Growth hormone secretion promoter

Abstract

The present specification discloses, as a specific embodiment of the present invention, a growth hormone secretion promoter comprising a somatostatin receptor subtype 5 ("SSTR5") antagonist as an active ingredient, and the like.

Description

Technical Field

[0001] The present invention relates to an embodiment of a growth hormone secretion promoter and the like comprising a somatostatin receptor subtype 5 (hereinafter sometimes abbreviated as "SSTR5") antagonist as an active ingredient, which can be used, for example, in the pharmaceutical field. Background Art

[0002] Somatostatin is a peptide hormone secreted by the hypothalamus, pancreatic delta cells, gastrointestinal endocrine cells, and other organs. It inhibits the secretion of multiple hormones (such as growth hormone and adrenocorticotropic hormone) through five types of somatostatin receptors (SSTR1-5), seven-transmembrane G protein-coupled receptors. Currently, somatostatin analogs (such as octreotide and pasireotide) are used clinically to improve various symptoms associated with excessive hormone secretion, such as acromegaly and Cushing's disease. However, because existing somatostatin analogs exhibit binding affinity for all SSTR1-5 receptors, it is unclear which SSTR activation leads to the inhibition of various hormone secretion. Of these five receptors, SSTR5 is a receptor primarily expressed in intestinal endocrine cells and pancreatic β cells. Somatostatin binding is known to inhibit the secretion of gastrointestinal hormones (e.g., glucagon-like peptide-1, peptide YY, etc.) and insulin. On the other hand, analyses using human pituitary tumor tissue have shown that SSTR5 is also expressed in various anterior pituitary hormone-producing cells, including growth hormone-secreting cells. However, other SSTRs are similarly expressed in these cells, and their receptor expression profiles have been shown to differ between different cells (Non-Patent Document 1). Regarding the relationship between SSTR5 and the control of growth hormone secretion, reports based on studies using cultured cells have suggested this relationship. However, this possibility has only been confirmed at the cellular level, and how SSTR5 controls the secretion of anterior pituitary hormones (including growth hormone) at the biological level remains unclear (Non-Patent Document 2). SSTR5 knockout mice exhibit elevated blood levels of adrenocorticotropic hormone, but not elevated blood levels of insulin-like growth factor-1 (whose production is enhanced by growth hormone). Therefore, it is still unclear whether SSTR5 antagonists exert an effect of enhancing growth hormone secretion (Non-Patent Document 3). Furthermore, as described above, since SSTR5 has been reported to be expressed in a variety of anterior pituitary hormone-producing cells, there is a strong concern that SSTR5 antagonists may also induce a promoting effect on the secretion of a variety of anterior pituitary hormones, thereby achieving not only an enhancement of the desired growth hormone secretion but also unintended side effects based on the promotion of secretion of other hormones. Therefore, although a number of SSTR5 antagonists have been reported to date (e.g., Patent Documents 1 to 22, Non-Patent Document 4), all of them are described as being useful for anti-diabetes, anti-obesity, anti-NASH, etc., without any description of their effects on promoting growth hormone secretion or diseases that can be ameliorated by promoting growth hormone secretion being presumed to be applicable diseases. Furthermore, there are no reports to date of SSTR5 antagonists exhibiting effects on promoting growth hormone secretion in humans. Reference List Patent Literature

[0003] Patent Document 1: WO 2014 / 142363 Patent Document 2: WO 2015 / 052910 Patent Document 3: WO 2015 / 064083 Patent Document 4: WO 2010 / 056717 Patent Document 5: WO 2010 / 129729 Patent Document 6: WO 2011 / 146324 Patent Document 7: WO 2012 / 024183 Patent Document 8: WO 2016 / 205032 Patent Document 9: WO 2006 / 094682 Patent Document 10: WO 2006 / 128803 Patent Document 11: WO 2007 / 025897 Patent Document 12: WO 2007 / 110340 Patent Document 13: WO 2008 / 000692 Patent Document 14: WO 2008 / 019967 Patent Document 15: WO 2008 / 031735 Patent Document 16: WO 2008 / 122510 Patent Document 17: WO 2008 / 145524 Patent Document 18: WO 2008 / 148710 Patent Document 19: WO 2021 / 113362 Patent Document 20: WO 2021 / 113363 Patent Document 21: WO 2021 / 113368 Patent Document 22: WO 2023 / 125486 Non-patent literature

[0004] Non-patent document 1: Journal of Molecular Endocrinology (2014), 53, R1-R19 Non-patent document 2: J Clin Endocrinol Metab, September, 2003, 88(9): 4239-4245 Non-patent document 3: Mol Endocrinol, January 2003, 17(1):93-106 Non-patent document 4: European Journal of Medicinal Chemistry 264(2024)116017 Summary of the Invention Technical issues

[0005] The present invention is directed to providing a novel growth hormone secretion promoter, etc., as an embodiment of the present invention. More specifically, as one of the specific embodiments of the present invention, the present invention aims to provide a growth hormone secretion promoter comprising a somatostatin receptor subtype 5 ("SSTR5") antagonist as an active ingredient. Solution to the problem

[0006] Against this backdrop, the inventors conducted in-depth research on the effects of somatostatin on the secretion of multiple hormones and found that, as described in detail in the following examples, in experiments using a highly selective SSTR5 antagonist, the drug had a significant growth hormone secretion-promoting effect in humans and, unexpectedly, did not affect the secretion of other anterior pituitary hormones (e.g., follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, prolactin, etc.), to which somatostatin is believed to contribute. Based on this new discovery, the inventors have completed the present invention, wherein SSTR5 antagonists have a growth hormone secretion-promoting effect and can be used to prevent or treat diseases that can be improved by promoting growth hormone secretion. Hereinafter, the present invention will be described with reference to specific embodiments. However, the present invention is not limited to these embodiments.

[0007] [1] A growth hormone secretion promoter comprising an SSTR5 antagonist as an active ingredient. [2] The growth hormone secretion promoter according to [1] above, which is an agent for preventing and / or treating a disease that can be improved by promoting growth hormone secretion. [3] A method for preventing and / or treating a disease that can be improved by promoting growth hormone secretion, comprising administering an effective amount of an SSTR5 antagonist to a human or animal in need thereof. [4] An SSTR5 antagonist for use in preventing and / or treating a disease that can be improved by promoting growth hormone secretion. [5] Use of an SSTR5 antagonist in the preparation of a medicament for preventing and / or treating a disease that can be improved by promoting growth hormone secretion. [6] The growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3], the SSTR5 antagonist as described in [4], or the use of the SSTR5 antagonist as described in [5], wherein the disease improved by promoting growth hormone secretion is one or more diseases selected from the following: growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, growth hormone deficiency in adults, cancer cachexia, short bowel syndrome, hair loss, skin lesions, age-related growth hormone deficiency, and infertility. [7] The growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3], the SSTR5 antagonist as described in [4], or the use of the SSTR5 antagonist as described in [5], wherein the disease improved by promoting growth hormone secretion is one or more diseases selected from the following: growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, and growth hormone deficiency in adults. [8] The growth hormone secretion promoter as described in [1] above, which is a growth promoter for animals (preferably livestock animals and / or aquatic animals) (i.e., a growth promoter for animals (preferably livestock animals and / or aquatic animals) comprising an SSTR5 antagonist as an active ingredient). [9] A method for promoting animal growth, comprising administering an effective amount of an SSTR5 antagonist to an animal in need of administration (preferably a livestock animal and / or aquatic animal).

[10] An SSTR5 antagonist for use in promoting the growth of animals (preferably livestock animals and / or aquatic animals).

[11] Use of an SSTR5 antagonist in the preparation of a growth promoter for animals (preferably livestock animals and / or aquatic animals).

[0008]

[12] The growth hormone secretion promoter as described in [1] above, the growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3] above, the SSTR5 antagonist as described in [4] above, the use of the SSTR5 antagonist as described in [5] above, the growth hormone secretion promoter as described in [8] above, the method for promoting growth as described in [9] above, the SSTR5 antagonist as described in

[10] above, or the use of the SSTR5 antagonist as described in

[11] above, wherein the SSTR5 antagonist (preferably an SSTR5 selective antagonist) is selected from the group consisting of WO 2014 / 142363, WO 2015 / 052910, WO 2015 / 064083, WO 2010 / 056717, WO 2010 / 129729, WO 2011 / 146324, WO 2012 / 024183, WO 2016 / 205032、WO 2006 / 094682、WO 2006 / 128803、WO 2007 / 025897、WO 2007 / 110340、WO 2008 / 000692、WO 2008 / 019967、WO 2008 / 031735、WO 2008 / 122510, WO 2008 / 145524, WO 2008 / 148710, WO 2021 / 113362, WO 2021 / 113363, WO 2021 / 113368, WO 2023 / 125486 and European Journal of Medicinal Chemistry 264(2024)116017 or a salt thereof.

[13] The growth hormone secretion promoter as described in [1] above, the growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3] above, the SSTR5 antagonist as described in [4] above, the use of the SSTR5 antagonist as described in [5] above, the growth hormone secretion promoter as described in [8] above, the method for promoting growth as described in [9] above, the SSTR5 antagonist as described in

[10] above, or the use of the SSTR5 antagonist as described in

[11] above, wherein the SSTR5 antagonist (preferably an SSTR5 selective antagonist) is selected from the group consisting of compounds or salts thereof described in WO 2015 / 052910 and WO 2015 / 064083.

[14] The growth hormone secretion promoter as described in [1] above, the growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3] above, the SSTR5 antagonist as described in [4] above, the use of the SSTR5 antagonist as described in [5] above, the growth hormone secretion promoter as described in [8] above, the method for promoting growth as described in [9] above, the SSTR5 antagonist as described in

[10] above, or the use of the SSTR5 antagonist as described in

[11] above, wherein the SSTR5 antagonist is selected from: 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((2-cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, and their salts.

[15] The growth hormone secretion promoter as described in [1] above, the growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3] above, the SSTR5 antagonist as described in [4] above, the use of the SSTR5 antagonist as described in [5] above, the growth hormone secretion promoter as described in [8] above, the method for promoting growth as described in [9] above, the SSTR5 antagonist as described in

[10] above, or the SSTR5 antagonist as described in

[11] above, wherein the SSTR5 antagonist is 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid or a salt thereof.

[0009] In the above embodiments

[12] to

[15] , the diseases that are preferably improved by promoting growth hormone secretion include one or more diseases selected from the following: growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, growth hormone deficiency in adults, cancer cachexia, short bowel syndrome, hair loss, skin damage, age-related growth hormone deficiency and infertility; more preferably, the diseases that are improved by promoting growth hormone secretion include one or more diseases selected from the following: growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome and growth hormone deficiency in adults.

[0010]

[16] The growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3] above, the SSTR5 antagonist as described in [4] above, or the use of the SSTR5 antagonist as described in [5] above, wherein the SSTR5 antagonist is 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid or a salt thereof, and the disease improved by promoting growth hormone secretion is one or more diseases selected from the following: growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, growth hormone deficiency in adults, cancer cachexia, short bowel syndrome, hair loss, skin lesions, age-related growth hormone deficiency, and infertility.

[17] The growth hormone secretion promoter as described in [2] above, the method for prevention and / or treatment as described in [3] above, the SSTR5 antagonist as described in [4] above, or the use of the SSTR5 antagonist as described in [5] above, wherein the SSTR5 antagonist is 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid or a salt thereof, and the disease improved by promoting growth hormone secretion is one or more diseases selected from the following: childhood growth hormone deficiency, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, and adult growth hormone deficiency. Advantageous Effects of the Invention

[0011] The present invention provides novel growth hormone secretagogues, etc., as embodiments of the present invention. More specifically, as one of the specific embodiments of the present invention, the present invention provides a growth hormone secretagogue comprising a somatostatin receptor subtype 5 ("SSTR5") antagonist as an active ingredient. This growth hormone secretagogue is expected to have a selective growth hormone secretion-promoting effect and to substantially not affect the secretion of other anterior pituitary hormones involved in somatostatin (such as all or part of follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, and prolactin). BRIEF DESCRIPTION OF THE DRAWINGS

[0012] [ Figure 1 ] Figure 1 Shown are changes over time in the blood growth hormone concentration evaluated in Example 3 described below. [ Figure 2 ] Figure 2 Shown are changes over time in the blood follicle-stimulating hormone concentration evaluated in Example 3 described below. [ Figure 3 ] Figure 3 Shown are changes in blood luteinizing hormone concentration over time evaluated in Example 3 described below. [ Figure 4 ] Figure 4 Shown are changes over time in the blood thyrotropin concentration evaluated in Example 3 described below. [ Figure 5 ] Figure 5 Shown are changes over time in the blood ACTH concentration evaluated in Example 3 described below. [ Figure 6 ] Figure 6 Shown are changes in blood prolactin concentration over time evaluated in Example 3 described below. DETAILED DESCRIPTION

[0013] The present specification discloses the above-mentioned embodiments, for example, a growth hormone secretion promoter comprising an SSTR5 antagonist as an active ingredient; a growth hormone secretion promoter as a medicament for preventing and / or treating a disease that is ameliorated by promoting growth hormone secretion; a method for preventing and / or treating a disease that is ameliorated by promoting growth hormone secretion, the method comprising administering an effective amount of an SSTR5 antagonist to a human or animal in need thereof; an SSTR5 antagonist for use in preventing and / or treating a disease that is ameliorated by promoting growth hormone secretion; and use of an SSTR5 antagonist in the preparation of a medicament for preventing and / or treating a disease that is ameliorated by promoting growth hormone secretion, etc.

[0014] The present invention is described in detail below based on its embodiments. Unless otherwise specified herein, all technical terms and scientific terms used in this specification have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0015] (SSTR5 antagonist) The somatostatin receptor is one of seven transmembrane G protein-coupled receptors. To date, five subtypes have been discovered, designated SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5. As used herein, "SSTR5 antagonists" refers to any compound that antagonizes SSTR5. Numerous "SSTR5 antagonists" are known in the art, and "SSTR5 antagonist" is widely recognized and used as a general technical term to refer to this group of compounds by those skilled in the art. In embodiments of the present invention, a person skilled in the art can appropriately select a preferred SSTR5 antagonist based on efficacy, safety, and other factors. In particular, among the five SSTRs, an SSTR5 antagonist (SSTR5 selective antagonist) having high selectivity for SSTR5 (SSTR5 selective antagonism) is preferably selected. This SSTR5 antagonism and selectivity for SSTR5 can be confirmed using methods known in the art.

[0016] Examples of such SSTR5 antagonists include WO 2014 / 142363, WO 2015 / 052910, WO 2015 / 064083, WO 2010 / 056717, WO 2010 / 129729, WO 2011 / 146324, WO 2012 / 024183, WO 2016 / 205032、WO 2006 / 094682、WO 2006 / 128803、WO 2007 / 025897、WO 2007 / 110340、WO 2008 / 000692、WO 2008 / 019967、WO 2008 / 031735、WO 2008 / 122510、WO 2008 / 145524, WO 2008 / 148710, WO 2021 / 113362, WO 2021 / 113363, WO 2021 / 113368, WO 2023 / 125486 and European Journal of Medicinal Chemistry 264 (2024) 116017 or a salt thereof.

[0017] Among them, preferred specific compounds include: 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (WO 2015 / 052910, the compound described in Example 4) or a salt thereof, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (WO 2015 / 052910, the compound described in Example 67), 6-(1-((2-cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (WO 2015 / 052910, the compound described in Example 35), 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid (WO 2015 / 052910, the compound described in Example 74), 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (the compound described in Example 44 of WO 2015 / 064083), 1-(1-((6-cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (WO 2015 / 064083, the compound described in Example 49), 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (WO 2015 / 064083, the compound described in Example 50), 4-{8-[(2-(cyclopropyl)-5-trifluoromethylphenyl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl}benzoic acid (the compound described in WO 2012 / 024183, Examples 4-50), 6-{8-[(4-ethoxy-2',3',4'-trifluorobiphenyl-2-yl)methyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl}pyridine-3-carboxylic acid (the compound described in Example 30 of WO 2011 / 146324), 4-[8-[(2-cyclopropyl-5-ethoxy-4-methyl-phenyl)methyl]-2-oxo-1,3,8-triazaspiro[4.5]dec-3-yl]benzoic acid (WO 2016 / 205032, the compound described in Example 1), N-[1-(2,6-diethoxy-4'-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-5-methyl-nicotinamide (the compound described in Example 153 of WO2006 / 128803), 6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid (the compound described in Example 70 of WO 2008 / 019967), 4-(8-((2-cyclopropyl-5-ethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzenesulfonic acid (WO 2021 / 113362, the compound described in Example 1), 4-(7-(2-cyclopropyl-5-ethoxy-4-methylbenzyl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-fluorobenzoic acid (WO 2023 / 125486, the compound described in Example 34), 4-(((1-((2,6-diethoxy-4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-4-fluoropiperidin-4-yl)methyl)amino)-2-methoxybenzoic acid (Compound 23 described in European Journal of Medicinal Chemistry 264(2024)116017), and their salts.

[0018] Furthermore, particularly preferred specific compounds include: 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((2-cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, and their salts.

[0019] The most preferred specific compounds are, for example, 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid or a salt thereof. Those skilled in the art can prepare the above-mentioned "SSTR5 antagonist" by appropriately utilizing the methods described in the above-mentioned patent documents and methods known in the art, and use it in the embodiments of the present invention.

[0020] As demonstrated using representative SSTR5 antagonists in the Examples section below, "SSTR5 antagonists" exert the desired growth hormone secretagogue effect based on their antagonism of SSTR5.

[0021] In embodiments of the present invention, the "SSTR5 antagonist" can be used in free form or in the form of a salt thereof (preferably a pharmaceutically acceptable salt thereof). Those skilled in the art can appropriately select from the two forms based on the properties of each SSTR5 antagonist used and practice the present invention. Examples of pharmaceutically acceptable salts include: salts formed with acids, such as salts formed with inorganic acids (e.g., hydrochlorides, hydrobromides, sulfates, phosphates, etc.), salts formed with organic acids (e.g., acetates, fumarates, oxalates, citrates, methanesulfonates, benzenesulfonates, toluenesulfonates, maleates, etc.); salts formed with bases, such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, etc.); salts formed with amino acids, such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamate, aspartate, etc.

[0022] In embodiments of the present invention, the SSTR5 antagonist can also be used in its prodrug form. Those skilled in the art can appropriately design prodrugs, and such prodrugs can be prepared by methods known per se. Alternatively, the prodrug can be converted into the target SSTR5 antagonist under physiological conditions, as described in "Molecular Design," Volume 7, "Development of Pharmaceuticals," published by Hirokawa Shoten in 1990, pp. 163-198.

[0023] (use) (1) Use as medicine The present inventors have conducted in-depth research and discovered for the first time that SSTR5 antagonists exhibit excellent growth hormone secretion-promoting effects through their SSTR5 antagonism. Due to this growth hormone secretion-promoting effect, SSTR5 antagonists can promote pituitary secretion of growth hormone in diseases caused by insufficient growth hormone secretion and / or diseases with relative growth hormone deficiency that are expected to be ameliorated by growth hormone supplementation (e.g., diseases suitable for growth hormone replacement therapy), thereby improving pathological conditions caused by growth hormone deficiency. Therefore, SSTR5 antagonists can be used to prevent and / or treat diseases in humans or animals (particularly humans) that can be ameliorated by promoting growth hormone secretion. Such diseases (particularly human diseases) that can be ameliorated by promoting growth hormone secretion include, but are not limited to, the following diseases and symptoms. (Disease Examples) Growth hormone deficiency in children, short stature in Turner syndrome, short stature in chondrodystrophy, short stature in children with chronic renal failure, short stature in Prader-Willi syndrome, short stature in SGA patients, short stature in Noonan syndrome, growth hormone deficiency in adults, cancer cachexia, short bowel syndrome, hair loss, skin injuries (such as trauma, burns, pressure sores, diabetic foot, etc.), age-related growth hormone deficiency (such as decreased bone mass, decreased muscle mass, increased body fat, abnormal lipid metabolism, fatty liver, fatigue, inattention, mental depression, emotional instability, dry and / or thinning skin, etc., all related to age) and infertility; etc. In this embodiment, for example, preferred are growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, growth hormone deficiency in adults, cancer cachexia, short bowel syndrome, hair loss, skin injuries (such as trauma, burns, pressure sores, diabetic foot, etc.) and age-related growth hormone deficiency (such as decreased bone mass, decreased muscle mass, increased body fat, abnormal lipid metabolism, fatty liver, fatigue, inattention, mental depression, emotional instability, dry and / or thinning skin, etc., all related to age); more preferred are growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome and growth hormone deficiency in adults.

[0024] In this specification, "prevention" includes preventing the occurrence of a disease (all pathological conditions or symptoms, or more than one pathological condition or symptom) and delaying the occurrence of the disease. "Prophylactically effective amount" refers to a dose of the SSTR5 antagonist sufficient to achieve this purpose. In this specification, "treatment" includes curing the disease (all pathological conditions or symptoms, or more than one pathological condition or symptom), improving the disease, and inhibiting the progression of the severity of the disease. "Therapeutically effective amount" refers to a dose of the SSTR5 antagonist sufficient to achieve this purpose.

[0025] (2) Use as a veterinary growth promoter As described above, since SSTR5 antagonists have excellent growth hormone secretion-stimulating effects through their SSTR5 antagonistic effects, they can also be used as veterinary growth promoters (fattening agents, etc.).

[0026] (Dosage form) In an embodiment of the present invention, the SSTR5 antagonist can be used alone or in the form of a pharmaceutical composition comprising the SSTR5 antagonist as an active ingredient and a pharmaceutically acceptable carrier.

[0027] Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled-release preparations (e.g., immediate-release preparations, sustained-release preparations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films and oral mucosal patches), injections (e.g., subcutaneous injections, intravenous injections (e.g., intravenous push injections), intramuscular injections, and intraperitoneal injections), drops, transdermal absorption preparations, ointments, lotions, adhesive preparations, suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), eye drops, etc.

[0028] In the present specification, various carriers conventionally used in the field of pharmaceutical technology can be used as "pharmaceutically acceptable carriers".

[0029] As specific examples of "pharmaceutically acceptable carriers", in solid preparations, excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silicon dioxide, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose, etc.), disintegrants (e.g., starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl starch, L-hydroxypropyl cellulose, etc.), etc. can be used.

[0030] In liquid preparations, solvents (e.g., water for injection, isotonic saline, alcohol, propylene glycol, polyethylene glycol, sesame oil, etc.), solubilizers (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants (e.g., stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, glycerol monostearate, etc.), hydrophilic polymers (e.g., polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerol, D-mannitol, etc.), buffers (e.g., phosphate, citrate, etc. buffers, etc.), and soothing agents (e.g., benzyl alcohol, etc.) can be used.

[0031] If necessary, formulation additives such as preservatives (eg, parabens, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (eg, sulfites, ascorbic acid, α-tocopherol, etc.), colorants, sweeteners, etc. may be added.

[0032] The aforementioned pharmaceutical compositions can be prepared, typically comprising 0.01% to 99% (w / w), preferably 0.1% to 85% (w / w), of the SSTR5 antagonist, based on the total weight of the formulation. This amount varies depending on the dosage form, route of administration, carrier, and the like. The pharmaceutical compositions can be prepared using conventional methods in the pharmaceutical technology field. The pharmaceutical compositions can be formulated as controlled-release formulations containing the active ingredient, such as immediate-release formulations and sustained-release formulations.

[0033] When used as a veterinary growth promoter, the SSTR5 antagonist can be administered to an animal in need thereof using conventional forms of administration in animal husbandry. The SSTR5 antagonist can also be administered, for example, alone or as a mixture with animal feed or water.

[0034] (Target group) The SSTR5 antagonists used in embodiments of the present invention are expected to have low toxicity, few side effects, and excellent performance as pharmaceuticals. Therefore, the SSTR5 antagonists can be safely administered to humans or animals (e.g., livestock animals (cattle, pigs, horses, sheep, chickens, etc.), aquatic animals (tuna, sea bream, salmon, trout, adult amberjack, toadfish, brown grouper, etc.), etc.), particularly humans.

[0035] (Route of administration) In an embodiment of the invention, the SSTR5 antagonist can be administered alone or as a pharmaceutical composition orally or parenterally (e.g., intravenously, by drip, intramuscularly, subcutaneously, intravenously, intranasally, intradermally, transdermally, intraocularly, intracerebrally, rectally, vaginally, intraperitoneally, or intralesionally).

[0036] (dose) The dosage of the SSTR5 antagonist varies depending on the subject, administration route, age, and symptoms of the subject, and is not particularly limited. A person of ordinary skill in the art can determine the dosage as appropriate. For example, when administered to humans, the dosage per administration is, for example, 0.1 to 320 mg, preferably 1 to 160 mg, of the SSTR5 antagonist as the active ingredient, orally administered per dose. A more preferred dosage is 1 to 80 mg (more specifically, 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, or 80 mg; another specific dosage is, for example, 15 mg, 25 mg, 35 mg, or 75 mg). This dosage can be administered as one to three divided doses per day. Furthermore, when administered in the form of a sustained-release formulation, administration can be done every other day or at longer intervals to match the dosage.

[0037] (in combination with other drugs) In embodiments of the present invention, SSTR5 antagonists can be used in combination with other drugs to prevent or treat target diseases. It is anticipated that these combined therapies will yield superior preventive and / or therapeutic effects. Furthermore, such combined therapies are also expected to reduce the dosage of other drugs and their side effects. Such combined therapies are also encompassed within the scope of the present invention. Drugs that can be used in combination with such SSTR5 antagonists (hereinafter sometimes referred to as concomitant drugs) can be selected according to the patient's disease type, the severity of their symptoms, etc. For example, concomitant use with growth hormone preparations (somatropin, semaglutide, somatrogon, lonapegsomatropin, PEG-somatropin, etc.), ghrelin-like drugs (anamorelin, LUM-201, etc.), human C-type natriuretic peptide preparations (vosoritide, etc.), glucagon-like peptide-2 preparations (teduglutide, etc.), follicle-stimulating hormone preparations (follitropin alfa, corifollitropin alfa, etc.), minoxidil, or finasteride is contemplated. The administration form of the concomitant drug is not particularly limited, and the SSTR5 antagonist and the concomitant drug can be administered in combination. For example, they can be used in the following forms: (1) combined administration of a preparation containing the SSTR5 antagonist and the concomitant drug; (2) simultaneous or separate administration of two separately formulated preparations of the SSTR5 antagonist and the concomitant drug via the same administration route; (3) simultaneous or separate administration of two separately formulated preparations of the SSTR5 antagonist and the concomitant drug via different administration routes, etc. The preferred form can be appropriately selected based on the actual situation in the medical environment. Those skilled in the art can appropriately prepare a preparation comprising the above-mentioned SSTR5 antagonist and a concomitant drug based on the pharmaceutical composition comprising the SSTR5 antagonist. The dosage of the concomitant drug can be appropriately selected based on clinically used dosages. Furthermore, the mixing ratio of the SSTR5 antagonist and the concomitant drug can be appropriately selected based on the disease and symptoms of the intended recipient, the route of administration, the type of concomitant drug, and the like. Generally, the dosage can be appropriately determined based on the typical clinical dosage of the concomitant drug and the actual circumstances of the medical setting. Example

[0038] The embodiments of the present invention will be described in more detail below with reference to examples. These examples do not limit the scope of the present invention in any way. Unless otherwise specified, the reagents, instruments, materials etc. used in the present invention are all commercially available, or those of ordinary skill in the art can suitably prepare them.

[0039] Example 1: Evaluation of the activity of human SSTR5 antagonists using intracellular cAMP concentration as an indicator Intracellular cAMP concentration was measured using the HTRF cAMP dynamic 2 kit (Cisbio). Test compounds diluted in assay buffer (5 mM HEPES (pH 7.5) (Invitrogen), 0.1% fatty acid-free BSA (Sigma), and 500 μM IBMX (Wako) in HBSS (Invitrogen)) were added to 384-well plates (Greiner) at 2 μL / well for a final concentration of 1 μM. A frozen stock of CHO (dhfr-) cells stably expressing the human SSTR5 gene (Accession No. NM_001053) was thawed in a 37°C incubator and suspended in culture medium (MEM alpha (Wako)) containing 10% dialyzed serum (Gemini) and 50 μg / mL gentamicin (Invitrogen). The cell suspension was centrifuged, resuspended in assay buffer, and 2 μL was added to each well (approximately 4,000 cells / well). The compound was incubated with the cells for 15 minutes, and 2 μL of detection buffer containing somatostatin 28 (Toray Research Center) at a final concentration of 0.1 nM and forskolin (Wako) at 0.3 μM was added to each well. The cells were incubated at room temperature for 30 minutes. 3 μL of cAMP-d2 and anti-cAMP-cryptate were added to each well, left at room temperature for 60 minutes, and fluorescence resonance energy transfer (FRET) intensity was measured using a multi-label reader, Envision (Perkin Elmer). The FRET intensity of the wells in the test compound group was converted to cAMP concentration using a calibration curve (created from the FRET intensity of the well group with any concentration of cAMP added to the detection buffer). The inhibitory activity of the compound was calculated using the following formula. Inhibitory activity (%) = (CB) / (AB) x 100 A: cAMP concentration calculated from wells containing 0.3 μM forskolin B: cAMP concentration calculated from wells containing 0.3 μM forskolin and 0.1 nM somatostatin 28 C: cAMP concentrations in wells containing 0.3 μM forskolin, 0.1 nM somatostatin 28, and 1 μM test compound. The inhibition rate (%) of the test compound on SSTR5 at 1 μM is shown in Table 1.

[0040] [Table 1-1]

[0041] [Table 1-2]

[0042] As can be clearly seen from Table 1, the test compound exhibited an excellent SSTR5 antagonistic activity.

[0043] Example 2: Evaluation of selectivity for human SSTR subtypes The selectivity of the test compounds for human SSTR isoforms was investigated by radiolabeled ligand binding assay. The membrane fraction of CHO-K1 cells expressing human SSTR1-5 was suspended in assay buffer (25 mM HEPES (pH 7.4), 5 mM MgCl2, 1 mM CaCl2, 10 μg / mL saponin, 0.5% fatty acid-free BSA) and the cells were stained with 1 μM test compound 1 and [ 125 I]Tyr 11 The cells were incubated for 1 hour in the presence of somatostatin 14 (Perkin Elmer). The membrane fraction-containing solution was then transferred to a filter plate, washed six times with wash buffer (25 mM HEPES, 5 mM MgCl2, 1 mM CaCl2), and then 50 μL of Microscint 20 (Packard) was added. Radioactivity was measured using a TopCount (Perkin Elmer). The results of the competitive activity of the test compounds against the binding of the labeled ligand to human SSTR isoforms are shown in Table 2.

[0044] [Table 2] Test compound 1 Human SSTR subtypes Ligand binding rate at 1 μM (%) SSTR 1 105.83 SSTR 2 100.31 SSTR 3 99.22 SSTR 4 109.00 SSTR 5 4.51

[0045] Table 2 clearly shows that, among human SSTR subtypes, test compound 1 selectively binds to SSTR5.

[0046] As shown in Example 3 below, Test Compound 1 exhibits a highly potent growth hormone secretagogue. Therefore, as described above, when practicing the present invention, it is considered preferable to use an antagonist with high selectivity for SSTR5 (SSTR5-selective antagonist). The desired degree of selectivity for SSTR5 varies with the specific compound used and cannot be universally determined; however, those skilled in the art can appropriately select selectivity based on the principle that the compound exhibits no significant effect on other SSTRs at the dose that exhibits the desired antagonistic effect on SSTR5. For example, the degree of selectivity for human SSTR subtypes can be assessed using the methods described in Example 2.

[0047] Example 3: Evaluation of the Enhancement Effect of Single Dose Administration of Test Compound 1 on Growth Hormone Secretion in Humans The examples in this section show the results of measurements of blood anterior pituitary hormone concentrations using blood samples from a dose-escalation study in healthy Japanese adult men from a randomized, double-blind, placebo-controlled Phase 1 study in healthy adults (jRCT2051210027) designed to examine the safety and tolerability, pharmacokinetic, and pharmacodynamic effects of a single administration of test compound 1. Trial Summary: In a randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study (consisting of seven cohorts), single doses of test compound 1 (1, 3, 10, 20, 40, 80, and 160 mg) or placebo were administered orally under fasting conditions. Eight subjects (six in the active drug group and two in the placebo group) participated in each cohort. Concomitant medications were prohibited from 28 days before admission until discharge. Inclusion criteria: Aged 20 to 45 years, weighing more than 50 kg, and with a BMI of 18.5-25.0 kg / m2 at the time of clinical trial consent 2 Healthy Japanese adult males within the specified range (the subjects' parents and grandparents were Japanese). Exclusion criteria: Subjects with cardiovascular disease, central nervous system disease, gastrointestinal disease, hematopoietic system disease, renal failure, metabolic or endocrine disease, severe allergy, asthma, hypoxemia, hypertension, convulsion or allergic rash during this clinical trial. Subjects with abnormal clinical test values ​​during screening indicating clinically difficult diseases. Experimental arrangements: Subjects were examined and tested 28-2 days and 1 day before administering test compound 1, and qualification was confirmed based on the above-mentioned inclusion criteria and exclusion criteria. Subjects who met all inclusion criteria and did not violate any exclusion criteria were randomized and received oral administration of compound 1 (1, 3, 10, 20, 40, 80 and 160 mg) at the medical institution conducting clinical trials at 9 o'clock. Subjects fasted for 10 hours before administration, fasted for 4 hours after administration until lunch time, and had lunch at 13:00 p.m. Blood was collected 0.5 hour before administration of test compound 1 and 1, 2, 4, 6, 8 and 10 hours after administration. Blood hormone concentration measurement The placebo administration group of all queues and the subject receiving 1mg or 10mg test compound 1 administration were used in the blood of 0.5 hour before administration and 2,4,6,8 and 10 hours after administration to measure the concentration of anterior pituitary hormone.Use human growth hormone Quantikine ELISA kit (manufactured by R&D Systems), follicle-stimulating hormone (people) ELISA kit (manufactured by Cayman Chemical), luteinizing hormone (people) ELISA kit (manufactured by Cayman Chemical), U-TSH ELISA (manufactured by BIOCHECK), ACTH ELISA kit (manufactured by MB Biosciences GmbH) and human prolactin Quantikine ELISA kit (manufactured by R&D Systems), growth hormone, follicle-stimulating hormone, luteinizing hormone, thyroid stimulating hormone, adrenocorticotropic hormone and prolactin concentration in blood were measured according to the scheme described in each test kit package insert. result Figure 1-6 Shown are changes in blood anterior pituitary hormone concentrations over time after oral administration of placebo (n=14) or test compound 1 at doses of 1 mg and 10 mg (n=6 each). Figure 1-6 It is clearly shown that the test compound 1 significantly enhances the secretion of human growth hormone. The test results clearly indicate that the test compound 1 and the SSTR5 antagonists represented by it are useful for preventing and / or treating diseases that can be improved by promoting the secretion of growth hormone.

[0048] In addition, Test Compound 1 did not substantially affect the secretion of other anterior pituitary hormones related to somatostatin (e.g., follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, and prolactin). This suggests that Test Compound 1 and the SSTR5 antagonists it represents are expected to have a selective growth hormone secretagogue effect and do not affect the secretion of all or some anterior pituitary hormones (e.g., follicle-stimulating hormone, luteinizing hormone, thyroid-stimulating hormone, adrenocorticotropic hormone, prolactin, etc.).

[0049] In the medical field, various treatments have been successfully conducted for diseases caused by insufficient growth hormone secretion and / or relative growth hormone deficiency, such as external supplementation of growth hormone (growth hormone replacement therapy). Regarding SSTR5 antagonists, the above-mentioned clinical trial results show that the test compound 1, which is a representative compound, has a clear "growth hormone secretion-promoting effect" in humans. In addition, it has been confirmed that the increase in blood growth hormone concentration caused by the test compound 1 is comparable to the blood growth hormone concentration achieved by children with growth hormone deficiency after receiving growth hormone replacement therapy (J Clin Endocrinol Metab. 2017, 102(5): 1578-1587). This clearly demonstrates that SSTR5 antagonists are effective in treating growth hormone deficiency in children, short stature due to Turner syndrome, short stature due to chondrodystrophy, short stature due to chronic renal failure in children, short stature due to Prader-Willi syndrome, short stature due to SGA, short stature due to Noonan syndrome, growth hormone deficiency in adults (all of which are diseases suitable for growth hormone replacement therapy), cancer cachexia, short bowel syndrome, hair loss, skin lesions, age-related growth hormone deficiency, infertility, and the like (for which growth hormone supplementation can improve pathology and symptoms). A person skilled in the art can easily understand the "disease effect" exerted by such SSTR5 antagonists based on the disease treatment status in a medical setting and the above-mentioned clinical trial results.

[0050] Furthermore, growth hormones have been supplemented externally to livestock animals, which is expected to promote their growth. Therefore, the test results of Test Compound 1 also clearly indicate that administering an SSTR5 antagonist to livestock and aquatic animals is expected to promote their growth (due to its growth hormone secretion effect). Those skilled in the art can readily understand the effects of an SSTR5 antagonist. Industrial Applicability

[0051] The present invention provides a growth hormone secretion promoter, etc., which can be used in the pharmaceutical field, for example.

[0052] This application is based on patent application No. 2023-049987 filed in Japan (filing date: March 27, 2023), the entire contents of which are incorporated herein.

Claims

1. A growth hormone secretion promoter comprising an SSTR5 antagonist as an active ingredient.

2. The growth hormone secretion promoter according to claim 1, wherein The growth hormone secretion promoter is an agent for preventing and / or treating diseases that can be improved by promoting growth hormone secretion.

3. The growth hormone secretion promoter according to claim 2, wherein The diseases improved by promoting growth hormone secretion are one or more diseases selected from the following diseases: growth hormone deficiency in children, short stature of Turner syndrome, short stature of chondrodystrophy, short stature of children with chronic renal failure, short stature of Prader-Willi syndrome, short stature of SGA, short stature of Noonan syndrome, growth hormone deficiency in adults, cancer cachexia, short bowel syndrome, hair loss, skin lesions, age-related growth hormone secretion deficiency and infertility.

4. The growth hormone secretion promoter according to claim 2, wherein The disease improved by promoting growth hormone secretion is one or more diseases selected from the following diseases: growth hormone deficiency in children, short stature of Turner syndrome, short stature of chondrodystrophy, short stature of chronic renal failure in children, short stature of Prader-Willi syndrome, short stature of SGA, short stature of Noonan syndrome and growth hormone deficiency in adults.

5. The growth hormone secretion promoter according to claim 1, wherein The growth hormone secretion promoter is a growth promoter for animals.

6. The growth hormone secretion promoter according to any one of claims 1 to 5, wherein The SSTR5 antagonist is selected from: WO 2014 / 142363, WO 2015 / 052910, WO 2015 / 064083, WO 2010 / 056717, WO 2010 / 129729, WO 2011 / 146324, WO 2012 / 024183, WO 2016 / 205032、WO 2006 / 094682、WO 2006 / 128803、WO 2007 / 025897、WO 2007 / 110340、WO 2008 / 000692、WO 2008 / 019967、WO 2008 / 031735、WO 2008 / 122510、WO 2008 / 145524, WO 2008 / 148710, WO 2021 / 113362, WO 2021 / 113363, WO 2021 / 113368, WO 2023 / 125486 and European Journal of Medicinal Chemistry 264 (2024) 116017 or a salt thereof.

7. The growth hormone secretion promoter according to any one of claims 1 to 5, wherein The SSTR5 antagonist is selected from the group consisting of the compounds described in WO 2015 / 052910 and WO 2015 / 064083 or their salts.

8. The growth hormone secretion promoter according to any one of claims 1 to 5, wherein The SSTR5 antagonist is selected from: 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((2-cyclopropyl-5-ethoxy-2',4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 6-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-ethyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid, 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-ethyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-cyclopropyl-2,4'-difluoro-3-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, 1-(1-((6-cyclopropyl-3-ethoxy-2,4'-difluorobiphenyl-4-yl)methyl)piperidin-4-yl)-3-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid, and their salts.

9. The growth hormone secretion promoter according to any one of claims 1 to 5, wherein The SSTR5 antagonist is 6-(1-((2-cyclopropyl-5-ethoxy-4'-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-5-oxo-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylic acid or a salt thereof.

10. A method for preventing and / or treating a disease that can be improved by promoting growth hormone secretion, the method comprising administering an effective amount of an SSTR5 antagonist to a human or animal in need thereof.

11. An SSTR5 antagonist for use in preventing and / or treating a disease that can be improved by promoting growth hormone secretion.

12. Use of an SSTR5 antagonist in the preparation of a medicament for preventing and / or treating a disease that can be improved by promoting growth hormone secretion.

13. A method for promoting animal growth, comprising administering an effective amount of an SSTR5 antagonist to an animal in need thereof.

14. An SSTR5 antagonist for use in promoting growth in animals.

15. Use of an SSTR5 antagonist in the preparation of a growth promoter for animals.

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