WO2020030089A1 - 苯并间二氧杂环戊烯衍生物在治疗与胃肠蠕动障碍相关疾病中的应用 - Google Patents

苯并间二氧杂环戊烯衍生物在治疗与胃肠蠕动障碍相关疾病中的应用 Download PDF

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WO2020030089A1
WO2020030089A1 PCT/CN2019/099941 CN2019099941W WO2020030089A1 WO 2020030089 A1 WO2020030089 A1 WO 2020030089A1 CN 2019099941 W CN2019099941 W CN 2019099941W WO 2020030089 A1 WO2020030089 A1 WO 2020030089A1
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gastrointestinal motility
pharmaceutically acceptable
medicament
acceptable salt
compound
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French (fr)
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赵旭阳
刘礼飞
冯仁田
龚永祥
李译
李琪
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浙江海正药业股份有限公司
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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
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Definitions

  • the invention belongs to the field of medicine and specifically relates to the application of benzo-dioxolene derivatives in the treatment of diseases related to gastrointestinal motility disorders.
  • Gastrointestinal movement is a complex, highly coordinated neuromuscular activity controlled by the autonomic nervous system, hormones, and the high-level central nervous system. Gastrointestinal motility disorders are clinically manifested as dyspepsia, bloating, nausea, and vomiting, and can cause reflux of the stomach and esophagus, causing esophageal ulcers, and severe cases can be life threatening.
  • the drugs used clinically to promote gastrointestinal motility include DA receptor antagonists such as domperidone, 5-HT4 receptor agonists such as mosapride, and motilin receptor agonists such as erythromycin. Although these drugs have a certain promotive effect, the lower symptom relief rate and adverse drug reactions have limited their application in clinical practice, so it is urgent to develop new promotive agents.
  • acetylcholinesterase inhibitors can prevent the degradation of acetylcholine, that is, it can increase the content of acetylcholine in the stomach and intestinal tissues, thereby promoting gastrointestinal motility and enhancing gastrointestinal motility. Therefore, acetylcholinesterase inhibitors can be considered for the treatment of diseases associated with gastrointestinal motility disorders, such as functional dyspepsia (FD).
  • FD functional dyspepsia
  • acetylcholinesterase inhibitor drugs currently used clinically to treat Alzheimer's disease such as donepezil, taclaline, carbaplatin, and galantamine, have not been used to treat gastrointestinal disorders.
  • FD functional dyspepsia
  • acotinide is the only acetylcholinesterase inhibitor drug used to treat functional dyspepsia (FD). It can be seen that the use of acetylcholinesterase inhibitors for the treatment of gastrointestinal motility disorders is not obvious.
  • a first aspect of the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as shown below in the manufacture of a medicament for treating a disease associated with gastrointestinal motility disorders, wherein the medicament is passed Promote the function of gastrointestinal motility,
  • a second aspect of the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention in the treatment of diseases associated with gastrointestinal motility disorders.
  • a third aspect of the present invention provides the use of a pharmaceutical composition in the manufacture of a medicament for treating a disease associated with gastrointestinal motility disorders, wherein the medicament functions by promoting gastrointestinal motility, and the pharmaceutical composition Including a compound of formula (I) or a pharmaceutically acceptable salt thereof as shown below, and a pharmaceutically acceptable carrier,
  • a fourth aspect of the present invention provides the use of the pharmaceutical composition according to the third aspect of the present invention in the treatment of diseases associated with gastrointestinal motility disorders.
  • a fifth aspect of the present invention provides a pharmaceutical composition for treating a disease related to gastrointestinal peristalsis, and the pharmaceutical composition is the pharmaceutical composition according to the third aspect of the present invention.
  • a sixth aspect of the present invention provides a method for treating a gastrointestinal motility-related disease, comprising using the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof (as described in the first aspect of the present invention) Or administration to a subject using a pharmaceutical composition (as described in the third aspect of the invention) comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable salt may be a salt formed by a compound of formula (I) with a suitable inorganic or organic acid.
  • the type of acid includes, but is not limited to, acetic acid, benzenesulfonic acid, Benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, formazan Sulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, benzoic acid, p-toluenesulfonic acid, etc .; inorganic acids are preferably used.
  • the pharmaceutically acceptable salt may be a hydrochloride or a phosphate; most preferably a compound of the following formula (I '):
  • the disease related to gastrointestinal motility disorder can be any disease caused by gastrointestinal motility disorder, and can also be any disease including one or more symptoms related to gastrointestinal motility disorder, including But it is not limited to functional dyspepsia (FD), postoperative intestinal obstruction, constipation, etc.
  • FD functional dyspepsia
  • constipation constipation
  • the compound of formula (I) or a pharmaceutically acceptable salt, pharmaceutical composition or medicament thereof may be administered 1-3 times a day.
  • the compound of formula (I) or a pharmaceutically acceptable salt, pharmaceutical composition or medicament thereof may be administered by an oral route, a duodenal route, parenteral injection (including intravenous (Intradermal, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical, rectal administration and so on.
  • parenteral injection including intravenous (Intradermal, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical, rectal administration and so on.
  • the compound of formula (I) or a pharmaceutically acceptable salt, pharmaceutical composition or medicament can be made into tablets, capsules, pills, powders, granules, powders, lozenges, solutions, suspensions Liquid and other dosage forms; can be made into conventional dosage forms, can also be made into sustained-release preparations or controlled-release preparations.
  • the pharmaceutical composition or medicament contains an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the pharmaceutically acceptable carrier refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound of formula (I) or a pharmaceutically acceptable salt thereof into a cell Or tissues, including but not limited to stabilizers, diluents, dispersants, suspending agents, thickeners, excipients, emulsifiers, wetting agents, flavoring agents, and the like.
  • the pharmaceutical composition or medicament may further contain other active ingredients in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the other active ingredient may be an acetylcholine ester
  • the enzyme inhibitor may also be a non-acetylcholinesterase inhibitor, as long as it can play an active role in combination with the compound of formula (I) or a pharmaceutically acceptable salt thereof without significant toxicity.
  • the present inventors have found that although the compound of formula (I) or a pharmaceutically acceptable salt thereof is a relatively weak acetylcholinesterase inhibitor, it can be very effective in treating diseases related to gastrointestinal motility disorders, such as functional dyspepsia Moreover, the dosage is significantly lower than the existing acetylcholinesterase inhibitors, such as acotamide, which has low toxicity and higher drug safety.
  • Figure 1 shows the effect of AD-35 on clonidine-induced delayed gastric emptying in mice. ###: p ⁇ 0.001 vs. blank control (Control), *: p ⁇ 0.05 vs. Model, **: p ⁇ 0.01 vs Model.
  • Figure 2 shows the effect of AD-35 on clonidine-induced delayed gastric emptying in rats, ###: p ⁇ 0.001 vs Control, *: p ⁇ 0.05 vs Model, **: p ⁇ 0.01 vs Model.
  • Figure 3 shows the improvement effect of compound AD-35 on loperamide-induced delayed intestinal advancing in mice, ###: p ⁇ 0.001 vs Control, *: p ⁇ 0.05 vs Model, **: p ⁇ 0.01 vs Model.
  • subject refers to individuals suffering from a disease, disorder, or condition, etc., and includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the Mammalia class: humans, non-human primates (such as chimpanzees and other apes and monkeys); domestic animals, such as cattle, horses, sheep, goats, pigs; domestic Animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs.
  • non-human mammals include, but are not limited to, birds, fish, and the like.
  • treating includes alleviating, reducing or ameliorating the symptoms of a disease or disorder, preventing other symptoms, ameliorating or preventing the underlying metabolic cause of the symptoms, inhibiting the disease or disorder, such as preventing the development of the disease or disorder, Alleviates a disease or condition, improves the disease or condition, alleviates the symptoms caused by the disease or condition, or suspends the symptoms of the disease or condition, and further, the term encompasses the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and / or a preventive effect.
  • the therapeutic effect refers to the cure or amelioration of the underlying disease being treated.
  • the cure or improvement of one or more physiological symptoms associated with the underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the drug may be administered to a patient at risk of developing a specific disease, or even to a patient who has one or more physiological symptoms of the disease even if no diagnosis of the disease has been made.
  • the term "effective dose” refers to an amount of at least one drug or compound or pharmaceutical composition sufficient after administration to adequately alleviate one or more symptoms of the disease or condition being treated. The result can be the reduction and / or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound, and is relatively non-toxic, that is, the substance can be administered to an individual without causing an adverse biological reaction or Interact with any of the components contained in the composition in an undesirable manner.
  • the chemical name of the compound AD-35 used in the examples is: 6- [2- [1- (2-pyridylmethyl) -4-piperidinyl] ethyl] spiro [[1,3] dioxane Penteno [4,5-f] isoindole-7,1'-cyclopropane] -5-one phosphate was synthesized with reference to WO2014005421A1 and WO2017177816A1.
  • the ICR mice used in the examples were purchased from Viton Lee Hua.
  • the SD rats used in the examples were purchased from Viton Lee Hua.
  • the model of the microplate reader used in the examples is MD5, MD, USA.
  • clonidine, acotidine, and loperamide used in the examples were purchased from Sigma, and the other reagents were all commercially available products unless otherwise specified.
  • mice Male ICR mice were randomly divided into groups according to body weight (25-32g), 20 mice in each group, and fasted for 24 hours.
  • drug group drug and dosages are shown in Fig. 1
  • the model group and the blank control group were given normal saline 55 minutes later
  • the model animal except the blank control group
  • clonidine 0.1 mg / kg
  • a 0.05% phenol red solution 0.4 ml / head
  • mice were sacrificed 30 minutes later. Take out the stomach and place it in 10ml 0.1M NaOH solution, cut the stomach tissue with scissors to release the stomach contents.
  • Gastric emptying rate (%) (1-sample phenol red content / standard sample phenol red content) ⁇ 100%.
  • the test results show that clonidine can significantly delay the gastric emptying effect of ICR mice; the control drug acotamide (100mg / kg) can significantly improve the delayed gastric emptying of mice induced by clonidine; AD-35 (1mg / kg) can significantly improve the delay of gastric emptying induced by clonidine in mice, and the dosage is less than that of acortimine. Obviously, the efficacy of AD-35 is much better than that of acoltide (as shown in Figure 1).
  • the model group and the blank control group were given normal saline 55 minutes later, the experimental animal (except the blank control group) was injected subcutaneously with clonidine (0.2 mg / kg) ), 5 minutes later, the rats were given a 0.05% phenol red solution (1.6 ml / head) by gavage, and 30 minutes later, the rats were sacrificed by cervical dislocation. Take out the stomach and place it in 50ml 0.1M NaOH solution. Cut the stomach tissue with scissors to release the stomach contents.
  • Gastric emptying rate (%) (1-sample phenol red content / standard sample phenol red content) ⁇ 100%.
  • test results show that clonidine can significantly delay the gastric emptying effect of SD rats; the control drug acotamide (100mg / kg) can significantly improve the delayed gastric emptying of rats induced by clonidine; AD-35 5mg / kg Both the 10 mg / kg and 10 mg / kg doses significantly improved delayed gastric emptying in rats induced by clonidine.
  • the efficacy of AD-35 is also far better than that of acortimine (as shown in Figure 2).
  • mice Male ICR mice (25-32g) were injected subcutaneously with loperamide (5mg / kg) once a day for 7 consecutive days to make a model (the blank control group was not injected with loperamide). On the seventh day, a plastic ball with a diameter of 3 mm was pushed into the rectum of the mouse by 3 cm, and the time when the plastic ball was discharged from the rectum was observed and recorded. Mice were randomly divided into groups according to the time when the plastic ball was excreted from the rectum, 20 mice in each group. On the second day after the grouping (denoted as day1), mice of different administration groups were administered orally with different doses of AD-35 (as shown in FIG. 3, once a day).
  • mice in each administration group were continuously given different doses of AD-35 on day1-day6 (model group and blank control group were given physiological saline), and loperamide (5mg / kg) was injected 30 minutes after each administration (model group injection The same dose of loperamide, the blank control group was not injected); after fasting for 4 hours on day 7, mice of different administration groups were given different doses of AD-35 by gavage (the model group and the blank control group were given normal saline). After 30 min, loperamide (5 mg / kg) was injected subcutaneously (except for the blank control group). After 30 min of loperamide injection, the plastic ball was pushed into the rectum of the mouse 3 cm, and the time when the plastic ball was discharged from the rectum was observed and recorded.
  • AD-35 is a relatively weak acetylcholinesterase inhibitor and is currently in a phase II clinical trial for Alzheimer's disease.
  • AD-35 is extremely safe at high doses (eg 120 mg).
  • AD-35 is a relatively weak acetylcholinesterase inhibitor, it has an excellent effect on promoting gastrointestinal motility.
  • the animal experiments of Examples 1-3 show that AD-35 (1 mg / kg) can significantly improve the gastric emptying delay induced by clonidine in mice, and is superior to acortimine (100 mg / kg). Therefore, AD-35 can be very effective in treating diseases related to gastrointestinal motility disorders, such as functional dyspepsia (FD).
  • FD functional dyspepsia

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Abstract

式(I)所示的苯并间二氧杂环戊烯衍生物、或其药学上可接受的盐及其药物组合物在治疗与胃肠蠕动障碍相关疾病中的应用。式(I)化合物或其药学上可接受的盐可以非常有效地治疗与胃肠蠕动障碍相关的疾病，而且毒性低，用药安全性更高。

Description

苯并间二氧杂环戊烯衍生物在治疗与胃肠蠕动障碍相关疾病中的应用 技术领域
本发明属于医药领域，具体涉及苯并间二氧杂环戊烯衍生物在治疗与胃肠蠕动障碍相关疾病中的应用。
背景技术
胃肠道的运动是一种复杂、高度协调的神经肌肉活动，由自主神经系统、激素以及高级中枢神经控制。胃肠动力障碍临床表现为易饱、腹胀、恶心、呕吐等消化不良症状，并可引起胃、食管反流，导致食管溃疡，严重者可威胁生命。临床上用于促进胃肠动力的药物主要有DA受体拮抗剂如多潘立酮、5-HT4受体激动剂如莫沙必利、胃动素受体激动剂如红霉素。虽然这些药物具有一定的促动力效应，但是较低的症状缓解率及药物不良反应，限制了其在临床实践中的应用，因此亟待研制新型的促动力剂。
由于乙酰胆碱酯酶抑制剂可以阻止乙酰胆碱的降解，即可以提高胃部和肠道组织中乙酰胆碱的含量，从而有促进胃肠蠕动、增强胃肠动力的作用。因此，乙酰胆碱酯酶抑制剂可以被考虑用于治疗与胃肠蠕动障碍相关的疾病，如功能性消化不良(FD)。然而，目前在临床上使用的治疗阿尔茨海默氏症的乙酰胆碱酯酶抑制剂药物，如多奈哌齐、他克林、卡巴拉汀和加兰他敏，均没有被用于治疗与胃肠蠕动障碍相关的任何疾病，包括功能性消化不良(FD)，因为这些乙酰胆碱酯酶抑制剂都有很强的副作用。到目前为止，阿考替胺是唯一一个用于治疗功能性消化不良(FD)的乙酰胆碱酯酶抑制剂药物。由此可见，将乙酰胆碱酯酶抑制剂用于治疗与胃肠蠕动障碍相关的疾病，并非是显而易见的。
发明内容
本发明的第一个方面提供了如下所示的式(I)化合物或其药学上可接受的盐在制备用于治疗与胃肠蠕动障碍相关的疾病的药物中的应用，其中所述药物通过促进胃肠蠕动发挥作用，
Figure PCTCN2019099941-appb-000001
本发明的第二个方面提供了本发明第一个方面所述的式(I)化合物或其药学上可接受的盐在治疗与胃肠蠕动障碍相关的疾病中的应用。
本发明的第三个方面提供了一种药物组合物在制备用于治疗与胃肠蠕动障碍相关的疾病的药物中的应用，其中所述药物通过促进胃肠蠕动发挥作用，所述药物组合物包括如下所示的式(I)化合物或其药学上可接受的盐，以及药学上可接受的载体，
Figure PCTCN2019099941-appb-000002
本发明的第四个方面提供了本发明第三个方面所述的药物组合物在治疗与胃肠蠕动障碍相关的疾病中的应用。
本发明的第五个方面提供了一种用于治疗与胃肠蠕动障碍相关的疾病的药物组合物，所述药物组合物为本发明第三个方面所述的药物组合物。
本发明的第六个方面提供了一种与胃肠蠕动障碍相关的疾病的治疗方法，包括使用前述式(I)化合物或其药学上可接受的盐(如本发明第一个方面所述)、或者使用包含所述式(I)化合物或其药学上可接受的盐的药物组合物(如本发明第三个方面所述)向受试者进行施用。
在根据本发明的一些实施方案中，所述药学上可接受的盐可以为式(I)化合物与合适的无机酸或有机酸形成的盐，酸的种类包括但不限于乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、苹果酸、马来酸、扁桃酸、甲磺酸、硝酸、磷酸、琥珀酸、硫酸、酒石酸、苯甲磺酸、对苯甲磺酸等；优选使用无机酸。
在根据本发明的一些优选的实施方案中，所述药学上可接受的盐可以为盐酸盐或磷酸盐；最优选如下式(I’)的化合物：
Figure PCTCN2019099941-appb-000003
在根据本发明的一些实施方案中，所述与胃肠蠕动障碍相关的疾病可以为胃肠蠕动障碍引起的任何疾病，也可以为包括一个或多个胃肠蠕动障碍相关症状的任何疾病，包括但不限于功能性消化不良(FD)、术后肠梗阻、便秘等。
在根据本发明的一些实施方案中，所述式(I)化合物或其药学上可接受的盐、药物组合物或药物可按每天1-3次施用。
在根据本发明的一些实施方案中，所述式(I)化合物或其药学上可接受的盐、药物组合物或药物可通过口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用、经直肠给药等方式进行施用。
在根据本发明的一些优选的实施方案中，通过口服施用；更优选地，在进餐前口服施用。通过口服施用时，所述式(I)化合物或其药学上可接受的盐、药物组合物或药物可制成片剂、胶囊剂、丸剂、粉剂、颗粒剂、散剂、锭剂、溶液、悬浮液等剂型；可制成常规剂型，也可制成缓释制剂或控释制剂。
在根据本发明的一些实施方案中，所述药物组合物或药物中含有有效剂量的所述式(I)化合物或其药学上可接受的盐。
在根据本发明的一些实施方案中，所述药学上可接受的载体是指相对无毒的化学化合物或试剂，其有助于将式(I)化合物或其药学上可接受的盐引入到细胞或组织中，包括但不限于稳定剂、稀释剂、分散剂、悬浮剂、增稠剂、赋形剂、乳化剂、润湿剂、矫味剂等。
在根据本发明的一些实施方案中，所述药物组合物或药物中还可含有其他活性成分与所述式(I)化合物或其药学上可接受的盐联合作用，其他活性成分可以为乙酰胆碱酯酶抑制剂，也可以为非乙酰胆碱酯酶抑制剂，只要能与所述式(I)化合物或其药学上可接受的盐联合发挥活性作用且无明显毒性即可。
本发明人发现，式(I)化合物或其药学上可接受的盐虽然为相对较弱的乙酰胆碱酯酶抑制剂，但可以非常有效地治疗与胃肠蠕动障碍相关的疾病，如功能性消化不良，而且用药量明显低于现有的乙酰胆碱酯酶抑制剂，如阿考替胺，毒性低，用药安全性更高。
附图说明
图1显示AD-35对可乐定诱导的小鼠胃排空延迟的改善作用，###:p＜0.001vs空白对照(Control),*：p＜0.05vs模型(Model),**：p＜0.01vs Model。
图2显示AD-35对可乐定诱导的大鼠胃排空延迟的改善作用，###:p＜0.001vs Control,*：p＜0.05vs Model,**：p＜0.01vs Model。
图3显示化合物AD-35对洛哌丁胺诱导小鼠肠道推进延迟的改善作用，###:p＜0.001vs Control,*：p＜0.05vs Model,**：p＜0.01vs Model。
具体实施方式
药学术语
本文所用的有关术语“受试者”是指患有疾病、病症或病况等的个体，包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员：人，非人的灵长类动物(例如黑猩猩和其它猿类和猴)；家畜，例如牛、马、绵羊、山羊、猪；家养动物，例如兔、狗和猫；实验室动物，包括啮齿类动物，例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状，预防其它症状，改善或预防导致症状的潜在代谢原因，抑制疾病或病症，例如阻止疾病或病症的发展，缓解疾病或病症，使疾病或病症好转，缓解由疾病或病症导致的症状，或者中止疾病或病症的症状，此外，该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外，对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果，例如尽管患者可能仍然受到潜在疾病的影响，但观察到患者情况改善。就预防效果而言，可向具有患特定疾病风险的患者施用所述药物，或者即便尚未做出疾病诊断，但向出现该疾病的一个或多个生理症状的患者施用所述药物。
本文所使用术语“有效剂量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药物或化合物或药物组合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物系统的任何其它所需变化。
本文所用术语“药学上可接受的”是指不影响化合物的生物活性或性质的物质(如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
以下结合实施例进一步描述本发明。
实施例中使用的化合物AD-35化学名称为：6-[2-[1-(2-吡啶甲基)-4-哌啶基]乙基]螺环 [[1,3]二氧杂环戊烯并[4,5-f]异吲哚-7,1'-环丙烷]-5-酮磷酸盐，参照WO 2014005421A1和WO 2017177816A1合成。
实施例中使用的ICR小鼠购自维通利华。
实施例中使用的SD大鼠购自维通利华。
实施例中使用的酶标仪型号为MD5，美国MD公司。
实施例中使用的可乐定、阿考替胺、洛哌丁胺均购自Sigma，其他试剂如无特殊说明均为市售产品。
实施例中使用的溶液如无特殊说明均为质量百分比浓度。
实施例1化合物AD-35对可乐定诱导的小鼠胃排空延迟的改善作用
雄性ICR小鼠按体重(25-32g)随机分组，每组20只，禁食24h。药物组给药(药物和剂量如图1所示，模型组和空白对照组给予生理盐水)55min后，在试验动物(空白对照组除外)皮下注射造模剂可乐定(0.1mg/kg)，5min后再灌胃给予0.05％的酚红溶液(0.4ml/只)，并于30min后处死小鼠。取出胃并置于10ml 0.1M NaOH溶液中，用剪刀剪碎胃组织以释放胃内容物，5000rpm离心10min后，取1ml上清液，加入0.1ml 20％的三氯乙酸，5000rpm离心20min，取0.5ml上清液，将0.2ml 0.5M NaOH溶液加入其中，充分混匀，然后取上清液于MD5酶标仪560nm处检测OD值；另取0.4ml酚红溶液置于10ml 0.1M NaOH溶液中，充分混匀，同样于560nm处检测OD值，得到标准样本酚红含量，即0％的胃排空率。按照下式计算胃排空率：
胃排空率(％)＝(1-样本酚红含量/标准样本酚红含量)×100％。
试验结果表明：可乐定能够显著延迟ICR小鼠的胃排空作用；对照药阿考替胺(100mg/kg)可显著改善由可乐定诱导的小鼠胃排空延迟；AD-35(1mg/kg)能够极其显著地改善由可乐定诱导的小鼠胃排空延迟，而且用药量小于阿考替胺用药量。显然，AD-35的药效远优于阿考替胺(如图1所示)。
实施例2化合物AD-35对可乐定诱导的大鼠胃排空延迟的改善作用
雄性SD大鼠按体重(220-260g)随机分组，每组20只，禁食24h。药物组给药(如图2所示剂量灌胃给药，模型组和空白对照组给予生理盐水)55min后，在试验动物(空 白对照组除外)皮下注射造模剂可乐定(0.2mg/kg)，5min后再灌胃给予0.05％的酚红溶液(1.6ml/只)，并于30min后采用颈椎脱臼法处死大鼠。取出胃并置于50ml 0.1M NaOH溶液中，用剪刀剪碎胃组织以释放胃内容物，5000rpm离心10min后，取1ml上清液，将0.1ml 20％三氯乙酸加入其中，然后5000rpm离心20min，取0.5ml上清液，将0.2ml0.5M NaOH溶液加入其中，充分混匀，取上清液于MD5酶标仪560nm处检测OD值；另取1.6ml酚红溶液置于50ml 0.1M NaOH溶液中，充分混匀，同样于560nm处检测OD值，得到标准样本酚红含量，即0％的胃排空率。按照下式计算胃排空率：
胃排空率(％)＝(1-样本酚红含量/标准样本酚红含量)×100％。
试验结果表明：可乐定能够显著延迟SD大鼠的胃排空作用；对照药阿考替胺(100mg/kg)可显著改善由可乐定诱导的大鼠胃排空延迟；AD-35 5mg/kg和10mg/kg的剂量均可显著改善由可乐定诱导的大鼠胃排空延迟。显然，就大鼠模型而言，AD-35的药效也远优于阿考替胺(如图2所示)。
实施例3化合物AD-35对洛哌丁胺诱导的小鼠肠道推进延迟的改善作用
雄性ICR小鼠(25-32g)皮下注射洛哌丁胺(5mg/kg)，每天1次，连续注射7天造模(空白对照组不注射洛哌丁胺)。第7天将直径3mm的塑料球推进小鼠直肠3cm，观察和记录塑料球从直肠排出的时间。根据塑料球从直肠排出的时间将小鼠随机分组，每组20只。于分组后的第2天(记为day1)对不同给药组的小鼠开始灌胃给予不同剂量的AD-35(如图3所示剂量，每天1次)。各给药组小鼠于day1-day6连续给予不同剂量的AD-35(模型组和空白对照组给予生理盐水)，每次给药30min后注射洛哌丁胺(5mg/kg)(模型组注射同剂量的洛哌丁胺，空白对照组不注射)；day 7禁食4h后，对不同给药组小鼠灌胃给予不同剂量的AD-35(模型组和空白对照组给予生理盐水)，30min后皮下注射洛哌丁胺(5mg/kg)(空白对照组除外)，洛哌丁胺注射30min后，将塑料球推进小鼠直肠3cm，观察和记录塑料球从直肠排出的时间。
试验结果表明：洛哌丁胺可显著性地延迟塑料球从ICR小鼠排出的时间，延迟小鼠的肠道推进；化合物AD-35在2.5mg/kg和5mg/kg剂量下均能显著性地缩短塑料球从肠道排出的时间，证明AD-35具有促进肠道推进的作用(如图3所示)。
根据现有技术的记载，AD-35是一个相对较弱的乙酰胆碱酯酶抑制剂，目前处于治疗 阿尔茨海默氏症的二期临床试验中。AD-35在高剂量(例如120毫克)下具有极高的安全性。令人惊讶的是，虽然AD-35是一个相对较弱的乙酰胆碱酯酶抑制剂，但它却有极好地促进胃肠蠕动的作用。实施例1-3的动物实验表明：AD-35(1mg/kg)能够极其显著地改善由可乐定诱导的小鼠胃排空延迟，优于阿考替胺(100mg/kg)的效果。因此，AD-35可以非常有效地治疗与胃肠蠕动障碍相关的疾病，如功能性消化不良(FD)。
除非特别限定，本发明所用术语均为本领域技术人员通常理解的含义。
本发明所描述的实施方式仅出于示例性目的，并非用以限制本发明的保护范围，本领域技术人员可在本发明的范围内作出各种其他替换、改变和改进，因而，本发明不限于上述实施方式，而仅由权利要求限定。

Claims (10)

  1. 如下所示的式(I)化合物或其药学上可接受的盐在制备用于治疗与胃肠蠕动障碍相关的疾病的药物中的应用，其中所述药物通过促进胃肠蠕动发挥作用，
    Figure PCTCN2019099941-appb-100001
  2. 根据权利要求1所述的应用，其中所述药学上可接受的盐为盐酸盐或磷酸盐。
  3. 根据权利要求1或2所述的应用，其中所述与胃肠蠕动障碍相关的疾病选自功能性消化不良(FD)、术后肠梗阻和便秘。
  4. 根据权利要求1-3中任一项所述的应用，其中所述药物按每天1-3次施用。
  5. 根据权利要求1-4中任一项所述的应用，其中所述药物在进餐前口服施用。
  6. 药物组合物在制备用于治疗与胃肠蠕动障碍相关的疾病的药物中的应用，其中所述药物通过促进胃肠蠕动发挥作用，所述药物组合物包括如下所示的式(I)化合物或其药学上可接受的盐，以及药学上可接受的载体，
    Figure PCTCN2019099941-appb-100002
  7. 根据权利要求6所述的应用，其中所述药学上可接受的盐为盐酸盐或磷酸盐。
  8. 根据权利要求6或7所述的应用，其中所述与胃肠蠕动障碍相关的疾病选自功能性消化不良(FD)、术后肠梗阻和便秘。
  9. 根据权利要求6-8中任一项所述的应用，其中所述药物按每天1-3次施用。
  10. 根据权利要求6-9中任一项所述的应用，其中所述药物在进餐前口服施用。
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1526381A (zh) * 2003-03-06 2004-09-08 山东绿叶天然药物研究开发有限公司 低剂量胆碱酯酶抑制剂在制备治疗胃肠动力障碍引起的消化系统疾病中的应用
US20090137629A1 (en) * 2002-01-22 2009-05-28 Yoichi Iimura Sigma receptor binding agent containing indanone derivative
CN103524515A (zh) * 2012-07-03 2014-01-22 浙江海正药业股份有限公司 具有乙酰胆碱酯酶抑制活性的苯并间二氧杂环戊烯衍生物及其制备方法和用途
CN105859732A (zh) * 2016-04-11 2016-08-17 浙江海正药业股份有限公司 制备ad-35的工艺

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9717788B2 (en) * 2007-03-02 2017-08-01 Glaxosmithkline Biologicals Sa Method of inducing an immune response against HIV employing HIV immunogens, adenoviral vectors encoding said immunogens, and adjuvant

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090137629A1 (en) * 2002-01-22 2009-05-28 Yoichi Iimura Sigma receptor binding agent containing indanone derivative
CN1526381A (zh) * 2003-03-06 2004-09-08 山东绿叶天然药物研究开发有限公司 低剂量胆碱酯酶抑制剂在制备治疗胃肠动力障碍引起的消化系统疾病中的应用
CN103524515A (zh) * 2012-07-03 2014-01-22 浙江海正药业股份有限公司 具有乙酰胆碱酯酶抑制活性的苯并间二氧杂环戊烯衍生物及其制备方法和用途
CN105859732A (zh) * 2016-04-11 2016-08-17 浙江海正药业股份有限公司 制备ad-35的工艺

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
LI, LIN ET AL.: "Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-a and IL -1beta in an A|25-35-induced Rat Model of Alzheimer's Disease", JOURNAL OF ALZHEIMER'S DISEASE, vol. 56, no. 4, 20 February 2017 (2017-02-20), pages 1403 - 1417 *
MENG, FANHAO: "Inhibitor of Acety lcholinesterase", MEDICINAL CHEMISTRY, 31 January 2016 (2016-01-31), pages 133 *

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