CN115772131A - Triazole derivatives having anticoagulant activity - Google Patents
Triazole derivatives having anticoagulant activity Download PDFInfo
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- CN115772131A CN115772131A CN202210763409.3A CN202210763409A CN115772131A CN 115772131 A CN115772131 A CN 115772131A CN 202210763409 A CN202210763409 A CN 202210763409A CN 115772131 A CN115772131 A CN 115772131A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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Abstract
The invention discloses a triazole derivative with anticoagulant activity, which has a structural general formula shown in the specification. The test result shows that the compound has higher activity and lower toxicity compared with acetylsalicylic acid, and is expected to become a new anticoagulant.
Description
Technical Field
The invention relates to the fields of chemistry and medicine, in particular pharmaceutical chemistry and pharmacology, and aims at enabling the synthesis of new drugs for the prevention of thrombosis and thromboembolic complications.
Background
Among the previous generation anticoagulant drugs, the following have been approved for clinical use: l-cysteine amide, N6- (aminoiminomethyl) -N2- (3-mercapto-1-oxopropyl) -L-lysyl-L-alpha-aspartyl-L-tryptophan-L-prolyl-, cyclic (1-6) -disulfide (eptifibatide, granatin Schwark, england Co., ltd., UK), N- (butylsulfonyl) -4- [4- (piperidinyl) butoxy]F (ab ') 2 fragments of the mouse monoclonal protein IIb-IIIa (L-phenylalanine hydrochloride monohydrate, agrastat coreviro, UK), and the antiplatelet fibrinogen receptor Glycoprotein (GP) ((ab'))
Framon CJSC,Russia).(L.E.Holmes,R.Gupta,S.Rajendran,J.Luu,J.K.French,C.P.Juergens.A randomised trial assessing the impact of three different glycoprotein IIb/IIIa antagonists on glycoprotein IIb/IIIa platelet receptor inhibition and clinical endpoints in patients with acute coronary syndromes.Cardiovascular Therapy.2016,no.21.doi:10.1111/1755-5922.12203.)
Although clinical trials indicate that these compounds may be most effective in interventional cardiology, their use is limited due to their high cost and risk of eliciting autoimmune responses (c.patono, f.andreotti, h.arnesen.antiplatlet agents for the treatment and presentation of atherothrombosis.european Heart journal.2011.vol.32.pp.2922-2932.).
The closest analogue and reference drug to the present invention is acetylsalicylic acid (2-acetylhydroxybenzoic acid or aspirin), which has been successfully used in actual medicine and proven effective in preventing and treating thrombotic and thromboembolic complications (2018Guidelines for the Early Management of Patents With administration of International linkages.
The disadvantages of this primary drug are the high frequency of aspirin resistance and the adverse clinical manifestations of the ulcerogenic and hemorrhagic effects.
Disclosure of Invention
The object of the present invention is to provide a triazole derivative having an anticoagulant activity to expand the range of bioactive substances having an anticoagulant activity.
The technical scheme of the invention is as follows:
triazole derivatives having anticoagulant activity and having the general formula:
the invention also provides application of the triazole derivative in preparation of a medicament, and the medicament has anticoagulant activity.
Compared with the prior art, the invention has the beneficial effects that: provides a triazole derivative with anticoagulant activity, expands the range of bioactive substances with anticoagulant activity, and is expected to reduce the defects of the existing anticoagulant drugs.
The specific implementation mode is as follows:
synthesis of the synthesized compounds and toxicity test.
The synthesis of the compounds claimed herein is as follows.
Example 1 Synthesis of 1- [ (4-n-octylphenyl) methyl ] -1H-benzotriazole (Ia).
0.17g (0.88 mmol) of n-octyl bromide is added to 0.20g (0.88 mmol) of 4- [ (1H-benzotri-ol-1-yl) methyl ] phenol in 6ml of methyl ethyl ketone, stirred vigorously under argon at 20 ℃ and then 0.58g (1.77 mmol) of cesium carbonate is added. The reaction mixture was boiled under reflux in an inert medium for 6 hours and then filtered from the inorganic precipitate. The solvent was removed under vacuum. The resulting white residue was washed with hot n-hexane and air dried.
Yield: 0.21g (70%); melting temperature (Tm): 65-67 ℃; delay factor (Rf): 0.69 (ethanol: carbon tetrachloride, 1.
Elemental analysis: c74.86; h8.10. C 21 H 27 N 3 O, estimated value,%: C74.74%; h8.07 percent.
Infrared (IR) spectrum, v, cm -1 :1254(C-O-C,val.),1453,1518,1620(arom.,val.)2873(C 8 H 17 ,val.).
High resolution NMR 1 HNMR) Spectroscopy (CDCl) 3 ),δ,ppm:0.87–0.90(3H,t,CH 3 ),1.30–1.75(12H,m,6CH 2 ),3.95–3.97(2H,t,CH 2 ),5.82(2H,s,CH 2 ),6.84–6.85(arom.2H,d,CH＝),7.28–7.30(arom.2H,d,CH＝),7.40–7.51(arom.2H,m,CH＝),8.06–8.10(arom.2H,m,CH＝).
The material is a white solid soluble in DMSO, DMF, chloroform, and acetone.
Example 2.1- [ (4-n-hexadecyloxyphenyl) methyl ] -1H-1,2, 4-triazole (Ib) synthesis.
We added 0.44g (1.42 mmol) of n-hexadecylbromide to a solution of 0.25g (1.42 mmol) of 4- [ (1H-1, 2, 4-triazol-1-yl) methyl ] phenol, stirred vigorously under argon at 20 ℃ and then added 0.93g (2.86 mmol) of cesium carbonate. The reaction mixture was boiled under reflux in an inert medium for 5 hours and then filtered from the inorganic precipitate. The solvent was removed under vacuum. The resulting white residue was recrystallized from n-hexane and air dried.
Yield: 0.40g (71%); tm: 68-70 ℃ (n-hexane); rf:0.44 (ethanol: carbon tetrachloride, 1.
Elemental analysis: it has been found that% C75.28%; h10.50%. C 25 H 41 N 3 O, estimated,%: C75.14%; h10.34%
Infrared Spectrum (KBr), v, cm -1 :1253(C-O-C,val.),1450,1463,1515,1615(arom.,val.),2848,2917(C 16 H 33 ,val.).
High resolution nuclear magnetic resonance spectroscopy (CDCl) 3 ),δppm:0.89–0.91(3H,t,CH 3 ),1.31–1.74(28H,m,14CH 2 ),3.97–3.99(2H,t,CH 2 ),5.78(2H,s,CH 2 ),6.75–6.76(arom.2H,d,CH＝),7.14–7.15(arom.2H,d,CH＝),7.95(arom.1H,s,CH＝),8.56(arom.1H,s,CH＝).
The substance is a white crystalline substance soluble in DMSO, DMF, chloroform and carbon tetrachloride.
Example 3 anticoagulant activity of compounds la, b.
In vitro experiments were performed on blood samples collected from healthy male blood donors aged 18-24 (n = 22). To investigate the effect of these compounds on hemostasis, BD was used
The vacuum blood collection system (Becton Dickinson and Company, USA) collects blood samples from the elbow vein. A 3.8% sodium citrate solution in a ratio of 9. All tests were performed on both platelet-rich and platelet-deficient plasma. Platelet rich plasma samples were obtained by centrifugation of the blood citrate at 1000rpm for 10 minutes, while platelet free plasma samples were obtained by centrifugation of the blood citrate at 3000rpm for 20 minutes. OPN-3.02 centrifuges (TNK DASTAN OJSC, gilgistan) were used in this study. The effect of this compound on platelet aggregation was studied using the Born method on an AT-02 aggregation meter (NPFMedtech, russia). The anticoagulant activity of compound I and aspirin was measured at a final concentration of 10 -3 mol/l. Adenosine Diphosphate (ADP) at a concentration of 20. Mu.g/ml and collagen (Russian standard) at a concentration of 5mg/ml were used as aggregation inducers. Platelet aggregation induced in ADPIn the aggregation process, the maximum aggregation amplitude, the aggregation rate, the time to reach maximum aggregation amplitude and the time to decomposition in the presence of the compound under study were evaluated. In collagen-induced platelet aggregation, the latency period during which phospholipase C is activated (leading to the formation of secondary messengers, secretion of platelet granules and thromboxane A) is assessed 2 Synthesis of (ii).
200 male white mice (2 months of age) with an average body weight of 20-21g were studied for acute toxicity and intraperitoneally injected with the synthesized compound and aspirin. Prior to the experiment, the animals were kept in a separate cage in vivo at the BSMU department of biochemistry for 14 days. The external temperature is kept between 18 ℃ and 22 ℃, and the illumination is combined with natural light and artificial light. The sterilization treatment was performed weekly using a stationary wall-mounted germicidal irradiation unit for 20 minutes. It can be used for drinking water for 24 hr, and feeding standard diets for natural products (vegetables, grains) and experimental animals (mice, rats, hamsters) meeting the standard of qualified statement (No. ROSS RU. PR 98, D00497, 2016, 7/2), and containing wheat, barley, soybean meal, fish meal, yeast and bran, vitamins and mineral complex, vegetable fat and antioxidant.
The study was conducted in accordance with good laboratory practice and federal law No. 61-FZ, 12 d 4/2010, article 11, "drug circulation" and the "new drug experiment (preclinical) research guidelines" (m., 2012).
In toxicity studies in mice, the study was conducted at a dose of 100-500mg/kg, with 50mg/kg being escalated. The amount of injected substance was calculated from the weight of the mouse and the maximum allowable amount of liquid that could be injected was taken into account. A group of control (untreated) animals was included in the experiment to assess the status and behavior of individuals in the control and experimental groups in comparison. This group of animals was excluded from the experiment at the end of the first day observation. The experiment groups were observed for 14 days.
Statistical analysis of the study results was performed using the statistical t10.0 statistical software package (StatSoft Inc, USA). The data were tested for normal distribution using the Shapiro-Wilk test. Analysis of variance was performed using the Kruskal-Wallis test. The critical significance level (p-value) for the statistical test was set to 0.05. The lethal dose was calculated as a 50% (LD 50) value by probe analysis using biostat5.9 software (analystsoftinc.).
Platelet release responses (lag phase) were prolonged by 15.7% (p < 0.05) and 10.3% (p < 0.05) for Ia and Ib, respectively, by adding the compound under study to the aggregometer cuvette (table 1); the platelet aggregation amplitude of the Ia group is reduced by 29.4 percent (p < 0.05), and the platelet aggregation amplitude of the Ib group is reduced by 23.5 percent (p < 0.05); the platelet aggregation rates were reduced by 13.6% (p < 0.05) and 7.4% (p < 0.05) for group Ia and group Ib, respectively, and the time to reach maximum aggregation was increased by 25.7% (p < 0.05) and 18.3% (p < 0.05), respectively, as compared to the control group. Meanwhile, aspirin was found to have no effect on platelet release, indicating that it had an effect on the level of platelet aggregation that was more than 2.2-fold lower than compound Ia (p < 0.05), an index of platelet aggregation rate that was 28.6% lower than compound Ia (p < 0.05), and a time required to achieve maximum aggregation that was more than 2.4-fold lower than compound Ia (p < 0.05). In addition, aspirin had an effect on the level of platelet aggregation 1.7-fold or more (p < 0.05) lower than that of compound Ib, an index of platelet aggregation rate 59.4% lower than that of compound Ib (p < 0.05), and the time required for maximum aggregation 1.7-fold or more lower than that of compound Ib (p < 0.05).
TABLE 1 index of anticoagulant activity of compounds Ia, b and acetylsalicylic acid, n =10
Note the latency of collagen-induced platelet aggregation; other parameters are ADP-induced platelet aggregation. * P is less than or equal to 0.05, P is less than or equal to 0.001-compared with a control group; (ii) a # P is less than or equal to 0.05, # # P is less than or equal to 0.001-compared with acetylsalicylic acid.
Example 4 acute toxicity study of Compounds Ia and b in mice.
Said compounds belong to the "low toxicity" class according to the chemical acute toxicity system of peltezomib and the toxicity standard of chemical compounds for intravenous injection. (Table 2).
Acute toxicity index, M + -SD, for the compounds described in Table 2 and acetylsalicylic acid
| Indicator | Acetylsalicylic acid | Ia | Ib |
| LD50,mg/kg | 302,9±32,6 | 560±27,9 | 610±39,7 |
Therefore, the compound is less toxic, and it more effectively inhibits activation and aggregation of platelets than aspirin.
Claims (4)
1. Triazole derivatives having anticoagulant activity, characterized by the following general structural formula:
2. the triazole derivative having anticoagulant activity according to claim 1, which is compound Ia, wherein R is 1- [ (4-n-octylphenyl) methyl ] -1H-benzotriazole.
3. The triazole derivative having anticoagulant activity according to claim 1, which is a compound Ib, wherein R is 1- [ (4-n-hexadecyloxyphenyl) methyl ] -1H-1,2, 4-triazole.
4. Use of a triazole derivative as claimed in any one of claims 1 to 3 in the preparation of a medicament having anticoagulant activity.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| RURU2021119727A | 2021-07-05 | ||
| RU2021119727A RU2770405C1 (en) | 2021-07-05 | 2021-07-05 | Triazole derivatives exhibiting antiaggregatory activity |
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| Publication Number | Publication Date |
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| CN115772131A true CN115772131A (en) | 2023-03-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202210763409.3A Pending CN115772131A (en) | 2021-07-05 | 2022-06-30 | Triazole derivatives having anticoagulant activity |
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| RU (1) | RU2770405C1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0840740B1 (en) * | 1995-07-11 | 2002-05-02 | AstraZeneca AB | New inhibitors of platelet aggregation |
| RU2488583C2 (en) * | 2009-03-05 | 2013-07-27 | Государственное образовательное учреждение высшего профессионального образования "Российский химико-технологический университет им. Д.И. Менделеева" (РХТУ им. Д.И. Менделеева) | SUBSTITUTED O-[ω-(AZOL-1-YL)ALKYL]-N-PHENYLCARBAMATES AS AGENTS WITH ANTIAGGREGATORY ACTIVITY, METHOD FOR PRODUCTION THEREOF (VERSIONS) AND PHARMACEUTICAL COMPOSITION BASED THEREON |
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