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US20070112065A1 - Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct - Google Patents

Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct Download PDF

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Publication number
US20070112065A1
US20070112065A1 US10/574,917 US57491704A US2007112065A1 US 20070112065 A1 US20070112065 A1 US 20070112065A1 US 57491704 A US57491704 A US 57491704A US 2007112065 A1 US2007112065 A1 US 2007112065A1
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Prior art keywords
nbp
butylphthalide
cerebral
treatment
infarct
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US10/574,917
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Yipu Feng
Xiaoliang Wang
Jinghua Yang
Ying Peng
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SHIJIAZHUANG PHARMA GROUP ZHONGQI PHAMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) Co Ltd
Institute of Materia Medica of CAMS and PUMC
Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology Co Ltd
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Institute of Materia Medica of CAMS and PUMC
Shijiazhuang Pharma Group Zhongqi Pharmaceutical Technology Co Ltd
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Assigned to SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD. reassignment SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHARMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FENG, MR. YIPU, PENG, MR. YING, WANG, MR. XIAOLIANG, YANG, MR. JINGHUA
Assigned to SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHAMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD., INSTITUTE OF MATERIA MEDICA, CHINESE ACADEMY OF MEDICAL SCIENCES reassignment SHIJIAZHUANG PHARMA. GROUP ZHONGQI PHAMACEUTICAL TECHNOLOGY (SHIJIAZHUANG) CO., LTD. CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE'S ADDRESS AND TO ADD A SECOND ASSIGNEE TO THE ASSIGNMENT PREVIOUSLY RECORDED ON REEL 017829, FRAME 0846. ASSIGNOR HEREBY CONFIRMS THE ASSIGNMENT OF THE ENTIRE INTEREST. Assignors: FENG, YIPU, PENG, YING, WANG, XIAOLIANG, YANG, JINGHUA
Publication of US20070112065A1 publication Critical patent/US20070112065A1/en
Abandoned legal-status Critical Current

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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

Definitions

  • the present invention relates to the use of L-n-butylphthalide and the composition comprising the same in the manufacture of medicaments for prevention and treatment of cerebral infarct, especially cerebral infarct induced by focal cerebral ischemia.
  • racemic butylphthalide (or butylphthalide, NBP) is a drug that has significant therapeutic effect on acute ischemic cerebral stroke.
  • the pharmacodynamical characteristics thereof include: 1. improving energy metabolism of the ischemic brain; 2. significantly reducing the area of cerebral infarct induced by focal cerebral ischemia in rat, and alleviating deficit of neural function; 3. alleviating the cerebral edema induced by focal cerebral ischemia; 4. significantly improving the focal cerebral blood flow in ischemic area and micro-circulation in cerebral pia mater of rats; and 5. significantly alleviating the memory disorder induced by focal cerebral ischemia. Moreover, it has less toxic side effect.
  • phase II and phase III were conducted on 542 cases, in which there are 192 cases using multi centered, random, double blinded placebo control. It was found that the total effective rate in the administration group is 70.7%, and the rate in placebo group is 41.0%. Thus good therapeutic effect was obtained.
  • the New Drug Certificate and Production Licence for the class I new drug have been approved on NBP for the treatment of acute ischemic cerebral stroke by the State Drug Administration of China in 2002 (National Drug License Nos. H20020374; H20020375; 2002H0551, and 2002H0552).
  • the present invention provides the use of L-n-butylphthalide (simplified as 1-NBP hereinafter) of formula (I) in the manufacture of the medicaments for prevention or treatment of cerebral infarct.
  • L-n-butylphthalide used in the present invention is obtained by firstly chemically synthesizing racemic n-butylphthalide, and then chemically resolving to produce a levorotary optical isomer of n-butylphthalide. After analyzing by nuclear magnetic spectroscopic analysis, mass spectrum analysis, infrared spectral analysis and the like, especially by using chiral gas chromatography column (Chiraldex G-TA) in HP 5890 gas chromatograph, it was confirmed that the product is a single optical stereoisomer, ie. levorotary n-butylphthalide, in terms of optical purity and chemical purity (specific optical activity > ⁇ 66.49°, optical purity >98%, and chemical purity >98%).
  • Transient focal cerebral ischemic rats were divided into 8 groups with 10 rats in each group.
  • Group 1) was vehicle control with 1 ml/kg of vegetable oil;
  • groups 2) and 3) were 40 and 80 mg/kg of dl-NBP;
  • groups 4) and 5) were 20 and 40 mg/kg of d-NBP;
  • groups 6) and 7) were 20 and 40 mg/kg of 1-NBP; and
  • group 8 was 0.1 mg/kg of MK801.
  • Animals in groups 1-7 were orally administered, and animals in group 8 were intraperitoneally administered.
  • the present invention was performed on the levels of biochemistry, molecular biology and on animal level, and consistent results were obtained, that is, the cerebral protective effect of 1-NBP is higher than those of d-NBP and dl-NBP, and the presence of d-NBP in dl-NBP antagonises the action of 1-NBP, so that the protective effect against cerebral ischemia of dl-NBP is reduced.
  • 1-NBP has so wide a therapeutic spectrum, that it can be used for the treatment of acute ischemic cerebral stroke, as well as secondary prevention of the cerebral stroke, prevention of cardiac infarct, and treatment of peripheral vascular diseases.
  • the present invention follows the development of international new drug discovery to increase therapeutic effect and reduce toxic side effect by resolving the racemic drug into optical monomers, making the characteristics of each clear, and developing the optical isomers with potent effect or low toxic side effect into chiral new drugs.
  • 1-NBP in racemic butylphthalide has relatively potent inhibitory effect against cerebral ischemia.
  • d-NBP not only has weak effect, but also antagonise the inhibitory effect of 1-NBP against cerebral ischemia. Therefore, it is reasonable to develop L-butylphthalide into a new chiral drug for the treatment of acute ischemic cerebral stroke.
  • the present invention also relates to the pharmaceutical composition
  • the pharmaceutical composition comprising the compound of the present invention as active ingredient, and conventional pharmaceutically acceptable vehicles or adjuvant.
  • the pharmaceutical composition of the present invention comprises 0.1-95% by weight of the compound of the present invention.
  • the pharmaceutical composition comprising the compound of the present invention may be prepared according to the method well known in the art.
  • the compound of the present invention may be combined with one or more solid or liquid pharmaceutically acceptable vehicles and/or adjuvant if desired, so as to be formulated into suitable administration forms or dosage forms for human use or veterinary use.
  • the compound of the present invention and the composition comprising the same may be administered in unit dosage form, and the administration route may be intestinal or parenteral, such as oral, intramuscular, subcutaneous, nasal, oral mucousal, transdermal, intraperitoneal, rectal administration, or the like.
  • the administration route of the compound of the present invention or the pharmaceutical composition comprising the same may be injection, including intravenous injection, intramuscular injection, subcutaneous injection, intracutaneous injection, and acupoint injection.
  • the administration formulation may be liquid formulation or solid formulation.
  • the liquid formulation may be solution, colloid, microparticulate, emulsion, and suspension.
  • Other formulations may also be used, such as tablet, capsule, pill, aerosol, pellet, powder, solution, suspension, emulsion, particulate, suppository, and lyophilized powder, and the like.
  • the compound of the present invention may be prepared to be conventional formulations, as well as sustained release formulations, control released formulations, targeting formulations, and various micro-particular administration systems.
  • vectors well known in the art may be widely used so as to prepare the unit dosage form into tablets.
  • examples of vectors are, for example, diluents and absorbants, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, bolus alba, microcrystalline cellulose, aluminum silicate, and the like; wetting agents and bonding agents, such as water, glycerol, polyethylene glycol, ethanol, propanol, starch slurry, dextrin, syrup, honey, glucose solution, gum arabic slurry, gelatin slurry, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, and the like; disintegrant, such as dry starch, alginate, agar powder, Phaeophyta starch, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene sorbitan
  • vectors are, for example, diluents and absorbants, such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaoline, talc powder, and the like; bonding agents, such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or panada; disintegrants, such as agar powder, dry starch, alginate, sodium lauryl sulfonate, methyl cellulose, ethyl cellulose, and the like.
  • diluents and absorbants such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, polyvinylpyrrolidone, kaoline, talc powder, and the like
  • bonding agents such as gum arabic, tragacanth gum, gelatin, ethanol, honey, liquid sugar, rice paste or panada
  • disintegrants such as agar powder, dry starch, alginate, sodium la
  • the compound of the present invention as active ingredients is mixed with various vectors described above, the thus obtained mixture is placed into the hard gelatin capsules or soft capsules.
  • the compound of the present invention as active ingredients may also be formulated into microcapsules, mixed with aqueous medium to form into suspensions, and filled into hard capsules or formulated into injections for use.
  • the compound of the present invention may be formulated into formulations for injection, such as solution, suspension, emulsion, lyophilized powder for injection, which may be aqueous or non-aqueous, may comprise one and/or more pharmaceutically acceptable vectors, diluent, bonding agent, lubricant, perservative, surfactant, or dispersant.
  • Diluent may be selected, for example, from water, ethanol, polyethylene glycol, 1,3-propylene glycol, ethyoxylated isostearyl alchol, multi-oxylated isostearyl alchol, polyoxyethylene sorbitan fatty acid ester, and the like.
  • suitable amount of sodium chloride, glucose or glycerol may be added into the formulations for injection in order to prepare isotonic injections.
  • Conventional solving agent, buffering agents, pH adjusting agents may also be added. These adjuvants are commonly used in the art.
  • coloring agents may be added to the pharmaceutical formulations if desired.
  • the medicament or the pharmaceutical composition may be administered by any administration method well known in the art.
  • the administration dose of the pharmaceutical composition comprising the compound of the present invention depends on many factors, such the nature or severity of the disease to be prevented or treated, sex, age, body weight, trait and individual response of the patient or the animal, the administration route, the administration frequency and therapeutic purpose. Therefore, the therapeutic dose in the present invention may vary in a wide range.
  • the dose of the pharmaceutical ingredients in the present invention is well known to those skilled in the art, and may be suitably adjusted depending on exact amount of the drug contained in the final formulation of the composition comprising the compound of the present invention, to reach a therapeutically effective dose, and thus accomplish the preventive or therapeutic purpose of the present invention.
  • the suitable daily dose preferably lies in the range from 0.1 to 100 mg/kg body weight, more preferably from 0.1 to 100 mg/day/person.
  • the dosage may be in unit dosage form or divided into more than one, for example 2, 3, or 4 dosage forms for administration, which depends on the clinical experience of the administers, and includes other dosage regimes using other therapeutic means.
  • Total dose needed in each therapy may be administered in more than one dosage, or administered in one dosage.
  • the compound or the composition of the present invention may be administered alone, or used in combination with other therapeutic agents or heteropathic agents with adjusted dosage.
  • tMCAO transient focal cerebral ischemic model
  • FIG. 1 is the digital photograph showing the effects on the cerebral infarct volume of rats of administering NBP by gavage 15 minutes after transient middle cerebral artery occlusion.
  • FIG. 2 shows the effects on the cerebral infarct volume of rats of administering NBP by gavage 15 minutes after transient middle cerebral artery occlusion.
  • the data are expressed as the volume percentage obtained by dividing infarct portion by that of the contralateral (normal) hemisphere, and expressed as mean ⁇ standard error. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, vs. vehicle group.
  • FIG. 3 shows the effects on the behavioral score of rats of administering NBP by gavage 15 minutes after transient middle cerebral artery occlusion. The data are expressed as mean ⁇ standard error. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001, vs. vehicle group.
  • d-, and dl-NBP were all provided by department of synthetic pharmaceutical chemistry of our institute, both optical and chemical purity of which are >99%, and the optical activity of which is ⁇ 66.49°, +66.88° and 0°, respectively. They were formulated with vegetable oil. MK801 is the product of Sigma, and was formulated with physiological brine. Triphenyltetrazolium chloride (TTC), which was manufactured by Beijing Chemical Plant, was formulated with distilled water into 4% solution for use.
  • TTC Triphenyltetrazolium chloride
  • mice Male Wistar rats weighed 280-320 g were used, with each 5 rats kept in one cage. Animals were allowed free access to food and water at room temperature controlled at 23° C. The rats were anesthetized with 40 mg/kg of sodium pentobarbital. Under the surgical microscope, a midline neck skin incision was make to expose the right common cartotid artery, and the internal carotid artery (ICA) and external carotid artery (ECA) were then separated free from surrounding nerves and fascia, and the anastomotic branch was ligated. The ECA were ligated and cut, pulled to be straight and in line with ICA.
  • ICA internal carotid artery
  • ECA external carotid artery
  • a nylon suture with rounded tip and the diameter of 0.28 mm (coated with poly-L-lysine) was introduced from ECA into the lumen of the ICA for about 20 mm, advancing endocranially to the starting point of middle cerebral artery.
  • the nylon suture was carefully withdrawn, and the ECA was ligated at the site of opening.
  • the rats were then sutured and placed back into the cage, and allowed to reperfuse for 24 h. Room temperature throughout the operation was kept at 24-25° C.
  • the rats were placed on the heating plate of 37° C. to maintain the body temperature throughout the operation.
  • the administration was performed 15 minutes after ischemia.
  • Rats were divided into eight groups with 10 rats in each group.
  • Group 1 was vehicle control with 1 ml/kg of vegetable oil; groups 2) and 3) were 40 and 80 mg/kg of dl-NBP; groups 4) and 5) were 20 and 40 mg/kg of d-NBP; groups 6) and 7) were 20 and 40 mg/kg of 1-NBP; and group 8 was 0.1 mg/kg of MK801. Animals in groups 1-7 were orally administered, and animals in group 8 were intraperitoneally administered.
  • contralateral shoulder flexion contralateral shoulder flexion, forelimb flexion; decreased resistance of contralateral shoulder to push; and normal walk.
  • contralateral shoulder flexion contralateral shoulder flexion, forelimb flexion; decreased resistance of contralateral shoulder to push; and circling when walking.
  • the rat was anesthetized with 100 mg/kg of sodium pentobarbital and decapitated.
  • the brain was then rapidly removed, cut into six coronal sections (each of the first to the fifth section was 2-mm-thick, and the sixth section was 4-mm-thick), then rapidly placed into 5 ml of the solution containing 1.5 ml of 14% TTC and 0.1 ml of 1M K 2 HPO 4 lightproofly. After incubation at 37° C. for 30 minutes, during which overturning was conducted every 7-8 minutes. After staining with TTC, the normal brain tissue showed rose colour, while the infarct tissue showed white with defined boundary.
  • cerebral infarct volume (%) (volume of un-operated hemisphere ⁇ volume of un-infarcted portion of operated hemisphere)/volume of un-operated hemisphere.
  • results were expressed as mean ⁇ standard error. Neurological behavioral score and cerebral infarct volume were statistically analyzed using one-way ANOVA and the difference between groups using posthoc LSD test. Result was considered to show a significant difference when p ⁇ 0.05.
  • the neurological score of most animals in vehicle control group were 2, manifested as contralateral forelimbs flexion and decreased resistance of contralateral extensor to lateral push. Contralateral circling occurred in fewer rats, and graded as 3. Even fewer animals only manifested as contralateral forelimb flexion and graded as 1; or had severe symptoms and unable to autonomously move, which was graded as 4. The mean of neurological score was 2.6 ⁇ 0.3.
  • the models previously used by us are permanent focal ischemia (by burning brain middle artery), while transient focal cerebral ischemic model (2 hours of ischemia plus 24 hours of reperfusion) is used in this study.
  • the latter has larger cerebral infarct volume than the former.
  • the dose of dl-NBP selected is the same as that of previous, dl-NBP has no reduction effect on cerebral infarct volume at the doses being used (40 mg/kg and 80 mg/kg). This difference between the results is due to the difference between the two models.
  • the present invention was conducted on the levels of biochemistry, molecular biology and on animal level, and consistent results were obtained, that is, the cerebral protective effect of 1-NBP is higher than that of d-NBP and dl-NBP, and the presence of d-NBP in dl-NBP antagonises the action of 1-NBP, so that the protective effect against cerebral ischemia of dl-NBP is reduced.
  • 1-NBP has so wide a therapeutic spectrum, that it can be used for the treatment of acute ischemic cerebral stroke, as well as secondary prevention of the cerebral stroke, prevention of cardiac infarct, and treatment of peripheral vascular diseases. It is expected to produce important social benefit and economic benefit, so that it is promising to develop 1-NBP into a drug for the treatment of cerebral stroke.
  • the therapeutic effect of levorotatory butylphthalide on focal cerebral ischemia has not been described in the references both here and abroad.

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US10/574,917 2003-10-10 2004-09-29 Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct Abandoned US20070112065A1 (en)

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CNA2003101002222A CN1605336A (zh) 2003-10-10 2003-10-10 左旋丁基苯酞在制备预防和治疗脑梗塞的药物中的应用
CN2003101002222 2003-10-10
PCT/CN2004/001123 WO2005034936A1 (en) 2003-10-10 2004-09-29 Use of l-butylphthalide in the manufacture of medicaments for prevention and treatment of cerebral infarct

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US20070167516A1 (en) * 2004-01-20 2007-07-19 Zhentao Liu Methods of using l-butylphthalide for the prevention and treatment of cerebral ischemia disease
US8598225B2 (en) 2003-10-10 2013-12-03 Cspc Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd. Use of L-butylphthalide in the manufacture of medicaments for treatment of cerebral infarct
US12312509B2 (en) 2019-12-20 2025-05-27 3M Innovative Properties Company Adhesive article comprising polymer and polymerizable cyclic olefins, adhesive compositions and methods
US12338316B2 (en) 2019-10-14 2025-06-24 3M Innovative Properties Company Compositions comprising cyclic olefins and thermally conductive filler

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US8552058B2 (en) 2004-06-18 2013-10-08 CSPC Zhongqi Pharmaceutical Technology (Shijazhuang) Co., Ltd. Application of L-n-butylphthalide in preventing and treating dementia
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PH12022551051A1 (en) * 2019-11-01 2023-05-03 Celagenex Res India Pvt Ltd Synergistic nutritional compositions for treating cerebrovascular diseases
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