CN102532261A - Bone remodeling activator-typrotide and medicament composition and application thereof - Google Patents
Bone remodeling activator-typrotide and medicament composition and application thereof Download PDFInfo
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- CN102532261A CN102532261A CN2010106119497A CN201010611949A CN102532261A CN 102532261 A CN102532261 A CN 102532261A CN 2010106119497 A CN2010106119497 A CN 2010106119497A CN 201010611949 A CN201010611949 A CN 201010611949A CN 102532261 A CN102532261 A CN 102532261A
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Abstract
The invention discloses a bone remodeling activator-typrotide and a medicament composition and application thereof, in particular typrotide compounds discovered by transforming the structure of C terminal osteogenic growth peptide 5 (OGP5), having activity of activating bone remodeling and shown as a general formula (I), and relates to a structural design and synthesis method for the new peptide and activation-depression-formation-repeat (ADFR) compounded with a bone absorption inhibiting medicament-bisphosphonate and used for treating osteoporosis (OP) of experimental rats. The modified OGP5 can obviously activate bone remodeling of OP suffering rats, and is expected to become an ideal medicament for improving bone quality and treating the OP, femoral head necrosis and bone trauma.
Description
Technical field
The present invention relates to one type and have sOGP C end pentapeptide (OGP5) the structure of modification compound that exciting bone is rebuild (Bone remodeling) function, belong to medical technical field.
Background technology
The pathogeny of osteoporosis (OP) is comparatively complicated.Factors such as clear and definite so far is involutional disorder of hormone secretion, some tumor promotions, chemotherapy (like vitamin A acid, widely apply cortin etc.) all can cause tangible bone loss, bone pain so that multiple fracture.
Research shows, the balance that osteoclast in the osseous tissue and scleroblast replace activation, condition each other is the important foundation of bone metabolism.Therefore osteoclast and activation scleroblast should be two important steps improving one of bone metabolism, repair osseous tissue always.Yet the medicine of treating OP at present clinically is to be the bone resorption inhibitor of target spot with the osteoclast basically, is main like two phosphonium salt classes, oestrogenic hormon and thyrocalcitonin etc.Put into practice verified application of overemphasizing bone resorption inhibitor, can only weaken the bone reconstruction ability that OP patient has originally failed, further reduce the bony remodeling position; Patient's fracture rates rise on the contrary [Blake, J.et al.JOGC, 2006; 28 (3): 185] [Ding Xiaoying is etc. foreign medical science internal medicine fascicle, to be unprofitable to the improving of bone mass; 2004,3 (4): 175].
The junket dried meat peptide that the present invention relates to is tied to form osteogenic growth peptide C end pentapeptide (OGP5) fragment and changes the structure compound.But OGP is the bioactive peptide that contains 14 residues of human body endogenous promoting mitosis.Its C-terminal pentapeptide (being called for short OGP5) is main active section, and it can promote bone forming, the bone density improving of laboratory animal and impel healing [Chen Y.et al.J.Pept.Res.2000, the 56:147 of fracture; Brager M.A.et al.J.Orthop.Res.2000,18:133].The action target spot of OGP5 is a scleroblast, is expected to suppress fit applications with the bone resorption that with the osteoclast cell is target spot, reaches fracture rates is descended, and really improves the result of treatment of bone mass.
Summary of the invention
The technical problem that the present invention will solve provides one type of new bone and rebuilds activator, particularly is exactly one type of new compound junket dried meat peptide.
Another technical problem that the present invention will solve provides the pharmaceutical composition that contains this compounds.
Another technical problem that the present invention will solve provides this compounds and in the preparation medicine, uses.
For solving technical problem of the present invention, the present invention adopts following technical scheme: the present invention is first guide structure with OGP5, changes second Gly into cyclic Pro, and the Tyr of N end and right side Phe can keep constant, also can change the side chain that has benzene ring structure equally into.Contain Tyr-Pro in the target compound or the Pro-Tyr fragment is basic characteristics, therefore be named as junket dried meat peptide (Typrotide writes a Chinese character in simplified form TPT).The C end of compound main chain is connected with and contains HN (CH
2)
nCONH (CH
2)
mThe prolongation chain of (n and m=1～10) structure is a positive sequence junket dried meat peptide, and perhaps N holds the prolongation chain that is connected with greater than 4 singly-bound length then to be inverted sequence junket dried meat peptide.
OGP5：H-Tyr-Gly-Phe-Gly-Gly-OH
TPT general formula: R
1-X
1-Pro-X
2-X
3-R
2
(I)
Wherein:
R
1Be selected from Suc (Succinic Acid list acyl), Ida (iminodiethanoic acid list acyl), Abu (gamma-amino butyryl), Aca (the amino hexanoyl of 6-), β-Ala, Gly (glycyl) or des (disappearance);
X
1, X
2Independently be selected from Tyr (tyrosyl), Phe (phenylalanyl), Phe (4-NO
2) (p-nitrophenyl alanyl), Trp (tryptophyl), Ser (Bzl) (O-benzyl seryl), Thr (Bzl) (O-benzyl threonyl), HO-Ph-CO (para hydroxybenzene formyl), Fer (3-methoxyl group-4-hydroxyl cinnyl; The asafoetide acyl), Hna (hydroxyl naphthoyl), Pic (pyridine-2-formyl), Hip (N-benzoyl-glycyl; Horse urea acyl) or Sal (o-hydroxy formyl, salicylyl);
X
3Be selected from β-Ala, Abu, Aca, Gly-Gly or des (disappearance);
R
2Be selected from OH, NH
2, Gol (H
2NCH
2CH
2OH, glycinol), NH (CH
2)
mCH
3And m is 0～10 integer, NH (CH
2)
nOH and n are 0～10 integer.
Tyr-Pro-Phe-β-Ala-NHEt 1
Tyr-Pro-Tyr-β-Ala-NHEt 2
Tyr-Pro-Tyr-β-Ala-Gol 3
3-Hna-Pro-Ty-rβ-Ala-NHPr 4
Hip-Pro-Tyr-β-Ala-NHPr 5
Fer-Pro-Phe(4-NO
2)-Aca-Gol 6
Tyr-Pro-Phe(4-NO
2)-Aca-NHMe 7
Fer-Pro-Phe-β-Ala-Gol 8
Fer-Pro-Phe-β-Ala-NHPr 9
Fer-Pro-Tyr-β-Ala-NHPr 10
Pic-Pro-Tyr-β-Ala-NHPr 11
Ida-Tyr-Pro-Tyr-β-Ala-NHMe 14
Ida-Phe-Pro-Tyr-β-Ala-NHMe 13
Suc-Tyr-Pro-Tyr-β-Ala-NHPr 14
Suc-Phe-Pro-Tyr-β-Ala-NHMe 15
Aca-Phe-Pro-Tyr-β-Ala-NHPr 16
Suc-Ser(Bzl)-Pro-Tyr-β-Ala-NHMe 17。
The present invention also provides the preparation method of junket dried meat peptide, and related junket dried meat peptide is the approach preparation through chemosynthesis.It is synthetic wherein to have plenty of the solid phase synthesis of employing mode, and the product that has also can be synthetic by traditional solution method.All amino acid starting material is Boc (tertiary butyloxycarbonyl acyl group) protection form.The amino acid starting material that relates to is: Boc-Tyr-OH, Boc-Pro-OH, Boc-Phe-OH, Boc-Ser (Bzl)-OH, Boc-Phe (4-NO
2)-OH, Boc-Aca-OH, Boc-β-Ala-OH.Condensation reagent has Cl-HOBt (5-chloro-I-hydroxybenzotriazole), HBTU (benzotriazole-N; N; N '; N '-tetramethyl-urea hexafluorophosphate), DIC (DIC), other reagent have NMM (N-methylmorpholine), TEA (triethylamine), TFA (trifluoroacetic acid), TESi (triethyl silicon).The condition that removes the Boc base is 50%TFA/CH
2Cl
2(DCM).It is 30%MeNH that ammonia is separated excision resin reagent
2/ EtOH, 70%EtNH
2/ H
2O, 100%PrNH
2
The evaluated biological activity that the present invention relates to is that the rat with spay (OVX) is the OP animal model, and positive control drug is Allan sodium phosphate (Alen).Be limited to 12 weeks of continuous subcutaneous injection after the spay during administration of junket dried meat peptide.Put to death the die mensuration (seeing embodiment for details) of indexs such as morphology and kinetics of animal subsequently.
The biological activity test result shows the bone morphology each item index of junket dried meat peptide to OP trouble mouse; Like BV/TV (TBV/full bone volume), TB.Th (bone trabecula width), Tb.sp (bone trabecula gap), Tb.N (bone trabecula node number), OV/BV (osteoid volume ratio), OS/BS (OS ratio); Reach bone kinetic parameter such as sL.s/BS (tsiklomitsin list mark lengths and bone trabecula girth ratio), dL.s/BS (ratio of area of tetracycline label length and bone trabecula girth), reach bone mineralising index such as MS/BS, MAR, MLT etc. and all obviously be superior to the Alen group.But wherein most indexs are the situation of enlivening of reactive bone reconstruction all, and provable thus junket dried meat peptide of the present invention is rebuild to activate to the bone of OP rat and brought into play vital role.By contrast, the activity that positive control wants Alen to have no excited bone to rebuild, this result can not reduce fracture clinically with two phosphonium salts, and the undesired result that increases fracture rates on the contrary is consistent.
The present invention also provides The compounds of this invention preparing with prevention or treating the application in the osteoporotic pharmaceutical composition.Application in the medicine of the concurrent osteopathia of preparation and tumour.Described and the concurrent osteopathia of tumour is selected from hypercalcemia, bone pain, scleromalacia or multiple myeloma.Application in the medicine that preparation promotion surgery bone is transplanted, traumatic fracture heals.Described medicine is the continuous medicine that passes through that cooperates with bone resorption inhibitor.
Further aspect of the present invention also relates to the pharmaceutical composition of The compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be through the pharmaceutically acceptable solid of The compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, process to be suitable for any formulation of human or animal's use.The content of The compounds of this invention in its pharmaceutical composition is generally 0.1-95 weight %.
The compounds of this invention or contain its pharmaceutical composition can the unit dosage form administration; Route of administration can be enteron aisle or non-enteron aisle, like oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be processed ordinary preparation, also process is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For The compounds of this invention is processed tablet, the various vehicle well known in the art that can be widely used comprises thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, lime carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, TKK 021, vinyl resin, carbomer, Vinylpyrrolidone polymer, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, Sodium Croscarmellose, sodium starch glycolate, sodium hydrogencarbonate and Citric Acid, polyoxyethylene sorbitol fatty ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Can also tablet further be processed coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.
For capsule is processed in the administration unit, can the effective constituent The compounds of this invention be mixed with thinner, glidant, mixture is directly placed hard capsule or soft capsule.Also can the effective constituent The compounds of this invention be processed particle or micropill with thinner, tamanori, disintegrating agent earlier, place hard capsule or soft capsule again.Each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind that are used to prepare the The compounds of this invention tablet also can be used for preparing the capsule of The compounds of this invention.
For The compounds of this invention is processed injection, can water, ethanol, Virahol, Ucar 35 or their mixture as solvent and add an amount of this area solubilizing agent commonly used, solubility promoter, pH and adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be Prist, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition, like needs, also can in pharmaceutical prepn, add tinting material, sanitas, spices, correctives or other additive.
For reaching the medication purpose, enhancing treatment effect, medicine of the present invention or pharmaceutical composition can be used any known medication administration.
The dosage of The compounds of this invention pharmaceutical composition according to prevent or treat the character and the severity of disease, the individual instances of patient or animal, route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope of the every day of The compounds of this invention is the 0.001-150mg/Kg body weight, is preferably the 0.1-100mg/Kg body weight, and more preferably the 1-60mg/Kg body weight most preferably is the 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or compsn can be taken separately, or merge use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust its dosage according to practical situation.
Term and abbreviation
TPT: junket dried meat peptide;
Suc: Succinic Acid list acyl;
Ida: iminodiethanoic acid list acyl;
Abu: gamma-amino butyryl;
The amino hexanoyl of Aca:6-;
Gly: glycyl
Des: disappearance;
Tyr: tyrosyl;
Phe: phenylalanyl;
Phe (4-NO
2): the p-nitrophenyl alanyl;
Trp: tryptophyl;
Ser (Bzl): O-benzyl seryl;
Thr (Bzl): O-benzyl threonyl;
HO-Ph-CO: para hydroxybenzene formyl;
Fer:3-methoxyl group-4-hydroxyl cinnyl has another name called the asafoetide acyl;
Hna: hydroxyl naphthoyl;
Pic: pyridine-2-formyl;
Hip:N-benzoyl-glycyl has another name called horse urea acyl;
Sal: the o-hydroxy formyl has another name called salicylyl;
Gol:H
2NCH
2CH
2OH has another name called glycinol;
OP: osteoporosis;
OGP5：H-Tyr-Gly-Phe-Gly-Gly-OH
Boc: tertiary butyloxycarbonyl acyl group
Cl-HOBt:5-chloro-I-hydroxybenzotriazole;
HBTU: benzotriazole-N, N, N ', N '-tetramethyl-urea hexafluorophosphate;
DIC: DIC;
The NMM:N-methylmorpholine;
TEA: triethylamine;
TFA: trifluoroacetic acid;
TESi: triethyl silicon.
Embodiment
For making the object of the invention, technical scheme and advantage clearer, will combine specific embodiment that embodiment of the present invention is done to describe in detail further below.
Embodiment 1
Tyr-Pro-Phe-β-Ala-NHEt's (1) is synthetic
1. Boc-β-Ala-OCH
2The preparation of-polystyrene resin
Take by weighing the heavy 20g (20mmol) of chloromethyl resin (substitution value 1mmol/g, degree of crosslinking 1%, granularity 100-200 order), Boc-β-Ala-OH 11.34g (60mmol), K
2CO
38.28g (60mmol) and KI 0.2g (0.12mmol), mixed together is in 300mL DMF (N, dinethylformamide).Behind 60 ℃ of revolving reaction 24h, the filtering supernatant.Resin is used following solvent filter wash successively: 60 ℃ of DMF (* 3 times), 50%EtOH (ethanol)/H
2O (* 3 times), DMF (* 5 times), 60 ℃ of 95%EtOH (* 5 times), Et
2O (ether * 2 time) drains afterwards.As under the ir lamp, 50 ℃ are dried to constant weight with resin.Weighing gets Boc-β-Ala-resin 23g, weightening finish 3.0g (theoretical Δ W=3.05g), and this step productive rate is 98%.
2. take off the Boc base, midbody β-Ala-OCH
2The preparation of-PS
Above-mentioned Boc-β-Ala-resin was shaken 10 minutes with 230ml 50%TFA/DCM (trifluoroacetic acid/dichloromethane) is mixed in sealable reaction tubes, extract acid solution, add 230mL 50%TFA/DCM again, shook again 30 minutes.Collect acid hydrolysis solution (being used for taking off next time for the first time the Boc reaction).Resin is successively through following solvent filter wash: DCM * 5,95%EtOH * 3,10%TEA/EtOAc (triethylamine/ETHYLE ACETATE) * 2, DMF * 3, EtOH * 3, Et
2O * 2, drain subsequent use.
3. the preparation of two peptide resin Phe-β-Ala-OCH2-PS
The activation of carboxyl group: get Boc-Phe-OH 1.5g (6mmol), Cl-HOBt 1.02g (6mmol), HBTU 2.276g (6mmol), be dissolved in jointly among the 10mL DMF, add NMM 0.67mL (6mmol) behind the CL.Hybrid reaction after three minutes with 2.3g (2mmol) β-Ala-OCH
2-polystyrene resin mixes in the reactive polypeptide pipe.Shake 3h under the room temperature, the filtering supernatant.Resin is successively through following solvent filter wash: DMF * 3, EtOH * 2, DMF * 3, EtOH * 5, Et
2O * 2.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the last amino of β-Ala is complete by acidylate, promptly Boc-Phe-OH is fully in the condensation.Handle (2. identical) through taking off the Boc base, obtain dipeptides Phe-β-Ala-OCH with step
2-polystyrene resin midbody 2.59g.
4. three peptide resin Pro-Phe-β-Ala-OCH
2The preparation of-polystyrene resin
With Boc-Pro-OH is carboxyl group, handles according to above-mentioned steps condensation and the step Boc protective condition that takes off 2. 3., obtains tripeptides Pro-Phe-β-Ala-OCH
2-polystyrene resin 2.78g.
5. tetrapeptide resin Tyr-Pro-Phe-β-Ala-OCH
2The preparation of-PS
With Boc-Tyr-OH is carboxyl group, handles according to the above-mentioned condensation and the condition of taking off Boc base, obtains tetrapeptide resin intermediate 3.09g.
6. ammonia is separated the excision resin, the preparation of product 1
Get tetrapeptide resin intermediate Tyr-Pro-Phe-β-Ala-OCH
2-PS 1.5g (1mmol) and 8ml contain 70%H
2The aqueous solution of NEt and 8ml THF (THF) blend are in sealable reactive polypeptide pipe.Room temperature is shaken reaction 30h, collects supernatant.Remaining resin is used twice of 95%EtOH filter wash again.Merging filtrate, and under 50 ℃, remove solvent under reduced pressure.Basic except that behind the neat solvent, adding 5ml toluene and 10ml 95%EtOH remove micro-moisture again under reduced pressure.Obtain subalbous residue, through anhydrous Et
2O fully grinds, and filters and collects powdered product 482mg (theoretical value is 523mg), and total recovery is 92.1%, and ESI-MS analyzes 524.2060 (M+H).
Embodiment 2
Tyr-Pro-Tyr-β-Ala-NHEt (2) and Tyr-Pro-Tyr-β-Ala-Gol's (3) is synthetic
1. 1. and condition 2., preparation β-Ala-OCH according to step among the embodiment 1
2-PS midbody 2.5g.
2. two peptide resin Tyr-β-Ala-OCH
2The preparation of-PS
The activation of carboxyl group: get Boc-Tyr-OH 1.686g (6mmol), Cl-HOBt 1.02g (6mmol), HBTU 2.276g (6mmol), be dissolved in jointly among the 10mL DMF, add NMM 0.67mL (6mmol) behind the CL.Hybrid reaction after three minutes with 2.3g (2mmol) β-Ala-OCH
2Resin mixes in the reactive polypeptide pipe.Shake 3h under the room temperature, the filtering supernatant.Resin is successively through following solvent filter wash: DMF * 3, EtOH * 2, DMF * 3, EtOH * 5, Et
2O * 2.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the last amino of β-Ala is complete by acidylate, promptly Boc-Tyr-OH is fully in the condensation.Handle (2. identical) through taking off the Boc base, obtain dipeptides Tyr-β-Ala-OCH with step
2-polystyrene resin midbody 2.62g.
3. three peptide resin Pro-Tyr-β-Ala-OCH
2The preparation of-polystyrene resin
With Boc-Pro-OH is carboxyl group, handles according to above-mentioned steps condensation and the step Boc protective condition that takes off 2. 2., obtains tripeptides Pro-Tyr-β-Ala-OCH
2-polystyrene resin 2.81g.
4. tetrapeptide resin Tyr-Pro-Tyr-β-Ala-OCH
2The preparation of-polystyrene resin
With Boc-Tyr-OH is carboxyl group, takes off the condition of Boc base according to the condensation of above-mentioned steps in 2. and handles, and obtains tetrapeptide resin intermediate 3.13g.
5. ammonia is separated the excision resin, the preparation of product 2
Get tetrapeptide resin intermediate Tyr-Pro-Tyr-β-Ala-OCH
2-PS 1.6g (1mmol) and 8ml contain 70%H
2The aqueous solution of NEt and 8ml THF blend are in sealable reactive polypeptide pipe.Room temperature is shaken reaction 30h, collects supernatant.Remaining resin is used twice of 95%EtOH filter wash again.Merging filtrate, and under 50 ℃, remove solvent under reduced pressure.Basic except that behind the neat solvent, adding 5ml toluene and 10ml 95%EtOH remove micro-moisture again under reduced pressure.Obtain subalbous residue, through anhydrous Et
2O fully grinds, and filter and collect the powder 479mg (theoretical 539mg) that obtains product 2, total recovery 88.8%, ESI-MS analyzes 540.2113 (M+H).
Getting the tetrapeptide resin (1.56g) that 4. another part step obtain mixes with thanomin (50mmol) and the 15ml 95%EtOH of 3ml.Room temperature is shaken reaction 50h, collects filtrating.Remaining resin mixes through 95%EtOH.Room temperature is shaken reaction 50h, collects filtrating.Remaining resin is through 95%EtOH filter wash twice, merging filtrate.Remove EtOH under reduced pressure under 50 ℃, obtain the light yellow debris of heavy-gravity.Add 200ml zero(ppm) water, place 3h.Filter collection white precipitate.Use EtOAc-nBuOH (1: 1) 200ml to mix again, in the paging funnel, extract, remove water layer, organic layer adds anhydrous sodium sulfate drying with after washing twice, concentrates evaporate to dryness, uses Et
2O grinds, and gets powdered product 3 heavy 453mg (theoretical 555mg), total recovery 81.6%, and ESI-MS analyzes 556.2301 (M+H).
Embodiment 3
1-Hna-Pro-Tyr-β-Ala-NHPr (4) and 1-Hna-Pro-Tyr-β-Ala-Gol's (5) is synthetic
1. according to step condition 1.～3. among the embodiment 2, prepare Pro-Tyr-β-Ala-OCH
2-PS midbody 2.8g.
2. tetrapeptide resin 1-Hna-Pro-Tyr-β-Ala-OCH
2The preparation of-PS
The activation of carboxyl group: get 1-Hna 1.128g (6mmol), Cl-HOBt 1.02g (6mmol), HBTU 2.276g (6mmol), be dissolved in jointly among the 10mL DMF, add NMM 0.89mL (8mmol) behind the CL.Hybrid reaction after three minutes with 2.8g (2mmol) Pro-Tyr-β-Ala-OCH
2-polystyrene resin mixes in the reactive polypeptide pipe.Shake 3h under the room temperature, the filtering supernatant.Resin is successively through following solvent filter wash: DMF * 3, EtOH * 2, DMF * 3, EtOH * 5, Et
2O * 2.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on the Tyr is complete by acidylate, promptly Boc-Tyr-OH is fully in the condensation.Handle (2. identical) through taking off the Boc base, obtain tetrapeptide 1-Hna-Pro-Tyr-β-Ala-OCH with step
2-polystyrene resin midbody 2.9g.
3. ammonia is separated the excision resin, product 4 and 5 preparation
Get 1/2 this midbody (1.45g, 1mmol), with 5ml propylamine and 8ml THF blend in sealable reactive polypeptide pipe.Room temperature is shaken reaction 30h, collects supernatant.Remaining resin is used twice of 95%EtOH filter wash again.Merging filtrate, and under 50 ℃, remove solvent under reduced pressure.Basic except that behind the neat solvent, adding 5ml toluene and 10ml 95%EtOH remove micro-moisture again under reduced pressure.Obtain flaxen residue, through anhydrous Et
2O fully grinds, and filters and collects the powder 510mg (theoretical heavy 560mg) that obtains product 4, and total recovery is 91%, and ESI-MS analyzes 556.3850 (M+H).
Getting the tetrapeptide resin (1.45g) that 2. another part step obtain mixes with thanomin (50mmol) and the 15ml 95%EtOH of 3ml.Room temperature is shaken reaction 50h, collects filtrating.Remaining resin mixes through 95%EtOH.Room temperature is shaken reaction 50h, collects filtrating.Remaining resin is through 95%EtOH filter wash twice, merging filtrate.Remove EtOH under reduced pressure under 50 ℃, obtain the light yellow debris of heavy-gravity.Add 200ml zero(ppm) water, place 3h.Filter collection white precipitate.Use EtOAc-nBuOH (1: 1) 200ml to mix again, in the paging funnel, extract, remove water layer, organic layer adds anhydrous sodium sulfate drying with after washing twice, concentrates evaporate to dryness, uses Et
2O grinds, and obtains the powder 478mg (theoretical heavy 562mg) of product 5, and total recovery is 85.0%, and ESI-MS analyzes 563.2131 (M+H).
Embodiment 4
Fer-Pro-Phe (4-NO
2)-Aca-Gol (6) and Tyr-Pro-Phe (4-NO
2)-Aca-NHMe's (7) is synthetic
1. Aca-OCH
2The preparation of-polystyrene resin
Take by weighing the heavy 10g (10mmol) of chloromethyl resin (substitution value 1mmol/g, degree of crosslinking 1%, granularity 100-200 order), Boc-Aca-OH 6.9g (30mmol), K
2CO
34.14g (30mmol) and KI 0.1g (0.06mmol), mixed together is in 150mL DMF (N, dinethylformamide).Behind 60 ℃ of revolving reaction 24h, the filtering supernatant.Resin is used following solvent filter wash successively: 60 ℃ of DMF (* 3 times), 50%EtOH (ethanol)/H
2O (* 3 times), DMF (* 5 times), 60 ℃ of 95%EtOH (* 5 times), Et
2O (ether * 2 time) drains afterwards.As under the ir lamp, 50 ℃ are dried to constant weight with resin.With above-mentioned Boc-Aca-OCH
2-polystyrene resin shook 10 minutes with 150ml 50%TFA/DCM (trifluoroacetic acid/dichloromethane) is mixed in sealable reaction tubes, extracted acid solution, added 150mL 50%TFA/DCM again, shook 30 minutes again.Collect acid hydrolysis solution (being used for taking off next time for the first time the Boc reaction).Resin is successively through following solvent filter wash: DCM * 5,95%EtOH * 3,10%TEA/EtOAc (triethylamine/ETHYLE ACETATE) * 2, DMF * 3, EtOH * 3, Et
2O * 2, drain weighing and get Boc-Aca-OCH2-polystyrene resin 10.93g, weightening finish 0.93g (theoretical Δ W=0.945g), this step productive rate is 98%.
2. two peptide resin Phe (4-NO
2)-Aca-OCH
2The preparation of-PS
The activation of carboxyl group: get Boc-Phe (4-NO
2)-OH 1.86g (6mmol), Cl-HOBt1.02g (6mmol), HBTU 2.276g (6mmol) are dissolved among the 10mLDMF jointly, add NMM 0.67mL (6mmol) behind the CL.Hybrid reaction after three minutes with 2.2g (2mmol) Aca-OCH
2Resin mixes in the reactive polypeptide pipe.Shake 3h under the room temperature, the filtering supernatant.Resin is successively through following solvent filter wash: DMF * 3, EtOH * 2, DMF * 3, EtOH * 5, Et
2O * 2.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on the Aca is complete by acidylate, promptly Boc-Phe-OH is fully in the condensation.Above-mentioned resin was shaken 10 minutes with 150ml 50%TFA/DCM (trifluoroacetic acid/dichloromethane) is mixed in sealable reaction tubes, extract acid solution, add 150mL 50%TFA/DCM again, shook again 30 minutes.Collect acid hydrolysis solution (being used for taking off next time for the first time the Boc reaction).Resin is successively through following solvent filter wash: DCM * 5,95%EtOH * 3,10%TEA/EtOAc (triethylamine/ETHYLE ACETATE) * 2, DMF * 3, EtOH * 3, Et
2O * 2, drain weighing and obtain dipeptides Phe (4-NO
2)-Aca-OCH
2-polystyrene resin midbody 2.79g.
3. three peptide resin Pro-Phe (4-NO
2)-Aca-OCH
2The preparation of-polystyrene resin
With Boc-Pro-OH is carboxyl group, handles according to above-mentioned steps condensation and the step Boc protective condition that takes off 2. 3., obtains tripeptides Pro-Phe (4-NO
2)-Aca-OCH
2-polystyrene resin 3.01g.
4. tetrapeptide resin Fer-Pro-Phe-Aca-OCH
2The preparation of-polystyrene resin
Getting above-mentioned steps three peptide resin 1.5g 3., is carboxyl group with the FLA, handles according to above-mentioned steps condensation condition 2., obtains tetrapeptide resin intermediate 1.55g.
5. tetrapeptide resin Tyr-Pro-Phe (4-NO
2)-Aca-OCH
2The preparation of-polystyrene resin
Getting above-mentioned steps three peptide resin 1.5g 4., is carboxyl group with Boc-Tyr, handles according to above-mentioned steps condensation and deprotection condition 2., obtains tetrapeptide resin intermediate 1.54g
6. ammonia is separated the excision resin, product 6 and 7 preparation
Get 4. gained tetrapeptide resin intermediate Fer-Pro-Phe-Aca-OCH of step
2-polystyrene resin 1.55g (0.94mmol) mixes with thanomin (50mmol) and the 15ml 95%EtOH of 3ml.Room temperature is shaken reaction 50h, collects filtrating.Remaining resin mixes through 95%EtOH.Room temperature is shaken reaction 50h, collects filtrating.Remaining resin is through 95%EtOH filter wash twice, merging filtrate.Remove EtOH under reduced pressure under 50 ℃, obtain the light yellow debris of heavy-gravity.Add 200ml zero(ppm) water, place 3h.Filter collection white precipitate.Use EtOAc-nBuOH (1: 1) 200ml to mix again, in the paging funnel, extract, remove water layer, organic layer adds anhydrous sodium sulfate drying with after washing twice, concentrates evaporate to dryness, uses Et
2O grinds, and obtains product 6 heavy 559mg (theoretical value 639mg) at last, total recovery 87.5%, and ESI-MS analyzes 640.2985 (M+H).
Other gets 4. gained tetrapeptide resin intermediate Tyr-Pro-Phe (4-NO of step
2)-Aca-OCH
2-polystyrene resin 1.54g (0.94mmol) and 15ml contain 33%H
2The aqueous solution of NMe mixes in sealable reactive polypeptide pipe.Room temperature is shaken reaction 30h, collects supernatant.Remaining resin is used twice of 95%EtOH filter wash again.Merging filtrate, and under 50 ℃, remove solvent under reduced pressure.Basic except that behind the neat solvent, adding 5ml toluene and 10ml 95%EtOH remove micro-moisture again under reduced pressure.Obtain flaxen residue, through anhydrous Et
2O fully grinds, filters to collect to obtain powdered product 7 heavy 497mg (theoretical value 596mg), and total recovery 83.5%, ESI-MS analyzes 597.2984 (M+H).
Embodiment 5
Fer-Pro-Phe-β-Ala-Gol (8) and Fer-Pro-Phe-β-Ala-NHPr's (9) is synthetic
1. according to step condition 1.～4. among the embodiment 1, prepare Pro-Phe-β-Ala-OCH
2-PS tripeptide intermediate 2.5g.
2. getting above-mentioned three peptide resin 2.5g, is carboxyl group with the FLA, handles according to the condensation condition 3. of step in the foregoing description 1, obtains tetrapeptide Fer-Pro-Phe-β-Ala-OCH
2-polystyrene resin midbody 2.62g.
3. according to step method 3. among the embodiment 3, obtain title product, the result is: product 8 heavy 478mg, and yield 86.6%, ESI-MS analyzes: 553.2721 (M+H).Product 9 heavy 508mg, yield 92.5%, ESI-MS analyzes: 551.2668 (M+H).
Embodiment 6
Fer-Pro-Tyr-β-Ala-NHPr (10) and Pic-Pro-Tyr-β-Ala-NHPr's (11) is synthetic
1. according to step condition 1.～3. among the embodiment 2, prepare Pro-Tyr-β-Ala-OCH
2-PS midbody 2.8g.
2. get 1.4g above-mentioned steps tripeptide intermediate 1.,, prepare Fer-Pro-Tyr-β-Ala-OCH as carboxyl group with FLA according to step condition 4. among the embodiment 4
2-PS midbody 1.45g.
3. get 1.4g above-mentioned steps tripeptide intermediate 1.,, prepare Pic-Pro-Tyr-β-Ala-OCH as carboxyl group with pyridine-2-formic acid according to step condition 4. among the embodiment 4
2-PS midbody 1.4g.
4. ammonia is separated the excision resin, product 10 and 11 preparation
According to step method 3. among the embodiment 3, separate the result who obtains title product with propylamine ammonia and be: product 10 heavy 519mg, total recovery 91.8%, ESI-MS analyzes 567.301 (M+H).Product 11 heavy 488mg, total recovery 85.9%, ESI-MS analyzes 569.2983 (M+H).
Embodiment 7
Ida-Tyr-Pro-Tyr-β-Ala-NHMe (12) and Ida-Phe-Pro-Tyr-β-Ala-NHMe's (13) is synthetic
1. according to step condition 1.～3. among the embodiment 2, prepare Pro-Tyr-β-Ala-OCH
2-PS midbody 2.8g.
2. get 1. tripeptides resin intermediate 1.4g of above-mentioned steps, according to step condition 4. among the embodiment 2, preparation Tyr-Pro-Tyr-β-Ala-OCH
2-PS midbody 1.56g.
3. get 1. tripeptides resin intermediate 1.4g of above-mentioned steps, according to step condition 2. among the embodiment 1, preparation Phe-Pro-Tyr-β-Ala-OCH
2-PS midbody 1.54g.
4. with above-mentioned steps 2. and tripeptides resin intermediate 3. place two solid state reaction pipes respectively.Other gets Boc-Ida-OH 1.4g (6mmol), DIC 0.76g (6mmol) is dissolved among the 15mLTHF; Mix back stirring reaction after 4 hours in ice-water bath; The reaction soln of getting half volume joins step 2. in the reaction tubes of gained resin; Second half volume solution joins step 3. in the resin intermediate of gained, mixes the back and in two reaction tubess, all adds NMM0.11mL (1mmol) and 0.3ml pyridine, shakes hybrid reaction 6h under the room temperature.。Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on Tyr or the Phe is complete by acidylate.Handle (2. identical) through taking off the Boc base, obtained tetrapeptide Ida-Tyr-Pro-Tyr-β-Ala-OCH respectively with step among the embodiment 1
2-polystyrene resin midbody 1.55g and Ida-Phe-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.53g.
5. separate method excision resin according to step methylamine 6. among the embodiment 4, the result who obtains title product is: product 12 heavy 576mg, and total recovery 90.0%, ESI-MS analyzes 641.2640 (M+H).Product 13 heavy 578mg, total recovery 92.6%, ESI-MS analyzes 625.2156 (M+H).
Embodiment 8
Suc-Tyr-Pro-Tyr-β-Ala-NHMe (14) and Suc-Phe-Pro-Tyr-β-Ala-NHMe's (15) is synthetic
1. according to step condition 1.～3. among the embodiment 2, prepare Pro-Tyr-β-Ala-OCH
2-PS midbody 2.8g.
2. get 1. tetrapeptide resin intermediate 1.4g of above-mentioned steps, according to condensation and the deprotection condition 4. of step among the embodiment 2, preparation Tyr-Pro-Tyr-β-Ala-OCH
2-PS midbody 1.56g.
3. get 1. tetrapeptide resin intermediate 1.4g of above-mentioned steps, according to condensation and the deprotection condition 3. of step among the embodiment 2, preparation Phe-Pro-Tyr-β-Ala-OCH
2-PS midbody 1.54g
4. with above-mentioned steps 2. and tetrapeptide resin intermediate 3. place two solid state reaction pipes respectively.Other gets succinic anhydride 1.4g (6mmol) and is dissolved among the 15mL THF; The solution of getting half volume joins step 2. in the reaction tubes of gained resin; Second half volume solution joins step 3. in the resin intermediate of gained; Mix the back and in two reaction tubess, add NMM0.11mL (1mmol) and 0.3ml pyridine, shake hybrid reaction 6h under the room temperature.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on Tyr or the Phe is complete by acidylate.Through washing and drying treatment, obtain pentapeptide Suc-Tyr-Pro-Tyr-β-Ala-OCH respectively
2-polystyrene resin midbody 1.55g and Suc-Phe-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.53g.
5. step methylamine is 6. separated method among the embodiment 4, obtains title product, and the result is: product 14 heavy 592mg, and yield 90.7%, ESI-MS analyzes 654.3057 (M+H).Product 15 heavy 558mg, yield 91.6%, ESI-MS analyzes 610.2298 (M+H).
Embodiment 9
Compd A ca-Phe-Pro-Tyr-β-Ala-NHPr's (16) is synthetic
1. according to step condition 1.～3. among the embodiment 2, prepare Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.4g.
2. get 1. tetrapeptide resin intermediate 1.4g of above-mentioned steps, according to condensation and the deprotection condition 3. of step among the embodiment 2, preparation tetrapeptide Phe-Pro-Tyr-β-Ala-OCH
2-PS midbody 1.54g
3. pentapeptide Aca-Phe-Pro-Tyr-β-Ala-OCH
2The preparation of-polystyrene resin midbody
The activation of carboxyl group: get Boc-Aca-OH 0.693g (3mmol), Cl-HOBt 0.51g (3mmol), HBTU 1.138g (3mmol), be dissolved in jointly among the 10mL DMF, add NMM 0.44mL (4mmol) behind the CL.Hybrid reaction after three minutes with 1.54g (1mmol) tetrapeptide Phe-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody mixes in the reactive polypeptide pipe.Shake 3h under the room temperature, the filtering supernatant.Resin is successively through following solvent filter wash: DMF * 3, EtOH * 2, DMF * 3, EtOH * 5, Et
2O * 2.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on the Phe is complete by acidylate, promptly Boc-Aca-OH is fully in the condensation.Above-mentioned resin was shaken 10 minutes with 150ml 50%TFA/DCM (trifluoroacetic acid/dichloromethane) is mixed in sealable reaction tubes, extract acid solution, add 150mL 50%TFA/DCM again, shook again 30 minutes.Collect acid hydrolysis solution (being used for taking off next time for the first time the Boc reaction).Resin is successively through following solvent filter wash: DCM * 5,95%EtOH * 3,10%TEA/EtOAc (triethylamine/ETHYLE ACETATE) * 2, DMF * 3, EtOH * 3, Et
2O * 2, drain weighing and obtain pentapeptide Aca-Phe-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.65g.
4. separate method according to step propylamine 3. among the embodiment 3, obtain product 16 heavy 561mg, total recovery 86.3%, ESI-MS analyzes 651.4781 (M+H).
Embodiment 10
Compound S uc-Ser (Bzl)-Pro-Tyr-β-Ala-NHMe's (17) is synthetic
1. according to step condition 1.～3. among the embodiment 2, prepare Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.4g.
2. tetrapeptide Ser (Bzl)-Pro-Tyr-β-Ala-OCH
2The preparation of-polystyrene resin midbody
The activation of carboxyl group: get Boc-Ser (Bzl)-OH 0.885g (3mmol), Cl-HOBt0.51g (3mmol), HBTU 1.138g (3mmol), be dissolved in jointly among the 10mLDMF, add NMM 0.44mL (4mmol) behind the CL.Hybrid reaction after three minutes with 1.54g (1mmol) tetrapeptide Phe-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody mixes in the reactive polypeptide pipe.Shake 3h under the room temperature, the filtering supernatant.Resin is successively through following solvent filter wash: DMF * 3, EtOH * 2, DMF * 3, EtOH * 5, Et
2O * 2.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on the Phe is complete by acidylate, promptly Boc-Aca-OH is fully in the condensation.Above-mentioned resin was shaken 10 minutes with 150ml 50%TFA/DCM (trifluoroacetic acid/dichloromethane) is mixed in sealable reaction tubes, extract acid solution, add 150mL 50%TFA/DCM again, shook again 30 minutes.Collect acid hydrolysis solution (being used for taking off next time for the first time the Boc reaction).Resin is successively through following solvent filter wash: DCM * 5,95%EtOH * 3,10%TEA/EtOAc (triethylamine/ETHYLE ACETATE) * 2, DMF * 3, EtOH * 3, Et
2O * 2, drain weighing and obtain pentapeptide Ser (Bzl)-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.7g.
3. get succinic anhydride 0.7g (3mmol) and be dissolved among the 15mL THF, join step 2. in the resin intermediate of gained, mix the back and in two reaction tubess, add NMM 0.11mL (1mmol) and 0.3ml pyridine, shake hybrid reaction 6h under the room temperature.Get resin sample 1～2mg in small test tube, add 106 ℃ of reactions of Kaiser reagent heating 5 minutes, resin does not see that change is blue.Show that the amino on the Ser is complete by acidylate.Through washing and drying treatment, obtain Suc-Ser (Bzl)-Pro-Tyr-β-Ala-OCH
2-polystyrene resin midbody 1.7g.
4. separate method according to step methylamine 6. among the embodiment 4, obtain title product 17 heavy 582mg, total recovery 91.1%, ESI-MS analyzes 640.2591 (M+H).
Pharmacological evaluation
Experimental example 1
Biological activity test and result
(1) animal model
With 4 month female SD rats is laboratory animal, after flexibility raised for 2 weeks,
Spay (OVX) is as the model that causes OP.
(2) grouping situation, below each group be 8 rats:
OVX group-spay is not given therapeutical agent
SHAM group-sham operated rats is not given therapeutical agent
Every day is to Allan sodium phosphate 100 μ g/kg body weight after the Alen group-modeling
1/3dAlen group-each bone is rebuild second of the cycle (15d) and was given Alen in five days.
Not administration in ten days in addition, the i.e. blank 5d of damping fluid 5d/Alen5d/
Give a kind of TPT 5d after three group-modelings of TPT, gave Alen 5d on the 6th～10 day, the 11st～15 day to any therapeutical agent.
(3) administering mode of therapeutical agent and dosage
The Alen-subcutaneous injection, 5 μ g/kg body weight/d
TPT-10nmol/100g body weight/d
(4) evaluating drug effect index
The ratio of BV/TV (%) TBV/full bone volume, the high more bone amount that shows of value is many more
Tb.Th (μ m) bone trabecula width, it is good more to be worth high more curative effect
Tb.SP (μ m) bone trabecula gap, it is good more to be worth more little curative effect
Bone trabecula node in the every visual field of Tb.N, The more the better
OV/BV (%) is the osteoid volume ratio relatively, and bone is rebuild and enlivened index, and is high more effective more
OS/BS (%) is the OS ratio relatively
The ratio reflection bone of sLS/BS (%) tsiklomitsin list mark lengths and bone trabecula girth is rebuild active, shows the activation frequency on bone trabecula surface, and is high more good more
The ratio of dLS/BS (%) area of tetracycline label length and bone trabecula girth, the same sLS/BS of meaning
MS/BS (%) bone mineralising surface, the whole double-tagging faces on the unit bone surface add the summation of half list index face, and are high more good more
MAR (μ m/d) mineralising deposition is high more good more
MLT (d) the mineralization delay time, short more good more
The bone forming speed of BFR (T) (μ m/d) tissue level, numerical value is high more good more
(5) bone morphology and biomechanics of bone parametric measurement result
Table 1. bone morphology parameter
Annotate: compare with SHAM;
and OVX compare; P＜0.05 △, P＜0.01 ▲; With
The Allan group compares, P＜0.05 ☆, P＜0.01 ★; Compare P＜0.05, P＜0.01 ■ with the 110L group; With
74F organizes relatively, P＜0.05 zero, P＜0.01 ●; Compare P＜0.05 ◇, P＜0.01 with Allan ADFR ◆
Table 2. bone kinetic parameter
Note: compared with SHAM group, ☆ P <0.05, ★ P <0.01; compared with OVX group □ P <0.05, ■ P <0.01; and Allen group than △ P <0.05, ▲ P <0.01; and 1/>3 Allen group than
with 110I than ○ P <0.05,
●P＜0.01。
The digital proof of table 1 and table 2, the function that the junket dried meat peptide activation bone of the present invention's preparation is rebuild obviously is superior to positive drug Allan sodium phosphate (Alen), and this function is to real raising bone mass, control and treatment fracture highly significant.
Claims (8)
1. the junket dried meat peptide compounds shown in general formula (I):
R
1Be selected from Suc, Ida, Abu, Aca, β-Ala, Gly or des;
X
1, X
2Independently be selected from Tyr, Phe, Phe (4-NO
2), Trp, Ser (Bzl), Thr (Bzl), HO-Ph-CO, Fer, Hna, Pic, Hip, Sal;
X
3Be selected from β-Ala, Abu, Aca, Gly-Gly or des;
R
2Be selected from OH, NH
2, Gol, NH (CH
2)
mCH
3And m is selected from 0～10 integer or NH (CH
2)
nOH and n are selected from 0～10 integer.
2. according to the compound of claim 1, it is characterized in that described compound is selected from following group:
Tyr-Pro-Phe-β-Ala-NHEt
Tyr-Pro-Tyr-β-Ala-NHEt
Tyr-Pro-Tyr-β-Ala-Gol
3-Hna-Pro-Tyr-β-Ala-NHPr
Hip-Pro-Tyr-β-Ala-NHPr
Fer-Pro-Phe(4-NO
2)-Aca-Gol
Tyr-Pro-Phe(4-NO
2)-Aca-NHMe
Fer-Pro-Phe-β-Ala-Gol
Fer-Pro-Phe-β-Ala-NHPr
Fer-Pro-Tyr-β-Ala-NHPr
Pic-Pro-Tyr-β-Ala-NHPr
Ida-Tyr-Pro-Tyr-β-Ala-NHMe
Ida-Phe-Pro-Tyr-β-Ala-NHMe
Suc-Tyr-Pro-Tyr-β-Ala-NHPr
Suc-Phe-Pro-Tyr-β-Ala-NHMe
Aca-Phe-Pro-Tyr-β-Ala-NHPr
Suc-Ser(Bzl)-Pro-Tyr-β-Ala-NHMe。
3. a pharmaceutical composition is characterized in that, contains among the claim 1-2 acceptable carrier on each compound and the pharmacopedics.
4. each compound is preparing with prevention or is treating the application in the osteoporotic medicine among the claim 1-2.
5. the application of each compound in the medicine of the concurrent osteopathia of preparation and tumour among the claim 1-2.
6. according to the application of claim 5, it is characterized in that the described and concurrent osteopathia of tumour is selected from hypercalcemia, bone pain, scleromalacia or multiple myeloma.
7. the application of each compound in the medicine that preparation promotion surgery bone is transplanted, traumatic fracture heals among the claim 1-2.
8. according to each application among the claim 4-7, it is characterized in that described medicine is the continuous medicine that passes through that cooperates with bone resorption inhibitor.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016184432A1 (en) * | 2015-05-21 | 2016-11-24 | 中国医学科学院药物研究所 | Tyramine derivative compound, pharmaceutical composition thereof, and application thereof |
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|---|---|---|---|---|
| CN1551779A (en) * | 2001-07-29 | 2004-12-01 | Ү·����ϣ������ѧ��ɭķ�о���չ�� | Osteogenis oligopeptide as blood-formation stimulation articles |
| CN1737009A (en) * | 2004-08-17 | 2006-02-22 | 中国医学科学院药物研究所 | Polypeptide compound and medicinal use thereof |
| CN101153053A (en) * | 2006-09-28 | 2008-04-02 | 中国医学科学院药物研究所 | Bone-peptide, producing method, pharmaceutical composition and uses thereof |
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2010
- 2010-12-29 CN CN2010106119497A patent/CN102532261A/en active Pending
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| CN1551779A (en) * | 2001-07-29 | 2004-12-01 | Ү·����ϣ������ѧ��ɭķ�о���չ�� | Osteogenis oligopeptide as blood-formation stimulation articles |
| CN1737009A (en) * | 2004-08-17 | 2006-02-22 | 中国医学科学院药物研究所 | Polypeptide compound and medicinal use thereof |
| CN101153053A (en) * | 2006-09-28 | 2008-04-02 | 中国医学科学院药物研究所 | Bone-peptide, producing method, pharmaceutical composition and uses thereof |
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| WO2016184432A1 (en) * | 2015-05-21 | 2016-11-24 | 中国医学科学院药物研究所 | Tyramine derivative compound, pharmaceutical composition thereof, and application thereof |
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