Anti-osteoporosis compound as well as derivatives, pharmaceutical composition, preparation method and application thereof

A technology for anti-osteoporosis compounds, which is applied in the field of anti-osteoporosis compounds and their derivatives, can solve the problems of uncertainty in taking estrogen, and achieve the effects of a wide range of drug targets, easy operation, and simple preparation methods

Active Publication Date: 2021-08-13
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Estrogen replacement therapy is an effective way to prevent osteoporosis, but it is not widely used unless patients have other medical conditions that are eligible for its use
Uncertainty and controversy surrounding women taking estrogen in first decade after menopause

Method used

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  • Anti-osteoporosis compound as well as derivatives, pharmaceutical composition, preparation method and application thereof
  • Anti-osteoporosis compound as well as derivatives, pharmaceutical composition, preparation method and application thereof
  • Anti-osteoporosis compound as well as derivatives, pharmaceutical composition, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0130] Preparation of test cells:

[0131] C57BL / 6 mice were killed by neck dislocation, soaked in 75% alcohol for disinfection, and the long bones of the hind limbs (femur and tibia) were peeled off under aseptic conditions, and the attached soft tissues were removed. Rinse out, filter the cell suspension with a cell sieve, seed the cells in a 10 cm diameter culture plate after quantification, and store in 5% CO 2 Cultivate overnight under saturated humidity conditions, centrifuge the next day to take supernatant non-adherent cells, replace with fresh complete medium (containing 30ng / mL M-CSF) and continue to culture for two days to obtain bone marrow osteoclast precursor cells.

[0132] Inhibition rate (PR%)=[enzyme activity (negative control group)-enzyme activity (experimental group)] / [enzyme activity (negative control group)-enzyme activity (blank control group)]×100%.

Embodiment 1

[0133] Example 1: N-(4-bromo-2-(3-hydroxyprop-1-yn-1-yl)-6-nitrophenyl)-2,2,2-trifluoroacetamide (compound 1- 1) Synthesis of

[0134]

[0135] Among them: (a) Ag 2 SO 4 , I 2 ,CH 3 OH, r.t., overnight; (b) (CF 3 CO) 2 O, anhydrous Et 3 N, anhydrous DCM, 0℃, 5min; r.t., 2h; (c) propargyl alcohol, PdCl 2 (PPh 3 ) 2 ,CuI,Et 3 N,DMF,N 2 , r.t., 12h.

[0136] (1) Synthesis of 4-bromo-2-iodo-6-nitroaniline (compound 1a-1)

[0137] Add iodine (9.70g, 38.23mmol) to a 500mL eggplant-shaped bottle, then add 250mL methanol to the bottle to dissolve the iodine, then add silver sulfate (11.92g, 38.23mmol) and 4-bromo-2-nitroaniline in turn (5.00 g, 25.49 mmol), stirred overnight at room temperature. After the reaction was detected by TLC, it was filtered and the reaction solvent was distilled off. After diluting the residue with dichloromethane (100mL), add saturated sodium thiosulfate solution (100mL), then extract with dichloromethane (100mL×3), dry over anhydrous sodi...

Embodiment 2

[0142] Example 2: 1-(7-(azetidin-3-ylamino)-2-methyl-5-(pyridin-3-yl)-1H-indol-3-yl)ethane-1 -Synthesis of ketone (compound 1-30)

[0143]

[0144] Among them: (a) 3-pyridylboronic acid, Pd(Ph 3 P) 4 , K 2 CO 3 ,1,4-dioxane,H 2 O, 100℃, 12h; (b) ethyl chloroformate, anhydrous pyridine, 0℃, 5min; r.t., 2h; (c) Pd(PPh 3 ) 4 , anhydrous Et 3 N,HCO 2 H,CH 3 CN,N 2 ,80℃,2h; (d)Pd / C,H 2 ,CH 3 OH / THF (v / v, 1 / 1), r.t., 5h; (e) EtOH, NaBH 4 ,rt,2h; (f)acetyl chloride,Et 2 AlCl,AlCl 3 ,N 2 , anhydrous DCM, 0℃, 5min; r.t., 5h; (g) CF 3 COOH, DCM, r.t., 1h.

[0145](1) 2,2,2-trifluoro-N-(2-(3-hydroxyprop-1-yn-1-yl)-6-nitro-4-(pyridin-3-yl)phenyl)ethyl Synthesis of Amide (Compound 2-1)

[0146] Compound 1-1 (100mg, 272.42μmol), 3-pyridineboronic acid (49.8mg, 408.63μmol), tetrakis (triphenylphosphine) palladium (31.5mg, 27.24μmol) and potassium carbonate (113.0mg, 817.26μmol) were added To a 25 mL three-necked round bottom flask, after replacing the air in the reacti...

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Abstract

The invention discloses an anti-osteoporosis compound as well as derivatives, a pharmaceutical composition, a preparation method and application thereof. The structure of the compound is shown in a formula (I), the derivatives of the compound relate to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, pharmaceutically acceptable salt or a mixture of the isomer, the diastereoisomer, the enantiomer, the tautomer, the solvate and the pharmaceutically acceptable salt of the compound, and the compound and the derivatives of the compound can inhibit the activity of tartrate-resistant acid phosphatase (TRAP) and influence the expression of osteoclast specificity mRNATRAP, NFATC1, C-FOS and CTSK. The compound has the anti-osteoporosis activity and can be used for preparing anti-osteoporosis medicines, and the synthesis method of the compound is simple, convenient and easy to operate.

Description

technical field [0001] The present invention relates to an anti-osteoporosis compound and its derivatives, pharmaceutical composition, preparation method and application, especially to an anti-osteoporosis compound and its derivatives which can be prepared as medicine for treating RANKL / bone loss disease, medicine Compositions, methods of preparation and applications. Background technique [0002] Osteoporosis is a bone disease that increases the risk of fractures. In osteoporosis, bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and diversity of non-collagenous proteins in bone is altered. The World Health Organization defines osteoporosis (in women) as bone mineral density 2.5 standard deviations below peak bone mass (mean for healthy women aged 30 years). Osteoporosis is most common in postmenopausal women (a condition called postmenopausal osteoporosis), but can also occur in men, and can occur in anyone with certain hormone di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/14C07D401/04C07D417/04A61K31/4439A61K31/427A61K31/404A61K31/4545A61P19/10A61P19/02A61P19/00A61P35/00A61P29/00A61P1/02
CPCC07D401/14C07D401/04C07D417/04A61K31/4439A61K31/427A61K31/404A61K31/4545A61P19/10A61P19/02A61P19/00A61P35/00A61P29/00A61P1/02
Inventor 焦宇陆涛陈亚东
Owner CHINA PHARM UNIV
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