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1,2-diazine derivatives and their preparation and use

A derivative, C1-C4 technology, applied in the field of 1,2-diazine derivatives and their preparations, can solve the problems of oral delivery of hydrophilic macromolecular drugs, unreachable, poor stability, etc., to achieve convenient treatment Disease mode, stability-enhancing effects

Active Publication Date: 2015-10-07
浙江维泰生物技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in these microparticle carrier delivery systems, the lipid-soluble drug delivery system cannot achieve a high encapsulation efficiency for hydrophilic macromolecular drugs.
In addition, they are less stable in the digestive tract
Ordinary liposoluble and microemulsion particle carrier delivery systems are basically unable to meet the oral delivery of hydrophilic macromolecular drugs

Method used

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  • 1,2-diazine derivatives and their preparation and use
  • 1,2-diazine derivatives and their preparation and use
  • 1,2-diazine derivatives and their preparation and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Preparation of 1,2-diazine derivatives

[0033] Method 1: Add hydrazine (10.0 equivalents) to a flask mixed with formamidine acetate (4.0 equivalents), sulfur (1.0 equivalents), and ω-cyano compound (1.0 equivalents), and stir the mixture vigorously at 25°C for 20 hours , was added to the acetic acid solution, stirred for 20 minutes and filtered, and the filtrate was collected. An aqueous solution of sodium nitrite (3.0 equivalents) was added to the collected acetic acid solution, and then the solution was cooled at 0°C for 1 hour. Under reduced pressure, acetic acid was removed with a rotary evaporator, and the residue was washed with acetonitrile, filtered, and then recrystallized to obtain pure tetrazole compound (0.5 eq, 50%). The structure of the compound was confirmed by H NMR or mass spectrometry.

[0034]

[0035]Method 2: Add hydrazine (10.0 equivalent) to a flask mixed with cyano compound (4.0 equivalent), sulfur (1.0 equivalent), and ω-cyan...

Embodiment 2

[0047] Example 2: Oral administration of heparin to rats

[0048] Heparin is an anticoagulant, which is a polymer composed of two polysaccharides connected alternately, and has anticoagulant effects both in vivo and in vitro. Clinically, it is mainly used for thromboembolic diseases, myocardial infarction, cardiovascular surgery, cardiac catheterization, extracorporeal circulation, hemodialysis, etc.

[0049] Preparation of heparin oral administration preparation: take 1,2-diazine derivative and dissolve in 30% propylene glycol aqueous solution according to the amount of compound and heparin shown in the table, and adjust the pH value to 7.4 with aqueous sodium hydroxide solution, then stir Allow 20 minutes for the solution to become a homogeneous oral dosing mixture.

[0050] Male rats with a weight of 200-250 grams were fasted for 24 hours, and ketamine (44 mg / kg) was injected intramuscularly into the rats 15 minutes before administration, and then a latex tube with a diame...

Embodiment 3

[0073] Embodiment 3: Oral administration of salmon calcitonin to rats

[0074] Salmon calcitonin inhibits the activity of osteoclasts; inhibits the dissolution of bone salts and prevents the release of calcium in bones; improves bone density and effectively relieves pain symptoms; reduces the risk of fractures; reduces blood calcium.

[0075] Preparation of oral dosage forms of salmon calcitonin: Dissolve the 1,2-diazine derivatives listed in Table 3 in an equivalent amount of sodium hydroxide aqueous solution, so that the pH of the solution is about 7-8. Calcitonin from salmon was weighed and dissolved in an appropriate amount of citric acid aqueous solution (0.08 equivalents), then the two solutions were mixed and fully stirred to form a homogeneous solution for later use.

[0076] Male rats with a weight of 200-250 grams were fasted for 24 hours, and ketamine (44 mg / kg) / chlorpromazine (1.5 mg / kg) was intramuscularly injected into the rats 15 minutes before administration, f...

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Abstract

The invention relates to 1,2-diazine derivatives and their preparation and use. The 1,2-diazine derivatives have a general chemical structural formula shown in the formula I, and in the formula I, R1 represents a substituent H, C1-C4 saturated alkyl, C3-C6 cycloalkyl, C6-C10 aromatic ring or C3-C7 heteroaromatic ring, X represents OH, COOH, CONR2R3 or CONHOH, R2 and R3 represent H, C1-C4 saturated alkyl, or C6-C10 aromatic ring, and n is an integer of 1, 2, 3, 4, 5, 6 and 7. The 1,2-diazine derivatives effectively realize administration of substances with bioactivity for organisms by an oral mode and improves stability of drugs with bioactivity in the gastrointestinal tract. The content of active substances entering into the organisms at least satisfies organism production demands. The 1,2-diazine derivatives realize oral administration of biomacromolecule drugs and provide a convenient mode of disease treatment for patients.

Description

technical field [0001] The present invention relates to 1,2-diazine derivatives, their preparations and their use in oral drug delivery. Specifically, the pharmaceutical composition prepared from biologically active substances and 1,2-diazine derivatives can deliver the biologically active substances to organisms in need of the biologically active substances through oral administration. Background technique [0002] Since the commonly used route of clinical administration of many macromolecular drugs with biological activity such as polysaccharides, proteins, polypeptides, etc. is injection, the drug dosage forms are mostly solution and freeze-dried powder injection, which makes the route of administration of such drugs relatively simple. , and frequent administration also makes patient compliance poor. The main reason for this single route of administration is that if this type of drug is administered orally, it is often hydrolyzed by strong gastric acid before being absorb...

Claims

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Application Information

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IPC IPC(8): C07D237/08C07D401/04A61K47/22A61K31/727A61K31/352A61K38/28A61K31/191A61K38/29A61K38/23
CPCA61K31/191A61K31/352A61K31/727A61K38/23A61K38/28A61K38/29A61K47/22C07D237/08C07D401/04
Inventor 王彦军张冬冬
Owner 浙江维泰生物技术有限公司
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