DESCRIPTION
THERAPEUTIC OR PROPHYLACTIC AGENT FOR BILIARY TRACT
DISEASES
TECHNICAL FIELD
[0001]
The present invention relates to a therapeutic or prophylactic agent for a
biliary tract diseases) comprising as an effective component a morphinan derivative
or a pfaarmaceutically acceptable acid addition salt thereof
BACKGROUND ART
[0002]
The biliary tract disease is a collective term for digestive diseases that oceur
in the gallbladder, bite dact, pancreas or pancreatic dnct A known example of the
cause of occurrence of a binary tract disease is increased biliary tract pressure due to
contraction of sphincter of Oddi in the duodenal papilla, which is the furthest
downstream of the biliary tract and corresponds 60 the distal part of the bile duct
formed by confluence of the common bile dnct and pancreatic duct Known
examples of die biliary tract disease censed by contraction of sphincter of Oddi
include biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary
dyskinesia, cholangitis and cholecystitis. Thetefore, drugs that inhibit contraction
of sphincter of Oddi are known to be useful as therapeutic agents for biliary tract
diseases caused by contraction of sphincter of Oddi
[0003]
Farther, examples of biliary tract diseases which are not caused by contraction
of sphincter of Oddi but may be exacerbated by contraction of sphincter of Oddi
include primary biliary cirrhosis (which may hereinafter be referred to as PBC).
PBC is a disease wherein interlobular bile ducth, which are bile ducts positioned
upstream of the common bile duct and inside the liver, are destroyed and bile statis
occurs. Obstruction of the common bile duct is known to cause exacerbation of
PBC (Non-patent Document 1). Therefore, it is thought that drugs that inhibit
contraction of sphincter of Oddi may ameliorate obstruction of the common bile duct
and hence inhibit exacerbation of PBC.
[0004]
Morphinan derivatives and pharmaceuticallyacceptable acid addition salts
thereof as effective components of the present invention (winch may hereinafter be
referred to as "compounds of the present invention"), with their ? opioid receptor
agonist activity, has been disclosed so far for uses as analgesics and diuretics (Patent
Document 1).
Further, they have already been disclosed also for uses in antitussives (Patent
Document 2), brain cell protecting agents (Patent Document 3), antipruritics (Patent
Document 4), therapeutic agents for hyponatremia (Patent Document 5). ORL-1
receptor antagonists (Patent Document 6) therapeutic agents for neuropathic rain
(Patent Document 7), antipruritics for cornea and conjunctiva (Patent Document 8),
therapeutic agents for psychoneurotic disorders (Patent Document 9), therapeutic
agents for drug dependence (Patent Document 10)- therapeutic agents for sepsis
(Patent Document 11), therapeutic agents for itching due to multiple sclerosis (Paient
Document 12), therapeutic agents for scinzophrenia (Patent Document 15) and
therapeutic agents for dyskinesia (Patent Document 14). However, no therapeutic
or prophylactic effect on biliary tract diseases has been disclosed yet.
[9005]
Examples of drugs which have actions to inhibit contraction of sphincter of
Oddi and are currently used as therapeutic agents for biliary tract diseases include
those having actions to promote uptake of Ca2+ into intracellular Ca-store sites, such
as trepibutone; those having actions to inhibit binding of Ca2+ in the extracellular
fluid to contractile proteins, such as hymecromoDe; those having actions to inhibit
eatechol-^methyftransferase (which may hereinafter be referred to as ^OM'l"),
and antiserotonin actions, such as flopropione; those having antimnscarimc actions,
such as tiquizium; those having airopine-like actions and papaverine-like actions,
such as oxapium; those having trypsin- and kaJlifcrern-irthibition actions although the
action mechanism for inhibition of contraction of sphincter of Oddi is unknown, such
as gabexate. However, these are drugs having neither structural similarity to the
compounds of the present invention nor the k opioid receptor agonist activity.
[0006]
Further, since opioids are kno"wn to cause the contractuksi of the sphincter of
Oddi and may therefore exacerbate biliary tract diseases, h is known that use of
opioids for patients suffering from binary tract diseases requires caution. Opioids
have been reported as follows .
[0007]
ft is described that since morphine, which has a roorphinan skeleton siniilarfy
to the compounds of the present invention but is different from the compounds of the
present mventioc in view of the feet that it is a u opioid receptor agonist, may cause
biliary tract spasm m. patients suffering from a gallbladder disorder or efoolehtin^sis,
it needs to be carefully adrnrnistered to obese patients (Non-parent Document 2).
[0008]
Fifftber, ft is described thai since oxycodone, which is a u. opioid receptor
agonist having a roorphiiian skeleton, may esse conb^ctkm of sphincter of Oddi and
therefore exacerbate symptoms in patients s»fferittg from a gallbladder disorder,
cfaojeirthiasis or pancreatitis, k needs to be carefbily aoVnimstered to these patie^s
(Non-patent Document 3). Similarry, it is described that since bupreootpfaine,
winch is a p opioid receptor partial agonist having a o»rphinan skeleton^ caoses
contraction of sphincter of Ockfi in wkaaL expernneiSs (wife do^) a4 high doses (at
not less than 0.1 mg/kg i.v.), it needs to be carefully administered to patients
suffering from a biliary tract disease (Non-patent Document 4). Further, it is
described that since tramadol, which is a u opioid receptor agonist having no
morphinan skeleton, causes contraction of sphincter of Oddi in animal experiments at
high doses, it needs to be carefully administered to patients suffering from a biliary
tract disease (Non-patent Document 5). Similarly, it is described that since
pentazocine, which is a u opioid receptor partial agonist having no morphinan
skeleton, may cause contraction of sphincter of Oddi at high doses, it needs to be
carefully administered to patients suffering from a biliary tract disease (Non-patent
Document 6).
[0009]
It is described thai k opioid receptor agonists having no morphinan skeleton
axe useful as therapeutic agents for gastrointestinal dysfunction, and examples of the
gastrointestinal disfunction include contraction of sphmcter of Oddi (Patent
Docxmierits 15 to 18). However, there is no description on inhibition, of ccstaetion
of sphincter of Oddi.
[0010]
Further, in terms of aa^xipfcine, which is kccwrt to have a irKTrphinan skeleton
and to have a *c opioid receptor agonist activity and a u. opioid receptor partial agonist
activity,, there are a report suggesting that it does not exert any action on contraction
of sphincter of Oddi {Non-patent Document 7) and a report lowing that it increases
the inner pressure ofhOiary tract by 6% arthoogh the action is not statistically
significant (Noo-patent Document 8). However, there is no report snggssting that
rjaibopoine mhibits contraction of sphincter of Oddi. Further, since butorphanol,
which is classified into a k opioid receptor agonist, increased tile inner pressure of
bOiary tract by 12% and this action was statistically significant (Nonpatent
Document 8), it has been shown to have contraction of sphincter of Oddi. Further,
it is described that since eptazocine, which is known to have do nKxpfaman skeleton
but act as a k agonist on opioid receptors, shows an action to cause contraction of
sphincter of Oddi at high doses in animal experiments, it needs to be carefully
administered to patients suffering from a biliary tract disease (Non-patent Document
9)-
[0011]
Leucine enkephalin and methionine enkephalin, which are endogenous 6
opioid receptor agonist peptides, are reported to cause transient contraction of
sphincter of OddL followed by showing a continuous contraction inhibition action
(Non-patent Document 10). Further, naloxone, which is a u opioid receptor
antagonist having a rrKKphman skeleton, is also known to have an action to inhibit
contraction of sphincter of Oddi (Non-patent Document 11).
[0012]
Thus, no suggestion has been made at all on mhibrtinn of contraction of
sphincter of Oddi by opioid k receptor agonists having a morrinhan skeleton similar
to the eorjupoonds of the present mventiori.
[0013]
ft has been disclosed that the cccnponnds of the present invention show
antagonistic actions on the ORL-1 receptor. Since nociceptin (wiaeh is sometimes
referred to as orpissim FQ), which is an eadogesoGS agonist pelade of this receptor,
is expressed in the excitatory motor netffous in fee myesfeeric plexus of sphincter of
Oddi and inhibits cfaoiioergic neutoUanstiHssiGiL, fe has been suggested feat
nociceptin may act o& sphincter of Oddi via a feedback asriomhibitorj mechanism
(Nan-pa£en£ Documeatf; 12).
[0014]
Thus, ORL-1 receptor agonists are cxsnsidjei^ to mhibd: contraction of
sphincter of Oddi, bc£ mhibctioa of contractkxx of sphincter of Oddi bj an
antagonistic action on the ORL-l receptor has not been suggested.
PRIOR ART DOCUMENTS
[Patent Documents]
[0015]
[Patent Document I] WO 93/015081
[Patent Document 2] WO 95/001178
[Patent Document 3] WO 95/0O33O7
[Patent Document 4] WO 98/023290
[Patent Document 5] WO 99005146
[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 Oil289
[Patest Document 11] WO 02089845
[Patent Document 12] WO 06/095836
[Patent 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 G5*X23799
[Patent Document 18] WO 04W3796
[Non-patent Documents]
[0016]
[Noc-pateflt DocxHnent 1] Hastier? et aL, EHgDis ScL, 43,2426 (1998)
[Non-patent Document 2] JAPIC etlncal dniss in Japan 2010, edited sad
pobiisfeed by Japan Pharmaceutical h&xnas&km Center, available from Marazen Co,
Ltd., p. 2705, Morphine hydrochloride hydrate.
[Non-patent Document 3] JAPIC ethical drugs in Japan 2010, edited and
published by Japan Pharmaceutical Information Center, available from Nferuzen Co.,
LtxL, p. 618, Oxycodone hydrochloride hydrate.
[Non-patent Document 4] JAPIC ethical drugs in Japan 2010, edited and
published by Japan Pharmaceutical Information Center, available from Maruzen Co.,
Ltd, p. 2166, Buprenorphioe hydrochloride.
[Non-patent Document 5] JAPIC ethical drugs in Japan 2010, edited and
published by Japan Pharmaceutical Information Center, available from Mamzen Co.;
Ltd., p. 1713, Tramadol hydrochloride.
[N'on-patent Document 6] JAPIC ethical druss m Japan 2010, edited and
published by Japan Pharmaceutical Information Center, available from Maruzen Co^
Ltd-, p. 2443, Pentazocine.
[Non-paient Document 7] Isenhower HL et al_ Am J Heaith-Syst VhsnxL^ 55,
480 (1998)
[Non-patent Document 8] Thompson DR_r Am J Gastroenterol, 96, 1266
(2001)
[Non-patent Docnment 9] JAPIC ethical drugs in Japan 2010, echoed aid
published by Japan Pharmaceutical Information Center, available from Maruzen. Co^
LfcL, p. 549, EptazDcioe hytkobrofflate.
[Noo-paleui DocuiaeHt 10] Beta: J et aL, GastroeoieroL, S6, IK (1984)
[Koor-paient Document 11] Behar J et aL, Motikiy of the Digestive Tract.,
New Yosfc Ravea, (1982X p. 397
[Noo^atexit Docameoi 12] O'Doimell AM et aL, J Comp NeoroL, 29,430
(2001)
SUMMARY OF THE INVENTION
PROBLEMS TO BE SOLVK) BY THE INVENTION
[0017]
The present invention aims to provide a therapeutic or prophylactic agent for
a biliary tract disease^) having an excellent effect, which agent comprises as an
effective component a specific compound having a morphinan skeleton or a
pharmaceutically acceptable acid addition salt thereof.
MEANS FOR SOLVING THE PROBLEMS
[00 IS]
The present inventors intensively studied to solve the above problems and
discovered chat specific compounds having a morphinan skeleton and
pharmaceutical!;)- acceptable acid addition salts thereof have excellent therapeutic
effects on biliary tract diseases, thereby completing the present invention.
[0019]
That is. the present invention relates to [1] to [5] below.
[ 1 ] A therapeutic or prophylactic agent for a biliary tract disease^), the agent
comprising as an effective component a compound represented by General Formula
(R below:
[0020]

[0021]
[wherein the doable line constituted by a dotted line attd a solM Hue represents a
doobte hood or single bond, R1 represejds Q-CT cycioaEtyia&yi, R2 represents Q-C5
linear or branched a&yl, aai B represents -CH=CH-]
or a pharmaceutically acceptable acid addition salt thereof.
[2] The therapeutic or prophylactic agent for a biliary tract diseases) according to
[I], wherein, in General Formula (I), R1 is cyclopropytmethvi, cyck>buryhnetnyl,
cyclopentjimethyl or cyclohexylmethyi, and R" is methyl, ethyi or propyl.
[3] The therapeutic or prophylactic agent for a biliary tract disease^) according to
[1], wherein the compound represented by General Formula (I) is (->-17-
(cyclopropyhnethyl)-3114|*Klihydro3y^pa-erK>xy^f^
fuiyl)acrylainido]morprnnan-
[4] The therapeutic or prophylactic agent for a biliary tract disease^) according to
any one of [11 to [3], wherein the biliary tract disease^) is'are biliaiy obstruction,
gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis,
cholecystitis and/or primary biliary cirrhosis.
[5] Tie therapeutic or prophylactic agent for a biliary tract disease^) according to
any one of [1] to [3], which agent exerts a therapentie or r^jphyiactic action on fee
biliary tract diseases) by inMhrtrng contraction of sphincter of OddL
[5] A compound represented by General Formula (I) below:
[0022]

[0023]
[wfeerein the doable line constituted by a dotted line and a solid line represents a
double bond or single bond, Rl represents C*-C? eycJoa&yiaftyt, R2 represents C1-C5
linear or branched alkyi, and B represents -CH=CH-]
or a phamiaceutically acceptable acid addition salt thereof which compound or
pharmaceutical!}- acceptable acid addition salt is used for therapy or prophylaxis of a
biliary tract diseases).
[7] A method of therapy or prophylaxis of a biliary tract disease^), the method
comprising administering an effective amount of a compound represented by General
Formula (I) below:
[0024]

[0025]
[¦wherein the double line constituted by a dotted line and a solid hue represents a
double borsi or single bond. RL represents C*-C- cycloaHryialkyl, R" represents Q-C*
linear or branched alkyL and B represents -CH=CH-]
or a pfcar23aceuticaily acceptable acid addition salt thereof to a patient who needs a
therapeutic or rxophylactic agent for a bdiaxy tract diseases 5).
EFFECT OF THE INVENTION
[0026]
The present invention provides a remarkable therapeutic or prophylactic effect
on biliary tract diseases.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027]
Fig. I is a diagram showing the influence of Conxpotxad I on contraction of
sphincter of Oddi in rabbit in Example 1. fhe abscissa indk^es a Sest sabstance,
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 mtravenocis
adrrunistration of the test substance and the value observed during the 3 minutes
immediately after the begirining of administration (mean ± standard error, N—1 i
cases, *p<0.05, paired t-test).
BEST MODE FOR CARRYING OUT THE INVENTION
[0028]
The therapeutic or prophylactic agent of the present invention for a biliary
tract diseases) comprises as an effective component a compound represented by
Genera! Formula (HI) or a pharmaceutical!}- acceptable acid addition salt thereof.
[0029]

[0030]
[wherein the double line constituted by a dotted line and a solid line
represents a double bond cc simde bood.
R1 represents Ci-Cs ahtyi, Q-C? cycfcialkyialkyi, C5-C7 cycloalkenyia&YL, C«-
Cu aryi, Cr-Ci3 aralkyi, C-tr-Cj alkenyl, alryi, furanr-2-yialkyi (the alfcylmoiety has 1
to 5 carbon atones)), or tbk>phei3r2-yialkyi (Ifae alkyi moiety has 1 to 5 csbon
atCHIl(5)).
[0031]
R14 represents hydrogen, hyskuny, nitro, Q-C5 a&aaioyioxy, C1-C5 atosyr
Ci-C5 a&yi or KR'R10. Here, R9 represents hydrogen or C[-C5 alkyL, Rf0 represents
hydrogen, C[-C5 alkyi or -(00)Rn, R11 represents hydrogen, phenyl or C.-C5 alkyL
[0032]
R^ represents hydrogen, hydroxy, C[-Cs alkanoyloxy or C1-C5 alkosy.
[0033]
A represents -XC(=Y)-T -XC(=Y)Z-, -X- or -XSOr (wherein X, Y and Z each
independently represent NR4, S or O, wherein R" represents hydrogen, Ci-Cs linear
or branched alkyl or C5-C12 aryL and, in eases where two or more R exist in the
formula, these may be the same or different).
[0334]
B represents a valence bond, C;-Cii linear or branched alkyieae (which may
be substituted by at least one substituent selected from the group consisting of C:-C5
alkoxy, Cy-Cf alkanoyloxy. hydroxy, fluorine, ehioro, bromo, iodo, amino, nhxo,
cyano_ trizhioramethyi axni pfoenoxy, and 1 to 3 methylene gronpfs) may be
substituted by earboayl): Cz-Cu linear or hrarjehed acyclic unsaturated rfydroearrjon
comprising 1 to 3 double bood^s) and- or triple bood(5) (which may be subsritttfed by
at least one subsrituent selected from the group consisting of Q-C5 aflcoxy. C1-C5
alkarjoyioxy. hydroxy', fracnae, chloro, bromo. iodo, amine, oitro- cyano,
trifhsuc uinethyi and pfaenoxy, and I to 3 rnethyleae grour* s) may be substkufed by
carbocyi); or C;-Cu linear or braecbed, saturated or renrstfrff^ed hyurocffboc
comprising I to 5 Maoether boed^s), ether bond(5) and/or mximo bood(3> (wleresi no
heteroatoai is directry bo*axl to A, and 1 to 3 metfeyieae greats) may be substituted
by caxfxnyl).
[0035]
R3 represents hytkogen or an organic group having any of tbe feBowine baskr
skeletons (wherein Q represents N, O or S; T represents CH2, NH, S or O; I
represents an ia£eger of 0 to 5; m and a each tndependeney represent si integer of 0
to 5; the sum of m and a is not more than 5; and each orgfmic group may be
substituted by at least one substrtuent selected from the group consisting of Q-C5
aliyi, Ci-Cj alkoxy, C1-C5 aDcanoyloxy, hydroxy, fluorine, chloro, bromo, iodo,
amino, nitro, cyano, isothlocyanato, trifluoromethyL, trifluororoethoxy and
methylenedioxy).
[0036]

[0037]
R7 represents hydrogen, and R represents hydrogen, hydroxy. Ct-Cs aflcosy
or Cl-C5 afkanoyloxy; or R3 mid R together represent -O-. -CH?- or -S-.
[0038]
R* represents hydrogen, C1-C5 alkyi. or C1-C5 alkaioyL
[0O39]
R12 and R13 together i^iaeaeat hytfrogen; one of these represents hydnwsa
and the other represents hydroxy; or these together represent oxo.
[0040]
General Formula (IH) inctotfes (±% (-) aad (±) isomers.]
The dooHe hue coostitsted by a dotted Hse aid a solid fine hi General
Fnrmiila (HI) represents a double bond or single bond, and the double line preferably
represents a single bond.
[0041]
Toe therapeutic or prophylactic agent of the present invention for a biliary
tract disease(s) preferably comprises, among the compounds represented by General
Formula (EH) and pharmaceutically acceptable acid addition salts thereof a
compound represented by the above-described General Formula (I) or a
pharmaceuticaliy acceptable acid addition salt thereof as an effective component
[0042]
The double line constituted by a dotted line and a solid line in General
Formula (1) represents a double bond or single bond, and the double Hue preferably
represents a single bond.
[0O43]
In General Formula (I), R1 represents Gr-O cycioalkylalkyL Among these,
R" is preferably cyclopcopytrne&yU c^k>butylrnethyL cyxk>pentylroethyi or
eyck>hexyimetfeyL especially preferably cyclopr upy Lwedryi.
[0044]
R~ represents C l-O Linear or branched alkyi. R~ is preferably methyl, ethyl
or propyl. Among these, methyl is more prefered-
[0045]
B represents -CH=CH-. B is preferably trass -CH=CH-.
[0046]
The compound represented by General Formula (I) is especially preferably a
(-)-cotnrx>uod wherein the double line constituted by a dotted line sd a solid hue
represents a angle bood; R1 represents cyckjrxopyfmemyl; R~ represoSs memyi; aid
B represents trsis -CFE=€H-. That is, the compound represented by General
Formula (I) is especially prefeabiy (-)-17^cy^o|Kut^kHe*ayi)-3,14p-d3rflfesy-
4pa-epoxy-6P-[N-meth>l-trans-3 However, the
present invention is not restricted thereto.
[0047]
These compounds represented by General Formula (I) and pharmaceutical!}'
acceptable acid addition salts drereof can be produced according to die method
described in JP 2525552 B. Among die compounds represented by General
Formula (HI), those wherein R12 and Rlj together represent hydrogen can be
produced according to the menx>d described in JP 2525552 B. Among the
compounds represented by General Formula (EH)., those wherein R" and R_J together
represent oxo can be produced byT for example, using, as a starting material, a
compound having 10-oxo obtained according to a document (Heterocycies, 63, 865
(2004), Bioorg. Med. Chem. Lett., 5, 1505 (1995)) and following the methods
described in Chem. Phann. Bull.. 52, 664 (2004) and JP 2525552 B. Further,
among the compounds represented by General Formula (I), those wberem R"
represents hydroxy and RLJ represents hydrogen can be produced according to die
method described in Chem. Pfaarra, Bull.. 52.664 (2004).
[0048]
Examples of die pfaannaceuiicalry acceptable acid addition salt in die present
inventKHi include inorganic add salts such as hydrochloric acid salt, suhiffie acid salt,
nitric acid salt, bydrofcromie acid safe, hydroiodic acid safe and phosphoric acid salt;
organic carboxylic acid salts sock as acetic acid salt, lactic acid salt, citric acid salt,
osaHc acid safe, gfe&aric acid safe, malic acid safe, tartaric acid safe, raraaric acid safe,
mandeiic acid safe, maleic acid safe, benzoic acid safe and pfeha&c acid safe; and
organic sulfonic acid safes such as raetkanesotfozric acid safe, edcHKSuhxxac acid safe,
benzeoesulfoinc acid safe, p-tot uenesulfonic acid safe and canipborsulfonic acid safe.
Among these, hydrochloric acid safe, bydrobrooik: acid safe, phosphoric acid safe,
tartaric acid safe, raethaoesulfonie acid safe and the like are ptefetably used, but,
needless to say, the phaimaceuticalfy acceptable acid addition sah of the present
invention is not restricted thereto.
[0049]
The "^b diary tract disease^ in the present invention includes digestive diseases
that occur in the gallbladder, bile duct, pancreas or pancreatic duct. Among these,
the therapeutic or prophylactic agent of the present invention for a biliary tract
disease(s) is preferably applicable to a biliary tract diseases) that occur(s) and/or
exacerbate^) 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.
[0050]
The compound represented by General Formula ;T) or a pharmaceutieaHy
acceptable acid addition sah thereof is purified to a level suitable for medical use,
and- alter passing a necessary safety test, the compound or acid addition salt may be
orally or parenterally adxmxtislered as it is or as a pharmaceutical composition
prepared as a mixture with a known phanriaceuticairy acceptable acid*», carrier^),
vehicle! 5) and or the like. Examples of its fecmulation include tablets, capsules,
orally iisintegratirig tablets, powders and granules in the case of oral administration;
and formulations for mtraveiaous rapid infusion, intravenous sustained infosiori,
intramuscular injection, subcutaneous injectiori or irstraderrnal injection, mid tapes
and patches, in die case of p^enfeal a'I.»acTy_l£ra^dc]rrjorphir^n hydrochloride (Compound 1) on the
Contraction of Sphincter of Oddi in Rabbits
The method described hi Wei JG et at, Worid J. Gastroenterol., 6,102 (2000)
was partially modified and used for measurement of a change in the pafaskai
pressure in sphincter of Oddi. The change in the perftsioG pressure reflects the
motility of a contractive change of ^pfaiaeter of OddL
[0058]
Male NZW rabbits (Japan SLC) winch 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 oat under anesthesia with, pentobarbital, wilh atificial
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 die 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-30O, Nihoa Kohden Corporation), the
contraction reaction of sphincter of Oddi was measured.
[0059]
To the rabbtL 5*'« aqueous raannitol sohrtioiL which is the vehicle for the
Compound 1 solution, was adnnmstered via the jugular vein. Further, not less than
30 minutes after the adrnxaistration of the vehicle, Compound 1 was administered to
the same tndrviduai at a dose of 0-2 ug."kg via the jugular vein. The admmisiration
vorame of the vehicle and Compound I was 1 ml ."kg, and the aoxohnstration was
carried out for 60 seconds.
[0060]
Fig. 1 shows me resuk of cakralatkxi of the rate of change in the masimsn
perfusion ptessme (Oddi muscle cooiractioe (Defta$4)) based on comparison between
use rakue observed during the 3 minutes niHHediafery before begirMHns of the
ruluimi^lr^ioo and tiip; vahtf eAsreryed ifariog tfie ^ rnmafes imm^atek ^Jer
fe%pnnmg o€tfee admraistrati^ cases), m contrast to
the feet that the rate of change in tbs maximum perfusJoo pressure was 9332% on
average in: me case of b^tsrf&aoQsmh\\\msii^€Ro£Q2\i§^Cas^om^l,^TaSs
of change in the masirnuni perfusion pressure was 99J51% ob average m fee case of
administration of the vehicle. Thus, in. the Compound 1-administered group, tie
rate of change in the maximum perfusion pressure was lower compared to the
vehicle-administered group, and this difference whs significant (*p<0.05, paired t-
test). This indicates that Compound 1 has an action to inhibit contraction of
sphincter of Oddi.
[0061]
Oxapium iodide, which has an action to inhibit contraction of shpinctr 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 mmH2O (corresponds
to 0.74 mmHg) when it is intravenously administered to a dog at a dose of 03 mg kg
(Tamasawa Y. et al, Kise to Rinsho. 6, 128 (1972). Further, gabesate mesilate
reduces the sphincter of Oddi perfusion pressure by 6.9 rarnH2O (corresponds to 0.51
mmHg) or 10.6 mmH2O (corresponds to 0.78 mmHg) when it is intravenously
admmistered 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 aduft 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
climcal doses of those drugs.
[0062]
In the present Example, by intravenocs administration of 0.2 µs/kg of
Compound I 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.
Compound 1 has a structure represented by Formula (II) below.
[0063]

INDUSTRIAL APPLICABILITY
[0064]
The present invention provides an excellent therapeutic effect oc biliary tract
diseases and is useful for therapy and/or prophylaxis of biliary tract diseases.
We Claim:
1. A therapeutic or prophylactic agent for a biliary tract disease(s), said agent
comprising as an effective component a compound represented by General Formula
(I) below:

[wherein the double line constituted by a dotted line and a solid line represents a
double bond or single bond, R1 represents C4-C7 eycloalkylalkyl, R2 represents C1-C5
linear or branched alkyl, and B represents -CN=CH-]
or a pharmaceutically acceptable acid addition salt thereof.
2. The therapeutic or prophylactic agent for a biliary tract disease(s) according to
claim 1. wherein, in General Formula (I) R is cyclopropylmethyl, cyclobutylmethyl
cyclcpentyhnethyl. or cyclobexylmethyl and R1 is methyl ethyl or propyl
3. The therapeutic or prophylactic agent for a biliary tract disease(s) according to
claim 1, wherein said compound represented by General Formula(I) is(-)-17-
(eyclopylmethyl)-3,14ß-dihydroxy-4,5a-epoxy-6ß-[N-methyl-trans-3-(3-
furyl)acrylamido]morphinan.
4. The therapeutic or prophylactic agent for a biliary tract disease(s) according to
any one of claims 1 to 3, wherehi said biliary tract disease(s) is/are biliary obstruction,
gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesa, cholangitis,
cholecystitis and/or primary biliary cirrhosis
5. The therapeutic or prophylactic agent for a biliary tract disease(s) according to
any one of claims I to 3, which agent exerts a therapeutic or prophylactic action on
the biliary tract disease(s) by inhibiting contraction of sphincter of Oddi.
6. A compound represented by General Formula (I) below:

[wherein the double line constrtuted by a dotted line and a solid line represents a
double bond or single bond, R1 represents C4-C7 cycloalkylalkyl, R2 represents C1-C5
linear or branched alkyl, and B represents -CH=CH-]
or a pharmaceutically acceptable acid addition salt thereof, which, compound or
pharmaceutically acceptable acid addition salt is used for therapy or prophylaxis of a
biliary tract disease(s).
7. A method of therapy or prophylaxis of a biliary tract disease(s), said method
comprising administering an effective amount of a compound represented by General
Formula (T) below:

[wherein the double line constituted by a dotted line and a solid line represents a
double bond or single bond, Rl represerds C4-C7 cycloalkylalkyl, R2 represents C1-C5
linear or branched alkyl, and B represents -CH=CH-]
or a pharmaceutically acceptable acid addition salt thereof to a patient who needs a
therapeutic or prophylactic agent for a biliary tract disease(s).