WO2009117888A1 - Inhibiteurs de phosphodiestérase iii, leurs procédés de fabrication et leurs utilisations médicales - Google Patents

Inhibiteurs de phosphodiestérase iii, leurs procédés de fabrication et leurs utilisations médicales Download PDF

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Publication number
WO2009117888A1
WO2009117888A1 PCT/CN2008/073394 CN2008073394W WO2009117888A1 WO 2009117888 A1 WO2009117888 A1 WO 2009117888A1 CN 2008073394 W CN2008073394 W CN 2008073394W WO 2009117888 A1 WO2009117888 A1 WO 2009117888A1
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WO
WIPO (PCT)
Prior art keywords
compound
mmol
mol
tetrazole
phenyl
Prior art date
Application number
PCT/CN2008/073394
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English (en)
Chinese (zh)
Inventor
高署
Original Assignee
合肥合源药业有限公司
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 合肥合源药业有限公司 filed Critical 合肥合源药业有限公司
Publication of WO2009117888A1 publication Critical patent/WO2009117888A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a class of phosphodiesterase III inhibitors, and the invention also discloses a preparation method thereof and use thereof for treating cardiovascular diseases.
  • Bradycardia refers to an adult heartbeat that is less than 60 beats per minute. It is a common clinical disease and is a type of arrhythmia [1] . Bradycardia includes sinus bradycardia, ectopic rhythm, atrial fibrillation with slow ventricular response, atrioventricular block and ventricular rhythm. The most common is sinus bradycardia, which is caused by both physiological and pathological conditions: Physiological bradycardia is generally a normal person, such as some physiological and psychological changes caused by long-term participation in physical exercise or strong physical labor. Sinus bradycardia.
  • Pathological bradycardia is mainly caused by drugs, systemic diseases or cardiovascular diseases, such as the use of ⁇ -blockers and anesthetics to cause bradycardia; some systemic diseases, such as hypothyroidism, obstructive jaundice Cardiovascular diseases such as acute myocardial infarction, chronic ischemic heart disease, etc.
  • bradycardia can be treated by implanting a cardiac pacing device. Although the safety of this method has been recognized, it is not the first choice for most patients due to its high cost and limited surgical success rate.
  • atropine isoproterenol or ephedrine can be used.
  • Atropine competes against the acetylcholine receptor for choline receptors, so it can relieve the vagus nerve from inhibiting the heart and speed up the heart rate.
  • Isoproterenol a ⁇ -receptor agonist, has a significant excitatory effect on the positive pacing point (sinus node) and accelerates conduction, thereby speeding up heart rate.
  • Ephedrine has an excitatory effect on ⁇ and ⁇ -receptors, and its effect is similar to that of isoproterenol.
  • the effect is weak but long-lasting, and the heart rate can be accelerated.
  • the increase in blood pressure can reflect the vagus nerve and slow down the heart rate, which can offset the effect of directly accelerating the heart rate, so its effect of accelerating heart rate is not obvious.
  • treatment with these drugs can cause side effects such as gastrointestinal discomfort, and inadvertent use can even cause serious consequences such as arrhythmia. Therefore, it is not necessary to develop an effective and safe anti-bradycardia drug.
  • Phosphodiesterase III (PDEIII) inhibitors have been used in cardiovascular disease patients such as amrinone and milrinone. By inhibiting PDEIII, platelet aggregation is inhibited, coronary blood flow and cAMP levels are increased, and heart rate is increased.
  • the present invention discloses a class of compounds of formula I, including pharmaceutically acceptable salts thereof:
  • R 2 represents an alkyl group of C1 to C8
  • R represents hydrogen, C1 to C8 alkyl, halogen, amino, hydroxy, nitro, cyano, C1 to C4 alkoxy, C1 to C4 sulfonyl, C1 to C4 alkanoyl or C1 to C4 alkane Amide group
  • n 2 ⁇ 6.
  • R preferably represents hydrogen or halogen.
  • n is preferably 3 or 4.
  • the preparation method of the compound of the present invention is as follows:
  • Kunming mice half an early half, weighing 18 - 22 g, 8 rats in each group, were randomly divided into: normal control group, model control group, atropine (Atr) control group, cilostazol control group, different compounds of the invention group. Except the normal control group, the other groups of mice were intragastrically administered (ig) Pro in the morning, and ig NS, Atr, cilostazol and the compound of the present invention were administered once a day for 7 days. The electrocardiogram (ECG) of each group was measured 2 hours after the last administration, and the changes in heart rate of each group were compared.
  • ECG electrocardiogram
  • Table 1 shows that the compounds of the present invention can significantly inhibit Pro-induced heart rate depression, and have anti-propranolol-induced bradycardia in mice.
  • mice were randomly divided into normal control group, atropine (Atr) control group and several groups of different compounds of the present invention, 8 rats in each group. Each half.
  • the administration method was the same as above.
  • the EC-2 test was performed using the BL-2 biological function test system, and the heart rate of the mice was recorded, followed by intravenous injection (iv) Ver 4 mg/kg, 3 Sec internal injection. At the end, the heart rate was re-recorded 2 min after the shoot and 2 min after the iv 4 mg/kg Ver.
  • Table 2 shows that the compounds of the present invention have an effect against verapamil-induced bradycardia in mice.
  • Rabbits were anesthetized with 3% sodium pentobarbital.
  • the common carotid arteries were surgically removed, blood was intubated, and anticoagulated with 3.8% sodium citrate (1:9), centrifuged at 1000 rpm for 5 min to prepare platelet-rich plasma.
  • PRP centrifuged at 3000 rpm for 15 min to prepare platelet poor plasma (PPP;).
  • PRP was transferred into a silicidation cuvette, heated at 37 ° C for 5 min, measured at 600 nm absorbance (A), PPP adjusted PRP A value between 0.6 and 0.7, 1.7 ml adjusted PRP was transferred to another silicidation
  • A absorbance
  • add 200 ul of the test drug measure the A value before adding ADP at 600 nm, then add 100 ⁇ ADP (20 ⁇ /ml), and then measure the A value at 2 min and 5 min after adding ADP, respectively.
  • the aggregation inhibition rate (AIR) of the drug was calculated.
  • the results are shown in Table 3. Compared with the blank group, 111 ⁇ /1111 aspirin significantly inhibited aggregation at 21 1 and 5 min (P ⁇ 0.01).
  • the compound of the present invention can significantly inhibit ADP-induced platelet aggregation, has an antithrombotic effect, and can be used for treating thrombosis-related diseases.
  • the invention also provides a pharmaceutical composition comprising a compound of the invention in combination or association with a pharmaceutically acceptable carrier. More particularly, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable carrier. The compound of the present invention may also be present in the form of a pharmaceutically acceptable salt.
  • the compounds of the present invention may be formulated for administration by a single or a combination of one or more pharmaceutically acceptable carriers.
  • a solvent, a diluent, or the like can be administered in an oral dosage form such as a tablet, a capsule, a dispersible powder, a granule, or the like.
  • These pharmaceutical preparations may contain, for example, from 0.05% to 90% by weight of the active ingredient in combination with the carrier, more usually from about 15% to 60% by weight of the active ingredient.
  • the dose of the compound of the present invention may be from 0.001 to 100 mg/kg/day, and may also deviate from this dose range depending on the degree of the disease or the difference in the dosage form.
  • the organic phase was combined, washed with 0.2 mol/L NaOH 20 ml X 3 times, dried over anhydrous NaSO 4 and evaporated to dryness.
  • the solid obtained twice. 5.4 g (0.03 mol) of the above solid and A1C1 3 8.01 g (0.06 mol) were combined, ground into powder, added to a 150 ml three-necked flask, mechanically stirred, heated to 120 ° C for 0.5 h, cooled, added with water and acetic acid each esters 50ml, layered separated and the aqueous layer was extracted with ethyl acetate 50mlX 3 times, the organic layers were combined, dried over anhydrous NaSO 4, filtered, and the solvent was removed under reduced pressure to give a pale yellow solid.
  • Example 3 0.5 g of the compound obtained in Example 3, 2 g of starch, and lg of dextrin were mixed, and an appropriate amount of 30% ethanol was used as a wetting agent, granulated, and tableted.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur des inhibiteurs de phosphodiestérase III représentés par la formule (I) dans le domaine de la chimie médicale, dans laquelle formule les définitions de R1, R2 et n sont telles que dans la description. L'invention porte également sur les procédés de fabrication et sur les utilisations des composés de formule (I) pour le traitement de maladies cardiovasculaires.
PCT/CN2008/073394 2008-03-24 2008-12-09 Inhibiteurs de phosphodiestérase iii, leurs procédés de fabrication et leurs utilisations médicales WO2009117888A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2008100244960A CN101544614B (zh) 2008-03-24 2008-03-24 磷酸二酯酶ⅲ抑制剂、其制法及其医药用途
CN200810024496.0 2008-03-24

Publications (1)

Publication Number Publication Date
WO2009117888A1 true WO2009117888A1 (fr) 2009-10-01

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PCT/CN2008/073394 WO2009117888A1 (fr) 2008-03-24 2008-12-09 Inhibiteurs de phosphodiestérase iii, leurs procédés de fabrication et leurs utilisations médicales

Country Status (2)

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CN (1) CN101544614B (fr)
WO (1) WO2009117888A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104529923A (zh) * 2015-01-13 2015-04-22 佛山市赛维斯医药科技有限公司 二烯四氮唑硝基苯类化合物、其制备方法和用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103351352B (zh) * 2013-07-15 2015-10-21 南通市华峰化工有限责任公司 一种5-苯基四氮唑新合成方法
CN104610184A (zh) * 2015-01-13 2015-05-13 佛山市赛维斯医药科技有限公司 苯二烯四氮唑类化合物、其制备方法和用途
CN104910089A (zh) * 2015-06-02 2015-09-16 安徽兴东化工有限公司 一种5-苯基四氮唑的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS579771A (en) * 1980-06-21 1982-01-19 Otsuka Pharmaceut Co Ltd Tetrazole derivative
EP0303478A1 (fr) * 1987-08-14 1989-02-15 Eli Lilly And Company Antagonistes de leucotriène

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS579771A (en) * 1980-06-21 1982-01-19 Otsuka Pharmaceut Co Ltd Tetrazole derivative
EP0303478A1 (fr) * 1987-08-14 1989-02-15 Eli Lilly And Company Antagonistes de leucotriène

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104529923A (zh) * 2015-01-13 2015-04-22 佛山市赛维斯医药科技有限公司 二烯四氮唑硝基苯类化合物、其制备方法和用途

Also Published As

Publication number Publication date
CN101544614B (zh) 2011-07-20
CN101544614A (zh) 2009-09-30

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