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WO2020194531A1 - Agent de réduction de substance urémique sanguine - Google Patents

Agent de réduction de substance urémique sanguine Download PDF

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Publication number
WO2020194531A1
WO2020194531A1 PCT/JP2019/012952 JP2019012952W WO2020194531A1 WO 2020194531 A1 WO2020194531 A1 WO 2020194531A1 JP 2019012952 W JP2019012952 W JP 2019012952W WO 2020194531 A1 WO2020194531 A1 WO 2020194531A1
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substituted
group
carbon atoms
unsubstituted
linear
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Japanese (ja)
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阿部　高明
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Tohoku University NUC
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Tohoku University NUC
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Priority to PCT/JP2019/012952 priority Critical patent/WO2020194531A1/fr
Priority to JP2019516729A priority patent/JP7256540B2/ja
Publication of WO2020194531A1 publication Critical patent/WO2020194531A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes

Definitions

  • the present invention is an agent for reducing the amount of uremic substance present in blood (in other words, the concentration of uremic substance in blood); an agent for preventing or ameliorating uremic disease; and preventing renal dysfunction. Or an agent for improvement;
  • the kidney is an organ that regulates homeostasis (balance) in the body.
  • As one of the renal functions it has the action of taking in waste products and toxins (uremic substances) in the blood, sending them out into the urine, and excreting them outside the body.
  • uremic substances waste products and toxins
  • uremic substances that should be excreted by the kidney are likely to be accumulated in the body, causing symptoms such as nausea and loss of appetite, as well as damage to cells in the kidney and further deterioration of renal function.
  • those with impaired renal function have a higher risk of suffering from stroke or myocardial infarction than healthy subjects. Therefore, prevention or treatment of symptoms and diseases (uremia) caused by the accumulation of such uremic substances not only treats symptoms such as nausea and loss of
  • Dialysis is considered to be the most effective treatment for uremia. In fact, if uremic substances are excreted from the body by dialysis therapy, even if renal function is abolished, the death of the patient due to the uremic substances can be avoided.
  • long-term dialysis has created new problems with complications such as anemia, renal osteodystrophy, renal cancer, epicarditis, aluminum osteopathy, amyloidosis, crystalline arthritis, and polycystic kidney disease. ..
  • QOL quality of life
  • lubiprostone (trade name: Amitiza [registered trademark]), which is a chloride channel activator, has a preventive or ameliorating effect on renal dysfunction (Patent Document 1).
  • linaclotide (trade name: Lindes [registered trademark]), which is a guanylate cyclase C receptor agonist, has a preventive or therapeutic effect on uremia (Patent Document 2).
  • elobixibat hydrate (trade name: Goofis [registered trademark]), which is a bile acid transporter inhibitor, has an effect of reducing blood uremic substances and an effect of improving uremia or renal dysfunction.
  • Goofis registered trademark
  • the subject of the present invention is an action of effectively reducing (reducing) the amount of a uremic substance present in blood; an action of effectively preventing or ameliorating uremia; and an action of effectively preventing or ameliorating renal dysfunction.
  • the purpose is to provide a substance having an action.
  • the present inventor is continuing diligent research to solve the above problems.
  • the compound group shown below has an action of effectively reducing the concentration of the elevated blood uremic substance and an action of effectively improving the decreased renal function, and the present invention was developed. It came to be completed.
  • R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively.
  • R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl
  • R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively.
  • R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl
  • the uremic substance is one or more substances selected from phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, trimethylamine-N-oxide, indoxyl sulfate, phenol, and indole.
  • the reducing agent according to any one of the above [1] to [3]. [5] The following formula (I);
  • R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively.
  • R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl
  • a preventive or ameliorating agent for uremia which comprises one or more compounds selected from the above group as an active ingredient.
  • the preventive or ameliorating agent according to the above [5] which is characterized by oral administration.
  • the prophylactic or ameliorating agent according to the above [5] or [6], wherein the uremia is diabetic nephropathy, nephrotic syndrome, or chronic nephritis syndrome.
  • R 1 and R 2 may be the same or different, respectively; hydrogen atom; substituted or unsubstituted linear or branched alkyl group having 1 to 10 carbon atoms; substituted or substituted, respectively.
  • R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl
  • a preventive or ameliorating agent for renal dysfunction which comprises one or more compounds selected from the above group as an active ingredient.
  • the preventive or ameliorating agent according to the above [9] which is characterized by oral administration.
  • blood uremia is caused by administering one or more compounds selected from the present compound group to a patient who needs reduction of blood uremia substances.
  • One or more compounds selected from the present compound group for use as a method for reducing substances or as a reducing agent for blood uremic substances, or for use in reducing blood uremic substances.
  • Use of one or more compounds selected from the present compound group, or one or more compounds selected from the present compound group for producing a reducing agent for blood uremia substances. can be mentioned.
  • uremia is caused by administering one or more compounds selected from the present compound group to a patient who needs prevention or amelioration (treatment) of uremia.
  • One or more compounds selected from the present compound group for use in (treatment), and one selected from the present compound group for producing a preventive or ameliorating (therapeutic) agent for uremia 1 The use of a species or two or more compounds can be mentioned.
  • the kidneys by administering one or more compounds selected from the present compound group to a patient in need of prevention or improvement (treatment) of renal dysfunction, the kidneys
  • One or more compounds selected from the present compound group for use as a method for preventing or ameliorating (treating) dysfunction or as a preventive or ameliorating (treating) agent for renal dysfunction, or renal dysfunction.
  • the use of one or more compounds selected from the above can be mentioned.
  • the compound group Since the compound group has an effect of reducing the elevated concentration of uremic substances in blood, the concentration of uremic substances in blood can be adjusted to a normal value, which is useful for prevention or amelioration of uremia. .. In addition, since the compound group has an action of improving renal dysfunction such as reduction of renal tubules, it is also useful for prevention or improvement of renal dysfunction.
  • Example 1 the concentrations of three uremic substances (phenyl sulfate, creatinine, and 1-methyladenosine) in blood were measured in three groups (normal breeding group, placebo group, and elobixibat group). It is a figure which shows the result (mean value ⁇ standard deviation). “#” And “####” in the figure indicate that there is a statistically significant difference (P ⁇ 0.05 and P ⁇ 0.001) between the placebo group and the placebo group by Dunnett's test, respectively. ..
  • Example 1 the results of analysis of renal tissues in three types of groups (normal breeding group, placebo group [“P group” in the figure], and elobixibat group [“E group” in the figure)) are shown. It is a figure.
  • FIG. 2A shows the result (mean ⁇ standard deviation) of analysis of the ratio (%) of renal tubules in the renal cortex
  • FIG. 2B is a histological image of renal tissue used for the analysis. “***” in the figure indicates that there is a statistically significant difference (P ⁇ 0.001) from the placebo group (P group) by Dunnett's test.
  • P group placebo group
  • E group erobixibat group
  • Example 2 four types of uremia in blood in three types of groups (normal breeding group, placebo group [“P group” in the figure], and erobixibat group [“E group” in the figure)). It is a figure which shows the result (average value ⁇ standard deviation) of measuring the concentration of a substance (phenyl sulfate, creatinine, trimethylamine-N-oxide [TMAO], and indoxyl sulfate).
  • TMAO trimethylamine-N-oxide
  • FIG. 5A shows phenyl sulfate in blood in two groups of db / db mice (normal breeding group [“C group” in the figure] and phenyl sulfate group [“PS group” in the figure]) in Example 3. It is a figure which shows the result of having measured the density
  • FIG. 5C shows two groups of KKAY mice (HFD-KKAY mice) bred on a high-fat feed [HFD] in Example 3 (normal breeding group [“C group” in the figure] and phenyl sulfate group [in the figure]. It is a figure which shows the result of having measured the concentration of phenyl sulfate in blood in "PS group”]), and FIG. 5D is a figure which shows the result of having analyzed the renal tissue in these two kinds of groups.
  • the size bar in the PAS image of FIG. 5D shows 200 ⁇ m
  • the size bar in the electron microscope image shows 1 ⁇ m
  • the size bars in the Elastica Masson image and the F4 / 80 image each show 80 ⁇ m.
  • “*” In FIGS. 5A and 5 indicates that there is a statistically significant difference (P ⁇ 0.05) by Student's test.
  • the present invention has been specified for the purpose of reducing the blood uremic substance reducing agent of the present invention for "to reduce the uremic substance in blood (more specifically, the amount of uremic substance present in blood)".
  • An agent containing one or more compounds selected from the compound group (hereinafter, may be referred to as “reducing agent”), and the preventive or ameliorating agent for uremia of the present invention is “uremia”.
  • An agent containing one or more compounds selected from the present compound group, which is specified for the purpose of "preventing or ameliorating uremia” hereinafter, may be referred to as “the present uremia preventive / ameliorating agent”).
  • the preventive or ameliorating agent for renal dysfunction of the present invention is one or more selected from the present compound group specified for the purpose of "preventing or ameliorating renal dysfunction". It is an agent containing the above compound (hereinafter, may be referred to as "the present agent for preventing / ameliorating renal dysfunction") (these agents may be collectively referred to as “the present agent”).
  • the present agent may use the present compound group as an active ingredient alone as a food or drink or a pharmaceutical product (formulation), or may be further mixed with an additive to form a composition (food or drink composition or pharmaceutical composition). ) May be used.
  • Such foods and drinks include, for example, health foods (functional foods, nutritional supplements, health supplements, nutritionally fortified foods, nutritionally adjusted foods, supplements, etc.), health functional foods (foods for specified health use, nutritional functional foods, functional foods, etc.). Labeled foods, etc.) can be mentioned.
  • uremic substance also referred to as” uremic toxin
  • uremic toxin is a substance (waste products, toxins, etc.) excreted by the normal kidney, and is caused by some cause such as decreased renal function. It means a substance that increases (accumulates) in the blood and causes uremia symptoms or diseases when the excretory function declines.
  • "Uremic substances” are usually classified into three types: water-soluble low-molecular-weight substances (500 daltons or less), medium-molecular-weight substances (more than 500 daltons), and protein-binding substances (Reference "Vanholder, R. , Et al: Kidney Int., 63 (5): 1934-1943, 2003 ”).
  • water-soluble low molecular weight substance examples include 1-methyladenosine, 1-methylguanosine, 1-methylinosine, and ADMA (Asymmetric dimethylarginine).
  • the medium-molecular-weight substance examples include adrenomedullin, atrial natriuretic peptide (ANP), ⁇ 2- microglobulin ( ⁇ 2- microglobulin), and ⁇ -endolphin ( ⁇ -). endorphin, Cholecystokinin, CC16 (Clara cell protein), Complement factor D, Cystatin C, Degranulation inhibiting protein 1, Delta sleep-inducing protein (Delta-sleep inducing protein), Endothelin, Hyaluronic acid, Interleukin-1 ⁇ , Interleukin-6, ⁇ -Ig light chain ( ⁇ -Ig light) Chain), ⁇ -Ig light chain, ⁇ -Ig light chain, Leptin, Methionine-enkephalin, Neuropeptide, Parathyroid hormone, Retinol- Binding protein), tumor necrosis factor (TNF) - ⁇ (Tumor necrosis factor- ⁇ ) and the like can be mentioned.
  • NBP atrial natri
  • protein-binding substance examples include 2-methoxyresorcinol, 3-deoxyglucosone, and CMPF (3-Carboxy-4-methyl-5-propyl-2-furanpropionate).
  • the uremic substance in the present invention includes one or more selected from phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, TMAO, indoxyl sulfate, and precursors thereof (eg, phenol, indole).
  • phenyl sulfate creatinine, 1-methyladenosine, urea nitrogen, TMAO, indoxyl sulfate, and precursors thereof (eg, phenol, indole).
  • TMAO urea nitrogen
  • indoxyl sulfate eg, phenol, indole
  • reduction of blood uremic substance means an action such as suppression of production (production) of uremic substance or its precursor and promotion of excretion of uremic substance or its precursor to the outside of the body. It means that the concentration of uremic substances contained in blood is reduced (decreased).
  • uremic diseases that is, the above-mentioned uremic substances (preferably phenyl sulfate, creatinine, 1-methyladenosine, urea nitrogen, TMAO, indoxyl sulfate, and these.
  • Symptoms or diseases caused by one or more substances selected from precursors [eg, phenol, indol]) are not particularly limited, and such symptoms or diseases include, for example, loss of appetite, nausea, and the like.
  • LPS Lipopolysaccharide
  • IgA nephropathy for example, IgA nephropathy, cystic kidney, liver dysfunction (for example, fulminant hepatitis, fatty liver, NASH, NAFLD) and cancer (for example, bile carcinogenesis, liver cancer)
  • inflammatory bowel diseases such as ulcerative colitis and Crohn's disease
  • arteriosclerosis-related diseases autoimmune diseases such as lupus, fatty liver disease and rheumatism
  • obesity metabolic syndrome
  • diabetes autism Parkinson's disease
  • Alzheimer's disease Sarcopenia
  • the target for prevention or improvement of the renal dysfunction prevention / ameliorating agent is not particularly limited as long as renal dysfunction, that is, a state in which some abnormality occurs due to a disease or trauma to the kidney and renal function is impaired.
  • Acute renal failure renal failure such as chronic renal failure; amyloid kidney; membranous nephropathy; focal glomerulosclerosis; IgA nephropathy; acute tubule necrosis; nephrosis syndrome; diabetic nephropathy; gout kidney; renal Emulsion; renal tumor; renal ischemic disorder; renal ischemic reperfusion disorder; etc. can be mentioned, and among these, renal failure can be preferably exemplified.
  • the compound selected from the present compound group includes a compound represented by the following formula (I), a pharmaceutically acceptable salt of the compound, a pharmaceutically acceptable ester of the compound, and Means the hydrate of the compound.
  • R 4 is a hydrogen atom; a linear or branched substituted or 1-10 carbon atoms non-substituted; substituted or a lower alkyl group of straight or branched chain having 1 to 10 carbon atoms and being substituted Alkyl carbonyl
  • alkyl group refers to one hydrogen atom from any carbon atom of an alkane (aliphatic saturated hydrocarbon) represented by the general formula C n H 2n + 2 (n is a positive integer). Means the remaining hydrocarbon groups excluding.
  • the alkyl group in the present invention has 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group has 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group is an alkyl group having 1 to 4 carbon atoms.
  • alkyl group examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group and 1-methylbutyl group.
  • alkoxy group as used herein means a group represented by an "-O-alkyl group”.
  • the "alkyl group” is as defined above.
  • substituted or unsubstituted linear or branched alkoxy group refers to "-O-substituted or unsubstituted linear or branched alkyl. It means "group”.
  • the alkyl group of the alkoxy group in the present invention has 1 to 10 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 10 carbon atoms.
  • the alkyl group of the alkoxy group is an alkyl group having 1 to 8 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, the alkyl group of the alkoxy group is an alkyl group having 1 to 4 carbon atoms.
  • alkoxy group examples include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, 1-methyl.
  • alkylcarbonyl group as used herein means a group represented by "-CO-alkyl group”.
  • the "alkyl group” is as defined above.
  • substituted or unsubstituted linear or branched alkylcarbonyl group with 1-10 carbon atoms is referred to as "-CO-substituted or unsubstituted direct.” It means “alkyl group of chain or branched chain”.
  • the alkyl group of the alkylcarbonyl group in the present invention has 1 to 10 carbon atoms.
  • alkylcarbonyl group examples include an acetyl group (ethanoyl group), an n-propionyl group (n-propanoyl group), an isopropionyl group (isopropanoyl group), an n-butylcarbonyl group, an isobutylcarbonyl group, and sec-.
  • alkenyl group has only one carbon-carbon double bond in the molecule and is represented by the general formula C n H 2n (n is a positive integer greater than or equal to 2 or 3). It means the remaining hydrocarbon group obtained by removing one hydrogen atom from an arbitrary carbon atom of an alkene (olefin hydrocarbon).
  • the alkenyl group in the present invention has 2 to 10 carbon atoms.
  • the alkenyl group is an alkenyl group having 2 to 10 carbon atoms.
  • the alkenyl group is an alkenyl group having 2 to 8 carbon atoms.
  • the alkenyl group is an alkenyl group having 2 to 6 carbon atoms.
  • the alkenyl group is an alkenyl group having 2 to 4 carbon atoms.
  • alkenyl group examples include ethenyl group (vinyl group), 1-propenyl group, 2-propenyl group (allyl group), 1-butenyl group, 2-butenyl group, 3-butenyl group, isobutenyl group, 1- Penthenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 1-octenyl group, 2-octenyl group, 3-octenyl group, 4- Examples thereof include an octenyl group.
  • alkenyloxy group means a group represented by "-O-alkenyl group”.
  • the "alkenyl group” is as defined above.
  • substituted or unsubstituted straight chain or branched chain alkenyl group refers to "-O-substituted or unsubstituted linear or branched chain alkenyl group”. means.
  • the alkenyl group of the alkenyloxy group in the present invention has 2 to 10 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 10 carbon atoms.
  • the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 8 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkenyl group of the alkenyloxy group is an alkenyl group having 2 to 4 carbon atoms.
  • alkenyloxy group examples include ethenyloxy group (vinyloxy group), 1-propenyloxy group, 2-propenyl group oxy (allyloxy group), 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, isobu.
  • cycloalkyl group is derived from any carbon atom of a cycloalkane (cyclic saturated hydrocarbon) represented by the general formula C n H 2n (n is a positive integer greater than or equal to 3). It means the remaining hydrocarbon groups excluding one hydrogen atom.
  • the "cycloalkyl group” of the present invention has 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 10 carbon atoms. In one embodiment of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 8 carbon atoms.
  • the cycloalkyl group is a cycloalkyl group having 3 to 6 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 4 carbon atoms.
  • cycloalkyl group examples include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group and the like.
  • cycloalkyloxy group as used herein means a group represented by "-O-cycloalkyl group”.
  • the "cycloalkyl group” is as defined above.
  • substituted or unsubstituted cycloalkyloxy group means "-O-substituted or unsubstituted cycloalkyloxy group”.
  • the "cycloalkyloxy group” of the present invention has 3 to 10 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 10 carbon atoms.
  • the cycloalkyloxy group is a cycloalkyloxy group having 3 to 8 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 6 carbon atoms. In one aspect of the present invention, the cycloalkyloxy group is a cycloalkyloxy group having 3 to 4 carbon atoms.
  • cycloalkyloxy group examples include cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group, cyclooctyloxy group, cyclononyloxy group, cyclodecyloxy group and the like. Can be mentioned.
  • aryl group refers to a compound having an aromatic ring, i.e., the remaining hydrocarbons except for one hydrogen atom attached to the ring atom of the aromatic ring of an aromatic hydrocarbon. It means a hydrogen group.
  • aromatic ring means a cyclic structure having a delocalized ⁇ -electron orbital or a compound having the cyclic structure, which constitutes a single ring or a plurality of rings only with hydrocarbons.
  • the aromatic ring may be a fused ring or a non-condensed ring (for example, biphenyl).
  • the aryl group in the present invention has 6 to 14 carbon atoms.
  • the aryl group is an aryl group having 6 to 14 carbon atoms in the ring.
  • the aryl group is an aryl group having 6 to 10 carbon atoms in the ring.
  • the aryl group is an aryl group (phenyl group) having 6 carbon atoms in the ring.
  • aryl group examples include phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, o-xylyl group, m-xylyl group, p-xylsilyl group, 1-naphthyl group and 2-naphthyl.
  • the groups can be mentioned.
  • aralkyl group used in the present specification, one of the hydrogen atoms of the alkyl group (C n H 2n + 1) refers to an alkyl group substituted with an aryl group.
  • the aralkyl group is an aralkyl group having 7 to 18 carbon atoms (including 6 to 14 carbon atoms in the ring).
  • the aralkyl group is an aralkyl group having 7 to 18 carbon atoms (including 6 to 14 carbon atoms in the ring).
  • the aralkyl group is an aralkyl group having 7 to 15 carbon atoms (including 6 to 14 carbon atoms in the ring).
  • the aralkyl group is an aralkyl group having 7 to 14 carbon atoms (including 6 to 10 carbon atoms in the ring). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 12 carbon atoms in the ring (of which the carbon number of the ring is & 10). In one aspect of the present invention, the aralkyl group is an aralkyl group having 7 to 8 carbon atoms in the ring (including 6 carbon atoms in the ring).
  • aralkyl group examples include a benzyl group (phenylmethyl group), a phenethyl group (phenylethyl group) and the like.
  • substituted means having one or more substituents
  • unsubstituted means a substituent. Means that there is no.
  • substituents are halogen atoms (fluorine atom (fluoro group), chlorine atom (chloro group), bromine atom (bromo group), and iodine atom (iodo group)), alkyl groups having a prime number of 1 to 4, and a prime number of 1.
  • linear used in the present specification means a structure in which atoms other than hydrogen atoms are connected in a straight line without branching.
  • branched chain means a structure in which one or more arbitrary carbon atoms are bonded to two or more other carbon atoms.
  • the term "pharmaceutically acceptable salt” is, within reasonable medical judgment, excessively toxic, to be used in contact with human or non-human mammalian tissues. Means those compounds, substances, compositions, and / or dosage forms that are suitable for a reasonable benefit / risk ratio without irritation, allergic response, and / or complications.
  • the pharmaceutically acceptable salt in the present compound group includes a base salt.
  • base salts include ammonium salts; alkali metal salts such as sodium salts, lithium salts and potassium salts; alkaline earth metal salts such as aluminum salts, calcium salts and magnesium salts; dicyclohexylamine salts and N-methyl-D-glucamine. Salts with organic bases such as; salts with amino acids such as arginine, lysine, ornithine; and the like.
  • the present compound group includes various isomers of the compound of the present invention represented by the formula (I) (for example, optical isomers, positional isomers, tautomers, etc.), solvent products such as hydrates, and the like. Crystal polymorphs and esters (eg, compounds of the invention represented by formula (I) with methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol. Esther,) is included.
  • crystal polymorphs and esters eg, compounds of the invention represented by formula (I) with methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, or tert-butanol. Esther, is included.
  • Examples of the compound of the present invention represented by the formula (I) include the following compound Nos. 1 to 20 can be preferably exemplified.
  • the compound of the present invention represented by the formula (I) can be synthesized by appropriately combining known reactions.
  • the raw material can be obtained by purchasing a commercially available product (for example, Goofis [elobixibat hydrate] manufactured by EA Pharma) or by synthesizing the commercially available product by adding a general protecting group or the like. ..
  • the reduction of the carbonyl group and the halogenation of the alcohol group can be synthesized by using a reducing agent or a halogenating reagent used in general organic chemistry.
  • any process can be applied to purification by protection / deprotection, which is widely used in organic chemistry.
  • the agent may be a pharmaceutically acceptable conventional carrier, binder, stabilizer, excipient, diluent, pH buffer, disintegrant, isotonic agent, additive, coating agent, as required. It may further contain additives such as solubilizers, lubricants, gliding agents, solubilizing agents, lubricants, flavoring agents, sweeteners, solvents, gelling agents, and nutrients. Specific examples of such additives include water, physiological saline, animal fats and oils, vegetable oils, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, and polyalkylene glycol. Polyvinyl alcohol and glycerin can be exemplified.
  • the administration form of the present drug includes oral administration in which the dosage form is powder, granules, tablets, capsules, syrup, suspension, etc., or injection or spray in the dosage form such as solution, emulsion, suspension, etc.
  • Parenteral administration which is administered intranasally, can be mentioned as a dosage form, and oral administration is preferable.
  • the dose of the drug is appropriately determined according to age, body weight, gender, symptoms, sensitivity to the drug, etc., and is, for example, in the range of 0.1 ⁇ g to 200 mg / kg (body body) / day.
  • the dose of elobixibat hydrate of 10 to 30 mg / kg body weight / day is specifically shown by an experiment using a model mouse.
  • Such a dose is a dose to humans based on the human equivalent dose (HED) 12.3 in mice (see the document “Guidance for Industry Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”). When converted to, it is 0.81 to 2.4 mg / kg body weight / day.
  • the dose of the present drug is preferably 0.01 to 100 mg / kg body weight / day, more preferably 0.03 to 60 mg / kg body weight / day, and further preferably 0.06 to 30 mg / kg body weight / day.
  • 0.1 to 10 mg / kg body weight / day is even more preferable, and 0.6 to 4.0 mg / kg body weight / day is most preferable.
  • the drug may be administered once or in multiple doses (for example, 2 to 4 doses) per day.
  • the administration target of the reducing agent is not particularly limited, but usually, a person who needs to reduce the blood uremic substance, specifically, the concentration of the uremic substance in the blood increases (increases) for some reason. ).
  • the target of administration of the uremia preventive / ameliorating agent is not particularly limited, but usually a person who needs prevention or amelioration (treatment) of uremia, specifically, a uremic substance in the body for some reason. Those who have accumulated uremia, or who have developed uremia, or who are at risk of developing uremia, or who are at risk of developing uremia.
  • the administration target of the renal dysfunction preventive / ameliorating agent is not particularly limited, but usually a person who needs prevention or improvement (treatment) of renal dysfunction, specifically, renal function due to some cause. Those who have decreased and suffered from renal dysfunction, those who have developed renal dysfunction, those who may suffer from renal dysfunction, or those who may develop renal dysfunction.
  • the reducing agent may contain a component that reduces blood uremic substances other than the compound group, but the compound group alone can effectively reduce blood uremic substances. Therefore, it is preferable that the compound does not contain any reducing action component (for example, protein, DNA, RNA, plant-derived extract, polymer) of a blood uremic substance other than the present compound group.
  • the uremia preventive / ameliorating agent may contain a component for preventing or improving uremia other than the present compound group, but the present compound group alone effectively prevents or ameliorate uremia. Therefore, it is preferable that the compounds do not contain components for preventing or improving uremia (for example, proteins, DNA, RNA, plant-derived extracts, polymers) other than the present compound group.
  • the present renal dysfunction preventive / ameliorating agent may contain a component for preventing or improving renal dysfunction other than the present compound group, but the present compound group alone can effectively prevent renal dysfunction. Since it can be prevented or ameliorated, those containing no components for preventing or improving renal dysfunction (for example, protein, DNA, RNA, plant-derived extract, polymer) other than the present compound group are preferable.
  • adenine dietary renal failure model mouse is a mouse in which the fed adenine crystallizes as insoluble 2,8-dihydroxyadenine in the renal tubule, resulting in renal damage (Cozzolino, M. et al. Kidney Int). . 64, 441-450 (2003), Tamagi, K. et al. Nephrol. Dial. Transplant 21, 651-659 (2006)).
  • the suspension containing Goofis was prepared by suspending Goofis (elobixibat hydrate) (manufactured by EA Pharma) in distilled water.
  • blood samples were collected from each of the 3 groups (normal breeding group, placebo group, and elobixibat group), plasma was prepared according to a conventional method, and "plasma sample after 1 week".
  • the placebo group and the elobixibat group were returned to the normal diet, and the animals were bred for another week while continuing the administration. Then, blood samples were collected from each group, plasma was prepared according to a conventional method, and "2. After a week, a plasma sample was obtained. In addition, renal tissue was collected from the placebo group and the elobixibat group, fixed with 10% neutral buffered formalin, paraffin-embedded, and then the paraffin-embedded renal tissue was sliced to prepare a renal tissue section. ..
  • the suspension containing Goofis was prepared by suspending Goofis (elobixibat hydrate) (manufactured by EA Pharma) in distilled water.
  • blood samples were collected from each of the 3 groups (normal breeding group, placebo group, and elobixibat group), plasma was prepared according to a conventional method, and "plasma sample after 1 week".
  • uremic substances phenyl sulfate, creatinine, TMAO
  • LC-MS / MS manufactured by Shimadzu Corporation
  • Paraffin-embedded renal tissue is sliced to prepare renal tissue sections, and analysis using an electron microscope and analysis according to the method described in the document "Matsuhashi, T., et al: EBioMedicine 20: 27-38, 2017” Analysis using the periodic acid-Schiff (PAS) staining method was performed (see FIG. 5B).
  • PAS periodic acid-Schiff
  • the concentration of phenyl sulfate in blood was measured by mass spectrometry using.
  • renal tissue was collected, fixed with 10% neutral buffered formalin, and embedded in paraffin. Paraffin-embedded renal tissue is sliced to prepare renal tissue sections, and analysis using an electron microscope and analysis according to the method described in the document "Matsuhashi, T., et al: EBioMedicine 20: 27-38, 2017" Analysis using the Elastica Masson staining method and analysis using the DAB staining method using an anti-F4 / 80 antibody were performed.
  • the mesangial region of the glomerulus in the phenyl sulfate group of db / db mice expanded, and the disappearance of the glomerular podocytes (podocytes) increased (see the arrow in FIG. 5B), and the glomerular basement membrane (see the arrow in FIG. 5B). GBM) thickened (see arrowhead in FIG. 5B).
  • the disappearance of podocyte foot processes in the phenyl sulfate group increased (see the arrow in the electron microscope image of FIG. 5D), and the GBM became thickened (see the arrowhead in the electron microscope image of FIG. 5D).
  • perivascular fibrotic regions were found in the podocytes of the HFD-KKAY mouse phenyl sulfate group (see arrowheads in the Elastica Masson and F4 / 80 images in FIG. 5D).
  • the compound group of the present invention such as erobixibat hydrate reduces the concentration of the elevated blood uremic substance (for example, phenyl sulfate), and diabetic nephropathy. It has been shown to be effective in preventing or ameliorating uremia such as nephrotic syndrome and chronic nephritis syndrome.
  • the present invention contributes to the medical treatment of uremia and renal dysfunction.

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Abstract

La présente invention aborde le problème de la fourniture d'une substance qui a : un effet de réduction efficace (diminution) de la quantité d'une substance urémique présente dans le sang; un effet de prévention ou d'amélioration efficace de l'urémie; et un effet de prévention ou d'amélioration efficace d'un dysfonctionnement rénal.　Par l'administration d'un composé représenté par la formule (I), etc., par exemple, par voie orale, la quantité d'une substance urémique présente dans le sang est diminuée et l'urémie et le dysfonctionnement rénal sont améliorés.
PCT/JP2019/012952 2019-03-26 2019-03-26 Agent de réduction de substance urémique sanguine Ceased WO2020194531A1 (fr)

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023164186A1 (fr) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Composés benzothia(dia)zépine pour traitement anti-vhb et anti-vhd
WO2023164183A1 (fr) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Composés de benzothia(dia)zépine pour le traitement du vhb et du vhd
WO2024121434A1 (fr) * 2022-12-09 2024-06-13 Albireo Ab Inhibiteurs d'asbt dans le traitement de maladies rénales
WO2024177984A1 (fr) * 2023-02-20 2024-08-29 Assembly Biosciences, Inc. Composés benzothia(dia)zépine pour traitement anti-vhb et anti-vhd
US12134606B2 (en) 2020-12-04 2024-11-05 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
US12187690B2 (en) 2019-02-06 2025-01-07 Albireo Ab Benzothiadiazepine compounds and their use as bile acid modulators
US12187812B2 (en) 2010-11-04 2025-01-07 Albireo Ab IBAT inhibitors for the treatment of liver diseases
US12202809B2 (en) 2019-12-04 2025-01-21 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
US12365658B2 (en) 2021-06-03 2025-07-22 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
US12447156B2 (en) 2020-11-12 2025-10-21 Albireo Ab Treating progressive familial intrahepatic cholestasis (PFIC) with IBAT inhibitors

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JP2014532663A (ja) * 2011-10-28 2014-12-08 ルメナ ファーマシューティカルズ，インク． 高胆汁血症および胆汁うっ滞性肝疾患の処置のための胆汁酸再利用阻害剤
JP2018127435A (ja) * 2017-02-10 2018-08-16 国立大学法人東北大学 尿毒症の予防又は改善剤

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JP2004516285A (ja) * 2000-12-21 2004-06-03 アストラゼネカ アクチボラグ １，５ベンゾチアゼピン及び抗高脂質血症剤としてのその使用
JP2014532663A (ja) * 2011-10-28 2014-12-08 ルメナ ファーマシューティカルズ，インク． 高胆汁血症および胆汁うっ滞性肝疾患の処置のための胆汁酸再利用阻害剤
JP2018127435A (ja) * 2017-02-10 2018-08-16 国立大学法人東北大学 尿毒症の予防又は改善剤

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12187812B2 (en) 2010-11-04 2025-01-07 Albireo Ab IBAT inhibitors for the treatment of liver diseases
US12187690B2 (en) 2019-02-06 2025-01-07 Albireo Ab Benzothiadiazepine compounds and their use as bile acid modulators
US12202809B2 (en) 2019-12-04 2025-01-21 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
US12447156B2 (en) 2020-11-12 2025-10-21 Albireo Ab Treating progressive familial intrahepatic cholestasis (PFIC) with IBAT inhibitors
US12134606B2 (en) 2020-12-04 2024-11-05 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
US12365658B2 (en) 2021-06-03 2025-07-22 Albireo Ab Benzothia(di)azepine compounds and their use as bile acid modulators
WO2023164186A1 (fr) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Composés benzothia(dia)zépine pour traitement anti-vhb et anti-vhd
WO2023164183A1 (fr) * 2022-02-25 2023-08-31 Assembly Biosciences, Inc. Composés de benzothia(dia)zépine pour le traitement du vhb et du vhd
WO2024121434A1 (fr) * 2022-12-09 2024-06-13 Albireo Ab Inhibiteurs d'asbt dans le traitement de maladies rénales
WO2024177984A1 (fr) * 2023-02-20 2024-08-29 Assembly Biosciences, Inc. Composés benzothia(dia)zépine pour traitement anti-vhb et anti-vhd

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