Therapeutic or prophylactic agent for biliary diseases

Abstract

A therapeutic or prophylactic agent for biliary tract diseases includes as an effective component a specific compound having a morphinan skeleton represented by Compound 1, or a pharmaceutically acceptable acid addition salt thereof: ##STR00001##

Claims

1. A method of treating a biliary tract disease(s) selected from the group consisting of biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis and primary biliary cirrhosis comprising administering an effective amount of a compound represented by (I) below: ##STR00008## wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, R.sup.1 represents C.sub.4-C.sub.7 cycloalkylalkyl, R.sup.2 represents C.sub.1-C.sub.5 linear or branched alkyl, and B represents CHCH or a pharmaceutically acceptable acid addition salt thereof to a patient with a gallbladder who has a biliary tract disease(s) that occur(s) and/or is/are exacerbated by the contraction of the sphincter of Oddi and is suffering from pathological contraction of the sphincter of Oddi.

2. The method according to claim 1, wherein, in (I), R.sup.1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and R.sup.2 is methyl, ethyl or propyl.

3. The method according to claim 1, wherein said compound represented by (I) is ()-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan.

4. The method according to claim 1, wherein a dosage per administration is 0.1 g to 100 mg of the compound or the pharmaceutically acceptable acid addition salt thereof.

5. The method according to claim 1, wherein a means of administration of the compound is orally or parenterally.

6. The method according to claim 1, wherein a dosage per administration is 0.2 g/kg body weight of the compound or the pharmaceutically acceptable acid addition salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWING

(1) FIG. 1 is a diagram showing the influence of Compound 1 on contraction of sphincter of Oddi in rabbit in Example 1. The abscissa indicates a test substance, and the ordinate indicates the rate of change in the maximum perfusion pressure (Oddi muscle contraction (Delta %)) based on comparison between the value observed during the 3 minutes immediately before beginning of intravenous administration of the test substance and the value observed during the 3 minutes immediately after the beginning of administration (meanstandard error; N=11 cases, *p<0.05, paired t-test).

DETAILED DESCRIPTION

(2) The therapeutic or prophylactic agent for a biliary tract disease(s) comprises as an effective component a compound represented by (III) or a pharmaceutically acceptable acid addition salt thereof:

(3) ##STR00005##
wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond,

(4) R.sup.1 represents C.sub.1-C.sub.5 alkyl, C.sub.4-C.sub.7 cycloalkylalkyl, C.sub.5-C.sub.7 cycloalkenylalkyl, C.sub.6-C.sub.12 aryl, C.sub.7-C.sub.13 aralkyl, C.sub.4-C.sub.7 alkenyl, allyl, furan-2-ylalkyl (the alkyl moiety has 1 to 5 carbon atom(s)), or thiophen-2-ylalkyl (the alkyl moiety has 1 to 5 carbon atom(s)),

(5) R.sup.14 represents hydrogen, hydroxy, nitro, C.sub.1-C.sub.5 alkanoyloxy, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkyl or NR.sup.9R.sup.10. Here, R.sup.9 represents hydrogen or C.sub.1-C.sub.5 alkyl, R.sup.10 represents hydrogen, C.sub.1-C.sub.5 alkyl or (CO)R.sup.11, R.sup.11 represents hydrogen, phenyl or C.sub.1-C.sub.5 alkyl,

(6) R.sup.3 represents hydrogen, hydroxy, C.sub.1-C.sub.5 alkanoyloxy or C.sub.1-C.sub.5 alkoxy,

(7) A represents XC(Y), XC(Y)Z, X or XSO.sub.2 (wherein X, Y and Z each independently represent NR.sup.4, S or O, wherein R.sup.4 represents hydrogen, C.sub.1-C.sub.5 linear or branched alkyl or C.sub.6-C.sub.12 aryl, and, in cases where two or more R.sup.4 exist in the formula, these may be the same or different),

(8) B represents a valence bond, C.sub.1-C.sub.14 linear or branched alkylene (which may be substituted by at least one substituent selected from the group consisting of C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkanoyloxy, hydroxy, fluorine, chloro, bromo, iodo, amino, nitro, cyano, trifluoromethyl and phenoxy, and 1 to 3 methylene group(s) may be substituted by carbonyl); C.sub.2-C.sub.14 linear or branched acyclic unsaturated hydrocarbon comprising 1 to 3 double bond(s) and/or triple bond(s) (which may be substituted by at least one substituent selected from the group consisting of C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkanoyloxy, hydroxy, fluorine, chloro, bromo, iodo, amino, nitro, cyano, trifluoromethyl and phenoxy, and 1 to 3 methylene group(s) may be substituted by carbonyl); or C.sub.1-C.sub.14 linear or branched, saturated or unsaturated hydrocarbon comprising 1 to 5 thioether bond(s), ether bond(s) and/or amino bond(s) (wherein no heteroatom is directly bound to A, and 1 to 3 methylene group(s) may be substituted by carbonyl),

(9) R.sup.5 represents hydrogen or an organic group having any of the following basic skeletons (wherein Q represents N, O or S; T represents CH.sub.2, NH, S or O; 1 represents an integer of 0 to 5; m and n each independently represent an integer of 0 to 5; the sum of m and n is not more than 5; and each organic group may be substituted by at least one substituent selected from the group consisting of C.sub.1-C.sub.5 alkyl, C.sub.1-C.sub.5 alkoxy, C.sub.1-C.sub.5 alkanoyloxy, hydroxy, fluorine, chloro, bromo, iodo, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy),

(10) ##STR00006##

(11) R.sup.6 represents hydrogen, and R.sup.7 represents hydrogen, hydroxy, C.sub.1-C.sub.5 alkoxy or C.sub.1-C.sub.5 alkanoyloxy; or R.sup.6 and R.sup.7 together represent O, CH.sub.2 or S,

(12) R.sup.8 represents hydrogen, C.sub.1-C.sub.5 alkyl or C.sub.1-C.sub.5 alkanoyl,

(13) R.sup.12 and R.sup.13 together represent hydrogen; one of these represents hydrogen and the other represents hydroxy; or these together represent oxo,

(14) (III) includes (+), () and () isomers.

(15) The double line constituted by a dotted line and a solid line in (III) represents a double bond or single bond, and the double line preferably represents a single bond.

(16) The therapeutic or prophylactic agent for a biliary tract disease(s) preferably comprises, among the compounds represented by (III) and pharmaceutically acceptable acid addition salts thereof, a compound represented by the above-described (I) or a pharmaceutically acceptable acid addition salt thereof as an effective component.

(17) The double line constituted by a dotted line and a solid line in (I) represents a double bond or single bond, and the double line preferably represents a single bond.

(18) In (I), R.sup.1 represents C.sub.4-C.sub.7 cycloalkylalkyl. Among these, R.sup.1 is preferably cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, especially preferably cyclopropylmethyl.

(19) R.sup.2 represents C.sub.1-C.sub.5 linear or branched alkyl. R.sup.2 is preferably methyl, ethyl or propyl. Among these, methyl is more preferred.

(20) B represents CHCH. B is preferably trans CHCH.

(21) The compound represented by (I) is especially preferably a ()-compound wherein the double line constituted by a dotted line and a solid line represents a single bond; R.sup.1 represents cyclopropylmethyl; R.sup.2 represents methyl; and B represents trans CHCH. That is, the compound represented by (I) is especially preferably ()-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan. However, the agent is not restricted thereto.

(22) These compounds represented by (I) and pharmaceutically acceptable acid addition salts thereof can be produced according to the method described in JP 2525552 B. Among the compounds represented by (III), those wherein R.sup.12 and R.sup.13 together represent hydrogen can be produced according to the method described in JP 2525552 B. Among the compounds represented by (III), those wherein R.sup.12 and R.sup.13 together represent oxo can be produced by, for example, using, as a starting material, a compound having 10-oxo obtained according to a document (Heterocycles, 63, 865 (2004), Bioorg. Med. Chem. Lett., 5, 1505 (1995)) and following the methods described in Chem. Pharm. Bull., 52, 664 (2004) and JP 2525552 B. Further, among the compounds represented by (I), those wherein R.sup.12 represents hydroxy and R.sup.13 represents hydrogen can be produced according to the method described in Chem. Pharm. Bull., 52, 664 (2004).

(23) Examples of the pharmaceutically acceptable acid addition salt include inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt, nitric acid salt, hydrobromic acid salt, hydroiodic acid salt and phosphoric acid salt; organic carboxylic acid salts such as acetic acid salt, lactic acid salt, citric acid salt, oxalic acid salt, glutaric acid salt, malic acid salt, tartaric acid salt, fumaric acid salt, mandelic acid salt, maleic acid salt, benzoic acid salt and phthalic acid salt; and organic sulfonic acid salts such as methanesulfonic acid salt, ethanesulfonic acid salt, benzenesulfonic acid salt, p-toluenesulfonic acid salt and camphorsulfonic acid salt. Among these, hydrochloric acid salt, hydrobromic acid salt, phosphoric acid salt, tartaric acid salt, methanesulfonic acid salt and the like are preferably used, but, needless to say, the pharmaceutically acceptable acid addition salt is not restricted thereto.

(24) The biliary tract disease includes digestive diseases that occur in the gallbladder, bile duct, pancreas or pancreatic duct. Among these, the therapeutic or prophylactic agent for a biliary tract disease(s) is preferably applicable to a biliary tract disease(s) that occur(s) and/or exacerbate(s) due to contraction of sphincter of Oddi, especially preferably biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis, primary biliary cirrhosis and/or the like.

(25) The compound represented by (I) or a pharmaceutically acceptable acid addition salt thereof is purified to a level suitable for medical use and, after passing a necessary safety test, the compound or acid addition salt may be orally or parenterally administered as it is or as a pharmaceutical composition prepared as a mixture with a known pharmaceutically acceptable acid(s), carrier(s), vehicle(s) and/or the like. Examples of its formulation include tablets, capsules, orally disintegrating tablets, powders and granules in the case of oral administration; and formulations for intravenous rapid infusion, intravenous sustained infusion, intramuscular injection, subcutaneous injection or intradermal injection, and tapes and patches, in the case of parenteral administration. However, the formulation is of course not limited thereto.

(26) The content of the compound represented by (I) or a pharmaceutically acceptable acid addition salt thereof is not restricted, and the compound or acid addition salt may be usually prepared such that the dose per administration is 0.1 g to 100 mg. The dose may be appropriately selected depending on the symptoms, age and body weight of the patient, administration method and/or the like, and the dose per adult per day is usually about 0.1 g to 20 mg, preferably about 1 g to 10 mg in terms of the amount of the compound represented by (I) or a pharmaceutically acceptable acid addition salt thereof, which may be administered at once or in several times.

(27) As the therapeutic or prophylactic agent for a biliary tract disease(s), the compound represented by (I) or a pharmaceutically acceptable acid addition salt thereof may be administered either alone or in combination with one or more drugs which are used for therapy or prophylaxis of a disease(s), or for alleviation or inhibition of a symptom(s).

(28) Examples of the drugs include cholagogues such as trepibutone (therapeutic agent for pancreatic/biliary tract diseases), hymecromone (therapeutic agent for biliary tract diseases), flopropione (pancreaticobiliar/urinary tract antispasmodic), tiquizium (antimuscarinic agent), oxapium (antispasmodic anticholinergic agent), gabexate (protease inhibitor), dehydrocholic acid, anetholtrithion, ursodeoxycholic acid and chenodeoxycholic acid.

(29) Examples of the drugs also include morphine, pentazocine, buprenorphine, oxycodone, fentanyl, remifentanil, tramadol, butorphanol and eptazocine, which are drugs to be administered for alleviation of pain due to biliary tract diseases and, at the same time, having side effects that promote contraction of sphincter of Oddi. It is also possible, by combining these drugs with our agent, to suppress side effects.

(30) These are merely examples and should not be interpreted in any restrictive way. The method for combining the drugs may be either combined use of the drugs or use of the drugs as a mixture.

(31) The fact that a compound represented by (I) or a pharmaceutically acceptable acid addition salt thereof as an effective component of the therapeutic or prophylactic agent is effective for therapy and/or prophylaxis of a biliary tract disease(s) can be confirmed by the method described in Examples below. The rabbit model for contraction of sphincter of Oddi is commonly used in basic research on biliary tract diseases (Wei J G et al., World J. Gastroenterol., 6, 102 (2000)), and, in cases where the drug shows an action to inhibit contraction of sphincter of Oddi in this model, the drug can be said to have a therapeutic and/or prophylactic effect on biliary tract diseases.

EXAMPLES

(32) Our agents and methods will now be described concretely by way of an Example.

Example 1

Effect of ()-17-(cyclopropylmethyl)-3,14-dihydroxy-4,5-epoxy-6-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride (Compound 1) on the Contraction of Sphincter of Oddi in Rabbits

(33) The method described in Wei J G et al., World J. Gastroenterol., 6, 102 (2000) was partially modified and used for measurement of a change in the perfusion pressure in sphincter of Oddi. The change in the perfusion pressure reflects the motility of a contractive change of sphincter of Oddi.

(34) Male NZW rabbits (Japan SLC) which had body weights of 2.0 to 2.5 kg upon delivery were fasted from the evening of the day before the experiment. The experiment was carried out under anesthesia with pentobarbital, with artificial ventilation. Each rabbit was immobilized in the supine position and subjected to abdominal incision to expose the periduodenal area and the common bile duct. A small incision was made in the common bile duct, and a cannula was inserted into the common bile duct toward the duodenum side, followed by indwelling its tip in sphincter of Oddi (sphincter ampullae). For biliary excretion, another cannula was inserted into the bile duct toward the gallbladder side and immobilized. From the other end of the cannula whose tip was indwelled in the sphincter of Oddi, physiological saline was continuously injected at a flow rate of 6 mL/hour to allow perfusion in the sphincter of Oddi. By recording the perfusion pressure with a blood pressure monitoring transducer (DX-300, Nihon Kohden Corporation), the contraction reaction of sphincter of Oddi was measured.

(35) To the rabbit, 5% aqueous mannitol solution, which is the vehicle for the Compound 1 solution, was administered via the jugular vein. Further, not less than 30 minutes after the administration of the vehicle, Compound 1 was administered to the same individual at a dose of 0.2 g/kg via the jugular vein. The administration volume of the vehicle and Compound 1 was 1 mL/kg, and the administration was carried out for 60 seconds.

(36) FIG. 1 shows the result of calculation of the rate of change in the maximum perfusion pressure (Oddi muscle contraction (Delta %)) based on comparison between the value observed during the 3 minutes immediately before beginning of the administration and the value observed during the 3 minutes immediately after beginning of the administration (meanstandard error; N=11 cases). In contrast to the fact that the rate of change in the maximum perfusion pressure was 93.32% on average in the case of intravenous administration of 0.2 g/kg Compound 1, the rate of change in the maximum perfusion pressure was 99.81% on average in the case of administration of the vehicle. Thus, in the Compound 1-administered group, the rate of change in the maximum perfusion pressure was lower compared to the vehicle-administered group, and this difference was significant (*p<0.05, paired t-test). This indicates that Compound 1 has an action to inhibit contraction of sphincter of Oddi.

(37) Oxapium iodide, which has an action to inhibit contraction of sphincter of Oddi and is currently clinically used as a therapeutic agent for biliary tract diseases, reduces the sphincter of Oddi perfusion pressure by about 10 mmH.sub.2O (corresponds to 0.74 mmHg) when it is intravenously administered to a dog at a dose of 0.3 mg/kg (Tamasawa Y. et al., Kiso to Rinsho, 6, 128 (1972)). Further, gabexate mesilate reduces the sphincter of Oddi perfusion pressure by 6.9 mmH.sub.2O (corresponds to 0.51 mmHg) or 10.6 mmH.sub.2O (corresponds to 0.78 mmHg) when it is intravenously administered to a dog at a dose of 1 mg/kg or 3 mg/kg, respectively (Yamasato T. et al., J Smooth Muscle Res., 27, 87 (1991). Since oxapium iodide is usually orally administered at a dose of 30 to 60 mg per adult per day dividedly in 3 times, and 100 mg of gabexate mesilate is usually dissolved in 500 mL of Ringer's solution and the resulting solution is administered by intravenous drip infusion at a rate of not more than 8 mL/minute, the above-described doses are considered to be equivalent to the clinical doses of those drugs.

(38) In this Example, by intravenous administration of 0.2 g/kg of Compound 1 to rabbits, the actual value of the maximum perfusion pressure was reduced by 0.95 mmHg on average. This result therefore indicates that, by using Compound 1, a therapeutic and prophylactic effect on biliary tract diseases can be clinically expected.

(39) Compound 1 has a structure represented by (II) below:

(40) ##STR00007##

INDUSTRIAL APPLICABILITY

(41) We provide an excellent therapeutic effect on biliary tract diseases and is useful for therapy and/or prophylaxis of biliary tract diseases.