WO2019072014A1 - 含A-失碳-5α雄甾烷化合物的升白制剂及其应用 - Google Patents

含A-失碳-5α雄甾烷化合物的升白制剂及其应用 Download PDF

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WO2019072014A1
WO2019072014A1 PCT/CN2018/100430 CN2018100430W WO2019072014A1 WO 2019072014 A1 WO2019072014 A1 WO 2019072014A1 CN 2018100430 W CN2018100430 W CN 2018100430W WO 2019072014 A1 WO2019072014 A1 WO 2019072014A1
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Prior art keywords
compound
carbon
androstane
active ingredient
deficient
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PCT/CN2018/100430
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English (en)
French (fr)
Inventor
陈雅君
谌志华
王文雅
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上海奥奇医药科技有限公司
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Priority to EP18866348.8A priority Critical patent/EP3692994A4/en
Priority to CA3079031A priority patent/CA3079031C/en
Priority to US16/755,698 priority patent/US20200289527A1/en
Priority to JP2020541841A priority patent/JP7123431B2/ja
Priority to AU2018348892A priority patent/AU2018348892B2/en
Publication of WO2019072014A1 publication Critical patent/WO2019072014A1/zh

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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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P7/06—Antianaemics

Definitions

  • the present invention belongs to the field of medicine, and in particular to a whitening preparation containing an A-carbon-inhibiting-5 ⁇ -androstane compound and its use.
  • Leukopenia refers to a white blood cell count in a person's peripheral blood that continues to be below 4.0 ⁇ 10 9 /L.
  • the cause of leukopenia is usually caused by drugs, radiation or other chemical poisons.
  • Leukopenia can cause symptoms such as low immunity, loss of appetite, and weakness in the limbs.
  • chemotherapy and radiotherapy are commonly used methods of cancer treatment.
  • chemotherapy and radiotherapy often lead to the reduction of white blood cells, while killing cancer cells, it also damages normal tissues, especially the inhibition of bone marrow hematopoietic function, resulting in continuous reduction of peripheral white blood cells. This condition not only hinders the continuation of chemotherapy and radiotherapy, but can also have serious consequences.
  • whitening drugs are often used in clinical practice to increase the number of white blood cells in the blood of patients, so that patients with radiotherapy and chemotherapy can proceed smoothly as scheduled, and the cycle treatment of radiotherapy and chemotherapy is guaranteed.
  • These whitening drugs mainly include: 1, Chinese herbal medicines, such as: ginseng, astragalus, Codonopsis, Ligustrum lucidum, spatholobus, medlar, rehmannia, etc.; 2, Chinese herbal compound preparations, such as Yulu Tang, Baoyuan Tang, Liuwei Dihuang oral Liquid, Shengbai Pill, Wuji Baifeng Pill, Jianpi Yishen Granule, Changan Shengbai Granule, Shengbai Tablet, Shenqi Tablet, Yangxue Shengbai Capsule, etc.; 3.
  • Chemical drugs such as Lixuesheng, Shark liver alcohol, Vitamin B, ascorbic acid, inosine, deoxyribonucleic acid, etc.; 4, biological agents, such as colony stimulating factor (CSF), granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GMCSF), etc. .
  • CSF colony stimulating factor
  • GCSF granulocyte colony-stimulating factor
  • GMCSF granulocyte-macrophage colony-stimulating factor
  • the efficacy of the first three types of Chinese and Western medicines is limited, although the effect of hematopoietic stimulating factors is significant, but the action time is short, easy to repeat, obvious side effects, and expensive, and the patient's economic burden is large.
  • the object of the present invention is to provide a drug for raising white blood cells with remarkable curative effect, small side effects and convenient use.
  • an A-carbon-reducing-5 alpha androstane compound for the preparation of a formulation or composition for augmenting the number of white blood cells; (b) for the prevention or treatment of leukopenia.
  • the structure of the A-carbon-deficient-5 ⁇ -androstane compound is as shown in Formula I:
  • R 1 and R 2 are each independently selected from: H, substituted or unsubstituted C 1-10 alkyl, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted benzene ring, substituted or unsubstituted Benzoyl, substituted or unsubstituted COC n H 2n+1 , substituted or unsubstituted COC r H 2r COOC m H 2m+1 , or -COC p H 2p COO-W; wherein, n, p, r m is independently an integer from 0 to 18, and W is H, Na + , K + , NH 4 + , 1/2Ca 2+ , 1/2Mg 2+ , 1/2(AlOH) 2+ , or 1/ 2Zn 2+ ,
  • the substitution means having one or more (e.g., 1-3) substituent groups selected from the group consisting of a hydroxyl group, a halogen, a nitro group, an amino group, an amine group, and a carboxyl group.
  • the A-carbon-deficient-5 alpha androstane compound is selected from the group consisting of
  • the composition is a pharmaceutical composition, a dietary supplement composition, or a health care product composition.
  • the composition comprises (a) an A-carbon-reduced-5 alpha androstenane compound; and (b) a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is in the form of a solid preparation or a liquid preparation.
  • the pharmaceutical composition is in the form of an oral dosage form, an injection, or a topical pharmaceutical dosage form.
  • the pharmaceutical composition is a tablet, granule, or capsule.
  • the formulation or composition contains from 0.001 to 99% by weight, preferably from 0.1 to 90% by weight, more preferably from 1 to 50% by weight, of the A-carbonic-5 alpha androstane compound, by formulation or The total weight of the composition.
  • the "increasing the number of white blood cells” means increasing the number of white blood cells in the blood of a subject.
  • the subject is a human, or a non-human mammal (e.g., a rodent).
  • the subject is a person with a decreased number of white blood cells.
  • the "decreased white blood cell number” means that the white blood cell number A1 of the subject is lower than A0 compared to the lower limit A0 of the number of white blood cells of a normal person; preferably, A1/A0 is 0.1-0.9. Preferably, it is from 0.2 to 0.8, more preferably from 0.3 to 0.7.
  • the A0 is 4 x 10 9 / L of blood.
  • the subject is a tumor patient.
  • the subject is a subject who has been, is, or is about to undergo tumor treatment.
  • the tumor treatment comprises: chemotherapy, radiation therapy, or a combination thereof.
  • the "increasing the number of white blood cells” means that the number of white blood cells C1 in the blood of a subject is increased as compared with the number of white blood cells C0 of the control.
  • the number of white blood cells C0 of the control is the number of white blood cells Czs of the subject before treatment or treatment with the drug of the present invention; or the number of white blood cells Cdz of the control group.
  • the "increasing white blood cell number” means C1/Czs ⁇ 1.2, preferably ⁇ 1.4, more preferably ⁇ 1.5 or ⁇ 2.0.
  • the "boosting leukocyte count” means C1/Cdz ⁇ 1.2, preferably ⁇ 1.4, more preferably ⁇ 1.5 or ⁇ 2.0.
  • a preparation product for increasing the number of white blood cells or preventing leukopenia comprising:
  • a first pharmaceutical composition comprising (a) a first active ingredient, said first active ingredient being an A-carbon-reducing-5 ⁇ -androstane compound; and (b) a pharmaceutically acceptable carrier ;as well as
  • a second pharmaceutical composition the second pharmaceutical composition being a whitening drug.
  • the whitening drug comprises (a) a second active ingredient, the second active ingredient being a whitening active ingredient different from the A-carbon-reducing-5 ⁇ -androstane compound; and (b) a pharmaceutically acceptable carrier.
  • the increase in the number of white blood cells is to increase the number of white blood cells in the mammal.
  • the whitening drug is selected from the group consisting of a Chinese herbal medicine, a traditional Chinese medicine compound preparation, a chemical medicine, a biological preparation, or a combination thereof.
  • the Chinese herbal medicine is selected from the group consisting of ginseng, astragalus, Codonopsis, Ligustrum lucidum, spatholobus, scorpion, rehmannia, or a combination thereof.
  • the traditional Chinese medicine compound preparation is selected from the group consisting of: Yulu Tang, Baoyuan Tang, Liuwei Dihuang Oral Liquid, Shengbai Pill, Wuji Baifeng Pill, Jianpi Yishen Granule, Changan Shengbai Granule, Shengbai Tablets, ginseng tablets, nourishing white capsules, or a combination thereof.
  • the chemical is selected from the group consisting of serotonin, squalyl alcohol, vitamin B, pingbai, inosine, deoxyribonucleic acid, or a combination thereof.
  • the biological agent is selected from the group consisting of colony stimulating factor (CSF), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), or Its combination.
  • CSF colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • first pharmaceutical composition and the second pharmaceutical composition are each independent or in combination.
  • a preparation product for treating a tumor comprising:
  • composition comprising: (a) a first active ingredient, the first active ingredient being an A-carbon-reducing-5 ⁇ -androstane compound; and (b) pharmaceutically acceptable Accepted carrier;
  • composition of the second aspect comprising: (a) a second active ingredient, wherein the second active ingredient is different from the A-carbon-reducing-5 ⁇ -androstane compound for treating a tumor An active ingredient; and (b) a pharmaceutically acceptable carrier.
  • the II active ingredient is selected from the group consisting of cyclophosphamide, ifosfamide, doxorubicin, 5-fluorouracil, cytarabine, fluoroguanosine, tegafur , gemcitabine, carmofur, hydroxyurea, methotrexate, actinomycin D, doxorubicin, daunorubicin, epirubicin, mitomycin, pilomycin, irinotecan, three Cephalosporin, hydroxycamptothecin, vinorelbine, paclitaxel, taxotere, topotecan, vincristine, vindesine, vinblastine, teniposide, etoposide, armetametan, ar Natrozole, aminoglutethimide, letrozole, formestane, betaprogesterone, tamoxifen, asparaginase, carboplatin, cisplatin, dacarbazin
  • first pharmaceutical composition and the second pharmaceutical composition are each independent or in combination.
  • a method of increasing the number of white blood cells comprising the steps of: (a) administering to a subject in need thereof an A-carbon-reducing-5 alpha androstane compound.
  • the subject comprises a human or non-human mammal, preferably a rodent (e.g., mouse, rat), a primate (e.g., a human).
  • rodent e.g., mouse, rat
  • primate e.g., a human
  • the subject is a tumor patient.
  • the tumor is selected from the group consisting of gastric cancer, liver cancer, leukemia, kidney tumor, lung cancer, small bowel cancer, bone cancer, prostate cancer, colorectal cancer, breast cancer, colon cancer, prostate cancer, and cervical cancer. , lymphoma, adrenal tumor, or bladder tumor.
  • the subject has, is, or is about to undergo chemotherapy and/or radiation therapy.
  • the subject has received chemotherapy or radiation therapy.
  • the subject has a white blood cell count below a lower limit of normal.
  • the subject has received chemotherapy or radiation therapy and the number of white blood cells is near or below the lower limit of normal.
  • the normal value ranges from 4 ⁇ 10 9 to 10 ⁇ 10 9 /L.
  • the number of white blood cells is 1 ⁇ 10 9 - 3.8 ⁇ 10 9 /L before the whitening treatment by the method of the present invention.
  • the normal value is 1.8 ⁇ 10 3 - 10.7 ⁇ 10 3 /uL.
  • the method is non-therapeutic.
  • A-carbon-reducing-5 ⁇ -androstane compounds are very effective in increasing the number of white blood cells in mammals, and their side effects are very low.
  • anti-tumor drugs such as cyclophosphamide and other chemotherapy drugs
  • radiotherapy administration of the A-carbon-lowering-5 ⁇ -androstane compound prior to chemotherapy or radiotherapy prevented a decrease in the number of white blood cells and did not decrease significantly over a long period of time.
  • the present invention has been completed.
  • the active ingredient for whitening is an A-carbon-reducing-5 ⁇ -androstane compound or a pharmaceutically acceptable salt thereof, or a prodrug.
  • A-carbon-free-5 ⁇ -androstane compound is a kind of compound with special structure independently developed by Li Ruilin et al.
  • the existing animal efficacy test shows that A-carbon-lowering-5 ⁇ -androstane compound has a better therapeutic effect on prostate hyperplasia.
  • the A-carbon-lowering-5 ⁇ -androstane compound has significant anti-malignant activity in vivo and in vitro, inhibits tumor proliferation and has the advantage of improving body weight loss. Selectively prevent the division of tumor cells without affecting normal cells, thereby inhibiting the spread of tumor cells.
  • the inventors have unexpectedly found that the A-carbon-inhibited-5 ⁇ -androstane compound has a remarkable whitening effect.
  • active ingredient active ingredient of the present invention
  • whitening active ingredient of the present invention are used interchangeably and mean A-carbon-reducing-5 ⁇ -androstane compound, especially having the following structure compound of:
  • R 1 and R 2 are as defined above.
  • the A-carbon-reduced-5 ⁇ -androstane compound may be one or more compounds selected from the group consisting of:
  • the present invention provides a pharmaceutical composition for increasing the number of white blood cells, the pharmaceutical composition comprising (a) an A-carbon-reducing-5 ⁇ -androstane compound; and (b) a pharmaceutically acceptable carrier, or a foodstuff Acceptable carrier.
  • the "active ingredient" in the pharmaceutical composition of the present invention means a compound of the formula (I) according to the present invention.
  • active ingredients and pharmaceutical compositions described herein can be used to increase the number of white blood cells.
  • it is used to prepare a whitening drug.
  • safety and effective amount is meant that the amount of active ingredient is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical compositions contain from 1 to 2000 mg of active ingredient per dose, more preferably from 10 to 200 mg of active ingredient per dose.
  • the "one dose” is a tablet or an injection.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • composition capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the compound of the formula (I) of the present invention can form a complex with a macromolecular compound or a polymer by non-bonding.
  • the compound of the formula (I) of the present invention can be linked as a small molecule to a macromolecular compound or a polymer by a chemical bond.
  • the macromolecular compound may be a biological macromolecule such as a polysaccharide, a protein, a nucleic acid, a polypeptide, or the like.
  • the administration form of the active ingredient or the pharmaceutical composition of the present invention is not particularly limited, and representative administration forms include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and the like.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient or carrier, such as sodium citrate or dicalcium phosphate, or mixed with one or more of the following ingredients:
  • a filler or a compatibilizer for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid;
  • binders such as, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia;
  • a humectant for example, glycerin
  • a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate;
  • an absorption accelerator for example, a quaternary amine compound
  • an adsorbent for example, kaolin
  • a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof.
  • the dosage form may also contain a buffer.
  • the solid dosage forms can also be prepared with coatings and shell materials, such as casings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the dose to be administered is usually 1 to 1000 mg, preferably 10 to 200 mg, more preferably 20 to 100 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the compounds of the invention may be administered alone or in combination with other therapeutic agents, particularly anticancer drugs or as a whitening drug.
  • the compounds of formula (I) may also be combined with other agents which are known to treat or ameliorate similar conditions.
  • the mode of administration and the dosage of the original drug remain unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • the compound of the formula (I) is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or several known drugs and a compound of the formula (I).
  • Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
  • the present invention provides an oral preparation of an A-carbon-reducing-5 ⁇ -androstane compound, which provides a basis for the study of pharmaceutical preparations by pre-prescription studies.
  • the water-insoluble drug A-carbon-free-5 ⁇ -androstane compound (solubility in water was 6.5 ⁇ g per ml, defined as insoluble in the pharmacopoeia.) Good dissolution and absorption in intestinal fluid, its in vivo Transport, uptake, and absorption mechanisms are all passively diffused, and intake is time and dose dependent.
  • the A-carbon deficient-5 alpha androstenane compound can be administered by the oral route.
  • oral administration is convenient, and the compliance of the patient can be improved. Therefore, the present invention is designed as an oral preparation such as a general oral tablet, an oral capsule, and other sustained-release preparations.
  • the oral preparation of the present invention is as follows:
  • Prescription composition Parts by weight Active ingredient 1-50 Filler 20-95 Disintegrator 0-20 Adhesive 0.1-30 Lubricant 0.1-5 Glidant 0.1-5
  • the active component is an A-carbon-reducing-5 ⁇ -androstane compound
  • the filler added may be one or several ingredients that increase the weight and volume of the tablet.
  • the filler is selected from one or more of lactose, sucrose, sorbitol, mannitol, polyethylene glycol, starch, and inorganic salts.
  • the filler is used in an amount of 20 to 95% by mass based on the total amount of the preparation, preferably 60 to 95%, more preferably 70 to 95%, most preferably 80 to 95%.
  • lactose is used as a filler, the amount of lactose is 20-95% of the total amount of the preparation.
  • sucrose When sucrose is used as a filler, the amount of sucrose is 10-30% of the total amount of the preparation, and when sorbitol is used as a filler, the amount of sorbitol is used. 20-95% of the total preparation, when mannitol is used as a filler, the amount of mannitol is 20-95% of the total amount of the preparation.
  • the inorganic salt When the inorganic salt is used as a filler, the amount of the inorganic salt is 5-20 of the total amount of the preparation. %.
  • the filler is lactose, mannitol, sorbitol or a mixture thereof; preferably, the filler is a mixture of lactose and mannitol.
  • the disintegrant is selected from the group consisting of crospovidone (PVPP), croscarmellose sodium (CC Na), sodium carboxymethyl starch (CMS-Na), and low-substituted hydroxypropyl cellulose (L).
  • PVPP crospovidone
  • CMS-Na sodium carboxymethyl starch
  • L low-substituted hydroxypropyl cellulose
  • PVPP crospovidone
  • CC Na croscarmellose sodium
  • CMS-Na sodium carboxymethyl starch
  • L low-substituted hydroxypropyl cellulose
  • One or more of -HPC of which PVPP and CC Na are preferred, and most preferred is CC Na.
  • the disintegrant is used in an amount ranging from 0 to 20%, usually from 1 to 10%, most preferably from 3 to 5%.
  • the lubricant is selected from the group consisting of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, hydrogenated vegetable oil, or two or more thereof, wherein magnesium stearate is most suitable. .
  • the lubricant is used in an amount ranging from 0.1 to 5%, usually from 0.2 to 4%, most preferably from 0.3 to 3%.
  • the binder used may be one or several ingredients which are advantageous for granulation.
  • the binder is selected from one or more of starch syrup, hydroxypropylmethylcellulose (HPMC), polyethylene glycol, povidone (PVP) or copolyvidone (Kollidon). PVP is preferred.
  • HPMC hydroxypropylmethylcellulose
  • PVP polyethylene glycol
  • PVP copolyvidone
  • Kollidon copolyvidone
  • the glidant is selected from one or two of micronized silica gel and talc, more preferably micronized silica gel.
  • the inorganic salt is selected from the group consisting of calcium sulfate (crystal water containing two molecules); calcium hydrogen phosphate; medicinal calcium carbonate and the like.
  • the tablets of the present invention may also contain other conceivable excipients well known to those skilled in the art, and the tablets of the present invention may be prepared by techniques well known in the art. For example, in the preparation of a tablet, a direct compression method, a wet granulation tableting method, or a dry granulation tableting method can be employed.
  • the present invention provides a common tablet of A-carbon-reducing-5 ⁇ -androstane compound, which is determined according to the pharmacodynamic study and determines the A-carbon-free 5 ⁇ -androstane compound to meet the clinical treatment needs.
  • the tablet specification is 1-100 mg/tablet, preferably 1-50 mg/tablet, such as 2.5 mg/tablet, 5 mg/tablet, 10 mg/tablet, 25 mg/tablet, and the like.
  • the whitening active ingredient of the present invention i.e., A-carbon-reducing-5 ⁇ -androstane compound
  • A-carbon-reducing-5 ⁇ -androstane compound is very effective in increasing the number of white blood cells in a mammal.
  • the whitening effect of the present invention does not cause an excessive increase in the number of white blood cells on the one hand (i.e., does not exceed the upper limit of the normal value), and on the other hand, it can be maintained for a long period of time, and the whitening effect is not significantly lowered over a long period of time. .
  • the active ingredient of the present invention can be used not only for the treatment of leukopenia but also for the prevention of leukopenia.
  • Combining the active ingredient of the present invention with other tumor treatment means can further reduce the side effects of other chemotherapeutic drugs and enhance the therapeutic effect, and has a synergistic effect.
  • ACP1 2 ⁇ , 17 ⁇ -bisethynyl-A-carbon-deficient-5 ⁇ -androstane-2 ⁇ , 17 ⁇ -dihydroxydiacetate compound (Ib)
  • ACP2 2 ⁇ , 17 ⁇ -bisethynyl-A-carbon-deficient-5 ⁇ -androstane-2 ⁇ , 17 ⁇ -bishydroxy-2 ⁇ -monosuccinate compound (Id)
  • ACP3 2 ⁇ , 17 ⁇ -bisethynyl-A-carbon-deficient-5 ⁇ -androstane-2 ⁇ , 17 ⁇ -dibutyrate compound (If)
  • ACP4 2 ⁇ , 17 ⁇ -bispropynyl-A-carbon-deficient-5 ⁇ -androstane-2 ⁇ , 17 ⁇ -dihydroxy compound (Ik)
  • ACP5 2 ⁇ , 17 ⁇ -bispropynyl-A-carbon-deficient-5 ⁇ -androstane-2 ⁇ , 17 ⁇ -dihydroxydipropionate compound (Il)
  • Example 1 Whitening effect of ACP on cyclophosphamide (CTX)-induced leukocyte count reduction in Lewis mice
  • the tumors with vigorous growth were prepared, and the cell suspension was prepared into a cell suspension at a concentration of about 5-10 ⁇ 10 6 /ml by a homogenization method under aseptic conditions. Each mouse was inoculated with 0.2 ml of the right iliac crest.
  • mice were vaccinated with Lewis lung cancer to form a transplant tumor model and randomized into groups of 10 animals each, and the whitening compound was administered on the day of tumor inoculation. Except for the high-dose ACP1-administered group, the other groups were administered CTX on the third day (150 mg/kg) and the fifth day (100 mg/kg), resulting in a leukopenia inhibition model of tumor-bearing mice.
  • mice were randomly selected for post-orbital venous plexus puncture, and the blood cell automatic analyzer (HEMAVET-950) was used to test blood routine. Thereafter, blood was collected by the same method on the 8th day and the 12th day after the last administration of the cyclophosphamide.
  • HEMAVET-950 blood cell automatic analyzer
  • cyclophosphamide CTX caused a decrease in peripheral blood leukocytes in mice, indicating successful modeling of leukopenia model animals.
  • the method was the same as 1.1, except that the number of mice in each group was 5; in the experimental group, ACP1 was replaced by ACP2, ACP3, ACP4, and ACP5, respectively, and only ACP medium dose + CTX 2.5 mg/kg was used.
  • the regimen; the chemotherapy control group was the same as the chemotherapy control group in 1.1. On the 10th day, blood samples were taken for blood test in the same manner.
  • the whitening active ingredient of the present invention can significantly alleviate and improve the number of white blood cells caused by antitumor drugs (such as cyclophosphamide), thereby being useful for preventing and/or treating leukopenia.
  • antitumor drugs such as cyclophosphamide
  • WBC White blood cell count
  • the compound of the present invention can significantly increase the number of white blood cells in tumor patients, and has a remarkable whitening effect.
  • the whitening active ingredient of the present invention has a significant improvement effect and can be used for the treatment of chemotherapy (or radiotherapy). Caused by leukopenia.

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Abstract

含A-失碳-5α雄甾烷化合物的升白制剂及其应用。A-失碳-5α雄甾烷化合物可预防、缓解和改善化疗或放疗所导致的白细胞数降低，用于制备一制剂或组合物，所述制剂或组合物（a）用于提升白细胞数量，或（b）用于预防或治疗白细胞减少症。

Description

含A-失碳-5α雄甾烷化合物的升白制剂及其应用 技术领域
本发明属于医药领域，具体地涉及含A-失碳-5α雄甾烷化合物的升白制剂及其应用。
背景技术
白细胞减少症指当人的外周血中的白细胞计数持续低于4.0×10 9/L以下。一般造成白细胞减少症原因有药物、放射线或其他化学毒物。白细胞减少会导致免疫力低下、食欲减退，四肢乏力等症状。
目前，化疗和放疗是常用的肿瘤治疗的手段。然而，化疗和放疗常常会导致白细胞减少，在杀灭癌细胞的同时，也会损伤正常组织，尤以对骨髓造血功能抑制最为明显，造成外周白细胞持续降低。这一状况不仅有碍化疗和放疗的继续进行，且可引起严重的后果。
目前临床上经常使用一些升白药物，用以升高患者血液中白细胞数目，使患者放化疗能如期顺利进行，保证放化疗的周期治疗。这些升白药物主要包括：1、中草药，如：人参、黄芪、党参、女贞子、鸡血藤、枸杞子、地黄等；2、中药复方制剂，如愚鲁汤、保元汤、六味地黄口服液、升白丸、乌鸡白凤丸、健脾益肾冲剂、长安升白冲剂、升白片、参芪片、养血升白胶囊等；3、化学药物，如利血生、鲨肝醇、维生素B、升白安、肌苷、脱氧核糖核酸等；4、生物制剂，如集落刺激因子(CSF)、粒细胞集落刺激因子(GCSF)、粒细胞-巨噬细胞集落刺激因子(GMCSF)等。其中前3类中西药物的疗效都较为有限，造血刺激因子虽然效果显著，但作用时间短，易于反复，副作用明显，且价格昂贵，患者经济负担较大。
因此，本领域临床迫切需要开发疗效显著、副作用小、使用方便的升高白细胞的药物。
发明内容
本发明的目的就是提供一种疗效显著、副作用小、使用方便的升高白细胞的药物。
在本发明的第一方面，提供了一种A-失碳-5α雄甾烷化合物的用途，用于制备一制剂或组合物，所述制剂或组合物(a)用于提升白细胞数量；或(b)用于预防或治 疗白细胞减少症。
在另一优选例中，所述A-失碳-5α雄甾烷化合物的结构如式I所示：
Figure PCTCN2018100430-appb-000001
式中，
R 1和R 2各自独立地选自：H、取代或未取代的C 1-10烷基、取代或未取代的C 3-8环烷基、取代或未取代的苯环、取代或未取代的苯甲酰基、取代或未取代的COC nH 2n+1、取代或未取代的COC rH 2rCOOC mH 2m+1、或-COC pH 2pCOO-W；其中，n、p、r、m各自独立地为0～18的整数，W为H、Na +、K +、NH 4 +、1/2Ca 2+、1/2Mg 2+、1/2(AlOH) 2+、或1/2Zn 2+，
所述取代是指具有一个或多个(如1-3个)选自下组的取代基团：羟基、卤素、硝基、氨基、胺基、羧基。
在另一优选例中，所述A-失碳-5α雄甾烷化合物选自下组：
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双乙酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-单琥珀酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双琥珀酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双丁酸酯化合物；
2α，17α-双羟丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
2α，17α-双氰基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双三氯乙酸酯化合物；
2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-丙酸酯-17β琥珀酸酯化合物；
2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；和/或
2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物。
在另一优选例中，所述组合物为药物组合物、膳食补充组合物、或保健品组合物。
在另一优选例中，所述组合物包含(a)A-失碳-5α雄甾烷化合物；和(b)药学上可接受的载体。
在另一优选例中，所述的药物组合物的剂型为固体制剂或液体制剂。
在另一优选例中，所述的药物组合物的剂型为口服剂型、注射剂、或外用药物剂型。
在另一优选例中，所述的药物组合物为片剂、颗粒剂、或胶囊。
在另一优选例中，所述制剂或组合物中含有0.001-99wt％，较佳地0.1-90wt％，更佳地1-50wt％的A-失碳-5α雄甾烷化合物，按制剂或组合物的总重量计。
在另一优选例中，所述“提升白细胞数量”指使得一对象的血液中白细胞数量上升。
在另一优选例中，所述的对象为人、或非人哺乳动物(如啮齿动物)。
在另一优选例中，所述的对象为白细胞数量下降的人。
在另一优选例中，所述的“白细胞数量下降”指与正常人的白细胞数量的下限A0相比，所述对象的白细胞数量A1低于A0；较佳地，A1/A0为0.1-0.9，较佳地0.2-0.8，更佳地0.3-0.7。
在另一优选例中，所述的A0为4×10 9个/L血液。
在另一优选例中，所述的对象为肿瘤患者。
在另一优选例中，所述的对象为已经、正在、或将要接受肿瘤治疗的对象。
在另一优选例中，所述的肿瘤治疗包括：化疗、放疗、或其组合。
在另一优选例中，所述“提升白细胞数量”指，与对照的白细胞数量C0相比，使得一对象的血液中白细胞数量C1增加。
在另一优选例中，所述的对照的白细胞数量C0为所述对象在用本发明药物进行治疗或处理之前的白细胞数量Czs；或者为对照组的白细胞数量Cdz。
在另一优选例中，所述“提升白细胞数量”指C1/Czs≥1.2，较佳地≥1.4，更佳地≥1.5或≥2.0。
在另一优选例中，所述“提升白细胞数量”指C1/Cdz≥1.2，较佳地≥1.4，更佳地≥1.5或≥2.0。
在本发明的第二方面，提供了一种用于提升白细胞数量或防治白细胞减少症的制剂产品，所述制剂产品包括：
第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性 成分为A-失碳-5α雄甾烷化合物；和(b)药学上可接受的载体；以及
第二药物组合物，所述的第二药物组合物为升白药物。
在另一优选例中，所述的升白药物含有(a)第二活性成分，所述第二活性成分为不同于A-失碳-5α雄甾烷化合物的升白活性成分；和(b)药学上可接受的载体。
在另一优选例中，所述提升白细胞数量为提升哺乳动物的白细胞数。
在另一优选例中，所述升白药物选自下组：中草药、中药复方制剂、化学药物、生物制剂、或其组合。
在另一优选例中，所述中草药选自下组：人参、黄芪、党参、女贞子、鸡血藤、枸杞子、地黄、或其组合。
在另一优选例中，所述中药复方制剂选自下组：愚鲁汤、保元汤、六味地黄口服液、升白丸、乌鸡白凤丸、健脾益肾冲剂、长安升白冲剂、升白片、参芪片、养血升白胶囊、或其组合。
在另一优选例中，所述化学药物选自下组：利血生、鲨肝醇、维生素B、升白安、肌苷、脱氧核糖核酸、或其组合。
在另一优选例中，所述生物制剂选自下组：集落刺激因子(CSF)、粒细胞集落刺激因子(G-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、或其组合。
在另一优选例中，所述的第一药物组合物和第二药物组合物为各自独立的、或合二为一的。
在本发明的第三方面，提供了一种用于治疗肿瘤的制剂产品，所述制剂产品包括：
(I)第I药物组合物，所述第I药物组合物含有(a)第I活性成分，所述第一活性成分为A-失碳-5α雄甾烷化合物；和(b)药学上可接受的载体；以及
(II)第II药物组合物，所述的第II药物组合物含有(a)第II活性成分，所述第二活性成分为不同于A-失碳-5α雄甾烷化合物的用于治疗肿瘤的活性成分；和(b)药学上可接受的载体。
在另一优选例中，所述的第II活性成分选自下组：环磷酰胺、异环磷酰胺、多西氟鸟啶、5-氟尿嘧啶、阿糖胞苷、氟鸟苷、替加氟、吉西他滨、卡莫氟、羟基脲、甲氨蝶呤、放线菌素D、阿霉素、柔红霉素、表柔比星、丝裂霉素、培洛霉素、伊立替康、三尖杉酯碱、羟基喜树碱、长春瑞宾、紫杉醇、泰索帝、拓扑替康、长春新碱、长春地辛、长春酰胺、替尼泊苷、依托泊苷、阿他美坦、阿那曲唑、氨鲁 米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酶、卡铂、顺铂、达卡巴嗪、奥沙利铂、米托蒽醌、丙卡巴肼、或其组合。
在另一优选例中，所述的第一药物组合物和第二药物组合物为各自独立的、或合二为一的。
在本发明的第四方面，提供了一种提升白细胞数量的方法，包括步骤：(a)给需要的对象施用A-失碳-5α雄甾烷化合物。
在另一优选例中，所述的对象包括人或非人哺乳动物，较佳地包括啮齿动物(如小鼠、大鼠)、灵长动物(如人)。
在另一优选例中，所述的对象为肿瘤患者。
在另一优选例中，所述肿瘤选自下组：胃癌、肝癌、白血病、肾脏肿瘤、肺癌、小肠癌、骨癌、前列腺癌、结直肠癌、乳腺癌、大肠癌、前列腺癌、宫颈癌、淋巴癌、肾上腺肿瘤、或膀胱肿瘤。
在另一优选例中，所述的对象已经、正在或将要接受化疗和/或放疗。
在另一优选例中，所述的对象接受过化疗或放疗。
在另一优选例中，所述的对象的白细胞数低于正常值下限。
在另一优选例中，所述的对象接受过化疗或放疗且白细胞数接近或低于正常值下限。
在另一优选例中，所述的对象为人时，所述正常值范围为4×10 9-10×10 9/L。
在另一优选例中，所述的对象为人时，在用本发明方法进行升白治疗之前，其白细胞数为1×10 9-3.8×10 9/L。
在另一优选例中，所述的对象为小鼠时，所述正常值为1.8×10 3-10.7×10 3/uL。
在另一优选例中，所述方法为非治疗性的。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过广泛而深入的研究，首次意外地发现，一类结构特殊的化合物-即A-失碳-5α雄甾烷化合物能够非常有效地提升哺乳动物的白细胞数量，并且其副 作用非常低。实验表明，有明显缓解和改善抗肿瘤药物(如环磷酰胺等化疗药)或放疗所导致白细胞数降低。此外，在进行化疗或放疗之前给予A-失碳-5α雄甾烷化合物，可预防白细胞数的下降，在较长时间内没有显著降低。在此基础上，完成了本发明。
活性组分
在本发明中，用于升白的活性组分为A-失碳-5α雄甾烷化合物或其药学上可接受的盐、或前药。
A-失碳-5α雄甾烷化合物是李瑞麟等人自主研发合成的一类具有特殊结构的化合物。已有的动物药效试验表明，A-失碳-5α雄甾烷化合物有较好的治疗前列腺增生作用。在进一步研究中发现A-失碳-5α雄甾烷化合物具有显著的体内和体外抗恶性肿瘤活性，抑制肿瘤增殖的同时具有改善动物体重降低的优势。在不影响正常细胞的前提下选择性阻止肿瘤细胞的分裂，从而抑制肿瘤细胞的扩散。
本发明人意外地发现，A-失碳-5α雄甾烷化合物居然具有显著升白的药效。
本发明中，术语“活性组分”、“本发明活性成分”、“本发明的升白活性成分”可互换使用，是指A-失碳-5α雄甾烷化合物，尤其是具有如下结构的化合物：
Figure PCTCN2018100430-appb-000002
式中，R 1和R 2如上定义。
较佳地，A-失碳-5α雄甾烷化合物可以是一种或多种选自下组的化合物：
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基化合物(Ia)；
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基双乙酸酯化合物(Ib)；
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基双丙酸酯化合物(Ic)；
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基-2β-单琥珀酸酯化合物(Id)；2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双琥珀酸酯化合物(Ie)；
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双丁酸酯化合物(If)；
2α,17α-双羟丙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基化合物(Ig)；
2α,17α-双氰基-A-失碳-5α-雄甾烷-2β,17β-双羟基化合物(Ih)；
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基双三氯乙酸酯化合物(Ii)；
2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基-2β-丙酸酯-17β琥珀酸酯化合物(Ij)；
2α,17α-双丙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基化合物(Ik)；或
2α,17α-双丙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基双丙酸酯化合物(Il)。
药物组合物
本发明提供一种用于提升白细胞数量的药物组合物，所述药物组合物包括(a)A-失碳-5α雄甾烷化合物；和(b)药学上可接受的载体、或食品学上可接受的载体。
本发明所述药物组合物中的“活性成分”是指本发明所述的式(I)化合物。
本发明所述的“活性成分”和药物组合物可用于提升白细胞数量。
在另一优选例中，用于制备升白药物。
“安全有效量”指的是：活性成分的量足以明显改善病情，而不至于产生严重的副作用。
通常，药物组合物含有1-2000mg活性成分/剂，更佳地，含有10-200mg活性成分/剂。较佳地，所述的“一剂”为一个药片或一支注射针剂。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。
“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。
药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2018100430-appb-000003
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在另一优选例中，本发明式(I)化合物可与大分子化合物或高分子通过非键合作用形成复合物。
在另一优选例中，本发明式(I)化合物作为小分子还可通过化学键与大分子化合物或高分子相连接。所述大分子化合物可以是生物大分子如高聚糖、蛋白、核酸、多肽等。
本发明的活性成分或药物组合物的施用方式没有特别限制，代表性的施用方式包括但不限于：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
在这些固体剂型中，活性成分与至少一种常规惰性赋形剂或载体混合，如柠檬酸钠或磷酸二钙，或与下述成分一种或多种混合：
(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；
(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；
(c)保湿剂，例如，甘油；
(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；
(e)缓溶剂，例如石蜡；
(f)吸收加速剂，例如，季胺化合物；
(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；
(h)吸附剂，例如，高岭土；和/或
(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。
胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
所述的固体剂型还可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～1000mg，较佳地10～200mg，更佳地20～100mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明化合物可以单独给药，或者与其他治疗药物(尤其是抗癌药、或升白药物)联合给药。
式(I)化合物也可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后服用式(I)化合物。当式(I)化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行药物联用时，式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
口服制剂
本发明提供一种活性组分为A-失碳-5α雄甾烷化合物的口服制剂，通过处方前研究为药物制剂的研究提供依据。
处方前研究结果表明：水不溶性药物A-失碳-5α雄甾烷化合物(水中溶解度为6.5微克每毫升，按药典定义为不溶。)在肠液中有较好的溶出和吸收，其在体内的转运、摄取和吸收机制均为被动扩散，且摄取量呈现时间和剂量依赖性。A-失碳-5α雄甾烷化合物可以通过口服途径给药。且由于癌症的治疗需要长期服药，口服给药方便，可以提高患者的顺应性，因此本发明将其设计为口服制剂，如普通口服片剂、口服胶囊以及其他缓控释制剂。
本发明的口服制剂，其组份和各组分的重量份如下：
处方组成 重量份
活性组分 1-50
填充剂 20-95
崩解剂 0-20
粘合剂 0.1-30
润滑剂 0.1-5
助流剂 0.1-5
所述的活性组分为A-失碳-5α雄甾烷化合物；
所添加的填充剂可以是一种或者几种增加片剂重量和体积的成分。本发明中，所述填充剂选自乳糖、蔗糖、山梨醇、甘露醇、聚乙二醇、淀粉以及无机盐中的一种或者两种以上。所述填充剂的用量占制剂总量的20-95％，较佳为60-95％，更佳为70-95％，最佳为80-95％。当乳糖作为填充剂时，乳糖的用量占制剂总量的20-95％，蔗糖作为填充剂时，蔗糖的用量占制剂总量的10-30％，山梨醇作为填充剂时，山梨醇的用量占制剂总量的20-95％，甘露醇作为填充剂时，甘露醇的用量占制剂总量的20-95％，无机盐作为填充剂时，无机盐的用量占制剂总量的5-20％。在另一优选例中，所述填充剂为乳糖、甘露醇、山梨醇或它们的混合物；较佳地，所述填充剂为乳糖和甘露醇的混合物。
所述的崩解剂选自交联聚维酮(PVPP)、交联羧甲基纤维素钠(CC Na)、羧甲基淀粉钠(CMS-Na)、低取代羟丙基纤维素(L-HPC)中的一种或者两种以上，其中以PVPP和CC Na为佳，最佳为CC Na。崩解剂的用量范围(与总重比)为0–20％，一般用量为1–10％，最佳为3–5％。
所述的润滑剂选自硬脂酸、硬脂酸钠、硬脂酸镁、硬脂酸钙、聚乙二醇、氢化植物油中的一种或者两种以上，其中以硬脂酸镁最为适宜。润滑剂的用量范围(与总重比)为0.1–5％，一般用量为0.2–4％，最佳为0.3–3％。
所采用的粘合剂可以是一种或几种有利于制粒的成分。所述的粘合剂选自淀粉浆、羟丙基甲基纤维素(HPMC)、聚乙二醇、聚维酮(PVP)或共聚维酮(Kollidon)中的一种或者两种以上。优选PVP。当淀粉浆作为粘合剂时，淀粉浆的用量占制剂总量的10-30％，当HPMC作为粘合剂时，HPMC的用量占制剂总量的2-5％，当PVP作为粘合剂时，PVP的用量占制剂总量的2-20％，当聚维酮作为粘合剂时，共聚维酮的用量占制剂总量的0.1-10％。
所述的助流剂，选自微粉硅胶和滑石粉中的一种或者两种，更优选为微粉硅胶。
在另一优选例中，所述无机盐选自：硫酸钙(含两个分子的结晶水)；磷酸氢钙；药用碳酸钙等。
通常而言，本发明片剂还可以含有本领域技术人员熟知的其他易想到的辅料，本发明片剂的制备可以采用本领域公知的制备技术。如在制备片剂时，可以采用直接压片法、湿法制粒压片法、干法制粒压片法。
本发明提供一种A-失碳-5α雄甾烷化合物的普通片剂，根据药效学研究确定的其临床给药剂量，为满足临床治疗需要，确定A-失碳-5α雄甾烷化合物片剂规格为 1-100mg/片，较佳地，为1-50mg/片，如2.5mg/片、5mg/片、10mg/片、25mg/片等。
本发明的主要优点包括：
(a)本发明升白活性成分(即A-失碳-5α雄甾烷化合物)能够非常有效地提升哺乳动物的白细胞数量。
(b)本发明升白活性成分的副作用非常低。
(c)本发明的升白效果一方面不会导致白细胞数量过度升高(即不会超出正常值上限)，另一方面可以长时间维持，在较长时间内这种升白效果没有显著降低。
(d)本发明活性成分不仅可以用于治疗白细胞减少症，还可用于预防白细胞减少症。
(e)将本发明活性成分与其他的肿瘤治疗手段(如化疗)结合，可以进一步减低其他化疗药的副作用并增强治疗治疗效果，具有协同作用。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，例如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件，或按照制造厂商所建议的条件。
材料
ACP1：2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基双乙酸酯化合物(Ib)
ACP2：2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基-2β-单琥珀酸酯化合物(Id)
ACP3：2α,17α-双乙炔基-A-失碳-5α-雄甾烷-2β,17β-双丁酸酯化合物(If)
ACP4：2α,17α-双丙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基化合物(Ik)
ACP5：2α,17α-双丙炔基-A-失碳-5α-雄甾烷-2β,17β-双羟基双丙酸酯化合物(Il)
实施例1 ACP对环磷酰胺(CTX)致Lewis小鼠白细胞数降低的升白作用
1.1 ACP1的升白作用
取生长旺盛的肿瘤，无菌条件下一匀浆法制备成细胞悬液约5-10×10 6/ml肿瘤细胞浓度。每只小鼠右腋皮下接种0.2ml。
将小鼠以Lewis肺癌接种造成移植性肿瘤模型并随机分组，每组10只动物， 并于接种肿瘤当日开始给予升白化合物。除高剂量单纯ACP1给药组外，其余各组在接种第3天(150mg/kg)和第5天(100mg/kg)施用CTX，造成化疗致荷瘤小鼠白细胞减少抑制模型。
实验开始时随机取10只小鼠进行眼眶后静脉丛穿刺采血，血细胞自动分析仪(HEMAVET-950)测试血液常规。此后，在环磷酰胺末次给药后，在第8天和第12天按相同方法采血测试血液常规。
ACP1的结果如表1所示。
表1 ACP1样品联合环磷酰胺对荷Lewis肺癌小鼠的升白试验
Figure PCTCN2018100430-appb-000004
注：与化疗对照组比较：*P＜0.05；(文献数据：小鼠白细胞的正常值范围1.8×10 3-10.7×10 3/uL)
结果：
在化疗对照组中，环磷酰胺CTX造成了小鼠外周血白细胞的减少，表明白细胞减少症的模型动物的造模成功。
在ACP给药组中，在第8天和第12天均表现出统计学上显著的升白效果，与化疗对照组相比，升白幅度在第8天为约200％至约500％不等，在第12天为60％至约100％。这表明，ACP1有明显的拮抗环磷酰胺致小鼠白细胞数降低的作用。
1.2 ACP2-5的升白作用
方法同1.1，不同点在于：每个组的小鼠数量为5只；在实验组中，分别用ACP2、ACP3、ACP4、和ACP5分别替换ACP1，并且仅采用ACP中剂量+CTX 2.5mg/kg的方案；化疗对照组同1.1中的化疗对照组。在第10天按相同方法采血测试血液常规。
实验结果表明，在化疗对照组中，环磷酰胺CTX造成了小鼠外周血白细胞的减少，表明白细胞减少症的模型动物的造模成功。
在各ACP给药组中，在第10天均表现出统计学上显著的升白效果，与化疗对照组相比，ACP2、ACP3、ACP4和ACP5的升白幅度相当，在第10天的升白幅度((C1/Cdz-100％))在70％至240％范围内。这表明，A-失碳-5α雄甾烷化合物均具有明显的拮抗环磷酰胺致小鼠白细胞数降低的作用。
上述实验结果提示，本发明升白活性成分有明显缓解和改善抗肿瘤药物(如环磷酰胺)所导致白细胞数降低，从而可用于预防和/或治疗白细胞减少症。
实施例2 ACP1对肿瘤患者的升白试验
以10位接受过化疗(使用的化疗药物有阿霉素、环磷酰胺、伊立替康、紫杉醇、顺铂、奥沙利铂、长春新碱、氟尿嘧啶等)且外周血中的白细胞数目发生减少的肿瘤患者作为受试者。在服药前一天(第0天)采血，测试血液常规，作为用本发明药物进行治疗之前的白细胞数量(Czs)。
10位受试者每天以不同的服药次数和剂量服用ACP(见表2)，分别在8天、15天、22天和28天对10位受试者采血，测试血液常规。
结果如表2所示。
表2 ACP1对肿瘤患者的升白试验
Figure PCTCN2018100430-appb-000005
Figure PCTCN2018100430-appb-000006
注：白细胞计数(WBC)正常值范围：4×10 9-10×10 9/L
结果表明，ACP1有明显的提升白细胞数量的作用。
(i)在服药后第8天时，大部分受试者的白细胞数(C1/Czs)均已显著增多(与升白处理前相比，白细胞上升幅度(C1/Czs-100％)＝约50％)。
(ii)在服药后第15天时，受试者的白细胞(C1/Czs)进一步上升，提升幅度平均约80％，最高达到约178％。
(iii)服药后第22天时，受试者的白细胞提升幅度平均约63％。
(iv)在服药后第28天时，受试者的白细胞提升幅度平均约50％。在整个28天的检测期内，受试者的白细胞数均没有明显降低，维持在正常白细胞水平。
因此，本发明化合物能明显提升肿瘤患者的白细胞数目，具有显著的升白作用。
这提示，对于已经用抗肿瘤药物进行化疗，从而导致白细胞数下降(接近或低于白细胞正常值下限)的对象，本发明升白活性成分有明显改善作用，从而可用于治疗化疗(或放疗)引起的白细胞减少。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种A-失碳-5α雄甾烷化合物的用途，其特征在于，用于制备一制剂或组合物，所述制剂或组合物(a)用于提升白细胞数量；或(b)用于预防或治疗白细胞减少症。
  2. 如权利要求1所述的用途，其特征在于，所述A-失碳-5α雄甾烷化合物的结构如式I所示：
    Figure PCTCN2018100430-appb-100001
    式中，
    R 1和R 2各自独立地选自：H、取代或未取代的C 1-10烷基、取代或未取代的C 3-8环烷基、取代或未取代的苯环、取代或未取代的苯甲酰基、取代或未取代的COC nH 2n+1、取代或未取代的COC rH 2rCOOC mH 2m+1、或-COC pH 2pCOO-W；其中，n、p、r、m各自独立地为0～18的整数，W为H、Na +、K +、NH 4 +、1/2Ca 2+、1/2Mg 2+、1/2(AlOH) 2+、或1/2Zn 2+，
    所述取代是指具有一个或多个(如1-3个)选自下组的取代基团：羟基、卤素、硝基、氨基、胺基、羧基。
  3. 如权利要求1所述的用途，其特征在于，所述A-失碳-5α雄甾烷化合物选自下组：
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双乙酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-单琥珀酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双琥珀酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双丁酸酯化合物；
    2α，17α-双羟丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
    2α，17α-双氰基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双三氯乙酸酯化合物；
    2α，17α-双乙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基-2β-丙酸酯-17β琥珀酸酯 化合物；
    2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基化合物；和/或
    2α，17α-双丙炔基-A-失碳-5α-雄甾烷-2β，17β-双羟基双丙酸酯化合物。
  4. 如权利要求1所述的用途，其特征在于，所述制剂或组合物中含有0.001-99wt％，较佳地0.1-90wt％，更佳地1-50wt％的A-失碳-5α雄甾烷化合物，按制剂或组合物的总重量计。
  5. 一种用于提升白细胞数量或防治白细胞减少症的制剂产品，其特征在于，所述制剂产品包括：
    第一药物组合物，所述第一药物组合物含有(a)第一活性成分，所述第一活性成分为A-失碳-5α雄甾烷化合物；和(b)药学上可接受的载体；以及
    第二药物组合物，所述的第二药物组合物为升白药物。
  6. 如权利要求5所述的制剂产品，其特征在于，所述的升白药物含有(a)第二活性成分，所述第二活性成分为不同于A-失碳-5α雄甾烷化合物的升白活性成分；和(b)药学上可接受的载体。
  7. 如权利要求5所述的制剂产品，其特征在于，所述升白药物选自下组：中草药、中药复方制剂、化学药物、生物制剂、或其组合。
  8. 一种用于治疗肿瘤的制剂产品，其特征在于，所述制剂产品包括：
    (I)第I药物组合物，所述第I药物组合物含有(a)第I活性成分，所述第一活性成分为A-失碳-5α雄甾烷化合物；和(b)药学上可接受的载体；以及
    (II)第II药物组合物，所述的第II药物组合物含有(a)第II活性成分，所述第二活性成分为不同于A-失碳-5α雄甾烷化合物的用于治疗肿瘤的活性成分；和(b)药学上可接受的载体。
  9. 如权利要求8所述的制剂产品，其特征在于，所述的第II活性成分选自下组：环磷酰胺、异环磷酰胺、多西氟鸟啶、5-氟尿嘧啶、阿糖胞苷、氟鸟苷、替加氟、吉西他滨、卡莫氟、羟基脲、甲氨蝶呤、放线菌素D、阿霉素、柔红霉素、表柔比星、丝裂霉素、培洛霉素、伊立替康、三尖杉酯碱、羟基喜树碱、长春瑞宾、紫杉醇、泰索帝、拓扑替康、长春新碱、长春地辛、长春酰胺、替尼泊苷、依托泊苷、阿他美坦、阿那曲唑、氨鲁米特、来曲唑、福美坦、甲他孕酮、他莫昔芬、门冬酰胺酶、卡铂、顺铂、达卡巴嗪、奥沙利铂、米托蒽醌、丙卡巴肼、或其组合。
  10. 一种提升白细胞数量的方法，其特征在于，包括步骤：(a)给需要的对象施用A-失碳-5α雄甾烷化合物。
PCT/CN2018/100430 2017-10-13 2018-08-14 含A-失碳-5α雄甾烷化合物的升白制剂及其应用 WO2019072014A1 (zh)

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