JP2020023490A - Pharmaceutical composition including compound having somatostatin receptor actuation activity - Google Patents

Abstract

To provide a pharmaceutical composition including a somatostatin receptor sub type 2 actuation compound.SOLUTION: There is provided a pharmaceutical composition including a compound expressed by the general formula (I) or a salt thereof, the pharmaceutical composition has strong actuation activity to the somatostatin receptor sub type 2, and can be orally administered to a user, so that, a patient can take the pharmaceutical composition easily and distress following to therapy can be reduced. The pharmaceutical composition of the invention comprises sufficiently weak hERG inhibition activity or phospholipid cis action to SSTR2 agonist activity, so that, side effects caused by the actions can be suppressed or reduced.SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition comprising a compound represented by the following general formula (I) having an agonistic activity of somatostatin receptor, particularly somatostatin receptor subtype 2, or a salt thereof.

  Acromegaly (acromegaly) is a hormonal disorder caused by excessive secretion of growth hormone from the pituitary gland due to pituitary adenomas and the like, and the affected patients have enlarged head and limb bones and soft tissues. Cause. Acromegaly is not necessarily a disease with a high prevalence of about 60 per 1 million, but its patients are affected by abnormalities in various parts of the body, 1 is a serious disease that increases the risk of death, such as occurrence of heart disease.

  Currently, the treatment of acromegaly patients involves surgery to remove adenomas that secrete growth hormone, radiation therapy, and external administration of an analog of somatostatin, a hormone that suppresses growth hormone secretion. Drug treatment is being performed. Such somatostatin analogs include octreotide acetate (Registered trademark: Sandostatin) from Novartis Pharmaceuticals, Inc. and lanreotide acetate (Registered trademark: somaturin) from Ipsen Pharma SA Co., Ltd. However, on the other hand, these drugs are peptide drugs and need to be administered by injection. It is said to be painful. In order to solve this problem, it is considered that the best option is to obtain a non-peptide type orally administrable low molecular weight compound instead of a peptide drug requiring injection.

  On the other hand, it has been clarified that there are five subtypes of somatostatin receptor from SSTR1 to SSTR5, and the above-mentioned octreotide acetate and lanreotide acetate are included in somatostatin receptor subtype 2 (SSTR2). It is said to bind with high affinity. These drugs also bind to somatostatin receptor subtype 3 (SSTR3) and somatostatin receptor subtype 5 (SSTR5) with moderate affinity, and somatostatin receptor subtype 1 (SSTR1) and somatostatin It has also been reported that it does not bind to receptor subtype 4 (SSTR4).

  Thus, as the differences in the affinity of octreotide acetate and lanreotide acetate for these receptor subtypes have been scientifically elucidated, several non-peptide, low-molecular somatostatin receptor agonists have been synthesized.

  For example, Patent Document 1 discloses a general formula (A):

(Wherein, R ^1A represents (1) a halogen atom, (2) C 1-4 alkyl optionally substituted with a substituent, or (3) C 1-4 alkoxy or the like;
pA represents an integer of 0-3;
when pA is 2 or more, a plurality of R ^1A may be the same or different;
R ^2A represents (1) a halogen atom, (2) —OR ^3A , (3) —COOR ^5A , or (4) optionally substituted C 1-4 alkyl;
R ^3A represents C 1-4 alkyl and the like;
R ^5A represents C 1-4 alkyl and the like;
qA represents an integer of 0-3;
when qA is 2 or more, a plurality of R ^2A may be the same or different;
Ring A _A represents a 5-10 membered monocyclic or bicyclic heterocyclic ring;
Ring G _A represents benzene, pyridine, pyrimidine, pyrazole, thiazole or furan ring and the like;
W _A and Y _A are each independently a nitrogen atom or a carbon atom;
rA represents 0 or 1;
Ring B _A represents a pyridine ring or the like when at least one of W _A and Y _A represents a nitrogen atom and rA represents 0 or 1;
L _A represents a bond or the like;
M _A represents a bond or the like;
Z _A is (C) 1-4 optionally substituted with (a) a halogen atom, (b) —NR ^53A R ^54A , (c) —OR ^55A , (d) —NR ^56A R ^57A and / or —OR ^58A. Alkyl and (e) a 5- to 10-membered monocyclic or bicyclic nitrogen-containing heterocyclic ring which may be substituted with a substituent selected from the group consisting of oxo;
R ^{53A to} R ^58A each independently represent a hydrogen atom, C 1-4 alkyl, C 1-4 haloalkyl, oxetanyl, or the like. )
Or a salt thereof, an N-oxide form thereof, a solvate thereof, or a prodrug thereof is an SSTR2-selective agonist, and prevents and / or prevents gastrointestinal symptoms associated with acromegaly and gastrointestinal obstruction. Or it is described as being useful for treatment.

  Patent Document 2 discloses a general formula (B):

(Wherein, R ^1B represents (1) a halogen atom, (2) a cyano group, (3) C 1-4 alkyl, (4) C 1-4 alkoxy, or the like;
pB represents an integer of 0-2;
when pB is 2, multiple R ^1B may be the same or different;
R ^2B and R ^3B each independently represent a hydrogen atom or C 1-4 alkyl;
R ^4B represents a hydrogen atom;
Alternatively, R ^2B and R ^4B may together with the atom to which they are attached form a 5-8 membered nitrogen-containing saturated heterocycle;
L _B represents (1) a ^{bond, (2) -CR AB = CR} BB →, or (3) -C (= O) -NR DB → ( binding sites in each group, the arrow a pyridine ring ));
R ^AB , R ^BB and R ^DB each independently represent a hydrogen atom or C 1-4 alkyl;
X ^1B and X ^2B each independently represent a halogen atom. )
Or a salt thereof, an N-oxide form thereof or a solvate thereof, or a prodrug thereof is an SSTR2-selective agonist, and prevents and / or prevents gastrointestinal symptoms associated with acromegaly and gastrointestinal obstruction. It is described as being useful for treatment.

  However, the below-mentioned compounds disclosed in the present invention, or salts thereof, and their pharmaceutical uses are not described in any prior art.

  Incidentally, for example, in the case of a medicament to be taken for a long period of time, such as in the treatment of acromegaly, it is desired that the medicine has as few side effects as possible. For example, when there is an hERG inhibitory activity or a phospholipidosis action other than the main action, there is a possibility that a serious side effect may occur in an organ in which a QT prolongation action or a drug accumulates.

WO 2014/007228 pamphlet WO 2015/046482 pamphlet

  An object of the present invention is to provide an SSTR2 agonistic activity that has a stronger SSTR2 agonistic activity, and that has a potential to cause side effects such as a hERG inhibitory activity that is more sufficiently separated and a phospholipidosis effect that is even weaker. It is an object of the present invention to provide a pharmaceutical composition comprising a low molecular weight compound which is sufficiently weak against the compound. Another object of the present invention is to provide a pharmaceutical composition which can be taken for a long time.

  The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a pharmaceutical composition containing a compound represented by the following general formula (I) or a salt thereof solves the above-mentioned problems. The present invention was completed by further study.

That is, the present invention
[1] General formula (I)

(Wherein, R ¹ represents 3-oxetanyl, 3,3,3-trifluoropropyl, ethyl, or a hydrogen atom, and R ² represents C 1-4 alkyl, C 1-4 alkoxy, halogen, nitrile, or C 1 Represents an alkoxycarbonyl group, R ³ represents a C 1-4 alkyl or a hydrogen atom, and R ⁴ represents a hydrogen atom, a C 1-4 alkyl, a C 5-5 optionally substituted with 1 to 3 R ^7. 6 represents a monocyclic carbocycle, or a 5- to 6-membered monocyclic heterocyclic ring which may be substituted by 1 to 3 R ⁸ , R ⁷ represents halogen or C 1-4 alkyl, and R ⁸ represents represents a halogen or C1~4 alkyl, when more than one ^{R 7} is substituted with C5~6 monocyclic carbocyclic ring, a plurality of ^{R 7} may be the same or different, two or more ^{R 8} is 5 When substituted with a ~ 6-membered monocyclic heterocycle , A plurality of ^{R 8} may be the same or different, ^{R 5} represents a C1~4 alkyl or a hydrogen atom,, ring1 is C5～6 monocyclic carbon ring, or a 5-6 membered monocyclic heterocycle R ⁶ represents C 1-4 alkyl, C 1-4 alkoxy, or halogen; m represents an integer of 0 to 3; n represents an integer of 0 to 3; R ² may be the same or different; when n is 2 or more, a plurality of R ⁶ may be the same or different; or a salt thereof (provided that rac- (3R, 4S) -4-amino-1- [3- (3,5-dimethoxyphenyl) -5- (4,6-dimethyl-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol, rac -(3R, 4S) -4-amino-1- [3 (6-Fluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol, and rac- (3R, 4S) -4- Amino-1- [3- (6-chloro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol) and A pharmaceutical composition comprising a pharmaceutically acceptable carrier,
[2] The compound represented by the general formula (I) is a compound represented by the general formula (IB)

(In the formula, R ^1-1 represents 3-oxetanyl, 3,3,3-trifluoropropyl, or ethyl, and the other symbols have the same meanings as in the above [1].)
The pharmaceutical composition according to the above [1], which is a compound represented by the formula:
[3] The compound represented by the general formula (IB) is a compound represented by the general formula (IB-1)

(In the formula, all symbols have the same meaning as in the above [1] or [2].)
The pharmaceutical composition according to the above [1] or [2], which is a compound represented by the formula:
[4] Any one of the above-mentioned [1] to [3], wherein R ² is C 1-4 alkoxy, halogen, or C 1-4 alkoxycarbonyl, and R ⁶ is C 1-4 alkoxy or halogen. The pharmaceutical composition according to
[5] The pharmaceutical composition according to any one of [1] to [4], wherein R ⁶ is halogen and n is 2.
[6] The compound is
(1) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- ( 3-oxetanylamino) -3-piperidinol,
(2) (3S, 4R) -1- [3- (3-chloro-5-fluorophenyl) -5- (5,6-difluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4 -[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
(3) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- ( Ethylamino) -3-piperidinol,
(4) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -4 -[(3,3,3-trifluoropropyl) amino] -3-piperidinol or (5) (3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro The above-mentioned [2], which is -5-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol. Pharmaceutical compositions,
[7] R ⁴ is optionally substituted with C 1-4 alkyl, C 5-6 monocyclic carbocyclic ring optionally substituted with 1 to 3 R ⁷ , or 1 to 3 R ⁸ The pharmaceutical composition according to the above [1], which is a 1 to 6-membered monocyclic heterocycle,
[8] The compound represented by the general formula (I) is a compound represented by the general formula (I-1):

(Wherein R ^4-1 is C 1-4 alkyl, C 5-6 monocyclic carbocyclic ring optionally substituted with 1-3 R ⁷ , or substituted with 1-3 R ^8. Represents a 5- to 6-membered monocyclic heterocycle, and other symbols have the same meanings as in the above [1].)
The pharmaceutical composition according to the above [7], which is a compound represented by the formula:
[9] The pharmaceutical composition of the above-mentioned [7] or [8], wherein R ² is C 1-4 alkoxy, halogen, or C 1-4 alkoxycarbonyl, and R ⁶ is C 1-4 alkoxy or halogen. ,
[10] The pharmaceutical composition according to any one of [7] to [9], wherein R ⁶ is halogen and n is 2.
[11] The compound is
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2- (1 -Methyl-1H-pyrazol-4-yl) -4-pyridinyl] -3-piperidinol,
(2) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate,
(3) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -2-methyl-3-pyridinyl} -5 -Fluoro-1H-benzimidazole-7-carboxylate,
(4) (3S, 4R) -4-amino-1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazole-2- Yl) -4-pyridinyl] -3-piperidinol,
(5) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(6) (3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (ethylamino) -3-piperidinol,
(7) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(8) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
(9) (3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4 -Pyridinyl] -4- (ethylamino) -3-piperidinol, or (10) methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3, The pharmaceutical composition according to the above [7], which is 5-difluorophenyl) -2- (4-morpholinyl) -3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate.
[12] The pharmaceutical composition according to the above [1], wherein R ⁴ is a hydrogen atom.
[13] The compound represented by the general formula (I) is a compound represented by the general formula (I-2)

(Wherein all symbols have the same meaning as in the above [1].)
The pharmaceutical composition according to the above [1] or [12], which is a compound represented by the formula:
[14] The pharmaceutical composition of the above-mentioned [12] or [13], wherein R ² is C1-4 alkoxy, halogen or C1-4 alkoxycarbonyl, and R ⁶ is C1-4 alkoxy or halogen. ,
[15] The pharmaceutical composition according to any one of [12] to [14], wherein R ⁶ is halogen and n is 2.
[16] The compound is
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(2) (3S, 4R) -4-amino-1- [3- (1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(3) (3S, 4R) -4-amino-1- [3- (2,5-difluorophenyl) -5- (6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -3 -Piperidinol, or (4) methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -3-pyridinyl} -5 The pharmaceutical composition according to the above [12], which is -fluoro-1H-benzimidazole-7-carboxylate.
[17] The pharmaceutical composition according to the above [1], wherein the compound represented by the general formula (I) or a salt thereof is a somatostatin receptor agonist.
[18] The pharmaceutical composition according to any one of [1] to [17], which is a prophylactic and / or therapeutic agent for a somatostatin-related disease.
[19] The pharmaceutical composition according to the above [18], wherein the somatostatin-related disease is acromegaly, a gastrointestinal symptom associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor.
[20] The pharmaceutical composition according to any one of [1] to [19], wherein the composition is repeatedly administered to a subject (patient) in need of the composition.
[21] The pharmaceutical composition according to any one of [1] to [20], which is administered to a patient who needs to take the drug over a long period of time.
[22] General formula (I)

(Wherein, R ¹ represents 3-oxetanyl, 3,3,3-trifluoropropyl, ethyl, or a hydrogen atom, and R ² represents C 1-4 alkyl, C 1-4 alkoxy, halogen, nitrile, or C 1 Represents an alkoxycarbonyl group, R ³ represents a C 1-4 alkyl or a hydrogen atom, and R ⁴ represents a hydrogen atom, a C 1-4 alkyl, a C 5-5 optionally substituted with 1 to 3 R ^7. 6 represents a monocyclic carbocycle, or a 5- to 6-membered monocyclic heterocyclic ring which may be substituted by 1 to 3 R ⁸ , R ⁷ represents halogen or C 1-4 alkyl, and R ⁸ represents represents a halogen or C1~4 alkyl, when more than one ^{R 7} is substituted with C5~6 monocyclic carbocyclic ring, a plurality of ^{R 7} may be the same or different, two or more ^{R 8} is 5 When substituted with a ~ 6-membered monocyclic heterocycle , A plurality of ^{R 8} may be the same or different, ^{R 5} represents a C1~4 alkyl or a hydrogen atom,, ring1 is C5～6 monocyclic carbon ring, or a 5-6 membered monocyclic heterocycle R ⁶ represents C 1-4 alkyl, C 1-4 alkoxy, or halogen; m represents an integer of 0 to 3; n represents an integer of 0 to 3; R ² may be the same or different; when n is 2 or more, a plurality of R ⁶ may be the same or different; or a salt thereof (provided that rac- (3R, 4S) -4-amino-1- [3- (3,5-dimethoxyphenyl) -5- (4,6-dimethyl-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol, rac -(3R, 4S) -4-amino-1- [3 (6-Fluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol, and rac- (3R, 4S) -4- Amino-1- [3- (6-chloro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol). A prophylactic and / or therapeutic agent for a somatostatin-related disease (eg, acromegaly, gastrointestinal symptoms associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor),
[23] The compound represented by the general formula (I) or a salt thereof according to [1], which is administered together with at least one drug selected from the group consisting of pegvisomant, bromocriptine, and cabergoline. A preventive and / or therapeutic agent for a somatostatin-related disease, comprising
[24] Prochlorperazine, levomepromazine, risperidone, metoclopramide, domperidone, diphenhydramine, chlorpheniramine, dimenhydrinate, promethazine, diprofylline, famotidine, cimetidine, scopolamine, tropisetron, granisetron, ondansetron, azasetron, ramosetron The aforementioned [1], wherein the drug is administered together with at least one drug selected from the group consisting of indisetron, palonosetron, cisapride, mosapride, dexamethasone, betamethasone, prednisolone, aprepitant, olanzapine, quetiapine, perospirone, methylnaltrexone and morphine. ] A somatostatin-related disease comprising the compound represented by the general formula (I) or a salt thereof. Prophylactic and / or therapeutic agents for the disease,
[25] octreotide, lanreotide, pasireotide, tolvaptan, captopril, enalapril, alacepril, delapril, lisinopril, imidapril, benazepril, cilazapril, temocapril, trandolapril, manidipine, nifedipine, amlodipine, 0, amlodipine, 0-121 , Losartan, candesartan cilexetil, eprosartan, valsartan, irbesartan, olmesartan medoxomil, E4177, 1-[[2 '-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazole-3-). Yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7-carboxylic acid, ethanol, butylcyanoacrylate Or a compound represented by the general formula (I) according to the above [1], wherein the compound is administered together with at least one drug selected from the group consisting of: An agent for preventing and / or treating a somatostatin-related disease comprising a salt, and
[26] octreotide, lanreotide, pasireotide, telotristat, loperamide, rabeprazole, famotidine, cimetidine, diazoxide, insulin, pegvisomant, mitotan, ketoconazole, interferon-α, cyclophosphamide, ifosfamide, everolimus, sunitinib, and indidnite Wherein the compound is administered together with at least one drug selected from the group consisting of a compound represented by the general formula (I) according to the above [1], or a salt thereof, for preventing a somatostatin-related disease. And / or therapeutic agents,
[1-1] (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4 A pharmaceutical composition comprising-(3-oxetanylamino) -3-piperidinol or a salt thereof;
[1-2] (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4 A pharmaceutical composition comprising-(ethylamino) -3-piperidinol, or a salt thereof;
[1-3] The pharmaceutical composition according to the above [1-1] or [1-2], which is a prophylactic and / or therapeutic agent for a somatostatin-related disease.
[1-4] The pharmaceutical composition according to [1-3], wherein the somatostatin-related disease is acromegaly, a gastrointestinal symptom associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor.
[1-5] The pharmaceutical composition according to the above [19] or [1-3], wherein the somatostatin-related disease is acromegaly;
[1-6] The pharmaceutical composition according to the above [19] or [1-3], wherein the somatostatin-related disease is autosomal dominant polycystic kidney disease.
[1-7] Any of the above-mentioned [1] to [21] and [1-1] to [1-6], wherein the composition is repeatedly administered to a subject (patient) in need of the composition. The pharmaceutical composition according to
[1-8] The method according to any one of [1] to [21] and [1-1] to [1-7], which is administered over a long period of time to a patient who needs to take the drug for a long period. Pharmaceutical compositions,
[2-1] (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4 -A prophylactic and / or therapeutic agent for a somatostatin-related disease, comprising-(3-oxetanylamino) -3-piperidinol or a salt thereof;
[2-2] (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4 An agent for preventing and / or treating somatostatin-related diseases, comprising-(ethylamino) -3-piperidinol or a salt thereof;
[2-3] The aforementioned [2-1] or [2-2], wherein the somatostatin-related disease is acromegaly, a gastrointestinal symptom associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor. Described agents,
[2-4] The agent according to any of [22] and [2-1] to [2-3], wherein the somatostatin-related disease is acromegaly,
[2-5] The agent according to the above [22] and [2-1] to [2-3], wherein the somatostatin-related disease is autosomal dominant polycystic kidney disease.
[2-6] The agent according to any of [22] to [26] and [2-1] to [2-5], which is repeatedly administered to a subject (patient) in need of the agent.
[2-7] The method according to any one of [22] to [26] and [2-1] to [2-6], which is administered to a patient who needs to take the drug for a long period of time. Agent, etc.

  A pharmaceutical composition (hereinafter, referred to as a pharmaceutical of the present invention) comprising a compound represented by the general formula (I) or a salt thereof (hereinafter, sometimes abbreviated as the compound of the present invention) disclosed in the present invention. May be abbreviated as a composition or the present pharmaceutical composition.) Is a pharmaceutical composition having a potent agonistic activity on somatostatin receptor subtype 2 (SSTR2) in particular, and is orally administered. Because it is possible to administer it, it does not require intramuscular injection at the time of administration as in the case of existing peptide drugs represented by octreotide acetate and lanreotide acetate, it can be easily taken and reduces the pain associated with patient treatment Can be. In addition, since the present pharmaceutical composition has sufficiently weak hERG inhibitory activity and / or phospholipidosis action with respect to SSTR2 agonist activity, it can suppress or reduce side effects caused by these actions. Therefore, the present pharmaceutical composition can be used safely in patients with somatostatin-related diseases requiring its administration, particularly in patients with acromegaly and gastrointestinal obstruction. In one embodiment, the pharmaceutical composition is excellent in safety and can be taken for a long time.

  In the present invention, “halogen” includes, for example, fluorine, chlorine, bromine and iodine atoms.

  In the present invention, “C1-4 alkyl” includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl groups.

  In the present invention, “C1-4 alkoxy” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and isobutoxy groups.

  In the present invention, "C1-4 alkoxycarbonyl" includes methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, and isobutoxycarbonyl groups.

  In the present invention, the “C5-6 monocyclic carbocycle” includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, and a benzene ring.

  In the present invention, the “5- to 6-membered monocyclic heterocycle” includes, for example, “5- to 6-membered monocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom. Ring heterocycle "and the like. The "5- to 6-membered monocyclic heterocycle containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 sulfur atom" includes, for example, pyrrole, imidazole, triazole, tetrazole, Pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, thiadiazole, thiazine, thiadiazine, pyrroline, pyrrolidine, imidazoline, Imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydro Limidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrooxazole, tetrahydrooxazole ( Oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxa Diazole (oxadia Lysine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine, tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine, Thiomorpholine, oxathiane, dioxolan, dioxane, dioxole ring and the like are included.

  In the present invention, unless otherwise specified, the symbols are clearly understood by those skilled in the art.

Indicates that it is connected to the other side of the paper (ie, α-configuration),

Represents α-configuration, β-configuration or any mixture thereof.

In the present invention, R ¹ is preferably, for example, 3-oxetanyl, 3,3,3-trifluoropropyl, or ethyl. Further, a hydrogen atom is also preferable.

In the present invention, R ² is preferably, for example, C 1-4 alkoxy, halogen, or C 1-4 alkoxy carbonyl. More preferably, for example, C1-4 alkoxy or halogen. Particularly preferred is, for example, fluorine.

In the present invention, R ³ is preferably, for example, a hydrogen atom.

In the present invention, R ⁴ is preferably, for example, a hydrogen atom or C1-4 alkyl. More preferably, for example, a hydrogen atom or methyl. Particularly preferred is, for example, methyl. Also, a hydrogen atom is particularly preferred.

In the present invention, R ⁵ is preferably, for example, a hydrogen atom.

  In the present invention, ring 1 is preferably, for example, a C5-6 monocyclic carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring. More preferably, for example, it is a benzene ring.

In the present invention, R ⁶ is preferably, for example, C 1-4 alkoxy or halogen. More preferably, for example, methoxy, fluorine or chlorine.

In the present invention, R ^2-1 is preferably, for example, fluorine.

In the present invention, R ^6-1 is preferably, for example, fluorine.

  In the present invention, m is preferably 2, for example.

  In the present invention, n is preferably 2, for example.

  In the present invention, the general formula (I) is preferably, for example, the general formula (IB):

(Wherein, R ^1-1 represents 3-oxetanyl, 3,3,3-trifluoropropyl, or ethyl, and the other symbols have the same meanings as described above), and general formula (IB-1):

(Wherein all symbols have the same meanings as described above), and general formula (I-1):

(Wherein R ^4-1 is C 1-4 alkyl, C 5-6 monocyclic carbocyclic ring optionally substituted with 1-3 R ⁷ , or substituted with 1-3 R ⁸ Represents a 5- to 6-membered monocyclic heterocycle, and the other symbols have the same meanings as described above.), General formula (I-2):

(Wherein all symbols have the same meanings as described above), and general formula (I-3):

(Wherein, R ^6-1 represents halogen, and other symbols have the same meanings as described above), and general formula (I-4):

(Wherein all symbols have the same meanings as described above), and general formula (I-5):

(In the formula, R ^2-1 represents halogen, the other symbols have the same meanings as described above, and the halogens represented by R ^2-1 and R ^6-1 may be the same or different.) Is mentioned. More preferably, for example, general formula (IA):

(Wherein all symbols have the same meanings as described above), and general formula (IB-A):

(Wherein all symbols have the same meanings as described above), and general formula (IB-1-1):

(Wherein all symbols have the same meanings as described above), and general formula (I-1-1):

(Wherein all symbols have the same meanings as described above), and general formula (I-2-1):

(Wherein all symbols have the same meanings as described above), and general formula (I-3-1):

(Wherein all symbols have the same meanings as described above), and general formula (I-4-1):

(Wherein all symbols have the same meanings as described above), General formula (I-5-1):

(Wherein all symbols have the same meanings as described above).

In the present invention, preferably as a compound, for example,
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2- (1 -Methyl-1H-pyrazol-4-yl) -4-pyridinyl] -3-piperidinol,
(2) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate,
(3) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -2-methyl-3-pyridinyl} -5 -Fluoro-1H-benzimidazole-7-carboxylate,
(4) (3S, 4R) -4-amino-1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazole-2- Yl) -4-pyridinyl] -3-piperidinol,
(5) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(6) (3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (ethylamino) -3-piperidinol,
(7) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(8) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
(9) (3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4 -Pyridinyl] -4- (ethylamino) -3-piperidinol, or (10) methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3, 5-difluorophenyl) -2- (4-morpholinyl) -3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate,
Or a salt thereof.

More preferably, for example,
(1) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate,
(2) (3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (ethylamino) -3-piperidinol,
(3) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(4) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol or (5) (3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl- 3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4- (ethylamino) -3-piperidinol,
Or a salt thereof.

Particularly preferably, for example,
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5- Fluoro-1H-benzimidazole-7-carboxylate, or a salt thereof.

  Also, (3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl ] -4- (Ethylamino) -3-piperidinol, or a salt thereof is also particularly preferred.

  Also, (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl ] -4- (3-oxetanylamino) -3-piperidinol, or a salt thereof is also particularly preferred.

  Also, (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl]- 4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol, or a salt thereof, is also particularly preferred.

  Also, (3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4- Pyridinyl] -4- (ethylamino) -3-piperidinol, or a salt thereof, is also particularly preferred.

Also,
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(2) (3S, 4R) -4-amino-1- [3- (1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(3) (3S, 4R) -4-amino-1- [3- (2,5-difluorophenyl) -5- (6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -3 -Piperidinol,
(4) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -3-pyridinyl} -5-fluoro-1H -Benzimidazole-7-carboxylate,
(5) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- ( 3-oxetanylamino) -3-piperidinol,
(6) (3S, 4R) -1- [3- (3-chloro-5-fluorophenyl) -5- (5,6-difluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4 -[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
(7) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- ( Ethylamino) -3-piperidinol,
(8) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -4 -[(3,3,3-trifluoropropyl) amino] -3-piperidinol, or (9) (3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro -5-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
Or a salt thereof is also preferred.

More preferably, for example,
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(2) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -3-pyridinyl} -5-fluoro-1H -Benzimidazole-7-carboxylate,
(3) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- ( 3-oxetanylamino) -3-piperidinol,
(4) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- ( Ethylamino) -3-piperidinol or (5) (3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro-5-methoxy-1H-benzimidazole-2- Yl) -4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
Or a salt thereof.

Particularly preferably, for example,
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3- Piperidinol or a salt thereof.

  Further, methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -3-pyridinyl} -5-fluoro-1H- Benzimidazole-7-carboxylate, or a salt thereof, is also particularly preferred.

  Also, (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- (3 -Oxetanylamino) -3-piperidinol, or a salt thereof, is also particularly preferred.

  Also, (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- (ethyl Amino) -3-piperidinol, or a salt thereof, is also particularly preferred.

  Also, (3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro-5-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4- [(3,3,3-trifluoropropyl) amino] -3-piperidinol, or a salt thereof, is also particularly preferred.

[Isomer]
In the present invention, all isomers are included unless otherwise indicated. For example, the alkyl group, the alkoxy group, and the like include straight-chain and branched ones. Further, isomers (E, Z, cis, trans) in double bonds, rings, and condensed rings, isomers due to the presence of asymmetric carbon (R, S, α, β, enantiomers, diastereomers) , An optically active substance having optical activity (D, L, d, l-form), a polar form (high-polarity form, low-polarity form) by chromatographic separation, an equilibrium compound, a rotamer, a mixture of any ratio thereof, All racemic mixtures are included in the present invention. In the present invention, all isomers due to tautomerism are also included.

[Salt, solvate]
The salts of the compounds represented by the general formula (I) disclosed in the present invention include all pharmaceutically acceptable ones. The pharmaceutically acceptable salt is preferably a low-toxic, water-soluble salt. Suitable salts include, for example, acid addition salts (eg, inorganic acid salts [eg, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.], organic acid salts [eg, : Acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, Toluenesulfonate, isethionate, glucuronate, gluconate, etc.], salts with acidic natural amino acids [eg, aspartate, glutamate, etc.] and the like.

Further salts include quaternary ammonium salts. The quaternary ammonium salt refers to a compound in which the nitrogen atom of the compound represented by the general formula (I) is quaternized by an R ⁰ group. Here, the R ⁰ group represents, for example, a C 1-8 alkyl group which may be substituted by a phenyl group.

  The compound represented by the general formula (I) can be converted to the above-mentioned salt, N-oxide or solvate by a known method.

  The N-oxide of the compound represented by the general formula (I) means a compound represented by the general formula (I) in which a nitrogen atom is oxidized. In addition, such an N-oxide may form a salt such as the above-mentioned acid addition salt.

  The compound represented by the general formula (I), a salt thereof, or an N-oxide thereof may form a solvate with, for example, water or an alcohol solvent (eg, ethanol). The solvate is preferably one having low toxicity and water solubility.

  The compound represented by the general formula (I) or a salt thereof may exist in an unsolvated form, or may exist in a solvated form with a pharmaceutically acceptable solvent such as water or ethanol. . Hydrates are preferred as solvates. The compound represented by the general formula (I) and a salt thereof can be converted to a solvate by a known method.

  The compound represented by the general formula (I) or a salt thereof can form a co-crystal with a suitable co-crystal former. The co-crystal is preferably a pharmaceutically acceptable co-crystal formed with a pharmaceutically acceptable co-crystal former. Co-crystals are typically defined as crystals in which two or more different molecules are formed by intermolecular interactions different from ionic bonds. Further, the co-crystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared in a known manner, for example by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. Suitable co-crystal formers include those described in WO 2006/007448.

  In the present invention, all references to the compound of the present invention are made of the compound represented by the general formula (I), a salt thereof, a solvate thereof (for example, hydrate), an N-oxide thereof, or a co-crystal thereof, or It includes a solvate (for example, a hydrate) of a salt of the compound represented by the formula (I), an N-oxide thereof, or a cocrystal thereof.

  That is, in the present invention, the compound represented by the general formula (I) or a salt thereof is a solvate (for example, a hydrate) of the compound represented by the general formula (I), its N-oxide, or its N-oxide. It includes a cocrystal, or a solvate (eg, hydrate) of a salt of the compound represented by the general formula (I), an N-oxide thereof, or a cocrystal thereof.

[Prodrug]
The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into the compound represented by the general formula (I) by a reaction with an enzyme, gastric acid, or the like in a living body. Examples of the prodrug of the compound represented by the general formula (I) include, when the compound represented by the general formula (I) has an amino group, a compound in which the amino group is acylated, alkylated, or phosphorylated ( For example, when the amino group of the compound represented by the general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, Tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, acetoxymethylation, tert-butylated compound, etc.) and the like; when the compound represented by the general formula (I) has a hydroxyl group, Acylated, alkylated, phosphorylated, borated compounds (for example, when the hydroxyl group of the compound represented by the general formula (I) is acetylated, Rumitoiru, propanoyl, pivaloyl, succinylated, fumaryl reduction, alanyl, dimethylaminomethylcarbonyl compounds, etc.) and the like. Further, prodrugs of the compound represented by the general formula (I) can be prepared under physiological conditions as described in Hirokawa Shoten, “Development of Drugs”, Vol. 7, “Molecular Design,” pp. 163-198 (1990). It may be changed to the compound represented by the general formula (I). These prodrugs of the compound represented by the general formula (I) can be produced by a method known per se. Further, the prodrug of the compound represented by the general formula (I) may form a salt such as the above-mentioned acid adduct salt, for example, like the compound represented by the general formula (I), For example, a solvate may be formed with water or an alcohol-based solvent (eg, ethanol).

[Labeled compound]
In the present invention, the compound represented by the general formula (I) or a salt thereof also includes a so-called labeled compound in which a part or all of each atom constituting the compound is replaced by its isotope. These labeling compounds can be produced by a method known per se. The isotopes used for labeling include, but are not limited to, for ^{example, 2 H, 3 H, 13} C, 14 C, 15 N, 16 N, 17 O, 18 O, 35 S, 36 Cl, 77 Br, ¹²⁵ I and the like can be suitably used.

[Production method]
[Method for producing compound of the present invention]
The compound represented by the general formula (I) or a salt thereof can be prepared by a known method, for example, a method shown below, a method similar thereto, a method shown in an example, a method according to an example, or a comprehensive organic compound. Transformations: A Guide to Functional Group Preparations, 2nd Edition [Richard C. Larock, John Wiley & Sons Inc, 1999] Can be produced by appropriately improving and combining the methods described in (1), but not limited thereto. In each of the following production methods, a raw material compound that has formed a salt may be used. Examples of such salts include those described as the salts of the compound represented by the above general formula (I).

Compounds of the present invention represented by the general formula (I) wherein R ¹ is a hydrogen atom, that is, compounds of the general formula (IA)

(Wherein all symbols have the same meanings as described above) are represented by the general formula (II)

(Wherein, R ¹⁰⁰ represents a group that can be deprotected under acidic conditions, and the other symbols have the same meanings as described above.). it can. At that time, a protection reaction and / or a deprotection reaction of a functional group may be performed as necessary.

  The deprotection reaction under acidic conditions is carried out, for example, by using an organic acid (eg, acetic acid, trifluoroacetic acid, trifluoromethane, etc.) in water or an organic solvent (eg, dichloromethane, chloroform, 1,4-dioxane, ethyl acetate, anisole, or a mixture thereof). Acetic acid, methanesulfonic acid, etc.), an inorganic acid (eg, hydrochloric acid, sulfuric acid, etc.), or a mixture thereof (eg, hydrogen bromide / acetic acid, etc.) at a temperature of 0 to 100 ° C.

  Examples of the group to be deprotected under acidic conditions include a t-butoxycarbonyl (Boc) group, a 2,2,2-trichloroethoxycarbonyl group, a 2-trimethylsilylethoxycarbonyl group, an allyloxycarbonyl (Alloc) group, and a vinyloxy group. Carbonyl group, benzyloxycarbonyl (Cbz) group, 1-methyl-1- (4-biphenyl) ethoxycarbonyl (Bpoc) group, formyl group, benzoyl group, p-methoxybenzyl group, benzyloxymethyl (BOM) group, -(Trimethylsilyl) ethoxymethyl (SEM) group, triphenylmethyl group, p-toluenesulfonyl group and the like.

  The group to be deprotected under acidic conditions is not particularly limited as long as it can be easily and selectively eliminated, in addition to the groups described above. For example, those described in Protective Groups in Organic Synthesis (TW Greene, John Wiley & Sons Inc, 1999) can also be used.

  As can be easily understood by those skilled in the art, the desired compound of the present invention can be easily produced by properly using these deprotection reactions.

  If necessary, subsequent to this reaction, an operation for converting into a target salt may be performed by a known method.

Compounds of the present invention represented by the general formula (I) wherein R ¹ is 3-oxetanyl, 3,3,3-trifluoropropyl or ethyl, that is, the general formula (IB)

(Wherein R ^1-1 represents 3-oxetanyl, 3,3,3-trifluoropropyl, or ethyl, and the other symbols have the same meanings as described above). ) And 3-oxetanone, 3,3,3-trifluoropropanal, or acetaldehyde, by subjecting them to a reductive amination reaction. At that time, a protection reaction and / or a deprotection reaction of a functional group may be performed as necessary.

  This reductive amination reaction is known, and the imine formed in the reaction may be isolated and then reduced, or the imine may be formed in the reaction system and reduced without isolation (one pot). . The reaction for producing this imine is known. For example, a dehydrating agent (eg, anhydrous magnesium sulfate, molecular weight) in an organic solvent (eg, methanol, ethanol, dichloromethane, chloroform, dichloroethane, benzene, toluene, or a mixed solvent thereof) is used. The reaction can be carried out in the presence or absence of a sieve (trade name) or in the presence or absence of an acid (eg, hydrochloric acid, acetic acid, etc.) at a temperature of from 20 ° C. to reflux. A reduction reaction of an imine is also known. For example, a reducing agent (eg, trihydrogen hydride) in an organic solvent (eg, tetrahydrofuran, diethyl ether, dichloroethane, dichloromethane, dimethylformamide, acetic acid, methanol, ethanol, or a mixture thereof) is used. In the presence of sodium acetoxyborohydride, sodium cyanoborohydride, sodium borohydride, zinc borohydride, diisobutylaluminum hydride, 2-picoline borane complex) at a temperature of 0 to 40 ° C., or a solvent (eg: Ethers (eg, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohols (eg, methanol, ethanol, etc.), benzenes (eg, benzene, toluene, etc.), nitriles (eg, acetonitrile, etc.), amides (Example: Dimethi Formamide, etc.), water, ethyl acetate, acetic acid, or a mixed solvent thereof) in the presence of a catalyst (eg, palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.) under normal pressure or pressure. Under a hydrogen atmosphere at a temperature of 0 to 200 ° C. In addition, reductive amination reactions performed without isolating the imine are known, and include, for example, a reducing agent (eg, hydrogenation) in an organic solvent (eg, dichloroethane, dichloromethane, dimethylformamide, acetic acid, or a mixture thereof). Sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, 2-picoline borane complex) at a temperature of 0 to 40 ° C.

  For example, a Lewis acid (eg, titanium tetrachloride, etc.) is used in the presence of a tertiary amine (eg, triethylamine, diisopropylethylamine, etc.) in an organic solvent (eg, dichloroethane, dichloromethane, or a mixed solvent thereof). And reacting at 0 to 40 ° C., and further at 0 to 40 ° C. in the presence of a reducing agent (eg, sodium triacetoxyborohydride, sodium cyanoborohydride, 2-picoline borane complex). Can also.

  If necessary, subsequent to this reaction, an operation for converting into a target salt may be performed by a known method.

The compound represented by the general formula (II) can be produced by the method described in the following reaction scheme 1. In Reaction Scheme 1, X ¹ represents bromine, chlorine, iodine, mesylate, or triflate, and other symbols have the same meanings as described above.

  The compound represented by the general formula (V) can be produced by subjecting a compound represented by the general formula (III) and a compound represented by the general formula (IV) to a coupling reaction.

This coupling reaction is known, for example, in an organic solvent (eg, benzene, toluene, dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, or a mixed solvent thereof). (Examples: sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutyl fluoride Ammonium, etc.) or an aqueous solution thereof, or a mixture thereof, and a catalyst (eg, bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) ((A-taPhos) ₂ PdCl ₂ ) , Tetrakis (bird) E sulfonyl) palladium (Pd (PPh _{3) 4),} bis (triphenylphosphine) palladium (PdCl ₂ (PPh _{3) 2),} palladium acetate (Pd (OAc) _2), palladium black, 1,1'- bis (diphenylphosphino ferrocene) dichloropalladium (PdCl2 (dppf) 2), dichloride diallyl palladium (PdCl ₂ (allyl) _2), etc. iodide phenyl bis (triphenylphosphine) palladium _{(PhPdI (PPh 3) 2)} ) The reaction can be carried out at room temperature to 150 ° C. in the presence.

  The compound represented by the general formula (II) can be produced by subjecting the compound represented by the general formula (V) and the compound represented by the general formula (VI) to a cyclization reaction.

  This cyclization reaction is known. For example, in an organic solvent (eg, ethanol, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide or a mixed solvent thereof), an acid (eg, acetic acid, sulfurous acid) is used. (Eg, sodium hydrogen) or sodium dithionite at room temperature to reflux.

Among the compounds represented by the general formula (III), ^{R 4} is C1~4 alkyl, optionally substituted with 1-3 ^{R 7 C5~6} monocyclic carbocyclic or 1-3 ^{R 8,} The compound which is a 5- to 6-membered monocyclic heterocyclic ring which may be substituted with, that is, the compound represented by the general formula (III-1) can be produced by the method described in the following reaction scheme 2. In the reaction scheme 2, X ² represents bromine or iodine, X ³ represents chlorine, R ^4-1 is C 1-4 alkyl, and C 5-6 mono optionally substituted with 1-3 R ^7. Represents a compound which is a carbocyclic ring or a 5- to 6-membered monocyclic heterocyclic ring which may be substituted by 1 to 3 R ⁸ , and other symbols have the same meanings as described above.

  The compound represented by the general formula (VIII) can be produced by subjecting the compound represented by the general formula (VII) to a formylation reaction.

  This formylation reaction is known. For example, a formylating agent is used in an organic solvent (eg, tetrahydrofuran, diethyl ether, or a mixed solvent thereof) in the presence of a base (eg, lithium diisopropylamide, n-butyllithium, etc.). (Example: N, N-dimethylformamide, methyl formate, ethyl formate, etc.) and reacting at -78 ° C to room temperature.

  The compound represented by the general formula (X) can be produced by subjecting a compound represented by the general formula (VIII) and a compound represented by the general formula (IX) to an addition reaction.

  This addition reaction is known. For example, a base in an organic solvent (eg, N, N-dimethylacetamide, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, 2-propanol, dimethylsulfoxide, or a mixed solvent thereof) is used. (Eg, triethylamine, N, N-diisopropylethylamine, sodium hydrogen carbonate, potassium carbonate, tripotassium phosphate, etc.) in the presence of a reaction at room temperature to 120 ° C.

  The compound represented by the general formula (III-1) can be produced by subjecting a compound represented by the general formula (X) and a compound represented by the general formula (XI) to a coupling reaction. The compound represented by the general formula (IX) is a known compound, or can be produced by a known method, for example, according to or according to the description in Japanese Patent Publication No. 2009-155283.

  This coupling reaction is known and can be performed under the same conditions as in the method for producing the compound represented by the general formula (V).

Among the compounds represented by the general formula (III), the compound in which R ⁴ is a hydrogen atom, that is, the compound represented by the general formula (III-2) can be produced by the method described in the following reaction scheme 3. it can. In Reaction Scheme 3, all symbols have the same meanings as described above.

  The compound represented by the general formula (III-2) can be produced by subjecting a compound represented by the general formula (XII) and a compound represented by the general formula (IX) to an addition reaction.

  This addition reaction is known and can be carried out under the same conditions as in the method for producing the compound represented by the general formula (X).

  Of the compounds of the present invention, compounds having optical activity can be produced using optically active starting materials or reagents, or optically resolving a racemic intermediate, and then leading to the compound of the present invention, or racemic Can be produced by optically resolving the compound of the present invention.

  The method of optical resolution is known.For example, after forming a salt or complex with another optically active compound and performing recrystallization, the target compound is isolated or directly using a chiral column or the like. Separation method and the like can be mentioned.

  The compounds represented by the general formulas (III), (IV), (VI), (VII), (IX), (XI) and (XII) used as starting compounds are known per se or known methods. For example, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)] can be easily used.

  In each reaction exemplified in this specification, any heating method such as a water bath, an oil bath, a sand bath, or a microwave may be used for heating.

  In each of the reactions exemplified in this specification, a solid-phase-supported reagent supported on a high-molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, or the like) may be used as appropriate.

  The product of each reaction exemplified in this specification may be purified by conventional purification means, for example, distillation under normal pressure or reduced pressure, silica gel, ion exchange resin, scavenger resin, or various types of chromatography using magnesium silicate (for example, High-performance liquid chromatography, thin-layer chromatography, column chromatography, etc.), or washing or recrystallization. Purification may be performed for each reaction, or may be performed after completion of some reactions.

[toxicity]
Since the toxicity of the compound of the present invention is low, it can be safely used as a pharmaceutical.

[Application to pharmaceutical products]
Since the compound of the present invention has somatostatin receptor agonist activity, it is used as an agent for preventing and / or treating somatostatin-related diseases (somatostatin itself or a disease in which a hormone regulated by somatostatin can be involved) in mammals, particularly humans. Can be used.

  In addition, the compound of the present invention has a sufficiently low hERG inhibitory activity and phospholipidosis-inducing ability, so that it can be taken for a long time.

  Therefore, the pharmaceutical composition of the present invention is repeatedly administered to a patient who needs to take it for a long period of time (repeated administration).

  In the present invention, "patients needing to take for a long period of time" is not particularly limited as long as they are patients taking for the purpose of preventing and treating chronic diseases, for example, patients with somatostatin-related diseases and the like. Can be mentioned.

  In the present invention, repeated administration means that administration is repeated, and each dose, each administration interval, and the like may be the same or different.

Examples of the somatostatin-related disease include, for example, hormonal disease (eg, acromegaly, giant disease, pituitary gigantism, Cushing's disease, Graves' disease, hyperthyroidism, etc.), and stunted growth [ateliosis] (eg, : Skeletal dysplasia, Noonan syndrome, obesity, obesity-associated growth failure, uterine insufficiency, developmental renal failure, syndrome X, etc.), cancer or adenoma [cancer or adenoma] (eg, leukemia, chondrosarcoma) , Melanoma, lipoma, meningioma, neuroblastoma, pituitary adenoma, headache associated with pituitary adenoma, nonfunctional pituitary adenoma, growth hormone producing adenoma, growth hormone releasing factor producing adenoma, gonadotropin producing adenoma, Prolactin producing adenoma, thyroid stimulating hormone producing adenoma, VIP producing adenoma, ACTH producing adenoma, thyroid cancer, medullary thyroid cancer, lung cancer, breast cancer, liver cancer, neuroendocrine tumor (neuroendocrine gland) Tumor), gastrointestinal pancreatic neuroendocrine tumor, gastrin-producing tumor, carcinoid syndrome, colorectal cancer, pancreatic cancer, islet cell tumor, insulin-producing tumor, glucagon-producing tumor, prostate cancer, cancer cachexia, colon vascular tumor, etc.) , Gastrointestinal disease (eg, gastrointestinal symptoms associated with gastrointestinal obstruction, gastroesophageal reflux, gastroduodenal reflux, excessive gastric acid secretion, peptic ulcer, Zollinger-Ellison syndrome, protein leaky gastroenteropathy, dumping syndrome) , Small intestine syndrome, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, irritable colon syndrome, intestinal fistula, functional dyspepsia, nausea, vomiting, abdominal bloating, etc., diarrhea [diarrhea] (eg: aqueous diarrhea) Syndrome, chronic secondary diarrhea, chemotherapy-induced diarrhea, intractable diarrhea associated with acquired immunodeficiency syndrome, diarrhea associated with irritable bowel syndrome, postoperative diarrhea, etc.), blood Vascular disease (eg, proliferative retinopathy, macular degeneration, age-related macular degeneration, gastrointestinal bleeding, bleeding from gastroduodenal ulcer, esophageal varices bleeding, variceal bleeding in patients with cirrhosis, Portal hypertension, hemorrhage of transplanted vessels, restenosis, scar scarring, psoriasis, systemic sclerosis (scleroderma), chronic allograft rejection, hypotension, atherosclerosis, PTCA Later restenosis, hypertrophic cardiomyopathy, arteriosclerosis, valvular heart disease, myocardial infarction, etc.), fibrosis (eg, dermal fibrosis, central nervous system fibrosis, nasal fibrosis, pulmonary fibrosis, liver) Fibrosis, renal fibrosis, chemotherapy-induced fibrosis, etc.), diabetes and diabetic complications (eg, diabetes, insulin-dependent diabetes, diabetic retinopathy, diabetic nephropathy, diabetic nephropathy) , The phenomenon of akebo, insulin refractory, hyperinsulinemia, high Lipidemia), inflammatory disease (eg, arthritis, rheumatoid arthritis, psoriasis, local inflammation, sunburn, eczema, etc.), central nervous system disease (eg, dementia, Alzheimer's disease) , Epilepsy, etc.), respiratory disease (eg, sleep apnea syndrome, etc.), pancreatic disease (eg, pancreatitis, acute pancreatitis, chronic pancreatitis, pancreatic fistula, pancreatic pseudocyst, ascites) , Pancreatic fistula, symptoms associated with pancreatic surgery, etc.), hepatic disease (eg, cystic liver, etc.), renal disease (eg, hepatorenal syndrome, cystic kidney, nephropathy, etc.), ovarian disease [ ovarian disease] (eg, polycystic ovary syndrome, etc.), bone and joint disease (eg, osteoporosis, osteoarthritis, etc.), pain, headache and the like. Further, the compound of the present invention is used for imaging a tumor having a somatostatin receptor by introducing a radioactive substance (eg, ¹²³ I, ¹²⁵ I, ¹¹¹ In, etc.) directly or via an appropriate spacer into the compound of the present invention. Alternatively, the compound of the present invention can be used for targeting a tumor having a somatostatin receptor by introducing a carcinostatic agent directly or via an appropriate spacer.

  Above all, acromegaly, giantosis, pituitary gigantism, pituitary adenoma, headache associated with pituitary adenoma, nonfunctional pituitary adenoma, growth hormone producing adenoma, neuroendocrine tumor (neuroendocrine tumor), gastrointestinal Pancreatic neuroendocrine tumor, gastrin-producing tumor, carcinoid syndrome, insulin-producing tumor, glucagon-producing tumor, gastrointestinal symptoms associated with gastrointestinal obstruction, cystic kidney, cystic liver, bleeding from esophageal varices, portal hypertension, diabetes The compound of the present invention is useful for the prevention and / or treatment of retinopathy, dementia, Alzheimer's disease, pain, headache, etc., and particularly, the prevention and / or treatment of acromegaly and gastrointestinal symptoms associated with gastrointestinal obstruction. In addition, the compound of the present invention is suitable. In the present invention, “treatment” includes not only the cure of the disease itself, but also the effect of improving or alleviating the symptoms associated with the disease, ie, “amelioration of symptoms”.

  The gastrointestinal symptoms associated with gastrointestinal obstruction include, for example, gastrointestinal symptoms associated with gastrointestinal obstruction in palliative medicine for patients with advanced or recurrent cancer (malignant gastrointestinal obstruction in patients with advanced or recurrent cancer). This can be improved. The compound of the present invention is used as an agent for improving gastrointestinal symptoms associated with gastrointestinal obstruction, or as an agent for improving gastrointestinal symptoms associated with gastrointestinal obstruction (malignant gastrointestinal obstruction in patients with advanced or recurrent cancer) in palliative medicine for patients with advanced or recurrent cancer. Is also useful.

  Cystic kidney also includes, for example, autosomal dominant polycystic kidney and autosomal recessive polycystic kidney.

  Cystic liver also includes, for example, multiple liver cysts associated with autosomal dominant polycystic liver disease and autosomal dominant polycystic kidney disease.

  Neuroendocrine tumor is a general term for non-cancerous or cancerous tumors derived from neuroendocrine cells. Neuroendocrine tumors are known to occur not only in endocrine organs but also in systemic organs. Neuroendocrine tumors occur most often in the digestive tract and lungs, such as the pancreas and gastrointestinal tract, but can also occur in the pituitary, parathyroid, thyroid, adrenal gland, and thymus. It may be caused by multiple endocrine tumor type 1 (MEN1), multiple endocrine tumor type 2 (MEN2), or complication of hyperparathyroidism.

  Neuroendocrine tumors are broadly classified according to their symptoms into functional neuroendocrine tumors in which hormone overproduction is observed and nonfunctional neuroendocrine tumors in which hormone overproduction is not observed. Examples of functional neuroendocrine tumors include carcinoid syndrome, serotonin-producing tumor, gastrin-producing tumor (gastrinoma, Zollinger-Ellison syndrome), glucagon-producing tumor (glucagonoma), insulin-producing tumor (insulinoma), and vasoactive intestinal peptide-producing tumor (VIP oma), somatostatin producing tumor (somatostatinoma), growth hormone releasing hormone producing tumor (GRH oma), adrenocorticotropic hormone producing tumor (ACTH oma), parathyroid hormone related protein producing tumor (PTHrP oma), colecist Kinin producing tumor (CCKoma), renin producing tumor, erythropoietin producing tumor, luteinizing hormone producing tumor (LH producing tumor), insulin-like growth factor-2 producing tumor (IGF-2), glucagon-like peptide-1 Producing tumor (GLP-1-producing tumor) and the like. Further, tumors metastasized from these tumors to other organs such as the liver are also included. Non-functional neuroendocrine tumors include, for example, noncancerous or cancerous tumors derived from endocrine cells and formed in the pancreas, gastrointestinal tract, lung, pituitary gland, parathyroid gland, thyroid gland, adrenal gland, and / or thymus. Is mentioned. Further, tumors metastasized from these tumors to other organs such as the liver are also included.

  As a test method for evaluating the pharmacological activity of the compound of the present invention other than that described in Examples, for example, there is an evaluation system for gastric acid secretion inhibitory action using rats. For example, the gastric acid secretion inhibitory effect of the compound of the present invention can be evaluated by using the following method.

(Evaluation of gastric acid secretion inhibitory action using rats)
A rat (7-week-old male Crl: CD (SD) IGS rat (Charles River Japan Co., Ltd.)) was fasted overnight from the day before the evaluation and water-free from 2 hours before the evaluation. Detain. After awakening the rats from anesthesia, continuous intravenous administration of a test compound dissolved in a vehicle (physiological saline (Otsuka Ishoku Ins., Otsuka Pharmaceutical Factory)) or the vehicle is started via an indwelling needle. One hour after the start of the administration, the rat is laparotomized under isoflurane anesthesia, and the pyloric part of the stomach is ligated with a thread. After closing the laparotomy, recover from anesthesia. At 5 hours from the start of administration (4 hours after ligation of the pylorus), the abdomen is opened again under isoflurane anesthesia, the cardia of the stomach is closed with forceps, and the blood is exsanguinated. The contents of the stomach are centrifuged at 500 × g for 15 minutes, and the supernatant is collected as gastric juice, and the amount of gastric juice (mL / 100 g BW) is determined as a value per body weight. Further, the acid concentration (mmol / mL) in the gastric juice is measured by a back titration using a COM-1600ST automatic titrator (Hitachi High-Tech (Hiranuma Sangyo)). The product of the gastric fluid volume and the acid concentration is defined as the gastric acid secretion (mmol / 100 g BW), and the gastric acid secretion inhibition rate (%) is expressed by the following formula. ]-[Gastric acid secretion in test compound administration group]) / [Gastric acid secretion in vehicle administration group] x 100%. According to the present evaluation system, for example, it has been obtained from the results of studies by the present inventors that octreotide exhibits a gastric acid secretion inhibition rate of 39% at an administration rate of 1 μg / kg / h.

  In addition to the above-listed diseases, the compounds of the present invention can be used for various pathological diseases related to somatostatin, such as Life Sciences, 1987, Vol. 40, pp. 419-437, and It can also be used for the prevention and / or treatment of diseases described in The European Journal of Medicine, 1993, Vol. 2, pp. 97-105.

  When the compound of the present invention is applied to medicines, the compound of the present invention is used not only as a single agent but also, for example, (1) complements and / or enhances its preventive, therapeutic and / or symptom-improving effects, and (2) its complement. In order to improve the kinetics / absorption, reduce the dose, and / or (3) reduce the side effects thereof, it may be used as a concomitant drug in combination with other active ingredients, for example, the drugs listed below.

  When the compound of the present invention is used for prevention and / or treatment of acromegaly, examples of the drug used in combination with the compound of the present invention include a somatostatin analog, a somatostatin receptor agonist, a growth hormone receptor antagonist, and a dopamine receptor. Agonists and the like.

  In addition, since patients with acromegaly often have lifestyle-related diseases such as diabetes, hypertension, hyperlipidemia, and obesity, and various other diseases, the compounds of the present invention may be used as, for example, drugs for treating diabetes (eg, : Insulin sensitizer, insulin secretagogue (eg, sulfonylurea), biguanide, insulin, α-glucosidase inhibitor, β3 adrenergic receptor agonist, dipeptidyl peptidase IV inhibitor, amylin agonist, phosphotyrosine phosphatase Inhibitors, gluconeogenesis inhibitors, SGLT (sodium-glucose co-transporter) inhibitors, or other drugs for treating diabetes, etc., drugs for treating diabetic complications (eg, aldose reductase inhibitors, glycation inhibitors, protein kinases) C inhibitor, neurotrophic factor, neurotrophic factor enhancer, nerve regeneration promoter, or other diabetes Drug for hypertension (eg, angiotensin converting enzyme inhibitor, calcium antagonist, potassium channel opener, angiotensin II antagonist, etc.), drug for hyperlipidemia (eg, HMG-CoA reductase inhibitor) , Fibrate compounds, squalene synthase inhibitors, antioxidants, etc.), anti-obesity agents (eg, pancreatic lipase inhibitors, central anti-obesity agents, peptide anorectic agents, cholecystokinin agonists, other anti-obesity agents) Etc.), Arthritis drugs, anti-anxiety drugs, antidepressants, osteoporosis drugs, antiepileptic drugs, chemotherapeutic drugs, immunotherapy drugs, anti-PD-1 antibodies, antithrombotic drugs, dementia drugs, erectile dysfunction improvers It may be used in combination with a drug for treating urinary incontinence / frequent urination, a drug for treating dysuria, a nonsteroidal anti-inflammatory drug, a local anesthetic, vitamins and the like. It can also be combined with other hormones that promote secretion of growth hormone (eg, GHRH), GH, IGF-1, cytokines, or cytokine action enhancers.

  Further, when the compound of the present invention is used for prevention and / or treatment of gastrointestinal symptoms associated with gastrointestinal obstruction, examples of the drug used in combination with the compound of the present invention include somatostatin analogs, somatostatin receptor agonists, dopamine D2 receptor Body antagonist, histamine H1 receptor antagonist, combination of histamine H1 receptor antagonist and PDE inhibitor, histamine H2 receptor antagonist, anticholinergic drug, serotonin 5HT3 receptor antagonist, serotonin 5HT4 receptor antagonist, Corticosteroids, NK1 receptor antagonists, atypical antipsychotics (MARTA), opioids, opioid antagonists and the like. In addition, for example, it may be combined with prochlorperazine, levomepromazine, or the like.

When the compound of the present invention is used for prevention and / or treatment of autosomal dominant polycystic kidney disease, examples of the drug used in combination with the compound of the present invention include somatostatin analogs, somatostatin receptor agonists, and vasopressin V2 receptor antagonists And antihypertensive agents (eg, angiotensin converting enzyme inhibitors, calcium antagonists, potassium channel openers, angiotensin II antagonists, etc.), sclerosing agents and the like.
Also, patients with autosomal dominant polycystic kidney disease are often associated with pain, cystic infection, cystic hemorrhage and various other diseases, the compounds of the present invention include, for example, nonsteroidal anti-inflammatory drugs, opioids, It may be used in combination with an antibacterial agent, a hemostatic agent and the like.

When the compound of the present invention is used for prevention and / or treatment of autosomal dominant polycystic liver disease, examples of the drug used in combination with the compound of the present invention include somatostatin analogs, somatostatin receptor agonists, and sclerosing agents. Can be
In addition, since patients with autosomal dominant polycystic liver disease often have pain, cystic infection, cystic hemorrhage and other various diseases, the compounds of the present invention include, for example, nonsteroidal anti-inflammatory drugs, opioids. , An antibacterial agent, a hemostat and the like.

When the compound of the present invention is used for the prevention and / or treatment of neuroendocrine tumors, drugs used in combination with the compound of the present invention include, for example, somatostatin analogs and somatostatin receptor agonists for the purpose of improving symptoms associated with excessive hormone production. Drugs, serotonin synthase inhibitors, opioid receptor agonists, proton pump inhibitors, histamine H2 receptor antagonists, antihyperglycemic drugs, insulin preparations, growth hormone receptor antagonists, steroid synthesis inhibitors, steroid production inhibitors Agents and the like.
In addition, for example, for the purpose of improving symptoms associated with tumor growth, somatostatin analogs and somatostatin receptor agonists, interferon preparations, alkylating agents, molecular targeting drugs, peptide receptor radionuclide therapeutics, and the like are included.
Further, for example, for the purpose of diagnosing a neuroendocrine tumors, somatostatin receptor scintigraphy (indium pentenoyl threo tides ^{(111 an In),} etc.) and the like.

  Examples of somatostatin analogs include octreotide, lanreotide, pasireotide, and the like.

  Examples of the somatostatin receptor agonist include the compounds described in WO2002 / 091125, the compounds described in WO2003 / 042234, the compounds described in WO2003 / 045926, and the compounds described in WO2003 / 045926. Compounds described in WO2008 / 051272, compounds described in WO2004 / 046107, compounds described in WO2017 / 003723, compounds described in WO2017 / 003724 And the like.

  Examples of the growth hormone receptor antagonist include pegvisomant and the like.

  Examples of the dopamine receptor agonist include bromocriptine, cabergoline, and the like.

  As insulin sensitizers, for example, vaglitazone (balaglitazone), netoglitazone (netoglitazone), pioglitazone (pioglitazone), riboglitazone (rivoglitazone), rosiglitazone (rosiglitazone), farglitazar (farglitazar), muraglitazar (muraglitazar), muraglitazar (muraglitazar) (Naveglitazar), ragaglitazar, tesaglitazar, reglixane, BM-13.1258, FK-614, KRP-297, LM-4156, LY-510929, MBX-102, MX-6054, R -119702, T-131, THR-0921, compounds described in WO 2001/038325, compounds described in WO 1999/058510 (for example, (E) -4- [4 -(5-methyl-2-phenyl-4-oxazolylmethoxy) benzyloxyimino] -4-phenylbutyric acid) and the like.

  Examples of the sulfonylurea agent include acetohexamide, chlorpropamide, glibenclamide, gliclazide, gliclazide, glimepiride, glipizide, glybuzole, and glyclopyramide. (Glyclopyramide), mitiglinide (mitiglinide), nateglinide (nateglinide), repaglinide (repaglinide), senaglinide (senaglinide), tolazamide, tolbutamide (tolbutamide), JTT-608 and the like.

  Examples of biguanide drugs include buformin (buformin), phenformin (fenformin), metformin (metformin) and the like.

  As insulin, for example, animal insulin extracted from bovine or porcine pancreas, semi-synthetic human insulin enzymatically synthesized from insulin extracted from porcine pancreas, human synthesized by genetic engineering using Escherichia coli or yeast Insulin, insulin zinc containing 0.45 to 0.9 (w / w)% zinc, zinc chloride, protamine sulfate and protamine insulin zinc produced from insulin, and the like. Insulin may be a fragment or derivative thereof (eg, INS-1 or the like) or an oral insulin preparation. Furthermore, insulin includes various types such as super-fast type, fast-acting type, biphasic type, intermediate type and continuous type, and these can be appropriately selected depending on the condition of the patient.

  Examples of the α-glucosidase inhibitor include acarbose, emiglitate, miglitol, voglibose, and the like.

  Examples of the β3 adrenergic receptor agonist include AJ-9677, AZ40140 and the like.

  Examples of dipeptidyl peptidase IV inhibitors include, for example, sitagliptin (sitagliptin), alogliptin (alogliptin), vildagliptin (vildagliptin), linagliptin (linagliptin), anagliptin (anagliptin), saxagliptin (tenaxegliptin), and eneligliptin (teneligliptin) , Carmegliptin, evogliptin, omarigliptin, omarigliptin, denagliptin, dutogliptin, gemigliptin, gosogliptin, gosogliptin-P, V-logP-N-me-gliptin-V-meP , P32 / 98, TS-021, TA-6666, KRP-104, DSP-7238, SYR-472 (trelagliptin), TAK-100 and the like. It is.

  Amylin agonists include, for example, pramlintide and the like.

  Examples of the phosphotyrosine phosphatase inhibitor include sodium vanadate and the like.

  Gluconeogenesis inhibitors include, for example, glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors, glucagon antagonists and the like.

  Examples of SGLT (sodium-glucose co-transporter) inhibitors include ipragliflozin, luseogliflozin, tofogliflozin, canagliflozin, dapagliflozin and the like. .

  Other therapeutic agents for diabetes include, for example, bromocriptine, leptin, BAY-27-9955, GLP-1 receptor agonists (eg: GLP-1, GLP-1MR agent, liraglutide), AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, exenatide (exenatide), etc., GPR40 agonist (eg, TAK-875 etc.) , GPR119 agonist, 11β-hydroxysteroid dehydrogenase inhibitor (eg, BVT-3498, etc.), adiponectin or an agonist thereof, IKK inhibitor (eg, AS-2868, etc.), leptin sensitizer, somatostatin receptor agonist ( Example: pamphlet of WO 2001/025228, country WO 2003/042204 pamphlet, WO 1998/044921 pamphlet, WO 1998/042855 pamphlet, WO 1999/022735 pamphlet, etc.), glucokinase activator (eg: RO- 28-1675).

  Examples of the aldose reductase inhibitor include tolrestat (tolrestat), epalrestat (epalrestat), imirestat (imirestat), zenarestat (zenarestat), fidarestat (fidarestat), zopolrestat (zopolrestat), minalrestat, and lanirestat. (Ranirestat), CT-112 and the like.

  Examples of the glycation inhibitor include pimagedine, ALT-946, ALT766, EXO-226 and the like.

  Examples of the protein kinase C inhibitor include ruboxistaurin mesylate and the like.

  Examples of the neurotrophic factor include NGF, NT-3, BDNF and the like.

  As the neurotrophic factor increasing drug, for example, a neurotrophin production / secretion enhancer described in WO 2001/014372 (eg: 4- (4-chlorophenyl) -2- (2-methyl-1-imidazolyl) ) -5- [3- (2-methylphenoxy) propyl] oxazole, etc.).

  Examples of the nerve regeneration promoter include Y-128, VX-853, prosaptide and the like.

  Other therapeutic drugs for diabetes complications include, for example, alprostadil, tiapride, cilostazol, mexiletine, ethyl icosapentate, memantine, pimagedrin ( pimagedline), AGE inhibitors (eg, ALT-946, alagebrium, pyridorin, pyridoxamine, etc.), active oxygen scavengers (eg, thioctic acid, etc.), somatostatin receptor activation Drugs (eg, BIM-23190), apoptosis signal-regulating kinase-1 (ASK-1) inhibitors and the like.

  As angiotensin converting enzyme inhibitors, for example, captopril (captopril), enalapril (enalapril), alacepril (alacepril), delapril (delapril), lisinopril (lisinopril), imidapril, imidapril, benazepril, priazapril, cilazapril (cil) Temocapril, trandolapril and the like can be mentioned.

  Examples of the calcium antagonist include manidipine, nifedipine, amlodipine, afonidipine, efonidipine, nicardipine, and the like.

  Examples of potassium channel openers include levcromakalim, AL0671, NIP-121 and the like.

  Examples of angiotensin II antagonists include, for example, losartan, candesartan cilexetil, eprosartan, valsartan, irbesartan, olmesartan medoxomil, [E41771- [ 2 '-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl] -2-ethoxy-1H-benzimidazole-7- Carboxylic acids and the like can be mentioned.

  Examples of the HMG-CoA reductase inhibitor include pravastatin (pravastatin), simvastatin (simvastatin), atorvastatin (atorvastatin), fluvastatin (fluvastatin), pitavastatin (pitavastatin), rosuvastatin and the like.

  Examples of the fibrate compounds include bezafibrate, clinofibrate, clofibrate, clofibrate, simfibrate, and fenofibrate.

  Examples of the squalene synthase inhibitor include, for example, compounds described in WO 1997/010224 (eg, N-[[(3R, 5S) -1- (3-acetoxy-2,2-dimethylpropyl)- 7-chloro-5- (2,3-dimethoxyphenyl) -2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl] acetyl] piperidine-4-acetic acid and the like ) And the like.

  Examples of the antioxidant include lipoic acid, probucol and the like.

  Examples of pancreatic lipase inhibitors include orlistat, cetilistat and the like.

  Examples of the central antiobesity agent include mazindol, dexfenfluramine, fluoxetine, fluoxetine, sibutramine, fenfluramine, phentermine, and amfepramone. Dexamfetamine, phenylpropanolamine, clobenzorex, and the like.

  Examples of the peptide anorectic include leptin, CNTF (ciliary neurotrophic factor) and the like.

  Cholecystokinin agonists include, for example, lintitript, FPL-15849 and the like.

  Other anti-obesity agents include lipstatin, MCH receptor antagonists (eg, SB-56849, SNAP-7941, compounds described in WO 2001/0882925, and WO 2001/082925). / 0878834), neuropeptide Y antagonists (eg, CP-422935), cannabinoid receptor antagonists (eg, SR-141716, rimonabant), ghrelin antagonists, 11β- Examples include hydroxysteroid dehydrogenase inhibitors (eg, BVT-3498, etc.), β3 agonists (eg, AJ-9677, AZ40140, etc.), and antifeedants (eg, P-57, etc.).

  Examples of the therapeutic agent for arthritis include ibuprofen and the like.

  Examples of anxiolytics include chlordiazepoxide, diazepam, diazepam, oxazolam, medazepam, medazepam, cloxazolam, cloxazolam, bromazepam, lorazepam, alprazolam, and alprazolam. (Fludiazepam) and the like.

  Examples of the antidepressant include fluoxetine (fluoxetine), fluvoxamine (fluvoxamine), imipramine (imipramine), paroxetine (paroxetine), and sertraline (sertraline).

  Examples of therapeutic agents for osteoporosis include alfacalcidol (alfacalcidol), calcitriol (calcitriol), elcatonin (elcatonin), salmon calcitonin (calcitonin salmon), estriol, estriol, ipriflavone, disedronate disodium (risedronate). disodium), pamidronate disodium, alendronate sodium hydrate, incadronate disodium and the like.

  Antiepileptic drugs include, for example, gabapentin, trileptal, keppra, zonegran, pregabalin, harkoseride, carbamazepine, and the like.

  Examples of chemotherapeutic agents include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), antimetabolites (eg, methotrexate), 5-fluorouracil, 5 -Fluorouracil derivatives (eg, doxifluridine), anticancer antibiotics (eg, mitomycin, doxorubicin), plant-derived anticancer agents (eg, vincristine, vindesine) , Paclitaxel and the like), cisplatin, carboplatin, etoposide and the like.

  Examples of the immunotherapeutic agent include a microorganism or bacterial component (eg, muramyl dipeptide derivative, picibanil, etc.), a polysaccharide having an immunopotentiating activity (eg, lentinan, sizofiran) , Krestin (registered trademark)), cytokines obtained by genetic engineering techniques (eg, interferon, interleukin: IL) (eg, IL-1, IL-2, IL-12, etc.) And the like, and colony stimulating factors (eg, granulocyte colony stimulating factor, erythropoietin (EPO), etc.).

  Examples of the anti-PD-1 antibody include nivolumab (nivolumab) and pembrolizumab (pembrolizumab).

  Examples of antithrombotic agents include heparin (eg, dalteparin, heparin), warfarin (eg, warfarin, etc.), antithrombin drugs (eg, argatroban, etc.), thrombolysis Drugs (eg, urokinase, urokinase, tisokinase, alteplase, nateplase, monteplase, monteplase, pamiteplase, etc.), platelet aggregation inhibitors (eg, ticlopidine, cilostazol) cilostazol), ethyl icosapentate (ethyl icosapentate), beraprost, sarpogrelate, and the like.

  Examples of the therapeutic agent for dementia include donepezil, galanthamine, rivastigmine, tacrine and the like.

  Examples of the erectile dysfunction improver include apomorphine, sildenafil and the like.

  Examples of the therapeutic agent for urinary incontinence / frequent urination include flavoxate, imidafenacin, oxybutynin, propiverine and the like.

  Examples of the therapeutic agent for dysuria include acetylcholinesterase inhibitors (eg, distigmine) and the like.

  Non-steroidal anti-inflammatory drugs include, for example, acetaminophen, aspirin, indometacin and the like.

  Examples of the local anesthetic include capsaicin, lidocaine, and the like.

  Examples of the vitamins include vitamin B1 and vitamin B12.

  Dopamine D2 receptor antagonists include, for example, prochlorperazine, levomepromazine, risperidone, risperidone, metoclopramide, domperidone, and the like.

  Examples of the histamine H1 receptor antagonist include diphenhydramine (diphenhydramine), chlorpheniramine (chlorpheniramine), dimenhydrinate (dimenhydrinate), and promethazine (promethazine).

  Examples of the combination of a histamine H1 receptor antagonist and a PDE inhibitor include a combination of diphenhydramine / diprophylline.

  Examples of the histamine H2 receptor antagonist include famotidine, cimetidine and the like.

  Examples of anticholinergic agents include scopolamine and the like.

  Examples of the serotonin 5HT3 receptor antagonist include tropisetron (tropisetron), granisetron (granisetron), ondansetron (ondansetron), azasetron (azasetron), ramosetron (ramosetron), indisetron (indisetron), and palonosetron (palonosetron). No.

  Serotonin 5HT4 receptor antagonists include, for example, cisapride, mosapride and the like.

  Examples of corticosteroids include dexamethasone, betamethasone, prednisolone, and the like.

  Examples of the NK1 receptor antagonist include aprepitant, fosaprepitant and the like.

  Atypical antipsychotics (MARTA) include, for example, olanzapine, quetiapine, perospirone, and the like.

  Opioids include, for example, morphine.

  Examples of the opioid antagonist include methylnaltrexone.

  Vasopressin V2 receptor antagonists include, for example, tolvaptan.

  Examples of the curing agent include ethanol, butyl cyanoacrylate, minomycin, tetracycline, and monoethanolamine oleate.

  Examples of hemostatic agents include tranexamic acid and the like.

  Serotonin synthase inhibitors include, for example, telotristat and the like.

  Opioid receptor agonists include, for example, loperamide.

  Examples of the proton pump inhibitor include rabeprazole and the like.

  Examples of the therapeutic agent for hypoglycemia include diazoxide.

  Examples of the growth hormone receptor antagonist include pegvisomant and the like.

  Examples of steroid synthesis inhibitors include mitotane.

  Examples of the steroid production inhibitor include ketoconazole and the like.

  Interferon preparations include, for example, interferon α.

  Examples of the molecular target drug include everolimus and sunitinib.

  The concomitant preparation of the compound of the present invention and these other drugs may be administered in the form of a combination preparation in which both components are combined in one preparation, or in the form of separate preparations administered by the same administration route or different administration routes. May be taken. When different preparations are administered, simultaneous administration is not necessarily required, and a time difference may be provided between administrations as necessary. In addition, when a time difference is provided between administrations, the order of administration is not particularly limited, and may be appropriately adjusted so as to obtain desired drug effects.

  The dosage of these other drugs used in combination with the compound of the present invention can be appropriately increased or decreased based on the clinically used dose of the drug or similar drug. The compounding ratio of the compound of the present invention and other drugs can be appropriately adjusted in consideration of the age and weight of the administration subject, administration method, administration time, target disease, symptoms, and the like. Approximately 1 part by weight of the compound of the present invention may be combined with other drugs in the range of 0.01 to 100 parts by weight. A plurality of other drugs may be used. The other drug may be a drug having the same mechanism as the above, in addition to those listed above. Such drugs include those found to date as well as those found to date.

  The dose of the compound of the present invention varies depending on age, body weight, symptom, therapeutic effect, administration method, treatment time, and the like, but is generally from 0.1 mg to 300 mg per day per adult per day. Oral administration several times, or parenteral administration once to several times a day in the range of 0.1 mg to 150 mg per adult per day, or intravenous in the range of 1 hour to 24 hours a day May be administered continuously.

  Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above-mentioned dose may be sufficient, or administration outside the range may be necessary.

  In order to use the compound of the present invention as a single agent or as a combination of the compound of the present invention and another drug for the purpose of preventing and / or treating the above-mentioned diseases, the substance as an active ingredient is usually After being formulated with pharmaceutically acceptable carriers such as various additives or solvents, it is administered systemically or locally in oral or parenteral form. Here, the pharmaceutically acceptable carrier means a substance other than the active ingredient, which is generally used for pharmaceutical preparations. The pharmaceutically acceptable carrier preferably has no pharmacological action at the dosage of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. A pharmaceutically acceptable carrier can also be used for the purpose of enhancing the usefulness of the active ingredient and the preparation, facilitating the preparation, stabilizing the quality, or improving the usability. Specifically, substances such as those described in Yakuji Nipponsha 2000, “Drug Additives Encyclopedia” (edited by the Japan Pharmaceutical Excipients Association) may be appropriately selected according to the purpose.

  Examples of dosage forms used for administration include, for example, preparations for oral administration (eg, tablets, capsules, granules, powders, oral liquids, syrups, oral jellies, etc.), oral preparations (eg, oral tablets, Oral sprays, oral semi-solids, mouthwashes, etc., injection preparations (eg, injections), dialysis preparations (eg, dialysis preparations), inhalation preparations (eg, inhalation preparations), Ophthalmic preparations (eg, eye drops, eye ointments, etc.), otic preparations (eg, ear drops, etc.), nasal preparations (eg, nasal drops, etc.), rectal preparations (eg, suppositories, Rectal semisolids, enema, etc.), vaginal preparations (eg, vaginal tablets, vaginal suppositories, etc.) and dermatological preparations (eg, external solids, external liquids, sprays, ointments, creams) , Gels, patches and the like).

[Formulation for oral administration]
Preparations for oral administration include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral jellies and the like. In addition, preparations for oral administration include a rapidly disintegrating preparation in which the release of the active ingredient from the preparation is not particularly controlled, and a release preparation adjusted for the purpose by a unique preparation design and manufacturing method. There are controlled release preparations such as preparations and sustained release preparations. Enteric-coated preparations are designed to release the active ingredient mainly in the small intestine without releasing it in the stomach, for the purpose of preventing the decomposition of the active ingredient in the stomach or reducing the stimulating effect of the active ingredient on the stomach. A preparation which is prepared by applying a film using an acid-insoluble enteric base. Sustained-release preparations refer to preparations in which the release rate, release time, and release site of the active ingredient are adjusted from the preparation for the purpose of reducing the number of administrations or reducing side effects. It can be manufactured by using Among the preparations for oral administration, capsules, granules, tablets, etc. are coated with a suitable coating agent such as sugars or sugar alcohols, high molecular compounds for the purpose of facilitating ingestion or preventing the decomposition of the active ingredient. A coating can also be applied.

(1) Tablets Tablets are solid preparations having a certain shape which are orally administered and are generally called tablets such as uncoated tablets, film-coated tablets, sugar-coated tablets, multilayer tablets, and dry coated tablets. In addition, quick-disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets and the like are included. When manufacturing uncoated tablets, the following methods (a), (b), or (c) are usually used:
(A) Additives such as excipients, binders, disintegrants, etc. are added to the active ingredient, mixed and homogenized, granulated by an appropriate method using water or a solution containing a binder, and then lubricated. And compression molding.
(B) Add the additives such as excipients, binders and disintegrants to the active ingredient and mix to obtain a homogeneous mixture. After mixing and homogenizing by adding a powdery agent and the like, compression molding;
(C) Additives such as excipients and binders are added to the active ingredient, mixed and homogenized, and the kneaded mixture moistened with a solvent is poured into a certain mold, molded and dried by an appropriate method. ;
Is used. A film-coated tablet can be usually produced by applying a thin coating to an uncoated tablet with an appropriate coating agent such as a polymer compound. Sugar-coated tablets can be usually produced by coating the uncoated tablets with a coating agent containing a saccharide or a sugar alcohol. The multilayer tablet can be produced by stacking powders having different compositions in layers by a suitable method, and compression-molding. A dry-coated tablet can be produced by covering an inner-core tablet with an outer layer having a different composition. Tablets can also be formed into enteric-coated tablets or sustained-release tablets using a known appropriate technique. Oral quick disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are those in which a unique function is imparted to the tablet by appropriate selection of additives, and should be manufactured according to the tablet manufacturing method. Can be. In addition, a rapidly disintegrating tablet in the mouth is a tablet that can be taken by dissolving or disintegrating quickly in the oral cavity; a chewable tablet is a tablet that can be taken by chewing; A dissolving or dispersing tablet; a dispersing tablet is a tablet that is taken by dispersing in water; a dissolving tablet is a tablet that is taken by dissolving in water. Effervescent tablets can be manufactured by using an appropriate acidic substance, carbonate, bicarbonate or the like as an additive.

(2) Capsule A capsule is a preparation filled in a capsule or encapsulated with a capsule base, and includes a hard capsule, a soft capsule and the like. Hard capsules are prepared by adding an additive such as an excipient to the active ingredient and mixing the mixture to obtain a homogeneous mixture. Can be manufactured. Soft capsules are manufactured by encapsulating the active ingredient with additives in a fixed shape with a suitable capsule base such as gelatin with increased plasticity by adding glycerin, D-sorbitol, etc. can do. Capsules can be made into enteric-coated capsules or sustained-release capsules using a known appropriate technique, and a colorant or a preservative can be added to the capsule base.

(3) Granules Granules are preparations granulated into granules, and include, in addition to what is generally called granules, effervescent granules and the like. When producing granules, the following methods (a), (b), or (c) are usually used:
(A) adding an excipient, a binder, a disintegrant, or other additives to the powdered active ingredient, mixing and homogenizing, and granulating by an appropriate method;
(B) adding an additive such as an excipient to the active ingredient previously prepared in a granular form, mixing and homogenizing the active ingredient;
(C) adding an additive such as an excipient to the active ingredient which has been previously made into granules and mixing the mixture, and granulating by an appropriate method;
Is used. The granules can be coated as necessary, or can be made into enteric-coated granules or sustained-release granules using a known appropriate technique. The effervescent granules can be produced by using an appropriate acidic substance, carbonate, bicarbonate or the like as an additive. The expanded granules refer to granules that dissolve or disperse while rapidly foaming in water. Granules can also be made into fine granules by adjusting the size of the particles.

(4) Powder The powder is a powdery preparation, which can be usually produced by adding an excipient or other additives to the active ingredient, mixing and mixing the active ingredient, and making the mixture homogeneous.

(5) Oral liquid preparation Oral liquid preparation is a liquid or fluid viscous gel-like preparation. In addition to those generally called oral liquid preparations, elixirs, suspensions, emulsions, limonade preparations and the like are available. included. Oral liquid preparations can usually be produced by adding an additive and purified water to the active ingredient, mixing and uniformly dissolving or emulsifying or suspending, and filtering as necessary. Elixir refers to a clear liquid oral solution containing ethanol having a sweet and aromatic taste, and is usually added to a solid active ingredient or a leachate thereof with ethanol, purified water, flavoring agent, sucrose, other saccharides, or It can be produced by adding a sweetener, dissolving the mixture, and forming a clear liquid by filtration or other methods. Suspensions are oral liquid preparations in which the active ingredient is finely and homogeneously suspended.Usually, a solid active ingredient is added with a suspending agent or other additives and purified water or oil, and suspended by an appropriate method. , By making the whole homogeneous. Emulsions are oral liquid preparations in which the active ingredient is finely and homogeneously emulsified, and can usually be produced by adding an emulsifier and purified water to a liquid active ingredient, emulsifying by an appropriate method, and homogenizing the whole. . The limonade agent refers to a clear liquid oral solution having a sweet and sour taste.

(6) Syrup The syrup is a viscous liquid or solid preparation containing a sugar or a sweetener, and includes a syrup preparation and the like. Syrups are usually prepared by dissolving, mixing, suspending or emulsifying a syrup, a solution of sucrose, other sugars or sweeteners, or adding a single syrup to the active ingredient, boiling the mixture if necessary, and then heating. It can be produced by filtration. A syrup preparation refers to a granular or powdery preparation that becomes a syrup when water is added, and is sometimes referred to as a dry syrup preparation. A syrup preparation can be usually produced using a sugar or a sweetener as an additive in accordance with the above-mentioned method for producing granules or powders.

(7) Oral jelly agent An oral jelly agent is a gel-like preparation having no fluidity, and is usually formed by adding an additive and a polymer gel base to an active ingredient, mixing the mixture, and gelling by an appropriate method. It can be manufactured by molding into a certain shape.

[Oral preparation]
(1) Oral tablets Oral tablets are solid preparations of a certain shape applied in the oral cavity, and include lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums and the like. Oral tablets can be usually produced according to the tablet production method. A troche is a tablet for the oral cavity that is gradually dissolved or disintegrated in the oral cavity and is applied locally to the oral cavity, pharynx, etc .; Buccal tablet is a buccal tablet that gradually dissolves the active ingredient between the molars and cheeks and is absorbed through the buccal mucosa; Tablets; gums are oral tablets that release the active ingredient by chewing.

(2) Oral spray Oral spray is a preparation in which the active ingredient is sprayed as a mist, powder, foam, paste, or the like. Usually, the active ingredient and additives are dissolved or suspended in a solvent or the like. After turbidity and filtration as necessary, fill the container with a liquefied gas or compressed gas, or prepare a solution or suspension using the active ingredient and additives, fill the container, and then use a spray pump. It can be manufactured by mounting.

(3) Semi-solid preparation for oral cavity A semi-solid preparation for oral cavity is a preparation applied to oral mucosa, and includes creams, gels, ointments and the like. Oral semi-solid preparations are usually prepared by emulsifying the active ingredient together with additives with an oily component such as purified water and petrolatum, or mixing the active ingredient and additives with a polymer gel or fat as a base to obtain a homogeneous mixture. It can be manufactured by the following. A cream refers to a semisolid preparation emulsified in an oil-in-water type or a water-in-oil type, and a lipophilic preparation emulsified in a water-in-oil type is sometimes referred to as an oily cream. Creams are usually made from petrolatum, higher alcohols, etc. as such or as an oil phase by adding additives such as emulsifiers, separately, purified water as such, or as an aqueous phase by adding additives such as emulsifiers, etc. The active ingredient is added to the above phase, the mixture is heated, and the oil phase and the aqueous phase are combined and stirred until the whole becomes homogeneous, followed by emulsification. The gel preparation refers to a gel preparation, and includes an aqueous gel preparation, an oily gel preparation and the like. The aqueous gel can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending the mixture, heating and cooling, or adding a gelling agent to crosslink the active ingredient. The oily gel can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. The ointment refers to a semisolid preparation in which the active ingredient is dissolved or dispersed in a base, and includes an oil-based ointment, a water-soluble ointment, and the like. Oily ointments are usually heated and melted with oily bases such as oils, waxes and hydrocarbons such as paraffin, and the active ingredient is added, mixed and dissolved or dispersed, and the whole is homogeneous. It can be manufactured by mixing and kneading until the mixture becomes. A water-soluble ointment can be usually produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, mixing and kneading until the whole becomes homogeneous.

(4) Mouthwash Mouthwash is a liquid preparation to be applied topically to the oral cavity, pharynx and the like, and includes a solid preparation to be dissolved and used at the time of use. The gargle can be usually produced by adding a solvent and an additive to the active ingredient, mixing and dissolving the active ingredient uniformly, and filtering if necessary. In the case of a solid preparation to be used by dissolving at the time of use, it can be usually produced according to the above-mentioned production method for tablets or granules.

[Injection formulation]
(1) Injectables Injectables are solutions, suspensions, or emulsions that are directly administered to body tissues or organs such as subcutaneous, intramuscular, or blood vessels, or solids that are dissolved or suspended at the time of use. Sterile preparations, including those commonly referred to as injections, lyophilized injections, powder injections, filled syringes, cartridges, infusions, implantable injections, and sustained injections. It is. When producing an injection, the following method (a) or (b) is usually used:
(A) For an injection, the active ingredient is used as such, or the active ingredient plus an additive is dissolved, suspended, or emulsified in water for injection, another aqueous solvent, a non-aqueous solvent, or the like for injection. Fill and seal in a container and sterilize;
(B) The active ingredient as it is or a substance obtained by adding an additive to the active ingredient is dissolved, suspended or emulsified in water for injection, another aqueous solvent, a non-aqueous solvent, or the like, and the mixture is aseptically filtered. Or aseptically prepared and homogeneously filled into a container for injection and sealed;
Is used. Freeze-dried injections are usually lyophilized after dissolving the active ingredient as it is or an additive such as an active ingredient and an excipient in water for injection, aseptically filtering and filling a container for injection, or It can be manufactured by freeze-drying in a dedicated container and then filling the container directly. Powder injections can be usually produced by aseptic filtration, then adding powder obtained by crystallization or a sterilized additive to the powder, and filling the powder into a container for injections. A pre-filled syringe can be usually produced by preparing a solution, suspension or emulsion using the active ingredient as it is or using the active ingredient and additives, and filling the syringe. The cartridge agent refers to an injection used by putting a cartridge filled with a drug solution into a dedicated syringe, and a cartridge filled with a drug solution usually contains the active ingredient as it is, or a solution using the active ingredient and additives, It can be manufactured by preparing a suspension or an emulsion and filling the cartridge. The infusion means an injection which is usually administered intravenously and has a volume of 100 mL or more. The implantable injection refers to a solid or gel injection which is applied subcutaneously, intramuscularly or the like using an implantable device or by surgery for the purpose of releasing the active ingredient for a long period of time. Implantable injections can be usually produced by using biodegradable polymer compounds and forming pellets, microspheres, or gels. A sustained injection is an injection applied intramuscularly or the like for the purpose of releasing the active ingredient over a long period of time. Usually, the active ingredient is dissolved or suspended in a vegetable oil or the like, or a biodegradable polymer compound is used. It can be manufactured by preparing a suspension of microspheres using

[Dialysis formulation]
(1) Dialysis Agent A dialysis agent is a liquid preparation or a solid preparation that dissolves at the time of use used for peritoneal dialysis or hemodialysis, and includes a peritoneal dialysis agent and a hemodialysis agent. Peritoneal dialysis agent refers to a sterile dialysis agent used for peritoneal dialysis. Usually, an additive is added to the active ingredient and dissolved in a solvent to make a fixed volume, or an additive is added to the active ingredient. Is sealed in a container, and sterilized as necessary. In the case of a solid preparation that dissolves at the time of use, it can be usually produced according to the above-mentioned production method for tablets or granules. Hemodialysis agent refers to a dialysis agent used for hemodialysis, which is usually a container prepared by adding an additive to an active ingredient and dissolving it in a solvent to a fixed volume, or adding an additive to the active ingredient. And can be manufactured by filling. In the case of a solid preparation that dissolves at the time of use, it can be usually produced according to the above-mentioned production method for tablets or granules.

[Formulation for inhalation]
(1) Inhalant An inhalant is a formulation for inhaling the active ingredient as an aerosol and applying it to the bronchi or lungs, and includes powder inhalants, inhalation liquids, inhalation aerosols and the like. Powder inhalant refers to a formulation inhaled as an aerosol of solid particles, prepared so that the inhaled amount is constant, and usually, the active ingredient is made into fine particles and, if necessary, mixed with an additive such as lactose. To be homogeneous. The inhalation liquid refers to a liquid inhalation applied by a nebulizer or the like, and usually a solvent and an appropriate isotonicity agent, a pH adjuster, etc. are added to the active ingredient, and the mixture is mixed and homogeneously dissolved or suspended. It can be produced by filtering as appropriate. The inhalable aerosol refers to a metered dose inhaler which sprays a fixed amount of an active ingredient together with a propellant filled in a container. Inhalation aerosols are usually prepared by adding a solvent and an appropriate dispersing agent, stabilizing agent, etc. to the active ingredient to form a solution or suspension, filling together with a liquid propellant into a pressure-resistant container, and attaching a metering valve. It can be manufactured by the following.

[Ophthalmic formulation]
(1) Eye drops An eye drop is a solid sterile preparation to be applied to ocular tissues such as the conjunctival sac and used in liquid form or dissolved or suspended at the time of use. An eye drop can be usually produced by adding an additive to an active ingredient, dissolving or suspending in a solvent or the like to make a fixed volume, or filling an active ingredient with an additive into a container. .

(2) Ophthalmic ointment Ophthalmic ointment is a semi-solid, sterile preparation to be applied to ocular tissues such as the conjunctival sac, and is usually mixed with a base such as petrolatum and a solution or fine powder of the active ingredient to make it homogeneous. And can be manufactured by filling a container.

[Otological preparations]
(1) Eardrops Eardrops are liquid, semi-solid, or solid preparations that are dissolved or suspended at the time of use, which are administered to the outer or middle ear. Ear drops are usually manufactured by adding an additive to an active ingredient and dissolving or suspending it in a solvent or the like to make a fixed volume, or filling an active ingredient with an additive into a container. it can.

[Rhinological preparations]
(1) Nasal drops Nasal drops are preparations to be administered to the nasal cavity or nasal mucosa, and include nasal drops, nasal drops and the like. Nasal drop powder refers to a fine powder nasal drop to be administered to the nasal cavity, which is usually manufactured by making the active ingredient into appropriately fine particles, mixing with additives as necessary, and homogenizing. Can be. The nasal solution is a liquid nasal solution or a solid nasal solution which is dissolved or suspended at the time of use. And can be produced by filtering. As an additive of the nasal solution, an isotonic agent, a pH adjuster and the like can be used.

[Rectal preparation]
(1) Suppositories Suppositories are semisolid preparations in a certain shape which are applied to the rectum, melt according to body temperature, or release the active ingredient by gradually dissolving or dispersing in water. Suppositories are usually prepared by adding additives such as dispersing agents and emulsifiers to the active ingredient and mixing them, and dissolving or uniformly dispersing them in a liquefied base by heating or the like. And then solidified / molded. As a suppository base, an oily base or a hydrophilic base is usually used.

(2) Rectal semi-solid agent Rectal semi-solid agent is a preparation to be applied to the perianal area or into the anus, and includes a rectal cream, a rectal gel, a rectal ointment, and the like. Rectal semi-solid preparations are usually prepared by emulsifying an active ingredient together with an additive with purified water and an oily ingredient such as petrolatum, or mixing the active ingredient and an additive based on a polymer gel or oil and fat with the active ingredient and an additive to make the mixture homogeneous. It can be manufactured by the following. Rectal creams are usually made from petrolatum, higher alcohols, etc. as such, or as an oil phase by adding additives such as emulsifiers, and separately, purified water as is, or as an aqueous phase, by adding additives such as emulsifiers, etc. The active ingredient can be prepared by adding an active ingredient to one of the phases, heating the mixture, stirring the oil phase and the aqueous phase together until the whole becomes homogeneous, and emulsifying the mixture. The rectal gel refers to a gel-like preparation, and includes an aqueous gel, an oily gel and the like. The aqueous gel can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending the mixture, heating and cooling, or adding a gelling agent to crosslink the active ingredient. The oily gel can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. The rectal ointment refers to a semisolid preparation in which the active ingredient is dissolved or dispersed in a base, and includes an oil-based ointment, a water-soluble ointment, and the like. Oily ointments are usually heated and melted with oily bases such as oils, waxes and hydrocarbons such as paraffin, and the active ingredient is added, mixed and dissolved or dispersed, and the whole is homogeneous. It can be manufactured by mixing and kneading until the mixture becomes. A water-soluble ointment can be usually produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, mixing and kneading until the whole becomes homogeneous.

(3) Enema An enema is a liquid or viscous gel preparation applied through the anus. Usually, purified water or an appropriate aqueous solvent is used to dissolve or suspend the active ingredient in a solvent or the like. It can be manufactured by filling a container with a fixed volume. Dispersants, stabilizers, pH regulators and the like can be used as additives for the enema.

[Vaginal preparations]
(1) Vaginal tablets Vaginal tablets are solid preparations of a certain shape which are applied to the vagina and gradually release or dissolve in water to release the active ingredient. can do.

(2) Vaginal suppositories Vaginal suppositories are semisolid preparations of a certain shape which are applied to the vagina and which release the active ingredient by melting at body temperature or gradually dissolving or dispersing in water. Usually, it can be manufactured according to the method for manufacturing rectal suppositories and the like.

[Skin preparation]
(1) Solid preparation for external use A solid preparation for external use is a solid preparation to be applied or sprayed on skin or nails including the scalp, and includes a powder for external use and the like. The topical powder refers to a powdered external solid preparation, which can be usually produced by adding an additive such as an excipient to the active ingredient, mixing the mixture to make the mixture homogeneous, and then forming a powder.

(2) External liquid preparation External liquid preparations are liquid preparations to be applied to skin or nails including the scalp, and include liniments, lotions and the like. A liquid preparation for external use can be usually produced by adding a solvent, an additive and the like to the active ingredient, dissolving, emulsifying, or suspending the active ingredient, and filtering if necessary. The liniment refers to a liquid or mud-like external liquid used by rubbing into the skin. Lotion refers to an external preparation in which the active ingredient is dissolved or emulsified or finely dispersed in an aqueous liquid, and is usually a solution, suspension, or emulsion using the active ingredient, an additive, and purified water. It can be manufactured by making the whole liquid homogeneous.

(3) Spray agent The spray agent is a preparation for spraying the active ingredient on the skin in the form of a mist, a powder, a foam, or a paste, and includes an external aerosol, a pump spray and the like. Sprays can be usually produced by preparing a solution or suspension of the active ingredient, filtering if necessary, and filling in a container. The external aerosol is a spray that sprays an active ingredient together with a liquefied gas or a compressed gas filled in a container. An external aerosol can be usually produced by preparing a solution or suspension of the active ingredient, filling the solution or suspension with a liquid propellant in a pressure-resistant container, and installing a continuous injection valve. If necessary, additives such as a dispersant and a stabilizer can be added to the external aerosol. A pump spray refers to a spray that sprays an active ingredient in a container with a pump. A pump spray can be usually produced by dissolving or suspending an active ingredient and an additive, and attaching a pump to a filled container.

(4) Ointment An ointment is a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base and applied to the skin, and includes oil-based ointments, water-soluble ointments, and the like. Oily ointments are usually heated and melted with oily bases such as oils, waxes and hydrocarbons such as paraffin, and the active ingredient is added, mixed and dissolved or dispersed, and the whole is homogeneous. It can be manufactured by mixing and kneading until the mixture becomes. A water-soluble ointment can be usually produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, mixing and kneading until the whole becomes homogeneous.

(5) Cream A cream is a semi-solid formulation emulsified in an oil-in-water or water-in-oil type, which is applied to the skin. A lipophilic formulation emulsified in a water-in-oil type is also called an oily cream. Sometimes. Creams are usually made from petrolatum, higher alcohols, etc. as such or as an oil phase by adding additives such as emulsifiers, separately, purified water as such, or as an aqueous phase by adding additives such as emulsifiers, etc. The active ingredient is added to the above phase, the mixture is heated, and the oil phase and the aqueous phase are combined and stirred until the whole becomes homogeneous, followed by emulsification.

(6) Gel The gel is a gel-form preparation to be applied to the skin, and includes an aqueous gel, an oil gel and the like. The aqueous gel can be produced by adding a polymer compound, other additives and purified water to the active ingredient, dissolving or suspending the mixture, heating and cooling, or adding a gelling agent to crosslink the active ingredient. The oily gel can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them.

(7) Patch The patch is a preparation to be stuck to the skin, and includes tapes, cataplasms and the like. Patches are usually manufactured by mixing a base with a high-molecular compound or a mixture thereof, mixing the active ingredient with the base, making the mixture homogeneous, and spreading the mixture on a support or a liner (peeled body) to form the patch. it can. A transdermal preparation can also be made by using a release controlling membrane. Additives such as an adhesive and an absorption enhancer can be used in the patch, if necessary. The tape means a patch using a base containing almost no water, and includes plasters, plasters and the like. Tapes are usually based on non-water-soluble natural or synthetic polymer compounds such as resins, plastics, and rubbers. It can be manufactured by rolling or encapsulating in a plastic film or the like and molding. Alternatively, it can be produced by encapsulating a mixture comprising an active ingredient and a base or other additives in a release body made of a release controlling film, a support and a liner (peeled body) and molding. A cataplasm refers to a patch using a water-containing base, and is usually mixed with an active ingredient and a liquid substance such as purified water and glycerin to make the whole homogeneous or a water-soluble polymer or a water-absorbent polymer. It can be produced by mixing a natural or synthetic polymer compound such as a molecule with purified water, kneading the mixture, adding an active ingredient, homogenizing the whole, spreading it on a cloth or the like, and molding.

  Unless defined otherwise, all technical, scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

  Further, in this specification, the contents of all patent documents and non-patent documents or references explicitly cited may be cited as a part of the present specification.

  Hereinafter, the present invention will be described in detail with reference to Examples and Biological Examples, but the present invention is not limited thereto. The compound names of the present invention and the compound names shown in the examples were given by ACD / Name (version 6.00, manufactured by Advanced Chemistry Development Inc.) or ChemDraw Ultra (version 12.0, manufactured by Cambridge Soft).

The description of Hi-flash SI or Hi-flash NH in parentheses shown in the column of medium pressure preparative liquid chromatography indicates the type of column used (Hi-flash SI: silica gel (Yamazen Co., Ltd.), Hi-flash NH: represents aminopropyl group-supporting silica gel (manufactured by Yamazen Corporation).
The HPLC retention time (min) is as follows:
Column: YMC Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); flow rate: 1.0 mL / min; column temperature: 40 ° C.; mobile phase (A): 0.1 % Trifluoroacetic acid aqueous solution; mobile phase (B): 0.1% trifluoroacetic acid-acetonitrile solution; gradient (indicating the ratio of mobile phase (A): mobile phase (B)): [0 min] 95: 5; [0.1 min] 95: 5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95: 5; [1.5 min] 95: 5; Detector: UV (PDA), ELSD, MS
It is a measured value in.

Numerical values shown in NMR are measured values (chemical shift values) of ¹ H-NMR using the measurement solvent described.

  In addition, Biological Example 4 described below is an example of a test showing the usefulness of the compound of the present invention for acromegaly. Biological Example 5 is a test showing the usefulness of the compound of the present invention for autosomal dominant polycystic kidney disease. Although the test is shown as an example, the disease targeted by the compound of the present invention is not limited to this. As described above, the compound of the present invention is useful for the prevention and / or treatment of all diseases in which somatostatin itself or a hormone regulated by somatostatin can be involved.

Reference Example 1
Tetrahydrofuran (hereinafter abbreviated as THF) of 2,5-dibromo-4-chloropyridine-3-carbaldehyde 3,5-dibromo-4-chloropyridine (CAS number 13626-17-0, MILESTONE, N24466) (2 g) ) To the solution (28 mL), lithium diisopropylamide (1 M THF solution, 7.74 mL) was added dropwise at -78 ° C over 20 minutes. After stirring at −78 ° C. for 5 minutes, N, N-dimethylformamide (hereinafter abbreviated as DMF) (0.688 mL) was added dropwise over 3 minutes. After stirring at −78 ° C. for 10 minutes, acetic acid (1.69 mL) was added, the reaction solution was heated to room temperature, diluted with water, and extracted with ethyl acetate. The residue obtained by concentrating the organic layer under reduced pressure was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10 to 0: 100) to obtain the following. The title compound having physical properties (1.95 g) was obtained.
HPLC retention time (min): 1.01;
MS (ESI, Pos.): 300 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 10.1, 8.86.

Reference example 2
tert-butyl (3aS, 7aR) -5- (2,5-dibromo-3-formylpyridin-4-yl) -2,2-dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine- 1 (2H) -carboxylate The compound (1.3 g) produced in Reference Example 1 and tert-butyl (3aS, 7aR) -2,2-dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine N, N-dimethylacetamide (hereinafter referred to as DMA) of -1 (2H) -carboxylate (CAS No. 1173005-74-7, a compound described in Example 8 of Japanese Patent Publication No. 2009-155283) (1.1 g). Triethylamine (1.8 mL) was added to the solution (13 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The residue obtained by concentrating the organic layer under reduced pressure was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10 to 0: 100) to obtain the following. The title compound (1.2 g) having physical properties was obtained.
HPLC retention time (min): 1.24;
MS (ESI, Pos.): 520 (M + H) ^<+> .

Reference Example 3
tert-butyl (3aS, 7aR) -5- [5-bromo-3-formyl-2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl] -2,2-dimethylhexahydro [ [1,3] oxazolo [5,4-c] pyridine-1 (2H) -carboxylate Under a nitrogen atmosphere, a solution of the compound (100 mg) prepared in Reference Example 2 in 1,4-dioxane (0.8 mL) was added with (1 -Methylpyrazol-4-yl) boronic acid (24 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (31.5 mg), and a 2 M aqueous solution of tripotassium phosphate (32 μL) were added. And stirred at 50 ° C. for 5 hours. After allowing to cool, the mixture was diluted with ethyl acetate, and the insolubles were filtered and concentrated under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10-0: 100) to give the title compound having the following physical data. Was.
HPLC retention time (min): 0.88;
MS (ESI, Pos.): 522 (M + H) ^<+> .

Reference example 4
tert-butyl (3aS, 7aR) -5- [5- (3,5-difluorophenyl) -3-formyl-2- (1-methyl-1H-pyrazol-4-yl) pyridin-4-yl] -2 1,2-Dioxane (1.0 mL) solution of the compound prepared in Reference Example 3 under a nitrogen atmosphere of 1,2 -dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 (2H) -carboxylate 3,5-Difluorophenylboronic acid (30.4 mg), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (31.5 mg), and a 2M aqueous solution of tripotassium phosphate (32 μL) The mixture was stirred at 90 ° C. for 1 hour. After allowing to cool, the mixture was diluted with ethyl acetate, and the insolubles were filtered and concentrated under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10-0: 100) to give the title compound (13 mg) having the following physical data. ) Got.
HPLC retention time (min): 0.92;
MS (ESI, Pos.): 554 (M + H) ^<+> .

Reference example 5
tert-butyl (3aS, 7aR) -5- [5- (3,5-difluorophenyl) -3- [7- (methoxycarbonyl) -1H-benzimidazol-2-yl] -2- (1-methyl- 1H-pyrazol-4-yl) pyridin-4-yl] -2,2-dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 (2H) -carboxylate Reference example under oxygen atmosphere To a solution of the compound (13 mg) prepared in 4 in ethanol (1.0 mL) was added methyl 2,3-diaminobenzoate (5.8 mg) and acetic acid (13.5 μL), and the mixture was stirred at 80 ° C. for 13 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10-0: 100) to give the title compound having the following physical data.
HPLC retention time (min): 0.95;
MS (ESI, Pos.): 700 (M + H) ⁺ .

Example 1
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2- (1-methyl-1H-pyrazole-4- Yl) -3-pyridinyl} -1H-benzimidazole-7-carboxylate

Under a nitrogen atmosphere, trifluoroacetic acid (87 μL) was added to a dichloromethane (1.0 mL) solution of the compound produced in Reference Example 5, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash NH) (ethyl acetate: methanol = 100: 0 to 80:20), and had the following physical property values. The compound of the present invention (7 mg) was obtained.
HPLC retention time (min): 0.57;
MS (ESI, Pos.): 560 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.38, 8.04, 8.02, 7.51-7.41, 7.28-7.18, 7.08-6.98, 6.85, 3.96, 3.72, 3.37-3.28, 3.21-3.09, 2.93-2.73, 2.46-2.37 , 2.23-2.17, 1.09-0.79.

Example 1 (1) to 1 (4)
Using a corresponding boronic acid compound instead of (1-methylpyrazol-4-yl) boronic acid and using a corresponding boronic acid compound instead of 3,5-difluorophenylboronic acid, methyl 2,3-diaminobenzoate Reference Example 3 → Reference Example 4 → Reference Example 5 → The same operation as in Example 1 was performed using the corresponding benzene-1,2-diamine compound in place of to obtain the compound of the present invention having the following physical property values. Was.

Example 1 (1)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -2,5-bis (3,5-difluorophenyl) pyridin-4-yl ] Piperidin-3-ol
HPLC retention time (min): 0.63;
MS (ESI, Pos.): 570 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 11.46, 8.43, 7.42, 7.20-7.09, 6.96-6.86, 6.82, 6.73-6.62, 3.64-3.42, 2.98-2.57, 2.29-2.20, 1.14-0.97, 0.81-0.63.

Example 1 (2)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2- (1-methyl- 1H-pyrazol-4-yl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.58;
MS (ESI, Pos.): 538 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.36, 7.54, 7.37, 7.20, 7.09-6.97, 6.89-6.83, 3.73, 3.42-3.34, 3.18-3.04, 2.89-2.68, 2.54-2.41, 2.28-2.16, 1.12 -0.98, 0.95-0.76.

Example 1 (3)
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2- (1-methyl-1H-pyrazole-3- Yl) -3-pyridinyl} -1H-benzimidazole-7-carboxylate
HPLC retention time (min): 0.60;
MS (ESI, Pos.): 560 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.43, 7.98, 7.95, 7.46-7.33, 7.29-7.20, 7.11-6.99, 6.01, 3.98, 3.67, 3.40-3.32, 3.22-3.10, 2.95-2.78, 2.50-2.40 , 2.25-2.15, 1.13-0.80.

Example 1 (4)
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2- (1-methyl-1H-pyrazole-5 Yl) -3-pyridinyl} -1H-benzimidazole-7-carboxylate
HPLC retention time (min): 0.63;
MS (ESI, Pos.): 560 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.50, 7.98, 7.92, 7.38, 7.35-7.24, 7.14, 7.12-7.01, 5.74, 3.97, 3.93, 3.41-3.35, 3.22-3.09, 2.96-2.79, 2.50-2.40 , 2.30-2.19, 1.11-0.84.

Reference Example 6
tert-butyl (3aS, 7aR) -5- (5-bromo-3-formyl-2-methylpyridin-4-yl) -2,2-dimethylhexahydro [1,3] oxazolo [5,4-c] Pyridine-1 (2H) -carboxylate To a solution of the compound (200 mg) prepared in Reference Example 2 in 1,4-dioxane (1.5 mL), a 2M aqueous solution of tripotassium phosphate (0.40 uL) and trimethylboroxine (16.9 mg) , And [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (22 mg) were added, and the mixture was stirred at 120 ° C. for 30 minutes. The reaction solution was returned to room temperature, diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was dried and concentrated. The obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10-0: 100) to give the title compound (58 mg) having the following physical data. ) Got.
HPLC retention time (min): 0.81;
MS (ESI, Pos.): 454 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 10.45, 8.57, 3.99-4.31, 3.15-3.58, 2.65, 2.14-2.48, 1.48-2.03, 1.48.

Example 2
(3S, 4R) -4-amino-1- [5- (3-chloro-5-fluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl ] -3-piperidinol

The compound prepared in Reference Example 6 was used in place of the compound prepared in Reference Example 3, and 3-chloro-5-fluorophenylboronic acid was used instead of 3,5-difluorophenylboronic acid. Reference Example 4 → Reference Example 5 → The same operation as in Example 1 was performed using 4-methoxybenzene-1,2-diamine instead of benzoate to obtain the compound of the present invention having the following physical property values.
HPLC retention time (min): 0.52;
MS (ESI, Pos.): 482 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.58-7.42, 7.37-7.20, 7.18-7.09, 7.00-6.90, 3.87, 3.43-3.36, 3.11-2.98, 2.91-2.70, 2.50-2.39, 2.36, 2.19 -2.07, 1.12-0.95.

Example 2 (1) to 2 (13)
The compound prepared in Reference Example 6 was used instead of the compound prepared in Reference Example 3, and the corresponding boronic acid compound was used instead of 3,5-difluorophenylboronic acid, and instead of methyl 2,3-diaminobenzoate. Using the corresponding benzene-1,2-diamine compound, the same operation as in Reference Example 4 → Reference Example 5 → Example 1 was performed to obtain a compound of the present invention having the following physical property values.

Example 2 (1)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl ] -3-piperidinol
HPLC retention time (min): 0.54;
MS (ESI, Pos.): 472 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.24, 7.61-7.54, 7.20, 7.08-6.96, 3.64-3.56, 3.17-3.04, 2.96-2.69, 2.34, 2.20-2.10, 1,34-1.18, 1.21-1.10 .

Example 2 (2)
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro- 1H-benzimidazole-7-carboxylate
HPLC retention time (min): 0.59;
MS (ESI, Pos.): 512 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.24, 7.80-7.70, 7.25-7.18, 7.08-6.96, 4.01, 3.41-3.36, 3.16-3.02, 2.90-2.80, 2.79-2.70, 2.54-2.41, 2.32, 2.21 -2.12, 1.34-1.18, 1.12-0.95.

Example 2 (3)
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5- Fluoro-1H-benzimidazole-7-carboxylate

HPLC retention time (min): 0.59;
MS (ESI, Pos.): 528 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 11.24, 8.32, 7.79-7.70, 7.16-7.09, 6.94-6.88, 4.01, 3.46-3.42, 3.14-3.05, 2.85-2.71, 2.67-2.59, 2.50, 2.22-2.15 , 1.03-0.93, 0.66-0.49.

Example 2 (4)
(3S, 4R) -4-amino-1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4 -Pyridinyl] -3-piperidinol
HPLC retention time (min): 0.58;
MS (ESI, Pos.): 488 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.36, 7.64, 7.56-7.49, 7.43-7.37, 3.69-3.65, 3.21-2.94, 2.42, 2.37-2.29, 1.40-1.20.

Example 2 (5)
(3S, 4R) -4-amino-1- [5- (3,5-difluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl]- 3-piperidinol
HPLC retention time (min): 0.50;
MS (ESI, Pos.): 466 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.54, 7.28-7.12, 7.10-6.92, 3.86, 3.40, 3.11-2.99, 2.88-2.75, 2.47-2.38, 2.35, 2.21-2.10, 1.10-0.90.

Example 2 (6)
(3S, 4R) -4-amino-1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4 -Pyridinyl] -3-piperidinol
HPLC retention time (min): 0.52;
MS (ESI, Pos.): 484 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.22, 7.40, 7.30, 7.24-7.16, 7.09-6.94, 3.94, 3.40, 3.10-2.98, 2.88-2.72, 2.50-2.40, 2.35, 2.21-2.10, 1.12-0.91 .

Example 2 (7)
Ethyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro- 1H-benzimidazole-7-carboxylate
HPLC retention time (min): 0.60;
MS (ESI, Pos.): 526 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.23, 7.79-7.70, 7.24-7.18, 7.05-6.95, 4.49, 3.38-3.35, 3.13-3.02, 2.88-2.72, 2.46-2.38, 2.32, 2.19-2.12, 1.43 , 1.07-0.85.

Example 2 (8)
(3S, 4R) -4-amino-1- [5- (3-chloro-5-fluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 500 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.50-7.20, 3.95, 3.45-3.37, 3.12-2.95, 2.89-2.70, 2.50-2.39, 2.35, 2.18-2.07, 1.14-0.92.

Example 2 (9)
(3S, 4R) -4-amino-1- [3- (5-chloro-6-fluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4 -Pyridinyl] -3-piperidinol
HPLC retention time (min): 0.59;
MS (ESI, Pos.): 488 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.23, 7.82-7.71, 7.59-7.47, 7.26-7.12, 7.10-6.94, 3.47-3.38, 3.15-2.98, 2.91-2.72, 2.57-2.41, 2.36, 2.24-2.12 , 1.21-0.87.

Example 2 (10)
(3S, 4R) -4-amino-1- [5- (2,5-difluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl]- 3-piperidinol
HPLC retention time (min): 0.50;
MS (ESI, Pos.): 466 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.20, 7.55, 7.34-7.17, 7.14, 6.96, 3.87, 3.43-3.36, 3.06-2.94, 2.89-2.72, 2.54-2.42, 2.38, 2.34-2.25, 1.11-0.97 , 0.95-0.80.

Example 2 (11)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -2-methyl-4-pyridinyl ] -3-piperidinol
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 472 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.35, 7.62, 7.41-7.23, 3.72-3.55, 3.13-2.88, 2.51-2.42, 2.39, 1.38-1.25.

Example 2 (12)
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro- 1H-benzimidazole-7-carboxylate Properties: amorphous;
HPLC retention time (min): 0.56;
MS (ESI, Pos.): 512 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.24, 7.78-7.70, 7.34-7.16, 4.01, 3.08-2.99, 2.86-2.73, 2.49-2.40, 2.38-2.27, 1.05-0.95, 0.84-0.69.

Example 2 (13)
(3S, 4R) -4-amino-1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl)- 4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.58;
MS (ESI, Pos.): 490 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.22, 7.40-7.30, 7.22-7.13, 7.07-6.97, 3.47-3.40, 3.17-3.03, 2.91-2.73, 2.60-2.50, 2.35, 2.22-2.14, 1.18-0.88 .

Example 3
(3S, 4R) -1- [5- (3-Chloro-5-fluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl] -4- (3-oxetanylamino) -3-piperidinol

Acetic acid (30 μL) was added to a suspension of the compound (48 mg) prepared in Example 2 in methanol (1.0 mL) under a nitrogen atmosphere, and then 3-oxetanone (58 μL) and 2-picoline borane complex (19.3 mg). In addition, the mixture was stirred at room temperature. After 13 hours, 3-oxetanone (39 μL) and 2-picoline borane complex (13.9 mg) were added, and the mixture was stirred at room temperature for 13 hours. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash NH) (ethyl acetate: methanol = 100: 5 to 80:20) to give the compound of the present invention (45 mg) having the following physical data. Obtained.
Properties: amorphous;
HPLC retention time (min): 0.54;
MS (ESI, Pos.): 538 (M + H) ⁺ ;
_{^{1 H-NMR (CD 3 OD}} ): δ 8.20, 7.65-7.50, 7.49-7.43, 7.38-7.22, 7.21-7.06, 7.00-6.91, 4.70-4.57, 4.41, 4.26, 3.97-3.82, 3.87, 3.43-3.38 , 3.13-3.01, 2.93-2.69, 2.35, 2.33-2.23, 2.17-2.06, 1.08-0.94.

Example 3 (1) to 3 (16)
The compound prepared in Reference Example 6 was used instead of the compound prepared in Reference Example 3, and the corresponding boronic acid compound was used instead of 3,5-difluorophenylboronic acid, and instead of methyl 2,3-diaminobenzoate. Using the corresponding benzene-1,2-diamine compound, and using the corresponding aldehyde compound instead of 3-oxetanone, the same operation as in Reference Example 4 → Reference Example 5 → Example 1 → Example 3 was performed. The compound of the present invention having the following physical properties was obtained.

Example 3 (1)
(3S, 4R) -1- [3- (6-Chloro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl] -4- (ethyl Amino) -3-piperidinol
HPLC retention time (min): 0.60;
MS (ESI, Pos.): 498 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.23, 7.68, 7.64, 7.31, 7.23-7.18, 7.07-6.96, 3.65-3.61, 3.19-3.05, 2.97-2.73, 2.63-2.50, 2.50-2.39, 2.35, 2.34 -2.26, 2.14-2.06, 1.20-1.05, 1.01, 0.97-0.90.

Example 3 (2)
(3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methylpyridin-4-yl] -4- ( Ethylamino) piperidin-3-ol
HPLC retention time (min): 0.53;
MS (ESI, Pos.): 494 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.55, 7.24-7.17, 7.15, 7.06-6.99, 6.96, 3.87, 3.65-3.61, 3.16-3.04, 2.96-2.86, 2.85-2.73, 2.62-2.50, 2.49 -2.37, 2.35, 2.33-2.24, 2.14-2.06, 1.17-1.05, 1.00, 1.00-0.93.

Example 3 (3)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-dimethoxyphenyl) -2-methyl-4-pyridinyl] -4- (Ethylamino) -3-piperidinol
HPLC retention time (min): 0.60;
MS (ESI, Pos.): 524 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.20, 7.61-7.51, 6.61-6.51, 3.83, 3.66-3.61, 3.20-3.12, 2.95-2.86, 2.82-2.71, 2.64-2.55, 2.52-2.42, 2.37, 2.36 -2.27, 2.24-2.16, 1.17-1.07, 1.03, 0.95-0.86.

Example 3 (4)
(3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl]- 4- (ethylamino) -3-piperidinol

HPLC retention time (min): 0.56;
MS (ESI, Pos.): 512 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.40, 7.30, 7.20, 7.01, 3.94, 3.66-3.60, 3.16-3.07, 2.91-2.86, 2.84-2.75, 2.61-2.37, 2.35, 2.36-2.26, 2.13 -2.05, 1.18-0.84, 1.01.

Example 3 (5)
(3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl]- 4- (3-oxetanylamino) -3-piperidinol

HPLC retention time (min): 0.59;
MS (ESI, Pos.): 544 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.22, 7.56, 7.45, 7.33-7.23, 4.65, 4.43, 4.31, 3.97-3.88, 3.43-3.38, 3.11-3.02, 2.90-2.68, 2.39-2.31, 2.34, 2.12 -2.05, 1.04-0.97.

Example 3 (6)
Methyl 2- {5- (3,5-dimethoxyphenyl) -4-[(3S, 4R) -4- (ethylamino) -3-hydroxy-1-piperidinyl] -2-methyl-3-pyridinyl} -5 -Fluoro-1H-benzimidazole-7-carboxylate
HPLC retention time (min): 0.61;
MS (ESI, Pos.): 564 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.22, 7.78-7.70, 6.64-6.57, 6.56-6.50, 4.01, 3.83, 3.60-3.53, 2.98-2.90, 2.79-2.68, 2.58-2.49, 2.46-2.37, 2.32 , 2.30-2.24, 2.23-2.16, 1.14-1.03, 0.99, 0.91-0.78.

Example 3 (7)
(3S, 4R) -1- [5- (3,5-dimethoxyphenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl] -4- (ethyl Amino) -3-piperidinol
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 518 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.18, 7.55, 7.15, 6.95, 6.62-6.56, 6.56-6.49, 3.90, 3.83, 3.65-3.60, 3.22-3.11, 2.96-2.86, 2.82-2.69, 2.60-2.51 , 2.47-2.39, 2.37, 2.31-2.22, 2.23-2.15, 1.15-1.05, 1.00, 0.94-0.84.

Example 3 (8)
(3S, 4R) -1- [5- (2,5-difluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl] -4- (ethyl Amino) -3-piperidinol
HPLC retention time (min): 0.53;
MS (ESI, Pos.): 494 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.20, 7.55, 7.33-7.13, 6.96, 3.87, 3.64-3.58, 3.13-3.05, 2.95-2.76, 2.61-2.49, 2.49-2.39, 2.38, 2.34-2.19, 1.14 -1.04, 0.99, 0.90-0.75.

Example 3 (9)
(3S, 4R) -1- [5- (2,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl]- 4- (ethylamino) -3-piperidinol
HPLC retention time (min): 0.56;
MS (ESI, Pos.): 512 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.20, 7.41, 7.35-7.15, 3.94, 3.64-3.57, 3.12-3.03, 2.94-2.75, 2.60-2.49, 2.48-2.40, 2.38, 2.35-2.20, 1.14-1.05 , 1.00, 0.88-0.72.

Example 3 (10)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -2-methyl-4-pyridinyl] -4- (Ethylamino) -3-piperidinol
HPLC retention time (min): 0.58;
MS (ESI, Pos.): 500 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.62-7.49, 7.33-7.15, 3.64-3.58, 3.11-3.01, 2.93-2.75, 2.61-2.51, 2.48-2.40, 2.40, 2.36-2.20, 1.13-1.05 , 1.01, 0.88-0.70.

Example 3 (11)
(3S, 4R) -1- [5- (3-Chloro-5-fluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl ] -4- (3-oxetanylamino) -3-piperidinol
HPLC retention time (min): 0.57;
MS (ESI, Pos.): 556 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.50-7.22, 4.70-4.58, 4.42, 4.28, 3.97-3.83, 3.95, 3.42-3.37, 3.12-3.00, 2.91-2.69, 2.34, 2.33-2.23, 2.13 -2.05, 1.06-0.95.

Example 3 (12)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl] -4- [(3,3,3-trifluoropropyl) amino] -3-piperidinol

HPLC retention time (min): 0.69;
MS (ESI, Pos.): 568 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.23, 7.65-7.50, 7.22-7.14, 7.06-6.95, 3.62-3.56, 3.13-3.02, 2.92-2.55, 2.42-2.11, 2.35, 1.18-0.85.

Example 3 (13)
(3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl]- 4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol
HPLC retention time (min): 0.71;
MS (ESI, Pos.): 584 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.22, 7.63-7.43, 7.35-7.22, 3.63-3.55, 3.12-3.00, 2.93-2.57, 2.42-2.09, 2.34, 1.18-0.90.

Example 3 (14)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -2-methyl-4-pyridinyl] -4- [(3,3,3-trifluoropropyl) amino] -3-piperidinol
HPLC retention time (min): 0.65;
MS (ESI, Pos.): 568 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.21, 7.62-7.50, 7.33-7.17, 3.59-3.50, 3.09-2.96, 2.90-2.55, 2.44-2.15, 2.37, 1.13-1.00, 0.92-0.77.

Example 3 (15)
(3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4- (Ethylamino) -3-piperidinol

Properties: amorphous;
HPLC retention time (min): 0.62;
MS (ESI, Pos.): 518 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.20, 7.38-7.29, 7.24-7.12, 7.05-6.96, 3.70-3.60, 3.23-3.10, 2.99-2.88, 2.84-2.71, 2.70-2.42, 2.34, 2.16-2.06 , 1.23-1.10, 1.06, 1.05-0.87.

Example 3 (16)
(3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol
HPLC retention time (min): 0.69;
MS (ESI, Pos.): 586 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.23, 7.43-7.37, 7.25-7.12, 7.08-6.97, 3.63-3.54, 3.14-3.02, 2.94-2.57, 2.42-2.12, 2.36, 1.21-0.90.

Reference Example 7
tert-butyl (3aS, 7aR) -5- (3-bromo-5-formylpyridin-4-yl) -2,2-dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 ( 2H) -Carboxylate 5-bromo-4-chloropyridine-3-carbaldehyde (CAS No. 1060802-24-5, ASTATECH Catalog No. 66142) (3.58 g) and tert-butyl (3aS, 7aR) -2,2. Triethylamine (4.53 mL) was added to a DMA solution (40 mL) of -dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 (2H) -carboxylate (4.99 g), and the mixture was heated at 100 ° C for 5 hours. Stirred. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The residue obtained by concentrating the organic layer under reduced pressure was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10 to 0: 100) to obtain the following. The title compound (6.08 g) having physical properties was obtained.
HPLC retention time (min): 0.84;
MS (ESI, Pos.): 440 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 10.30, 8.74, 8.72, 4.19-3.93, 3.83-3.72, 3.58-3.27, 2.43-2.17, 2.11-1.94, 1.74-1.43.

Reference Example 8
tert-butyl (3aS, 7aR) -5- [3- (3,5-difluorophenyl) -5-formylpyridin-4-yl] -2,2-dimethylhexahydro [1,3] oxazolo [5,4 -C] pyridine-1 (2H) -carboxylate In a solution of the compound (100 mg) prepared in Reference Example 7 in 1,4-dioxane (10 mL), tripotassium phosphate (144 mg), water (3 mL), 3,5 -Difluorophenylboronic acid (54 mg) and bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium (II) (4.8 mg) were added, and the mixture was stirred at 100 ° C for 1 hour. The reaction solution was returned to room temperature, diluted with ethyl acetate, and washed with water and saturated saline. The organic layer was concentrated under reduced pressure to give the title compound (107 mg) having the following physical data.
HPLC retention time (min): 0.92;
MS (ESI, Pos.): 474 (M + H) ^<+> .

Reference Example 9
tert-butyl (3aS, 7aR) -5- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) pyridin-4-yl] -2, 2-dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 (2H) -carboxylate The compound prepared in Reference Example 8 (56 mg), and 1,2-diamino-4,5-difluoro Sodium bisulfite (25 mg) was added to a solution of benzene (19 mg) in DMA (3 mL), and the mixture was stirred at 120 ° C. for 5 hours. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to give the title compound (70 mg) having the following physical data.
HPLC retention time (min): 0.95;
MS (ESI, Pos.): 598 (M + H) ^<+> .

Example 4
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3- Piperidinol

To a solution of the compound (70 mg) produced in Reference Example 9 in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL) at room temperature, and the mixture was stirred for 30 minutes and concentrated. The obtained residue was purified by medium pressure preparative liquid chromatography (Hi-flash NH) (ethyl acetate: methanol = 100: 0 to 80:20) to give the compound of the present invention (37 mg) having the following physical data. I got
HPLC retention time (min): 0.53;
MS (ESI, Pos.): 458 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.91, 8.35, 7.58, 7.28-6.99, 3.73-3.69, 3.18-2.94, 2.92-2.74, 2.65-2.58, 2.39-2.33, 1.60-1.28.

Examples 4 (1) to 4 (16)
Reference example using a corresponding boronic acid compound instead of 3,5-difluorophenylboronic acid and a corresponding benzene-1,2-diamine compound instead of 1,2-diamino-4,5-difluorobenzene. 8 → Reference Example 9 → The same operation as in Example 4 was performed to obtain the compound of the present invention having the following physical property values.

Example 4 (1)
(3S, 4R) -4-amino-1- [3- (3,5-difluorophenyl) -5- (5,7-dimethyl-1H-benzimidazol-2-yl) -4-pyridinyl] -3- Piperidinol
HPLC retention time (min): 0.52;
MS (ESI, Pos.): 450 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.85, 8.31, 7.28, 7.14-7.05, 6.95, 3.67, 3.17-3.06, 3.05-2.93, 2.88-2.80, 2.62, 2.60-2.52, 2.44, 2.38-2.31, 1.60 -1.42, 1.36-1.27.

Example 4 (2)
(3S, 4R) -4-amino-1- [3- (3,5-difluorophenyl) -5- (7-methyl-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.47;
MS (ESI, Pos.): 436 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.86, 8.33, 7.52-7.46, 7.23-7.16, 7.14-7.04, 3.70-3.64, 3.18-3.08, 3.06-2.93, 2.89-2.80, 2.65, 2.62-2.54, 2.38-2.31, 1.60-1.43, 1.36-1.26.

Example 4 (3)
(3S, 4R) -4-amino-1- [3- (5,7-dimethyl-1H-benzimidazol-2-yl) -5-phenyl-4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.50;
MS (ESI, Pos.): 414 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.89, 8.45, 7.62-7.54, 7.51, 7.27, 3.87, 3.53-3.42, 3.27-2.98, 2.68, 2.66-2.59, 2.53, 1.79-1.62, 1.42-1.32.

Example 4 (4)
(3S, 4R) -4-amino-1- [3- (1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.47;
MS (ESI, Pos.): 422 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.93, 8.36, 7.73-7.68, 7.36-7.32, 7.17-7.08, 3.71, 3.18-3.11, 3.08-2.95, 2.91-2.83, 2.64-2.54, 2.43-2.35, 1.62 -1.47, 1.38-1.30.

Example 4 (5)
2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -3-pyridinyl} -1H-benzimidazole-5-carbonitrile
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 447 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.95, 8.39, 8.13, 7.82, 7.62, 7.15-7.03, 3.77-3.72, 3.20-2.97, 2.93-2.85, 2.78-2.69, 2.43-2.35, 1.63-1.28.

Example 4 (6)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -3- Piperidinol
HPLC retention time (min): 0.73;
MS (ESI, Pos.): 458 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.95, 8.33, 7.62-7.53, 7.40-7.17, 3.73-3.69, 3.12-2.87, 2.63-2.54, 2.44-2.31, 1.55-1.28.

Example 4 (7)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3-fluorophenyl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.63;
MS (ESI, Pos.): 440 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.91, 8.34, 7.62-7.50, 7.27-7.17, 3.72-3.68, 3.18-2.93, 2.87-2.77, 2.70-2.60, 2.36-2.26, 1.62-1.43, 1.41-1.30 .

Example 4 (8)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-dimethoxyphenyl) -4-pyridinyl] -3- Piperidinol
HPLC retention time (min): 0.56;
MS (ESI, Pos.): 482 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.89, 8.34, 7.59, 6.62-6.50, 3.83, 3.82-3.78, 3.20-2.86, 2.50-2.41, 1.78-1.60, 1.52-1.40.

Example 4 (9)
(3S, 4R) -4-amino-1- [3- (5-chloro-2-fluorophenyl) -5- (5,6-difluoro-1H-benzimidazol-2-yl) -4-pyridinyl]- 3-piperidinol
HPLC retention time (min): 0.58;
MS (ESI, Pos.): 474 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.89, 8.41, 7.70-7.50, 7.40-7.26, 3.90-3.86, 3.28-2.95, 2.60-2.48, 1.80-1.62, 1.57-1.43.

Example 4 (10)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-dimethyl-3-furyl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 440 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.90, 8.22, 7.56, 6.02, 3.90-3.82, 3.14-2.75, 2.31, 2.22, 1.75-1.57, 1.52-1.39.

Example 4 (11)
(3S, 4R) -4-amino-1- [3- (3,5-difluorophenyl) -5- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl]- 3-piperidinol
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 470 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.88, 8.32, 7.41, 7.31, 7.15-7.04, 3.95, 3.73-3.68, 3.17-3.06, 3.06-2.97, 2.89-2.80, 2.65-2.56, 2.39-2.31, 1.62 -1.45, 1.40-1.25.

Example 4 (12)
(3S, 4R) -4-Amino-1- [3- (3,5-difluorophenyl) -5- (6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.56;
MS (ESI, Pos.): 452 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.85, 8.32, 7.57, 7.19-7.03, 6.95, 3.87, 3.80-3.75, 3.20-3.10, 3.07-2.95, 2.96-2.80, 2.43-2.37, 1.75-1.57, 1.46 -1.34.

Example 4 (13)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,3,5-trifluorophenyl) -4-pyridinyl] -3-piperidinol
HPLC retention time (min): 0.58;
MS (ESI, Pos.): 476 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.94, 8.36, 7.58, 7.43-7.30, 7.20-7.03, 3.78-3.72, 3.12-2.89, 2.74-2.62, 2.50-2.37, 1.57-1.28.

Example 4 (14)
(3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluoro-2-methoxyphenyl) -4-pyridinyl ] -3-piperidinol
HPLC retention time (min): 0.57;
MS (ESI, Pos.): 488 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.95, 8.89, 8.34, 7.59, 7.27-7.15, 7.13-7.05, 6.96-6.85, 3.90, 3.87-3.76, 3.61, 3.28-2.87, 2.54-2.30, 1.75-1.37 .

Example 4 (15)
(3S, 4R) -4-amino-1- [3- (2,5-difluorophenyl) -5- (6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol < Properties: amorphous;
HPLC retention time (min): 0.57;
MS (ESI, Pos.): 452 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.92, 8.29, 7.55, 7.39-7.13, 7.15, 6.94, 3.87, 3.72-3.67, 3.10-2.86, 2.61-2.51, 2.44-2.28, 1.60-1.42, 1.26-1.23 .

Example 4 (16)
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -3-pyridinyl} -5-fluoro-1H-benzimidazole -7-carboxylate

Properties: amorphous;
HPLC retention time (min): 0.59;
MS (ESI, Pos.): 498 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 8.62, 8.34, 7.89, 7.64, 7.55-7.30, 3.95. 2.98-2.07, 1.15-1.05.

Example 5
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- (3-oxetanyl Amino) -3-piperidinol

To a solution of the compound prepared in Example 4 (72 mg) and 3-oxetanone (90 mg) in methanol (5 mL) was added 2-picoline borane complex (34 mg) and acetic acid (0.1 mL), and the mixture was stirred at room temperature for 24 hours. The residue obtained by concentrating the reaction solution under reduced pressure was purified by medium pressure preparative liquid chromatography (Hi-flash NH) (ethyl acetate: methanol = 100: 0 to 80:20) to obtain the following physical properties. The compound of the present invention having the formula (60 mg) was obtained.
Properties: amorphous;
HPLC retention time (min): 0.59;
MS (ESI, Pos.): 514 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 12.55, 9.34, 8.36, 7.67-7.55, 7.29-7.16, 6.99-6.79, 4.89-4.80, 4.50-4.36, 4.08-3.97, 3.75-3.69, 3.18-2.85, 2.55- 2.45, 2.37-2.29, 1.65-1.50, 1.40-1.31.

Example 5 (1) to 5 (9)
3-oxetanone, using a corresponding boronic acid compound in place of 3,5-difluorophenylboronic acid and using a corresponding benzene-1,2-diamine compound in place of 1,2-diamino-4,5-difluorobenzene In the same manner as in Reference Example 8 → Reference Example 9 → Example 4 → Example 5 except that the corresponding aldehyde compound was used, a compound of the present invention having the following physical properties was obtained.

Example 5 (1)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4-[(3, 3,3-trifluoropropyl) amino] -3-piperidinol
HPLC retention time (min): 0.69;
MS (ESI, Pos.): 554 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.91, 8.35, 7.59, 7.17-7.03, 3.92-3.88, 3.20-2.74, 2.55-2.30, 1.58-1.39.

Example 5 (2)
(3S, 4R) -1- [3- (3-chloro-5-fluorophenyl) -5- (5,6-difluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4- (3 -Oxetanylamino) -3-piperidinol
HPLC retention time (min): 0.60;
MS (ESI, Pos.): 530 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 12.51, 9.36, 8.37, 7.67-7.58, 7.35-6.91, 4.89-4.80, 4.50-4.37, 4.07-3.98, 3.74-3.63, 3.19-2.85, 2.55-2.45, 2.36- 2.28, 1.54-1.33.

Example 5 (3)
(3S, 4R) -1- [3- (3-chloro-5-fluorophenyl) -5- (5,6-difluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4-[( 3,3,3-trifluoropropyl) amino] -3-piperidinol

HPLC retention time (min): 0.70;
MS (ESI, Pos.): 570 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 12.58, 9.36, 8.37, 7.67-7.58, 7.26-7.11, 7.01-6.91, 3.86-3.81, 33.19-3.04, 2.99-2.86, 2.61-2.52, 2.44-2.24, 1.51- 1.37.

Example 5 (4)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- (ethylamino) -3-piperidinol

HPLC retention time (min): 0.60;
MS (ESI, Pos.): 486 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.96, 8.34, 7.66-7.58, 7.39-7.18, 3.97-3.93, 3.11-2.89, 2.76-2.30, 1.61-1.42, 1.16.

Example 5 (5)
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -4-[( 3,3,3-trifluoropropyl) amino] -3-piperidinol
HPLC retention time (min): 0.72;
MS (ESI, Pos.): 566 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.93, 8.34, 7.64-7.54, 6.87-6.73, 3.92-3.85, 3.87, 3.21-2.96, 2.94-2.75, 2.55-2.28, 1.58-1.38.

Example 5 (6)
(3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro-5-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4-[( 3,3,3-trifluoropropyl) amino] -3-piperidinol

HPLC retention time (min): 0.67;
MS (ESI, Pos.): 566 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.87, 8.30, 7.41, 7.30, 7.14-7.05, 3.94, 3.99-3.82, 3.17-3.07, 3.05-2.97, 2.92-2.71, 2.57-2.45, 2.44-2.28, 1.56 -1.47, 1.47-1.36.

Example 5 (7)
(3S, 4R) -1- [3- (2,5-difluorophenyl) -5- (6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4- (3-oxetanylamino) -3-piperidinol
HPLC retention time (min): 0.55;
MS (ESI, Pos.): 508 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.93, 8.29, 7.60, 7.41-7.14, 6.96, 4.82-4.68, 4.54, 4.43, 4.09-3.98, 3.89, 3.72-3.67, 3.12-2.87, 2.47-2.30, 1.62 -1.43, 1.33-1.22.

Example 5 (8)
(3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro-5-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4- (3 -Oxetanylamino) -3-piperidinol
HPLC retention time (min): 0.57;
MS (ESI, Pos.): 526 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.87, 8.32-8.28, 7.45, 7.35, 7.21-7.04, 4.73, 4.56, 4.45, 4.13-4.00, 3.95, 3.81-3.64, 3.16-3.05, 3.03-2.88, 2.87 -2.73, 2.50-2.39, 2.36-2.26, 1.62-1.44, 1.36-1.18.

Example 5 (9)
(3S, 4R) -1- [3- (2,5-difluorophenyl) -5- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4- (3 -Oxetanylamino) -3-piperidinol
HPLC retention time (min): 0.56;
MS (ESI, Pos.): 526 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.93, 8.29, 7.48, 7.41-7.15, 7.35, 4.81-4.66, 4.55, 4.44, 4.13-3.97, 3.96, 3.72-3.66, 3.12-2.84, 2.46-2.27, 1.61 -1.42, 1.34-1.22.

Reference example 10
tert-butyl (3aS, 7aR) -5- (2-bromo-3-formylpyridin-4-yl) -2,2-dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 ( 2H) -carboxylate 2-bromo-4-chloropyridine-3-carbaldehyde (4.5 g) (CAS number 1289197-78-9, SIGMA ALDRICH catalog number 762180) and tert-butyl (3aS, 7aR) -2,2 Triethylamine (8.5 mL) was added to a solution of -dimethylhexahydro [1,3] oxazolo [5,4-c] pyridine-1 (2H) -carboxylate (5.2 g) in DMA (45 mL), and the mixture was heated at 80 ° C for 2 hours. Stirred. The reaction solution was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The residue obtained by concentrating the organic layer under reduced pressure was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (n-hexane: ethyl acetate = 90: 10 to 0: 100) to obtain the following. The title compound (7.5 g) having physical properties was obtained.
HPLC retention time (min): 0.99;
MS (ESI, Pos.): 440 (M + H) ^<+> .

Reference Example 11
tert-butyl (3aS, 7aR) -5- [3-formyl-2- (morpholin-4-yl) pyridin-4-yl] -2,2-dimethylhexahydro [1,3] oxazolo [5,4- c] Pyridine-1 (2H) -carboxylate The compound (300 mg) produced in Reference Example 10 was dissolved in DMA (3.0 mL), and triethylamine (0.190 mL) and morpholine (70.7 μL) were added. After the reaction solution was stirred at 100 ° C. for 1 hour, it was heated to 120 ° C. and stirred for 17 hours. The reaction was cooled to room temperature and water was added. After the organic layer was extracted three times with ethyl acetate, the organic layers were combined and washed with saturated saline. Sodium sulfate was added to the organic layer, followed by filtration. The residue obtained by concentrating the filtrate was purified by medium pressure preparative liquid chromatography (Hi-flash SI) (hexane-ethyl acetate = 90: 10-0: 100) to give the title compound.

Reference Example 12
tert-butyl (3aS, 7aR) -5- [5-bromo-3-formyl-2- (morpholin-4-yl) pyridin-4-yl] -2,2-dimethylhexahydro [1,3] oxazolo [ 5,4-c] pyridine-1 (2H) -carboxylate The compound produced in Reference Example 11 was dissolved in acetonitrile (1.5 mL), N-bromosuccinimide (94.6 mg) was added, and the mixture was stirred at room temperature for 10 minutes. A 10% aqueous solution of sodium thiosulfate and a saturated aqueous solution of sodium hydrogen sulfate were sequentially added to the reaction solution to terminate the reaction. The reaction solution was extracted twice with ethyl acetate, and the organic layers were combined. The organic layer was washed with saturated saline and dried over sodium sulfate. The extract was filtered and concentrated, and the obtained residue was purified by silica gel column chromatography (Fuji Silysia SI50) (n-hexane: ethyl acetate = 90: 10-0: 100) to give the title having the following physical properties. The compound (192 mg) was obtained.
¹ H-NMR (CDCl ₃ ): δ 9.66, 8.15, 4.16-4.09, 3.98, 3.96-3.72, 3.64, 3.62-3.47, 3.30, 2.38-2.05, 1.74-1.61, 1.58-1.41.

Example 6
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2- (4-morpholinyl) -3-pyridinyl}- 5-fluoro-1H-benzimidazole-7-carboxylate

Reference Example 4 was repeated using the compound prepared in Reference Example 12 in place of the compound prepared in Reference Example 3 and using methyl 2,3-diamino-5-fluorobenzoate instead of methyl 2,3-diaminobenzoate. → Reference Example 5 → The same operation as in Example 1 was performed to obtain the compound of the present invention having the following physical properties.
Properties: amorphous;
HPLC retention time (min): 0.65;
MS (ESI, Pos.): 583 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 8.10, 7.74, 7.71, 7.09, 6.99, 4.03, 3.47, 3.40-3.34, 3.15-2.95, 2.92-2.74, 2.46-2.37, 2.25-2.18, 1.10-0.82.

Biological Example 1 :
Evaluation of SSTR2 agonist activity using human SSTR2-expressing cells [Operation]
(1) Isolation of human SSTR2 gene Human brain cDNA was purchased from Ambion (catalog number: 7962; lot number: 040200121). The PCR primers hSSTR2_F1_XhoI: 5'-CACCCTCGAGGACATGGCGGATGAGCCACTCAAT-3 '(SEQ ID NO: 1), and hSSTR2_R1_EcoRI: 5'-CCTTGAATTCGATACTGGTTTGGAGGTCTCCAT-3', the sequence of which has been designed based on the sequence of SEQ ID NO.

  PCR reaction using KOD-plus- (Toyobo) using human brain cDNA as a template (95 ° C. for 2 minutes → [98 ° C. for 10 seconds, 60 ° C. for 30 seconds, 68 ° C. for 90 seconds] × 30 times) Was performed. After the amplified PCR product was subjected to 1% agarose gel electrophoresis, the product was purified using QIAquick Gel Extraction Kit (QIAGEN), and cut with restriction enzymes XhoI and EcoRI. The digested fragment was inserted into an expression vector (pIRESneo-Myc) using DNA Ligation Kit Ver. 2 (Takara) and transformed into Escherichia coli DH5a. This plasmid pIRESneo-Myc / hSSTR2 was prepared and its DNA sequence was confirmed.

(2) Culture of CHO-K1 cells CHO-K1 (-) is a Ham's F-12 medium (containing fetal bovine serum (10%), penicillin (100 U / mL), streptomycin (0.1 mg / mL)). Was used for culturing. The transduced cells were cultured by adding Geneticin (1 mg / mL) to the medium.

(3) Transduction into CHO-K1 cells The plasmid pIRESneo-Myc / hSSTR2 was transduced into CHO-K1 (-) cells using Lipofectamine 2000 (Invitrogen). Forty-eight hours later, the medium was replaced with a medium containing 1 mg / mL geneticin, selection was performed, and stable overexpressing cells (SSTR2-CHO-K1) were established.

(4) Evaluation of SSTR2 agonistic activity The human SSTR2 agonistic activity of the test compound was evaluated by the following procedure using the inhibitory effect on forskolin-stimulated intracellular cyclic AMP (cAMP) production as an index. SSTR2-CHO- suspended in Ham's F-12 medium (containing fetal bovine serum (10%), penicillin (100 U / mL), streptomycin (0.1 mg / mL)) containing 0.25 mg / mL geneticin K1 cells were seeded at a density of 4.0 × 10 ⁴ cells / 0.1 mL per well in a 96-well plate. The next day, the medium was removed, and 0.1 mL of a wash buffer [Hank's balanced salt containing 0.1% bovine serum albumin (BSA), 20 mmol / L 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES)] was used. Solution (HBSS)]. Assay buffer [HBSS containing 500 nmol / L 3-isobutyl-1-methylxanthine (IBMX), 0.1% BSA, 20 mmol / L HEPES] was added at 0.06 mL per well, and 5% carbon dioxide and 37 ° C. Incubated under conditions for 15 minutes. Subsequently, 0.06 mL of an assay buffer containing a test compound at twice the final concentration and 0.02 mmol / L forskolin was added per well, and 30% under the conditions of 5% carbon dioxide and 37 ° C. Incubated for minutes. Thereafter, 0.12 mL of Assay / Lysis buffer attached to the cAMP-Screen (registered trademark) kit (manufactured by Applied Biosystems) was added per well, and the mixture was incubated for 30 minutes at 5% carbon dioxide and 37 ° C. . The cAMP concentration in the sample was measured by ELISA according to the instructions attached to the kit. The 50% effective concentration (EC ₅₀ value) of the agonistic effect on human SSTR2 is defined as the response rate (%) of the inhibitory effect on cAMP production induced by forskolin, and the response rate of 1000 nmol / L octreotide as 100% for each sample. The calculated values were calculated by nonlinear regression analysis using the common logarithmic concentration of the test compound as an independent variable and the response rate of the corresponding concentration as a dependent variable.

[result]
The compounds of the present invention, showed the following _{The EC 50} values 1 nmol / L, exhibited potent SSTR2 agonist activity. For example, the compound produced in Example 1 (2) is 0.032 nmol / L, the compound produced in Example 2 (3) is 0.019 nmol / L, and the compound produced in Example 2 (12) is 0.016 nmol / L. / L, 0.017 nmol / L for the compound produced in Example 2 (13), 0.027 nmol / L for the compound produced in Example 3, and 0.056 nmol / L for the compound produced in Example 3 (4). The compound prepared in Example 3 (5) was 0.023 nmol / L, the compound prepared in Example 3 (12) was 1.0 nmol / L, and the compound prepared in Example 3 (15) was 0.47 nmol / L. L, the compound prepared in Example 4 was 0.015 nmol / L, the compound prepared in Example 4 (4) was 0.0093 nmol / L, and the compound prepared in Example 4 (15) was 0.012 nmo. / L, 0.0050 nmol / L for the compound produced in Example 4 (16), 0.14 nmol / L for the compound produced in Example 5, and 0.28 nmol / L for the compound produced in Example 5 (3). The compound prepared in Example 5 (4) was 0.031 nmol / L, the compound prepared in Example 5 (5) was 0.42 nmol / L, and the compound prepared in Example 5 (6) was 0.067 nmol / L. L, the compound prepared in example 6 exhibited _{EC 50} values of 0.081nmol / L.

In addition, according to this evaluation system, for example, the compound of Example 21 (27) described in WO 2014/007228 pamphlet is 0.026 nmol / L, and the compound of Example 21 (28) is 0.019 nmol / L. L, the compound of example 21 (29) showed an _{EC 50} value of 0.038nmol / L.

Biological Example 2 :
Evaluation of hERG K ⁺ channel inhibitory effect using human ERG-expressing cells
[operation]
(1) Culture of CHO-K1 Cells Introduced with Human ERG (Ether-a-go-go Related Gene) Gene CHO-K1 Cells Introduced with Human ERG (Ether-a-go-go Related Gene) Gene The cells were subcultured in a F-12 medium [F-12 Nutrient Mixture (HAM)] containing 100% inactivated fetal calf serum, 100 IU / mL Penicillin-100 µg / mL Streptomycin and 200 µg / mL Geneticin.

(2) Evaluation of hERG K ⁺ channel inhibitory action Patch clamping was carried out fully automatically using CHO-K1 cells into which human ERG gene formed by perforated patch formation with amphotericin B was introduced. For the experiments, a 384-well PatchPlate ™ was used, and the cell suspension and compound were added. The IKr current was measured at a holding voltage of −80 mV, a depolarization potential of +40 mV (for 2 seconds), and a repolarization potential of −50 mV (for 2 seconds) as command voltages. The stimulus frequency was twice (single pulse stimulation) before and after drug treatment (evaluated concentrations of each compound were 1, 3, and 10 μmol / L for 5 minutes), and the maximum Ikr current was measured. The inhibition rate (%) of the human ERG gene-introduced CHO-K1 cells was determined by correcting the rate of change in the maximum tail current before and after the addition of the test substance with the rate of change in the vehicle-treated group (inhibition rate (% ) = (1-current change rate before and after test substance addition / current change rate before and after medium addition) × 100). The 50% inhibitory concentration (IC ₅₀ value) was calculated from a straight line connecting two points sandwiching the inhibition rate of 50%.

[result]
The compound of the present invention showed an IC ₅₀ value of 3 μmol / L or more, and the hERG inhibitory activity was sufficiently weaker than the SSTR2 agonist activity. For example, the compound produced in Example 1 (2) is 10 μmol / L, the compound produced in Example 2 (3) is 5.2 μmol / L, and the compound produced in Example 2 (12) is 9.4 μmol / L. The compound manufactured in Example 2 (13) was 10 μmol / L, the compound manufactured in Example 3 was 10 μmol / L, the compound manufactured in Example 3 (4) was 10 μmol / L, and the compound manufactured in Example 3 (5) was The compound prepared was 9.6 μmol / L, the compound prepared in Example 3 (12) was 5.1 μmol / L, the compound prepared in Example 3 (15) was 5.8 μmol / L, and prepared in Example 4. The compound was 6.9 μmol / L, the compound prepared in Example 4 (4) was 6.7 μmol / L, the compound prepared in Example 4 (15) was 9.1 μmol / L, prepared in Example 4 (16). 3.9 μmol / L of the compound The compound produced in Example 5 was 7.6 μmol / L, the compound produced in Example 5 (3) was 10 μmol / L, the compound produced in Example 5 (4) was 8.4 μmol / L, Example 5 ( The compound produced in 5) exhibited an IC ₅₀ value of 10 μmol / L, the compound produced in Example 5 (6) exhibited an IC ₅₀ value of 10 μmol / L, and the compound produced in Example 6 exhibited an IC ₅₀ value of 4.4 μmol / L.

According to this evaluation system, for example, the compound of Example 21 (27) described in WO 2014/007228 pamphlet was 1.0 μmol / L, and the compound of Example 21 (28) was 1.6 μmol / L. L, the compound of Example 21 (29) showed an IC ₅₀ value of 0.10 μmol / L.

Biological Example 3 :
Evaluation of phospholipidosis-inducing ability using cultured cell lines [Operation]
CHL / IU cells derived from Chinese hamster lung were suspended in a MEM-E culture solution containing non-essential amino acids, sodium pyruvate, and 10% fetal bovine serum, and then seeded in a 96-well plate. For cells cultured overnight in an incubator (5% carbon dioxide, 95% air, 37 ° C.), the culture solution contains the test substance at a concentration of 6.25, 12.5, 25, 50, and 100 μmol / L. And NBD-PE (fluorescent label N- (7-nitrobenz-2-oxa-1,3-diazol-4-yl) -1,2-dihexadecanoyl-) obtained from Molecular Probes. After replacement with a solution containing sn-glycero-3-phosphoethanolamine (triethylammonium salt), the cells were further cultured for 24 hours. The ability to induce phospholipidosis was evaluated by measuring the concentration of NBD-PE incorporated into cells. Specifically, after washing the cells twice with PBS, the fluorescence (excitation wavelength: 485 nm, fluorescence wavelength: 535 nm) of NBD-PE taken into the cells is measured by SpectraMax plate reader of Molecular Device. It evaluated by measuring in. In addition, after measuring the fluorescence of NBD-PE, the cell viability was evaluated using Premix WST-1 Cell Proliferation Assay System obtained from Takara Bio Inc. At a dose at which the cell viability becomes 50% or more, the maximum response of amiodarone as a positive control (the concentration of NBD-PE incorporated into cells after administration of amiodarone was 100%) was 25% or more (test compound). When NBD-PE concentration incorporated after administration) was observed, it was determined that the ability to induce phospholipidosis was positive.

[result]
The compound of the present invention was determined to have a positive phospholipidosis-inducing ability at 6.25 μmol / L or more, indicating that the phospholipidosis-inducing ability was sufficiently low in vitro. For example, the compound prepared in Example 1 (2), the compound prepared in Example 3, the compound prepared in Example 3 (5), the compound prepared in Example 3 (12), the compound prepared in Example 5 The compound prepared in Example 5 (3), the compound prepared in Example 5 (4), the compound prepared in Example 5 (5), and the compound prepared in Example 5 (6) have the ability to induce phospholipidosis. Was determined to be negative. Further, for example, the compound produced in Example 2 (3) is 12.5 μmol / L or more, the compound produced in Example 2 (12) is 50 μmol / L or more, and the compound produced in Example 2 (13) is 25 μmol / L. / L or more, the compound produced in Example 3 (4) is 50 μmol / L or more, the compound produced in Example 3 (15) is 25 μmol / L or more, and the compound produced in Example 4 is 12.5 μmol / L or more. The compound prepared in Example 4 (4) was 25 μmol / L, the compound prepared in Example 4 (15) was 25 μmol / L, the compound prepared in Example 4 (16) was 25 μmol / L, and the compound prepared in Example 6 was 25 μmol / L. The prepared compound was determined to be positive for phospholipidosis-inducing ability at 50 μmol / L.

  Furthermore, according to this evaluation system, for example, the compound of Example 21 (27) described in WO 2014/007228 pamphlet is 3.125 μmol / L or more, and the compound of Example 21 (28) is 3.125 μmol / L. / L, the compound of Example 21 (29) was judged to be positive for phospholipidosis-inducing ability at 1.56 μmol / L or more.

Biological Example 4 :
Evaluation of growth hormone (GH) secretion inhibitory action using rats [Operation]
Oral administration of vehicle (distilled water (Otsuka distilled water, Otsuka Pharmaceutical Factory)) or a test compound dissolved in the vehicle to rats (7-week-old male Crl: CD (SD) IGS rats (Charles River Japan Co., Ltd.)) After 7 hours and 57 minutes, 50 mg / kg sodium pentobarbital (Somnopentyl, Kyoritsu Pharmaceutical Co., Ltd.) was administered through the tail vein to anesthetize. Three minutes after the administration of sodium pentobarbital, 0.01 mg / kg of growth hormone releasing hormone (GHRH, Bachem) was administered from the tail vein to induce GH secretion. In order to measure the blood GH concentration, 0.2 mL of blood was collected from the jugular vein 5 minutes after the administration of GHRH. The collected blood was centrifuged at 13,000 xg for 5 minutes at 4 ° C to obtain plasma. The blood GH concentration was measured using a Rat / Mouse Growth Hormone ELISA (Millipore) according to the protocol of the kit. The inhibition rate of GH secretion (%) is calculated by using the obtained value of the blood GH concentration, and the mathematical formula ｛[the inhibition rate of GH secretion (%)] = ([blood GH concentration of vehicle-administered group] − [test The blood GH concentration of the compound-administered group]) / [blood GH concentration of the vehicle-administered group] × 100 °. In the formula, the vehicle administration group refers to a group of animals to which the vehicle is administered, and the test compound administration group refers to a group of animals to which the test compound dissolved in the vehicle is administered.

[result]
The compound of the present invention showed a strong GH secretion inhibitory action. For example, the compound produced in Example 2 (3) was 76% at a dose of 1 mg / kg, the compound produced in Example 3 (4) was 71% at a dose of 1 mg / kg, and Example 3 (5) The compound prepared in Example 3 was 83% at a dose of 1 mg / kg, the compound prepared in Example 3 (12) was 85% at a dose of 1 mg / kg, and the compound prepared in Example 3 (15) was 1 mg / kg. 66%, the compound prepared in Example 4 (16) was 67% at a dose of 1 mg / kg, the compound prepared in Example 5 was 92% at a dose of 1 mg / kg, Example 5 ( The compound produced in 4) showed a 90% GH secretion inhibitory rate at a dose of 1 mg / kg, and the compound produced in Example 5 (6) showed a GH secretion inhibition rate of 83% at a dose of 1 mg / kg.

Biological Example 5 :
Evaluation of renal and liver weight increase inhibitory effects in polycystic kidney rats [Operation]
In a PCK rat (12-week-old male PCK / CrljCrl-Pkhd1pck / CrlCrlj rat (Charles River Japan Co., Ltd.)), a medium (distilled water (Otsuka distilled water; Otsuka Pharmaceutical Factory)) or a test compound dissolved in the medium was used. Oral administration once a day. On the 84th day from the start of the administration, isoflurane inhalation anesthetic solution (Mylan Pharmaceutical Co., Ltd.) was inhaled and anesthetized. After the abdominal aorta was cut off and exsanguinated to death, both kidneys and liver were excised and weighed using an electronic balance. The renal weight increase inhibition rate (%) and the liver weight increase inhibition rate (%) were calculated using the obtained renal weight and liver weight values, using the formula {[renal weight increase inhibition rate (%)] = ([vehicle administration Group kidney weight]-[kidney weight of test compound administration group]) / [kidney weight of vehicle administration group] x 100} and {[liver weight increase inhibition rate (%)] = ([liver weight of vehicle administration group] -[Liver weight of test compound administration group]) / [liver weight of vehicle administration group] x 100%. In the formula, the vehicle administration group refers to a group of animals to which the vehicle is administered, and the test compound administration group refers to a group of animals to which the test compound dissolved in the vehicle is administered.

[result]
The compound of the present invention showed a potent renal weight increase inhibitory action and liver weight increase inhibitory action in polycystic kidney rats. The compound produced in Example 5 (4) showed a 23% inhibition of kidney weight increase and a 35% inhibition of liver weight increase at a dose of 1 mg / kg.

Formulation Example 1 :
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5- Tablets containing 5 mg of fluoro-1H-benzimidazole-7-carboxylate The following components are mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 5 mg of the active ingredient. .
-Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5 -Fluoro-1H-benzimidazole-7-carboxylate: 50 g
・ Carboxymethylcellulose calcium (disintegrant): 20 g
-Magnesium stearate (lubricant): 10 g
・ Microcrystalline cellulose: 920 g
Formulation Example 2 :
(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- (3-oxetanyl Tablets containing 5 mg of amino) -3-piperidinol The following components are mixed by a conventional method and then tableted to give 10,000 tablets containing 5 mg of the active ingredient in one tablet.
-(3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- (3- Oxetanylamino) -3-piperidinol: 50 g
・ Carboxymethylcellulose calcium (disintegrant): 20 g
-Magnesium stearate (lubricant): 10 g
・ Microcrystalline cellulose: 920 g
Formulation Example 3 :
Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2- (4-morpholinyl) -3-pyridinyl}- Injection containing 20 mg of 5-fluoro-1H-benzimidazole-7-carboxylate The following components were mixed by a conventional method, then the solution was sterilized by a conventional method, filled into ampoules by 5 mL each, and freeze-dried by a conventional method. 10000 ampules containing 20 mg of active ingredient per ampule can be obtained.
-Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3,5-difluorophenyl) -2- (4-morpholinyl) -3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate: 200 g
・ Mannitol: 20g
・ Distilled water: 50L

  Since the pharmaceutical composition comprising the compound of the present invention is a pharmaceutical composition having a strong agonistic activity on somatostatin receptor, particularly on somatostatin receptor subtype 2, somatostatin itself or a hormone regulated by somatostatin is involved. It is useful as an agent for preventing and / or treating various diseases that can occur, especially acromegaly and digestive symptoms associated with gastrointestinal obstruction.

Claims (28)

General formula (I)
(Wherein, R ¹ represents 3-oxetanyl, 3,3,3-trifluoropropyl, ethyl, or a hydrogen atom, and R ² represents C 1-4 alkyl, C 1-4 alkoxy, halogen, nitrile, or C 1 Represents an alkoxycarbonyl group, R ³ represents a C 1-4 alkyl or a hydrogen atom, and R ⁴ represents a hydrogen atom, a C 1-4 alkyl, a C 5-5 optionally substituted with 1 to 3 R ^7. 6 represents a monocyclic carbocycle, or a 5- to 6-membered monocyclic heterocyclic ring which may be substituted by 1 to 3 R ⁸ , R ⁷ represents halogen or C 1-4 alkyl, and R ⁸ represents represents a halogen or C1~4 alkyl, when more than one ^{R 7} is substituted with C5~6 monocyclic carbocyclic ring, a plurality of ^{R 7} may be the same or different, two or more ^{R 8} is 5 When substituted with a ~ 6-membered monocyclic heterocycle , A plurality of ^{R 8} may be the same or different, ^{R 5} represents a C1~4 alkyl or a hydrogen atom,, ring1 is C5～6 monocyclic carbon ring, or a 5-6 membered monocyclic heterocycle R ⁶ represents C 1-4 alkyl, C 1-4 alkoxy, or halogen; m represents an integer of 0 to 3; n represents an integer of 0 to 3; R ² may be the same or different; when n is 2 or more, a plurality of R ⁶ may be the same or different; or a salt thereof (provided that rac- (3R, 4S) -4-amino-1- [3- (3,5-dimethoxyphenyl) -5- (4,6-dimethyl-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol, rac -(3R, 4S) -4-amino-1- [3 (6-Fluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol, and rac- (3R, 4S) -4- Amino-1- [3- (6-chloro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol) and A pharmaceutical composition comprising a pharmaceutically acceptable carrier. The compound represented by the general formula (I) is represented by the general formula (IB)
(In the formula, R ^1-1 represents 3-oxetanyl, 3,3,3-trifluoropropyl, or ethyl, and the other symbols have the same meaning as in claim 1.)
The pharmaceutical composition according to claim 1, which is a compound represented by the formula: The compound represented by the general formula (IB) is represented by the general formula (IB-1)
(In the formula, all symbols have the same meaning as in claim 1 or 2.)
The pharmaceutical composition according to claim 1, which is a compound represented by the formula: The pharmaceutical composition according to any one of claims 1 to 3, wherein R ² is C 1-4 alkoxy, halogen, or C 1-4 alkoxycarbonyl, and R ⁶ is C 1-4 alkoxy, or halogen. . The pharmaceutical composition according to any one of claims 1 to 4, wherein R ⁶ is halogen and n is 2. The compound is
(1) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- ( 3-oxetanylamino) -3-piperidinol,
(2) (3S, 4R) -1- [3- (3-chloro-5-fluorophenyl) -5- (5,6-difluoro-1H-benzimidazol-2-yl) -4-pyridinyl] -4 -[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
(3) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- ( Ethylamino) -3-piperidinol,
(4) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -4 -[(3,3,3-trifluoropropyl) amino] -3-piperidinol, or (5) (3S, 4R) -1- [3- (3,5-difluorophenyl) -5- (6-fluoro The medicine according to claim 2, which is -5-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol. Composition. R ⁴ is C 1-4 alkyl, C 5-6 monocyclic carbocyclic ring optionally substituted with 1-3 R ⁷ , or 5-6 member optionally substituted with 1-3 R ⁸ The pharmaceutical composition according to claim 1, which is a monocyclic heterocycle. The compound represented by the general formula (I) is represented by the general formula (I-1)
(Wherein R ^4-1 is C 1-4 alkyl, C 5-6 monocyclic carbocyclic ring optionally substituted with 1-3 R ⁷ , or substituted with 1-3 R ^8. Represents a 5- to 6-membered monocyclic heterocycle, and the other symbols have the same meanings as in claim 1.)
The pharmaceutical composition according to claim 1, which is a compound represented by the formula: R ² is C1 -4 alkoxy, halogen or C1 -4 alkoxycarbonyl,, ^{R 6} is C1 -4 alkoxy or halogen, claim 7 or 8 pharmaceutical composition according. The pharmaceutical composition according to any one of claims 7 to 9, wherein R ⁶ is halogen and n is 2. The compound is
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2- (1 -Methyl-1H-pyrazol-4-yl) -4-pyridinyl] -3-piperidinol,
(2) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3-chloro-5-fluorophenyl) -2-methyl-3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate,
(3) Methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -2-methyl-3-pyridinyl} -5 -Fluoro-1H-benzimidazole-7-carboxylate,
(4) (3S, 4R) -4-amino-1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazole-2- Yl) -4-pyridinyl] -3-piperidinol,
(5) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4-pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(6) (3S, 4R) -1- [5- (3,5-difluorophenyl) -3- (5-fluoro-6-methoxy-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (ethylamino) -3-piperidinol,
(7) (3S, 4R) -1- [5- (3-chloro-5-fluorophenyl) -3- (5,6-difluoro-1H-benzimidazol-2-yl) -2-methyl-4- Pyridinyl] -4- (3-oxetanylamino) -3-piperidinol,
(8) (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -2-methyl-4-pyridinyl] -4-[(3,3,3-trifluoropropyl) amino] -3-piperidinol,
(9) (3S, 4R) -1- [5- (3,5-difluorophenyl) -2-methyl-3- (5,6,7-trifluoro-1H-benzimidazol-2-yl) -4 -Pyridinyl] -4- (ethylamino) -3-piperidinol, or (10) methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (3, The pharmaceutical composition according to claim 7, which is 5-difluorophenyl) -2- (4-morpholinyl) -3-pyridinyl} -5-fluoro-1H-benzimidazole-7-carboxylate. The pharmaceutical composition according to claim 1, wherein R ⁴ is a hydrogen atom. The compound represented by the general formula (I) is represented by the general formula (I-2)
(Wherein all symbols have the same meaning as in claim 1)
The pharmaceutical composition according to claim 1 or 12, which is a compound represented by the formula: R ² is C1~4 alkoxy, halogen or C1~4 alkoxycarbonyl, ^{R 6} is a C1~4 alkoxy or halogen, claim 12 or 13 pharmaceutical composition. R ⁶ is a halogen, n is 2, the pharmaceutical composition according to any one of claims 12 to 14. The compound is
(1) (3S, 4R) -4-amino-1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(2) (3S, 4R) -4-amino-1- [3- (1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -3-piperidinol,
(3) (3S, 4R) -4-amino-1- [3- (2,5-difluorophenyl) -5- (6-methoxy-1H-benzimidazol-2-yl) -4-pyridinyl] -3 -Piperidinol, or (4) methyl 2- {4-[(3S, 4R) -4-amino-3-hydroxy-1-piperidinyl] -5- (2,5-difluorophenyl) -3-pyridinyl} -5 The pharmaceutical composition according to claim 12, which is -fluoro-1H-benzimidazole-7-carboxylate.   The pharmaceutical composition according to claim 1, wherein the compound represented by the general formula (I) or a salt thereof is a somatostatin receptor agonist.   The pharmaceutical composition according to any one of claims 1 to 17, which is an agent for preventing and / or treating a somatostatin-related disease.   19. The pharmaceutical composition according to claim 18, wherein the somatostatin-related disease is acromegaly, gastrointestinal symptoms associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor.   (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- (3-oxetanyl A pharmaceutical composition comprising (amino) -3-piperidinol, or a salt thereof.   (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- (ethylamino) A pharmaceutical composition comprising -3-piperidinol or a salt thereof.   22. The pharmaceutical composition according to claim 20, which is a prophylactic and / or therapeutic agent for a somatostatin-related disease.   23. The pharmaceutical composition according to claim 22, wherein the somatostatin-related disease is acromegaly, gastrointestinal symptoms associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor. General formula (I)
(Wherein, R ¹ represents 3-oxetanyl, 3,3,3-trifluoropropyl, ethyl, or a hydrogen atom, and R ² represents C 1-4 alkyl, C 1-4 alkoxy, halogen, nitrile, or C 1 Represents an alkoxycarbonyl group, R ³ represents a C 1-4 alkyl or a hydrogen atom, and R ⁴ represents a hydrogen atom, a C 1-4 alkyl, a C 5-5 optionally substituted with 1 to 3 R ^7. 6 represents a monocyclic carbocycle, or a 5- to 6-membered monocyclic heterocyclic ring which may be substituted by 1 to 3 R ⁸ , R ⁷ represents halogen or C 1-4 alkyl, and R ⁸ represents represents a halogen or C1~4 alkyl, when more than one ^{R 7} is substituted with C5~6 monocyclic carbocyclic ring, a plurality of ^{R 7} may be the same or different, two or more ^{R 8} is 5 When substituted with a ~ 6-membered monocyclic heterocycle , A plurality of ^{R 8} may be the same or different, ^{R 5} represents a C1~4 alkyl or a hydrogen atom,, ring1 is C5～6 monocyclic carbon ring, or a 5-6 membered monocyclic heterocycle R ⁶ represents C 1-4 alkyl, C 1-4 alkoxy, or halogen; m represents an integer of 0 to 3; n represents an integer of 0 to 3; R ² may be the same or different; when n is 2 or more, a plurality of R ⁶ may be the same or different; or a salt thereof (provided that rac- (3R, 4S) -4-amino-1- [3- (3,5-dimethoxyphenyl) -5- (4,6-dimethyl-1H-benzimidazol-2-yl) -4-pyridinyl] -3-piperidinol, rac -(3R, 4S) -4-amino-1- [3 (6-Fluoro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol, and rac- (3R, 4S) -4- Amino-1- [3- (6-chloro-1H-benzimidazol-2-yl) -5- (3-fluoro-5-methoxyphenyl) -4-pyridinyl] -3-piperidinol. A preventive and / or therapeutic agent for a somatostatin-related disease, comprising the agent.   25. The agent according to claim 24, wherein the somatostatin-related disease is acromegaly, gastrointestinal symptoms associated with gastrointestinal obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor.   (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (3,5-difluorophenyl) -4-pyridinyl] -4- (3-oxetanyl An agent for preventing and / or treating somatostatin-related diseases, comprising amino) -3-piperidinol or a salt thereof.   (3S, 4R) -1- [3- (5,6-difluoro-1H-benzimidazol-2-yl) -5- (2,5-difluorophenyl) -4-pyridinyl] -4- (ethylamino) An agent for preventing and / or treating somatostatin-related diseases, comprising -3-piperidinol or a salt thereof.   28. The agent according to claim 26 or 27, wherein the somatostatin-related disease is acromegaly, a gastrointestinal symptom associated with gastrointestinal tract obstruction, autosomal dominant polycystic kidney disease, or neuroendocrine tumor.