Medicine and pharmaceutical composition for preventing or treating interstitial pneumonia

Abstract

To provide means for preventing or treating interstitial pneumonia with excellent efficacy and safety.SOLUTION: One aspect of the present invention relates to a medicine for preventing or treating interstitial pneumonia, comprising an adrenomedullin derivative as an active ingredient. Another aspect of the present invention relates to a medicine composition for preventing or treating interstitial pneumonia, comprising an adrenomedullin derivative and one or more pharmaceutically acceptable carriers.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a medicament and a pharmaceutical composition for preventing or treating interstitial pneumonia. In particular, one aspect of the present invention relates to a medicament and a pharmaceutical composition for preventing or treating interstitial pneumonia, which contain an adrenomedullin derivative as an active ingredient. [Background technology]

[0002] Interstitial pneumonia is a disease in which inflammation or damage occurs in the alveolar walls, causing them to thicken and harden (fibrosis), reducing the efficiency of gas exchange between oxygen and carbon dioxide in the alveoli. Known causes of interstitial pneumonia include collagen diseases such as rheumatoid arthritis or dermatomyositis (autoimmune interstitial pneumonia), chronic inhalation of dust, mold, or pet hair (pneumoconiosis or chronic hypersensitivity pneumonitis), and taking drugs or supplements (drug-induced interstitial pneumonia). In contrast, interstitial pneumonia with an unidentified cause is collectively called "idiopathic interstitial pneumonia."

[0003] Idiopathic interstitial pneumonia is a designated intractable disease. Most cases of idiopathic interstitial pneumonia are intractable diseases in which pulmonary fibrosis progresses gradually over a chronic course. The cause of most cases of idiopathic interstitial pneumonia is unknown, and it is said that there is no cure. When respiratory failure occurs in idiopathic interstitial pneumonia, the patient's quality of life declines significantly. The average survival time of patients after a diagnosis of idiopathic interstitial pneumonia has been confirmed is reported to be 3 to 5 years.

[0004] Pirfenidone was approved as an anti-fibrotic drug for the treatment of idiopathic interstitial pneumonia in 2008, and nintedanib was approved in 2015. However, the efficacy of these drugs is not satisfactory, and they have many side effects.

[0005] Adrenomedullin (hereinafter, also referred to as "AM") is a physiologically active peptide that was isolated and identified from brown cell tissue in 1993 (Non-Patent Document 1). When first discovered, AM was found to exert a strong vasodilatory antihypertensive effect. For example, Patent Document 1 describes a peptide having antihypertensive effect that contains the amino acid sequence of human AM.

[0006] Subsequent research has revealed that AM exerts a variety of pharmacological actions, including cardiovascular protection, anti-inflammatory, angiogenic, and tissue repair promoting actions. In addition, with the aim of applying the pharmacological actions of AM to disease treatment, research has been conducted into the administration of AM to patients with various diseases. In particular, AM is expected to be useful as a therapeutic agent for inflammatory bowel disease, pulmonary hypertension, peripheral vascular disease, and acute myocardial infarction.

[0007] For example, Patent Document 2 describes a preventive or therapeutic agent for non-bacterial inflammatory bowel disease that contains as an active ingredient adrenomedullin or a derivative thereof that has activity in suppressing non-bacterial inflammation, or a salt thereof that has activity in suppressing non-bacterial inflammation.

[0008] Patent Document 3 describes a method for preventing or treating inflammatory bowel disease in a patient in need of such prevention or treatment for which the use of steroid preparations, immunosuppressants or biological preparations is difficult or insufficiently effective, the method comprising administering to the patient an effective amount of adrenomedullin, a derivative thereof having inflammation-suppressing activity, or a salt of the adrenomedullin or the derivative having inflammation-suppressing activity.

[0009] Non-Patent Document 2 describes that adrenomedullin can improve pulmonary fibrosis by regulating TGF-β-Smads signaling and differentiation of myofibroblasts.

[0010] Since AM is a peptide, it has a short half-life in the body due to metabolic reactions in the body (for example, in blood). For this reason, when administering AM to a subject, it is necessary to select a continuous administration method such as continuous intravenous infusion. In addition, AM has a strong vasodilatory effect in addition to pharmacological effects such as cardiovascular protection, anti-inflammatory, angiogenic, and tissue repair promotion. For this reason, when administering AM to a subject, there is a possibility that undesirable side effects such as excessive blood pressure reduction will occur due to the strong vasodilatory effect. In view of these problems, long-lasting adrenomedullin derivatives have been developed that can substantially suppress undesirable side effects while maintaining the pharmacological effects of adrenomedullin (Patent Documents 4 to 6). [Prior art documents] [Patent documents]

[0011] [Patent Document 1] Patent No. 2774769 [Patent Document 2] Patent No. 4830093 [Patent Document 3] Patent No. 5954736 [Patent Document 4] International Publication No. 2015 / 141819 [Patent Document 5] International Publication No. 2017 / 047788 [Patent Document 6] International Publication No. 2018 / 181638 [Non-patent literature]

[0012] [Non-Patent Document 1] Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochem Biophys Res Commun, April 30, 1993, Volume 192(2), pp. 553-560 [Non-Patent Document 2] Wei Y., Tanaka M., Sakurai T., Kamiyoshi A., Ichikawa-Shindo Y., Kawate H., Cui N., Kakihara S., Zhao Y., Aruga K., Sanjo H., Shindo T. Adrenomedullin Ameliorates Pulmonary Fibrosis by Regulating TGF-β-Smads Signaling and Myofibroblast Differentiation. Endocrinology, 2021, Volume 162(8), pp. 1-22 Summary of the Invention [Problem to be solved by the invention]

[0013] As mentioned above, AM is known to have an effect of improving pulmonary fibrosis. Therefore, it was expected that AM could be used as a lead compound to develop a therapeutic drug for interstitial pneumonia. However, when AM itself is used as an active ingredient of a pharmaceutical, there are problems such as a short half-life, which may shorten the period during which it can be effective, a limited administration route, and / or a possibility of causing undesirable side effects.

[0014] Therefore, an object of the present invention is to provide a means for preventing or treating interstitial pneumonia that is highly effective and safe. [Means for solving the problem]

[0015] The present inventors have investigated various means for solving the above problems. The present inventors have found that AM derivatives have a therapeutic effect on interstitial pneumonia such as pulmonary fibrosis. Based on the above findings, the present inventors have completed the present invention.

[0016] That is, the present invention includes the following aspects and embodiments. (Embodiment 1) A pharmaceutical for preventing or treating interstitial pneumonia, comprising an adrenomedullin derivative as an active ingredient. (Embodiment 2) The adrenomedullin derivative is Formula (AI): AL n -B (AI) [In the formula, A is a modifying group which is a polyethylene glycol group; L is a divalent linking group, n is an integer of 0 or 1, B is a peptide moiety derived from adrenomedullin or an adrenomedullin analog; However, the peptide portion B is bonded to the modifying group A or the linking group L via its N-terminal amino group. or a salt thereof, or a solvate thereof; or Formula (BI): A-CH2-B (BI) [In the formula, A is a modifying group comprising one or more polyethylene glycol groups; B is a peptide moiety derived from adrenomedullin or an adrenomedullin analog; However, peptide portion B is linked to the remainder by a covalent bond between the nitrogen atom of its N-terminal α-amino group and the carbon atom of a methylene group. or a salt thereof, or a solvate thereof, The pharmaceutical composition according to embodiment 1. (Embodiment 3) The adrenomedullin or adrenomedullin analog is (i) a peptide consisting of the amino acid sequence of adrenomedullin, (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) A peptide according to (ii), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (iv) A peptide in which 1 to 30 amino acid residues are deleted, substituted or added in any one of the peptides (i) to (iii) and which has adrenomedullin activity. (v) A peptide in which the C-terminus is amidated in any one of the peptides (i) to (iv), and (vi) A peptide having a glycine residue added to the C-terminus of any of the peptides (i) to (iv). The pharmaceutical according to embodiment 2, wherein the peptide is selected from the group consisting of: (Embodiment 4) The adrenomedullin or adrenomedullin analog is (i) a peptide consisting of the amino acid sequence of adrenomedullin, (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (v) A peptide having an amidated C-terminus in the peptide of (i) or (ii), and (vi) A peptide having a glycine residue added to the C-terminus of the peptide (i) or (ii). The pharmaceutical according to embodiment 2 or 3, wherein the peptide is selected from the group consisting of: (Embodiment 5) The adrenomedullin or adrenomedullin analog is (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) A peptide according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity; (h) a peptide in which 1 to 30 amino acid residues are deleted, substituted or added in any one of the peptides (a) to (g) and which has adrenomedullin activity; (i) any one of the peptides (a) to (h) whose C-terminus is amidated; and (j) any one of the peptides (a) to (h) having a glycine residue added to the C-terminus; The pharmaceutical according to embodiment 2, wherein the peptide is selected from the group consisting of: (Embodiment 6) The adrenomedullin or adrenomedullin analog is (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) any one of the peptides (a) to (f) whose C-terminus is amidated; and (j) any one of the peptides (a) to (f) having a glycine residue added to the C-terminus; The pharmaceutical according to embodiment 2 or 5, wherein the peptide is selected from the group consisting of: (Embodiment 7) The pharmaceutical composition according to any one of embodiments 1 to 6, wherein the interstitial pneumonia is pulmonary fibrosis. (Embodiment 8) The pharmaceutical composition according to any one of the above embodiments 1 to 7, wherein the interstitial pneumonia is idiopathic interstitial pneumonia, hypersensitivity pneumonitis, collagen disease lung, idiopathic nonspecific interstitial pneumonia, or the like. (Embodiment 9) A pharmaceutical composition for preventing or treating interstitial pneumonia, comprising an adrenomedullin derivative and one or more pharma- ceutically acceptable carriers. Effect of the Invention

[0017] The present invention makes it possible to provide a means for preventing or treating interstitial pneumonia that is highly effective and safe. [Brief description of the drawings]

[0018] [Figure 1] In Test I, the appearance of lungs excised from bleomycin (BLM)-induced pulmonary fibrosis model mice in the control group and the PEG-AM-administered group is shown. [Diagram 2] The results of measuring the weight of the lungs excised from the BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM administration group in Test I are shown. A is a graph showing the weight of the lungs excised from the mice of the control group and the PEG-AM administration group. The vertical axis shows the average value and standard error (g) of the actual lung weight. B is a graph showing the ratio of the weight of the excised lung to the body weight of the mice of the control group and the PEG-AM administration group. The vertical axis shows the average value and standard error of the lung weight per mouse body weight. [Diagram 3] This shows the change over time in body weight of the BLM-induced pulmonary fibrosis model mice in the control group and the PEG-AM-administered group in Test I. The horizontal axis shows the time (days) elapsed from the start of the test, and the vertical axis shows the average body weight and standard error (g). [Figure 4] The images show histological examinations of lungs excised from BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM administration group in Test I. The left column shows the results for the control group, and the right column shows the results for the PEG-AM administration group. The top row shows HE stained images of lung sections from the control group and the PEG-AM administration group, the middle row shows MT stained images of lung sections from the control group and the PEG-AM administration group, and the bottom row shows α-SMA immunostained images of lung sections from the control group and the PEG-AM administration group using anti-α-SMA antibody. All scale bars indicate 100 μm. [Diagram 5]The results of histological examination of lungs excised from BLM-induced pulmonary fibrosis model mice in the control group and the PEG-AM-administered group in Study I are shown. A is a graph showing the results of MT staining of lung sections from the control group and the PEG-AM-administered group. The vertical axis shows the mean and standard error (×400) of the percentage of the area of ​​lesions confirmed to be positive in MT staining. B is a graph showing the results of α-SMA immunostaining of lung sections from the control group and the PEG-AM-administered group. The vertical axis shows the mean and standard error (×400) of the percentage of the area of ​​lesions confirmed to be positive in α-SMA immunostaining. [Figure 6] This shows the severity of pulmonary fibrosis in the BLM-induced pulmonary fibrosis model mice in the control group and the PEG-AM-administered group, evaluated using the modified Ashcroft score in Test I. The vertical axis shows the mean and standard error (×200) of the modified Ashcroft score. [Figure 7] This shows the expression levels of various genes in the lungs excised from the BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM-administered group in Test I. The vertical axis shows the average and standard error (relative value) of the gene expression levels quantified by real-time qPCR analysis. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Adrenomedullin (AM) is a physiologically active peptide that was isolated and identified from brown cell tissue in 1993 (Non-Patent Document 1). When it was first discovered, AM was found to have a strong vasodilatory antihypertensive effect. Subsequent research has revealed that AM exerts a variety of pharmacological actions, including cardiovascular protection, anti-inflammatory, angiogenic, and tissue repair promotion. Furthermore, research has been conducted into the administration of AM to patients with various diseases, with the aim of applying the pharmacological action of AM to disease treatment.

[0020] To date, the ameliorative effect of AM on pulmonary fibrosis has been reported (Non-Patent Document 2). For this reason, it was expected that AM could be used as a lead compound to develop a therapeutic drug for interstitial pneumonia. However, when AM itself is used as an active ingredient in a pharmaceutical, there are problems in that the half-life is short, which may shorten the period during which it can be effective, the administration route may be limited, and / or undesirable side effects may occur.

[0021] The present inventors have found that AM derivatives, which are known to be capable of exerting a long-lasting pharmacological effect, have a therapeutic effect against interstitial pneumonia such as pulmonary fibrosis. Therefore, one aspect of the present invention relates to a medicament for preventing or treating interstitial pneumonia, which comprises an AM derivative as an active ingredient.

[0022] In each embodiment of the present invention, an AM derivative is used as an active ingredient. In each embodiment of the present invention, "adrenomedullin derivative" or "adrenomedullin derivative" refers to a compound having a peptide portion corresponding to AM or an AM analog described below, and a modifying group. In each embodiment of the present invention, the use of an AM derivative as an active ingredient can prevent or treat interstitial pneumonia while substantially avoiding the occurrence of undesirable side effects.

[0023] In each aspect of the present invention, the interstitial pneumonia is, for example, pulmonary fibrosis. In one embodiment, the interstitial pneumonia is, for example, idiopathic interstitial pneumonia, hypersensitivity pneumonia, collagen disease lung, or idiopathic nonspecific interstitial pneumonia, and is particularly idiopathic interstitial pneumonia. The interstitial pneumonias exemplified above may show a pathological condition of progressive pulmonary fibrosis, and are therefore also called interstitial lung disease with progressive fibrosis (PF-ILD). The AM derivatives can suppress fibrosis in the interstitial pneumonias exemplified above, for example, suppress the progression of fibrosis or improve the pathological condition. Therefore, in each aspect of the present invention, by using the AM derivatives as an active ingredient, it is possible to prevent or treat interstitial pneumonia through suppressing fibrosis in the interstitial pneumonias exemplified above, for example, suppressing the progression of fibrosis or improving the pathological condition.

[0024] In each embodiment of the present invention, the preventive or therapeutic effect of the AM derivative used as an active ingredient against interstitial pneumonia can be evaluated based on the results of, but not limited to, histological examination of the subject's lungs, severity evaluation of interstitial pneumonia in the subject using an interstitial pneumonia evaluation score such as the Modified Ashcroft score (Hubner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 2008, Vol. 44, pp. 507-511, 514-507), expression analysis of marker genes for interstitial pneumonia (e.g., α-SMA, a myofibroblast marker, and collagen α1, fibronectin, and osteopontin, which are thought to be causative agents of fibrosis), and the like.

[0025] In each aspect of the present invention, "prevention" means substantially preventing or partially reducing the occurrence (onset or manifestation) of interstitial pneumonia in a subject who may develop the disease in the future, such as a healthy subject. In addition, in each aspect of the present invention, "treatment" means suppressing (e.g., suppressing progression), alleviating, repairing, and / or curing the disease that has developed (onset or manifested) in a subject who currently has interstitial pneumonia. In addition, in each aspect of the present invention, "amelioration" means partially or completely suppressing (e.g., suppressing progression), alleviating, and / or repairing interstitial pneumonia that has developed (onset or manifested) in a subject who has interstitial pneumonia.

[0026] In each aspect of the present invention, the AM may be not only a human-derived peptide (SEQ ID NO: 1, Non-Patent Document 1) isolated and identified from human brown cell tissue, but also a peptide (orthologue) derived from other non-human mammals (e.g., warm-blooded animals), such as pigs (SEQ ID NO: 4), dogs (SEQ ID NO: 6), cows (SEQ ID NO: 8), rats (SEQ ID NO: 10) or mice (SEQ ID NO: 12). In vivo, these peptides have two cysteine ​​residues in their amino acid sequences that form a disulfide bond, and the C-terminus is amidated. In the present specification, the peptide having a disulfide bond and a C-terminal amide group may be referred to as "natural adrenomedullin" or simply "adrenomedullin". In each aspect of the present invention, any of the above peptides may be applied as an AM.

[0027] In each aspect of the present invention, "adrenomedullin activity" means, for example, various physiological effects exemplified below, and in particular, effects on the respiratory system, such as the inhibition of pulmonary fibrosis that can be a cause of interstitial pneumonia.

[0028] (1) Cardiovascular system: vasodilatory effect, blood pressure lowering effect, blood pressure elevation suppression effect, cardiac output increase / heart failure improvement effect, pulmonary hypertension improvement effect, angiogenic effect, lymphangiogenic effect, vascular endothelial function improvement effect, anti-arteriosclerotic effect, myocardial protective effect (e.g., myocardial protective effect in ischemia-reperfusion injury or inflammation), suppression of remodeling after myocardial infarction, suppression of cardiac hypertrophy, and angiotensin-converting enzyme suppression effect. (2) Kidneys and water-electrolyte system: diuretic effect, natriuretic effect, antidiuretic hormone suppression effect, aldosterone lowering effect, renal protective effect (e.g., myocardial protective effect in hypertension or ischemia-reperfusion injury), suppression of drinking behavior, and suppression of salt requirement. (3) Brain and nervous system: Neuroprotective and brain damage suppressive effects, anti-inflammatory effects, apoptosis suppressive effects (e.g., apoptosis suppressive effects in ischemia-reperfusion injury or inflammation), maintenance of autoregulation function, suppression of oxidative stress, improvement of dementia, and sympathetic nervous system suppression effects. (4) Genitourinary organs: erection improvement effect, blood flow improvement effect, and implantation promotion effect. (5) Digestive system: Anti-ulcer effect, tissue repair effect, mucosal regeneration effect, blood flow improvement effect, anti-inflammatory effect, and liver function improvement effect. (6) Orthopedics: Stimulating effect on osteoblasts and improving arthritis. (7) Endocrine metabolic system: Adipocyte differentiation effect, lipolysis control effect, insulin sensitivity improvement effect, insulin secretion control effect, antidiuretic hormone secretion inhibition effect, and aldosterone secretion inhibition effect. (8) Respiratory system: Bronchodilator effect, lung protection effect, emphysema improvement effect, pulmonary fibrosis inhibition effect, pneumonia inhibition effect, bronchitis inhibition effect, and respiratory improvement effect. (9) Immune system: Promotes the degradation of C3b. (10) Others: antiviral effect, circulation improving effect, anti-inflammatory effect, cytokine control effect, organ protection effect, oxidative stress suppression effect, tissue repair effect (e.g., anti-bedsore effect), sepsis improvement effect, septic shock improvement effect, multiple organ failure suppression effect, autoimmune disease suppression effect, diabetic retinopathy suppression effect, antibacterial effect, hair growth effect, and hair nourishing effect.

[0029] In the present specification, "C-terminal amidation" means one aspect of post-translational modification of peptides in vivo, specifically, a reaction in which the main chain carboxyl group of the C-terminal amino acid residue of a peptide is converted into the form of an amide group. In addition, in the present specification, "formation of a disulfide bond of a cysteine ​​residue" or "disulfidation of a cysteine ​​residue" means one aspect of post-translational modification of peptides in vivo, specifically, a reaction in which two cysteine ​​residues in the amino acid sequence of a peptide form a disulfide bond (-SS-). Many physiologically active peptides produced in vivo are first biosynthesized as precursor proteins with larger molecular weights, which undergo post-translational modification reactions such as C-terminal amidation and / or disulfidation of cysteine ​​residues during intracellular translocation to become mature physiologically active peptides. C-terminal amidation usually proceeds by the action of a C-terminal amidating enzyme on a precursor protein. In the case of a physiologically active peptide having a C-terminal amide group, a Gly residue is bound to the C-terminal carboxyl group to be amidated in the precursor protein, and the Gly residue is converted to a C-terminal amide group by a C-terminal amidating enzyme. In addition, the C-terminal propeptide of the precursor protein has a repeat sequence of a combination of basic amino acid residues such as Lys-Arg or Arg-Arg (Mizuno, Seikagaku, Vol. 61, No. 12, pp. 1435-1461 (1989)). Disulfidation of cysteine ​​residues can proceed under oxidative conditions. In vivo, disulfidation of cysteine ​​residues usually proceeds by the action of protein disulfide isomerase on precursor proteins.

[0030] In each aspect of the present invention, "an analog of adrenomedullin" and "adrenomedullin analog" refer to a peptide in which the peptide chain of the natural AM described above is partially modified. Even when the AM derivative contains such an AM analog, for example, an AM analog having AM activity, particularly an AM analog having an effect on the respiratory system, as the peptide portion, the pharmaceutical of this aspect can prevent or treat interstitial pneumonia through AM activity substantially equivalent to that of the natural AM.

[0031] The adrenomedullin or adrenomedullin analog is (i) a peptide consisting of the amino acid sequence of adrenomedullin, (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) A peptide according to (ii), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (iv) A peptide in which 1 to 30 amino acid residues are deleted, substituted or added in any one of the peptides (i) to (iii) and which has adrenomedullin activity. (v) A peptide in which the C-terminus is amidated in any one of the peptides (i) to (iv), and (vi) A peptide having a glycine residue added to the C-terminus of any of the peptides (i) to (iv). It is preferred that the peptide is selected from the group consisting of:

[0032] In one embodiment, the adrenomedullin or adrenomedullin analog is (i) a peptide consisting of the amino acid sequence of adrenomedullin, (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (v) A peptide having an amidated C-terminus in the peptide of (i) or (ii), and (vi) A peptide having a glycine residue added to the C-terminus of the peptide (i) or (ii). It is more preferable that the peptide is selected from the group consisting of (ii), (v) and (vi).

[0033] Among the peptides (i) to (vi), the peptide included in (v) consisting of the amino acid sequence of AM, having an amidated C-terminus, and having two cysteine ​​residues in the amino acid sequence forming a disulfide bond corresponds to a mature native AM. The peptide consisting of the amino acid sequence of AM in (i) corresponds to a native AM in its (immature) form before undergoing post-translational modifications of C-terminal amidation and disulfidation of cysteine ​​residues. Among the peptides (i) to (vi), the other peptides except for those described above correspond to analogs of AM.

[0034] The peptide (ii) can be formed by converting the thiol groups of the two cysteine ​​residues of the peptide (i) into disulfide bonds by air oxidation or by oxidation with an appropriate oxidizing agent. By using the peptide (ii), the three-dimensional structure of the peptide can be made similar to that of a natural AM. This makes it possible to make the AM activity of the peptide (ii) substantially equivalent to that of a natural AM.

[0035] The peptide (iii) can be formed by substituting the disulfide bond of the peptide (ii) with an ethylene group. Substitution of the disulfide bond with an ethylene group can be performed by a method well known in the art (O. Keller et al., Helv. Chim. Acta, 1974, vol. 57, p. 1253). The peptide (iii) can be used to stabilize the three-dimensional structure of the peptide. This allows the peptide (iii) to continuously express AM activity in vivo.

[0036] In the peptide (iv), the number of deleted, substituted or added amino acid residues is usually in the range of 1 to 30, preferably in the range of 1 to 15, more preferably in the range of 1 to 10, even more preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. A suitable peptide (iv) is a peptide in which amino acid residues at positions 1 to 20, 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5 or 1 to 3 from the N-terminus, or amino acid residues at positions 26 to 52 from the N-terminus, are deleted in any of the peptides (i) to (iii), and the peptide has AM activity. A more suitable peptide (iv) is a peptide in which amino acid residues at positions 1 to 15, 1 to 10 or 1 to 5 from the N-terminus, or amino acid residues at positions 26 to 52 from the N-terminus, are deleted in any of the peptides (i) to (iii), and the peptide has AM activity. In the suitable peptide, one or more (for example, 1 to 5, 1 to 3, or 1 or 2) amino acid residues may be further deleted, substituted, or added. By using the peptide of (iv) above, the AM activity of the peptide can be made substantially equivalent to that of a natural AM. Furthermore, by using the peptide of (iv) above, the peptide can continuously express AM activity in vivo.

[0037] The peptide (vi) can be converted to the peptide (v) by the action of a C-terminal amidating enzyme, which converts the C-terminal glycine residue into a C-terminal amide group. Thus, by administering the peptide (vi) to a subject, a C-terminally amidated peptide can be formed in the subject's living body after a certain period of time. This allows the peptide (vi) to continuously express AM activity in the living body.

[0038] The adrenomedullin or adrenomedullin analog is (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) A peptide according to any one of (a) to (f), in which the disulfide bond is substituted with an ethylene group, and which has adrenomedullin activity; (h) a peptide in which 1 to 30 amino acid residues are deleted, substituted or added in any one of the peptides (a) to (g) and which has adrenomedullin activity; (i) any one of the peptides (a) to (h) whose C-terminus is amidated; and (j) any one of the peptides (a) to (h) having a glycine residue added to the C-terminus; More preferably, the peptide is selected from the group consisting of:

[0039] In one embodiment, the adrenomedullin or adrenomedullin analog is (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) any one of the peptides (a) to (f) whose C-terminus is amidated; and (j) any one of the peptides (a) to (f) having a glycine residue added to the C-terminus; It is even more preferable that the peptide is selected from the group consisting of:

[0040] In the peptide (h), the number of deleted, substituted or added amino acid residues is usually in the range of 1 to 30, for example, in the range of 1 to 15, preferably in the range of 1 to 12, more preferably in the range of 1 to 10, even more preferably in the range of 1 to 8, particularly preferably in the range of 1 to 5, and most preferably in the range of 1 to 3. A suitable peptide (h) is a peptide in which the amino acid residues at positions 1 to 15, 1 to 12, 1 to 10, 1 to 8, 1 to 5, or 1 to 3 from the N-terminus are deleted, or the amino acid residues at positions 26 to 52 from the N-terminus are deleted in any of the peptides (a) to (g), and the peptide has AM activity. A more suitable peptide (h) is a peptide in which the amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5 from the N-terminus are deleted, or the amino acid residues at positions 26 to 52 from the N-terminus are deleted in any of the peptides (a) to (d), and the peptide has AM activity, or a peptide in which the amino acid residues at positions 1 to 13, 1 to 8, or 1 to 5 from the N-terminus are deleted in any of the peptides (e) or (f), and the peptide has AM activity. In the suitable peptides, one or more amino acid residues (for example, 1 to 5, 1 to 3, or 1 or 2) may be further deleted, substituted, or added. By using the peptide of (h) above, the AM activity of the peptide can be made substantially equivalent to that of a natural AM. Furthermore, by using the peptide of (h) above, the peptide can continuously express AM activity in vivo.

[0041] Even when the AM derivative contains an AM analog as described above, for example an AM analog having AM activity, particularly an AM analog having an effect on the respiratory system, as the peptide portion of the AM derivative, the pharmaceutical of this embodiment can prevent or treat interstitial pneumonia through AM activity that is substantially equivalent to that of natural AM.

[0042] In each aspect of the present invention, the AM derivative may be, but is not limited to, a compound disclosed in the specifications of International Publication No. 2015 / 141819 (Patent Document 4), International Publication No. 2017 / 047788 (Patent Document 5), and International Publication No. 2018 / 181638 (Patent Document 6). A person skilled in the art can prepare an AM derivative having AM activity by purchasing an AM derivative having AM activity, applying an appropriate conversion reaction to a purchased compound, or preparing the compound by himself based on the above-mentioned documents. The AM derivative disclosed in the above-mentioned documents can exert the pharmacological effect of AM without substantially causing undesirable side effects. Therefore, in each aspect of the present invention, by using the AM derivative disclosed in the above-mentioned documents as an active ingredient, it is possible to prevent or treat interstitial pneumonia while substantially avoiding the occurrence of undesirable side effects.

[0043] In one embodiment, the adrenomedullin derivative has the formula (AI): AL n -B (AI) The compound represented by formula (AI) is an adrenomedullin derivative represented by formula (I) disclosed in International Publication No. 2015 / 141819 (Patent Document 4).

[0044] In formula (AI), B is a peptide moiety derived from AM or an AM analog. The AM or AM analog is preferably a peptide selected from the group consisting of (i) to (vi) described above, more preferably a peptide selected from the group consisting of (i), (ii), (v) and (vi) described above, even more preferably a peptide selected from the group consisting of (ii), (v) and (vi) described above, even more preferably a peptide selected from the group consisting of (a) to (j) described above, and particularly preferably a peptide selected from the group consisting of (a) to (f), (i) and (j) described above.

[0045] In formula (AI), A is a modifying group. A is preferably a modifying group selected from the group consisting of palmitoyl group, polyethylene glycol (PEG) group, myristoyl group, sugar group and peptide group, more preferably a modifying group selected from the group consisting of palmitoyl group and PEG group, and even more preferably a PEG group. The sugar group is preferably a monovalent group (e.g., a glycosyl group) derived from a monosaccharide, a disaccharide, an oligosaccharide or a polysaccharide. The peptide group is preferably a monovalent group (e.g., a monovalent group that forms a bond via an N-terminal amino group, a C-terminal carboxyl group or a side chain group) derived from polyglycine, polyglutamic acid, polylysine or polyasparagine, etc. The PEG group preferably has an average molecular weight in the range of 200 to 60,000, more preferably an average molecular weight in the range of 5,000 to 60,000. When the average molecular weight of the PEG group is 200 or more, the compound represented by formula (AI) of this embodiment can continuously express AM activity in vivo for a long period of time. The AM activity of the compound represented by formula (AI) of the present embodiment can be made substantially equivalent to that of a natural AM by chemically modifying the N-terminal amino group of the AM or its analog with the modifying group A. Furthermore, the compound represented by formula (AI) of the present embodiment can continuously express AM activity in vivo.

[0046] In formula (AI), L is a divalent linking group. The divalent linking group L is preferably a substituted or unsubstituted divalent hydrocarbon group, more preferably a substituted or unsubstituted divalent aliphatic hydrocarbon group, a substituted or unsubstituted divalent alicyclic group, or a substituted or unsubstituted divalent aromatic group, and is preferably a substituted or unsubstituted C1-C 10 Alkylene group, C2-C 10 Alkenylene group or C2-C 10More preferably, it is an alkynylene group. The group preferably contains one or more heteroatoms, and more preferably contains a divalent group containing one or more heteroatoms, such as oxo(carbonyl), thiocarbonyl, carbamate, or carbonimidoyl. The divalent group containing one or more heteroatoms is preferably located at one or both ends of the divalent linking group L, and more preferably at the end that forms a bond with the peptide portion B. In this case, the compound represented by formula (AI) can be cleaved at the divalent linking group L by a metabolic reaction in vivo, such as hydrolysis, to release an AM or an AM analog. A particularly suitable divalent linking group L is 1-oxo-1,6-hexanediyl. By having a divalent linking group L having the above characteristics, the compound represented by formula (AI) of this embodiment can continuously express AM activity in vivo.

[0047] In formula (AI), n is an integer of 0 or 1. When n is 0, the compound represented by formula (AI) of this embodiment is represented by formula (A-Ia): AB (A-Ia) It is a compound represented by the formula:

[0048] In formula (A-Ia), A and B have the same meaning as defined in formula (AI).

[0049] In formula (AI), peptide portion B is bonded to the modifying group A or the linking group L via a group in the region near its N-terminus. Peptide portion B is preferably bonded to the modifying group A or the linking group L via its N-terminal amino group. In this embodiment, the "group in the region near its N-terminus" of peptide portion B means a group of an amino acid residue contained in the region from the N-terminal amino acid residue to the 13th amino acid residue of peptide portion B (for example, the α-amino group of the N-terminal amino acid residue, or an amino group, carboxyl group, hydroxyl group, imidazole group or guanidine group in the side chain of each amino acid residue), and a modifying group bonded to the amino acid residue.

[0050] In this embodiment, the "N-terminal amino group of peptide portion B" means the α-amino group of the N-terminal amino acid residue of peptide portion B. Due to the above-mentioned bond form, the compound represented by formula (AI) of this embodiment can continuously express AM activity in vivo.

[0051] Particularly preferred compounds of formula (AI) are A is a modifying group that is a palmitoyl group; n is 0, B is a peptide moiety derived from adrenomedullin or an adrenomedullin analog; provided that the peptide portion B is linked to the modifying group A via its N-terminal amino group, or A is a modifying group that is a PEG group; L is a divalent linking group which is a substituted or unsubstituted divalent hydrocarbon group, said group containing one or more heteroatoms; n is 1, B is a peptide moiety derived from adrenomedullin or an adrenomedullin analog; provided that the peptide portion B is bound to the modifying group A or the linking group L via its N-terminal amino group; and B is as follows: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) any one of the peptides (a) to (f) whose C-terminus is amidated; and (j) any one of the peptides (a) to (f) having a glycine residue added to the C-terminus; or a peptide selected from the group consisting of: the below described: (h') a peptide having any one of the peptides (a) to (d) deleted from the N-terminus of amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5, or amino acid residues at positions 26 to 52, and having adrenomedullin activity; or a peptide having any one of the peptides (e) or (f) deleted from the N-terminus of amino acid residues at positions 1 to 13, 1 to 8, or 1 to 5, and having adrenomedullin activity; (i) a peptide having an amidated C-terminus in the peptide (h'); and (j) the peptide of (h') having a glycine residue added to the C-terminus; The peptide portion is derived from adrenomedullin or an adrenomedullin analog, which is a peptide selected from the group consisting of: The compound represented by formula (AI) of the present embodiment having the above characteristics is an AM derivative in which the nitrogen atom of the α-amino group at the N-terminus of AM is linked to the remainder by forming an amide bond (hereinafter also referred to as "amide-linked AM derivative"). The compound represented by formula (AI) of the present embodiment having the above characteristics can continuously express AM activity substantially equivalent to that of natural AM in a living body. Therefore, the pharmaceutical agent of the present embodiment containing the compound represented by formula (AI) as an active ingredient can continuously prevent or treat interstitial pneumonia in a living body.

[0052] The compound represented by formula (AI) of this embodiment can be prepared by purchasing, applying an appropriate conversion reaction to a compound purchased based on International Publication No. 2015 / 141819 (Patent Document 4), or by self-preparation based on the above-mentioned document.

[0053] In another embodiment, the adrenomedullin derivative has the formula (BI): A-CH2-B (BI) The compound represented by formula (BI) is an AM derivative represented by formula (I) disclosed in International Publication No. 2017 / 047788 (Patent Document 5).

[0054] In formula (BI), B is a peptide moiety derived from AM or an AM analog. The AM or AM analog is preferably a peptide selected from the group consisting of (i) to (vi) described above, more preferably a peptide selected from the group consisting of (i), (ii), (v) and (vi) described above, even more preferably a peptide selected from the group consisting of (ii), (v) and (vi) described above, even more preferably a peptide selected from the group consisting of (a) to (j) described above, and particularly preferably a peptide selected from the group consisting of (a) to (f), (i) and (j) described above.

[0055] In formula (BI), A is a modifying group containing one or more PEG groups. The embodiment in which the modifying group A contains one or more PEG groups is not particularly limited. For example, one or more PEG groups may be located at the terminal end of the modifying group A, or may be located inside the modifying group A. In addition, the modifying group A may be any of various groups known in the art as a linear or branched group containing a PEG group. Known groups that can be used as the modifying group A include, but are not limited to, groups disclosed in, for example, WO 95 / 11924, WO 2006 / 084089, WO 98 / 41562, WO 2005 / 079838, WO 2002 / 060978, WO 2001 / 048052, WO 98 / 055500, WO 96 / 021469, WO 2003 / 040211, and JP-A-04-108827. By using a group containing one or more PEG groups as the modifying group A, the compound represented by formula (BI) can continuously express AM activity in vivo.

[0056] In formula (BI), A is represented by the following formula (II): [ka] It is preferable that the modifying group is represented by the following formula:

[0057] In formula (II), a is an integer equal to or greater than 1; m is an integer equal to or greater than 1, L 1 is a linear or branched linking group having a valence of m+1, where L 1 If there are multiple L 1 may be the same or different from each other, L 2 and L 2’ are each independently a bond or a divalent linking group, provided that L 2’ If there are multiple L 2’ may be the same or different from each other, M 1 is a PEG group, where M 1 When there are multiple M 1 may be the same or different from each other, M 2 is a bond or a PEG group, where M 2 When there are multiple M 2 may be the same or different from each other, R 1 is hydrogen or a monovalent group, * indicates the bonding position to the remainder.

[0058] m is a linking group L 1 For example, when m is 1, L 1 is a divalent linking group that is unbranched toward the terminals, i.e., a linear group. When m is 2 or more, L 1 is a trivalent or higher linking group, and is a group having two or more branches toward the terminal. m is usually an integer of 1 or more and 5 or less, preferably in the range of 1 to 5, more preferably in the range of 1 to 4, and even more preferably in the range of 1 to 3. 1 When the branch number m is within the above range, the modifying group A containing a PEG group can have a linear or branched structure.

[0059] a is a PEG group M 1 and M 2 , and a linking group L 1 and L2’ For example, when a is 1, the unit does not have a repeating structure. When a is 2 or more and m is 1, the unit has a linear repeating structure. When a is 2 or more and m is 2 or more, the unit has a dendritic branched repeating structure. a is usually an integer of 1 or more and 5 or less, preferably in the range of 1 to 5, and more preferably in the range of 1 to 2. PEG group M 1 and M 2 , and a linking group L 1 and L 2’ When the repeating number a of the units is within the above range, the modifying group A containing a PEG group can have a linear or branched chain structure.

[0060] M 1 and M 2 In the formula (III), the PEG group is typically represented by the formula (III): # -(CH2CH2O) n - ** (III) In formula (III), ** represents L 1 and # is O or L. 2’The weight average molecular weight of the PEG group represented by formula (III), as a total in the modifying group A, is usually 1 kDa or more, preferably 5 kDa or more, more preferably 10 kDa or more, and even more preferably 20 kDa or more, and is usually 2000 kDa or less, preferably 1000 kDa or less, more preferably 100 kDa or less, and even more preferably 80 kDa or less, and particularly preferably 60 kDa or less. The PEG group represented by formula (III), as a total in the modifying group A, usually has a weight average molecular weight in the range of 1 to 2000 kDa, for example, in the range of 1 to 1000 kDa, preferably in the range of 1 to 100 kDa, more preferably in the range of 5 to 80 kDa, even more preferably in the range of 10 to 60 kDa, and particularly preferably in the range of 20 to 60 kDa. When the total weight-average molecular weight of the PEG groups represented by formula (III) in the modifying group A is within the above range, the AM activity of the compound represented by formula (BI) of the present embodiment can be substantially equivalent to that of a natural AM. In addition, the compound represented by formula (BI) of the present embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0061] In formula (III), n is the number of repeats of the ethylene oxide unit defined based on the weight average molecular weight. When defined based on the preferred range of the weight average molecular weight, n is usually an integer of about 20 or more, preferably about 110 or more, more preferably about 230 or more, and even more preferably about 460 or more, and is usually an integer of about 45000 or less, preferably about 22000 or less, more preferably about 2200 or less, even more preferably about 1820 or less, and particularly preferably about 1360 or less. When defined based on the preferred range of the weight average molecular weight, n is usually in the range of about 20 to 45000, for example, in the range of about 20 to 22000, preferably in the range of about 20 to 2200, more preferably in the range of about 110 to 1820, even more preferably in the range of about 230 to 1360, and particularly preferably in the range of about 460 to 1360. When the number of repeats n is in the above range, the total weight average molecular weight of the PEG groups contained in the modifying group represented by formula (II) falls within the above range. Therefore, when the repeat number n is within the above range, the AM activity of the compound represented by formula (BI) of this embodiment can be substantially equivalent to that of a natural AM. Furthermore, the compound represented by formula (BI) of this embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0062] R 1 is hydrogen, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, substituted or unsubstituted C2-C 20 Alkynyl, substituted or unsubstituted C3-C 20 Cycloalkyl, substituted or unsubstituted C4-C 20 Cycloalkenyl, substituted or unsubstituted C4-C 20 Cycloalkynyl, substituted or unsubstituted 3-6 membered heterocycloalkyl, substituted or unsubstituted C7-C 20 Cycloalkylalkyl, substituted or unsubstituted 3-6 membered heterocycloalkyl-C1-C 20 Alkyl, substituted or unsubstituted C4-C 20Aryl, substituted or unsubstituted C5-C 20 Arylalkyl, substituted or unsubstituted 5-15 membered heteroaryl, substituted or unsubstituted 5-15 membered heteroaryl-C1-C 20 Alkyl or substituted or unsubstituted acyl is preferred, and hydrogen, substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C2-C 20 Alkenyl, or substituted or unsubstituted C2-C 20 Alkynyl is more preferred, hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl is even more preferred, and methyl is particularly preferred. When the above groups are substituted, the substituents are each independently selected from halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted amino, and substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C2-C5 alkenyl, substituted or unsubstituted C2-C5 alkynyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C3-C6 cycloalkenyl, substituted or unsubstituted C3-C6 cycloalkynyl, substituted or unsubstituted amino. R is preferably a monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, unsubstituted C1 to C5 alkyl, unsubstituted C2 to C5 alkenyl, unsubstituted C2 to C5 alkynyl, unsubstituted C3 to C6 cycloalkyl, unsubstituted C3 to C6 cycloalkenyl, unsubstituted C3 to C6 cycloalkynyl, unsubstituted amino, and unsubstituted C1 to C5 alkoxy. 1 When is the above group, the AM activity of the compound represented by formula (BI) of the present embodiment can be substantially equivalent to that of a natural AM. Furthermore, the compound represented by formula (BI) of the present embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0063] L 1 is a linear or branched linking group having a valence of m+1. 1is preferably a substituted or unsubstituted m+1 valent linear or branched hydrocarbon group. The group may contain one or more heteroatoms, alicyclic groups, aromatic groups, amide groups (-CO-NH-), ester groups (-CO-O-), or urethane groups (-O-CO-NH-). When the group is substituted, the substituents are preferably each independently a monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, and substituted or unsubstituted linear or branched hydrocarbon groups.

[0064] L 2 and L 2’ are each independently a bond or a divalent linking group. 2 and L 2’ When is a divalent linking group, L 2 and L 2’ are preferably each independently a substituted or unsubstituted divalent hydrocarbon group, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-), and are each independently a substituted or unsubstituted C1 to C 20 Alkylene, substituted or unsubstituted C2-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted C3-C 20 Cycloalkylene, substituted or unsubstituted C4-C 20 Cycloalkenylene, substituted or unsubstituted C4-C 20 Cycloalkynylene, substituted or unsubstituted 3-6 membered heterocycloalkylene, substituted or unsubstituted C7-C 20 Cycloalkylalkylene, substituted or unsubstituted 3-6 membered heterocycloalkyl-C 20 Alkylene, substituted or unsubstituted C4-C 20 Arylene, substituted or unsubstituted C5-C 20 Arylalkylene, substituted or unsubstituted 5-15 membered heteroarylene, or substituted or unsubstituted 5-15 membered heteroaryl-C 20More preferably, it is an alkylene, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-), which may contain one or more heteroatoms, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-). When the above groups are substituted, the substituents are preferably each independently a monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, and substituted or unsubstituted straight-chain or branched-chain hydrocarbon groups, and more preferably a monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, unsubstituted C1-C5 alkyl, unsubstituted C2-C5 alkenyl, unsubstituted C2-C5 alkynyl, unsubstituted C3-C6 cycloalkyl, unsubstituted C3-C6 cycloalkenyl, unsubstituted C3-C6 cycloalkynyl, unsubstituted amino, and unsubstituted C1-C5 alkoxy.

[0065] L 1 , L 2 and L 2’ When is the above group, the AM activity of the compound represented by formula (BI) of the present embodiment can be substantially equivalent to that of a natural AM. Furthermore, the compound represented by formula (BI) of the present embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0066] In formula (BI), suitable modifying groups A are represented by the following formulae (V), (VI), (VII) or (VIII): [ka] It is a modifying group represented by the formula:

[0067] In formulae (V), (VI), (VII) and (VIII), a is an integer equal to or greater than 1; M 3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’are, independently of each other, a bond or a PEG group, provided that M 3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’ When there are multiple M 3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’ may be the same or different, and M 3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’ at least one of which is a PEG group; R 1 , R 1’ , R 1’’ and R 1’’’ are each independently a hydrogen atom or a monovalent radical, R 2 is a bond or a divalent group, R 3 , R 3’ and R 3’’ are each independently a bond or a divalent group, provided that R 3 , R 3’ and R 3’’ If there are multiple R 3 , R 3’ and R 3’’ may be the same or different from each other, * indicates the bonding position to the remainder.

[0068] a is a PEG group M 3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’ is the number of repetitions of the unit containing the following. For example, when a is 1, the unit does not have a repetitive structure. In formula (V), when a is 2 or more, the unit has a linear repetitive structure. In formulas (VI), (VII) and (VIII), when a is 2 or more, the unit has a dendritic branched repetitive structure. a is usually an integer of 1 or more and 5 or less, preferably in the range of 1 to 5, and more preferably in the range of 1 to 2. PEG group M3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’ When the repeat number a of the unit containing the following is within the above range, the modifying group A containing a PEG group can have a linear or branched structure.

[0069] M 3 , M 3’ , M 3’’ , M 3’’’ and M 3’’’’ When is a PEG group, the PEG group is usually a group represented by formula (III). The PEG group represented by formula (III) has the same meaning as above. In this case, the AM activity of the compound represented by formula (BI) of this embodiment can be substantially equivalent to that of natural AM. In addition, the compound represented by formula (BI) of this embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0070] R 1 has the same meaning as above. 1’ , R 1’’ and R 1’’’ R 1 In this case, the AM activity of the compound represented by formula (BI) of the present embodiment can be substantially equivalent to that of a natural AM. In addition, the compound represented by formula (BI) of the present embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0071] R 2 is preferably a bond, a substituted or unsubstituted divalent hydrocarbon group, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-), and is preferably a bond, a substituted or unsubstituted C1 to C 20 Alkylene, substituted or unsubstituted C2-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted C3-C 20Cycloalkylene, substituted or unsubstituted C4-C 20 Cycloalkenylene, substituted or unsubstituted C4-C 20 Cycloalkynylene, substituted or unsubstituted 3-6 membered heterocycloalkylene, substituted or unsubstituted C7-C 20 Cycloalkylalkylene, substituted or unsubstituted 3-6 membered heterocycloalkyl-C 20 Alkylene, substituted or unsubstituted C4-C 20 Arylene, substituted or unsubstituted C5-C 20 Arylalkylene, substituted or unsubstituted 5-15 membered heteroarylene, or substituted or unsubstituted 5-15 membered heteroaryl-C 20 More preferably, it is an alkylene, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-). The divalent hydrocarbon group may contain one or more heteroatoms, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-). When the group is substituted, the substituents are each independently selected from halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C3 to C6 cycloalkenyl, substituted or unsubstituted C3 to C6 cycloalkynyl, substituted or unsubstituted amino, and substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C3 to C6 cycloalkenyl, substituted or unsubstituted C3 to C6 cycloalkynyl, substituted or unsubstituted amino. R is preferably a monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, unsubstituted C1 to C5 alkyl, unsubstituted C2 to C5 alkenyl, unsubstituted C2 to C5 alkynyl, unsubstituted C3 to C6 cycloalkyl, unsubstituted C3 to C6 cycloalkenyl, unsubstituted C3 to C6 cycloalkynyl, unsubstituted amino, and unsubstituted C1 to C5 alkoxy. 2 is preferably a bond or a substituted or unsubstituted C1-C 10It is an alkylene group, more preferably a bond, methylene, ethylene, propylene or butylene, and even more preferably a bond or ethylene.

[0072] R 3 , R 3’ and R 3’’ are preferably each independently a bond, a substituted or unsubstituted divalent hydrocarbon group, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-), and 20 Alkylene, substituted or unsubstituted C2-C 20 Alkenylene, substituted or unsubstituted C2-C 20 Alkynylene, substituted or unsubstituted C3-C 20 Cycloalkylene, substituted or unsubstituted C4-C 20 Cycloalkenylene, substituted or unsubstituted C4-C 20 Cycloalkynylene, substituted or unsubstituted 3-6 membered heterocycloalkylene, substituted or unsubstituted C7-C 20 Cycloalkylalkylene, substituted or unsubstituted 3-6 membered heterocycloalkyl-C 20 Alkylene, substituted or unsubstituted C4-C 20 Arylene, substituted or unsubstituted C5-C 20 Arylalkylene, substituted or unsubstituted 5-15 membered heteroarylene, or substituted or unsubstituted 5-15 membered heteroaryl-C 20More preferably, it is an alkylene, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-). The divalent hydrocarbon group may contain one or more heteroatoms, an amide group (-CO-NH-), an ester group (-CO-O-), or a urethane group (-O-CO-NH-). When the group is substituted, the substituents are each independently selected from halogen (fluorine, chlorine, bromine, or iodine), cyano, nitro, substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C3 to C6 cycloalkenyl, substituted or unsubstituted C3 to C6 cycloalkynyl, substituted or unsubstituted amino, and substituted or unsubstituted C1 to C5 alkyl, substituted or unsubstituted C2 to C5 alkenyl, substituted or unsubstituted C2 to C5 alkynyl, substituted or unsubstituted C3 to C6 cycloalkyl, substituted or unsubstituted C3 to C6 cycloalkenyl, substituted or unsubstituted C3 to C6 cycloalkynyl, substituted or unsubstituted amino. R is preferably a monovalent group selected from the group consisting of halogen (fluorine, chlorine, bromine or iodine), cyano, nitro, unsubstituted C1 to C5 alkyl, unsubstituted C2 to C5 alkenyl, unsubstituted C2 to C5 alkynyl, unsubstituted C3 to C6 cycloalkyl, unsubstituted C3 to C6 cycloalkenyl, unsubstituted C3 to C6 cycloalkynyl, unsubstituted amino, and unsubstituted C1 to C5 alkoxy. 3 , R 3’ and R 3’’ are preferably each independently a bond, a substituted or unsubstituted C1-C 10 Substituted or unsubstituted C1-C including alkylene and amide groups 10 They are alkylene groups or amide groups (-CO-NH-), and more preferably, independently of each other, a bond, methylene, ethylene, -CO-NH-(CH2)4-, -CH2-O-CO-NH-(CH2)3- or -CO-NH-.

[0073] R 2 , R 3 , R 3’ and R 3’’When is the above group, the AM activity of the compound represented by formula (BI) of the present embodiment can be substantially equivalent to that of a natural AM. Furthermore, the compound represented by formula (BI) of the present embodiment can continuously express AM activity in vivo while substantially suppressing undesirable side effects.

[0074] In formula (BI), particularly preferred modifying groups A are represented by the following formulae (V-1-1), (VI-1-1), (VII-1-1), (VII-1-2), (VII-2-1), or (VIII-1-1): [ka] [In the formula, n has the same meaning as defined above, n' has the same meaning as defined above for n, * indicates the attachment point to the remainder.] It is a modifying group represented by the formula:

[0075] In formula (V-1-1), the PEG groups preferably have a combined weight average molecular weight of 5 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 60 kDa or 80 kDa.

[0076] In formula (VI-1-1), the PEG groups preferably have a combined weight average molecular weight of 40 kDa.

[0077] In formula (VII-1-1), the PEG groups preferably have a combined weight average molecular weight of 5 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 60 kDa or 80 kDa.

[0078] In formula (VII-1-2), the PEG groups preferably have a weight average molecular weight of 50 kDa in total. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 40 kDa, (CH2CH2O) n’The ethylene oxide units have a total weight average molecular weight of 10 kDa.

[0079] In formula (VII-2-1), the PEG groups preferably have a weight average molecular weight of 40 kDa in total. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 30 kDa, (CH2CH2O) n’ The ethylene oxide units have a total weight average molecular weight of 10 kDa. Alternatively, the PEG groups preferably have a total weight average molecular weight of 60 kDa. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 50 kDa, (CH2CH2O) n’ The ethylene oxide units have a total weight average molecular weight of 10 kDa. Alternatively, the PEG groups preferably have a total weight average molecular weight of 80 kDa. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 70 kDa, (CH2CH2O) n’ The ethylene oxide units have a total weight average molecular weight of 10 kDa.

[0080] In formula (VIII-1-1), the PEG groups preferably have a combined weight average molecular weight of 40 kDa.

[0081] By using the above group as the modifying group A in formula (BI), the compound represented by formula (BI) of this embodiment can maintain the pharmacological action of natural AM while substantially suppressing undesirable side effects, and can sustainably express AM activity in vivo.

[0082] In formula (BI), the peptide moiety B is linked to the remainder by covalently bonding the nitrogen atom of the α-amino group at its N-terminus to the carbon atom of the methylene group. In each aspect of the present invention, when the modifying group A containing one or more PEG groups and the peptide moiety B are linked in the above-mentioned linking manner, it may be described as an "alkylamine-linked AM derivative". As described in International Publication No. 2015 / 141819 (Patent Document 4), the alkylamine-linked AM derivative has higher AM activity than an AM derivative in which the nitrogen atom of the α-amino group at the N-terminus of the AM is linked to the remainder by forming an amide bond (amide-linked AM derivative). In addition, the alkylamine-linked AM derivative represented by formula (BI) of this embodiment has more suppressed undesirable side effects (e.g., excessive blood pressure reduction, tachycardia associated with reflex sympathetic nerve activity increase, and / or increased renin activity, etc.) than the amide-linked AM derivative. Therefore, the compound represented by formula (BI) of this embodiment can continuously express AM activity in vivo while suppressing undesirable side effects more than known AM derivatives.

[0083] Particularly preferred compounds of the present embodiment represented by formula (BI) are A is a modifying group containing a PEG group represented by formula (V-1-1), (VI-1-1), (VII-1-1), (VII-1-2), (VII-2-1), or (VIII-1-1), B is as follows: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) any one of the peptides (a) to (f) whose C-terminus is amidated; and (j) any one of the peptides (a) to (f) having a glycine residue added to the C-terminus; or a peptide selected from the group consisting of: the below described: (h') a peptide having any one of the peptides (a) to (d) deleted from the N-terminus of amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5, or amino acid residues at positions 26 to 52, and having adrenomedullin activity; or a peptide having any one of the peptides (e) or (f) deleted from the N-terminus of amino acid residues at positions 1 to 13, 1 to 8, or 1 to 5, and having adrenomedullin activity; (i) a peptide having an amidated C-terminus in the peptide (h'); and (j) the peptide of (h') having a glycine residue added to the C-terminus; The peptide moiety is derived from adrenomedullin or an adrenomedullin analog, which is a peptide selected from the group consisting of: The compound represented by formula (BI) of this embodiment having the above characteristics can sustain AM activity in vivo while maintaining the pharmacological action of natural AM and substantially suppressing undesirable side effects. Therefore, the pharmaceutical of this embodiment containing the compound represented by formula (BI) as an active ingredient can prevent or treat interstitial pneumonia while substantially suppressing undesirable side effects.

[0084] The compound represented by formula (BI) of this embodiment can be prepared by purchasing, applying an appropriate conversion reaction to a compound purchased based on International Publication No. 2017 / 047788 (Patent Document 5), or by self-preparation based on the above-mentioned document.

[0085] In another embodiment, the AM derivative has the formula (X): A'-CO-B (X) or a salt thereof, or a solvate thereof. In this specification, the compound represented by formula (X) may be referred to as a "urethane-linked AM derivative".

[0086] In formula (X), B is a peptide moiety derived from AM or an AM analogue. The peptide moiety B has the same meaning as defined above for the compound of formula (BI).

[0087] In formula (X), A' is a modifying group containing one or more PEG groups. However, A' is linked to the remainder by a covalent bond between an oxygen atom of the modifying group containing a PEG group and a carbon atom of a carbonyl group. When the modifying group A' has such a structure, the compound represented by formula (X) of this embodiment can have a structure in which the modifying group A' and the peptide portion B are linked via a urethane bond.

[0088] In formula (X), A' is represented by the following formula (XI), (XI') or (XII): R1 -OM 1 -* (XI) [ka] It is preferable that the modifying group is represented by the following formula:

[0089] In formulae (XI), (XI') and (XII), * indicates the position of attachment to the remainder.

[0090] In formulae (XI), (XI') and (XII), a, R 1 , R 1’ , R 2 , R 3 , R 3’ , R 3’’ , M 1 , M 3 , M 3’ and M 3’’ has the same meaning as defined above for compounds of formula (I).

[0091] In formula (X), particularly preferred modifying groups A′ are represented by the following formulae (XI-1-1), (XII-1-1) or (XII-2-1): CH3O-(CH2CH2O) n -* (XI-1-1) [ka] [In the formula, n has the same meaning as defined above, n' has the same meaning as defined above for n, * indicates the attachment point to the remainder.] It is a modifying group represented by the formula:

[0092] In formula (XI-1-1), the PEG groups preferably have a combined weight average molecular weight of 5 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 60 kDa or 80 kDa.

[0093] In formula (XII-1-1), the PEG groups preferably have a combined weight average molecular weight of 5 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 60 kDa or 80 kDa.

[0094] In formula (XII-2-1), the PEG groups preferably have a weight average molecular weight of 40 kDa in total. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 30 kDa, (CH2CH2O) n’ The ethylene oxide units have a total weight average molecular weight of 10 kDa. Alternatively, the PEG groups preferably have a total weight average molecular weight of 60 kDa. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 50 kDa, (CH2CH2O) n’ The ethylene oxide units have a total weight average molecular weight of 10 kDa. Alternatively, the PEG groups preferably have a total weight average molecular weight of 80 kDa. In this case, typically, (CH2CH2O) n The ethylene oxide units have a total weight average molecular weight of 70 kDa, (CH2CH2O) n’ The ethylene oxide units have a total weight average molecular weight of 10 kDa.

[0095] By using the above-mentioned group as the modifying group A' in formula (X), the compound represented by formula (X) of this embodiment can sustainably express AM activity in vivo while maintaining the pharmacological action of natural AM.

[0096] In formula (X), the peptide portion B is linked to the remainder by covalently bonding the nitrogen atom of the α-amino group at its N-terminus to the carbon atom of the carbonyl group. The urethane-linked AM derivative has higher AM activity than the amide-linked AM derivative described in WO 2015 / 141819 (Patent Document 4). Therefore, the compound represented by formula (X) of this embodiment can persistently express higher AM activity in vivo than known AM derivatives.

[0097] Particularly preferred compounds of formula (X) are A' is a modifying group containing a PEG group represented by formula (XI-1-1), (XII-1-1) or (XII-2-1), B is as follows: (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residue at position 16 and the cysteine ​​residue at position 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) any one of the peptides (a) to (f) whose C-terminus is amidated; and (j) any one of the peptides (a) to (f) having a glycine residue added to the C-terminus; or a peptide selected from the group consisting of: the below described: (h') a peptide having any one of the peptides (a) to (d) deleted from the N-terminus of amino acid residues at positions 1 to 15, 1 to 10, or 1 to 5, or amino acid residues at positions 26 to 52, and having adrenomedullin activity; or a peptide having any one of the peptides (e) or (f) deleted from the N-terminus of amino acid residues at positions 1 to 13, 1 to 8, or 1 to 5, and having adrenomedullin activity; (i) a peptide having an amidated C-terminus in the peptide (h'); and (j) the peptide of (h') having a glycine residue added to the C-terminus; The peptide moiety is derived from adrenomedullin or an adrenomedullin analog, which is a peptide selected from the group consisting of: The compound represented by formula (X) of the present embodiment having the above characteristics can continuously express higher AM activity in vivo compared to known AM derivatives. Therefore, the pharmaceutical agent of the present embodiment containing the compound represented by formula (X) as an active ingredient can substantially suppress undesirable side effects and prevent or treat interstitial pneumonia.

[0098] The compound represented by formula (X) of this embodiment can be prepared by purchasing, applying an appropriate conversion reaction to a compound purchased based on International Publication No. 2017 / 047788 (Patent Document 5), or by self-preparation based on the above-mentioned document.

[0099] In each aspect of the present invention, the AM derivative used as an active ingredient includes not only the compound itself but also its salt.When the AM derivative is in the form of a salt, it is preferably a pharma- ceutically acceptable salt.The counter ion of the AM derivative salt includes, but is not limited to, cations such as sodium ion, potassium ion, calcium ion, magnesium ion, or substituted or unsubstituted ammonium ion, or chloride ion, bromide ion, iodide ion, phosphate ion, nitrate ion, sulfate ion, carbonate ion, bicarbonate ion, perchlorate ion, formate ion, acetate ion, trifluoroacetate ion, propionate ion, lactate ion, maleate ion, hydroxymaleate ion, methylmaleate ion, fumarate ion, adipate ion, benzoate ion, 2-acetoxybenzoate ion, p-aminobenzoate ion, etc. Preferred anions include amine, nicotinate, cinnamate, ascorbate, pamoate, succinate, salicylate, bismethylenesalicylate, oxalate, tartrate, malate, citrate, gluconate, aspartate, stearate, palmitate, itaconate, glycolate, glutamate, benzenesulfonate, cyclohexylsulfamate, methanesulfonate, ethanesulfonate, isethionate, benzenesulfonate, p-toluenesulfonate, or naphthalenesulfonate. When the AM derivative is in the form of a salt with the above counter ion, the AM activity of the compound can be substantially equivalent to that of natural AM.

[0100] In each aspect of the present invention, the AM derivative used as an active ingredient includes not only the compound itself but also the solvate of the compound or its salt. When the AM derivative or its salt is in the form of a solvate, it is preferably a pharma- ceutically acceptable solvate. The solvent that can form a solvate with the compound or its salt is, but is not limited to, for example, water or an organic solvent such as methanol, ethanol, 2-propanol (isopropyl alcohol), dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, acetonitrile or ethyl acetate. When the AM derivative or its salt is in the form of a solvate with the above-mentioned solvent, the AM activity of the compound can be substantially equivalent to that of natural AM.

[0101] In each embodiment of the present invention, the AM derivatives used as active ingredients also include mixtures of stereoisomers of the compounds, such as individual enantiomers and diastereomers of the compounds, as well as racemates.

[0102] By containing the AM derivative having the above-mentioned characteristics as an active ingredient, the medicine of this embodiment can prevent or treat interstitial pneumonia.

[0103] It is known that the binding activity of PEG-AM to the AM receptor is about 30 times lower than that of AM (Akashi E., Nagata S., Yamasaki M., Kitamura K. Activation of Calcitonin Gene-Related Peptide and Adrenomedullin Receptors by PEGylated Adrenomedullin Biol. Pharm. Bull., 2020, Vol. 43(11), pp. 1799-1803). From such a comparison of physiological characteristics in vitro, it was predicted that the human equivalent dose (HED) of the AM derivative would be higher than that of the AM. However, as shown in the examples, the AM derivative has a therapeutic effect on interstitial pneumonia at a much lower dose than the dose predicted from the physiological characteristics in vitro. Therefore, by containing an AM derivative having the above characteristics as an active ingredient, the pharmaceutical of this embodiment can prevent or treat interstitial pneumonia at a low dose.

[0104] In the pharmaceutical of this embodiment, the AM derivative used as an active ingredient may be used alone or in combination with one or more pharma- ceutically acceptable ingredients. The pharmaceutical of this embodiment may be formulated into various dosage forms commonly used in the art according to the desired administration method. Thus, the pharmaceutical of this embodiment may also be provided in the form of a pharmaceutical composition containing the AM derivative and one or more pharma- ceutically acceptable carriers. In this embodiment, the pharmaceutical composition may contain, in addition to the ingredients, one or more pharma- ceutically acceptable vehicles (e.g., solvents such as sterilized water or solutions such as saline), excipients, binders, vehicles, solubilizers, preservatives, stabilizers, disintegrants, disintegration inhibitors, swelling agents, lubricants, surfactants, emulsifiers, oily liquids (e.g., vegetable oils), suspending agents, buffers, soothing agents, antioxidants, sweeteners, and flavoring agents.

[0105] The dosage form of the pharmaceutical of this embodiment is not particularly limited, and may be a preparation for use in parenteral administration, a preparation for use in transmucosal (e.g., nasal, sublingual, or oral mucosa), transdermal, transanal (enema), or transvaginal administration, or a preparation for use in oral administration. The dosage form of the pharmaceutical of this embodiment may be a preparation in a unit dose form or a preparation in a multiple dose form. Preparations for use in parenteral administration include, for example, injections such as sterile solutions or suspensions with water or other pharma- ceutically acceptable liquids. Examples of additives that can be mixed with the injection include, but are not limited to, vehicles such as isotonic solutions containing physiological saline, glucose, or other auxiliary agents (e.g., D-sorbitol, D-mannitol, or sodium chloride), solubilizing agents such as alcohols (e.g., ethanol or benzyl alcohol), esters (e.g., benzyl benzoate), and polyalcohols (e.g., propylene glycol or polyethylene glycol), nonionic surfactants such as polysorbate 80 or polyoxyethylene hydrogenated castor oil, oily liquids such as sesame oil or soybean oil, buffers such as phosphate buffer or sodium acetate buffer, pain-relieving agents such as benzalkonium chloride or procaine hydrochloride, stabilizers such as human serum albumin or polyethylene glycol, preservatives, and antioxidants. The prepared injection is usually filled into a suitable container (e.g., a vial or an ampoule) and stored under an appropriate environment until use.

[0106] Additives contained in the formulation for use in transmucosal administration include, for example, vehicles, emulsifiers, suspending agents, antibacterial agents (e.g., chlorobutanol), isotonic agents (e.g., sodium chloride), pH adjusting agents, and penetrants. Additives contained in the formulation for use in transdermal administration include, for example, vehicles, antipruritic agents, antifoaming agents, emollients, surfactants, emulsifiers, thickening agents, suspending agents, buffers, viscosity-increasing agents, moisturizing agents, antioxidants, chemical stabilizers, coloring agents, and decolorizing agents. Additives contained in the formulation for use in anal administration include, for example, vehicles, emulsifiers, and solid fatty bases. Additives contained in the formulation for use in vaginal administration include, for example, vehicles, buffers, oily liquids, suspending agents, wetting agents, surfactants, antioxidants, antibacterial agents, and isotonic agents.

[0107] Examples of preparations for oral administration include tablets, pills, powders, capsules, soft capsules, microcapsules, elixirs, liquids, syrups, slurries, and suspensions. Tablets may be formulated as sugar-coated tablets or gelatin-coated tablets, enteric-coated tablets, orally disintegrating tablets (OD tablets) or film-coated tablets, or as double- or multi-layered tablets, if desired.

[0108] Examples of additives that can be mixed into tablets or capsules include, but are not limited to, binders such as water, ethanol, propanol, simple syrup, glucose solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, gelatin, corn starch, tragacanth gum, and gum arabic; excipients such as crystalline cellulose, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and silicic acid; dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, and monoglyceryl stearate. Examples of the additives include disintegrating agents such as cornstarch, starch, lactose, or polyvinylpyrrolidone; disintegration inhibitors such as white sugar, stearic cocoa butter, or hydrogenated oil; bulking agents such as cornstarch, gelatin, or alginic acid; lubricants such as magnesium stearate; absorption promoters such as quaternary ammonium salts or sodium lauryl sulfate; moisturizing agents such as glycerin or starch; adsorbents such as starch, lactose, kaolin, bentonite, or colloidal silicic acid; lubricants such as purified talc, stearates (e.g., magnesium stearate), boric acid powder, or polyethylene glycol; sweeteners such as sucrose, lactose, or saccharin; and flavoring agents such as peppermint, saffron oil, or cherry. When the preparation is a capsule, it may further contain a liquid carrier such as oil or fat.

[0109] The medicament of this embodiment can also be formulated as a depot preparation. In this case, the medicament of this embodiment in the form of a depot preparation can be administered, for example, by subcutaneous or intramuscular implantation or intramuscular injection. By applying the medicament of this embodiment to a depot preparation, the AM activity of the AM derivative used as an active ingredient can be sustained for a long period of time.

[0110] The pharmaceutical agent of this embodiment can also be used in combination with one or more other pharmaceutical agents useful as pharmaceuticals. In this case, the pharmaceutical agent of this embodiment may be provided in the form of a single pharmaceutical agent containing an AM derivative and one or more other pharmaceutical agents, or in the form of a pharmaceutical combination or kit containing multiple preparations in which the AM derivative and one or more other pharmaceutical agents are separately formulated. In the case of a pharmaceutical combination or kit, each preparation can be administered simultaneously or separately (for example, consecutively).

[0111] When AM derivatives are applied to medicinal uses, AM derivatives include not only the compounds themselves, but also pharma- ceutically acceptable salts of the compounds and their pharma-ceutically acceptable solvates.The pharma-ceutically acceptable salts of AM derivatives and their pharma-ceutically acceptable solvates are not limited, but are preferably, for example, the salts or solvates exemplified above.When AM derivatives are in the form of the above-mentioned salts or solvates, the compounds can be applied to desired medicinal uses.

[0112] The AM derivative used as the active ingredient of the medicament of this embodiment is derived from AM, which is a natural physiologically active peptide. Therefore, the AM derivative is safe and has low toxicity. Therefore, the medicament of this embodiment can be applied to various subjects who need to prevent or treat interstitial pneumonia. The subject is preferably a human or non-human mammalian subject or patient (e.g., a warm-blooded animal such as a pig, a dog, a cow, a rat, a mouse, a guinea pig, a rabbit, a chicken, a sheep, a cat, a monkey, a Mandrill or a chimpanzee), and more preferably a human patient. By administering the medicament of this embodiment to the subject, interstitial pneumonia in the subject can be prevented or treated.

[0113] When the pharmaceutical of this embodiment is administered to a subject, particularly a human patient, the exact dosage and administration should be ultimately determined by the attending physician in consideration of many factors, such as the subject's age, sex, symptoms to be prevented or treated, the exact state (e.g., severity) of the disease and / or disorder, and the administration route. Therefore, in the pharmaceutical of this embodiment, the AM derivative, which is the active ingredient, is administered to the subject in a therapeutically effective dosage and administration (e.g., dosage amount, number of administrations, and administration route). For example, when the pharmaceutical of this embodiment is administered to a human patient, the dosage of the AM derivative used as the active ingredient is usually in the range of 0.1 to 100,000 μg / kg / administration, for example, 10.0 to 1,000 μg / kg / administration, in terms of AM.

[0114] The medicament of this embodiment may be administered by any administration route. The medicament of this embodiment is preferably administered by a parenteral route such as intravenous administration, enema administration, subcutaneous administration, intramuscular administration or intraperitoneal administration, and more preferably administered intravenously. By using the medicament of this embodiment containing the AM derivative as an active ingredient in the above-mentioned usage and dosage (e.g., dosage, number of administrations and administration route), interstitial pneumonia in a subject can be more effectively prevented or treated.

[0115] The AM derivative used as the active ingredient of the medicament of this embodiment can be used to prevent or treat interstitial pneumonia in subjects who may develop interstitial pneumonia in the future or in subjects who currently have interstitial pneumonia. Therefore, another embodiment of the present invention is a method for preventing or treating interstitial pneumonia, comprising administering an effective amount of an AM derivative, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, to a subject in need of prevention or treatment of interstitial pneumonia. The AM derivative, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof administered in the method of this embodiment has the same characteristics as the active ingredient of the medicament of this embodiment described above. In addition, the method of this embodiment can be carried out in the same manner and dosage as the medicament of this embodiment described above. By administering an effective amount of an AM derivative to a subject in need of prevention or treatment of interstitial pneumonia, the disease can be prevented or treated.

[0116] Another aspect of the present invention is an AM derivative, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, for use in the prevention or treatment of interstitial pneumonia. Yet another aspect of the present invention is the use of an AM derivative, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, for the manufacture of a medicament for use in the prevention or treatment of interstitial pneumonia. Yet another aspect of the present invention is the use of an AM derivative, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof, for use in the prevention or treatment of interstitial pneumonia. The compound etc. of this aspect has the same characteristics as the active ingredient of the medicament of this aspect described above. In addition, the compound etc. of this aspect can be used in the same manner and dosage as the medicament of this aspect described above. By using an AM derivative, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate thereof in the prevention or treatment of interstitial pneumonia, the disease can be prevented or treated. EXAMPLES

[0117] The present invention will be described in more detail below with reference to examples, although the technical scope of the present invention is not limited to these examples.

[0118] <Test I: Pharmacological test of AM derivatives using bleomycin-induced pulmonary fibrosis model mice> [I-1: Preparation of medication] h. AM(1-52): Mature native human adrenomedullin. A peptide consisting of the amino acid sequence of SEQ ID NO: 1, in which the C-terminus is amidated and the cysteine ​​residues at positions 16 and 21 form a disulfide bond. PEG-AM: An alkylamine-linked adrenomedullin derivative having a PEG group (a group represented by formula (VII-1-1)) having a weight-average molecular weight of 60 kDa. An AM derivative in which a PEG group with a weight-average molecular weight of 60 kDa is linked to h. AM(1-52) via a covalent bond between the N-terminal α-amino group and the carbon atom of the methylene group. PEG-AM was prepared based on International Publication No. 2017 / 047788 (Patent Document 5).

[0119] In this test, PEG-AM was prepared as the drug to be administered.

[0120] [I-2: Creation of model mice] Pulmonary fibrosis was induced in male C57BL / 6 mice (Charles River Japan, Kanagawa, Japan) aged 10 to 12 weeks by a single intratracheal administration of bleomycin (BLM) (Nippon Kayaku, Tokyo, Japan) at 2 mg / kg body weight in 50 μl of sterile saline. The day of BLM administration was designated as day 0 of the study. The obtained BLM-induced pulmonary fibrosis model mice were divided into a control group and a PEG-AM administration group (n=10). The PEG-AM administration group received PEG-AM at a dose of 25 nmol / kg body weight via tail vein injection on days 0 and 7 of the study. The control group received the same volume of PBS via tail vein injection on days 0 and 7 of the study. The body weight of the mice was measured every day from day 0 to day 14 of the study, and the average body weight and standard error for each group were calculated. On day 14 of the study, lungs were removed from each mouse. The weights of the excised lungs were measured, and the mean and standard error of the lung weights in each group were calculated. The left lung was formalin-fixed, paraffin-embedded, and used for histological analysis, and the right lung was snap-frozen and used for real-time qPCR analysis.

[0121] [I-3: Histological examination] The lung sections obtained in I-2 were fixed in 4% formalin neutral buffer, embedded in paraffin, and cut into 4 μm-thick sections. Some sections were stained with hematoxylin / eosin (HE) and Masson's trichrome (MT). Anti-α-SMA antibody (RRID:AB_2223500, Cat# M0851, Dako) was used for immunohistochemical staining. To visualize α-SMA labeling, biotin-labeled secondary antibody and 3,3'-diaminobenzidine (DAB) (Histofine kit, Nichirei, Tokyo, Japan) were used. Nuclei were counterstained with hematoxylin. Examination was performed using a microscope (BZ-X710; Keyence, Osaka, Japan). Quantification was performed using a BZ analyzer (Keyence).

[0122] [I-4: Assessment of the severity of pulmonary fibrosis] The severity of pulmonary fibrosis was assessed using the modified Ashcroft score (Hubner RH, Gitter W, El Mokhtari NE, Mathiak M, Both M, Bolte H, Freitag-Wolf S, Bewig B. Standardized quantification of pulmonary fibrosis in histological samples. Biotechniques 2008, Vol. 44, pp. 507-511, 514-507). Details of the modified Ashcroft score are shown in Table 1.

[0123] [Table 1]

[0124] [I-5: Real-time qPCR analysis] Total RNA was prepared using TRI REAGEN (Molecular Research Center, Cincinnati, OH, USA) and DNA-free DNA Removal Kit (Ambion, Naugatuck, CT, USA) according to the manufacturer's instructions. For cDNA synthesis, RNA was reverse transcribed using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA). PCR primers and probes were designed using NCBI Primer-BLAST (https: / / www.ncbi.nlm.nih.gov / tools / primer-blast / ) and synthesized at Integrated DNA Technologies (Coralville, IA, USA). Real-time qPCR was performed on an ABI Prism 7300 Sequence Detection System (Applied Biosystems) using SYBR Green (Toyobo, Osaka, Japan) or Realtime PCR Master Mix (Toyobo) and TaqMan probes (MBL, Aichi, Japan). The reaction was carried out at 50°C for 2 min, 95°C for 2 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. Relative mRNA levels were normalized to mouse glyceraldehyde-3-phosphate dehydrogenase mRNA (Pre-Developed TaqMan assay reagents; Applied Biosystems) and calculated using the comparative cycle threshold method (ΔΔCt). The sequences of the PCR primers and probes are shown in Table 2.

[0125] [Table 2]

[0126] [I-6: Changes in lung appearance and lung weight] FIG. 1 shows the appearance of the lungs excised from the BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM administration group, and FIG. 2 shows the results of measuring the weight of the lungs. In FIG. 2, A is a graph showing the weight of the lungs excised from the mice of the control group and the PEG-AM administration group. The vertical axis shows the average value and standard error (g) of the actual lung weight. B is a graph showing the ratio of the weight of the excised lung to the body weight of the mice of the control group and the PEG-AM administration group. The vertical axis shows the average value and standard error of the lung weight per body weight of the mouse. In FIG. 2, "*" and "**" indicate that there was a significant difference from the control group (*: p<0.05, **: p<0.01). In addition, FIG. 3 shows the change in body weight over time of the BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM administration group. In the figure, the horizontal axis shows the time (days) elapsed from the start of the test. The vertical axis shows the average value and standard error (g) of the body weight.

[0127] As shown in FIG. 1, pulmonary fibrosis was confirmed in the control group. In contrast, pulmonary fibrosis was suppressed in the PEG-AM-administered group. Furthermore, as shown in FIG. 2, the lung weight was significantly reduced in the PEG-AM-administered group compared to the control group. As shown in FIG. 3, both the control group and the PEG-AM-administered group lost weight from the third day after the start of the test. However, no significant difference in weight loss was confirmed between the control group and the PEG-AM-administered group.

[0128] [I-7: Results of lung histological examination and severity assessment of pulmonary fibrosis] Histological examination images of lungs excised from BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM administration group are shown in FIG. 4. In the figure, the left column shows the results of the control group, and the right column shows the results of the PEG-AM administration group. The upper row shows HE stained images of lung sections of the control group and the PEG-AM administration group, the middle row shows MT stained images of lung sections of the control group and the PEG-AM administration group, and the lower row shows α-SMA immunostained images of lung sections of the control group and the PEG-AM administration group using anti-α-SMA antibody. The scale bar indicates 100 μm. The results of histological examination of lungs excised from BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM administration group are shown in FIG. 5. In the figure, A is a graph showing the results of MT staining of lung sections of the control group and the PEG-AM administration group. The vertical axis shows the average and standard error (×400) of the percentage of the area of ​​lesions confirmed to be positive in MT staining. (B) is a graph showing the results of α-SMA immunostaining of lung sections from the control group and the PEG-AM administration group. The vertical axis shows the mean percentage of the area of ​​lesions confirmed to be positive in α-SMA immunostaining and the standard error (×400). "**" and "***" indicate significant differences from the control group (**: p<0.01, ***: p<0.001).

[0129] The severity of pulmonary fibrosis in the BLM-induced pulmonary fibrosis model mice in the control group and the PEG-AM-administered group, evaluated using the modified Ashcroft score, is shown in Figure 6. In the figure, the vertical axis indicates the mean value and standard error (x200) of the modified Ashcroft score. "*" indicates that there was a significant difference from the control group (*: p<0.05).

[0130] As shown in Figures 4 and 5, the MT staining-positive area, which indicates fibrotic lesions (Figure 5A), and the myofibroblast marker α-SMA-positive area (Figure 5B) were both significantly reduced in the PEG-AM-administered group compared to the control group. In addition, as shown in Figure 6, the severity of pulmonary fibrosis, as expressed by the modified Ashcroft score, was also significantly reduced in the PEG-AM-administered group compared to the control group.

[0131] [I-8: Results of real-time qPCR analysis] The expression levels of various genes in the lungs excised from the BLM-induced pulmonary fibrosis model mice of the control group and the PEG-AM-administered group are shown in Figure 7. In the figure, the vertical axis indicates the average and standard error (relative value) of the gene expression levels quantified by real-time qPCR analysis. "*" and "**" indicate significant differences from the control group (*: p<0.05, **: p<0.01).

[0132] As shown in Figure 7, in the PEG-AM-administered group, the gene expression levels of α-SMA, a myofibroblast marker, as well as collagen α1, fibronectin, and osteopontin, which are thought to be substances that cause fibrosis, were significantly reduced compared to the control group.

[0133] These results demonstrate that the AM derivative PEG-AM has therapeutic effects against interstitial pneumonia such as pulmonary fibrosis. In this study, PEG-AM was administered at 25 nmol / kg body weight / day to mice with BLM-induced pulmonary fibrosis model. The human equivalent dose (HED) calculated based on the dose in this study is approximately 2 nmol / kg human body weight / day. Thus, the HED of the AM derivative is an appropriate initial dose for first-in-human (FIH) studies, and therefore can be used as an active ingredient in pharmaceuticals.

[0134] It is known that the binding activity of PEG-AM to the AM receptor is about 30 times lower than that of AM (Akashi E., Nagata S., Yamasaki M., Kitamura K. Activation of Calcitonin Gene-Related Peptide and Adrenomedullin Receptors by PEGylated Adrenomedullin Biol. Pharm. Bull., 2020, Vol. 43(11), pp. 1799-1803). From such a comparison of physiological characteristics in vitro, it was predicted that the HED of the AM derivative would be higher than that of the AM. However, when the results of pharmacological tests of AM and AM derivatives using BLM-induced pulmonary fibrosis model mice were compared, the HED of AM was 5.8 μg / kg human body weight / day, which is about 1 / 3 of the non-toxic amount (16 μg / kg human body weight / day) (Non-Patent Document 2), whereas the HED of PEG-AM was about 2 nmol / kg human body weight / day, which was less than 1 / 10 of the non-toxic amount. Thus, it was revealed that the AM derivative has a therapeutic effect against interstitial pneumonia at a dose far lower than the dose expected from the physiological characteristics in vitro.

[0135] The present invention is not limited to the above-described embodiments, but includes various modified examples. For example, the above-described embodiments have been described in detail to clearly explain the present invention, and the present invention is not necessarily limited to those including all of the configurations described. In addition, it is possible to add, delete, and / or replace part of the configuration of each embodiment with other configurations.

Claims

1. A pharmaceutical for preventing or treating interstitial pneumonia, comprising an adrenomedullin derivative as an active ingredient.

2. The adrenomedullin derivative is Formula (AI): A-L n -B (A-I) [In the formula, A is a modifying group which is a polyethylene glycol group; L is a divalent linking group, n is an integer of 0 or 1, B is a peptide moiety derived from adrenomedullin or an adrenomedullin analog; However, the peptide portion B is bonded to the modifying group A or the linking group L via its N-terminal amino group. or a salt thereof, or a solvate thereof; or Formula (BI): A-CH 2 -B (B-I) [In the formula, A is a modifying group comprising one or more polyethylene glycol groups; B is a peptide moiety derived from adrenomedullin or an adrenomedullin analog; However, peptide portion B is linked to the remainder by a covalent bond between the nitrogen atom of its N-terminal α-amino group and the carbon atom of a methylene group. or a salt thereof, or a solvate thereof, The pharmaceutical composition according to claim 1.

3. The adrenomedullin or adrenomedullin analog is (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (iii) A peptide according to (ii), in which the disulfide bond is replaced by an ethylene group, and which has adrenomedullin activity; (iv) A peptide in which 1 to 30 amino acid residues are deleted, substituted or added in any one of the peptides (i) to (iii) and which has adrenomedullin activity. (v) any one of the peptides (i) to (iv) above, wherein the C-terminus is amidated; and (vi) Any of the peptides (i) to (iv) above, wherein a glycine residue is added to the C-terminus. The pharmaceutical according to claim 2, which is a peptide selected from the group consisting of:

4. The adrenomedullin or adrenomedullin analog is (i) a peptide consisting of the amino acid sequence of adrenomedullin; (ii) a peptide consisting of the amino acid sequence of adrenomedullin, in which two cysteine ​​residues in the amino acid sequence form a disulfide bond; (v) A peptide having an amidated C-terminus in the peptide (i) or (ii), and (vi) A peptide having a glycine residue added to the C-terminus of the peptide (i) or (ii). The pharmaceutical according to claim 3, which is a peptide selected from the group consisting of:

5. The adrenomedullin or adrenomedullin analog is (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (g) any one of the peptides (a) to (f), in which the disulfide bond is replaced by an ethylene group, and the peptide has adrenomedullin activity; (h) a peptide in which 1 to 30 amino acid residues are deleted, substituted or added in any one of the peptides (a) to (g) and which has adrenomedullin activity; (i) any one of the peptides (a) to (h) whose C-terminus is amidated; and (j) any one of the peptides (a) to (h) above, wherein a glycine residue has been added to the C-terminus; The pharmaceutical according to claim 2, which is a peptide selected from the group consisting of:

6. The adrenomedullin or adrenomedullin analog is (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1, or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (b) a peptide consisting of the amino acid sequence of SEQ ID NO: 4, or a peptide consisting of the amino acid sequence of SEQ ID NO: 4 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 6, or a peptide consisting of the amino acid sequence of SEQ ID NO: 6 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 8, or a peptide consisting of the amino acid sequence of SEQ ID NO: 8 and in which the cysteine ​​residues at positions 16 and 21 form a disulfide bond; (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 10, or a peptide consisting of the amino acid sequence of SEQ ID NO: 10 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 12, or a peptide consisting of the amino acid sequence of SEQ ID NO: 12 and in which the cysteine ​​residues at positions 14 and 19 form a disulfide bond; (i) any one of the peptides (a) to (f) whose C-terminus is amidated; and (j) any one of the peptides (a) to (f) above, wherein a glycine residue has been added to the C-terminus; The pharmaceutical according to claim 5, which is a peptide selected from the group consisting of:

7. The pharmaceutical composition according to claim 1, wherein the interstitial pneumonia is pulmonary fibrosis.

8. The pharmaceutical composition according to claim 1, wherein the interstitial pneumonia is idiopathic interstitial pneumonia, hypersensitivity pneumonitis, collagen disease lung, idiopathic nonspecific interstitial pneumonia, or the like.

9. A pharmaceutical composition for preventing or treating interstitial pneumonia, comprising an adrenomedullin derivative and one or more pharma- ceutically acceptable carriers.

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