TW202016101A - New salts of piperidinol derivatives and new crystalline forms - Google Patents

Abstract

Provided is an agonist of somatostatin receptor subtype 2. The salts of (3S, 4R)1-[3-(5, 6-difluoro-1H-benzoimidazol-2-yl)-5-(3, 5-difluorophenyl)-4-pyridinyl]-4-(3-oxetanylamino)-3-piperdinol and the likes disclosed in the present invention are low molecular compounds having a strong agonist activity to somatostatin receptor subtype 2, and can relief the pain accompanying with treatment for patients due to the ability of oral administration and easy taking. Further, because the SSTR2 agonist activity, hERG deterrent activity and/or phospholipidosis action are weak enough to inhibit or relief the side effects caused by the above actions thereof.

Description

Novel salts and novel crystal forms of piperidinol derivatives

The present invention relates to piperidinol derivatives, that is, (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5- Difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol (hereinafter, sometimes abbreviated as compound I) in novel crystal form, novel in compound I The novel crystal forms of salts and/or their salts (hereinafter, sometimes merged and referred to simply as the compounds of the present invention).

Terminal hypertrophy (giant apex) is a hormonal disorder caused by excessive secretion of growth hormone from the pituitary gland due to pituitary adenoma and other causes. It can cause hypertrophy of the bones and soft tissues of the head or hands and feet for the affected patients. The prevalence of terminal hypertrophy is about 60 per 1 million people. It may not be a disease with a high prevalence. However, its patients suffer from difficulties in life due to abnormalities in various parts of the body, and heart disease occurs in 1 in 3 patients. It is a major disease with an increased risk of death.

For the treatment of patients with terminal hypertrophy, nowadays, in addition to the surgical removal of growth hormone-secreting adenoma or radiotherapy, the so-called hormones that inhibit the growth hormone secretion, which are analogs of somatostatin, are also administered externally Medication etc. For such somatostatin analogs, there are octreotide acetate (registered trademark: Sandstatin) of Novartis Pharmaceuticals, and lanreotide acetate (registered trademark: Somatuline) of Ibsen Pharmaceuticals SAS, although these The usefulness of the medicine has been confirmed, On the other hand, since these drugs are peptide drugs, they must be administered by injection. When the continuous preparation is injected into the muscle every few weeks, it is accompanied by considerable pain. In order to solve this problem, it is not a peptide medicine that must be injected, but a non-peptide low-molecular compound that can be administered orally has become the best choice.

On the other hand, it has been known so far that the receptors of somatostatin exist SSTR1 to SSTR5, a total of 5 subtypes. The above octreotide acetate or lanreotide acetate has high affinity for somatostatin receptor subtype 2 (SSTR2), Can be combined on it. In addition, it is also reported that these drugs bind to somatostatin receptor subtype 3 (SSTR3) or somatostatin receptor subtype 5 (SSTR5) with a moderate degree of affinity. SSTR1) or somatostatin receptor subtype 4 (SSTR4) does not bind.

Thus, with the scientific explanation of the differences in the affinity of octreotide acetate or lanreotide acetate for these receptor subtypes, several non-peptide, low molecular somatostatin receptor acting drugs have been synthesized.

For example, Patent Literature 1 mainly describes the general formula (A):

(In the formula, R ^1A represents (1) halogen atom, (2) C1-4 alkyl group which may be substituted with a substituent, or (3) C1-4 alkoxy group, etc.; pA represents an integer of 0-3; in pA In the case of 2 or more, a plurality of R ^1A may be the same or different; R ^2A represents (1) halogen atom, (2)-OR ^3A , (3)-COOR ^5A , or (4) C1- which may be substituted 4 alkyl, etc.; R ^3A represents C1-4 alkyl, etc.; R ^5A represents C1-4 alkyl, etc.; qA represents an integer of 0-3; when qA is 2 or more, a plurality of R ^2A may be the same or phase 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; W _A and Y _A each independently represent Nitrogen atom or carbon atom; rA represents 0 or 1; ring B _A in which at least one of W _A and Y _A represents a nitrogen atom and rA represents 0 or 1, represents a pyridine ring, etc.; L _A represents a bonding bond, etc.; M _A represents a bonding bond, etc.; Z _A represents that it can be selected from (a) halogen atom, (b)-NR ^53A R ^54A , (c)-OR ^55A , (d) can be selected through -NR ^56A R ^57A and/or -OR ^58A substituted C1-4 alkyl, and (e) pendant groups in the group consisting of 5-10 membered monocyclic or bicyclic nitrogen-containing heterocyclic ring substituted; R ^53A -R ^58A Each independently represents a compound represented by a hydrogen atom, a C1-4 alkyl group, a C1-4 haloalkyl group, an oxetanyl group, etc.), a salt thereof, an N-oxide body thereof, a solvate thereof, or another The prodrug is a selective SSTR2 agonist, which is useful for the prevention and/or treatment of terminal hypertrophy or gastrointestinal symptoms accompanied by gastrointestinal occlusion.

In addition, Patent Document 2 mainly describes the general formula (B):

(In the formula, R ^1B represents (1) halogen atom, (2) cyano group, (3) C1-4 alkyl group, (4) C1-4 alkoxy group, etc.; pB represents an integer of 0-2; where pB is In the case of 2, a plurality of R ^1B may be the same or different; R ^2B and R ^3B each independently represent a hydrogen atom or a C1-4 alkyl group; R ^4B represents a hydrogen atom; or R ^2B and R ^4B may bond with them The atoms of the junction together form a 5-8 membered nitrogen-containing saturated heterocyclic ring; L _B represents (1) a bond, (2)-CR ^AB =CR ^BB →, or (3)-C(=O)-NR ^DB → (In each group, an arrow indicates a bonding site with a pyridine ring); R ^AB , R ^BB, and R ^DB each independently represent a hydrogen atom or a C1-4 alkyl group; X ^1B and X ^2B each independently represent a halogen atom) The compounds shown, their salts, their N-oxides or their solvates, or their prodrugs are SSTR2 selective agonists for the prevention and/or prevention of gastrointestinal symptoms associated with terminal hypertrophy or gastrointestinal occlusion. Or therapeutically useful.

In addition, in Patent Document 3, the general formula (C) is mainly described:

(In the formula, R ^1C represents 3-oxetanyl, etc., R ^2C represents halogen, etc., R ^3C represents hydrogen atom, etc., R ^4C represents hydrogen atom, etc., R ^5C represents hydrogen atom, etc., ring1 ^C represents C5~6 single Ring carbocycles, etc., R ^6C represents halogen, mC represents an integer of 0~3, nC represents an integer of 0~3, when mC is 2 or more, a plurality of R ^2C may be the same or different, and nC is 2 or more At the time, a plurality of R ^6C may be the same or different) The compound or salt thereof is an SSTR2 selective agonist, in the prevention and/or treatment of terminal hypertrophy or gastrointestinal symptoms accompanied by gastrointestinal occlusion it works. In addition, it mainly describes that the compound shown in Example 5 was obtained as amorphous (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)- 5-(3,5-difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol (Compound I). In addition, Patent Document 3 is a document that was published internationally on August 16, 2018 after the Japanese Patent Application (Japanese Patent Application No. 2018-114082) that belongs to the priority basis of the present application.

However, the novel crystals of the compounds described below, the salts of the compounds or the novel crystals of the compounds disclosed in the present invention are not described in any prior art.

[Prior Technical Literature] [Patent Literature]

[Patent Literature 1] International Publication No. 2014/007228 Brochure

[Patent Document 2] International Publication No. 2015/046482 pamphlet

[Patent Document 3] International Publication No. 2018/147300 Brochure

For example, as in the treatment of terminal hypertrophy, long-term use of medicines is expected, so it is expected that side effects are as few as possible. For example, in addition to the main effect, in the case of hERG blocking activity or phospholipid deposition, there is a possibility of QT prolonging effect or serious side effects on organs accumulating medicine. The subject of the present invention is to provide a more potent SSTR2 agonist activity, and hERG hinders the activity of a more sufficient deviation, or the phospholipid deposition effect is further weakened, and the possibility of side effects is very weak compared to the SSTR2 agonist activity. Molecular compound.

Furthermore, as with the basic compounds of compound I, salts may be present. In the presence of salt, depending on the salt, solubility, dissolution rate, or stability to heat, light, humidity, etc. are different. Therefore, in the manufacture of pharmaceutical products, it is a very important issue to select the most suitable salt of the original drug for its indication or dosage form.

In addition, in the case of crystalline compounds, there may be crystalline polymorphism. In the presence of polymorphic crystals, depending on the crystal form, solubility, dissolution rate, or stability to heat, light, humidity, etc. are different. In the manufacture of pharmaceutical products, it is a very important issue to select the crystal form of the original drug most suitable for its indication or dosage form.

The inventors repeated the results of intensive review to solve the above-mentioned problems and found that (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-( 3,5-difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol, and the new crystalline forms of their salts, and Found that (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl The novel crystal form of ]-4-(3-oxetanylamino)-3-piperidinol can solve the above problems, and the present invention has been completed by further review.

That is, the present invention relates to

[1](3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl ] Crystallization of 4-(3-oxetanylamino)-3-piperidinol (Compound I);

[2] The crystal of Compound I as described in [1], which has a peak at at least about 11.2, 13.0, 17.8, 19.8, 22.1, and 22.6 degrees 2θ in the powder X-ray diffraction spectrum;

[3] The crystal of compound I as described in [2] has a powder X-ray diffraction spectrum at about 8.8, 11.2, 13.0, 13.8, 14.2, 15.8, 16.2, 17.8, 18.7, 19.0, 19.3, 19.8, 20.2, 20.6, 21.3, 22.1, 22.6, 23.6, 24.3, 24.7, 25.9, 26.2, 26.4, 26.7, 27.1, 27.8, 28.6, 31.4, 31.7 and 32.7 degrees have peaks at 2θ;

[4] The crystal of Compound I described in any one of [1] to [3] has the characteristics of the powder X-ray diffraction spectrum shown in FIG. 32;

[5] The crystal of compound I as described in any one of [1] to [4], which has an endothermic peak with an initial temperature of about 268°C or a peak temperature of about 271°C in differential scanning calorimetry;

[6] The crystal of compound I as described in [5], which has the characteristics of a differential scanning calorimetry chart shown in FIG. 33;

[7](3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl ]-4-(3-oxetanylamino)-3-piperidinol (Compound I) phosphate;

[8] The compound I phosphate described in [7], which is in a crystalline form;

[9] The crystal of Compound I phosphate as described in [8] has a peak in powder X-ray diffraction spectrum at least at about 6.5, 16.3, 18.8, 19.9, 24.3 and 25.0 degrees 2θ;

[10] The crystal of Compound I phosphate as described in [9], which is in powder X-ray diffraction spectrum at about 6.5, 9.9, 12.4, 12.7, 12.8, 15.8, 16.3, 18.0, 18.8, 19.5, 19.9, 20.5, 20.8, 21.2, 21.5, 22.8, 22.9, 24.3, 25.0, 25.8, 26.8, 28.2, 28.6, 29.1 and 31.1 degrees have peaks at 2θ;

[11] The crystal of the compound I phosphate according to any one of [8] to [10], which has the characteristics of the powder X-ray diffraction spectrum shown in FIG. 1;

[12] The crystal of Compound I phosphate as described in any one of [8] to [11] has an endothermic peak with an initial temperature of about 236°C or a peak temperature of about 248°C in differential scanning calorimetry ;

[13] The crystal of Compound I phosphate as described in [12], which has the characteristics of a differential scanning calorimetry chart shown in FIG. 2;

[14] A pharmaceutical composition containing the compound or crystal described in any one of [1] to [13] and a pharmaceutically acceptable carrier;

[15] The pharmaceutical composition as described in [14], which is a preventive and/or therapeutic agent for somatostatin-related diseases;

[16] The pharmaceutical composition according to [15], wherein the somatostatin-related disease is terminal hypertrophy, or gastrointestinal symptoms accompanied by gastrointestinal occlusion;

[17] An agent for preventing and/or treating somatostatin-related diseases, which contains the compound or crystal according to any one of [1] to [13];

[18] A method for preventing and/or treating somatostatin-related diseases, characterized in that an effective amount of the compound or crystal described in any one of [1] to [13] is administered to a mammal;

[19] The compound or crystal according to any one of [1] to [13], which is used for the prevention and/or treatment of somatostatin-related diseases;

[20] The use of the compound or crystal as described in any one of [1] to [13], which is used to produce a prostatin-related disease preventive and/or therapeutic agent;

[21] Compound I phosphate N hydrate (N=3~4);

[22] The crystal of Compound I phosphate N hydrate (N=3~4) as described in [21];

[23] Compound I adipate;

[24] The crystal of Compound I adipic acid salt as described in [23];

[25] 1/2 fumarate of Compound I;

[26] Crystallization of 1/2 fumarate of Compound I as described in [25];

[27] Compound I hydrochloride;

[28] The crystal of Compound I hydrochloride as described in [27];

[29] Compound I lactate;

[30] Crystal of Compound I lactate as described in [29];

[31] Compound I ethanesulfonate;

[32] The crystal of Compound I ethanesulfonate as described in [31];

[33] Compound I besylate monohydrate;

[34] The crystal of Compound I besylate monohydrate as described in [33];

[35] 1/2 adipate of Compound I;

[36] Crystallization of 1/2 adipate of Compound I as described in [35];

[37] N hydrate of compound I (N=1~2);

[38] Crystallization of N hydrate (N=1 to 2) of Compound I as described in [37];

[39] Compound 1 monohydrate;

[40] Crystallization of the monohydrate of Compound I as described in [39];

[41] N hydrate of compound I (N=0.5~1); and

[42] The crystal of N hydrate (N=0.5~1) of Compound I as described in [41].

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4- Pyridyl]-4-(3-oxetanylamino)-3-piperidinol (hereinafter, sometimes abbreviated as Compound I) in novel crystal form, novel salt of Compound I and/or their salts The novel crystalline form (hereinafter, sometimes abbreviated as the compound of the present invention) is a low-molecular compound with strong action activity on somatostatin receptors, especially somatostatin receptor subtype 2 (SSTR2). Oral administration is better than administration of existing peptide medicines typified by octreotide acetate or lanreotide acetate, which must be injected intramuscularly, and can be easily taken, which can alleviate the pain associated with the treatment of patients. In addition, the compound of the present invention has a sufficiently weak hERG inhibitory activity and/or phospholipid deposition action relative to the SSTR2 agonist activity, and can suppress or reduce side effects due to these actions. Therefore, patients in need of somatostatin-related diseases to be administered, especially patients with terminal hypertrophy or gastrointestinal occlusion, can safely use the compounds of the present invention.

In addition, since the compound of the present invention is excellent in chemical stability, the weight change due to the increase in humidity is very small, and it is very useful as an original medicine for pharmaceutical products.

Figure 1 shows the powder X-ray diffraction spectrum of the Type A crystal of Compound I phosphate.

Figure 2 shows the differential scanning calorimetry (DSC) chart of the Type A crystal of Compound I phosphate.

Figure 3 shows a thermogravimetric (TG) diagram of the Type A crystal of Compound I phosphate.

Figure 4 shows the powder X-ray diffraction spectrum of the D-type crystal of Compound I phosphate N hydrate (N=3~4).

Figure 5 shows the differential scanning calorimetry (DSC) chart of the D-type crystal of Compound I phosphate N hydrate (N=3~4).

Figure 6 shows the thermogravimetric (TG) diagram of the D-type crystal of Compound I phosphate N hydrate (N=3~4).

Fig. 7 shows the powder X-ray diffraction spectrum of the type B crystal of Compound I adipic acid salt.

Figure 8 shows a differential scanning calorimetry (DSC) chart of the Type B crystal of Compound I adipic acid salt.

Fig. 9 shows a powder X-ray diffraction spectrum of type I crystals of 1/2 fumarate of Compound I.

FIG. 10 shows a differential scanning calorimetry (DSC) chart of type I crystals of 1/2 fumarate of Compound I.

Figure 11 shows the powder X-ray diffraction spectrum of the type A crystal of Compound I hydrochloride.

Figure 12 shows a differential scanning calorimetry (DSC) chart of the Type A crystal of Compound I hydrochloride.

Figure 13 shows the powder X-ray diffraction spectrum of the C-type crystal of Compound I lactate.

Figure 14 shows a differential scanning calorimetry (DSC) chart of the Form C crystal of Compound I lactate.

Figure 15 shows the powder X-ray diffraction spectrum of the Type A crystal of Compound I ethanesulfonate.

Figure 16 shows a differential scanning calorimetry (DSC) chart of Form A crystals of Compound I ethanesulfonate.

Figure 17 shows the powder X-ray diffraction spectrum of the C-type crystal of Compound I besylate monohydrate.

Figure 18 shows a differential scanning calorimetry (DSC) chart of the Type C crystal of Compound I besylate monohydrate.

Figure 19 shows a thermogravimetric (TG) chart of the Type C crystal of Compound I besylate monohydrate.

Figure 20 shows the powder X-ray diffraction spectrum of the F-type crystal of 1/2 adipate of Compound I.

Figure 21 shows a differential scanning calorimetry (DSC) chart of the F-type crystal of 1/2 adipate of Compound I.

Fig. 22 shows the powder X-ray diffraction spectrum of the Type B crystal of NL-malate (N=1~2) of Compound I.

Figure 23 shows the differential scanning calorimetry (DSC) chart of the crystalline form B of NL-malate (N=1~2) of Compound I.

Figure 24 shows the powder X-ray diffraction spectrum of the C-type crystal of the N hydrate (N=1~2) of Compound I.

FIG. 25 shows a differential scanning calorimetry (DSC) chart of the C-type crystal of N hydrate (N=1 to 2) of Compound I.

Figure 26 shows a thermogravimetric (TG) chart of the C-type crystals of N hydrate (N=1 to 2) of Compound I.

Figure 27 shows the water vapor adsorption/desorption isotherm (DVS) of the C-type crystals of the N hydrate of Compound I (N=1 to 2).

Figure 28 shows the powder X-ray diffraction spectrum of the D-type crystal of the monohydrate of Compound I.

Figure 29 shows a differential scanning calorimetry (DSC) chart of the D-type crystal of the monohydrate of Compound I.

Figure 30 shows a thermogravimetric (TG) chart of the D-type crystal of the monohydrate of Compound I.

Figure 31 shows the water vapor adsorption/desorption isotherm (DVS) of the D-type crystal of the monohydrate of Compound I.

Figure 32 shows the powder X-ray diffraction spectrum of the B-type crystal of Compound I.

Figure 33 shows a differential scanning calorimetry (DSC) chart of the Type B crystal of Compound I.

Figure 34 shows a thermogravimetric (TG) chart of the Type B crystal of Compound I.

Figure 35 shows the water vapor adsorption/desorption isotherm (DVS) of the B-type crystal of Compound I.

Figure 36 shows the powder X-ray diffraction spectrum of the O-type crystal of N hydrate (N=0.5~1) of Compound 1.

Figure 37 shows the powder X-ray diffraction spectrum of type A crystal of N hydrate (N=0.5~1) of compound I.

In the present invention, the compounds of the present invention preferably include, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate N hydrate (N=3~4),

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol adipate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol 1/2 fumarate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol hydrochloride,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol lactate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol ethanesulfonate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol benzenesulfonate monohydrate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol 1/2 adipic acid salt,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol N hydrate (N=1~2),

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol monohydrate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Crystallization of (3-oxetanylamino)-3-piperidinol, or

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol N hydrate (N=0.5~1).

Furthermore, in the present invention, the compounds of the present invention preferably include, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate crystals,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate N hydrate (N=3~4),

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol adipate crystals,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol 1/2 fumarate crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol hydrochloride crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol lactate crystals,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol ethylsulfonate crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol benzene sulfonate monohydrate crystals,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol 1/2 adipate crystals,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol N hydrate (N=1~2),

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol monohydrate crystals,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Crystallization of (3-oxetanylamino)-3-piperidinol, or

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Crystallization of (3-oxetanylamino)-3-piperidinol N hydrate (N=0.5~1).

Furthermore, in the present invention, the compounds of the present invention preferably include, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate type A crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate N hydrate (N=3~4) D type crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol adipate B type crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Type I crystal of (3-oxetanylamino)-3-piperidinol 1/2 fumarate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Form A crystal of (3-oxetanylamino)-3-piperidinol hydrochloride,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -C type crystal of (3-oxetanylamino)-3-piperidinol lactate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol ethylsulfonate type A crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -C type crystal of (3-oxetanylamino)-3-piperidinol benzenesulfonate monohydrate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -F-type crystal of (3-oxetanylamino)-3-piperidinol 1/2 adipate,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -C type crystal of (3-oxetanylamino)-3-piperidinol N hydrate (N=1~2),

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol monohydrate D-type crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol type B crystal,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -O-type crystal of (3-oxetanylamino)-3-piperidinol N hydrate (N=0.5~1), or

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Form A crystal of (3-oxetanylamino)-3-piperidinol N hydrate (N=0.5~1).

In the present invention, the compounds of the present invention are more preferably exemplified by, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate, or

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Crystallization of (3-oxetanylamino)-3-piperidinol.

Furthermore, in the present invention, the compounds of the present invention are more preferably exemplified by, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate crystals, or

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Crystallization of (3-oxetanylamino)-3-piperidinol.

Furthermore, in the present invention, the compounds of the present invention are more preferably exemplified by, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Form A crystal of (3-oxetanylamino)-3-piperidinol phosphate, or

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Form B crystal of (3-oxetanylamino)-3-piperidinol.

In the present invention, as for the compound of the present invention, particularly preferably, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate.

In addition, in the present invention, particularly preferred compounds of the present invention include, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Form A crystal of (3-oxetanylamino)-3-piperidinol phosphate.

In addition, in the present invention, particularly preferred compounds of the present invention include, for example,

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -Form B crystal of (3-oxetanylamino)-3-piperidinol.

The powder X-ray diffraction spectrum of the Type A crystal of Compound I phosphate preferably has peaks at least at about 6.5, 16.3, 18.8, 19.9, 24.3, and 25.0 degrees 2θ, more preferably at least about 6.45 , 16.28, 18.78, 19.89, 24.26, and 24.96 degrees 2θ peaks, particularly preferably having about 6.45, 9.88, 12.38, 12.66, 12.81, 15.77, 16.28, 17.96, 18.78, 19.51, 19.89, 20.48, 20.8, 21.17, 21.53 , 22.75, 22.92, 24.26, 24.96, 25.82, 26.83, 28.16, 28.55, 29.12 and 31.12 degrees 2θ peaks.

For the powder X-ray diffraction spectrum of the D-type crystal of Compound I phosphate N hydrate (N=3~4), it is preferably at least about 6.82, 7.66, 13.66, 14.13, 16.98 and 26.89 degrees 2θ The peaks are more preferably peaks having 2θ at about 6.82, 7.66, 9.99, 13.66, 14.13, 15.41, 16.98, 19.83, 20.55, 21.26, 21.8, 22.97, 23.7, 25.05, 26.89 and 28.48 degrees.

The powder X-ray diffraction spectrum of the type B crystal of the adipate salt of Compound I preferably has at least peaks at about 5.65, 9.57, 12.05, 18.39, and 19.26 degrees 2θ, and more preferably has peaks at about 5.65, 9.57, 10.02, 10.9, 12.05, 13.5, 14.07, 15.74, 16.05, 17.76, 18.39, 19.26, 20.21, 21.73, 22.42, 23.23, 23.98, 24.28, 25.13, 25.53, 27.77, 28.37, 28.94, 29.52 and 30.25 degrees 2θ peak.

For the powder X-ray diffraction spectrum of the type I crystal of 1/2 fumarate of Compound I, it is preferable to have at least peaks at about 11.19, 18.57, 19.82, 21.16, and 22.57 degrees 2θ, more preferably At about 6.98, 8.82, 11.19, 11.46, 13.02, 13.76, 15.48, 15.78, 17.76, 18.23, 18.57, 19.32, 19.55, 19.82, 20.21, 20.71, 21.16, 22.12, 22.57, 23.09, 24.3, 24.69, 26.67, 27.78, The peaks of 2θ at 28.64, 31.62, 32.6 and 34.14 degrees.

The powder X-ray diffraction spectrum of the Type A crystal of the hydrochloride of Compound I preferably has peaks at least at about 6.7, 18.8, 21.71, 24.71, and 27.71 degrees 2θ, and more preferably at about 6.7, 13.16 , 13.71, 14.4, 14.78, 15.01, 15.55, 16.12, 16.48, 16.96, 17.83, 18.8, 20.26, 20.64, 21.05, 21.71, 22.82, 23.8, 24.03, 24.71, 25.09, 26.09, 27.71, 29.07, 29.76, 30.67, 31.05 And 34.1 degrees 2θ peak.

The powder X-ray diffraction spectrum of the C-type crystal of Compound I lactate preferably has peaks at least at about 5.53, 6.58, 15.98, 17.78, 18.44, and 19.37 degrees 2θ, and more preferably has peaks at about 5.53, Peaks of 6.58, 7.86, 9.97, 10.82, 10.96, 12.08, 12.86, 14.08, 14.98, 15.98, 16.62, 17.78, 18.44, 19.07, 19.37, 20.71, 22.12, 23.23, 24.3, 28.12 and 28.55 degrees 2θ.

In terms of the powder X-ray diffraction spectrum of the Type A crystal of Compound I ethanesulfonate, it is preferable to have at least peaks at about 7.57, 11.91, 13.69, 18.03, 20.35, and 24 degrees 2θ, more preferably About 6.65, 7.57, 8.82, 11.2, 11.91, 12.48, 13.28, 13.69, 15, 16.61, 16.91, 18.03, 19.59, 19.85, 20.07, 20.35, 20.96, 21.28, 21.78, 22.1, 22.42, 22.57, 22.92, 24 , 24.21, 25.06, 25.39, 25.71, 26.14, 26.94, 28.07, 28.69, 29.42, 30.73, 31.37, 32.69 and 33.09 degrees 2θ peaks.

For the powder X-ray diffraction spectrum of the C-type crystal of Compound I benzenesulfonate monohydrate, it is preferable to have at least peaks at about 6.32, 9.98, 16.67, 18.33, 19.01, 21.87, and 26.96 degrees 2θ, more Preferably, it has about 6.32, 9.66, 9.98, 10.88, 11.67, 12.69, 14.18, 14.44, 15.71, 15.97, 16.35, 16.67, 17.28, 18, 18.33, 19.01, 19.34, 19.8, 20.76, 21.12, 21.37, 21.87, 22.39 , 23.05, 24.44, 24.78, 25.6, 26.01, 26.96, 27.57, 27.84, 29.01 and 32.14 degrees 2θ peaks.

The powder X-ray diffraction spectrum of the F-type crystal of 1/2 adipate of Compound I preferably has at least peaks at about 5.95, 8.82, 14.89, 17.23, 18.01 and 19.03 degrees 2θ, more preferably For about 5.95, 7.16, 8.82, 10.46, 11.02, 11.67, 13.01, 14.38, 14.89, 15.9, 17.23, 18.01, 18.91, 19.03, 19.48, 20.31, 21.78, 22.39, 22.89, 23.17, 23.53, 24.66, 25.1, The peaks of 2θ at 25.62, 29.19 and 30.04 degrees.

For the powder X-ray diffraction spectrum of the C-type crystal of the N hydrate of Compound I (N=1 to 2), it is preferable to have at least peaks at about 5.57, 9.59, 21.66, 23.94, and 26.31 degrees 2θ. It is preferred to have about 5.57, 9.17, 9.59, 10.03, 11.16, 12.44, 13.07, 13.9, 14.73, 15.03, 16.01, 17.23, 17.66, 18.46, 19.3, 19.57, 21.66, 22.42, 23.94, 24.6, 25.05, 26.31 and 27.95 Degree 2θ peak.

In terms of the powder X-ray diffraction spectrum of the D-type crystal of the monohydrate of Compound I, it is preferable to have a value of at least about 9.92, 17.21, 18.1, 20.55, 21.96, 22.87, and 26.19 degrees 2θ The peaks are more preferably about 7.28, 9.92, 10.86, 11.38, 12.11, 15.69, 16.42, 16.89, 17.21, 18.1, 18.42, 18.67, 19.48, 19.96, 20.16, 20.55, 20.82, 21.07, 21.46, 21.96, 22.5, The peaks of 22.87, 23.46, 23.96, 24.85, 25.26, 26.19, 26.87, 27.8, 28.51, 28.87 and 30.05 degrees 2θ.

The powder X-ray diffraction spectrum of the B-type crystal of Compound I preferably has peaks at least at about 11.2, 13.0, 17.8, 19.8, 22.1, and 22.6 degrees 2θ, and more preferably at least at about 11.21, 13.03 , 17.78, 19.84, 22.12, and 22.55 degrees 2θ peaks, particularly preferably having about 8.83, 11.21, 13.03, 13.77, 14.19, 15.78, 16.15, 17.78, 18.74, 19, 19.32, 19.84, 20.23, 20.62, 21.28, 22.12 , 22.55, 23.55, 24.3, 24.69, 25.92, 26.15, 26.39, 26.69, 27.07, 27.8, 28.61, 31.43, 31.71 and 32.68 degrees 2θ peaks.

For the powder X-ray diffraction spectrum of the O-type crystal of N hydrate (N=0.5~1) of Compound I, it is preferable to have at least peaks at about 6.88, 13.22, 16.37, 20.12, 22.62 and 25.34 degrees 2θ , More preferably about 6.88, 8.26, 9.94, 12.55, 13.22, 13.6, 15.05, 15.81, 16.37, 16.62, 17.12, 17.71, 20.12, 20.57, 20.87, 22.62, 23, 23.72, 24.37, 25.34, 26.62 and 30.17 Degree 2θ peak.

The powder X-ray diffraction spectrum of the type A crystal of N hydrate (N=0.5~1) of Compound I preferably has at least about 9.81, 10.82, 13.48, 19.42, 21.01, 23.94 and 28.5 degrees 2θ The peaks are more preferably about 5.66, 9.81, 10.21, 10.82, 11.38, 13.48, 14.63, 15.03, 15.47, 16.02, 17.12, 17.82, 18.48, 19.42, 20.59, 21.01, 21.55, 21.8, 22.68, 23.48, 23.94 , 25.32 and 28.5 degrees 2θ peak.

The Type A crystal of Compound I phosphate is characterized by at least one physicochemical data of (a) and (b) below. It is preferable that the characteristics are given by the physicochemical data of both (a) and (b). (a) The following The powder X-ray diffraction spectrum chart shown in Fig. 1, the diffraction angle (2θ) shown in Table 1 below has about 6.5, 9.9, 12.4, 12.7, 12.8, 15.8 in the powder X-ray diffraction spectrum. 16.3, 18.0, 18.8, 19.5, 19.9, 20.5, 20.8, 21.2, 21.5, 22.8, 22.9, 24.3, 25.0, 25.8, 26.8, 28.2, 28.6, 29.1 and 31.1 degrees 2θ peak, or in powder X-ray diffraction spectrum Has peaks of at least about 6.5, 16.3, 18.8, 19.9, 24.3, and 25.0 degrees 2θ; (b) in the differential scanning calorimetry (DSC) chart shown in Figure 2 below, or DSC, with an initial temperature An endothermic peak of about 236°C or a peak temperature of about 248°C.

The type B crystal of compound I is given a characteristic by at least one physicochemical data of (c) and (d) below. It is preferable that the characteristics are given by the physicochemical data of both (c) and (d). (c) In the powder X-ray diffraction spectrum chart shown in the following Figure 32, the diffraction angle (2θ) shown in Table 16 below, and the powder X-ray diffraction spectrum, it has about 8.8, 11.2, 13.0 , 13.8, 14.2, 15.8, 16.2, 17.8, 18.7, 19.0, 19.3, 19.8, 20.2, 20.6, 21.3, 22.1, 22.6, 23.6, 24.3, 24.7, 25.9, 26.2, 26.4, 26.7, 27.1, 27.8, 28.6, 31.4 , 31.7 and 32.7 degrees 2θ peak, in powder X-ray diffraction spectrum, at least about 11.2, 13.0, 17.8, 19.8, 22.1 and 22.6 degrees 2θ peak, (d) shown in Figure 33 below The differential scanning calorimetry (DSC) chart, or DSC, has an endothermic peak with an initial temperature of about 268°C or a peak temperature of about 271°C.

In the present invention, each crystal form of the compound of the present invention is specified by the physicochemical data described in this specification. However, each spectral data may be slightly changed due to its nature and should not be interpreted strictly.

For example, in powder X-ray diffraction spectrum data, the diffraction angle (2θ) or the overall pattern is important in terms of its properties and the identification of crystal homogeneity, and the relative intensity varies with the direction of crystal growth, particle size, and measurement. Conditions can vary somewhat.

In addition, the differential scanning calorimetry (DSC) data is also important in determining the identity of crystals, and the overall pattern is also important, and may vary somewhat depending on the measurement conditions.

Therefore, in terms of the crystal form of the compound of the present invention, powder X-ray diffraction spectrum, DSC, and patterns, all of which are similar in general, are included in the crystal form of the present invention.

In this specification, in terms of differential scanning calorimetry (DSC) data, the indicated starting temperature means the temperature at the intersection of the line corresponding to the point of maximum gradient (curvature point) of the curve and the extension of the baseline .

In this specification, in terms of differential scanning calorimetry (DSC) data, the endothermic start temperature shown means a temperature corresponding to the temperature at which endotherm starts.

In this specification, the description of the diffraction angle (2θ (degree)) in the powder X-ray diffraction pattern and the start temperature (°C) and peak temperature (°C) of the endothermic peak in the DSC analysis are intended to include this data measurement method The generally allowable error range in the mean means its approximate diffraction angle and the starting temperature and peak temperature of the endothermic peak. For example, the "approximate" of the diffraction angle (2θ (degrees)) in powder X-ray diffraction is ±0.2 degrees for one aspect and ±0.1 degrees for another aspect. The initial temperature (°C) or "about" of the peak temperature (°C) in the DSC analysis is ±2°C for one aspect and ±1°C for another aspect. In addition, the "approximately" before the initial figure is also attached to the subsequent figure. For example, about 15.3, 16.9, 17.4, 19.3, and 19.6 degrees 2θ means about 15.3, about 16.9, about 17.4, about 19.3, and about 19.6 degrees 2θ.

In this specification, the value of the diffraction angle (2θ (degrees)) in the powder X-ray diffraction pattern is a value that is rounded down to 2 digits below the decimal point, or a value below 1 decimal point, or Represents an integer value. In this specification, the value of the diffraction angle (2θ (degree)) in the powder X-ray diffraction pattern is preferably rounded to a value below 1 decimal point, and indicated by 2 numbers below the decimal point , It is better to replace it with a value that is rounded to one decimal place.

In one embodiment of the present invention, each crystal form of the compound of the present invention is substantially pure. The reference to "substantially pure" means that the specific crystalline form accounts for at least 50% of the compounds present. Furthermore, in another embodiment, each crystal form accounts for at least 75%, at least 85%, at least 90%, at least 95%, or about 94% to 98% of the compounds of the present invention present. Among them,% is preferably mole %.

In the present invention, hydrate means that the medicinal product is under normal storage-use environment (temperature, relative humidity, etc.), and it is not particularly limited as long as it is a crystal that stably retains a considerable amount of moisture. For example, among them, monohydrate means that the medicinal product stably maintains the crystal of 1 equivalent of water under the normal storage-use environment (temperature, relative humidity, etc.).

In the present invention, the crystalline form of the compound of the present invention can be produced according to the examples, for example. In addition, seed crystals may or may not be used for recrystallization.

It is a type B crystal of Compound I of the compound of the present invention. For example, a free compound of the compound produced in Example 1 described below can be prepared, for example, as the compound produced in Examples 2 to 10 described later. After the salt of I or its hydrate is purified, it is neutralized to form the free compound of compound I, and then produced by recrystallization or solvent-mediated transfer. Or, for example, it may be made into a crystalline polymorph other than the type B crystal of Compound I such as the compound produced in Examples 11 and/or 12 described later or its hydrate, and then subjected to recrystallization or solvent-mediated transfer, etc. And manufacture.

In this specification, the powder X-ray diffraction spectrum chart described in the drawings described below shows the diffraction angle (2θ) (degrees) on the horizontal axis (2-Theta-Scale), and the diffraction intensity on the vertical axis ( Lin(Counts)).

In this specification, the DSC described in the diagram described later indicates the temperature (Temperature (°C)) on the horizontal axis and the heat flow (Heat Flow (W/g)) on the vertical axis.

In this specification, the thermogravimetric measurement (TG) described in the drawings described below shows the temperature (Temperature (°C)) on the horizontal axis and the rate of change in weight (Weight (%)) on the vertical axis.

In this specification, the water vapor adsorption/desorption isotherms described in the drawings described below show the relative humidity (RH (%)) on the horizontal axis, and each humidity based on drying (0%RH) The weight change rate (Change in Mass (%)-Ref) is shown on the vertical axis.

[toxicity]

Since the compound of the present invention has low toxicity, it can be safely used as a medicine.

[Application to pharmaceutical products]

Since the compound of the present invention has somatostatin receptor kinetic activity, it can be used as a hormone for preventing and/or treating somatostatin-related diseases (related to somatostatin itself or somatostatin) in mammals, especially humans The resulting disease).

Examples of such diseases include hormonal disease (eg, terminal hypertrophy, gigantism, pituitary gigantism, Cushing's disease, Graves' disease, hyperthyroidism, etc.), hypoplasia [ateliosis] (eg: abnormal bone formation, Noonan syndrome, obesity, hypoplasia with obesity, uterine hypoplasia, renal failure with hypoplasia, syndrome X, etc.), cancer or adenoma ] (Eg leukemia, chondrosarcoma, melanoma, lipoma, medullary tumor, neuroblastoma, pituitary adenoma, headache with pituitary adenoma, non-functional pituitary adenoma, growth hormone-producing glands Tumor, growth hormone releasing factor adenoma, gonadotropin producing adenoma, prolactin producing adenoma, thyroid stimulating hormone producing adenoma, VIP producing adenoma, ACTH producing adenoma, craniopharyngeal tumor, Germ cell tumor, thyroid cancer, medullary thyroid cancer, lung cancer, breast cancer, liver cancer, neuroendocrine tumor (neuroendocrine gland tumor), gastrointestinal pancreatic neuroendocrine gland tumor, gastrin-producing tumor, cancer-like syndrome, colorectal cancer , Pancreatic cancer, islet cell tumors, insulin-producing tumors, glucagon-producing tumors, prostate cancer, cancerous cachexia, colorectal vascular tumors, etc., gastrointestinal diseases (eg, digestive organs with digestive tract occlusion) Symptoms, gastroesophageal reflux, gastroduodenal reflux, excessive gastric acid secretion, peptic ulcer, Zollinger-Ellison syndrome, protein leaking gastrointestinal syndrome, dumping syndrome, short intestinal syndrome, inflammatory bowel disease, Crohn's disease , Allergic bowel syndrome, allergic colon syndrome, intestinal epithelial fistula, functional dyspepsia, vomiting, vomiting, abdominal bloating, etc.), diarrhea (for example: watery diarrhea syndrome, chronic secondary diarrhea, chemotherapy-induced diarrhea, Refractory diarrhea with acquired immune insufficiency syndrome, dysentery with irritable bowel syndrome, dysentery after surgery, etc.), vascular disease (e.g., proliferative omental disease, macular degeneration, macular degeneration with age, gastrointestinal tract) Bleeding, bleeding with gastroduodenal ulcers, bleeding from esophageal venous tumors, bleeding from venous tumors in patients with cirrhosis, portal hypertension, bleeding from transplanted blood vessels, restenosis, scarring of injuries, psoriasis, systemic sclerosis (Scleroderma), chronic rejection of allograft, hypotension, atherosclerosis, restenosis after PTCA, hypertrophic cardiomyopathy, arteriosclerosis, heart valve disease, myocardial infarction, etc.), fiber Disease (for example: skin fibrosis, central nervous system fibrosis, rhinofibrosis, pulmonary fibrosis, liver fibrosis, renal fibrosis, chemotherapy-induced fibrosis, etc.), diabetes and its complications (for example: diabetes, insulin Dependent diabetes, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, dawn phenomenon, insulin refractory disease, hyperinsulinemia, hyperlipidemia, etc.), inflammatory diseases (for example: arthritis, rheumatoid arthritis) Symptoms, psoriasis, local inflammation, sunburn, eczema, etc.) , Central nervous system diseases (for example: cognition, Alzheimer's disease, epilepsy, etc.), respiratory diseases (for example: apnea syndrome during sleep, etc.), pancreatic diseases (for example: pancreatitis, acute pancreatitis, chronic pancreas Inflammation, pancreatic epithelial fistula, pancreatic pseudocyst, ascites, pancreatic fluid fistula, symptoms accompanying pancreatic surgery, etc.), liver disease (eg, cystic liver, etc.), kidney disease (eg, hepatorenal syndrome, cystic kidney, Nephropathy, etc.), ovarian diseases (for example, polycystic ovary syndrome, etc.), bone and joint diseases (for example, osteoporosis, deformed joint disease, etc.), pain, headache, etc. Furthermore, it can be used to image tumors with somatostatin receptors by introducing radioactive substances (for example: ¹²³ I, ¹²⁵ I, ¹¹¹ In, etc.) directly or through appropriate spacers into the compounds of the present invention, and, It can also be used to target tumors with somatostatin receptors by introducing cancer-making agents directly or through appropriate spacers into the compounds of the present invention.

Among them, the compound of the present invention is effective against terminal hypertrophy, gigantism, pituitary gigantism, pituitary adenoma, headache with pituitary adenoma, non-functional pituitary adenoma, growth hormone-producing adenoma, and neuroendocrine tumor ( Neuroendocrine gland tumors), neuroendocrine gland tumors of the gastrointestinal pancreas, gastrin-producing tumors, cancer-like syndromes, insulin-producing tumors, glucagon-producing tumors, gastrointestinal symptoms with digestive tract occlusion, cystic kidney disease , Cystic liver, hemorrhage of esophageal venous aneurysm, portal hypertension, diabetic omental disease, cognitive disorders, Alzheimer's disease, pain, headache, etc. are useful for prevention and/or treatment, in particular, the compounds of the present invention are suitable For the prevention and/or treatment of terminal hypertrophy or gastrointestinal symptoms accompanied by gastrointestinal occlusion. In the present invention, "treatment" includes not only the treatment of the disease itself, but also the effect of improving or alleviating the symptoms accompanying the disease, that is, "symptom improvement".

With regard to digestive organ symptoms accompanying digestive tract occlusion, for example, the compound of the present invention can also improve digestive organ symptoms including digestive tract occlusion associated with ‧ relapsed cancer patients (malignant digestive tract occlusion for patients with recurrent cancer) . The compound of the present invention is also used as a digestive organ symptom-improving agent accompanying digestive tract occlusion, or as a digestive tract occlusion treatment for ‧ relapse cancer patients (malignant digestive tract occlusion for ‧ recurrent cancer patients) It is useful.

The cystic kidney includes, for example, somatic dominant multiple cystic kidney and somatic recessive multiple cystic kidney.

Cystic liver includes, for example, somatic dominant polycystic liver disease and somatic dominant polycystic kidney disease.

Neuroendocrine tumors are the general term for non-cancerous or cancerous tumors derived from neuroendocrine cells. It is known that neuroendocrine tumors not only occur in endocrine organs, but also in organs throughout the body. nerve Endocrine tumors, especially in the pancreas or digestive tract and other digestive organs, or lungs, but also in the stomach, pancreas, pituitary gland, parathyroid gland, thyroid gland, accessory kidney, or thymus. Multiple endocrine neoplasia type 1 (MEN1) or multiple endocrine neoplasia type 2 (MEN2) sometimes occurs with the merger of parathyroidism.

Neuroendocrine tumors can be roughly divided into functional neuroendocrine tumors with excess hormones and non-functional neuroendocrine tumors without hormone excess. Examples of functional neuroendocrine tumors include cancer-like syndromes, serotonin-producing tumors, gastrin-producing tumors (gastrinoma, Zollinger-Ellison syndrome), and glucagon-producing tumors. Tumor (glucagonoma), insulin-producing tumor (insulinoma), vasoactive intestinal peptide tumor (VIP tumor), somatostatin-producing tumor (somatostatin tumor), growth hormone-releasing hormone-producing tumor Tumors (GRH tumors), para-renal cortex stimulating hormone-producing tumors (ACTH tumors), parathyroid hormone-associated tumors (PTHrP tumors), cholecystokinin-producing tumors (CCK tumors), renin-producing tumors, erythropoiesis Protopoietin-producing tumors, luteinizing hormone-producing tumors (LH-producing tumors), insulin-like growth factor-2 tumors (IGF-2), glucagon-like peptide-1 tumors (GLP-1 tumors) )Wait. Furthermore, tumors that have metastasized from these tumors to other organs such as liver, lymph nodes, peritoneum, bone, lung, ovary, uterus, and fallopian tube may also be included. Examples of non-functional neuroendocrine tumors include non-cancerous or cancerous cells derived from endocrine cells formed in the pancreas, digestive tract, lung, pituitary gland, parathyroid gland, thyroid gland, accessory kidney, and/or thymus. The tumor, etc. It also includes tumors that have metastasized from these tumors to other organs such as the liver, lymph nodes, peritoneum, bone, lung, ovary, uterus, and fallopian tubes.

For the test methods other than those described in the Examples for evaluating the pharmacological activity of the compound of the present invention, for example, an evaluation system for the gastric acid secretion inhibitory effect of rats is used. 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 effect in rats)

On the day before the evaluation, fast for one night, and evaluate the tail of rats that were water-free for 2 hours (7-week-old male Crl: CD (SD) IGS rat (Charles River Co., Ltd., Japan)) on isoflurane Leave the indwelling needle under anesthesia. After awakening the rat from anesthesia, the medium (physiological saline (Otsuka Raw Food Injection, Otsuka Pharmaceutical Factory Co., Ltd.)) or the test compound dissolved in the medium is continuously administered intravenously via an indwelling needle. One hour after the start of administration, the rats were opened under isoflurane anesthesia, and the pylorus of the stomach was ligated with silk thread. After closing the incised abdomen, allow it to recover from anesthesia. Open the abdomen again under isoflurane anesthesia 5 hours after the start of the administration (4 hours after the pylorus ligation), and seal the cardia of the stomach with forceps before bleeding to death. The contents of the stomach were centrifuged at 500×g for 15 minutes, and the supernatant was recovered as gastric juice, and then the amount of gastric juice (mL/100g BW) per body weight was determined. Furthermore, the acid concentration (mmol/mL) in the gastric juice was measured by reverse titration using a COM-1600ST automatic titration device (Hitachi High-Technologies (Hiruma Industries)). Take the product of gastric juice volume and acid concentration as the gastric acid secretion (mmol/100g BW), by the mathematical formula {[inhibition rate of gastric acid secretion (%)] = ([gastric acid secretion of medium administration group]-[experiment The gastric acid secretion amount of the compound-administered group])/[the gastric acid secretion amount of the medium-administered group]×100} calculate the inhibition rate (%) of gastric acid secretion. According to this evaluation system, for example, octreotide exhibits a gastric acid secretion inhibition rate of 39% at a rate of 1 μg/kg/h, which can be obtained from the review results of the inventors.

In addition, the compounds of the present invention, in addition to the diseases listed above, can also be used to prevent and/or treat various pathological diseases related to somatostatin, for example, in Life Sciences (1987), Volume 40, 419 -437 pages, or the diseases described in The European Journal of Medicine, 1993, volume 2, pages 97-105, etc.

When the compound of the present invention is suitably used as a medicinal agent, the compound of the present invention can be used not only in a single dose, for example, for (1) its prevention, treatment, and/or symptom-improving effect complementation and/or enhancement, (2) Its dynamics ‧ improved absorption, reduced dosage, and/or (3) reduced side effects, it can also be combined with other active ingredients, such as the drugs listed below, as a concomitant.

When the compound of the present invention is used for the prevention and/or treatment of terminal hypertrophy, the drugs used in combination with the compound of the present invention include, for example, somatostatin analogs, somatostatin receptor acting drugs, Growth hormone receptor antagonists, dopamine receptor acting drugs, etc.

In addition, patients with terminal hypertrophy are often associated with lifestyle-related diseases such as diabetes, hypertension, hyperlipidemia, and obesity, or other various diseases. Insulin secretion promoting drugs (eg, sulfonylurea agents, etc.), biguanides, insulin, α-glucosidase inhibitors, β3 adrenergic receptor activators, dipeptidyl peptidase IV inhibitors, amyloid agonists 、Phosphotyrosine phosphatase inhibitors, sugar nascent inhibitors, SGLT (sodium-glucose co-transporter) inhibitors, or other diabetes treatment drugs, etc.), diabetes complications treatment drugs (for example: aldose reductase inhibitors, Glycosylation inhibitors, protein kinase C inhibitors, neurotrophic factors, neurotrophic factor-increasing drugs, nerve regeneration promoting drugs, or other diabetic complications treatment drugs, etc., hypertension treatment drugs (for example: angiotensin-converting enzyme inhibitor drugs, Calcium antagonists, potassium channel opening drugs, angiotensin II antagonists, etc.), hyperlipidemia treatment drugs (for example: HMG-CoA reductase inhibitors, fibrate compounds, squalene synthase inhibitors , Anti-oxidants, etc.), anti-obesity drugs (for example: pancreatic lipase inhibitors, central anti-obesity drugs, peptide appetite suppressants, cholecystokinin agonists, other anti-obesity drugs, etc.), arthritis treatment drugs, anti-obesity drugs Restless drugs, antidepressants, osteoporosis treatment drugs, antiepileptic drugs, chemotherapy drugs, immunotherapy drugs, anti-PD-1 antibodies, antithrombotic drugs, cognitive disease treatment drugs, erectile dysfunction improvement drugs, urinary incontinence/frequent urination Therapeutic drugs, dysuria drugs, nonsteroidal anti-inflammatory drugs, local anesthetics, vitamins, etc. are used in combination. In addition, it may be combined with hormones that promote secretion of other growth hormones (for example, GHRH), GH, IGF-1, cytokines, or cytokine action enhancers.

Furthermore, when the compound of the present invention is used for the prevention and/or treatment of symptoms of digestive organs accompanied by gastrointestinal occlusion, the drugs used in combination with the compound of the present invention include, for example, somatostatin analogs, Statin receptor activator, dopamine D2 receptor antagonist, histamine H1 receptor antagonist, admixture of histamine H1 receptor antagonist and PDE inhibitor, histamine H2 receptor antagonist, anticholinergic agent, serotonin 5HT3 Receptor antagonists, serotonin 5HT4 receptor antagonists, corticosteroids, NK1 receptor antagonists, non-formal antipsychotics (MARTA), opioids, opioid antagonists, etc. In other aspects, for example, it may be combined with prochlorperazine, levomepromazine, and the like.

When the compound of the present invention is used for the prevention and/or treatment of somatic dominant multiple cystic kidney disease, the drugs used in combination with the compound of the present invention include, for example, somatostatin analogs, somatostatin Agonist receptor action drugs, vasopressin V2 receptor antagonists, hypertension treatment drugs (for example: angiotensin-converting enzyme inhibitors, calcium antagonists, potassium channel opening drugs, angiotensin II antagonists, etc.), sclerosis Agent.

In addition, since patients with somatic dominant multiple cystic kidney disease often have pain, cystic infection, cystic hemorrhage, or other various diseases, the compounds of the present invention may also be combined with, for example, nonsteroidal anti-inflammatory drugs, opioids, and antibacterial drugs , Hemostatic drugs and other combinations.

When the compound of the present invention is used for the prevention and/or treatment of somatic dominant polycystic liver disease, the drugs used in combination with the compound of the present invention include, for example, somatostatin analogs, somatostatin Hormone receptors act as medicine, sclerosing agent, etc.

In addition, since patients with somatic dominant polycystic liver disease often suffer from pain, cyst infection, cyst bleeding or other various diseases, the compounds of the present invention may also be combined with, for example, nonsteroidal anti-inflammatory drugs, opioids, antibacterial Used in combination with medicines, hemostatic drugs, etc.

In the case where the compound of the present invention is used for the prevention and/or treatment of neuroendocrine tumors, as for drugs that can be used in combination with the compound of the present invention, for example, for the purpose of improving symptoms accompanied by excessive production of hormones, phytostatic Hormone analogues and somatostatin receptor activators, serotonin synthetase inhibitors, opioid receptor activators, proton pump inhibitors, histamine H2 receptor antagonists, hypoglycemia treatment drugs, insulin preparations, growth hormone Receptor antagonists, steroid synthesis inhibitors, steroid production inhibitors, etc.

Also, for example, for the purpose of improving symptoms accompanying tumor proliferation, somatostatin analogs and somatostatin receptor activators, interferon preparations, alkylating agents, molecular target drugs, peptide receptor radioactive nucleus therapy Medicine etc.

In addition, for example, for the purpose of diagnosing neuroendocrine tumors, somatostatin receptor scintillation scanning (indium pentriotide ( ¹¹¹ In), etc.) and the like can be cited.

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

Examples of somatostatin receptor acting drugs include compounds described in International Publication No. 2002/091125, International Publication No. 2003/042234, and International Publication No. 2003/045926. , The compound described in International Publication No. 2008/051272 pamphlet, the compound described in International Publication No. 2004/046107 pamphlet, the compound described in International Publication No. 2017/003723 pamphlet, the compound described in International Publication No. 2017/003724 pamphlet, etc.

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

Examples of the dopamine receptor activator include bromocriptine and cabergoline.

唑基甲氧基)苄基氧基亞胺基]-4-苯基酪酸)等。 Examples of the insulin resistance-improving drug include baglitazone (balaglitazone), nagoglitazone (netoglitazone), pioglitazone (rivoglitazone), rosiglitazone (rosiglitazone), Farglitazar, 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, the compounds described in International Publication No. 2001/038325 pamphlet, The compound described in International Publication No. 1999/058510 pamphlet (for example, (E)-4-[4-(5-methyl-2-phenyl-4-

Oxazolylmethoxy)benzyloxyimino]-4-phenylbutyric acid) etc.

Examples of sulfonylurea agents include acetohexamide, chlorpropamide, glibenclamide, gliclazide, and glimepiride. (glimepiride), glipizide, glybuzole, glypyramide, glyclopyramide, mitiglinide, nateglinide, repaglinide ), senaglinide (senaglinide), tolazamide (tolazamide), tolbutamide (tolbutamide), JTT-608 and so on.

Examples of biguanides include buformin, fenformin, metformin, and the like.

As for insulin, for example, animal insulin extracted from bovine or porcine pancreas, insulin extracted from porcine pancreas, semi-synthetic human insulin synthesized by enzyme method, genetically synthesized using coliform or yeast Human insulin, insulin containing 0.45 to 0.9 (w/w)% zinc Zinc, protamine insulin zinc made from zinc chloride, protamine sulfate, and insulin. In addition, insulin may be a fragment or derivative (for example, INS-1, etc.), or it may be an oral insulin preparation. In addition, although insulin includes super fast-acting type, fast-acting type, biphasic type, intermediate type, sustained type, etc., these can also be appropriately selected according to the morbidity of the patient.

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

Examples of the β3 adrenergic receptor acting drug include AJ-9677 and AZ40140.

Examples of the dipeptidyl peptidase IV inhibitors include sitagliptin, alogliptin, vildagliptin, linagliptin, and Anagliptin, saxagliptin, teneligliptin, bisegliptin, carmegliptin, evogliptin, octoliptin Gliagtin (omarigliptin), denagliptin (denagliptin), dugliptin (dutogliptin), gemgliptin (gemigliptin), gosagliptin (gosogliptin), meglitin (melogliptin), NVP-DPP -728, PT-100, P32/98, TS-021, TA-6666, KRP-104, DSP-7238, SYR-472 (trelagliptin), TAK-100, etc.

Examples of amyloid agonists include pramlintide and the like.

Examples of phosphotyrosine phosphatase inhibitors include sodium vanadate.

Examples of the glyconeogenesis inhibitory drugs include glycogen phosphorylase inhibitory drugs, glucose-6-phosphatase inhibitory drugs, and glucagon antagonists.

Examples of SGLT (sodium-glucose co-transporter) inhibitors include ipragliflozin, luseogliflozin, tofogliflozin, and canagliflozin. , Dapagliflozin, etc.

Examples of diabetes therapeutics other than the above include bromocriptine, leptin, BAY-27-9955, and GLP-1 receptor agonist (eg, GLP-1, GLP- 1MR agent, liraglutide, AC-2993 (exendin-4), BIM-51077, Aib (8,35) hGLP-1 (7,37) NH2, CJC-1131, exenatide ), etc.), GPR40 agonist (e.g. TAK-875, etc.), GPR119 agonist, 11β-hydroxysteroid dehydrogenase inhibitor (e.g. BVT-3498, etc.), adiponectin or its active agent, IKK inhibitor Medicines (for example: AS-2868, etc.), leptin resistance-improving drugs, somatostatin receptor acting drugs (for example: International Publication No. 2001/025228 brochure, International Publication No. 2003/042204 brochure, International Publication No. 1998/ 044921 pamphlet, International Publication No. 1998/045285 pamphlet, International Publication No. 1999/022735 pamphlet, etc. compounds, glucokinase activating drugs (for example: RO-28-1675, etc.), etc.

Examples of aldose reductase inhibitors include tolrestat, epalrestat, emirestat, imirestat, zenarestat, and festastat ( fidarestat), zopolrestat (zopolrestat), minastastat (minalrestat), ranirestat (ranirestat), CT-112, etc.

Examples of saccharification inhibitors include pimagedine, ALT-946, ALT766, and EXO-226.

Examples of protein kinase C inhibitors include ruboxistaurin mesylate.

Examples of neurotrophic factors include NGF, NT-3, and BDNF.

唑等)等。 Examples of neurotrophic factor-increasing drugs include neurotrophic factor production/secretion promoting drugs described in International Publication No. 2001/014372 (for example: 4-(4-chlorophenyl)-2-(2-methyl Yl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]

Azole, etc.) etc.

Examples of the nerve regeneration promoting drug include Y-128, VX-853, and prosaptide.

Examples of therapeutic drugs for diabetes comorbidities other than the above include, for example, alprostadil, tiapride, cilostazol, mexiletine, eicosapentaene Ethyl icosapentate, memantine, pimagedline, AGE inhibitors (eg ALT-946, alagbrium, pyridorin, pyridine Pyridoxamine, etc.), active oxygen elimination drugs (for example: thioctic acid, etc.), somatostatin receptor acting drugs (for example: BIM-23190), apoptosis signal regulating kinase-1 (ASK- 1) Obstruction medicine, etc.

Examples of angiotensin-converting enzyme inhibitors include captopril, enalapril, alapril, delapril, and lisinopril (lisinopril), midapril (imidapril), benazepril (benazepril), cilazapril (cilazapril), temocapril (temocapril), trandolapril (trandolapril), etc.

Examples of calcium antagonists include manidipine, nifedipine, amlodipine, efonidipine, and nicardipine.

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

二唑-3-基)聯苯-4-基]甲基]-2-乙氧基-1H-苯并咪唑-7-羧酸等。 Examples of angiotensin II antagonists include losartan, candesartan cilexetil, eprosartan, valsartan, and irbesartan. (irbesartan), olmesartan medoxomil, E4177, 1-[(2'-(2,5-dihydro-5-pentoxy-4H-1,2,4-

Diazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid and the like.

Examples of HMG-CoA reductase inhibitors include pravastatin, simvastatin, atorvastatin, fluvastatin, and pitavastatin. , Rosuvastatin (rosuvastatin) and so on.

Fibrate compounds include, for example, bezafibrate, clinofibrate, clofibrate, simfibrate, and fenofibrate. )Wait.

Examples of squalene synthetase inhibitors include compounds described in International Publication No. 1997/010224 pamphlet (for example: N-[[(3R,5S)-1-(3-acetoxy-2 ,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1- Benzoxazepine-3-yl]acetoyl]piperidine-4-acetic acid, etc.) etc.

Examples of the antioxidant include lipoic acid and probucol.

Examples of pancreatic lipase inhibitors include orlistat and cetilistat.

Examples of central anti-obesity drugs include mazindol, dexfenfluramine, dexfenfluramine, fluoxetine, sibutramine, and fenfluramine. ), phentermine, phenpropine, amfepramone, dexamfetamine, phenylpropanolamine, clobenzorex, etc.

Examples of the peptide appetite suppressant include leptin and CNTF (hair-like neurotrophic factor).

Examples of cholecystokinin agonists include lintitript and FPL-15849.

Anti-obesity drugs other than those mentioned above include, for example, lipstatin and MCH receptor antagonists (for example: compounds described in SB-568849, SNAP-7941, International Publication No. 2001/082925 pamphlet, and International Publication No. 2001/087834, the compounds described in the pamphlet, etc.), neuropeptide Y antagonists (for example: CP-422935, etc.), cannabinoid receptor antagonists (for example: SR-141716, rimonabant, etc.) , Cerebrointestinal peptide antagonists, 11β-hydroxysteroid dehydrogenase inhibitors (for example: BVT-3498, etc.), β3 agonists (for example: AJ-9677, AZ40140, etc.), feeding inhibitors (for example: P-57, etc. )Wait.

Examples of arthritis treatment drugs include ibuprofen and the like.

Examples of anti-restorative drugs include chlordiazepoxide, diazepam, oxazolam, medazepam, cloxazolam, and bromazepam. (bromazepam), lorazepam (lorazepam), alprazolam (alprazolam), fludiazepam (fludiazepam), etc.

As for antidepressants, for example, fluoxetine, fluvoxamine, imipramine, paroxetine, sertraline, etc.

For the treatment of osteoporosis, for example, alfacalcidol (alfacalcidol), calcitriol (calcitriol), elcatonin (elcatonin), salmon calcitonin (calcitonin salmon), estriol (estriol) ), ipriflavone, risedronate disodium, pamidronate disodium, alendronate sodium hydrate, icarronate disodium (incadronate disodium) etc.

Examples of antiepileptic drugs include gabapentin, trileptal, keppra, zonegran, pregabalin, and harkoseride. ), carbamazepine, etc.

Examples of chemotherapeutic drugs include alkylating agents (eg, cyclophosphamide, ifosfamide, etc.), and metabolic antagonists (eg, methotrexate) , 5-fluorouracil (5-fluorouracil), 5-fluorouracil derivatives (for example: dexifluororidine (doxifluridine), etc.), anti-cancer antibiotics (for example: mitomycin (mitomycin), doxorubicin (doxorubicin, etc.), plant-derived anticancer agents (eg, vincristine, vindesine, paclitaxel, etc.), cisplatin, carboplatin, etopo Glycosides (etoposide) and so on.

As for immunotherapy drugs, for example, microorganisms or bacterial components (for example: muramyl dipeptide derivatives, picibanil, etc.), and polysaccharides with immune-enhancing activity (for example: Lentinan (lentinan), sizofiran (sizofiran), Krestin (Krestin: registered trademark), etc.), cytokines obtained by genetic engineering methods (for example: interferon (interferon), interleukin ( interleukin: IL) (for example: IL-1, IL-2, IL-12, etc.), colony stimulating factors (for example: granulococcus colony stimulating factor, erythropoietin: EPO, etc.), etc.

Examples of anti-PD-1 antibodies include nivolumab and pembrolizumab.

Examples of antithrombotic drugs include heparin (for example, dalteparin, heparin, etc.), warfarin (for example: warfarin, etc.), and antithrombin drugs. (Eg: argatroban, etc.), thrombolytic drugs (eg: urokinase, tisokinase, alteplase, nateplase, monteplase) General enzyme (monteplase), (Pamiteplase, etc.), platelet aggregation inhibitors (for example: ticlopidine (ticlopidine), cilostazol (cilostazol), ethyl icosapentate (ethyl icosapentate), beraprost ( beraprost), sarpogrelate, etc.).

Examples of drugs for treating cognitive disorders include donepezil, galanthamine, rivastigmine, and tacrine.

Examples of drugs for improving erectile dysfunction include apomorphine and sildenafil.

Examples of urinary incontinence/frequent urinary treatment drugs include flavoxate, imidafenacin, oxybutynin, and propiverine.

Examples of drugs for treating dysuria include, for example, acetylcholinesterase inhibitors (for example, dirigmine).

Examples of non-steroidal anti-inflammatory drugs include acetaminophen, aspirin, and indometacin.

Examples of local anesthetics include capsaicin and lidocaine.

Examples of vitamins include vitamin B1 and vitamin B12.

Examples of dopamine D2 receptor antagonists include prochlorperazine, levomepromazine, risperidone, metoclopramide, and dopamine Ketone (domperidone) and so on.

Examples of histamine H1 receptor antagonists include diphenhydramine, chlorpheniramine, dimenhydrinate, and promethazine.

Examples of admixtures of histamine H1 receptor antagonists and PDE inhibitors include diphenhydramine/diprophylline admixtures.

Examples of histamine H2 receptor antagonists include famotidine and cimetidine.

Examples of anticholinergic drugs include scopolamine.

Examples of serotonin 5HT3 receptor antagonists include tropisetron, granisetron, ondansetron, azasetron, and remosetron. (ramosetron), indisetron (indisetron), palonosetron (palonosetron) and so on.

Examples of serotonin 5HT4 receptor antagonists include cisapride and mosapride.

Examples of corticosteroids include dexamethasone, betamethasone, and prednisolone.

Examples of NK1 receptor antagonists include aprepitant and fosaprepitant.

Examples of non-formal antipsychotic drugs (MARTA) include olanzapine, quetiapine, perospirone and the like.

Examples of opioids include morphine.

Examples of opioid antagonists include methylnaltrexone.

Examples of vasopressin V2 receptor antagonists include tolvaptan and the like.

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

Examples of hemostatic agents include tranexamic acid and the like.

Examples of serotonin synthase inhibitors include telotristat.

Examples of the opioid receptor acting drugs include loperamide and the like.

Examples of proton pump inhibitors include rabeprazole.

Examples of drugs for treating hypoglycemia include diazoxide and the like.

Examples of growth hormone receptor antagonists include pegvisomant.

Examples of steroid synthesis inhibitors include mitotane and the like.

Examples of steroid production inhibitors include ketoconazole and the like.

Examples of the interferon preparation include interferon α (interferon α).

Examples of molecular target drugs include everolimus and sunitinib.

The combination of the compound of the present invention and these other agents can be administered in the form of an admixture in which two components are blended in one preparation, or individual preparations can be administered in the same administration route or different administration systems Form. In the case of administration of individual preparations, it may not be necessary to administer at the same time, as needed The time difference between casting and setting. In addition, in the case of the time difference between administration and setting, the order of administration is not particularly limited, as long as it is properly adjusted to obtain the desired medicinal effect.

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 dosage of the drug or similar drugs. In addition, the blending ratio of the compound of the present invention and other agents can be appropriately adjusted in consideration of the age or weight of the subject, the method of administration, the time of administration, the disease and symptoms of the subject. In general, other agents can be combined in the range of 0.01 to 100 parts by weight with respect to 1 part by weight of the compound of the present invention. Plural kinds of other medicines can be used. In addition, other medicines may be medicines having the same mechanism as those listed above. This type of drug includes not only those who have been discovered today, but also those who will be discovered in the future.

The dosage of the compound of the present invention varies with age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but it is usually carried out in the range of 0.1 mg to 300 mg per person per adult per day Oral administration from 1 to several times, or non-oral administration of 1 to several times per day in the range of 0.1mg to 150mg per adult per person, or 1 hour to 1 hour per day Continuous intravenous administration within 24 hours.

Of course, as mentioned above, since the amount of injection varies according to various conditions, there may be a case where a smaller amount than the above-mentioned amount of injection is sufficient, and there may also be cases where the amount must be given beyond this range.

When the compound of the present invention is used as a single agent, or the compound of the present invention is combined with other agents to form a co-administration agent, when used for the purpose of prevention and/or treatment of the above diseases, the substance may be an effective ingredient of the substance and usually various additives or solvents Such pharmaceutically acceptable carriers are formulated together and administered systemically or locally, orally or parenterally. Among them, the pharmaceutically acceptable carrier means substances other than the active ingredients generally used in the preparation of pharmaceutical products. The pharmaceutically acceptable carrier is preferably one that does not show a pharmacological effect in the dosage of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. Also, pharmacy The above acceptable carrier can also be used for the purpose of improving the usefulness of the active ingredient and the preparation, making the preparation easier, stabilizing the quality, or improving the usability. Specifically, as long as the substance is appropriately selected according to the purpose, for example, it is described in the Pharmaceutical Affairs Daily 2000 "Pharmaceutical Additives Code" (edited by the Japan Pharmaceutical Additives Association).

The dosage form used for administration includes, for example, formulations for oral administration (eg, tablets, capsules, granules, powders, oral liquids, syrups, oral gels, etc.), oral cavity Preparations (for example: oral lozenges, oral sprays, oral semi-solid preparations, mouthwashes, etc.), injection preparations (for example: injections, etc.), dialysis preparations (for example: dialysis agents, etc.), inhalation Preparations (eg, inhalants, etc.), ophthalmic preparations (eg, eye drops, eye ointments, etc.), otic preparations (eg, ear drops, etc.), nasal preparations (eg, nose drops, etc.) , Rectal preparations (for example: suppositories, semi-solid rectal preparations, intestinal injections, etc.), vaginal preparations (for example: vaginal tablets, vaginal suppositories, etc.), and skin preparations (for example: external solid preparations, external liquid preparations) , Sprays, ointments, creams, gels, adhesives, etc.).

[Preparation for oral administration]

The preparations for oral administration include, for example, tablets, capsules, granules, powders, oral liquids, syrups, oral gels, and the like. In addition, preparations for oral administration include rapidly disintegrating preparations in which the release of the active ingredient from the preparation is not specifically adjusted, and, for example, enteric preparations or slow-release preparations whose release characteristics are adjusted according to the purpose through inherent preparation design and preparation methods Release-adjusting preparations and other release-adjusting preparations. Enteric preparations mean preparations designed in such a way that the active ingredients are not released in the stomach and are mainly released in the small intestine in order to prevent the active ingredients from decomposing in the stomach or to reduce the stimulation of the active ingredients on the stomach. It can be manufactured by applying a film using an acid-insoluble enteric base. The sustained-release preparation means a preparation that adjusts the release rate, release time, and release site of the active ingredient from the preparation for the purpose of reducing the number of administrations or reducing side effects. Generally, it can be manufactured by using an appropriate sustained-release agent. In preparations for oral administration, capsules and granules Agents, lozenges, etc. may be applied with suitable coating agents such as sugars, sugar alcohols, polymer compounds, etc. for the purpose of easy administration or prevention of decomposition of active ingredients.

(1) Lozenges

Lozenges are solid preparations with a certain shape administered orally, in addition to general lozenges such as naked lozenges, film-coated lozenges, sugar-coated lozenges, multi-layered lozenges, and cored lozenges, and also include oral rapid disintegrating lozenges. , Chewing tablets, foaming tablets, dispersing tablets, dissolving tablets, etc. When manufacturing bare ingots, the following methods (a), (b), or (c) can generally be used:

(a) Add additives such as excipients, binders, and disintegrants to the active ingredients and mix them to homogeneity. After using a solution containing water or a binder to form granules by an appropriate method, add lubricants and mix , And compression molding;

(b) Add additives such as excipients, binders, and disintegrants to the active ingredients and mix them to homogenize, then perform direct compression molding, or add active ingredients and lubricants to the granules made with additives in advance and mix to homogenize After that, compression molding;

(c) By adding additives such as excipients, binders, etc. to the active ingredients, they are mixed to be homogeneous, and the kneaded compound wetted by the solvent is poured into a certain mold for molding, and then dried by an appropriate method.

Film-coated tablets can usually be produced by applying a thin coating of a suitable coating agent such as a polymer compound to the bare tablet. Sugar-coated tablets can generally be manufactured by applying a skin as a coating agent containing sugars or sugar alcohols to bare tablets. Multi-layer ingots can be manufactured by suitable methods, by layering different powders and granules of the composition in layers and by compression molding. Core ingots can be manufactured by coating inner core ingots with different compositions. In addition, the lozenges can also be formed into enteric-coated tablets or sustained-release tablets using well-known appropriate techniques. Rapidly disintegrating tablets, chewable tablets, foaming tablets, dispersing tablets, and dissolving tablets in the oral cavity can be manufactured according to the above-mentioned tablet manufacturing method by appropriately selecting additives and giving unique functions to the tablets. Furthermore, the rapid disintegration tablet in the oral cavity means that it can be quickly dissolved or disintegrated in the oral cavity Tablets taken; chewable tablets mean tablets taken by chewing; foamed tablets mean tablets that rapidly foam in water while dissolving or dispersing; dispersible tablets mean tablets taken in water and dissolved; dissolved Lozenges mean lozenges that are dissolved in water and taken. The foamed ingot can be manufactured by using an appropriate acidic substance, carbonate, bicarbonate, etc. as an additive.

(2) Capsule

Capsules are preparations filled in capsules or coated with capsule bases, including hard capsules and soft capsules. Hard capsules can be manufactured by adding additives such as excipients to the active ingredient and mixing them into homogenous ones, or forming granules or shaped articles by an appropriate method, as they are in capsules, or simply filling them in a simple form. Soft gelatin capsules can be manufactured by coating additives in a suitable shape with plasticizers such as glycerin, D-sorbitol and other plastics-enhancing gelatin added with additives to the active ingredient. Capsules can also be formed into enteric capsules or sustained-release capsules using well-known appropriate techniques, and colorants or preservatives can also be added to the capsule base.

(3) Granules

Granules are granulated preparations. In addition to the granules, they also include foamable granules. When manufacturing granules, the following methods (a), (b), or (c) are generally used:

(a) After adding excipients, binders, disintegrating agents, or other additives to the powdery active ingredients and mixing them to homogenization, granules are formed by an appropriate method;

(b) Add additives such as excipients to the active ingredients that have been granulated in advance, and mix to become homogeneous;

(c) Add additives such as excipients to the active ingredients that have been granulated in advance, mix them, and form granules by an appropriate method.

In the granules, the skin may be applied as needed, or a well-known appropriate method may be used to form enteric granules or sustained-release granules. Foaming granules can be prepared by combining appropriate acidic substances, carbonates, carbonic acid Hydrogen salts are used for additives. Furthermore, the foamed granules mean granules that rapidly foam while dissolving or dispersing in water. Granules can also be formed into fine granules by adjusting the size of the particles.

(4) Powder

Powders are powdered preparations, and can usually be manufactured by adding excipients or other additives to the active ingredient, mixing and homogenizing.

(5) oral solution

Oral liquid preparations are liquid or fluid viscous, gel-like preparations. In addition to those generally called oral liquid preparations, they also contain elixirs, suspensions, emulsions, lemon juices, etc. Oral liquid preparations can usually be manufactured by adding additives and purified water to the active ingredients, mixing and uniformly dissolving, or emulsifying or suspending, and filtering as necessary. Elixir means a sweet and aromatic clear liquid oral solution containing ethanol, usually by adding ethanol, purified water, perfume, and white sugar, other sugars to the solid active ingredient or its leachate, or Sweeteners are manufactured by dissolving, filtering or other methods to form a clear liquid. Suspending agent means an oral liquid agent that finely and homogeneously suspends the active ingredient. Usually, the suspension can be suspended in an appropriate method by adding a suspending agent or other additives and refined water or oil to the solid active ingredient to homogenize the whole. manufacture. Emulsion means an oral liquid agent in which the active ingredient is finely and homogeneously emulsified. Generally, it can be produced by adding an emulsifier and purified water to the liquid active ingredient, emulsifying it by an appropriate method, and homogenizing the whole. In addition, the lemon juice agent means a clear liquid oral liquid agent having sweet and sour taste.

(6) Syrup

Syrup is a viscous liquid or solid preparation containing sugars or sweeteners, and contains agents for syrup and the like. Syrups can usually be dissolved, mixed, suspended, or emulsified by adding active ingredients to a solution of white sugar, other sugars, or sweeteners, or a simple syrup, and if necessary, the mixture is boiled and filtered while hot And manufacture. The syrup agent means a granular or powder preparation that becomes syrup if water is added, also known as dry sugar Slurry. The agent for syrup can usually be produced using sugars or sweeteners as additives according to the manufacturing method of the aforementioned granules or powders.

(7) Oral gel

Oral gels are non-fluid, shaped, gel-like preparations, which can usually be manufactured by adding additives and high-molecular gum bases to the active ingredients and mixing them, gelling them in an appropriate method, and forming into a certain shape. .

[Oral preparation]

(1) Oral lozenges

Oral lozenges are solid preparations of a certain shape suitable for use in the oral cavity, including throat tablets, sublingual tablets, buccal tablets, adherent tablets, chewing gum, etc. Oral lozenges can generally be manufactured according to the manufacturing method of the aforementioned lozenges. In addition, a throat tablet means an oral lozenge that can slowly dissolve or disintegrate in the oral cavity and is suitable for local use in the oral cavity, pharynx, etc.; a sublingual lozenge means that the active ingredient dissolves quickly under the tongue and is absorbed from the oral mucosa Oral lozenges; oral lozenges mean oral lozenges that slowly dissolve active ingredients between molars and cheeks and are absorbed from the oral mucosa; adherent lozenges mean oral lozenges used for attachment to oral mucosa; chewing gum An agent means an oral lozenge that releases the active ingredient by chewing.

(2) Oral spray

Oral sprays are preparations in which the active ingredients are sprayed into a mist, powder, foam, or paste. Usually, the active ingredients and additives are dissolved or suspended in a solvent or the like. After filtration, if necessary, the The liquefied gas or compressed gas is filled in the container together, or the solution or suspension is prepared by using active ingredients and additives, filled in the container, and manufactured by installing a jet pump.

(3) Semi-solid preparation for oral cavity

Oral semi-solid preparations are preparations suitable for oral mucosa, including creams, glues, ointments, etc. Oral semi-solid preparations can usually be manufactured by emulsifying the active ingredients and additives in oily ingredients such as purified water and petrolatum, or using polymer gums or oils as a base, mixing them with the active ingredients and additives, and homogenizing it. . Cream refers to a semi-solid preparation emulsified in an oil-in-water or water-in-oil type. The lipophilic preparation emulsified in a water-in-oil type is also called an oily cream. Creams can usually be formed by adding petroleum jelly, higher alcohols, etc., or additives such as emulsifiers to form an oil phase. In addition, adding purified water as it is, or additives such as emulsifiers, to form an aqueous phase, it is effective to add in either phase The ingredients are heated separately, the oil phase and the water phase are combined, stirred until the whole becomes homogeneous, and emulsified to produce. Glue means a gel-like preparation, including water-based glue, oily glue and so on. The water-based glue can be manufactured by dissolving or suspending the active ingredient by adding a polymer compound, other additives, and purified water, heating and cooling, or by adding a gelling agent for cross-linking. The oily adhesive can be produced by adding and mixing liquid oily bases such as glycols and higher alcohols and other additives to the active ingredient. Ointment means a semi-solid preparation that dissolves or disperses the active ingredient in the base, and includes oily ointment, water-soluble ointment and the like. Grease-based ointments can usually be produced by heating and melting fat-based bases such as greases, waxes, paraffins, and other hydrocarbons, adding active ingredients, mixing to dissolve or disperse them, and kneading until the whole becomes homogeneous. The water-soluble ointment can usually be produced by heating and melting a water-soluble base such as polyethylene glycol (Macrogol), adding active ingredients, and kneading until the whole becomes homogeneous.

(4) Coughing agent

The cough-containing agent is a local liquid preparation suitable for oral cavity, pharynx, etc., and also includes a solid preparation used when dissolved. Coughing agents are usually manufactured by adding solvents and additives to the active ingredients, mixing them to dissolve them homogeneously, and filtering as necessary. In the case of a solid preparation used for dissolution during use, it can usually be manufactured according to the manufacturing method of the aforementioned lozenges or granules.

[Preparation for injection]

(1) Injection

Injections are solid sterile preparations that are directly administered to subcutaneous, intramuscular, or blood vessel tissues or organs such as solutions, suspensions, or emulsions, or dissolved or suspended when used, except for those who are generally called injections. In addition, freeze-dried injections, powder injections, prefilled syringes, cartridges, infusions, implantable injections, and continuous injections are also included. When manufacturing injections, the following methods (a) or (b) are usually used:

(a) The active ingredient is added as it is, or the additive is added to the active ingredient, dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents, etc. to form a homogenous one, and filled in the container for injection, And sealed, sterilized;

(b) The active ingredient is added as it is, or the additive is added to the active ingredient, dissolved, suspended, or emulsified in water for injection, other aqueous solvents, or non-aqueous solvents, etc., and homogenized, and then it is sterile filtered or aseptically It is prepared in a homogenous manner, filled in a container for injections, and sealed.

Freeze-dried injections can usually be prepared by dissolving the active ingredients as they are, or by dissolving the additives such as active ingredients and excipients in water for injection, performing sterile filtration, filling the containers for injections, and freeze-drying them, or freeze-drying them in special containers. It is manufactured by directly filling the container. Powder injections can usually be manufactured by aseptic filtration, adding the powder obtained by crystallization or adding sterilized additives to the powder, and filling the container for injection. Pre-filled syringes can usually be prepared by using the active ingredient as it is, or the active ingredient and additives, preparing a solution, suspension, or emulsion, and filling the syringe. Cartridge means an injection used by filling a cartridge filled with a drug solution into a syringe for use. The cartridge filled with a drug solution can usually be prepared by using the active ingredient as it is, or the active ingredient and additives, to prepare a solution, The suspension or emulsion is filled in a cartridge and manufactured. Infusion means to administer intravenously, through Often injections above 100mL. Implantable injection means solid or colloidal injection suitable for the purpose of long-term release of active ingredients by using instruments implanted subcutaneously, intramuscularly, or for surgery. Implantable injections can usually be produced by using biodegradable polymer compounds to form pellets, microspheres, or gels. Sustained injection means an injection that is suitable for intramuscular use for the purpose of releasing the active ingredient for a long period of time. Usually, the active ingredient can be dissolved or suspended in vegetable oil or the like, or a biodegradable polymer compound is used to form a suspension of microspheres. And manufacture.

[Preparation for dialysis]

(1) Dialysis agent

The agent for dialysis is a liquid preparation used for peritoneal dialysis or hemodialysis or a solid preparation dissolved during use, and includes an agent for peritoneal dialysis and an agent for hemodialysis. Peritoneal dialysis agent means a sterile dialysis agent used for peritoneal dialysis. Usually, an additive is added to the active ingredient and dissolved in the solvent to form a certain volume, or the additive is added to the active ingredient to fill the container. , Sealed and sterilized if necessary. In the case of a solid preparation that dissolves during use, it can usually be manufactured according to the manufacturing method of the aforementioned lozenges or granules. Hemodialysis agent means a dialysis agent used for hemodialysis. Usually, it can be manufactured by adding an additive to the active ingredient, dissolving it in a solvent to form a certain volume, or filling the container with an additive to the active ingredient. . In the case of a solid preparation that dissolves during use, it can usually be manufactured according to the manufacturing method of the aforementioned lozenges or granules.

[Preparation for inhalation]

(1) Inhalant

An inhalant is an inhalation of an active ingredient as an aerosol (aerosol) and is suitable for bronchial or lung preparations, and includes powder inhalers, inhalation liquids, and inhalation aerosols. Powder inhaler means a preparation in which the amount of inhalation is adjusted into a prescribed manner to form an aerosol of solid particles and usually inhaled by making the active ingredient fine The particles are produced by mixing with additives such as lactose to make them homogeneous. Inhalation liquid means a liquid inhalation used by a nebulizer, etc., usually can be mixed and uniformly dissolved or suspended by adding a solvent and an appropriate isotonicity agent, pH adjusting agent, etc. to the active ingredient, as needed Manufactured by filtration. Inhalation aerosol means a fixed-quantity spray inhaler that sprays a certain amount of active ingredient together with the propellant filled in the container. Inhalation aerosols can usually be formed by adding solvents and appropriate dispersants, stabilizers, etc. to the active ingredients to form a solution or suspension, filling it with a liquid propellant in a pressure-resistant container, and installing a quantitative valve And manufacture.

[Ophthalmic preparation]

(1) Eye drops

Eye drops are liquid sterile preparations suitable for eye tissues such as conjunctival sacs, or solid sterile preparations used when dissolved or suspended when used. Eye drops can usually be manufactured by adding additives to the active ingredient, dissolving or suspending them in a solvent, etc. to form a certain volume, or adding additives to the active ingredient to fill the container.

(2) Eye ointment

Eye ointment is a semi-solid sterile preparation suitable for ocular tissues such as conjunctival sac. It can usually be made by mixing a base such as petroleum jelly with a solution or fine powder of active ingredients to make it homogeneous and filling it into a container.

[Preparation for otology]

(1) Ear drops

Eardrops are liquid, semisolid preparations that are administered to the outer or middle ear, or solid preparations that are dissolved or suspended when used. Eardrops can usually be manufactured by adding additives to the active ingredient, dissolving or suspending them in a solvent or the like to a prescribed capacity, or adding additives to the active ingredient to fill the container.

[Nasal preparation]

(1) Nasal agent

Nasal preparations are preparations administered to the nasal cavity or nasal mucosa, and include nasal preparation powders, nasal preparations, etc. Nose powder refers to a micro-powder nostril administered to the nasal cavity. It can usually be produced by mixing the active ingredients into moderately fine particles and mixing them with additives as needed to make it homogeneous. Nasal drip means a liquid nasal drip administered to the nasal cavity, or a solid nasal drip used to dissolve or suspend when used. Usually, it can be dissolved or suspended by adding solvents and additives to the active ingredients. , And filter and manufacture as needed. As for the additives for nasal drops, isotonicity agents, pH adjusting agents and the like can be used.

[Preparation for rectum]

(1) Suppositories

Suppositories are semi-solid preparations of the prescribed shape that are suitable for use in the rectum, melting at body temperature, or slowly dissolving or dispersing in water to release the active ingredient. Suppositories can usually be prepared by adding additives such as dispersants and emulsifiers to the active ingredients and mixing them into uniforms, heating them and dissolving or evenly dispersing them in the liquefied base, and then filling the container with a certain amount to perform Manufactured by curing/forming. As the base of suppositories, generally, an oily base or a hydrophilic base can be used.

(2) Semi-solid preparation for rectum

The rectal semi-solid preparation is a preparation suitable for use in or around the anus, and includes a rectal cream, a rectal gel, and a rectal ointment. Rectal semi-solid preparations can usually be manufactured by emulsifying active ingredients and additives together with oily ingredients such as purified water and petrolatum, or using polymer gums or fats as a base and mixing them with the active ingredients and additives to make them homogeneous. Rectal creams can usually be formed by adding petroleum jelly, higher alcohol, etc., or adding additives such as emulsifiers to form the oil phase. In addition, the purified water as is, or adding emulsifiers and other additives to form the water phase, in either phase Add active ingredients to them, heat them separately, combine the oil phase and the water phase, and stir and emulsify the whole until homogeneous. Rectal glue means a gel-like preparation, including water-based glue, oily glue and the like. The water-based adhesive can be added by adding a polymer compound to the active ingredient Products, other additives and purified water to dissolve or suspend them, heating and cooling, or adding gelling agents for cross-linking. The oily adhesive can be produced by adding and mixing liquid oily bases such as glycols and higher alcohols and other additives to the active ingredient. Rectal ointment refers to a semi-solid preparation in which the active ingredient is dissolved or dispersed in a base, and includes an oily ointment, a water-soluble ointment, and the like. Grease-based ointments can usually be produced by heating and melting grease-based bases such as greases, waxes, paraffins, and other hydrocarbons, adding active ingredients, mixing them, dissolving or dispersing them, and kneading until the whole becomes homogeneous. The water-soluble ointment can usually be produced by heating and melting a water-soluble base such as polyethylene glycol, adding active ingredients, and kneading until the whole becomes homogeneous.

(3) Enema

Enema is a liquid or viscous gel preparation suitable for passing into the anus. Usually, by using purified water or an appropriate aqueous solvent, the active ingredient is dissolved or suspended in the solvent, etc. to become a certain volume and filled in the container Made in China. As an additive for an enema, a dispersant, a stabilizer, a pH adjuster, etc. can be used.

[Vagina preparation]

(1) vaginal tablets

A vaginal tablet is a solid preparation of a certain shape that is suitable for the vagina and slowly dissolves or disperses in water to release the active ingredient. It can usually be manufactured according to the manufacturing method of the aforementioned tablet.

(2) Suppositories for vagina

Suppositories for the vagina are semi-solid preparations of a certain shape that are suitable for the vagina, melt by body temperature, or slowly dissolve or disperse in water to release the active ingredient, and can generally be manufactured according to the manufacturing methods of the aforementioned suppository for rectum and the like.

[Skin preparation]

(1) External solid agent

The external solid agent is a solid preparation that is coated or spread on the skin or nails including the scalp, and includes an external powder and the like. The external powder means a powdery solid preparation for external use. Usually, it can be manufactured by adding additives such as excipients to the active ingredient, mixing it into a homogeneous material, and then producing it in powder form.

(2) External liquid

The external liquid preparation is a liquid preparation applied to the skin or nails including the scalp, and includes a lotion, lotion, and the like. Liquid preparations for external use can usually be manufactured by adding solvents, additives, etc. to the active ingredients to dissolve, emulsify, or suspend them, and filter them as necessary. Rubbing means liquid or muddy liquid for rubbing into the skin. Lotion means an external liquid solution that dissolves or emulsifies or finely disperses active ingredients in an aqueous liquid. Usually, the entire system can be formed by using active ingredients, additives, and purified water to form a solution, suspension, or emulsion. Made homogeneous.

(3) Spray

Sprays are preparations in which the active ingredients are sprayed on the skin in the form of mist, powder, foam, or paste, and include external aerosols and pump sprays. Sprays can usually be prepared by preparing solutions or suspensions of active ingredients, filtering them as needed, and filling them in containers. External aerosol means a spray in which the active ingredient is sprayed together with the liquefied gas or compressed gas filled in the container. External aerosols can usually be manufactured by preparing a solution or suspension of active ingredients, filling a pressure-resistant container with a liquid propellant, and installing a continuous spray valve. In external aerosols, additives such as dispersants and stabilizers can also be added as needed. Pump spray means a spray that sprays the active ingredients in the container by a pump. Pump sprays can usually be manufactured by dissolving or suspending active ingredients and additives, and installing pumps in filled containers.

(4) Ointment

Ointments are semi-solid preparations that are applied to the skin and dissolve or disperse the active ingredients in the base. They include oily ointments and water-soluble ointments. Grease-based ointment can usually be obtained by combining grease, wax, paraffin Grease-based bases such as hydrocarbons are melted by heating, the active ingredients are added, mixed to dissolve or disperse, and kneaded until the whole becomes homogeneous and manufactured. The water-soluble ointment can usually be produced by heating and melting a water-soluble base such as polyethylene glycol, adding active ingredients, and kneading until the whole becomes homogeneous.

(5) Cream

Creams are semi-solid preparations that are applied to the skin and emulsified in an oil-in-water or water-in-oil type, and lipophilic preparations emulsified in a water-in-oil type are also called oily creams. Creams can usually be prepared by adding petroleum jelly, higher alcohol, etc., or adding additives such as emulsifiers to the oil phase. In addition, refining water as is, or adding emulsifiers and other additives to the water phase, either Add active ingredients to the phase, heat them separately, combine the oil phase and the water phase, knead until the whole becomes homogeneous, and emulsify to manufacture.

(6) Adhesive

The adhesive is a gel-like preparation applied to the skin, and includes an aqueous adhesive, an oily adhesive, and the like. The water-based adhesive can be manufactured by adding a polymer compound, other additives and purified water to the active ingredient to dissolve or suspend it, heating and cooling, or adding a gelling agent to bridge. Oily adhesives can be produced by adding liquid oily bases such as glycols and higher alcohols and other additives to the active ingredients and mixing them.

(7) Adhesive

Adhesives are preparations that are attached to the skin and include adhesive tapes, dressings, and the like. Adhesives can usually be produced by using a high molecular compound or a mixture of these as a base, mixing the active ingredient with the base to form a homogenous material, and forming it on a support or a liner (peeling body). In addition, a percutaneous absorption type preparation can also be formed using a release regulating film. For adhesives, additives such as adhesives or absorption accelerators can also be used as needed. The adhesive plaster means a patch using a base that hardly contains water, and includes plasters, plasters, and the like. Adhesives are usually made by using water-insoluble natural or synthetic polymer compounds such as resins, plastics, and rubbers as the base, so that the active ingredients are as they are, or all the additives added to the active ingredients are homogenized, and then spread on the cloth or exhibition. In Plastic film, etc., or enclosed in it, made by molding. Moreover, it can also be manufactured by encapsulating a mixture composed of an active ingredient and a base or other additives into a release body formed of a release regulating film, a support, and a liner body (peeling body), and molding. A compress means a patch using a water-based base. Usually, the active ingredient is mixed with liquid substances such as purified water and glycerin to make the whole homogeneous, or water-soluble polymers, water-absorbing polymers and other natural Or a synthetic polymer compound is kneaded with purified water, and the active ingredient is added to make the whole homogeneous, and it is manufactured by spread molding on cloth and the like.

Unless otherwise defined, all technical, scientific terms, and abbreviations used in this specification have the same meaning as those generally understood by those skilled in the art to which the field of the invention belongs.

In addition, in this specification, the contents of all patent documents and non-patent documents or references explicitly cited are cited as if they were all part of this specification.

[Example]

Hereinafter, the present invention will be described in detail through examples and biological examples, but the present invention is not limited to these. The compound names of the present invention and the compound names shown in the examples are named according to 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 medium pressure fractionation liquid chromatography indicates the type of column used (Hi-flash SI: silicone (made by Shanshan Co., Ltd.), Hi-flash NH: aminopropyl support type silicone rubber (made by Shanshan Co., Ltd.)).

HPLC retention time (minutes) is the measured value under the following conditions:

Column: YMC Triart C ₁₈ (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0mm 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 (record the ratio of mobile phase (A): mobile phase (B)): [0 points] 95: 5; [0.1 points ] 95:5; [1.2 points] 5:95; [1.4 points] 5:95; [1.41 points] 95:5; [1.5 points] 95:5; detectors: UV (PDA), ELSD, MS.

The numerical value shown at the NMR point is the measured value (chemical shift value) of ¹ H-NMR when the measurement solvent described is used.

In addition, the biological Example 4 described later is an example of a test showing the usefulness of the compound of the present invention for terminal hypertrophy, but it is not intended to limit the target disease of the compound of the present invention. As described above, the compound of the present invention is useful for preventing and/or treating all diseases in which somatostatin itself or hormones regulated by somatostatin are involved.

Reference Example 1

唑并[5,4-c]吡啶-1(2H)-羧酸三級丁酯 (3aS,7aR)-5-(3-bromo-5-methylpyridin-4-yl)-2,2-dimethylhexahydro[1,3]

Triazolo[5,4-c]pyridine-1(2H)-carboxylic acid tertiary butyl ester

唑并[5,4-c]吡啶-1(2H)-羧酸三級丁酯(CAS編號1173005-74-7，日本專利公開公報第2009-155283號之實施例8記載的化合物)(4.99g)之N,N-二甲基乙醯胺(以下，簡稱為DMA)溶液(40mL)中添加三乙基胺(4.53mL)，於100℃攪拌5小時。將反應液冷卻至室溫後，用水稀釋，並以乙酸乙酯萃取。藉由將有機層於減壓下濃縮所得到之殘餘物以中壓分取液體層析(Hi-flash SI)(n-己烷：乙酸乙酯=90：10~0：100)精製，得到具有以下之物性值的標題化合物(6.08g)。 In 5-bromo-4-chloropyridine-3-carbaldehyde (CAS number 1060802-24-5, ASTATECH company catalog number 66142) (3.58g) and (3aS, 7aR)-2,2-dimethylhexahydro[ 1,3]

Triazolo[5,4-c]pyridine-1(2H)-carboxylic acid tertiary butyl ester (CAS No. 1173005-74-7, compound described in Example 8 of Japanese Patent Publication No. 2009-155283) (4.99 g) To a solution (40 mL) of N,N-dimethylacetamide (hereinafter, abbreviated as DMA) was added triethylamine (4.53 mL) and stirred at 100°C for 5 hours. After cooling the reaction solution to room temperature, it was diluted with water and extracted with ethyl acetate. The residue obtained by concentrating the organic layer under reduced pressure was purified by medium-pressure liquid chromatography (Hi-flash SI) (n-hexane:ethyl acetate=90:10~0:100) to obtain The title compound (6.08g) having the following physical properties.

HPLC retention time (minutes): 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 2

唑并[5,4-c]吡啶-1(2H)-羧酸三級丁酯 (3aS,7aR)-5-[3-(3,5-difluorophenyl)-5-methylpyridin-4-yl]-2,2-dimethylhexahydro[1,3]

Triazolo[5,4-c]pyridine-1(2H)-carboxylic acid tertiary butyl ester

烷(10mL)溶液中，添加磷酸三鉀(144mg)、水(3mL)、3,5-二氟苯基硼酸(54mg)、及雙(二-三級丁基(4-二甲基胺基苯基)膦)二氯鈀(II)(4.8mg)，並於100℃攪拌1小時。讓反應液回至室溫，並用乙酸乙酯稀釋後，以水及飽和食鹽水洗淨。將有機層於減壓下濃縮，得到具有以下之物性值的標題化合物(107mg)。 1,4-Di of the compound (100 mg) produced in Reference Example 1

To the alkane (10mL) solution, add tripotassium phosphate (144mg), water (3mL), 3,5-difluorophenylboronic acid (54mg), and bis(di-tertiary butyl (4-dimethylamino) Phenyl)phosphine) dichloropalladium (II) (4.8 mg), and 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 brine. The organic layer was concentrated under reduced pressure to obtain the title compound (107 mg) having the following physical properties.

HPLC retention time (minutes): 0.92; MS (ESI, Pos.): 474 (M+H) ⁺ .

Reference Example 3

唑并[5,4-c]吡啶-1(2H)-羧酸三級丁酯 (3aS,7aR)-5-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)pyridin-4-yl]-2 ,2-dimethylhexahydro[1,3]

Triazolo[5,4-c]pyridine-1(2H)-carboxylic acid tertiary butyl ester

To the DMA (3 mL) solution of the compound (56 mg) produced in Reference Example 2 and 1,2-diamino-4,5-difluorobenzene (19 mg), add sodium bisulfite (25 mg), and add Stir at 120°C for 5 hours. After cooling the reaction solution to room temperature, it was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain the title compound (70 mg) having the following physical properties.

HPLC retention time (min): 0.95; MS (ESI, Pos.): 598 (M+H) ⁺ .

Reference Example 4

(3S,4R)-4-amino-1-(3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4- Pyridyl]-3-piperidinol

To a dichloromethane (2 mL) solution of the compound (70 mg) produced in Reference Example 3, trifluoroacetic acid (2 mL) was added at room temperature, stirred for 30 minutes, and concentrated. By refining the obtained residue by medium-pressure liquid chromatography (Hi-flash NH) (ethyl acetate: methanol=100:0 to 80:20), the compound of the present invention having the following physical property values ( 37mg).

HPLC retention time (minutes): 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.

Example 1

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

(In the structural formula, the dotted line indicates the other side of the paper surface (that is, α-configuration) bonding)

To a solution of the compound (72 mg) produced in Reference Example 4 and 3-oxetanone (90 mg) in methanol (5 mL), 2-picoline borane complex (34 mg) and acetic acid (0.1 mL) were added , Stir at room temperature for 24 hours. By concentrating the reaction solution under reduced pressure, the resulting residue was purified by medium pressure liquid chromatography (Hi-flash NH) (ethyl acetate: methanol=100:0~80:20) to obtain The title compound (60 mg) with the following physical properties.

Properties: amorphous; HPLC retention time (minutes): 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 2

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol phosphate type A crystal

The compound (1 g) produced in Example 1 was dissolved in ethanol (3 mL) at 75° C., and a phosphoric acid aqueous solution (225 mg) having a concentration of 85% was added and stirred. Ethanol (1 mL) and ethyl acetate (3 mL) were added, cooled to 25°C, and stirred for 1 hour. The resulting precipitate was collected by filtration, and dried to obtain crystals (1.17 g) of the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 8.85, 8.36, 7.67-7.58, 7.19-7.04, 4.85-4.75, 4.74-4.67, 4.65-4.58, 4.43-4.27, 3.91-3.77, 3.28-3.12, 3.11-2.83 , 2.38, 1.78-1.59, 1.55-1.41.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 1, the graph of differential scanning calorimetry (DSC) is shown in FIG. 2, and the thermogravimetric measurement (TG ) Is shown in Figure 3.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] Table 1 shows the results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays.

[Table 1] (Table 1)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.09mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~300℃)

Endothermic: initial temperature is about 236℃, peak temperature is about 248℃

Fever: The starting temperature of the fever peak is about 270℃

(3) Thermogravimetric measurement (TG)

Installation: TGA851e by Mettler Toledo

Sample volume: 1.85mg

Sample tank: aluminum tank (without cover)

Nitrogen flow: 60mL/min

Heating rate: 10℃/min (4) Analytical data of single crystal X-ray diffraction spectrum structure

Device: Physical and Chemical SuperNova

Target: CuKα(λ=1.54184Å)

Voltage: 50kV

Current: 0.8mA

Scanning width: 1°

[Result] The data of crystallography is the following.

Lattice constant: a=9.4124(3)Å b=21.7324(6)Å c=27.2349(9)Å

Space Group: P212121(#19)

R factor: 0.4750

Table 2 below shows the position parameters (partial atomic coordinates) of the A-type crystals of phosphate at room temperature (×10 ⁴ ).

[Table 2-1] (Table 2)

[Table 2-2] (Table 2) continued -1

[Table 2-3] (Table 2) continued-2

[Table 2-4] (Table 2) continued-3

[Table 2-5] (Table 2) continued -4

Example 3

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -D crystal of (3-oxetanylamino)-3-piperidinol phosphate N hydrate (N=3~4)

Distilled water (100 μL) was added to the compound (20 mg) produced in Example 2 to suspend it, and stirred at 25°C overnight. The crystals were collected by filtration and dried to obtain crystals (20 mg) of the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 8.83, 8.35, 7.82-7.58, 7.29-7.06, 4.82-4.68, 4.63, 4.42-4.30, 3.93-3.78, 3.24-3.12, 3.11-2.74, 2.38, 1.79-1.59 , 1.54-1.41.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 4, the graph of differential scanning calorimetry (DSC) is shown in FIG. 5, and the graph of thermogravimetric measurement (TG) is shown in FIG. 6 Figure.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 3.

[Table 3] (Table 3)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 0.93mg

Sample tank: aluminum tank (with cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (5~230℃)

Endothermic: initial temperature is about 52℃, peak temperature is about 91℃

Fever: Fever start temperature is about 119℃

(3) Thermogravimetric measurement (TG)

Device: STA7200RV manufactured by Hitachi High-Technologies Corporation

Sample volume: 1.30mg

Sample tank: aluminum (without cover)

Nitrogen flow: 100mL/min

Heating rate: 10℃/min

[Result] From about room temperature to about 119°C, it showed a weight loss of about 9.7%.

Example 4

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol adipate type B crystal

Adipic acid (1.31 g) and isopropyl acetate (92 mL) were added to the compound (4.61 g) produced in Example 1, and stirred at 25°C for 2 days. The produced precipitate was collected by filtration and dried to obtain crystals (5.54 g) of the title compound having the following physical properties.

¹ H-NMR(CD ₃ OD): δ 8.90,8.34,7.69-7.57,7.16-7.04,4.81-4.68,4.58,4.47,4.15-4.06,3.73-3.66,3.18-3.07,3.05-2.92,2.92-2.75 , 2.58-2.49, 2.38-2.19, 1.72-1.47, 1.39-1.27.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 7, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 8.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 4.

[Table 4] (Table 4)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e differential scanning calorie analysis device made by Mettler Toledo

Sample volume: 1.12mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~150℃)

Endothermic: the initial temperature is about 140 ℃, the peak temperature is about 145 ℃

Example 5

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol 1/2 fumarate type I crystal

Fumaric acid (620 mg) and isopropyl acetate (55 mL) were added to the compound (5.5 g) produced in Example 1, and stirred at 80°C for 15 minutes. N-Heptane (55 mL) was added, and the mixture was further stirred at 80°C for 30 minutes. By cooling to 25°C, the resulting precipitate was collected by filtration and dried to obtain crystals (5.9 g) of the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 8.86, 8.34, 7.65-7.56, 7.15-7.05, 6.68, 4.84-4.71, 4.63, 4.53, 4.27-4.17, 3.79-3.74, 3.20-3.10, 3.07-2.93, 2.92 -2.82, 2.81-2.72, 2.36, 1.73-1.52, 1.44-1.35.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 9, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 10.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 5.

[Table 5] (Table 5)

(2) Differential scanning calorimetry (DSC)

Device: Discovery DSC by TA Instruments

Sample volume: 1.02mg

Sample tank: aluminum tank (with cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~220℃)

Endothermic: initial temperature is about 184℃, peak temperature is about 191℃

Fever: Fever start temperature is about 193℃

Example 6

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol hydrochloride type A crystal

The compound (4.5 g) produced in Example 1 was suspended in ethanol (63 mL), 2N hydrogen chloride/ethanol solution (4.4 mL) was added, and stirred at 25° C. for 6 hours. The resulting precipitate was collected by filtration and dried to obtain crystals (4.1 g) of the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 8.80, 8.37, 7.68-7.56, 7.25-7.05, 4.87-4.78, 4.72, 4.64, 4.56-4.40, 3.87-3.80, 3.28-3.14, 3.08-2.97, 2.97-2.88 , 2.43, 1.87-1.64, 1.61-1.44.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 11, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 12.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Result] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 6.

[Table 6] (Table 6)

(2) Differential scanning calorimetry (DSC)

Device: Discovery DSC by TA Instruments

Sample volume: 1.48mg

Sample tank: aluminum tank (with cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~220℃)

Fever: The initial temperature is about 226℃, the peak temperature is about 235℃

Example 7

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -C type crystal of (3-oxetanylamino)-3-piperidinol lactate

To a solution of the compound (53 mg) prepared in Example 1 in acetone (0.4 mL), a solution of lactic acid (9.5 mg) in acetone (0.15 mL) was added and stirred. Add acetone (0.5mL) and stir for 3-5 days. The precipitated crystals were collected by filtration, washed with acetone, and dried to obtain crystals (30 mg) of the title compound having the following physical properties.

¹ H-NMR (DMSO-d6): δ 13.42, 8.88, 8.34, 7.84-7.75, 7.39-7.32, 7.25, 5.78, 4.61-4.52, 4.38, 4.27, 4.03, 3.97-3.87, 3.56-3.51, 3.00-2.91 , 2.89-2.78, 2.72-2.65, 2.54-2.50, 2.39-2.28, 2.18, 1.39-1.26, 1.22, 1.20-1.11.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 13, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 14.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Result] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 7.

[Table 7] (Table 7)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.48mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~190℃)

Endothermic: initial temperature is about 170℃, peak temperature is about 177℃

Example 8

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol ethanesulfonate type A crystal

The compound (10.7 g) produced in Example 1 was dissolved in methanol (54 mL), ethanesulfonic acid (2.5 g) was added, and stirred at 23° C. for 2 hours. The resulting precipitate was collected by filtration and dried to obtain crystals (10.9 g) of the title compound having the following physical properties.

¹ H-NMR(DMSO-d6): δ 8.75,8.33,7.82-7.68,7.36-7.19,4.71-4.53,4.43-4.34,3.75-3.68,3.14-2.99,2.93-2.81,2.76-2.64,2.41,2.25 , 1.62-1.46, 1.45-1.34, 1.05.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 15, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 16.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 8.

[Table 8-1] (Table 8)

[Table 8-2] (Table 8) continued

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 0.89mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~260℃)

Fever: The initial temperature is about 239℃, the peak temperature is about 244℃

(3) Analysis data of single crystal X-ray diffraction spectrum structure

Device: Physical and Chemical SuperNova

Target: CuKα(λ=1.54184Å)

Voltage: 50kV

Current: 0.8mA

Scanning width: 1°

[Result] The data of crystallography is the following.

Lattice constant: a=11.9406(4)Å b=8.9151(3)Å c=13.6153(4)Å

Space Group: P21(#4)

R factor: 0.0399

Table 9 below shows the positional parameters (partial atomic coordinates) of the crystallization of ethanesulfonate at room temperature (×10 ⁴ ).

[Table 9-1] (Table 9)

[Table 9-2] (Table 9) continued -1

[Table 9-3] (Table 9) continued-2

[Table 9-4] (Table 9) continued -3

Example 9

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol benzene sulfonate monohydrate C-type crystal

To the compound (135 mg) produced in Example 1 and benzenesulfonic acid monohydrate (47 mg), 0.14 mL of tetrahydrofuran was added and stirred for 2 to 4 days. The precipitated crystals were collected by filtration, washed with tetrahydrofuran, and dried to obtain crystals (130 mg) of the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 8.71, 8.28, 7.74-7.68, 7.58-7.46, 7.37-7.28, 7.11-6.98, 4.78-4.70, 4.63, 4.55, 4.38, 3.77-3.72, 3.20-3.07, 2.98 -2.89, 2.88-2.80, 2.35, 1.73-1.60, 1.45-1.36.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 17, the graph of differential scanning calorimetry (DSC) is shown in FIG. 18, and the graph of thermogravimetric measurement (TG) is shown. In Figure 19.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 10.

[Table 10] (Table 10)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.02mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~220℃)

Endothermic: initial temperature is about 121℃, peak temperature is about 143℃

Fever: The initial temperature is about 179℃, the peak temperature is about 187℃

(3) Thermogravimetric measurement (TG)

Installation: TGA851e by Mettler Toledo

Sample volume: 2.05mg

Sample tank: aluminum (without cover)

Nitrogen flow: 60mL/min

Heating rate: 10℃/min

[Result] From about 110°C to about 150°C, it showed a weight loss of about 2.7%.

Example 10

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol 1/2 adipate F-type crystal

To the compound (5.5 g) produced in Example 1, adipic acid (783 mg) and ethyl acetate (55 mL) were added, and the mixture was stirred at 55°C for 30 minutes. By cooling to 25°C, the resulting precipitate was collected by filtration and dried to obtain crystals (5.2 g) of the title compound having the following physical properties.

¹ H-NMR (DMSO-d6): δ 13.40, 8.86, 8.33, 7.86-7.68, 7.42-7.18, 5.77, 4.60-4.50, 4.36, 4.26, 3.97-3.85, 3.52, 3.03-2.90, 2.88-2.75, 2.74 -2.59, 2.37-2.07, 1.55-1.44, 1.43-1.23, 1.23-1.07.

The powder X-ray diffraction spectrum of the pulverized product of the crystal jet mill measured under the following conditions is shown in FIG. 20, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 21.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 11.

[Table 11] (Table 11)

(2) Differential scanning calorimetry (DSC)

Device: Discovery DSC by TA Instruments

Sample volume: 0.99mg

Sample tank: aluminum tank (with cover)

Nitrogen flow rate: 40mL/min

Heating rate: 10℃/min (25~170℃)

Endothermic: initial temperature 140℃, peak temperature 150℃

Comparative example 1

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol N L-malate (N=1~2) B type crystal

The compound (20 mg) produced in Example 1 was dissolved in ethanol (400 μL) at 80°C, and L-malic acid (16 mg) was added. By cooling to 25°C, the resulting precipitate was collected by filtration and dried to obtain crystals (29 mg) of the title compound having the following physical properties.

¹ H-NMR (CD ₃ OD): δ 8.85, 8.36, 7.66-7.57, 7.18-7.05, 4.86-4.73, 4.66, 4.57, 4.39, 4.36-4.24, 3.83-3.75, 3.22-3.12, 3.07-2.94, 2.93 -2.83, 2.82-2.74, 2.66-2.51,2.37, 1.78-1.57, 1.54-1.37.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 22, and the graph of differential scanning calorimetry (DSC) is shown in FIG. 23.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 12.

[Table 12-1] (Table 12)

[Table 12-2] (Table 12) continued

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.28mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (5~300℃)

Endotherm: endotherm starts at 10℃, endotherm ends at 90℃

Heat absorption: 150℃ for heat generation and 180℃ for heat absorption

Example 11

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -C type crystal of (3-oxetanylamino)-3-piperidinol N hydrate (N=1~2)

400 mL of methanol and 72 mL of 4N sodium hydroxide aqueous solution were added to the compound (80 g) produced in Example 6 and stirred, while adding 2 L of water and stirred for 3 to 4 hours. The crystals were collected by filtration, washed with water, and dried to obtain crystals (12.7 g) of the title compound having the following physical properties.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 24, the graph of differential scanning calorimetry (DSC) is shown in FIG. 25, and the graph of thermogravimetric measurement (TG) is shown. In Figure 26.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Result] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 13.

[Table 13] (Table 13)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.01mg

Sample tank: aluminum tank (without cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (10~170℃)

Endothermic: endothermic peak temperature 29℃, 62℃, 144℃

(3) Thermogravimetric measurement (TG)

Installation: TGA851e by Mettler Toledo

Sample volume: 2.03mg

Sample tank: aluminum tank (without cover)

Nitrogen flow: 60mL/min

Heating rate: 10℃/min

[Result] From about room temperature to about 80°C, it showed a weight loss of about 6.0%.

Example 12

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -D crystal of (3-oxetanylamino)-3-piperidinol monohydrate

To the compound (100 mg) produced in Example 11, 1.8 mL of cyclohexane, 0.2 mL of ethanol or isopropanol were added, and the mixture was stirred at 70 to 90°C. Stop heating after 30~60 minutes and stir at room temperature for 10~50 minutes. The crystals were collected by filtration, washed with cyclohexane, and dried to obtain crystals (75 mg) of the title compound having the following physical properties.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 28, the graph of differential scanning calorimetry (DSC) is shown in FIG. 29, and the graph of thermogravimetric measurement (TG) is shown. In Figure 30.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 14.

[Table 14] (Table 14)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.14mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~240℃)

[Result] In the DSC graph, two endotherms and heat generation were observed. The second endotherm is generated by the melting of the crystal.

1st endotherm: initial temperature 60℃, peak temperature 87℃

2nd endotherm: initial temperature 222℃, peak temperature 223℃

Fever: initial temperature 225℃, peak temperature 226℃

(3) Thermogravimetric measurement (TG)

Installation: TGA851e by Mettler Toledo

Sample volume: 2.04mg

Sample tank: aluminum tank (without cover)

Nitrogen flow: 60mL/min

Heating rate: 10℃/min

[Result] From about room temperature to about 90°C, it showed a weight loss of about 3.0%.

(4) Analysis data of single crystal X-ray diffraction spectrum structure

Device: Physical and Chemical SuperNova

Target: CuKα(λ=1.54184Å)

Voltage: 50kV

Current: 0.8mA

Scanning width: 1°

[Result] The data of crystallography is the following.

Lattice constant: a=9.4921(3)Å b=10.4225(3)Å c=12.8067(4)Å

Space Group: P1(#1)

R factor: 0.0358

Table 15 below shows the positional parameters (partial atomic coordinates) (×10 ⁴ ) of the D-type crystal at -180°C.

[Table 15-1] (Table 15)

[Table 15-2] (Table 15) continued -1

[Table 15-3] (Table 15) continued-2

[Table 15-4] (Table 15) continued-3

[Table 15-5] (Table 15) continued -4

Example 13

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol type B crystal

To the compound (205 mg) produced in Example 12, 10 mL of a mixed solvent of isopropanol/n-heptane=1/9 v/v was added, stirred, and heated at 80 to 100°C. Stop heating after 1~2 hours and stir at room temperature for 10~50 minutes. The crystals were collected by filtration, washed with n-heptane, and dried to obtain crystals (180 mg) of the title compound having the following physical properties.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 32, the graph of differential scanning calorimetry (DSC) is shown in FIG. 33, and the graph of thermogravimetric measurement (TG) is shown. In Figure 34.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 16.

[Table 16] (Table 16)

(2) Differential scanning calorimetry (DSC)

Device: DSC822e by Mettler Toledo

Sample volume: 1.12mg

Sample tank: aluminum tank (with opening cover)

Nitrogen flow: 40mL/min

Heating rate: 10℃/min (25~280℃)

[Result] In the DSC graph, the endothermic heat generated by the decomposition of the crystal can be observed.

Endothermic: The endothermic onset temperature is about 248℃ (the initial temperature is about 268℃, the peak temperature is about 271℃)

(3) Thermogravimetric measurement (TG)

Installation: TGA851e by Mettler Toledo

Sample volume: 2.04mg

Sample tank: aluminum (without cover)

Nitrogen flow: 60mL/min

Heating rate: 10℃/min

[Result] In this crystal, the DSC chart (Figure 33) shows an endotherm from about 248°C. In addition, in the TG chart (Figure 34), no weight reduction was observed up to the former temperature.

Example 14

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -O-type crystal of (3-oxetanylamino)-3-piperidinol N hydrate (N=0.5~1)

Acetonitrile (1 mL) was added to the compound (100 mg) produced in Example 1, stirred at 55°C for 1 day, and cooled to 25°C. The resulting precipitate was collected by filtration and dried in air to obtain crystals (80 mg) of the title compound having the following physical properties.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 36.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10 degrees/minute

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 17.

[Table 17] (Table 17)

Example 15

(3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]-4 -(3-oxetanylamino)-3-piperidinol N hydrate (N=0.5~1) type A crystal

Tertiary butyl methyl ether (400 μL) was added to the compound (10 mg) produced in Example 1, and stirred at 25° C. for 6 days. The resulting precipitate was collected by filtration and dried to obtain crystals (10 mg) of the title compound having the following physical properties.

The powder X-ray diffraction spectrum of the crystal measured under the following conditions is shown in FIG. 37.

(1) Powder X-ray diffraction spectrum

Device: Physical and Chemical System SmartLab

Target: Cu

Voltage: 45kV

Current: 200mA

Scanning speed: 10/min

[Results] The results of the diffraction angle (2θ) (degree) and relative intensity (%) obtained by powder X-ray diffraction spectroscopy using Cu-Kα rays are shown in Table 18.

[Table 18] (Table 18)

Example 16: Chemical stability test

Regarding the crystals of Example 2, Example 6, and Comparative Example 1, a chemical stability test was conducted according to the following methods and conditions.

[Method] Weigh about 0.9~1.1mg of uncrushed crystals in a test tube, and conduct a chemical stability test under the storage condition of 80°C for 1 week. After storage, by HPLC, the ratio of the area percentage of the compound stored in the sample under each condition to the area percentage of the compound stored in the sample at -20°C was calculated as the residual rate (%).

<storage conditions>

80℃: 1 week

The comparison object of each sample is stored at -20℃.

<HPLC analysis>

‧Sample modulation

The evaluation sample was dissolved in a mixed solution (1/1) of acetonitrile/20 mmol/L dipotassium hydrogen phosphate aqueous solution (adjusted to pH 8.0 with phosphoric acid) to prepare a 0.5 mg/mL (concentration as free body) solution.

‧Analysis conditions

Detector: UV absorbance photometer (measurement wavelength: 210nm)

Column: Agilent Poroshell 120 EC-C18 (150×4.6mm, 2.7μm)

Column temperature: 25℃

Sample rack temperature: 15℃

Mobile phase: Liquid A: 20mmol/L dipotassium hydrogen phosphate aqueous solution (adjusted to pH 8.0 with phosphoric acid), Liquid B: acetonitrile

Gradient conditions: Liquid A/B = 90/10 (0-0.5 points) → 30/70 (40.5-50 points) → 90/10 (50.1-60 points)

Flow rate: 0.8mL/min

Measuring range: 50 points

Injection volume: 5μL

<result>

Table 19 shows the results of the chemical stability tests conducted at 80°C and one week of storage conditions, respectively.

According to the results shown in Table 19, the compounds of the present invention produced in Examples 2 and 6 are excellent in chemical stability, but the compounds produced in Comparative Example 1 are not excellent in chemical stability. That is, it is shown that from the viewpoint of crystallization, chemical stability is not necessarily good.

[Table 19] (Table 19)

In addition, the stability test of this chemistry is also carried out under other storage conditions, for example, 40° C. for 4 weeks. In addition, for the evaluation crystals, pulverized crystals were also used. For example, a MC-ONE type jet mill manufactured by JETPHARMA was used, and the crystals were pulverized at a supply pressure of 3.0 bar and a pulverization pressure of 2.0 bar. In addition, as for the column used for HPLC analysis, for example, Agilent Poroshell HPH-C18 (150×4.6 mm, 2.7 μm) was also used. As a result, any of the compounds of the present invention showed excellent chemical stability of about 99%.

Example 17: Water Vapor Adsorption/Desorption Isotherm Determination (DVS)

Each crystal of the pulverized compounds of Example 11, Example 12, and Example 13 was subjected to water vapor adsorption/desorption isotherm measurement according to the following conditions and methods.

[condition]

Device: SMS-made DVS Intrinsic

Sample volume: about 10mg

Temperature: 25℃

Relative humidity change: 0%~90% or 95% (5%STEP)

Benchmark when moving to STEP: weight change rate 0.002%/min

[Calculation method] Based on 25°C and drying time (0%RH), the weight change rate when changing humidity stepwise (relative humidity 0%RH to 95%RH) is measured over time.

[Results] The measurement results of the compound of the invention produced in Example 11 are shown in FIG. 27, and the measurement results of the compound of the invention produced in Example 12 are shown in FIG. 31, the invention produced in Example 13. The measurement results of the compounds are shown in Figure 35.

The compounds of the present invention show very little weight change with increased humidity. In particular, the weight change rate of the compound of the present invention produced in Example 13 was about 0.4%, the weight change rate of the compound of the present invention produced in Example 11 was about 9%, and the compound of the present invention produced in Example 13 and the examples 11 The compound of the present invention produced had a very small weight change with increasing humidity, and it was shown to be more excellent as an original drug for pharmaceuticals.

Biological Example 1:

Evaluation of SSTR2 motility activity using human SSTR2 expressing cells

[operating]

(1) Isolation of human SSTR2 gene

The human brain cDNA line was purchased from Ambion (catalogue number: 7962; batch number: 040200121). HSSTR2_F1_XhoI for PCR primer: 5’-CACCCTCGAGGACATGGCGGATGAGCCACTCAAT-3’ (sequence number 1), and hSSTR2_R1_EcoRI: 5'-CCTTGAATTCGATACTGGTTTGGAGGTCTCCATT-3' (sequence number 2) is designed based on the sequence of GenBank NM_001050.

Using the human brain cDNA as a template, a KOD-plus- (Toyobo) was used to perform a PCR reaction (95°C, 2 minutes → [98°C, 10 seconds, 60°C, 30 seconds, 68°C, 90 seconds] × 30 times). After the amplified PCR products were electrophoresed on a 1% agarose gel, it was purified using QIAquick Gel Extraction Kit (QIAGEN) to cut off the restriction enzymes XhoI and EcoRI. The cut fragments were ligated to the expression vector (pIRESneo-Myc) using DNA ligation kit Ver. 2 (Takara) to transform E. coli DH5a. Modulate its plastid pIRESneo-Myc/hSSTR2 and confirm the DNA sequence.

(2)Cultivation of CHO-K1 cells

The CHO-K1(-) line was cultured using Ham's F-12 medium (containing fetal bovine serum (10%), penicillin (100 U/mL), and streptomycin (0.1 mg/mL)). Furthermore, the transduced cells were cultured in the aforementioned medium supplemented with geneticin (1 mg/mL).

(3) Transduction of CHO-K1 cells

Using Lipofectamine 2000 (Invitrogen), the plastid pIRESneo-Myc/hSSTR2 was transfected into CHO-K1(-) cells. After 48 hours, it was replaced with a medium containing 1 mg/mL geneticin without selection, and stable stable excess expression cells (SSTR2-CHO-K1) were established.

(4) Evaluation of the activity of SSTR2

The human SSTR2 action activity of the test compound was evaluated using the inhibitory effect of forskolin on intracellular cyclic AMP (cAMP) as an index, and evaluated in the following order. SSTR2-CHO-suspended in Ham's F-12 medium (containing fetal bovine serum (10%), penicillin (100U/mL), streptomycin (0.1mg/mL)) containing 0.25 mg/mL geneticin K1 cells were seeded in 96-well culture plates at a density of 4.0×10 ⁴ cells/0.1 mL per well. The next day, the medium was removed, and 0.1 mL of washing buffer [containing 0.1% bovine serum albumin (BSA), 20 mmol/L of 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) Hanks Balanced Salt Solution (HBSS)] Wash twice. Add 0.06 mL of assay buffer [HBSS containing 500 nmol/L 3-isobutyl-1-methylxanthine (IBMX), 0.1% BSA, 20 mmol/L HEPES] in each well, and add 5% CO2 Incubate at 37°C for 15 minutes. Then, a test buffer containing twice the final concentration of the test compound and 0.02 mmol/L forskolin is added to each well, and 0.06 mL is added, and incubated at 5% carbon dioxide at 37°C for 30 minutes . Then, add 0.12mL of the assay/lysis buffer attached to the cAMP-Screen (registered trademark) kit (manufactured by Applied Biosystems) and incubate for 30 minutes under the conditions of 5% carbon dioxide and 37°C . The cAMP concentration in the sample was determined by ELISA according to the instructions attached to the kit. For the 50% effective concentration (EC ₅₀ value) of the agonist effect of human SSTR2, the reaction rate of octreotide of 1000 nmol/L can be regarded as 100%, and the production of cAMP stimulated by forskolin can be obtained for each sample. The reaction rate of inhibition (%) is calculated by non-linear regression analysis using the common logarithmic concentration of the test compound as the independent variable and the response rate of the corresponding concentration as the dependent variable.

[result]

The compound (amorphous) produced in Example 1 showed an EC ₅₀ value of 0.14 nmol/L. In the case where the amorphous form of the free compound has pharmacological activity, generally, the corresponding salt or crystalline polymorphism also has the same pharmacological activity, which can be easily deduced by those skilled in the art. Therefore, any of the compounds of the present invention clearly exhibited strong SSTR2 agonistic activity.

Furthermore, according to this evaluation system, for example, the compound of Example 21 (27) described in International Publication No. 2014/007228 pamphlet shows an EC ₅₀ value of 0.026 nmol/L, and the compound of Example 21 (28) shows 0.019 nmol/L For the EC ₅₀ value of L, the compound of Example 21 (29) showed an EC ₅₀ value of 0.038 nmol/L.

Biological Example 2:

Evaluation of hERG K ⁺ channel blocking effect using human ERG expression cells

[operating]

(1) Cultivation of CHO-K1 cells into which human ERG (ether-a-go-go related gene) genes have been introduced

CHO-K1 cells introduced with human ERG (ether-a-go-go related gene) gene to contain 10% non-activated fetal bovine serum, 100IU/mL penicillin-100μg/mL streptomycin and 200μg/mL geneticin The F-12 medium [F-12 Nutrient Mixture (HAM)] was subcultured.

(2) Evaluation of hERG K ⁺ channel blocking effect

Using CHO-K1 cells into which the human ERG gene has been introduced, patch clamp is automatically performed, wherein the CHO-K1 cells are formed into a perforated patch by amphotericin B (amphotericin B). In the experiment, 384-well PatchPlateTM was used to add cell suspension and compounds. The IKr current is measured with respect to the command voltage at a holding potential of -80 mV, a depolarizing potential of +40 mV (2 seconds), and a repolarizing potential of -50 mV (2 seconds). The stimulation frequency was two single pulse stimulations before and after drug treatment (the evaluation concentration of each compound was 1, 3, and 10 μmol/L, 5 minutes incubation), and the maximum current of Ikr was measured. The blocking rate (%) of CHO-K1 cells into which the human ERG gene was introduced was obtained by correcting the rate of change of the maximum tail current before and after the addition of the test substance to the rate of change of the media treatment group [blocking rate ( %)=(1-Current change rate before and after test substance addition/Current change rate before and after medium addition)×100]. The 50% blocking concentration (IC ₅₀ value) is calculated from a straight line connecting two points at which the blocking blocking rate is 50%.

[result]

The compound (amorphous) produced in Example 1 showed an IC ₅₀ value of 7.6 μmol/L. In the case where the amorphous form of the free-form compound has pharmacological activity, it usually has the same pharmacological activity in the corresponding salt or crystalline polymorph. If it is a person skilled in the art, it can be easily deduced by analogy. Therefore, it is apparent that any of the compounds of the present invention has a very weak hERG inhibitory activity compared to the SSTR2 action activity.

Furthermore, according to this evaluation system, for example, the compound of Example 21 (27) described in International Publication No. 2014/007228 shows an IC ₅₀ value of 1.0 μmol/L, and the compound of Example 21 (28) shows 1.6 μmol/ The IC ₅₀ value of L. The compound of Example 21 (29) showed an IC ₅₀ value of 0.10 μmol/L.

Biological Example 3:

Evaluation of the ability to induce phospholipid deposition using cultured cell lines

[operating]

-1,3-二唑-4-基)-1,2-二-十六醯基-sn-甘油-3-磷醯基乙醇胺三乙基銨鹽)者交換後，進一步付諸於24小時之培養。磷脂沉積誘發能力，係藉由測定被細胞內攝取之NBD-PE濃度而評價。具體而言，將細胞以PBS洗淨2次後，藉由使用分子裝置(Molecular device)公司之SpectraMax plate reader測定被細胞內攝取的NBD-PE之螢光(激發波長：485nm，螢光波長：535nm)而評價。又，NBD-PE之螢光測定後，使用從Takara Bio公司購入之Premix WST-1細胞增殖檢定系統(Premix WST-1 Cell Proliferation Assay System)評價細胞生存率。在細胞生存率成為50%以上之用量中，為陽性對照之胺碘酮(amiodarone)之最大反應(將胺碘酮投與後，被細胞內攝取之NBD-PE濃度當作100%)的25%以上之反 應(受驗化合物投與後攝取的NBD-PE濃度)出現的情況，判斷磷脂沉積誘發能力為陽性。 After suspending CHL/IU cells derived from Chinese hamster lungs in MEM-E medium containing non-essential amino acids, sodium pyruvate, and 10% fetal bovine serum, they were seeded in 96-well culture plates. Cultivate the cells overnight in an incubator (5% carbon dioxide, 95% air, 37°C), mix the culture medium with the test substance containing concentrations of 6.25, 12.5, 25, 50, 100 μmol/L. NBD-PE (fluorescent logo N-(7-nitrobenzo-2-

-1,3-diazol-4-yl)-1,2-di-hexadecyl-sn-glycerol-3-phosphoethanolamine triethylammonium salt) after exchange, further put it into 24 hours Of cultivation. The ability to induce phospholipid deposition was evaluated by measuring the concentration of NBD-PE taken up by the cells. Specifically, after washing the cells twice with PBS, the fluorescence of NBD-PE (excitation wavelength: 485 nm, fluorescence wavelength: 535nm). After the fluorescence measurement of NBD-PE, the cell survival rate was evaluated using the Premix WST-1 Cell Proliferation Assay System purchased from Takara Bio. 25% of the maximum response of amiodarone (the concentration of NBD-PE taken into the cell after administration of amiodarone after the administration of amiodarone is 100%) in the dosage where the cell survival rate becomes more than 50% When the reaction of more than% (the concentration of NBD-PE taken after administration of the test compound) occurs, the ability to induce phospholipid deposition is judged to be positive.

[result]

Judging the compound (amorphous) produced in Example 1, the phospholipid deposition inducing ability was negative. In the case where the amorphous form of the free-form compound has pharmacological activity, it usually has the same pharmacological activity in the corresponding salt or crystalline polymorph. If one is skilled in the art, it can be easily deduced by analogy. Therefore, the compound of the present invention clearly has a very low ability to induce phospholipid deposition in test tubes.

Furthermore, according to this evaluation system, for example, the compound of Example 21 (27) described in International Publication No. 2014/007228 is 3.125 μmol/L or more, and the compound of Example 21 (28) is 3.125 μmol/L, The compound of Example 21 (29) was 1.56 μmol/L or more, and the ability to induce phospholipid deposition was judged to be positive.

Biological Example 4:

Evaluation of the inhibitory effect of growth hormone (GH) secretion using rats

[operating]

For rats (7-week-old male Crl: CD (SD) IGS rats (Charles River Co., Ltd. of Japan)), the medium (distilled water (Otsuka distilled water, Otsuka Pharmaceutical Works Co., Ltd.)) or dissolution in the medium was tested The compound was administered orally. After 7 hours and 57 minutes, 50 mg/kg of pentobarbital sodium (Somnopentyl, Kyoritsu Pharmaceutical Co., Ltd.) was administered from the tail vein for anesthesia. Three minutes after the administration of pentobarbital sodium, 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 GH concentration in blood, 5 minutes after the GHRH administration, 0.2 mL of blood was collected from the jugular vein. The collected blood was centrifuged at 13,000×g for 5 minutes at 4°C to obtain plasma. The blood GH concentration was determined using the Rat/Mouse Growth Hormone ELISA (Millipore), according to the set Procedure manual for determination. The inhibition rate of GH secretion (%) is the value of the blood GH concentration obtained by the mathematical formula {[Inhibition rate of GH secretion (%)]=([GH concentration in blood of medium administration group]- [GH concentration in blood of test compound administration group])/[GH concentration in blood of medium administration group]×100}. Furthermore, the medium administration group in the formula means a group of animals to which the medium is administered, and the test compound administration group means a group of animals to which the test compound dissolved in the medium is administered.

[result]

The compound (amorphous) produced in Example 1 showed a 92% GH secretion inhibition rate at a dose of 1 mg/kg. In the case where the amorphous form of the free-form compound has pharmacological activity, it usually has the same pharmacological activity in the corresponding salt or crystalline polymorph. If it is a person skilled in the art, it can be easily deduced by analogy. Therefore, the compound of the present invention clearly shows a strong GH secretion inhibitory effect.

Preparation Example 1:

Contains (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]- 5-mg ingot of form B crystal of 4-(3-oxetanylamino)-3-piperidinol

The following ingredients are mixed according to the usual method and then tabletted to obtain 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-pyridyl]- Type B crystal of 4-(3-oxetanylamino)-3-piperidinol: 50g

‧Carboxymethylcellulose calcium (disintegrating agent): 20g

‧Magnesium stearate (lubricant): 10g

‧Microcrystalline cellulose: 920g

Preparation Example 2:

Contains (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]- 20 mg injection of 4-(3-oxetanylamino)-3-piperidinol type B crystal

After mixing the following ingredients according to the usual method, the solution is sterilized according to the usual method, filled into ampoules with 5 mL each, and freeze-dried according to the usual method to obtain 10,000 ampoules containing 20 mg of the active ingredient in 1 ampule.

‧(3S,4R)-1-[3-(5,6-Difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]- Type B crystal of 4-(3-oxetanylamino)-3-piperidinol: 200g

‧Mannitol: 20g

‧Distilled water: 50L

[Industry availability]

Since the compound of the present invention is a compound with strong agonistic activity on somatostatin receptors, especially somatostatin receptor subtype 2, it is involved in various diseases as somatostatin itself or hormones regulated by somatostatin, especially The prevention and/or treatment of terminal hypertrophy or gastrointestinal symptoms accompanied by digestive tract occlusion is useful.

<110> Nissho Ono Pharmaceutical Industry Co., Ltd.

<120> Novel salts and novel crystal forms of piperidinol derivatives

<130> P19-066TW

<150> JP 2018-114082

<151> 2018-06-15

<160> 2

<170> PatentIn Ver.3.5.1

<210> 1

<211> 34

<212> DNA

<213> Man-made sequence

<220>

<223> Forward primer hSSTR2_F1_XhoI

<400> 1

<210> 2

<211> 34

<212> DNA

<213> Man-made sequence

<220>

<223> Reverse primer hSSTR2_R1_EcoRI

<400> 2

Claims (20)

A (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]- Crystallization of 4-(3-oxetanylamino)-3-piperidinol. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Yl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol, which has at least about 11.2, 13.0, 17.8 in the powder X-ray diffraction spectrum , 19.8, 22.1 and 22.6 degrees 2θ peaks. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Yl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol, which has a powder X-ray diffraction spectrum of about 8.8, 11.2, 13.0, 13.8, 14.2, 15.8, 16.2, 17.8, 18.7, 19.0, 19.3, 19.8, 20.2, 20.6, 21.3, 22.1, 22.6, 23.6, 24.3, 24.7, 25.9, 26.2, 26.4, 26.7, 27.1, 27.8, 28.6, 31.4, Peaks of 2θ at 31.7 and 32.7 degrees. (3S, 4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3 ,5-difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol, which has the powder X-ray diffraction shown in Figure 32 Characterized by the spectrogram. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3 as described in any of items 1 to 4 of the patent application ,5-difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol, which has a starting temperature of An endothermic peak at about 268°C or a peak temperature of about 271°C. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Yl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol crystals, which are characterized by the differential scanning calorimetry chart shown in FIG. 33. A (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorophenyl)-4-pyridyl]- 4-(3-oxetanylamino)-3-piperidinol phosphate. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Yl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol phosphate, which is in crystalline form. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Yl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol phosphate, which has a powder X-ray diffraction spectrum of at least about 6.5, 16.3 , 18.8, 19.9, 24.3 and 25.0 degrees 2θ peaks. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Group)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol phosphate, which has a powder X-ray diffraction spectrum of about 6.5, 9.9, 12.4, 12.7, 12.8, 15.8, 16.3, 18.0, 18.8, 19.5, 19.9, 20.5, 20.8, 21.2, 21.5, 22.8, 22.9, 24.3, 25.0, 25.8, 26.8, 28.2, 28.6, 29.1 and 31.1 degrees 2θ peaks. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3 ,5-difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol phosphate, which has the powder X-ray shown in Figure 1 The characteristics of the diffraction spectrum. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3 as described in any of items 8 to 11 of the patent application ,5-difluorophenyl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol phosphate, which has a starting point in differential scanning calorimetry An endothermic peak with a temperature of about 236°C or a peak temperature of about 248°C. (3S,4R)-1-[3-(5,6-difluoro-1H-benzimidazol-2-yl)-5-(3,5-difluorobenzene Yl)-4-pyridyl]-4-(3-oxetanylamino)-3-piperidinol phosphate crystal, which has the characteristics of the differential scanning calorimetry chart shown in FIG. 2. A pharmaceutical composition containing the compound or the crystalline and pharmaceutically acceptable carrier as described in any one of claims 1 to 13. The pharmaceutical composition as described in item 14 of the patent application scope is a preventive and/or therapeutic agent for somatostatin-related diseases. The pharmaceutical composition as described in item 15 of the patent application, wherein the somatostatin-related diseases are terminal hypertrophy or gastrointestinal symptoms accompanied by gastrointestinal occlusion. A preventive and/or therapeutic agent for somatostatin-related diseases, which contains the compound or crystal as described in any one of claims 1 to 13 of the patent application. A method for preventing and/or treating somatostatin-related diseases, which is to administer an effective amount of a compound or crystal as described in any one of claims 1 to 13 to a mammal. The compound or crystal as described in any one of claims 1 to 13 is used for the prevention and/or treatment of somatostatin-related diseases. The use of the compound or crystal described in any one of patent application items 1 to 13 for the manufacture of a prophylactic and/or therapeutic agent for somatostatin-related diseases.

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