TW202207929A - Diagnostic aid, preventive agent or therapeutic agent for biliary tract disease - Google Patents

Abstract

The present invention relates to a diagnostic aid, a preventive agent or therapeutic agent for biliary tract diseases or the like, which contains an SSTR5 antagonist as an active ingredient.

Description

Auxiliary, preventive or therapeutic agent for diagnosis of biliary tract disease

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

The passage of bile from the liver to the duodenum is collectively referred to as the "biliary tract" and is further divided into intrahepatic bile ducts, extrahepatic bile ducts (ie, bile ducts), gallbladder, and duodenal papilla. Diseases occurring in this "biliary tract" (hereafter referred to simply as "biliary tract diseases") include, for example, cholelithiasis, cholestasis, and primary sclerosing cholangitis (PSC). , Primary biliary cirrhosis (PBC), functional biliary disorders (functional gallbladder disorders, Oddi sphincter disorders, papillary sphincter disorders) as representatives.

For these diseases, although the current situation is surgical or drug therapy (for example, ursodeoxycholic acid for cholelithiasis or PBC), especially for drug therapy, its treatment The effectiveness is difficult to say high, and its prognosis is not necessarily satisfactory. Furthermore, there is no effective preventive method for these diseases through drugs.

Cholelithiasis is generally classified into cholecystolithiasis, choledocholithiasis and intrahepatic calculi. In the case of cholecystolithiasis, cholesterol calculi are mostly seen. Bilirubin stones. In addition, for common bile duct stones, in addition to the primary stones in the common bile duct, stones caused by gallbladder stones and intrahepatic stones can also be seen. Despite the high prevalence of cholelithiasis and the greater number of patients with asymptomatic gallstones, treatment options are limited. Among them, in the treatment of cholecystolithiasis, in most cases, drug therapy or cholecystectomy using bile acid preparations is applied. For the treatment of gallstone dissolution using bile acid preparations, ursodeoxycholic acid is generally used, but the dissolution of cholesterol stones requires a considerable number of days, so long-term medication is required. Furthermore, the recurrence rate of cholecystolithiasis is also high. higher. In addition, the absence of options other than ursodeoxycholic acid is also a problem with regard to pharmacotherapy. On the other hand, with regard to cholecystectomy, although cholelithiasis itself is not a fatal disease, the mortality rate associated with the operation is high, which is a huge problem. Therefore, there are also patients (the elderly, those suffering from pre-existing diseases, etc.) who are at high risk for surgery or those who do not desire surgery. Against this background, there is an unmet need for existing treatments in cholelithiasis. Furthermore, for patients with cholelithiasis, the risk of concurrent acute cholecystitis, acute cholangitis, gallbladder cancer, jaundice, pancreatitis, liver dysfunction, etc. is increased, so there is also a preventive method for developing cholelithiasis. need.

Biliary sludge is a disease in which bile sludge and biliary sand are accumulated in the gallbladder for some reason. In bedridden patients/patients admitted to the Intensive Care Unit (ICU)/bariatric surgery patients/cancer patients/eating disorder patients/patients with It can be seen in patients with eating disorder drugs/patients with long-term intravenous nutrition intake. For these patients, due to the inability to obtain sufficient gallbladder contraction caused by eating, the bile sludge and gallstone will accumulate in the gallbladder and cause bile stagnation, thus increasing the risk of inducing cholangitis/cholecystitis/hepatitis. improve. At present, there is no effective preventive and therapeutic method for cholestasis through drugs, and such development is being pursued.

Primary sclerosing cholangitis (PSC) is a chronic liver disease caused by bile stagnation due to stenosis of the bile ducts inside and outside the liver, and its etiology is still unknown. Since chronic cholestasis is the main symptom of morbidity, cholestatic cirrhosis often develops later due to the progression of liver fibrosis. There is no effective drug treatment for this disease, and only ursodeoxycholic acid or fibrates are used as symptomatic therapy to improve symptoms. From the above background, the development of an effective drug therapy for this disease is being pursued.

As such, the prevention or treatment of biliary tract diseases through drugs has not been fully established, and a drug therapy with a new mechanism of action with higher efficacy is awaited.

Endoscopic retrograde cholangiopancreatography (ERCP) is widely used for the early diagnosis of tumors of the pancreatic duct and the diagnosis and treatment of biliary diseases such as stones. Universal use. Compared with surgical abdominal incision, ERCP is non-invasive, but it can be complicated by severe acute cholangitis or acute pancreatitis as postoperative complications, which has become a clinical problem. It is generally believed that this postoperative complication is due to the difficulty in visually recognizing the inserted part of the catheter under the endoscope when the catheter is placed through the nipple. It is caused by inflammation/edema of papilla of Vater. Therefore, it is possible to improve the visibility of the nipple under the endoscope during the ERCP operation, or to simplify the transnipple treatment of the catheter by relaxing the sphincter of Ode, thereby making the physical examination of the nipple easier. The reduction of sexual stimulation can be expected to simplify the operation of ERCP and reduce the risk of postoperative complications. Furthermore, it is generally believed that these also contribute to the improvement of diagnostic and therapeutic techniques for biliary tract diseases performed through ERCP.

Thus, in the diagnosis of biliary tract diseases, drugs with a new mechanism of action that can assist their operation are waiting to be created.

Somatostatin is a peptide hormone secreted by the hypothalamus, pancreatic delta cells, endocrine cells of the digestive tract, etc., through 5 somatostatin receptors (SSTR1 -5) and suppress Regulately control the secretion of various hormones. Currently, in the clinic, somatostatin analog preparations such as octreotide or pasireotide are used to ameliorate the concomitant hypersecretion of hormones such as acromegaly or Cushing's disease. item symptoms. On the other hand, somatostatin analog preparations are known to have actions such as suppressing gallbladder contraction and reducing bile flow (Non-Patent Documents 1 to 5). However, since the somatostatin analog preparations all showed binding affinity for SSTR1-5, it was completely unknown which SSTR activation these effects depended on.

Among SSTR1-5, SSTR5 in particular is known to be a receptor expressed mainly in small enteroendocrine cells or pancreatic β cells, and is known to inhibit GLP-1 and PYY and other digestive tracts by binding to somatostatin secretion of hormones or insulin. So far, various SSTR5 antagonists have been known (Patent Documents 1 to 18), but it has not been suggested or reported that SSTR5 antagonists cause gallbladder contraction or are effective in biliary diseases.

[Prior Art Literature]

[Patent Literature]

[Patent Document 1] International Publication No. 2014/142363

[Patent Document 2] International Publication No. 2015/052910

[Patent Document 3] International Publication No. 2015/064083

[Patent Document 4] International Publication No. 2010/056717

[Patent Document 5] International Publication No. 2010/129729

[Patent Document 6] International Publication No. 2011/146324

[Patent Document 7] International Publication No. 2012/024183

[Patent Document 8] International Publication No. 2016/205032

[Patent Document 9] International Publication No. 2006/094682

[Patent Document 10] International Publication No. 2006/128803

[Patent Document 11] International Publication No. 2007/025897

[Patent Document 12] International Publication No. 2007/110340

[Patent Document 13] International Publication No. 2008/000692

[Patent Document 14] International Publication No. 2008/019967

[Patent Document 15] International Publication No. 2008/031735

[Patent Document 16] International Publication No. 2008/122510

[Patent Document 17] International Publication No. 2008/145524

[Patent Document 18] International Publication No. 2008/148710

[Non-patent literature]

[Non-Patent Document 1] Gut. 1996, 38:775-583

[Non-Patent Document 2] Dig Dis Sci. 1994, 39:284-288

[Non-Patent Document 3] Dig Dis Sci. 1992, 37:773-777

[Non-Patent Document 4] Endocrine. 2012, 42:366-374

[Non-Patent Document 5] Pituitary. 2021, 24:242-251

As mentioned above, it is difficult to say that a method of diagnosis aid, prevention or treatment of biliary tract disease by drug has been established, and the development of a diagnosis aid, prevention or treatment agent with high clinical effect is an urgent task in the field of medicine. .

The inventors of the present invention, as a result of repeated efforts under such circumstances, found for the first time that SSTR5 antagonists are effective in assisting diagnosis, prevention or treatment of biliary tract diseases, 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, comprising an SSTR5 antagonist as an active ingredient.

[2] A method for diagnosis assistance, prevention or treatment of biliary tract diseases, comprising administering an effective amount of an SSTR5 antagonist to a mammal in need of administration of the SSTR5 antagonist.

[3] An SSTR5 antagonist for use in diagnosis assistance, prevention or treatment of biliary tract diseases.

[4] Use of an SSTR5 antagonist for the manufacture of a medicament for diagnosis assistance, prevention or treatment of biliary tract diseases.

[5] The agent for assisting in diagnosis, prevention or treatment of biliary tract diseases according to the above [1], the method for assisting in diagnosis, prevention or treatment of biliary tract diseases according to the above [2], and the above [3] The SSTR5 antagonist, or the use of the SSTR5 antagonist described in the above [4], wherein the SSTR5 antagonist is selected from 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. 2011/146324, International Publication No. 2012/024183, International Publication No. 2016/205032, International Publication No. 2006/094682, International Publication No. 2012/024183 International Publication No. 2006/128803, International Publication No. 2007/025897, International Publication No. 2007/110340, International Publication No. 2008/000692, International Publication No. 2008/019967, International Publication No. 2008/031735, International Publication No. The compound or its salt described in No. 2008/122510, International Publication No. 2008/145524, and International Publication No. 2008/148710.

[6] The agent for assisting in diagnosis, prevention or treatment of biliary tract diseases according to the above [1], the method for assisting in diagnosis, prevention or treatment of biliary tract diseases according to the above [2], and the above [3] The SSTR5 antagonist, or the use of the SSTR5 antagonist described in the above [4], wherein the SSTR5 antagonist is selected from the compounds and salts described in International Publication No. 2015/052910 and International Publication No. 2015/064083.

[7] The agent for assisting in diagnosis, prevention or treatment of biliary tract disease according to the above [1], the method for assisting in diagnosis, prevention or treatment of biliary tract disease according to the above [2], and the above [3] The SSTR5 antagonist, or the use of the SSTR5 antagonist described in the above [4], wherein the SSTR5 antagonist is selected from the following:

啶-3-甲酸、 6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-pendoxyl-2-propane base-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

啶-3-甲酸、 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy- 2-propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

啶-3-甲酸、 6-(1-((2-Cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy -2-Propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

啶-3-甲酸、 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5 -Pendant oxy-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2 - side oxy-1,2-dihydropyridine-4-carboxylic acid,

1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl- 2-Pendant oxy-1,2-dihydropyridine-4-carboxylic acid,

1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2 - side oxy-1,2-dihydropyridine-4-carboxylic acid,

and such salts.

[8] The agent for diagnosis aid, prevention or treatment of biliary tract disease according to any one of the above [1] to [7]; the diagnosis aid, prevention or treatment method for biliary tract disease; for use in biliary tract disease SSTR5 antagonists for diagnosis assistance, prevention or treatment of diseases; or use of SSTR5 antagonists for the manufacture of medicines for diagnosis assistance, prevention or treatment of biliary tract diseases, wherein the biliary tract diseases are selected from cholelithiasis At least one of , biliary sludge, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), functional biliary disorder (functional gallbladder disorder, sphincter of Odey disorder, papillary sphincter disorder) one.

[9] The diagnostic aid for biliary tract disease according to any one of the above [1] to [8]; the diagnostic aid for biliary tract disease; the SSTR5 antagonist for use in the diagnosis aid for biliary tract disease ; or the use of SSTR5 antagonists for the manufacture of medicines for the diagnosis of biliary diseases, wherein the diagnosis aid is catheterization of the papilla of Vater during endoscopic retrograde cholangiopancreatography (ERCP). Auxiliary tube.

According to the present invention, it is possible to provide a medicament that can be used safely and effectively for diagnosis assistance, prevention or treatment of biliary tract diseases.

The present invention relates to: a diagnostic aid, prevention or treatment agent for biliary tract disease, which contains SSTR5 antagonist as an active ingredient; a diagnostic aid, prevention or treatment method for biliary tract disease, which comprises an effective amount of SSTR5 antagonist The SSTR5 antagonist is administered to a mammal requiring administration of the SSTR5 antagonist; a SSTR5 antagonist, which is used for diagnosis assistance, prevention or treatment of biliary tract diseases; the use of a SSTR5 antagonist, which is used for the manufacture of biliary tract Medicines used to assist in the diagnosis, prevention or treatment of diseases.

Hereinafter, the present invention will be described in detail. Unless otherwise specified, all technical and scientific terms used in this specification have the same meaning as commonly understood by those with ordinary knowledge in the technical field to which the present invention belongs. significance.

(for SSTR5 antagonists of the present invention)

Somatostatin receptor is one of the seven transmembrane G protein-coupled receptors. So far, five subtypes have been found, named SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5 respectively. In the present specification, the term "SSTR5 antagonist" refers to all compounds having an antagonistic action against SSTR5. Many "SSTR5 antagonists" are already known in their technical fields, and those of ordinary skill in the art will recognize "SSTR5 antagonists" as an inclusive technical term referring to this group of compounds, and widely used.

In carrying out the present invention, a preferred SSTR5 antagonist can be appropriately selected from the viewpoints of efficacy, safety, and the like, as long as one has ordinary knowledge in the technical field. In particular, it is preferable to select those with higher selectivity for SSTR5 (SSTR5 selective antagonism) among the 5 SSTRs (SSTR5 selective antagonist). Such SSTR5 antagonism or selectivity for SSTR5 can be confirmed according to methods known in the art.

Such SSTR5 antagonists include, for example, International Publication No. WO 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. 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. 2006/128803, International Publication No. 2007/025897, International Publication No. 2007/110340, International Publication No. 2008/000692, International Publication No. 2008/019967, International Publication The compound or salt thereof described in International Publication No. 2008/031735, International Publication No. 2008/122510, International Publication No. 2008/145524, and International Publication No. 2008/148710.

Among these, preferred specific compounds include:

啶-3-甲酸(國際公開第2015/052910號，實施例4所記載之化合物)或其鹽、 6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-pendoxyl-2-propane base-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid (International Publication No. 2015/052910, the compound described in Example 4) or a salt thereof,

啶-3-甲酸(國際公開第2015/052910號，實施例67所記載之化合物)、 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy- 2-propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid (International Publication No. 2015/052910, the compound described in Example 67),

啶-3-甲酸(國際公開第2015/052910號，實施例35所記載之化合物)、 6-(1-((2-Cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy -2-Propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid (International Publication No. 2015/052910, the compound described in Example 35),

啶-3-甲酸(國際公開第2015/052910號，實施例74所記載之化合物)、 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5 -Pendant oxy-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid (International Publication No. 2015/052910, the compound described in Example 74),

1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2 -Pendant oxy-1,2-dihydropyridine-4-carboxylic acid (International Publication No. 2015/064083, the compound described in Example 44),

1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl- 2-Pendant oxy-1,2-dihydropyridine-4-carboxylic acid (International Publication No. 2015/064083, the compound described in Example 49),

1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2 -Pendant oxy-1,2-dihydropyridine-4-carboxylic acid (International Publication No. 2015/064083, the compound described in Example 50),

4-{8-[(2-(Cyclopropyl)-5-trifluoromethylphenyl)methyl]-2-oxy-1-oxa-3,8-diazaspiro[4.5] Dec-3-yl}benzoic acid (International Publication No. 2012/024183, the compound described in Examples 4-50),

6-{8-[(4-Ethoxy-2',3',4'-trifluorobiphenyl-2-yl)methyl]-1-oxa-2,8-diazaspiro[4.5 ]dec-2-en-3-yl}pyridine-3-carboxylic acid (International Publication No. 2011/146324, the compound described in Example 30),

4-[8-[(2-Cyclopropyl-5-ethoxy-4-methyl-phenyl)methyl]-2-oxy-1,3,8-triazaspiro[4.5] Decan-3-yl]benzoic acid (International Publication No. 2016/205032, the compound described in Example 1),

N-[1-(2,6-diethoxy-4'-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-5-methyl-nicotinamide (International Publication No. 2006/128803, the compound described in Example 153),

6-[1-(4-Chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid (International Publication No. 2008/019967, described in Example 70 compound),

or such salt,

Furthermore, particularly preferred specific compounds include:

啶-3-甲酸、 6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-pendoxyl-2-propane base-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

啶-3-甲酸、 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy- 2-propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

啶-3-甲酸、 6-(1-((2-Cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy -2-Propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

啶-3-甲酸、 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5 -Pendant oxy-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid,

1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2 - side oxy-1,2-dihydropyridine-4-carboxylic acid,

1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl- 2-Pendant oxy-1,2-dihydropyridine-4-carboxylic acid,

1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2 - side oxy-1,2-dihydropyridine-4-carboxylic acid,

or such salt,

The best specific compounds can be listed as follows:

啶-3-甲酸或其鹽。 6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-pendoxyl-2-propane base-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid or a salt thereof.

Anyone with ordinary knowledge in the technical field can appropriately utilize the methods described in the above-mentioned patent documents or methods known in the technical field to produce the "SSTR5 antagonist" of the present invention and use it to practice the present invention.

As demonstrated by the use of representative SSTR5 antagonists in the paragraphs of the following examples, "SSTR5 antagonists" exert the desired diagnostic aid, preventive or therapeutic effect on biliary tract diseases based on their antagonizing effect on SSTR5.

In carrying out the present invention, the "SSTR5 antagonist" can be used in either the free form or the form of a salt thereof (preferably a pharmaceutically acceptable salt thereof). Depending on the properties of the individual SSTR5 antagonists to be used, those with ordinary knowledge in the technical field can appropriately select from two forms to carry out the present invention.

Pharmaceutically acceptable salts include, for example, salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, phosphate, acetate, fumarate, oxalate, citrate, and methanesulfonic acid. Salts, benzenesulfonates, p-toluenesulfonates, maleates, etc. and salts of organic acids, etc. and salts of acids; and alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium salts, etc. and alkalis Salts; glycinate, lysine, arginine, ornithine, glutamate, aspartate, etc. and salts of amino acids, etc.

In practicing the present invention, SSTR5 antagonists can also be used in the form of their prodrugs. The prodrug can be appropriately designed by those with ordinary knowledge in the technical field, and the prodrug can be produced by a method known per se. The prodrug can also be an SSTR5 antagonist that can be converted into a target under physiological conditions as described in Molecular Design, Vol.

(for the biliary tract disease of the present invention)

As a result of intensive review by the present inventors, it was found for the first time that gallbladder contraction can be induced by SSTR5 antagonism.

In addition, as a result of further investigation based on this insight, it was found that the following effects can be expected due to SSTR5 antagonism.

1) Increase in bile flow

2) The secretion-promoting effect of cholecystokinin (CCK)

3) Relaxation of the sphincter of Oddi

Therefore, SSTR5 antagonists can be effective for the prevention and/or treatment of, for example, the biliary tract diseases listed below.

1. Diseases involving decreased motor function of the gallbladder or stagnation of bile

For example, cholelithiasis (cholecystolithiasis, choledocholithiasis, etc.), cholestasis, primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC), progressive familial intrahepatic cholestasis Intrahepatic cholestasis type 1 (PFIC1), progressive familial intrahepatic cholestasis type 2 (PFIC2), Alagille syndrome, etc.

Here, the prevention of cholelithiasis, more specifically, the prevention of secondary recurrence after remission by treatment with ursodeoxycholic acid, and the prevention of cholelithiasis after bariatric surgery can be mentioned. Prevention of stone disease.

In addition, the combined administration of extracorporeal shock wave lithotripsy (ESWL) and SSTR5 antagonist can be expected to improve the remission rate, shorten the treatment period, and reduce the recurrence rate of cholelithiasis, and this combined therapy can be used as a substitute for cholecystectomy. therapy.

2. Diseases involving the secretion-promoting action of cholecystokinin (CCK)

SSTR5 antagonists function as pancreatic juice secretion promoters, and promote pancreatic juice secretion by promoting the secretion of cholecystokinin (CCK), thereby facilitating the collection of pancreatic juice and enabling early detection (diagnosis of pancreatic cancer) auxiliary).

3. Diseases involving insufficiency of the sphincter of Oddi

For example, functional biliary tract disorders (functional gallbladder disorders, Odey sphincter disorders, papillary sphincter abnormalities) and so on.

Furthermore, SSTR5 antagonists can be used to assist in the diagnosis of biliary diseases. More specifically, for example, it can be used as an adjuvant for catheter intubation of Vater's papilla during endoscopic retrograde cholangiopancreatography (ERCP). That is, due to the promotion of gallbladder contraction caused by SSTR5 antagonists, the increase of bile secretion caused by the increase of bile flow, or the relaxation of the sphincter of Ode, it can be expected that during ERCP operation, under the endoscope. , The visibility of the nipple is improved, and the catheter intubation becomes easier. Along with this, physical stimulation such as the contact of the duct to the nipple is reduced, and it is expected to reduce the risk of postoperative complications such as severe acute cholangitis and acute pancreatitis. Furthermore, since the operation of ERCP can also be simplified, it is expected that SSTR5 antagonists can contribute to the diagnosis of biliary tract diseases as an adjuvant of ERCP.

SSTR5 antagonists are expected to be used in the above various applications, especially as prophylactic and/or therapeutic agents for cholelithiasis, cholestasis, PSC, PBC, functional biliary disorders, or as ERCP for the An adjuvant for catheter intubation in the nipple.

In this specification, "diagnosis" refers to the appropriate use of medicines, medical instruments, etc. to carry out examinations or examinations, and experts such as doctors use various information obtained thereby to judge the state of the patient's disease, including at the time of diagnosis. Use of diagnostic drugs or diagnostic aids (diagnostic aids).

In the present specification, "prevention" includes preventing the onset of a disease (as a whole, or one or a plurality of morbidities) and delaying the onset of the disease. The so-called "prophylactically effective amount" refers to the amount of SSTR5 antagonist sufficient to achieve this purpose.

In the present specification, the term "treatment" includes curing a disease (as a whole, or one or a plurality of diseases), ameliorating the disease, and inhibiting the progression of the severity of the disease. The so-called "therapeutically effective amount" refers to the amount of SSTR5 antagonist sufficient to achieve this purpose.

(for injection form)

In carrying out the present invention, the SSTR5 antagonist can be used alone or in the form of a pharmaceutical composition containing the SSTR5 antagonist as an active ingredient and a pharmaceutically acceptable carrier.

Such pharmaceutical compositions include, for example, lozenges (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules, microcapsules), troches, syrups, liquids, emulsions, suspensions, release-controlling formulations (e.g., immediate-release formulations, sustained-release formulations, sustained-release microcapsules), Aerosol (aerosol), film (eg, orally disintegrating film, oral mucoadhesive film), injection (eg, subcutaneous injection, intravenous injection (eg, bolus), intramuscular injection, intraperitoneal injection) , spot drops, transdermal preparations, ointments, lotions, patches, suppositories (eg, rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalation) , eye drops, etc.

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

As a specific example of "pharmaceutically acceptable carrier", for example, in solid preparations, excipients (such as lactose, white sugar, D-mannitol, starch, corn starch, crystalline cellulose, light weight, etc.) can be used. Anhydrous silicic acid, etc.), lubricants (such as magnesium stearate, talc, colloidal silica, etc.), binders (such as crystalline cellulose, sugar, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose, etc.) and disintegrants (such as starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.) and so on.

In liquid preparations, solvents (such as water for injection, isotonic saline, alcohols, propylene glycol, macrogol, sesame oil, etc.), dissolution aids (such as polyethylene glycol, propylene glycol, D- Mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, chlorine Surfactants such as benzalkonium chloride and glycerol monostearate; such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, Hydrophilic polymers such as hydroxypropyl cellulose, etc.), isotonicity agents (such as glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol, etc.), buffers (eg, phosphate, citrate, etc. buffers, etc.), pain relievers (eg, benzyl alcohol, etc.), and the like.

Preservatives (such as p-hydroxybenzoates, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (such as sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. can also be added as needed. Additives such as preparations.

The pharmaceutical composition of the present invention varies depending on the dosage form, administration method, carrier, etc., and can be obtained by using 0.01-99% (w/w) relative to the total amount of the preparation, preferably 0.1-85% ( w/w) by adding SSTR5 antagonists. The pharmaceutical composition can be produced by a method commonly used in the field of formulation technology, depending on its form. The pharmaceutical composition of the present invention can also be formed into release-controlling preparations such as immediate-release preparations or sustained-release preparations containing active ingredients.

(for the recipient)

The SSTR5 antagonists used in the present invention can be expected to have low toxicity and fewer side effects, and also have excellent properties as pharmaceuticals. Thus, SSTR5 antagonists can be safely administered to mammals (eg, humans, monkeys, dogs, horses, etc.).

(for route of administration)

In practicing the present invention, the SSTR5 antagonists can be administered orally or parenterally (eg, intravenous, drip, intramuscular, subcutaneous, intravisceral, intranasal, intradermal, transdermal) alone or in the form of pharmaceutical compositions , ocular, intracerebral, intrarectal, intravaginal, intraperitoneal administration and administration to lesions).

(for dose)

The dose of the SSTR5 antagonist to be administered varies depending on the subject, the route of administration, and the age or symptoms of the subject, and is not particularly limited. For example, the dose of the SSTR5 antagonist which is an active ingredient is 0.1 (preferably 0.5) to 320 mg per oral administration, and in the case of non-oral administration The dosage is 0.01-100 mg, preferably 0.05-64 mg. This dose can be divided into 1 to 3 times per day and administered. In addition, in the case of administration in the form of a sustained-release preparation, it can also be administered at intervals of every other day or longer so as to correspond to the administration amount.

(For concomitant use with other agents)

In carrying out the present invention, the SSTR5 antagonist can be used in combination with other drugs to prevent or treat a target disease, and it can be expected to bring about excellent preventive and/or therapeutic effects when used in combination with other drugs. In addition, it can also be expected that the dosage of other drugs can be reduced by this combination therapy, thereby reducing the side effects they have.

In carrying out the present invention as described above, a drug that can be used in combination with an SSTR5 antagonist (hereinafter, abbreviated as a concomitant drug) can be appropriately selected in consideration of the type of the patient's disease, the severity of its symptoms, and the like. For example, in order to prevent or treat cholelithiasis or primary biliary cirrhosis (PBC), bile acid preparations (ursodeoxycholic acid, etc.), lipid disorders therapeutic drugs (fibrates, statins, etc.) can be used in combination etc.), farnesoid X receptor agonists (obeticholic acid, etc.).

SSTR5 antagonists act synergistically with ursodeoxycholic acid, and can be expected to increase the remission rate, shorten the treatment period, and reduce the recurrence rate of cholelithiasis. In addition, there is a possibility of this as an alternative therapy for cholecystectomy.

The administration form of the concomitant drug is not particularly limited, and at the time of administration, the SSTR5 antagonist and the concomitant drug may be combined. For example, it can be used in the following forms: (1) administration of a preparation containing an SSTR5 antagonist and a concomitant drug in combination; (2) two preparations are obtained by separately formulating the SSTR5 antagonist and the concomitant drug, and these 2 (3) The SSTR5 antagonist and the concomitant drug are separately formulated to obtain two kinds of preparations, and the two kinds of preparations are administered simultaneously or separately by different routes of administration, etc. . The preferred form can be appropriately selected according to the actual state of the medical field.

The above-mentioned preparation containing the SSTR5 antagonist and the concomitant drug in combination is based on the previously described pharmaceutical composition containing the SSTR5 antagonist, and can be appropriately produced by those with ordinary knowledge in the technical field.

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. In addition, the blending ratio of the SSTR5 antagonist and the concomitant drug can be appropriately selected depending on the disease or symptom of the subject to be administered, the route of administration, the type of the concomitant drug to be used, and the like. In general, it can be appropriately determined in accordance with the actual conditions of the medical field based on the general clinical dosage of the concomitant drug to be used.

[Example]

Hereinafter, the present invention will be described in further detail based on examples, but these examples do not limit the scope of the present invention. In addition, the reagents, apparatuses, and materials used in the present invention can be obtained commercially, or can be appropriately prepared by those with ordinary knowledge in the technical field, unless otherwise specified.

Example 1: Assessment of Human SSTR5 Antagonist Activity Using Intracellular cAMP Concentration as an Indicator

The determination of intracellular cAMP concentration was carried out using the HTRF cAMP dynamic 2 kit (Cisbio). Test compounds diluted in assay buffer (containing 5 mM HEPES (pH 7.5) (Invitrogen), 0.1% fatty acid-free BSA (Sigma), 500 μM IBMX (Wako) in HBSS (Invitrogen)) at final concentrations 2 μL /well was added to each 384-well white plate (Greiner) as 1 μM . A frozen stock of CHO (dhfr-) cells expressing the human SSTR5 gene (Accession No. NM_001053 ) was thawed in a 37°C incubator and suspended in 50 μg/mL cyanide containing 10% dialysis serum (Gemini). in subculture medium (MEM alpha (Wako)) of gentamicin (Invitrogen). After the cell suspension was centrifuged, the cells were resuspended in assay buffer, and 2 μL was added to each well so as to obtain approximately 4,000 cells/well. After incubating the compounds and cells for 15 minutes, each was added with assay buffer 2 containing final concentrations of 0.1 nM somatostatin 28 (Toray Research Center) and 0.3 μM forskolin (Wako). μL /well, incubated at room temperature for 30 minutes. 3 μL /well of each cAMP-d2 and anti-cAMP cryptate (anti-cAMP-cryptate) were added to each well, and after standing at room temperature for 60 minutes, fluorescence resonance energy transfer was measured using a Multi-label reader Envision (Perkin Elmer). (fluorescence resonance energy transfer, FRET) intensity. The FRET intensity of the well to which the test compound group was added was converted into the cAMP concentration using a calibration curve prepared from the FRET intensity of the well group obtained by adding an arbitrary concentration of cAMP to the assay buffer. The inhibitory activity of the compound was calculated according to the following formula.

Barrier activity (%)=(C-B)/(A-B)×100

A: cAMP concentration calculated from wells to which 0.3 μM forskolin was added

B: cAMP concentration calculated from wells to which 0.3 μM forskolin and 0.1 nM somatostatin 28 were added

C: cAMP concentration in wells to which 0.3 μM forskolin, 0.1 nM somatostatin 28 and 1 μM test compound were added

Table 1 shows the inhibition rate (%) of the test compound to SSTR5 at 1 μM .

[Table 1-1]

[Table 1-2]

As can be seen from Table 1, the present test compound showed excellent SSTR5 antagonism.

Example 2: Assessment of selectivity for human SSTR isoforms

The selectivity of test compounds for human SSTR isoforms was examined by radiolabeled ligand binding assays. Membrane fractions of CHO-K1 cells expressing human SSTR1-5 were suspended in assay buffer (25 mM HEPES (pH 7.4), 5 mM MgCl ₂ , 1 mM CaCl ₂ , 10 μg /mL saponin, 0.5% BSA without fatty acid) in the presence of 1 μM of test compound 1 and [ ¹²⁵ I]Tyr ¹¹ -sostatin 14 (Perkin Elmer) for 1 hour. Then, the solution containing the membrane fraction was transferred to a filter plate, and the filter was washed 6 times with washing buffer (25 mM HEPES, 5 mM MgCl ₂ , 1 mM CaCl ₂ ), and 50 μL of Microscint20 (Packard) was added to remove Radioactivity was determined by TopCount (Perkin Elmer). The results of the competitive activity of the test compounds for binding of human SSTR isoforms to the labeled ligand are shown in Table 2.

[Table 2]

As can be seen from Table 2, Test Compound 1 showed selective binding to SSTR5 among human SSTR subtypes.

Example 3: Assessment of gallbladder contraction using normal mice

Nine-week-old male C57BL/6J Jcl mice (CLEA, Japan) were fasted overnight and orally administered a 0.5% (w/v) methylcellulose suspension containing 0.1 mg/kg of test compound 1 (1 group of 6). 30, 60, 120, and 240 minutes after compound administration, mice were laparotomized under isoflurane (Pfizer) anesthesia and bled to death by severing a large abdominal vein, and gallbladders were immediately taken and collected. Tissue weight was determined. In addition, in order to calculate the bile residual rate, the gallbladder was collected in the same manner as in the compound-non-administered group, and the tissue weight was measured (6 animals per group). The residual rate of bile was calculated according to the following formula.

Residual rate of bile (%) = gallbladder weight of each individual ÷ average value of gallbladder weight of the compound not administered group × 100

The results are shown in Table 3. The significance at each time point relative to the compound-non-administered group was assessed by Dunnett's test, and the significance level relative to the compound-non-administered group was indicated by *: p<0.05, **: p<0.01.

[table 3]

As can be seen from Table 3, Test Compound 1 was shown to induce gallbladder contraction through SSTR5 antagonism. The results of this test clearly show that SSTR5 antagonists are useful for the treatment and prevention of cholelithiasis, cholestasis, and functional biliary disorders, for inhibiting the progression of PSC and PBC, and for assisting ERCP.

Example 4: Assessment of potentiation of corn oil-induced gallbladder contraction using normal mice

Nine-week-old male C57BL/6J Jcl mice (CLEA, Japan) were fasted overnight and administered orally with 0.5% (w/v) methylcellulose suspension (vehicle) or 1 mg/kg for the test Compound 1 (suspended in vehicle) (5 in 1 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, the mice were subjected to laparotomy under isoflurane (Pfizer) anesthesia and cut through The large abdominal vein was severed and exsanguinated to death, and the gallbladder was immediately harvested and the tissue weight was measured. The bile residual rate was calculated according to the following formula.

Bile residual rate (%) = gallbladder weight of each individual ÷ average gallbladder weight of vehicle group × 100

The results are shown in Table 4.

[Table 4]

As can be seen from Table 4, the test compound 1 showed an enhancing effect on the gallbladder contraction induced by corn oil. If the gallbladder contraction caused by eating is insufficient, the risk of gallstones and biliary sludge will increase, so the experimental results clearly show that SSTR5 antagonists further enhance gallbladder contraction caused by eating, and are useful for the treatment and prevention of gallstones disease, cholestasis, functional biliary disorder, and is used to inhibit the progression of PSC and PBC.

Example 5: Evaluation of the preventive effect of gallstones in mice using the diet-induced gallstone model

10-week-old male C57BL/6J Jcl mice (CLEA, Japan) were fed a lithogenic diet (D18022301, Research Diets Inc.), and 0.5% (w/v) methyl was orally administered once a day. Cellulose suspension (vehicle), 1 mg/kg test compound 1 (suspended in vehicle), or 60 mg/kg ursodeoxycholic acid (Wako, suspended in vehicle) as a positive control for 56 days (1 group of 12). In addition, the mice of the same age as the normal control group were fed a general diet (CE-2, Japan CLEA), and 0.5% (w/v) methyl cellulose was orally administered. Suspension (1 group of 6). After 56 days of administration, the mice were fasted overnight, laparotomy was performed under isoflurane (Pfizer) anesthesia, and they were bled to death by severing the large abdominal vein. Then, the gallbladder was collected, the presence or absence of gallstones in the gallbladder was visually confirmed, and the incidence of gallstones in each group was calculated. In addition, bile was recovered from the gallbladder, and the phospholipids, cholesterol, and total bile acids in bile were measured using LabAssay Phospholipid (Wako), cholesterol E-Test Wako (Wako), and total bile acid-Test Wako (Wako), respectively, and the bile was calculated. of cholesterol saturation (J Lipid Res. 1978, 19:945).

The incidence of gallstones and the cholesterol saturation of bile are shown in Table 5. The significance of the incidence of gallstones in each compound-administered group relative to the vehicle group was evaluated by χ2 test, and the significance level was expressed as ##: p<0.01. In addition, the significance of the cholesterol saturation of each compound-administered group relative to the vehicle group was evaluated by Dunnett's test, and the significance level was represented by **: p<0.01.

[table 5]

As can be seen from Table 5, the test compound 1 has a preventive effect on the onset of gallstones, and its action is different from ursodeoxycholic acid, which is an existing therapeutic drug, and belongs to a mechanism that does not affect the cholesterol saturation of bile. The results of this test clearly show that SSTR5 antagonists are useful for the prevention and treatment of cholelithiasis and cholestasis.

Example 6: Evaluation of the therapeutic effect of cholelithiasis in mice using diet and compound-induced cholelithiasis

8-week-old male C57BL/6J Jcl mice (CLEA, Japan) were fed lithogenic diet (D18022301, Research Diets Inc.), once a day, orally suspended in 0.5% (w/v) methylcellulose Gallstones were induced with 1 mg/kg devazepide (TOCRIS Bioscience) in a vegan solution (vehicle) for 6 weeks. Then, the feed was changed to general feed (CE-2, Japan CLEA), and 1 mg/kg of test compound 1 (suspended in vehicle), 60 mg/kg of ursodeoxycholic acid (Wako, suspended in vehicle) or vehicle (10 per group). After 12 weeks of repeated administration, the mice were fasted overnight, laparotomy was performed under isoflurane (Pfizer) anesthesia, and they were bled to death by severing the large abdominal vein. Then, the gallbladder was collected, the presence or absence of gallstones in the gallbladder was visually confirmed, and the retention rate of gallstones in each group was calculated. In addition, gallstones were collected from some mice after 6-week gallstone induction treatment, the presence or absence of gallstones was confirmed, and the gallstone retention rate (Pre group) was calculated.

The gallstone retention rate is shown in Table 6. The significance of the gallstone retention rate of each compound administration group relative to the vehicle group was evaluated by χ2 test, and the significance level was expressed as ##: p<0.01.

[Table 6]

As can be seen from Table 6, the test compound 1 exhibited a remission-promoting effect of gallstones in the gallstone model. The results of this trial clearly show that SSTR5 antagonists are useful in the treatment of cholelithiasis.

Example 7: Assessment of bile flow enhancement in mice using compound-induced PSC model

9-week-old male Jcl:ICR mice (CLEA, Japan) were fed a diet containing 0.025% (w/w) 3,5-diethoxycarbonyl-1,4-dihydrocolinine (3,5-diethoxycarbonyl- 1,4-dihydrocollidine) (Sigma) powder CE-2 (Japan CLEA), 0.5% (w/v) methylcellulose suspension (vehicle), 1 mg/kg test compound was orally administered once a day 1 (suspended in vehicle) (1 group of 8). In addition, CE-2 was fed to mice of the same age as a normal control group, and the vehicle was orally administered (one group of 8 mice). 28 to 31 days after the administration, the mice were fasted overnight, laparotomy was performed under isoflurane (Pfizer) anesthesia, the cystic duct was ligated, and the common bile duct was cannulated. The bile was collected for 30 minutes, the weight was measured, 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 relative to the vehicle group was evaluated by Dunnett's test, and the significance level was indicated by *: p<0.05.

[Table 7]

As can be seen from Table 7, the test compound 1 showed an increase in bile flow on the PSC model. The results of this test clearly show that SSTR5 antagonists are useful for the treatment and prevention of cholelithiasis, cholestasis, and functional biliary disorders, for inhibiting the progression of PSC and PBC, and for assisting ERCP.

Example 8: Assessment of hepatoprotective effect in mice using compound-induced PSC model

9-week-old male Jcl:ICR mice (CLEA, Japan) were fed a powdered CE- 2 (Japan CLEA), 0.5% (w/v) methylcellulose suspension (vehicle) and 1 mg/kg test compound 1 (suspended in vehicle) were orally administered once a day for 30 days (1 group of 8). In addition, CE-2 was fed to mice of the same age as a normal control group, and the vehicle was orally administered (one group of 8 mice). After the administration on the 28th, blood samples were collected from the tail vein of the mice, and plasma aspartate transaminase (AST) and alanine transaminase (ALT) were measured with an automatic analyzer 7180 (Hitachi High-Tech). and alkaline phosphatase (ALP) values. After 30 days of administration, laparotomy was performed under isoflurane (Pfizer) anesthesia, and the large abdominal vein was cut to exsanguinate to death, and the liver was collected. The content of collagen in liver was measured by Total collagen assay kit (QuickZyme Biosciences), and the content per 1 mg of liver was calculated.

The AST, ALT, ALP values and liver collagen content in plasma are shown in Table 8. The significance of the compound-administered group relative to the vehicle group was assessed by Student's t-test when the variance between the 2 groups was homoscedastic, and when the variance was unequal (heteroscedastic) It was assessed by Welch's test, and the level of significance relative to the vehicle group is indicated by *: p<0.05 (Student's t-test), #: p<0.05 (Welch's test).

[Table 8]

As can be seen from Table 8, the test compound 1 showed inhibition of the progression of pathology in the PSC model. The results of this assay clearly show that SSTR5 antagonists are useful for inhibiting PSC progression/treatment of PSC.

[Industrial Availability]

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

This application is based on Japanese Patent Application No. 2020-084727 (filing date: May 13, 2020) filed in Japan, and the entire contents of which are included in this specification.

Claims (8)

A diagnostic aid, preventive or therapeutic agent for biliary tract diseases, which contains an SSTR5 antagonist as an active ingredient. The diagnostic aid, prevention or treatment agent for biliary tract disease according to claim 1, wherein the SSTR5 antagonist is selected from the following: 6-(1-((2-Cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-pendoxyl-2-propane base-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid, 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy- 2-propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid, 6-(1-((2-Cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-sideoxy -2-Propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid, 6-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5 -Pendant oxy-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid, 1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2 - side oxy-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-Cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl- 2-Pendant oxy-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-Cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2 - side oxy-1,2-dihydropyridine-4-carboxylic acid, and such salts. The diagnostic aid, prevention or treatment agent for biliary tract disease according to claim 1, wherein the SSTR5 antagonist is 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobicarbonate Phen-4-yl)methyl)piperidin-4-yl)-5-oxy-2-propyl-5,6,7,8-tetrahydro-1,6-

pyridine-3-carboxylic acid or a salt thereof. The prophylactic or therapeutic agent for biliary tract disease according to any one of claims 1 to 3, wherein the biliary tract disease is selected from cholelithiasis, cholestasis, and primary sclerosing cholangitis (PSC) , at least one of primary biliary cirrhosis (PBC) and functional biliary disorder. The diagnostic aid for biliary tract diseases according to any one of claims 1 to 3, wherein the diagnostic aid is catheterization of Vater's papilla during endoscopic retrograde cholangiopancreatography (ERCP). Auxiliary tube. A diagnostic aid, prevention or treatment method for biliary diseases, comprising administering an effective amount of an SSTR5 antagonist to a mammal in need of administration of the SSTR5 antagonist. An SSTR5 antagonist, which is used for diagnosis assistance, prevention or treatment of biliary tract diseases. A use of an SSTR5 antagonist, which is used in the manufacture of a medicament for diagnosis assistance, prevention or treatment of biliary tract diseases.