JP2019085362A - Agent for reducing in-blood uremic substance - Google Patents

Abstract

To provide an agent for reducing in-blood uremic substance having the action of reducing (decreasing) the concentration of in-blood uremic substance effectively, and an agent for preventing or improving uremia.SOLUTION: An agent for reducing in-blood uremic substance contains a compound illustrated by the following formula as an active ingredient, and is orally administered.SELECTED DRAWING: None

Description

  The present invention relates to an agent for reducing uremic substances in blood and an agent for preventing or improving uremia.

  The kidney is an organ that regulates homeostasis (balance) in the body. One of the renal functions is to take in waste products and toxins (uremic substances) in the blood and send them out into the urine for excretion outside the body. When such renal function is reduced, uremic substances that should be excreted by the kidney are likely to be accumulated in the body, and in addition to symptoms such as nausea and anorexia, cells in the kidney are damaged to cause further reduction of renal function. In addition, it is also known that those with impaired renal function have a higher risk of suffering from stroke and myocardial infarction than healthy individuals. Therefore, preventing or treating symptoms or diseases (uremia) caused by accumulation of such uremic substances is not only treating symptoms such as nausea or appetite loss or exacerbation of renal disorder but also stroke or It is also necessary from the viewpoint of preventing heart disease.

  Dialysis is considered the most effective treatment of uremia. In fact, if uremic substances are discharged out of the body by dialysis, even if the renal function is abolished, the death of the patient due to the uremic substances can be avoided. However, complications such as anemia, renal osteodystrophy, renal cancer, epicarditis, aluminum osteopathy, amyloidosis, crystalline arthritis, and polycystic kidney disease have become new problems by long-term dialysis. . In addition, there are medical and economic problems, such as a decrease in the quality of life (QOL) in terms of social life of patients who frequently attend dialysis facilities and the occurrence of high costs.

  On the other hand, Mizagliflozin which is one of the inhibitors of sodium-dependent glucose co-transporter 1 (SGLT1), ie, 3-((3- (4-((5-isopropyl-3-) (((2S, 3R, 4S, 5R, 6S) -3,4,5-trihydroxy-6- (hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy) -1H-pyrazol-4-yl) methyl )) 3-Methylphenoxy) propyl) amino) -2,2-dimethylpropanamide inhibits the function of highly expressed SGLT1 present in the small intestine and suppresses the absorption of sugar, so it is useful as a therapeutic agent for diabetes It is reported (patent document 1). However, the relationship between Mizagliflozin and the reducing action of uremic substances has not been known so far.

WO 2004/018491 pamphlet

  The object of the present invention is to reduce blood uremic substance concentration effectively, to have an agent for reducing blood uremic substance, and to effectively improve uremia. To provide a preventive or ameliorating agent for

  The inventor of the present invention has been diligently researched to solve the above problems. In the process, the compound represented by the following formula (I) was found to have the effect of effectively reducing the concentration of the uremic substance in blood, and the present invention was achieved.

That is, the present invention is as follows.
[1] the following formula (I);

[In the formula,
R ¹ is a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _2-6 alkenyl, substituted or unsubstituted linear or branched C _2-6 alkenyloxy, substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl (C _1-6 alkyl) group;
R ² represents a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _1-6 alkoxy (substituted or unsubstituted linear or branched C _1-6 alkyl) group, or substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group;
R ³ , R ⁴ , R ⁵ and R ^{6, which} may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted linear or branched C ₁ or C _{1 A -6} alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group;
X ¹ is O, S, NH, CH ₂ , SO or SO ₂ ;
X ² is a substituted or unsubstituted linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group, And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is O, S or NH; and X ⁵ is a direct bond, substituted or substituted A linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group; X ⁶ is substituted or substituted Unbranched linear or branched C _1-6 alkyl group, hydroxyl group, or group -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ may be the same or different, and each is a hydrogen atom , Substituted or substituted (A straight or branched C _1-6 alkyl group, or a substituted or unsubstituted straight or branched C _1-6 alkoxy group)
And at least one compound selected from the group consisting of pharmaceutically acceptable salts thereof (hereinafter, these may be collectively referred to as "the present compound group"). An agent for reducing blood uremic substance, characterized in that it contains as an ingredient.
[2] The reducing agent according to the above-mentioned [1], which is orally administered.
[3] The reducing agent according to the above [1] or [2], wherein the compound is a compound represented by the following formula:

[4] The uremic substance is one or two selected from creatinine, urea, 1-methyladenosine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, quinolinic acid, uridine, p-cresol and indole The reducing agent according to any one of the above [1] to [3], which is a substance of a species or more.
[5] the following formula (I);

[In the formula,
R ¹ is a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _2-6 alkenyl, substituted or unsubstituted linear or branched C _2-6 alkenyloxy, substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl (C _1-6 alkyl) group;
R ² represents a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _1-6 alkoxy (substituted or unsubstituted linear or branched C _1-6 alkyl) group, or substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group;
R ³ , R ⁴ , R ⁵ and R ^{6, which} may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted linear or branched C ₁ or C _{1 A -6} alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group;
X ¹ is O, S, NH, CH ₂ , SO or SO ₂ ;
X ² is a substituted or unsubstituted linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group, And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is O, S or NH; and X ⁵ is a direct bond, substituted or substituted A linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group; X ⁶ is substituted or substituted Unbranched linear or branched C _1-6 alkyl group, hydroxyl group, or group -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ may be the same or different, and each is a hydrogen atom , Substituted or substituted (A straight or branched C _1-6 alkyl group, or a substituted or unsubstituted straight or branched C _1-6 alkoxy group)
An agent for the prophylaxis or amelioration of uremia, comprising, as an active ingredient, one or more compounds selected from the group consisting of a compound of the formula: and a pharmaceutically acceptable salt thereof.
[6] The prophylactic or ameliorating agent according to the above-mentioned [5], which is orally administered.
[7] The preventive or ameliorating agent according to the above [5] or [6], wherein the compound is a compound represented by the following formula:

[8] The uremic agent is one or two selected from creatinine, urea, 1-methyladenosine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, quinolinic acid, uridine, p-cresol and indole The preventive or ameliorating agent according to any one of the above [5] to [7], which is a substance of a species or more.

  In another embodiment of the present invention, blood uremia is caused by administering one or more compounds selected from the present compound group to a patient in need of blood uremic substance reduction. Method for reducing substances or for use as a reducing agent for blood uremic substances, for use in the reduction of one or more compounds selected from the present compound group, or blood uremic substances And the use of one or more compounds selected from the present compound group for producing one or more compounds selected from the present compound group, or an agent for reducing blood uremic substance. It can be mentioned.

  In another embodiment of the present invention, uremia is prevented by administering one or more compounds selected from the present compound group to a patient in need of blood uremic substance reduction. Or one or more compounds selected from the subject compound group for use as a method for improving (treating) or as an agent for preventing or ameliorating (treating) uremia, or preventing or ameliorating uremia (treatment Or one or more compounds selected from the subject compounds, or one or more compounds selected from the subject compounds for producing an agent for the prophylaxis or amelioration (treatment) of uremia, for use in Mention may be made of the use of two or more compounds.

  According to the present invention, the increase (increase) in uremic substance concentration in blood can be reduced (suppressed) or prevented, and the uremic substance concentration in blood can be adjusted to a normal value, so that uremic prevention or amelioration can be achieved. Useful for (treatment).

Two types of uremic substances (creatinine concentration and urea) in blood in five groups (normally fed CMC group and normally fed KWA group 30 and adenine diet fed CMC group, adenine diet fed KWA group 10 and adenine diet fed KWA group 30) It is a figure which shows the result of having measured the density | concentration of nitrogen [BUN]. The figure which shows the result of having measured the concentration of four kinds of uremic substances (1-methyl adenosine, trimethylamine-N-oxide [TMAO], p-cresyl sulfate, and indoxyl sulfate) in the blood in the above five groups. is there. “*” In the figure indicates that there is a statistically significant difference (p <0.05) by Tukey's test.

  The agent for reducing blood uremic substance of the present invention is an active ingredient of one or more compounds selected from the present compound group, which has a limited application of “to reduce uremic substance in blood”. And the agent for preventing or ameliorating uremia of the present invention have a limited use of "for preventing or ameliorating uremia". Or an agent containing one or more compounds selected from the present compound group as an active ingredient (hereinafter sometimes referred to as the “prophylactic / improvable agent”) (these agents are collectively referred to as “the present agent” Agent)). The agent may be used alone as a food or drink or a medicine (preparation) for the present compound group which is an active ingredient, and further, an additive is mixed to form a composition (food or drink composition or pharmaceutical composition You may use as). Such food and drink include, for example, health food (functional food, nutraceuticals, health supplements, fortified food, nutritionally adjusted food, supplements, etc.), health food (food for specified health use, nutrition food, function) Display food etc.) can be mentioned.

  In the present invention, the "uratic substance (also referred to as" uremic toxin ") is a substance excreted by normal kidney (waste products, toxins, etc.) and excreted due to any cause such as renal function deterioration A substance that increases (accumulates) in the blood and causes uremic symptoms or disease when function declines. The "uremic agents" are generally classified into three of water-soluble low molecular weight substances (500 daltons or less), medium molecular types (more than 500 daltons), and protein-bound substances (see "Vanholder, R. , et al: Kidney Int., 63 (5): 1934-1943, 2003 ").

Specific examples of the water-soluble low-molecular-weight substance include 1-methyladenosine, 1-methylguanosine, 1-methylinosine, and ADMA (asymmetric dimethylarginine), α-Keto-δ-guanidinovaleric acid (α-keto-δ-guanidinovaleric acid), α-N-acetylarginine (α-N-acetylarginine), arabitol (Arabitol), arginic acid (Argininic acid), benzyl alcohol (Benzylalcohol) ), Β-guanidinopropionic acid (β-guanidinopropionic acid), β-lipotropin (β-lipotropin), creatine (creatine), creatinine (creatinine), cytidine (Cytidine), dimethylglycine (Dimethylglycine), erythritol (Erythritol), γ -Guanidinobutyric acid (γ-guanidinobutyric acid), guanidine (Guanidine), guanidinoacetic acid (Guanidinoacetic acid), guanidinoacetic acid (Guanidinoacetic acid) Nijinokohaku acid (Guanidonosuccinic acid), hypoxanthine (Hypoxanthine), malondialdehyde (Malondialdehyde), mannitol (Mannitol), methyl guanidine (Methylguanidine), myo-inositol ^{(Myoinositol), N 2, N} 2 - dimethyl-guanosine (N ^2, N ^{2 -dimethylguanosine), N 4} - acetyl cytidine ^{(N 4 -acetylcytidine), N 6} - methyl adenosine ^{(N 6 -methyladenosine), N 6} - threonyl carbamoyl adenosine (N ⁶ -threonylcarbamoyladenosine), orotic acid (orotic acid), Orotidine (Orotidine), Oxalate (Oxalate), Phenylacetylglutamine (Phenylactylglutamine), Pseudouridine (Pseudouridine), SDMA (Symmetric dimethylarginine), Sorbitol (Sorbitol), Taulysamine (Taurocyamine), Threitol (Threitol), Thymine (Thymine) , Uracil (Uracil And urea (Urea), uric acid (Uric acid), uridine (Uridine), xanthine (Xanthine), xanthosine (Xanthosine), trimethylamine-N-oxide (TMAO; trimethylamine-N-oxide) and the like.

Specific examples of the above-mentioned medium molecular type substances include adrenomedullin (Adrenomedullin), atrial natriuretic peptide (Atrial Natriuretic Peptide; ANP), β ₂ -microglobulin (β ₂ -microglobulin), and β-endorphin (β- endorphin), cholecystokinin (Cholecystokinin), CC16 (Clara cell protein), complement factor D (Complement factor D), cystetin C (Cystatin C), degranulation inhibitory protein 1 (Degranulation inhibiting protein 1), delta sleep inducing peptide (Delta-sleep inducing peptide), endothelin (Endothelin), hyaluronic acid (Hyaluronic acid), interleukin-1 beta (Interleukin-1 beta), interleukin-6 (Interleukin-6), κ-Ig light chain (κ-Ig light) chain, λ-Ig light chain, leptin, methionine-enkephalin, nerve pep De (Neuropeptide), parathyroid hormone (Parathyroid hormone), retinol binding protein (Retinol-binding protein), tumor necrosis factor (TNF) -α (Tumor necrosis factor-α), and the like.

Specific examples of the protein-binding substance include 2-methoxyresorcinol, 3-deoxyglucosone, CMPF (3-Carboxy-4-methyl-5-propyl-2-furanpropionate). ), Fructose lysine (Fructose lysine), Glyoxal (Glyoxal), Hippuric acid (Hippuric acid), homocysteine (Homocysteine), hydroquinone (Hydroquinone), indole-3-acetic acid (Indole-3-acetic acid), indoxyl sulfuric acid (Indoxyl) Sulfate) or its precursor (indole [Indole]), kynurenine (Kinurenine), kynurenic acid (Kynurenic acid), leptin (Leptin), melatonin (Melatonin), methylglyoxal (Methylglyoxal), N-carboxymethyl lysine (N- (N- ( carboxylylysine), p-cresyl sulfate or its precursor (p-cresol [p-cresol]), pentosidine (Pento) sine), phenyl sulfate (Phenol) or its precursor (Phenol), P-OH-hippuric acid (P-OHhippuric axid), putrescine (Putrescine), quinolinic acid (Quinolinic acid), retinol binding protein (Retinol) -binding protein), spermidine (spermidine), spermine (Spermine) and the like.
In the above-mentioned uremic substance, 1,5-anhydro-glucitol (1,5-Anhydro-glucitol; 1,5-AG), the reduction effect of which was specifically confirmed in Examples of the present invention, 3 Also included are 3-hydroxyglutaric acid, aconitic acid, cholesterol, glutamine, mesaconic acid, oxalic acid, and sarcosine.

  Uremic agents in the present invention are selected from creatinine, urea, 1-methyl adenosine, TMAO, p-cresyl sulfate, indoxyl sulfate, quinolinic acid, uridine, and precursors thereof (p-cresol and indole) One or more substances are preferred.

  In the present invention, the “reduction of the uremic substance” means the suppression of production (production) of the uremic substance or its precursor, and the promotion of excretion of the uremic substance or its precursor out of the blood, etc. It means that the concentration of uremic substance contained in is reduced (decreased).

  In the present invention, the compound selected from the present compound group means a compound represented by the following formula (I), or a pharmacologically acceptable salt thereof.

During the ceremony
R ¹ is a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _2-6 alkenyl, substituted or unsubstituted linear or branched C _2-6 alkenyloxy, substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl (C _1-6 alkyl) group;
R ² represents a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _1-6 alkoxy (substituted or unsubstituted linear or branched C _1-6 alkyl) group, or substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group;
R ³ , R ⁴ , R ⁵ and R ^{6, which} may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted linear or branched C ₁ or C _{1 A -6} alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group;
X ¹ is O, S, NH, CH ₂ , SO or SO ₂ ;
X ² is a substituted or unsubstituted linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group, And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is O, S or NH; and X ⁵ is a direct bond, substituted or substituted A linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group; X ⁶ is substituted or substituted Unbranched linear or branched C _1-6 alkyl group, hydroxyl group, or group -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ may be the same or different, and each is a hydrogen atom , Substituted or substituted Which do not straight or branched C _1-6 alkyl group, or substituted or unsubstituted linear or a C _1-6 alkoxy group branched)).

  The term "straight chain" as used herein means a structure in which atoms other than hydrogen atoms are linked in a straight line without branching.

  The term "branched" as used herein refers to a structure in which two or more other carbon atoms are bonded to one or more arbitrary carbon atoms.

As used herein, “C _1-6 ”, “C _2-6 ”, “C _1-8 ”, “C _2-8 ”, and “C _3-7 ” each have the number of carbon atoms Represents a number. "Ci- ₆ " means "having any number of carbon atoms from 1 to 6 carbon atoms". " _C2-6 " means "having any number of carbon atoms from 2 to 6 carbon atoms". "Ci- ₈ " means "having any number of carbon atoms from 1 to 8 carbon atoms". " _C2-8 " means "having any number of carbon atoms from 2 to 8 carbon atoms". " _C3-7 " means "having any number of carbon atoms from 3 to 7 carbon atoms".

The term “C _1-6 alkyl group” as used herein is an alkane (aliphatic saturated hydrocarbon) represented by the general formula C _n H _{2 n + 2} (n represents a positive integer from 1 to 6) And the remaining hydrocarbon group excluding one hydrogen atom from any carbon atom of In one aspect of the present _{invention, C 1-6} alkyl group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present invention, a C1-6 alkyl group is a _C1- C4 alkyl group. In one aspect of the present _{invention, C 1-6} alkyl group is an alkyl group having 1 to 3 carbon atoms.
Examples of “C _1-6 alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1-methylbutyl group Group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group , 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethyl group Butyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1-ethyl-1-methylpropyl Group, 1-ethyl-2-methylpropyl group, n-hexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1,1-dimethylbutyl group, 1 , 2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1,1,2-trimethylpropyl group, 1 And -ethylbutyl group, 2-ethylbutyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group and the like can be mentioned.

The term "C _1-6 alkoxy group" used in this specification, - means a group represented by "O-C _1-6 alkyl group". The "C _1-6 alkyl group" is as defined above. As used herein, the term "substituted or unsubstituted linear or branched C _1-6 alkoxy group" refers to "-O-substituted or unsubstituted linear or branched It refers to _{C 1-6} alkyl group "Edakusari. In one aspect of the present invention, the alkyl group in the C _1-6 alkoxy group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present _{invention, C 1-6} alkyl group in _{C 1-6} alkoxy group is an alkyl group having 1 to 6 carbon atoms. In one aspect of the present _{invention, C 1-6} alkyl group in _{C 1-6} alkoxy group is an alkyl group having 1 to 4 carbon atoms. In one aspect of the present _{invention, C 1-6} alkyl group in _{C 1-6} alkoxy group is an alkyl group having 1 to 3 carbon atoms.
Examples of “C _1-6 alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentoxy group, 1- Methyl butoxy, 2-methyl butoxy, 3-methyl butoxy, 1-ethyl propoxy, 1,1-dimethyl propoxy, 1, 2- dimethyl propoxy, 2, 2- dimethyl propoxy, n-hexyl Oxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3 -Dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy And 1,1,2-trimethylpropoxy group, 1-ethyl butoxy group, 2-ethyl butoxy group, 1-ethyl-1-methyl propoxy group, 1-ethyl-2-methyl propoxy group and the like.

The term “C _2-6 alkenyl group” as used herein has only one carbon-carbon double bond in the molecule and has the general formula C _n H _{2 n} (n is a positive integer from 2 to 6) And the remaining hydrocarbon group obtained by removing one hydrogen atom from any carbon atom of an alkene (olefin hydrocarbon) represented by In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkenyl group is an alkenyl group having 2 to 4 carbon atoms. In one aspect of the present invention, the alkyl group is a C2-C3 alkenyl group.
Examples of “C _2-6 alkenyl group” 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-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group etc. can be mentioned.

The term " _C2-6 alkenyloxy group" used in the present specification means a group represented by "-O- _C2-6 alkenyl group". The "C _2-6 alkenyl group" is as defined above. The term “substituted or unsubstituted linear or branched C _2-6 alkenyl group” as used herein refers to “—O-substituted or unsubstituted linear or branched It means a _{C 2-6} alkenyl group "of Edakusari. In one aspect of the present invention, the alkenyl group in the C _2-6 alkenyloxy group is an alkenyl group having 2 to 6 carbon atoms. In one aspect of the present invention, the alkenyl group in the C _2-6 alkenyloxy group is an alkenyl group having a carbon number of 2 to 5. In one aspect of the present invention, the alkenyl group in the C _2-6 alkenyloxy group is an alkenyl group having 2 to 4 carbon atoms. In one aspect of the present invention, the alkenyl group in the C _2-6 alkenyloxy group is an alkenyl group having a carbon number of 2 to 3.
Examples of "C _2-6 alkenyloxy group" include ethenyl group (vinyloxy group), 1-propenyloxy group, 2-propenyl group oxy (allyloxy group), 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group , Isobutenyloxy group, 1-pentenyloxy group, 2-pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 1-hexenyloxy group, 2-hexenyloxy group, 3-hexenyloxy group, 1 -Octenyl oxy group, 2-octenyl oxy group, 3- octenyl oxy group, 4- octenyl oxy group etc. can be mentioned.

The term “C _3-8 cycloalkyl group” as used herein is a cycloalkane (cyclic saturated hydrocarbon) represented by the general formula C _n H _{2 n} (which represents a positive integer from 3 to 8) And the remaining hydrocarbon group excluding one hydrogen atom from any carbon atom of In one aspect of the present invention, the C _3-8 cycloalkyl group is a C _3-8 cycloalkyl group. In one aspect of the present invention, 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 5 carbon atoms. In one aspect of the present invention, the cycloalkyl group is a cycloalkyl group having 3 to 4 carbon atoms.
Examples of the "cycloalkyl group" include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like.

As used herein, the term "aryl group" refers to a compound having an aromatic ring, ie, carbonization of the remaining remaining one hydrogen atom bonded to the ring atom of the aromatic ring of the aromatic hydrocarbon. It means a hydrogen group. In addition, the term "aromatic ring" means a compound having a cyclic structure having a delocalized π electron orbital or a cyclic structure having a single or a plurality of rings consisting of hydrocarbons alone. When the aromatic ring constitutes a plurality of rings, the aromatic ring may be a fused ring or a non-fused ring (for example, biphenyl).
In one aspect of the present invention, the aryl group is an aryl group having 6 to 22 carbon atoms in the ring. In one aspect of the present invention, the aryl group is an aryl group having 6 to 18 carbon atoms in the ring. In one aspect of the present invention, the aryl group is an aryl group having 6 to 14 carbon atoms in the ring. In one aspect of the present invention, the aryl group is an aryl group having 6 to 10 carbon atoms in the ring. In one aspect of the present invention, the aryl group is an aryl group having 6 carbon atoms in the ring (phenyl group).
Examples of “aryl group” include phenyl group, o-tolyl group, m-tolyl group, p-tolyl group, naphthyl group, o-xylyl group, m-xylyl group, p-xylyl group, 1-naphthyl group, 2 -A naphthyl group etc. can be mentioned.

The term "aryl (C _1-6 alkyl) group" used in the present specification, one of the hydrogen atoms of the C _1-6 alkyl group means an alkyl group substituted with an aryl group. In one aspect of the present invention, aryl _{(C 1-6} alkyl) group, an aryl _{(C 1-6} alkyl) group 7 to 26 carbon atoms (of which the number of carbon atoms of the aryl group having 6 to 22). In one aspect of the present invention, aryl _{(C 1-6} alkyl) group, an aryl _{(C 1-6} alkyl) group having a carbon number of 7 to 22 (of which 6 to 18 ring carbon atoms). In one aspect of the present invention, aryl _{(C 1-6} alkyl) group, an aryl _{(C 1-6} alkyl) group having a carbon number of 7 to 18 (of which 6 to 14 ring carbon atoms). In one aspect of the present invention, aryl _{(C 1-6} alkyl) group, an aryl _{(C 1-6} alkyl) group having a carbon number of 7 to 14 (of which 6 to 14 ring carbon atoms). In one aspect of the present invention, aryl _{(C 1-6} alkyl) group, an aryl _{(C 1-6} alkyl) group having a carbon number of rings 7-8 (of ring carbon atoms 6). However, also in any aspect, carbon number of an alkyl group is 1-6.
Examples of the “aryl (C _1-6 alkyl) group” include a benzyl group (phenylmethyl group), a phenethyl group (phenylethyl group) and the like.

  The term "halogen atom" as used herein means fluoro (F), chloro (Cl), bromo (Br) or iodo (I). The term "halogenated" as used herein means a group in which one or more hydrogen atoms on one or more carbon atoms of the group have been replaced by a halogen atom. In a group in which two or more hydrogen atoms are replaced by halogen atoms, the two or more halogen atoms may be the same or different.

The term "C _1-8 alkylene group" as used herein is a straight or branched chain represented by the general formula C _n H _{2 n + 2} (where n represents a positive integer from 1 to 8) hydrogen from an alkane (saturated aliphatic hydrocarbon) means two by removing divalent _substituent, -C _{n H 2n -,} or represented as _C n _{H 2n} =.
Examples of “C _1-8 alkylene group” include methylene group (—CH ₂ —), ethylene group (—CH ₂ —CH ₂ —), propylene group (—CH ₂ —CH ₂ —CH ₂ —), (2 - dimethyl) ethylene group _{(-CH 2 -C (CH 3)} 2 -) and the like.

The term "C _2-8 alkenylene group" as used herein is a straight or branched chain represented by the general formula C _n H _{2 n} (where n represents a positive integer from 1 to 8) It means a divalent substituent in which two hydrogens have been removed from an alkene (aliphatic unsaturated hydrocarbon having one double bond), and is represented by —C _n H _{2 n−2} — or C _n H _{2 n−2 と} expressed.
Examples of “C _2-8 alkenylene group” include —CH = CH—, —CH = CH—CH ₂ —, —CH ₂ —CH = CH—CH ₂ —, —CH ₂ —CH ₂ —CH = CH and the like can be given - -CH ₂ -CH _2.

In the definition of X ^{5 in} the compound of the formula (I), “X ⁵ is a direct bond” means that X ⁵ has no substituent, and two adjacent groups (X ⁴ and CO) are directly linked to each other. Means to That is, the direct bond in the group -X ⁴ -X ⁵ -CO-X ⁶ means that X ⁵ is -X ⁴ -CO-X ⁶ .

In the term "substituted or unsubstituted" as used herein, "substituted" means having one or more substituents, "unsubstituted" means a substituent It means not having at all.
In the present invention, the substituent is not particularly limited. As a substituent, for example, a halogen atom, a straight or branched C _1-6 alkyl group which is not substituted, a straight or branched C _1-6 alkoxy group which is not substituted, a straight chain which is not substituted Chain or branched C _2-6 alkenyl group, unsubstituted linear or branched C _2-6 alkenyloxy group, C _3-8 cycloalkyl group, halogenated alkyl group, halogenated alkyloxy group And a cyano group, a hydroxyl group, an amino group, a nitro group, a carboxyl group, a phenyl group, and a naphthyl group.

As compounds of the above formula (I), R ¹ is a hydrogen atom or a substituted or unsubstituted linear or branched C _1-6 alkyl group; R ² is substituted or substituted R ³ , R ⁴ and R ⁵ are all hydrogen atoms; R ⁶ is a substituted or unsubstituted straight or branched C _1-6 alkyl group; It is a C _1-6 alkyl group or branched-chain; X ¹ is, O, or be S; X ² is substituted or unsubstituted straight or C _1-8 alkylene branched And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is NH and X ⁵ is a substituted or unsubstituted linear or be a _{C 1-8} alkylene group branched; ^{X 6} is a group -N ^{7 R} 8 ^(wherein, R ⁷ and R ⁸ may be the same or different, each represent a hydrogen atom, or not been or substituted substituted by straight-chain or branched-chain C _1-6 alkyl group Compounds) can be mentioned as one embodiment.

As compounds of the above formula (I), R ¹ is a hydrogen atom; R ² is a linear or branched C _1-6 alkyl group which is unsubstituted; R ³ , R ⁴ and R ⁵ is any hydrogen atom; R ⁶ is an unsubstituted linear or branched C _1-6 alkyl group; X ¹ is O; X ² is unsubstituted A straight or branched C _1-8 alkylene group; and X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is NH; X ⁵ Is a linear or branched C _1-8 alkylene group which is not substituted; X ⁶ is a group -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are both hydrogen atoms) Can be mentioned as one other embodiment.

As compounds of the above formula (I), R ¹ is a hydrogen atom; R ² is a branched unsubstituted C _3-6 alkyl group which is not substituted; R ³ , R ⁴ and R ⁵ are Each is a hydrogen atom; R ⁶ is an unsubstituted linear C _1-6 alkyl group; X ¹ is O; and X ² is an unsubstituted linear C _1-6 And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is NH; and X ⁵ is a branched C which is not substituted. _A compound having a _1-6 alkylene group; and X ⁶ is a group -NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are both hydrogen atoms) is mentioned as another embodiment it can.

As compounds of the above formula (I), R ¹ is a hydrogen atom; R ² is a branched unsubstituted C _3-6 alkyl group which is not substituted; R ³ , R ⁴ and R ⁵ are All are hydrogen atoms; R ⁶ is an unsubstituted linear C _1-4 alkyl group; X ¹ is O; and X ² is an unsubstituted linear C _2-4 And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is NH; and X ⁵ is a branched C which is not substituted. _A compound in which the compound is a _2-4 alkylene group; and X ⁶ is a group —NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ are both hydrogen atoms) is mentioned as one other embodiment it can.

  Specific examples of the compound represented by the formula (I) will be listed below, but the compound represented by the formula (I) is not limited to these compounds.

  As used herein, the term "pharmaceutically acceptable salt" refers to excessive toxic, irritating, allergic responses for use in contact with human and animal tissues within the scope of sound medical judgment. Or those compounds, substances, compositions and / or dosage forms that are suitable according to an appropriate benefit / risk ratio without any other problems or complications.

  As the pharmaceutically acceptable salts in the present compound group, acid addition salts and base salts are present. Examples of pharmaceutically acceptable acid addition salts in the present compound group include acetate, adipate, ascorbate, benzoate, benzene sulfonate, bicarbonate, bisulfate, butyrate, camphor Acid salt, camphor sulfonate, choline, citrate, cyclohexyl sulfamate, diethylene diamine, ethane sulfonate, formate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethyl sulfone Acid salts, heptanoic acid salt, hexanoic acid salt, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2 -Naphthalene sulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate Propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate and undecanoic acid Contains salt.

  Examples of pharmaceutically acceptable base salts in the present compound group 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 salts with organic bases such as N-methyl-D-glucamine; and salts with amino acids such as arginine, lysine, ornithine and the like. Furthermore, the basic nitrogen-containing group is a lower alkyl halide such as methyl, ethyl, propyl and butyl; dialkyl sulfates such as dimethyl, diethyl and dibutyl; diamyl sulfate; long such as decyl, lauryl, myristyl and stearyl It may be quaternized with materials such as chain halides; aryl alkyl halides such as benzyl bromide and others. While nontoxic, physiologically acceptable salts are preferred, other salts may be useful, such as when isolating or purifying the product.

  Various isomers (eg, optical isomers, positional isomers, tautomers, etc.) of the compound of the present invention represented by the formula (I), solvates such as hydrates, crystal polymorphs, and esters All prodrugs such as are included in the scope of the present invention.

Further, compounds in which one or more atoms constituting the compound of the present invention represented by the formula (I) are isotopes, and pharmaceutically acceptable salts thereof are also included in the present invention. Examples of isotopes contained in the compound of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, bromine and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, respectively. ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ⁷⁵ Fr, ⁷⁶ Br, ⁷⁷ Br, ⁸² Br, and ³⁷ Cl.

  The compounds of the present invention represented by the formula (I) may be commercially available products, or may be combined appropriately with known reactions with reference to methods described in the literature (WO 2004/018491 pamphlet) and the like. Can be synthesized by The raw material can be synthesized by adding a general protective group or the like to a commercially available product or a commercially available product. The reduction of the carbonyl group and the halogenation of the alcohol group can be synthesized by a reducing agent, a halogenating reagent and the like used in general organic chemistry. In addition, purification by protection / deprotection which is widely used in organic chemistry is applicable to any process.

  The agent is a pharmaceutically acceptable common carrier, a binder, a stabilizer, an excipient, a diluent, a pH buffer, a disintegrant, an isotonic agent, an additive, a coating agent, if necessary. Examples of such additives further include compounding ingredients such as solubilizers, lubricants, glidants, solubilizers, lubricants, flavors, sweeteners, solvents, gelling agents, and nutritional agents. As such compounding ingredients, specifically, water, physiological saline, animal fats and oils, vegetable oil, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, Polyvinyl alcohol and glycerin can be exemplified.

  The uremic agent, which is a disease to be prevented or ameliorated by the preventive / improval agent of the present invention, includes the above uremic substances (preferably p-cresyl sulfate, phenyl sulfate, indoxyl sulfate, 1-methyl adenosine, creatinine, and precursors thereof The condition or disease is not particularly limited as long as it is a symptom or a disease caused by one or more substances selected from the body [p-cresol, phenol, and indole]. Examples of such a condition or a disease include anorexia, nausea Gastrointestinal abnormalities such as vomiting, halitosis, canker sores, enteritis, etc .; Nervous system such as apathy, apathy, memory loss, depression, somnolence, coma, polyneuritis, coordination dyskinesia, dysphagia etc Abnormalities; arteriosclerosis, anemia, erythropoiesis disorder, hypertension, ischemic heart disease, pericarditis, myocarditis, (blood) coagulation disorders, heart failure, cardiovascular disorders and other cardiovascular disorders; pigmentation, pruritus , Subcutaneous hemorrhage, skin atrophy, infection, atopy, skin disorder such as hair loss (disease); albuminuria, acute renal failure, acute tubular necrosis, renal anemia, chronic renal failure, tubulointerstitial disorder, acute nephritis, chronic Nephritis, nephrosis, diabetic nephropathy, arteriosclerotic nephropathy, renal bone disorder (eg, renal osteodystrophy), renal dysfunction such as flooding, etc .; stroke; myocardial infarction; cancer; autism; Failure, bone disorder, hyperparathyroidism, insulin resistance, malnutrition, inflammation, tremor, etc. can be mentioned. In addition, the above uremia is a symptom involving LPS (Lipopolysaccharide) such as IgA nephropathy, cystic kidney, liver dysfunction (eg, fulminant hepatitis, fatty liver, NASH, NAFLD), cancer (eg, bile carcinogenesis), etc. Or inflammatory diseases such as ulcerative colitis, Crohn's disease, arteriosclerosis-related diseases, autoimmune diseases such as lupus, scleroderma, rheumatism, etc. obesity, metabolic syndrome, diabetes, autism, Parkinson's disease, Alzheimer's disease Diseases, including sarcopenia. Uremia is a symptom or disease caused by a factor other than the uremic substance without causing the uremic substance (eg, obesity, diabetes caused by an increase in SGLT1 without causing the uremic substance) Diabetic renal dysfunction is not included.

  The dosage form of the agent may be orally administered in the form of powder, granules, tablets, capsules, syrups, suspensions, etc., or injection or spray of forms such as solution, emulsion, suspension etc. Parenteral administration can be mentioned which is intranasal administration in the form of an agent, oral administration being preferred.

  The dose of the agent is appropriately determined according to age, body weight, sex, symptoms, sensitivity to drugs, etc. Usually, the dose in the range of 1 μg to 200 mg / day, preferably in the range of 2 μg to 2000 μg / day, more preferably in the range of 3 to 200 μg / day, still more preferably 4 to 20 μg / day Although the dose range of day is to be administered once or divided into multiple doses (for example, 2 to 4 times) per day, the dose may be adjusted according to the state of improvement of symptoms.

  The subject of administration of the agent is not particularly limited, but usually, the person who needs reduction of blood uremic substance, specifically, the concentration of uremic substance in blood is due to the decrease in renal function etc. Those who have increased (elevated) or those who have accumulated uremic substances in the body.

  Although the present reducing agent may contain a component for reducing blood uremic substance other than the present compound group, the present compound group alone exerts an excellent reducing effect on blood uremic substance Therefore, compounds which do not contain a blood uremic substance reducing action component (eg, protein, DNA, RNA, plant-derived extract) other than the present compound group are preferable. In addition, although the agent for preventing / ameliorating the present invention may contain a component for preventing or ameliorating uremia other than the present compound group, the present compound group alone exhibits an excellent effect for preventing or ameliorating uremia. Therefore, it is preferable to use one that does not contain components for preventing or ameliorating uremia (eg, proteins, DNA, RNA, extracts derived from plants) other than the present compound group.

  Hereinafter, the present invention will be more specifically described by way of examples, but the technical scope of the present invention is not limited to these examples.

  Model mice that developed chronic renal failure by feeding adenine to confirm that the present compound group has an effect of reducing uremic substances (hereinafter, "adenine feeding renal failure model mouse") Mizagliflozin was administered to analyze the concentration of uremic substances in blood. The adenine-fed renal failure model mouse is a mouse that causes renal damage by crystallizing fed adenine as insoluble 2,8-dihydroxyadenine in the renal tubule (Cozzolino, M. et al. Kidney Int 64, 441-450 (2003), Tamagaki, K. et al. Nephrol. Dial. Transplant 21, 651-659 (2006)).

[Method]
According to the following procedures [1] to [4], analysis using an adenine-fed renal failure model mouse was performed.
[1] Male C57BL / 6 mice (purchased from Japan CLEA Co., Ltd.) were bred on a normal diet (CE-2, manufactured by Japan CLEA) until 6 weeks of age.
[2] At 7 weeks of age, a normal rearing group (n = 8) reared on a normal feed and an adenine dietary rearing group (n = 25) reared on a normal feed containing 2% adenine (Wako) Divided into
[3] The adenine diet rearing group returns the feed to the normal diet after 6 weeks of adenine diet rearing (13 weeks old), and the three groups (adenine diet rearing CMC group [n = 8], adenine diet rearing KWA 10 group Divided into [n = 8], and adenine diet-reared KWA 30 group [n = 9]), and orally administered 0.5% carboxymethylcellulose (CMC) as a solvent twice a day to the adenine diet-reared CMC group, Oral administration of 0.5% CMC containing 10 (mg / kg body weight) of Mizagliflozin (Kidsei Pharmaceutical Co., Ltd.) twice a day to the adenine diet-reared KWA 10 group, and 30 (mg to the adenine diet-reared KWA 30 group 0.5% CMC containing Mizagliflozin / kg body weight) was orally administered twice a day.
On the other hand, the normal rearing group is divided into two groups (normal rearing CMC group [n = 4] and normal rearing KWA 30 group [n = 4]) after 6 weeks of normal rearing (13 weeks old), and normal rearing CMC The group was orally administered 0.5% CMC twice a day, and the normal rearing KWA 30 group was orally administered 0.5% CMC containing 30 (mg / kg body weight) Mizagliflozin twice a day.
[4] After orally administering the above [3] for 10 days, a blood sample is collected on the 11th, plasma is prepared according to a standard method, and a blood test creatinine kit (Fuji The concentrations of two uremic substances (creatinine concentration and BUN) in blood were measured using Dry Chem Slide CRE-PIII) and urea nitrogen kit (Fuji Dry Chem Slide BUN-P III) (all manufactured by FUJIFILM) See Figure 1).
In addition, based on a part of the prepared plasma, four types of uremia in blood are determined by mass spectrometry using a liquid chromatograph-tandem mass spectrometer (LC-MS / MS) (manufactured by Shimadzu Corporation). The concentrations of the substances (1-methyl adenosine, TMAO, p-cresyl sulfate and indoxyl sulfate) were determined (see FIG. 2).
Furthermore, based on a part of the prepared plasma, using a gas chromatograph-tandem mass spectrometer (GC-MS / MS) (manufactured by Shimadzu Corporation), ten kinds of uremic substances (quinolinic acid, Uridine, 1, 5-AG, 3-hydroxyglutaric acid, 3-hydroxyglutaric acid, aconitic acid, cholesterol [Cholesterol], glutamine, mesaconic acid [mesaconic acid], oxalic acid, sarcosine [sarcosine]) (See Table 1) and the concentrations of two types of bile acids (cholic acid and chenodeoxycholic acid; CDCA) in feces (see Table 2).

[result]
First, eight uremic substances (creatinine and BUN [see FIG. 1]) in the blood of adenine-fed renal failure model mice (Adenine-fed CMC group); 1-methyladenosine, TMAO, p-cresyl sulfate, and indoxyl It was confirmed that the concentrations of sulfuric acid (see FIG. 2); and quinolinic acid and uridine (see Table 1) were higher than those of control mice fed a normal diet (normally fed CMC group) (FIG. 1 and FIG. 2, and Table 1). Next, when Mizagliflozin is administered to an adenine-fed renal failure model mouse, the concentration of the eight uremic substances that were elevated decreases in a dose-dependent manner (see FIGS. 1 and 2 and Table 1), and the dose Depending on the concentration of eight uremic substances (1,5-AG, 3-hydroxyglutaric acid, aconitic acid, cholesterol, glutamine, mesaconic acid, oxalic acid and sarcosine) in blood depending on the concentration (Table 1) Reference) was shown. In addition, when Mizagliflozin was administered to an adenine-fed renal failure model mouse, it was shown that the bile acid (cholic acid and CDCA) concentration in feces was increased (see Table 2).
The results show that the present compound group such as Mizagliflozin and the like are uremic substances (creatinine, BUN, 1-methyladenosine, TMAO, p-cresyl sulfate, indoxyl sulfate, quinolinic acid, uridine, An effect of reducing 1,5-AG, 3-hydroxyglutaric acid, aconitic acid, cholesterol, glutamine, mesaconic acid, oxalic acid, sarcosine, etc.) and improving renal dysfunction such as renal failure or in vivo bile acid It shows that it has the effect of raising the concentration of (cholate and CDCA) and improves physical condition, and it is also shown that it is effective in the amelioration of symptoms and diseases caused by uremic substances, ie, uremia. Since BUN is nitrogen contained in urine, the fact that the concentration of BUN in the blood decreased by the administration of the present compound group means that the concentration of urea in the blood decreased.

The numerical values in the table indicate the concentrations of various uremic substances in blood in each group (mean value ± standard deviation [SD]). In addition, a numerical value is shown as a relative value when the value in a normal breeding CMC group is set to 1. Also, "*" and "**" in the table indicate that there is a statistically significant difference (p <0.05 and p <0.01, respectively) according to Tukey's test to the normal breeding CMC group . In addition, “#” and “##” in the table indicate that there is a statistically significant difference (p <0.05 and p <0.01, respectively) by Tukey's test for the adenine diet-reared CMC group. Show.

The numerical values in the table indicate the concentration (average value) of cholic acid and CDCA in feces in each group. In addition, a numerical value is shown as a relative value when the value in a normal breeding CMC group is set to 1.

  The present invention contributes to the prevention or amelioration (treatment) of a symptom or disease caused by accumulation (increase) of a uremic substance in blood.

Claims (8)

The following formula (I);
[In the formula,
R ¹ is a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _2-6 alkenyl, substituted or unsubstituted linear or branched C _2-6 alkenyloxy, substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl (C _1-6 alkyl) group;
R ² represents a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _1-6 alkoxy (substituted or unsubstituted linear or branched C _1-6 alkyl) group, or substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group;
R ³ , R ⁴ , R ⁵ and R ^{6, which} may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted linear or branched C ₁ or C _{1 A -6} alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group;
X ¹ is O, S, NH, CH ₂ , SO or SO ₂ ;
X ² is a substituted or unsubstituted linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group, And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is O, S or NH; and X ⁵ is a direct bond, substituted or substituted A linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group; X ⁶ is substituted or substituted Unbranched linear or branched C _1-6 alkyl group, hydroxyl group, or group -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ may be the same or different, and each is a hydrogen atom , Substituted or substituted (A straight or branched C _1-6 alkyl group, or a substituted or unsubstituted straight or branched C _1-6 alkoxy group)
An agent for reducing blood uremic substance, which comprises, as an active ingredient, one or more compounds selected from the group consisting of a compound of the formula: and a pharmaceutically acceptable salt thereof.   The agent according to claim 1, wherein the agent is orally administered. The reducing agent according to claim 1 or 2, wherein the compound is a compound represented by the following formula.
  The uremic agent is one or more selected from creatinine, urea, 1-methyladenosine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, quinolinic acid, uridine, p-cresol, and indole The reducing agent according to any one of claims 1 to 3, which is a substance. The following formula (I);
[In the formula,
R ¹ is a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _2-6 alkenyl, substituted or unsubstituted linear or branched C _2-6 alkenyloxy, substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted aryl (C _1-6 alkyl) group;
R ² represents a hydrogen atom, a substituted or unsubstituted linear or branched C _1-6 alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group , Substituted or unsubstituted linear or branched C _1-6 alkoxy (substituted or unsubstituted linear or branched C _1-6 alkyl) group, or substituted or unsubstituted An unsubstituted C _3-8 cycloalkyl group;
R ³ , R ⁴ , R ⁵ and R ^{6, which} may be the same or different, each represents a hydrogen atom, a halogen atom, a hydroxyl group, a substituted or unsubstituted linear or branched C ₁ or C _{1 A -6} alkyl group, or a substituted or unsubstituted linear or branched C _1-6 alkoxy group;
X ¹ is O, S, NH, CH ₂ , SO or SO ₂ ;
X ² is a substituted or unsubstituted linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group, And X ³ is a group -X ⁴ -X ⁵ -CO-X ^{6 wherein} X ⁴ is O, S or NH; and X ⁵ is a direct bond, substituted or substituted A linear or branched C _1-8 alkylene group, or a substituted or unsubstituted linear or branched C _2-8 alkenylene group; X ⁶ is substituted or substituted Unbranched linear or branched C _1-6 alkyl group, hydroxyl group, or group -NR ⁷ R ⁸ (wherein, R ⁷ and R ⁸ may be the same or different, and each is a hydrogen atom , Substituted or substituted (A straight or branched C _1-6 alkyl group, or a substituted or unsubstituted straight or branched C _1-6 alkoxy group)
An agent for the prophylaxis or amelioration of uremia, comprising, as an active ingredient, one or more compounds selected from the group consisting of a compound of the formula: and a pharmaceutically acceptable salt thereof.   The prophylactic or ameliorating agent according to claim 5, which is orally administered. The preventive or ameliorating agent according to claim 5 or 6, wherein the compound is a compound represented by the following formula.
  The uremic agent is one or more selected from creatinine, urea, 1-methyladenosine, trimethylamine-N-oxide, p-cresyl sulfate, indoxyl sulfate, quinolinic acid, uridine, p-cresol, and indole The preventive or ameliorating agent according to any one of claims 5 to 7, which is a substance.