WO2011047597A1 - 二羟基苯并吡喃酮化合物、其药物组合物及其预防和治疗骨折和骨质疏松的应用 - Google Patents

二羟基苯并吡喃酮化合物、其药物组合物及其预防和治疗骨折和骨质疏松的应用 Download PDF

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WO2011047597A1
WO2011047597A1 PCT/CN2010/077382 CN2010077382W WO2011047597A1 WO 2011047597 A1 WO2011047597 A1 WO 2011047597A1 CN 2010077382 W CN2010077382 W CN 2010077382W WO 2011047597 A1 WO2011047597 A1 WO 2011047597A1
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compound
group
pharmaceutically acceptable
osteoporosis
formula
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PCT/CN2010/077382
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English (en)
French (fr)
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李靖
孟坤
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北京盛诺基医药科技有限公司
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones

Definitions

  • Dihydroxybenzopyrone compound Dihydroxybenzopyrone compound, pharmaceutical composition thereof and application thereof for preventing and treating bone fracture and osteoporosis
  • This invention relates to the use of dihydroxybenzopyrones.
  • the compounds of the present invention are useful for preventing bone fractures, reducing the incidence of fractures, and promoting the repair of damaged bones after fractures, as well as preventing and treating osteoporosis.
  • the invention further relates to pharmaceutical compositions comprising these compounds, and to the use of said compounds, alone or in combination with other agents, to prevent fractures and to promote repair of damaged bones after fracture, and to prevent and treat osteoporosis.
  • Estrogen is a steroid hormone produced by the endocrine system in the body and plays an important role in the reproductive system, cardiovascular system, central nervous system, immune system and skeletal system. Recent studies have shown that estrogen exerts biological effects through two signaling pathways, the nuclear pathway and the cell membrane pathway; estrogen and its receptor signal transduction system are widely involved in cell growth, differentiation and apoptosis in multiple system tissues in vivo. . A large number of studies have confirmed the presence of estrogen receptors in the skeletal system, and their receptor expression levels are associated with skeletal development and osteoporosis; ER- ⁇ -mediated signal transduction pathways are likely to be involved in osteoporosis The formation and development process.
  • Estrogen has been used to treat osteoporosis for many years. Clinical observations have found that estrogen has a positive effect on reducing rapid bone loss after menopause, increasing bone mass, alleviating bone pain caused by osteoporosis, and reducing the incidence of fracture. Numerous studies have also confirmed that estrogen receptors are present in the skeletal system, and their receptor expression levels are associated with skeletal development and osteoporosis; estrogen receptor-mediated signal transduction pathways are involved in the formation of osteoporosis and development process. Selective estrogen receptor modulators developed for estrogen receptors, such as raloxifene, exhibit potent estrogen stimulatory effects on the skeletal system, increase bone density, and improve osteoporosis.
  • estrogen receptors are divided into two subtypes, alpha and beta; wherein ER-ct includes three homologs, ER-a66, ER-a46 and ER-a36.
  • the isoform ER-a36 is from the first ER-a66 gene
  • the promoter in the intron starts transcription and is encoded by ER- (a partial exon of x66. Therefore, ER-CL36 lacks two transcriptional functional regions, retaining the DNA-binding functional region and the dimerization functional region; It is important that the hormone ligand binding region of ER-a36 lacks a partial helix region, thus completely changing its specificity and affinity for binding to hormone ligands.
  • ER-CL36 is mainly distributed in cell membranes and cytoplasm, and is present in small amounts in In the nucleus, ER-CL36 regulates cell growth and apoptosis through the estrogen cell membrane signal transduction pathway (1. ZY,
  • the compounds of the present invention are useful as modulators of ER-ct and ER- ⁇ bioinformatics systems for the prevention and treatment of fractures and osteoporosis.
  • the present invention relates to a compound of formula (I), and a pharmaceutically acceptable salt thereof:
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl;
  • R 2 , R 3 and R 4 are independently of each other selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, isopropyl, hydroxy, carboxy;
  • R 5 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, isopropyl, carboxy; or R 5 is OR 6 , wherein R 6 is selected from the group consisting of methyl, ethyl, propyl, isopropyl.
  • the compound of formula (I) is: 2-(3-chloro-4-methoxyphenyl)-5,7-dihydroxy-8-(3-methyl- 2-butenyl-)-4H-benzopyran-4-one, ie a compound of formula (I) Structure with ( ⁇ ):
  • the pharmaceutical preparation comprises a compound of the formula (1), (I I ) or a pharmaceutically acceptable salt of the compound, and a pharmaceutically acceptable carrier, diluent or excipient.
  • composition comprising a compound of the formula (1), (II) or a pharmaceutically acceptable salt of the compound.
  • the compound of the formula (1), (II) and a pharmaceutically acceptable salt thereof for the preparation of a medicament for a disease regulated by an estrogen receptor ER-ct or ER- ⁇ subtype, the ER- The ct subtype includes ER-(x36, ER-a46 and ER-a66.
  • the formula (1), (ID compound and pharmaceutically acceptable salt thereof are modulators of the estrogen receptor ER-a and ER- ⁇ subtypes.
  • compound of formula (I) includes compounds of the formulae as defined herein, as well as all embodiments, preferred embodiments, more preferred embodiments and particularly preferred embodiments of the compounds, including the compounds disclosed in the specific names or examples, Each of these compounds is a particularly preferred embodiment of a compound defined by the formula.
  • compound of the present invention means any compound of the formula (I) as defined above.
  • the invention also relates to salts, polymorphs, solvates and hydrates of the compounds of the invention.
  • pharmaceutically acceptable salt as used herein, unless otherwise stated, includes salts which may be present in the compounds of the invention.
  • halogen or "halo”, unless otherwise indicated, denotes fluoro, chloro, bromo and iodo.
  • treatment refers to a process of reversing, alleviating, inhibiting a disease or a condition, or preventing such a disease or condition.
  • treatment refers to the act of treatment, wherein the treatment is as defined above.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a A pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be administered orally in the form of a tablet, a capsule, a pill, a powder, a sustained release, a solution, or a suspension; the pharmaceutical composition may also be administered parenterally in the form of a sterile solution, suspension or emulsion.
  • the pharmaceutical composition may also be administered topically in the form of an ointment or cream; the pharmaceutical composition may also be administered rectally in the form of a suppository.
  • the pharmaceutical compositions may be presented in unit dosage form suitable for single administration of precise dosages.
  • the pharmaceutical composition includes a conventional pharmaceutical carrier or excipient and a compound of the present invention as an active ingredient.
  • the pharmaceutical composition may include other medical or pharmaceutical preparations, carriers, adjuvants, and suitable pharmaceutical carriers including inert diluents or fillers, water, and various organic solvents.
  • the pharmaceutical composition of the present invention may contain other ingredients such as a flavoring agent, a binder, an excipient, etc., if necessary.
  • the tablets may contain various excipients, for example citric acid and various disintegrating agents such as starch, alginic acid and certain complex silicates and binders such as sucrose, gelatin and arabic may be used. gum.
  • the tablets may also contain lubricants such as magnesium stearate, sodium lauryl sulfate and talc, which are often used in tablets.
  • a similar type of solid composition can also be used with soft and hard filled capsules.
  • Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols.
  • the aqueous suspension or elixirs can be combined with various sweetening or flavoring agents, pigments or dyes and, if desired, with emulsifiers or suspending agents, and diluents such as water, ethanol, Propylene glycol, glycerol or a combination thereof is administered in combination.
  • Exemplary parenteral administration forms include solutions or suspensions of the active compounds in sterile solutions, for example, propylene glycol or aqueous dextrose. Such dosage forms can be suitably buffered if desired.
  • the aqueous composition of the present invention may include other pharmaceutically acceptable solutes, including additives and other drugs, as the case may be. Suitable additives are those well known in the art including, but not limited to, antioxidants, antibacterials, surfactants, chelating agents, sugars, and preservatives.
  • the aqueous composition of the present invention can be administered by injection, wherein the injection can be intramuscular, intravenous or subcutaneous.
  • the compounds of the invention may be administered alone in terms of the intended route of administration and standard pharmaceutical practice, but are often administered with a suitable pharmaceutical excipient, diluent or carrier known in the art. If appropriate, adjuvants may be added, including adjuvants, antioxidants, flavoring agents, or coloring agents.
  • suitable pharmaceutical compositions to provide immediate, delayed, modified, sustained, pulsatile or controlled release, depending on the particular route of administration and the specificity of the release profile, and Need to respond.
  • the compounds of the invention may be administered in the following routes, for example, but not limited to, orally known in the art. (including oral, sublingual, etc.) forms.
  • oral refers to an oral administration method in which the oral use amount of the animal is expressly specified, for example, in a food or beverage, directly into the oral cavity, or freely selected.
  • animal refers to warm-blooded animals such as dogs and humans that have adaptive functions in the animal kingdom.
  • Typical oral solid forms can include tablets, powders, multiparticulate formulations (granules), capsules, chewables, lozenges, films, patches, and the like.
  • Typical oral liquid (including semi-solid and gelatinous) forms can include solutions, elixirs, gels, sprays, liquid-filled chews, and the like.
  • Other oral administration forms may also be employed in which the active agent is suspended in a liquid or semi-solid carrier phase, such as a suspension.
  • parenteral administration means that the route of administration does not pass through the mouth.
  • parenteral administration may include topical and transdermal, rectal, vaginal, nasal, inhalation and parenteral administration (requiring means of penetration through the skin barrier by needle and needle-free methods, including implants) And reservoir).
  • compositions of the invention include tablets.
  • the tablets are prepared by a process selected from the group consisting of direct compression or wet, dry or melt granulation, melt coagulation processes and extrusion.
  • the tablet core portion of the compositions of the present invention may be single or multi-layered, coated with a suitable coating material well known in the art.
  • the oral liquid form of the compound of the present invention is preferably a solution or suspension in which the active compound is sufficiently dissolved or partially dissolved.
  • the solution comprises the active compound and a pharmaceutically acceptable solvent suitable for oral administration.
  • the solvent is a solvent which exhibits good solubility for the compounds of the present invention. These solvents typically comprise a major portion of the formulation, i.e., greater than 50% by weight, preferably greater than 80%, such as 95%.
  • the solution further comprises an adjuvant or an additive.
  • the additive or adjuvant is a taste masking agent, a palatant, a flavoring agent, an antioxidant, a stabilizer, a texture modifier, a viscosity modifier, and a solubilizer.
  • Another embodiment is a process for the preparation of a preferred oral liquid form of a compound of the invention (see the pharmaceutical composition portion) wherein, in a suitable temperature range, each preferred component is optionally mechanically agitated or in a manner which facilitates dissolution rate Mix by ultrasonic agitation.
  • the preparation of the compounds of the invention can be carried out according to methods of preparation well known to those skilled in the chemical arts. Unless otherwise specified, the definition of a general group is as defined above. Examples of the method of preparing the compounds of the present invention are provided by Example 1 and its description in the following specific embodiments.
  • the 24-week-old SD rats were treated with sham operation (Sham) or ovariectomy (OVX), and were randomly divided into groups of 8 animals after the recovery. Eight weeks after the rats received different interventions, the uterus of each animal was collected and the uterine weight was weighed. The femur of each animal was collected and the femur bone mineral density (Femur BMD) was measured.
  • ER-CL36 receptor in rat endometrium was determined by immunohistochemistry. Western blot was used to detect ER-a66 and ER-a36 in rat endometrium and distal femoral cancellous bone. Receptor protein expression.
  • Figure 1 Effect of compound ( ⁇ ) on femur bone density and uterine weight in rats.
  • Femur BMD femur bone mineral density, femur bone density; Uterine weight: subuterine weight. #P ⁇ 0.05, compared with the sham operation group; *P ⁇ 0.05, compared with the ovariectomy group.
  • A is the sham operation group
  • B is the ovariectomy group
  • C is the estradiol group
  • D is the raloxifene group
  • E is the compound ( ⁇ ) group.
  • Figure 4 Effect of compound ( ⁇ ) on the expression of ER-CL36 receptor protein in cancellous bone of distal femur.
  • 1 in Figure 3 and Figure 4 is the sham operation group; 2 is the oophorectomy group; 3 is the raloxifene group; 4 is the estradiol group; 5 is the compound ( ⁇ ) group.
  • the present invention relates to a compound of formula (I), and a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in the prevention and treatment of fractures and osteoporosis.
  • the compound of the example ( ⁇ ) is now taken as an example and will be described in detail.
  • the specific experimental method of this experiment is as described above.
  • the experiment was divided into 5 groups, namely sham operation group (Sham), ovariectomy group (OVX), estradiol group (E2), compound (II) group (compound (II)), and raloxifene group ( Ral);
  • the dose of the compound ( ⁇ ) is 100 ⁇ ⁇ /13 ⁇ 4.
  • ER-a36 protein was negatively expressed (Figure 2 and Figure 3).
  • the cancellous bone tissues of the distal femur of each group were extracted.
  • Western blot analysis showed that the expression of ER-a36 receptor protein in ovariectomized rats was significantly higher than that in other groups.
  • the ER-C136 receptor in estradiol rats The protein expression was less than that of the sham-operated group, and the expression of ER-CL36 receptor protein was significantly reduced in the raloxifene group and the compound ( ⁇ ) group (Fig. 4).

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Description

说明书
二羟基苯并吡喃酮化合物、 其药物组合物及其预防和治疗骨 折和骨质疏松的应用 技术领域
本发明涉及二羟基苯并吡喃酮类化合物的用途。本发明化合物适用于预防骨 折、降低骨折发生率以及骨折后促进损伤骨骼的修复，以及预防和治疗骨质疏松。 本发明还涉及包含这些化合物的药物组合物， 并且涉及使用所述化合物， 单独使 用或与其他药剂联合使用，预防骨折和促进骨折后损伤骨骼的修复， 以及预防和 治疗骨质疏松。
背景技术
雌激素是由体内内分泌系统产生的一种类固醇激素，在生殖系统、心血管系 统、 中枢神经系统、免疫系统和骨骼系统中都发挥着重要的作用。近年来的研究 表明， 雌激素通过细胞核途径和细胞膜途径两种信号转导通路发挥生物效应； 雌 激素及其受体信号转导系统广泛参与体内多个系统组织中细胞生长、分化和凋亡 过程。 已有大量研究证实雌激素受体 ( 存在于骨骼系统中，且其受体表达水平与 骨骼发育、 骨质疏松存在相关性； ER-α介导的信号转导途径很可能参与了骨质 疏松的形成和发展过程。
医学研究早已证实血清雌激素浓度低于特定水平时，将发生快速、持续的骨 丧失， 产生骨质疏松症。雌激素用于治疗骨质疏松症已有很多年。 临床观察发现 雌激素对减少绝经后的快速骨丢失、增加骨量、缓解骨质疏松造成的骨痛、 降低 骨折发生率具有肯定的疗效。大量研究还证实雌激素受体存在于骨骼系统中， 且 其受体表达水平与骨骼发育、骨质疏松存在相关性； 雌激素受体介导的信号转导 途径参与了骨质疏松的形成和发展过程。针对雌激素受体研发成功的选择性雌激 素受体调节剂，如雷诺西芬 (Raloxifene), 能够对骨骼系统表现出有效的雌激素激 动效应， 增加骨骼密度， 改善骨质疏松症。
目前研究证实雌激素受体分为 α和 β两种亚型； 其中 ER-ct包括三个同源异 构体 ER-a66、 ER-a46和 ER-a36。 异构体 ER-a36从位于 ER-a66基因的第一个 内含子中的启动子开始转录，利用 ER-(x66的部分外显子进行编码。因此， ER-CL36 缺失两个转录功能区， 保留了 DNA结合功能区和二聚化功能区； 更为重要的是 ER-a36 的激素配体结合区缺失了部分螺旋区， 从而完全改变了其与激素配体结 合的专一性和亲和力。 ER-CL36 主要分布于细胞膜和细胞浆中， 少量存在于细胞 核中。 ER-CL36可以通过雌激素的细胞膜信号转导途径调节细胞生长和凋亡（1. ZY，
Wang; XT, Zhang; P, Shen; BW, Loggie; YC, Chang; TF, Deuel. A variant of estrogen receptor-α, hER-a36: Transduction of estrogen- and antiestrogen- dependent membrane-initiated mitogenic signaling. PNAS. 2006, 103(24):9063-9068. 2. L， Lee; J, Cao; H, Deng; P, Chen; Z， Gatalica; ZY, Wang. ER-a36, a novel variant of ER-a, is expressed in ER-positive and -negative human breast carcinomas. Anticancer Res.
2008, 28(lB):479-483. )
发明内容
本发明的化合物用作调节 ER-ct和 ER-β生物信息系统， 可以用于预防和治 疗骨折和骨质疏松。
本发明涉及式 (I)的化合物， 及其药学上可接受的盐：
Figure imgf000004_0001
其中，
R1选自氢、 甲基、 乙基、 丙基、 异丙基；
R2、 R3和 R4彼此独立地选自氢、 卤素、 甲基、 乙基、 丙基、 异丙基、 羟基、 羧基；
R5选自氢、 卤素、 甲基、 乙基、 丙基、 异丙基、 羧基； 或者 R5是 OR6, 其 中 R6选自甲基、 乙基、 丙基、 异丙基。
在本发明的一个特别优选实施方案中， 式 (I)的化合物是： 2-(3-氯 -4-甲氧基 苯基) -5,7-二羟基 -8-(3-甲基 -2-丁烯基 -)-4H-苯并吡喃 -4-酮， 也即式 (I)的化合物具 有式 (Π)的结构:
Figure imgf000005_0001
(Π)
所述药物制剂， 包含式 （1 )、 ( I I ) 所述化合物或所述化合物的药学上可接 受的盐， 及药学上可接受的载体、 稀释剂或赋型剂。
所述药物组合物， 包含式 （1 )、 ( II ) 所述化合物或所述化合物的药学上可 接受的盐。
所述式 （1 )、 ( I I ) 化合物及其药学上可接受的盐在制备用于预防、 治疗骨 折和骨质疏松症药物中的应用。
所述式（1 )、 ( II )化合物及其药学上可接受的盐在制备受雌激素受体 ER-ct 或 ER-β亚型调控的相关疾病的药物中的应用， 所述 ER-ct亚型包括 ER-(x36， ER-a46禾口 ER-a66。
所述式 （1 )、 ( ID 化合物及其药学上可接受的盐是作为雌激素受体 ER-a 和 ER-β亚型的调节剂。
术语"式 (I)化合物"包括如这里定义的式 化合物以及这化合物的所有实施 方案， 优选实施方案， 更优选实施方案以及特别优选实施方案， 包括有具体名称 的或实施例中公开的化合物，这些化合物的每个都是通式定义的化合物的特别优 选实施方案。 关于"本发明的化合物"是指上述定义的式 (I)中的任何化合物。
本发明还涉及到本发明的化合物的盐， 多晶型物， 溶剂化物和水合物。 这里 使用的术语"药学上可接受的盐"， 除非另有所述， 包括可以在本发明的化合物中 存在的盐。
术语"卤素"或"卤"， 除非另外说明， 表示氟、 氯、 溴和碘基。
用于本发明的动词"治疗"， 除非另有所述， 是指逆转、 减轻、 抑制疾病或病 症的过程， 或预防这样的疾病或病症。 这里使用的名词"治疗"是指治疗的行为， 其中的治疗如上面所定义。
本发明还涉及一种药物组合物，所述的药物组合物包括式 (I)的化合物和一种 药学上可接受的载体。 例如， 药物组合物可以以片剂、 胶囊、 丸剂、 粉末、 缓释 剂、 溶液、 悬浮液的形式口服给药； 药物组合物也可以以无菌液、 悬浮液或乳液 的形式肠胃外注射给药； 药物组合物也可以以软膏或霜膏的形式局部给药； 药物 组合物也可以以栓剂的形式直肠给药。药物组合物可以做成单位剂型， 其适于精 确剂量的单一给药。药物组合物包括常规的药物载体或赋形剂和作为活性成分的 本发明的化合物。 另外， 药物组合物可以包括其它医学或药学制剂、 载体、 助剂 合适的药物载体包括惰性稀释剂或填料、水和各种有机溶剂。如果需要， 本 发明的药物组合物可以含有其它成分， 例如调味剂、 粘合剂、 赋形剂等等。 因此 对于口服给药， 片剂可以包含各种赋形剂， 例如可以使用柠檬酸和各种崩解剂例 如淀粉、褐藻酸和某些复杂的硅酸盐和粘合剂例如蔗糖、明胶和阿拉伯胶。另外， 片剂还可以包含经常在片剂中使用的润滑剂例如硬脂酸镁、十二烷基硫酸钠和滑 石粉。固体组合物的一个相似类型也可以使用软的和硬的填充胶囊。优选的材料 包括乳糖或奶糖和高分子量的聚乙二醇。当希望通过可口服给予本发明活性化合 物时，水悬浮液或酏剂可以与各种增甜剂或调味剂、色素或染料以及根据需要与 乳化剂或悬浮剂， 以及稀释剂例如水、 乙醇、 丙二醇、 甘油或其组合结合给药。
示范性的胃肠外给药形式包括活性化合物在无菌溶液中的溶液或悬浮液，例 如， 丙二醇或右旋糖水溶液。 如果需要， 这样的剂型可以适当地缓冲。 视情况而 定，本发明的含水组合物可以包括其它药学上可接受的溶质， 包括添加剂及其它 药物。合适的添加剂是本领域熟知的那些，包括但不限于，抗氧化剂、抗菌药物、 表面活性剂、螯合剂、糖、 以及防腐剂。本发明的含水组合物可以通过注射给药， 其中注射可以是肌肉注射、 静脉注射或皮下注射。
在给药的预定途径和标准药物操作方面，本发明的化合物可以单独给药， 但 常常与本领域公知的合适的药物赋形剂、稀释剂或载体一起给药。如果合适的话， 可以加入辅助剂， 所述的辅助剂包括防腐剂、 抗氧化剂、 调味剂、 或着色剂。 本 发明的化合物可以配制成合适的药物组合物， 以提供直接的、 延迟的、 改性的、 持久的、脉冲的或控制的释放， 取决于具体给药途径以及释放分布的特异性， 与 治疗需要相对应。
本发明的化合物可以按以下路线给药， 例如， 但不限于， 本领域公知的口服 (包括口腔、 舌下等等） 形式。 在这种情况下， "口服"是指口服给药方式， 其中 动物的口服使用量是明文规定的， 例如在食物或饮料中， 直接放入口腔中， 或者 是自由选择使用量。在本发明中， 术语"动物"是指动物界拥有适应性机能的温血 动物， 例如犬和人类。
典型的口服的固体形式可以包括片剂、 粉剂、 多微粒制剂 （颗粒）、 胶囊、 咀嚼剂、 锭剂、 膜剂、 贴片等等。 典型的口服液体（包括半固体和胶质）形式可 以包括溶液、 酏剂、 凝胶剂、 喷雾剂、 液体填充的咀嚼剂等等。 也可以使用其它 口服给药形式， 其中活性剂悬浮在液体或半固体载体相中， 例如悬浮液。
本发明的化合物还可以通过胃肠外给药。术语胃肠外给药是指给药路线不通 过口腔。 优选对于本发明的化合物， 胃肠外给药可以包括局部和经皮、 直肠、 阴 道、 鼻腔、 吸入和注射给药 （需要通过针和无针方法渗透皮肤屏障的给药方式， 包括植入物和储层）。
本发明的组合物包括片剂。在一种优选实施方案中， 片剂通过选自直接压片 或湿、 干或熔融造粒、 熔融凝结方法和挤出的方法制备。 在另一个实施方案中， 本发明的组合物的片剂核部分可以是单层或多层的，用本领域公知的合适包衣材 料进行包衣。
本发明化合物的口服液形式优选是溶液或悬浮液，其中活性化合物是充分溶 解或部分溶解的。在一种实施方案中， 溶液包含活性化合物和药学上有先例的适 于口服的溶剂。在一种优选实施方案中， 溶剂是一种对本发明的化合物显现出良 好溶解度的溶剂。这些溶剂通常占配方的主要部分， 即大于 50% (按重量计算）， 优选大于 80%， 例如 95%。 在一种优选实施方案中， 溶液进一步包含辅助剂或 添加剂。 在其一种优选的实施方案中， 添加剂或辅助剂是一种掩味剂、 可口剂、 调味剂、 抗氧化剂、 稳定剂、 质地改性剂、 粘度调节剂和增溶剂。
另一个实施方案是制备本发明化合物的优选口服液形式的方法（参见药物组 合物部分）， 其中在适宜温度范围内， 各个优选组分以一种有利于溶解速度的方 式任选通过机械搅拌或超声波搅拌混合。
本发明的化合物的制备可按照化学领域熟练技术人员公知的制备方法合成。 除非另有规定，一般基团的定义如前面定义。本发明化合物制备方法的实施例通 过下面的具体实施方法中的实施例 1及其说明提供。 24周龄 SD大鼠分别接受假手术（sham operation, Sham)或者卵巢切除手术 (ovariectomy, OVX)处理， 待大鼠术后恢复健康后随机分组， 每组 8只动物。 大 鼠接受不同干预措施 8周后采集各只动物子宫并称量子宫重量 (uterine weight), 采集各只动物股骨并测定股骨骨密度 (femur bone mineral density, Femur BMD)。 采用免疫组化方法对大鼠子宫内膜中 ER-CL36 受体表达情况进行测定， 采用 Western blot方法检测大鼠子宫内膜和股骨远端松质骨组织中 ER-a66和 ER-a36 两种受体蛋白表达量。
附图说明
图 1化合物 (Π)对大鼠股骨骨密度和子宫重量的影响。
1， 假手术组； 2， 卵巢切除组； 3， 雌二醇组； 4， 雷诺昔芬组； 5， 化合物 （II) 组。 Femur BMD: femur bone mineral density, 股骨骨密度； Uterine weight: 子 宫重量。 #P<0.05， 与假手术组比较； *P<0.05， 与卵巢切除组比较。
图 2 化合物 (Π)对子宫内膜 ER-CL36受体表达的影响。
其中 A为假手术组， B为 卵巢切除组， C为雌二醇组， D为雷诺昔芬组， E为 化合物 (Π)组。
图 3化合物 (Π)对子宫内膜 ER-CL36受体蛋白表达的影响。
图 4化合物 (Π)对股骨远端松质骨 ER-CL36受体蛋白表达的影响。
其中图 3、 图 4中的 1为假手术组； 2为卵巢切除组； 3为雷诺昔芬组； 4为雌二 醇组； 5为化合物 (Π)组。
具体实施方法
下面的实施例说明制备本发明的化合物的方法。应该理解， 本发明并不受下 面提供的具体内容的限制。
实施例 1
Figure imgf000008_0001
(Π) 2-C3-氯 -4-甲氧基苯基) -5，7-二羟基 -8- 3-甲基 -2-丁烯基 )-4H-苯并吡喃 -4-酮 （化合 物 （Π))的制备：
(1) 在 0°C条件下将乙酰氯 （16.5g， 210mmol)加入含有 1-氯 -2-苯甲醚 (10.0g， 70.1mmol)和三氯化铝 (28.0g， 210mmol)的二氯甲烷 (150ml)中， 室温下搅拌 12小 时； 将混合液倒入冰水中， 用二氯甲烷萃取。用饱和的含水碳酸氢钠和卤水清洗 萃取的有机相， 用硫酸镁干燥， 减压浓縮得到 3-氯 -4-甲氧基苯乙酮为白色固体 物 (12.8g， 99%产率）。 LCMS(ESI): m/z 185 [M+H]+。
(2) 将氢化钠 （8.5g， 0.21mol,) 加入含有 3-氯 -4-甲氧基苯乙酮 （26.0g， 0.141mol) 的无水二噁烷 （150ml)中， 搅拌 30分钟， 加入碳酸二甲酯 C20.0g， 0.23mol), 回流 搅拌 4 小时。 将棕色反应液倒入水 (600ml)中， 过滤橙色沉淀并用乙酸乙酯和石 油醚 (v/v=10: l)清洗， 得到淡黄色固体 (26.5g， 77%产率）。 LCMS(ESI): m/z 257 [M+H]+。
(3) 将前述 (2)反应得到的淡黄色固体 (12.2g， 50mmol)和 1，3，5-三羟基苯 （8.1g， 50mmol) 混合后在微波反应器中反应 (160°C， 运行 1分钟保持 3分钟)三次。 用 乙酸乙酯稀释反应介质，滤过后得到反应产物 (3.2g， 20.2%产率)。 1HNMR(400M, DMSO-J6) δ=12.84 (s, 1H), 10.89 (brs, 1H, 8.15 (d， J=2.0 Hz, 1H), 8.04 (dd， =2.0 Hz, J2=8.8 Hz, 1H), 7.30 (d， /=8.8， 2H), 6.96 (s， 1H), 6.53 (d， J=2.0 Hz, 1H), 6.20 (d， J=2.0 Ηζ,ΙΗ), 3.95 (s， 3H); LCMS(ESI): m z 319 [M+H]+。
(4) 将 N，N-二异丙基乙胺 C3.3g， 25.8mmol)加入含有前述 C3)反应产物 C6.8g， 21.5mmol) 的二甲基甲酰胺 (80ml)中， 再加入氯甲基甲醚 (2.10g， 26.0mmol)后室 温下搅拌 4 小时； 反应介质倒入水 (400ml)中， 滤过后得到不需纯化即可使用的 棕色粗产物。 1HNMR(400M, DMSO-J6) δ=12.79 (s, 1H), 8.15 (d, /=2.0 Hz, 1H)， 8.04 (dd， /尸 2.0 Hz, J2=8.4 Hz, 1H), 7.27 (d， J=8.4, 1H), 7.00 (s, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.0 Ηζ, ΙΗ), 5.31 (s， 2H), 3.95 (s， 3H), 3.41 (s， 3H); LCMS(ESI): m z 363 [M+H]+。
(5) 将浓度为 10%的四丁基氢氧化铵 (200.0g， 43mmol)溶液加入含有前述 (4)反应 得到的粗产物 (7.8g， 21.5mmol)的二氯甲烷 (100ml)和甲苯 (100ml)混合液中， 再加 入 1-溴 -3-甲基 -2-丁烯 (12.5g， 86mmol);混合物在室温下反应 3小时，用水 (100ml) 稀释反应介质， 再用乙酸乙酯萃取后再硅胶上层析得到产物 (4.5g， 48%产率)。 1HNMR(400M, CDC13) δ=7.91 (d, J=2.0 Hz, 1H)， 7.74 (dd， Λ=2.4 Hz, /2=8.8 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H)， 6.77 (d, J=2.0 Hz, 1H)， 6.57 (s, 1H)， 6.47 (d, J=2.4Hz, lH), 5.58 (t， J=6A Hz, 1H), 5.27 (s， 2H), 4.67 (d， J=6A Hz, 1H), 3.98 (s， 3H), 3.54 (s， 3H); LCMS(ESI): m/z 431 [M+H]+。
(6) 前述 (5)反应产物 (4.5g， 10.4mmol)和 N，N-二乙苯胺 (400ml)混合后于 217 °C搅 拌 3小时，冷却后混合物加入稀盐酸中， 滤过后得到的固体再用醋酸乙酯和石油 醚（v/v=l : l)混合液重结晶得到反应产物（1.6g， 35.6% yield). 1HNMR(400M, acetone-J6) δ=12.87 (s， 1H), 8.09 (s， 1H), 8.04 (d， J=8.8, 1H), 7.35 (d， J=8.8, 1H)， 6.78 (s, 1H), 6.58 (s, 1H), 5.39 (s, 1H), 5.26 (t, /=6.8， 1H), 4.04 (s, 3H), 3.59 (d, J=6.4 Hz, 2H), 3.49 (s， 3H), 1.87 (s， 3H), 1.69 (s， 3H); LCMS(ESI): m/z 431 [M+H]+.
(7) 于 20 °C时，将前述 (6)反应产物 (0.5g， 2.0mmol)溶于二氯甲烷 (20ml)和乙酸 (20ml)中， 加入浓盐酸 (0.15mL)后维持 20°C搅拌 18小时。 过滤混合液得到橙色 固体，用饱和碳酸氢钠漂洗后得到 2-(3-氯 -4-甲氧基苯基) -5,7-二羟基 -8-(3-甲基 -2- 丁烯基 )-4H-苯并吡喃 -4-酮 （化合物 （Π》为黄色粉末 (0.32g， 41.5 %产率）。 1HNMR(400M, DMSO-J6) δ=12.77 (s, 1H), 10.86 (s, 1H), 8.06 (s, 1H), 8.01 (d, J=8.8, 1H), 7.33 (d， J=8.8, 1H), 6.95 (s, 1H), 6.31 (s, 1H), 5.16 (t， J=6A, 1H), 3.95 (s， 3H), 3.43 (d, J=6.4 Hz, 2H), 1.78 (s, 3H), 1.64 (s, 3H); LCMS(ESI): m/z 387 [M+H]+。
实验例 2 式 (I)化合物的生物实验
前面已经描述了本发明涉及式 (I)化合物及其药学上可接受的盐或药物组合 物适用于预防和治疗骨折和骨质疏松。 现以实施例化合物 (Π)为例， 对其进行详 细说明。
(1) 本实验具体实验方法如前所述。实验分为 5组，分别是假手术组 (Sham), 卵巢切除组 (OVX)，雌二醇组 (E2)，化合物 (II)组 (化合物 (II))，雷诺昔芬 (raloxifene) 组 (Ral); 化合物 (Π)所用剂量是 100μ§/1¾。
(2) 实验结果： 通过实验发现卵巢切除后大鼠股骨密度和子宫重量均比假手 术组大鼠显著减少， 化合物 (Π)可以显著增加大鼠股骨的骨密度， 同时化合物 (Π) 对大鼠子宫重量无明显影响（图 1 )。 免疫组化和 Western blot检测发现假手术组 和卵巢切除组大鼠子宫内膜腺体 ER-CL36蛋白表达阳性； 雷诺昔芬组大鼠子宫内 膜腺体 ER-CL36 蛋白有微弱表达； 雌二醇组和化合物 (Π)组大鼠子宫内膜腺体
ER-a36 蛋白呈阴性表达 （图 2 和图 3 )。 提取各组大鼠股骨远端松质骨组织， Western blot检测显示卵巢切除组大鼠的 ER-a36受体蛋白表达量明显多于其他各 组， 雌二醇组大鼠的 ER-C136受体蛋白表达量少于假手术组， 雷诺昔芬组和化合 物 (Π)组大鼠的 ER-CL36受体蛋白表达量明显减少 （图 4)。

Claims

权利要求书
1. 式 （I ) 的化 上可接受的盐:
Figure imgf000012_0001
( I )
其中，
R1选自氢、 甲基、 乙基、 丙基、 异丙基；
R2、 R3和 R4彼此独立地选自氢、 卤素、 甲基、 乙基、 丙基、 异丙基、 羟基、 羧基；
R5选自氢、 卤素、 甲基、 乙基、 丙基、 异丙基、 羧基； 或者 R5是 OR6, 其 中 R6选自甲基、 乙基、 丙基、 异丙基。
2. 根据权利要求 1， 所述式（I)化合物中的 R1是甲基， R2是氯， R3、 R4和 R5都是氢； 也即权利要求 1所述的化合物是具有式（Π)结构的化合物或其药学 上可接受的盐：
Figure imgf000012_0002
(II)
3.一种药物制剂，包含选自权利要求 1-2任一项所述化合物或所述化合物的 药学上可接受的盐， 及药学上可接受的载体、 稀释剂或赋型剂。
4. 一种药物组合物， 包含选自权利要求 1-2任一项所述化合物或所述化合 物的药学上可接受的盐。
5.权利要求 1-2任一项所述化合物及其药学上可接受的盐在制备用于预防、 治疗骨折和骨质疏松症药物中的应用。
6. 权利要求 1-2任一项所述化合物及其在药学上可接受的盐在制备受雌激 素受体 ER-ct或 ER-β亚型调控的相关疾病的药物中的应用。
7. 根据权力要求 6任一所述的应用， 所述 ER-α亚型包括 ER-a36， ER-a46 禾口 ER-a66。
8. 根据权利要求 7任一所述的应用， 所述式 （I ) 或式 （Π) 化合物及其药 学上可接受的盐是作为雌激素受体 ER-a和 ER-β亚型的调节剂。
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