WO2020224452A1 - 一种调节人体体重失衡的化合物、其组合物及其应用 - Google Patents

一种调节人体体重失衡的化合物、其组合物及其应用 Download PDF

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WO2020224452A1
WO2020224452A1 PCT/CN2020/086698 CN2020086698W WO2020224452A1 WO 2020224452 A1 WO2020224452 A1 WO 2020224452A1 CN 2020086698 W CN2020086698 W CN 2020086698W WO 2020224452 A1 WO2020224452 A1 WO 2020224452A1
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compound
weight imbalance
formula
regulator
weight
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PCT/CN2020/086698
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English (en)
French (fr)
Inventor
孙明杰
邓桂兴
李苌清
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广州新创忆药物临床研究有限公司
广州新创意生物医药有限公司
湘北威尔曼制药股份有限公司
广州威尔曼新药研发有限公司
南京康福顺药业有限公司
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Application filed by 广州新创忆药物临床研究有限公司, 广州新创意生物医药有限公司, 湘北威尔曼制药股份有限公司, 广州威尔曼新药研发有限公司, 南京康福顺药业有限公司 filed Critical 广州新创忆药物临床研究有限公司
Priority to US17/608,203 priority Critical patent/US20220193104A1/en
Priority to EP20802344.0A priority patent/EP3949972A4/en
Priority to CN202080002053.0A priority patent/CN112188894B/zh
Publication of WO2020224452A1 publication Critical patent/WO2020224452A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, ***e
    • 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
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present invention relates to a new application of a compound, in particular to a new application of geraniolin bisulfate derivative, especially an application in regulating human body weight imbalance.
  • the metabolism of normal human body can maintain weight balance within a certain range. Underweight or overweight are sub-healthy or pathological conditions. There are many reasons for human body weight imbalance, such as genetic factors, insufficient physical activity, insufficient or excessive intake of nutrients, disease factors, and drug use.
  • Obesity can cause many diseases.
  • Obese people are more than 4 times more likely to suffer from diabetes than normal people; the proportion of hypertension is 20%-50%, which is significantly higher than that of normal people; the probability of suffering from myocardial infarction, stroke and other cardiovascular and cerebrovascular diseases is also significantly higher than that of normal people .
  • Obesity also increases the risk of malignant tumors. It also causes gout, irregular menstruation, sleep apnea and many other diseases.
  • Obesity is not only a predisposing factor of the disease, but also closely related to the prognosis of the disease. For example, after the weight of diabetic patients is controlled, blood sugar can be better controlled. Obesity and related diseases have seriously affected people's health and quality of life.
  • Weight loss can effectively improve the health of patients with obesity-related diseases and complications. Lifestyle intervention therapy led by diet and exercise is the recommended method, but for many people, lifestyle changes are very difficult, and this method is not always effective.
  • the use of drugs is one of the necessary options for weight loss.
  • the American Endocrine Society's guidelines (Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline) point out that if the weight loss is ⁇ 5% within 3 months after using the drug, it is recommended to continue taking the drug.
  • the purpose of the present invention is to provide new applications of geraniolin hydrogensulfate derivatives. To achieve the above objective, the present invention adopts the following technical solutions.
  • Each R is independently selected from H or -SO 3 H, R 1 is selected from H or -SO 3 H, and R and R 1 are not all H; preferably, R is -SO 3 H.
  • the compounds are selected from metal salts or metal complexes of hydrogen sulfate esters having the general structure of formula (I).
  • the metal is selected from sodium, potassium, calcium, aluminum or magnesium.
  • the compound is a metal complex formed by combining a hydrogen sulfate with the general structure of formula (I) and a metal hydroxide.
  • the compound is selected from the group consisting of sodium salt, potassium salt, aluminum complex, magnesium complex or magnesium-aluminum complex of hydrogen sulfate having the general structure of formula (I) .
  • the compounds have the structure of formula (II):
  • R 2 is SO 3 Na, R 3 is H; or
  • R 2 is SO 3 Na
  • R 3 is SO 3 Na
  • R 2 is SO 3 [Al 2 (OH) 5 ], R 3 is H; or
  • R 2 is SO 3 [Al 2 (OH) 5 ]
  • R 3 is SO 3 [Al 2 (OH) 5 ].
  • the weight imbalance regulator is an oral preparation. Oral preparations are more conducive to taking.
  • weight imbalance means that the BMI index is not lower than 24, or not lower than 25, 26, 27, or 28.
  • Each R is independently selected from H or -SO 3 H, R 1 is selected from H or -SO 3 H, and R and R 1 are not all H; preferably, R is -SO 3 H.
  • the compound in the preparation of the weight imbalance regulator synergist is selected from the metal salt or metal complex of the hydrogen sulfate having the general structure of formula (I).
  • the metal is selected from sodium, potassium, calcium, aluminum or magnesium.
  • the compound in the preparation of the weight imbalance regulator synergist is a metal complex formed by combining a hydrogen sulfate with the general structure of formula (I) and a metal hydroxide.
  • the compound in the preparation of the weight imbalance regulator synergist is selected from sodium salt, potassium salt, aluminum complex, magnesium complex or magnesium hydrogen sulfate ester having the general structure of formula (I) Aluminum composite.
  • the compound in the preparation of the weight imbalance regulator synergist has the structure of formula (II):
  • R 2 is SO 3 Na, R 3 is H; or
  • R 2 is SO 3 Na
  • R 3 is SO 3 Na
  • R 2 is SO 3 [Al 2 (OH) 5 ], R 3 is H; or
  • R 2 is SO 3 [Al 2 (OH) 5 ]
  • R 3 is SO 3 [Al 2 (OH) 5 ].
  • the weight imbalance regulator in the weight imbalance regulator synergist is selected from the group consisting of norepinephrine promoters, selective serotonin receptor agonists, At least one of a lipase inhibitor or a glucagon-like peptide 1 receptor agonist.
  • the weight imbalance regulator in the weight imbalance regulator synergist is selected from the group consisting of phentermine, bupropion, lorcaserin, oretamine. Stalag, cetilistat, liraglutide, metformin, zonisamide, topiramate, naltrexone, AMG-598, amitifadine, tesofensine, RZL-12, and other well-known weight imbalance regulators or those with weight imbalance regulation functions Compound.
  • a compound for preparing a weight imbalance regulator or a weight imbalance regulator synergist wherein the compound is a hydrogen sulfate having a general structure of formula (I), or a metal hydrogen sulfate having a general structure of formula (I) At least one of salt and metal complex:
  • Each R is independently selected from H or -SO 3 H, R 1 is selected from H or -SO 3 H, and R and R 1 are not all H; preferably, R is -SO 3 H.
  • the compounds are selected from metal salts or metal complexes of hydrogen sulfate esters having the general structure of formula (I).
  • the metal is selected from sodium, potassium, calcium, aluminum, or magnesium.
  • the compound is a metal complex formed by combining a hydrogen sulfate with a general structure of formula (I) and a metal hydroxide Things.
  • the compound is selected from the group consisting of sodium salt, potassium salt, and aluminum complex of hydrogen sulfate ester having the general structure of formula (I) , Magnesium compound or magnesium-aluminum compound.
  • the compound has the structure of formula (II):
  • R 2 is SO 3 Na, R 3 is H; or
  • R 2 is SO 3 Na
  • R 3 is SO 3 Na
  • R 2 is SO 3 [Al 2 (OH) 5 ], R 3 is H; or
  • R 2 is SO 3 [Al 2 (OH) 5 ]
  • R 3 is SO 3 [Al 2 (OH) 5 ].
  • weight imbalance refers to a BMI index of not less than 24, or not less than 25, 26, 27, or 28.
  • the weight imbalance regulator in the weight imbalance regulator synergist is selected from norepinephrine promoters, selective serum At least one of a receptor agonist, a lipase inhibitor, or a glucagon-like peptide 1 receptor agonist.
  • the weight imbalance regulator in the weight imbalance regulator synergist is selected from phentermine, bupropion, and Carserin, orlistat, cetilistat, liraglutide, metformin, zonisamide, topiramate, naltrexone, AMG-598, amitifadine, tesofensine, RZL-12, and other well-known weight imbalance regulators or Compound with weight imbalance regulation function.
  • a method for regulating weight imbalance comprising orally administering an effective amount of a compound to a weight imbalance, wherein the compound is a hydrogen sulfate having a general structure of formula (I) or a hydrogen sulfate having a general structure of formula (I) At least one of the metal salt and metal compound:
  • Each R is independently selected from H or -SO 3 H, R 1 is selected from H or -SO 3 H, and R and R 1 are not all H; preferably, R is -SO 3 H.
  • the compound is selected from metal salts or metal complexes of hydrogen sulfate having the general structure of formula (I).
  • the metal is selected from sodium, potassium, calcium, aluminum, or magnesium.
  • the compound is a metal complex formed by combining a hydrogen sulfate with the general structure of formula (I) and a metal hydroxide.
  • the compound is selected from sodium salt, potassium salt, aluminum complex, magnesium complex or magnesium-aluminum complex of hydrogen sulfate having the general structure of formula (I).
  • the compound has the structure of formula (II):
  • R 2 is SO 3 Na, R 3 is H; or
  • R 2 is SO 3 Na
  • R 3 is SO 3 Na
  • R 2 is SO 3 [Al 2 (OH) 5 ], R 3 is H; or
  • R 2 is SO 3 [Al 2 (OH) 5 ]
  • R 3 is SO 3 [Al 2 (OH) 5 ].
  • the weight imbalance means that the BMI index is not lower than 24, or not lower than 25, 26, 27, 28.
  • the method further includes administering other weight imbalance adjusting agents. That is, in addition to administering the compound, the method also administers other substances that can be used to regulate weight imbalance.
  • the other weight imbalance regulator is selected from norepinephrine promoters, selective serotonin receptor agonists, lipase inhibitors, or glucagon-like peptide 1 receptor agonists At least one of the agents.
  • the other weight imbalance regulator is selected from phentermine, bupropion, lorcaserin, orlistat, cetilistat, liraglutide, metformin, zonisat Amine, topiramate, naltrexone, AMG-598, amitifadine, tesofensine, RZL-12, and other well-known weight imbalance regulators or compounds with weight imbalance regulation functions.
  • the oral dose of the compound is 0.05g-50g/day, 0.1g-30g/day, 0.5g-20g/day, 1g-18g/day, or 1g-9g/day.
  • the oral frequency of the compound is 1 to 3 times per day.
  • the method is for therapeutic or non-therapeutic purposes.
  • Non-therapeutic purposes can be prevention purposes, or health care purposes.
  • the degree of weight imbalance is reduced after the method is adjusted.
  • the BMI value of the weight imbalance is closer to the normal range.
  • the BMI index of the weight imbalance is not less than 24, or not less than 25, 26, 27, 28, and after adjustment by the method, the BMI value of the weight imbalance is reduced.
  • the method does not damage the digestive function of the weight imbalance.
  • a composition for regulating weight imbalance comprising an active ingredient, characterized in that: the active ingredient includes a hydrogen sulfate having a general structure of formula (I) or a hydrogen sulfate having a general structure of formula (I) At least one of the metal salt and metal compound:
  • Each R is independently selected from H or -SO 3 H, R 1 is selected from H or -SO 3 H, and R and R 1 are not all H; preferably, R is -SO 3 H.
  • the active ingredient includes a metal salt or metal complex of hydrogen sulfate having the general structure of formula (I).
  • the metal is selected from sodium, potassium, calcium, aluminum, or magnesium.
  • the active ingredient includes a metal complex formed by combining a hydrogen sulfate having a general structure of formula (I) and a metal hydroxide.
  • the active ingredient includes sodium salt, potassium salt, aluminum complex, magnesium complex, or magnesium-aluminum complex of hydrogen sulfate having the general structure of formula (I) .
  • the active ingredient includes a compound having a structure of formula (II):
  • R 2 is SO 3 Na, R 3 is H; or
  • R 2 is SO 3 Na
  • R 3 is SO 3 Na
  • R 2 is SO 3 [Al 2 (OH) 5 ], R 3 is H; or
  • R 2 is SO 3 [Al 2 (OH) 5 ]
  • R 3 is SO 3 [Al 2 (OH) 5 ].
  • the composition further includes at least one pharmaceutically acceptable excipient.
  • the composition further includes at least one other weight imbalance regulator.
  • the other weight imbalance regulator is selected from norepinephrine promoters, selective serotonin receptor agonists, lipase inhibitors or glucagon-like At least one of peptide 1 receptor agonists.
  • the other weight imbalance regulator is selected from phentermine, bupropion, lorcaserin, orlistat, cetilistat, lira Lutide, metformin, zonisamide, topiramate, naltrexone, AMG-598, amitifadine, tesofensine, RZL-12, and other well-known weight imbalance regulators or compounds with weight imbalance regulation functions.
  • the composition for regulating weight imbalance, is an oral formulation.
  • the inventors unexpectedly discovered that the geraniolin hydrogensulfate with the general formula (I), or its metal salt or its metal compound used to regulate body weight imbalance has high safety, low side effects and significant effects. advantage.
  • weight imbalance weight imbalance.
  • BMI body mass index
  • BMI weight (kg) ⁇ height (m) squared, which is a commonly used standard to measure whether weight is unbalanced.
  • the human body BMI is 18.5-24. The larger the value deviates from the normal range, the more serious the weight imbalance.
  • 24 ⁇ BMI ⁇ 28 is overweight, and BMI ⁇ 28 is obesity.
  • the weight imbalance in the present invention includes weight imbalance caused by various reasons, and the specific cause may be diet, medicine, disease, and the like.
  • the weight imbalance in the present invention also includes weight imbalances that are accompanied by other diseases, such as diabetes, hypertension, hyperlipidemia, hypercholesterolemia, fatty liver, stroke, cerebral thrombosis, heart disease, malignant tumors, and hypertension. Weight imbalances that accompany these diseases such as uricemia, gout, osteoarthritis, irregular menstruation, polycystic ovary syndrome, or sleep apnea syndrome.
  • diseases such as diabetes, hypertension, hyperlipidemia, hypercholesterolemia, fatty liver, stroke, cerebral thrombosis, heart disease, malignant tumors, and hypertension.
  • Weight imbalances that accompany these diseases such as uricemia, gout, osteoarthritis, irregular menstruation, polycystic ovary syndrome, or sleep apnea syndrome.
  • the term "regulate weight imbalance” means that the degree of weight imbalance is reduced through adjustment or control. For example, compared to the BMI value before adjustment, the BMI value after adjustment is closer to the normal range.
  • treatment refers to eradicating, alleviating, reducing or ameliorating a disease or symptom, for example, delaying the development of the disease or symptom, reducing the degree of the disease or symptom, causing the regression of the disease or symptom, reducing the symptoms caused by the disease or symptom, Or stop the disease or symptoms, etc.
  • prevention refers to the reduction, reduction or alleviation of the risk of specific diseases or symptoms in the future to a certain extent.
  • the term "effective amount” refers to the amount of at least one drug or compound administered which is sufficient to reduce the disease or symptom to be regulated, treated or prevented to a certain degree.
  • pharmaceutically acceptable excipient refers to a substance that does not eliminate the biological activity of the compound of the present invention, and is relatively non-toxic, and can be administered to an individual without causing undesirable biological effects , It will not interact with any other components contained in the composition in a harmful way.
  • composition refers to a composition containing active ingredients, the composition is suitable for direct administration to the human body, the composition may or may not include one or more pharmaceutically suitable excipients, including but not Limited to excipients, preservatives, solubilizers, fillers, binders, adsorbents, disintegrants, lubricants, other carriers, other inert ingredients, or combinations thereof.
  • metal salt refers to a compound containing a metal element, in which the metal element part and the other part of the compound are combined together mainly through anion and cation interaction.
  • metal complex refers to a compound containing a metal element, in which the metal element part and the other parts of the compound are bonded together mainly through covalent bonds, coordination bonds or intermolecular forces.
  • the compound of the present invention is a geraniol hydrogensulfate derivative, including geraniol hydrogensulfate, a metal salt of geraniol hydrogensulfate, or a metal complex of geraniol hydrogensulfate.
  • it also includes its solvates, polymorphs, optical isomers, prodrugs, active metabolites and other derivatives with substantially equivalent pharmacological activities, which are all within the protection scope of the present invention.
  • formula (I) or formula (II) for brevity, the hydrogen atom, charge identification and/or chiral center identification are omitted.
  • Dosmalfate a specific compound in the compounds of the present invention, is a safe and effective cytoprotective agent with good curative effect on peptic ulcers. It has been used as a medicine for many years. "Dosmaate tablets. The mechanism of dosmaate in the treatment of peptic ulcer may be to reduce the activity of pepsin and increase the concentration of prostaglandin E2.
  • Geranioside Diosmin, a flavonoid compound, has a good effect of enhancing venous tone, improving microcirculation, promoting lymphatic drainage, and reducing edema. It has achieved good clinical effects as a drug for venous diseases. It has been on the market as a drug for many years, such as Diosmin tablets under the trade name "Aimelan".
  • the pharmaceutical composition of the present invention can be prepared by conventional methods in the pharmaceutical field. Intervention or treatment of the human body can use standard procedures in the medical field.
  • each R is independently selected from H or -SO 3 H, R 1 is selected from H or -SO 3 H, and R and R 1 are not all H; preferably, R is -SO 3 H.
  • the hydrogen sulfate of formula (I) can be prepared by using Diosmin as a raw material through sulfation.
  • the sulfating agent used in the sulfation process is well known in the art, such as chlorosulfonic acid and the like.
  • the metal salt can be obtained by further alkalizing the hydrogen sulfate.
  • common alkalis can be used as alkalizing agents, such as alkalis containing Na, K, Ca, Al or Mg, so as to form pharmaceutically suitable metal salts.
  • alkalizing agents such as alkalis containing Na, K, Ca, Al or Mg, so as to form pharmaceutically suitable metal salts.
  • Those skilled in the art can obtain different metal salts by selecting different alkalizing reagents. For example, sodium salt, potassium salt, etc.
  • the metal composite can be obtained by further replacing the metal salt.
  • the replacement reagent used can be a basic salt, preferably a basic salt containing hydroxide (or called metal hydroxy salt), so as to obtain a combination of hydrogen sulfate and metal hydroxide Complex.
  • Patent document EP0558435A1 describes that the sodium salt is treated with basic aluminum chloride to obtain an aluminum composite. Those skilled in the art can also choose different replacement reagents to obtain different metal composites.
  • reaction formula lists the specific preparation process of heptahydrogen sulfate, octahydrogen sulfate, sodium salt, and aluminum compound.
  • Compound 2 Structure of formula (II), R 2 is all SO 3 Na, and R 3 is SO 3 Na.
  • the hydrogen sulfate of formula (I), its metal salt, and its metal complex can also be purchased commercially, or prepared according to other existing methods.
  • the number of ulcer foci (a) and the area of ulcer foci (mm 2 ) of each patient were checked before and after treatment, and the curative effect after treatment was judged according to the following criteria:
  • the healing rate is used as an indicator of efficacy.
  • the number of red blood cells, the number of white blood cells, ALT, AST, serum creatinine, urine protein and other laboratory test items were checked.
  • the routine clinical diagnostic criteria were used to determine whether the test items were normal, and the normal rate was calculated.
  • Normal rate of inspection indicators number of patients with normal inspection indicators ⁇ total number of patients in this group ⁇ 100%
  • Loose stool rate number of patients with loose stool ⁇ total number of patients in this group ⁇ 100%
  • Constipation rate number of patients with constipation ⁇ total number of patients in this group ⁇ 100%.
  • Weight change rate (weight after treatment-weight before treatment) ⁇ weight before treatment ⁇ 100%
  • the compound has good safety, basically does not affect the patient's red blood cell count, white blood cell count, ALT, AST, serum creatinine, urine protein and other laboratory test items, and basically has no effect on normal digestive function.
  • the compound has a significant effect on the weight of the patient.
  • peptic ulcers will cause patients to eat less food and poor digestion.
  • Peptic ulcers have been reported to cause weight loss. After the peptic ulcer is relieved, the patient's digestive ability is restored, and the weight may increase to varying degrees.
  • doximamate tablets we unexpectedly found that after 4 weeks of use, with the relief of ulcers, patients in each dose group showed varying degrees of weight loss.
  • Test drugs compound 1, compound 2, compound 3, compound 4 in Example 1, as well as sucralfate and diosmin.
  • mice Clean-grade healthy adult male SD rats were selected and randomly grouped: blank group, model group, compound 1 group, compound 2 group, compound 3 group, compound 4 group, diosmin group, sucralfate group. Except for the blank group and the model group, each group has three subgroups: low dose, middle dose, and high dose. 6 animals in each subgroup.
  • the animals in the blank group were fed with ordinary feed every day.
  • the animals in each group except the blank group were fed with formula feed every day.
  • the formula feed contains 5% cholesterol, 6% sucrose, 20% egg yolk, 6% peanut butter, 12% whole milk powder, 6% sesame oil (the percentage is the mass percentage), and the others are common feed components.
  • Each test drug was mixed with 5% methyl cellulose solution, and the animals in each group except the blank group and the model group were given by gavage respectively, the dose was 100mg/kg (low dose), 400mg/kg (medium dose) , 1600mg/kg (high dose); the blank group and the model group are not administered, and the same amount of 5% methylcellulose solution is intragastrically administered. Once a day for 4 weeks.
  • BMI index is 25.
  • Mr. Sun male, 64 years old, suffering from obesity and hyperuricemia, uric acid level 680 ⁇ mol/L, weight 85kg, BMI index up to 32.
  • Dosmaate tablets were used three times a day (once in the morning, noon and in the evening), 3g each time, normal eating, continuous use for two months, the weight was significantly reduced, reduced to 75kg, BMI index 28.2. Although no uric acid-lowering drugs were used during this period, the uric acid level was also reduced to 600 ⁇ mol/L.

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Abstract

一种调节人体体重失衡的化合物、其组合物及其应用。发明人意外发现香叶木苷硫酸氢酯衍生物具有调节人体体重失衡的作用，有望开发为安全有效的体重失衡调节剂，或作为增效剂，提高现有体重失衡调节剂的调节效果。

Description

一种调节人体体重失衡的化合物、其组合物及其应用 技术领域
本发明涉及一种化合物的新应用，特别涉及香叶木苷硫酸氢酯衍生物的新应用，特别是在调节人体体重失衡方面的应用。
背景技术
正常人体的新陈代谢可以维持体重平衡在一定范围之内。体重过轻或过重都属于亚健康或者病理状态。造成人体体重失衡的原因有很多，例如遗传因素、身体运动量不足、摄入营养不足或过剩、疾病因素、药物使用等。
目前，肥胖或超重已经成为全球性的健康问题。肥胖可以引发多种疾病。肥胖人群患糖尿病的几率是正常人群的4倍以上；患高血压的比例达20％～50％，显著高于正常人群；患心肌梗塞、中风等心脑血管疾病的几率也显著高于正常人群。肥胖还增加患恶性肿瘤的几率。另外还导致痛风、***、睡眠呼吸暂停等多种其他疾病。肥胖不仅是疾病的诱发因素，而且与疾病的预后息息相关。例如糖尿病人的体重得到控制后可以更好地控制血糖。肥胖及其相关疾病已经严重影响了人们的健康及生活质量。
减轻体重可以有效改善有肥胖相关疾病及合并症的患者的健康状况。以饮食、锻炼为主导的生活方式干预疗法是较为推荐的方法，但是对于许多人而言，生活方式的改变非常困难，而且这种方式也并非总是有效。使用药物是减轻体重的必要选择之一。美国内分泌学会指南(Pharmacological Management of Obesity:An Endocrine Society Clinical Practice Guideline)指出，如果使用药物后3个月内体重下降≥5％，建议继续服药。
然而目前在欧洲和中国，药监部门批准上市的减肥药物仅有一种奥利司他；美国药监部门(FDA)批准上市的减肥药物种类也非常有限，而且都存在较多的不良反应。芬特明及其类似药物通过促进去甲肾上腺素释放显著降低体重，但是其具有血压升高、心悸、心动过速、心肌缺血等不良反应，严重限制了其在心血管疾病患者中的使用；氯卡色林是选择性血清素受体(5-HT2C)激动剂，可以抑制食欲从而减轻体重，但其心血管疾病风险、心脏瓣膜疾病风险和致癌性风险仍然需要在长期使用中进一步确认；奥利司他是胰腺及胃脂肪酶抑制剂，通过减少脂肪吸收而减轻体重，但其降低体重的效果有限，并且可引起脂肪消化不良、维生素和矿物质吸收障碍等不良反应；利拉鲁肽是胰高血糖素样肽1(GLP-1)受体激动剂，通过调整食物和热量的摄取来减轻体重，但需要注射使用，影响了患者顺应性。一些治疗其他疾病的药物也有一定的辅助降低体重的作用，例如降糖药物二甲双胍、SGLT2抑制剂，抗癫痫药唑尼沙胺、托吡酯等，但是往往疗效有限。目前对于新型减肥药物仍然存在巨大的临床 需求。
发明内容
本发明的目的在于提供香叶木苷硫酸氢酯衍生物的新应用。为达到上述目的，本发明采取如下的技术方案。
本发明第一方面的技术方案是：
化合物在制备体重失衡调节剂中的应用，其中，化合物为具有式(Ⅰ)通式结构的硫酸氢酯，或具有式(Ⅰ)通式结构的硫酸氢酯的金属盐和金属复合物中的至少一种：
Figure PCTCN2020086698-appb-000001
式(I)中：
各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
在一些化合物在制备体重失衡调节剂中的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的金属盐或金属复合物。
在一些化合物在制备体重失衡调节剂中的实例中，所述金属选自钠、钾、钙、铝或镁。
在一些化合物在制备体重失衡调节剂中的实例中，所述化合物为具有式(Ⅰ)通式结构的硫酸氢酯与金属氢氧化物结合所形成的金属复合物。
在一些化合物在制备体重失衡调节剂中的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的钠盐、钾盐、铝复合物、镁复合物或镁铝复合物。
在一些化合物在制备体重失衡调节剂中的实例中，所述化合物具有式(II)结构：
Figure PCTCN2020086698-appb-000002
式(II)中，
R 2为SO 3Na，R 3为H；或
R 2为SO 3Na，R 3为SO 3Na；或
R 2为SO 3[Al 2(OH) 5]，R 3为H；或
R 2为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
在一些化合物在制备体重失衡调节剂中的实例中，所述体重失衡调节剂为口服制剂。口服制剂更利于服用。
在一些化合物在制备体重失衡调节剂中的实例中，体重失衡指BMI指数不低于24，或不低于25、26、27、28。
本发明第二方面的技术方案是：
化合物在制备体重失衡调节剂增效剂中的应用，其中，化合物为具有式(Ⅰ)通式结构的硫酸氢酯，或具有式(Ⅰ)通式结构的硫酸氢酯的金属盐和金属复合物中的至少一种：
Figure PCTCN2020086698-appb-000003
式(I)中：
各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的金属盐或金属复合物。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述金属选自钠、钾、钙、铝或镁。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述化合物为具有式(Ⅰ)通式结构的硫酸氢酯与金属氢氧化物结合所形成的金属复合物。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的钠盐、钾盐、铝复合物、镁复合物或镁铝复合物。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述化合物具有式(II)结构：
Figure PCTCN2020086698-appb-000004
式(II)中，
R 2为SO 3Na，R 3为H；或
R 2为SO 3Na，R 3为SO 3Na；或
R 2为SO 3[Al 2(OH) 5]，R 3为H；或
R 2为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述体重失衡调节剂增效剂中的体重失衡调节剂选自去甲肾上腺素促进剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种。通过联合使用，有望进一步提高现有体重失衡调节剂的疗效，或减少其副作用。
在一些化合物在制备体重失衡调节剂增效剂中的实例中，所述体重失衡调节剂增效剂中的体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine、RZL-12，以及其他公知的体重失衡调节剂或具有体重失衡调节功能的化合物。
本发明第三方面的技术方案是：
用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物，其中，化合物为具有式(Ⅰ)通式结构的硫酸氢酯，或具有式(Ⅰ)通式结构的硫酸氢酯的金属盐和金属复合物中的至少一种：
Figure PCTCN2020086698-appb-000005
式(I)中：
各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的金属盐或金属复合物。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述金属选自钠、钾、钙、铝或镁。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述化合物为具有式(Ⅰ)通式结构的硫酸氢酯与金属氢氧化物结合所形成的金属复合物。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的钠盐、钾盐、铝复合物、镁复合物或镁铝复合物。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述化合物具有式(II)结构：
Figure PCTCN2020086698-appb-000006
式(II)中，
R 2为SO 3Na，R 3为H；或
R 2为SO 3Na，R 3为SO 3Na；或
R 2为SO 3[Al 2(OH) 5]，R 3为H；或
R 2为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，体重失衡指BMI指数不低于24，或不低于25、26、27、28。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述体重失衡调节剂增效剂中的体重失衡调节剂选自去甲肾上腺素促进剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种。通过联合使用，有望进一步提高现有体重失衡调节剂的疗效，或减少其副作用。
在一些用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物的实例中，所述体重失衡调节剂增效剂中的体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine、RZL-12，以及其他公 知的体重失衡调节剂或具有体重失衡调节功能的化合物。
本发明第四方面的技术方案是：
一种调节体重失衡的方法，包括向体重失衡者口服给予有效量的化合物，其中，化合物为具有式(Ⅰ)通式结构的硫酸氢酯，或具有式(Ⅰ)通式结构的硫酸氢酯的金属盐和金属复合物中的至少一种：
Figure PCTCN2020086698-appb-000007
式(I)中：
各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
在一些调节体重失衡的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的金属盐或金属复合物。
在一些调节体重失衡的实例中，所述金属选自钠、钾、钙、铝或镁。
在一些实例中，所述化合物为具有式(Ⅰ)通式结构的硫酸氢酯与金属氢氧化物结合所形成的金属复合物。
在一些调节体重失衡的实例中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的钠盐、钾盐、铝复合物、镁复合物或镁铝复合物。
在一些调节体重失衡的实例中，所述化合物具有式(II)结构：
Figure PCTCN2020086698-appb-000008
式(II)中，
R 2为SO 3Na，R 3为H；或
R 2为SO 3Na，R 3为SO 3Na；或
R 2为SO 3[Al 2(OH) 5]，R 3为H；或
R 2为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
在一些调节体重失衡的实例中，所述体重失衡指BMI指数不低于24，或不低于25、26、27、28。
在一些调节体重失衡的实例中，所述方法还包括给予其他的体重失衡调节剂。即，所述方法除给予所述化合物之外，还给予其他的可用于调节体重失衡的物质。
在一些调节体重失衡的实例中，所述其他的体重失衡调节剂选自去甲肾上腺素促进剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种。通过将所述化合物与所述其他的体重失衡调节剂联合使用或制备成复方制剂使用，有望进一步提高现有体重失衡调节剂的疗效，或减少其副作用。
在一些调节体重失衡的实例中，所述其他的体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine、RZL-12，以及其他公知的体重失衡调节剂或具有体重失衡调节功能的化合物。
在一些调节体重失衡的实例中，所述化合物的口服量为0.05g～50g/天、0.1g～30g/天、0.5g～20g/天、1g～18g/天，或者1g～9g/天。
在一些调节体重失衡的实例中，所述化合物的口服次数为1～3次/天。
在一些调节体重失衡的实例中，所述方法为治疗目的，或非治疗目的。非治疗目的可以是预防目的，或保健目的。
在一些调节体重失衡的实例中，经过所述方法调节后，体重失衡的程度得到减轻。
在一些调节体重失衡的实例中，经过所述方法调节后，体重失衡者的BMI值更接近正常范围。
在一些调节体重失衡的实例中，所述体重失衡者BMI指数不低于24，或不低于25、26、27、28，经过所述方法调节后，减少了体重失衡者的BMI值。
在一些调节体重失衡的实例中，所述方法不损伤体重失衡者的消化功能。
本发明第五方面的技术方案是：
一种用于调节体重失衡的组合物，包括活性成分，其特征在于：所述活性成分包括具有式(Ⅰ)通式结构的硫酸氢酯，或具有式(Ⅰ)通式结构的硫酸氢酯的金属盐和金属复合物中的至少一种：
Figure PCTCN2020086698-appb-000009
式(I)中：
各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
在一些用于调节体重失衡的组合物的实例中，所述活性成分包括具有式(Ⅰ)通式结构的硫酸氢酯的金属盐或金属复合物。
在一些用于调节体重失衡的组合物的实例中，所述金属选自钠、钾、钙、铝或镁。
在一些用于调节体重失衡的组合物的实例中，所述活性成分包括具有式(Ⅰ)通式结构的硫酸氢酯与金属氢氧化物结合所形成的金属复合物。
在一些用于调节体重失衡的组合物的实例中，所述活性成分包括具有式(Ⅰ)通式结构的硫酸氢酯的钠盐、钾盐、铝复合物、镁复合物或镁铝复合物。
在一些用于调节体重失衡的组合物的实例中，所述活性成分包括具有式(II)结构的化合物：
Figure PCTCN2020086698-appb-000010
式(II)中，
R 2为SO 3Na，R 3为H；或
R 2为SO 3Na，R 3为SO 3Na；或
R 2为SO 3[Al 2(OH) 5]，R 3为H；或
R 2为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
在一些用于调节体重失衡的组合物的实例中，所述组合物还包括至少一种药学上可接受的辅料。
在一些用于调节体重失衡的组合物的实例中，所述组合物还包括至少一种其他的体重失衡调节剂。
在一些用于调节体重失衡的组合物的实例中，所述其他的体重失衡调节剂选自去甲肾上腺素促进 剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种。通过联合使用，有望进一步提高现有体重失衡调节剂的疗效，或减少其副作用。
在一些用于调节体重失衡的组合物的实例中，优选的，所述其他的体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine、RZL-12，以及其他公知的体重失衡调节剂或具有体重失衡调节功能的化合物。
在一些用于调节体重失衡的组合物的实例中，所述组合物为口服制剂。
本发明的有益效果是：
发明人意外发现，通式如式(Ⅰ)所述的香叶木苷硫酸氢酯，或其金属盐或其金属复合物用于调节人体体重失衡时，具有安全性高，副作用小，效果显著的优点。
具体实施方式
下文提供了一些例示性的实施方式及其描述，旨在为了使本领域技术人员在参考这些实施方式之后可以更好地了解本发明的技术方案和技术效果，但不用于限制本发明。即这些实施方式和描述仅具有例示性和阐释性，而不具有限制性。
术语：
除非另有定义，否则本文所用的所有技术及科学术语均具有与所主张标的物所属领域的技术人员通常所了解含义相同的含义。在本文中对于术语存在多种定义时，以此部分中的定义为准。
标准化学术语的定义可参见著作，例如卡雷(Carey)和松德贝里(Sundberg)，高等有机化学(ADVANCED ORGANIC CHEMISTRY)，第5版，A卷(2007)及B卷(2010)，施普林格出版社(Springer)。
术语“体重失衡”：即weight imbalance。本发明中主要是指体重超重(overweight)或者肥胖(obesity)，即身体质量指数BMI等于或大于24。身体质量指数(body mass index,BMI)可通过体重和身高进行计算得到，BMI＝体重(kg)÷身高(m)的平方，是衡量体重是否失衡的常用标准。正常情况下人体BMI为18.5～24，值偏离正常范围越大说明体重失衡越严重，具体地，24≤BMI<28为体重超重，BMI≥28为肥胖。本发明中的体重失衡包括各种原因引起的体重失衡，具体的原因可以是饮食、药物、疾病等。本发明中的体重失衡还包括在伴随其他疾病的同时所表现出的体重失衡，例如糖尿病、高血压、高血脂、高胆固醇血症、脂肪肝、中风、脑血栓、心脏病、恶性肿瘤、高尿酸血症、痛风、骨关节炎、***、***、或者睡眠呼吸暂停综合症等这些疾病所伴随的体重失衡。
术语“调节体重失衡”，即通过调整或控制使体重失衡的程度得到减轻。例如，相对于调节之前的BMI值，调节之后的BMI值更加接近于正常范围。
术语“治疗”是指根除、缓和、减少或改善疾病或症状，例如，延缓疾病或症状的发展、减轻疾病或症状的程度、引起疾病或症状的消退、减轻由疾病或症状所引起的症状、或终止疾病或症状等。
术语“预防”是指在一定程度上减少、降低或减轻将来发生特定疾病或症状的风险。
术语“有效量”是指足以将所调节、治疗或预防的疾病或症状减轻到一定程度的所给与的至少一种药物或化合物的量。
术语“药学上可接受的辅料”是指一种物质，其不会消除本发明所述化合物的生物活性，且相对无毒性，可将所述物质给与个体而不会引起不期望的生物效应，也不会以有害方式与组合物中所含有的任一其它组份相互作用。
术语“药物组合物”是指含有活性成分的组合物，该组合物适于直接给与人体使用，该组合物中可以包括或不包括一种或多种医药上所适宜的辅料，包括但不限于赋形剂、防腐剂、增溶剂、填充剂、粘合剂、吸附剂、崩解剂、润滑剂、其它载剂、其它惰性成份、或它们的组合等。
术语“金属盐”，是指一种含有金属元素的化合物，其中金属元素部分与化合物的其他部分主要通过阴阳离子相互作用力结合在一起。
术语“金属复合物”，是指一种含有金属元素的化合物，其中金属元素部分与化合物的其他部分主要通过共价键、配位键或分子间作用力结合在一起。
本发明的化合物，为香叶木苷硫酸氢酯衍生物，包括香叶木苷硫酸氢酯，香叶木苷硫酸氢酯的金属盐，或者香叶木苷硫酸氢酯的金属复合物。另外还包括其溶剂化物、多晶型物、光学异构体、前药、活性代谢物等药理活性基本相当的其他衍生物，这些都在本发明的保护范围之内。式(I)或式(II)中，为简洁起见，省略了氢原子、电荷标识和/或手性中心标识。本发明化合物中的一种具体化合物多司马酯(Dosmalfate)是一种安全有效的细胞保护剂，对消化道溃疡有较好的疗效，已经作为药品上市使用多年，例如商品名为“卫多美”的多司马酯片。多司马酯治疗消化道溃疡的机理可能是降低胃蛋白酶活性、升高***素E2的浓度等。香叶木苷：即地奥司明(Diosmin)，为黄酮类化合物，具有良好的增强静脉张力、改善微循环、促进淋巴回流、减轻水肿的作用，作为静脉疾病治疗药物取得了良好的临床疗效。已经作为药品上市多年，例如商品名为“爱脉朗”的地奥司明片。
本发明药物组合物的制备可采用制药领域的常规方法。对人体的干预或治疗可使用医疗领域的标准规程。
实施例1 本发明化合物的制备
式(Ⅰ)硫酸氢酯
Figure PCTCN2020086698-appb-000011
式(I)中：各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
式(I)硫酸氢酯的制备可以以地奥司明(Diosmin)为原料，经过硫酸化而得到。硫酸化过程中使用的硫酸化试剂(sulfating agent)是本领域熟知的，例如氯磺酸等。原料地奥司明结构中有八个羟基，通过控制反应条件，可实现将不同位置不同数量的羟基硫酸化从而得到不同的硫酸氢酯。例如，一种七硫酸氢酯记载于专利文献EP0558435A1中，一种八硫酸氢酯记载于专利文献EP0302155A1中。
硫酸氢酯金属盐
通过进一步将硫酸氢酯碱化可以得到其金属盐。碱化过程可以使用常用的碱作为碱化试剂(alkalizing agent)，例如含Na、K、Ca、Al或Mg的碱，以便于形成药学上所适用的金属盐。本领域技术人员通过选用不同的碱化试剂可以得到不同的金属盐。例如钠盐、钾盐等。
硫酸氢酯金属复合物
通过进一步将金属盐进行置换可以得到金属复合物。所用的置换试剂可以是碱式盐(alkali salt)，优选是含有氢氧根的碱式盐(或称为金属羟基盐metal hydroxy salts)，以便得到硫酸氢酯与金属氢氧化物结合所形成的复合物。专利文献EP0558435A1中记载了将钠盐用碱式氯化铝处理得到铝复合物。本领域技术人员也可以选用不同的置换试剂，从而得到不同的金属复合物。
下面的反应式列举了具体的七硫酸氢酯、八硫酸氢酯、钠盐、铝复合物的制备过程。
Figure PCTCN2020086698-appb-000012
其中的几种代表性的具体化合物是：
Figure PCTCN2020086698-appb-000013
化合物1：式(II)结构，R 2全部为SO 3Na，R 3为H。
化合物2：式(II)结构，R 2全部为SO 3Na，R 3为SO 3Na。
化合物3：式(II)结构，R 2全部为SO 3[Al 2(OH) 5]，R 3为H。
化合物4：式(II)结构，R 2全部为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
式(Ⅰ)硫酸氢酯、其金属盐、其金属复合物也可以通过商业购买获得，或根据现有的其他方法制备得到。
实施例2 本发明化合物的临床应用：
在患有胃溃疡或十二指肠溃疡的患者中研究了本发明化合物治疗溃疡的有效性和安全性。
诊断患有胃溃疡或十二指肠溃疡的患者(80人)，使用化合物3的片剂(多司马酯片，湘北威尔曼制药股份有限公司生产)治疗4周，治疗期间患者未使用其他药物。用药剂量以每日3g的标准剂量为基础，并依据患者个体情况酌情增加或减少剂量。
本发明化合物对溃疡治疗的有效性：
分别在治疗前后检查了每位患者的溃疡灶数目(个)和溃疡灶面积(mm 2)，并按照以下标准对治疗后的疗效进行判断：
完全愈合：治疗后内窥镜检查溃疡及其周围炎症全部消失；
基本愈合：治疗后内窥镜检查溃疡消失，仍有炎症；部分愈合：治疗后内窥镜检查溃疡面积缩小50％及以上；
未愈合：治疗后内窥镜检查溃疡面积不及50％。
以愈合率作为疗效判定指标。
愈合率＝(完全愈合的患者数+基本愈合的患者数)÷该组患者总人数×100％。
主要结果见表1。
表1 药物治疗后消化道溃疡愈合情况
剂量组(克/天) 人数 溃疡愈合率
0.5g组 10 30.0％
1g组 18 55.6％
3g组 37 62.2％
9g组 10 80.0％
18g组 5 80.0％
从表1的数据可知，可看出化合物能有效促进溃疡愈合。
本发明化合物的安全性和体重调节作用：
分别在治疗前后检查了红细胞数、白细胞数、ALT、AST、血清肌酐、尿蛋白等实验室检查项目，用常规临床诊断标准判断检查项目是否正常，并计算正常率。
检查指标正常率＝检查指标正常的患者人数÷该组患者总人数×100％
还分别在治疗前后考察了药物对患者正常消化功能的影响，以便溏率和便秘率来判断：
便溏率＝便溏的患者人数÷该组患者总人数×100％
便秘率＝便秘的患者人数÷该组患者总人数×100％。
还分别考察了治疗前后患者体重的变化：
体重变化率＝(治疗后体重-治疗前体重)÷治疗前体重×100％
主要结果见表2。
表2 药物治疗前后常规检查指标的变化情况
Figure PCTCN2020086698-appb-000014
从表2可看出化合物的安全性良好，基本不影响患者的红细胞数、白细胞数、ALT、AST、血清肌酐、尿蛋白等实验室检查项目，对正常消化功能也基本没有影响。
出人意料的是化合物对患者体重有明显的影响。通常情况下，消化道溃疡会导致患者进食减少，消化能力变差，已有报道消化道溃疡会导致体重减轻。在消化道溃疡得到缓解后，患者的消化能力恢复，体重多可出现不同程度的增加。但在多司马酯片的临床应用中，我们意外发现使用4周后，伴随溃疡的缓解，各剂量组患者出现了体重不同程度的下降。
实施例3 本发明化合物对肥胖模型动物体重的调节作用
在动物试验中进一步研究了本发明化合物对体重的调节作用。
试验药物：实施例1中的化合物1、化合物2、化合物3、化合物4，以及硫糖铝、地奥司明。
实验动物：选取清洁级健康成年雄性SD大鼠，随机分组：空白组、模型组、化合物1组、化合物2组、化合物3组、化合物4组、地奥司明组、硫糖铝组。除空白组和模型组外，每组分别设置低剂量、中剂量、高剂量三个亚组。每个亚组6只动物。
试验方法：
空白组动物每天用普通饲料喂养。除空白组外的其余各组动物每天用配方饲料喂养。配方饲料中含有5％胆固醇，6％蔗糖，20％鸡蛋黄，6％花生酱，12％全脂奶粉，6％芝麻油(百分含量为质量百分含量)，其他为普通饲料组分。
将各试验药物分别与5％甲基纤维素溶液混合，除空白组和模型组之外的其余各组动物分别灌胃给药，剂量100mg/kg(低剂量)、400mg/kg(中剂量)、1600mg/kg(高剂量)；空白组与模型组不给药，分别灌胃等量的5％甲基纤维素溶液。每天一次，持续4周。
试验过程中各组动物均能够正常饮食，未出现厌食情况。动物大便性状正常，未出现明显的腹泻。
各组动物最后一次给药后，禁食不禁水12h后，称体重。
用戊巴比妥钠麻醉后测量体长(从鼻到***的距离)，计算体质量指数BMI(BMI＝体重÷体长的平方)。
对各组数据进行统计分析，筛选出主要结果如表3所示(注：表中部分试验药物仅列出了中剂量亚组的情况)。
表3 本发明化合物对肥胖模型大鼠BMI的影响
组别 BMI(kg/m 2)
空白组 5.33±0.21*
模型组 7.73±0.27
化合物3低剂量亚组 6.72±0.32*
化合物3中剂量亚组 6.06±0.29*
化合物3高剂量亚组 5.85±0.23*
化合物1中剂量亚组 6.50±0.32*
化合物2中剂量亚组 6.63±0.26*
化合物4中剂量亚组 6.12±0.35*
地奥司明中剂量亚组 7.60±0.39
硫糖铝中剂量亚组 7.87±0.34
*：表示与模型组相比，P<0.05。
从表3的试验结果可以看出：
1)模型组动物与空白组动物相比，BMI出现大幅增加，说明造模成功；
2)与模型组相比，使用化合物1、化合物2、化合物3、化合物4后，动物BMI均能显著降低， 提示药物具有预防体重增加的作用。相比而言，相同剂量下，化合物3和化合物4效果优于化合物1和化合物2。
3)硫糖铝或地奥司明与模型组相比未显示出显著的差异。
实施例4 本发明化合物在体重失衡者中的调节情况
由于已有数据显示多司马酯片具有良好的安全性，在满足医学伦理的情况下，几名体重失衡的人自愿试用了化合物3的片剂(多司马酯片)。
高先生，男，36岁，无消化***或代谢***疾病，仅有轻度的体重失衡，BMI指数为25。每天使用多司马酯片两次(早上和晚上各一次)，每次1g，正常进食。连续使用两个月后，BMI减少到22，体重恢复到正常水平。使用期间未出现任何与药物多司马酯片有关的不良反应。
陈女士，女，60岁，患有***，体重62kg，BMI指数29。使用多司马酯片连续三个月，每日三次(早上、中午和晚上各一次)，每次1.5g后，体重降低到55kg，BMI指数25.7。使用期间仅出现轻度的便秘，未见其他不良反应。
孙先生，男，64岁，患有肥胖症和高尿酸血症，尿酸水平680μmol/L，体重85kg，BMI指数达32。每天使用三次多司马酯片(早上、中午和晚上各一次)，每次3g，正常进食，连续使用两个月，体重显著减轻，降低到75kg，BMI指数28.2。期间虽然未使用降尿酸的药物，尿酸水平也降低到600μmol/L。
上述数据表明本发明的化合物可以安全、高效地调节人体体重失衡。
上文仅描述了本发明的部分实施例，本领域技术人员应知晓这些实施例仅是作为实例对本发明进行阐述，而非意在限制本发明的保护范围。本领域技术人员可以基于本发明的构思对本发明方案进行变更、改变和替代。本发明的保护范围由权利要求书所界定，涵盖其等同的方案，也应当涵盖本领域技术人员基于本发明作出的这些变更、改变和替代。

Claims (20)

  1. 化合物在制备体重失衡调节剂中的应用，其中，所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯，或具有式(Ⅰ)通式结构的硫酸氢酯的金属盐和金属复合物中的至少一种：
    Figure PCTCN2020086698-appb-100001
    式(Ⅰ)中：
    各个R独立选自H或-SO 3H，R 1选自H或-SO 3H，且R和R 1不全为H；优选的，R为-SO 3H。
  2. 根据权利要求1所述的应用，其特征在于：所述金属盐或金属复合物中的金属元素选自钠、钾、钙、铝或镁。
  3. 根据权利要求1所述的应用，其特征在于：所述金属复合物是具有式(Ⅰ)通式结构的硫酸氢酯与金属氢氧化物结合所形成的金属复合物。
  4. 根据权利要求1所述的应用，其特征在于：所述化合物选自具有式(Ⅰ)通式结构的硫酸氢酯的钠盐、钾盐、铝复合物、镁复合物或镁铝复合物。
  5. 根据权利要求1所述的应用，其特征在于：所述化合物具有式(II)所示的结构：
    Figure PCTCN2020086698-appb-100002
    式(II)中：
    R 2为SO 3Na，R 3为H；或
    R 2为SO 3Na，R 3为SO 3Na；或
    R 2为SO 3[Al 2(OH) 5]，R 3为H；或
    R 2为SO 3[Al 2(OH) 5]，R 3为SO 3[Al 2(OH) 5]。
  6. 根据权利要求1～5任一项所述的应用，其特征在于：所述体重失衡调节剂为口服制剂。
  7. 根据权利要求1～5任一项所述的应用，其特征在于：体重失衡指BMI指数不低于24。
  8. 权利要求1～5任一项所述的化合物在制备体重失衡调节剂增效剂中的应用。
  9. 根据权利要求8所述的应用，其特征在于：所述体重失衡调节剂选自去甲肾上腺素促进剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种；优选的，所述体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine或RZL-12。
  10. 用于制备体重失衡调节剂或体重失衡调节剂增效剂的化合物，其中，所述化合物为权利要求1～5任一项所述的化合物。
  11. 一种调节体重失衡的方法，包括给体重失衡者口服给予有效量的化合物，其中，所述化合物为权利要求1～5任一项所述的化合物。
  12. 根据权利要求11所述的方法，其特征在于：体重失衡指BMI指数不低于24。
  13. 根据权利要求11所述的方法，其特征在于：还包括给予体重失衡调节剂。
  14. 根据权利要求13所述的方法，其特征在于：所述体重失衡调节剂选自去甲肾上腺素促进剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种；优选的，所述体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine或RZL-12。
  15. 根据权利要求11～14任一项所述的方法，其特征在于：所述化合物的口服量为0.05g～50g/天、0.1g～30g/天、0.5g～20g/天、1g～18g/天，或者1g～9g/天。
  16. 根据权利要求15所述的方法，其特征在于：所述化合物的口服次数为1～3次/天。
  17. 根据权利要求11所述的方法，其特征在于：所述方法为治疗目的或非治疗目的。
  18. 一种用于调节体重失衡的组合物，包括活性成分，其特征在于：所述活性成分包括权利要求1～5任一项所述的化合物。
  19. 根据权利要求18所述的组合物，其特征在于：所述组合物还包括至少一种体重失衡调节剂，所述体重失衡调节剂选自去甲肾上腺素促进剂、选择性血清素受体激动剂、脂肪酶抑制剂或者胰高血糖素样肽1受体激动剂中的至少一种；优选的，所述体重失衡调节剂选自芬特明、安非他酮、氯卡色林、奥利司他、cetilistat、利拉鲁肽、二甲双胍、唑尼沙胺、托吡酯、纳曲酮、AMG-598、amitifadine、tesofensine或RZL-12。
  20. 根据权利要求18或19所述的组合物，其特征在于：所述组合物为口服制剂。
PCT/CN2020/086698 2019-05-05 2020-04-24 一种调节人体体重失衡的化合物、其组合物及其应用 WO2020224452A1 (zh)

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