CA2787323C - Therapeutic or prophylactic agent for biliary tract diseases - Google Patents
Therapeutic or prophylactic agent for biliary tract diseases Download PDFInfo
- Publication number
- CA2787323C CA2787323C CA2787323A CA2787323A CA2787323C CA 2787323 C CA2787323 C CA 2787323C CA 2787323 A CA2787323 A CA 2787323A CA 2787323 A CA2787323 A CA 2787323A CA 2787323 C CA2787323 C CA 2787323C
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- Prior art keywords
- biliary tract
- biliary
- tract disease
- oddi
- patent document
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
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- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- ZGSDGGRVFIYKKE-OXQOHEQNSA-N tiquizium Chemical compound C([C@H]1CCCC[N@@+]1(C1)C)CC1=C(C=1SC=CC=1)C1=CC=CS1 ZGSDGGRVFIYKKE-OXQOHEQNSA-N 0.000 description 1
- 229950000029 tiquizium Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960003107 tramadol hydrochloride Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
-
- 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
-
- 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
-
- 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:
-
- 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
-
- 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
Abstract
The present invention aims to provide a novel drug which has an excellent therapeutic effect on biliary tract diseases and is useful for therapy and/or prophylaxis of biliary tract diseases. More particularly, the present invention provides a therapeutic or prophylactic agent for biliary tract diseases, which agent comprises as an effective component a specific compound having a morphinan skeleton represented by Compound 1, or a pharmaceutically acceptable acid addition salt thereof. (see Compound 1)
Description
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 disease(s) comprising as an effective component a morphinan derivative or a pharmaceutically acceptable acid addition salt thereof BACKGROUND ART
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 disease(s) comprising as an effective component a morphinan derivative or a pharmaceutically acceptable acid addition salt thereof BACKGROUND ART
[0002]
The biliary tract disease is a collective tem' for digestive diseases that occur in the gallbladder, bile duct, pancreas or pancreatic duct. A known example of the cause of occurrence of a biliary 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 to the distal part of the bile duct formed by confluence of the common bile duct and pancreatic duct. Known examples of the biliary tract disease caused by contraction of sphincter of Oddi include biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary 2 O dyskinesia, cholangitis and cholecystitis. Therefore, 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.
The biliary tract disease is a collective tem' for digestive diseases that occur in the gallbladder, bile duct, pancreas or pancreatic duct. A known example of the cause of occurrence of a biliary 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 to the distal part of the bile duct formed by confluence of the common bile duct and pancreatic duct. Known examples of the biliary tract disease caused by contraction of sphincter of Oddi include biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary 2 O dyskinesia, cholangitis and cholecystitis. Therefore, 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]
Further, examples of biliary tract diseases which are not caused by contraction 2 5 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 ducts, 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.
Further, examples of biliary tract diseases which are not caused by contraction 2 5 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 ducts, 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 pharmaceutically acceptable acid addition salts thereof as effective components of the present invention (which may hereinafter be referred to as "compounds of the present invention-), with their le opioid receptor 0 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 1 5 receptor antagonists (Patent Document 6), therapeutic agents for neuropathic pain (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 Doctunent 10). therapeutic agents for sepsis (Patent Document 11), therapeutic agents for itching due to multiple sclerosis (Patent C Document 12), therapeutic agents for schi7ophrenia (Patent Document 13) and therapeutic agents for dy-skinesia (Patent Document 14). However, 110 therapeutic or prophylactic effect on biliary- tract diseases has been disclosed yet.
Morphinan derivatives and pharmaceutically acceptable acid addition salts thereof as effective components of the present invention (which may hereinafter be referred to as "compounds of the present invention-), with their le opioid receptor 0 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 1 5 receptor antagonists (Patent Document 6), therapeutic agents for neuropathic pain (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 Doctunent 10). therapeutic agents for sepsis (Patent Document 11), therapeutic agents for itching due to multiple sclerosis (Patent C Document 12), therapeutic agents for schi7ophrenia (Patent Document 13) and therapeutic agents for dy-skinesia (Patent Document 14). However, 110 therapeutic or prophylactic effect on biliary- tract diseases has been disclosed yet.
[0005]
Examples of drugs which have actions to inhibit contraction of sphincter of 2 3 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 hy-mecromone; those having actions to inhibit catechol-0-methy-ltransferase (which may hereinafter be referred to as "COMT"), and antiserotonin actions, such as flopropione; those having antimuscarinic actions, such as tiquizium; those having atropine-like actions and papaverine-like actions, such as oxapium; those having trypsin- and kallikrein-inhibition 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.
Examples of drugs which have actions to inhibit contraction of sphincter of 2 3 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 hy-mecromone; those having actions to inhibit catechol-0-methy-ltransferase (which may hereinafter be referred to as "COMT"), and antiserotonin actions, such as flopropione; those having antimuscarinic actions, such as tiquizium; those having atropine-like actions and papaverine-like actions, such as oxapium; those having trypsin- and kallikrein-inhibition 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 known to cause the contractuion of the sphincter of Oddi and may therefore exacerbate biliary tract diseases, it is known that use of opioids for patients suffering from biliary- tract diseases requires caution.
Opioids have been reported as follows.
Further, since opioids are known to cause the contractuion of the sphincter of Oddi and may therefore exacerbate biliary tract diseases, it is known that use of opioids for patients suffering from biliary- tract diseases requires caution.
Opioids have been reported as follows.
[0007]
It is described that since morphine, which has a morphinan skeleton similarly to the compounds of the present invention but is different from the compounds of the present invention in view of the fact that it is a p. opioid receptor agonist, may cause biliary tract spasm in patients suffering from a gallbladder disorder or cholelithiasis, it needs to be carefully administered to these patients (Non-patent Document 2).
It is described that since morphine, which has a morphinan skeleton similarly to the compounds of the present invention but is different from the compounds of the present invention in view of the fact that it is a p. opioid receptor agonist, may cause biliary tract spasm in patients suffering from a gallbladder disorder or cholelithiasis, it needs to be carefully administered to these patients (Non-patent Document 2).
[0008]
Further, it is described that since oxy-codone, which is ail opioid receptor agonist having a morphinan skeleton, may cause contraction of sphincter of Oddi and therefore exacerbate symptoms in patients suffering from a gallbladder disorder, cholelithiasis or pancreatitis, it needs to be carefully administered to these patients 2 5 (Non-patent Document 3). Similarly, it is described that since buprenorphine, which is all opioid receptor partial agonist having a morphinan skeleton, causes contraction of sphincter of Oddi in animal experiments (with dogs) at 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 all 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 II 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 binary tract disease (Non-patent O Document 6).
[00091 It is described that k opioid receptor agonists having no morphinan skeleton are useful as therapeutic agents for gastrointestinal dysfunction, and examples of the gasllointestinal dysfunction include contraction of sphincter of Oddi (Patent _ 5 Documents 15 to 18). However, there is no description on inhibition of contraction of sphincter of Oddi.
[0010]
Further, in terms of nalbuphine, which is known to have a morphinan skeleton and to have a K opioid receptor agonist activity and a opioid receptor pcutial agonist 2 2 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 showing that it increases the inner pressure of biliary tract by 6% although the action is not statistically significant (Non-patent Document 8). However, there is no report suggesting that nalbuphine inhibits contraction of sphincter of Oddi. Further, since butorphanol, 2 5 which is classified into a x opioid receptor agonist, increased the inner pressure of biliary tract by 12% and this action was statistically significant (Non-patent Docimient 8), it has been shown to have contraction of sphincter of Oddi.
Further, it is described that since epta7ocine, which is known to have no morphinan 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 5 9).
[0011]
Leucine enkephalin and methionine enkephalin, which are endogenous 6 opioid receptor agonist peptides, are reported to cause transient contraction of sphincter of Oddi, followed by showing a continuous contraction inhibition action (Non-patent Document 10). Further, naloxone, which is a t opioid receptor antagonist having a morphinan skeleton, is also known to have an action to inhibit contraction of sphincter of Oddi (NTon-patent Document 11).
[0012]
Thus, no suggestion has been made at all on inhibition of contraction of sphincter of Oddi by opioid îc receptor agonists having a morphinan skeleton similar to the compounds of the present invention.
[0013]
It has been disclosed that the compounds of the present invention show antagonistic actions on the ORL-1 receptor. Since nociceptin (which is sometimes referred to as orphanin FQ), which is an endogenous agonist peptide of this receptor, is expressed in the excitatory motor neurons in the my-enteric plexus of sphincter of Oddi and inhibits cholinerc neurotransmission, it has been suggested that nociceptin may act on sphincter of Oddi via a feedback autoinhibitory mechanism (Non-patent Document 12).
25 [0014]
Thus, ORL-1 receptor agonists are considered to inhibit contraction of sphincter of Oddi, but inhibition of contraction of sphincter of Oddi by an antaaronistic action on the ORL-1 receptor has not been suggested.
PRIOR ART DOCUMENTS
[Patent Documents]
[0015]
[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 I 3 [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 [Patent Document 13] WO 09 001764 [Patent Document 141 WO 08 133297 [Patent Document 15] WO 05004796 [Patent Document 16] WO 05'049564 [Patent Document 17] WO 05/023799 [Patent Document 18] WO 04/093796 [Non-patent Documents]
[0016]
2 5 [Non-patent Document 1] Hastier P et al., Dig Dis Sci., 43, 2426 (1998) [Non-patent Document 2] JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2705, Morphine hydrochloride hydrate.
[Non-patent Document 3] JAM ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., 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, Buprenorphine hydrochloride.
[N'on-patent Document 5] JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Lnfottuation Center, available from Maruzen Co., Ltd., p. 1713. Tramadol hydrochloride.
[Non-patent Document 6] JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2448, Pentazocine.
[Non-patent Document 7] Isenhower HI. et al.. ,Lkm J Health-Syst Pharm., 55, 5 480(1998) [Non-patent Document 8] Thompson DR., Am J Gastroenterol.. 96, 1266 (2001) [Non-patent Document 9] JAPIC ethical drags in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co..
Ltd., p. 549, Epza7ocine hy-drobromate.
[Non-patent Document 10] Behar J et al., Gastroenterol., 86, 134 (1984) [Non-patent Document 11] Behar J et al., Motiltiy of the Digestive Tract, New York: Raven, (1982), p. 397 [Non-patent Docurnent 121 O'Donnell AM et al., J Comp Netzrol., 29, 430 25 (2001) SUMMARY OF THE INVENTION
[0017]
The present invention aims to provide a therapeutic or prophylactic agent for a biliary tract disease(s) 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
[0018]
The present inventors intensively studied to solve the above problems and discovered that specific compounds having a morphinan skeleton and 3 pharmaceutically 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(s), the ag.ent - comprising as an effective component a compound represented by General Foituula (I) below:
[0020]
OH
Rt.N 4/0 NAB
xe)"0 .0 [0021]
2 C [wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, RI represents C4.-c7 cy-cloalkylalkyl, R2 represents C1-05 linear or branched alkyl, and B represents -CH-1-1-]
Further, it is described that since oxy-codone, which is ail opioid receptor agonist having a morphinan skeleton, may cause contraction of sphincter of Oddi and therefore exacerbate symptoms in patients suffering from a gallbladder disorder, cholelithiasis or pancreatitis, it needs to be carefully administered to these patients 2 5 (Non-patent Document 3). Similarly, it is described that since buprenorphine, which is all opioid receptor partial agonist having a morphinan skeleton, causes contraction of sphincter of Oddi in animal experiments (with dogs) at 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 all 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 II 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 binary tract disease (Non-patent O Document 6).
[00091 It is described that k opioid receptor agonists having no morphinan skeleton are useful as therapeutic agents for gastrointestinal dysfunction, and examples of the gasllointestinal dysfunction include contraction of sphincter of Oddi (Patent _ 5 Documents 15 to 18). However, there is no description on inhibition of contraction of sphincter of Oddi.
[0010]
Further, in terms of nalbuphine, which is known to have a morphinan skeleton and to have a K opioid receptor agonist activity and a opioid receptor pcutial agonist 2 2 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 showing that it increases the inner pressure of biliary tract by 6% although the action is not statistically significant (Non-patent Document 8). However, there is no report suggesting that nalbuphine inhibits contraction of sphincter of Oddi. Further, since butorphanol, 2 5 which is classified into a x opioid receptor agonist, increased the inner pressure of biliary tract by 12% and this action was statistically significant (Non-patent Docimient 8), it has been shown to have contraction of sphincter of Oddi.
Further, it is described that since epta7ocine, which is known to have no morphinan 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 5 9).
[0011]
Leucine enkephalin and methionine enkephalin, which are endogenous 6 opioid receptor agonist peptides, are reported to cause transient contraction of sphincter of Oddi, followed by showing a continuous contraction inhibition action (Non-patent Document 10). Further, naloxone, which is a t opioid receptor antagonist having a morphinan skeleton, is also known to have an action to inhibit contraction of sphincter of Oddi (NTon-patent Document 11).
[0012]
Thus, no suggestion has been made at all on inhibition of contraction of sphincter of Oddi by opioid îc receptor agonists having a morphinan skeleton similar to the compounds of the present invention.
[0013]
It has been disclosed that the compounds of the present invention show antagonistic actions on the ORL-1 receptor. Since nociceptin (which is sometimes referred to as orphanin FQ), which is an endogenous agonist peptide of this receptor, is expressed in the excitatory motor neurons in the my-enteric plexus of sphincter of Oddi and inhibits cholinerc neurotransmission, it has been suggested that nociceptin may act on sphincter of Oddi via a feedback autoinhibitory mechanism (Non-patent Document 12).
25 [0014]
Thus, ORL-1 receptor agonists are considered to inhibit contraction of sphincter of Oddi, but inhibition of contraction of sphincter of Oddi by an antaaronistic action on the ORL-1 receptor has not been suggested.
PRIOR ART DOCUMENTS
[Patent Documents]
[0015]
[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 I 3 [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 [Patent Document 13] WO 09 001764 [Patent Document 141 WO 08 133297 [Patent Document 15] WO 05004796 [Patent Document 16] WO 05'049564 [Patent Document 17] WO 05/023799 [Patent Document 18] WO 04/093796 [Non-patent Documents]
[0016]
2 5 [Non-patent Document 1] Hastier P et al., Dig Dis Sci., 43, 2426 (1998) [Non-patent Document 2] JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2705, Morphine hydrochloride hydrate.
[Non-patent Document 3] JAM ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., 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, Buprenorphine hydrochloride.
[N'on-patent Document 5] JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Lnfottuation Center, available from Maruzen Co., Ltd., p. 1713. Tramadol hydrochloride.
[Non-patent Document 6] JAPIC ethical drugs in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co., Ltd., p. 2448, Pentazocine.
[Non-patent Document 7] Isenhower HI. et al.. ,Lkm J Health-Syst Pharm., 55, 5 480(1998) [Non-patent Document 8] Thompson DR., Am J Gastroenterol.. 96, 1266 (2001) [Non-patent Document 9] JAPIC ethical drags in Japan 2010, edited and published by Japan Pharmaceutical Information Center, available from Maruzen Co..
Ltd., p. 549, Epza7ocine hy-drobromate.
[Non-patent Document 10] Behar J et al., Gastroenterol., 86, 134 (1984) [Non-patent Document 11] Behar J et al., Motiltiy of the Digestive Tract, New York: Raven, (1982), p. 397 [Non-patent Docurnent 121 O'Donnell AM et al., J Comp Netzrol., 29, 430 25 (2001) SUMMARY OF THE INVENTION
[0017]
The present invention aims to provide a therapeutic or prophylactic agent for a biliary tract disease(s) 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
[0018]
The present inventors intensively studied to solve the above problems and discovered that specific compounds having a morphinan skeleton and 3 pharmaceutically 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(s), the ag.ent - comprising as an effective component a compound represented by General Foituula (I) below:
[0020]
OH
Rt.N 4/0 NAB
xe)"0 .0 [0021]
2 C [wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, RI represents C4.-c7 cy-cloalkylalkyl, R2 represents C1-05 linear or branched alkyl, and B represents -CH-1-1-]
9 or a pharmaceutically acceptable acid addition salt thereof [2] The therapeutic or prophylactic agent for a biliary tract disease(s) according to [1], wherein, in General Formula (I), R1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and R2 is methyl, ethyl or propyl.
[3] The therapeutic or prophylactic agent for a biliary tract disease(s) according to [1], wherein the compound represented by General Formula (I) is (+17-(cyclopropylmethyl)-3,143-dihydroxy-4,5a-epoxy-6134N-methy1-trans-3-(3-furypacrylamido]morphinan.
[4] The therapeutic or prophylactic agent for a biliary tract disease(s) according to [1], wherein the compound represented by General Formula (I) is (+17-(cyclopropylmethyl)-3,140-1 0 dihydroxy-4,5a-epoxy-6134N-methy1-trans-3-(3-furyl)acrylamido]morphinan hydrochloride.
[5] The therapeutic or prophylactic agent for a biliary tract disease(s) according to any one of [1] to [4], wherein the biliary tract disease(s) is/are biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis and/or primary biliary cirrhosis.
[6] The therapeutic or prophylactic agent for a biliary tract disease(s) according to any one of [1] to [5], which agent exerts a therapeutic or prophylactic action on the biliary tract disease(s) by inhibiting contraction of sphincter of Oddi.
[7] A compound represented by General Formula (I) below:
[0022]
OH
. N
'10 I
4111' OH
(I) [0023]
[wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, RI represents C4-C7 cycloalkylalkyl, R2 represents C1-05 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).
[8] A use of a compound represented by General Formula (I) as defined in [1] to [4], for 5 the treatment or prophylaxis of a biliary tract disease.
[0024]
[9] A pharmaceutical composition for use in the treatment or prophylaxis of a biliary tract disease comprising a compound represented by General Formula (I) as defined in [1] to [4], and a pharmaceutically acceptable carrier.
[3] The therapeutic or prophylactic agent for a biliary tract disease(s) according to [1], wherein the compound represented by General Formula (I) is (+17-(cyclopropylmethyl)-3,143-dihydroxy-4,5a-epoxy-6134N-methy1-trans-3-(3-furypacrylamido]morphinan.
[4] The therapeutic or prophylactic agent for a biliary tract disease(s) according to [1], wherein the compound represented by General Formula (I) is (+17-(cyclopropylmethyl)-3,140-1 0 dihydroxy-4,5a-epoxy-6134N-methy1-trans-3-(3-furyl)acrylamido]morphinan hydrochloride.
[5] The therapeutic or prophylactic agent for a biliary tract disease(s) according to any one of [1] to [4], wherein the biliary tract disease(s) is/are biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis and/or primary biliary cirrhosis.
[6] The therapeutic or prophylactic agent for a biliary tract disease(s) according to any one of [1] to [5], which agent exerts a therapeutic or prophylactic action on the biliary tract disease(s) by inhibiting contraction of sphincter of Oddi.
[7] A compound represented by General Formula (I) below:
[0022]
OH
. N
'10 I
4111' OH
(I) [0023]
[wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, RI represents C4-C7 cycloalkylalkyl, R2 represents C1-05 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).
[8] A use of a compound represented by General Formula (I) as defined in [1] to [4], for 5 the treatment or prophylaxis of a biliary tract disease.
[0024]
[9] A pharmaceutical composition for use in the treatment or prophylaxis of a biliary tract disease comprising a compound represented by General Formula (I) as defined in [1] to [4], and a pharmaceutically acceptable carrier.
10 [0025]
[10] Use according to [8] or composition according to [9] wherein the biliary tract disease is as defined in [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. 1 is a diagram showing the influence of Compound 1 on contraction of 2 0 sphincter of Oddi in rabbit in Example 1. The abscissa indicates a test substance,
[10] Use according to [8] or composition according to [9] wherein the biliary tract disease is as defined in [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. 1 is a diagram showing the influence of Compound 1 on contraction of 2 0 sphincter of Oddi in rabbit in Example 1. The abscissa indicates a test substance,
11 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 (mean standard error; N=11 cases, *p<0.05, paired t-test).
BEST MODE FOR CARRYLNG OUT THE LNVENTION
[0028]
The therapeutic or prophylactic agent of the present invention for a biliary-.
_ C tract disease(s) comprises as an effective component a compound represented by General Formula (111) or a pharmaceutically acceptable acid addition salt thereof [0029]
R1,N
ISO A.-11.õ R5 R12, Re R8 1313 Olt R7 1:10 [0030]
1 5 [wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond.
RI represents CI-05 alkyl, C4-C7 cycloalkylalkyl, C5-C7 cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl, C4-C7 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 2( atom(s)).
[0031]
RI-4 represents hydrogen,. hydroxy-, nitro, C1-05 alkanoyloxy, C1-05 alkoxy,
BEST MODE FOR CARRYLNG OUT THE LNVENTION
[0028]
The therapeutic or prophylactic agent of the present invention for a biliary-.
_ C tract disease(s) comprises as an effective component a compound represented by General Formula (111) or a pharmaceutically acceptable acid addition salt thereof [0029]
R1,N
ISO A.-11.õ R5 R12, Re R8 1313 Olt R7 1:10 [0030]
1 5 [wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond.
RI represents CI-05 alkyl, C4-C7 cycloalkylalkyl, C5-C7 cycloalkenylalkyl, C6-C12 aryl, C7-C13 aralkyl, C4-C7 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 2( atom(s)).
[0031]
RI-4 represents hydrogen,. hydroxy-, nitro, C1-05 alkanoyloxy, C1-05 alkoxy,
12 Cr-05 alkyl or IN-R9RI . Here, R9 represents hydrogen or CI-05 alkyl, RI
represents hydrogen, CI-Cc alkyl or -(C=0)RI I, R1' represents hydrogen, phenyl or CI-05 alkyl.
[0032]
R3 represents hydrogen, hydroxy-, C t-05 alkanoyloxy or C1-05 alkoxy-.
[0033}
A represents -XC(=Y)-, -XC(=Y)Z-, -X- or -XS02- (wherein X, Y and Z each independently represent NR4. S or 0, wherein R4 represents hydrogen. CI-05 linear or branched alkyl or C6-Cp aryl, and, in cases where two or more R4 exist in the formula, these may- be the same or different).
[0034]
B represents a valence bond, C -C,4 linear or brqnched alkylene (which may be substituted by at least one substituent selected from the group consisting of CI-05 alkoxy, CI-05aIkovIoxv, hydroxy, fluorine, chloro, bromo, iodo, amino. nitro.
cyano. trifluoromethy-1 and phenoxy, and 1 to 3 methylene group(s) may be substituted by carbonyl): C,-C 14 linear or branched acyclic unsaturated hydrocarbon comprising 1 to 3 double bond(s) arid ortriple bond(s) (which may be substituted by at least one substituent selected from the group consisting of CI-Cc alkoxy-.
Ci-05 alkanovloxy, hydroxy, fluorine. chloro. bromo, iodo. amino, nitro, cy-ano, trifluoromethyi and phenoxy, and 1 to 3 methylene group(s) may be substituted by : carbonyl); or C -C,4I linear or branched, saturated or unsaturated hydrocarbon comprising 1 to 5 thioether bond(s), ether bond(s) andior amino bond(s) (wherein no heteroatom is directly bound to A, and 1 to 3 methylene group(s) may be substituted by carbonyl).
[0035]
23 R5 represents hydrogen or an organic group having any of the following basic skeletons (wherein Q represents N, O or S; T represents CH7, NH, S or 0; I
represents an integer of 0 to 5; m and n each independently represent an integer of 0
represents hydrogen, CI-Cc alkyl or -(C=0)RI I, R1' represents hydrogen, phenyl or CI-05 alkyl.
[0032]
R3 represents hydrogen, hydroxy-, C t-05 alkanoyloxy or C1-05 alkoxy-.
[0033}
A represents -XC(=Y)-, -XC(=Y)Z-, -X- or -XS02- (wherein X, Y and Z each independently represent NR4. S or 0, wherein R4 represents hydrogen. CI-05 linear or branched alkyl or C6-Cp aryl, and, in cases where two or more R4 exist in the formula, these may- be the same or different).
[0034]
B represents a valence bond, C -C,4 linear or brqnched alkylene (which may be substituted by at least one substituent selected from the group consisting of CI-05 alkoxy, CI-05aIkovIoxv, hydroxy, fluorine, chloro, bromo, iodo, amino. nitro.
cyano. trifluoromethy-1 and phenoxy, and 1 to 3 methylene group(s) may be substituted by carbonyl): C,-C 14 linear or branched acyclic unsaturated hydrocarbon comprising 1 to 3 double bond(s) arid ortriple bond(s) (which may be substituted by at least one substituent selected from the group consisting of CI-Cc alkoxy-.
Ci-05 alkanovloxy, hydroxy, fluorine. chloro. bromo, iodo. amino, nitro, cy-ano, trifluoromethyi and phenoxy, and 1 to 3 methylene group(s) may be substituted by : carbonyl); or C -C,4I linear or branched, saturated or unsaturated hydrocarbon comprising 1 to 5 thioether bond(s), ether bond(s) andior amino bond(s) (wherein no heteroatom is directly bound to A, and 1 to 3 methylene group(s) may be substituted by carbonyl).
[0035]
23 R5 represents hydrogen or an organic group having any of the following basic skeletons (wherein Q represents N, O or S; T represents CH7, NH, S or 0; I
represents an integer of 0 to 5; m and n each independently represent an integer of 0
13 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 C1-05 alkoxy, C1-05 alkanoyloxy, hydroxy, fluorine, chloro, bromo, iodo, amino, nitro, cyano, isothiocyanato, trifluoromethyl, trifluoromethoxy and methylenedioxy).
[0036J
100 *IP*
Q:N.O.S
T-el-EriNKS,0 1=0-5 m,naG
(01-i,)rn (CI-cm _____________ T m*1E-S5 OE-gamic' wows re:I:sew:tell by It?
[003 7]
R6 represents hydrogen. and R- represents hydrogen, hydroxy. C1-05 alkox-y 12 or C,-05 allonoylox-y; or R6 and R7 together repaesent -0-, -CH,- or -S-.
[0038]
le represents hydrogen, C1-05 alkyl or CI-05 alkanoyl.
[0039]
R'2 and R13 together represent hydrogen; one of these represents hydrogen 1 5 and the other represents hydroxy; or these together represent oxo.
[0040]
General Formula (III) includes (+), (-) and ( ) isomers.]
The double line constituted by a dotted line and a solid line in General
[0036J
100 *IP*
Q:N.O.S
T-el-EriNKS,0 1=0-5 m,naG
(01-i,)rn (CI-cm _____________ T m*1E-S5 OE-gamic' wows re:I:sew:tell by It?
[003 7]
R6 represents hydrogen. and R- represents hydrogen, hydroxy. C1-05 alkox-y 12 or C,-05 allonoylox-y; or R6 and R7 together repaesent -0-, -CH,- or -S-.
[0038]
le represents hydrogen, C1-05 alkyl or CI-05 alkanoyl.
[0039]
R'2 and R13 together represent hydrogen; one of these represents hydrogen 1 5 and the other represents hydroxy; or these together represent oxo.
[0040]
General Formula (III) includes (+), (-) and ( ) isomers.]
The double line constituted by a dotted line and a solid line in General
14 F01.111tila (III) represents a double bond or single bond, and the double line preferably represents a single bond.
[0041]
The therapeutic or prophylactic agent of the present invention for a biliary tract disease(s) preferably comprises, among the compounds represented by General Formula (111) and pharmaceutically acceptable acid addition salts thereof, a compound represented by the above-described General Formula (I) or a pharmaceutically- 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 a) represents a double bond or single bond. gnd the double line preferably represents a single bond.
[0043]
In General Foimula (I). RI represents C4-C7 cycloalkylalkyl. Among these.
RI is preferably- cyclopropylmethyl_ cy-clobutylmethyl, cyclopentylmethyt or cyclohe\-y-Imethyl. especially preferably cyclopropy-Imethyl.
[0044]
R2 represents C [-Ci linear or branched alkyl. R2 is preferably methyl. ethyl or propy-1. Among these, methyl is more preferred.
23 [0045]
B represents -CH¨CH-. B is preferably trans -CH--CH-.
[0046]
The compound represented by General Formula (I) is especially preferably a (-)-compound wherein the double line constituted by a dotted line and a solid line 2 5 represents a single bond; RI represents cyclopropylmethyl; R2 represents methyl; and B represents trans -CH=CH-. That is, the compound represented by General Founula (I) is especially preferably (+I 7-(cyclopropylmethyl)-3,l4f3-dihy-droxy-4,5a-epoxy-6P-[N-methy1-trans-3-(3-furyl)acry-lamido]morphinan However, the present invention is not restricted thereto.
[0047]
These compounds represented by General Formula (I) and pharmaceutically--5 acceptable acid addition salts thereof can be produced according to the method described in JP 2525552 B. Among the compounds represented by General Formula (III), those wherein R12 and Rt3 together represent hydrogen can be produced according to the method described in JP 2525552 B. Among the compounds represented by General Formula (111), those wherein R12 and RI3 together represent oxo can be produced by. for example, using, as a starting material, a compoimd 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 General Foimula (I). those wherein R12 represents hy-droxy and R13 represents hydrogen can be produced according to the naethod described in Chem. Pharm. Bull.. 52. 664 (2004).
[0048]
Examples of the pharmaceutically acceptable acid addition salt in the present invention include inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt_ nitric acid salt, hy-drobromic acid salt, hydroiodic acid salt and phosphoric acid salt;
organic carboxylic acid salts such as acetic acid saltõ 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, 2 3 benzenesulfonic acid salt, p-toluenesulfonic acid salt and camphorsplfonic 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 of the present invention is not restricted thereto.
[90491 The "biliary 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 disease(s) that occur(s) andlor exacerbate(s) due to contraction of sphincter of Oddi, especially preferably biliary obstruction . gallbladder disorder, cholelithiasis, pancreatitis. biliary dyskinesia, cholangitis. choleQ,stitis, primarv biliary cirrhosis and or the like.
[0050]
The compound represented by General Foituula (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 E 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. pov.ders and _granules in the case of oral administration:
qnd formulations for inn'a.-enous rapid infusion. intravenous sustained infusion, 2 7., intramuscular injection. subcutaneous injection or intra.delmal injection, and tapes and patches,. in the case of parenteral administration. However, the formulation is of course not limited thereto.
[00511 The content of the compound represented by General Formula (I) or a 2 5 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 lig to 100 mg. The dose may be appopriately selected depending on the symptoms, age and body weight of the patient, administration method andlor the like, and the dose per adult per day is usually about 0.1 lag to 20 mg, preferably about 1 1.1g to 10 mg in terms of the amount of the compound represented by General Formula (I) or a pharmaceutically acceptable acid addition salt thereof, which may be administered at once or in several times.
[0052]
As the therapeutic or prophylactic agent of the present invention for a biliary tract disease(s), the compound represented by General Formula (T) 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).
[00531 Examples of the drugs include cholagogues such as trepibutone (therapeutic agent for pancreatic/biliary tract diseases). hyrnecromone (therapeutic agent for biliary tract diseases). flopropione (pancreaticobiliar 'urinary tract antispasmodic).
tiqui7ium (antimuscarinic agent). oxapium (antispasmodic anticholinergic agent).
gabexate (protease inhibitor). dehydrocholic acid. anetholtrithion, ursodeoxycholic acid and chenodeoxycholic acid.
[00541 Examples of the drugs also include morphine, pentazocine, buprenorphine, oxycodone, fentanyl, reraifentanil, 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 the drug of the present invention, to 2 5 suppress the side effects.
[0055]
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.
[0056]
The fact that a compound represented by General Formula (I) or a 3 pharmaceutically- acceptable acid addition salt thereof as an effective component of the therapeutic or prophylactic agent of the present invention is effective for therapy andior 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 JG et al._ :oWorld 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 9nd or prophylactic effect on biliary tract diseases.
EXAMPLES
[0057]
The present invention vi1i now be described concretely by way of an Example.
Example 1 Effect of ( -)-17-(cyclopropy-tmethy t)-3.140-dihy-droxy-4.5a-epoxy-60-[N-metJayl-trans-3-(3-fury1)acry larnidolmorphinan hydrochloride (Compound 1) on the Contraction of Sphincter of Oddi in Rabbits 2 7 The method described in Wei JG 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.
[0058]
23 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 conied 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 mf /hour to allow perfusion in the sphincter of Oddi. By recording the perfusion pressure with a 7 C blood pressure monitoring transducer (DX-300, Nihon Kohden Corporation), the contraction reaction of sphincter of Oddi was measured.
[0059]
To the rabbit. 5% aqueous marmitol 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 ttakg via the jugular vein. The administration volume of the vehicle and Compound 1 was 1 m121(g., and the administration was carried out for 60 seconds.
[0060]
2 0 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 beginnina of the adrninistration and the value observed during the 3 minutes immediately after beginning of the administration (mean - standard error; N=11 cases). In contrast to 2 3 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 tig/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 eroup, the rate of change in the maximum perfusion pressure was lower compared to the vehicle-administered uoup, 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.
[00611 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 mm}170 (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 mm1-120 (corresponds to 0.51 mmHg) or 10.6 mm1120 (corresponds to 0.78 mmag,) when it is intravenously administered to a dog, at a dose of 1 merkg- or 3 me kg. respectively (Yarnasato T. et al.. J Smooth Muscle Res.. 27, 87 (1991). Since oxapiurn iodide is usually orally administered at a dose of 30 to 60 mg per adult per day dividedly in 3 times, and 100 M.c.", of gabexate mesilate is usually dissolved in 500 mI of Ringer's solution and the resulting solution is administered by intravenous drip infusion at a rate of not more than 8 m I ;Minute, the above-described doses are considered to be equivalent to the 20 clinical doses of those drugs.
[0062]
In the present Example, by intravenous administration of 0.2 gelg of Compound 1 to rabbits, the actual value of the MaXiTTIPTI1 perfusion pressure was reduced by 0.95 mmHg on average. This result therefore indicates that, by using 2 5 Compound 1, a therapeutic and prophylactic effect on biliary tract diseases can be clinically expected.
Compound 1 has a structure represented by Formula (11) below.
[0063]
OH
N
= HCI
OHMe ( ) INDUSTRIAL APPLICABILITY
[0064j The present invention provides a.n excellent therapeutic effect on biliary tract diseases and is useful for therapy and or prophylaxis of biliary tract diseases.
[0041]
The therapeutic or prophylactic agent of the present invention for a biliary tract disease(s) preferably comprises, among the compounds represented by General Formula (111) and pharmaceutically acceptable acid addition salts thereof, a compound represented by the above-described General Formula (I) or a pharmaceutically- 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 a) represents a double bond or single bond. gnd the double line preferably represents a single bond.
[0043]
In General Foimula (I). RI represents C4-C7 cycloalkylalkyl. Among these.
RI is preferably- cyclopropylmethyl_ cy-clobutylmethyl, cyclopentylmethyt or cyclohe\-y-Imethyl. especially preferably cyclopropy-Imethyl.
[0044]
R2 represents C [-Ci linear or branched alkyl. R2 is preferably methyl. ethyl or propy-1. Among these, methyl is more preferred.
23 [0045]
B represents -CH¨CH-. B is preferably trans -CH--CH-.
[0046]
The compound represented by General Formula (I) is especially preferably a (-)-compound wherein the double line constituted by a dotted line and a solid line 2 5 represents a single bond; RI represents cyclopropylmethyl; R2 represents methyl; and B represents trans -CH=CH-. That is, the compound represented by General Founula (I) is especially preferably (+I 7-(cyclopropylmethyl)-3,l4f3-dihy-droxy-4,5a-epoxy-6P-[N-methy1-trans-3-(3-furyl)acry-lamido]morphinan However, the present invention is not restricted thereto.
[0047]
These compounds represented by General Formula (I) and pharmaceutically--5 acceptable acid addition salts thereof can be produced according to the method described in JP 2525552 B. Among the compounds represented by General Formula (III), those wherein R12 and Rt3 together represent hydrogen can be produced according to the method described in JP 2525552 B. Among the compounds represented by General Formula (111), those wherein R12 and RI3 together represent oxo can be produced by. for example, using, as a starting material, a compoimd 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 General Foimula (I). those wherein R12 represents hy-droxy and R13 represents hydrogen can be produced according to the naethod described in Chem. Pharm. Bull.. 52. 664 (2004).
[0048]
Examples of the pharmaceutically acceptable acid addition salt in the present invention include inorganic acid salts such as hydrochloric acid salt, sulfuric acid salt_ nitric acid salt, hy-drobromic acid salt, hydroiodic acid salt and phosphoric acid salt;
organic carboxylic acid salts such as acetic acid saltõ 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, 2 3 benzenesulfonic acid salt, p-toluenesulfonic acid salt and camphorsplfonic 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 of the present invention is not restricted thereto.
[90491 The "biliary 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 disease(s) that occur(s) andlor exacerbate(s) due to contraction of sphincter of Oddi, especially preferably biliary obstruction . gallbladder disorder, cholelithiasis, pancreatitis. biliary dyskinesia, cholangitis. choleQ,stitis, primarv biliary cirrhosis and or the like.
[0050]
The compound represented by General Foituula (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 E 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. pov.ders and _granules in the case of oral administration:
qnd formulations for inn'a.-enous rapid infusion. intravenous sustained infusion, 2 7., intramuscular injection. subcutaneous injection or intra.delmal injection, and tapes and patches,. in the case of parenteral administration. However, the formulation is of course not limited thereto.
[00511 The content of the compound represented by General Formula (I) or a 2 5 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 lig to 100 mg. The dose may be appopriately selected depending on the symptoms, age and body weight of the patient, administration method andlor the like, and the dose per adult per day is usually about 0.1 lag to 20 mg, preferably about 1 1.1g to 10 mg in terms of the amount of the compound represented by General Formula (I) or a pharmaceutically acceptable acid addition salt thereof, which may be administered at once or in several times.
[0052]
As the therapeutic or prophylactic agent of the present invention for a biliary tract disease(s), the compound represented by General Formula (T) 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).
[00531 Examples of the drugs include cholagogues such as trepibutone (therapeutic agent for pancreatic/biliary tract diseases). hyrnecromone (therapeutic agent for biliary tract diseases). flopropione (pancreaticobiliar 'urinary tract antispasmodic).
tiqui7ium (antimuscarinic agent). oxapium (antispasmodic anticholinergic agent).
gabexate (protease inhibitor). dehydrocholic acid. anetholtrithion, ursodeoxycholic acid and chenodeoxycholic acid.
[00541 Examples of the drugs also include morphine, pentazocine, buprenorphine, oxycodone, fentanyl, reraifentanil, 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 the drug of the present invention, to 2 5 suppress the side effects.
[0055]
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.
[0056]
The fact that a compound represented by General Formula (I) or a 3 pharmaceutically- acceptable acid addition salt thereof as an effective component of the therapeutic or prophylactic agent of the present invention is effective for therapy andior 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 JG et al._ :oWorld 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 9nd or prophylactic effect on biliary tract diseases.
EXAMPLES
[0057]
The present invention vi1i now be described concretely by way of an Example.
Example 1 Effect of ( -)-17-(cyclopropy-tmethy t)-3.140-dihy-droxy-4.5a-epoxy-60-[N-metJayl-trans-3-(3-fury1)acry larnidolmorphinan hydrochloride (Compound 1) on the Contraction of Sphincter of Oddi in Rabbits 2 7 The method described in Wei JG 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.
[0058]
23 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 conied 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 mf /hour to allow perfusion in the sphincter of Oddi. By recording the perfusion pressure with a 7 C blood pressure monitoring transducer (DX-300, Nihon Kohden Corporation), the contraction reaction of sphincter of Oddi was measured.
[0059]
To the rabbit. 5% aqueous marmitol 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 ttakg via the jugular vein. The administration volume of the vehicle and Compound 1 was 1 m121(g., and the administration was carried out for 60 seconds.
[0060]
2 0 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 beginnina of the adrninistration and the value observed during the 3 minutes immediately after beginning of the administration (mean - standard error; N=11 cases). In contrast to 2 3 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 tig/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 eroup, the rate of change in the maximum perfusion pressure was lower compared to the vehicle-administered uoup, 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.
[00611 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 mm}170 (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 mm1-120 (corresponds to 0.51 mmHg) or 10.6 mm1120 (corresponds to 0.78 mmag,) when it is intravenously administered to a dog, at a dose of 1 merkg- or 3 me kg. respectively (Yarnasato T. et al.. J Smooth Muscle Res.. 27, 87 (1991). Since oxapiurn iodide is usually orally administered at a dose of 30 to 60 mg per adult per day dividedly in 3 times, and 100 M.c.", of gabexate mesilate is usually dissolved in 500 mI of Ringer's solution and the resulting solution is administered by intravenous drip infusion at a rate of not more than 8 m I ;Minute, the above-described doses are considered to be equivalent to the 20 clinical doses of those drugs.
[0062]
In the present Example, by intravenous administration of 0.2 gelg of Compound 1 to rabbits, the actual value of the MaXiTTIPTI1 perfusion pressure was reduced by 0.95 mmHg on average. This result therefore indicates that, by using 2 5 Compound 1, a therapeutic and prophylactic effect on biliary tract diseases can be clinically expected.
Compound 1 has a structure represented by Formula (11) below.
[0063]
OH
N
= HCI
OHMe ( ) INDUSTRIAL APPLICABILITY
[0064j The present invention provides a.n excellent therapeutic effect on biliary tract diseases and is useful for therapy and or prophylaxis of biliary tract diseases.
Claims (9)
1. Use of a compound represented by General Formula (I) below:
or a pharmaceutically acceptable acid addition salt thereof, wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, R1 represents C4-C7 cycloalkylalkyl, R2 represents Ci-05 linear or branched alkyl, and B represents -CH=CH-, for treatment or prophylaxis of a biliary tract disease.
or a pharmaceutically acceptable acid addition salt thereof, wherein the double line constituted by a dotted line and a solid line represents a double bond or single bond, R1 represents C4-C7 cycloalkylalkyl, R2 represents Ci-05 linear or branched alkyl, and B represents -CH=CH-, for treatment or prophylaxis of a biliary tract disease.
2.1 i Use according to claim 1, wherein, in General Formula (I), R s cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl, and R2 is methyl, ethyl or propyl.
3. Use according to claim 1, wherein said compound represented by General Formula (I) is (-)-17-(cyclopropylmethyl)-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-6.beta.-[N-methyl-trans-3-(3-furypacrylamido]morphinan.
4. Use according to claim 1 of the compound (-)-17-(cyclopropylmethyl)-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-6.beta.-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride.
5. Use of a compound as defined in claim 1, 2, 3 or 4, for inhibiting contraction of sphincter of Oddi in the treatment or prevention of biliary tract disease.
6. Use according to any one of claims 1 to 5, wherein said biliary tract disease is biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis or primary biliary cirrhosis.
7. A pharmaceutical composition for use in the treatment or prophylaxis of a biliary tract disease comprising a compound as defined in claim 1, 2 or 3, or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
8. A pharmaceutical composition for use in the treatment or prophylaxis of a biliary tract disease comprising a (-)-17-(cyclopropylmethyl)-3,14.beta.-dihydroxy-4,5.alpha.-epoxy-6.beta.-[N-methyl-trans-3-(3-furyl)acrylamido]morphinan hydrochloride, and a pharmaceutically acceptable carrier.
9. The pharmaceutical composition according to claim 7 or 8, wherein said biliary tract disease is biliary obstruction, gallbladder disorder, cholelithiasis, pancreatitis, biliary dyskinesia, cholangitis, cholecystitis or primary biliary cirrhosis.
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| JP2010018730 | 2010-01-29 | ||
| PCT/JP2011/051737 WO2011093441A1 (en) | 2010-01-29 | 2011-01-28 | Therapeutic or prophylactic agent for biliary diseases |
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| EP (1) | EP2529739B1 (en) |
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| US9006262B2 (en) | 2011-01-31 | 2015-04-14 | Toray Industries, Inc. | Therapeutic or prophylactic agent for cachexia |
| EP3291676B1 (en) | 2015-04-30 | 2022-08-17 | Memorial Sloan Kettering Cancer Center | Mitragynine analogs and uses thereof |
| CN106110220B (en) * | 2016-08-22 | 2020-01-07 | 陕西盘龙药业集团股份有限公司 | Preparation process of Chinese patent medicine for treating biliary tract diseases |
| US20210015813A1 (en) | 2018-03-08 | 2021-01-21 | Victoria Link Ltd. | Treatment of demyelinating diseases |
| CN112703000A (en) | 2018-07-23 | 2021-04-23 | 特雷维治疗股份有限公司 | Treatment of chronic cough, shortness of breath and dyspnea |
| WO2020205735A1 (en) * | 2019-03-29 | 2020-10-08 | Humanwell Pharmaceutical US | Novel morphinans useful for treating medical disorders |
| KR20240035395A (en) | 2021-06-14 | 2024-03-15 | 스코르피온 테라퓨틱스, 인코퍼레이티드 | Urea derivatives that can be used in cancer treatment |
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| US4946848A (en) * | 1985-10-29 | 1990-08-07 | Baker Cumins Dermatologicals, Inc. | Method of treating pruritus with nalmefene and clonidine |
| EP0591275B1 (en) * | 1991-06-24 | 1999-03-31 | Zeneca Limited | Use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione in the treatment of tyrosinaemia and pharmaceutical compositions |
| WO1993015081A1 (en) | 1992-01-23 | 1993-08-05 | Toray Industries, Inc. | Morphinan derivative and medicinal use |
| CA2143318A1 (en) | 1993-06-30 | 1995-01-12 | Hiroshi Nagase | Antitussive agents |
| JP3948026B2 (en) | 1993-07-19 | 2007-07-25 | 東レ株式会社 | Brain cell protectant |
| JP4040673B2 (en) * | 1994-05-31 | 2008-01-30 | マリンクロッド・ケミカル・インコーポレイテッド | Production of nalbuphine with low levels of beta-epimer |
| US6174891B1 (en) * | 1996-11-25 | 2001-01-16 | Toray Industries, Inc. | Antipruritic agent |
| AU6117298A (en) | 1997-07-25 | 1999-02-16 | Toray Industries, Inc. | Hyponatremia remedies |
| JP4359711B2 (en) | 1997-09-02 | 2009-11-04 | 東レ株式会社 | Drug addiction treatment |
| JP2000053572A (en) * | 1998-08-11 | 2000-02-22 | Toray Ind Inc | Orli (opioid orphan)receptor antagonist |
| DE60039444D1 (en) | 1999-08-24 | 2008-08-21 | Toray Industries | REMEDIES FOR NEUROPATHIC PAIN AND EXPERIMENTAL MODELS OF NEUROPATHIC PAIN |
| JP2001163784A (en) | 1999-12-06 | 2001-06-19 | Toray Ind Inc | Antipruritic for cornea or conjunctiva |
| DE60231388D1 (en) | 2001-03-30 | 2009-04-16 | Toray Industries | MEANS TO TREAT THE SYNDROME OF UNRANDY LEGS |
| JP4239592B2 (en) | 2001-05-08 | 2009-03-18 | 東レ株式会社 | Sepsis treatment |
| US20030054030A1 (en) * | 2001-09-13 | 2003-03-20 | Gary Gordon | Method and compositions for the treatment of pruritus |
| DE10161963A1 (en) * | 2001-12-17 | 2003-07-03 | Johannes Schuetz | 6-aminomorphine derivatives, production process therefor and their use |
| US6852713B2 (en) | 2003-04-16 | 2005-02-08 | Adolor Corporation | Lactam derivatives and methods of their use |
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| US7160902B2 (en) | 2003-11-14 | 2007-01-09 | Adolor Corporation | Amide derivatives and methods of their use |
| CN101137658B (en) | 2005-03-10 | 2011-06-08 | 东丽株式会社 | Antipruritic agent for pruritus caused by multiple sclerosis |
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| ES2671897T3 (en) * | 2008-02-14 | 2018-06-11 | Alkermes, Inc. | Selective opioid compounds |
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| CA2787323A1 (en) | 2011-08-04 |
| CN102711759B (en) | 2015-05-13 |
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| AU2011211223A1 (en) | 2012-09-20 |
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| PL2529739T3 (en) | 2016-12-30 |
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