WO2002102379A1 - Sophoridine et son utilisation en tant qu'analgesique - Google Patents

Sophoridine et son utilisation en tant qu'analgesique Download PDF

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WO2002102379A1
WO2002102379A1 PCT/CN2002/000421 CN0200421W WO02102379A1 WO 2002102379 A1 WO2002102379 A1 WO 2002102379A1 CN 0200421 W CN0200421 W CN 0200421W WO 02102379 A1 WO02102379 A1 WO 02102379A1
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sophoridine
pharmaceutical composition
composition according
group
derivative
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French (fr)
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Hongfu Ju
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TONGHUA FANGDA PHARMACEUTICALS Ltd
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TONGHUA FANGDA PHARMACEUTICALS Ltd
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Priority to EP02754130A priority Critical patent/EP1407771A4/en
Priority to US10/480,387 priority patent/US20040198761A1/en
Publication of WO2002102379A1 publication Critical patent/WO2002102379A1/zh
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Priority to US11/483,625 priority patent/US20060251751A1/en
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates generally to sophoridine and its analogs or derivatives. More specifically, the present invention relates to sophoridine and its derivatives or analogs derived from natural or chemical synthetic sources, and to a pharmaceutical composition which acts as an analgesic agent or produces an analgesic agent or has both antitumor and analgesic effects. Applications.
  • analgesics widely used in clinical practice mainly include two categories: one is as a receptor agonist that binds to the opioid receptor of the central nervous system to simulate endogenous analgesics
  • opioid analgesics that activate the analgesic system in the body and exert analgesic effects, including benzomorphin, pethidine, and morphinane-related analgesics; another Central prostaglandin synthase that regulates hypothalamus temperature
  • NAIDS which includes salicylic acids, acetanilides, pyrazolones, anthranilates, arylacetates and arylpropionic acids.
  • acetanilides acetanilides
  • pyrazolones pyrazolones
  • anthranilates arylacetates
  • arylpropionic acids due to the severe tolerance and dependence (ie addiction) of the former, and the latter drugs often show only a limited analgesic effect, these known analgesics are generally insufficient. ideal.
  • Sophoridine is the earliest (1933) alkaloid isolated from the leguminous plant Sophora flavus. So far, more than a dozen alkaloids with a bis- 1 cilidine structure have been discovered and isolated from bitter beans, including matrine, matrine, almanine, sophoroline Sophocarpine, Ma trine oxide, Sophoramine, and sophoridine.
  • Li Xuemei et al. See, for example, Li Xuemei et al., The Anticancer Effect of Huaiding, Chinese Journal of Pharmacology 8 (2): 153-158, 1987; Chinese Patent 93100881 ⁇ 6) disclosed the antitumor biological activity of sophoridine, and proved The antitumor biological activity of sophoridine on a variety of tumors, including human uterotrophoblastoma.
  • natural extracted or chemically synthesized sophoridine compounds or their derivatives or analogs are commonly used as clinically applicable analgesics, especially for pain caused by various advanced cancer patients and various other causes. Analgesics have not been reported so far.
  • An object of the present invention is to provide a new pharmaceutical composition having analgesic effect on pain caused by mammals for various reasons, which is characterized in that the pharmaceutical composition contains a therapeutically effective amount of acacia as a basic active ingredient.
  • the sophoridine derivative is selected from the group consisting of an alkyl group containing 1 to 6 carbon atoms, a ring bond group, Halofluorenyl, aryl, aryl, aryloxy, acyl, hydroxy, mercapto or sulfo, carboxyl or alkoxy, or alkylaryloxy substituted derivatives or their derivatives according to this purpose of the invention
  • the base analogs include a sophoridine analog or a salt thereof selected from the group consisting of sophoroline, matrine, oxymatrine, matrine, ramaniline, sophoramine.
  • said mammal is a human or a large domestic livestock selected from pigs, cattle, horses, and sheep, or selected from dogs, cats, mice, rats, guinea pigs or Rabbit pet animal.
  • said mammal is a human.
  • said mammalian pain includes due to advanced tumor, mechanical or chemical trauma, burns, muscle spasms, pathological nerve injury, infectious or non-infectious inflammatory injury, foreign body Stimulation, metabolic or endocrine disorders, and pain caused by tissue hypoxia.
  • said sophoridine or a derivative or analog thereof is of natural or chemical synthetic origin.
  • the pharmaceutical composition in addition to the analgesic effect of the pharmaceutical composition, also has antitumor, antimicrobial, anti-inflammatory and anti-central nervous tissue degeneration activities.
  • the pharmaceutical composition contains, in addition to a therapeutically effective amount of sophoridine or a derivative or analog thereof, one or more auxiliary or synergistic effects.
  • Other active ingredients of natural or synthetic origin are also included.
  • said other active ingredients include, but are not limited to, other natural or synthetic analgesics, antineoplastic agents, anti-microbial agents, anti-inflammatory agents, and immunomodulators.
  • the pharmaceutical composition is a topical, intravenous, intramuscular, intranasal, intradermal, subcutaneous, body cavity, organ cavity, tumor or non-tumor normal tissue For internal administration. 01- 100mg ⁇ According to a preferred embodiment of this object of the present invention, wherein the therapeutic composition of sophoridine and its derivatives or analogs in said pharmaceutical composition is about 0.01 to 100 mg per kilogram of body weight.
  • Another object of the present invention is to provide the use of sophoridine or a derivative or analog thereof as defined above as a basic active ingredient in the production of medicines for analgesia, anti-tumor, anti-gout, anti-inflammatory and anti-degenerative diseases of the central nervous system. .
  • the present invention relates to a pharmaceutical composition using bitter bean alkaloid sophoridine or a derivative or analog thereof as a basic active ingredient.
  • the composition can effectively inhibit or alleviate pain in mammals, including humans, for various reasons without causing undesirable tolerance and dependence.
  • Sophoridine A monomeric alkaloid isolated from the leguminous plant Sophora alopecuroides. Sophoridine and sophorophylline are both stereoisomers of matrine. Li Xuemei et al. Used the tumor-bearing animal model based on the structural similarity between sophoridine and matrine known to have antitumor activity, and proved that sophoridine also has biological activities that kill tumor cells and inhibit tumor growth. Moreover, it was found that sophoridine does not substantially inhibit the bone marrow hematopoietic function and immune function of the treated individual within the effective dose range (see Li Xuemei et al., Anticancer Effect of Sophoridine, Chinese Journal of Pharmacology 8 (2): 153-158, 1987 ).
  • sophoridine has different degrees of therapeutic effect on uterine epithelial trophoblastoma (chorionic epithelial carcinoma, malignant hydatidiform mole), malignant lymphoma, gastric cancer, and small cell lung cancer.
  • sophoridine in clinical trials for patients with advanced tumors including breast cancer, liver cancer, small cell tumors, malignant lymphoma, pancreatic cancer, and gastric cancer.
  • its derivatives or analogs can not only inhibit tumor cell proliferation to varying degrees, but also significantly inhibit or relieve severe pain caused by tumor tissue malignant hyperplasia in patients with advanced tumors.
  • an alkaloid having a bis-cilidine structure, especially sophoridine or a derivative or analog thereof is used in patients with advanced tumors, it can produce the same or similar analgesic effects as opioid analgesics.
  • the clinical trial results further show that after the drug was solubilized for a long time in a large dose of sophoridine or its derivatives or analogues, the patient did not see any opioid central nerve block analgesics. Addiction effect.
  • alkaloids having a bisquinolocilidine structure can not only effectively inhibit or alleviate pain in patients with advanced tumors Moreover, it can effectively inhibit or alleviate the pain caused by mammals due to mechanical or chemical trauma, burns, muscle spasms, pathological nerve injuries, infectious and non-infectious inflammatory injuries, foreign body stimulation, and tissue ischemia.
  • the deductive or chemical wounds include sharp wounds, electric shocks, blunt wounds, and wounds caused by chemicals such as strong acids or alkalis; burns include infectious or non-infectious first, second, or third degree Burns; muscle spasms including smooth muscle spasms such as stomach cramps and intestinal spasms, as well as osteoporosis spasm; pathological nerve injuries include neuritis, trigeminal neuralgia, sciatica, and spinal fissure and spinal hyperostosis caused by nerve compression and Nerve damage; infectious and non-infectious inflammatory damage include local or systemic infections caused by pathogenic microorganisms such as bacteria, fungi or viruses, as well as rheumatoid arthritis, rheumatoid arthritis caused by immune dysfunction or metabolic disorders or endocrine disorders Arthritis, gout, dysmenorrhea and other autoimmune diseases; foreign body stimuli include kidney or gallstone irritation, and irritation caused by foreign body invasion in any part of the body
  • the mammal to be treated for analgesia includes humans or primates, or large agricultural animals selected from pigs, cattle, horses, and sheep, and selected from dogs, cats, mice, animals, and animals. Rat, guinea pig or rabbit pet animal. Among them, humans are particularly preferred.
  • the present invention provides a pharmaceutical composition containing sophoridine or a derivative or analog thereof effective in suppressing or alleviating pain, and containing one or more pharmacologically acceptable carriers or excipients .
  • Said pharmaceutical composition can effectively inhibit or alleviate the pain caused by mammalian body due to various reasons, in particular it can inhibit or alleviate the pain caused by malignant hyperplasia of tumor tissue in patients with advanced tumors without causing drug resistance And dependence, that is, the unbearable withdrawal syndrome does not occur after discontinuation.
  • Sophora From the above-ground parts of natural leguminous Sophora plant Sophora can be obtained according to conventional methods well known to those skilled in the art, by dipping in a dilute acid solution, ion exchange chromatography, extraction with an organic solvent (such as chloroform, petroleum ether, etc.) and recrystallization. Extraction and separation of sophoridine (for example, see Wu Yunguang, Study on the Extraction and Isolation of Anticancer Effective Ingredients from West Bean Roots, New Medical Information (West Bean Root Research Supplement) (4), 1974; Zhao Boguang, Main Alkaloids in Sophora diffusa Dynamic content distribution and thin layer quantification in organs, Acta Pharm Sin 15 (3), 182, 1980).
  • sophoridine for example, see Wu Yunguang, Study on the Extraction and Isolation of Anticancer Effective Ingredients from West Bean Roots, New Medical Information (West Bean Root Research Supplement) (4), 1974; Zhao Boguang, Main Alkaloids in Sophora diffusa Dynamic content distribution and
  • the inorganic or organic acid salts of sophoridine having better solubility or absorption or storage stability can be prepared according to conventional methods.
  • the inorganic salts referred to here include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, hypocarbonic acid, boric acid, and silicates.
  • the organic acid salts include, but are not limited to, formic acid, acetic acid, propionic acid, butyric acid, and apples. Acids, salicylic acid, maleic acid, citric acid, fumaric acid, maleic acid, tartaric acid, fatty acids and pyruvate.
  • sophoridine as a starting material by repeated recrystallization, and follow the reaction steps such as hydrogenation, oxidation, alkylation, acylation, cyclization, dehydrogenation, esterification, and acylation known in the field of chemical synthesis.
  • sophoridine derivatives or analogs suitable for various clinical symptoms or research purposes Preparation of sophoridine derivatives or analogs suitable for various clinical symptoms or research purposes.
  • sophoridine or a derivative or analog thereof used for the purpose of the present invention may be completely artificially synthesized according to a method known in the field of chemical synthesis, so as to reduce the production cost of the pharmaceutical composition and facilitate further discovery and screening.
  • a new sophoridine derivative or analogue with good analgesic and antitumor effects and significantly reduced toxic effects.
  • sophoridine derivative refers to naturally occurring, semi-synthetic, or fully synthetic sophoridine that is substituted at any position in the basic ring structure of sophoridine A chemical derivative or analog of a base.
  • the substituent group includes but is not limited to ⁇ & (such as methyl, ethyl, propyl, and butyl) containing one or more (preferably 1 to 6) carbon atoms, substituted alkyl , Alkenyl, substituted alkenyl, aryl, dienyl, arylene, arylalkenyl, substituted aryl, heterocyclic or substituted heterocyclic group, cycloalkyl, substituted ring, halogen (Such as Cl, Br, 1), haloalkyl, acyl, hydroxy, mercapto, sulfo, carbonyl, alkoxy, aryl, and alkylaryloxy groups.
  • sophoridine analogs used in this specification includes, but is not limited to, matrine, oxymatrine, lammatine, sophoroline, sophoramine, which can be extracted and isolated from natural sources by known methods. Bases, matrines or their natural, semi-synthetic or fully synthetic chemical derivatives.
  • the present invention is preferably naturally occurring sophoridine or a derivative thereof, and the present invention is exemplified as a representative compound, the above-mentioned alkaloids having a bisquinolocilidine structure, regardless of It is natural or semi-synthetic or fully synthetic, and can be used to prepare the pharmaceutical composition having analgesic and / or antitumor and / or anti-inflammatory effects of the present invention, and these compounds are all included in the pending rights of the present invention Within requirements.
  • sophoridine or its derivatives or analogs have excellent analgesic effects, and are particularly suitable for certain patients with advanced tumors, as well as being suitable for inhibiting, relieving and treating certain Inflammatory diseases due to immune or metabolic disorders, such as rheumatoid arthritis and gout.
  • these compounds may work by increasing the concentration of neurotransmitters such as acetylcholine in the central and peripheral nervous systems.
  • neurotransmitters such as acetylcholine
  • Sophoridine or a derivative or analog thereof is mixed with one or more pharmaceutically acceptable carriers or excipients or diluents in an appropriate ratio and sterilized according to known methods.
  • the pharmaceutical composition of the present invention is provided.
  • the pharmaceutical composition of the present invention can be formulated to be suitable for intravenous, intramuscular, body cavity (such as chest cavity, abdominal cavity, spinal cavity, intracranial and intra-articular condyles), intra-tissue, intradermal or subcutaneous Injectable solutions or ⁇ ⁇ 1 doses for administration; or powders, tablets, granules, pills, emulsions, suspensions, capsules, elixirs suitable for oral administration; or suitable for topical administration And sprays, creams, creams, ointments, gels, lozenges, or suppositories for administration by absorption through the skin or mucous membranes.
  • intravenous, intramuscular, body cavity such as chest cavity, abdominal cavity, spinal cavity, intracranial and intra-articular condyles
  • intra-tissue intradermal or subcutaneous Injectable solutions or ⁇ ⁇ 1 doses for administration
  • injectable solutions suitable for parenteral administration for example, sterile distilled water, water for injection, isotonic sodium chloride or glucose solution, or low-concentration (eg, 1-100 fflM) phosphate buffered saline can be used. (PBS), and a solvent or dispersion medium containing ethanol and polyol (such as ethylene glycol, propylene glycol, and liquid polyethylene glycol, etc.) as a carrier or diluent.
  • the injectable preparations should be sterile and flowable and suitable for administration by syringe.
  • the formulation must be stable under production, transportation and storage conditions and resistant to contamination by microorganisms such as bacteria and fungi.
  • anti-oxidants such as ascorbic acid
  • antibiotics such as penicillin and streptomyces or other antifungal agents
  • preservatives such as sodium benzoate, trichloro-tert-butanol, duricol, sorbic acid, etc.
  • solubilizers and surfactants to maintain the required particle size in the dispersant.
  • disaccharides such as sucrose, lactose, and galactose, or six-carbon polyhydric alcohols such as mannitol and sorbitol, and corn can be used.
  • Starch, gelatin, lipid, microcrystalline cellulose, etc. are used as carriers or excipients.
  • disintegrating agents, lubricants, buffer salts, coloring agents, sweeteners, flavoring agents, dispersing agents and surfactants can also be added to these oral preparations.
  • the pharmaceutical composition is made into a microgel tincture or a liposome encapsulation.
  • sophoridine or a derivative or analog thereof may be dissolved in an aqueous medium or other appropriate carrier or matrix, and mixed with a suitable transdermal absorbent such as dimethyl Blend sulfoxide or laurazolone to make a spray or aerosol.
  • a suitable transdermal absorbent such as dimethyl Blend sulfoxide or laurazolone
  • the pharmaceutical composition of the present invention can also be made into an emulsion, cream, ointment, gel, or suppository (such as a vaginal suppository or suppository) suitable for topical or absorption through the skin or mucous membranes using an appropriate base or excipient. Rectal suppositories).
  • glycerol magnesium stearate, polyethylene glycol, polyacrylamide, cholesterol, lecithin, methyl cellulose or carboxymethyl cellulose, talc, lactose, dextran, starch, etc. can be used as a base Or excipients.
  • the pharmaceutical composition of the present invention may contain one or more of the same, similar, or different biological activities in addition to sophoridine or a derivative or analog thereof as a basic active ingredient, and Other natural or synthetic other medicinal ingredients or mixtures thereof that have an auxiliary or synergistic effect on the basic active ingredients, but do not antagonize each other.
  • the other active ingredients include, but are not limited to, natural or synthetic analgesics (such as aspirin, buta Thermal analgesics, or opioid analgesics, etc.), antineoplastic agents (such as nitrogen mustard, cyclophosphamide, methotrexate, vincristine, paclitaxel, daunorubicin, etc.), antimicrobial agents (such as sorbic acid, Mycotoxins, Scutellaria baicalensis, etc.), and immunomodulators (such as thymosin, triptolide, etc.).
  • natural or synthetic analgesics such as aspirin, buta Thermal analgesics, or opioid analgesics, etc.
  • antineoplastic agents such as nitrogen mustard, cyclophosphamide, methotrexate, vincristine, paclitaxel, daunorubicin, etc.
  • antimicrobial agents such as sorbic acid, Mycotoxins, Scutellaria baicalensis, etc
  • the oral administration dose of the pharmaceutical composition of the present invention is
  • intravenous injection dose is 0.01-100mg / kg / day, preferably 0. 05-80mg / kg / day, preferably 0.1-50mg / kg / day.
  • the exact dosage should be based on the condition or illness to be treated Factors such as the nature, severity, age, weight, general health of the patient, and the patient's sensitivity, tolerance, and mode of administration to the drug used are determined by the clinician according to the principle of individualization.
  • the invention further relates to the use of sophoridine and / or its derivatives or analogs in the production of analgesics, antitumor drugs, antigout drugs, anti-inflammatory drugs and anti-neurodegenerative diseases.
  • sophoridine Based on the significant analgesic effect of sophoridine and its derivatives or analogs found by the present inventors on pain including advanced tumors and other causes (see Examples 1 and 2), and sophoridine which has been proven in the prior art And its analogues (such as matrine or oxymatrine) in inhibiting the growth of malignant tumor cells such as human chorionic epithelial cell carcinoma and malignant lymphoma (for example, see Xuemei Li et al., Anticancer Effect of Huai Ding, China Pharmacology 8 (2): 153-158, 1987; Chinese Patent 93100881. 6), it is possible to use sophoridine or a derivative thereof as a basic active ingredient for preparing an analgesic and / or antineoplastic pharmaceutical composition.
  • sophoridine or its derivatives can also be used as auxiliary active ingredients in combination with other known analgesics and / or tumor drugs to improve the use of these therapeutic drugs and reduce certain analgesics (such as Dependent or addictive opioid analgesics), or antitumor chemotherapeutics (such as most alkylating agents, antimetabolites that are likely to cause bone marrow hematopoietic or immune function suppression) (see Experimental Example 3 and 4), thereby greatly reducing the pain caused to patients by long-term use of these drugs, and significantly improving the survival of patients.
  • analgesics such as Dependent or addictive opioid analgesics
  • antitumor chemotherapeutics such as most alkylating agents, antimetabolites that are likely to cause bone marrow hematopoietic or immune function suppression
  • sophoridine or its derivatives or analogs can also use sophoridine or its derivatives or analogs as auxiliary active ingredients in combination with other known opioid analgesics or non-steroidal antipyretic and analgesic anti-inflammatory drugs or anti-gout drugs (such as (See Experimental Example 4), to make a new pharmaceutical composition for inhibiting or alleviating the symptoms of infectious or non-infectious inflammatory reactive diseases, in order to further improve the antipyretic and analgesic effects and reduce the pain of patients or other treated individuals .
  • opioid analgesics or non-steroidal antipyretic and analgesic anti-inflammatory drugs or anti-gout drugs such as (See Experimental Example 4
  • sophoridine or its derivatives may be caused by the significant increase in acetylcholine levels of the central nervous system by these compounds through biochemical pathways that are not yet known ( Data not shown). Therefore, sophoridine or its derivatives or analogs can also be expected to be used to produce drugs for treating central nervous degenerative diseases such as Alzheimer's disease.
  • the following examples are intended to further illustrate, but not limit the invention. It should be clearly pointed out that without departing from the spirit and principles of the present invention, it is within the scope of the claims of the present invention.
  • Example 1 Analgesic effect of sophoridine on mouse models (hot plate method)
  • This example aims to observe the analgesic effect of bitter bean alkaloid sophoridine on a mouse model by a hot plate method.
  • Kunming mice with an average body weight of 18-22 g were used as experimental animals, and the hot plate method (see Editor-in-Chief Li Yikui, Experimental Methodology of Traditional Chinese Medicine Pharmacology, pp. 351-353, Shanghai Science and Technology Press) was used to conduct experiments. Pain experiment.
  • Eligible animals with a pain threshold between 5-30 seconds were selected from all candidate mice and randomly divided into six groups of 10 animals each Animals. Animals in each experimental group were injected with sophoridine (0.1 ml / 10 g body weight) via tail vein at doses of 25, 20, 15, 10, and 5 mg / kg body weight, respectively. Animals in the negative control group were injected with an equal volume of saline through the tail vein.
  • sophoridine has the potential to act as a powerful analgesic for inhibiting or relieving pain in mammals for a variety of reasons.
  • Example 2 The analgesic effect of sophoridine on a mouse model (acetic acid-induced writhing method) This experiment aims to observe the sedative effect of Sophora alkaloid sophoridine on a mouse model by the acetic acid-induced writhing method in the abdominal cavity. Pain effect.
  • the purpose of this example is to compare the analgesic effect of sophoridine and morphine on mice by a hot plate method, and further observe the synergistic analgesic effect of sophoridine and morphine in combination.
  • the sophoridine group also includes five different dose groups of 25, 20, 15, 10, and 5 mg / kg; the morphine group and the sophoridine + morphine group were administered at the doses shown in Table 3. The pain thresholds of the animals in each group were recorded at 15, 30, 60 and 90 minutes after the administration. The results are shown in Listing 3 below.
  • the data shown in J 3 can further see that there is a linear positive correlation between the analgesic effect of sophoridine on mice and the dose administered, in which the 25 mg / kg and 20 mg / kg groups are compared with the base pain threshold, The analgesic effect exhibited is particularly obvious.
  • the experimental results of this example show that compared with the positive control group administered with morphine hydrochloride, the experimental group of animals receiving higher doses of sophoridine appears to have a pain threshold slightly higher than that of hydrochloric acid at 15 minutes after administration. Morphine group. Therefore, it can be considered that sophoridine (25mg / kg) has similar or better analgesic effect to morphine hydrochloride than the strong analgesics of mammals.
  • Each experimental group includes: opioid receptor antagonist naloxone group (2mg / kg); sophoridine group (20mg / kg); morphine group (10mg / kg); naloxone (2mg / kg) + morphine hydrochloride ( 10 mg / kg) group; naloxone (2 mg / kg) + sophoridine (20 mg / kg) group.
  • Animal pain thresholds (seconds) were recorded at 15, 30, 60 and 90 minutes after dosing. The results are shown in Listing 4 below.
  • ⁇ fd shows that the administration of naloxone, an opioid receptor antagonist, did not significantly inhibit the pain response in mice.
  • naloxone is associated with morphine hydrochloride In combination, it can significantly inhibit the analgesic activity of morphine hydrochloride.
  • Huai Dingcheng when naloxone was combined with Huai Dingcheng, its analgesic effect on sophoridine did not show a statistically significant antagonistic effect. Therefore, these results clearly indicate that sophoridine does not exert its analgesic effect by activating CNS opioid receptors.
  • Example 4 Analgesic effect of total alkaloids of Sophora alopecuroides on a mouse model (hot plate method) This example aims to observe the ground of Sophora alopecuroids including sophoridine, matrine, sophoridine and matrine Analgesic effect of some total alkaloids (its hydrochloride) on mouse models.
  • Kunming mice with an average body weight of 15-20 g were used as experimental animals, according to the hot-plate method described in the literature (see Li Yikui, Pharmacology of Traditional Chinese Medicine, pp. 351-353, Shanghai Science and Technology Press) Analgesic test.
  • the temperature of the metal plate is reduced to approximately 55 ⁇ 0.5 ° C.
  • Eligible animals with a pain threshold between 5-30 seconds were selected from all candidate mice and randomly divided into six groups of 10 animals each. Animals in each experimental group were injected with total alkaloids of Sophora alopecuroides via tail vein, and the doses were 25, 20, 15, 10, and 5 mg / kg, respectively. Animals in the negative control group were injected with an equal volume of saline through the tail vein. Ten minutes after the administration, the pain threshold of the mice in each group was measured again in the same manner as described above. The results are shown in Listing 5 below.

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Description

槐定碱及其作为镇痛剂的应用 发明领域
本发明总地涉及槐定碱及其类似物或衍生物。 更具体的说， 本 发明涉及天然或化学合成来源的槐定碱和其衍生物或类似物，及其 作为镇痛剂或生产镇痛剂或兼有抗肿瘤和镇痛效果的药物组合物 中的应用。
发明背景
目前临床上广泛使用的镇痛药物主要包括两大类：一类是作为 受体激动剂与中枢神经系统的阿片受体结合，模拟内源性镇痛物质
(如脑啡肽）的功能， 激活体内抗痛系统而发挥镇痛作用的阿片类 镇痛药， 其中包括苯并吗啡烷类、哌替啶类以及与吗啡烷相关的镇 痛药； 另一类是通过抑制下视丘脑体温调节中枢前列腺素合成酶
(环氧合酶） 而抑制体神经传导的疼痛的非固醇类抗炎止痛药
( NSAIDS ), 其中包括水杨酸类、 乙酰苯胺类、 吡唑酮类、 邻氨基 甲酸类、 芳基乙酸类及芳基丙酸类化合物。 然而， 由于前者存在有 严重的耐受性和依赖性（即成瘾性）， 而后一类药物则常常只表现 出很有限的止痛效果， 所以从总体上看， 这些已知镇痛药均不够理 想。
槐定碱 ( Sophoridine )是最早（ 1933年） 由 Oreknow等 ^ 豆科植物苦豆子中分离的一种生物碱。 迄今为止， 已从苦豆子中发 现并分离了十余种具有双1 西里啶结构的生物碱，其中主要包括 苦参碱 ( Matrine )、 苦豆碱 ( Aloperine )、 拉马宁碱、 槐果碱 ( Sophocarpine )、 氧化苦参戚 ( Ma trine oxide )、 槐胺碱 ( Sophoramine ), 以及槐定碱。
与许多天然来源的植物生物碱一样，从苦豆子中分离提取的生 物碱也具有多方面的生物学活性。 例如在中国，人们很早就已将苦 参碱广泛用作全身性抗炎剂 （如参见 Cho etal. , IRCS Med. Sci. 14: 441-442, 1986 ； Chinease Tranditional Medicine Encyclopedia, Hsin-Wen-Feng Publishing Co. , Taiwan, Vol. 1, pp. 230-232, 1985 )0另外，美国专利 5, 908, 628 号描述了由包括苦豆子在内的十二种中国传统草药组成的，具有镇 痛和抗炎性貭的药物组合物。美国专利 5， 041, 450号公开了苦参碱 及其衍生物在治疗眼炎及作为眼病止痛剂的应用。 李雪梅等人（如 参见李雪梅等， 槐定的抗癌作用， 中国药理学报 8 ( 2 ) : 153- 158, 1987; 中国专利 93100881· 6 )公开了槐定碱的抗肿瘤生物学活性， 并证明槐定碱对包括人子宫滋养细胞瘤在内的多种肿瘤的抗肿瘤 生物学活性。 然而， 以天然提取的或化学合成的槐定碱化合物或其 衍生物或类似物作为临床普遍适用的镇痛剂，特别是作为用于各种 晚期癌症病人的及其他各种原因导致的疼痛的镇痛剂，迄今尚未见 报导。
发明筒迷
本发明的一个目的是提供一种新的，对哺乳动物因各种原因导 致的疼痛具有止痛作用的药物组合物，其特征在于所说的药物组合 物含有作为基本活性成份的治疗有效量的槐定碱或其衍生物或类 似物， 以及一种或多种药理上可接受的载体或赋形剂。
根据本发明这一目的的一个优选实施方案，其中所说的槐定碱 衍生物是槐定减基本环结构任何位置上被选自含有 1至 6个碳原子 的链烷基、 环鍵基、 卤代垅基、 芳基、 芳貌基、 芳氧基、 酰基、 羟 基、 巯基或磺基、羧基或烷氧基， 或烷基芳氧基取代的衍生物或其 根据本发明这一目的的一个优选实施方案，其中的所说的槐定 碱类似物包括选自槐果碱、 苦参碱、 氧化苦参碱、 苦豆碱、 拉马宁 碱、 槐胺碱的槐定碱类似物或其盐。
根据本发明这一目的的一个优选实施方案，其中所说的哺乳动 物是人或选自猪、牛、 马、羊的家用大牲畜， 或选自狗、猫、 小鼠、 大鼠、 豚鼠或兔的宠物动物。
根据本发明这一目的的一个优选实施方案，其中所说的哺乳动 物是人。
根据本发明这一目的的一个优选实施方案，其中所说哺乳动物 的疼痛包括因晚期肿瘤、 机械或化学创伤、 烧伤、 肌肉痉挛、 病理 性神经损伤、 感染性或非感染性炎性损伤、 异物刺激、 代谢紊乱或 内分泌紊乱， 以及组织缺氧所导致的疼痛。
根据本发明这一目的的一个优选实施方案，其中所说的槐定碱 或其衍生物或类似物是天然的或化学合成来源的。
根据本发明这一目的的一个优选实施方案，其中所说的药物组 合物除具有镇痛作用外， 还具有抗肿瘤、 抗微生物、 抗炎和抗中枢 神经组织退化活性。
根据本发明这一目的的一个优选实施方案，其中所说的药物组 合物除含有治疗有效剂量的槐定碱或其衍生物或类似物外，还含有 一种或多种具有辅助或协同作用的天然或合成来源的其他活性成 份。
根据本发明这一目的的一个优选实施方案，其中所说的其他活 性成份包括但不只限于其他天然或合成的镇痛剂、 抗肿瘤剂、抗微 生物剂、 抗炎剂及免疫调节剂。
根据本发明这一目的的一个优选实施方案，其中所说的药物组 合物是以局部、 静脉内、 肌肉内、 鼻内、 皮内、 皮下、 体腔内、 器 官腔内、 肿瘤或非肿瘤正常組织内给药途径投用的。 根据本发明这一目的的一个优选实施方案，其中所说的药物组 合物中槐定碱及其衍生物或类似物的治疗有效剂量约为每公斤体 重 0. 01- 100mg。
本发明的另一个目的是提供如上限定的槐定碱或其衍生物或 类似物作为基本活性成份在生产镇痛、 抗肿瘤、 抗痛风、 抗炎及抗 中枢神经退化性疾病的药物中的应用。
发明详述
本发明涉及以苦豆子生物碱槐定碱或其衍生物或类似物为基 本活性成份的药物組合物。该组合物可有效的抑制或緩解包括人在 内的哺乳动物因各种原因导致的疼痛， 而不至于产生不希望的耐受 性和依赖性。
槐定 从豆科植物苦豆子中分离的一种单体生物碱。 已知槐 定碱和槐果碱均为苦参碱 ( Matrine )的立体异构体。 李雪梅等曾 基于槐定碱与已知具有抗肿瘤活性的苦参碱的结构相似性，使用带 瘤动物模型， 证明槐定碱同样具有杀伤肿瘤细胞， 抑制肿瘤生长的 生物学活性。而且发现槐定碱在有效剂量范围内基本上不抑制被治 疗个体的骨髓造血功能和免疫功能（参见李雪梅等， 槐定碱的抗癌 作用， 中国药理学报 8 ( 2 ): 153-158， 1987 )。 研究者在其进一步 的临床试用中发现，槐定碱对子宫上皮滋养层细胞瘤（绒毛膜上皮 癌、 恶性葡萄胎）、 恶性淋巴瘤、 胃癌、 小细胞肺癌均具有不同程 度的治疗作用。
本发明人基于上述现有技术研究成果，在对包括乳腺癌、肝癌、 小细胞肿瘤、 恶性淋巴瘤、 胰腺癌和胃癌在内多种肿瘤晚期病人自 愿者进行临床试验治疗中发现，槐定碱或其衍生物或类似物不仅可 在不同程度上抑制肿瘤细胞的增殖，而且可显著地抑制或緩解晚期 肿瘤病人因肿瘤组织恶性增生所导致的剧烈疼痛。特别令人惊奇的 是， 当将具有双 ^西里啶结构的生物碱， 特别是槐定碱或其衍生 物或类似物用于晚期肿瘤病人时，其可产生与阿片类镇痛药相同或 相似的镇痛效果。 而且临床试用结果进一步显示， 给所说的肿瘤病 人长时间大剂量投用槐定碱或其衍生物或类似物停药后，未见病人 出现任何如服用阿片类中枢神经阻断性镇痛药所致的成瘾作用。
本发明人的实验研究和临^见察进一步发现，具有双喹诺西里 啶结构的生物碱， 特别是槐定碱或其衍生物或类似物， 不仅可有效 地抑制或緩解晚期肿瘤病人的疼痛，而且可有效地抑制或緩解哺乳 动物因机械或化学创伤、 烧伤、 肌肉痉挛、 病理性神经损伤、 感染 性和非感染性炎性损伤、 异物刺激以及组织缺血等原因所致的疼 痛。
根据本发明，其中所说的积减或化学创伤包括锐器伤、电击伤、 钝器伤及强酸或强碱等化学物质引起的创伤；烧伤包括感染性或非 感染性一、 二或三度烧伤； 肌肉痉挛包括胃痉挛、 肠痉挛等平滑肌 痉挛， 以及骨賂肌痉挛； 病理性神经损伤包括神经炎、三叉神经痛、 坐骨神经痛， 以及脊推裂和脊推骨质增生引起的神经压迫和神经损 伤； 感染性和非感染性炎性损伤包括由细菌、真菌或病毒等病原微 生物引起的局部或全身性感染， 以及因免疫功能失调或代谢失调或 内分泌紊乱引起的风湿性关节炎、 类风湿性关节炎、 痛风、 痛经及 其他自家免疫病； 异物刺激包括腎或胆结石刺激， 以及身体任何部 位因异物侵入所遭受的刺激；組织缺血包括人或哺乳动物的心、脑、 肾及肢体动脉供血不足或梗塞所致的缺血（如导致心绞痛、 头痛或 肾绞痛）。
根据本发明，其中所说的待进行镇痛治疗的哺乳动物包括人或 灵长类动物， 或选自猪、 牛、 马、 羊的农用大牲畜， 以及选自狗、 猫、 小鼠、 大鼠、 豚鼠或兔的宠物动物。 但其中特别优选的是人。 为了实现上述目的，本发明提供一种含有抑制或緩解疼痛有效 量的槐定碱或其衍生物或类似物，并含有一种或多种药理上可接受 的载体或赋形剂的药物组合物。所说的药物組合物可有效地抑制或 緩解哺乳动物机体因各种原因引起的疼痛，特别是可抑制或緩解晚 期肿瘤病人因肿瘤组织恶性增生所导致的疼痛， 而不会引起药物耐 受性和依赖性， 即停药后不会出现难以忍受的戒断反应综合症。
可以按照本领域技术人员熟知的常规方法， 经稀酸溶液浸泡、 离子交换层析、 有机溶剂 （如氯仿、 石油醚等）萃取及重结晶等步 骤从天然豆科槐属植物苦豆子的地上部分提取并分离槐定碱 (例如 参见吴运光，西豆根抗癌有效成份提取分离的研究，新医药资料（西 豆根研究增刊）（4 )， 1974; 赵博光， 苦豆草主要生物碱在不同器 官中的含量动态分布及薄层定量， 药学学报 15 ( 3 )， 182， 1980 )。 另外，可按照常规方法制备有更好溶解度或吸收率或储存稳定性的 槐定碱的无机酸或有机酸盐。这里所说的无机盐包括但不只限于盐 酸、 硫酸、 硝酸、 磷酸、 碳酸、 次碳酸、 硼酸及硅酸盐； 所说的有 机酸盐包括但不只限于甲酸、 乙酸、 丙酸、丁酸、苹果酸、 水杨酸、 顺乌头酸、柠檬酸、富马酸、马来酸、 酒石酸、脂肪酸及丙酮酸盐。 也可以以反复重结晶的高纯度槐定碱为起始材料，按照化学合成领 域已知的氢化、 氧化、 烷基化、 酰化、 环化、 脱氢、 酯化、 酰氨化 等反应步骤，制备适于各种临床症用或研究目的的槐定碱衍生物或 类似物。 或者， 可按照化学合成领域已知的方法， 全人工合成用于 本发明目的的槐定碱或其衍生物或类似物， 以降低药物组合物的生 产成本， 并有利于进一步发现和筛选具有更好的止痛和抗肿瘤效 果， 并显著降低了毒付作用的新的槐定碱衍生物或类似物。
本说明书中使用的术语 "槐定碱衍生物"是指槐定碱的基本环 结构的任何位置上被取代的天然存在的、半合成的或全合成的槐定 碱的化学衍生物或类似物。其中所说的取代基基团包括但不只限于 含有一个或多个（最好是 1至 6个）碳原子的^ & (如甲基、 乙基、 丙基和丁基）、 取代的烷基、 链烯基、 取代的链烯基、 芳基、 二烯 基、 芳坑基、 芳烯基、 取代的芳基、 杂环或取代的杂环基团、 环烷 基、取代的环 、 卤素（如 Cl、 Br、 1 )、 卤代烷基、酰基、羟基、 巯基、 磺基、 羰基、 、 烷氧基、 芳 及烷基芳氧基基团。
本说明书中使用的术语 "槐定碱类似物" 包括但不只限于可按 已知方法从天然来源提取并分离得到的苦参碱、 氧化苦参碱、拉马 宁碱、 槐果碱、 槐胺碱、 苦豆碱或它们的天然的、 半合成的或全合 成的化学衍生物。
应明确指出的是， 虽然本发明优选的是天然存在的槐定碱或其 衍生物， 并以其作为代表性化合物举例描述本发明， 但上述这些具 有双喹诺西里啶结构的生物碱，无论其为天然的或半合成或全合成 的，均可用于制备本发明的具有镇痛和 /或抗肿瘤和 /或抗炎作用的 药物组合物，并且这些化合物均包括在本发明的待批权利要求范围 内。
作为本发明的药物组合物的基本活性成份，槐定碱或其衍生物 或类似物表现有极好的镇痛作用， 特别适用于某些晚期肿瘤病人， 同时适用于抑制、緩解和治疗某些因免疫功能或代谢紊乱导致的炎 性反应性疾病， 如类风湿性关节炎和痛风。 尽管不拘泥于理论， 但 推测这些化合物可能是通过增加中枢和外周神经系统的神经递质 (如乙酰胆碱）的浓度而发挥作用的。而且，我们的初步研究发现， 槐定碱或其衍生物或类似物的镇痛作用似乎并不是通过中枢神经 阿片受体介导的。
可按照制药工业中 已知的方法 （如参见 Remington' s Pharmaceutical Science. 15th ed. , Mack Publ ishing Company, 1980 )将槐定碱或其衍生物或类似物与一种或多种医药 上可接受的载体或赋形剂或稀释剂按适当的比例混合，并按已知方 法除菌后制成本发明的药物組合物。
根据给药途径的不同，可将本发明的药物组合物配制成适于静 脉内、肌肉内、体腔内（如胸腔、腹腔、脊髓腔、颅内及关节嚢内）、 组织内、 皮内或皮下给药的可注射的溶液剂或^ · 1剂； 或适于口服 给药的粉末剂、 片剂、 颗粒剂、 丸剂、 乳剂、 悬浮剂、 胶嚢剂、 酏 剂； 或适于局部给药和通过皮肤或粘膜吸收给药的喷雾剂、 霜剂、 乳剂、 软膏剂、 凝胶剂、 含片或栓剂。
为了制备适于胃肠道外途径给药的可注射溶液剂，例如可以使 用无菌蒸馏水、注射用水、等渗氯化钠或葡萄糖溶液，或低浓度（如 1-lOO fflM)磷酸盐緩冲盐水（PBS )、 以及含有乙醇、 多元醇（如乙 二醇、 丙二醇及液态聚乙二醇等）的溶剂或分散介质作为载体或稀 释剂。 在任何情况下， 所说的可注射制剂均应是无菌和可流动并适 于通过注射器注射给药的。 另外， 在生产、运输和储存条件下， 所 说的制剂还必须是稳定的， 并能够对抗细菌和真菌等微生物的污 染。 必要时， 可加入抗氧化剂 （如抗坏盐酸）、 抗生素（如青霉素 和链霉或其他抗真菌剂）及防腐剂 （如苯甲酸钠、 三氯叔丁醇、 度 米酚,、 山梨酸等）， 以及增溶剂和用于维持分散剂中所需颗粒大小 的表面活性剂。
为了制备适于口服给药的片剂、粉末剂、 胶嚢剂、颗粒剂或乳 剂， 可以使用蔗糖、 乳糖、 半乳糖等二糖， 或甘露醇、 山梨醇等六 碳多羟基醇， 以及玉米淀粉、 明胶、 脂质、 微晶纤维素等作为载体 或赋形剂。 必要时， 也可在这些口服制剂中加入崩解剂、 润滑剂、 緩冲盐、 着色剂、 甜味剂、 香料、 分散剂及表面活性剂。
另外， 也可使用制药工业中已知的方法和辅助成份， 将本发明 的药物组合物制成微胶嚢剂或脂质体包裹剂。
为了制备适于外用或局部给药的制剂，例如可以将槐定碱或其 衍生物或类似物溶解于含水介质或其他适当的载体或基质中，并与 适当的透皮吸收剂如二甲基亚砜或月桂氮卓酮混合，制成喷雾剂或 气雾剂。 另外， 也可使用适当的基质或赋形剂将本发明的药物组合 物制成适于局部或通过皮肤或粘膜吸收给药的乳剂、 霜剂、 软膏、 凝胶剂或栓剂 （如阴道栓剂或直肠栓剂）。 为此， 可使用甘油、 硬 脂酸镁、 聚乙二醇、 聚丙烯酰胺、 胆固醇、 卵磷脂、 甲基纤维素或 羧曱基纤维素、滑石粉、乳糖、 葡聚糖、淀粉等作为基质或赋形剂。
根据使用目的的不同，本发明的药物組合物除含有作为基本活 性成分的槐定碱或其衍生物或类似物外 ,还可含有一种或多种具有 相同、相似或不同生物学活性， 并对基本活性成分表现有辅助或协 同作用，但彼此又互不拮抗的天然或合成的其他药物成份或其混合 物。
根据本发明，所说的其他活性成分包括但不只限于天然来源的 或合成的镇痛剂 （如阿斯匹林、 保泰松、 丁酸衍生物、 芬那酯衍生 物等非固醇类解热镇痛剂， 或阿片类镇痛剂等）、 抗肿瘤剂 （如氮 芥、 环磷酰胺、 氨甲喋呤、 长春新碱、 紫杉醇、 柔红霉素等）、 抗 微生物剂 （如山梨酸、 制霉菌素、 黄芩等）， 以及免疫调节剂 （如 胸腺素、 雷公藤总甙等）。
一般说来， 本发明的药物组合物的口服给药剂量为
0. 1- 100mg/kg/天， 较好为 1 - 80mg/kg/天， 最好为 5-50mg/kg/天； 腹腔内或肌肉内注射给药剂量为 0. 05-100mg/kg/天， 较好为 0. l-80m/kg/天， 最好为 0. 5-50mg/kg/天； 静脉内注射给药剂量为 0. 01-100mg/kg/天 ， 较好为 0. 05-80mg/kg/天， 最好为 0. 1- 50mg/kg/天。 当然，确切的给药剂量应根据待治疗的病症或病 理状态的性质、 严重程度、 病人的年龄、 体重、 一般健康状态， 以 及病人对所用药物的敏感性、 耐受性和给药方式等因素， 按照个体 化的原则由临床医生确定。
本发明进一步涉及槐定碱和 /或其衍生物或类似物在生产镇痛 药、 抗肿瘤药物、 抗痛风药物、 抗炎药物及抗神经退化性疾病药物 中的应用。
基于本发明人发现的槐定碱及其衍生物或类似物对包括晚期 肿瘤及其他原因所致疼痛的显著镇痛效果（参见实施例 1和 2 ),以 及现有技术已证实的槐定碱及其类似物（如苦参碱或氧化苦参碱 ) 对子宫绒毛膜上皮细胞癌、恶性淋巴瘤等恶性肿瘤细胞生长的抑制 活性（如参见李雪梅等， 槐定的抗癌作用， 中国药理学报 8 ( 2 ): 153-158, 1987; 中国专利 93100881. 6 ), 有可能以槐定碱或其衍 生物作为基本活性成份， 用于制备镇痛和 /或抗肿瘤药物组合物。 或者， 也可将槐定碱或其衍生物作为辅助活性成份， 与其他已知的 镇痛和 /或 肿瘤药物联合使用， 以改善这些治疗药物的使用效果 并減少某些鎮痛药（如易于导致依赖性或成瘾性的阿片类镇痛药 ), 或抗肿瘤化学药物（如易于导致骨髓造血功能或免疫功能抑制的大 多数烷化剂、抗代谢剂）的用量（如参见实验例 3和 4 )，从而大大 減少因长期使用这些药物给病人带来的痛苦，并显著改善病人的生 存廣量。 例如， 对于某些因长期使用肿瘤化疗药物导致外周血白细 胞和血小板水平过低及其他相关毒性反应，而不宜继续使用这些高 毒性化疗药物的肿瘤病人，可以单独或与小剂量其他化疗药物联合 使用槐定碱和 /或其衍生物或类似物， 以作为一种有效的 目对付 作用很低的替代药物，在不至于造成较大付作用的前提下达到预期 的治疗效果。
同样，基于本发明证实的槐定碱或其衍生物或类似物的显著镇 痛作用， 也可以将槐定碱或其衍生物或类似物作为辅助活性成分， 与其他已知的阿片类镇痛药或非固醇类解热止痛抗炎药物或抗痛 风药物联合使用 （如参见实验例 4 ), 以制成新的药物组合物， 用 于抑制或緩解感染或非感染性炎性反应性疾病症状， 以期进一步改 善解热镇痛效果并減少病人或其他被治疗个体的痛苦。 另外， 本发 明人的初步实验研究还发现，槐定碱或其衍生物的镇痛作用可能是 由于这些化合物通过目前尚不清楚的生物化学途径显著地增加中 枢神经系统的乙酰胆碱水平所导致的 （数据未示出）。 因此， 槐定 碱或其衍生物或类似物也可望被用于生产治疗中枢神经退化性疾 病如早老性痴呆的药物。 下列实施例旨在进一步举例说明， 而不是限制本发明。应明确 指出的是， 在不违背本发明的精神和原则的前提下， 对本发明的个 杈利要求范围内。 实施例 1: 槐定碱对小鼠模型的镇痛作用 （热板法）
本实施例旨在以热板法观察苦豆子生物碱槐定碱对小鼠模型 的镇痛作用。
以平均体重为 18-22g的昆明种小鼠为实验动物， 按照文献中 已描述的热板法 （参见李仪奎主编， 中药药理实验方法学， pp. 351-353, 上海科学技术出版社）进行镇痛实验。
将金属板温度调节到大约 55 ± 0· 5Ό。 给药前， 首先观察并记 录各小鼠自踏上热板至出现舔足行为的时间间隔（秒数）， 并将这 一时间间隔定为待试小鼠的痛闹值。从所有候选小鼠中挑选出痛阈 值在 5-30秒之间的合格动物， 并将它们随机分成六组， 每组 10只 动物。 各实验組动物分别按照 25、 20、 15、 10和 5mg/kg体重的给 药剂量经尾静脉注射槐定碱（ 0. lml/10g体重）。阴性对照组动物则 经尾静脉注射等体积的生理盐水。 给药后 10分钟再次按上述同样 方法检测各组小鼠的痛阈值。 实验过程中， 如个别动物在热板上停 留 60秒以上仍未出现前述的痛觉反应， 即将该小鼠从热板上取出， 终止实验观察。 实验结果如下列表 1中所示。
表 1 槐定碱对小鼠模型的镇痛作用 （热板法） 组别 给药剂量 给药前痛阈值 给药后 10分钟痛阈值 (10只/组） (mg/kg) (X±SD) (X士 SD) 对照组 12· 8 ±3.91 15.3 + 5.77 实验组 25 16.4 ±6.48 48.6 + 19.14*"
20 12.4 + 4.25 57.1 ±6.10'" 15 14.7 ±4.62 38.5 + 17.19"
10 11.7±4.59 24.8±15.99
16.3 ±6.02 25.8 ±20.74 注：与盐水组比较 **P<0.07; ***P<0.001。 从上表所示的数据可以看出， 给被试动物投用 （静脉内注射） 苦豆子生物碱槐定碱后，可显著地提高动物因经受热刺激所导致的 疼痛反应的痛阈值， 特别是较高剂量组（15- 25mg/kg)。 这些观察 结果表明， 槐定碱有可能作为一种强用力的镇痛剂， 用于抑制或緩 解哺乳动物因各种原因引起的疼痛。 实施例 2: 槐定碱对小鼠模型的镇痛作用 （醋酸诱导的扭体法） 本实验旨在以腹腔内醋酸诱导的扭体法观察苦豆子生物碱槐 定碱对小鼠模型的镇痛作用。
以平均体重 18- 24g的雄雌性各 30只昆明种小鼠为实验对象， 按照文献中已描述的醋酸诱导的扭体法（参见李仪奎主编， 中药药 理实验方法学， pp. 351-353,上海科学技术出版社）进行镇痛试验。 被试动物经腹腔内注射 0. 6%冰醋酸（ 0· 2ml/只） 以诱发疼痛反应， 并将动物随机分成六组， 每组 10只。 各实验组动物分别经尾静脉 内注射 25、 20、 15、 10和 5mg/kg槐定碱。 阴性对照组动物则经尾 静脉内注射等体积的生理盐水。 给药后 15分钟内观察动物出现的 驱体扭动反应的次数。 结果如下列表 2所示。
表 2 槐定碱对醋酸诱导的扭体反应的影响
組别 给药剂量（mg/kg ) 扭体反应次数（X ± SD )
33. 1 + 7. 40 『
1. 5 ± 1. 35'" 9. 9 ± 6. 31"* 14. 1 ± 9. 64"* 23. 2 ± 6. 43"
注：与盐水组比较 **ρ<0. 01, ***p<0. 001
从上列表 2中可以看出， 与生理盐水对照組相比， 静脉注射槐 定碱组 ( 5-25 mg/kg )动物均表现显著减少了因腹腔内注射水醋酸 所造成的痛觉反应 （即减少了动物的驱体扭动反应次数）。 因此， 本实验观察进一步证明槐定碱对小鼠的显著鎮痛作用。本实验的结 果显示，槐定碱的镇痛效果与给药剂量之间存在有良好的线性效量 关系。 实施例 3:
( 1 )槐定碱与吗啡镇痛作用的比较和槐定碱与吗啡联合用药 的协同镇痛效果
本实施例旨在以热板法比较槐定碱与吗 #对小鼠的镇痛效果， 并进一步观察槐定碱与吗啡联合用药的协同鎮痛作用。
基本上按照实施例 1中所述的方法筛选实验组动物并分组。其 中槐定碱组同样包括 25、 20、 15、 10和 5mg/kg五个不同给药剂量 组； 吗啡组和槐定碱 +吗啡组分别按表 3中所示的剂量给药。 给药 后 15、 30、 60和 90分钟分别记录各组动物的痛阈值。 结果如下列 表 3中所示。
表 3 槐定碱与盐酸吗啡镇痛作的比较 組别 给药剂量 给药前痛阈值 给药后痛阈值（秒）（X±SD)
( 10只 /组）（ mg/kg (秒） (X ±SD) 15 min 30 min 60 min 90 min 盐水組 - 17.4 ±4.9 16.2 ± 5.5 17.7 + 8. 18.9 + 6.1 18.2 ± 6.1 槐定碱组 25 15.4 ± 4.0 44.3 ± 14.9'" 28.3 ± 11.4" 20.3±4.9 18.8 ±6· 2
20 16.9 ±2.5 36.8±18.2" 24.6 ± 7.7" 23.0±9.9 19.3 ±6. 15 16.45 ± 3.9 32.9 ±19.2' 31.3 ±17.5' 15.2 ±10.2 15.8 ± 5. ' 10 18.6 + 4.9 20.2 + 7.2 28.0 ±18.3 12.6 ± 5.9 20.5 ±15.
17.45±2.6 17.5 + 3.3 16.6 + 6. 16.0±4.5 19.3 ± 5.4 吗啡組 10 19.7 ± 4.4 35, 1 ± 15. 44.8 ± 14.6'" 32.4士 16.2" 27.5 + 16. 槐定碱
吗啡组 20+10 19.1 ± 4.4 60± 0 57.2 ±8.9"' 49.6士 12. Τ" 39.9 ± 17. 注： 与基础痛阈比较 *ρ<0.05， **ρ<0.01, ***ρ<0.001。
J 3中所示的数据可进一步看出，槐定碱对小鼠的镇痛效果 与给药剂量之间呈线性正相关关系，其中 25mg/kg和 20mg/kg组与 基 痛阈相比，表现出的镇痛效果尤为明显。 特别是本实施例的实 验结果显示， 与投用盐酸吗啡的阳性对照组相比， 投用较高剂量槐 定碱的实验组动物在给药后 15分钟所表现的痛阈值似乎略高于盐 酸吗啡组。 因此可以认为， 槐定碱（25mg/kg)对哺乳动物表现有 相似或优于常规强镇痛药盐酸吗啡的镇痛作用，故其很有可能作为 一种广泛适用的鎮痛药，总地或部分地替代具有很大依赖性和成瘾 性的阿片类镇痛药。 ( 2) 阿片受体拮抗剂对槐定碱的镇痛作用的影响 本实施例旨在通过前述热板法初步观察槐定碱是否通过动物 的中枢神经系统 (CNS) 的阿片受体发挥其镇痛作用。
基本上按照实施例 1中所述的方法筛选实验组动物。各实验组 包括： 阿片受体拮抗剂纳络酮组（2mg/kg);槐定碱组（20mg/kg); 吗啡組 (10mg/kg ); 纳络酮（2mg/kg) +盐酸吗啡（10mg/kg)组； 纳络酮（2mg/kg) +槐定碱 (20mg/kg)组。 给药后 15、 30、 60和 90分钟分别记录动物的痛阈值（秒数）。 结果如下列表 4中所示。
表 4 阿片受体拮抗剂纳络酮对槐定碱镇痛作用的影响 组别 给药剂量 给药前痛阈值 给药后痛阈值（秒）（X±SD)
(10只 /組）（mg/kg) (秒）（X±SD) 15 min 30 min 60 min 盐水組 一 16. 18.2 ± 6. 19.7±6.0 16.9 + 6.5 17. 6.0 纳络酮组 2 18· 5 ±2. 17.4±7.7 15.8±6.0 19.0±8.7 18.1±4.0 槐定碱组 20 17.9±2.6 34.5 ±16.2" 23.8 ±7.0 21.8±8.9 18.3 ± 6.6 吗啡组 10 19.8± 4.0 36.0 + 13.5 43.5 ± 12.5，" 31.6 ± 15.8' 26.3 ± 15.5 纳络酮
+吗啡组 2+1 15.7 + 3.6 17.9 + 15.6 26.1 ± 16.5 24.7 + 15.3 16.0±Π. Ο 纳络酮 +
槐定碱组 2+20 18.3 + 5.1 33.2 + 10.0" 21.9 + 13.4 17.7±6.0 16.0±5.7 注： 与盐水组比较 *ρ<0.05, **ρ<0.01。
^fd 所示的数据可以看出，单独投用阿片受体拮抗剂纳络酮 对小鼠的疼痛反应没有明显抑制作用。 然而， 纳络酮与盐酸吗啡联 合用药， 其可显著地抑制盐酸吗啡的镇痛活性。 另一方面， 当纳络 酮与槐定誠联合用药时，其对槐定碱的镇痛作用没有表现出统计学 上有意义拮抗作用。 因此， 这些结果清楚地表明槐定碱并不是通过 激活 CNS阿片受体而发挥其镇痛作用的。 实施例 4 : 苦豆子总生物碱对小鼠模型的镇痛作用 （热板法） 本实施例旨在观察包括槐定碱、 苦豆碱、槐定碱和苦参碱在内 的苦豆子地上部分总生物碱（其盐酸盐）对小鼠模型的镇痛作用。
以平均体重为 15- 20g的昆明种小鼠为实验动物， 按照文献中 已描述的热板法 （参见李仪奎主编， 中药药理实难方法学， pp. 351-353 , 上海科学技术出版社）进行镇痛试验。
将金属板温度谓节到大约 55 ± 0. 5°C。 给药前， 首先观察并记 录各小鼠自踏上热板至出现舔足行为的时间间隔（秒数）， 并将这 一时间间隔定为小鼠的痛阈值。从所有候选小鼠中挑逸出痛阈值在 5-30秒之间的合格动物，并将它们随机分成六组，每组 10只动物。 各实验组动物经尾静脉注射苦豆子总生物碱，给药量分别为 25、20、 15、 10和 5mg/kg。 阴性对照组动物则经尾静脉注射等体积的生理 盐水。给药后 10分钟再次按上述同样方法检测各组小鼠的痛阈值。 结果如下列表 5所示。
表 5 苦豆子总生物碱粗提物对小鼠模型的镇痛作用（热板法） 組别 给药剂量 给药前痛阚值 给药后 10分钟痛阈值
(10只/組） （mg/kg) (X±SD) (X±SD) 对照組 一 10.6 ±2.56 14.3 ±3.65 实验组 25 15· 3 ± 6.20 45.5 ±16.10·"·
20 11.6 ± 5.25 50.8 ±10· 17"，
15 13.8 + 6.50 35.6 + 12.15"
10 12.3± 3.85 19.2±10.80
5 15.3± 5.80 23.7 ±15.75 注： 与盐水组比较 **Ρ<0· 07; ***Ρ<0· 001。 从上表所示的数据可以看出， 给被试小鼠投用 （静脉内注射） 苦豆子总生物减 ( 15-25mg/kg )后， 可显著地提高动物因遭受热刺 激所导致的疼痛反应的痛阔值。 这些结果表明， 与槐定碱单体化合 物相似， 包括槐定碱、 苦豆碱、 槐^^和苦参碱在内的苦豆子总生 物碱粗提物对哺乳动物实驗模型同样具有显著的镇痛作用。

Claims

权 利 要 求
1、 一种对哺乳动物因各种原因导致的疼痛具有止痛作用的药 物组合物，其特征在于所说的药物组合物含有作为基本活性成份的 治疗有效量的槐定碱或其衍生物或类似物， 以及一种或多种药理上 可接受的载体或赋形剂。
2、 根据权利要求 1的药物組合物， 其中所说的槐定碱衍生物 是槐定 基本环结构任何位置上被选自含有 1至 6个碳原子的链烷 基、 环烷基、 卤代烷基、 芳基、 芳 、 芳 #L^、 酰基、 羟基、 巯 基或磺基、 羧基或烷氧基， 或烷基芳氧基取代的衍生物或其盐。
3、 根据权利要求 1的药物组合物， 其中的所说的槐定碱类似 物选自槐定碱、槐果碱、苦参碱、氧化苦参碱、拉马宁碱、苦豆碱、 槐胺碱的槐定碱类似物或其盐。
4、 根据权利要求 1的药物组合物， 其中所说的哺乳动物是人 或选自猪、 牛、 马、 羊的家用大牲畜， 或选自狗、猫、 小鼠、 大鼠、 豚鼠或兔的宠物动物。
5、根据权利要求 1的药物组合物， 其中所说的哺乳动物是人。
6、 根据权利要求 1的药物组合物， 其中所说哺乳动物的疼痛 包括因晚期肿瘤、 机械或化学创伤、 烧伤、 肌肉痉挛、 病理性神经 损伤、感染性或非感染性损伤、异物刺激、代谢紊乱或内分泌紊乱， 以及组织缺氧所导致的疼痛。
7、 根据权利要求 1的药物组合物， 其中所说的槐定碱或其衍 生物或类似物是天然的或化学合成来源的。
8、 根据权利要求 1的药物组合物， 其中所说的药物组合物还 具有抗肿瘤、 抗微生物、 抗炎和抗中枢神经組织退化活性。
9、 根据权利要求 1的药物组合物， 其中所说的药物組合物除 含有治疗有效剂量的槐定碱或其衍生物或类似物外，还含有一种或 多种具有辅助或协同作用的天然或合成来源的其他活性成份。
10、根据权利要求 9的药物組合物， 其中所说的其他活性成分 包括其他天然或合成的鎮痛剂、 抗肿瘤剂、 抗微生物剂、 抗炎剂及 免疫调节剂。
11、根据权利要求 1的药物组合物， 其中所说的药物组合物是 以局部、静脉内、 肌肉内、鼻内、皮内、皮下、体腔内、 器官腔内、 肿瘤或非肿瘤正常组织内给药途径投用的。
12、根据权利要求 1的药物组合物， 其中所说的药物组合物中 槐定碱及其衍生物或类似物的治疗有效剂量约为每公斤体重 0. 0卜 100mg。
13、 根据权利要求 1-11中任一项的槐定碱或其衍生物或类似 物在生产镇痛、 抗肿瘤、 抗痛风、 抗炎及抗中枢神经退化性疾病的 药物中的应用。
PCT/CN2002/000421 2001-06-14 2002-06-14 Sophoridine et son utilisation en tant qu'analgesique Ceased WO2002102379A1 (fr)

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CN101152178B (zh) * 2007-10-11 2010-10-06 蔡海德 槐定碱纳米脂质体药物及其制备
CN101721706B (zh) * 2008-10-13 2012-03-21 青岛启元生物技术有限公司 含有苦参素药物组合物在制备治疗疼痛药物中的应用
CN104522001B (zh) * 2012-09-21 2016-08-24 上海韬鸿化工科技有限公司 驱蚊凉席
CN104189048A (zh) * 2014-09-18 2014-12-10 江苏天晟药业有限公司 一种用于止痛的中药组合物及其制备方法和应用
CN104490879A (zh) * 2014-12-04 2015-04-08 宁夏医科大学 苦豆碱作为治疗炎性痛药物的用途
CN108354935A (zh) * 2018-03-29 2018-08-03 上海壹志医药科技有限公司 槐胺碱的新药物用途
CN111317754B (zh) * 2018-12-13 2022-02-18 泰州医药城国科化物生物医药科技有限公司 一种北豆根总碱的制备方法及应用
CN114573585B (zh) * 2020-12-01 2023-12-15 中国医学科学院药物研究所 一类苦豆子提取的生物碱、其药物组合物及其在防治肿瘤中的应用

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CN1343490A (zh) 2002-04-10
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US20060251751A1 (en) 2006-11-09
EP1407771A1 (en) 2004-04-14

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