Phenylazole compound and pharmaceutical composition

Abstract

To provide a novel compound that can increase the systemic exposure of various drugs by inhibiting CYPs.SOLUTION: The compound is represented by the general formula (1) in the figure (where X1 to X4 each independently represent a hydrogen atom or a halogen atom; Y represents a carbon atom or an oxygen atom; Z represents a hydroxyl group, a nitrile group, -CO2R1, -CH2R2, or -CH2OCOR3). Specifically, the compound is, e.g., 4-[(4-imidazol 1-ylphenoxy)methyl]benzonitrile, methyl 4-[(4-imidazol 1-ylphenoxy)methyl]benzoate, [4-[(4-imidazol 1-ylphenoxy)methyl]phenyl]methanol, or the like.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a novel phenylazole compound and a pharmaceutical composition containing the same.

Background Art

[0002] The CIP (cytochrome P450) family is known as the main enzyme in the metabolism of various drugs, and typical molecular species include CYP3A4, CYP1A2, CYP2C8, CYP2C9, CYP2D6, etc. Among them, CYP3A4 makes the greatest contribution to drug metabolism. CYP is present not only in the liver but also in the small intestine. Most of the CYP present in the small intestine is CYP3A4.

[0003] Since CYP has a common point of having a heme containing iron ions at the catalytic site, it has low substrate specificity, and one molecular species metabolizes a large number of drugs. Therefore, many drugs are metabolized by CYP present in the liver and small intestine, resulting in a decrease in the systemic exposure (absorption amount) after oral administration. Therefore, by formulating a CYP inhibitor, drug metabolism is suppressed. However, when CYP is inhibited, the metabolism of other drugs by CYP is also inhibited, which may lead to an unexpected enhancement of the efficacy of other drugs, an enhancement of side effects, and the emergence of new effects. Currently clinically applied CYP inhibitors migrate into the systemic circulation and inhibit the metabolism of other drugs by CYP, which causes drug interactions and has the problem that there are many drugs with contraindications for combined use (Non-Patent Documents 2 and 3).

[0004] For example, HIV protease inhibitors widely used as therapeutic drugs for HIV infection are metabolized by CYP present in the liver and small intestine, so the systemic exposure amount decreases. So far, drugs formulated with a CYP inhibitor have been developed for the purpose of increasing the systemic exposure amount of HIV protease inhibitors (Non-Patent Document 1). For example, Genvoya (registered trademark) combination tablets contain an HIV integrase inhibitor and an HIV reverse transcriptase inhibitor combined with cobicistat, a CYP3A inhibitor. Due to the CYP3A inhibitory effect of cobicistat, 16 drugs are contraindicated for concomitant use (Non-Patent Document 2). In addition, Norvir (registered trademark) tablets 100 mg contain ritonavir, an HIV protease inhibitor, as an active ingredient. Since ritonavir has an inhibitory effect on CYP3A, it inhibits the metabolism of other drugs metabolized by CYP3A and increases their blood concentrations. For this reason, 30 drugs are contraindicated for concomitant use, and more than 50 drugs are noted for caution regarding concomitant use (Non-Patent Document 3).

[0005] Therefore, it is desirable that the CYP inhibitor inhibits the CYP-mediated metabolism of the target drug in the small intestine before being absorbed into the body and entering the systemic circulation. If the dosage is sufficient to inhibit the metabolism of the target drug in the small intestine, not much strong CYP inhibitory activity will be exhibited even after entering the systemic circulation, so the inhibition of CYP-mediated metabolism of drugs other than the target drug will be reduced.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a novel compound capable of increasing the systemic exposure of various drugs by inhibiting CYP, and a pharmaceutical composition containing the same. In particular, an object of the present invention is to provide a compound capable of efficiently increasing the systemic exposure of various drugs by inhibiting CYP3A4, which occupies most of the CYP present in the small intestine, and a pharmaceutical composition containing the same.

Means for Solving the Problems

[0008] The present inventors have conducted extensive research to solve the above problems, and have found that a compound represented by the general formula (1)

Chemical formula

[0009] The present invention has been completed based on the above findings, and provides the following [1] to [6]. 〔1〕 The following general formula (1)

Chemical formula

Advantages of the Invention

[0010] Since the compounds of the present invention strongly inhibit CYP, they can suppress the metabolic disappearance of drugs by CYP and prevent unexpected reduction of drug efficacy. Among the compounds of the present invention, those that strongly inhibit CYP3A4 are particularly notable. CYP3A4 is highly expressed not only in the liver but also in the small intestine, and most of the CYP present in the small intestine is CYP3A4. Many orally administered drugs are decomposed by CYP3A4 in the small intestine, resulting in a reduced amount of drug absorbed into the body. However, since the compounds of the present invention strongly inhibit CYP3A4, they suppress the drug decomposition by CYP3A4 in the small intestine and function as a booster (pharmacokinetic enhancement factor) that promotes the absorption of orally administered drugs. Among the compounds represented by the general formula (1), compounds in which Z is an ester group are easily decomposed in the small intestine and blood. Therefore, they are inactivated by decomposition when passing through the small intestine and after entering the body, and it is difficult for them to inhibit CYP present in the liver. In this way, by selectively inhibiting CYP present in the small intestine and selectively inhibiting the intestinal metabolism of drugs, the amount of drug transferred into the blood can be increased. Also, when the CYP inhibitory effect in the liver is absent or weak, it does not affect the disappearance of drugs from the body, so it is safe.

Embodiments for Carrying Out the Invention

[0011] Hereinafter, the present invention will be described in detail. (1) The compound of the present invention The compounds of the present invention are represented by the following general formula (1)

Chemical Formula

[0012] X 1 ~X 4 All are hydrogen atoms, or one, two, three, or four of X 1 ~X 4 are the same halogen atom, and the rest are preferably hydrogen atoms. The halogen atom is preferably a chlorine atom or a fluorine atom. When one of X 1 ~X 4 is a halogen atom, it is preferable that X 2 or X 3 is a chlorine atom or a fluorine atom.

[0013] R 1 When it is an optionally substituted linear or branched alkyl group having 1 to 6 carbon atoms, the substituent, R 2 When it is an optionally substituted linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms, the substituent; R 3 When it is an optionally substituted linear or branched alkyl group having 1 to 6 carbon atoms, examples of the substituent include an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an aryl group, a hydroxyl group, an amino group, a cyano group, and a halogen atom.

[0014] Z is -CO2R 1 or -CH2OCOR 3It is preferably an ester functional group. As a result, when passing through the small intestine or after entering the body, the CYP inhibitory activity is likely to be reduced or lost due to the decomposition of the ester bond, and it becomes a compound that exhibits CYP inhibitory action specifically in the small intestine. Since the types of enzymes that cleave the ester bond are different in the small intestine, in the blood, and in the liver, by selecting the structure of Z, it is possible to select a compound that reduces or eliminates the activity of CYP in a specific part of the body.

[0015] (2) Method for producing the compound of the present invention In the general formula (1), when n is 0 and Y is an oxygen atom, the compound can be synthesized, for example, by reacting the raw material compound A1 and the raw material compound B1 under a strong base according to the following reaction formula I.

Chemical formula

[0016] In the general formula (1), when n is 1 and Y is an oxygen atom, the compound can be synthesized, for example, by reacting the raw material compound A2 and the raw material compound B1 under a strong base according to the following reaction formula II.

Chemical formula

[0017] In the general formula (1), when n is 0 and Y is a carbon atom, the compound can be synthesized, for example, by reacting the raw material compound A3 and the raw material compound B2 under a strong base according to the following reaction formula III to synthesize an intermediate, and further, for example, by reducing the carbon-carbon double bond by catalytic hydrogenation using a metal catalyst such as palladium, nickel, or platinum.

Chemical formula

[0018] In the general formula (1), when n is 1 and Y is a carbon atom, the compound can be synthesized, for example, in Reaction Scheme III, by using starting compound A4 instead of starting compound A3, reacting with starting compound B2 under a strong base to obtain an intermediate, and further reducing the carbon-carbon double bond.

Chemical formula

[0019] Specific conditions can be appropriately determined by those skilled in the art based on the description of the examples.

[0020] (3) Pharmaceutical composition The pharmaceutical composition of the present invention is a composition containing the compound of the present invention described above. One or more of the compounds of the present invention can be used. The pharmaceutical composition of the present invention can contain additives in addition to the compound of the present invention. Examples of additives include excipients, binders, disintegrants, lubricants, fluidizing agents, glazing agents, colorants, flavoring agents, sweeteners, fragrances, preservatives or antiseptics, pH adjusters, isotonic agents, buffers, solubilizing agents, soothing agents, antioxidants, thickeners, surfactants, chelating agents, etc. One or more additives can be used.

[0021] In addition, the pharmaceutical composition of the present invention can contain one or more pharmacological active ingredients (drugs) other than the compound of the present invention, if necessary. In particular, it is preferably formulated with drugs that are metabolized or are likely to be metabolized by CYP, or drugs that promote the metabolism of other drugs by CYP by inducing CYP. By formulating the compound of the present invention together with such drugs, it is possible to suppress the disappearance of these drugs due to metabolism and the promotion of the disappearance of these drugs by further promoting the metabolism of other drugs.

[0022] Drugs that are metabolized by or susceptible to CYP3A4 include triazolam, midazolam, flunitrazepam, amitriptyline, imipramine, clomipramine, ethosuximide, carbamazepine, clonazepam, diltiazem, nicardipine, nisoldipine, nifedipine, felodipine, penidipine, verapamil, amiodarone, quinidine, disopyramide, lidocaine, simvastatin, ethinyl estradiol, dexamethasone, testosterone, norethisterone, prednisolone, methylprednisolone, itraconazole, ketoconazole, erythromycin, cyclosporine, tacrolimus, ergotamine, and the like. Drugs that induce CYP3A4 include omeprazole, lansoprazole, carbamazepine, phenytoin, phenobarbital, primidone, dexamethasone, rifampicin, and the like.

[0023] When the pharmaceutical composition of the present invention does not contain a pharmacologically active ingredient other than the compound of the present invention, it can be a pharmaceutical composition used in combination with a drug that is metabolized by or susceptible to CYP or a drug that promotes the metabolism of other drugs by CYP by inducing CYP. In this case, the pharmaceutical composition of the present invention can be used as a CYP inhibitor, particularly a CYP3A4 inhibitor, and particularly a CYP3A4 selective inhibitor, and by this action, it can be used as a booster (drug absorption promoter, pharmacokinetic enhancer) of other drugs. In addition, the compound of the present invention itself can also be used as a CYP inhibitor, a CYP3A4 inhibitor, a CYP3A4 selective inhibitor, or a booster (drug absorption promoter, pharmacokinetic enhancer) of other drugs.

[0024] The pharmaceutical composition of the present invention can adopt various dosage forms. Oral administration preparations include solid preparations such as tablets, powders, granules, pills, capsules, and liquid preparations such as solutions, elixirs, suspensions, emulsions, lemonades, and syrups. Parenteral administration preparations include injections, transdermal absorbents, inhalants, suppositories, eye drops, nasal drops, and the like. Oral administration preparations are preferred for efficiently inhibiting CYP in the small intestine.

Example

[0025] Hereinafter, the present invention will be described in more detail with reference to examples. (1) Synthesis of phenylazole compound Compound 1 500 mg (3.12 mmol) of p-(1-imidazolyl)phenol, 5 mL of THF, and 920 mg (4.68 mmol) of 4-bromomethylbenzonitrile were placed in a 30 mL eggplant-shaped flask, cooled to 0 °C, and then 150 mg (3.74 mmol) of sodium hydride was added, followed by stirring at 0 °C for 21 hours. After completion of the reaction, water was added, followed by addition of an aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel chromatography (ethyl acetate:methanol = 20:1) to obtain the target compound 1 as a white solid. The yield was 186 mg and the yield was 22%. The results of NMR and mass spectrometry are shown below. 1 H-NMR (400 MHz, CDCl3) δ (ppm) 5.17 (s, 2H) 7.04 (d, J = 8.4 Hz, 2H) 7.20 (d, J = 7.6 Hz, 2H) 7.32 (d, J = 9.2 Hz, 2H) 7.57 (d, J = 8.0 Hz, 2H) 7.71 (d, J = 8.4 Hz, 2H) 7.77 (s, 1H) EI-LR-MS m / z = 275 (M + ) EI-HR-MS (M + ) Calcd for C 17 H 13 ON3 275.1059 Found m / z 275.1055 The obtained compound 1 was 4-[(4-imidazol-1-ylphenoxy)methyl]benzonitrile having the following structure. [Chemical formula]

[0026] Compounds 2 to 5 were synthesized according to the following scheme. [Chemical formula]

[0027] Compound 2 To a 100 mL eggplant-shaped flask, 2.43 g (11.7 mmol) of methyl 4-bromobenzoate, 1.89 g (11.7 mmol) of p-(1-imidazolyl)phenol, and 2.43 g (17.6 mmol) of potassium carbonate were added. After purging with argon, 13 mL of DMF was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water and a small amount of 10% aqueous sodium hydroxide solution were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off using an evaporator and the residue was purified by silica gel chromatography (chloroform:methanol = 10:1) to obtain the target compound 2. The yield was 2550 mg and the yield rate was 71%. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.93 (s, 3H) 5.18 (s, 2H) 7.04 - 7.06 (m, 2H) 7.19 - 7.21 (m, 2H) 7.30 - 7.32 (m, 2H) 7.52 (d, J = 8.0 Hz, 2H) 7.76 (s, 1H) 8.07 - 8.09 (m, 2H) EI - LR - MS m / z = 308(M + ) EI - HR - MS(M + ) Calcd for C 18 H 16 N2O3 308.1161 Found m / z 308.1163 The obtained compound 2 was methyl 4 - [(4 - imidazol - 1 - ylphenoxy)methyl]benzoate having the following structure.

Chemical Structure

[0028] Compound 3 1.02 g (3.24 mmol) of compound 2 was placed in a 300 mL eggplant - shaped flask, 7.5 mL of dichloroethane was added, and the mixture was cooled to - 20°C. 8 mL (8.10 mmol) of DIBAL - H was added dropwise, and the mixture was stirred for four and a half hours. After completion of the reaction, an aqueous solution of Rochelle salt was added, and the mixture was stirred at room temperature for 1 hour. A small amount of aqueous sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off using an evaporator and the residue was purified by silica gel chromatography to obtain the target compound 3. The yield was 313.8 mg and the yield rate was 34.6%. The results of NMR and mass spectrometry are shown below. 1 1H - NMR (400 MHz, CDCl3) δ (ppm) 4.50 (d, J = 5.6 Hz, 2H)) 5.14 (s, 2H) 5.19 (t, 1H) 7.07 (s, 1H) 7.12 - 7.14 (m, 2H) 7.34 (d, J = 7.6 Hz, 2H) 7.41 - 7.43 (m, 2H) 7.54 (d, J = 8.0 Hz, 2H) 7.64 (m, 2H) 8.12 (s, 1H) EI - LR - MS m / z = 280 (M + ) EI - HR - MS (M + ) Calcd for C 17 H 16 N2O2 280.1212 Found m / z 280.1214 The obtained compound 3 was [4 - [(4 - imidazol - 1 - ylphenoxy)methyl]phenyl]methanol having the following structure.

Chemical formula

[0029] Compound 4 200 mg (0.71 mmol) of compound 3 and 5 mL of pyridine were placed in a 50 mL eggplant - shaped flask. After cooling to 0 °C, 0.26 mL (2.86 mmol) of acetic anhydride was added, and then the mixture was stirred at room temperature for 2 hours. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off using an evaporator, and the residue was purified by silica gel chromatography (ethyl acetate: chloroform = 1:1) to obtain compound 4 as a white solid. The yield was 166 mg, and the yield rate was 73%. The results of NMR and mass spectrometry are shown below. 1 1H - NMR (400 MHz, CDCl3) δ (ppm) 2.11 (s, 3H) 5.12 (d, J = 5.2 Hz, 4H) 4.46 (t, J = 4.8 Hz, 2H) 7.05 (d, J = 8.0 Hz, 2H) 7.19 (d, J = 6.4 Hz, 2H) 7.30 (d, J = 8.4 Hz, 2H) 7.40 (d, J = 7.6 Hz, 2H) 7.45 (d, J = 7.6 Hz, 2H) 7.76 (s, 1H) EI-LR-MS m / z = 322 (M + ) EI-HR-MS (M + ) Calcd for C 19 H 18 O3N2 322.1317 Found m / z 322.1313 The obtained compound 4 was [4-[(4-imidazol-1-ylphenoxy)methyl]phenyl]methyl acetate having the following structure.

Chemical Structure

[0030] Compound 5 In a 100 mL eggplant-shaped flask, 0.12 g (0.43 mmol) of compound 3, 0.1 mL of propionyl chloride, and 4 mL of pyridine were added, and the mixture was stirred at room temperature for 17 hours. Water was added, the mixture was extracted with chloroform, sodium hydroxide was added, and it was dried over anhydrous magnesium sulfate. The solvent was distilled off using an evaporator and purified by silica gel chromatography (ethyl acetate) to obtain the target compound 5 as a yellow solid. The yield was 30.5 mg and the yield rate was 21%. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.17 (t, J = 7.4 Hz, 3H)) 2.39 (q, 2H) 3.93 (s, 2H) 5.11 (s, 2H) 5.14 (s, 2H) 7.04 - 7.06 (m, 4H) 7.20 (d, J = 8.0 Hz, 4H) 7.29 - 7.32 (m, 4H) 7.39 - 7.41 (m, 2H) 7.51 - 7.53 (d, J = 8.0 Hz, 2H) 7.77 (s, 2H) 8.07 - 8.09 (m, 2H) EI - LR - MS m / z = 336(M + ) EI - HR - MS(M + ) Calcd for C 20 H 20 N2O3 336.1474 Found m / z 336.1470 The obtained compound 5 was [4 - [(4 - imidazol - 1 - ylphenoxy)methyl]phenyl]methyl propanoate having the following structure.

Chemical formula

[0031] Compounds 6 - 11 were synthesized from compound 2 according to the following scheme.

Chemical formula

[0032] Compound 6 To a 30 mL eggplant - shaped flask, 0.16 g (0.52 mmol) of compound 2, 0.14 g (1.04 mmol) of potassium carbonate, and 6 mL of butanol were added and stirred for 2 days. Saturated brine was added, and the mixture was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and purified by silica gel chromatography (ethyl acetate:hexane = 4:1) to obtain the target compound 6. The yield was 77.7 mg and the yield rate was 43%. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ (ppm) 0.97 - 1.01 (t, J = 7.6 Hz, 3H) 1.44 - 1.52 (m, 2H) 1.73 - 1.80 (m, 2H) 4.32 - 4.36 (t, J = 6.6 Hz, 2H) 5.18 (s, 2H) 7.04 - 7.06 (m, 2H) 7.19 - 7.21 (m, 2H) 7.30 - 7.32 (m, 2H) 7.50 - 7.52 (m, 2H) 7.77 (s, 1H) 8.07 - 8.09 (d, J = 8.4 Hz, 2H) EI-LR-MS m / z = 350 (M + ) EI-HR-MS (M + ) Calcd for C 21 H 22 N2O3 350.1630 Found m / z 350.1632 The obtained compound 6 was butyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate having the following structure.

Chemical formula

[0033] Compound 7 In the same manner as the synthesis of Compound 6, except that 3-methyl-1-butanol was used instead of butanol and the reaction temperature was adjusted as appropriate, the target compound 7 was obtained. The results of NMR and mass spectrometry are shown below. 1 H-NMR (400 MHz, CDCl3) δ (ppm) 0.98 (d, J = 6.8 Hz, 6H)) 1.02 (d, J = 6.4 Hz, 1H) 1.26 - 1.32 (m, 1H) 1.65 - 1.70 (m, 4H) 1.77 - 1.83 (m, 1H) 4.36 (t, J = 6.8 Hz, 2H) 5.18 (s, 2H) 7.03 - 7.06 (m, 2H) 7.19 (d, J = 8.4 Hz, 2H) 7.30 - 7.32 (m, 2H) 7.51 (d, J = 8.4 Hz, 2H) 7.76 (s, 1H) 8.06 - 8.08 (m, 2H) EI-LR-MS m / z = 364 (M + ) EI-HR-MS (M + ) Calcd for C 22 H 24 N2O3 364.1787 Found m / z 364.1785 The obtained compound 7 was isopentyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate having the following structure.

Chemical Structure

[0034] Compound 8 Compound 6 was synthesized in the same manner, except that propanol was used instead of butanol, and the reaction temperature was appropriately adjusted to obtain the target compound 8. The results of NMR are shown below. 1 H-NMR (400 MHz, CDCl3) δ (ppm) 1.04 (d, J = 8.2 Hz, 3H) 1.78 - 1.83 (m, 2H) 4.29 (t, J = 6.6 Hz, 2H) 5.18 (s, 2H) 7.04 - 7.06 (m, 2H) 7.18 - 7.20 (m, 2H) 7.30 - 7.32 (m, 2H) 7.51 (d, J = 8.4 Hz, 2H) 7.76 (s, 1H) 8.07 - 8.10 (m, 2H) EI-LR-MS m / z = 364 (M + ) EI-HR-MS (M + ) Calcd for C 22 H 24 N2O3 364.1787 Found m / z 364.1785 The obtained compound 8 was propyl 4 - [(4 - imidazol - 1 - ylphenoxy)methyl]benzoate having the following structure.

Chemical Structure

[0035] Compound 9 Compound 6 was synthesized in the same manner, except that 2,2,2 - trifluoroethanol was used instead of butanol, and the reaction temperature was appropriately adjusted to obtain the target compound 9. The results of NMR are shown below. 1 1H-NMR (400 MHz, CDCl3) δ (ppm) 1.25 (s, 1H) 1.64 (s, 3H) 4.68 - 4.75 (m, 2H) 7.04 - 7.06 (m, 2H) 7.19 - 7.21 (m, 2H) 7.30 - 7.33 (m, 2H) 7.56 (d, J = 8.0 Hz, 2H) 7.76 (s, 1H) 8.12 (d, J = 8.4 Hz, 2H) The obtained compound 9 was 2,2,2-trifluoroethyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate having the following structure.

Chemical formula

[0036] Compound 10 In the same manner as in the synthesis of compound 6, except that 2-phenylethanol was used instead of butanol and the reaction temperature was appropriately adjusted, the target compound 10 was obtained. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ (ppm) 3.09 (t, J = 6.8 Hz, 1H) 4.54 (t, J = 7.0 Hz, 2H) 5.17 (s, 2H) 7.04 (d, J = 9.2 Hz, 2H) 7.19 (m, 2H) 7.30 - 7.33 (m, 7H) 7.51 (d, J = 8.8 Hz, 2H) 7.77 (s, 1H) 8.05 (d, J = 8.4 Hz, 2H) EI-LR-MS m / z = 398(M + ) EI-HR-MS(M + ) Calcd for C 25 H 22 N2O3 398.1630 Found m / z 398.1634 The obtained compound 10 was 2-phenylethyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate having the following structure.

Chemical Structure

[0037] Compound 11 In the same manner as the synthesis of compound 6, except that hexanol was used instead of butanol and the reaction temperature was appropriately adjusted, the target compound 11 was obtained. The results of NMR and mass spectrometry are shown below. 1 H-NMR(400 MHz, CDCl3) δ(ppm) 0.91 (t, J = 7.2 Hz, 3H) 1.33 - 1.35 (m, 4H) 1.75 - 1.79 (m, 2H) 4.32 (t, J = 6.6 Hz, 2H) 5.18 (s, 2H) 7.05 (d, J = 8.8 Hz, 2H) 7.20 (d, J = 8.0 Hz, 2H) 7.31 (d, J = 9.2 Hz, 2H) 7.51 (d, J = 8.4 Hz, 2H) 7.77 (s, 1H) 8.08 (d, J = 8.4 Hz, 2H) EI-LR-MS m / z = 378 (M + ) EI-HR-MS (M + ) Calcd for C23H26N2O 378.1943 Found m / z 378.1948 The obtained compound 11 was hexyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate having the following structure.

Chemical formula

[0038] Compound 12 Compound 12 was synthesized according to the following scheme.

Chemical formula

Chemical Structure

[0039] Compound 13 In the same manner as the synthesis of Compound 8, except that Compound 12 was used instead of Compound 2 and the reaction temperature was appropriately adjusted, the target Compound 13 was obtained. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ(ppm) 1.03(t, J = 7.6 Hz, 3H) 1.74 - 1.84(m, 2H) 3.0(s, 4H) 4.27(t, 6.6 Hz, 2H) 7.20 - 7.32(m, 8H) 7.83(s, 1H) 7.96(d, 8.0 Hz, 2H) EI-LR-MS m / z = 334(M + ) EI-HR-MS(M + ) Calcd for C 21 H 22 O2N2 334.1681 Found m / z 334.1683 The obtained Compound 13 was propyl 4-[2-(4-imidazol-1-ylphenyl)ethyl]benzoate having the following structure.

Chemical Structure

[0040] Compound 14 In the same manner as the synthesis of Compound 6, except that Compound 12 was used instead of Compound 2, ethanol was used instead of butanol, and the reaction temperature was appropriately adjusted, the target Compound 14 was obtained. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ(ppm) 1.39 (t, J = 7.0 Hz, 3H) 3.0 (s, 4H) 4.33 - 4.41 (m, 2H) 7.18 - 7.31 (m, 8H) 7.83 (s, 1H) 7.96 (d, J = 8.4 Hz, 2H) EI - LR - MS m / z = 320 (M + ) EI - HR - MS (M + ) Calcd for C 20 H 20 O2N2 320.1525 Found m / z 320.1526 The obtained compound 14 was ethyl 4 - [2 - (4 - imidazol - 1 - yl phenyl) ethyl] benzoate having the following structure.

Chemical Structure

[0041] Compound 15 Compound 15 was synthesized according to the following scheme.

Chemical Structure

Chemical formula

[0042] Compound 16 Compound 16 was synthesized according to the following scheme.

Chemical formula

Chemical Structure

[0043] Compound 17 In the same manner as the synthesis of compound 6, but using compound 16 instead of compound 2, ethanol instead of butanol, and appropriately adjusting the reaction temperature, the target compound 17 was obtained. The yield was 49.5 mg and the yield rate was 62%. The results of mass spectrometry are shown below. EI - LR - MS m / z = 354 (M + ) EI - HR - MS (M + ) Calcd for C 20 H 19 O2N2Cl 354.1135 Found m / z 354.1133 The obtained compound 17 was ethyl 4-[2-(2-chloro-4-imidazol-1-yl-phenyl)ethyl]benzoate having the following structure. [Chemical formula]

[0044] Compound 18 Compound 18 was synthesized according to the following scheme. [Chemical formula] 543.1 mg of 2-chloro-4-imidazol-1-ylbenzaldehyde was placed in a 200 ml eggplant-shaped flask, and THF (27 mL) and methanol (27 mL) were added. This solution was cooled to 0 °C, 239 mg (6.3 mmol) of sodium borohydride was added, and the mixture was stirred for 2 hours. After completion of the reaction, water was added and the organic solvent was distilled off using an evaporator. The mixture was extracted with ethyl acetate, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain the alcohol form as a crude product. 27 ml of THF was added to this alcohol form, and while stirring at 0 °C, 156 mg (3.9 mmol) of 60% sodium hydride was added, and the mixture was stirred for 30 minutes. Then, 714.7 mg (3.12 mmol) of methyl 4-bromomethylbenzoate was added, and after stirring for 10 minutes, the mixture was further stirred at room temperature for 22 hours. After completion of the reaction, the mixture was cooled to 0 °C, water was added, and the organic solvent was distilled off using an evaporator. The mixture was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate. Purification by silica gel chromatography (ethyl acetate:hexane = 1:1) gave the target compound 18. The yield was 302.5 mg and the yield rate was 56%. The results of NMR and mass spectrometry are shown below. 1 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.267 (d, J = 3.2 Hz, 2H) 7.333 (dd, J = 2.3, 8.2 Hz) 7.435 (d, J = 2.3 Hz, 1H) 7.484 (d, J = 8.7 Hz, 2H) 7.659 (d, J = 8.2 Hz, 1H) 7.862 (s, 1H) 8.062 (d, J = 8.0 Hz, 2H) EI-LR-MS m / z = 356 (M + ) EI-HR-MS (M + ) Calcd for C 19 H 17 ClN2O3 356.0928 Found m / z = 356.0927 The obtained compound 18 was methyl 4-[(2-chloro-4-imidazol-1-yl-phenyl)methoxymethyl]benzoate having the following structure.

Chemical Structure

[0045] Compound 19 In the same manner as the synthesis of compound 6, but using compound 18 instead of compound 2, ethanol instead of butanol, and appropriately adjusting the reaction temperature, the target compound 19 was obtained. The yield was 86.5 mg and the yield rate was 83%. The results of NMR and mass spectrometry are shown below. 1 H-NMR (400 MHz, CDCl3) δ (ppm) 1.402 (t, J = 6.7 Hz, 3H) 4.386 (dd, J = 7.3, 14 Hz, 2H) 4.695 (s, 2H) 4.723 (s, 2H) 7.219 (s, 1H) 7.266 (s, 1H) 7.330 (doublet of doublets, J = 1.8, 8.2 Hz, 1H) 7.445 (doublet, J = 2.3 Hz, 1H) 7.467 (doublet, J = 8.7 Hz, 2H) 7.656 (doublet, J = 8.2 Hz, 1H) 7.851 (singlet, 1H) 8.066 (doublet, J = 8.2 Hz, 2H) EI-LR-MS m / z = 370 (M + ) EI-HR-MS (M + ) Calculated for C 20 H 19 ClN2O3 370.1084 Found m / z = 370.1086 The obtained compound 19 was ethyl 4 - [(2 - chloro - 4 - imidazol - 1 - yl - phenyl)methoxymethyl]benzoate having the following structure.

Chemical Structure

[0046] (2) Evaluation of CYP3A4 inhibitory activity The CYP3A4 inhibitory activity of the phenylazole compound synthesized as described above was evaluated by confirming the effect on the metabolism of midazolam by rat liver microsomes (manufactured by Sekisui Xenotech, LLC, product number: R1000). Rat liver microsomes contain CYP3A4, and midazolam is a typical substrate compound of CYP3A4. The evaluation was carried out by mixing midazolam, each test compound, and rat liver microsomes, quantifying the change in the concentration of midazolam over a reaction time of 10 minutes, and calculating the metabolic rate (pmol / mg / min). Specifically, 1 nmol / mL of midazolam, 10 nmol / mL of each test compound, and rat liver microsomes (protein concentration 0.04 mg / mL) were mixed, and the metabolic reaction was initiated by adding 1.3 μmol / mL of NADPH as a coenzyme under incubation at 37°C. At 0, 2, 5, and 10 minutes after the start of the reaction, 50 μL of the test solution was collected, the reaction was stopped by mixing with 450 μL of acetonitrile, and after thorough mixing, centrifugation (15,000 rpm, 10 min, 4°C, KUBOTA model 3700) was performed, and the supernatant was subjected to LC-MSMS measurement to measure the midazolam concentration. As positive controls for CYP3A4 inhibitors, 1-aminobenzotriazole and ketoconazole were used. The same operations were also performed for the control without adding the test compound. The metabolic rate of midazolam for a reaction time of 10 minutes was calculated according to the following formula 1. Metabolic rate of midazolam for a reaction time of 10 minutes (pmol / mg / min) = Amount of midazolam disappearance in 10 minutes / 10 / Protein amount ····· Formula 1 Next, the midazolam metabolism inhibition rate was calculated according to the following formula 2. The midazolam metabolism inhibition rate represents the CYP3A4 inhibition rate. Midazolam metabolism inhibition rate (%) = {1 - (Metabolic rate of midazolam (pmol / mg / min) under test compound addition conditions / Metabolic rate of midazolam (pmol / mg / min) of the control)} × 100 ····· Formula 2

[0047] The results are shown in Table 1.

Table 1

Industrial Applicability

[0048] Since the phenylazole compound of the present invention strongly inhibits CYP, it is useful as a booster that suppresses the metabolism and disappearance of drugs by CYP and increases the in vivo exposure amount of drugs.

Claims

1. A compound represented by the following general formula (1), a salt thereof, or a hydrate thereof. 【Chemical 1】 (wherein, X 1 ~X 4 are each independently a hydrogen atom or a halogen atom; Y is a carbon atom or an oxygen atom; Z is a nitrile group, -CO 2 R 1 , -CH 2 R 2 , or -CH 2 OCOR 3 ; n represents 0 or 1. R 1 is a linear or branched alkyl group having 1 to 6 carbon atoms, a trifluoromethyl group, a trifluoroethyl group, or a phenylethyl group; R 2 is a hydroxyl group or a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms; R 3 represents a linear or branched alkyl group having 1 to 6 carbon atoms.)

2. In general formula (1), X 1 ~X 4 are all hydrogen atoms, or one, two, three, or four of X 1 ~X 4 are the same halogen atom and the rest are hydrogen atoms, the compound, salt, or hydrate thereof according to claim 1.

3. Z is -CO 2 R 1 or -CH 2 OCOR 3 The compound, salt or hydrate thereof according to claim 1 or 2, wherein Z is as defined above.

4. 4-[(4-Imidazol-1-ylphenoxy)methyl]benzonitrile, methyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, [4-[(4-imidazol-1-ylphenoxy)methyl]phenyl]methanol, [4-[(4-imidazol-1-ylphenoxy)methyl]phenyl]methyl acetate, [4-[(4-imidazol-1-ylphenoxy)methyl phenyl]methyl propanoate, butyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, isopentyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, propyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, 2,2,2-trifluoroethyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, 2-phenylethyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, hexyl 4-[(4-imidazol-1-ylphenoxy)methyl]benzoate, methyl 4-[2-(4-imidazol-1-ylphenyl)ethyl]benzoate, propyl 4-[2-(4-imidazol-1-ylphenyl)ethyl]benzoate, ethyl 4-[2-(4-imidazol-1-ylphenyl)ethyl]benzoate, methyl 4-[2-(2,3,5,6-tetrafluoro-4-imidazol-1-yl-phenyl)ethyl]benzoate, methyl 4-[2-(2-chloro-4-imidazol-1-yl-phenyl)ethyl]benzoate, ethyl 4-[2-(2-chloro-4-imidazol-1-yl-phenyl)ethyl]benzoate, methyl 4-[(2-chloro-4-imidazol-1-yl-phenyl)methoxymethyl]benzoate, or ethyl 4-[(2-chloro-4-imidazol-1-yl-phenyl)methoxymethyl]benzoate, a salt thereof, or a hydrate thereof.

5. A pharmaceutical composition comprising the compound, a salt thereof, or a hydrate thereof according to any one of Claims 1 to 4.

6. The pharmaceutical composition according to Claim 5, which is a CYP inhibitor or a drug booster.

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