CN102276546A - Compound used as aggrecanase modifier and application thereof - Google Patents
Compound used as aggrecanase modifier and application thereof Download PDFInfo
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- CN102276546A CN102276546A CN2011101435914A CN201110143591A CN102276546A CN 102276546 A CN102276546 A CN 102276546A CN 2011101435914 A CN2011101435914 A CN 2011101435914A CN 201110143591 A CN201110143591 A CN 201110143591A CN 102276546 A CN102276546 A CN 102276546A
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- replaces
- oxadiazole
- butyric acid
- biphenyl
- substituted formyl
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- 0 CN=C(C1(CC1)c1ccccc1)OC([C@](CCC(O)=O)NC(c(cc1)ccc1-c1ccccc1)=O)=* Chemical compound CN=C(C1(CC1)c1ccccc1)OC([C@](CCC(O)=O)NC(c(cc1)ccc1-c1ccccc1)=O)=* 0.000 description 1
Abstract
The invention discloses a 4-benzamido-4-(1,3,4-oxadiazole)-2-substituted butyric acid compound with structural feature shown as a formula (I) or a pharmaceutically acceptable salt, stereoisomer or predrug molecule thereof and application of the compound and the pharmaceutically acceptable salt or stereoisomer thereof to preparation of medicaments for treating bone and joint diseases. The medicaments consisting of the compound can be individually used for treating the bone and joint diseases and can also be combined with other related medicaments to treat the bone and joint diseases. Each group in the formula is defined in the specification in details.
Description
Technical field
The invention belongs to chemical field of medicaments, relate to particularly and have the compound of a class, and contain pharmaceutical composition and these compounds or the application of composition in the preparation medicine of this compound as the poly-enzyme conditioning agent of albumen.
Background technology:
Osteoarthritis (osteoarthritis, OA) be a kind of be the chronic joint disease of principal feature with carrying out property of joint cartilage destruction, be middle-aged and old modal joint diseases.Along with the aging of society, the morbidity of osteoarthritis raises year by year.Only be subjected to the osteoarthritis puzzlement in the U.S. with regard to 1/10th population is arranged, 80% patient has autonomic activities to a certain degree limited, and 25% patient can't take care of oneself, and causes about 60,000,000,000 dollars of direct economic loss every year.Kneed osteoarthritis morbidity is 9.56% in the population of China.The person surpasses 80% more than 70 years old.Osteoarthritis is to cause main diseases that the elderly loses self care ability therefore, has a strong impact on people's quality of life.Therefore, find that at this class disease the curative drug of new medicine target and development of new has important social and is worth and economic worth.
The pathogenesis research of osteoarthritis has become focus at present, and its main pathological characteristics is articular chondrocytes epimatrix (extracellular matrixc, degraded ECM).Joint cartilage mainly is made up of the chondrocyte who is dispersed in distribution and a large amount of matrix, and the chondrocyte only accounts for a very little part, and matrix is the essential substance basis that cartilaginous tissue is finished its unique physiologic function.Mainly being made up of II collagen type (collagen) and proteoglycan (proteoglycan) of cartilage matrix, they account for about 90% of normal cartilage dry weight.II Collagen Type VI and other collagen constitute the mesh skeleton of joint cartilage, and proteoglycan and hyaluronic acid are cross-linked with each other and form the hairbrush spline structure, and the chondrocyte is wherein buried.So its hairbrush spline structure can contain a large amount of water because proteoglycan contains a large amount of hydrophilic radicals, thereby has guaranteed that joint cartilage has good elasticity and crushing resistance, can bear the immense pressure of body weight.The outer matrix of joint cartilage always is among the running balance of synthetic and catabolism, for keeping articulation structure and function plays important effect.Early stage at bone and joint diseases, the proteoglycan degraded has destroyed the function of cartilage matrix and the integrity of structure, makes cartilage lose elasticity and anti-load performance, has finally caused the function of joint forfeiture of irreversibility.
Proteoglycan is a kind of template proteoglycan that a plurality of functional domains are arranged, and its core protein is made up of 3 spheric regions (G1, G2, G3).Each territory is all contained cysteine residues and is connected with hydrogen bond, and G1 and G2 are separated by territory between ball, and G2 and G3 have asked glycosaminoglycan (GAG) attachment region, are rich in chondroitin sulfate (CS) and keratan sulfate (KS) in the GAG attachment region.Studies show that: proteoglycan enzyme (Aggrecanase) is the major protein enzyme that participates in the proteoglycan degraded, and this degradation process mainly occurs in the early stage (pertinent literature: Tortorella MD, J Biol Chem, 2000 of osteoarthritis pathology, 275 (24), 18566-18573; Kuno K, FEBS Lett, 2000,478,241-245).Proteoglycan core protein interglobular areas territory Glu
373-Ala
374The site is the site of action of proteoglycan enzyme, and this site is the key position of proteoglycan degraded.In addition, the proteoglycan enzyme also can act on 4 sites, the i.e. Glu in CS-2 zone in the core protein enrichment region
1545-Gly
1546, Glu
1714-Gly
1715, Glu
1819-Ala
1820And Glu
1919-Leu
1920, progressively complete proteoglycan is hydrolyzed into little fragment.
The proteoglycan enzyme is the enzyme that up-to-date in recent years clone and separate goes out, belong to the properdin and metalloprotease (A Disintegrin and Metalloproteinase with Thrombospondin motifs, the ADAMTS) family member that have thrombospondin original mold body.The main two proteinoid glycanases that exist in the cartilage, i.e. aggrecanase-1 and aggrecanase-2, they all belong to the ADAMTS family member, therefore are hereinafter referred to as ADAMTS-4 and ADAMTS-5 again.
Experiment in vivo and vitro confirms: the activity of arrestin glycanase, can effectively prevent the degraded of chondroproteoglycan in the osteoarthritis process, and stop cartilage degeneration (pertinent literature: Malfait AM, J Biol Chem, 2002,277 (25), 22201～22208; Glasson SS, Nature, 2006,434 (7033), 644～648; Majumdar MK, Arthritis Rheum, 2007,56 (11), 3670～3674).Therefore, the micromolecular inhibitor of proteoglycan enzyme can delay and stop the degraded of chondroproteoglycan, can be used for osteoarthritis, rheumatic arthritis, the treatment of bone and joint diseases such as Kaschin-Beck disease.
The glutamic acid derivatives compounds of (I) constitutional features that the present invention relates to have formula.This compounds can effectively suppress aggrecanase-1 and aggrecanase-2 activity, is the novel proteoglycan enzyme inhibitors of a class.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of compound as proteoglycan enzyme conditioning agent.
The technical scheme that solves the problems of the technologies described above is as follows:
4-benzoylamino-4-(1,3, the 4-oxadiazole)-2-with formula (I) constitutional features replaces butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs:
M and n are optional to be 1,2 or 3;
Following a is 0 or 1; B is 0 or 1;
R
1Certainly optional:
3) (C=O)
aO
bAryl;
4) (C=O)
aO
bHeteroaryl;
R
2Certainly optional:
8)H；
9) halogen;
10)OH；
11) (C=O)
aO
bC
1-C
5Alkyl;
12) (C=O)
aO
bAryl;
13) O
bC
1-C
5Perfluoroalkyl;
14) (C=O)
aO
bC
3-C
6Cycloalkyl;
R
3And R
4Independent separately certainly optional:
6)H；
7) C
1-C
5Alkyl;
8) C
1-C
5Perfluoroalkyl;
9) C
3-C
6Cycloalkyl;
10) C
3-C
6Heterocyclylalkyl;
Described alkyl, aryl, cycloalkyl, Heterocyclylalkyl and heteroaryl are optional by 0,1, and 2 or 3 are selected from R
5Substituting group replaces;
R
5Be selected from:
1)H；
2) C
3-C
6Cycloalkyl;
3) heterocyclic radical;
4) C
1-C
3Alkyl;
5) C
1-C
3Contain fluoroalkyl;
6) C
0-C
3The alkylidenyl-heterocyclic base.
Preferably, described R
1Certainly optional:
3) aryl;
4) heteroaryl.
Preferably, described R
2Certainly optional:
7)H；
8)F，Cl，Br；
9)OH，OCH
3，OEt，OCF
3；
10) methyl, ethyl, sec.-propyl, the tertiary butyl;
11) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
12)CF
3。
Preferably, described R
3Or R
4Certainly optional:
6)H；
7) methyl, hexyl;
8)CF
3；
9) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
10) C
3-C
6Heterocyclylalkyl.
Another object of the present invention provides the application of above-claimed cpd.
The technical scheme that realizes above-mentioned purpose is as follows:
Above-mentioned 4-benzoylamino-4-(1,3,4-oxadiazole)-2-replaces the application of conditioning agent in the medicine of preparation treatment bone and joint diseases as proteoglycan enzyme-1 (aggrecanase-1) or proteoglycan enzyme-2 (aggrecanase-2) of butyric acid compounds and pharmacy acceptable salt thereof or steric isomer or its prodrugs.
Another object of the present invention provides a kind of pharmaceutical composition for the treatment of bone and joint diseases.
The technical scheme that realizes above-mentioned purpose is as follows:
A kind of pharmaceutical composition for the treatment of bone and joint diseases, its main active ingredient are to replace butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs by above-mentioned 4-benzoylamino-4-(1,3, the 4-oxadiazole)-2-.
The described 4-benzoylamino-4-(1 that goes up of the application, 3, the 4-oxadiazole)-2-replaces butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs and can be used for osteoarthritis, rheumatic arthritis, the treatment of bone and joint diseases such as Kaschin-Beck disease.The application also related to independent use or with analgesic agent present application or that just locating the development phase; non-steroidal anti-inflammatory drugs, adrenocortical hormone, Chondroprotective agents; the heavy absorption agent of bone, medication combined medication such as matrix metallo-proteinase inhibitor increases its clinical effectiveness.
4-benzoylamino-the 4-(1 that the present invention relates to, 3, the 4-oxadiazole)-2-replacement butyric acid compounds and pharmacy acceptable salt thereof, the activity that can effectively suppress two proteinoid glycanases, prevent the degraded of chondroproteoglycan in the osteoarthritis process, stop cartilage degeneration, can be used for osteoarthritis, rheumatic arthritis, Kaschin-Beck disease or the like joint cartilage integrity is impaired and cause one group of treatment of diseases of relevant sings and symptoms.
Embodiment
In the compound of the present invention, as any variable (R for example
1, R
2Deng) in any component, occur surpassing once, then its each definition that occurs is independent of other each definition that occurs.Equally, allow the combination of substituting group and variable, as long as this combination makes compound stable.The line that puts loop systems from substituting group under represents that the key of indication can be connected on any annular atoms that can replace.If loop systems is many rings, it means that this key only is connected on any suitable carbon atom of adjacent loops.Be appreciated that those of ordinary skills can select the substituting group and the replacement form of The compounds of this invention, thereby provide chemically stable, and can be by the method for art technology and following proposition, raw material that self-control obtains easily and easy synthetic compound.Replace if substituting group self is exceeded a group, should understand these groups can be on the identical carbon atoms or on the different carbon atom, as long as make Stability Analysis of Structures.Phrase " is chosen wantonly and is replaced by one or more substituting groups " and is considered to " choose wantonly and replaced by at least one substituting group " quite with phrase, and embodiment preferred will have 0-3 substituting group in the case.
Term used herein " alkyl " and " alkylidene group " mean and comprise saturated fatty alkyl side chain and straight chain with particular carbon atom number.For example, " C
1-C
5Alkyl " in " C
1-C
5" definition comprise the group of arranging with straight or branched with 1,2,3,4 or 5 carbon atom.For example, " C
1-C
5Alkyl " specifically comprise methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, amyl group.Term " C
3-C
6Cycloalkyl " refer to have the monocycle saturated fatty alkyl of particular carbon atom number.For example, " C
3-C
6Cycloalkyl " comprise cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl etc.
6 atom bicyclic carbocyclic nearly in the stable monocycle of 6 atoms or each ring nearly in term used herein " heteroaryl " the representative ring, wherein at least one ring is for aromatic nucleus and contain 1-4 heteroatoms that is selected from O, N and S.Heteroaryl in this range of definition includes but not limited to: imidazolyl, triazolyl, pyrazolyl, base, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidyl, the pyrryl of muttering of barking.For the definition of following heteroaryl, " heteroaryl " also is interpreted as and comprises any N-oxide derivative that contains the heteroaryl of nitrogen.The heteroaryl substituting group be dicyclo and to contain a ring be non-aromaticity or do not contain in the heteroatomic example, should understand the aromatic nucleus or connect of respectively hanging oneself through containing heteroatomic ring.
Used herein term " heterocycle " or " heterocyclic radical " are meant and contain 1-4 heteroatomic 5 yuan of-6 yuan of aromaticity or non-aromaticity heterocycle that is selected from O, N and S, and comprise bicyclic radicals." heterocyclic radical " therefore comprises the heteroaryl that picture is mentioned, also comprises its dihydro and tetrahydro-analogue." heterocyclic radical " further example includes but not limited to: imidazolyl, indazolyl, isothiazolyl isoxazolyl oxadiazole base oxazolyl, oxetanyl (oxetanyl), pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidyl, pyrryl quinoxalinyl, tetrazyl, thiadiazolyl group, thiazolyl, thienyl, triazolyl, 1, the 4-alkyl dioxin, pyrrolidyl, the glyoxalidine base, the dihydro-isoxazole base, dihydro isothiazolyl Er Qing oxadiazole base dihydro-oxazole base, the dihydro pyrazinyl, the pyrazoline base, the dihydropyridine base, the dihydro-pyrimidin base, the pyrrolin base, the dihydro tetrazyl, the thiodiazoline base, dihydro-thiazolyl, the dihydro-thiophene base, the dihydro triazolyl, the dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl, and N-oxide compound.The connection of heterocyclic substituent can realize by carbon atom or by heteroatoms.
In one embodiment, heterocycle is selected from imidazolyl, pyridyl, 1-pyrrolidone, 2-piperidone, 2-pyrimidone, 2-Pyrrolidone, thienyl, oxazolyl, triazol radical, isoxazolyl.
As understood by one of ordinary skill in the art, used herein " halogen " (" halo ") or " halogen " mean and comprise chlorine, fluorine, bromine and iodine.
Unless otherwise defined, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic radical substituting group can be unsubstituted or replacement.For example, (C
1-C
6) alkyl can by one, two or three be selected from OH, halogen, alkoxyl group, dialkyl amido or heterocyclic radical for example the substituting group of morpholinyl, piperidyl etc. replace.
In some example, definition " heterocyclic radical " makes it form 4-7 unit's monocycle jointly with the nitrogen that is connected them or each ring is the bicyclic heterocycle of 4-7 unit, and optional containing denitrogenates outer one or two and is selected from the other heteroatoms of N, O and S, and described heterocycle is optional to be replaced by one or more substituting groups that are selected from R.The heterocyclic example that can so form includes but not limited to following heterocycle, must keep the optional substituting group that is selected from R by one or more (and preferred, two or three) of heterocycle firmly in mind and replace:
The present invention includes the free form of formula I compound, also comprise its pharmacy acceptable salt and steric isomer.Some specific exemplary compounds are the compound of free form herein.In addition, can be by the conventional chemical method from the synthetic pharmacy acceptable salt of the present invention of the The compounds of this invention that contains acidic moiety.Usually, by with the salt of suitable inorganic or organic bases prepared in reaction acidic cpd.Similarly, by in the combination of appropriate solvent or multiple solvent, reacting the salt of basic cpd with suitable inorganic or organic acid.
Therefore, the pharmacy acceptable salt of The compounds of this invention comprises by acid The compounds of this invention and conventional the non-toxic salt inorganic or The compounds of this invention that the organic bases reaction forms.For example, Chang Gui non-toxic salt comprises that the salt that derives from mineral alkali comprises aluminium salt, ammonium salt, calcium salt, mantoquita, molysite, ferrous salt, lithium salts, magnesium salts, manganese salt, manganous salt, sylvite, sodium salt, zinc salt etc.Preferred especially ammonium salt, calcium salt, magnesium salts, sylvite and sodium salt.Derive from the salt of pharmaceutically acceptable organic nontoxic alkali, described alkali comprises primary amine, the salt of secondary amine and tertiary amine, the amine that replaces comprises naturally occurring replacement amine, cyclic amine and deacidite be arginine for example, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, 2 one DEAE diethylaminoethanols, 2 one dimethylaminoethanols, monoethanolamine, thanomin, quadrol, N one ethyl morpholine, N one ethyl piperidine, glucosamine, glucosamine, Histidine, hydroxocobalamin, isopropylamine, Methionin, methyl glucoside amine, morpholine, piperazine, piperidines, the croak smack one's lips, the polyamines resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, tromethane etc.
If The compounds of this invention is an alkalescence, the pharmacy acceptable salt of invention compound comprises by alkaline The compounds of this invention and conventional the non-toxic salt inorganic or The compounds of this invention that organic acid reaction forms.For example, conventional non-toxic salt comprises and derives from for example salt of hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc. of mineral acid, also comprise from organic acid for example acetate, propionic acid, succsinic acid, oxyacetic acid, stearic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, pounce on the salt of preparations such as acid, toxilic acid, hydroxymaleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2 one acetoxyl groups, one phenylformic acid, fumaric acid, toluenesulphonic acids, methylsulfonic acid, ethane disulfonic acid, oxalic acid, hydroxyethylsulfonic acid, trifluoroacetic acid.
Berg etc., " Pharmaceutical Salts " J.Pharm.Sci.1977:66:1-19 more detailed description the preparation of pharmacy acceptable salt mentioned above and other typical pharmacy acceptable salt.
Since under physiological condition in the compound acidic moiety of deprotonation for example carboxyl can be anionic, and this electric charge that has can be had for example former quantum balancing counteracting of quaternary nitrogen of cationic protonated or alkylating basic moiety by inside then, is potential inner salt or zwitter-ion so should note The compounds of this invention.
Except that standard method known or illustration in experimental arrangement in the literature, also can adopt prepared in reaction The compounds of this invention as showing in the following scheme.Therefore, following illustrative approach is for illustrative purposes rather than is confined to listed compound or any specific substituting group.The substituting group number that shows in the scheme must not meet number used in the claim, and for clarity sake, shows that single substituting group is connected under the definition of formula I hereinbefore to allow on the compound of multi-substituent.
Scheme
As shown in option A among the I compound can be that starting raw material passes through 5 step reactions by Boc-Glu (ochx)-OH synthetic.
Option A
In one embodiment, the application's compound and pharmacologically acceptable salts thereof of providing a kind of utilization to have formula I can be used for treating people or other mammiferous bone and joint diseases.
In one embodiment, designed compound and the pharmacologically acceptable salts thereof of the application can be used for the treatment of or control osteoarthrosis relative diseases such as osteoarthritis, rheumatic arthritis, Kaschin-Beck disease.
In one embodiment; compound that the application is designed and pharmacologically acceptable salts thereof can with analgesic agent present application or that just locating the development phase; non-steroidal anti-inflammatory drugs; adrenocortical hormone; Chondroprotective agents; the heavy absorption agent of bone, medication combined medication such as matrix metallo-proteinase inhibitor increases its clinical effectiveness.
Take mode and dosage range
According to the standard pharmaceutical technology, The compounds of this invention can give Mammals, preferred people with pharmaceutically acceptable acceptor, auxiliary material or thinner combination separately or in medicinal compositions.Can be oral or subcutaneous, intramuscular injection, intraperitoneal, vein, rectum and part, eyes, lung, nasal cavity, parenteral give compound.
In one embodiment, when utilizing formula I compounds for treating or patient such as control cancer etc., the taking dose scope is in oral 0.1～500 mg/day/kg body weight.Suitable administering mode is a single dose administration or every day secondary, three times, four inferior multiple dosings or utilize slow release method administration every day.For multiple large mammal, its preferred dosage scope is 0.1～1500 mg/day/kg body weight, is preferable over 0.5～100 mg/day/kg body weight.For mean body weight is 70 kilograms patient, and its, dosage was 1～500 milligram every day.For some special high-activity compounds, adult patient's dosage every day can hang down and reach 0.1 mg/day.
Formulation
This medicinal compositions that contains activeconstituents can be made into and is suitable for the oral administration form, but for example tablet, lozenge, lozenge, water or oil suspension dispersion powder or granule, emulsion, hard capsule or soft capsule or syrup or elixir.Can be according to the composition of any currently known methods preparation expection orally give in the medicinal compositions manufacturing field, and for pharmaceutically purified and agreeable to the taste preparation are provided, this composition can contain one or more medicaments that is selected from sweeting agent, seasonings, tinting material and sanitas.Tablet contains activeconstituents and the nontoxic acceptable accessories that is applicable to the manufacturing tablet.These auxiliary materials for example can be, and inert diluent is lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate for example; Granulation agent (granulating) and disintegrating agent be Microcrystalline Cellulose, cross-linked carboxymethyl cellulose sodium (sodium crosscarmellose), W-Gum or Lalgine for example; Tackiness agent is starch, gelatin, polyvinylpyrrolidone or gum arabic for example; Reach lubricant for example Magnesium Stearate, stearic acid or talcum powder.Thereby tablet is dressing or cover the undesirable taste of medicine or prolong in gi tract disintegration and absorption and thereby provide the drug effect of last much longer by the known technology dressing not.For example, the raw material that can adopt water-soluble taste masking is hydroxypropyl-methylcellulose gum or hydroxypropylcellulose for example, or adopts time-delay raw material for example ethyl cellulose, cellulose acetate butyrate.Tabules can be 0.1 milligram/sheet, 0.2 milligram/sheet, 0.25 milligram/sheet, 0.5 milligram/sheet, and 1 milligram/sheet, 2 milligrams/sheet, 5 milligrams/sheet, 10 milligrams/sheet, 25 milligrams/sheet, 50 milligrams/sheet, 100 milligrams/sheet, 250 milligrams/sheet of and.Other formulation such as capsule etc. can be done similar dosage reference.
The preparation that orally uses also can be made into hard-gelatin capsules, and wherein activeconstituents is mixed in inert solid diluent, for example in lime carbonate, calcium phosphate or the white bole; Or make Gelseal, wherein activeconstituents is mixed in water-soluble carrier for example in macrogol or oil medium such as peanut oil, whiteruss or the sweet oil.
Aqueous suspension contains and the auxiliary material blended active material that is suitable for making aqueous suspension.This auxiliary material is for example Xylo-Mucine, methylcellulose gum, Vltra tears, sodium alginate, polyvinylpyrrolidone, tragakanta and a gum arabic of suspending agent; Dispersion agent or wetting agent can be for example Yelkin TTS of naturally occurring phosphatide, or the condensation product of alkylene oxide and lipid acid polyoxyethylene stearic acid ester for example, or the condensation product of alkylene oxide and long chain aliphatic alcohol 17 carbon vinyloxy group hexadecanols (heptadecaethyleneoxycetanol) for example, or alkylene oxide and derive from lipid acid and the condensation product of the partial ester of hexitol polyoxyethylene sorbitol monooleate for example, or alkylene oxide and derive from lipid acid and the condensation product of the partial ester of hexitan polyethylene dehydrated sorbitol mono-fatty acid ester for example.This aqueous suspension also can contain one or more sanitass for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl ester, one or more tinting materials, and one or more seasoningss and one or more sweeting agents be sucrose, asccharin or aspartame for example.
Can be by activeconstituents being suspended in vegetables oil for example in peanut oil, sweet oil, sesame oil or the Oleum Cocois, or mineral oil for example prepares oil-based suspension in the whiteruss.This oil-based suspension can contain thickening material for example beeswax, solid paraffin or hexadecanol.Can add sweeting agent mentioned above and seasonings and be fit to oral preparation to provide.Can for example Butylated Hydroxyanisole (butylated hydroxyanisol) or alpha-tocopherol store these compositions by adding antioxidant.
But dispersion powder or granule are suitable for preparing aqueous suspension and providing and dispersion agent or wetting agent, suspending agent and one or more sanitas blended activeconstituentss by adding entry.Suitable dispersion agent or wetting agent and suspending agent be the example explanation by above relating to.Also can there be other auxiliary materials for example sweeting agent, seasonings and tinting material.These compositions can by add antioxidant for example xitix store.
The present composition also can be made into the form of water external emulsion.Oil phase can be vegetables oil for example sweet oil or peanut oil, or mineral oil for example whiteruss or its mixture.Suitable emulsifying agent can be for example soybean lecithin of naturally occurring phosphatide, reach the ester class or derive from lipid acid and the partial ester of hexitan mixture, the condensation product of for example sorbitan monooleate, and described partial ester and alkylene oxide is the polyoxyethylene sorbitan monooleate for example.This emulsion also can contain sweeting agent, seasonings, sanitas and antioxidant.
For example glycerine, propylene glycol, sorbyl alcohol or sucrose prepare syrup and elixir can to use sweeting agent.This preparation also can contain wetting agent, sanitas, seasonings and tinting material and antioxidant.
Medicinal compositions can be made into the aqueous solution of sterile injectable.In acceptable carrier and solvent, can adopt water, ringer's solution and isotonic sodium chlorrde solution.
This sterile injectable preparation also can be made into activeconstituents and is dissolved in sterile injectable oil-in-water microemulsion in the oil phase.For example, at first activeconstituents is dissolved in the mixture of soya-bean oil and Yelkin TTS, then oil solution is put into the mixture of water and glycerine and handled and make microemulsion.
This injectable solution or microemulsion can pass through local bolus injection (local bolus injection) and import in patient's blood flow.Selectable, in this way give the constant circulation concentration that solution or micro emulsion help keeping compound.For keeping this constant density, can utilize the continuous intravenous injection delivery apparatus.An embodiment of this device is DeltecCADD-PLUS
TMModel 5400 intravenous injection pumps.
This medicinal compositions can be made into sterile injectable solution or the oily suspension form that is used for intramuscular or subcutaneous administration.Can use the dispersion agent above mention or wetting agent and suspending agent to prepare this suspension according to known technology.Sterile injectable preparation also can be made into sterile injectable solution or the suspension in nontoxic parenteral acceptable diluent or solvent, for example as the solution in 1,3 butylene glycol.In addition, the conventional fixed oil that adopts is as solvent or suspension medium.For this purpose, can adopt any non-irritating fixed oil to comprise synthetic monoglyceride or triglyceride.In addition, find in injectable formulation, to use for example oleic acid of lipid acid.
Formula I compound also can rectal administration the suppository form administration.Can prepare these compositions by hybrid medicine and suitable nonirritant auxiliary material, thus its be at normal temperatures solid but under rectal temperature for liquid and therefore in rectum fusing discharge medicine.This raw material comprises the mixture and the cithrol of theobroma oil, glycogelatin, hydrogenant vegetables oil, various molecular weight polyisoprene ethylene glycol.
Use for the part, adopt emulsifiable paste, ointment, gelifying agent, solution or the suspension etc. (be this application purpose, topical application comprises mouth wass and mouth wash shua) that contain formula I～II compound.
The compounds of this invention can be in suitable nose the part of carrier and delivery apparatus use with nose in form administration, or use the form administration of the skin patch that those of ordinary skills know through skin.After the administration of transdermal delivery system form, the dosage of whole dosage regimen is naturally than intermittently administration is continuous.The compounds of this invention also can be sent by suppository, and the matrix of employing is the mixture and the cithrol of theobroma oil, glycogelatin, hydrogenant vegetables oil, various molecular weight polyisoprene ethylene glycol for example.
If give the experimenter The compounds of this invention, normally by the doctor that prescribes usually according to each patient's age, body weight, sex and reaction, and the corresponding change dosage of patient's serious symptom and determine per daily dose.
Drug metabolite and prodrug
The compound that the application is related and the meta-bolites of pharmacologically acceptable salts thereof, and the prodrug that can change the structure of related compound of the application and pharmacologically acceptable salts thereof in vivo into are also contained in the application's the claim.
Drug combination
Formula I compound can or improve the other medicines coupling of similar symptom to known treatment.During Combined Preparation, the original Gei Yaofangshi ﹠amp of medicine; Dosage remains unchanged, and simultaneously or take formula I compound subsequently.When formula I compound and other one or more medicines were taken simultaneously, preferred use contained the medicinal compositions of one or more known drugs and formula I compound simultaneously.Drug combination is also included within the eclipsed time period and takes formula I compound and other one or more known drugs.When formula I compound and other one or more medicines carried out drug combination, the dosage the when dosage of formula I compound or known drug may be than their independent medications was lower.
Can carry out the medicine of drug combination or activeconstituents with formula I compound comprises but is not limited to:
Analgesic agent, non-steroidal anti-inflammatory drugs, adrenocortical hormone, Chondroprotective agents, the heavy absorption agent of bone, matrix metallo-proteinase inhibitor etc.
In one embodiment, can carry out the medicine of drug combination or activeconstituents with formula I compound comprises but is not limited to: hyaluronate sodium, glucosamine, Ibuprofen BP/EP, the U.S. zinc of ammonia sugar, nimesulide, paracetamol, acetylsalicylic acid, Sulindac, excellent appropriate, Nuo Delun, celecoxib, ten thousand networks, protect pine, Limethason, Cyclomycin family antibiotic (as Vibravenos), glucosaminoglycan, Ado-Met, ethyl phosphine hydrochlorate, clodronate salt, pamldronate, Alendronate etc. or their combination.
The present invention will be further described for following examples, but this embodiment is used to limit protection scope of the present invention.
Embodiment 1
(S)-4-(5-benzyl-1,3,4-oxadiazole-2-replaces)-4-biphenyl-4-substituted formyl amido butyric acid
(S)-4-(5-beasyl-1，3，4-oxadiasol-2-yl)-4-bipbeayl-4-ylcarboxamidobutanoicacid(PLJ-1)
Under 0 ℃ of condition, at Boc-L-L-glutamic acid ' CH of Y-cyclohexyl B (1.0eq)
2Cl
2Add benzyl hydrazides A (1.0eq) in the solution, HATU (1.1eq), DIPEA (2.0eq), room temperature condition stirs 24h down then, and reaction solution is used saturated NaHCO successively
3, 5% citric acid and H
2O washing, organic phase anhydrous Na afterwards
2SO
4Drying is filtered the back and is concentrated, and gets Compound C through column chromatography.Under 0 ℃ of condition, to Compound C (1.0eq) and Et
3N (2.5eq) is at CH
2Cl
2Solution in add Ph simultaneously
3P (2.0eq) and CBr
4(2.0eq), mixture stirs 1h after rising to room temperature.Reaction solution is used saturated NaHCO successively
3, and H
2O washing, organic phase anhydrous Na afterwards
2SO
4Drying is filtered the back and is concentrated, through column chromatography De oxadiazole D.Compound D is at CH
2Cl
2Solution dropwise dripped TFA, concentrate after stirring 2h then under the room temperature, residue is dissolved among the EtOAc, uses saturated NaHCO successively
3, and H
2O washing, organic phase anhydrous Na afterwards
2SO
4Drying is filtered the back and is concentrated.Residue is dissolved in CH
2Cl
2In, add biphenyl carboxylic acids (0.9eq) under 0 ℃ of condition, EDCI (1.0eq), HOBT (1.0eq), Et
3N (2.0eq).Reaction solution at room temperature stirs 16h then, uses saturated NaHCO afterwards successively
3, 5% citric acid and H
2The O washing, the organic phase anhydrous Na
2SO
4Drying is filtered the back and is concentrated, and gets intermediate B through column chromatography.THF/MeOH/H at B
2Add LiOH (3.0eq) in O (1: 1: the 1) solution, behind the stirring 5h, steam and remove MeOH and THF under the room temperature, resistates is transferred pH=2 with concentrated hydrochloric acid, separates out the solid after-filtration, drying, recrystallization (CH
2Cl
2/ MeOH) must target product TM.
1H?NMR(400MHz，)δ10.92(s，1H)，8.01(d，J＝8.0Hz，2H)，7.77-7.20(m，4H)，7.49(t，J＝7.6Hz，2H)，7.41(t，J＝7.2Hz，1H)，7.34-7.27(m，5H)，5.17-5.13(m，1H)，4.25(s，2H)，2.21-2.14(m，2H)，2.14-2.06(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
26H
23N
3O
4[M+H]
+，442.1761，found?442.1759.
Embodiment 2
(S)-4-biphenyl-4-substituted formyl amido-4-(5-styroyl-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-phenethyl-1，3，4-oxadiazol-2-y1)butanoic?acid(PLJ-2)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.22(s，1H)，9.09(d，J＝8.0Hz，1H)，7.99(d，J＝8.4Hz，2H)，7.80(d，J＝8.0Hz，2H)，7.74(d，J＝7.6Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.42(t，J＝7.6Hz，1H)，7.25-7.15(m，5H)，5.39-5.33(m，1H)，3.16(t，J＝7.2Hz，2H)，3.01(t，J＝7.2Hz，2H)，2.39(t，J＝7.2Hz，2H)，2.31-2.15(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
27H
25N
3O
4[M+H]
+，456.1918，found?456.1912.
Embodiment 3
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3-hydrocinnamyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(3-phenylpropyl)-1，3，4-oxadiazol-2-y1)butanoic?acid(PLJ-3)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.22(s，1H)，9.15(d，J＝7.6Hz，1H)，7.99(d，J＝8.0Hz，2H)，7.98(d，J＝8.4Hz，2H)，7.43(d，J＝7.2Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.41(t，J＝7.6Hz，1H)，7.25(t，J＝7.2Hz，1H)，7.19-7.15(t，3H)，5.38-5.32(m，1H)，2.83(t，J＝7.6Hz，2H)，2.63(t，J＝7.6Hz，2H)，2.41(t，J＝7.2Hz，2H)，2.32-2.25(m，1H)，2.23-2.14(m，1H)，2.01-1.93(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
28H
27N
3O
4[M+H]
+，470.2074，found?470.2074.
Embodiment 4
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-luorobenzyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-fluorobenzyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-4)
Synthetic method such as embodiment 1.
HRMS(ESI)：Exact?mass?calcd?for?C
26H
22FN
3O
4[M+H]
+，460.1667，found?460.1664.
Embodiment 5
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-methoxy-benzyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-methoxybeasyl)-1，3，4-oxadiazol-2-yl)butanoic?acid?(PLJ-5)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ10.23(s，1H)，7.99(d，J＝8.0Hz，2H)，7.98-7.72(m，4H)，7.49(t，J＝7.2Hz，2H)，7.41(t，J＝7.2Hz，1H)，7.20(t，J＝8.4Hz，2H)，6.87(t，J＝8.4Hz，2H)，5.23-5.19(m，1H)，4.16(s，2H)，3.71(s，3H)，2.26(t，2H)，2.20-2.10(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
27H
25N
3O
5[M+H]
+，472.1867，found?472.1857.
Embodiment 6
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3,4,5-trimethoxy benzyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(3，4，5-trimethoxybeasyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-6)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ9.32(s，1H)，7.96(d，J＝8.4Hz，2H)，7.78(d，J＝8.4Hz，2H)，7.73(d，J＝7.6Hz，2H)，7.50(t，J＝7.2Hz，2H)，7.42(t，J＝7.2Hz，1H)，6.58(s，2H)，5.36-5.30(m，1H)，4.19(s，2H)，3.68(s，6H)，3，60(s，3H)，2.39(t，J＝7.2Hz，2H)，2.32-2.14(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
29H
29N
3O
7[M+H]
+，532.2078，found?532.2068.
Embodiment 7
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3,4,5-trimethoxy styroyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(3，4，5-trimethoxyphenethyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-7)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.15(s，1H)，9.13(d，J＝7.6Hz，1H)，7.99(d，J＝8.0Hz，2H)，7.80(d，J＝8.0Hz，2H)，7.74(d，J＝7.6Hz，2H)，7.50(t，J＝7.2Hz，2H)，7.41(t，J＝7.2Hz，1H)，6.54(s，2H)，5.40-5.34(m，1H)，3.71(s，6H)，3，60(s，3H)，3.16(t，J＝7.6Hz，2H)，2.94(t，J＝7.6Hz，2H)，2.41(t，J＝6.8Hz，2H)，2.32-2.16(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
30H
31N
3O
7[M+H]
+，546.2235，found?546.2234.
Embodiment 8
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-methylbenzene ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-methylphenethyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-8)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ10.39(s，1H)，8.03(d，J＝7.6Hz，2H)，7.77(d，J＝7.6Hz，2H)，7.73(d，J＝7.6Hz，2H)，7.49(t，J＝7.2Hz，2H)，7.40(t，J＝7.2Hz，1H)，7.07(d，J＝7.2Hz，2H)，7.01(d，J＝7.2Hz，2H)，5.23-5.19(m，1H)，3.10(t，J＝6.8Hz，2H)，2.94(t，J＝6.8Hz，2H)，2.24(s，2H)，2.21(s，3H)，2.16-2.08(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
28H
27N
3O
4[M+H]
+，470.2074，found?470.2076.
Embodiment 9
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-fluorobenzene ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-fluorophenethyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-9)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ9.73(s，1H)，8.01(d，J＝8.4Hz，2H)，7.79(d，J＝8.4Hz，2H)，7.73(d，J＝7.2Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.41(t，J＝7.2Hz，1H)，7.27-7.24(m，2H)，7.03(t，J＝8.8Hz，2H)，5.31-5.26(m，1H)，3.14(t，J＝7.2Hz，2H)，2.99(t，J＝7.2Hz，2H)，2.32(t，2H)，2.25-2.10(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
27H
24FN
3O
4[M+H]
+，474.1824，found?474.1831.
Embodiment 10
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-anisole ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-methoxyphenethyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-10)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ9.16(s，1H)，8.00(d，J＝8.4Hz，2H)，7.80(d，J＝8.4Hz，2H)，7.74(d，J＝7.6Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.42(t，J＝7.6Hz，1H)，7.12(d，J＝8.4Hz，2H)，6.76(d，J＝8.4Hz，2H)，5.38-5.32(m，1H)，3.67(s，3H)，3.11(t，J＝7.6Hz，2H)，2.94(t，J＝7.6Hz，2H)，2.38(t，J＝7.2Hz，2H)，2.30-2.14(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
28H
27N
3O
5[M+H]
+，486.2023，found?486.2027.
Embodiment 11
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-methyl isophthalic acid-phenyl third-2-replacement)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(2-methyl-1-phenylpropan-2-yl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-11)
Synthetic method such as embodiment 1.
HRMS(ESI)：Exact?mass?calcd?for?C
29H
29N
3O
4[M+H]
+，484.2231，found?484.2225.
Embodiment 12
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-methyl-2-hydrocinnamyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(2-methyl-2-phenylpropyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-12)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.19(s，1H)，8.98(d，J＝7.6Hz，1H)，7.96(d，J＝8.0Hz，2H)，7.80(d，J＝8.0Hz，2H)，7.55(d，J＝7.6Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.41(t，J＝7.2Hz，1H)，7.34(d，J＝7.6Hz，2H)，7.22(t，J＝7.6Hz，2H)，7.10(t，J＝7.2Hz，1H)，5.27-5.22(m，1H)，3.16(s，2H)，2.32(t，J＝7.2Hz，2H)，2.16-2.06(m，2H)，1.38(s，6H)；
HRMS(ESI)：Exact?mass?calcd?for?C
29H
29N
3O
4[M+H]
+，484.2231，found?484.2236.
Embodiment 13
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-(3,4, the 5-trimethoxyphenyl) propane-2-replaces)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(2-(3，4，5-trimethoxyphenyl)propan-2-yl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-13)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ9.50(s，1H)，7.93(d，J＝8.4Hz，2H)，7.76(d，J＝8.4Hz，2H)，7.72(d，J＝7.6Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.41(t，J＝7.2Hz，1H)，6.42(s，2H)，5.29-5.23(m，1H)，3.69(s，6H)，3.59(s，3H)，2.36(t，J＝6.8Hz，2H)，2.27-2.11(m，2H)，1.38(s，6H)，1.71(d，J＝2.0Hz，6H)；
HRMS(ESI)：Exact?mass?calcd?for?C
31H
33N
3O
7[M+H]
+，560.2391，found?560.2390.
Embodiment 14
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-phenyl third-2-replacement)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(2-phenylpropan-2-yl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-14)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.14(s，1H)，9.06(d，J＝8.0Hz，1H)，7.92(d，J＝8.4Hz，2H)，7.78(d，J＝8.4Hz，2H)，7.73(d，J＝7.2Hz，2H)，7.50(t，J＝7.6Hz，2H)，7.41(t，J＝7.2Hz，1H)，7.32(t，J＝7.2Hz，1H)，7.26-7.22(m，3H)，5.34-5.29(m，1H)，2.40(t，J＝7.2Hz，2H)，2.30-2.11(m，2H)，1.72(s，6H)；
HRMS(ESI)：Exact?mass?calcd?for?C
28H
27N
3O
4[M+H]
+，470.2074，found?470.2076.
Embodiment 15
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(1-phenycyclopropyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(1-phenylcyclopropyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-15)
Synthetic method such as embodiment 1.
1H?NMR(500MHz，DMSO-d
6)δ12.20(s，1H)，9.09(d，J＝6.5Hz，1H)，7.94(d，J＝7.5Hz，2H)，7.79(d，J＝7.5Hz，2H)，7.74(d，J＝7.0Hz，2H)，7.50(t，J＝7.0Hz，2H)，7.42(t，J＝7.0Hz，1H)，7.34-7.28(m，5H)，5.32-5.27(m，1H)，2.40(t，2H)，2.27-2.23(m，1H)，2.18-2.12(m，1H)，1.58(br，2H)，1.46(br，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
28H
25N
3O
4[M+H]
+，468.1918，found?468.1925.
Embodiment 16
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3,5-dimethyl benzene ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(3，5-dimethylphenethyl)-1，3，4-oxadiazol-2-y1)butanoic?acid(PLJ-16)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.39(s，1H)，9.30(d，J＝6.0Hz，1H)，8.00(d，J＝8.0Hz，2H)，7.79(d，J＝8.0Hz，2H)，7.74(d，J＝7.2Hz，2H)，7.50(t，J＝7.2Hz，2H)，7.41(t，J＝7.2Hz，1H)，6.80(s，3H)，5.36-5.31(m，1H)，3.11(t，J＝7.2Hz，2H)，2.92(t，J＝7.2Hz，2H)，2.37(t，J＝6.8Hz，2H)，2.25-2.18(m，8H)；
HRMS(ESI)：Exact?mass?calcd?for?C
29H
29N
3O
4[M+H]
+，484.2231，found?484.2232.
Embodiment 17
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-leptodactyline)-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-hydroxyphenethyl)-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-17)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.21(s，1H)，9.18(s，1H)，9.08(d，J＝7.6Hz，1H)，7.99(d，J＝7.6Hz，2H)，7.80(d，J＝7.2Hz，2H)，7.74(d，J＝6.8Hz，2H)，7.52-7.37(m，3H)，6.99(d，J＝7.6Hz，2H)，6.62(t，J＝7.6Hz，2H)，5.39-5.34(m，1H)，3.07(t，J＝6.8Hz，2H)，2.88(t，J＝6.8Hz，2H)，2.40(t，J＝6.0Hz，2H)，2.31-2.15(m，2H)；HRMS(ESI)：Exact?mass?calcd?for?C
27H
25N
3O
5[M+H]
+，472.1867，found?472.1860.
Embodiment 18
(S)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces)-4-(4-(pyridine-3-replaces) benzamide) butyric acid
(S)-4-(5-phenethyl-1，3，4-oxadiazol-2-yl)-4-(4-(pyridin-3-yl)benzamido)butanoicacid(PLJ-18)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.21(s，1H)，9.13(d，J＝7.2Hz，1H)，8.97(s，1H)，8.61(d，J＝3.6Hz，1H)，8.16(d，J＝8.0Hz，1H)，8.03(d，J＝8.4Hz，2H)，7.89(d，J＝8.0Hz，2H)，7.52(dd，J＝7.2Hz，J＝4.8Hz，1H)，7.24-7.16(m，5H)，5.39-5.33(m，1H)，3.16(t，J＝7.2Hz，2H)，3.01(t，J＝7.2Hz，2H)，2.39(t，J＝7.2Hz，2H)，2.29-2.17(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
26H
24N
4O
4[M+H]
+，457.1870，found?457.1861.
Embodiment 19
(S)-4-(4-(isoquinoline 99.9-4-replaces) benzamide)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces) butyric acid
(S)-4-(4-(isoquinolin-4-yl)benzamido)-4-(5-phenethyl-1，3，4-oxadiazol-2-yl)butanoic?acid(PLJ-19)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.25(s，1H)，9.16(d，J＝8.0Hz，1H)，8.98(dd，J＝4.0Hz，J＝0.8Hz，1H)，8.24(d，J＝8.4Hz，1H)，8.13-8.08(m，3H)，7.89(t，J＝7.6Hz，1H)，7.65-7.62(m，3H)，7.57(dd，J＝8.8Hz，J＝4.4Hz，1H)，7.26-7.15(m，5H)，5.43-5.37(m，1H)，3.17(t，J＝7.2Hz，2H)，3.02(t，J＝7.2Hz，2H)，2.42(t，J＝7.2Hz，2H)，2.33-2.16(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
30H
26N
4O
4[M+H]
+，507.2027，found?507.2019.
Embodiment 20
(S)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces)-4-(4-(pyridine-4-replaces) benzamide) butyric acid
(S)-4-(5-phenethyl-1，3，4-oxadiazol-2-yl)-4-(4-(pyridin-4-yl)benzamido)butanoicacid(PLJ-20)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.24(s，1H)，9.15(d，J＝8.0Hz，1H)，8.69(d，J＝6.0Hz，2H)，8.05(d，J＝8.4Hz，2H)，7.96(d，J＝8.4Hz，2H)，7.80(d，J＝6.4Hz，2H)，7.25-7.14(m，5H)，5.40-5.34(m，1H)，3.16(t，J＝7.6Hz，2H)，3.01(t，J＝7.6Hz，2H)，2.40(t，J＝7.2Hz，2H)，2.31-2.15(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
26H
24N
4O
4?[M+H]
+，457.1870，found?457.1871.
Embodiment 21
(S)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces)-4-(4-(quinoline-4-replaces) benzamide) butyric acid
(S)-4-(5-phenethyl-1，3，4-oxadiazol-2-yl)-4-(4-(pyridin-4-yl)benzamido)butanoic?acid(PLJ-21)
Synthetic method such as embodiment 1.
1H?NMR(400MHz，DMSO-d
6)δ12.25(s，1H)，9.19(d，J＝7.6Hz，1H)，8.98(d，J＝4.0Hz，1H)，8.12(t，3H)，7.86-7.80(m，2H)，7.70(d，J＝7.6Hz，2H)，7.62(t，J＝7.6Hz，1H)，7.51(d，J＝7.6Hz，1H)，7.26-7.17(m，5H)，5.43-5.37(m，1H)，3.17(t，J＝7.2Hz，2H)，3.02(t，J＝7.2Hz，2H)，2.42(t，J＝6.8Hz，2H)，2.33-2.16(m，2H)；
HRMS(ESI)：Exact?mass?calcd?for?C
30H
26N
4O
4[M+H]
+，507.2027，found?507.2026.
Embodiment 22
Experiment material: proteoglycan enzyme-1 (ADAMTS-4/aggrecanase-1) and proteoglycan enzyme-2 (ADAMTS-5/aggrecanase-2) are available from R﹠amp; D company, its purity is not less than 90%.The substrate of ADAMTS4 and ADAMTS5 is to buy from Zhongtai Bio-Chem. Co., Ltd., Hangzhou according to document, and its purity is not less than 93%.
The screening experiment of ADAMTS4 inhibitor is to use the band fluorescently-labeled polypeptide segment K of 6-Fam/QSY-9 (6-Fam)-DVQEFRGVTAVIRC (Qsy-9)-KGK as substrate.Its experimental procedure is as follows, earlier will be with MMP solution (100mMTris-HCl, 100mMNaCl, 10 μ M CaCl2,0.05%Brij, pH7.5) Pei Zhi DMSO control group or medicine group and recombinant human ADAMTS4 were hatched 10 minutes at 37 degree, add substrate afterwards in 37 degree reactions, use excitation wavelength 488nm, emission wavelength 522nm to carry out dynamics and measure 30 minutes, per five minutes readings once, experimental result is carried out match and is calculated IC with Graphpad ptism 4 softwares
50
The screening experiment of ADAMTS5 inhibitor is to use the band fluorescently-labeled polypeptide segment 6-Fam-Thr-Glu-Set-Glu～Set-Arg-Gly-Ala-Ile-Tyr-Cys of 6-Fam/QSY-9 (Qsy9)-Lys-Lys as substrate.Its experimental procedure is as follows, earlier will be with TNC solution (50mM Tris-HCl, pH7.5,150mM NaCl, 10mM CaCl2,0.05%Brij-35and 0.02%NaN3) the DMSO control group of configuration or medicine group spend 37 with recombinant human ADAMTS5 and hatched 10 minutes, add substrate afterwards in 37 degree reactions, use excitation wavelength 488nm, emission wavelength 522nm to carry out dynamics and measure 60 minutes, per five minutes readings once, experimental result is carried out match and is calculated IC with Graphpad ptism 4 softwares
50
Compound used therefor is respectively the prepared compound of embodiment 1-21, represents with the embodiment label in table.
The compound that wherein behaves oneself best is PLJ-6
((5-(3,4,5-trimethoxybenzyl)-1,3,4-oxadiazol-2-yl) butanoic acid) is respectively 1.2uM and 0.8uM to the IC50 of ADAMTS-4 and ADAMTS-5 to (S)-4-biphenyl-4-ylcarboxamido-4-;
Next is Compound P LJ-7
((5-(3,4,5-trimethoxyphenethyl)-1,3,4-oxadiazol-2-yl) butanoic acid) is respectively 3.3uM and 4.3uM to the IC50 of ADAMTS-4 and ADAMTS-5 to (S)-4-biphenyl-4-ylcarboxamido-4-;
Moreover be Compound P LJ-10
((S)-4-biphenyl-4-ylcarboxamido-4-(5-(4-methoxyphenethyl)-1,3,4-oxadiazol-2-yl) butanoic acid) is to the IC of ADAMTS-4 and ADAMTS-5
50Be respectively 4.9uM and 24.3uM.
Claims (8)
1. 4-benzoylamino-4-(1,3, the 4-the oxadiazole)-2-that has formula (I) constitutional features replaces butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs:
M and n are optional to be 1,2 or 3;
Following a is 0 or 1; B is 0 or 1;
R
1Certainly optional:
1) (C=O)
aO
bAryl;
2) (C=O)
aO
bHeteroaryl;
R
2Certainly optional:
1)H；
2) halogen;
3)OH；
4) (C=O)
aO
bC
1-C
5Alkyl;
5) (C=O)
aO
bAryl;
6) O
bC
1-C
5Perfluoroalkyl;
7) (C=O)
aO
bC
3-C
6Cycloalkyl;
R
3And R
4Independent separately certainly optional:
1)H；
2) C
1-C
5Alkyl;
3) C
1-C
5Perfluoroalkyl;
4) C
3-C
6Cycloalkyl;
5) C
3-C
6Heterocyclylalkyl;
Described alkyl, aryl, cycloalkyl, Heterocyclylalkyl and heteroaryl are optional by 0,1, and 2 or 3 are selected from R
5Substituting group replaces;
R
5Be selected from:
1)H；
2) C
3-C
6Cycloalkyl;
3) heterocyclic radical;
4) C
1-C
3Alkyl;
5) C
1-C
3Contain fluoroalkyl;
6) C
0-C
3The alkylidenyl-heterocyclic base.
2. 4-benzoylamino-4-according to claim 1 (1,3, the 4-oxadiazole)-2-replaces butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs, it is characterized in that described R
1Certainly optional:
1) aryl;
2) heteroaryl.
3. 4-benzoylamino-4-according to claim 1 (1,3, the 4-oxadiazole)-2-replaces butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs, it is characterized in that described R
2Certainly optional:
1)H；
2)F，Cl，Br；
3)OH，OCH
3，OEt，OCF
3；
4) methyl, ethyl, sec.-propyl, the tertiary butyl;
5) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
6)CF
3。
4. 4-benzoylamino-4-according to claim 1 (1,3, the 4-oxadiazole)-2-replaces butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs, it is characterized in that described R
3Or R
4Certainly optional:
1)H；
2) methyl, hexyl;
3)CF
3；
4) cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
5) C
3-C
6Heterocyclylalkyl.
5. 4-benzoylamino-4-(1 according to claim 1,3, the 4-oxadiazole)-2-replacement butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs, it is characterized in that, described 4-benzoylamino-4-(1,3,4-oxadiazole)-2-replaces the butyric acid compounds and is:
(S)-4-(5-benzyl-1,3,4-oxadiazole-2-replaces)-4-biphenyl-4-substituted formyl amido butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-styroyl-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3-hydrocinnamyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-luorobenzyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-methoxy-benzyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3,4,5-trimethoxy benzyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3,4,5-trimethoxy styroyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-methylbenzene ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-fluorobenzene ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-anisole ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-methyl isophthalic acid-phenyl third-2-replacement)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-methyl-2-hydrocinnamyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-(3,4, the 5-trimethoxyphenyl) propane-2-replaces)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(2-phenyl third-2-replacement)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(1-phenycyclopropyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(3,5-dimethyl benzene ethyl)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-biphenyl-4-substituted formyl amido-4-(5-(4-leptodactyline)-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces)-4-(4-(pyridine-3-replaces) benzamide) butyric acid;
(S)-4-(4-(isoquinoline 99.9-4-replaces) benzamide)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces) butyric acid;
(S)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces)-4-(4-(pyridine-4-replaces) benzamide) butyric acid; Or
(S)-4-(5-styroyl-1,3,4-oxadiazole-2-replaces)-4-(4-(quinoline-4-replaces) benzamide) butyric acid.
6. each described 4-benzoylamino-4-(1 of claim 1-5,3,4-oxadiazole)-2-replaces the application of conditioning agent in the medicine of preparation treatment bone and joint diseases as proteoglycan enzyme-1 or proteoglycan enzyme-2 of butyric acid compounds and pharmacy acceptable salt thereof or steric isomer or its prodrugs.
7.-plant the pharmaceutical composition of treatment bone and joint diseases, it is characterized in that, its main active ingredient is to replace butyric acid compounds or its pharmacy acceptable salt or steric isomer or its prodrugs by above-mentioned 4-benzoylamino-4-(1,3, the 4-oxadiazole)-2-.
8. the pharmaceutical composition of treatment bone and joint diseases according to claim 7 is characterized in that, described bone and joint diseases is an osteoarthritis, rheumatic arthritis, any in the Kaschin-Beck disease.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570731A (en) * | 2012-07-30 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Pyrimidotricyclic compounds or pyrimidotetracyclic compounds, pharmaceutical composition and applications thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1202161A (en) * | 1995-11-14 | 1998-12-16 | 杜邦麦克药品公司 | Macrocyclic compounds as metalloprotease inhibitors |
| CN1678311A (en) * | 2002-06-27 | 2005-10-05 | 诺沃挪第克公司 | Aryl carbonyl derivatives as therapeutic agents |
-
2011
- 2011-05-31 CN CN201110143591.4A patent/CN102276546B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1202161A (en) * | 1995-11-14 | 1998-12-16 | 杜邦麦克药品公司 | Macrocyclic compounds as metalloprotease inhibitors |
| CN1678311A (en) * | 2002-06-27 | 2005-10-05 | 诺沃挪第克公司 | Aryl carbonyl derivatives as therapeutic agents |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103570731A (en) * | 2012-07-30 | 2014-02-12 | 中国科学院广州生物医药与健康研究院 | Pyrimidotricyclic compounds or pyrimidotetracyclic compounds, pharmaceutical composition and applications thereof |
| CN103570731B (en) * | 2012-07-30 | 2016-05-18 | 中国科学院广州生物医药与健康研究院 | Pyrimido three encircles or pyrimido Fourth Ring compounds and Pharmaceutical composition and application |
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