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Anti-osteoporosis compound and derivative thereof, pharmaceutical composition, preparation method and application

An anti-osteoporosis and compound technology, applied in the field of anti-osteoporosis compounds and derivatives thereof, can solve the problem of uncertainty in taking estrogen, and achieve the effects of wide drug action targets, simple preparation method and excellent effect

Active Publication Date: 2022-06-28
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 and derivative thereof, pharmaceutical composition, preparation method and application
  • Anti-osteoporosis compound and derivative thereof, pharmaceutical composition, preparation method and application
  • Anti-osteoporosis compound and derivative thereof, pharmaceutical composition, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0130] Preparation of test cells:

[0131] C57BL / 6 mice were sacrificed by cervical dislocation, sterilized by immersion in 75% alcohol, the hind limb long bones (femur, tibia) were peeled off under sterile conditions, the attached soft tissues were removed, and the inner surface of the bone marrow cavity was repeatedly washed with complete medium to remove the cells in the bone marrow cavity completely. Washed out, the cell suspension was filtered with a cell sieve, and the cells were quantified and seeded in a 10 cm diameter culture plate under 5% CO. 2 The cells were cultured overnight under saturated humidity conditions, and the supernatant non-adherent cells were collected by centrifugation the next day, and replaced with fresh and complete medium (containing 30 ng / mL M-CSF) 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...

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

[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 (9.70 g, 38.23 mmol) to a 500 mL eggplant-shaped flask, add 250 mL of methanol to the flask to dissolve the iodine, then add silver sulfate (11.92 g, 38.23 mmol) and 4-bromo-2-nitroaniline in sequence (5.00 g, 25.49 mmol) and stirred at room temperature overnight. After the completion of the reaction was detected by TLC, the mixture was filtered and the reaction solvent was evaporated. After the residue was diluted with dichloromethane (100 mL), saturated sodium thiosulfate solution (100 mL) was added, then extracted with dichloromet...

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] Of which: (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 (100 mg, 272.42 μmol), 3-pyridineboronic acid (49.8 mg, 408.63 μmol), tetrakis(triphenylphosphine)palladium (31.5 mg, 27.24 μmol) and potassium carbonate (113.0 mg, 817.26 μmol) were added Into a 25 mL three-necked round bottom flask, after replacing the air in the reaction system ...

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Abstract

The invention discloses an anti-osteoporosis compound and its derivatives, pharmaceutical composition, preparation method and application. The structure of the compound is as formula (I), and the derivative of the compound relates to isomers, diastereomers, enantiomers, tautomers, solvates, and pharmaceutically acceptable salts of the compound Or their mixtures, the compound and its derivatives can inhibit the activity of tartrate-resistant acid phosphatase (TRAP) and affect the expression of osteoclast-specific mRNATRAP, NFATC1, C-FOS and CTSK, thereby affecting the formation of osteoclasts and having anti-bone Osteoporosis activity, can be used for the preparation of anti-osteoporosis drugs, and the synthesis method of this type of compound is simple and easy to operate.

Description

technical field [0001] The present invention relates to an anti-osteoporosis compound and derivatives thereof, a pharmaceutical composition, a preparation method and application thereof, in particular to an anti-osteoporosis compound and its derivatives which can be prepared as a drug for treating RANKL / bone loss diseases, and a drug Compositions, methods of preparation and uses. 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 are altered. The World Health Organization defines osteoporosis (in women) as a bone mineral density 2.5 standard deviations below peak bone mass (average for healthy women at age 30). Osteoporosis is most common in postmenopausal women (the condition is called postmenopausal osteoporosis), but can also occur in men, and can occur in anyone with...

Claims

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Application Information

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Patent Type & Authority Patents(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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