WO2011093441A1 - 胆道疾患の治療又は予防剤 - Google Patents
胆道疾患の治療又は予防剤 Download PDFInfo
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- WO2011093441A1 WO2011093441A1 PCT/JP2011/051737 JP2011051737W WO2011093441A1 WO 2011093441 A1 WO2011093441 A1 WO 2011093441A1 JP 2011051737 W JP2011051737 W JP 2011051737W WO 2011093441 A1 WO2011093441 A1 WO 2011093441A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
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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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
Definitions
- the present invention relates to a therapeutic or prophylactic agent for biliary tract diseases comprising a morphinan derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
- Biliary tract disease is a general term for gastrointestinal diseases that develop in the gallbladder, bile duct, pancreas and pancreatic duct.
- One of the causes of biliary tract disease is known to be an increase in biliary resistance pressure due to contraction of the Oddi sphincter of the duodenal papilla, which is the terminal part of the bile duct after the common bile duct and pancreatic duct, which are the most downstream of the biliary tract, merge. Yes.
- biliary diseases that develop due to Oddi sphincter contraction
- biliary obstruction gallbladder disorders, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis and the like are known. Therefore, it is known that a drug that suppresses the contraction of the Oddi sphincter is useful as a therapeutic agent for a biliary tract disease caused by contraction of the Oddi sphincter.
- PBC primary biliary cirrhosis
- a biliary tract disease that is not caused by Oddi sphincter contraction but may be exacerbated by Oddi sphincter contraction.
- PBC is a disease in which the interlobular bile duct, which is a bile duct in the liver upstream of the common bile duct, is destroyed and the bile is stagnant, but it is known to be worsened by the blockage of the common bile duct (non-patent document). 1). Therefore, it is considered that a drug that suppresses the contraction of the Oddi sphincter can improve common bile duct obstruction and suppress deterioration of PBC.
- the morphinan derivative which is the active ingredient of the present invention or a pharmacologically acceptable acid addition salt thereof (hereinafter sometimes referred to as “the compound of the present application”) has so far had opioid ⁇ receptor agonist activity.
- the compound of the present application uses as analgesics and diuretics (Patent Document 1).
- antitussive drugs Patent Document 2
- brain cell protective drugs Patent Document 3
- antipruritic drugs Patent Document 4
- hyponatremia treatment drugs Patent Document 5
- ORL-1 receptor antagonist Patent Document 5
- therapeutic agent for neuropathic pain Patent Document 7
- antidiarrheal agent for cornea or conjunctiva Patent Document 8
- therapeutic agent for neuropsychiatric disorder Patent Document 9
- drug-dependent therapeutic agent Patent Document 10
- Use as a therapeutic agent for sepsis (patent document 11), a therapeutic agent for itch associated with multiple sclerosis (patent document 12), a therapeutic agent for schizophrenia (patent document 13), a therapeutic agent for dyskinesia (patent document 14), etc. It is disclosed. However, nothing is disclosed about the treatment or prevention effect of biliary tract diseases.
- drugs that have an action of suppressing the contraction of the Oddi sphincter and are used as a therapeutic agent for biliary tract diseases have an action of promoting the uptake of Ca 2+ into intracellular Ca-Store Site
- Those having an inhibitory action on binding of extracellular fluid Ca 2+ to contractile proteins such as Himechromon, and catechol-O-methyltransferase (hereinafter sometimes referred to as “COMT”) inhibitory action and anti-serotonin, such as furopropion
- It has an action, an antimuscarinic action such as thikidium, an atropine-like and papaverine-like action such as oxapium, and an action mechanism that suppresses the contraction of the Oddi sphincter like gabexate is not clear, Trypsin, kallikrein inhibitory action, etc. are known That is, there is no structural similarity with the Compound is a drug that does not also have opioid ⁇ receptor agonist.
- Opioids are also known to contract the Oddi sphincter and may exacerbate biliary tract disease, so it is also known that caution is required for use in patients with biliary tract disease. . There are the following reports on opioids.
- Morphine which has a morphinan skeleton similar to the compound of the present application but is different from the compound of the present application in that it is an opioid ⁇ receptor agonist, may cause biliary convulsions, so patients with gallbladder disorders and gallstones It is described that it is necessary to administer prudently (Non-patent Document 2).
- Non-patent Document 3 oxycodone, an opioid mu receptor agonist with a morphinan skeleton, contracts the Oddi sphincter and may exacerbate symptoms in patients with gallbladder disorders, cholelithiasis, or pancreatitis and must be administered with caution. Is described (Non-patent Document 3).
- buprenorphine an opioid ⁇ receptor partial agonist with a morphinan skeleton, contracts the Oddi sphincter at high doses (0.1 mg / kg iv or higher) in animal experiments (dogs) and has biliary tract diseases It is described that it is necessary to carefully administer to patients (Non-Patent Document 4).
- tramadol an opioid mu receptor agonist that does not have a morphinan skeleton, contracts the Oddi sphincter when administered in large doses in animal studies, so it may be necessary to administer it carefully to patients with biliary tract disease.
- pentazocine an opioid mu receptor partial agonist that does not have a morphinan skeleton, contracts the Oddi sphincter when administered in large doses, so it must be carefully administered to patients with biliary tract disease (Non-Patent Document 6).
- opioid ⁇ receptor agonists that do not have a morphinan skeleton are useful as therapeutic agents for gastrointestinal dysfunction, and one example of such gastrointestinal dysfunction is Oddi sphincter contraction (Patent Documents 15 to 18). ) Is not described to suppress Oddi sphincter contraction.
- Non-patent Document 7 nalbuphine, which has a morphinan skeleton and is known to exhibit opioid ⁇ receptor agonist and opioid ⁇ receptor partial agonist, is reported to have no effect on Oddi sphincter contraction.
- Non-Patent Document 8 There is a report (Non-Patent Document 8) that increases the internal biliary pressure by 6%, but it is not statistically significant, but there is no report that suppresses the contraction of the Oddi sphincter.
- butorphanol which is classified as an opioid ⁇ receptor agonist, increases the intra-biliary pressure by 12%, which is a statistically significant effect (Non-patent Document 8) and therefore has an Oddi sphincter contractile action.
- Non-patent Document 9 eptazosin, which does not have a morphinan skeleton but is known to act as a kappa agonist for opioid receptors, has an effect of contracting the Oddi sphincter when administered in large quantities in animal experiments. It is described that it is necessary to administer carefully to patients with biliary tract diseases (Non-patent Document 9).
- Non-patent Document 10 leucine enkephalin and methionine enkephalin, which are endogenous opioid ⁇ receptor agonist peptides, have been reported to cause a transient contraction on the Oddi sphincter and then show a sustained contraction-inhibiting action.
- opioid ⁇ receptor antagonist naloxone having a morphinan skeleton has an action of suppressing contraction of the Oddi sphincter (Non-patent Document 11).
- an opioid ⁇ receptor agonist having a morphinan skeleton like the present compound suppresses contraction of the Oddi sphincter.
- nociceptin (or sometimes described as orphanin FQ), which is an endogenous agonist peptide of the receptor, is available.
- Osidi is expressed in the excitatory motor nerves of the myenteric nerve layer of the Oddi sphincter, and suppresses cholinergic neurotransmission, indicating that nociceptin may act on the Oddi sphincter via a feedback self-suppression mechanism (Non-patent Document 12).
- the ORL-1 receptor agonist suppresses the contraction of the Oddi sphincter, and it has not been suggested that the ORL-1 receptor antagonism suppresses the contraction of the Oddi sphincter.
- Hastier P et al. , Dig Dis Sci. , 43, 2426 (1998) Edited and published by Japan Pharmaceutical Information Center, JAPIC Medical Drug Collection 2010, Maruzen Co., Ltd., p. 2705, Morphine hydrochloride hydrate Edited and published by Japan Pharmaceutical Information Center, JAPIC Medical Drug Collection 2010, Maruzen Co., Ltd., p. 618, oxycodone hydrochloride hydrate Edited and published by Japan Pharmaceutical Information Center, JAPIC Medical Drug Collection 2010, Maruzen Co., Ltd., p. 2166, buprenorphine hydrochloride Edited and published by Japan Pharmaceutical Information Center, JAPIC Medical Drug Collection 2010, Maruzen Co., Ltd., p.
- An object of the present invention is to provide a therapeutic or preventive agent for biliary tract diseases having an excellent effect comprising a specific compound having a morphinan skeleton or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
- a double line consisting of a dotted line and a solid line represents a double bond or a single bond
- R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms
- R 2 represents a linear or branched alkyl having 1 to 5 carbon atoms.
- R 1 is cyclopropylmethyl, cyclobutylmethyl, and cyclopentylmethyl or cyclohexylmethyl
- R 2 is methyl, ethyl or propyl, treatment of biliary disease according to [1] Or a preventive agent.
- the compound represented by the general formula (I) is ( ⁇ )-17- (cyclopropylmethyl) -3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6 ⁇ - [N-methyl-trans-3- ( The agent for treating or preventing biliary tract diseases according to [1], which is 3-furyl) acrylamide] morphinan.
- a therapeutic or prophylactic agent for diseases [5] The therapeutic or prophylactic agent for biliary tract diseases according to any one of [1] to [3], which exhibits a therapeutic or prophylactic effect on biliary tract diseases by suppressing Oddi sphincter contraction. [6] The following general formula (I) used for treatment or prevention of biliary tract diseases
- a double line consisting of a dotted line and a solid line represents a double bond or a single bond
- R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms
- R 2 represents a linear or branched alkyl having 1 to 5 carbon atoms
- B represents —CH ⁇ CH—] or a pharmacologically acceptable acid addition salt thereof.
- a double line consisting of a dotted line and a solid line represents a double bond or a single bond
- R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms
- R 2 represents a linear or branched alkyl having 1 to 5 carbon atoms.
- B represents —CH ⁇ CH—] or an effective amount of a pharmacologically acceptable acid addition salt thereof is administered to a patient in need of an agent for treating or preventing biliary tract diseases.
- a method of treating or preventing biliary tract diseases is administered to a patient in need of an agent for treating or preventing biliary tract diseases.
- the present invention provides a remarkable therapeutic or preventive effect for biliary tract diseases.
- Example 1 it is the figure which showed the influence of the compound 1 with respect to rabbit Oddi sphincter contraction.
- the abscissa indicates the test substance, and the ordinate indicates the rate of change in the maximum perfusion resistance pressure for 3 minutes immediately after the start of administration (Oddi muscle contraction (Delta%)) relative to the maximum perfusion resistance pressure for 3 minutes immediately before the start of intravenous administration of the test substance.
- Average value ⁇ standard error, N 11 cases, * p ⁇ 0.05, paired t test).
- the therapeutic or prophylactic agent for biliary tract diseases of the present invention contains a compound represented by the general formula (III) or a pharmacologically acceptable acid addition salt thereof as an active ingredient.
- R 1 is alkyl having 1 to 5 carbons, cycloalkylalkyl having 4 to 7 carbons, cycloalkenylalkyl having 5 to 7 carbons, aryl having 6 to 12 carbons, aralkyl having 7 to 13 carbons, carbon number 4 To alkenyl, allyl, furan-2-ylalkyl (the alkyl part has 1 to 5 carbon atoms) or thiophen-2-ylalkyl (the alkyl part has 1 to 5 carbon atoms).
- R 14 represents hydrogen, hydroxy, nitro, alkanoyloxy having 1 to 5 carbons, alkoxy having 1 to 5 carbons, alkyl having 1 to 5 carbons, or NR 9 R 10 .
- R 9 represents hydrogen or alkyl having 1 to 5 carbon atoms
- R 10 represents hydrogen, alkyl having 1 to 5 carbon atoms or — (C ⁇ O) R 11
- R 11 represents hydrogen, phenyl or carbon
- the alkyl of the number 1 to 5 is represented.
- R 3 represents hydrogen, hydroxy, alkanoyloxy having 1 to 5 carbons or alkoxy having 1 to 5 carbons.
- A is —XC ( ⁇ Y) —, —XC ( ⁇ Y) Z—, —X— or —XSO 2 — (wherein X, Y and Z each independently represent NR 4 , S or O.
- R 4 represents hydrogen, straight-chain or branched alkyl having 1 to 5 carbon atoms or aryl having 6 to 12 carbon atoms, and when two or more R 4 are present, they may be the same or different from each other).
- B is a valence bond, linear or branched alkylene having 1 to 14 carbons (provided that alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, fluorine, chlorine, bromine, iodine, amino, nitro , Cyano, trifluoromethyl and phenoxy, which may be substituted with at least one substituent selected from the group consisting of 1 to 3 methylene groups may be substituted with a carbonyl group) And / or a C2-C14 linear or branched non-cyclic unsaturated hydrocarbon containing 1 to 3 triple bonds (however, alkoxy having 1 to 5 carbons, alkanoyloxy having 1 to 5 carbons, hydroxy, At least selected from the group consisting of fluorine, chlorine, bromine, iodine, amino, nitro, cyano, trifluoromethyl and phenoxy 1 to 3 methylene groups may be replaced by a carbonyl group) or a carbon number containing 1
- R 5 is hydrogen or an organic group having any of the following basic skeletons (wherein, Q represents N, O or S, T represents CH 2 , NH, S or O, and l represents 0) M and n each independently represents an integer of 0 to 5, the total of m and n is 5 or less, and each organic group is an alkyl having 1 to 5 carbons, an alkyl having 1 to 5 carbons.
- R 6 represents hydrogen
- R 7 represents hydrogen, hydroxy, alkoxy having 1 to 5 carbons or alkanoyloxy having 1 to 5 carbons, or R 6 and R 7 together represent —O—, —CH 2 represents-or -S-.
- R 8 represents hydrogen, alkyl having 1 to 5 carbons or alkanoyl having 1 to 5 carbons.
- R 12 and R 13 both represent hydrogen, either one represents hydrogen and the other represents hydroxy, or together represent oxo.
- general formula (III) includes (+) isomer, ( ⁇ ) isomer, ( ⁇ ) isomer]
- the double line of the dotted line and the solid line in the general formula (III) represents a double bond or a single bond, and is preferably a single bond.
- the therapeutic or prophylactic agent for biliary tract diseases of the present invention is the compound represented by the general formula (I) already shown among the compounds represented by the general formula (III) or pharmacologically acceptable acid addition salts thereof. Or it is preferable to contain the pharmacologically acceptable acid addition salt as an active ingredient.
- the double line of the dotted line and the solid line in the general formula (I) represents a double bond or a single bond, and is preferably a single bond.
- R 1 represents a cycloalkylalkyl having 4 to 7 carbon atoms.
- R 1 cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl is preferable, and cyclopropylmethyl is particularly preferable.
- R 2 represents a linear or branched alkyl having 1 to 5 carbon atoms.
- R 2 is preferably methyl, ethyl or propyl. Of these, methyl is preferred.
- B is preferably trans-form —CH ⁇ CH—.
- a double line of a dotted line and a solid line is a single bond
- R 1 is cyclopropylmethyl
- R 2 is methyl
- B is trans-form —CH ⁇
- a compound that is CH— and is in the ( ⁇ ) form, ie, ( ⁇ )-17- (cyclopropylmethyl) -3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6 ⁇ - [N-methyl-trans-3- (3-Furyl) acrylamide] morphinan is particularly preferred, but the invention is not limited thereto.
- Examples of the pharmacologically acceptable acid addition salt in the present invention include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydroiodide or phosphate, acetate, and lactate. , Citrate, oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate or phthalate And organic sulfonates such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphor-sulfonate, and the like. Of these, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate and the like are preferably used, but of course not limited thereto.
- biliary tract disease includes gastrointestinal diseases that develop in the gallbladder, bile duct, pancreas and pancreatic duct.
- the therapeutic or preventive agent for biliary tract diseases of the present invention is preferably a biliary tract disease that develops or worsens due to Oddi sphincter contraction, particularly preferably biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis It can be used for the treatment or prevention of cholecystitis, primary biliary cirrhosis and the like.
- the compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof is purified to a pharmaceutical use and passes a necessary safety test. It can be administered orally or parenterally as a pharmaceutical composition mixed with acceptable acids, carriers, excipients and the like.
- the dosage form for oral administration is tablets, capsules, buccal disintegrants, powders or granules, etc.
- parenteral administration intravenous rapid infusion, continuous intravenous infusion, intramuscular injection, subcutaneous injection, intradermal injection , Tape agents, patch agents, etc. can be selected, but of course not limited thereto.
- the content of the compound represented by the general formula (I) or the pharmacologically acceptable acid addition salt thereof in the pharmaceutical composition is not particularly limited, but is usually adjusted to be 0.1 ⁇ g to 100 mg per dose. obtain.
- the dose can be appropriately selected according to the patient's symptom, age, weight, administration method, etc.
- the amount of the acid addition salt tolerated is about 0.1 ⁇ g to 20 mg, preferably about 1 ⁇ g to 10 mg, and can be administered once or divided into several times.
- the therapeutic or preventive agent for biliary tract diseases of the present invention is a compound represented by the general formula (I) or a pharmacologically acceptable acid addition salt thereof alone, or treatment or prevention of diseases, reduction or suppression of symptoms. Can be administered in combination with one or more drugs used for.
- trepibuton pancreatic / biliary tract disease treatment
- hymechromone biliary tract disease treatment
- furopropion pancreaticobiliary / urinary tract antispasmodic
- thikidium antimuscarinic agent
- oxapium antispasmodic anticholinergic agent
- gabexate protein
- dehydrocholic acid inhibitors dehydrocholic acid, annetortichithione, ursodeoxycholic acid, conodeoxycholic acid and the like.
- drugs such as morphine, pentazocine, buprenorphine, oxycodone, fentanyl, remifentanil, tramadol, butorphanol, and eptazocine are administered for the purpose of alleviating pain due to biliary tract diseases, and at the same time have the side effect of enhancing Oddi sphincter contraction. Although some of these are drugs, the side effects can be suppressed by combining these drugs with the drug of the present invention.
- the method of a combination may use each chemical
- the compound represented by the general formula (I) or the pharmacologically acceptable acid addition salt thereof, which is an active ingredient of the therapeutic or prophylactic agent of the present invention, is effective for treating or preventing biliary tract diseases. It can confirm by the method as described in the Example described in.
- the rabbit Oddi sphincter contraction model used in this method is a model generally used in basic research on biliary tract diseases (Wei JG et al., World J. Gastroenterol., 6, 102 (2000)). Inhibiting the action of Oddi sphincter contraction indicates that the drug has therapeutic and prophylactic effects on biliary tract diseases.
- Example 1 ( ⁇ )-17- (Cyclopropylmethyl) -3,14 ⁇ -dihydroxy-4,5 ⁇ -epoxy-6 ⁇ - [N-methyl-trans-3- (3-furyl) acrylamide] on rabbit Oddi sphincter contraction Effect of morphinan hydrochloride (Compound 1) Wei JG et al. , World J .; Gastroenterol. , 6, 102 (2000), the perfusion resistance pressure change of the Oddi sphincter was measured. In addition, the perfusion resistance pressure change of the Oddi sphincter reflects the mobility of the contraction change of the Oddi sphincter.
- NZW male rabbits (Japan SLC) weighing 2.0 to 2.5 kg at the time of arrival were fasted from the evening before the experiment.
- the experiment was performed under pentobarbital anesthesia and artificial ventilation. After fixing the rabbit in the dorsal position, the abdomen was cut open to expose the duodenum and the common bile duct. A small incision was made in the common bile duct, a cannula was inserted into the common bile duct toward the duodenum, and the tip was placed in the Oddi sphincter (enormous sphincter). For excretion of bile, another cannula was inserted and fixed to the gallbladder side in the common bile duct.
- Rabbits were administered a 5% mannitol solution, which is a solvent for the Compound 1 solution, into the jugular vein. Further, at intervals of 30 minutes or more after the administration of the solvent, Compound 1 was administered into the jugular vein at a dose of 0.2 ⁇ g / kg to the same individual. The administration volume of the solvent and Compound 1 was 1 mL / kg, and administration was performed over 60 seconds.
- the rate of change in maximum perfusion resistance pressure averaged 93.32%
- solvent administration the rate of change in maximum perfusion resistance pressure averaged 99.32%. It was 81%.
- the change rate of the maximum perfusion resistance pressure was decreased in the compound 1 administration group compared with the solvent administration group, and the difference was statistically significant (* p ⁇ 0.05, paired test). ). This indicates that Compound 1 has an inhibitory effect on Oddi sphincter contraction.
- Oxapium iodide which has an Oddi sphincter contractile inhibitory action and is currently used clinically as a therapeutic agent for biliary tract diseases, is administered to dogs intravenously at a dose of 0.3 mg / kg. Is reduced by about 10 mmH 2 O (0.74 mmHg when converted to mmHg) (Tamazawa Yoshii et al., Basic and Clinical, 6, 128 (1972)). Also, when gabexate mesylate is intravenously administered to dogs at a dose of 1 mg / kg or 3 mg / kg, the Oddi sphincter perfusion resistance pressure is 6.9 mmH 2 O (0.51 mmHg in terms of mmHg) or 10.
- Oxapium iodide is usually orally administered to adults as a daily dose of 30 to 60 mg in three doses, and gabexate mesylate is usually dissolved in 100 mL of Ringer's solution and intravenously infused at 8 mL / min or less. From the above, it is considered that the above dose is equivalent to the clinical dose of each drug.
- the present invention has an excellent biliary tract disease treatment effect and is useful for the treatment or prevention of biliary tract diseases.
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Abstract
Description
また、鎮咳薬(特許文献2)、脳細胞保護薬(特許文献3)、止痒薬(特許文献4)、低ナトリウム血症治療薬(特許文献5)、ORL-1受容体拮抗薬(特許文献6)、神経因性疼痛治療薬(特許文献7)、角膜又は結膜用止痒薬(特許文献8)、精神神経疾患治療薬(特許文献9)、薬物依存治療薬(特許文献10)、敗血症治療薬(特許文献11)、多発性硬化症に伴う痒みの治療薬(特許文献12)、統合失調症治療薬(特許文献13)及びジスキネジア治療薬(特許文献14)などとしての用途も既に開示されている。しかしながら、胆道疾患の治療又は予防効果については、なんら開示されていない。
[1]下記一般式(I)
[2]一般式(I)において、R1がシクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル又はシクロヘキシルメチルであり、R2がメチル、エチル又はプロピルである、[1]に記載の胆道疾患の治療又は予防剤。
[3]一般式(I)で表される化合物が(-)-17-(シクロプロピルメチル)-3,14β-ジヒドロキシ-4,5α-エポキシ-6β-[N-メチル-トランス-3-(3-フリル)アクリルアミド]モルヒナンである、[1]に記載の胆道疾患の治療又は予防剤。
[4]胆道疾患が、胆道閉塞、胆嚢障害、胆石症、膵炎、胆道ジスキネジー、胆管炎、胆嚢炎又は原発性胆汁性肝硬変である、[1]乃至[3]のいずれか一項記載の胆道疾患の治療又は予防剤。
[5]Oddi括約筋収縮を抑制することにより、胆道疾患の治療又は予防作用を発現する、[1]乃至[3]のいずれか一項記載の胆道疾患の治療又は予防剤。
[6]胆道疾患の治療又は予防のために用いる、下記一般式(I)
[7]下記一般式(I)
R1は炭素数1から5のアルキル、炭素数4から7のシクロアルキルアルキル、炭素数5から7のシクロアルケニルアルキル、炭素数6から12のアリール、炭素数7から13のアラルキル、炭素数4から7のアルケニル、アリル、フラン-2-イルアルキル(アルキル部の炭素数は1から5)又はチオフェン-2-イルアルキル(アルキル部の炭素数は1から5)を表す。
一般式(III)中の点線と実線の二重線は二重結合又は単結合を表し、単結合であることが好ましい。
R13が一緒になってオキソを表す化合物は、たとえば文献(Heterocycles,63,865(2004),Bioorg.Med.Chem.Lett.,5,1505(1995))に従って得られる10-オキソを有する化合物を原料として、これよりChem.Pharm.Bull.,52,664(2004)及び特許第2525552に記載の方法に従って製造することができる。さらに、一般式(1)で表される化合物のうちR12が水酸基でR13が水素である化合物は、Chem.Pharm.Bull.,52,664(2004)に記載の方法に従って製造することができる。
実施例1 ウサギOddi括約筋収縮に対する(-)-17-(シクロプロピルメチル)-3,14β-ジヒドロキシ-4,5α-エポキシ-6β-[N-メチル-トランス-3-(3-フリル)アクリルアミド]モルヒナン塩酸塩(化合物1)の効果
Wei JG et al.,World J. Gastroenterol.,6,102(2000)に記載の方法を一部変更し、Oddi括約筋の灌流抵抗圧変化を測定した。なお、Oddi括約筋の灌流抵抗圧変化はOddi括約筋の収縮変化のmotilityを反映する。
なお、化合物1の構造は下記式(II)で表される。
Claims (7)
- 一般式(I)において、R1がシクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル又はシクロヘキシルメチルであり、R2がメチル、エチル又はプロピルである、請求項1記載の胆道疾患の治療又は予防剤。
- 一般式(I)で表される化合物が(-)-17-(シクロプロピルメチル)-3,14β-ジヒドロキシ-4,5α-エポキシ-6β-[N-メチル-トランス-3-(3-フリル)アクリルアミド]モルヒナンである、請求項1記載の胆道疾患の治療又は予防剤。
- 胆道疾患が、胆道閉塞、胆嚢障害、胆石症、膵炎、胆道ジスキネジー、胆管炎、胆嚢炎又は原発性胆汁性肝硬変である、請求項1乃至3のいずれか一項記載の胆道疾患の治療又は予防剤。
- Oddi括約筋収縮を抑制することにより、胆道疾患の治療又は予防作用を発現する、請求項1乃至3のいずれか一項記載の胆道疾患の治療又は予防剤。
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CN201180007520.XA CN102711759B (zh) | 2010-01-29 | 2011-01-28 | 胆道疾病的治疗或预防药 |
AU2011211223A AU2011211223B2 (en) | 2010-01-29 | 2011-01-28 | Therapeutic or prophylactic agent for biliary diseases |
CA2787323A CA2787323C (en) | 2010-01-29 | 2011-01-28 | Therapeutic or prophylactic agent for biliary tract diseases |
JP2011505302A JP5867081B2 (ja) | 2010-01-29 | 2011-01-28 | 胆道疾患の治療又は予防剤 |
BR112012018765A BR112012018765B1 (pt) | 2010-01-29 | 2011-01-28 | uso de um derivado de morfinano como agente profilático ou terapêutico em doenças do trato biliar |
RU2012136826/04A RU2554857C2 (ru) | 2010-01-29 | 2011-01-28 | Терапевтическое или профилактическое средство для заболеваний желчных путей |
US13/522,784 US10131672B2 (en) | 2010-01-29 | 2011-01-28 | Therapeutic or prophylactic agent for biliary diseases |
ES11737151.8T ES2582628T3 (es) | 2010-01-29 | 2011-01-28 | Agente terapéutico o profiláctico para enfermedades de las vías biliares |
MX2012008509A MX362830B (es) | 2010-01-29 | 2011-01-28 | Agente terapeutico o profilactico para enfermedades del tracto biliar. |
EP11737151.8A EP2529739B1 (en) | 2010-01-29 | 2011-01-28 | Therapeutic or prophylactic agent for biliary diseases |
KR1020127022530A KR101732042B1 (ko) | 2010-01-29 | 2011-01-28 | 담도 질환의 치료 또는 예방제 |
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WO2012105475A1 (ja) | 2011-01-31 | 2012-08-09 | 東レ株式会社 | 悪液質の治療又は予防剤 |
US11897871B1 (en) | 2021-06-14 | 2024-02-13 | Scorpion Therapeutics, Inc. | Methods for treating cancer |
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CN106110220B (zh) * | 2016-08-22 | 2020-01-07 | 陕西盘龙药业集团股份有限公司 | 一种治疗胆道疾病的中成药的制备工艺 |
US20210015813A1 (en) | 2018-03-08 | 2021-01-21 | Victoria Link Ltd. | Treatment of demyelinating diseases |
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Cited By (3)
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WO2012105475A1 (ja) | 2011-01-31 | 2012-08-09 | 東レ株式会社 | 悪液質の治療又は予防剤 |
US9006262B2 (en) | 2011-01-31 | 2015-04-14 | Toray Industries, Inc. | Therapeutic or prophylactic agent for cachexia |
US11897871B1 (en) | 2021-06-14 | 2024-02-13 | Scorpion Therapeutics, Inc. | Methods for treating cancer |
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EP2529739B1 (en) | 2016-07-13 |
MY173491A (en) | 2020-01-29 |
RU2554857C2 (ru) | 2015-06-27 |
KR101732042B1 (ko) | 2017-05-02 |
CA2787323A1 (en) | 2011-08-04 |
PL2529739T3 (pl) | 2016-12-30 |
CN102711759A (zh) | 2012-10-03 |
AU2011211223A1 (en) | 2012-09-20 |
BR112012018765B1 (pt) | 2019-09-03 |
AU2011211223B2 (en) | 2014-10-23 |
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RU2012136826A (ru) | 2014-03-10 |
ES2582628T3 (es) | 2016-09-14 |
CA2787323C (en) | 2017-08-29 |
CN102711759B (zh) | 2015-05-13 |
JPWO2011093441A1 (ja) | 2013-06-06 |
TWI477505B (zh) | 2015-03-21 |
EP2529739A1 (en) | 2012-12-05 |
BR112012018765A2 (pt) | 2016-05-03 |
EP2529739A4 (en) | 2015-03-11 |
US10131672B2 (en) | 2018-11-20 |
TW201200521A (en) | 2012-01-01 |
JP5867081B2 (ja) | 2016-02-24 |
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US20130203797A1 (en) | 2013-08-08 |
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