Classifications

• • 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
  • 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
• • 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
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• This invention relates to a therapeutic and/or preventive agent for gastroparesis symptom which comprises an erythromycin derivative as an active ingredient, as well as a method for treating and/or preventing gastroparesis symptom which comprises administering an effective dose of the therapeutic and/or preventive agent to patients, a drug to be used for the treatment and/or prophylaxis, the use of the erythromycin derivative in the manufacture of the drug, as well as a kit containing the erythromycin derivative and an instruction manual for administering a pharmaceutical composition containing the erythromycin derivative as an active ingredient.
• Erythromycin and its derivatives are known to have motilin agonistic actions, among which accelerating gastric emptying is considered as a typical action (Janssens, Peeters et al. 1990).
• Gastroparesis is a symptom in the digestive tract that manifests itself in association with diabetes mellitus and the like; conventionally, it is considered a symptom that occurs from delayed gastric emptying and in Japan, the identification of delayed gastric emptying is employed to make definitive diagnosis of gastroparesis.
• An idea of treating patients with delayed gastric emptying by accelerating gastric emptying using motilin agonists was put forth and the drugs were shown to accelerate gastric emptying in clinical settings (Maganti, Onyemere et al.
• those compounds have been shown to accelerate gastric emptying in a clinical study (Fang, McCallum et al. 2001). However, it is not known whether those compounds, unlike the aforementioned erythromycin derivative ABT-229, are capable of improving gastroparesis symptom. Hence, as already mentioned above, there is a need to provide therapeutic and/or preventive agents against gastroparesis symptom that is capable for continuous medication.
• the inventors of the present invention have found that specific kinds of erythromycin derivatives are suitable for continuous medication, can improve the symptom in the upper digestive tract and are appropriately used as therapeutic and/or preventive agents against gastroparesis symptom.
• the inventors have also found that the compounds of the present invention are of a different type than the erythromycin derivative ABT229 which accelerated gastric emptying in clinical settings but did not improve gastroparesis symptom.
• the inventors have found that the erythromycin derivatives of the present invention, without delayed gastric emptying or not, can improve gastroparesis symptom itself and, hence, gastric dyspepsia per se which is caused by such symptom.
• the present invention relates to a therapeutic and/or preventive agent against gastroparesis symptom which comprises as an active ingredient a compound of formula (1) or a pharmaceutically acceptable salt thereof:
• Ri represents a Ci-C 6 alkyl group and R 2 represents a Ci-Ce alkyl group
• the present invention also relates to a method for treating and/or preventing gastroparesis symptom in a patient having disease in the gastrointestinal tract, which comprises administering to the patient a therapeutic and/or preventive agent against gastroparesis symptom comprising a compound of the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient in a sufficient dose to treat and/or prevent the gastroparesis symptom in the patient.
• the present invention further relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof in the manufacture of drugs to be used for the treatment and/or prevention.
• the present invention additionally relates to a kit containing a compound of the formula (1) or a pharmaceutically acceptable salt and an instruction manual for administering a pharmaceutical composition containing the compound or its pharmaceutically acceptable salt as an active ingredient.
• Fig. 1 which is titled "Effect of GM-611 on gastroparesis symptom in diabetic patients with a normal level of gastric emptying", is a graph showing results of evaluating the percentage of responders who were in the patients the gastroparesis symptom regardless a normal level of gastric emptying and who perceived an adequate relief of gastroparesis symptom by the administration of the therapeutic and/or preventive agent against gastroparesis symptom according to the present invention; MlR (month 1 responder) refers to patients who had adequate relief in at least 50% of weekly evaluations for the first one month of medication and CR (complete responder) refers to patients who were evaluated as monthly responder for three consecutive months. Fig.
• Fig. 4 which is titled "Effect of GM-611 on gastroparesis symptom in diabetic patients of diabetic history longer than 10 years with a normal level of gastric emptying", is a graph showing results of evaluating the percentage of responders who were in the diabetic patients of diabetic history longer than 10 years with the gastroparesis symptom regardless a normal level of gastric emptying and who perceived an adequate relief of gastroparesis symptom by the administration of the therapeutic and/or preventive agent against gastroparesis symptom according to the present invention; MlR (month 1 responder) refers to patients who had adequate relief in at least 50% of weekly evaluations for the first one month of medication and CR (complete responder) refers to patients who were evaluated as monthly responder for three consecutive months.
• MlR month 1 responder
• CR complete responder
• R 1 in the formula (1) is an isopropyl group.
• R 2 in the formula (1) is a methyl group.
• the disease to be treated and/or prevented by the present invention is symptomatic gastroparesis and it is, in a preferred embodiment, symptomatic gastroparesis not involving delayed gastric emptying and, in a more preferred embodiment, it is symptomatic gastroparesis in diabetes mellitus.
• Ri and R 2 each independently represent a Ci-C 6 alkyl group.
• the Ci-C 6 alkyl group refers to a linear or branched alkyl group containing 1 to 6 carbon atoms. Specific examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, a neopentyl group, a hexyl group, etc.
• the compound of the formula (1) may form a salt.
• Exemplary salts that can be formed include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodi ⁇ acid and sulfuric acid, as well as with organic acids such as acetic acid, oxalic acid, maleic acid, fumaric acid, methanesulfonic acid, with a fumarate being preferred.
• the compound of the formula (1) or salts thereof may in turn form hydrates.
• a preferred compound of the formula (1) is one where R 1 is an isopropyl group and R 2 is a methyl group, namely, 8,9-didehydro-N-demethyl-9-deoxo-6, 11-dideoxy-6,9-epoxy-12 ⁇ O-methyl-N-(1-methylethyl)-11-oxoerythromycin. More preferred is a fumarate of this compound, namely, 8,9- didehydro-N-demethyl-9-deoxo-6,ll-dideoxy-6,9-epoxy-12-O- methyl-N-(1-methylethyl)-11-oxoerythromycin, (2E)-2- butenedioate [hereunder designated as GM-611].
• the compound of the formula (1) used in the present invention is known and can be synthesized as described in, e.g. Bioorg & Med Chem Lett, Vol. 4, No. 11, page 1347, 1994; JP 6-56843 A (WO93/24509) ; JP 9-100291 A (WO97/06177); W002/18403 or W002/30943.
• the disease to be treated and/or prevented by the present invention is symptomatic gastroparesis.
• Symptomatic gastroparesis is a condition of the upper digestive tract which, irrespective of its etiology, causes the patient to have a similar type of unidentified complaint to gastroparesis.
• patients with symptomatic gastroparesis are included patients with a normal level of gastric emptying and patients suffering diabetes mellitus.
• the term "therapeutic and/or preventive agent” refers to a drug used for either treatment or prevention or for both treatment and prevention purposes. More specifically, this term refers to a drug used for treating and/or preventing the disease of interest mentioned above or inhibiting the disease from progressing to more advanced stages, thereby preventing further deterioration and/or keeping it in the present state.
• the therapeutic and/or preventive agent against symptomatic gastroparesis preferably enables the patient to perceive an improvement in the symptom and can also be administered over an extended period of time with sustained improvement in the symptom.
• the patient can be considered to "perceive an improvement in the symptom" if the patient, when interviewed, answers that "there was an adequate relief in the overall evaluation of gastroparesis symptom as compared with the time before the therapy started.”
• the pharmaceutical composition of the present invention may be prepared in various dosage forms by mixing the compound of the formula (1) as an active ingredient with a physiologically acceptable solid or liquid pharmaceutical carrier as appropriate for the intended route of administration.
• Possible routes of administration include oral administration, parenteral administration (e.g., intravenous injection), sustained release- administration using sustained-release preparations, and local administration using local delivery catheters or the like.
• Pharmaceutical carriers include commonly used excipients, binders, disintegrating agents, lubricants, coating agents, solubilizers, emulsifiers, suspending agents, stabilizers, fats/oils, and solvents.
• Dosage forms include tablets, granules, pills, capsules, solutions, syrups, suspensions, emulsions, and injections.
• the dose of a compound of the formula (1) according to the present invention may be chosen as appropriate for the age of a patient, the type of the disease to be treated and/or prevented, the severity of symptom, the intended route of administration and so on, the daily dose for adults may be from 0.1 to 200 mg, preferably from 1 to 100 mg. More specifically, when administered with a particularly preferred compound GM-611, an adult patient preferably receives 2 mg to 60 mg of the compound, which may be given in a single or divided doses.
• GM-611 (8,9-didehydro-N- demethyl-9-deoxo-6,11-dideoxy-6,9-epoxy-12-O-methyl-N-(1- methylethyl)-ll-oxoerythromycin, (2E)-2-butenedioate) was used as a compound of the formula (1).
• This compound was synthesized in the laboratories of Chugai Pharmaceutical Co., Ltd. as described in WO02/18403 and WO02/30943. To evaluate the efficacy of GM-611 in improving subjective gastroparesis symptom, diabetic patients on insulin therapy were selected.
• the compound of the present invention has a gastric emptying accelerating action and an improvement in delayed gastric emptying might contribute to an improvement in the symptom, making it impossible to determine whether the compound was a direct agent for improving the symptom; patients with a normal level of gastric emptying were selected in order to avoid this artifact.
• the compound of the present invention was administered twice daily at meals for 3 months in order to assess its efficacy.
• the placebo was GM-611-free tablets. All assessment in the subjective gastroparesis symptom was evaluated by an electric diary by phone. Starting one week after the initiation of medication, the patients were interviewed every week and asked whether in the past 7 days, you have had adequate relief of your gastroparesis symptoms, and the yes/no answers were recorded. Patients who had an adequate relief at a frequency of at least 50% of weekly evaluations for one month of medication were evaluated as "monthly responders”. Patients who who were evaluated as monthly responder for three consecutive months, were asigned as "complete responders" (CR). [Results]
• the present inventors assumed that only the tendency toward improvement was recognized because the patients, who were too heterogenous in their pathological state, had such large individual variation that the drug efficacy was difficult to demonstrate. Hence, in order to obtain more definite results about the presence or absence of the drug efficacy, the inventors conducted additional analyses in patients who were more homogenous in their pathological state. To this end, three methods were used, one by selecting the patients with diabetes to type 1, another by selecting the patients to cases of good glycemic control, and the third by selecting the patients to cases having a longer history of diabetes. The results of the analyses in those homogenous sub-groups are described in the following Examples 2, 3 and 4.
• Example 2 Effect of GM-611 on gastroparesis symptom in patients of type 1 diabetes with a normal level of gastric emptying
• Example 3 Effect of GM-611 on gastroparesis symptom in diabetic patients of good glycemic control with a normal level of gastric emptying Since symptoms in the gastrointestinal tract are considered to depend on whether blood glucose level is properly controlled, only diabetic patients with good glycemic control whose values of hemoglobin A lc (an index for the success of blood glucose control) were no more than 8% were subjected to the assessment of the efficacy of GM-611 in improving subjective gastroparesis symptom. The placebo was GM-611-free tablets. [Results]
• P 0.010; CR rate in whole GM-611 treated group vs. placebo group by chi-square test.
• the fact that GM-611 apparently showed a significant improvement in gastroparesis symptom in a dose-dependent manner in the plausibly more homogenous patient groups was considered to show that the compound of the present invention can improve subjective gastroparesis symptom.
• Example 4 Effect of GM-611 on gastroparesis symptom in diabetic patients of diabetic history longer than 10 years with a normal level of gastric emptying
• P 0.001; CR rate in whole GM-611 treated group vs. placebo group by chi-square test.
• the fact that GM-611 apparently showed a significant improvement in gastroparesis symptom in a dose-dependent manner in the plausibly more homogenous patient groups was considered to show that the compound of the present invention can improve subjective gastroparesis symptom.
• Example 1 GM-611 showed only a tendency to improve the symptom; however, in the analysis using more homogeneous patients (Examples 2, 3 and 4), the compound of the present invention apparently showed significant improvements in subjective gastroparesis symptom, eventually leading to the accomplishment of the present invention.
• GM-611 a motilin-receptor agonist,accelerates gastric emptying in patients with symptomatic gastroparesis (GP).
• the inventors of the present invention found for the first time that erythromycin derivatives of the formula (1) had an efficacy of improving gastroparesis symptom, which contributed to clinically improving the symptom in patients with symptomatic gastroparesis.
• This action of the derivatives in improving gastroparesis symptom has not been recognized in ABT-229, an erythromycin derivative conventionally held as an analogous drug, and it was for the first time discovered from the compounds of the present invention.
• the compounds of the formula (1) according to the present invention are also appropriate for long-term clinical use because of their weaker antibacterial action than that of erythromycin.
• the present invention provides pharmaceutical agents that are safe and exhibit potent therapeutic and/or preventive effect in the treatment of gastroparesis symptom.

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• 2005
  • 2005-12-27 TW TW094146785A patent/TW200633714A/zh unknown
  • 2005-12-28 US US11/813,026 patent/US7803779B2/en not_active Expired - Fee Related
  • 2005-12-28 WO PCT/JP2005/024263 patent/WO2006070937A1/en not_active Ceased
  • 2005-12-28 JP JP2007531116A patent/JP2008525314A/ja not_active Withdrawn
  • 2005-12-28 EP EP05824559A patent/EP1835920A1/en not_active Withdrawn

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