetic example 1
In the present embodiment, synthesis has obtained the DFO-SF compound shown in formula (4), i.e. according to the reaction mechanism mechanism of reaction institute shown in Fig. 1
The finalization compound shown.
1. the preparation of compound (a)
60ml toluene, 95ml benzyl alcohol, 6g iminodiacetic acid and 10.3g is added in the three-neck flask of a 250ml
Toluene-4-sulfonic acid, reactant mixture reacts 18h at 80 DEG C, and solution is become clarification from milky turbidity, and order separates out white the most afterwards
Solid, is dissolved in 100ml chloroform by white solid after filtration, dropping triethylamine is until solution is clear the most wherein
Clearly, this solution uses 500mL saturated sodium bicarbonate aqueous solution washed once, and uses anhydrous magnesium sulfate to be dried, and vacuum is spin-dried for
After water white transparency oily thing 13.6g, productivity is 96wt%.
2. the preparation of compound (b)
Taking a 50ml round-bottomed flask, add 6.28g above-claimed cpd (a), add 30ml chloroform, stirring obtains
Being added thereto to 2.2g succinic anhydride after settled solution, react 3h at 50 DEG C, vacuum is spin-dried for, and obtains water white transparency oily thing
8.41g, obtains 7.19g product after crossing post (silica gel column chromatography), and productivity is 86wt%.
3. the preparation of compound (c)
Take a 50ml round-bottomed flask, add 0.7g compound (b), 5ml DMF and 0.45g PyBOP, in condition of ice bath
Lower stirring 10min, continues stirring after adding 3g NMM.Take a 15ml test tube, weigh 0.5g and desferrioxamine, add 5ml DMF, drip
Adding 5M KOH aqueous solution, to clarification, this settled solution is added above-mentioned round-bottomed flask, react 96h under room temperature, white solid is analysed
Going out, leach this white precipitate, use 30mLDMF to wash secondary, use 30mLTHF to wash once, vacuum is spin-dried for obtaining white solid
0.38g, productivity is 58wt%.
4. the preparation of compound (d)
Take a 25ml round-bottomed flask, add the product (i.e. compound (c)) of 0.38g previous step, be added thereto to
15ml DMF, 0.04g Pd/C, is placed in this round-bottomed flask in hydriding reactor, pressure be 1.1MPa, temperature be the condition of 50 DEG C
Reacting 3h under Xia, filter final vacuum and be spin-dried for DMF, add 20 milliliters of ethanol, filter after stirring 1h, vacuum is spin-dried for obtaining white solid
0.31g, the fusing point recording this product is 141.8-147.7 DEG C, and productivity is 99wt%.Elementary analysis C33H57N7O14, theoretical value
(%): C 51.09, H 7.41, N 12.64；Actual value (%): C 51.05, H 7.44, N 12.69.1H-NMR(d-DMSO)δ
Ppm:9.55 (m, 2H, ES:-CH2COO-), 6.69-7.71 (m, 3H, ES:-NH-), 3.95-4.15 (m, 4H, ES:-CH2-),
3.44-3.47 (m, 6H, ES:-CH2-), 2.98-3.03 (m, 6H, ES:-CH2-), 2.51-2.59 (m, 4H, ES:-CH2-), 2.5
(m, 2H, ES:-CH2-), 2.45-2.49 (m, 4H, ES:-CH2-), 1.97 (m, 2H, ES:-CH2-), 1.49-1.54 (m, 3H,
ES:-OH), 1.47 (m, 3H, ES:-CH2<), 1.35-1.42 (m, 12H, ES:-CH2-), 1.2-1.26 (m, 6H, ES:-CH2-)。
MS (EI) m/z:776.4.
Synthetic example 2
Repeating the step of above example 1 the most completely, difference is, uses shown in following structural formula a
Desferrioxamining derivant a, the molecular formula of this derivant a of desferrioxamining is C26H50N6O9, and molecular weight is 590.71, the linker of use
Group is glutaric anhydride, and the sub-diamino dicarboxylic acid of use is 2,2'-hydrazine-1,2-diyl oxalic acid.The mass spectral characteristi of products therefrom
Result is as follows: MS (ESI) m/z:836.2 (theoretical value 834.91), and its molecular formula is C35H62N8O15, and result proves this product
Have with the structure shown in following formula (5):
Synthetic example 3
Repeating the step of above example 1 the most completely, difference is, uses and has following structural formula b institute
Showing derivant b of desferrioxamining of structure, its molecular formula is C27H52N6O9, and molecular weight is 604.74, and the linking group of use is for oneself
Dicarboxylic anhydride, the iminodicarboxylic acid of use is 2,2'-methylene-allophanamide diyl oxalic acid.The Theoretical molecular formula of products therefrom is
C38H68N8O15, mass spectral characteristi result is as follows: MS (ESI) m/z:878.2 (theoretical value 876.99), it was demonstrated that prepared and had formula
(6) product of structure shown in.
Synthetic example 4
Repeating the step of above example 1 the most completely, difference is, uses and has following structural formula c institute
Showing derivant c of desferrioxamining of structure, its molecular formula is C28H54N6O9, and molecular weight is 618.76, and the linking group of use is pungent
Dicarboxylic anhydride, the iminodicarboxylic acid of use is 2,2'-propyl group-1,3-allophanamide diyl oxalic acid.The Theoretical molecular formula of products therefrom
For C43H78N8O15, mass spectral characteristi result is as follows: MS (ESI) m/z:948.2 (theoretical value 947.12), result proves this enforcement
The product that example prepares has the structure shown in following formula (7).
Embodiment 5 iron ion complex performance is tested
Characterize the compound prepared in the above example complexing power to ferric ion in the present embodiment.Specifically
For, ferric ammonium citrate (ferric ammoniumcitrate, FAC), as ferric ion donor, is dissolved in distilled water
Form solution, be added thereto to compound prepared by above synthetic example 1-4 of same molar respectively and do not carry out this
Invent desferrioxamining of described substituting modification, free iron in application Beckman DXC600 automatic clinical chemistry analyzer detection solution
Content, to understand whether the compound of the present invention has the characteristic of good chelated iron ion.Fig. 2 shows prepared by embodiment 1
DFO-SF and the unsubstituted DFO complexation situation to iron ion, the comparison in Fig. 2 be only use distilled water and without FAC
In the case of the iron ion content that records.The compound that embodiment of the present invention 2-4 prepares have also been obtained and the compound of embodiment 1
Essentially identical effect.
This experiment in vitro shows, after substituting modification, the compound of the present invention still can realize gratifying ferrum
Ion complexation performance.
Embodiment 6 stimulates cell to express hypoxia inducible factor (HIF)-α and the performance of downstream target gene thereof
Have studied in this embodiment the present invention compound stimulate cell express hypoxia inducible factor (HIF)-α and under
The performance of trip target gene.Specifically, take out the mice cranium of raw latter 48 hours, be cut into 1 × 1 × 1mm3Fritter, Trypsin
Enzyme and NTx enzymic digestion, separation, purification newborn mice cranium osteoblast；With 2 × 104/cm2Cell density be seeded to
6 well culture plates；Cell, when adherent growth at the bottom of culture plate to 80% mixing, uses the compound of embodiment of the present invention 1-4 respectively
Concentration is that above-described newborn mice cranium osteoblast is cultivated by the conditioned medium of 200 μMs (DFO net concentrations),
Use the conditioned medium that DFO concentration is 200 μMs of unsubstituted modification as control experiment.Culture fluid intervenes cultured osteoblast-like cells in vitro
After 48 hours, harvesting, according to the step that the following specifically describes detect respectively HIF-1 α protein expression situation and HIF-1 α and
Target gene mrna expression situation downstream, to understand whether the performance of DFO changes because being modified by SF.
The detection (Westernblot method) of 1.HIF-1 α protein expression situation
(1) extract in total protein of cell cell culture well plate add 100 μ l protein lysate RIPA (Beyotime,
China) and 1 μ l protease inhibitor PMSF (Beyotime, China), is positioned on ice；Careful scraping cells is scraped with cell,
Cell is transferred in 0.5ml centrifuge tube, places 30 minutes on ice；4 DEG C, 12000g is centrifuged 15 minutes, is carefully shifted by supernatant
To sterile centrifugation tube ,-80 DEG C save backup, and this is total protein of cell.(2) protein quantification test kit (Beyotime is used
China) measure protein concentration to mainly comprise the following steps: take 1.2ml protein standard preparation liquid and add in 30mg BSA standard protein, fully
The protein standard solution (can use immediately after preparation, it is also possible to-20 DEG C long-term preservations) of 25mg/ml it is configured to after dissolving；Take suitable
Amount 25mg/ml protein standard, is diluted to final concentration of 0.5mg/ml；According to sample size, add 1 volume by 50 volume BCA reagent A
BCA reagent B (50:1) prepares appropriate BCA working solution, fully mixes；Standard substance are added to 96 by 0,1,2,4,8,12,16,20 μ l
In the standard sample wells of orifice plate, add standard dilutions and supply 20 μ l；Add proper volume sample in the sample well of 96 orifice plates, add
Standard dilutions is to 20 μ l；Each hole adds 200 μ l BCA working solutions, places 30 minutes for 37 DEG C；Measure A562,540-595nm
Between wavelength also can accept；The protein concentration of sample is calculated according to standard curve.(3) protein electrophoresis (electrophresis apparatus, Bio-
Rad, USA) glass plate, encapsulating are installed, in order, it is 30 μ g that every well adds protein content；The loading hole not being loaded adds
30 μ l sample-loading buffer balances；Electrophoresis about 75-90min under 120V voltage conditions, stops electrophoresis when bromophenol blue arrives bottom glue.
(4) cut glue, transferring film cuts required purpose band by the albumen Marker (Thermo, USA) of pre-dyed, is immersed by glue and is ready in advance
Transferring film buffer in；Clip pvdf membrane (Millipore, Germany), and make marks in right corner, activate with methanol infiltration,
Immerse in transferring film buffer.Transfer device " sandwich structure " is installed and is followed successively by filter paper → film → glue → filter paper from top to bottom, often
Layer is both needed to guarantee bubble-free；Transferring film box (Bio-Rad, USA) ice is covered, 200mA constant current transferring film, transferring film time about about 2h
(the albumen transferring film time that molecular weight is little can suitably shorten).(5) film is immersed in 5% defatted milk powder by immunoreation, put shaking table in
Room temperature is shaken 1 hour；Taking out film and separately load a moderate plastic bag, the HIF-1 α that addition presses 1:500 dilution with 2%BSA resists
Body (Novus, USA) (one resists), after envelope, is placed in shaking table, shaken over night under the conditions of 4 DEG C；Abandon one to resist, wash film 3 times；Film is separately filled
Enter a moderate plastic bag, add the anti-mouse two anti-(Abbkine, USA) pressing 1:5000 dilution with 2%BSA, incubated at room 1-
2h；Abandon two to resist, wash film 3 times.(6) development in Image Quant LAS 4000mini machine, developer solution it are developed in
(Millipore Germany) is that Millipore A, B liquid is by 1:1 proportions；Preserve histogram picture.
2.HIF-1 α and the detection of downstream target gene mrna expression situation thereof
" one-step method " extracting cell total rna illustrated by test kit (Sigma, USA), mainly comprises the following steps: every milliliter
Trizol liquid adds 0.2ml chloroform, high vibration 15 seconds, left at room temperature 3 minutes；In 4 DEG C, 12000g is centrifuged 15 minutes, takes
The colourless liquid phase in upper strata, moves into the test tube without RNase of new sterilizing；By the amount of initial Trizol liquid, every milliliter adds 0.5ml isopropyl
Alcohol precipitation RNA, puts room temperature lower 10 minutes；4 DEG C, 12000g is centrifuged 10 minutes, at the bottom of test tube and sidewall visible white glue sample droplet；
By the amount of initial Trizol liquid, add 75% washing with alcohol of equivalent；Vibrating gently, 4 DEG C, 7500g is centrifuged 5 minutes；Dry RNA
(being sure not to dry completely, dry in the air under general room temperature 5min), is dissolved in RNA in DEPC water；56～60 DEG C, hatch 10min；Light splitting light
Degree counts detection rna content and concentration, and RNA identifies and the most quantitative.Application PCR Reverse Transcriptase kit (Takara, Japan), RNA is anti-
Transcribe and obtain cDNA, mainly comprise the following steps: take 1 μ g total serum IgE, random primer 1 μ l, add distilled water that DEPC processes to 12 μ l, 70 DEG C
Hatch 5 minutes；It is subsequently placed on ice, is sequentially added into 5x reaction buffer 4 μ l, 10nM dNTP2 μ l, RNase inhibitor 0.5 μ l,
Add DEPC process distilled water to 19 μ l, 25 DEG C hatch 5 minutes after add reverse transcriptase (M-MLV) 1 μ l, making cumulative volume is 20 μ
l；According to 25 DEG C 10 minutes, 42 DEG C 60 minutes, within 10 minutes, hatch on PCR couveuse for 70 DEG C, complete to be placed on terminate on ice reaction；
The cDNA Direct PCR of reverse transcription or-20 DEG C of preservations.Separately design and synthesize hypoxia inducible factor (HIF)-1 α and target downstream
Gene order primer (the HIF-1 α primer sequence of gene VEGF (VEGF) and Heme oxygenase (HO)-1
Row: upstream-GGTATTATTCAGCACGAC, downstream-GAGGGAAACATTACATC；VEGF primer sequence: upstream-
AGTCCCATGAAGTGATCAAGTTCA, downstream-ATCCGCATGATCTGCATGG；HO-1 primer sequence: upstream-
AAGCCGAGAATGCTGAGTTCA, downstream-GCCGTGTAGATATGGTACAAGGA)；By PCR fluorescence quantitative kit
(Takara, Japan) illustrates, formation reaction system (Green, 10 μ l；ROX Reference Dye II, 0.4 μ l；
Upstream and downstream primer, each 0.8 μ l；CDNA, 2.0 μ l；Distilled water, complements to 20 μ l.)；Real-time PCR instrument (AB Applied
Biosystems, 7500Real Time PCR System) detection by quantitative comparative analysis SF-DFO stimulate cell to express HIF-1
(reaction condition is as follows: 94 DEG C 5 minutes, 94 DEG C of 30s, 55 DEG C of 30s, 72 DEG C for the situation of α and downstream target gene (VEGF, HO-1) thereof
30s, after so circulating 35 times, 72 DEG C are terminated reaction in 5 minutes).
The result that the DFO of the prepared DFO-SF of the embodiment of the present invention 1 and unsubstituted modification records is shown in Fig. 3 and Fig. 4.From figure
3 with the result of Fig. 4 it will be seen that compared with the DFO of unsubstituted modification, the DFO-SF that the embodiment of the present invention 1 prepares has similar
Stimulating osteoblast express HIF-1 α and target gene VEGF (VEGF), the property of oxygenase (HO)-1
Energy.Compound prepared by embodiment of the present invention 2-4 also shows the effect identical with the compound of embodiment 1.
Embodiment 7 drives bone characteristic present
In this embodiment, isotope is used14DFO or DFO in the compound of C flag embodiment of the present invention 1-4 derives
After compound structure, this compound is configured to aqueous solution mice is carried out lumbar injection or tail vein injection, when difference
Phase eye socket is put to death after taking blood, collects kidney, femur, spleen, lung, liver and muscular tissue, uses liquid scintillation counter
(WALLAC company, Trilux 1450Micro Beta) measures radioactive intensity in each internal organs, and the cpm/mg tissue that will record
It is converted into dpm/mg tissue.Fig. 5 shows the characterization result of the DFO-SF compound of the embodiment of the present invention 1, shows this compound
In Mice Body inner structure stable performance, and DFO concentration in osseous tissue can be driven by the substituting modification of the present invention.The present invention
Compound prepared by embodiment 2-4 also shows and the same effect of embodiment 1.
In sum, skeleton is had no adverse effects by the compound that the synthesis of embodiment of the present invention 1-4 obtains, and to bone metabolism
There is higher activity, the formation of bone matrix can be promoted, can be used to (DFO) targeting of desferrioxamining is imported and dense gathered in osseous tissue
In, and then play the effect of the preventing and treating osteoclasia of chelated iron ion, stimulation osseous tissue angiogenesis.The bone affinity chemical combination of the present invention
Thing can specifically increase medicine concentration in osseous tissue, improves it and improves osteoporosis osteoblast and osteoclast merit
The useful effect of cells characteristic phenotype, can be maintained.Simultaneously as after modified group and combination of desferrioxamining, to each activity
Affect less, body is had no side effect, it is possible to improve osteopathia medicine and meet the stability of compound, and reduce medicine
Systematicness ill effect.
Claims (10)
1. the compound shown in formula (1), and pharmaceutically acceptable salt, ester, amide, carboxylic acid halides, hydrate or solvent close
Thing:
Wherein R1Selected from following group: substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Thiazolinyl, replacement or
Unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R2-R4It is each independently selected from following group: hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or
Unsubstituted C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine,
Bromine and iodine；
R5-R7It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted
C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R8-R45It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or unsubstituted
C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；
M is selected from following integer: 1,2,3,4,5,6,7,8,9,10,11 and 12；
A is derived from the group of the organic multicomponent acid comprising 1-8 nitrogen-atoms and 2-6 carboxyl, by one of them nitrogen-atoms
It is connected with the other parts of compound shown in formula (1).
2. compound as claimed in claim 1, it is characterised in that described A group is selected from following group, by shown nitrogen
The singly-bound of atom is connected with the other parts of compound shown in formula (1):
In above group, n is selected from following integer: 1,2,3,4,5 and 6.
3. compound as claimed in claim 1 or 2, it is characterised in that
R1Selected from following group: substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, replacement or unsubstituted
C1-C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R2-R4It is each independently selected from following group: hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-
C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R5-R7It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted
C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R8-R45It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted
C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine.
4. the method being used for preparing the compound as according to any one of claim 1-3, the method comprises the following steps:
I () makes the organic multicomponent comprising 1-8 nitrogen-atoms and 2-6 carboxyl acid react with alcohol, with to the acid of described organic multicomponent
All of carboxyl is protected；
(ii) acid of the carboxyl making step (i) prepared is protected organic multicomponent and C3-C14The anhydride reaction of diacid；
(iii) make the product of step (ii) and there is the derivatives reaction of desferrioxamining or desferrioxamine of formula (2)；
(iv) carboxyl being protected of the product prepared to step (iii) carries out deprotection, obtains the compound of formula (1):
Wherein R1Selected from following group: substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-C10Thiazolinyl, replacement or
Unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；The most substituted or unsubstituted
C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl, substituted or unsubstituted C1-C4
Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R2-R4It is each independently selected from following group: hydroxyl, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted C1-
C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；Preferably
Hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alkoxyl,
Substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R5-R7It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, substituted or unsubstituted
C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；Excellent
Select hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4 alkane
Epoxide, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine；
R8-R45It is each independently selected from following group: hydrogen, hydroxyl, substituted or unsubstituted C1-C10Alkyl, replacement or unsubstituted
C1-C10Thiazolinyl, substituted or unsubstituted C1-C10Alkoxyl, substituted or unsubstituted C1-C10Alkenyloxy group, fluorine, chlorine, bromine and iodine；
Hydrogen, hydroxyl, substituted or unsubstituted C1-C4Alkyl, substituted or unsubstituted C1-C4Thiazolinyl, substituted or unsubstituted C1-C4Alcoxyl
Base, substituted or unsubstituted C1-C4Alkenyloxy group, fluorine, chlorine, bromine and iodine.
5. method as claimed in claim 4, it is characterised in that the reaction of described step (i) in a solvent, exists catalyst
In the case of carry out,
Described alcohol is selected from: C1-C10Alkylol and C7-C16Aryl alcohol；Preferably benzyl alcohol；
Described solvent is selected from: benzene, toluene, hexamethylene, acetone, ether, dimethyl ether, dipropyl ether and they in the middle of any two kinds
Or more kinds of mixture；
Described catalyst is selected from following acid catalyst: sulphuric acid, hydrochloric acid, phosphoric acid, nitric acid, C1-C6Alkyl sulfonic acid, benzenesulfonic acid, first
Benzenesulfonic acid；Preferably p-methyl benzenesulfonic acid；
Comprise one or more in following compound of the organic multicomponent acid of 1-8 nitrogen-atoms and 2-6 carboxyl:
6. method as claimed in claim 4, it is characterised in that described step (ii) is being carried out in following solvent: bag
Containing the liquid alkane of one or more halogen atoms, described halogen atom is selected from fluorine, chlorine, bromine, iodine；Preferably, step (ii) uses
Solvent is selected from monochloro methane, dichloromethane, chloroform, carbon tetrachloride and any mixture thereof.
7. method as claimed in claim 4, it is characterised in that described step (iii) in a solvent, at the bar using catalyst
Carry out under part,
Described solvent is selected from: benzene, toluene, hexamethylene, acetone, ether, dimethyl ether, dipropyl ether, N,N-dimethylformamide and
Any two or more mixture in the middle of them；
Described catalyst is selected from: hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus (PyBOP), 1H-benzotriazole-
1-base oxo three (dimethylamino) phosphorus hexafluorophosphate (BOP), 1-hydroxy benzo triazole (HOBT) and N, N'-dicyclohexyl
Carbodiimide (DCC), preferably hexafluorophosphoric acid benzotriazole-1-base-epoxide tripyrrole alkyl phosphorus (PyBOP).
8. method as claimed in claim 4, it is characterised in that the carboxyl deprotection reaction of described step (iv) is at catalyst
In the presence of carried out by hydrogenation,
Described catalyst is selected from loaded noble metal catalyst, preferably load type palladium, platinum, rhodium catalyst, more preferably palladium carbon.
9. a pharmaceutical composition, this pharmaceutical composition comprises:
The compound of the formula (1) according to any one of (i) claim 1-3 and pharmaceutically acceptable salt, ester, amide, acyl
Halogen, hydrate or solvate；
(ii) one or more in pharmaceutically acceptable optional excipient, filler, carrier and diluent；
(iii) the optional pharmaceutical active being different from component (i), described pharmaceutical active is selected from: Alendronate sodium sheet,
Zolendronate sodium, Pamidronate Disodium, vitamin D, risedronate sodium, teriparatide, Strontium Ranelate, raloxifene, calcitonin,
Estrogen, nilestriol, female pregnant sharp, tamoxifen, ipriflavone, clodronate disodium sheet, GUSONGBAO KELI, premarin, purple
Bamboo like dimension, solid Su An, etidronate disodium sheet, Bang Telin, tridin, calcium gluconate tablet, Zinc calcium gluconate oral solution,
The strange calcium carbonate D3 of Premelle Cycle, ribavirin tablet, elcatonin, Yi Weite, Bei Bang, Calcitonin Salmon, kidney osteocomma, calcareacarbonica, calcium that
Sheet, vitamin D 2 and calcium colloid injection, Gai Ruining, clodronate disodium capsule, Alfacalcidol, injection bone peptide, cervus and cucumis polypeptide are noted
Penetrate agent, DANHONG ZHUSHEYE, Flos Carthami injection, cefradine, clindamycin, vancomycin, low molecular dextran aminoacid, hydroxyl
Hydroxyethyl starch injection, Low molecular heparin sodium injection, sodium lactate ringer's injection, Mannitol sodium chloride injection.
10. the compound of the formula (1) according to any one of claim 1-3 and pharmaceutically acceptable salt, ester, amide, acyl
Halogen, hydrate or solvate are used for treating osteoporosis, osteonecrosis, delayed fracture healing or disunion and bone lacks in preparation
Application in the medicine damaged.
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