WO2012058976A1 - 一种二膦酸化合物及其制备方法及应用 - Google Patents
一种二膦酸化合物及其制备方法及应用 Download PDFInfo
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- WO2012058976A1 WO2012058976A1 PCT/CN2011/078808 CN2011078808W WO2012058976A1 WO 2012058976 A1 WO2012058976 A1 WO 2012058976A1 CN 2011078808 W CN2011078808 W CN 2011078808W WO 2012058976 A1 WO2012058976 A1 WO 2012058976A1
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- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 206010047623 Vitamin C deficiency Diseases 0.000 description 1
- 229930003316 Vitamin D Natural products 0.000 description 1
- 206010047626 Vitamin D Deficiency Diseases 0.000 description 1
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- RGCKGOZRHPZPFP-UHFFFAOYSA-N alizarin Chemical compound C1=CC=C2C(=O)C3=C(O)C(O)=CC=C3C(=O)C2=C1 RGCKGOZRHPZPFP-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
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- BBBFJLBPOGFECG-VJVYQDLKSA-N calcitonin Chemical compound N([C@H](C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(N)=O)C(C)C)C(=O)[C@@H]1CSSC[C@H](N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1 BBBFJLBPOGFECG-VJVYQDLKSA-N 0.000 description 1
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 description 1
- 235000008696 isoflavones Nutrition 0.000 description 1
- DWKPPFQULDPWHX-VKHMYHEASA-N l-alanyl ester Chemical compound COC(=O)[C@H](C)N DWKPPFQULDPWHX-VKHMYHEASA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000009245 menopause Effects 0.000 description 1
- NWHFCRJVWNLNHP-UHFFFAOYSA-N methyl 2-(4-nitrophenyl)propanoate Chemical compound COC(=O)C(C)C1=CC=C([N+]([O-])=O)C=C1 NWHFCRJVWNLNHP-UHFFFAOYSA-N 0.000 description 1
- OCICDTOQZOSSQU-UHFFFAOYSA-N methyl 2-[4-(aminomethyl)phenyl]acetate Chemical compound COC(=O)CC1=CC=C(CN)C=C1 OCICDTOQZOSSQU-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
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- HJZKOAYDRQLPME-UHFFFAOYSA-N oxidronic acid Chemical compound OP(=O)(O)C(O)P(O)(O)=O HJZKOAYDRQLPME-UHFFFAOYSA-N 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229940046231 pamidronate Drugs 0.000 description 1
- 239000000199 parathyroid hormone Substances 0.000 description 1
- 229960001319 parathyroid hormone Drugs 0.000 description 1
- 210000003460 periosteum Anatomy 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000010339 sodium tetraborate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
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- XXUZFRDUEGQHOV-UHFFFAOYSA-J strontium ranelate Chemical compound [Sr+2].[Sr+2].[O-]C(=O)CN(CC([O-])=O)C=1SC(C([O-])=O)=C(CC([O-])=O)C=1C#N XXUZFRDUEGQHOV-UHFFFAOYSA-J 0.000 description 1
- 229940079488 strontium ranelate Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 1
- 229950003937 tolonium Drugs 0.000 description 1
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- BSVBQGMMJUBVOD-UHFFFAOYSA-N trisodium borate Chemical compound [Na+].[Na+].[Na+].[O-]B([O-])[O-] BSVBQGMMJUBVOD-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
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- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
- C07F9/6541—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4025—Esters of poly(thio)phosphonic acids
- C07F9/4028—Esters of poly(thio)phosphonic acids containing no further substituents than -PO3H2 groups in free or esterified form
- C07F9/4031—Acyclic unsaturated derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/5475—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and selenium with or without oxygen or sulfur as ring hetero atoms; having nitrogen and tellurium with or without oxygen or sulfur as ring hetero atoms
Definitions
- This invention relates to a novel bisphosphonate compound, and to a process for preparing the novel bisphosphonate compound.
- Bone metabolic diseases are diseases in which abnormalities such as bone formation, bone resorption, and deposition of bone minerals are caused by factors such as congenital or acquired factors that interfere with normal bone metabolism.
- Bone metabolic diseases mainly include: osteoporosis, vitamin D deficiency, vitamin C deficiency, renal bone disease and other diseases.
- Osteoporosis is a common and frequently-occurring disease in bone metabolic diseases.
- Osteoporosis is a systemic, systemic bone disease characterized by decreased bone mass, increased bone microstructural damage, and increased fracture risk.
- osteoporosis With the continuous improvement of human living standards, the prolongation of human life and the arrival of an aging society, osteoporosis has become a common and frequently-occurring disease that seriously threatens the health of middle-aged and elderly people; especially women have estrogen levels during menopause. Rapid changes, affecting the balance of bone formation and bone resorption, resulting in a large loss of postmenopausal bone mass, accelerated bone resorption and / or slower bone formation, leading to osteoporosis, or even severe osteoporotic fractures .
- China is not only the most populous country in the world, but also the country with the largest number of patients with osteoporosis.
- the incidence of osteoporosis in men is 14.6%, and that of women is 61.8%.
- the overall incidence rate was 6.97%, and a total of 88.26 million middle-aged and elderly people were at risk of osteoporosis.
- China will enter the peak period of ageing, with the population over 60 years old accounting for 27% of the total population, reaching 400 million people. Therefore, the research and development of drugs for the prevention and treatment of osteoporosis has considerable practical significance and great social value for improving people's life and health and improving the quality of life in China.
- bone resorption inhibitors such as various bisphosphonate compounds, isopropyl isoflavones, calcitonin, estrogens, selective estrogens.
- Receptor modulators one type of bone-promoting drugs, such as fluoride, parathyroid hormone, insulin-like growth factor, protein synthesis hormone; one type of drugs that promote ossification, such as calcium, vitamin D and its derivatives
- a bisphosphonate (salt) drug i.e., a bisphosphonate or a pharmaceutically acceptable salt thereof, is a synthetic analog of natural pyrophosphate having the basic structure as shown in Formula I:
- the R', R" side chain in the molecular structure of the bisphosphonate can affect the ability of its pro-bone ability.
- R' has little effect on the osteogenic ability of bisphosphonate drugs; and the structure of R" is the main factor affecting the ability of bisphosphonate drugs to be osteogenic.
- bisphosphonate drugs have been marketed.
- the structure of R" is usually divided into the following three categories: First, R" nitrogen-free bisphosphonate, represented by etidronate (Etidr 0na te), clodronate (Clodronate), early In the 1970s, it has been used in clinical practice. Second, the R" structure contains amino groups.
- the anti-bone resorption effect is stronger than that of the drug containing no nitrogen diphosphonic acid.
- the representative drug is pamidronate (Adan). Sodium phosphate (Alendronate).
- the R" structure is a nitrogen-containing heterocyclic bisphosphonate drug, which has stronger anti-bone absorption ability and is more convenient for clinical use.
- the representative drug is zoledronic acid (Zoledronate), which is osteogenic. It is more than 10 000 times stronger than the nitrogen-free etidronate. However, whether it contains N (including -NH 2 or N-containing heterocyclic ring) or N-free bisphosphonic acid drugs, it inhibits osteoclast activity.
- the treatment of osteoporosis has a weak effect on the proliferation of osteoblasts.
- bisphosphonate drugs although they have an increasing inhibitory effect on osteoclasts, may also lead to a corresponding increase in the risk of fractures in patients, and It has not been reported that listed bisphosphonate drugs have an effect of promoting osteoblasts.
- the object of the present invention is to overcome the shortcomings of the existing bisphosphonate compounds which mainly inhibit the activity of osteoclasts and have a weak effect on the proliferation of osteoblasts, and provide a novel bisphosphonate compound, and the bisphosphonic acid.
- the bisphosphonate compound provided by the present invention can exert a two-way regulation effect on osteoblasts and osteoclasts.
- R 3 is Se or S
- R4 and R 5 are independently selected from hydrogen, halogen, -CN, -N0 2, -OH, -OR ', -COOR', -OCOOR ', -COR', -CON (R ') 2, -OCON (R ') 2 , -SR, -S0 2 R, -S0 2 N(R') 2 , -SOR' group, C1 ⁇ C10 alkyl group, C1 ⁇ C10 substituted alkyl group, alkenyl group, substituted alkenyl group, a block group, a substituted block aryl group or a substituted aryl group, wherein each R and R' is independently selected from g H, an alkyl group, an aryl group, a substituted alkyl group or a substituted aryl group; and R 5 may also constitute 3 to 7 a cycloalkane of a carbon atom, the cycloalkane may be substituted, the substituent is a C
- R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, CN, -N0 2 , -OH, -OR', -COOR', -OCOOR', -COR', -CON(R') 2 , -OCON(R') 2 , -SR, -S0 2 R, -S0 2 N(R') 2 , -SO R' group, alkyl group, alkenyl group, Block, aryl, substituted alkyl, substituted alkenyl, substituted or substituted aryl, wherein each R and R' are independently selected from H, alkyl, aryl, substituted alkyl or substituted aryl.
- R 3 is Se or S
- R4 and R 5 are independently selected from hydrogen, halogen, a CN, -N0 2, -OH, or C1 ⁇ C10 alkyl group;
- R 7 , R 8 and R 9 are independently of each other selected from the group consisting of hydrogen, halogen, -CN, -N0 2 or -OH alkyl.
- H and OH are preferred.
- It may also be a halogen, preferably F, C1 or Br.
- R 2 is ⁇ Clt Ar ⁇ H ⁇ or ⁇ CH 2 , wherein Ar is a substituted aryl group, and the substituent is a C1 to C6 alkyl group substituted at a different position, C1 to C6 Optionally substituted alkyl, halogen, a CN, -N0 2 or -OH.
- R 3 is preferably Se.
- R 7 , R 8 and R 9 are preferably hydrogen.
- the present invention also provides two preparation methods of the above bisphosphonate compound having the structure of the formula II.
- a method for preparing the above structural bisphosphonic acid compound of formula II comprising the steps of:
- Methylene diphosphonate tetraisopropyl ester and NaH undergo a methylene proton activation reaction with a reaction time of 11! ⁇ 4h, the reaction temperature is -5 ° C ⁇ 40 ° C, the molar ratio of NaH to methylene diphosphonic acid tetraisopropyl ester is 1:1 ⁇ 3: 1;
- a compound A having a bromine and a nitro group is added for alkylation, and the reaction temperature is 60 ° C to 150 ° C, and the reaction time is 21! ⁇ 5h, the molar ratio of the compound A to the methylene diphosphonic acid tetraisopropyl ester is 1:1 ⁇ 3:1; after the reaction is completed, the organic solvent is added to the reaction liquid for extraction, the organic phase is collected and spin-dried to obtain a methylene group.
- Compound I substituted with a nitro group-containing compound
- the organic solvent may be methylene chloride, chloroform, ethyl acetate or petroleum ether.
- the alkali solution in the step (4) is a NaHC0 3 solution.
- the organic solvent of the o-/thioselenochlorobenzoyl chloride compound in the step (4) is diethyl ether, dichloromethane, chloroform or ethyl acetate.
- the o-sulfur/selenium chlorobenzoyl chloride in the step (4) is prepared by the following method:
- the selenium/thioether compound obtained in the step a is added to the SOC1 2 and refluxed at 60 ° C to 90 ° C for 21! ⁇ 5h, the solvent is distilled off under reduced pressure, the molar ratio of the selenium / thioether compound to S0C1 2 is 1: 2 ⁇ 1: 50; petroleum ether is added to the residue, and refluxed at 30 ° C ⁇ 90 ° C 21! ⁇ 4h, filtered while hot, place the filtrate at room temperature for 81! ⁇ 24h, the precipitated solid is dried at 20 ° C ⁇ 50 ° C 121! ⁇ 48h, obtaining an adjacent selenium/thiochlorobenzoyl chloride compound;
- the alkaline solution of the Se/S ion is a reaction of selenium powder or sulfur powder with potassium borohydride and NaOH in aqueous solution at room temperature 31! ⁇ 10h obtained, wherein the molar ratio of potassium borohydride, NaOH and selenium powder / sulfur powder is 1: 10 ⁇ 5: 1;
- the diazonium salt solution is an anthranilic acid containing a substituent, an ortho-carbamic acid cyclohexane having a substituent or a ⁇ -alanine hydrochloride solution containing a substituent and a NaN0 2 solution at -20 ° C to 5 °.
- the molar ratio of NaN0 2 to the anthranilic acid having a substituent, the ortho-carbamic acid cyclohexane having a substituent or the ⁇ alanine having a substituent is 1:1 to 3:1.
- the alkaline solution of the Se/S ion is a reaction of selenium powder or sulfur powder with potassium borohydride and NaOH in aqueous solution at room temperature. 31! ⁇ lOh obtained, wherein the molar ratio of potassium borohydride, NaOH and selenium powder / sulfur powder is 1:10 ⁇ 5:1;
- the diazonium salt solution is a substituent-containing anthranilic acid, a substituted ortho-carbamic acid cyclohexane or a substituted ⁇ -alanine (compound C) hydrochloric acid solution and a NaN0 2 solution at -20°.
- Another method for preparing the above compound having a ⁇ structure bisphosphonate comprises the following steps:
- the organic solvent solution of the ortho-selenium/thiochlorobenzoyl chloride compound is added to the omega amino acid methyl ester (compound oxime) having a pH of 7 to 14 and reacted at room temperature for 31! ⁇ 8h, the molar ratio of o-selenium/thiochlorobenzoyl chloride compound to compound B is 1:1 ⁇ 3:1, the reaction solution is filtered, and the precipitate is washed with diethyl ether, and dried at 411 ⁇ 2411 at 50 ⁇ 100 to obtain compound ⁇ 11 ;
- the compound VIII obtained in the step (2) is reacted with phosphorous acid and phosphorus trichloride at a temperature of from 90 ° C to 120 ° C for 21! ⁇ 6h, add water to the reaction, add lg compound VIII to lmL ⁇ 50mL water, reflux at 90 ° C ⁇ 110 ° C 11! ⁇ 3h, the molar ratio of compound VIII to phosphorous acid is 1:1 ⁇ 1:5, the molar ratio of compound VIII to phosphorus trichloride is 1:2 ⁇ 1:6, the reaction solution is filtered, and the alcohol solution is added to the filtrate. Place 1 at 5 ° C ⁇ 5 ° C!
- the organic solvent may be diethyl ether, dichloromethane, chloroform or ethyl acetate.
- the existing nitrogen-containing bisphosphonates are currently the most widely used drugs for the treatment of osteoporosis, such as the already marketed sodium alendronate and zoledronic acid, which mainly inhibit the synthesis of farnesyl diphosphonic acid.
- the enzyme causes a decrease in the level of protein in the osteoclast, thereby inhibiting the activity of osteoclasts and exerting an effect of treating osteoporosis.
- the existing nitrogen-containing diphosphonic acid compounds and their salts are increasingly active, that is, the compounds have an increasing inhibitory effect on osteoclasts, but their effects on osteoblast proliferation are weak. The risk of a patient's fracture may increase accordingly.
- the present invention provides a novel bisphosphonate compound and a method and use for preparing the same, and structural features of the compound have been identified.
- alendronate sodium which has been marketed and widely used as a positive control drug
- the results show that the novel bisphosphonate compound provided by the present invention exhibits an activity in inhibiting the activity of osteoclasts.
- the activity of sodium lendronate is relatively high; it has a higher activity in affecting the proliferation of osteoblasts, while the positive contrast drug has a weaker effect on the proliferation of osteoblasts.
- a dosing regimen using the bisphosphonate compound of the present invention is provided.
- the bisphosphonic acid has the structure of Formula II:
- R 3 is Se or S; preferably Se;
- R 7 , R 8 and R 9 are independently of each other selected from the group consisting of hydrogen, halogen, -CN, -N0 2 or -OH alkyl.
- R4 and R 5 are independently selected from hydrogen, halogen, -CN, -N0 2, -OH, -OR ', -COOR', -OCOOR ', -COR', -CON (R ') 2, -OCON (R ') 2 , -SR, -S0 2 R, -S0 2 N(R') 2 , -SOR' group, C1 ⁇ C10 alkyl group, C1 ⁇ C10 substituted alkyl group, alkenyl group, substituted alkenyl group, a block group, a substituted block aryl group or a substituted aryl group, wherein each R and R' is independently selected from the group consisting of g H, alkyl group, aryl group, substituted alkyl group or substituted aryl group; R4 and R 5 may also be composed of 3 to 7 a cycloalkane of a carbon atom, the cycloalkane may be substituted, the substituent is
- R 7 , R 8 and R 9 are independently selected from the group consisting of hydrogen, halogen, CN, -N0 2 , -OH, -OR', -COOR', -OCOOR', -COR', -CON(R') 2 , -OCON(R') 2 , -SR, -S0 2 R, -S0 2 N(R') 2 , -SO R' group, alkyl, alkenyl, block, aryl, substituted alkyl, substituted Alkenyl, substituted or substituted aryl, wherein each R and R' are independently selected from H, decyl, aryl, substituted alkyl or substituted aryl; R 7 , and preferably hydrogen.
- some bisphosphonate compounds have the structure of formula III, and other bisphosphonate compounds of formula IV
- R1 When the structure of R1 is H in the bisphosphonate compound listed, it can be prepared by the following method:
- a compound A having a bromine and a nitro group is added for alkylation, and the reaction temperature is 60 ° C to 150 ° C, and the reaction time is 21! ⁇ 5h, the molar ratio of compound A to methylene diphosphonic acid tetraisopropyl ester is 1: 1 ⁇ 3: 1; after the reaction is completed, an organic solvent is added to the reaction solution for extraction, and the organic phase is collected and spin-dried to obtain a methylene group.
- Compound I substituted with a nitro group-containing compound
- the alkaline solution of Se/S ions is reacted with the diazonium salt solution at a temperature of 60 ° C to 100 ° C. 21! ⁇ 8h, the reaction solution is adjusted to pH value less than 5 with acid, the precipitate is filtered, the filter residue is washed with water, the precipitate is dissolved by adding an alkali solution, filtered, and the filtrate is acidified to a pH of less than 5 to precipitate, and the precipitate is collected at 80 ° C to 150 ° C. Drying to obtain a selenium/thioether compound (Compound III);
- the organic solvent in the step (2) may be dichloromethane, chloroform, ethyl acetate or petroleum ether.
- the alkali solution in the step (4) is a NaHC0 3 solution
- the organic solvent of the o-/thioselenochlorobenzoyl chloride compound is diethyl ether, dichloromethane, chloroform or ethyl acetate.
- the o-sulfur/selenium chlorobenzoyl chloride compound described in the step (4) is prepared by the following method:
- the selenium/thioether compound obtained in the step a is added to the SOC1 2 and refluxed at 60 ° C to 90 ° C for 21! ⁇ 5h, the solvent is distilled off under reduced pressure, the molar ratio of the selenium/thioether compound to S0C1 2 is 1:2 ⁇ 1: 50; petroleum ether is added to the residue at 30 ° C ⁇ 90 ° C reflux 21! ⁇ 4h, filtered while hot, place the filtrate at room temperature for 81! ⁇ 24h, the precipitated solid is dried at 20 ° C ⁇ 50 ° C 121! ⁇ 48h, obtaining an adjacent selenium/thiochlorobenzoyl chloride compound;
- the alkaline solution of the Se/S ion is a reaction of selenium powder or sulfur powder with potassium borohydride and NaOH in aqueous solution at room temperature 31! ⁇ 10h obtained, wherein the molar ratio of potassium borohydride, NaOH and selenium powder / sulfur powder is 1:10 ⁇ 5:1;
- the diazonium salt solution is a substituent-containing anthranilic acid, a substituted ortho-carbamic acid cyclohexane or a substituted ⁇ -alanine hydrochloride solution and a NaN0 2 solution at -20 ° C to 5 °
- the molar ratio of NaN0 2 to the anthranilic acid having a substituent, the ortho-carbamic acid cyclohexane having a substituent or the ⁇ alanine having a substituent is 1:1 to 3:1.
- the alkaline solution of the Se/S ion is a reaction of selenium powder or sulfur powder with potassium borohydride and NaOH in aqueous solution at room temperature 31! ⁇ 10h obtained, wherein the molar ratio of potassium borohydride, NaOH and selenium powder / sulfur powder is 1:10 ⁇ 5:1;
- the diazonium salt solution is a substituent-containing anthranilic acid, a substituted ortho-carbamic acid cyclohexane or a substituted ⁇ -alanine (compound C) hydrochloric acid solution and a NaN0 2 solution at -20°.
- R1 is an OH structure in the bisphosphonate compounds listed, it can be prepared by the following method:
- the organic solvent solution of the o-selenium/thiochlorobenzoyl chloride compound is added to the omega amino acid methyl ester (compound oxime) having a pH of 7 to 14 and reacted at room temperature for 31! ⁇ 8h, the molar ratio of o-selenium/thiochlorobenzoyl chloride compound to compound B is 1 ⁇ 3:1, the reaction solution is filtered, and the precipitate is washed with diethyl ether, and dried at 411 ⁇ 2411 at 50 ⁇ 100 to obtain compound ⁇ 11 ;
- the compound VIII obtained in the step (2) is reacted with phosphorous acid and phosphorus trichloride at a temperature of from 90 ° C to 120 ° C. 21! ⁇ 6h, water is added to the reaction, lg compound VIII is added to lmL ⁇ 50mL water, and refluxed at 90 °C ⁇ 110 °C 11! ⁇ 3h, the molar ratio of compound VIII to phosphorous acid is 1:1 ⁇ 1:5, the molar ratio of compound VIII to phosphorus trichloride is 1:2 ⁇ 1:6, the reaction solution is filtered, and the alcohol solution is added to the filtrate. Place 1 at 5 ° C ⁇ 5 ° C!
- the organic solvent in the step (1) may be diethyl ether, dichloromethane, chloroform or ethyl acetate.
- the preparation method of the o-sulfur/selenium chlorobenzoyl chloride compound described in the step (4) is as described above.
- Example 1 The bisphosphonate compound exemplified in this example is 4-(3-carbonylbenzo[d][l,2]selenoazole-2(3H))-benzylmethylmethylenediphosphonic acid, and the structural formula is as follows:
- anthranilic acid was added to 500 mL of water and 400 mL of concentrated HC1 to completely dissolve it, and then placed in an ice water bath at 0 ° C to 5 ° C.
- the dropping speed is controlled at a temperature between 0 °C and 5 °C.
- the reaction end point is judged by the starch potassium iodide test paper. Take a drop of the solution on the starch potassium iodide test paper, and if the test paper turns blue, the reaction is complete), and obtain a diazonium salt solution.
- the diazonium salt solution was added dropwise to the Se ion alkaline solution prepared above, and after the completion of the dropwise addition, the temperature was raised to 60 ° C for 5 hours, and the reaction was stopped.
- the pH of the reaction mixture was adjusted to less than 3 with concentrated hydrochloric acid to give a pale yellow precipitate, which was filtered and washed with water.
- NaHC0 3 to dissolve and boil, filter, and acidify with filtrate and dilute hydrochloric acid to adjust the pH value to less than 3 to obtain a pale yellow precipitate, and filter to obtain a white or light yellow filter cake, and dry the filter cake at 100 ° C to obtain 2, 2'-Diselenized benzoic acid.
- Elemental analysis The Selenium content determination method of the 2005 edition of the pharmacopoeia measured Se 16.9%, and the 2005 version of the pharmacopoeia phosphorus content determination method measured P 13.5%.
- the white solid was identified as 4-(3-carbonylbenzo[d][l,2]selenoazole-2(3H))-benzylmethylmethylenediphosphonic acid as identified above.
- the bisphosphonate compound exemplified in this example is 4-(3-carbonylbenzo[d][l,2]selazole- 2(3H))-benzyl-l-hydroxymethylenediphosphonic acid. , structural formula such as
- the bisphosphonate compound exemplified in this example is 2-(3-carbonylbenzo[d][l,2]selazole- 2(3H)ethyl-methylenediphosphonic acid, and the structural formula is as follows:
- the bisphosphonate compound exemplified in this example is 2-(3-carbonylbenzo[d][l,2]selenoazole 2(3H))-ethyl-l-hydroxyl- Methylene diphosphonic acid, the structural formula is as follows:
- the white solid was identified as 2-(3-carbonylbenzo[d][l,2]selenoazole 2(3H))-ethyl 1-hydroxymonomethylene diphosphonic acid.
- the bisphosphonate compound exemplified in the present example is 4 (4,5-dimethyl--1,2-selenazapidine-3-one)benzylidene-methylenediphosphonic acid, and the structural formula is as follows:
- the diazonium salt solution was added dropwise to the above Se ion solution, and after the completion of the dropwise addition, the temperature of the reaction solution was raised to 60 ° C for 5 hours, and the reaction was stopped.
- the pH of the reaction mixture was adjusted to less than 3 with concentrated hydrochloric acid to give a white precipitate, which was filtered and washed with water.
- NaHC0 3 to dissolve and boil, filter, filtrate and acidify with dilute hydrochloric acid, adjust the pH to less than 1 to obtain a white precipitate, filter to obtain a white filter cake, dry the filter cake at 100 ° C to obtain 3,3' selenization - 2 Methyl butyric acid.
- the pale yellow solid was identified as 4-(4,5-dimethyl--1,2-selenoindazin-3-one)-benzylmethylmonomethylene diphosphonic acid.
- the bisphosphonate compound exemplified in this example is 4 (4,5-dimethyl--1,2-selenium pentanthein-3-one) benzyl 1 monohydroxy-methylene diphosphonic acid, structural formula as follows:
- 8.5g of phosphorous acid is heated to melt at 90 ° C ⁇ 120 ° C, add 50g of 4 (4,5-dimethyl-1,2-selenium pentacridin-3-one) methyl phenylacetate, stir to dissolve 28 g of phosphorus trichloride was slowly added dropwise, stirring was continued for 4 h, and after the product became hard, it was refluxed with water at 105 ° C for 2 h.
- the reaction solution was filtered, and methanol was added to the filtrate, and the mixture was placed at 5 ° C for 17h, filtered, and the solid was washed with cold water and dried at 100 ° C for 6h to give a white solid.
- the white solid was identified as 4-(4,5-dimethyl-1,2-selenoindazin-3-one)-benzyl-1-hydroxyl-methylenediphosphonic acid.
- the bisphosphonate compound exemplified in this example is 4-(3-carbonylcyclohexane([d][l,2]selazole- 2(3H)benzylmethyl-methylenediphosphonic acid, and the structural formula is as follows:
- This bisphosphonate compound was synthesized in the same manner as in Example 5 except that 2-aminocyclohexanecarboxylic acid was used instead of 2-methyl- ⁇ -buty acid to give a white solid.
- the bisphosphonate compound exemplified in this example is 4-(3-carbonylcyclohexane([d][l,2]selenoazole 2(3H))-benzyl-1-hydroxymonomethylene diphosphonic acid, Structure
- the white solid was identified as 4-(3-carbonylcyclohexane[d][l,2]selenocarbazole-2(3H))-benzyl-1-hydroxyl-methylenediphosphonic acid.
- the bisphosphonate compound exemplified in this example is 4-(3-carbonyl-5 chlorobenzo[d][l,2]selazole- 2(3H))-benzylmethylmethylene diphosphonic acid, Structural formula
- the bisphosphonate compound exemplified in this example is 4-(3-carbonyl-5 chlorobenzo[d][l,2]selazole- 2(3H))-benzyl group
- the bisphosphonate compound exemplified in this example is 4-(2-methylbenzo[d][l,2]selenoxazole-3(2H)-one)-benzylmethylmethylene diphosphonic acid,
- the structure is as follows:
- the bisphosphonate compound exemplified in this example is 4-(2-methylbenzo[d][l,2]selenoxazole-3(2H)-one)-benzylmethylmethylene diphosphonic acid, Structural formula
- the white solid was identified as 4-(2-methylbenzo[d][l,2]selenoxazole-3(2H)-one)-benzyl-l-hydroxy-methylene diphosphonic acid .
- the bisphosphonate compound exemplified in this example is 4-(3-carbonylbenzo[d][l,2]selazole- 2(3H)phenethyl-methylenediphosphonic acid, and the structural formula is as follows:
- Example 14 The bisphosphonate compound exemplified in this example is 4-(3-carbonylbenzo[d][l,2]selenocarbazole-2(3H))-phenethyl-l-hydroxymonomethylene diphosphonic acid. , structural formula such as
- the white solid was identified as 4-(3-carbonylbenzo[d][l,2]selazole- 2(3H))-phenethyl-l-hydroxy-methylene diphosphonic acid.
- the bisphosphonate compound exemplified in this example is 4-(3-carbonylbenzo[d][l,2]thiazol-2(3H))-benzylmethylmethylenediphosphonic acid, and the structural formula is as follows:
- Example 2 The same synthetic procedure as in Example 1 except that the selenium powder was replaced with sulfur powder to obtain a yellow solid.
- the bisphosphonate compound exemplified in this example is 4-(3-carbonylbenzo[d][l,2]thiazol-2(3H))-benzyl-l-hydroxymonomethylene diphosphonic acid.
- the structure is as follows: ⁇ The same synthetic process as in Example 2 except that the selenium powder was replaced with sulfur powder to obtain a yellow solid.
- the yellow solid was identified as 4-(3-carbonylbenzo[d][l,2]selazole- 2(3H))-phenethyl-l-hydroxymonomethylene diphosphonic acid.
- Test drug SC-1 ⁇ 16; homemade, see examples.
- Positive control drug alendronate sodium (ALEN), China National Institute for the Control of Pharmaceutical and Biological Products (batch number: 100901-200601)
- Blank control To remove the test drug or drug solvent other than ALEN.
- MG63 osteoblast cell line (Key Laboratory of Human Diseases Biotherapy, Ministry of Education, Sichuan University) showed cell adhesion growth 24 hours after resuscitation, cytoplasm began to stretch, and replaced fresh F-12 medium containing 10% fetal bovine serum. Change the liquid every 48 hours. After the cells are 70% ⁇ 80% confluent, digest with 0.25% trypsin to digest and round the adherent cells, then aspirate the digestive juice and add F containing 10% fetal bovine serum. The -12 medium was terminated for digestion, then the cells were blown, de-walled, adjusted to the desired cell density, and transferred to a culture flask and a culture plate for the experiment.
- MTT assay was used to analyze the effect of drugs on the proliferation of osteoblast cell line MG63.
- the method was as follows: freshly-packed MTT (5mg/mL) 100 ⁇ per well in 96-well plate, incubate for 4h at 37°C, intermittently oscillate, discard Clear, add 200 ⁇ L of DMSO (DMSO, sigma) to each well, shake for 10 min on a micro-oscillator, take an equal amount of liquid in a new well plate, and measure the absorbance at 490 nm.
- each SC compound promotes the calcium deposition effect of osteoblasts, especially SC-1, SC-2, SC-4, SC-6, SC-9, SC-10, SC-11. , SC-12, SC-13 , SC-14, SC-15 more significant effect, but it can be suppressed to varying degrees of high concentrations (10- 5 mol / L) of the groups of compounds are calcium deposition into bone cells.
- the Alen group did not find an increase in calcium deposition in osteoblasts in the low concentration group.
- the osteoclast culture was modified by Chambers method, and the newborn Japanese big ear (provided by the West China Basic Animal Center of Sichuan University within 1 week of birth) was sacrificed by cervical dislocation, soaked in 75% ethanol for 5 min, and the long bones of the extremities were taken under aseptic conditions.
- SC compounds have been shown by in vitro cell assays to show that SC compounds can inhibit the differentiation and maturation of osteoclasts on the one hand. On the other hand, it can promote the proliferation and differentiation of osteoblasts, increase the bone formation activity, regulate the metabolic balance of bone formation-bone resorption, and finally restore the normal metabolic activity of bone tissue.
- the SC compound obtained by the present invention is characterized in that it can promote the proliferation of osteoblasts while still maintaining the effect of inhibiting osteoclast activity of the bisphosphonate drug. Therefore, the SC compound of the present invention has a two-way regulation effect in the treatment of osteoporosis.
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ABDOU W.M. ET AL.: "Synthesis, properties, and perspectives of gem-diphosphono substituted-thiazoles", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 43, no. 5, 2008, pages 1015 - 1024, XP022639695 * |
HUDOCK M.P. ET AL.: "Inhibition of Trypanosoma cruzi Hexokinase by Bisphosphonates", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 1, 2006, pages 215 - 223, XP055007041 * |
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