WO2022166599A1 - Pqq 及其衍生物的新应用 - Google Patents

Pqq 及其衍生物的新应用 Download PDF

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Publication number
WO2022166599A1
WO2022166599A1 PCT/CN2022/072881 CN2022072881W WO2022166599A1 WO 2022166599 A1 WO2022166599 A1 WO 2022166599A1 CN 2022072881 W CN2022072881 W CN 2022072881W WO 2022166599 A1 WO2022166599 A1 WO 2022166599A1
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Prior art keywords
dysmenorrhea
day
menstrual
pyrroloquinoline quinone
derivative
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French (fr)
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郭凌
张筱文
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Guangzhou Hutongyouwu Biotechnology Co Ltd
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Guangzhou Hutongyouwu Biotechnology Co Ltd
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Priority to KR1020237024739A priority Critical patent/KR20230142708A/ko
Priority to EP22748878.0A priority patent/EP4269410A4/en
Priority to CA3205533A priority patent/CA3205533A1/en
Priority to JP2023544270A priority patent/JP2024504705A/ja
Priority to AU2022217222A priority patent/AU2022217222A1/en
Priority to CN202280008391.4A priority patent/CN116669732A/zh
Publication of WO2022166599A1 publication Critical patent/WO2022166599A1/zh
Priority to US18/224,107 priority patent/US20230398109A1/en
Anticipated expiration legal-status Critical
Priority to AU2024266789A priority patent/AU2024266789B2/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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to new applications of existing compounds.
  • Dysmenorrhea (dysmenorrhea) is one of the most common gynecological symptoms, which refers to patients with lower abdominal pain, heaviness, and backache or other discomfort before and after menstruation or during menstruation, and the symptoms seriously affect the quality of life.
  • Dysmenorrhea is divided into two categories: primary dysmenorrhea and secondary dysmenorrhea.
  • Primary dysmenorrhea refers to dysmenorrhea without organic lesions in reproductive organs;
  • secondary dysmenorrhea refers to dysmenorrhea caused by pelvic organic diseases. The cause of dysmenorrhea is not fully understood.
  • pathogenesis and treatment plan of secondary dysmenorrhea are different from those of primary dysmenorrhea. It is often manifested in various ways of pain: lower abdominal pain, lower abdominal distension, pain in the anus, pain during sexual intercourse, etc.
  • vitamin C supplementation significantly reduced endometriotic cyst volume and weight in a dose-dependent manner.
  • vitamin C supplementation does not have any relieving effect on human dysmenorrhea, let alone a therapeutic effect.
  • dysmenorrhea There is currently no particularly effective treatment for dysmenorrhea.
  • the traditional treatment of dysmenorrhea is dominated by hormone drugs.
  • hormonal or hormone-like therapy is associated with serious side effects, including but not limited to infertility, which limits its scope of application.
  • Pyrroloquinoline Quinone is a tricarboxylic acid quinone compound, CAS No. 72909-34-3, IUPAC named 4,5-dioxo-1 H -pyrrolo[2,3-f] quinoline-2,7,9-tricarboxylic acid.
  • PQQ is widely present in various food materials.
  • the content of PQQ in ingredients is about 3.65-61ng/g, parsley and green peppers in vegetables, kiwi and papaya in fruits, green tea and oolong tea in drinks, tofu that people often eat, the content of PQQ is about 30ng/g .
  • PQQ can stimulate the rapid growth of microorganisms, plants, animals and human cells; remove excess free radicals in the body and protect the body from oxidative damage; accelerate the oxidation of acetaldehyde to acetic acid to reduce the content of acetaldehyde in the body, thereby It is expected to reduce the toxic damage to the liver caused by alcohol consumption.
  • CN110870866A discloses the application of pyrroloquinoline quinone in the preparation of medicines for preventing and treating acute altitude sickness and acute altitude hypoxia injury;
  • CN110151764A discloses that pyrroloquinoline quinone can reduce lipopolysaccharide-induced animal fibroblasts and intestinal inflammation;
  • CN106265730A discloses Application of pyrroloquinoline quinone (PQQ) in reversing tumor multidrug resistance;
  • CN105963297A discloses the application of pyrroloquinoline quinone in adjuvant therapy after chemotherapy;
  • CN103191115A discloses pyrroloquinoline quinone in the treatment and/or improvement of diabetic foot Applications.
  • the purpose of the present invention is to provide the application of PQQ in the preparation of medicines for preventing and treating primary dysmenorrhea, secondary dysmenorrhea and infertility and abnormal menstruation caused by secondary dysmenorrhea.
  • a first aspect of the present invention provides:
  • compositions for preventing, relieving or treating diseases selected from:
  • the concomitant condition of secondary dysmenorrhea is infertility caused by the treatment of secondary dysmenorrhea.
  • the menstrual abnormality includes at least one of abnormally increased menstrual bleeding, abnormally increased menstrual bleeding duration, and a menstrual cycle longer than 35 days.
  • the abnormally increased menstrual bleeding refers to menstrual bleeding that is greater than 50% of a woman's normal menstrual bleeding.
  • the abnormally increased menstrual bleeding duration refers to menstrual bleeding duration of not less than 8 days.
  • the derivative of pyrroloquinoline quinone is one that can be digested or metabolized in vivo to yield pyrroloquinoline quinone.
  • the derivative of pyrroloquinoline quinone is one that can be hydrolyzed in the digestive tract to yield pyrroloquinoline quinone.
  • the derivative of pyrroloquinoline quinone is a pharmaceutically or food acceptable salt, C2-C6 ester, amide, hydrate, crystal, co-crystal or solvate.
  • the oral dosage calculated as pyrroloquinoline quinone, is:
  • the composition is a food, nutraceutical or pharmaceutical.
  • composition further contains pharmaceutically or food acceptable excipients.
  • the adjuvant is selected from at least one of carriers, solvents, antioxidants, and preservatives.
  • a second aspect of the present invention provides:
  • a method for preventing, relieving or treating a disease characterized in that: the disease is selected from:
  • At least one of pyrroloquinoline quinone or a derivative thereof is administered to the patient (oral or injection, etc.) for prevention, remission or treatment.
  • the oral dosage calculated as pyrroloquinoline quinone, is:
  • the dosage of pyrroloquinoline quinone or its derivatives is adjusted according to the individual conditions of the patient, including but not limited to weight and severity of the disease.
  • the concomitant condition of secondary dysmenorrhea is infertility caused by the treatment of secondary dysmenorrhea.
  • the menstrual abnormality includes at least one of abnormally increased menstrual bleeding, abnormally increased menstrual bleeding duration, and a menstrual cycle longer than 35 days.
  • the patient may receive at least one of the following benefits:
  • the amount of menstrual bleeding is reduced to no more than 50%, 40%, 30% of the normal menstrual bleeding of women, preferably 10%, and more preferably the normal average bleeding;
  • the duration of menstrual bleeding is shortened to no longer than 10 days, preferably to no longer than 9 days, 8 days, and 7 days.
  • the pain index or pain level was determined according to WHO criteria.
  • the concomitant condition of secondary dysmenorrhea is infertility caused by the treatment of secondary dysmenorrhea.
  • the menstrual abnormality includes at least one of abnormally increased menstrual bleeding, abnormally increased menstrual bleeding duration, and a menstrual cycle longer than 35 days.
  • the abnormally increased menstrual bleeding refers to menstrual bleeding that is greater than 50% of a woman's normal menstrual bleeding.
  • the abnormally increased menstrual bleeding duration refers to menstrual bleeding duration of not less than 8 days.
  • the derivative of pyrroloquinoline quinone is one that can be digested or metabolized in vivo to yield pyrroloquinoline quinone.
  • the derivative of pyrroloquinoline quinone is one that can be hydrolyzed in the digestive tract to yield pyrroloquinoline quinone.
  • the derivative of pyrroloquinoline quinone is a pharmaceutically or food acceptable salt, C2-C6 ester, amide, hydrate, crystal, co-crystal or solvate.
  • PQQ can effectively prevent, relieve or treat primary dysmenorrhea, secondary dysmenorrhea and menstrual abnormalities.
  • patients after taking PQQ treatment, patients can achieve: 1. 100% dysmenorrhea relief rate; 2. the average monthly menstrual bleeding duration is reduced from about 2 weeks to about 1 week, returning to the normal average level; 3. monthly The average amount of menstrual bleeding decreased by more than 30% and basically returned to the normal average level; 4. Two patients with chronic infertility caused by secondary dysmenorrhea became pregnant within the 3-month treatment period.
  • Figure 1 is the change of the dysmenorrhea index (VAS score) in the treatment of secondary dysmenorrhea;
  • Figure 2 shows the change of menstrual duration in patients with abnormal menstruation (irregular menstruation);
  • Figure 3 shows the changes in the amount of sanitary napkins treated for patients with abnormal menstruation (irregular menstruation).
  • the pharmaceutically or food-acceptable derivatives of the compound especially its simple derivatives, especially one of its lower esters, lower ethers, lower alkyl substituents, pharmaceutically acceptable salts, and lower amides, That is, the number of carbon atoms is 1 to 6, preferably 2 to 6, and a derivative obtained by condensation of a carboxylic acid, alcohol, or amine of 2 to 4 with the parent compound.
  • the derivative of the pyrroloquinoline quinone has the following general formula:
  • R 1 to R 3 are the same or different, and are selected from H, C1 to C6 hydrocarbon groups, natural amino acid residues, Na, K, Li and other pharmaceutically acceptable groups.
  • salts of compounds can be synthesized from the parent compound by conventional chemical methods, as described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: The method described in 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • these salts can be prepared by reacting the free base of the compound and the acid in water or an organic solvent or a mixture of the two; usually, using a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile .
  • Acid addition salts can be prepared from a variety of acids (inorganic and organic).
  • acid addition salts include salts made from acids selected from acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (eg L-ascorbic acid), L-aspartic acid , benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, Caprylic acid, cinnamic acid, citric acid, cyclonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-isethionic acid, formic acid, fumaric acid, galactose acid, gentisic acid, glucoheptonic acid, D
  • PQQ can effectively relieve or treat primary dysmenorrhea, secondary dysmenorrhea and menstrual abnormalities during research on the application of PQQ.
  • patients after taking PQQ treatment, patients can achieve: 1. 100% dysmenorrhea relief rate; 2. the average monthly menstrual bleeding duration is reduced from about 2 weeks to about 1 week, returning to the normal average level; 3. monthly The average amount of menstrual bleeding decreased by more than 30% and basically returned to the normal average level; 4. Two patients with chronic infertility caused by secondary dysmenorrhea became pregnant within the 3-month treatment period. Specifically as follows:
  • Experiment number 100 people, who have been diagnosed with primary dysmenorrhea, 50 people in the experimental group and the control group.
  • Experimental method experimental group, oral PQQ preparation; control group: oral placebo. The duration of the experiment was 3 months, and menstrual pain was asked and recorded.
  • the experimental group proved that the drug has the effect of treating primary dysmenorrhea, with significant statistical significance.
  • Experiment number 100 people, who have been diagnosed with secondary dysmenorrhea, 50 people in the experimental group and the control group.
  • Experimental method experimental group, oral PQQ preparation; control group: oral placebo. The duration of the experiment was 3 months, and menstrual pain and pregnancy were asked and recorded.
  • the experimental group proved that the drug has the effect of treating secondary dysmenorrhea, with significant statistical significance.
  • the dysmenorrhea index is determined based on the VAS scoring standard, that is, patients self-evaluate the intensity of pain and the degree of psychologically unpleasant experience according to the degree of pain they feel, including:
  • Unbearable pain is severe pain.
  • the average dysmenorrhea index changes are shown in Figure 1. It can be seen from the figure that the dysmenorrhea index of the PQQ group decreased significantly, while the dysmenorrhea index of the control group did not change significantly. It was proved that oral PQQ preparation can significantly improve secondary dysmenorrhea.
  • Experiment number 100 people, who have been diagnosed with menstrual abnormalities, 50 people in the experimental group and the control group.
  • Experimental method experimental group, oral PQQ preparation; control group: oral placebo.
  • the duration of the experiment was 3 months, and menstrual conditions were measured and recorded (recording of menstrual duration, sanitary napkin counting and sanitary napkin weighing).
  • the experimental results are shown in Figures 2 and 3.
  • the experimental group compared with before the start of the experiment, the menstrual duration: the average monthly menstrual bleeding duration was reduced from about 2 weeks to about 1 week; the amount of menstrual bleeding: the average monthly menstrual bleeding volume decreased by more than 30%. %; control group: compared with before the start of the experiment, menstrual duration: no significant improvement; menstrual bleeding volume: no significant improvement.
  • the experimental group proved that the drug has the effect of treating menstrual abnormalities, with significant statistical significance.

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Abstract

一种PQQ及其衍生物的新应用。PQQ可以有效缓解或治疗原发性痛经、继发性痛经和月经异常。经过服用PQQ治疗，病人可以达到：1.痛经缓解率100％；2.每月月经出血平均时长由约2周减少到约1周，恢复到正常平均水平；3.每月月经出血量平均减少超过30％，基本恢复到正常平均水平；4.两名继发性痛经引起的长年不孕不育病人，在3个月治疗期内怀孕。

Description

PQQ及其衍生物的新应用 技术领域
本发明涉及已有化合物的新应用。
 背景技术
痛经（dysmenorrhea）为最常见的妇科症状之一，指行经前后或月经期出现下腹部疼痛、坠胀，伴有腰酸或其他不适，症状严重影响生活质量者。痛经分为原发性痛经和继发性两类，原发性痛经指生殖器官无器质性病变的痛经；继发性痛经指由盆腔器质性疾病等引起的痛经。痛经的病因尚未完全明确。一般认为继发性痛经的发病原因、处理方案与原发性痛经不同。常常表现为各种疼痛方式：下腹痛、下腹坠胀、肛门坠痛、性交痛等。
大多数哺乳动物并没有规律的经期，且以隐性月经为主，与人体的继发性痛经指征几乎不具有可比性。虽然部分灵长类动物也存在月经，但是其未见有继发性痛经的表现。这导致在继发性药物的开发过程中，缺乏实际可用的动物模型，限制了其药物开发的进程。已有的论文也表明，痛经动物或细胞模型中的实验结果，应用于人体时，往往是没有效果的。如Durak, Yildirim, et al.( "Effect of vitamin C on the growth of experimentally induced endometriotic cysts." Journal of Obstetrics and Gynaecology Research 39.7 (2013): 1253-1258)指出，补充维生素C剂量依赖性显著减少了子宫内膜异位囊肿的体积和重量。然而周知补充维生素C对人类痛经没有任何缓解作用，更不用说治疗作用了。
目前没有特别有效的痛经治疗药物。传统的痛经治疗药物，以激素类药物为主。然而激素或类激素治疗伴随有严重的副作用，包括但不限于不孕不育，这使得其应用范围受限。
吡咯喹啉醌（Pyrroloquinoline Quinone，简称PQQ）是一种三羧酸醌类化合物，CAS No. 72909-34-3，IUPAC命名为4,5-dioxo-1 H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid。PQQ广泛存在于各种食材中。PQQ在食材中的含量在3.65～61ng/g左右，蔬菜中欧芹、青椒，水果中的奇异果、木瓜，饮品中的绿茶、乌龙茶人们常吃的豆腐中，PQQ的含量都约为30ng/g。已有研究表明PQQ能够刺激微生物、植物、动物以及人体细胞快速生长；清除体内多余的自由基，保护机体免受氧化损伤；加快乙醛氧化成乙酸的速度来降低乙醛在体内的含量，从而有望减轻饮酒对肝脏造成的毒性损伤。CN110870866A公开了吡咯喹啉醌在防治急性高原反应和急性高原缺氧损伤药物制备中的应用；CN110151764A公开了吡咯喹啉醌可减轻脂多糖诱导的动物成纤维细胞和肠道炎症反应；CN106265730A公开了吡咯喹啉醌（PQQ）在逆转肿瘤多药耐药中的应用；CN105963297A公开了吡咯喹啉醌在化疗后辅助治疗中的应用；CN103191115A公开了吡咯喹啉醌在糖尿病足治疗和/或改善中的应用。
技术解决方案
本发明的目的在于提供PQQ在制备预防、治疗原发性痛经、继发性痛经及继发性痛经引起的不孕不育、月经异常药物中的应用。
本发明所采取的技术方案是：
本发明的第一个方面，提供：
吡咯喹啉醌及其衍生物在制备预防、缓解或治疗疾病组合物中的应用，所述疾病选自：
原发性痛经；
继发性痛经和/或其伴随症；
月经异常。
在一些实例中，继发性痛经的伴随症为治疗继发性痛经引起的不孕不育。
在一些实例中，月经异常包括月经出血量异常增多、月经出血时长异常增长和月经周期长于35天至少一种。
在一些实例中，所述月经出血量异常增多指月经出血量高于女性正常月经出血量的50%。
在一些实例中，所述月经出血时长异常增长指月经出血时长不低于8天。
在一些实例中，吡咯喹啉醌的衍生物为其可在体内消化或代谢得到吡咯喹啉醌的衍生物。
在一些实例中，吡咯喹啉醌的衍生物为其可在消化道内水解得到吡咯喹啉醌的衍生物。
在一些实例中，吡咯喹啉醌的衍生物为其药学上或食品学上可接受的盐、C2～C6酯、酰胺、水合物、晶体、共晶或溶剂化物。
在一些实例中，以吡咯喹啉醌计，其口服用量为：
预防原发性痛经或继发性痛经，约5 mg/天～约10 mg/天；
改善或治疗轻度痛经，约15 mg/天～约20mg/天；
改善或治疗中度痛经，约20 mg/天～约30mg/天；
改善或治疗重度痛经，约25 mg/天～约100 mg/天；
改善或治疗月经异常，约20 mg/天～约50mg/天。
在一些实例中，所述组合物为食品、保健品或药品。
在一些实例中，所述组合物还含有药学上或食品学上可接受的辅料。
在一些实例中，所述辅料选自载体、溶剂、抗氧化剂、防腐剂中的至少一种。
本发明的第二个方面，提供：
一种预防、缓解或治疗疾病的方法，其特征在于：所述疾病选自：
原发性痛经；
继发性痛经和/或其伴随症；
月经异常；
对病人进行诊断，确定其具有原发性痛经、继发性痛经或月经异常；
给予该病人（口服或注射等）预防、缓解或治疗量的吡咯喹啉醌或其衍生物中的至少一种。
在一些实例中，以吡咯喹啉醌计，其口服用量为：
预防原发性痛经或继发性痛经，约5 mg/天～约10 mg/天；
改善或治疗轻度痛经，约15 mg/天～约20mg/天；
改善或治疗中度痛经，约20 mg/天～约30mg/天；
改善或治疗重度痛经，约25 mg/天～约100 mg/天；
改善或治疗月经异常，约20 mg/天～约50mg/天。
在一些实例中，吡咯喹啉醌或其衍生物的用量根据病人的个体情况进行相应的调整，所述个体情况包括但不限于体重、病情的严重程度。
在一些实例中，继发性痛经的伴随症为治疗继发性痛经引起的不孕不育。
在一些实例中，月经异常包括月经出血量异常增多、月经出血时长异常增长和月经周期长于35天至少一种。
在一些实例中，预防、缓解或治疗后，病人可以获得如下收益中的至少一种：
1)      可以怀孕；
2)      痛经缓解，优选缓解至经期痛经疼痛指数平均分值下降1分以上或者疼痛等级下降一个等级；
3)      月经出血量减少到不超出女性正常月经出血量的50%、40%、30%，优选10%，更佳为正常平均出血量；
4)      月经出血时长缩短至不长于10天，优选缩短至不长于9天、8天、7天。
疼痛指数或疼痛等级根据WHO的标准确定。
在一些实例中，继发性痛经的伴随症为治疗继发性痛经引起的不孕不育。
在一些实例中，月经异常包括月经出血量异常增多、月经出血时长异常增长和月经周期长于35天至少一种。
在一些实例中，所述月经出血量异常增多指月经出血量高于女性正常月经出血量的50%。
在一些实例中，所述月经出血时长异常增长指月经出血时长不低于8天。
在一些实例中，吡咯喹啉醌的衍生物为其可在体内消化或代谢得到吡咯喹啉醌的衍生物。
在一些实例中，吡咯喹啉醌的衍生物为其可在消化道内水解得到吡咯喹啉醌的衍生物。
在一些实例中，吡咯喹啉醌的衍生物为其药学上或食品学上可接受的盐、C2～C6酯、酰胺、水合物、晶体、共晶或溶剂化物。
 有益效果
发明人在研究中意外发现，PQQ可以有效预防、缓解或治疗原发性痛经、继发性痛经和月经异常。
在一些实例中，经过服用PQQ治疗，病人可以达到：1.痛经缓解率100%；2.每月月经出血平均时长由约2周减少到约1周，恢复到正常平均水平；3.每月月经出血量平均减少超过30%，基本恢复到正常平均水平；4.两名继发性痛经引起的长年不孕不育病人，在3个月治疗期内怀孕。
 附图说明
图1是继发性痛经治疗的痛经指数(VAS score)变化情况；
图2是月经异常（月经不调）病人治疗的月经时长变化情况；
图3是月经异常（月经不调）病人治疗的卫生巾用量变化情况。
 本发明的实施方式
本发明中，化合物药学上或食品学上可接受的衍生物，尤其指其简单衍生物，特别是其低级酯、低级醚、低级烷基取代物、药用盐、低级酰胺中的一种，即碳原子数在1～6，优选为2～6，2～4的羧酸、醇、胺与母化合物缩合得到的衍生物。特别的，所述吡咯喹啉醌的衍生物具有如下通式：
Figure 662577dest_path_image001
式中，R 1～R 3相同或不同，选自H、C1～C6的烃基、天然氨基酸残基、Na、K、Li等药学上可接受的基团。
化合物药学上可接受的药用盐可以通过常规的化学方法从母体化合物合成，如在 Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor),ISBN:3-90639-026-8, Hardcover, 388 pages, August 2002中描述的方法。一般来说，这些盐可以由化合物的游离碱和酸在水或有机溶剂或二者的混合液中反应制得；通常，使用非水介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。
酸加成盐可以通过各种酸（无机酸和有机酸）制得。酸加成盐的实例包括由酸制成的盐，所述酸选自由乙酸、2,2-二氯乙酸、已二酸、藻酸、抗坏血酸（如L-抗坏血酸）、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、（+）樟脑酸、樟脑-磺酸、（+）-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟乙基磺酸、甲酸、富马酸、半乳糖酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、葡萄糖醛酸（如D-葡萄糖醛酸）、谷氨酸（如L-谷氨酸）、α-酮戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、（+）-L-乳酸、（±）-DL-乳酸、乳糖酸、马来酸、苹果酸、（-）-L-苹果酸、丙二酸、（±）-DL-扁桃酸、甲基磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、丁二酸、硫酸、单宁酸、（+）-L-酒石酸、硫氰酸、 p-甲苯磺酸、十一碳烯酸和戊酸，以及酰化氨基酸和阳离子交换树脂组成的组。
发明人在研究中PQQ的应用时意外发现，PQQ可以有效缓解或治疗原发性痛经、继发性痛经和月经异常。
在一些实例中，经过服用PQQ治疗，病人可以达到：1.痛经缓解率100%；2.每月月经出血平均时长由约2周减少到约1周，恢复到正常平均水平；3.每月月经出血量平均减少超过30%，基本恢复到正常平均水平；4.两名继发性痛经引起的长年不孕不育病人，在3个月治疗期内怀孕。具体如下所示：
原发性痛经病人的治疗：
实验人数：100人，已经确诊为原发性痛经，实验组和对照组各50人。
实验方法：实验组，口服PQQ制剂；对照组：口服安慰剂。实验时长3个月，询问并记录月经疼痛情况。
实验结果：
实验组：与实验开始前相比，痛经指数出现改善人数100%。
对照组：与实验开始前相比，痛经指数出现改善人数不足20%，且改善程度平均值低于实验组。
Figure 330319dest_path_image002
与对照组相比，实验组证明药物具有治疗原发性痛经的作用，具有显著的统计学意义。
继发性痛经病人的治疗：
实验人数：100人，已经确诊为继发性痛经，实验组和对照组各50人。
实验方法：实验组，口服PQQ制剂；对照组：口服安慰剂。实验时长3个月，询问并记录月经疼痛情况以及怀孕情况。
实验结果：
实验组：与实验开始前相比，痛经指数出现改善人数100%； 2例怀孕。
对照组：与实验开始前相比，痛经指数出现改善人数不足5%，且改善程度平均值远低于实验组；未见怀孕。
Figure 999198dest_path_image003
与对照组相比，实验组证明药物具有治疗继发性痛经的作用，具有显著的统计学意义。
基于VAS评分标准确定痛经指数，即患者根据自己感受到的疼痛程度，自我评价疼痛的强度及心理上不愉快的体验程度，其中：
0分：无痛；
1-3分：轻度疼痛；
4-6分：中度疼痛；
7-9分：重度疼痛；
10分：不可忍受的疼痛即剧痛。
平均痛经指数变化如图1所示，从图中可以看出，PQQ组的痛经指数显著下降，而对照组的痛经指数没有显著变化。证明口服PQQ制剂可以显著改善继发性痛经。
月经异常病人的治疗：
实验人数：100人，已经确诊为月经异常，实验组和对照组各50人。
实验方法：实验组，口服PQQ制剂；对照组：口服安慰剂。实验时长3个月，测量并记录月经期间情况(记录月经时长，进行卫生巾计数以及卫生巾称重)。
实验结果：
实验结果如图2和图3所示。由图2和图3可知，实验组：与实验开始前相比，月经时长：每月月经出血平均时长由约2周减少到约1周；月经出血量：每月月经出血量平均减少超过30%；对照组：与实验开始前相比，月经时长：无显著改善；月经出血量：无显著改善。
与对照组相比，实验组证明药物具有治疗月经异常的作用，具有显著的统计学意义。

Claims (17)

  1. 吡咯喹啉醌及其衍生物在制备预防、缓解或治疗疾病组合物中的应用，其特征在于：所述疾病选自：
    原发性痛经；
    继发性痛经和/或其伴随症；
    月经异常。
  2. 根据权利要求1所述的应用，其特征在于：
    继发性痛经的伴随症为继发性痛经引起的不孕不育；
    月经异常包括月经出血量异常增多、月经出血时长异常增长和月经周期长于35天至少一种。
  3. 根据权利要求2所述的应用，其特征在于：
    所述月经出血量异常增多指月经出血量高于女性正常月经出血量的50%；
    所述月经出血时长异常增长指月经出血时长不低于8天。
  4. 根据权利要求1所述的应用，其特征在于：吡咯喹啉醌的衍生物为其可在体内消化或代谢得到吡咯喹啉醌的衍生物。
  5. 根据权利要求4所述的应用，其特征在于：吡咯喹啉醌的衍生物为其可在消化道内水解得到吡咯喹啉醌的衍生物。
  6. 根据权利要求4所述的应用，其特征在于：吡咯喹啉醌的衍生物为其药学上或食品学上可接受的盐、C2～C6酯、酰胺、水合物、晶体、共晶或溶剂化物。
  7. 根据权利要求1所述的应用，其特征在于：以吡咯喹啉醌计，其口服用量为：
    预防原发性痛经或继发性痛经，约5 mg/天～约10 mg/天；
    改善或治疗轻度痛经，约15 mg/天～约20mg/天；
    改善或治疗中度痛经，约20 mg/天～约30mg/天；
    改善或治疗重度痛经，约25 mg/天～约100 mg/天；
    改善或治疗月经异常，约20 mg/天～约50mg/天。
  8. 根据权利要求1所述的应用，其特征在于：所述组合物为食品、保健品或药品。
  9. 根据权利要求1所述的应用，其特征在于：所述组合物还含有药学上或食品学上可接受的辅料。
  10. 根据权利要求9所述的应用，其特征在于：所述辅料选自载体、溶剂、抗氧化剂、防腐剂中的至少一种。
  11. 一种预防、缓解或治疗疾病的方法，其特征在于：所述疾病选自：
    原发性痛经；
    继发性痛经和/或其伴随症；
    月经异常；
    其治疗方法包括：
    对病人进行诊断，确定其具有原发性痛经、继发性痛经或月经异常；
    给予该病人预防、缓解或治疗量的吡咯喹啉醌或其衍生物中的至少一种；
    优选的，以吡咯喹啉醌计，其口服用量为：
    预防原发性痛经或继发性痛经，约5 mg/天～约10 mg/天；
    改善或治疗轻度痛经，约15 mg/天～约20mg/天；
    改善或治疗中度痛经，约20 mg/天～约30mg/天；
    改善或治疗重度痛经，约25 mg/天～约100 mg/天；
    改善或治疗月经异常，约20 mg/天～约50mg/天。
  12. 根据权利要求11所述的方法，其特征在于：
    继发性痛经的伴随症为治疗继发性痛经引起的不孕不育；
    月经异常包括月经出血量异常增多、月经出血时长异常增长和月经周期长于35天至少一种。
  13. 根据权利要求11所述的方法，其特征在于：预防、缓解或治疗后，使用者可以获得如下收益中的至少一种：
    可以怀孕；
    痛经缓解，优选缓解至经期痛经疼痛指数平均分值下降1分以上或者疼痛等级下降一个等级；
    月经出血量减少到不超出女性正常月经出血量的50%、40%、30%，优选10%，更佳为正常平均出血量；
    月经出血时长缩短至不长于10天，优选缩短至不长于9天、8天、7天。
  14. 根据权利要求11所述的方法，其特征在于：吡咯喹啉醌的衍生物为其可在体内消化或代谢得到吡咯喹啉醌的衍生物。
  15. 根据权利要求14所述的方法，其特征在于：吡咯喹啉醌的衍生物为其可在消化道内水解得到吡咯喹啉醌的衍生物。
  16. 根据权利要求14所述的方法，其特征在于：吡咯喹啉醌的衍生物为其药学上或食品学上可接受的盐、C2～C6酯、酰胺、水合物、晶体、共晶或溶剂化物。
  17. 根据权利要求11所述的方法，其特征在于：吡咯喹啉醌或其衍生物的使用次数为每天一次。
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