Therapeutical or preventive means for diseases of biliary tracts

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to therapeutic or preventive means in case of disease(s) of biliary tracts, which are caused or are aggravated by sphincter of Oddi contraction. As effective component, claimed means contains compound, presented by general formula

.

In formula (I) double line, which contains from dotted line and solid line, represents double bond or single bond, R1 represents C4-C7-cycloalkylalkyl, R2 represents linear or branched C1-C5-alkyl, and B represents - CH=CH-.

EFFECT: invention also relates to compound of formula (I) and to method of treatment or prevention in case of disease(s) of biliary tracts, which are caused or intensified by sphincter of Oddi contraction.

6 cl, 1 dwg, 1 ex

 

The technical field to which the invention relates

The present invention relates to a therapeutic or preventive agent for a disease (one or more) of the biliary tract, containing an effective component, which is a derivative morphinan, or its pharmaceutically acceptable acid-additive salt.

Background of the invention

The term "biliary tract disease" is a group name for diseases of the digestive system, which affects the gall bladder, bile duct, pancreas, or pancreatic duct. Known example of a pathogenetic factor in diseases of the biliary tract is increased pressure in the biliary tract, due to the reduced sphincter of Oddi in the papilla of the duodenum, which is the most far on the path of excretion of bile via the bile ducts and which corresponds to the distal part of bile duct, formed by the confluence of the common bile duct and pancreatic duct. Known examples of diseases of the biliary tract caused by contraction of the sphincter of Oddi, include obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, and cholecystitis. Therefore, it is known that drugs that inhibit with�increment of the sphincter of Oddi, can be used as therapeutic agents in diseases of the biliary tract caused by contraction of the sphincter of Oddi.

In addition, examples of diseases of the biliary tract, the cause of which is not the contraction of the sphincter of Oddi, but which can be exacerbated with contraction of the sphincter of Oddi, include primary biliary cirrhosis (which is referred to in this document may be referred to by the acronym PBC). PBC is a disease in which damaged interlobular bile ducts in the path of the higher excretion of bile common bile duct inside the liver, and comes stagnation of bile. Obstruction of the common bile duct is known to exacerbate the BS (non-Patent document 1). So I think that drugs that inhibit the contraction of the sphincter of Oddi, can relieve obstruction of the common bile duct and through this, they can inhibit the exacerbation of RVS.

Derivatives morphinan and their pharmaceutically acceptable acid-additive salts, which are effective components of the present invention (hereinafter in this document may be referred to as "compounds according to the present invention"), with their agonist activity of κ-opioid receptors, have been disclosed for use as analgesics and diuretics (Patent document 1)./p>

In addition, they have already been disclosed for use in anti-cough (Patent document 2), as a means of protecting brain cells (Patent document 3), as antipruritic agents (Patent document 4), therapeutic agents for hyponatremia (Patent document 5), antagonists of the receptor ORL-1 (Patent document 6), therapeutic agents for neuropathic pain (Patent document 7), antipruritic agents to the cornea and conjunctiva (Patent document 8), therapeutic agents for psychoneurotic disorders (Patent document 9), therapeutic agents for drug or drug dependence (Patent document 10), therapeutic agents for sepsis (Patent document 11), therapeutic agents for itching in multiple sclerosis (Patent document 12), therapeutic agents for schizophrenia (Patent document 13) and therapeutic agents for psoriasis (Patent document 14). However, have not yet been disclosed therapeutic or preventive effects against diseases of the biliary tract.

Examples of drugs that inhibit the contraction of the sphincter of Oddi and are used as therapeutic agents in diseases of the biliary tract include medicines (such as threebutton), which contribute to W�the grip of CA 2+in places intracellular storage of CA; drugs (such as hymecromone) that inhibit the binding of CA2+with contractile proteins in the extracellular fluid; drugs (such as floration) that inhibit catechol-O-methyltransferase (hereinafter in this document may be indicated by the abbreviation "IRTS") and have antiserotonin action; drugs (such as Hikvision) that have antimuscarinic effects; drugs (such as exopium) who are atropine-like action and papaverinopodobnymi action; drugs (such as gabexate) that inhibit trypsin and kallikrein, although the mechanism of inhibition of the contraction of the sphincter of Oddi is unknown. However, these substances are drugs that do not have any structural similarity with the compounds according to the present invention, or agonist activity of κ-opioid receptors.

In addition, since it is known that opioids cause contraction of the sphincter of Oddi and therefore may exacerbate diseases of the biliary tract, the use of opioids in patients suffering from diseases of the biliary tract, requires caution. Messages, containing information about opioids, were as follows.

It has been described that since morphine, which �has morfinovoi structure, similar to the structure of the compounds according to the present invention, but which differ from the compounds according to the present invention in that it is an agonist of μ-opioid receptors, it can cause spasm of the biliary tract in patients suffering from a disorder of the gallbladder or biliary disease, and therefore, such patients should be entered with care (non-Patent document 2).

It has also been described, what is oxycodone, which is an agonist of μ-opioid receptors, with morfinovoi structure, can cause contraction of the sphincter of Oddi and thereby exacerbate symptoms in patients suffering from gallbladder disorder, cholelithiasis or pancreatitis, and therefore, such patients should be entered with care (non-Patent document 3). Similarly, it was described that the buprenorphine, which is a partial agonist of µ-opioid receptors, with morfinovoi structure, in experiments with animals (dogs) in high doses (not less than 0.1 mg/kg intravenously) causes contraction of the sphincter of Oddi, and therefore, patients suffering from diseases of the biliary tract, it must be administered with caution (non-Patent document 4). It has also been described that tramadol, which is an agonist of μ-opioid receptors, not having machinenbau �of structure, in experiments with animals in high doses, causes contraction of the sphincter of Oddi, and therefore, patients suffering from diseases of the biliary tract, it must be administered with caution (non-Patent document 5). Similarly, it was described that pentazocine, which is a partial agonist of µ-opioid receptors that do not have machinenbau patterns, in high doses, can cause contraction of the sphincter of Oddi, and therefore, patients suffering from diseases of the biliary tract, it must be administered with caution (non-Patent document 6).

It has been described that the agonist of κ-opioid receptors, not having machinenbau patterns, can be used as therapeutic agents for gastrointestinal dysfunction, and examples of gastrointestinal dysfunction include reducing sphincter of Oddi (Patent documents 15 to 18). However, there is no description of inhibiting contraction of the sphincter of Oddi.

In addition, there is a message that nalbuphine, which is known to have morfinovoi structure and possesses agonist activity of κ-opioid receptors and partial agonist activity of μ-opioid receptors, has no effect on the contraction of the sphincter of Oddi (non-Patent document 7); and there is a message showing that it is 6% increases the internal pressure of the biliary tract, hotelit the effect is not statistically significant (non-Patent document 8). However, there are no reports indicating that nalbuphine inhibits the contraction of the sphincter of Oddi. In addition, as butorphanol, which belong to the class of agonists κ-opioid receptors, was significantly increased internal pressure of the biliary tract by 12% (non-Patent document 8), it was shown that it caused the contraction of the sphincter of Oddi. It has also been described that since tazocin, which, as we know, does not have machinenbau structure, but acts on the opioid κ receptor as agonist at high doses in experiments with animals demonstrates the action that causes the contraction of the sphincter of Oddi, patients suffering from disease of the biliary tract, it should be administered with caution (non-Patent document 9).

Latinastolen and matinenance, which are peptide agonists of δ-opioid receptors was reported to cause a transient contraction of the sphincter of Oddi, followed by a demonstration of continuous inhibition of the reduction (non-Patent document 10). In addition, the naloxone is an antagonist of μ-opioid receptors, with morfinovoi structure, as it is known, also inhibits the contraction of the sphincter of Oddi (non-Patent document 11).

Thus, absent any evidence of inhibition of the contraction of the sphincter� Oddi agonists κ-opioid receptors, having morfinovoi structure and are similar to the compounds according to the present invention.

It was revealed that the compounds according to the present invention show an antagonistic effect on the receptor ORL-1. Because nociceptin (sometimes referred to as organism FQ) is an endogenous peptide agonist of this receptor, is expressed in excitatory motor neurons in the intermuscular plexus of the sphincter of Oddi and inhibits cholinergic neurotransmission, suggesting that nociceptin can act on the sphincter of Oddi by autoinhibitory by a feedback mechanism (non-Patent document 12).

Thus, it is believed that agonists of the receptor ORL-1 inhibit the contraction of the sphincter of Oddi, but don't assume that the contraction of the sphincter of Oddi inhibited the antagonistic effect on the receptor ORL-1.

Prototype documents

[Patent documents]

[Patent document 1] WO 93/015081

[Patent document 2] WO 95/001178

[Patent document 3] WO 95/003307

[Patent document 4] WO 98/023290

[Patent document 5] WO 99/005146

[Patent document 6] JP 2000-53572 A

[Patent document 7] WO 01/014383

[Patent document 8] JP 2001-163784 A

[Patent document 9] WO 02/078744

[Patent document 10] WO 99/011289

[Patent document 11] WO 02/089845

[Patent document 12] WO 06/095836

[P�issued document 13] WO 09/001764

[Patent document 14] WO 08/133297

[Patent document 15] WO 05/004796

[Patent document 16] WO 05/049564

[Patent document 17] WO 05/023799

[Patent document 18] WO 04/093796

[Non-patent documents]

[Non-patent document 1] Hastier P, et al., Dig Dis Sci., 43, 2426 (1998)

[Non-patent document 2] JAPIC ethical drugs in Japan 2010, revision and publication of the Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2705, the hydrate of the hydrochloride of morphine.

[Non-patent document 3] JAPIC ethical drugs in Japan 2010, revision and publication of the Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 618, the hydrate of the hydrochloride of oxycodone.

[Non-patent document 4] JAPIC ethical drugs in Japan 2010, revision and publication of the Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2166, buprenorphine hydrochloride.

[Non-patent document 5] JAPIC ethical drugs in Japan 2010, revision and publication of the Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 1713, hydrochloride tramadol.

[Non-patent document 6] JAPIC ethical drugs in Japan 2010, revision and publication of the Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2448, pentazocine.

[Non-patent document 7] Isenhower HL et al., Am J Health-Syst Pharm., 55, 480 (1998)

[Non-patent document 8] Thompson Dr., Am J Gastroenterol., 96, 1266 (2001)

[Non-patent document 9] JAPIC ethical drugs in Japan 2010, revision and publication of the Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 549, Hydrobromic of eptazocine.

[Non-patent document 10] Behar J, et al., Gastroenterol., 86, 134 (1984)

[Non-patent docum�NT 11] Behar J, et al., Motility of the Digestive Tract., New York: Raven, (1982), p. 397

[Non-patent document 12] O'donnell AM, et al., J Comp Neurol., 29, 430 (2001)

Summary of the invention

The problem solved by the invention

The aim of the present invention is the provision of a therapeutic or preventive agent having an effect in the disease (one or more) of the biliary tract and containing as an effective component, a specific compound having morfinovoi structure, or its pharmaceutically acceptable acid-additive salts.

Means to solve the above mentioned problems

Through intensive research, with the objective of fulfilling the above objectives, the authors present invention found that specific compounds having morfinovoi structure, and their pharmaceutically acceptable acid-additive salts have excellent therapeutic effects in diseases of the biliary tract, and thus was established the present invention.

In accordance with this present invention relates to information set forth in items below. [1]-[5]

[1] a Therapeutic or prophylactic agent for a disease (one or more) of the biliary tract, and as an effective component the tool contains a compound represented by following General formula (I):

[where the double line composed of a dashed line and a solid line represents a double bond or single bond, R1represents C4-C7-cycloalkenyl, R2represents a linear or branched C1-C5-alkyl, and B represents-CH=CH-]

or its pharmaceutically acceptable acid-additive salt.

[2] therapeutic or prophylactic agent for a disease (one or more) of the biliary tract according to claim [1], where in the General formula (I) R1represents cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and R2is methyl, ethyl or propyl.

[3] therapeutic or prophylactic agent for a disease (one or more) of the biliary tract according to claim [1], where the connection represented by the General formula (I) represents the (-)-17-(cyclopropylmethyl)-3,14 β-dihydroxy-4,5 α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamido]morphinan.

[4] therapeutic or prophylactic agent for a disease (one or more) of the biliary tract according to any one of claims. [1]-[3], where the specified disease (one or more) of the biliary tract is a blockage of the bile ducts, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis and/or primary biliary cirrhosis.

[5] a Therapeutic or prophylactic agent for a disease (one or more) of the biliary tract according to any one of claims. [1]-[3], wherein the tool has a therapeutic or preventive effect of the disease (one or more) of the biliary tract by inhibiting contraction of the sphincter of Oddi.

[6] a Compound represented by following General formula (I):

[where the double line composed of a dashed line and a solid line represents a double bond or single bond, R1represents C4-C7-cycloalkenyl, R2represents a linear or branched C1-C5-alkyl, and B represents-CH=CH-]

or its pharmaceutically acceptable acid-additive salt, and the specified connection or its pharmaceutically acceptable acid-additive salt used for the treatment or prophylaxis of a disease (one or more) of the biliary tract.

[7] a method for the treatment or prophylaxis of a disease (one or more) of the biliary tract, and said method includes the introduction of an effective amount of compounds represented by following General formula (I):

[where the double line composed of a dashed line and a solid line represents a double bond or single SV�of his favorite roles R1represents C4-C7-cycloalkenyl, R2represents a linear or branched C1-C5-alkyl, and B represents-CH=CH-]

or its pharmaceutically acceptable acid-additive salts to a patient in need of therapeutic or prophylactic agent for the disease (one or more) of the biliary tract.

The effect of the invention

The present invention provides a significant therapeutic or preventive effect against diseases of the biliary tract.

Brief description of the drawings

Fig. 1 is a graph showing the effect of Compound 1 on the contraction of the sphincter of Oddi the rabbit in Example 1. The abscissa is indicated the test compound, and the ordinate indicates the degree of change of the maximum perfusion pressure (contraction of the muscle of Oddi (Delta %)), based on comparison of values observed for 3 minutes immediately before intravenous injection of the test compounds, with the value observed for 3 minutes immediately after the start of injection (mean value ± standard error; N=11, *p<0,05, bilateral student test).

Best mode for carrying out the invention

Therapeutic or prophylactic agent according to the present Fig�structure for the disease (one or more) of the biliary tract contains as an effective component the compound represented by the General formula (III), or its pharmaceutically acceptable acid-additive salt.

[where the double line composed of a dashed line and a solid line represents a double bond or single bond.

R1represents C1-C5-alkyl, C4-C7-cycloalkenyl, C5-C7-cycloalkenyl, C6-C12-aryl, C7-C13-aralkyl, C4-C7-alkenyl, allyl, furan-2-illlil (alkyl fragment has 1 to 5 carbon atoms) or a thiophene-2-illlil (alkyl fragment has from 1 to 5 carbon atoms).

R14represents hydrogen, a hydroxy-group, nitro group, C1-C5-alkanoyloxy, C1-C5-alkoxygroup, C1-C5-alkyl or NR9R10. Here R9represents hydrogen or C1-C5-alkyl, R10represents hydrogen, C1-C5-alkyl or -(C=O)R11, R11represents hydrogen, phenyl or C1-C5-alkyl.

R3represents hydrogen, a hydroxy-group, C1-C5-alkanoyloxy or C1-C5-alkoxygroup.

A represents-XC(=Y)-, -XC(=Y)Z-, -X - or-xso extension2- (where each of X, Y and Z independently represents NR4, S or O, where R4represents hydrogen, Lin�any or branched C 1-C5-alkyl or C6-C12-aryl, and in the case where the formula has two or more radicals R4they may be the same or different.

B represents a valence bond, a linear or branched C1-C14-alkylene (which may be substituted by at least one Deputy, selected from the group consisting of C1-C5-alkoxygroup, C1-C5-alkanoyloxy, hydroxy-group, fluorine, chlorine, bromine, iodine, amino group, nitro group, cyanide groups, triptoreline and fenoxaprop, and from 1 to 3 methylene groups may be replaced by carbonyl); a linear or branched acyclic unsaturated C2-C14-hydrocarbon containing from 1 to 3 double bonds and/or triple bonds (which may be substituted by at least one Deputy, selected from the group consisting of C1-C5-alkoxygroup, C1-C5-alkanoyloxy, hydroxy-group, fluorine, chlorine, bromine, iodine, amine group, nitro group, cyanide groups, triptoreline and fenoxaprop, and from 1 to 3 methylene groups may be replaced by carbonyl; or a linear or branched, saturated or unsaturated C1-C14-hydrocarbon containing from 1 to 5 thioether linkages, simple ester linkages and/or amine linkages (where none of the heteroatoms are not linked to the benefits from cyc�tively, and 1 to 3 methylene groups may be replaced by a carbonyl).

R5represents hydrogen or an organic group having any of the following principal structures (where Q is an N, O or S; T represents CH2NH, S or O; 1 is an integer from 0 to 5; each value of m and n independently represents an integer from 0 to 5; the sum of m and n does not exceed 5; and each organic group may be substituted by at least one Deputy, selected from the group consisting of C1-C5-alkyl, C1-C5-alkoxygroup, C1-C5-alkanoyloxy, hydroxy-group, fluorine, chlorine, bromine, iodine, amino group, nitro group, cyanide groups, isothiocyanato, trifloromethyl, cryptometer and methylendioxy).

R6represents hydrogen, and R7represents hydrogen, a hydroxy-group, C1-C5-alkoxygroup or C1-C5-alkanoyloxy; or R6and R7together represent-O-, -CH2- or-S-.

R8represents hydrogen, C1-C5-alkyl or C1-C5-alkanoyl.

R12and R13together represent hydrogen; one of these radicals represents hydrogen and the other represents a hydroxy-group; or they are both PR�astavliaut oxoprop.

General formula (III) includes (+), (-) and (±) isomers.]

The double line composed of a dashed line and a solid line in the General formula (III) represents a double bond or single bond (preferably a double line represents a single bond).

Therapeutic or prophylactic agent according to the present invention for the disease (one or more) of the biliary tract, preferably, contains, among the compounds represented by the General formula (III) and their pharmaceutically acceptable acid-additive salts, the connection represented by the above General formula (I) or its pharmaceutically acceptable acid-additive salt as an effective component.

The double line composed of a dashed line and a solid line in the General formula (I) represents a double bond or single bond (preferably a double line represents a single bond).

In the General formula (I) R1represents C4-C7-cycloalkenyl. Among them, R1represents, preferably, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl (particularly preferred cyclopropylmethyl).

R2represents a linear or branched C1-C5-alkyl. R2represents, preferably, methyl, ethyl and�and propyl. Among them, preferred is methyl.

B represents-CH=CH-. Preferably, B represents TRANS-CH=CH-.

The connection represented by the General formula (I), particularly preferably represents a (-)-compound wherein the double line composed of a dashed line and a solid line represents a single bond; R1represents a cyclopropylmethyl; R2is methyl; and B represents TRANS-CH=CH-. This means that a particularly preferred compound represented by the General formula (I) is (-)-17-(cyclopropylmethyl)-3,14 β-dihydroxy-4,5 α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamido]morphinan. However, the present invention is not limited to this connection.

These compounds represented by the General formula (I) and their pharmaceutically acceptable acid-additive salts can be obtained according to the method described in JP 2525552 B. Among the compounds represented by the General formula (III), compounds in which R12and R13together represent hydrogen, can be obtained according to the method described in JP 2525552 B. Among the compounds represented by the General formula (III), compounds in which R12and R13together represent oxoprop, can be obtained, for example, using as starting material a compound having 10-oxoprop, poluchennogo described in the 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. in addition, among the compounds represented by the General formula (I), the compounds where R12represents a hydroxy-group, and R13represents hydrogen, can be obtained according to the method described in Chem. Pharm. Bull., 52, 664 (2004).

Examples of pharmaceutically acceptable acid-additive salts, in the present invention include salts of inorganic acids, such salt is hydrochloric acid salt, sulfuric acid salt, nitric acid salt, Hydrobromic acid salt itestosterone acid salt and phosphoric acid; salts of organic carboxylic acids, such as salt of acetic acid, salt, lactic acid, salt of 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; and salts of organic sulfonic acids, such as salt, methanesulfonic acid salt econsultancy acid salt of mixture of Benzenesulfonic acid salt, p-toluensulfonate acid and salt camphorsulfonic acid. Of these, preferred for use are the salt of hydrochloric acid, Hydrobromic acid salt, salt of phosphoric acid�located the whereabouts, salt of tartaric acid salt, methanesulfonic acid, etc., but (needless to say) pharmaceutically acceptable acid-additive salt according to the present invention is not limited to these salts.

The term "biliary tract disease" in the present invention includes diseases of the digestive system, which affects the gall bladder, bile duct, pancreas, or pancreatic duct. Among these diseases therapeutic or preventive agent according to the present invention for the disease (one or more) of the biliary tract is preferably applicable when the disease (one or more) of the biliary tract, which is manifested, or exacerbated due to contraction of sphincter of Oddi (particularly preferably, when blockage of the bile ducts, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis, primary biliary cirrhosis, and/or similar diseases).

The connection represented by the General formula (I) or its pharmaceutically acceptable acid-additive salt is purified to a level suitable for medical use and, after passing the necessary safety tests, this compound or its acid-additive salt can be administered orally or parenterally in �x native form or in the form of pharmaceutical compositions prepared as a mixture with known pharmaceutically acceptable acid (one or more), a carrier (one or more filler (one or more) and/or T. p. Example of their preparations include tablets, capsules, pills, crumbling in your mouth, powders and pellets (in the case of oral administration), as well as finished products for rapid intravenous infusion, long-term intravenous infusion, intramuscular injection, subcutaneous injection or intradermal injection, tape and plasters (in case of parenteral administration). However, the finished shape is certainly not limited to them.

The content of the compound represented by the General formula (I) or its pharmaceutically acceptable acid-additive salt is not limited, and is usually specified compound or its acid-additive salt can be produced in such a way that the administered dose ranged from 0.1 μg to 100 mg. the Dose may be appropriately selected depending on symptoms, age and body weight of the patient, method of administration and/or the like, and the usual daily dose for an adult can range from about 0.1 µg to 20 mg (preferably, from about 1 µg to 10 mg) in units of the number of compounds represented by the General formula (I) or its pharmaceutically acceptable acid-additive salts, which can be entered once or in several PR�reservoirs.

As a therapeutic or prophylactic agent for a disease (one or more) of the biliary tract according to the present invention, the compound represented by the General formula (I) or its pharmaceutically acceptable acid additive salt can be entered either individually or in combination with one or more drugs used for the treatment or prophylaxis of a disease (one or more) or for alleviating or inhibiting the symptoms (one or more).

Examples of these medicines include cholagogue, such as threebutton (therapeutic agent for diseases of the pancreas and biliary tract), hymecromone (therapeutic agent for diseases of the biliary tract), floration (antispasmodic for the pancreas and its ducts, biliary and urinary tract), Hikvision (antimuscarinic agent), oxepin (antispasmodic anticholinergic agent), gabexate (protease inhibitor), dehydrocholic acid, retaliation, ursodeoxycholic acid and chenodeoxycholic acid.

Examples of these drugs include morphine, pentazocine, buprenorphine, oxycodone, fentanyl, Remifentanil, tramadol, butorphanol and eptazocine, which are drugs injected for pain relief, abusable�Noah diseases of the biliary tract, and at the same time, with side effects that contribute to the reduction of the sphincter of Oddi. Combining these drugs with medicament according to the present invention, it is also possible to suppress the side effects.

The information presented is given merely as examples, and should not be interpreted in any limiting manner. A method of combining drugs can be either the use, or the use of these medicines in the form of a mixture.

The fact that the connection represented by the General formula (I) or its pharmaceutically acceptable acid-additive salt as an effective component of a therapeutic or prophylactic agent according to the present invention is effective for the treatment and/or prophylaxis of a disease (one or more) of the biliary tract can be confirmed by the method described below in the "Examples" section. Model reduction of the sphincter of Oddi in rabbits is widely used in basic research of diseases of the biliary tract (Wei JG, et al., World J. GastroenteroI., 6, 102 (2000)), in the case where the drug demonstrated an inhibitory effect against contractions of the sphincter of Oddi in this model, it can be argued that this medicine has patients�vicissim and/or preventive effect against diseases of the biliary tract.

Examples

The present invention will be further described on a specific Example.

Example1

The influence of the hydrochloride of (-)-17-(cyclopropylmethyl)-3,14 β-dihydroxy-4,5 α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamido]morphinan (Compound 1) on the contraction of the sphincter of Oddi in rabbits

This method is described in publication Wei JG, et al., World J. GastroenteroI., 6, 102 (2000), was partially modified and used to measure changes in perfusion pressure in the sphincter of Oddi. The change in perfusion pressure reflects the variability of the contractility of the sphincter of Oddi.

Male NZW rabbits (Japan SLC), which had a body weight of 2.0 to 2.5 kg, after receipt in the laboratory have not received food from the evening preceding the experiment. The experiment was conducted under anesthesia with pentobarbital artificial ventilation. Each rabbit immobilizovana in the supine position and performed abdominal incision, exposing periduodenal region and the common bile duct. In the common bile duct was doing a small cut and he was injected with a cannula in the direction of the duodenum, leaving the top in the sphincter of Oddi (in the ampulla sphincter). For excretion of bile another cannula was introduced and immobilizovana in the bile duct in the direction of the gallbladder. At the other end of the cannula, the top of which was introduced in the sphincter of Od�and, continuously injected with a physiological salt solution at a rate of 6 ml/hour, while perfusion in the sphincter of Oddi. The contractile response of the sphincter of Oddi was measured by recording the perfusion pressure by monitoringo pressure sensor blood (DX-300, Nihon Kohden Corporation).

In the rabbit jugular vein was injected with 5% aqueous solution of mannitol, who served as environment for solution of Compound 1. Then, no later than 30 minutes after injection of the solvent, the same animal in the jugular vein was injected with Compound 1 at a dose of 0.2 mcg/kg injection volume of the solvent and the Compound 1 was 1 ml/kg, duration of injection was 60 seconds.

Fig. 1 shows the result of calculating the degree of change in the maximum perfusion pressure (contraction of the muscle of Oddi (Delta %)), based on comparison of values observed for 3 minutes immediately before the start of the introduction, with the value observed for 3 minutes immediately after the start of administration (mean ± standard error; N=11 cases). Unlike change the maximum perfusion pressure when administered intravenously to 0.2 mg/kg of Compound 1 (average 93,32%), with the introduction of solvent average change maximum perfusion pressure was 99,81%. Thus, in the group with the introduction of Compound 1 degree change in the maximum perfusion pressure beyond�I was less than in the group with the introduction of the solvent, and this difference was statistically significant (*p<0,05, paired student's criterion). This indicates that Compound 1 has the ability to inhibit the contraction of the sphincter of Oddi.

Iodide okapia, which has the ability to inhibit the contraction of the sphincter of Oddi and which is used as a therapeutic agent in diseases of the biliary tract, when administered intravenously to the dog at a dose of 0.3 mg/kg reduces the perfusion pressure of the sphincter of Oddi approximately 10 mm H2O (0.74 mm Hg) (Tamasawa Y. et al., Kiso to Rinsho, 6, 128 (1972)). Furthermore, the introduction of the dog nelfinavir of gabexate at a dose of 1 mg/kg or 3 mg/kg reduces the perfusion pressure of the sphincter of Oddi 6.9 mm H2O (0.51 mm Hg) or 10.6 mm H2O (0,78 mm Hg), respectively (T. Yamasato et al., J Smooth Muscle Res., 27, 87 (1991). As an adult iodide okapia usually administered orally at a dose of 30 to 60 mg, divided into 3 doses, and 100 mg of nelfinavir gabexate usually dissolved in 500 ml of ringer's solution and the solution obtained as a result of this, is administered by intravenous drip infusion at a maximum speed of 8 ml/min, the above doses are considered equivalent to clinical doses of these medicines.

In the present Example, when administered intravenously to rabbits to 0.2 mg/kg of Compound 1 the real value of the maximum perfusion pressure reducin�axis on average 0.95 mm Hg. This result indicates that the application of Compound 1 can be clinically expected therapeutic and prophylactic effect against diseases of the biliary tract.

Compound 1 has a structure represented by following Formula (II).

Applicability in a production environment

The present invention provides excellent therapeutic effect against diseases of the biliary tract and can be used for the treatment and/or prevention of diseases of the biliary tract.

1. Therapeutic or prophylactic agent for the disease(ies) of the biliary tract, which are caused or exacerbated by the contraction of the sphincter of Oddi, and the specified agent contains as an effective component a compound represented by following General formula (I):

where the double line composed of a dashed line and a solid line represents a double bond or single bond, R1represents C4-C7-cycloalkenyl, R2represents a linear or branched C1-C5-alkyl, and b is a - CH=CH-,
or its pharmaceutically acceptable acid-additive salt.

2. The tool of claim 1, wherein in the General formula (I) R1represents cyclopropylmethyl, cyclobutylmethyl, cyclopent�lmutil or cyclohexylmethyl, a R2is methyl, ethyl or propyl.

3. A compound according to claim 1, where the specified compound represented by the General formula (I) is (-)-17-(cyclopropylmethyl)-3,14 β-dihydroxy-4,5 α-epoxy-6β-[N-methyl-TRANS-3-(3-furyl)acrylamido]morphinans.

4. Tool according to any one of claims. 1-3, where the specified disease (one or more) of the biliary tract is a blockage of the bile ducts, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis and/or primary biliary cirrhosis.

5. The connection represented by following General formula (I):

where the double line composed of a dashed line and a solid line represents a double bond or single bond, R1represents C4-C7-cycloalkenyl, R2represents a linear or branched C1-C5-alkyl, and b is a-CH=CH-,
or its pharmaceutically acceptable acid-additive salt, and the specified connection or its pharmaceutically acceptable acid-additive salt is used to treat or prevent the disease(ies) of the biliary tract, which are caused or exacerbated by the contraction of the sphincter of Oddi.

6. A method for the treatment or prevention of disease(ies) of the biliary tract, which are caused or amostra�tsya contraction of the sphincter of Oddi, wherein said method comprises administration to a patient in need of therapeutic or prophylactic agent in the disease(ies) of the biliary tract, an effective amount of compounds represented by following General formula (I):

where the double line composed of a dashed line and a solid line represents a double bond or single bond, R1represents C4-C7-cycloalkenyl, R2represents a linear or branched C1-C5-alkyl, and b is a-CH=CH-, or its pharmaceutically acceptable acid-additive salt.



 

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10 cl, 11 ex, 4 tbl, 20 dwg

FIELD: medicine, pharmaceutics.

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19 cl, 20 ex, 12 tbl

FIELD: medicine, pharmaceutics.

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FIELD: medicine, pharmaceutics.

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3 cl, 9 dwg, 1 ex

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5 tbl, 2 ex

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19 cl, 6 tbl, 2 ex

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