[go: up one dir, main page]

WO2018133765A1 - Procédé de préparation d'acide benzoïque à base de lactamide et ses applications - Google Patents

Procédé de préparation d'acide benzoïque à base de lactamide et ses applications Download PDF

Info

Publication number
WO2018133765A1
WO2018133765A1 PCT/CN2018/072740 CN2018072740W WO2018133765A1 WO 2018133765 A1 WO2018133765 A1 WO 2018133765A1 CN 2018072740 W CN2018072740 W CN 2018072740W WO 2018133765 A1 WO2018133765 A1 WO 2018133765A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
compound
lactamidobenzoic
reacted
viia
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2018/072740
Other languages
English (en)
Chinese (zh)
Inventor
于治国
赵云丽
张启丽
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shenyang Pharmaceutical University
Original Assignee
Shenyang Pharmaceutical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shenyang Pharmaceutical University filed Critical Shenyang Pharmaceutical University
Publication of WO2018133765A1 publication Critical patent/WO2018133765A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the invention belongs to the field of pharmaceutical synthesis and pharmacology, and relates to a preparation method and application of 2-lactamaminobenzoic acid, in particular to (R)-2-lactamidobenzoic acid (R-HPABA) and (S)-2-milk Preparation of amidobenzoic acid (S-HPABA) and new medical uses.
  • antithrombotic drugs have been developed and applied, and are classified into antiplatelet agglutination drugs, anticoagulants and thrombolytic drugs according to their target and mechanism of action.
  • aspirin and clopidogrel are clinically recognized drugs for the treatment of platelet aggregation-related diseases, such as in the treatment of thrombosis and atherosclerosis.
  • the above-mentioned similar drugs have been extensively studied in antithrombotic and have been clinically applied for a long time, but there are side effects such as narrow therapeutic window, bleeding risk, drug resistance, and other unexpected drug interactions have been the focus of attention.
  • 2-Amilylaminobenzoic acid is a new compound isolated from the metabolites of microorganisms and can be obtained by chemical synthesis without the stimulating effect of gastrointestinal tract like aspirin. It has a promising medical use.
  • Still another object of the present invention is to provide the use of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid for the preparation of an antiplatelet aggregation or antithrombotic drug.
  • the present invention provides a benzoic acid compound having the following formula:
  • R 3 —H; —F;—Cl;—Br
  • R 4 —H; —F;—Cl;—Br
  • R 5 —H; —F; —Cl;—Br.
  • the present invention provides the compound (R)-2-lactoamidobenzoic acid and (S)-2-lactoamidobenzoic acid having the following structure, and the English name is R-/S-2-lactoylaminobenzoic acid:
  • the (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid are respectively:
  • the (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid provided by the invention has the following specific steps:
  • step (d) there are two methods for obtaining 2-lactamamidobenzoic acid; the organic solvents used in the two methods are tetrahydrofuran and methanol, and the former is reacted with a potassium carbonate solution, and the ratio of the substances is from 1 to 2:5. The latter is reacted with a sodium hydroxide solution in an amount ratio of 1 to 2:5.
  • step (d) the reaction is completed, extracted with dichloromethane and adjusted to pH 1-4 with hydrochloric acid.
  • the (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid has remarkable antiplatelet aggregation and antithrombotic activity.
  • the raw materials for preparation thereof are widely used, the cost is not high, and it has no stimulating effect on the stomach, and has superior advantages compared with aspirin, and has a very promising application prospect.
  • Figure 1 is a graph showing the platelet toxicity of (R)-2-lactamidobenzoic acid and (S)-2-lactamylbenzoic acid.
  • Figure 2 is a graph showing the effect of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid on cyclooxygenase-1 (COX-1) activity.
  • the method was the same as the 1.2 synthesis method except that L-lactic acid was replaced by D-lactic acid. According to the synthesis method of S-2-lactic acid aminobenzoic acid, 8.50 g of R-2-lactic acid aminobenzoic acid was obtained, and the total yield was 52.9%.
  • Aspirin ASP, purity >99.5%
  • (R)-2-lactamaminobenzoic acid homemade, optical purity >99.3%
  • (S)-2-lactamidobenzoic acid homemade, optical purity >98.8%)
  • dimethyl sulfoxide DMSO
  • ADP adenosine diphosphate
  • collagen COLL
  • arachidonic acid AA
  • thromboxane B 2 TXB 2
  • enzyme-linked immunosorbent assay kit 6-ketone -Prostaglandin F1 ⁇ (6-keto-PGF1 ⁇ ) enzyme-linked immunosorbent assay kit, epoxidase-1 (COX-1) enzyme-linked immunosorbent assay kit, lactate dehydrogenase (LDH) assay kit, carboxymethyl fiber Sodium (CMC-Na).
  • mice male, SPF grade, body weight 18-22 g, SCXK 2015-0001.
  • Lactate dehydrogenase (LDH) is considered to be an indicator of cell viability. Therefore, this test evaluates (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzene by measuring the release of LDH. Formic acid is toxic to platelets. (R)-2-lactamaminobenzoic acid or (S)-2-lactamylbenzoic acid (150 ⁇ g/mL) was incubated with PRP for different times and assayed using the LDH Toxicity Assay Kit according to the instructions. The extent of LDH release is expressed as a percentage of the maximum release (0.3% Triton X-100).
  • KM mice were randomly divided into 8 groups of 8 animals each. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control).
  • the drug was administered by intragastric administration once a day for 7 days.
  • Urethane was anesthetized (1 g/kg, i.p.) 1 h after the last administration. A length of about 5 mm was cut from the tip of the mouse and rapidly inserted into physiological saline at 37 °C. The time from the start of bleeding to the second bleeding within 15 minutes was observed and recorded.
  • the experimental grouping and administration were as shown in 1.3.3, and urethane was anesthetized 1 hour after the last administration.
  • SD rats were randomly divided into 8 groups, 5 in each group. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control).
  • the drug was administered by intragastric administration once a day for 7 days.
  • Urethane was anesthetized (1 g/kg, ip) 1 h after the last administration. Blood was taken from the abdominal aorta, PRP was prepared, and stored at -20 °C before analysis. The concentrations were determined by the TXB 2 and 6-keto-PGF1 ⁇ enzyme-linked immunosorbent kit according to the instructions.
  • SD rats were randomly divided into 4 groups, 5 in each group. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid (200 mg/kg), CMC-Na (blank control) .
  • the drug was administered by intragastric administration once a day for 7 days.
  • Urethane was anesthetized (1 g/kg, i.p.) 1 h after the last administration. Blood was taken from the abdominal aorta, PRP was prepared, and stored at -20 °C before analysis. The concentration was determined by the COX-1 enzyme-linked immunosorbent assay kit according to the instructions.
  • FIG. 2 The experimental results are shown in Fig. 2.
  • (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid and aspirin can significantly inhibit COX-1 compared with the control group.
  • Active, and the effect of S-2-lactamidobenzoic acid is comparable to that of aspirin, and the effect is superior to R-2-lactamidobenzoic acid.
  • the experimental results of the present invention indicate that the anti-platelet aggregation of (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzoic acid may further inhibit thromboxane by inhibiting the activity of cyclooxygenase-1. Generation of A 2 (precursor compound of TXB 2 ).
  • mice male, SPF grade, body weight 18-22 g, SCXK 2015-0001.
  • KM mice were randomly divided into 8 groups of 10 animals each. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control).
  • the drug was administered by intragastric administration once a day for 7 days.
  • a mixture of collagen 500 ⁇ g/kg
  • epinephrine 50 ⁇ g/kg
  • the number of mice with hemiplegia, death or recovery within 15 min was observed and recorded.
  • Inhibition rate (%) ((number of deaths in the blank group - number of deaths in the administration group) / number of deaths in the blank group) x 100%.
  • SD rats were randomly divided into 8 groups, 5 in each group. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control).
  • the drug was administered by intragastric administration once a day for 7 days.
  • Urethane was anesthetized (1 g/kg, ip) 1 h after the last administration.
  • (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzoic acid can significantly improve the recovery rate of pulmonary thrombosis compared with the blank group.
  • medium and high doses of (R)-2-lactamidobenzoic acid and high doses of (S)-2-lactamidobenzoic acid are superior to aspirin, and medium and high doses (R)
  • the -2-lactamidobenzoic acid acts more than the same concentration of S-2-lactamamibenzoic acid.
  • the experimental results of the present invention indicate that (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid has an anti-pulmonary thrombosis effect. Its antithrombotic effect may be produced by its anti-platelet aggregation.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une nouvelle utilisation médicale d'un composé chiral. Le nom chimique est l'acide benzoïque à base de R-/S-2-lactamide, ayant une formule structurale présentée ci-dessous. Le composé est à l'origine extrait d'un métabolite secondaire de microorganismes, et peut être obtenu par synthèse chimique. Selon l'invention, des expériences pharmacologiques initiales ont montré que le composé présente de bonnes activités analgésiques et anti-inflammatoires, et avait moins de stimulation dans le tractus digestif. Selon l'invention, des études récentes montrent qu'un énantiomère du composé présente une meilleure agglutination antiplaquettaire et des activités antithrombotiques et par conséquent, le composé est supposé devenir un nouveau médicament d'agglutination antiplaquettaire non stéroïdien et antithrombotique.
PCT/CN2018/072740 2017-01-19 2018-01-16 Procédé de préparation d'acide benzoïque à base de lactamide et ses applications Ceased WO2018133765A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710043164.6A CN106831475B (zh) 2017-01-19 2017-01-19 2-乳酰氨基苯甲酸的制备方法与应用
CN2017100431640.6 2017-01-19

Publications (1)

Publication Number Publication Date
WO2018133765A1 true WO2018133765A1 (fr) 2018-07-26

Family

ID=59119326

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/072740 Ceased WO2018133765A1 (fr) 2017-01-19 2018-01-16 Procédé de préparation d'acide benzoïque à base de lactamide et ses applications

Country Status (2)

Country Link
CN (1) CN106831475B (fr)
WO (1) WO2018133765A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106831475B (zh) * 2017-01-19 2018-11-27 沈阳药科大学 2-乳酰氨基苯甲酸的制备方法与应用
CN113717049A (zh) * 2021-08-05 2021-11-30 江西兄弟医药有限公司 一种制备（s）-乙酰氧基丙酰氯的半连续方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101402565A (zh) * 2008-11-14 2009-04-08 郑州大学 卤代2－（a－羟基戊基）苯甲酸盐及其制法和用途
CN103864638A (zh) * 2012-12-14 2014-06-18 沈阳药科大学 一种苯甲酸类化合物及其制备方法和应用
CN106831475A (zh) * 2017-01-19 2017-06-13 沈阳药科大学 2‑乳酰氨基苯甲酸的制备方法与应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101402565A (zh) * 2008-11-14 2009-04-08 郑州大学 卤代2－（a－羟基戊基）苯甲酸盐及其制法和用途
CN103864638A (zh) * 2012-12-14 2014-06-18 沈阳药科大学 一种苯甲酸类化合物及其制备方法和应用
CN106831475A (zh) * 2017-01-19 2017-06-13 沈阳药科大学 2‑乳酰氨基苯甲酸的制备方法与应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ZHANG, QILI ET AL.: "The Determination of 2-(2-hydroxypropanamido) Benzoic Acid Enantiomers and Their Corresponding Prodrugs in Rat Plasma by UHPLC-MS/MS and Application to Comparative Pharmacokinetic Study After a Single Oral Dose", JOURNAL OF CHROMATOGRAPHY B, vol. 1041 and, 12 November 2016 (2016-11-12), pages 175 - 182, XP055504907 *

Also Published As

Publication number Publication date
CN106831475A (zh) 2017-06-13
CN106831475B (zh) 2018-11-27

Similar Documents

Publication Publication Date Title
AU668107B2 (en) Oxygen substituted derivatives of nucleophile-nitric oxide adducts as nitric oxide donor prodrugs
KR101708073B1 (ko) 록소프로펜 유도체 및 그것을 함유하는 의약
TWI714566B (zh) 軸手性異構體及其製備方法和製藥用途
JP2018520168A (ja) 新たなピラジン誘導体及びその調製方法並びに医薬応用
CN111303058B (zh) 续随子醇衍生物及其制备方法和用途
JP2018526448A (ja) 一酸化窒素を放出可能なプロドラッグ分子
JP2015526396A (ja) 置換トロポロン誘導体およびその使用方法
JP2009209129A (ja) ４−カルバモイル−５−ヒドロキシ−イミダゾール誘導体のスルホン酸塩化合物
CN103193789A (zh) 一种光学活性的丁苯酞开环衍生物、制备方法及医药用途
WO2018133765A1 (fr) Procédé de préparation d'acide benzoïque à base de lactamide et ses applications
CN108084233B (zh) 一种糖基修饰的丁苯酞开环衍生物的制备方法及医药用途
WO1994002457A1 (fr) Derive de prostaglandine
JPH03163061A (ja) ピリジンカルボキシイミダミド誘導体、その製造中間体、製造法および用途
CN109503548A (zh) 一种丁苯酞衍生物及其制备方法和应用
JPH0551374A (ja) スルホンアミド誘導体、その製造法および該化合物を含有する、ロイコトリエン仲介疾病または医学的症状に使用するための医薬調剤
CN116874469B (zh) 一种氧代吡啶类化合物、中间体及其制备方法和用途
JPS60218377A (ja) ４−フエニルフタラジン誘導体及びそれを有効成分とする循環改善剤
JPS585195B2 (ja) シンキナヒテンネンサンシユツセイプロスタンサンルイエンタイ ノ セイホウ
JP5695797B2 (ja) 新規抗血小板化合物の付加塩
JPS63275593A (ja) β−アミノエチルリン酸エステル誘導体
CN105175377A (zh) 一类白杨素取代水杨酸酯酚醚类化合物及其制法和用途
JPS604177B2 (ja) ベンゾフラン誘導体の製造方法
CN103450087B (zh) 丹皮酚与奥扎格雷偶联物的制备方法
CN103467383B (zh) 一种丹皮酚与奥扎格雷偶联物及其药物组合物、医药用途
HU197003B (en) Process for producing new isoxazole derivatives and pharmaceuticals comprising same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18741908

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18741908

Country of ref document: EP

Kind code of ref document: A1