WO2018209973A1 - Composés deutérés de résistance à l'endommagement du cerveau et leur utilisation médicale - Google Patents

Composés deutérés de résistance à l'endommagement du cerveau et leur utilisation médicale Download PDF

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Publication number
WO2018209973A1
WO2018209973A1 PCT/CN2018/000168 CN2018000168W WO2018209973A1 WO 2018209973 A1 WO2018209973 A1 WO 2018209973A1 CN 2018000168 W CN2018000168 W CN 2018000168W WO 2018209973 A1 WO2018209973 A1 WO 2018209973A1
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WO
WIPO (PCT)
Prior art keywords
isomer
preparation
formula
nmr
nbp
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PCT/CN2018/000168
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English (en)
Chinese (zh)
Inventor
仲伯华
杨家俊
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泰州华元医药科技有限公司
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Publication of WO2018209973A1 publication Critical patent/WO2018209973A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/80—Phthalic acid esters

Definitions

  • the present invention relates to a deuterated derivative of cerebrovascularly active 3-n-butylphenylhydrazine, a pharmaceutical composition containing the same as an active ingredient, and the derivative and a pharmaceutical composition thereof for the preparation of a medicament for treating brain damage use.
  • NBP 3-n-Butylphthalide
  • HPBA hydroxybutyl-benzoic acid
  • 3-n-butylphthalide has low oral bioavailability and has been found to have certain liver side effects in clinical applications (1.
  • Cui LY et al. Chinese J Neurology, 2008; 41:727-730.2.
  • Cui LY Et al. Chinese J Neurology, 2005; 38: 251-254.3.
  • Cui LY et al. Chin Med J (Engl), 2013; 126: 3405-3410.
  • the present invention provides a compound represented by Structural Formula I:
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are each independently H or ⁇ (D);
  • X and Y are OH;
  • Y may also be condensed to O; at the same time, at least one of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 must be D.
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are each independently H or ⁇ (D); at the same time, R1, R2, R3, At least one of R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 must be D.
  • the present invention provides a compound represented by Structural Formula Ib and a pharmaceutically acceptable salt thereof:
  • R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 are each independently H or ⁇ (D); at the same time, R1, R2, R3, At least one of R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 and R14 must be D.
  • the compound represented by Structural Formulas Ia and Ib has one chiral center in the molecule and a pair of chiral isomers. A single S-isomer or R-isomer can be obtained by resolution or chiral synthesis.
  • the invention therefore also provides the S-isomer or R-isomer of the compound represented by Structural Formula Ia or Ib and pharmaceutically acceptable salts thereof.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound represented by Formula I as an active ingredient, and a suitable excipient.
  • These pharmaceutical compositions may be solutions, tablets, capsules or injections; these pharmaceutical compositions may be administered by injection or orally.
  • the present invention also provides the use of a compound represented by Formula I and a pharmaceutical composition thereof for the preparation of a medicament for treating brain damage.
  • NBP (1.9 g, 10.0 mmol) was dissolved in 20 ml of methanol, and 10 ml of 1N KOH solution was added dropwise with stirring, and then the mixture was heated to 50 ° C, and the reaction was stirred for 0.5 h. The solvent was evaporated under reduced pressure. Filter and dry to obtain 1.8 g of HPBK.
  • HPPK HPPK was dissolved in water, cooled in an ice bath, and 5% diluted hydrochloric acid was added dropwise to pH 2, and the mixture was extracted with diethyl ether (15 mL ⁇ 3), and the mixture was combined, dried over anhydrous sodium sulfate and evaporated to dryness 1.2g.
  • Example 2.1 d 4 -i and D 2 O were subjected to a hydrazine exchange reaction to obtain d 7 -i; referring to the method of Example 2.2, d 7 -i was reduced with NaBH 4 to obtain Ia-6. .
  • the Grignard reagent BrMgCD 2 CD 2 CD 2 CD 3 was prepared by the method of Reference Example 1.1 using d 9 -bromo n-butane ( ⁇ abundance: 98%); the phthalic acid was obtained by the method of Reference Example 1.2. The anhydride was reacted with BrMgCD 2 CD 2 CD 2 CD 3 to obtain d 9 -i; referring to the method of Reference Example 1.3, d 9 -i was reduced with NaBH 4 to obtain Ia-8.
  • Ia-1 was hydrolyzed with KOH to obtain Ib-1.
  • Ia-2 was hydrolyzed with KOH to obtain Ib-2.
  • Ia-3 was hydrolyzed with KOH to obtain Ib-3.
  • Ia-4 was hydrolyzed with KOH to obtain Ib-4.
  • Ia-5 was hydrolyzed with KOH to obtain Ib-5.
  • Ia-6 was hydrolyzed with KOH to obtain Ib-6.
  • Ia-7 was hydrolyzed with KOH to obtain Ib-7.
  • Ia-8 was hydrolyzed with KOH to obtain Ib-8.
  • Ia-9 was hydrolyzed with KOH to obtain Ib-9.
  • test compound Male Sprague-Dawley rats were randomized into groups of 5 each.
  • the test compound was formulated into a suspension of sodium carboxymethylcellulose and administered intragastrically once every 12 hours for 3 consecutive days.
  • a fishing line with a diameter of about 0.2 mm was inserted through the internal carotid artery into the beginning of the middle cerebral artery.
  • the insertion line length was about 17.5 ⁇ . 0.5mm, at the same time there is a significant sense of resistance to block the blood flow of the middle cerebral artery, ligation of the internal carotid artery and the fishing line. After 1h, pull out the fishing line.
  • the sham-operated control group was the same as the surgery group except that the fishing line was not inserted.
  • the behavioral defects of the animals were graded according to Bederson's method. The criteria were as follows: Grade 0: no neurological symptoms were observed in rats; Grade 1: When the tail was suspended, the contralateral forelimbs of the animals showed brachial and elbow flexion. , shoulder rotation, elbow abduction, close to the chest wall; Level 2: the animal is placed on a smooth plane, when the lateral movement of the surgery is moved, the resistance is reduced; Level 3: the animal is free to walk to the opposite side of the surgery or Turning circle; level 4: soft palate, limbs have no spontaneous activity.
  • the abdominal aorta was taken for blood and the brain was weighed.
  • the brain was divided into 5 slices on average.
  • the second brain slices were routinely dehydrated, embedded in paraffin, and stained with HE. The histopathological changes were observed under light microscope.
  • the other four tablets were placed with 2% triphenyltetramine chloride.
  • test compound Male Sprague-Dawley rats (220-240 g), randomized, 5 rats/group; the test compound was formulated with 0.5% sodium carboxymethylcellulose to a concentration of 300 mg/kg, administered intragastrically, once a day, continuously. Drug for 14 days. After the last administration, fasting can not help but water for 12 hours, anesthesia, blood was taken from the abdominal aorta, serum was prepared for blood biochemical indicators and immunological indicators; EDTA anticoagulation was prepared for routine blood determination.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des composés représentés par la formule structurale (I), des isomères S et des isomères R de ceux-ci, ainsi que des sels pharmaceutiquement acceptables desdits composés. Dans la formule (I), R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 et R14 sont indépendamment et de manière séparée H ou deutérium (D); X et Y sont indépendamment et de manière séparée OH; X et Y sont condensés en O; de plus, au moins l'un de R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 et R14 doit être D. L'invention concerne également l'utilisation de l'un quelconque des composés ou de la composition pharmaceutique associée dans la préparation d'un médicament pour le traitement de lésions cérébrales.
PCT/CN2018/000168 2017-05-19 2018-05-09 Composés deutérés de résistance à l'endommagement du cerveau et leur utilisation médicale WO2018209973A1 (fr)

Applications Claiming Priority (2)

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CN201710355024.2 2017-05-19
CN201710355024.2A CN108947946B (zh) 2017-05-19 2017-05-19 抗脑损伤氘代化合物及其医药用途

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Publication number Priority date Publication date Assignee Title
WO2019242765A1 (fr) * 2018-06-22 2019-12-26 成都海创药业有限公司 Composé de butylphtalide deutéré et son utilisation
CN111943921A (zh) * 2019-05-17 2020-11-17 扬子江药业集团有限公司 一种丁苯酞的制备方法
CN112608226A (zh) * 2020-12-16 2021-04-06 云南昊邦制药有限公司 一种羟戊基苯甲酸钾d7的合成方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1100097A (zh) * 1993-09-09 1995-03-15 中国医学科学院药物研究所 芹菜甲素作为制备预防和治疗脑缺血引起的疾病的药物中的应用
CN103356521A (zh) * 2012-04-01 2013-10-23 石药集团恩必普药业有限公司 丁苯酞或其衍生物在制备治疗或预防放射性脑损伤的药物中的应用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105456252B (zh) * 2015-06-30 2019-03-15 石药集团恩必普药业有限公司 丁苯酞或其衍生在制备治疗或预防脑瘫的药物中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1100097A (zh) * 1993-09-09 1995-03-15 中国医学科学院药物研究所 芹菜甲素作为制备预防和治疗脑缺血引起的疾病的药物中的应用
CN103356521A (zh) * 2012-04-01 2013-10-23 石药集团恩必普药业有限公司 丁苯酞或其衍生物在制备治疗或预防放射性脑损伤的药物中的应用

Non-Patent Citations (2)

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Title
WANG, ZHENYUE, RESOURCEOLOGY OF CHINESE DRUGS, 28 February 2007 (2007-02-28) *
XU, BAILING ET AL.: "Study on Mechanism of the Rearrangement Reaction of 3-n-Bu-tylphthalide by Deuterium-Labelling", CHINESE CHEMICAL LETTERS, vol. 6, no. 8, 31 December 1997 (1997-12-31), pages 481, 482 *

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CN108947946A (zh) 2018-12-07

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