Agent for treating or preventing chronic kidney disease containing pyrazole amide compound
阅读说明：本技术 含有吡唑酰胺化合物的慢性肾脏病的治疗或预防剂 (Agent for treating or preventing chronic kidney disease containing pyrazole amide compound ) 是由 齐藤友幸 太田毅 角谷真 米良泰子 于 2019-09-10 设计创作，主要内容包括：本发明的目的是提供化合物A或其药学上可接受的盐、或化合物A的一水合物的新的药物用途。本发明涉及含有化合物A或其药学上可接受的盐、或化合物A的一水合物作为有效成分的慢性肾脏病的治疗剂或预防剂。(An object of the present invention is to provide a novel pharmaceutical use of compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a. The present invention relates to a therapeutic or prophylactic agent for chronic kidney diseases, which contains compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a as an active ingredient.)
1. A therapeutic or prophylactic agent for chronic kidney disease, characterized by comprising the following chemical structural formula:
[ solution 1]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 2]
The compounds shown.
2. A renal function improving agent characterized by comprising the following chemical structural formula:
[ solution 3]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 4]
The compounds shown.
3. An improver for 1 or more than 2 parameters selected from the group consisting of GFR, eGFR, serum creatinine value, blood urea nitrogen value, creatinine clearance rate, urine protein value and urine albumin value, characterized by comprising the following chemical structural formula:
[ solution 5]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 6]
The compounds shown.
4. The agent according to any one of claims 1 to 3, characterized by comprising a compound of the following formula,
[ solution 7]
。
5. The agent according to any one of claims 1 to 3, characterized by comprising a compound of the following formula,
[ solution 8]
。
Technical Field
The present invention relates to 2- {4- [ (9R) -9-Hydroxy-2- (3-Hydroxy-3-methylbutyloxy) -9- (trifluoromethyl) -9H-fluoren-4-yl ] -1H-pyrazol-1-yl } -2-methylpropanamide (2- {4- [ (9R) -9-Hydroxy-2- (3-Hydroxy-3-methylyloxy) -9- (trifluoromethyloxy) -9H-fluoro-4-yl ] -1H-pyrazoyl-1-yl } -2-methylpropanamide) (hereinafter referred to as Compound A) or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a. More specifically, the present invention relates to a therapeutic or prophylactic agent for chronic kidney disease, which comprises compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a.
Background
Chronic Kidney Disease (CKD) is a disease in which kidney damage and reduced kidney function persist. CKD, if advanced, leads to end-stage renal failure (ESRD), requiring dialysis, kidney transplantation. Further, many clinical studies have shown that CKD increases the risk of morbidity and mortality in cardiovascular diseases such as myocardial infarction, stroke, heart failure, etc. Therefore, it is important to prevent the severity of CKD and to suppress the onset of cardiovascular diseases.
CKD is defined as a decrease in renal damage and/or Glomerular Filtration Rate (GFR) (less than 60 mL/min/1.73 m)2) The state lasts for more than 3 months. Renal impairment is diagnosed by urine abnormalities, image diagnosis, blood, and pathology, and the presence of proteinuria in urine abnormalities (proteinuria of 0.15 g/gCr or more, or albuminuria of 30 mg/gCr or more) is particularly important. GFR was measured by inulin clearance, but was also evaluated briefly by estimating GFR (eGFR) using serum creatinine values.
Although CKD has few subjective symptoms at the initial stage, if the disease progresses, symptoms such as nocturia, edema, anemia, a sense of lassitude, shortness of breath, and the like are observed.
As animal models showing CKD-like renal damage and reduced renal function, salt-loaded SDT-obese rats, 5/6 kidney extirpated rats, and the like are known (non-patent documents 1 and 2).
2- {4- [ (9R) -9-hydroxy-2- (3-hydroxy-3-methylbutoxy) -9- (trifluoromethyl) -9H-fluoren-4-yl ] -1H-pyrazol-1-yl } -2-methylpropanamide or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a, which is compound a, is described in patent document 1 and patent document 2. Patent document 1 describes that compound a and its monohydrate have pyruvate dehydrogenase kinase (PDHK) inhibitory activity and are useful as agents for diabetes, insulin resistance syndrome, metabolic syndrome, hyperglycemia, hyperlactacidosis, diabetic complications, heart failure, cardiomyopathy, myocardial ischemia, myocardial infarction, angina pectoris, dyslipidemia, atherosclerosis, peripheral artery disease, intermittent claudication, chronic obstructive pulmonary disease, cerebral ischemia, stroke, mitochondrial disease, mitochondrial encephalomyopathy, cancer, or pulmonary hypertension. Patent document 2 describes a method for producing compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a.
Documents of the prior art
Patent document
Patent document 1: international publication No. 2014/142290
Patent document 2: international publication No. 2018/021508
Non-patent document
Non-patent document 1
KATSUDA, Yoshiaki, et al. Physiological changes induced by salt intake in female Spontaneously Diabetic Torii‐Lepr(fa) (SDT fatty) rat, a novel obese type 2 diabetic model. Animal science journal, 2014, 85(5), 588-594.
Non-patent document 2
TSUPRYKOV, Oleg, et al. The dipeptidyl peptidase inhibitor linagliptin and the angiotensin II receptor blocker telmisartan show renal benefit by different pathways in rats with 5/6 nephrectomy. Kidney international, 2016, 89(5), 1049-1061。
Disclosure of Invention
Problems to be solved by the invention
The present invention addresses the problem of providing a therapeutic agent for CKD.
Means for solving the problems
The present inventors have found that in an experiment using a disease model animal showing CKD-like renal impairment and reduced renal function, compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a significantly reduces the severity of the disease. Then, the present inventors have found, based on this finding, that compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a is effective as a pharmaceutical agent for CKD, and have completed the present invention.
Namely, the present invention is as follows.
[1] A therapeutic or prophylactic agent for chronic kidney disease, characterized by comprising the following chemical structural formula:
[ solution 1]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 2]
The compounds shown.
[2] A renal function improving agent characterized by comprising the following chemical structural formula:
[ solution 3]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 4]
The compounds shown.
[3] An improver for 1 or more than 2 parameters selected from the group consisting of GFR, eGFR, serum creatinine value, blood urea nitrogen value, creatinine clearance rate, urine protein value and urine albumin value, characterized by comprising the following chemical structural formula:
[ solution 5]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 6]
The compounds shown.
[4] An agent for improving GFR, characterized by comprising the following chemical structural formula:
[ solution 7]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 8]
The compounds shown.
[5] An eGFR improver characterized by comprising the following chemical structural formula:
[ solution 9]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 10]
The compounds shown.
[6] An agent for improving serum creatinine level, characterized by comprising the following chemical structural formula:
[ solution 11]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 12]
The compounds shown.
[7] An agent for improving a blood urea nitrogen value, characterized by comprising the following chemical structural formula:
[ solution 13]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 14]
The compounds shown.
[8] An agent for improving creatinine clearance, characterized by comprising the following chemical structural formula:
[ solution 15]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 16]
The compounds shown.
[9] An agent for improving a urine protein value, characterized by comprising the following chemical structural formula:
[ solution 17]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 18]
The compounds shown.
[10] An agent for improving urinary albumin value, characterized by comprising the following chemical structural formula:
[ solution 19]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 20]
The compounds shown.
[11] The agent according to any one of the above [ 1] to [ 10], which is characterized by containing a compound represented by the following chemical structural formula:
[ solution 21]
[12] The agent according to any one of the above [ 1] to [ 10], which is characterized by containing a compound represented by the following chemical structural formula:
[ solution 22]
[13] The preparation of the aforementioned [ 1], wherein the chronic kidney disease is a chronic kidney disease other than diabetic nephropathy.
[14] The preparation of the above [ 1], wherein the chronic kidney disease is a chronic kidney disease other than a chronic kidney disease which is a primary disease of diabetes.
[15] A method for preventing or treating chronic kidney disease in a mammal, comprising administering to the mammal an effective amount of a compound of the formula:
[ solution 23]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 24]
The compounds shown.
[16] The following chemical structural formula for use in the prevention or treatment of chronic kidney disease:
[ solution 25]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 26]
The compounds shown.
[17] The following chemical structural formula:
[ solution 27]
A compound represented by the formula or a pharmaceutically acceptable salt thereof, or the following chemical structural formula:
[ solution 28]
Use of the compound for producing a therapeutic or prophylactic agent for chronic kidney diseases.
Effects of the invention
Compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a in the present invention is effective as a therapeutic or prophylactic agent for CKD.
Drawings
FIG. 1: figure 1 shows urinary protein excretion from saline-loaded SDT-obese rats when administered orally with liquid medication (normal), saline (vehicle), or saline and the monohydrate of compound a (compound a).
FIG. 2: fig. 2 shows representative examples of images of kidney tissues of saline-loaded SDT-obese rats when (a) water, (b) saline, or (c) saline and the monohydrate of compound a were orally administered, respectively.
FIG. 3: fig. 3 shows urinary protein excretion amounts of 5/6 kidney extirpated rats (vehicle), 5/6 kidney extirpated rats orally administered with monohydrate of compound a (compound a), and rats not subjected to kidney extirpation treatment (pseudo-treatment).
Detailed Description
The terms in this specification are defined as follows.
Compound a is 2- {4- [ (9R) -9-hydroxy-2- (3-hydroxy-3-methylbutoxy) -9- (trifluoromethyl) -9H-fluoren-4-yl ] -1H-pyrazol-1-yl } -2-methylpropanamide, represented by the following chemical structural formula:
[ solution 29]
The "pharmaceutically acceptable salt" may be any salt as long as it is known in the art without accompanying excessive toxicity. Specifically, there may be mentioned: salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, and the like. Pharmaceutically acceptable salts in various forms are well known in the art and are described, for example, in the following references:
(a) berge et al, J. pharm. Sci., 66, p1-19 (1977),
(b) Stahl et al, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002),
(c) Paulekuhn et al, J. Med. chem., 50, p6665-6672 (2007).
Various pharmaceutically acceptable salts thereof can be obtained by reacting compound a with an inorganic acid, an organic acid, an inorganic base or an organic base according to a method known per se. A pharmaceutically acceptable salt of compound a can be formed from 1 molecule of compound a with 1/2 molecules, 1 molecule, or more than 2 molecules of an acid or base.
Examples of the salt with an inorganic acid include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid.
Examples of the salt with an organic acid include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1, 2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hydroxyacetylarsonic acid, hexylisophthalic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis (salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1, 5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, benzoic acid, benzenesulfonic acid, calcium ede, Salts of fruit acids, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theachloric acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid or glutamic acid.
Examples of the salt with an inorganic base include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium.
Examples of the salt with an organic base include a salt with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris (hydroxymethyl) methylamine, arginine, or lysine.
Compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a can be produced by a known method, for example, a method described in patent document 1 or patent document 2.
Compound a or a pharmaceutically acceptable salt thereof is sometimes also present in the form of a solvate. The "solvate" refers to a substance in which a solvent molecule is coordinated to compound a or a pharmaceutically acceptable salt thereof, and includes a hydrate. The solvate is preferably a pharmaceutically acceptable solvate, and examples thereof include a hydrate, an ethanol solvate, and a dimethylsulfoxide solvate of compound a or a pharmaceutically acceptable salt thereof. Specifically, there may be mentioned hemihydrate, 1 hydrate, 2 hydrate or 1 ethanol solvate of compound a, 2/3 ethanol solvate of 1 hydrate or 2 hydrochloride of a pharmaceutically acceptable salt of compound a, and the like. The solvate can be obtained by a known method.
As the solvate, a hydrate of compound a is preferable, and a monohydrate of compound a is more preferable, which is represented by the following structural formula:
[ solution 30]
The therapeutic or prophylactic agent for CKD of the present invention can be produced by appropriately mixing or the like compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a with at least 1 or more pharmaceutically acceptable carriers, and the like, according to a method known in the art of pharmaceutical preparations. The content of compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a in the preparation varies depending on the dosage form, the dose, and the like, and is, for example, 0.1 to 100% by weight of the whole preparation.
The therapeutic or prophylactic agent of the present invention can be administered orally or non-orally. Examples of administration include oral administration, or non-oral administration such as intravenous, intramuscular, subcutaneous, transdermal, topical, and rectal administration. Examples of dosage forms suitable for oral administration include tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions and the like, and examples of dosage forms suitable for non-oral administration include external preparations, suppositories, injections, eye drops, eye ointments, patches, gels, inserts, nasal preparations, pulmonary preparations and the like. They may be prepared according to methods well known in the art of pharmaceutical formulation.
Examples of the "pharmaceutically acceptable carrier" include various organic or inorganic carrier substances which are generally used as a raw material for a preparation, and examples thereof include excipients, disintegrants, binders, fluidizers, lubricants and the like in a solid preparation, solvents, co-solvents, suspending agents, isotonic agents, buffers, painless agents and the like in a liquid preparation, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption accelerators, gelling agents, preservatives, fillers, dissolving agents, co-solvents, suspending agents and the like in a semisolid preparation. Additives such as preservatives, antioxidants, coloring agents, and sweeteners may also be used as necessary.
Examples of the "excipient" include lactose, white sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic, and the like.
Examples of the "disintegrant" include carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low-substitution hydroxypropyl cellulose, hydroxypropyl methylcellulose, crystalline cellulose, and the like.
Examples of the "binder" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, white sugar, dextrin, starch, gelatin, sodium carboxymethylcellulose, and gum arabic.
Examples of the "fluidizing agent" include light anhydrous silicic acid and magnesium stearate.
Examples of the "lubricant" include magnesium stearate, calcium stearate, and talc.
Examples of the "solvent" include pure water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and the like.
Examples of the "cosolvent" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.
Examples of the "suspending agent" include benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, and glyceryl monostearate.
Examples of the "isotonic agent" include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.
Examples of the "painless agent" include benzyl alcohol and the like.
Examples of the "base" include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1, 3-butylene glycol, phenol, etc.), higher fatty acids and esters thereof, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, etc.), hydrophilic vaseline, purified lanolin, water-absorbing ointment, hydrogenated lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives (methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, etc.), propylene glycol, polyethylene glycol (polyethylene glycol 200 to 600, etc.), and combinations of 2 or more thereof.
Examples of the "preservative" include ethyl p-hydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
Examples of the "antioxidant" include sodium sulfite and ascorbic acid.
Examples of the "colorant" include food colors (food red No. 2 or 3, food yellow No. 4 or 5, and the like), β -carotene, and the like.
Examples of the "sweetener" include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.
The dose of the therapeutic or prophylactic agent of the present invention to mammals including humans (e.g., human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc.) varies depending on the subject of administration, disease, symptom, dosage form, route of administration, etc., and for example, in the case of human, when orally administered to an adult patient (body weight of about 60 kg), 0.1mg to 1g, preferably 30mg to 900mg, is usually administered in 1 to several times per 1 day in terms of compound a as an active ingredient, regardless of before, after, and between meals. The administration period is not particularly limited.
The cause of CKD is, for example, a Disease listed in Table 1 ("viral kit Disease" Merck Manual Professional Version, "Anna Malkina, update of month 10 2018, URL: https:// www.merckmanuals.com/en-pr/Professional/genetic-disorders/viral-kit-Disease).
As CKD caused by diabetes, diabetic nephropathy and diabetic nephropathy can be cited. In several embodiments, CKD is CKD that does not include diabetic nephropathy, preferably CKD that does not cause diabetes (primary disease).
In several other embodiments, the CKD is a CKD due to 1 or 2 or more diseases selected from the group consisting of,
(1) chronic tubulointerstitial nephropathy,
(2) (A) focal segmental glomerulosclerosis,
(B) Idiopathic crescentic glomerulonephritis,
(C) IgA nephropathy,
(D) Membrane proliferative glomerulonephritis,
(E) Membranous nephropathy,
(3) (A) amyloidosis,
(B) anti-GBM antibody disease (Goodpasture syndrome),
(C) Granulomatous polyangiitis,
(D) Hemolytic uremic syndrome,
(E) Mixed cryoglobulinemia,
(F) Glomerulonephritis after infection,
(G) Systemic lupus erythematosus,
(4) (A) autosomal dominant interstitial nephropathy (medullary sponge kidney),
(B) Hereditary nephritis (Alport syndrome),
(C) Nail-patella syndrome,
(D) Multiple kidney capsules,
(5) High blood pressure,
(6) (A) prostate hyperplasia
(B) Posterior urethral valve
(C) Retroperitoneal fibrosis
(D) Ureteral obstruction (congenital, calculus, cancer),
(E) Vesicoureteral reflux, and
(7) renal macrovascular disease.
In still other several forms, CKD is CKD that is a cause of diabetes, preferably Diabetic Kidney Disease (DKD) or diabetic nephropathy. Under the present circumstances, CKD patients with diabetes are being treated with blood pressure management based on ARB, ACE inhibitors, and the like (instead of drugs for diabetes) (Kidney Int Suppl (2012) Vol.2, pp.363-369; Am J Kidney Dis (2013) Vol.62, pp.201-213; Nephol Dial transfer (2014) Vol.29, pp.490-496). While such blood pressure management is undoubtedly beneficial to their patient population, it cannot be concluded that the blood pressure reduction strategy has met all the treatment needs (Lancet (2015) vol.385, pp.2047-2056). As specifically illustrated in the test examples below, compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a surprisingly reduces the severity of the disease, thus providing an additional option for treating or preventing DKD or diabetic nephropathy.
In the present specification, "treatment" means (1) improvement of renal function, renal impairment, or CKD symptoms, (2) prevention or delay of reduction in renal function, progression of renal impairment, or exacerbation or delay of CKD symptoms, or (3) prevention of reduction in renal function, progression of renal impairment, or relapse of CKD symptoms.
As used herein, "prevent" means that (4) GFR or eGFR is reduced to less than 60 mL/min/1.73 m2And (4) the inhibition or prevention of the increase of the urine albumin amount to 0.15 g/gCr or more, or the increase of the urine albumin amount to 30 mg/gCr or more continues for 3 months or more.
In the present specification, "improvement in renal function" means a delay in the cessation or reduction of increase or reduction in renal function. Renal function can be assessed by changes in parameters such as GFR, eGFR, creatinine clearance, serum creatinine levels in urine, blood urea nitrogen levels, urine protein levels, urine albumin levels, and the like.
The "improvement in renal function" is preferably an improvement in renal function in CKD patients.
An improvement in GFR, eGFR, serum creatinine value, blood urea nitrogen value, creatinine clearance, urine protein value or urine albumin value means an improvement in 1 or 2 or more parameters selected from the group consisting of GFR, eGFR, serum creatinine value, blood urea nitrogen value, creatinine clearance, urine protein value and urine albumin value, preferably an improvement in each of the above parameters in CKD patients.
In the present specification, "improvement of GFR" means a delay in stopping or decreasing of rising or decreasing of GFR. As one mode, "improvement in GFR" refers to improvement in GFR in patients with a GFR of 90 ml/min or less.
In the present specification, "improvement of eGFR" means a delay in stopping or decreasing of rising or decreasing of eGFR. As an embodiment, "improvement of eGFR" means that eGFR is 90 ml/min/1.73 m2Improvement of eGFR in the following patients.
In the present specification, "improvement of creatinine clearance" means an increase in creatinine clearance or a delay in the cessation or decrease of decrease. As one mode, "improvement in creatinine clearance" refers to improvement in creatinine clearance in patients having a creatinine clearance of 100 mL/min or less.
In the present specification, "improvement of serum creatinine level" means a decrease in serum creatinine level or a delay in the stop or rise of the rise. In one embodiment, the term "improvement in serum creatinine level" refers to an improvement in serum creatinine level in a patient having a serum creatinine level of 1.2mg/dl or more.
In the present specification, "improvement of blood urea nitrogen value" means reduction of blood urea nitrogen value, or delay of stop or rise of rise. In one embodiment, the term "improvement in blood urea nitrogen value" refers to improvement in blood urea nitrogen value in a patient having a blood urea nitrogen value of 20mg/dl or more.
In the present specification, "improvement of urine protein value" means reduction of urine protein value, or delay of stop or rise of rise. In one embodiment, the term "improvement in urine protein value" refers to improvement in urine protein value in a patient having a urine protein value of 0.15 g/gCr or more.
In the present specification, "improvement of urine albumin value" means reduction of urine albumin value, or delay of stop or rise of rise. In one embodiment, the term "improvement in urinary albumin value" refers to improvement in urinary albumin value in a patient having a urinary albumin value of 30 mg/gCr or more.
An index of the severity of CKD includes, for example, GFR classification. Compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a can be used to prevent or delay progression of stages based on GFR classification. For example, compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a can be used to prevent or delay progression from stage G1 to G2, G2 to G3a, G3a to G3b, G3b to G4, G4 to G5.
Compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a is useful for treating or preventing CKD due to ameliorating damaging changes in glomeruli, tubules, or renal vessels.
More specifically, compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a improves sclerosis, fibrosis, disintegration, hypertrophy, or exudative changes of glomeruli, improves dilation of renal tubules, or improves hypertrophy of arteriolar walls or fibrotic, necrotic changes of arterial walls in renal blood vessels.
Compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a can be used for treating or preventing symptoms of nocturia, edema, anemia, a feeling of burnout, shortness of breath, and the like, of CKD.
The pharmaceutical composition of the present invention can be used in combination (hereinafter also referred to as concomitant use) with 1 or more other agents (hereinafter also referred to as concomitant use agents) by a general method employed in the field of pharmaceuticals.
The administration timing of the pharmaceutical preparation containing compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a and the concomitant pharmaceutical preparation is not limited, and they may be administered as a compounding agent or both preparations may be administered simultaneously or at a constant interval to a subject.
In addition, the present invention may be used in the form of a pharmaceutical composition comprising the pharmaceutical composition of the present invention and a combined preparation. The dose of the concomitant drug may be determined in accordance with the dose used clinically, and may be appropriately selected depending on the administration subject, disease, symptom, formulation, administration route, administration time, combination, and the like. The administration form of the concomitant drug is not particularly limited as long as the drug containing compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a is combined with the concomitant drug.
Examples of the concomitant agent include: angiotensin Converting Enzyme (ACE) inhibitors, angiotensin II receptor Antagonists (ARBs), calcium antagonists, diuretics, alpha blockers, beta blockers, and the like.
The "angiotensin converting enzyme inhibitor" is not limited to the following, and examples thereof include: benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, imidapril, alacepril, delapril, cilazapril, temocapril, and the like. The angiotensin converting enzyme inhibitor may also be used in the form of a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
The "angiotensin II receptor antagonist" is not limited to the following, and examples thereof include: candesartan, eprosartan, irbesartan, telmisartan, valsartan, losartan, olmesartan and the like. The angiotensin II receptor antagonist may also be used in the form of a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
The "calcium antagonist" is not limited to the following, and examples thereof include: amlodipine, nifedipine, nicardipine, diltiazem, manidipine, benidipine, nilvadipine, nitrendipine, nisoldipine, barnidipine, and the like. The calcium antagonist may also be used in the form of a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
The "diuretic" is not limited to the following, and examples thereof include: spironolactone, hydrochlorothiazide, furosemide, triamterene, and the like. Diuretics may also be used in the form of pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.
The "α -blocker" is not limited to the following, and examples thereof include: doxazosin, prazosin, bunazosin, terazosin, urapidil, and the like. The alpha blocker may also be used in the form of a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
The "β -blocker" is not limited to the following, and examples thereof include: metoprolol, atenolol, bisoprolol, arotinolol, celiprolol, betaxolol, and the like. The beta blocker may also be used in the form of a pharmaceutically acceptable salt, or a pharmaceutically acceptable prodrug thereof.
As one embodiment of the practice of the present invention, there is provided a method for treating or preventing chronic kidney disease, which comprises administering a therapeutically effective amount of compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a to a mammal. Definitions and the like are based on the foregoing.
In the present specification, an "effective amount" means an amount of a drug or pharmaceutical agent that elicits a biological or medical response, e.g., that of a tissue, system, animal or human. Furthermore, a "therapeutically effective amount" means any amount that results in improved treatment, cure, prevention, or amelioration of a disease, injury, or side effect, or a reduction in the rate of progression of a disease, as compared to a corresponding subject that has not received that amount.
One embodiment of the practice of the present invention is a pharmaceutical composition for treating or preventing chronic kidney disease, which contains compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a. Definitions and the like are based on the foregoing.
One embodiment of the practice of the present invention includes the use of compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a for the production of a therapeutic or prophylactic agent for chronic kidney disease. Definitions and the like are based on the foregoing.
One embodiment of the practice of the present invention includes compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a, which is used for treating or preventing chronic kidney disease. Definitions and the like are based on the foregoing.
Another embodiment of the present invention provides an agent for treating or preventing Chronic Kidney Disease (CKD), which comprises a fused heterocyclic compound selected from the following formulae:
[ solution 31]
The method of using, the effective amount of the fused heterocyclic compound, the method of formulating, etc. are the same as or based on the aforementioned manner of using compound a or a pharmaceutically acceptable salt thereof.
[ examples ]
The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.
Examples of the formulation of the present invention include the following formulations. However, the present invention is not limited to these examples.
Formulation example 1: manufacture of capsules
1) Monohydrate of Compound A50 mg
2) Microcrystalline cellulose 10mg
3) Lactose 19mg
4) Magnesium stearate 1mg
Mixing 1), 2), 3) and 4), and filling into gelatin capsule.
Preparation example 2: manufacture of tablets
1) 50g of monohydrate of Compound A
2) Lactose 50g
3) Corn starch 15g
4) Carboxymethyl cellulose calcium 44g
5) Magnesium stearate 1g
The total amount of 1), 2) and 3) and 30g of 4) were kneaded with water, vacuum-dried, and granulated. To the granulated powder were mixed 14g of 4) and 1g of 5), and the mixture was tabletted with a tableting machine. Thus, 1000 tablets containing 50mg of the monohydrate of compound a per 1 tablet were obtained.
Test example 1: inhibition of urinary protein excretion and renal lesion progression by oral administration of monohydrate of Compound A in saline-loaded SDT-obese rat model
Saline-loaded spontaneous diabetic Torii obese (SDT-obese) rats were used to evaluate the urinary protein excretion amount and the renal lesion progression inhibitory effect caused by compound a. Evaluation was carried out with reference to non-patent document 1. As the experimental animals, 6-week-old male SDT-obese rats (Japanese クレア Co., Ltd.) were used. A usual powdered feed (CRF-1 powder, オリエンタル Yeast Co., Ltd.) containing 0.005w/w% of a monohydrate of Compound A as a free form of Compound A was prepared.
1w/v% saline was administered to the control group (vehicle) and the compound A administration group (compound A). In addition, the group to which saline-free water was administered was used as a pathological control group (normal). Compound a was orally administered for 14 weeks by feeding the above feed containing compound a while saline was administered to the compound a administration group. The above-mentioned usual powder feed without compound a was fed to the control group and the pathological control group. Urine was collected for 6 hours (10 weeks after the start of administration), and the kidney was removed (14 weeks after the start of administration).
After the urine amount was measured for urine, the urine protein concentration was measured by absorbance at a wavelength of 590 nm using a total protein quantification kit (トネイン TP, tsukamur pharmaceutical co. The urinary protein excretion (mg/6 hours) was calculated from the urine volume and the protein concentration.
For kidney, tissue was fixed with 10% neutral buffered formalin (Wako pure chemical industries, Ltd.), and tissue sections were stained with hematoxylin-eosin (HE).
The mean and standard deviation of the urine protein excretion amount of each group were calculated, and the results are shown in FIG. 1. A representative example of a kidney tissue image is shown in fig. 2.
Test example 2: 5/6 inhibition of urinary protein excretion and renal lesion progression by oral administration of monohydrate of Compound A in rat model of renal extirpation
5/6 kidney extirpated rats were used to evaluate the urinary protein excretion amount and the renal lesion progression inhibitory effect caused by Compound A. Evaluation was carried out with reference to non-patent document 2. The experimental animals used were male Wistar rats (japan エスエルシー co., ltd.) whose right kidney was 60% and left kidney was all removed at 7 weeks of age and 8 weeks of age. A group that was similarly operated except for the kidney extirpation treatment was used as a pseudo treatment group (pseudo treatment). A usual powdered feed (CRF-1 powder, オリエンタル Yeast Co., Ltd.) containing 0.0218 to 0.0317w/w% of a monohydrate of Compound A as a free form of Compound A was prepared.
The group to which compound a was administered (compound a) was fed the above-mentioned feed containing compound a from 21 weeks of age, and compound a was orally administered for 10 weeks. The control group (vehicle) and the sham-treated group were fed the above-mentioned normal powder feed without compound a. Urine was collected for 24 hours (5 weeks after the start of administration), and the kidney was removed (10 weeks after the start of administration).
After the urine amount was measured for urine, the protein concentration was measured by absorbance at a wavelength of 590 nm using a total protein quantification kit (トネイン TP, tsukamur pharmaceutical co. The urinary protein excretion (mg/day) was calculated from the urine volume and protein concentration.
For kidney, tissue was fixed with 10% neutral buffered formalin (Wako pure chemical industries, Ltd.), and tissue sections were stained with hematoxylin-eosin (HE).
The mean and standard deviation of the urine protein excretion amount of each group were calculated, and the results are shown in fig. 3. The damage of each part of the kidney tissue was evaluated by a score, and is shown in table 2.
Reference example 1: urinary protein excretion and renal lesion progression inhibition by oral administration of fused heterocyclic compounds in saline-loaded SDT-obese rat model
Herein, the fused heterocyclic compound refers to a compound selected from the following formulae:
[ solution 32]
The saline-loaded SDT-obese rat model was used to evaluate the urinary protein excretion amount and the renal lesion progression inhibitory effect caused by the aforementioned fused heterocyclic compound. As the experimental animals, 6-week-old male SDT-obese rats (Japanese クレア Co., Ltd.) were used. Each of the fused heterocyclic compounds can be obtained by the method described in patent document 3 (international publication No. 2019/151274). A usual powdered feed (CRF-1 powder, オリエンタル Yeast Co., Ltd.) containing each fused heterocyclic compound was prepared.
The control group (vehicle) and the fused heterocyclic compound-administered group were given 1w/v% saline. In addition, the group to which saline-free water was administered was used as a pathological control group (normal). 14-week oral administration of the fused heterocyclic compound was performed by feeding the above-mentioned feed containing the aforementioned fused heterocyclic compound while saline was administered to the fused heterocyclic compound administration group. The control group and the pathological control group were fed with the above-mentioned usual powdered feed without the aforementioned fused heterocyclic compound. Urine was collected for 6 hours (10 weeks after the start of administration), and the kidney was removed (14 weeks after the start of administration).
After the urine amount was measured for urine, the urine protein concentration was measured by absorbance at a wavelength of 590 nm using a total protein quantification kit (トネイン TP, tsukamur pharmaceutical co. The urinary protein excretion (mg/6 hours) was calculated from the urine volume and the protein concentration.
For kidney, tissue was fixed with 10% neutral buffered formalin (Wako pure chemical industries, Ltd.), and tissue sections were stained with hematoxylin-eosin (HE).
The mean and standard deviation of the urine protein excretion of each group were calculated.
Reference example 2: 5/6 inhibition of urinary protein excretion and renal lesion progression by oral administration of fused heterocyclic compound in rat model with renal extirpation
5/6 Kidney extirpated rats were used to evaluate the urinary protein excretion amount and the renal lesion progression inhibitory effect caused by the aforementioned fused heterocyclic compounds. The experimental animals used were male Wistar rats (japan エスエルシー co., ltd.) whose right kidney was 60% and left kidney was all removed at 7 weeks of age and 8 weeks of age. A group that was similarly operated except for the kidney extirpation treatment was used as a pseudo treatment group (pseudo treatment). A usual powdered feed (CRF-1 powder, オリエンタル Yeast Co., Ltd.) containing each fused heterocyclic compound was prepared.
The fused heterocyclic compound administration group was fed with the above feed containing the fused heterocyclic compound from 21 weeks of age, and oral administration of the fused heterocyclic compound was performed for 10 weeks. The control group (vehicle) and the sham-treated group were fed the above-mentioned usual powder feed without the aforementioned fused heterocyclic compound. Urine was collected for 24 hours (5 weeks after the start of administration), and the kidney was removed (10 weeks after the start of administration).
After the urine amount was measured for urine, the protein concentration was measured by absorbance at a wavelength of 590 nm using a total protein quantification kit (トネイン TP, tsukamur pharmaceutical co. The urinary protein excretion (mg/day) was calculated from the urine volume and protein concentration.
For kidney, tissue was fixed with 10% neutral buffered formalin (Wako pure chemical industries, Ltd.), and tissue sections were stained with hematoxylin-eosin (HE).
The mean and standard deviation of the urine protein excretion of each group were calculated.
Industrial applicability
The present invention provides a novel pharmaceutical use of compound a or a pharmaceutically acceptable salt thereof, or a monohydrate of compound a for a disease in which CKD is a subject.
The present application is based on Japanese patent application 2018-169632, the contents of which are all included in the present specification.
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