WO2021230264A1 - Agent for diagnosis-assisting, preventing or treating diseases in biliary system - Google Patents

Abstract

The present invention relates to an agent for diagnosis-assisting, preventing, or treating diseases in a biliary system, the agent containing an SSTR5 antagonist as an active ingredient.

Description

Diagnostic aid / prevention / therapeutic agent for biliary tract diseases

The present invention relates to a diagnostic aid, prevention or therapeutic agent for biliary tract diseases containing a somatostatin receptor subtype 5 (hereinafter, may be abbreviated as "SSTR5") antagonist as an active ingredient, and relates to the field of medicine. It is useful in.

The path of bile from the liver to the duodenum is collectively called the "bile duct" and is further divided into the intrahepatic bile duct, the extrahepatic bile duct (that is, the bile duct), the gallbladder, and the duodenal papilla. Diseases that occur in this "biliary tract" (hereinafter, may be abbreviated as "biliary tract disease") include, for example, cholelithiasis, cholecystosis, primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (primary biliary cirrhosis). PBC) and functional biliary tract disorders (functional gallbladder disorders, Oddi sphincter muscle disorders, papillary sphincter muscle abnormalities) are typical examples.
Surgical and drug therapies (eg, ursodeoxycholic acid for cholelithiasis and PBC) are given to these diseases, but the therapeutic efficacy is not high, especially in drug therapy, and the prognosis is However, the current situation is that it is not always satisfactory. Furthermore, at present, no effective preventive method with drugs for these diseases has been established.
Cholelithiasis is generally classified into gallbladder stone disease, common bile duct stone disease and intrahepatic stone disease, and cholesterol stones are often found in gallbladder stone disease, and bilirubin stone is often found in common bile duct stone disease and intrahepatic stone disease. In addition to the stones originating from the common bile duct, gallbladder stones and stones caused by the fall of intrahepatic stones are also observed in the common bile duct stones. Although the prevalence of gallstones is high and more patients have asymptomatic gallstones, their treatment is limited. Of these, drug therapy using bile acid preparations or cholecystectomy is often applied to the treatment of gallbladder stone disease. Ursodeoxycholic acid is commonly used in gallstone dissolving therapy with bile acid preparations, but it takes a considerable number of days to dissolve cholesterol stones, which requires long-term drug administration and gallbladder stone disease. The recurrence rate is also high. Another problem is that drug therapy has no choice but to use ursodeoxycholic acid. On the other hand, cholecystectomy has a very big problem that the mortality rate related to surgery is high even though cholecystectomy itself is not a fatal disease. Therefore, there are patients who are at high risk for surgery (elderly people, people with chronic diseases, etc.) and patients who do not want surgery. From the above background, there are needs for cholelithiasis that cannot be met by existing treatment methods. Furthermore, since patients with cholelithiasis have an increased risk of developing acute cholecystitis, acute cholangitis, gallbladder cancer, jaundice, pancreatitis, hepatic dysfunction, etc., there is also a need for the development of preventive methods for cholelithiasis.
Cholecystosis is a disease in which bile mud and bile sand accumulate in the bile sac for some reason, and is a long-term lying patient, a patient admitted to the intensive care unit (ICU), an obesity surgery patient, a cancer patient, and feeding. It is recognized in patients with disabilities, patients taking drugs with eating disorders, patients taking long-term intravenous nutrition, etc. In those patients, the accumulation of biliary sludge and gall bladder in the gallbladder due to insufficient dietary contraction of the gallbladder causes cholestasis, which is at risk of inducing cholangitis, cholecystitis, and hepatitis. It will increase. Currently, there are no effective drug prophylaxis and treatments for biliary sludge, and their development is sought.
Primary sclerosing cholangitis (PSC) is a chronic liver disease that causes cholestasis due to stenosis of the bile ducts inside and outside the liver, and its etiology is still unknown. Since chronic cholestasis is the main sign of the pathology, subsequent progression of hepatic fibrosis often leads to cholestasis cirrhosis. There is no effective drug treatment for this disease, and only ursodeoxycholic acid, fibrates, etc. are used as symptomatic treatments to improve the symptoms. From the above background, the development of an effective drug treatment method for this disease is required.
As described above, a drug-based preventive or therapeutic method for biliary tract diseases has not yet been sufficiently established, and the creation of a drug therapy having a highly effective new mechanism of action is awaited.
Endoscopic retrograde cholangiopancreatography (ERCP), which uses an endoscope to image the bile duct and pancreatic duct, is general-purpose for the purpose of early diagnosis of pancreatobiliary tumors or diagnosis and treatment of biliary tract diseases such as stones. Has been done. Although ERCP is less invasive than surgical abdominal incision, it is a clinical problem that serious postoperative complications such as acute cholangitis and acute pancreatitis occur. This postoperative complication is inflammation of the papilla of Vater due to physical irritation associated with the contact of the catheter with the papilla site because it is difficult to see the insertion part under an endoscope during transpapillary treatment of the catheter.・ It is thought that it develops due to edema. Therefore, it is possible to reduce the physical irritation to the nipple site by improving the visibility of the nipple under the endoscope or simplifying the transpapillary treatment of the catheter by relaxing the Oddi sphincter during ERCP treatment. If possible, it can be expected that the ERCP procedure will be simplified and the risk of postoperative complications will be reduced. Furthermore, these are considered to contribute to the improvement of diagnostic and therapeutic techniques for biliary tract diseases by ERCP.
Thus, even in the diagnosis of biliary tract diseases, the creation of drugs with new action mechanisms that can assist the procedure is awaited.

Somatostatin is a peptide hormone secreted from the hypothalamus, pancreatic δ cells, gastrointestinal endocrine cells, etc., and is mediated by five types of somatostatin receptors (SSTR1-5), which are 7-transmembrane G protein-conjugated receptors. It suppressively controls the secretion of various hormones. Currently, clinically, somatostatin analogs such as octreotide and pasireotide are used to improve various symptoms associated with hormone hypersecretion such as acromegaly and Cushing's disease. On the other hand, somatostatin analog preparations are known to have effects such as suppression of gallbladder contraction and reduction of bile flow (Non-Patent Documents 1 to 5). However, since somatostatin analog preparations show binding affinity for all of SSTR1-5, it is not clear at all which SSTR activation is based on these actions.
Among SSTR1-5, SSTR5 is a receptor mainly expressed in small intestinal endocrine cells and pancreatic β cells, and suppresses the secretion of gastrointestinal hormones such as GLP-1 and PYY and insulin by binding to somatostatin. Is known to control. Although various SSTR5 antagonists have been known to date (Patent Documents 1 to 18), there have been suggestions that SSTR5 antagonists induce gallbladder contraction and are effective for the biliary tract disease. No reports have been made.

International Publication No. 2014/142363 International Publication No. 2015/05/2910 International Publication No. 2015/064083 International Publication No. 2010/056717 International Publication No. 2010/129729 International Publication No. 2011/146324 International Publication No. 2012/024183 International Publication No. 2016/205032 International Publication No. 2006/09462 International Publication No. 2006/128803 International Publication No. 2007/025897 International Publication No. 2007/11340 International Publication No. 2008/000692 International Publication No. 2008/019967 International Publication No. 2008/031735 International Publication No. 2008/122510 International Publication No. 2008/145524 International Publication No. 2008/148710

As mentioned above, it cannot be said that diagnostic assistance, prevention or treatment methods using drugs for biliary tract diseases have been established yet, and development of diagnostic assistance, prevention or therapeutic agents with high clinical effects is an urgent task in the pharmaceutical field. It was an issue.

As a result of repeated diligent studies under such circumstances, the present inventors have found for the first time that the SSTR5 antagonist is effective in assisting, preventing or treating a biliary tract disease, and completed the present invention.
That is, the present invention is as follows.

[1] A diagnostic aid, preventive or therapeutic agent for biliary tract diseases, which contains an SSTR5 antagonist as an active ingredient.
[2] A method for assisting, preventing or treating a biliary tract disease, which comprises administering an effective amount of an SSTR5 antagonist to a mammal in need thereof.
[3] An SSTR5 antagonist used for assisting, preventing or treating biliary tract diseases.
[4] Use of SSTR5 antagonists to produce drugs for diagnostic assistance, prevention or treatment of biliary tract diseases.

[5] SSTR5 antagonists are available in International Publication No. 2014/142363, International Publication No. 2015/052910, International Publication No. 2015/064083, International Publication No. 2010/056717, International Publication No. 2010/129729, International Publication No. No. 2011/146324, International Publication No. 2012/024183, International Publication No. 2016/205032, International Publication No. 2006/094682, International Publication No. 2006/12883, International Publication No. 2007/0258997, International Publication No. 2007 / 110340, International Publication No. 2008/000692, International Publication No. 2008/019967, International Publication No. 2008/031735, International Publication No. 2008/122510, International Publication No. 2008/145524 and International Publication No. 2008/148710 The diagnostic aid, preventive or therapeutic agent for biliary tract disease according to [1] above, the diagnostic aid for biliary tract disease according to [2] above, which is selected from the compounds described in No. or salts thereof. Prophylactic or therapeutic method, use of the SSTR5 antagonist according to [3] above, or the SSTR5 antagonist according to [4] above.
[6] The biliary tract disease according to the above [1], wherein the SSTR5 antagonist is selected from the compounds and salts thereof described in International Publication No. 2015/052910 and International Publication No. 2015/064083. Diagnostic assistance, prevention or therapeutic agent, diagnostic assistance, prevention or treatment method for biliary tract disease according to the above [2], SSTR5 antagonist according to the above [3], or SSTR5 antagonist according to the above [4]. use.
[7] The SSTR5 antagonist is
6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7,8 -Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
6- (1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
6-(1-((2-Cyclopropyl-5-ethoxy-2', 4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6 7,8-Tetrahydro-1,6-naphthalidine-3-carboxylic acid,
6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -2-ethyl-5-oxo-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-ethyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid,
1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2- Dihydropyridine-4-carboxylic acid,
1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid,
And their salts, the diagnostic aid, prevention or therapeutic agent for biliary tract disease according to the above [1], and the diagnostic aid, prevention or treatment method for the biliary tract disease according to the above [2]. , The use of the SSTR5 antagonist according to the above [3], or the SSTR5 antagonist according to the above [4].

[8] Biliary tract diseases include cholelithiasis, cholangiopathy, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and functional biliary tract disorder (functional cholecyst disorder, Oddi sphincter muscle disorder, papillary sphincter muscle). The diagnostic aid, preventive or therapeutic agent for biliary tract disease according to any one of the above [1] to [7], which is at least one selected from (abnormality); diagnostic aid, prevention or therapeutic agent for biliary tract disease. Treatment method; SSTR5 antagonist used for assisting, preventing or treating biliary tract disease; or use of SSTR5 antagonist for producing a drug for assisting, preventing or treating biliary tract disease.
[9] The biliary tract according to any one of the above [1] to [8], wherein the diagnostic aid is an assist in injecting a catheter into the papilla of Vater during endoscopic retrograde cholangiopancreatography (ERCP). Diagnostic aids for systemic diseases; Methods for assisting diagnosis of biliary tract diseases; SSTR5 antagonists used for assisting diagnosis of biliary tract diseases; Use of.

According to the present invention, a drug that can be effectively and safely used for assisting, preventing or treating a biliary tract disease is provided.

The present invention comprises a diagnostic aid, prophylaxis or therapeutic agent for biliary tract diseases comprising an SSTR5 antagonist as an active ingredient; comprising administering an effective amount of the SSTR5 antagonist to a mammal in need thereof. Assistive, preventive or therapeutic method of disease; SSTR5 antagonist for use in assisting, preventing or treating biliary tract disease; for producing pharmaceuticals for assisting, preventing or treating biliary tract disease. Regarding the use of SSTR5 antagonists;

Hereinafter, the present invention will be described in detail, but unless otherwise specified, all technical terms and scientific terms used in the present specification have the same meanings as those generally understood by those skilled in the art to which the present invention belongs. Have.

(About the SSTR5 antagonist of the present invention)
The somatostatin receptor is one of the 7 transmembrane G protein conjugated receptors, and 5 subtypes have been found so far, named SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5, respectively. ing. As used herein, the term "SSTR5 antagonist" refers to all compounds having an antagonistic effect on the SSTR5. Many "SSTR5 antagonists" are already known in the art, and those skilled in the art recognize and widely use "SSTR5 antagonists" as a comprehensive technical term for these groups of compounds.
In carrying out the present invention, those skilled in the art can appropriately select a preferred SSTR5 antagonist from the viewpoints of efficacy, safety, and the like. In particular, among the five SSTRs, it is preferable to select one having high selectivity (SSTR5 selective antagonistic action) for SSTR5 (SSTR5 selective antagonistic agent). Such SSTR5 antagonistic activity and selectivity for SSTR5 can be confirmed according to a method known in the art.

Examples of such SSTR5 antagonists include International Publication No. 2014/142363, International Publication No. 2015/052910, International Publication No. 2015/064083, International Publication No. 2010/056717, and International Publication No. 2010/129729. , International Publication No. 2011/146324, International Publication No. 2012/024183, International Publication No. 2016/205032, International Publication No. 2006/094682, International Publication No. 2006/12883, International Publication No. 2007/0258997, International Publication No. Publication No. 2007/11340, International Publication No. 2008/000692, International Publication No. 2008/019967, International Publication No. 2008/031735, International Publication No. 2008/122510, International Publication No. 2008/145524 and International Publication No. Examples thereof include the compounds described in 2008/148710 or salts thereof.

Among these, the preferable specific compound is
6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7,8 -Tetrahydro-1,6-naphthylidine-3-carboxylic acid (International Publication No. 2015/052910, compound described in Example 4) or a salt thereof,
6- (1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid (International Publication No. 2015/052910, compound according to Example 67),
6-(1-((2-Cyclopropyl-5-ethoxy-2', 4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6 7,8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid (International Publication No. 2015/052910, compound described in Example 35),
6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -2-ethyl-5-oxo-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid (International Publication No. 2015/052910, compound described in Example 74),
1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-ethyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid (International Publication No. 2015/064083, compound according to Example 44),
1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2- Dihydropyridine-4-carboxylic acid (International Publication No. 2015/064083, compound according to Example 49),.
1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid (International Publication No. 2015/064083, compound according to Example 50),
4- {8-[(2- (Cyclopropyl) -5-trifluoromethylphenyl) methyl] -2-oxo-1-oxa-3,8-diazaspiro [4.5] deku-3-yl} benzoic acid (Compounds of International Publication No. 2012/024183, Example 4-50),
6- {8-[(4-ethoxy-2', 3', 4'-trifluorobiphenyl-2-yl) methyl] -1-oxa-2,8-diazaspiro [4.5] deku-2-ene -3-yl} Pyridine-3-carboxylic acid (compound according to International Publication No. 2011/146324, Example 30),
4- [8-[(2-Cyclopropyl-5-ethoxy-4-methyl-phenyl) methyl] -2-oxo-1,3,8-triazaspiro [4.5] decane-3-yl] benzoic acid ( International Publication No. 2016/205032, compound according to Example 1),
N- [1- (2,6-diethoxy-4'-fluoro-biphenyl-4-ylmethyl) -piperidine-4-yl] -5-methyl-nicotinamide (International Publication No. 2006/128803, Example 153) The compound described),
6- [1- (4-Chloro-3,5-diethoxy-benzyl) -piperidine-4-ylamino] -nicotinic acid (International Publication No. 2008/019967, compound according to Example 70),
Or their salt,

Further, as a particularly preferable specific compound,
6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7,8 -Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
6- (1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
6-(1-((2-Cyclopropyl-5-ethoxy-2', 4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6 7,8-Tetrahydro-1,6-naphthalidine-3-carboxylic acid,
6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -2-ethyl-5-oxo-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-ethyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid,
1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2- Dihydropyridine-4-carboxylic acid,
1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid,
Or their salt,

The most preferable specific compound is
6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7,8 -Tetrahydro-1,6-naphthylidine-3-carboxylic acid or a salt thereof,
Can be mentioned.
The "SSTR5 antagonist" of the present invention can be manufactured by a person skilled in the art by appropriately utilizing the methods described in the above patent documents and the methods known in the art, and used for the practice of the present invention. be able to.

As demonstrated using the representative SSTR5 antagonists in the Examples section below, the "SSTR5 antagonist" has a diagnostic aid, prophylactic or therapeutic effect on the desired biliary tract disease based on its antagonism to the SSTR5. It is the one that demonstrates.

In carrying out the present invention, the "SSTR5 antagonist" can be used in either the free form or in the form of a salt thereof (preferably a pharmaceutically acceptable salt thereof). Those skilled in the art can appropriately select from both forms and carry out the present invention based on the characteristics of the individual SSTR5 antagonists used.
Pharmaceutically acceptable salts include, for example, salts with inorganic acids such as hydrochlorides, hydrobromates, sulfates, phosphates, acetates, fumarates, oxalates, citrates, etc. Salts with acids such as salts with organic acids such as methanesulfonates, benzenesulfonates, tosylates, maleates, etc .; and alkali metal salts such as sodium salts, potassium salts, calcium salts, etc. Salts with bases such as alkaline earth metal salts; salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, asparaginate and the like can be mentioned.

In carrying out the present invention, the SSTR5 antagonist can also be used in the form of its prodrug. A person skilled in the art can appropriately design the prodrug, and the prodrug can be produced by a method known per se. Even if the prodrug changes to the desired SSTR5 antagonist under physiological conditions, as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198. good.

(Regarding the biliary tract disease of the present invention)
As a result of diligent studies, the present inventors have found for the first time that the contraction of the gallbladder is induced by the antagonism of SSTR5.
In addition, as a result of further diligent studies based on this finding, it was also found that the following effects are expected by the SSTR5 antagonistic action.
1) Bile flow increasing action 2) Cholecystokinin (CCK) secretion promoting action 3) Oddi sphincter relaxing action Therefore, the SSTR5 antagonist can be used, for example, for biliary tract diseases listed below. May be effective in prevention and / or treatment.
1. 1. Diseases related to decreased motor function of the bile sac and stagnation of bile For example, cholelithiasis (cholelithiasis, total cholelithiasis, etc.), cholecystosis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC) ), Progressive familial intrahepatic bile stagnation type 1 (PFIC1), Progressive familial intrahepatic bile stagnation type 2 (PFIC2), Alasir syndrome, etc.
Here, with respect to the prevention of cholelithiasis, more specifically, prevention of secondary recurrence after remission by treatment with ursodeoxycholic acid and prevention of cholelithiasis after barrier surgery can be mentioned.
In addition, the combination of extracorporeal shock wave lithotripsy (ESWL) and the administration of SSTR5 antagonist can be expected to improve the remission rate of cholelithiasis, shorten the treatment period, and reduce the recurrence rate, and the combination therapy is an alternative to cholecystectomy. It can be a therapy.
2. 2. Diseases related to the secretory-promoting action of cholecystokinin (CCK) The SSTR5 antagonist functions as a pancreatic juice secretagogue and promotes pancreatic juice secretion by the secretory-promoting action of cholecystokinin (CCK), facilitating pancreatic juice collection. , Can lead to early detection of pancreatic cancer (diagnosis assistance).
3. 3. Diseases associated with dysfunction of the Sphincter of Oddi For example, functional biliary tract disorders (functional gallbladder disorders, Oddi sphincter disorders, papillary sphincter abnormalities), etc.

Furthermore, SSTR5 antagonists may be useful in assisting in the diagnosis of biliary tract diseases. More specifically, for example, it may be useful as an adjunct to catheter intubation into the papilla of Vater during endoscopic retrograde cholangiopancreatography (ERCP). That is, the promotion of gallbladder contraction by the SSTR5 antagonist and the increase in bile secretion due to the increase in bile flow, or the relaxation of the Oddi sphincter muscle improve the visibility of the papilla under endoscopy during ERCP treatment, and catheter intubation is performed. It is expected to be simple. Along with this, physical irritation such as catheter contact with the nipple site is reduced, and it is expected that the risk of postoperative complications such as severe acute cholangitis and acute pancreatitis will be reduced. Furthermore, since the ERCP procedure can be simplified, it is expected that the SSTR5 antagonist can contribute to the improvement of the diagnosis of biliary tract diseases as an adjunct to ERCP.

Among the above various uses, the SSTR5 antagonist can be used as a preventive and / or therapeutic agent for cholelithiasis, biliary sludge, PSC, PBC, functional biliary tract disorders, or for catheter infusion into the papilla of Vater during ERCP. It is expected to be particularly effective as an auxiliary agent.

In the present specification, "diagnosis" refers to diagnosis and examination using drugs, medical devices, etc. as appropriate, and specialists such as doctors judge the state of the patient's illness using various information obtained there. This includes the use of diagnostic agents or diagnostic aids (diagnosis aids) for diagnosis.

In the present specification, "prevention" includes prevention of the onset of a disease (entire pathological condition or one or more pathological conditions) and delay of the onset of the disease. "Prophylactically effective amount" means a dose of the SSTR5 antagonist sufficient to achieve such purpose.

As used herein, "treatment" includes cure of a disease (whole condition, or one or more conditions), amelioration of the disease, and suppression of the progression of the severity of the disease. "Therapeutic effective amount" means a dose of the SSTR5 antagonist sufficient to achieve such purpose.

(Regarding the dosage form)
In carrying out the present invention, the SSTR5 antagonist may be used in either form alone or in the form of a pharmaceutical composition comprising the SSTR5 antagonist as an active ingredient with a pharmaceutically acceptable carrier. can.

Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), suppositories, powders, granules, capsules (soft capsules, microcapsules, etc.). Includes), troches, suppositories, liquids, emulsions, suspensions, release-controlled formulations (eg, immediate-release, sustained-release, sustained-release microcapsules), aerosols, films (eg, oral). Internal disintegration film, oral mucosal adhesive film), injection (eg, subcutaneous injection, intravenous injection (eg, bolus), intramuscular injection, intraperitoneal injection), drip, transdermal absorption type preparation, ointment Examples thereof include agents, lotions, patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal agents, pulmonary agents (inhalants), eye drops and the like.

In the present specification, as the "medically acceptable carrier", various carriers commonly used in the field of pharmaceutical technology can be used.

Specific examples of the "pharmaceutically acceptable carrier" include excipients (eg, lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.) and slips in solid preparations. Swamps (eg magnesium stearate, talc, colloidal silica, etc.), excipients (eg crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, etc. Methyl cellulose, sodium carboxymethyl cellulose, etc.) and disintegrants (eg, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, L-hydroxypropyl cellulose, etc.), and the like can be used.

In liquid formulations, solvents (eg, water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizers (eg, polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, etc.) Surfactants such as ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalconium chloride, glycerin monostearate, etc. Activators; eg, polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydrophilic polymers such as hydroxypropylcellulose, etc.), isotonic agents (eg, glucose, D-sorbitol, sodium chloride, glycerin, etc.) D-mannitol and the like), buffers (eg, buffers such as phosphates and citrates), and soothing agents (eg, benzyl alcohol and the like), and the like can be used.

If necessary, preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (eg, sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. Further formulation additives may be added.

The pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., but the SSTR5 antagonist is usually 0.01 to 99% (w / w), preferably 0.1 to 85%, based on the total amount of the preparation. It can be produced by adding it in a ratio of (w / w). The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, depending on its form. The pharmaceutical composition of the present invention may be formed into a release-controlled preparation such as an immediate-release preparation or a sustained-release preparation containing the active ingredient.

(About the subject of administration)
The SSTR5 antagonist used in the present invention is expected to have low toxicity and few side effects, and has excellent properties as a pharmaceutical product. Therefore, the SSTR5 antagonist can be safely administered to mammals (eg, humans, monkeys, dogs, horses, etc.).

(Route of administration)
In carrying out the present invention, the SSTR5 antagonist may be used alone or as a pharmaceutical composition orally or parenterally (eg, intravenous, infusion, intramuscular, subcutaneous, organ, intranasal, intradermal, It can be administered transdermally, instilled, intracerebrally, in the rectum, intravaginally, intraperitoneally, and into lesions).

(About dosage)
The dose of the SSTR5 antagonist varies depending on the subject, the route of administration, and the age and symptoms of the subject, but is not particularly limited. For example, the dose is 0.1 (preferably 0.5) to 320 mg per dose as an active ingredient, SSTR5 antagonist, and the dose is 0.01 to 320 mg for parenteral administration. It is 100 mg, preferably 0.05 to 64 mg. The dose can be administered in 1 to 3 divided doses per day. In addition, when administered in the form of a sustained release preparation, it is also possible to administer the drug every other day or at intervals of longer so as to correspond to the dose.

(About combined use with other drugs)
In carrying out the present invention, the SSTR5 antagonist can be used for the prevention or treatment of a target disease in combination with other drugs, and excellent preventive and / or therapeutic effects can be expected when used in combination with other drugs. It can also be expected that such combination therapy will reduce the dose of other drugs and reduce the side effects of these drugs.
A drug that can be used in combination with an SSTR5 antagonist in carrying out the present invention (hereinafter, may be abbreviated as a concomitant drug) is appropriately used in view of the type of the patient's disease, the severity of the symptom, and the like. You can choose. For example, for the prevention or treatment of cholelithiasis or primary biliary cirrhosis (PBC), bile acid preparations (ursodeoxycholic acid, etc.), therapeutic agents for dyslipidemia (fibrates, statins, etc.), farnesoid X receptor agonists. (Obeticholic acid, etc.) can be used in combination.
The SSTR5 antagonist acts synergistically in combination with ursodeoxycholic acid, and is expected to improve the remission rate of cholelithiasis, shorten the treatment period, and reduce the recurrence rate. It may also be an alternative therapy to cholecystectomy.
The administration form of the concomitant drug is not particularly limited, and the SSTR5 antagonist and the concomitant drug can be combined at the time of administration. For example, (1) administration of a preparation containing a combination of an SSTR5 antagonist and a concomitant drug, and (2) simultaneous formulation of two preparations obtained by separately formulating an SSTR5 antagonist and a concomitant drug on the same route of administration. Alternatively, it can be used in the form of separate administration, (3) simultaneous or separate administration of two formulations obtained by separately formulating the SSTR5 antagonist and the concomitant drug by different routes of administration. The preferred form can be appropriately selected according to the actual conditions of the medical field.
A pharmaceutical product containing the above-mentioned SSTR5 antagonist in combination with a concomitant drug can be appropriately produced by a person skilled in the art according to the pharmaceutical composition containing the SSTR5 antagonist described above.
The dose of the concomitant drug may be appropriately selected based on the clinically used dose. The compounding ratio of the SSTR5 antagonist and the concomitant drug can be appropriately selected depending on the disease or symptom to be administered, the route of administration, the type of the concomitant drug to be used, and the like. Usually, it can be appropriately determined according to the actual conditions of the medical field based on the general clinical dose of the concomitant drug to be used.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the scope of the present invention at all. Further, unless otherwise specified, the reagents, devices and materials used in the present invention are commercially available or can be appropriately prepared by those skilled in the art.

Example 1 Evaluation of human SSTR5 antagonist activity using the intracellular cAMP concentration as an index The measurement of the intracellular cAMP concentration was carried out using an HTRF cAMP dynamic 2 kit (Cisbio). 384-well white plate diluted with assay buffer (5 mM HEPES (pH 7.5) (Invitrogen), 0.1% fatty-acid free BSA (Sigma), 500 μM IBMX (Wako) -containing HBSS (Invitrogen)). (Greener) was added in increments of 2 μL / well so that the final concentration was 1 μM. A frozen stock of CHO (dhfr-) cells stably expressing the human SSTR5 gene (Accession No. NM_001053) was thawed in a constant temperature bath at 37 ° C., and a passage containing 10% dialysis serum (Gemini) and 50 μg / mL gentamicin (Invitrogen) was added. It was suspended in a substitute medium (MEM alpha (Wako)). After centrifuging the cell suspension, the cells were resuspended in assay buffer and 2 μL was added to each well to a concentration of approximately 4,000 cells / well. After incubating the compound and cells for 15 minutes, assay buffer containing 2 μL / well containing somatostatin 28 (Toray Research Center) at a final concentration of 0.1 nM and forskolin (Wako) at 0.3 μM was added, and the mixture was incubated at room temperature for 30 minutes. bottom. 3 μL / well of cAMP-d2 and anti-cAMP-cryptate were added, and the mixture was allowed to stand at room temperature for 60 minutes. .. A calibration curve prepared from the FRET intensity of the well group to which the cAMP of an arbitrary concentration was added to the assay buffer was used, and the FRET intensity of the well to which the test compound group was added was converted into the cAMP concentration. The inhibitory activity of the compound was calculated by the following formula.
Inhibitory activity (%) = (CB) / (AB) × 100
A: cAMP concentration calculated from the well to which 0.3 μM forskolin was added B: 0.3 μM forskolin, 0.1 nM somatostatin 28 cAMP concentration calculated from the well to which C: 0.3 μM forskolin, 0.1 nM somatostatin 28 and 1 μM Table 1 shows the inhibition rate (%) of the cAMP concentration test compound in the wells to which the test compound was added to SSTR5 at 1 μM.

As is clear from Table 1, this test compound showed excellent SSTR5 antagonistic activity.

Example 2 Evaluation of selectivity for human SSTR subtype The selectivity of the test compound for the human SSTR subtype was examined by the radiolabeled ligand binding assay. The membrane fraction of CHO-K1 cells expressing human SSTR1-5 was subjected to assay buffer (25 mM HEPES (pH 7.4), 5 mM MgCl ₂ , 1 mM CaCl ₂ , 10 μg / mL sapоnin, 0.5% fatty-acid free BSA). ) And incubated for 1 hour in the presence of 1 μM test compound 1 and [ ¹²⁵ I] Tyr ^{11-somatostatin 14 (Perkin Elmer).} Then, the solution containing the membrane fraction was transferred onto the filter plate, the filter was _{washed 6 times with wash buffer (25 mM HEPES, 5 mM MgCl 2} , 1 mM CaCl ₂ ), 50 μL of Microsint 20 (Packard) was added, and TоpCоunt (TоpCоunt) was added. Radioactivity was measured with Perkin Elmer). Table 2 shows the results of the competitive activity of the test compounds on the binding of the human SSTR subtype and the labeled ligand.

As is clear from Table 2, test compound 1 was shown to selectively bind to SSTR5 among the human SSTR subtypes.

Example 3 Gallbladder contraction effect evaluation test using normal mice A 9-week-old male C57BL / 6JJcl mouse (Claire Japan) was fasted overnight and 0.5% (w) containing 0.1 mg / kg of test compound 1. / V) Methylcellulose suspension was orally administered (6 animals per group). Thirty, sixty, 120 and 240 minutes after administration of the compound, mice were opened under isoflurane (Pfizer) anesthesia and exsanguinated by abdominal vena cava transection, and the gallbladder was immediately collected and the tissue weight was measured. In addition, in order to calculate the bile residual rate, the gallbladder was similarly collected in the compound-non-administered group and the tissue weight was measured (6 animals in one group). The bile residual rate was calculated by the following formula.
Bile residual rate (%) = Gallbladder weight of each individual / Average value of gallbladder weight in the compound-non-administered group x 100
The results are shown in Table 3. The significance of each time point for the compound-non-administered group was evaluated by Dunnett's test, and the significance level for the compound-non-administered group was shown by *: p <0.05 and **: p <0.01.

As is clear from Table 3, test compound 1 was shown to induce gallbladder contraction by SSTR5 antagonism. The results of this study clearly demonstrate that SSTR5 antagonists are useful in the treatment and prevention of cholelithiasis, biliary sludge, and functional biliary tract disorders, in suppressing the progression of PSC and PBC pathologies, and in assisting ERCP. ..

Example 4 Evaluation of enhancing effect on corn oil-induced gallbladder contraction using normal mice A 9-week-old male C57BL / 6J Jcl mouse (Claire Japan) was fasted overnight and 0.5% (w / v) methylcellulose suspension. A turbid solution (oil) or 1 mg / kg test compound 1 (suspended in oil) was orally administered (5 mice per group). After 100 minutes, 10 mL / kg of corn oil (Wako) was orally administered to the corn oil-administered group. 120 minutes after administration of the test compound, mice were opened under isoflurane (Pfizer) anesthesia and exsanguinated by abdominal vena cava transection, and the gallbladder was immediately collected and the tissue weight was measured. The bile residual rate was calculated by the following formula.
Bile residual rate (%) = gallbladder weight of each individual ÷ average value of gallbladder weight of vehicle group × 100
The results are shown in Table 4.

As is clear from Table 4, test compound 1 has an enhancing effect on gallbladder contraction caused by corn oil. Insufficient dietary gallbladder contractions increase the risk of gallstones and sludge, so the results of this study show that SSTR5 antagonists further enhance dietary gallbladder contractions, resulting in cholelithiasis, biliary sludge. It clearly shows that it is useful for the treatment and prevention of functional biliary tract disorders and for suppressing the progression of PSC and PBC pathologies.

Example 5 Evaluation of gallstone prevention effect using diet-induced gallstone model mice A 10-week-old male C57BL / 6J Jcl mouse (Claire Japan) was fed with a lithium diet (D180222301, Research Diets Inc.) and 0.5%. (W / v) Methylcellulose suspension (vehicle), 1 mg / kg test compound 1 (suspended in vehicle) or 60 mg / kg ursodeoxycholic acid (suspended in Wako, vehicle) as a positive control once daily. Orally administered for 56 days (12 animals per group). In addition, as a normal control group, mice of the same week age were fed a general feed (CE-2, Japan Claire) and orally administered a 0.5% (w / v) methylcellulose suspension (6 animals per group). After 56 days of administration, the mice were fasted overnight, abdominalized under isoflurane (Pfizer) anesthesia, and exsanguinated by abdominal vena cava amputation. After that, the gallbladder was collected and visually confirmed for the presence of gallstones in the gallbladder, and the incidence of gallstones in each group was calculated. In addition, bile is collected from the bile sac and phospholipids, cholesterol and total bile acid in the bile are measured using LabAssay Phosphoripid (Wako), Cholesterol E-Test Wako (Wako) and Total Bile Acid-Test Wako (Wako), respectively. Then, the cholesterol saturation of bile was calculated (J Lipid Res. 1978, 19: 945).
The gallstone incidence and bile cholesterol saturation are shown in Table 5. The significance of each compound-administered group to the Vehicle group in the incidence of gallstones was evaluated by the χ2 test, and the significance level was shown by ##: p <0.01. The significance of each compound-administered group to the vehicle group in cholesterol saturation was evaluated by Dunnett's test, and the significance level was shown by **: p <0.01.

As is clear from Table 5, test compound 1 has a preventive effect on the onset of gallstones, and its action is different from the existing therapeutic drug ursodeoxycholic acid, and it is a mechanism that does not affect the cholesterol saturation of bile. showed that. The results of this test clearly show that SSTR5 antagonists are useful in the prevention and treatment of cholelithiasis and biliary sludge.

Example 6 Evaluation of gallstone treatment effect using diet and compound-induced gallstone model mice Eight-week-old male C57BL / 6J Jcl mice (Claire Japan) were fed with a lithogenic diet (D180222301, Research Diets Inc.). Gallstones were induced by oral administration of 1 mg / kg debazepide (TOCRIS Bioscience) suspended in a 5% (w / v) methylcellulose solution (vehicle) once daily for 6 weeks. After that, the diet was switched to a general feed (CE-2, Japan Claire), and 1 mg / kg test compound 1 (suspended in vehicle), 60 mg / kg ursodeoxycholic acid (suspended in Wako, vehicle) or vehicle was administered daily. It was orally administered once (10 animals per group). After repeated administration for 12 weeks, the mice were fasted overnight, abdominalized under isoflurane (Pfizer) anesthesia, and exsanguinated by abdominal vena cava amputation. After that, the gallbladder was collected and visually confirmed for the presence of gallstones in the gallbladder, and the gallstone prevalence in each group was calculated. In some mice, the gallbladder was collected after 6 weeks of gallstone induction treatment to confirm the presence or absence of gallstones, and the gallstone prevalence was calculated (pre group).
Table 6 shows the gallstone retention rate. The significance of gallstone prevalence in each compound-administered group with respect to the Vehicle group was evaluated by the χ2 test, and the significance level was shown by ##: p <0.01.

As is clear from Table 6, test compound 1 showed a gallstone remission promoting effect in the gallstone model. The results of this test clearly show that SSTR5 antagonists are useful in the treatment of cholelithiasis.

Example 7 Evaluation of effect of increasing bile flow rate using compound-induced PSC model mice 0.025% (w / w) 3,5-diethoxycarbonyl-1,4 in 9-week-old male Jcl: ICR mice (Claire Japan) -Feed powder CE-2 (Nippon Claire) containing dihydrocollidine (Sigma), 0.5% (w / v) methylcellulose suspension (vehicle), 1 mg / kg test compound 1 (suspended in vehickle) 1 Orally administered once daily (8 animals per group). In addition, as a normal control group, CE-2 was fed to mice of the same week age and vehicle was orally administered (8 mice in 1 group). After 28-31 days of administration, mice were fasted overnight, abdomen was opened under isoflurane (Pfizer) anesthesia, the cystic duct was ligated, and a cannula was intubated into the common bile duct. Bile was collected for 30 minutes, weighed, and the bile flow rate (μL / min / 100 g body weight) was calculated.
The results are shown in Table 7. The significance of the compound-administered group with respect to the Vehicle group was evaluated by Dunnett's test, and the significance level was shown by *: p <0.05.

As is clear from Table 7, test compound 1 showed an effect of increasing bile flow rate on the PSC model. The results of this study clearly show that SSTR5 antagonists are useful for the treatment and prevention of cholelithiasis, biliary sludge, and functional biliary tract disorders, suppressing the progression of PSC and PBC pathologies, and assisting ERCP. ..

Example 8 Evaluation of hepatoprotective effect using compound-induced PSC model mice 0.025% (w / w) 3,5-diethoxycarbonyl-1,4- in 9-week-old male Jcl: ICR mice (Claire Japan) Feeding powder CE-2 (Nippon Claire) containing dihydrocollidine (Sigma), 0.5% (w / v) methylcellulose suspension (vehicle), 1 mg / kg test compound 1 (suspended in vehickle) daily. It was orally administered once for 30 days (8 animals per group). In addition, as a normal control group, CE-2 was fed to mice of the same week age and vehicle was orally administered (8 mice in 1 group). Blood samples were taken from the tail vein of mice after 28 days of administration, and plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels were measured with an automatic analyzer 7180 (Hitachi High-Tech). bottom. After administration for 30 days, the abdomen was opened under isoflurane (Pfizer) anesthesia and exsanguinated by abdominal vena cava amputation, and the liver was collected. The collagen content in the liver was measured by a Total collagen assay kit (QuickZyme Biosciences), and the content per 1 mg of the liver was calculated.
Table 8 shows plasma AST, ALT, ALP levels and liver collagen content. The significance of the compound-administered group with respect to the Vehicle group was evaluated by Student's t-test when the two groups were homoscedastic, and by Welch's test when the two groups were unequally dispersed. (Student's t-test), #: p <0.05 (Welch's test).

As is clear from Table 8, test compound 1 was shown to suppress the progression of pathological conditions with respect to the PSC model. The results of this test clearly show that the SSTR5 antagonist is useful for suppressing / treating the progression of PSC.

The present invention provides a diagnostic aid, a preventive or therapeutic agent for biliary tract diseases, and is useful in the field of medicine.

This application is based on Japanese Patent Application No. 2020-084727 (Filing date: May 13, 2020), the contents of which are all included in the present specification.

Claims (8)

1. A diagnostic aid, preventive or therapeutic agent for biliary tract diseases containing an SSTR5 antagonist as an active ingredient.
2. The SSTR5 antagonist is 6- (1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5, 6,7,8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
   6- (1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
   6-(1-((2-Cyclopropyl-5-ethoxy-2', 4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5,6 7,8-Tetrahydro-1,6-naphthalidine-3-carboxylic acid,
   6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -2-ethyl-5-oxo-5,6,7 , 8-Tetrahydro-1,6-naphthylidine-3-carboxylic acid,
   1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-ethyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid,
   1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2- Dihydropyridine-4-carboxylic acid,
   1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl) methyl) piperidine-4-yl) -3-methyl-2-oxo-1,2-dihydropyridine -4-Carboxylic acid,
   And their salt,
   The diagnostic aid, prophylactic or therapeutic agent for biliary tract disease according to claim 1, which is selected from.
3. The SSTR5 antagonist is 6- (1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl) methyl) piperidine-4-yl) -5-oxo-2-propyl-5, The diagnostic aid, prophylaxis or therapeutic agent for biliary tract disease according to claim 1, which is 6,7,8-tetrahydro-1,6-naphthalidine-3-carboxylic acid or a salt thereof.
4. Claims 1-3, wherein the biliary system disease is at least one selected from cholelithiasis, biliary sludge, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), and functional biliary tract disorder. The prophylactic or therapeutic agent for biliary diseases according to any one of the above.
5. The diagnostic aid for biliary tract disease according to any one of claims 1 to 3, wherein the diagnostic aid assists in intubation of a catheter into the papilla of Vater during endoscopic retrograde cholangiopancreatography (ERCP). ..
6. A method for assisting, preventing or treating a biliary tract disease, which comprises administering an effective amount of an SSTR5 antagonist to a mammal in need thereof.
7. SSTR5 antagonist used for diagnostic assistance, prevention or treatment of biliary tract diseases.
8. Use of SSTR5 antagonists to manufacture drugs for diagnostic assistance, prevention or treatment of biliary tract diseases.