JP2008106017A - Compound having selective oatp-inhibiting property, and selective oatp-inhibiting agent containing the compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound for selectively inhibiting OATP, and to provide an inhibiting agent for selectively inhibiting OATP. <P>SOLUTION: The compound is represented by formula 1, wherein X is a phenyl group or a biphenyl group substituted with a carboxyl group or a sulfonic group; Y is carbonyl (-CO-), sulfinyl (-SO-) or sulfonyl (-SO<SB>2</SB>-); Z is a functional group represented by -NH(R<SB>1</SB>) and R<SB>1</SB>is an alkyl, a cycloalkylaryl. The selective OATP inhibiting agent comprises the compound or its salt. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a compound that selectively inhibits an organic anion transporter (OATP) group, in particular, an amide type carboxylic acid, sulfonic acid, or a salt thereof. The organic anion transporter (OATP) in the present invention refers to a series of proteins belonging to the gene family in which the gene encoding the protein is defined as the Solute carrier organic anion transporter family (SLCO) by The Human Genome Organization. It does not distinguish what is called by another name. The present invention also relates to a selective inhibitor of OATP containing the compound. Furthermore, the present invention relates to a method of analyzing the function of OATP based on the inhibitory action of OATP and using it for calculation of the contribution ratio of OATP to the pharmacokinetics, estimation of drug interaction, and the like.

  In recent years, transporters are one of the proteins that are attracting attention as proteins involved in intracellular transport of drugs. Since the cells constituting the living body are encased in a cell membrane called a lipid bilayer membrane, water-soluble substances such as sugars and amino acids essential for the living body cannot pass through the cell membrane as they are. For this reason, the cell membrane is equipped with a transporter for taking up such nutrients, and one such transporter is a transporter.

  The transporter not only plays a major role in maintaining the homeostasis in relation to the transport of substances such as nutrients in the living body described above, but also various kinds of functions such as uptake of water-soluble drugs and excretion of metabolites thereof. It is also greatly involved in the pharmacokinetics of exogenous drugs, and its biological significance is very large. For example, when a drug is administered, its pharmacokinetics is determined by four steps: 1) absorption from the administration site into the circulating blood, 2) tissue distribution, 3) liver metabolism, and 4) bile or urinary excretion. However, it is known that the transporter has a large role at any of these stages (Non-Patent Document 1).

  For example, the blood-brain barrier (BBB) has transporters independently and independently for transporting water-soluble sugars, amino acids, monocarboxylic acids, amines, carnitines, or hormones that are necessary for the brain. It is expressed. On the other hand, drugs such as cyclosporine and vincristine that are foreign substances pass through the membrane once because they are fat-soluble, but are excreted by various transporters such as P-gp and MRP expressed in the blood brain barrier. The As a result, these drugs are prevented from flowing into the brain, and their influence on the brain is avoided (Non-Patent Document 1).

  Many transporters also work for nutrient absorption in the digestive tract, and it is known that LAT transports amino acids, PEPT transports peptides, and SGLT transports sugars. Furthermore, SGLT1 also acts to absorb various glycosides, suggesting the possibility of promoting absorption by glycosylation of drugs. Thus, it is expected that the transporter can be used to improve the pharmacokinetics of drugs (Non-patent Document 2).

Under these circumstances, research on transporters has become active in recent years, and the actual situation has gradually become clear, and the molecular recognition mechanism of transporters is being elucidated (Non-patent Document 3).
For example, in recent years, the mechanism of action of urate reabsorption inhibitors such as probenecid and benzbromarone, which are widely used as therapeutic agents for gout, has been elucidated, and the inhibition of reabsorption is based on the inhibitory action of URAT1, a urate transporter. (Non-Patent Document 4).

  The role of transporters in drug development, such as the transporter being expected as a target molecule in drug development in recent years and the active development of drugs using transporters, triggered by the elucidation of the mechanism of action Is getting larger and larger (Patent Documents 1 to 5).

  It is known that there are many types of transporters as described above, and one of them is an organic anion transporting polypeptide (OATP) discovered by bile acid uptake studies. . Bile acid is biosynthesized from cholesterol inside hepatocytes, then secreted into the digestive tract and re-absorbed from the digestive tract to enter the hepatic circulation. A protein responsible for the absorption of bile acids taken into the blood into hepatocytes is OATP (Non-patent Document 5).

As the name suggests, OATP is a transporter that mainly recognizes and selectively transports an anionic compound, and as the anionic compound, in addition to the aforementioned bile acids, Examples of exogenous anionic compounds such as prostaglandin E ₂ , thromboxane B ₂ , leukotriene C ₄ , and thyroid hormone include pravastatin and methotrexate. The OATP is also known to be involved in the transport of conjugates of hydrophobic drugs (acid conjugates such as glutathione, glucuronic acid, and sulfuric acid) (Non-patent Document 5).

The OATP has many subtypes such as OATP-A, B, C, D, E, and 8. Of these, OATP-A is highly expressed in the brain, and OATP-B, C, and 8 are liver. In addition, OATP-B, D, and E are known to be widely expressed in peripheral organs. In particular, OATP-C and OATP-8 are selectively and highly expressed in the liver. Taurocholic acid (TCA), a bile acid, estrone-3-sulfate (E ₁ -3S), a sex hormone derivative, dehydroepi Because it shows wide molecular recognition (see the figure below) such as androsterone sulfate (DHEAS), statin drugs (pravastatin, fluvastatin) and antituberculosis drugs (rifampicin), which are therapeutic agents for hyperlipidemia (see Non-Patent Document 5, And 6) play a large role in liver drug transport. For example, pravastatin, which is well known as a hyperlipidemic drug, is known to exhibit a high migration to the target liver compared to other statin drugs. Is involved. In other words, pravastatin is highly transported through the liver by being transported through OATP-C highly expressed in the liver.

In addition to liver, OATP-8 is highly expressed in various gastrointestinal solid cancers such as gastric cancer, colorectal cancer, pancreatic cancer, and so development of anticancer drugs using OATP-8 is expected ( Non-patent document 5).
For these reasons, research is being actively conducted to elucidate the drug transport mechanism of OATP. Elucidation of drug transport function is very important in investigating pharmacokinetics when developing new drugs. For example, to estimate pharmacokinetics in drug development, it is necessary to obtain information on transporters involved in the transport of individual drugs, and it is necessary to estimate the contribution rate of each transporter to the pharmacokinetics. come. In order to confirm the transport activity of the transporter for such a purpose, it is necessary to discover a specific inhibitor of each transporter (Non-Patent Documents 5, 7, and 8).
Currently, many drugs such as sulfobromophthalein (BSP), estrone-3-sulfate (E ₁ -3S), dehydroepiandrosterone sulfate (DHEAS) are known as drugs that inhibit OATP (non-patented) Reference 9). The selectivity for these OATPs is low, the drugs that can be used for the above purpose are limited, and an agent that selectively inhibits OATP is desired.

JP 2004-339159 A Japanese Patent Laid-Open No. 2004-081196 JP 2005-247716 A Reissue 2004/032966 WO03 / 066574 pamphlet

YAKUGAKU ZASSHI Vo.122 (12), pp. 1037 (2002) Pharmacia Vol. 39, pp.441 (2003) Protein Nucleic Acid Enzyme Vol.46, No.5, pp.583-586 (2001) Pharmacia Vol.39, pp.431 (2003) Protein Nucleic Acid Enzyme Vol.46, No.5, pp.612-620 (2001) Annu. Rev Pharmacol Toxicol Vol.45, pp.689-723 (2005) Fifth Formulation Research Forum Program (Fifth Formulation Research Forum sponsored by the 2003 International Exchange Foundation for the Promotion of Life Science) Pharmacology and treatment, 2003, 31 supplement, S-81 Gastroenterology Vol.120, pp525-533 (2001)

  An object of the present invention is to provide a compound that selectively inhibits OATP. Another object of the present invention is to provide an inhibitor that selectively inhibits OATP, which is useful for transporter research and drug development.

  As a result of studies to solve the above problems, the present inventors have found that specific compounds, particularly amide-type carboxylic acids, sulfonic acids, or salts thereof have excellent OATP selective inhibitory properties. To complete the present invention. Therefore, this invention provides the compound shown by following formula 1, and its salt.

で示される官能基であり、式中R₁はカルボン酸（-COOH）、又はスルホン酸（-SO₃H）を示し； In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);

Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, and R ₃ is hydrogen, or a substituted or unsubstituted carbon atom 1 to 6 alkyl groups, and R ₂ and R ₃ may be bonded to each other to form a ring structure.
However, Z does not include the following functional groups.

In addition, Z in Formula 1 is a functional group represented by —N (R ₂ ) (R ₃ ). In the formula, R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, preferably 3 to 6 carbon atoms. Preferred examples include n-propyl group, isopropyl group, and tert-butyl group. In addition, R ₂ is a substituted or unsubstituted cyclic alkyl group having 3 to 10 carbon atoms, preferably 5 to 10 carbon atoms. Preferred examples include a cyclopentyl group, a cyclohexyl group, and cycloheptyl. Groups, and adamantyl groups. Further, the R ₂ is a substituted or unsubstituted aromatic ring having 6 to 12 ring members, preferably 6 to 10 ring members. Preferred examples include a phenyl group, a chlorophenyl group, and a trifluorophenyl group. There is. R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, preferably hydrogen. R ₂ and R ₃ may be bonded to each other to form a ring structure.
Moreover, this invention provides the OATP selective inhibitor which uses the compound or its salt shown by the following formula 1 as an active ingredient.

で示される官能基であり、式中R₁はカルボン酸（-COOH）、又はスルホン酸（-SO₃H）を示し； In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);

Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure.
The present invention also provides a reagent for functional analysis of OATP in transport of chemical substances, which contains a compound represented by the following formula 1 or a salt thereof as an active ingredient.

で示される官能基であり、式中R₁はカルボン酸（-COOH）、又はスルホン酸（-SO₃H）を示し； In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);

Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure.
The present invention also provides a reagent for calculating the contribution ratio of OATP in the transport of chemical substances, which comprises a compound represented by the following formula 1 or a salt thereof as an active ingredient.

で示される官能基であり、式中R₁はカルボン酸（-COOH）、又はスルホン酸（-SO₃H）を示し； In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);

Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure.
The present invention also provides a chemical liver transition inhibitor comprising a compound represented by the following formula 1 or a salt thereof as an active ingredient.

で示される官能基であり、式中R₁はカルボン酸（-COOH）、又はスルホン酸（-SO₃H）を示し； In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);

Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure.
Furthermore, this invention provides the chemical | medical agent which reduces the toxic expression in the liver of the chemical substance which has a liver toxicity containing the compound shown by following formula 1, or its salt as an active ingredient.

で示される官能基であり、式中R₁はカルボン酸（-COOH）、又はスルホン酸（-SO₃H）を示し； In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);

Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure.

(Definition)
In the present specification, the “alkyl group” refers to a linear, branched or cyclic saturated hydrocarbon group. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, pentyl group, neopentyl group, hexyl group, and cyclohexyl group.

In the present specification, the “cyclic alkyl group” means a cyclic hydrocarbon group, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, an adamantyl group, and the like. .
In the present specification, the “aromatic ring” means an aromatic ring composed of a hydrocarbon. For example, a monocyclic ring includes a benzene ring, and a polycyclic ring includes a naphthalene ring and an anthracene ring.
In the present specification, the “heteroaromatic ring” means an aromatic ring containing one or more heteroatoms of nitrogen atom, oxygen atom, or sulfur atom in the ring. For example, in a single ring, pyrrole ring, furan ring, thiophene ring, pyridine ring, pyrimidine ring, pyridazine ring, pyrazine ring, imidazole ring, pyrazole ring, oxazole ring, thiazole ring, thiadiazole ring, oxadiazole ring, There are triazole rings. Examples of the polycyclic ring include a quinoline ring, isoquinoline ring, benzimidazole ring, indazole ring, benzthiazole ring, benzoxazole ring, indole ring, benzfuran ring, and benzthiophene ring.

  In the present specification, the “substituted” group included in the expression of each substituent is an alkyl group, a hydroxyl group, a thiol group, a formyl group, a carboxyl group, a sulfonyl group, an amino group, an amide group. , Carbamoyl group, cyano group, alkoxy group, phenoxy group, benzyloxy group, alkoxycarbonyl group, alkylamino group, acylamino group, alkoxycarbonylamino group, alkylthio group, aminosulfonyl group, dialkylaminosulfonyl group, methanesulfonyl group, p -Toluenesulfonyl group, phenyl group, morpholino group, halogen atom, haloalkyl group and the like, which represents one or more cases. Here, the alkoxy group means an alkyl group bonded through an oxygen atom, and the acylamino group means an alkyl group or a phenyl group bonded to an amino group through a carbonyl group. means.

  According to the present invention, there are provided a compound having OATP selective inhibitory activity, a novel carboxylic acid, sulfonic acid, and a salt thereof, and a selective inhibitor of OATP containing the compound. This novel OATP inhibitor can be used for OATP function analysis based on the OATP inhibitory action, and also inhibits liver metabolism and bile excretion by inhibiting the concomitant drug's liver translocation. It can be increased to promote the transition to the target organ, and furthermore, the occurrence of toxicity in the liver can be reduced.

(New compound)
Specific and preferred examples of the novel compound represented by Formula 1 of the present invention are as follows. For reference, the structural formulas of these compounds are shown in FIG.
2 '-(4-Phenylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 1);
2 '-[4- (4-tert-butyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (compound 2);
2 '-[4- (4-Dimethylamino-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 3);
2 '-[4- (morpholin-4-yl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (compound 4);
2 '-[4- (3-Benzyloxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 5);

2 '-[4- (3-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (compound 6);
2 '-[4- (4-Methoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 7);
2 '-[4- (4-Phenoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 8);
2 '-[4- (4-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (compound 9);
2 '-[4- (2-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (compound 10);

2 '-(4-Cyclohexylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 11);
2 '-(4-Isopropylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 12);
2 '-(4-propylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 13);
2 '-(4-Hexylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 14);
2 '-[4- (Piperidin-1-carbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid
(Compound 15);
2 '-(4-Methylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 16);

2 '-[4- (adamantan-1-ylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 17);
2 '-[4- (4-Chloro-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid
(Compound 18);
2 '-(4-p-Tolylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 19);
2 '-(4- (3-Chloro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 20);
2 '-(4-Cycloheptylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 21);
2 '-(4- (4-Fluoro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 22);

2 '-(4- (3,5-dichloro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 23);
2 '-(4- (4-trifluoromethyl-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 24);
2 '-(4-Cyclopentylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid
(Compound 25);
N- (4-Phenylcarbamoyl-phenyl) -phthalamic acid
(Compound 26);
2- (4-Phenylcarbamoyl-phenylcarbamoyl) -benzenesulfonic acid
(Compound 27).

  The compounds of the present invention can be used in the form of salts. The salt is not particularly limited, and can be an organic salt or an inorganic salt depending on the application. For example, an addition salt of an organic acid or an inorganic acid. Examples of the inorganic acid addition salt include hydrofluoride, hydrochloride, hydrobromide, nitrate, sulfate, hydrogen sulfate, phosphate, primary hydrogen phosphate, and secondary hydrogen phosphate. And acetate. In addition, salt formation can also be performed using a basic compound such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate and the like.

  Organic acid addition salts are derived from fatty acid monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkanedioic acids, amino acids, or nontoxic organic acids such as aromatic acids, fatty acids, aromatic sulfonic acids, etc. Salts such as methanesulfonate, sulfamate, tartrate, fumarate, glycolate, citrate, maleate, malate, succinate, acetate, benzoate, ascorbine Acid salt, p-toluenesulfonate, benzenesulfonate, naphthalenesulfonate, propionate, lactate, pyruvate, oxalate, stearate, cinnamate, aspartate, salicylate And gluconate.

Organic base adducts include salts derived from organic bases such as ammonia, alkylamines, aromatic amines, such as ammonium salts, dimethylamine salts, triethylamine salts, tetrabutylammonium salts, cyclohexylamine salts, piperidine salts, guanidino salts. And aniline salts.
Such salts usually have good dispersibility, absorbability and the like, and have advantageous properties as a reagent or formulation. Such salts are well known in the technical field of the present invention and can be easily prepared by contact with an appropriate acid or base compound.

(Production of new compounds)
The method for producing the compound of the present invention will be comprehensively described with reference to FIG. In addition, manufacture of the compound of this invention is not limited to the method of FIG.
(Production Example 1)
Production Example 1 is a method for producing a carboxylic acid represented by Formula 6-1 in FIG. Hereinafter, description will be given with reference to FIG.
(Process 1-1a)
4-tert-Butoxycarbonylamino-benzoic acid (1) is dissolved in an organic solvent (eg, dimethylformamide (hereinafter DMF), chloroform, etc.) and a condensing agent (eg, N-ethyl-N- (3-dimethylamino) is dissolved. Propyl) carbodiimide (hereinafter referred to as WSCI) hydrochloride), an auxiliary agent (for example, 1-hydroxybenzotriazole (hereinafter referred to as HOBt)) and the like, and after reacting at room temperature for 30 to 60 minutes, And the desired compound (3) is obtained by stirring at room temperature for 1.5 to 72 hours.

(Process 1-1b)
4-tert-butoxycarbonylamino-benzoic acid (1) and the compound represented by (2) are dissolved in an organic solvent (for example, chloroform), a reagent (for example, dichlorotriphenylphosphorane) is added, and the mixture is heated to reflux. The desired compound (3) can be obtained by reacting for 4 hours.

(Process 1-2)
The compound (3) obtained in the step 1-1a or 1-1b is dissolved in an organic solvent (for example, methanol, etc.), for example, a strong acid such as hydrochloric acid is added, and the mixture is stirred at room temperature for 2 to 24 hours. By doing so, the target compound (4) can be obtained.
(Process 1-3)
The compound (4) obtained in step 1-2 is dissolved in an organic solvent (for example, DMF), diphenic anhydride (5-1) is added, and a base (for example, pyridine) is added at room temperature. The target compound (6-1) can be obtained by stirring for ˜60 hours.

(Production Example 2)
Production Example 2 is a method for producing a carboxylic acid represented by Formula 6-2 in FIG. Hereinafter, description will be given with reference to FIG.
(Process 2-1)
The compound (4) obtained in step 1-2 is dissolved in an organic solvent (for example, DMF), phthalic anhydride (5-2) is added, a base (for example, pyridine) is added, and 16 to The target compound (6-2) can be obtained by stirring for 60 hours.

(Production Example 3)
Production Example 3 is a method for producing a sulfonic acid represented by Formula 6-3 in FIG. Hereinafter, description will be given with reference to FIG.
(Process 3-1)
The compound (4) obtained in step 1-3 is dissolved in an organic solvent (such as DMF), 2-sulfobenzoic anhydride (5-3) is added, and a base (such as pyridine) is added to room temperature. The desired compound (6-3) can be obtained by stirring for 16 to 60 hours.

(Use of new compounds, etc.)
The compounds of the present invention and salts thereof can be used as selective inhibitors of organic anion transporters (OATP). The OATP selective inhibitor of the present invention, a reagent for analyzing the function of OATP in the transport of chemical substances, a reagent for calculating the contribution rate of OATP in the transport of chemical substances, a drug that reduces the toxic expression in the liver of chemical substances, In addition, in the liver transport inhibitors of chemical substances, not only the compounds of the present invention but also the range of similar compounds described in the explanation of each drug can be used.

In the present invention, the organic anion transporter (OATP) refers to a transporter polypeptide (protein) that recognizes an anionic chemical substance and selectively transports it. Therefore, the OATP selective inhibitor of the present invention includes biological anionic chemical substances such as amino acids and nucleic acids, various endogenous chemical substances such as bile acids, prostaglandin E ₂ , thromboxane B ₂ , leukotriene C ₄ , and thyroid hormone. It selectively inhibits transporters involved in the transport of exogenous chemical substances that are anionic drugs, and conjugates of hydrophobic drugs (acid conjugates such as glutathione, glucuronic acid, and sulfuric acid).

  Further, the OATP selective inhibitor of the present invention can be used for calculation of the contribution ratio of OATP to pharmacokinetics based on the inhibitory action of OATP, estimation of drug interaction, and the like. In the drug uptake test, when the compound of the present invention is used in combination with another drug, the transport of the drug by OATP is inhibited. Therefore, when the uptake amount is reduced as compared with the case where the compound of the present invention is not used in combination, it can be estimated that OATP is involved in the uptake of the drug. In addition, it is possible to calculate the contribution ratio of OATP in relation to transportation from the amount of reduction at that time. Furthermore, changes in the efficacy of the concomitant drug can be estimated from this change in the amount taken up.

In addition, the liver migration inhibitor of the chemical substance of the present invention inhibits the activity of OATP highly expressed in the liver, such as OATP-C and OATP-8, thereby inhibiting the liver migration of anionic drugs. .
When a compound of the present invention is used in combination with a compound that cannot be maintained in effective blood concentration by being transported to the liver by OATP and metabolized by the liver, the transition to the liver is suppressed by the OATP inhibitory action, and metabolism is suppressed. As a result, the effective blood concentration is maintained. Similarly, for drugs that are transported to the liver by OATP and have been found to exhibit toxicity in the liver, combined use with the compound of the present invention suppresses the transition to the liver and reduces the toxicity to the liver. Will be.

In the case where the chemical substance migration inhibitor of the present invention and the drug that lowers the toxicity of the chemical substance in the liver are used as pharmaceuticals, the dosage and formulation method are as follows.
The agent of the present invention can be administered orally or parenterally. For oral administration, hard capsule, soft capsule, tablet, granule, granule, powder, fine granule, pill, troche tablet, active ingredient continuous release agent, elixir, emulsion, syrup, liquid, It can be dispensed in the form of a suspension or the like. For parenteral administration, administration by infusion, intravenous injection, subcutaneous injection, intramuscular injection, transdermal administration by ointment and transdermal agent, fat suppository, water-soluble suppository, rectal administration by suppository, external use There are forms such as pills, eye drops and nasal drops. Further, the preparation can be easily performed by a conventional method using a normal carrier in the pharmaceutical field.

  When formulating the drug of the present invention into an oral dosage form, it is used as a formulation component such as a widely used carrier, such as a filler, a bulking agent, a binder, a disintegrant, a disintegration inhibitor, a buffer, an isotonic agent, Emulsifiers, dispersants, stabilizers, coating agents, surfactants, absorption accelerators, humectants, wetting agents, adsorbents, lubricants, excipients, and the like can be used. Moreover, you may use additives, such as a coloring agent, a preservative, a fragrance | flavor, a flavor agent, and a sweetener, as needed.

  Specific examples include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, simple syrup, glucose solution, starch solution, Gelatin solution, binders such as carboxymethylcellulose, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearin Disintegrants such as acid monoglycerides, starch, lactose, disintegration inhibitors such as sucrose, stearic acid, cocoa butter, hydrogenated oil, quaternary ammonium salts, absorption enhancers such as sodium lauryl sulfate, glycerin, starch What humectant, starch, lactose, kaolin, bentonite, colloidal adsorbent such as silicic acid, purified talc, and the like lubricants such as stearic acid salts. In addition, for each of the above dosage forms, it is possible to use known drug delivery system techniques for sustained release, topical application (troche, buccal, sublingual tablet, etc.), drug release control, enteric, gastric, etc. Can be applied.

  The content of the compound or a salt thereof in a drug containing the compound of the present invention varies depending on the dosage form, but is usually 0.1 to 100% by weight, preferably 0.3 to 30% in the total composition. It is about wt%. The dose of the compound is appropriately determined depending on the sex, age, weight, disease difference, symptom level, therapeutic effect, administration method, etc. of the subject patient. .1 to 5000 mg, preferably 1 to 3000 mg, in the case of parenteral administration, it is administered within a range of 0.1 to 5000 mg, preferably 0.3 to 3000 mg per day for adults, once a day or divided into several times . Of course, since the dose varies depending on various conditions, an amount smaller than the above dose may be sufficient or may be necessary beyond the range.

  Based on the following examples, a method for producing a compound that inhibits OATP of the present invention will be specifically described. The 4-tert-butoxycarbonylamino-benzoic acid used in this example is manufactured by Watanabe Chemical Industry (Hiroshima), and other reagents are commercially available products (for example, Tokyo Kasei Corporation (Tokyo), Kanto Chemical Co. (Tokyo), etc.). In addition, unless otherwise indicated, the "process" in the following Example means the process of the manufacture example described in the best form for implementing invention.

Example 1 Synthesis of 2 ′-(4-phenylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 1) (Example 1-1): (4-phenylcarbamoyl-phenyl) -carbamic acid tert -Butyl ester synthesis
Using 200 mg of 4-tert-butoxycarbonylamino-benzoic acid and 71.1 mg of aniline as the compound (2), according to Step 1-1a, 64.0 mg of the title compound was obtained as a milky white solid.
MS (FAB, Pos): m / z = 313 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.50 (9H, s), 7.06-7.10 (1H, m), 7.32-7.36 (2H, m), 7.59 (2H, d, J = 8.7Hz) , 7.75 (2H, dd, J = 1.1, 8.6Hz), 7.88-7.91 (2H, m), 9.70 (1H, s), 10.08 (1H, s).

Example 1-2: Synthesis of 2 ′-(4-phenylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid Step 1-2 and Step using 73.8 mg of the compound obtained in Example 1-1 According to 1-3, 49.3 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 437 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 7.08 (1H, tt, J = 1.1,7.5Hz), 7.22-7.25 (2H, m), 7.31-7.35 (2H, m), 7.41 (1H, dt, J = 1.4,9.0Hz), 7.48-7.55 (3H, m), 7.63 (2H, d ,, J = 8.8Hz), 7.64 (1H, dd, J = 1.7,7.1Hz), 7.74 (2H, dd, J = 1.1,8.6Hz), 7.81 (1H, dd, J = 1.1,7.8Hz), 7.84-7.86 (2H, m), 19.09 (1H, s), 10.37 (1H, br).

Example 2 Synthesis of 2 ′-[4- (4-tert-butyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 2) (Example 2-1): [4- Synthesis of (4-tert-butyl-phenylcarbamoyl) -phenyl] -carbamic acid tert-butyl ester
Using 50.2 mg of 4-tert-butoxycarbonylamino-benzoic acid and 28.5 mg of 4-tert-butylphenylamine as compound (2), 73.7 mg of the title compound was obtained as a white solid according to Step 1-1a.
MS (FAB, Pos): m / z = 369 [M + H] ^+
1 H NMR (500 MHz, CDCl ₃ ): δ = 1.32 (9H, s), 1.54 (9H, s), 6.68 (1H, s), 7.39 (2H, d, J = 8.5Hz), 7.48 (2H, s, J = 8.8Hz), 7.55 (2H, d, J = 8.8Hz), 7.82 (2H, d, J = 8.8Hz).

Example 2-2: Synthesis of 2 ′-[4- (4-tert-butyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid 73.7 mg of the compound obtained in Example 2-1 Used, according to steps 1-2 and 1-3, 38.8 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 493 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.27 (9H, s), 7.22 (2H, t, J = 7.8Hz), 7.35 (2H, d, J = 8.8Hz), 7.40 (1H, t , J = 7.7Hz), 7.48-7.54 (3H, m), 7.58 (2H, d, J = 8.5Hz), 7.64 (3H, m), 7.80 (1H, d, J = 7.6Hz), 7.85 (2H , d, J = 8.8Hz), 10.02 (1H, s), 12.80 (1H, br).

Example 3 Synthesis of 2 ′-[4- (4-Dimethylamino-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 3) (Example 3-1): [4- ( Synthesis of 4-dimethylamino-phenylcarbamoyl) -phenyl] -carbamic acid tert-butyl ester
Using 54.3 mg of 4-tert-butoxycarbonylamino-benzoic acid and 25.9 mg of N, N-dimethyl-benzene-1,4-diamine as compound (2), following step 1-1a, 29.4 mg of the title compound Was obtained as a white solid.
MS (EI, Pos): m / z = 355 [M] ^+
1 H NMR (500 MHz, CDCl ₃ ): δ = 1.54 (9H, s), 2.94 (6H, s), 6.66 (1H, s), 6.75 (2H, d, J = 9.0), 7.47 (4H, d , J = 8.3Hz), 7.61 (1H, s), 7.82 (2H, d, J = 8.5Hz).

Example 3-2: Synthesis of 2 ′-[4- (4-dimethylamino-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid 27.4 mg of the compound obtained in Example 3-1 was used. According to steps 1-2 and 1-3, 13.1 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 480 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 2.85 (6H, s), 6.70 (1H, dd, J = 2.0,7.1Hz), 6.92 (2H, dd, J = 1.2,7.2Hz), 7.06 (1H, dd, J = 3.1,5.9Hz), 7.19-7.29 (2H, m), 7.30-7.37 (4H, m), 7.41-7.45 (3H, m), 7.51 (2H, dd, J = 5.5, 8.8Hz), 7.75 (1H, d, J = 8.8Hz), 9.79 (1H, s).

Example 4 Synthesis of 2 ′-[4- (morpholin-4-yl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 4) (Example 4-1): [4- Synthesis of (4-morpholin-4-yl-phenylcarbamoyl) -phenyl] -carbamic acid tert-butyl ester
Using 49.5 mg of 4-tert-butoxycarbonylamino-benzoic acid, 33.9 mg of 4-morpholin-4-yl-phenylamine as compound (2), and 18.3 mg of the title compound as a brown solid according to Step 1-1a Obtained.
MS (FAB, Pos): m / z = 397 [M] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.49 (9H, s), 3.06 (4H, t, J = 4.9Hz), 3.74 (4H, t, J = 4.8Hz), 6.93 (2H, dd , J = 2.3,7.1Hz), 7.56 (2H, d, J = 8.8Hz), 7.60 (2H, d, J = 9.3Hz), 7.87 (2H, dd, J = 2.0,7.1Hz), 9.68 (1H , s), 9.90 (1H, s).

Example 4-2: Synthesis of 2 ′-[4- (morpholin-4-yl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid 18.3 mg of the compound obtained in Example 4-1 Used, according to Steps 1-2 and 1-3, 8.1 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 521 [M] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 2.91 (2H, br), 3.06 (2H, t, J = 4.8Hz), 3.73 (2H, t, J = 4.8Hz), 6.91 (2H, d , J = 9.3Hz), 7.07-7.08 (1H, m), 7.23-7.26 (2H, m), 7.42-7.46 (2H, m), 7.52 (1H, d, J = 8.8Hz), 7.57-7.60 ( 3H, m), 7.76 (1H, d, J = 8.8Hz), 9.87 (1H, s).

Example 5 Synthesis of 2 ′-[4- (3-Benzyloxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 5) (Example 5-1): [4- ( Synthesis of 3-benzyloxy-phenylcarbamoyl) -phenyl] -carbamic acid tert-butyl ester
Using 49.8 mg of 4-tert-butoxycarbonylamino-benzoic acid and 37.9 mg of 3-benzyloxy-phenylamine as compound (2), following the procedure 1-1a, 30.0 mg of the title compound was obtained as a white solid. .
MS (FAB, Pos): m / z = 419 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.50 (9H, s), 5.09 (2H, s), 6.73 (1H, ddd, J = 0.8,2.4,8.3Hz), 7.24 (1H, t, J = 8.2Hz), 7.35 (2H, ddd, J = 0.9,2.9,7.3Hz), 7.40 (2H, dt, J = 1.2,7.1Hz), 7.46 (2H, dd, J = 1.1,7.6Hz), 7.56-7.59 (3H, m), 7.88 (2H, dd, J = 2.1,7.1Hz), 9.70 (1H, s), 10.05 (1H, s).

Example 5-2: Synthesis of 2 ′-[4- (3-benzyloxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid 34.2 mg of the compound obtained in Example 5-1 was used. According to Step 1-2 and Step 1-3, 8.6 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 543 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 5.08 (2H, s), 6.73 (4H, ddd, J = 0.8,2.6,8.1Hz), 6.89 (1H, br), 7.06 (1H, br) , 7.20-7.24 (3H, m), 7.31-7.35 (2H, m), 7.38-7.41 (2H, m), 7.43-7.47 (4H, m), 7.53 (4H, m), 7.58 (1H, t, J = 4.4Hz), 7.76 (2H, d, J = 8.5Hz), 10.02 (1H, s).

Example 6 Synthesis of 2 ′-[4- (3-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 6) (Example 6-1): 3- (4 of -tert-Butoxycarbonylamino-benzoylamino) -benzoic acid methyl ester
Using 75.0 mg of 4-tert-butoxycarbonylamino-benzoic acid and 68.2 mg of 3-aminobenzoic acid methyl ester as compound (2), the title compound 57.0 mg was obtained as a white solid according to Step 1-1a. .
MS (FAB, Pos): m / z = 371 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.50 (9H, s), 3.87 (3H, s), 7.48-7.51 (2H, m), 7.59 (2H, d, J = 8.8Hz), 7.68 (1H, dt, J = 1.3,7.8Hz), 7.92 (2H, dd, J = 2.0,6.8Hz), 7.08 (1H, ddd, J = 1.0,2.2,8.1Hz), 8.45 (1H, t, J = 2.0Hz), 9.72 (1H, s), 10.30 (1H, s).

Example 6-2: Synthesis of 2 ′-[4- (3-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid Using 82.3 mg of the compound obtained in Example 6-1 In accordance with Step 1-2 and Step 1-3, 84.6 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 495 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 3.87 (3H, s), 7.18-7.23 (2H, m), 7.37-7.42 (2H, m), 7.46-7.54 (4H, m), 7.60 ( 2H, d, J = 8.8Hz), 7.65-7.69 (2H, m), 7.78 (1H, d, J = 7.6Hz), 7.88 (2H, d, J = 8.8Hz), 8.05 (1H, ddd, J = 1.0,2.2,8.3Hz), 8.44 (1H, t, J = 1.8Hz), 10.31 (1H, s), 10.67 (1H, br).

Example 7: Synthesis of 2 '-[4- (4-methoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 7) (Example 7-1): [4- (4 -Methoxy-phenylcarbamoyl) -phenyl] -carbamic acid tert-butyl ester synthesis
Using 75.0 mg of 4-tert-butoxycarbonylamino-benzoic acid, 57.9 mg of p-anisidine as compound (2), and according to Step 1-1a, 69.0 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 343 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.49 (9H, s), 3.74 (3H, s), 6.91 (2H, dd, J = 2.3,6.8Hz), 7.57 (2H, d, J = 8.5Hz), 7.65 (2H, dd, J = 2.2,6.8Hz), 7.88 (2H, dd, J = 2.0,6.8Hz), 9.68 (1H, s), 9.96 (1H, s).

Example 7-2: Synthesis of 2 ′-[4- (4-methoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid Using 65.4 mg of the compound obtained in Example 7-1, According to steps 1-2 and 1-3, 46.7 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 495 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 3.73 (3H, s), 6.90 (2H, dd, J = 2.3,71.Hz), 7.01-7.02 (1H, m), 7.11-7.13 (1H , m), 7.28-7.30 (2H, m), 7.45-7.47 (2H, m), 7.54 (2H, d, J = 8.8Hz), 7.60-7.64 (4H, m), 7.79 (2H, d, J =, 8.8Hz), 9.96 (1H, s).

Example 8: Synthesis of 2 ′-[4- (4-phenoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 8) (Example 8-1): [4- (4 Of -Phenoxy-phenylcarbamoyl) -phenyl] -carbamic acid tert-butyl ester
Using 75.0 mg of 4-tert-butoxycarbonylamino-benzoic acid and 83.3 mg of 4-aminodiphenyl ether as compound (2), and following step 1-1a, 47.4 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 405 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.50 (9H, s), 6.97-7.04 (4H, m), 7.11 (1H, tt, J = 1.0,6.9Hz), 7.36-7.40 (2H, m), 7.59 (2H, d, J = 8.8Hz), 7.77 (2H, dt, J = 2.8,7.2HZ), 7.88 (2H, dt, J = 2.2,9.3Hz), 9.70 (1H, s), 10.12 (1H, s).

Example 8-2: Synthesis of 2 ′-[4- (4-phenoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid Using 43.8 mg of the compound obtained in Example 8-1, According to steps 1-2 and 1-3, 36.7 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 529 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 6.99 (2H, dt, J = 1.0,7.9Hz), 7.01 (2H, d, J = 9.0Hz), 7.04-7.04 (1H, m), 7.10 (1H, tt, J = 1.1,7.6Hz), 7.14-7.15 (1H, m), 7.30-7.34 (2H, m), 7.36-7.39 (2H, m), 7.46-7.48 (2H, m), 7.56 (2H, d, J = 8.5Hz), 7.62-7.66 (2H, m), 7.76 (2H, d, J = 9.0Hz), 7.82 (2H, d, J = 8.5Hz), 10.14 (1H, s) .

Example 9: Synthesis of 2 '-[4- (4-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 9) (Example 9-1): 4- (4 of -tert-Butoxycarbonylamino-benzoylamino) -benzoic acid methyl ester
Using 124.5 mg of 4-tert-butoxycarbonylamino-benzoic acid and 76.6 mg of 4-aminobenzoic acid methyl ester as compound (2), the title compound 81.2 mg was obtained as a white solid according to Step 1-1b. .
MS (FAB, Pos): m / z = 371 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.50 (9H, s). 3.35 (3H, s), 7.60 (2H, d, J = 9.0), 7.90-7.97 (6H, m), 9.74 ( 1H, s), 10.40 (1H, s).

Example 9-2: Synthesis of 2 ′-[4- (4-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid Using 77.7 mg of the compound obtained in Example 9-1 According to steps 1-2 and 1-3, 18.2 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 495 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 3.36 (3H, s), 7.12 (1H, d, J = 7.3Hz), 7.23 (2Ht, J = 7.1Hz), 7.41 (2H, q, J = 7.2Hz), 7.48-7.55 (3H, m), 7.61 (2H, d, J = 8.8Hz), 7.67 (1H, dd, = 1.1,7.3Hz), 7.81 (2H, d, J = 7.8Hz) , 7.87 (2H, d, J = 8.8Hz), 7.93-7.96 (3H, m), 10.41 (1H, s).

Example 10 Synthesis of 2 ′-[4- (2-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 10) (Example 10-1): 2- (4 of -tert-Butoxycarbonylamino-benzoylamino) -benzoic acid methyl ester
According to Step 1-1b, using 124.5 mg of 4-tert-butoxycarbonylamino-benzoic acid and 76.2 mg of anthranilic acid methyl ester as compound (2), 99.2 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 371 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.50 (9H, s), 3.90 (3H, s), 7.23 (1H, t, J = 7.1Hz), 7.65 (2H, d, J = 8.5Hz ), 7.68-7.70 (1H, m), 7.88 (2H, dJ = 8.8Hz), 8.02 (1H, dd, J = 1.6,8.1Hz), 8.58 (1H, dd, J = 1.0,8.5Hz), 9.79 (1H, s), 11.54 (1H, s).

Example 10-2: Synthesis of 2 ′-[4- (2-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid Using 92.5 mg of the compound obtained in Example 10-1 According to steps 1-2 and 1-3, 34.1 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 495 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 3.89 (3H, s), 7.15 (1H, d, J = 7.6Hz), 7.19-7.24 (2H, m), 7.35-7.38 (1H, m) , 7.41-7.44 (1H, m), 7.47-7.53 (2H, m), 7.63-7.69 (4H, m), 7.75 (1H, d, J = 7.8Hz), 7.81-7.84 (2H, m), 8.01 (1H, dd, J = 1.5,7.9Hz), 8.55 (1H, dd, J = 0.7,8.4Hz), 11.50 (1H, s).

Example 11: Synthesis of 2 '-(4-cyclohexylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 11)
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and 45.0 mg of cyclohexylamine as the compound (2), according to steps 1-1a, 1-2 and 1-3, 126.5 mg of the title compound Obtained as a white solid.
MS (FAB, Pos): m / z = 443 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.13 (1H, d, J = 12.5Hz), 1.23-1.32 (4H, m), 1.60 (1H, d, J = 12.7Hz), 1.71 (2H , s), 1.78 (2H, s), 3.71 (1H, s), 7.21-7.23 (2H, m), 7.40 (1H, t, J = 7.6Hz), 7.47-7.54 (4H, m), 7.65 ( 1H, dd, J = 1.6,7,6Hz), 7.72 (2H, d, J = 8.8Hz), 7.81 (1H, d, J = 7.8Hz), 8.03 (1H, d, J = 8.1Hz), 12.82 (1H, s).

Example 12 Synthesis of 2 ′-(4-Isopropylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 12)
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and about 50 mg of isopropylamine as compound (2), according to Step 1-1a, Step 1-2 and Step 1-3, Obtained as a white solid.
MS (FAB, Pos): m / z = 403 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.14 (6H, d, J = 6.6Hz), 4.02-4.08 (1H, m), 7.21-7.24 (2H, m), 7.40 (1H, dt, J = 1.3,7.6Hz), 7.47-7.54 (5H, m), 7.65 (1H, dd, J = 1.4,7.6Hz), 7.72 (2H, dd, J = 1.8,6.9Hz), 7.82 (1H, dd , J = 1.2,6.6Hz), 8.06 (1H, d, J = 7.8Hz), 10.18 (1H, s), 12.8 (1H, br).

Example 13: Synthesis of 2 '-(4-propylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 13)
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and 0.05 ml of propylamine as the compound (2), according to Step 1-1a, Step 1-2 and Step 1-3, 20.0 mg of the title compound was obtained. Obtained as a white solid.
MS (FAB, Pos): m / z = 403 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): 0.87 (3H, t, J = 7.3Hz), 1.50 (2H, q, J = 7.3Hz), 3.16-3.20 (2h, m), 7.20-7.23 (2H , m), 7.39-7.43 (2H, m), 7.46-7.54 (5H, m), 7.64-7.65 (1H, m), 7.71 (H, s), 7.73 (1H, s), 7.80 (2H, d , J = 7.6Hz), 8.31 (1H, t, J = 5.6Hz).

Example 14: Synthesis of 2 '-(4-hexylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 14)
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and 0.04 ml of hexylamine as compound (2), according to Step 1-1a, Step 1-2 and Step 1-3, 39.6 mg of the title compound is obtained. Obtained as a white solid.
MS (FAB, Pos): m / z = 445 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 0.86 (3H, t, J = 6.8Hz), 1.24-1.30 (6H, m), 1.48 (2H, m), 3.29 (2H, q, J = 6.6Hz), 7.21-7.23 (2H, m), 7.40 (1H, dt, J = 1.2,7.6Hz), 7.47-7.54 (5H, m), 7.63-7.65 (1H, m), 7.71-7.72 (2H , dd, J = 2.0,6.9Hz), 7.81 (1H, dd, J = 1.2,7.6Hz), 7.29 (1H, t, J = 5.7Hz), 10.25 (1H, br).

Example 15: Synthesis of 2 '-[4- (piperidine-1-carbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 15)
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and 0.06 ml of piperidine as compound (2) according to steps 1-1a, 1-2 and 1-3, 34.3 mg of the title compound is white. Obtained as a solid.
MS (FAB, Pos): m / z = 429 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.47 (4H, br), 1.59 (2H, d, J = 4.6Hz), 3.35-3.38 (4H, m), 7.21-7.26 (4H, m) , 7.41 (1H, dt, J = 1.2,7.6Hz), 7.47-7.53 (5H, m), 7.64 (1H, dd, J = 1.6,7.6Hz), 7.82 (1H, d, J = 7.8Hz), 10.22 (1H, br).

Example 16: Synthesis of 2 '-(4-methylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid [Compound 16]
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and 0.1 ml of methylamine as compound (2), following the steps 1-1a, 1-2 and 1-3, 14.4 mg of the title compound Obtained as a white solid.
MS (FAB, Pos): m / z = 375 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 3.80 (3H, s), 7.13 (1H, d, J = 7.1Hz), 7.19 (1H, d, J = 7.1Hz), 7.35 (1H, q , J = 7.3Hz), 7.42 (1H, d, J = 2.7Hz), 7.48-7.53 (2H, m), 7.59-7.64 (3H, m), 7.74 (1H, d, J = 8.1Hz), 7.83 (2H, dd, J = 1.8,6.8Hz).

Example 17: Synthesis of 2 '-[4- (adamantan-1-ylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 17) (Example 17-1): [4- (adamantane) Synthesis of -1-ylcarbamoyl) -phenyl] -carboxylic acid tert-butyl ester
Using 118.6 mg of 4-tert-butoxycarbonylamino-benzoic acid and 83.2 mg of 1-adamantylamine as compound (2) and according to Step 1-1a, 130.0 mg of the title compound was obtained as a white solid.
MS (EI, Pos): m / z = 371 [M] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.48 (9H, s), 1.65 (6H, s), 2.05 (9H, s), 7.40 (1H, s), 7,47 (2H, d, J = 8.8Hz), 7.69 (2H, d, J = 8.8Hz), 9.57 (1H, s).

Example 17-2: Synthesis of 2 ′-[4- (adamantan-1-ylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid Using 126.5 mg of the compound obtained in Example 17-1, According to steps 1-2 and 1-3, 65.9 mg of the title compound was obtained as a white solid.
MS (FAB, Pos): m / z = 495 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ = 1.64 (6H, s), 2.04 (9H, s), 7.22 (2H, dt, J = 1.6,6.9Hz), 7.41 (2H, dt, J = 1.1,6.4Hz), 7.46-7.53 (5H, m), 7.65 (3H, dt, J = 1.8,7.3Hz), 7.80 (1H, d, J = 7.8Hz).

Example 18: Synthesis of 2 '-[4- (4-chloro-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid (Compound 18)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 51.0 mg of 4-chloroaniline as compound (2) according to steps 1-1a, 1-2 and 1-3, the title compound 101.3 mg Was obtained as a white solid.
MS (FAB, Pos): m / z = 470 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ (ppm) = 7.23-7.25 (2H, m), 7.38-7.43 (3H, m), 7.61 (2H, d, J = 8.8Hz), 7.67 (1H , dd, J = 1.2,7.3Hz), 7.77-7.86 (5H, m), 8.32 (1H, s), 10.22 (1H, s), 10.29 (1H, br).

Example 19: Synthesis of 2 '-(4-p-tolylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 19)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 42.9 mg mg of 4-methylaniline as compound (2) according to steps 1-1a, 1-2 and 1-3, the title compound 176.1 mg was obtained as a white solid
MS (FAB, Pos): m / z = 451 [M + H] ^+
1 H NMR (500 MHz, CD3OD): δ (ppm) = 2.31 (3H.s), 7.15 (2H, dd, J = 0.5,8.8Hz), 7.20-7.25 (2H, m), 7.40-7.54 (7H , m), 7.68-7.70 (1H, m), 7.80 (2H, dd, J = 2.0,6.8Hz), 7.86 (1H, ddd, J = 0.5,1.5,7.8Hz), 7.91 (1H, d, J = 2.0Hz).

Example 20 Synthesis of 2 ′-(4- (3-Chloro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 20)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 0.045 ml of 3-chloroaniline as compound (2) according to steps 1-1a, 1-2 and 1-3, the title compound 53.4 mg Was obtained as a white solid.
MS (FAB, Pos): m / z = 471 [M + H] ^+
1 H NMR (500 MHz, CD3OD): δ (ppm) = 7.12 (1H, dq, J = 1.0,8.1Hz), 7.21-7.24 (2H, m), 7.31 (1H, t, J = 8.1Hz), 7.41 (1H, dt, J = 1.2,7.6Hz), 7.46-7.54 (5H, m), 7.56 (1H, dq, J = 1.0,8.3Hz), 7.68-7.70 (1H, m), 7.79-7.87 ( 4H, m).

Example 21: Synthesis of 2 '-(4-cycloheptylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 21)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and using 74.3 mg of cycloheptylamine as compound (2), following steps 1-1a, 1-2 and 1-3, 46.7 mg of the title compound Obtained as a white solid.
MS (FAB, Pos): m / z = 457 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.37-1.66 (10H, m), 1.78-1.83 (2H, m), 3.87-3.94 (1H, m), 7.00 (1H, br) , 7.11 (1H, dd, J = 2.0,8.6Hz), 7.28 (2H, d, J = 3.4Hz), 7.43-7.47 (4H, m), 7.60 (2H.dd, J = 2.7,8.8Hz), 7.66 (2H, d, J = 8.8Hz), 8.04 (1H, d, J = 8.1Hz).

Example 22 Synthesis of 2 ′-(4- (4-Fluoro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 22)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 47.8 mg of 4-fluoroaniline as compound (2) according to steps 1-1a, 1-2 and 1-3, the title compound 99.8 mg Was obtained as a white solid.
MS (FAB, Pos): m / z = 455 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ (ppm) = 7.18 (2H, dtmJ = 2.2,9.0Hz), 7.24 (1H, d, J = 7.1Hz), 7.41 (1H, dt, J = 1.2 , 7.6Hz), 7.48-7.55 (3H, m), 7.60 (2H, d, J = 8.8Hz), 7.67 (1H, d, J = 7.1Hz), 7.75-7.77 (2H, m), 7.82-7.86 (3H, m), 10.15 (1H, s), 10.26 (1H, br).

Example 23: Synthesis of 2 '-(4- (3,5-dichloro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 23)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 69.7 mg of 3,5-dichloroaniline as compound (2) according to steps 1-1a, 1-2 and 1-3, the title compound 62.2 mg was obtained as a white solid.
MS (FAB, Pos): m / z = 505 [M + H] ^+
1 H NMR (500 MHz, DMSO-D6): δ (ppm) = 7.23-7.25 (2H, m), 7.31 (1H, t, J =, 1.8Hz), 7.41 (1H, dt, J = 1.1,7.6 Hz), 7.49-7.55 (3H, m), 7.62 (2H, d, J = 8.5Hz), 7.67 (1H, dd, J = 1.2,7.3Hz), 7.83 (1H, dd, J = 1.0,7.8Hz) ), 7.86 (2H, d, J = 8.8Hz), 7.88 (2H, d, J = 2.0Hz), 10.31 (1H, br), 10.37 (1H, s).

Example 24: Synthesis of 2 '-(4- (4-trifluoromethyl-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 24)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 69.3 mg of 4-trifluoromethylaniline as compound (2), following the steps 1-1a, 1-2 and 1-3, the title compound 26.9 mg was obtained as a white solid.
MS (FAB, Pos): m / z = 505 [M + H] +
1H NMR (500 MHz, DMSO-D6): δ (ppm) = 7.23-7.26 (2H, m), 7.41 (1H, dt, J = 1.2,7.8Hz), 7.47-7.55 (3H, m), 7.62 ( 2H, d, J = 8.5Hz), 7.67 (1H, dd, J = 1.5,6.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.83 (1H, dd, J = 1.0,7.8Hz), 7.89 (2H, d, J = 9.0Hz), 7.99 (2H, d, J = 8.5Hz), 10.31 (1H, s), 10.43 (1H, s).

Example 25: Synthesis of 2 '-(4-cyclopentylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid (Compound 25)
Using 100 mg of 4-tert-butoxycarbonylamino-benzoic acid and 36.6 mg of cyclopentylamine as compound (2) according to steps 1-1a, 1-2 and 1-3, 26.1 mg of the title compound Obtained as a solid.
MS (FAB, Pos): m / z = 429 [M + H] +
1H NMR (500 MHz, DMSO-D6): δ (ppm) = 1.47-1.53 (4H, m), 1.67-1.68 (2H, m), 1.86-1.87 (2H, m), 4.16-4.22 (1H, m ), 7.21-7.23 (2H, m), 7.40 (1H, dt, J = 0.7,7.3hz), 7.47-7.54 (5H, m), 7.65 (1H, dd, J = 1.3,7.6Hz), 7.72 ( 2H, d, J = 8.8Hz), 7.81 (1H, d, J = 7.8Hz), 8.11 (1H, d, J = 7.3Hz).

Example 26: Synthesis of N- (4-phenylcarbamoyl-phenyl) -phthalamic acid [Compound 26] (Example 26-1): Synthesis of 4-amino-N-phenyl-benzamide In Example 1-1 Using 357.2 mg of the obtained compound, 434.4 mg of the crude product of the title compound was obtained as a white solid according to Step 1-2.
MS (FAB, Pos): m / z = 213 [M + H] +

Example 26-2: Synthesis of N- (4-phenylcarbamoyl-phenyl) -phthalamic acid 60.0 mg of the compound obtained in Example 26-1 was used and 98.1 mg of the title compound was converted to white according to Step 2-1. Obtained as a solid.
MS (FAB, Pos): m / z = 361 [M + H] +
1H NMR (500 MHz, DMSO): 7.10 (1H, tt, J = 1.1,6.3Hz), 7.35 (2H, dt, J = 1.5,7.0Hz), 7.59 (1H, d, J = 7.3Hz), 7.60 (1H, dt, J = 1.2,7.6Hz), 7.68 (1H, dt, J = 1.1,7.4Hz), 7.78 (2H, d, J = 7.6Hz), 7.83 (2H, d, J = 8.8Hz) , 7.91 (1H, dd, J = 0.7,7.8Hz), 7.97 (2H, d, J = 8.8Hz), 10.14 (1H, s), 10.64 (1H, s), 13.11 (1H, s).

Example 27 Synthesis of 2- (4-phenylcarbamoyl-phenylcarbamoyl) -benzenesulfonic acid (Compound 27) Using 60.0 mg of the compound obtained in Example 26-1 according to Step 3-1, the title Compound 20.8 mg was obtained as a milky white solid.
MS (FAB, Pos): m / z = 397 [M + H] +
1H NMR (500 MHz, DMSO): 7.09 (1H, tt, J = 1.1,7.3Hz), 7.35 (2H, dt, J = 1.6,7.0Hz), 7.52 (2H, dt, J = 2.7,4.8Hz) , 7.75-7.80 (5H, m), 7.91 (1H, dd, J = 2.1,7.2Hz), 7.98 (2H, d, J = 8.8Hz), 10.16 (1H, s), 11.61 (1H, s).

(Example 28)
In this example, the activity test of the compound of the present invention was conducted. The results are shown in Table 1 and the graph of FIG. The reagents, experimental animals, test procedures, etc. used in this activity test are as follows.
(reagent)
Tritium-labeled estrone-3-sulfate (hereinafter [ ³ (← superscript) H] E ₁ (← subscript) -3S) (2.12 TBq / mmol) manufactured by PerkinElmer Life Science Products (Boston, USA) Was used. Collagenase A manufactured by Roche Diagnostics GmbH (Mannheim, Germany) was used.
(Experimental animals)
As an experimental animal, Xenopus laevis (female) provided by the Saitama Experimental Animal Supply Station (Saitama) was used.

(Solution adjustment)
The solution used for this activity test was prepared with the following composition.
OR2 solution (pH 7.5)
NaCl 82.5 mM
KCl 2.0 mM
MgCl ₂・ 6H ₂ O 1.0 mM
HEPES 5.0 mM

MBS (pH7.4)
NaCl 88.0 mM
KCl 1.0 mM
NaHCO 2.4 mM
MgSO ₄ 0.82 mM
Ca (NO ₃ ) ₂ 0.33 mM
CaCl ₂ 0.41 mM
HEPES 10.0 mM

Defolicate solution (pH 7.6)
NaCl 110 mM
EDTA 1.0 mM
HEPES 10.0 mM

(CRNA synthesis)
CRNA synthesis and capping by T7 RNA polymerase was performed using the mMESSAGE mMACHINE kit (Ambion, Austin, USA). After extraction with phenol-chloroform isoamyl alcohol, ethanol precipitation was performed. After washing with 70% ethanol, it was dissolved in water containing no DNase-RNase-.

(Preparation of Xenopus oocytes and cRNA injection)
After laparotomy of Xenopus laevis, Xenopus oocytes were removed and washed with OR2 solution. This was treated with 2 mg / mL collagenase A-containing OR2 solution for 35 to 40 minutes, washed again with OR2 solution, and replaced with MBS. The follicular cell layer was removed in the defolicate solution using tweezers under a stereomicroscope (Olympus, Tokyo). cRNA was heat treated at 65 ° C. for 5 minutes. CRNA was injected into the oocyte from which the follicular cells had been removed at a rate of 50 nL (about 25 ng) / oocyte using a digital microdispenser (Drummond Scientific, Bluemar, USA). As a control, water containing no DNase-RNase- was injected. Injected Xenopus oocytes were cultured in MBS for 3 days. During the culture, the medium was changed twice a day.

(Preparation of test MBS solution)
In this activity test, a solution containing [ ³ (← superscript) H] E ₁ (← subscript) -3S and the inhibitor of the present invention was used. [ ³ (← superscript) H] E ₁ (← subscript) -3S has a specific activity of 2.12 TBq / mmol [3 (← superscript) H] E ₁ (← subscript) -3S, finally 10 nM Thus, the inhibitor was prepared to a target concentration (0.1 to 10 μM) by appropriately diluting a 10 mM DMSO solution with MBS. In all cases, the final DMSO concentration was adjusted to 0.1%.
(Uptake test in Xenopus oocyte expression system)
Uptake was initiated by injecting the cRNA into Xenopus oocytes, culturing for 3 days, and placing in a test MBS solution. After 60 minutes, uptake was stopped by washing 3 times with ice-cold MBS. Xenopus oocytes were solubilized with 5% SDS, creatazole-I was added, and the radioactivity was measured with a liquid scintillation counter.

(Data analysis)
Data are shown as mean ± SEM. In addition, the amount of substrate uptake is the amount of protein or cell-to-medium obtained by correcting the amount of uptake (pmol / mg protein or pmol / oocyte) corrected by the substrate concentration (μM). It was expressed as ratio (C / M Ratio) (μL / mg protein or μL / oocyte). The calculation of IC ₅₀ was performed by the nonlinear least squares analysis program MULTI based on the following equation (Yamaoka et al., J. Pharmacobiodyn 4: 879-885 1981).
% of Control = 100 × IC ₅₀ ^r / (IC ₅₀ ^r + I ^r )
IC ₅₀ : 50% inhibitor concentration, I: inhibitor concentration, r: Hill coefficient.
(result)
Next, the results of Compound 11 and the following known compound 28 are shown.

阻害剤濃度 10μMでは、試験を行ったすべての化合物は、OATP-B, OATP -C,及びOATP- 8のE1-3S輸送を有意に阻害した。その結果を、図３に示す。
なお、本発明の化合物28では、OATP-B, OATP -C, OATP -8のE1-3S輸送に対するIC₅₀値はそれぞれ0.11 μM, 13.21 μM, 0.89 μMと算出された。化合物11によるIC₅₀値はそれぞれ0.27 μM, 14.90 μM, 0.52 μMと算出された（表１）。

At an inhibitor concentration of 10 μM, all compounds tested significantly inhibited E1-3S transport of OATP-B, OATP-C, and OATP-8. The result is shown in FIG.
For compound 28 of the present invention, the IC ₅₀ values for E1-3S transport of OATP-B, OATP-C, and OATP-8 were calculated to be 0.11 μM, 13.21 μM, and 0.89 μM, respectively. IC ₅₀ values for Compound 11 were calculated to be 0.27 μM, 14.90 μM, and 0.52 μM, respectively (Table 1).

(Test example)
The following methods can be considered as a test when the compound of the present invention is used in combination with an existing drug.
A buffer containing a radiolabeled drug and an inhibitor is used in a test for preparing a test solution . The labeled drug and inhibitor are prepared to a desired concentration by appropriately diluting a 10 mM DMSO solution with a buffer.
Uptake test in hepatocytes Free hepatocytes are suspended in Krebs-Hensley buffer and preincubated for 3 minutes at 37 ° C. The solution containing the ligand is added to the reaction, and the reaction is started. After a predetermined time (for example, 30, 60, 90 seconds, etc.), the cells are filtered by the silicon layer method to separate the cells from the medium and react. Stop. Specifically, 50 μL of 2 mol / L sodium hydroxide aqueous solution was added to a 0.4 mL centrifuge tube, the upper layer was covered with 100 μL of a mixture of silicon oil and mineral oil (specific gravity 1.015), and a 200 μL sample was placed on it. Centrifugation is performed, and hepatocytes are collected in a sodium hydroxide layer. After solubilizing the cells with sodium hydroxide solution, the sodium hydroxide layer is recovered and neutralized with an acid (eg, hydrochloric acid). A counting solution is added, and the radioactivity is measured with a liquid scintillation counter to calculate the amount of drug taken up by the cells. The amount of cellular protein can be measured by using a protein assay kit with bovine serum albumin as a standard according to the method of Bradford.

FIG. 1 is a reaction explanatory diagram comprehensively explaining a method for producing a compound of the present invention. FIG. 2 shows the structural formula of a preferred compound of the invention. Figure 3 shows that [ ³ (← superscript) H] E ₁ (← subscript) -3S uptake of Xenopus laevis oocytes expressing OATP-B, OATP-C, and OATP-8 at 10 μM inhibitor. It is a graph which shows the inhibitory effect. The values shown in this graph are values obtained by subtracting the amount of Xenopus oocytes into which water was injected (OATP-B: black, OATP-C: gray, OATP-8: white).

Claims (11)

Compounds represented by the following formula 1 and salts thereof:

(In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);
Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, and R ₃ is hydrogen, or a substituted or unsubstituted carbon atom 1 to 6 alkyl groups, and R ₂ and R ₃ may be bonded to each other to form a ring structure;
However, Z does not contain the following functional groups:

). X is

2. The compound according to claim 1, wherein Y is carbonyl (—CO—), or a salt thereof. 3. The compound according to claim 2, wherein R ₁ is a carboxylic acid, or a salt thereof. The compound according to claim 1 or a salt thereof selected from the group consisting of the following compounds:
2 '-(4-phenylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-[4- (4-tert-butyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (4-Dimethylamino-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (morpholin-4-yl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (3-Benzyloxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (3-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (4-Methoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (4-Phenoxy-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (4-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (2-methoxycarbonyl-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-(4-cyclohexylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4-Isopropylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4-propylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4-hexylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-[4- (piperidine-1-carbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-(4-methylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-[4- (adamantan-1-ylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-[4- (4-Chloro-phenylcarbamoyl) -phenylcarbamoyl] -biphenyl-2-carboxylic acid;
2 '-(4-p-tolylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 ′-(4- (3-chloro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4-cycloheptylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4- (4-Fluoro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4- (3,5-dichloro-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4- (4-trifluoromethyl-phenylcarbamoyl) -phenylcarbamoyl) -biphenyl-2-carboxylic acid;
2 '-(4-cyclopentylcarbamoyl-phenylcarbamoyl) -biphenyl-2-carboxylic acid;
N- (4-phenylcarbamoyl-phenyl) -phthalamic acid; and
2- (4-Phenylcarbamoyl-phenylcarbamoyl) -benzenesulfonic acid. An OATP selective inhibitor comprising a compound represented by the following formula 1, or a salt thereof:

(In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);
Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure. ). A reagent for analyzing the function of OATP in transport of chemical substances, including a compound represented by the following formula 1 or a salt thereof:

(In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);
Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure. ). A reagent for calculating the contribution ratio of OATP in the transport of chemical substances, including a compound represented by the following formula 1, or a salt thereof:

(In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);
Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure. ). Inhibitor of hepatic migration of chemical substances, including a compound represented by the following formula 1 or a salt thereof:

(In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);
Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure. ).   The inhibitor according to claim 8, wherein the chemical substance is selected from the group consisting of an endogenous chemical substance, an exogenous chemical substance, and a conjugate of a hydrophobic drug. A drug containing a compound represented by the following formula 1, or a salt thereof, that reduces the liver toxicity of a chemical substance having hepatotoxicity:

(In Formula 1, X is

Wherein R ₁ represents a carboxylic acid (—COOH) or a sulfonic acid (—SO ₃ H);
Y represents carbonyl (—CO—), sulfinyl (—SO—), or sulfonyl (—SO ₂ —); and
Z is a functional group represented by —N (R ₂ ) (R ₃ ), wherein R ₂ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or substituted. A cyclic alkyl group having 3 to 10 carbon atoms, a substituted or unsubstituted aromatic ring having 6 to 12 carbon atoms, or a substituted or unsubstituted heteroaromatic ring having 5 to 12 carbon atoms R ₃ is hydrogen or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, and R ₂ and R ₃ may be bonded to each other to form a ring structure. ).   11. The agent according to claim 10, wherein the chemical substance is selected from the group consisting of an endogenous chemical substance, an exogenous chemical substance, and a conjugate of a hydrophobic drug.

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