WO2012121285A1

WO2012121285A1 - Labeling precursor compound, radioactively labeling compound, and processes for producing those compounds

Info

Publication number: WO2012121285A1
Application number: PCT/JP2012/055807
Authority: WO
Inventors: 佐治英郎; 木村寛之; 杉山雄一; 前田和哉
Original assignee: 国立大学法人京都大学; 国立大学法人東京大学
Priority date: 2011-03-07
Filing date: 2012-03-07
Publication date: 2012-09-13
Also published as: JPWO2012121285A1

Abstract

Provided is a labeling precursor compound which enables the provision of a PET probe comprising a statin compound. A labeling precursor compound represented by formula (I) or formula (IV). In formulae (I) and (IV), R¹¹ and R¹² independently represent H, a C_1-4 alkyl group, a C_1-3 alkoxy group or the like; R¹⁵ represents a C_3-6 cycloalkyl group or the like; Y represents a C_1-2 alkyl group, -CH=CH-, -CH=CH-CH₂- or the like; Z¹ represents -Q-CH₂-W-CH₂-CO₂R¹⁶ or a group represented by formula (II) or (III); Q represents -C(O)- or -CH(OH)-; W represents -C(O)- or -CH(OH)-; and R¹⁶ represents H, an alkyl group or the like. In formula (I), L¹ represents -O(CH₂)_m- or the like; m represents an integer of 1-4; X¹ represents a reactive functional group; and R¹⁴ represents H, a C_1-4 alkyl group or the like. In formula (IV), M represents a boronic acid ester.

Description

Labeled precursor compound, radiolabeled compound, and production method thereof

The present invention relates to a labeling precursor compound, a radioactive labeling compound, and a production method thereof.

In order to increase the probability of success in clinical trials, it is most important to select compounds that exhibit favorable pharmacokinetic properties in humans as development candidates. Under these circumstances, in Europe and the United States, guidelines for “early human clinical trials” (European EMEA; January 2003, US FDA; 2006) are a new method for verifying the pharmacokinetics in humans before the start of full-scale clinical trials. January). On the other hand, in June 2008, the Ministry of Health, Labor and Welfare announced the “Guidance on Implementation of Microdose Clinical Trials” in June 2008 (Non-Patent Document 1), and has a legal basis for full-scale implementation of early clinical trials in Japan. It was maintained. A microdose clinical study (MD clinical study) is a study in which a test substance with a very low dose (microdose) of 1/100 or 100 μg or less of the effective dose is administered to a healthy person in a single phase I clinical This is an epoch-making test that enables verification of the pharmacokinetics of the test substance in humans by conducting it before the test. The specific purpose is to clarify the absorption, blood kinetics, excretion characteristics, metabolite profile, etc. of the test substance, and to obtain information on the localization of the test substance in the body using molecular imaging technology. Etc. In February 2010, guidelines for non-clinical tests for early exploratory clinical trials, non-clinical tests for immunotoxicity, etc. are shown (Non-patent Document 2).

It is considered that the time transition of the drug concentration in the drug target tissue (in the vicinity of the target molecule) is important as a factor determining the drug efficacy and side effects. For example, pravastatin, one of the HMG-CoA reductase inhibitors, is mainly taken up by the multi-drug resistance associated protein (MRP) 2 after hepatic uptake by the organic anion transport polypeptide (OATP) 1B1 which is an uptake transporter. It is known to be excreted in bile. Therefore, an attempt was made to simulate the effect of changes in transport activity of OATP1B1 and MRP2 on blood and liver exposure of pravastatin using a physiological pharmacokinetic (PBPK) model including blood, liver, and peripheral tissues. (For example, Non-Patent Document 3). Furthermore, attempts have been made to perform molecular imaging using MD clinical trials and positron emission tomography (PET) and to utilize them for new drug development (for example, Non-Patent Document 4).

As described above, it is known that statin drugs such as pravastatin are compounds that are transported from the blood to the liver by OATPs that are liver uptake transporters. For this reason, various attempts have been made to obtain PET probes of these compounds. However, there have been no reports of successful synthesis of PET probes at this time. In the first place, there has been no report on a successful example of a labeled precursor of a statin drug for radiolabeling to obtain a PET probe.

The present invention provides a labeled precursor compound, a radiolabeled compound, and a method for producing them, which can provide a PET probe of a statin drug.

In one aspect, the present invention provides a compound of formula (I)

[In the formula (I), R ¹¹ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR ¹⁷ R ¹⁸ . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R ¹⁷ and R ¹⁸ each independently represent a C _1-2 alkyl group, R ¹² represents a hydrogen atom, C _1-4 An alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom; R ¹⁴ represents a hydrogen atom, a C _1-4 alkyl group; , A fluorine atom, a chlorine atom, or a bromine atom, R ¹⁵ represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or a phenyl group, and L ¹ represents — (CH ₂ ) _m —, _{_{-O (CH 2) m -,}} - (AO) n , Or -O _{(AO) n} - indicates, m represents an integer of 1 ~ 4, AO _represents an _{C 2-4} oxyalkylene group, n is an integer of 2 ~ 4, ^{X 1} is represents a reactive functional group, _{_{_{Y, -CH 2 -, - CH 2}}} CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH ₂ - indicates, Z ¹ represents —Q—CH ₂ —W—CH ₂ —CO ₂ R ¹⁶ , a group represented by the following formula (II), or a group represented by the following formula (III), and Q and W are: Each independently represents —C (O) —, —CH (OH) —, or —CH (OR ¹⁹ ) —, R ¹⁹ independently represents a C _1-4 alkyl group, and R ¹⁶ represents hydrogen. Atom, alkyl group, NH ₄ , sodium, potassium, or 1/2 calcium is shown. ]

It is related with the label | marker precursor compound or salt represented by these.

In another aspect, the present invention provides a compound of formula (IV)

[In the formula (IV), R ¹¹ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR ¹⁷ R ¹⁸ . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R ¹⁷ and R ¹⁸ each independently represent a C _1-2 alkyl group, R ¹² represents a hydrogen atom, C _1-4 An alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom, and R ¹⁵ represents a C _1-6 alkyl group, C _{3 -6 represents a} cycloalkyl group or a phenyl group, Y represents —CH ₂ —, —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ —CH═CH—, or —CH═CH—CH ₂ Z ¹ represents —Q—CH ₂ —W—CH _2- CO ₂ R ¹⁶ represents a group represented by the following formula (II) or a group represented by the following formula (III), and Q and W are each independently —C (O) —, —CH (OH) —, or —CH (OR ¹⁹ ) —, R ¹⁹ independently represents a C _1-4 alkyl group, and R ¹⁶ represents a hydrogen atom, an alkyl group, NH ₄ , sodium, potassium, or 1/2 represents calcium, and M represents a boronic acid ester group. ]

It is related with the label | marker precursor compound or its salt represented by these.

The present invention provides, as still another aspect, the formula (V)

[In the formula (V), R ¹¹ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR ¹⁷ R ¹⁸ . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R ¹⁷ and R ¹⁸ each independently represent a C _1-2 alkyl group, R ¹² represents a hydrogen atom, C _1-4 An alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom, L ² represents a bond, — (CH ₂ ) _m —, —O (CH ₂ ) _m —, — (AO) _n —, or —O (AO) _n —, m represents an integer of 0 to 4, and AO represents a C _2-4 oxyalkylene group. N represents an integer of 2 to 4, X ² represents a radionuclide, R ¹⁴ represents a hydrogen atom, a C _1-4 alkyl group, a fluorine atom, a chlorine atom, or a bromine atom; R ¹⁵ represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or a phenyl group; Y _{_{_{is, -CH 2 -, - CH 2}}} CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH ₂ - indicates, ^{Z 1} is, -Q-CH ₂ —W—CH ₂ —CO ₂ R ¹⁶ , a group represented by the following formula (II), or a group represented by the following formula (III), and Q and W are each independently -C (O)-, -CH (OH)-, or -CH (OR ¹⁹ )-, R ¹⁹ independently represents a C _1-4 alkyl group, R ¹⁶ represents a hydrogen atom, alkyl Represents the group NH ₄ , sodium, potassium, or 1/2 calcium. ]

The radiolabeled compound represented by these, or its salt.

As another aspect, the present invention relates to a method for producing the radiolabeled compound of the present invention, which comprises labeling the label precursor compound of the present invention with a labeling substance.

The present invention provides, as still another aspect, the formula (VI)

[In the formula (VI), R ¹¹ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR ¹⁷ R ¹⁸ . A benzyloxy group, a fluorine atom, a chlorine atom or a bromine atom, R ¹⁷ and R ¹⁸ each independently represent a C _1-2 alkyl group, R ¹² represents a hydrogen atom, C _1-4 An alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom, and R ¹⁵ represents a C _1-6 alkyl group, C _{3 -6 represents a} cycloalkyl group or a phenyl group, Y represents —CH ₂ —, —CH ₂ CH ₂ —, —CH═CH—, —CH ₂ —CH═CH—, or —CH═CH—CH ₂ Z ¹ represents —Q—CH ₂ —W—CH _2- CO ₂ R ¹⁶ represents a group represented by the following formula (II) or a group represented by the following formula (III), and Q and W are each independently —C (O) —, —CH (OH) —, or —CH (OR ¹⁹ ) —, R ¹⁹ independently represents a C _1-4 alkyl group, and R ¹⁶ represents a hydrogen atom, an alkyl group, NH ₄ , sodium, potassium, or X represents 1/2 calcium, and X ³ represents a sulfonate group, a halogen atom, a nitro group, or a trimethylammonium group. ]

A coupling reaction of a compound represented by the formula or a salt thereof with a boronic acid ester or diboron ester,
Formula (IV)

[In the formula (IV), R ¹¹ , R ¹² , R ¹⁵ , Y, and Z ¹ are as defined in the formula (VI), and M represents a boronic ester group. ] Or a salt thereof.

According to the present invention, a statin drug imaging probe, preferably a PET probe of a mevalonolactone derivative can be provided.

FIG. 1 is a graph showing the time course and saturation of transport of pitavastatin and PTVS6 by the liver uptake transporter (OATP1B1, OATP1B3). FIG. 2 is a graph showing an example of the results of changes over time in the distribution of [ ¹⁸ F] PTVS2. FIG. 3 is a graph showing another example of the results of changes over time in the distribution of [ ¹⁸ F] PTVS2. FIG. 4 is an image showing an example of the result of PET imaging using [ ¹⁸ F] PTVS2. FIG. 5 is a graph showing an example of the results of metabolic stability evaluation by an in vitro experiment using human liver microsomes.

The present invention is based on the finding that a compound represented by formula (I) and formula (IV) can provide a PET probe of a statin drug.

MD clinical trials can be carried out with simpler toxicity test data compared to normal clinical trials, and their effective use is expected to contribute greatly to improving the efficiency and success probability of drug development. In addition, it is considered that the time transition of the drug concentration in the medicinal target tissue for each individual is important as a factor determining the drug efficacy and side-effect variation of the drug among individuals. Therefore, there is a need for an imaging probe that can quantitatively measure the function of a transporter that takes drugs into tissues.

The HMG-CoA reductase inhibitor is a drug that exhibits a medicinal effect (serum cholesterol lowering) by inhibiting HMG-CoA reductase in the liver, such as pravastatin (US4346227), simvastatin, lovastatin, rosuvastatin, and pitavastatin Various statin drugs such as JP-A-1-279866, EP304063, US5856336 and the like are known. Among these, pitavastatin and rosuvastatin are known to be taken up mainly by OATP1B1 in human hepatocytes, and the present inventors have focused on pitavastatin and attempted to make a PET probe. Pitavastatin is a quinoline mevalonate compound having the following structure, and is commercially available as an HMG-CoA reductase inhibitor.

In making the PET probe, the present inventors tried to label pitavastatin using various direct labeling methods. However, the labeling reaction did not proceed, and the target radiolabeled compound was not obtained. Therefore, the present inventors constructed a new synthetic route, and in the process, by using the compounds represented by formula (I) and formula (IV) as a labeling precursor, PET of pitavastatin or a derivative thereof It has been found that a probe can be manufactured.

According to the present invention, a PET probe radiolabeled with a statin drug can be provided. Moreover, according to the present invention, in one aspect thereof, a PET probe radiolabeled with pitavastatin or a derivative thereof can be provided. Thus, according to the present invention, for example, in vivo parameters obtained by PET imaging using the radiolabeled compound of the present invention, human gene expression cells, human frozen hepatocytes, human bile duct side membrane vesicles, and / or Based on in vitro parameters related to transport and metabolism obtained using human liver microsomes, it is preferable that a model that predicts the time course of the test drug concentration in the liver in the human body can be constructed. . Furthermore, it is preferable that quantitative variation prediction of pharmacokinetics can be performed when there is a genetic polymorphism and / or drug-drug interaction as a factor of inter-individual variation in drug hepatic uptake / excretion process. .

It is known that pitavastatin is hardly metabolized in the liver and is excreted in bile in a form that hardly changes. Furthermore, as shown in the examples described later, the pitavastatin derivative, which is a cold form of the radiolabeled compound represented by the formula (V), is also metabolically stable with almost no metabolism in hepatocytes. Data that there is. For this reason, the radiolabeled compound represented by the formula (V) of the present invention is also considered to be metabolically stable. Therefore, it can be said that the radiolabeled compound of the present invention is extremely useful as a PET probe, and can be a very useful PET probe for measuring or evaluating intrahepatic kinetics.

In the present specification, the compounds represented by the formulas (I), (IV), (V), and (VI) have at least one or two asymmetric carbon atoms, and each has at least 2, 3 or 4 kinds of Optical isomers exist. Therefore, the compounds represented by the formulas (I), (IV), (V), and (VI) all include all of these optical isomers and all of these mixtures. Similarly, the compounds represented by the formulas (X), (XI), (XII), (XIII) and (XIV) have two asymmetric carbon atoms, and each has at least 2, 3 or 4 kinds of them. Because of the presence of optical isomers, these compounds are intended to encompass all of these optical isomers and all of their mixtures.

As used herein, examples of the “salt of a compound” include alkali metal salts, sulfates, acetates, nitrates, and phosphates. Examples of the alkali metal salt include sodium salt, potassium salt, and lithium salt.

[Labeled precursor compound (I)]
In one aspect, the present invention relates to a labeled precursor compound represented by the formula (I) or a salt thereof (hereinafter also referred to as “labeled precursor compound (I) of the present invention”).

The labeled precursor compound (I) of the present invention can provide, for example, a PET probe of a pitavastatin derivative. The PET probe obtained by radioactively labeling the labeled precursor compound (I) of the present invention exhibits, for example, a transport property in a similar liver uptake transporter (OATP) that is very similar to pitavastatin. For this reason, by performing PET imaging using the obtained PET probe, for example, the construction of a model for predicting the time transition of the concentration in the human in vivo liver, the gene as an inter-individual variation factor of the drug hepatic uptake / excretion process Prediction of polymorphism and / or drug interaction can be performed. By using the obtained PET probe, for example, the function of an organ, preferably the function of a drug transporter in the organ can be evaluated.

In the formula (I), R ¹¹ is represented by a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR ¹⁷ R ^18. A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom. Examples of the C _1-4 alkyl group include a methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group and t-butyl group. Examples of the C _1-3 alkoxy group include a methoxy group, an ethoxy group, an n-propoxy group, and an i-propoxy group.
R ¹⁷ and R ¹⁸ each independently represent a C _1-2 alkyl group, and examples thereof include a methyl group and an ethyl group. R ¹¹ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C _1-3 alkyl group, a C _1-3 alkoxy group, a dimethylamino group, or a benzyloxy group.

In the formula (I), R ¹² represents a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or bromine. Indicates an atom. The C _1-4 alkyl group and the C _1-3 alkoxy group are as R ¹¹ . R ¹² is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a C _1-3 alkyl group, or a C _1-3 alkoxy group.

In the formula (I), R ¹⁴ represents a hydrogen atom, a C _1-4 alkyl group, a fluorine atom, a chlorine atom, or a bromine atom. The C _1-4 alkyl group is as R ¹¹ . Among them, R ¹⁴ is preferably a hydrogen atom, a methyl group, or a fluorine atom, and more preferably a hydrogen atom. When R ¹⁴ is other than a hydrogen atom, R ¹⁴ is preferably in the ortho or meta position relative to the —L ¹ —X ¹ group.

In the formula (I), R ¹⁵ represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or a phenyl group. Examples of the C _1-6 alkyl group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, and an n-pentyl group. And n-hexyl. C _3-6 cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Among them, R ¹⁵ is preferably a primary or secondary C _1-6 alkyl group or a C _3-6 cycloalkyl group, more preferably an ethyl group, an n-propyl group, an i-propyl group, or a cyclopropyl group. And more preferably an i-propyl group or a cyclopropyl group.

In the formula (I), ^{L 1} _{_{is, - (CH 2) m -}} , - O (CH 2) m -, - (AO) n -, or -O _{(AO) n} - indicates, in ^{L 1,} AO _Represents a C _2-4 oxyalkylene group, and examples thereof include an oxyethylene group, an oxypropylene group, and an oxybutylene group, with an oxyethylene group being preferred. m represents an integer of 1 to 4, preferably 1, 2 or 3, more preferably 2. n represents an integer of 2 to 4, preferably 2 or 3. L ¹ is preferably — (CH ₂ ) ₂ — or —O (CH ₂ ) _m —, more preferably —O (CH ₂ ) ₂ —.

In the formula (I), X ¹ represents a reactive functional group. Examples of the reactive functional group include a functional group capable of reacting with a labeling substance that performs radiolabeling, and examples thereof include a sulfonate group, a halogen atom, a nitro group, a trimethylammonium group, and an alkyl silicon group. Examples of the sulfonate group include a mesylate (OMs) group, a tosylate (OTs) group, and a triflate (OTf) group. Examples of the halogen atom include a bromine atom, an iodine atom, and a chlorine atom.

In the formula (I), the —L ¹ -X ¹ group is any of 2-position, 3-position and 4-position when the carbon connected to the quinoline ring in the phenyl substituted at the 4-position of the quinoline ring is the 1-position. It is preferable that it is in the 3rd or 4th position, more preferably in the 4th position.

In formula (I), Y _{_{_{is, -CH 2 -, - CH 2}}} CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH ₂ - indicates, preferably —CH ₂ CH ₂ — or —CH═CH—, more preferably —CH═CH—.

In the formula (I), Z ¹ represents —Q—CH ₂ —W—CH ₂ —CO ₂ R ¹⁶ , a group represented by the following formula (II), or a group represented by the following formula (III). . Q and W each independently represent —C (O) —, —CH (OH) —, or —CH (OR ¹⁹ ) —. R ¹⁹ represents a C _1-4 alkyl group, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, sec-butyl group, and t-butyl. Groups and the like. Z ¹ is —CH (OR ¹⁹ ) —CH ₂ —CH (OR ¹⁹ ) —CH ₂ —CO ₂ R ¹⁶ , —CH (OR ¹⁹ ) —CH ₂ —C (O) —CH ₂ —CO ₂ R ¹⁶ And a group represented by the following formula (II) or a group represented by the following formula (III) is preferred, and more preferably —CH (OH) —CH ₂ —CH (OH) —CH ₂ —CO ₂ R ¹⁶ , —CH (OH) —CH ₂ —C (O) —CH ₂ —CO ₂ R ¹⁶ , a group represented by the following formula (II), or a group represented by the following formula (III).

In Z ¹ and formula (III), R ¹⁶ represents a hydrogen atom, an alkyl group, NH ₄ , sodium, potassium, or 1/2 calcium. The alkyl group is preferably a physiologically hydrolyzable alkyl group, such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, and a t-butyl group. Etc. R ¹⁶ is preferably a hydrogen atom or a t-butyl group.

Examples of the form of the labeled precursor compound (I) include solutions and powders, and powders are preferable from the viewpoint of handling, and lyophilized powders (lyophilized preparations) are more preferable. The labeled precursor compound (I) can be synthesized by referring to the following examples and the description in JP-A No. 5-310700.

An example of a preferred form of the labeled precursor compound (I) includes a compound represented by the following formula (X) or a salt thereof.

In the formula (X), Y, Z ¹ and X ¹ are the same as those in the labeled precursor compound (I) of the present invention and are as shown in the formula (I). X ¹ preferably represents a mesylate group, a tosylate group, a triflate group, or a fluorine atom. —YZ ¹ is preferably a group represented by the following formula (II ′) or a group represented by the following formula (III ′). In the formula (III ′), R ¹⁶ represents a hydrogen atom, a physiologically hydrolyzable alkyl group, NH ₄ , sodium, potassium, or 1/2 calcium.

The labeling precursor compound (I) of the present invention can be used as a labeling precursor for producing a radiolabeled compound. Therefore, the present invention provides, as another aspect, the use of compound (I) as a labeling precursor, the use of compound (I) for producing a radiolabeled compound, or the use of compound (I) as a radiolabeling precursor. On how to do.

[Labeled precursor compound (IV)]
In still another aspect, the present invention relates to a labeled precursor compound represented by formula (IV) or a salt thereof (hereinafter also referred to as “labeled precursor compound (IV) of the present invention”). According to the labeled precursor compound (IV) of the present invention, for example, a PET probe of pitavastatin or a derivative thereof can be provided.

In the formula (IV), R ¹¹ , R ¹² , R ¹⁵ , Y and Z ¹ are the same as in the labeled precursor compound (I) of the present invention and are as shown in the formula (I). M represents a boronic acid ester group. In the present specification, the “boronic acid ester group” refers to a product obtained by esterification of an alcohol and a corresponding boronic acid. Examples of the alcohol include methanol, ethanol, n-propanol, n-butanol, t-butanol, ethylene glycol, and pinacol. Examples of the boronic acid ester group include —B (OR ³¹ ) (OR ³² ), —B (OR ³³ O), and groups represented by the following formulae. R ³¹ , R ³² , R ³³ , R ³⁴ , R ³⁵ , R ³⁶ , and R ³⁷ are each independently a C _1-6 alkyl group, which may be substituted, and among them, a methyl group is preferable.

Examples of the form of the labeled precursor compound (IV) of the present invention include a solution and a powder. From the viewpoint of handling, a powder is preferable, and a lyophilized powder (lyophilized preparation) is more preferable. is there.

An example of a preferred form of the labeled precursor compound (IV) includes a compound represented by the following formula (XI) or a salt thereof. In the formula (XI), Y and Z ¹ are the same as in the labeled precursor compound (I) of the present invention and are as shown in the formula (I). —YZ ¹ preferably represents a group represented by the above formula (II ′) or a group represented by the above formula (III ′).

The labeling precursor compound (IV) of the present invention can be manufactured based on the manufacturing method of the labeling precursor compound described later, Examples and the like.

The label precursor compound (IV) of the present invention can be used as a label precursor for producing a radiolabeled compound. Accordingly, the present invention provides, as another aspect, the use of compound (IV) as a radiolabeled precursor, the use of compound (IV) to produce a radiolabeled compound, or compound (IV) as a radiolabeled precursor. Relates to the method used.

[Method for producing labeled precursor compound (VI)]
The present invention provides a method for producing a compound represented by the formula (IV), which further comprises a coupling reaction between a compound represented by the formula (VI) and a boronic acid ester or a diboron ester as another embodiment. (Hereinafter also referred to as “a method for producing a labeled precursor compound of the present invention”). According to the method for producing a labeled precursor compound of the present invention, the labeled precursor compound (IV) of the present invention can be efficiently produced. The production method of the present invention can be carried out, for example, with reference to the following schemes and examples.

In the formula (VI), R ¹¹ , R ¹² , R ¹⁵ , Y, and Z ¹ are as shown in the formula (I). In the formula (VI), X ³ represents a sulfonate group, a halogen atom, a nitro group, or a quaternary ammonium. The sulfonate group and the halogen atom are as shown in the formula (I). Examples of the quaternary ammonium include trimethylammonium. X ³ is preferably an OMs group, an OTs group, an OTf group, a bromine atom, an iodine atom, or a chlorine atom.

The compound represented by the formula (VI) can be appropriately synthesized by referring to the method for producing a mevalonolactone derivative described later and the description in Examples.

The coupling reaction can be performed by reacting the compound represented by the formula (VI) with a boronic acid ester or diboron ester in an inert solvent in the presence of a catalyst and a base, for example.

Examples of boronic esters include 2- (bromomethyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and 2-allenyl-4,4,5,5-tetramethyl-1 3,2-dioxaborolane and the like. Examples of the diboron ester include bis (pinacolato) diboron, bis (hexylene glycolato) diboron, and bis (neopentyl glycolato) diboron. Especially, it is preferable to perform a coupling reaction using diboron ester, More preferably, it is bis (pinacolato) diboron.

Although it does not restrict | limit especially as a catalyst, Metal compounds, such as a palladium compound and platinum / indium, a phase transfer catalyst, etc. can be used. Examples of the palladium compound include PdCl ₂ (dppf) CH ₂ Cl ₂ , Pd (PPh ₃ ) _{4 and the} like, and one kind may be used, or two or more kinds may be used in combination. Examples of the base include carbon salt, potassium acetate, NaOH, Et ₃ N, K ₃ PO _{4 and the} like. Examples of the carbonate include sodium carbonate, cesium carbonate, and potassium carbonate. Among these, potassium carbonate is preferable as the base from the viewpoint of efficiently obtaining the target compound. The coupling reaction may be performed under microwave irradiation from the viewpoint of improving the reaction efficiency.

Examples of the inert solvent include alcohol solvents, nitrile solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents, and aromatic hydrocarbon solvents. Examples of alcohol solvents include methanol, ethanol, propanol, 2-propanol, butanol, isobutanol, and tert-butanol. Examples of the nitrile solvent include acetonitrile, propionitrile, and the like. Examples of the amide solvent include N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, and the like. Examples of the halogenated hydrocarbon solvent include dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like. Examples of the ether solvent include diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane, and the like. Examples of the aromatic hydrocarbon solvent include benzene, toluene, and xylene. These may be used alone or in combination of two or more. Among them, the inert solvent is preferably THF and / or dichloromethane.

[Radiolabeled compound]
As another aspect, the present invention relates to a radiolabeled compound represented by formula (V) or a salt thereof (hereinafter also referred to as “the radiolabeled compound of the present invention”). The radiolabeled compounds of the present invention exhibit transport properties in similar liver uptake transporters OATP1B1 and OATP1B3, which are very similar to, for example, pitavastatin. For this reason, uptake in OATP1B1 and OATP1B3 can be evaluated in humans by performing PET imaging using the radiolabeled compound of the present invention. According to the radiolabeled compound of the present invention, for example, the construction of a model for predicting the time transition of the test drug concentration of the liver in the human body, the gene polymorphism as an inter-individual variation factor of the hepatic uptake / excretion process of the drug and / or Or prediction of the interaction between drugs can be performed. According to the radiolabeled compound of the present invention, for example, the function of an organ can be evaluated, and preferably the function of a drug transporter in an organ can be evaluated.

In the formula (V), R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , Y, and Z ¹ are the same as the labeled precursor compound (I) of the present invention, and are as shown in the formula (I). is there.

In the formula (V), L ² represents a bond, — (CH ₂ ) _m —, —O (CH ₂ ) _m —, — (AO) _n —, or —O (AO) _n —, and L ² In the formula, AO represents a C _2-4 oxyalkylene group, and examples thereof include an oxyethylene group, an oxypropylene group, and an oxybutylene group, and preferably an oxyethylene group. m represents an integer of 0 to 4, preferably 0, 1, 2, or 3, more preferably 2. n represents an integer of 2 to 4, preferably 2 or 3. L ² is preferably a bond, — (CH ₂ ) ₂ —, or —O (CH ₂ ) _m —, more preferably a bond or —O (CH ₂ ) ₂ —.

In the formula (V), X ² represents a radionuclide. The radionuclide is not particularly limited, but is preferably a positron emitting nuclide, more preferably ¹¹ C or ¹⁸ F, and even more preferably ¹⁸ F.

In the formula (V), the —L ² —X ² group is any one of the 2-position, 3-position and 4-position when the carbon connected to the quinoline ring in the phenyl substituted at the 4-position of the quinoline ring is the 1-position. It is preferable that it is in the 3rd or 4th position, more preferably in the 4th position.

An example of a preferred form of the radiolabeled compound (IV) of the present invention includes a compound represented by the following formula (XII) or a salt thereof.

In the formula (XII), in the formula (XII), Y and Z ¹ are the same as in the labeled precursor compound (I) of the present invention, and are as shown in the formula (I). —YZ ¹ preferably represents a group represented by the above formula (II ′) or a group represented by the above formula (III ′). In the formula (XII), L ² and X ² are the same as the labeled precursor compound (IV) of the present invention, and are as shown in the formula (IV). —L ² —X ² preferably represents a [ ¹⁸ F] fluorine atom or —O— (CH ₂ ) ₂ — [ ¹⁸ F] F.

The radiolabeled compound of the present invention can be used for imaging, for example, PET imaging, and preferably performs imaging for evaluation of inter-individual variability and drug metabolism / transport function in a human body. it can. The radiolabeled compound of the present invention can be used as a PET probe. For example, it can be used as a composition, imaging reagent, contrast agent, diagnostic imaging agent, and the like used in the imaging described above. Possible forms of these compositions, diagnostic imaging agents, and the like include, for example, solutions and powders. In view of the half-life of radionuclides and decay of radioactivity, solutions are preferable, and injection solutions are more preferable. .

The imaging composition, imaging reagent, contrast agent, and diagnostic imaging agent containing the radiolabeled compound of the present invention may contain, for example, a pharmaceutical additive such as a carrier. In this specification, a pharmaceutical additive refers to a compound that has been approved as a pharmaceutical additive in the Japanese Pharmacopoeia, the American Pharmacopoeia, and / or the European Pharmacopoeia. As the carrier, for example, an aqueous solvent and a non-aqueous solvent can be used. Examples of the aqueous solvent include potassium phosphate buffer, physiological saline, Ringer's solution, and distilled water. Examples of the non-aqueous solvent include polyethylene glycol, vegetable oil, ethanol, glycerin, dimethyl sulfoxide, and propylene glycol.

The radiolabeled compound of the present invention can be produced, for example, by labeling the labeling precursor compound (I) or (IV) of the present invention with a labeling substance. Accordingly, the present invention, as yet another aspect, relates to a method for producing the radiolabeled compound of the present invention, which comprises labeling the labeled precursor compound (I) or (IV) of the present invention with a labeling substance. According to the production method of the present invention, the radiolabeled compound (V) of the present invention can be efficiently produced.

The labeling substance can be appropriately determined according to the type of radionuclide to be labeled and the labeling precursor compound. When the radionuclide is ¹⁸ F, it can be carried out by a known method using, for example, [ ¹⁸ F] KF, 1- [ ¹⁸ F] fluoro-4-iodobenzene or the like. The labeling reaction can be performed, for example, in the presence of a catalyst and a base in an inert solvent, and examples of the catalyst, the base, and the inert solvent include those described above.

The radiolabeled compound of the present invention can be produced, for example, by referring to the following scheme and examples.

The radiolabeled compound (V) of the present invention can be used in an imaging method, an OATP uptake function evaluation method, an uptake transporter function observation method, a bile excretion transporter function observation method, etc., which will be described later. Therefore, the present invention provides, as still another aspect, the use of compound (V) as an imaging agent, the use of compound (V) for the production of an imaging agent, the method of using compound (V) as an imaging agent, Alternatively, the present invention relates to the use of the compound (V) used for the imaging method, the evaluation method of the OATP uptake function, the observation method of the uptake transporter function, or the observation method of the bile excretion transporter function.

[Imaging method]
In still another aspect, the present invention relates to an imaging method including detecting a radioactive signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound of the present invention. According to the imaging method of the present invention, for example, it is possible to evaluate inter-individual fluctuations in pharmacokinetics and in vivo drug transport functions in humans. Examples of the subject include humans and / or mammals other than humans.

The detection of the signal is preferably performed over time, and more preferably, it is preferably started immediately after administration of the radiolabeled compound of the present invention.

The detection of the signal may be performed from the whole subject or may be performed locally, at least, the uptake transporter for taking up the radiolabeled compound of the present invention, and / or the excretion of the radiolabeled compound of the present invention. It is preferably performed in an organ or an in vivo tissue expressing the excretion transporter. Examples of organs that express the transporter include liver, small intestine, brain and kidney.

The imaging method of the present invention may include, for example, reconstructing a detected signal to convert it into an image and displaying it, and / or quantifying the detected signal to present an accumulation amount. . The display includes, for example, displaying on a monitor and printing. The presentation includes, for example, storing the calculated accumulation amount and outputting it to the outside.

[Evaluation method of OATP uptake function]
In still another aspect, the present invention relates to a method for evaluating the uptake function in an organic anion transport polypeptide, which comprises detecting a radio signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound of the present invention. . According to the evaluation method of the present invention, inter-individual variability and drug transport function can be evaluated in the human body. Based on the results obtained by the evaluation method of the present invention, for example, for a drug having another similar transport route, obtain an optimum prescription design judgment criterion such as a dose and a dose interval according to the drug transport function of the subject. be able to. Examples of the subject include humans and / or mammals other than humans. Signal detection and the like can be performed in the same manner as the imaging method of the present invention.

Organic anion transport polypeptides (OATP) are various OATPs including OATP1B1 and OATP1B3 in the case of humans, and various Oats including Oatp1a1, Oatp1a4 and Oatp1b2 in the case of mice and rats.

Examples of organs for evaluating the uptake function include OATP-expressing organs, such as liver, small intestine, brain and kidney. Among them, as described above, pitavastatin is expressed on the blood vessel side of hepatocytes and is known to be mainly taken up by the liver transporter OATP1B1 involved in the uptake of blood into hepatocytes. Is preferred.

[Observation method of import transporter function]
In still another aspect, the present invention relates to a method for observing an uptake transporter function expressed in hepatocytes, which comprises detecting a radio signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound of the present invention. . According to the observation method of the present invention, the uptake transporter function expressed in the liver can be observed by imaging using the radiolabeled compound of the present invention.

According to the observation method of the present invention, the uptake transporter function can be measured, analyzed, and / or evaluated based on the detected radioactive signal. Thereby, according to the observation method of the present invention, for example, the inter-individual variation in the liver uptake transporter function and / or the drug transport function can be evaluated in the human body. In addition, based on the measurement, analysis, and / or evaluation results obtained by the observation method of the present invention, for example, for drugs having other similar transport routes, the dose and the dose interval according to the drug transport function of the subject It is possible to obtain the optimum prescription design criteria. The subject, signal detection, and the like are as described above.

In the observation method of the present invention, the uptake transporter to be observed is preferably OATP. The observation method of the present invention more preferably measures the uptake transporter function in OATP expressed in the liver, and measures and / or evaluates the hepatic uptake function of the subject.

The observation of the uptake transporter function is preferably performed by performing imaging over time. The observation method of the present invention includes, for example, measuring, evaluating, or measuring the uptake of the radiolabeled compound of the present invention in the uptake transporter by performing detection of the radioactive signal over time and comparing the detected signal over time. It may include analyzing. Measurement, evaluation or analysis of the uptake of the radiolabeled compound of the present invention includes, for example, comparison of images obtained by reconstructing the detected signal, quantification of the uptake based on the detected signal, etc. Is mentioned.

[Observation of bile excretion transporter function]
In still another aspect, the present invention relates to a method for observing a biliary excretion transporter function, which comprises detecting a radio signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound of the present invention. It has been found that the radiolabeled compound of the present invention is metabolically stable with almost no metabolism in the liver. Therefore, according to the measurement method of the present invention, the bile excretion transporter function can be evaluated in vivo by performing imaging using the radiolabeled compound of the present invention.

According to the observation method of the present invention, the bile excretion transporter function can be measured, analyzed, and / or evaluated based on the detected radioactive signal. Thereby, according to the observation method of the present invention, for example, the inter-individual variation in the bile excretion transporter function and / or the drug transport function can be evaluated in the human body. In addition, based on the measurement, analysis, and / or evaluation results obtained by the observation method of the present invention, for example, for drugs having other similar transport routes, the dose and the dose interval according to the drug transport function of the subject It is possible to obtain the optimum prescription design criteria. The subject, signal detection, and the like are as described above.

As bile excretion transporters, for example, MDR1 (multidrug resistance-1; P-glycoprotein), MRP2 (multidrug resistance-associated protein 2), BCRP (breast cancer resistance-protein), and BSEP (bile salmon export-pump) are known. ing.

The observation of the bile excretion function is preferably performed by performing imaging over time. The observation method of the present invention is, for example, measuring and evaluating the excretion of the radiolabeled compound of the present invention in the bile excretion transporter by performing detection of the radioactive signal over time and comparing the detected signal with time. Or it may include analyzing. Measurement, evaluation, or analysis of the emission of the radiolabeled compound of the present invention includes, for example, comparison of images obtained by reconstructing the detected signal, or quantification of emission based on the detected signal. Can be mentioned.

Observation of the uptake transporter function expressed in the liver and observation of the bile excretion transporter function may be performed simultaneously. By simultaneously observing the transporter function of the uptake transporter and the bile excretion transporter, for example, there is a possibility that the bile excretion mechanism in hepatocytes can be more accurately evaluated.

In the present invention, the method for observing the transporter function is not particularly limited to the above. For example, the function of the excretion transporter that can be used as a substrate by the labeled compound of the present invention other than the biliary excretion transporter may be observed. .

[kit]
In still another aspect, the present invention relates to a kit containing a labeled precursor compound (I), a labeled precursor compound (IV), or a radiolabeled compound (V). The kit of the present invention can be used for, for example, synthesis of radiolabeled compounds, imaging, and measurement or evaluation of OATP uptake function, liver uptake transporter function, and bile excretion transporter function. It is preferable that the kit of this invention contains the instruction manual according to each form. The instruction manual may be included in the kit or may be provided on the web.

The kit of the present invention may further include a container for containing the labeled precursor compound (I), the labeled precursor compound (IV), or the radiolabeled compound (V). Examples of the container include a syringe and a vial.

The kit of the present invention may further include, for example, a component for preparing a molecular probe such as a buffer and an osmotic pressure regulator, and / or a device used for administration of a peptide derivative such as a syringe.

[New production method of mevalonolactone derivatives]
In still another aspect, the present invention relates to a new method for producing a mevalonolactone derivative. That is, the present invention provides a compound represented by the formula (IV) by a coupling reaction between a compound represented by the formula (VI) and a boronic acid ester or diboron ester (Step 1), and the formula ( The present invention relates to a method for producing a compound represented by formula (VIII), which comprises reacting a compound represented by IV) with a compound represented by formula (VII) (step 2). According to the synthesis method of the present invention, pitavastatin or a derivative thereof can be easily obtained.

The manufacturing method of this invention can be performed based on the following scheme, for example.

(Process 1)
The coupling reaction between the compound represented by the formula (VI) and the boronic acid ester or diboron ester can be carried out in the same manner as in the method for producing a labeled precursor compound of the present invention. R ¹¹ , R ¹² , R ¹⁵ , Y, Z ¹ and X ³ , the boronic acid ester, and the diboron ester in the formula (VI) are as described above.

(Process 2)
The reaction between the compound represented by formula (IV) and the compound represented by formula (VII) can be carried out by reacting these compounds in an inert solvent in the presence of a catalyst and a base. The compound represented by the formula (IV) is the labeled precursor compound (IV) of the present invention.

In the formula (VII), R ¹³ represents a hydrogen atom, a C _1-4 alkyl group, a C _1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a benzyloxy group, a fluorine atom, chlorine An atom, a bromine atom, a trifluoromethyl group, a phenoxy group, or a phenyl group is shown. R ³³ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, or a methyl group, and more preferably a fluorine atom. R ¹³ may be in any of the 2-position, the 3-position and the 4-position when the carbon to which X ⁴ is bonded in phenyl is the 1-position, preferably the 3-position or 4-position, and more preferably 4 It is rank.

In the formula (VII), R ¹⁴ is as shown in the formula (I). When R ¹⁴ is other than a hydrogen atom, R ¹⁴ is preferably in the ortho position or the meta position with respect to R ¹³ .

In the formula (VII), X ⁴ is a reactive functional group. Examples of the reactive functional group include a functional group capable of reacting with a boronic acid ester group. For example, those represented by the above formula (I) can be used, and among them, an iodine atom or the like is preferable.

In the formula (VIII), R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , Y, and Z ¹ are as described above.

Although it does not restrict | limit especially as a catalyst, Metal catalysts, such as a palladium compound and platinum / indium, etc. can be used. Examples of the palladium compound include PdCl ₂ (dppf) CH ₂ Cl ₂ , Pd (PPh ₃ ) ₄ , and the combined use of PdCl ₂ (dppf) CH ₂ Cl ₂ and Pd (PPh ₃ ) ₄ . Examples of the base include carbon salt, potassium acetate, NaOH, Et ₃ N, K ₃ PO _{4 and the} like. Examples of the carbonate include sodium carbonate, cerium carbonate, and potassium carbonate. Among these, sodium carbonate is preferable as the base from the viewpoint of efficiently obtaining the target compound. From the viewpoint of greatly shortening the reaction time and improving the production efficiency, the coupling reaction is preferably performed under microwave irradiation.

The compound represented by the formula (VI) is obtained by, for example, reacting the compound represented by the formula (IXa) with a base, followed by a condensation reaction with the compound represented by the formula (Xa) or the formula (XIa). The obtained compound can be obtained by deprotection, hydrolysis and / or lactonization. This synthesis can be performed based on the description of the following scheme and examples.

Examples of the base include sodium compounds, potassium compounds, and alkyl lithium compounds. Sodium hydride etc. are mentioned as a sodium compound. Examples of the potassium compound include t-butoxy potassium. Examples of the alkyl lithium compound include butyl lithium.

In the formula (IXa), R ¹¹ , R ¹² , R ¹⁵ , and X ³ are as described above.

In the formulas (Xa) and (XIa), R ^38a and R ^38b represent a hydroxyl-protecting group. R ^38a and R ^38b are each independently a methoxymethyl group, a 2-methoxymethyl group, a tetrahydroxypyranyl group, a 4-methocaesitetrahydropyranyl group, a 2-ethoxyethyl group, a 1-methyl-1- It represents a methoxyethyl group, a triphenylmethyl group, or a trimethylsilyl group, or R ^38a and R ^38b together represent isopropylidene, cyclopentylidene, cyclohexylidene, or benzylidene. In the formula (Xa), R ¹⁶ is as described above.

In the formulas (Xa) and (XIa), -Y ¹ represents -P ⁺ R ⁴¹ R ⁴² R ⁴³ Hal ^- or -P (W ¹ ) R ⁴⁴ R ⁴⁵ . R ⁴¹ , R ⁴² and R ⁴³ are each independently a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a 2-chloroethyl group, a 2,2,2-trifluoroethyl group, a phenyl group, A methylphenyl group, a methoxyphenyl group, a pentafluorophenyl group, or a benzyl group; Hal represents a chlorine atom, a bromine atom, or an iodine atom. R ⁴⁴ and R ⁴⁵ are each independently a methyl group, ethyl group, propyl group, isopropyl group, butyl group, 2-chloroethyl group, 2,2,2-trifluoroethyl group, phenyl group, methoxyphenyl group, Methylphenyl, pentafluorophenyl, benzyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, phenoxy, methoxyphenyl Represents an oxy group, a methylphenyloxy group, a pentafluorophenyloxy group, a methylphenyloxy group, or a benzyloxy group, or R ⁴⁴ and R ⁴⁵ together form a 5- or 6-membered ring; Also good. W ¹ represents an oxygen atom or a sulfur atom. In the formulas (Xa) and (XIa), —Y ¹ is preferably P (W ¹ ) R ⁴⁴ R ⁴⁵ , more preferably —POR ⁴⁴ R ⁴⁵ , more preferably R ⁴⁴ and R ⁴⁵ are methoxy groups. -POR ⁴⁴ R ⁴⁵ .

The compound represented by the formula (VI) is obtained by, for example, reacting the compound represented by the formula (IXb) with a base, followed by a condensation reaction with the compound represented by the formula (Xb) or the formula (XIb). The obtained compound may be obtained by deprotection, hydrolysis and / or lactonization. This synthesis can be performed based on the description of the following scheme and examples.

R ¹¹ , R ¹² , R ¹⁵ , Y ¹ , and X ³ in formula (IXb), R ^38a , R ^38b , and R ¹⁶ in formula (Xb) and formula (XIb), the bases used are as described above. is there.

[New mevalonolactone derivatives]
In still another aspect, the present invention relates to a new mevalonolactone derivative. That is, the present invention relates to a compound represented by the formula (XIII) or a salt thereof (hereinafter also referred to as “compound (XIII) of the present invention”). According to the compound (XIII) of the present invention, it can be easily produced as compared with the conventional mevalonolactone derivative, and can be produced at an inexpensive production cost. In addition, the compound (XIII) of the present invention can exhibit the same actions and effects as, for example, conventional pitavastatin.

In the formula (XIII), R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , Y and Z ¹ are the same as those in the labeled precursor compound (I) of the present invention and are as shown in the formula (I). In the formula (XIII), L ³ represents —O (CH ₂ ) _m —, — (AO) _n —, or —O (AO) _n —, m represents an integer of 0 to 4, and AO represents , C _2-4 oxyalkylene group, n represents an integer of _2-4 . —L ³ — is preferably —O (CH ₂ ) _m —, more preferably —O (CH ₂ ) ₂ —. In the formula (XIII), X ⁵ is a halogen atom, preferably a bromine atom, an iodine atom, or a chlorine atom, more preferably a fluorine atom.

An example of a preferred form of the compound (XIII) of the present invention includes a compound represented by the following formula (XIV). In the formula (XIV), —YZ ¹ is the same as in the formula (I), and X ⁵ is the same as in the formula (XIII).

The compound (XIII) of the present invention can be used, for example, as an HMG-CoA reductase inhibitor. The compound (XIII) of the present invention can also be used for the treatment of hyperlipidemia, arteriosclerosis and the like. Therefore, the present invention provides, as still another aspect, the use of compound (XIII) as an HMG-CoA reductase inhibitor, the use of compound (XIII) for the production of an HMG-CoA reductase inhibitor, compound (XIII ) As a HMG-CoA reductase inhibitor, compound (XIII) for use in a method for treating hyperlipidemia and / or arteriosclerosis, non-pharmacological treatment of hyperlipidemia and / or arteriosclerosis It relates to the use of compound (XIII) for the method or compound (XIII) for the manufacture of a therapeutic agent for hyperlipidemia and / or arteriosclerosis.

Hereinafter, the present invention will be further described using examples. However, the present invention is not construed as being limited to the following examples.

The following abbreviations are used in the description of the present specification.
DMA: N, N′-dimethylacetamide KM: methyl 3-cyclopropyl-3-oxopropionate TFA: trifluoroacetic acid TBSCl: t-butyldimethylsilyl chloride DMF: N, N′-dimethylformamide THF: tetrahydrofuran KM: 3 -Methyl cyclopropyl-3-oxopropanoate PPh ₃ : Triphenylphosphine Ph ₂ POEt: Ethoxydiphenylphosphine TMP: 2,2,6,6-tetramethylpiperidine DIO: tert-Butyl (3R, 5S) -6-oxo -3,5-O-isopropylidene-3,5-dihydroxyhexanoate
TBAF: tetrabutylammonium fluoride TsCl: p-toluenesulfonyl chloride
Kryptofix (registered trademark) 2.2.2 (product name: manufactured by Merck): 4,7,13,16,21,24-Hexaoxa-1,10-diazabicyclo [8.8.8] hexacosane
BuONO: t-butyl nitrite DIBAL: diisobutylammonium hydride TBAB: tetrabutylammonium bromide TEMPO: [(2,2,6,6-tetramethylpiperidinyl) oxy] radical (Bpin) ₂ : bispinacolato diboron DMSO: dimethyl sulfoxide MsCl: methanesulfonyl chloride

In this specification, the following devices were used as measuring devices.
NMR
Spectrometer: ADVANCE DRX (BRUKER BIOSPIN)
Magnet: UltraShield 400MHz / 54mm
Standard substance: TMS (tetramethylsilane)
MS
Measuring device: Micromass AQ (Waters)
Ionization: ESI

Production Example 1 Production of Label Precursor Compound According to the following scheme, PTVS1, which is a label precursor compound, was produced. The scheme will be specifically described below.

Synthesis of Compound (i-2) Under a nitrogen stream, a solution of Compound (i-1) (2.57 g, 6.27 mmol) in methylene chloride (10 mL) was cooled in an ice-water bath, and TFA / thioanisole = 10/1 (10 mL). ) Was added dropwise. The mixture was stirred for 2 days while gradually warming to room temperature, TFA / thioanisole = 10/1 (10 mL) was added and stirred overnight, and then the reaction solution was concentrated. The concentrate was added dropwise to saturated aqueous sodium bicarbonate (200 mL) cooled in an ice-water bath, and extracted twice with ethyl acetate (140 mL, 50 mL). The obtained organic layers were combined, washed with saturated brine (100 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 35 g, developing solvent: n-hexane / ethyl acetate = 4/1 → 0/1). The target compound (i-2) was obtained as a light brown solid in a yield of 63%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.02-1.09 (m, 2H), 1.34-1.39 (m, 2H), 2.16-2.22 (m, 1H), 3.67 (s, 3H), 5.64 ( br. s., 1H), 6.92-6.96 (m, 2H), 7.24-7.28 (m, 2H), 7.36-7.40 (m, 1H), 7.59-7.61 (m, 1H), 7.65-7.69 (m, 1H), 7.97-8.01 (m, 1H).

Synthesis of Compound (i-3) Under a nitrogen stream, 2-bromoethanol (3.00 g, 24.0 mmol) in DMF (15 mL) solution was charged with imidazole (4.08 g, 60.0 mmol) and TBSCl (4.34 g, 28.8 mmol). In addition, the mixture was stirred at room temperature for 3.5 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed successively with 0.5M hydrochloric acid (30mL), water (30mL), saturated aqueous sodium bicarbonate (50mL), water (30mL) and saturated brine (30mL), and each aqueous layer was washed with ethyl acetate (50mL). Extracted in The organic layers were combined, dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. (2-Bromoethoxy) (t-butyl) dimethylsilane (5.30 g, 22.1 mmol) was obtained as a colorless oil in a yield of 92%.

Under a nitrogen stream, potassium carbonate (1.10 g, 7.96 mmol) was added to a DMF (13 mL) solution of compound (i-2) (1.27 g, 3.97 mmol), and (2-bromoethoxy) (t-butyl) dimethylsilane was added. (1.73 g, 7.23 mmol) was added dropwise. After stirring at room temperature for 13.5 hours, the mixture was heated and stirred in a 55 ° C. water bath for 3 hours. Ethyl acetate (50 mL) was added to the reaction solution, washed successively with water (50 mL) and saturated brine (30 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 30 g, developing solvent: toluene / ethyl acetate = 40/1). The target compound (i-3) (1.65 g, 3.45 mmol) was obtained as a pale yellow solid in a yield of 86%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.15 (s, 6H), 0.95 (s, 9H), 1.03-1.10 (m, 2H), 1.35-1.56 (m, 2H), 2.17-2.21 ( m, 1H), 3.65 (s, 3H), 4.04 (t, J = 5.04 Hz, 2H), 4.13 (t, J = 5.04 Hz, 2H), 7.02-7.04 (m, 2H), 7.29-7.31 (m , 2H), 7.36-7.39 (m, 1H), 7.58-7.60 (m, 1H), 7.64-7.68 (m, 1H), 7.97-7.99 (m, 1H).

Synthesis of Compound (i-4) A THF (30 mL) solution of Compound (i-3) (1.50 g, 3.13 mmol) was cooled in an ice-water bath under a nitrogen stream. Lithium ammonium hydride (360 mg, 9.48 mmol) was added in three portions, and the mixture was stirred for 20 minutes in an ice-water bath and 1.5 hours at room temperature. The reaction solution was cooled in an ice-water bath, and water (360 μL), 15% aqueous sodium hydroxide solution (360 μL), and water (1 mL) were successively added dropwise. Ethyl acetate (20 mL) was added, and the mixture was filtered through Celite, dried over sodium sulfate, filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The target compound (i-4) (1.45 g, 3.22 mmol) was obtained as a yellow oil in a crude yield of 102%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.15 (s, 6H), 0.95 (s, 9H), 1.09-1.11 (m, 2H), 1.37-1.39 (m, 2H), 2.05 (s, 2H), 2.55-2.65 (m, 1H), 4.05 (t, J = 5.04 Hz, 2H), 4.14 (t, J = 5.04 Hz, 2H), 4.79 (br.s., 1H), 7.06-7.09 ( m, 2H), 7.23-7.25 (m, 2H), 7.32-7.34 (m, 1H), 7.38-7.42 (m, 1H), 7.58-7.63 (m, 1H), 7.96-7.98 (m, 1H). MS (ES ⁺ ) 450.1

Synthesis of Compound (i-5) Carbon tetrabromide (1.83 g, 5.82 mmol) was added to a suspension of compound (i-4) (1.30 g, 2.89 mmol) in methylene chloride (15 mL) under a nitrogen stream. The solution was cooled in an ice-water bath, and a solution of PPh ₃ (1.52 g, 5.79 mmol) in methylene chloride (1.5 mL) was added dropwise. After stirring in an ice water bath for 30 minutes, saturated aqueous sodium hydrogen carbonate (40 mL) was added dropwise, and the mixture was extracted twice with chloroform (35 mL, 15 mL). The organic layer was dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 50 g, developing solvent: chloroform). The target compound (i-5) (1.28 g, 2.49 mmol) was obtained as a yellow oil in a yield of 86%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.16 (s, 6H), 0.96 (s, 9H), 1.13-1.16 (m, 2H), 1.38-1.40 (m, 2H), 2.50-2.54 ( m, 1H), 4.06 (t, J = 5.04 Hz, 2H), 4.17 (t, J = 5.04 Hz, 2H), 4.65 (s, 2H), 7.09-7.11 (m, 2H), 7.30-7.36 (m , 4H), 7.59-7.64 (m, 1H), 7.95-7.97 (m, 1H). MS (ES ⁺ ) 512.3

Synthesis of Compound (i-6) Under a nitrogen stream, Ph ₂ POEt (0.70 g, 3.04 mmol) was added to a toluene (28 mL) solution of Compound (i-5) (1.28 g, 2.49 mmol) and stirred for 3 hours. Refluxed. After cooling to room temperature, the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 20 g, developing solvent: chloroform / ethyl acetate = 50/1 → 1/3). The target compound (i-6) (1.55 g, 2.44 mmol) was obtained as a yellow amorphous solid in a crude yield of 97%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.18 (s, 6H), 0.93-0.98 (m, 2H), 0.97 (s, 9H), 1.23-1.29 (m, 2H), 2.50-2.54 ( m, 1H), 4.05-4.16 (m, 6H), 6.69-6.87 (m, 4H), 7.13-7.58 (m, 12H), 7.81-7.86 (m, 1H), 7.93-7.95 (m, 1H). MS (ES ⁺ ) 634.2

Synthesis of Compound (i-7) Under a nitrogen stream, a solution of TMP (0.45 g, 3.18 mmol) in THF (10 mL) was cooled in a dry ice-acetone bath, and 1.6 M n-BuLi in n-hexane (3.50). mL, 5.62 mmol) was added dropwise, and the mixture was stirred at −20 ° C. for 10 minutes. After cooling to −70 ° C. or lower, a solution of compound (i-6) (1.55 g, 2.44 mmol) in THF (20 mL) was added dropwise, followed by stirring at the same temperature for 30 minutes. At the same temperature, a solution of DIO (1.00 g, 3.90 mmol) in THF (10 mL) was added dropwise. After stirring overnight while gradually warming to room temperature, saturated aqueous sodium bicarbonate (20 mL) was added dropwise, and water (40 mL) was added. In addition, the mixture was extracted twice with ethyl acetate (60 mL, 30 mL). The obtained organic layers were combined, washed with saturated brine (60 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 40 g, developing solvent: toluene / ethyl acetate = 50/1 → 1/1). The target compound (i-7) (569 mg, 844 μmol) was obtained as a tan oil in a yield of 34%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.16 (s, 6H), 0.96 (s, 9H), 1.00-1.13 (m, 2H), 1.23-1.35 (m, 2H), 1.40 (s, 3H), 1.46 (s, 9H), 1.57 (s, 3H), 2.29-2.47 (m, 5H), 4.02-4.07 (m, 2H), 4.10-4.16 (m, 2H), 4.20-4.30 (m, 1H), 4.35-4.45 (m, 1H), 5.68 (dd, J = 16.37, 6.04 Hz, 1H), 6.56 (dd, J = 16.37, 1.13 Hz, 1H), 6.99-7.03 (m, 2H), 7.10 -7.31 (m, 3H), 7.42-7.44 (m, 1H), 7.55-7.60 (m, 1H), 7.93-7.95 (m, 1H).

Synthesis of Compound (i-8) Under a nitrogen stream, a solution of Compound (i-7) (540 mg, 801 μmol) in THF (6 mL) was cooled in an ice-water bath, and 1M TBAF in THF (1.60 mL, 1.60 mmol) was added. The solution was added dropwise and stirred at room temperature for 40 minutes. To the reaction solution was added 10% aqueous ammonium chloride solution (6 mL), and the mixture was extracted twice with ethyl acetate (36 mL, 10 mL). The obtained organic layers were combined, washed with saturated brine (10 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 10 g, developing solvent: toluene / ethyl acetate = 4/1). The target compound (i-8) (294 mg, 525 μmol) was obtained as a colorless oil in a yield of 65%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.96-1.06 (m, 2H), 1.25-1.32 (m, 1H), 1.37 (s, 3H), 1.47 (s, 9H), 1.57 (s, 3H), 2.23-2.31 (m, 2H), 2.40-2.48 (m, 3H), 4.02-4.14 (m, 2H), 4.16-4.27 (m, 3H), 4.35-4.45 (m, 1H), 5.62 ( dd, J = 16.37, 6.04 Hz, 1H), 6.56 (dd, J = 16.37, 1.13 Hz, 1H), 6.99-7.05 (m, 2H), 7.10-7.22 (m, 2H), 7.28-7.32 (m, 1H), 7.26-7.32 (m, 1H), 7.42-7.46 (m, 1H), 7.56-7.62 (m, 1H), 7.93-7.95 (m, 1H). MS (ES ⁺ ) 559.69

Synthesis of Compound (i-9) Under a nitrogen stream, N-methylimidazole (70 μL, 886 μmol) and triethylamine (122 μL, 880 μmol) were added to a solution of compound (i-8) (246 mg, 439 μg) in methylene chloride (4 mL). The mixture was cooled in an ice-water bath, and a solution of p-toluenesulfonyl chloride (169 mg, 886 μmol) in acetonitrile (1.5 mL) was added dropwise. The mixture was stirred for 2 hours while gradually warming to room temperature, cooled in an ice-water bath, saturated aqueous sodium bicarbonate (10 mL), and chloroform (12 mL) were added to separate the layers. The organic layer was washed twice with water (10 mL, 10 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 10 g, developing solvent: toluene / ethyl acetate = 4/1). The target compound (i-9) (285 mg, 399 μmol) was obtained as a pale yellow amorphous solid in a yield of 90%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.00-1.11 (m, 2H), 1.25-1.32 (m, 2H), 1.37 (s, 3H), 1.45-1.46 (m, 1H), 1.46 ( s, 9H), 1.56 (s, 3H), 2.22-2.32 (m, 2H), 2.34-2.43 (m, 2H), 2.47 (s, 3H), 4.26-4.45 (m, 6H), 5.66 (dd, J = 16.24, 6.17 Hz, 1H), 6.54 (dd, J = 16.37, 1.26 Hz, 1H), 6.88-6.93 (m, 2H), 7.10-7.40 (m, 6H), 7.56-7.62 (m, 1H) , 7.86-7.90 (m, 2H), 7.93-7.95 (m, 1H). MS (ES ⁺ ) 714.4

Under a synthetic nitrogen stream of PTVS1, a solution of compound (i-9) (201 mg, 281 μmol) in methylene chloride (2 mL) was cooled in an ice-water bath, and TFA (2 mL, 26.9 mmol) was added dropwise. The mixture was stirred for 20 hours while gradually warming to room temperature. The reaction solution was cooled in an ice-water bath, washed twice with saturated aqueous sodium hydrogen carbonate (20 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 10 g, developing solvent: toluene / ethyl acetate = 1/1). The target compound (PTVS1) (100 mg, 166 μmol) was obtained in a yield of 59% as a reddish white amorphous solid.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.02-1.09 (m, 2H), 1.32-1.35 (m, 2H), 1.61-1.78 (m, 2H), 2.05 (s, 3H), 2.37- 2.75 (m, 5H), 4.29-4.32 (m, 2H), 4.41-4.43 (m, 2H), 5.12-5.20 (m, 1H), 5.61 (dd, J = 16.24, 6.17 Hz, 1H), 6.71 ( dd, J = 16.24, 1.38 Hz, 1H), 6.93-6.99 (m, 1H), 7.13-7.41 (m, 8H), 7.58-7.62 (m, 1H), 7.84-7.88 (m, 1H), 7.95- 7.97 (m, 1H). MS (ES ⁺ ) 600.2

According to the manufacturer following scheme (Production Example 2) radiolabeled compound performs radiolabeled PTVS1 obtained in Production Example 1 as a labeling precursor compound was prepared is a radiolabeled compound ^[18 F] PTVS2. The scheme will be specifically described below.

Under a He gas stream, a solution of Kryptofix (registered trademark) 2.2.2 (10.0 mg) in acetonitrile (0.5 mL) was added to [ ¹⁸ F] KF, and the solvent was distilled off by heating under reduced pressure. A solution of PTVS1 (0.5 mg) in acetonitrile (0.05 mL) was added, and a fluorination reaction was performed at 80 to 100 ° C. for 10 minutes. After cooling to room temperature, EtOH (0.08 mL) and 1N NaOH (0.06 mL) were added and reacted at room temperature for 15 minutes. After completion of the reaction, it was introduced into HPLC and separated and purified. The desired radiolabeled compound ([ ¹⁸ F] PTVS2) was obtained with a radiochemical yield of 79% and a radiochemical purity of> 99%.

By performing the radiolabeling using PTVS1 a labeled precursor compound of the present invention could produce ^[18 F] PTVS2 a radiolabeled compound of high purity in high yield.

(Production Example 3) Production of Radiolabeled Compound According to the following scheme, the compound (i-9) obtained in Production Example 1 was subjected to radiolabeling as a labeled precursor compound, and [ ¹⁸ F] PTVS2 as a radiolabeled compound was obtained. Manufactured. The scheme will be specifically described below.

Under a He gas stream, a solution of Kryptofix (registered trademark) 2.2.2 (10.0 mg) in acetonitrile (0.5 mL) was added to [ ¹⁸ F] KF, and the solvent was distilled off by heating under reduced pressure. A solution of compound (i-9) (0.5 mg) in acetonitrile (0.05 mL) was added, and a fluorination reaction was performed at 80 to 100 ° C. for 10 minutes. After cooling to room temperature, a TFA (0.05 mL) solution was added and reacted at room temperature for 15 minutes. After completion of the reaction, it was introduced into HPLC and separated and purified. The desired radiolabeled compound ([ ¹⁸ F] PTVS2) was obtained with a radiochemical yield of 70% and a radiochemical purity> 99%.

By performing the radiolabeling using labeling precursor compound, compound of the present invention (i-9), it was able to produce ^[18 F] PTVS2 a radiolabeled compound of high purity in high yield.

(Production Example 4) Production of PTVS3 and PTVS4 According to the following scheme, labeled precursor compounds PTVS3 and PTVS4 were produced. The scheme will be specifically described below.

Synthesis of Compound (ii-2) Compound (ii-1) (16.6 g, 140 mmol) was added to a toluene (280 mL) solution of KM (20.0 g, 140 mmol) in a nitrogen stream. The reaction vessel was immersed in a water bath (15 ° C.), and tin (IV) chloride (73.3 g, 281 mmol) was added dropwise. After stirring at room temperature for 30 minutes, the mixture was stirred at reflux temperature for 3 hours. The mixture was cooled to room temperature, and a saturated sodium carbonate aqueous solution (700 g) was added dropwise to grind the precipitated solid. The filtrate obtained by filtering the reaction solution through Celite was separated, and the aqueous layer was extracted with ethyl acetate (300 mL). The combined organic layers were washed with 20% brine (300 mL), dried over sodium sulfate, and the solvent was distilled off. The target compound (ii-2) (28.5 g) was obtained as a purple solid in a yield of 83.9%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.93-0.96 (m, 2H), 1.21-1.29 (m, 2H), 2.59-2.66 (m, 2H), 3.98 (s, 3H), 6.61 ( br. s., 2H), 7.34-7.40 (m, 1H), 7.61-7.65 (m, 1H). MS (ES ⁺ ) 243.2

Synthesis of Compound (ii-3) In a nitrogen stream, acetonitrile (350 mL) and copper (I) bromide (29.5 g, 206 mmol) were added to Compound (ii-2) (28.5 g, 117 mmol). The reaction vessel was immersed in a water bath (15 ° C.), and t-butyl nitrite (18.2 g, 176 mmol) was added dropwise. After stirring at 40 ° C. for 2.5 hours, the mixture was stirred overnight at room temperature. Toluene (200 mL) and 5% aqueous sodium hydrogen carbonate solution (200 mL) were added and the mixture was filtered through Celite, and the resulting filtrate was separated. The aqueous layer was extracted with toluene (200 mL), and the obtained organic layers were combined, washed with 20% brine (200 mL), dried over sodium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (silica gel: 300 g, developing solvent: toluene / ethyl acetate = 20/1). The target compound (ii-3) (20.9 g) was obtained as an orange oil in a yield of 58.0%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.02-1.19 (m, 2H), 1.27-1.36 (m, 2H), 2.03-2.10 (m, 1H), 4.07 (s, 3H), 7.54- 7.58 (m, 1H), 7.70-7.74 (m, 1H), 7.91-7.96 (m, 1H), 8.14-8.16 (m, 1H). MS (ES ⁺ ) 306.1

Synthesis of Compound (ii-4) In a nitrogen stream, a solution of compound (ii-3) (21.9 g, 71.8 mmol) in toluene (165 mL) was cooled in a salt ice bath. A toluene solution (156 mL, 158 mmol) of 1.01 M DIBAL was added dropwise and stirred at room temperature for 1 hour. The mixture was cooled again in a salt ice bath, and ethanol (5 mL) and 5% Rochelle salt aqueous solution (10 mL) were successively added dropwise. A 15% aqueous Rochelle salt solution (340 mL) and ethyl acetate (100 mL) were added and separated at room temperature, and the organic layer was washed with saturated brine (200 mL). The aqueous layers were extracted with ethyl acetate (100 mL), the organic layers were combined and dried over sodium sulfate, and the solvent was distilled off. Compound (ii-4) (19.4 g) was obtained as a pale yellow solid in a yield of 97.5%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.02-1.15 (m, 2H), 1.24-1.31 (m, 2H), 2.23 (br.s., 1H), 2.51-2.571 (m, 1H) , 5.24 (s, 2H), 7.49-7.53 (m, 1H), 7.63-7.67 (m, 1H), 7.88-7.94 (m, 1H), 8.11-8.13 (m, 1H). MS (ES ⁺ ) 278.1

Synthesis of Compound (ii-5) In a nitrogen stream, compound (ii-4) (7.01 g, 25.2 mmol) was added to methylene chloride (50 mL), potassium bromide (0.60 g, 5.04 mmol), 5% aqueous sodium bicarbonate solution ( 30 mL), TBAB (170 mg, 0.527 mmol), and TEMPO (473 mg, 3.02 mmol) were added. The reaction solution was ice-cooled, and a 10% sodium hypochlorite aqueous solution was added dropwise and stirred at room temperature until the raw materials disappeared. The reaction solution was separated, and the aqueous layer was extracted with chloroform (40 mL). The organic layers were combined and dried over sodium sulfate, the solvent was distilled off, and the resulting solid was washed with n-heptane. The target compound (ii-5) (57.9 g) was obtained as a pale yellow solid in a yield of 83.3%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.01-1.14 (m, 2H), 1.30-1.37 (m, 2H), 3.00-3.07 (m, 1H), 7.57-7.62 (m, 1H), 7.77-7.81 (m, 1H), 7.91-7.93 (m, 1H), 8.28-8.31 (m, 1H), 10.77 (s, 1H). MS (ES ⁺ ) 276.1

Synthesis of Compound (ii-6) In a nitrogen stream, THF (12.5 mL) was added to 60% sodium hydride (0.73 g, 18.2 mmol) and ice-cooled. A solution of (R) -ketophosphonate (7.00 g, 18.3 mmol) in THF (48 mL) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. A solution of compound (ii-5) in THF (75 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes and then stirred at room temperature for 3.5 hours. The reaction solution was ice-cooled again and quenched by dropwise addition of saturated aqueous ammonium chloride solution (70 mL). To the reaction solution, THF (40 mL) and water (20 mL) were added for liquid separation, and the aqueous layer was extracted with ethyl acetate (40 mL). The organic layers were combined, washed with saturated brine (100 mL), dried over sodium sulfate, and the solvent was evaporated. The resulting reddish brown oily residue was purified by silica gel column chromatography (silica gel: 100 g, developing solvent: toluene / ethyl acetate = 100/1 → 50/1). The target compound (ii-6) (8.57 g) was obtained as a yellow oil in a yield of 92.5%.
¹ H NMR (400 MHz, CDCL ₃ -d) δ: 0.10 (s, 3H), 0.11 (s, 3H), 0.86 (s, 9H), 1.01-1.08 (m, 2H), 1.33-1.37 (m, 2H), 2.28-2.34 (m, 1H), 2.59 (dd, J = 15.11, 6.04 Hz, 1H), 2.66 (dd, J = 15.11, 6.04 Hz, 1H), 2.98 (dd, J = 15.61, 5.79 Hz , 1H), 3.07 (dd, J = 15.61, 6.55 Hz, 1H), 3.71 (s, 3H), 4.74-4.80 (m, 1H), 6.72 (d, J = 16.62 Hz, 1H), 7.53-7.58 ( m, 1H), 7.68-7.72 (m, 1H), 7.90-7.93 (m, 1H), 7.93 (d, J = 16.62 Hz, 1H), 8.17-8.19 (m, 1H). MS (ES ⁺ ) 532.2

Synthesis of compound (ii-7) In a nitrogen stream, a solution of compound (ii-6) (8.57 g, 16.0 mmol) in THF (80 mL) was ice-cooled, and acetic acid (0.76 g, 12.6 mmol) and triethylamine (1.21 g, A solution of 11.9 mmol) in THF (30 mL) was added. 1M TBAF in THF (24 mL, 24 mmol) was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 3 hours. The reaction mixture was ice-cooled again, water (120 mL) was added, and the mixture was extracted with ethyl acetate (130 mL). The aqueous layer was extracted with ethyl acetate (50 mL), and the obtained organic layers were combined, washed with saturated brine (100 mL), dried over sodium sulfate, and the solvent was evaporated. The resulting reddish brown oily residue was purified by silica gel column chromatography (silica gel: 110 g, developing solvent: toluene / ethyl acetate = 5/1). The target compound (ii-7) (4.03 g) was obtained as a yellow oil in a yield of 59.8%.
¹ H NMR (400 MHz, CDCL ₃ -d) δ: 1.04-1.09 (m, 2H), 1.33-1.38 (m, 2H), 2.27-2.37 (m, 1H), 2.66 (d, J = 6.29 Hz, 2H), 3.00-3.06 (m, 2H), 3.75 (s, 3H), 4.64-4.68 (m, 1H), 6.72 (d, J = 16.62 Hz, 1H), 7.53-7.57 (m, 1H), 7.68 -7.72 (m, 1H), 7.90-7.94 (m, 1H), 7.95 (d, J = 16.62 Hz, 1H), 8.16-8.19 (m, 1H). MS (ES ⁺ ) 418.1

Synthesis of Compound (ii-8) In a nitrogen stream, methanol (6 mL) was added to a THF (30 mL) solution of Compound (ii-7) (4.03 g, 9.63 mmol) and cooled in a dry ice-acetone bath. 1.0 M Et ₂ BOMe in THF (10.8 mL, 108 mmol) was added, and the mixture was stirred at the same temperature for 20 min. Sodium borohydride (452 mg, 10.7 mmol) was added and stirred at the same temperature for 1 hour. A solution of acetic acid (5.7 mL) in ethyl acetate (27 mL) was added dropwise, and the mixture was stirred at the same temperature for 10 min and then at room temperature for 3 hr. 5% Aqueous sodium hydrogen carbonate solution (100 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The aqueous layer was extracted with ethyl acetate (40 mL), and the resulting organic layers were combined, washed with saturated brine (100 mL), and dried over sodium sulfate. The operation of distilling off the solvent, adding methanol and concentrating was repeated three times, and the resulting yellow solid was washed with diisopropyl ether. Compound (ii-8) (2.93 g) was obtained as a yellow solid in a yield of 72.0%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.00-1.05 (m, 2H), 1.26-1.32 (m, 2H), 1.81-1.94 (m, 2H), 2.41-2.47 (m, 1H), 2.59 (d, J = 6.29 Hz, 2H), 3.50 (br. S., 1H), 3.74 (br. S., 1H), 3.75 (s, 3H), 4.40-4.48 (m, 1H), 4.73- 4.78 (m, 1H), 6.11 (dd, J = 16.11, 5.79 Hz, 1H), 6.90 (dd, J = 16.24, 1.38 Hz, 1H), 7.49-7.53 (m, 1H), 7.62-7.66 (m, 1H), 7.88-7.90 (m, 1H), 8.14-8.16 (m, 1H). MS (ES ⁺ ) 420.1

PTVS3 synthetic compound (ii-8) (1.01 g, 2.40 mmol), (BPin) ₂ (0.79 g, 3.12 mmol), potassium carbonate (0.99 g, 7.20 mmol), and PdCl ₂ (dppf) CH ₂ Cl ₂ ( 0.19 g, 0.240 mmol) was added, and the system was purged with argon. Dimethyl sulfoxide (40 mL) was added, and degassing and argon substitution were performed three times. The mixture was stirred at 70 ° C. for 4 hours, cooled to room temperature, silica gel (4.14 g) was added, and the mixture was filtered through Celite. Ethyl acetate (40 mL) was added to the filtrate, washed twice with water and once with saturated brine, and dried over sodium sulfate. The solvent was distilled off, and methanol azeotropy was performed 3 times, and then purified with an ODS column. The obtained brown candy was powdered with diisopropyl ether / n-heptane = 1/1 and collected by filtration. The target compound (PTVS3) (0.29 g) was obtained as a light brown solid in a yield of 25.9%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.98-1.01 (m, 2H), 1.23-1.26 (m, 2H), 1.47 (s, 12H), 1.79-1.89 (m, 2H), 2.26- 2.47 (m, 1H), 2.55-2.57 (m, 2H), 3.31 (br. S., 1H), 3.74 (s, 3H), 3.75 (br. S., 1H), 4.35-4.48 (m, 1H ), 4.65-4.78 (m, 1H), 6.05 (dd, J = 15.86, 5.54 Hz, 1H), 7.21 (dd, J = 16.24, 1.38 Hz, 1H), 7.39-7.43 (m, 1H), 7.55- 7.59 (m, 1H), 7.89-7.94 (m, 2H). MS (ES ⁺ ) 467.3

Synthesis of PTVS4 PTVS3 (36.9 mg, 0.0789 mmol), 1-fluoro-4-iodobenzene (26.2 mg, 0.118 mmol), sodium carbonate (25.0 mg, 0.236 mmol), and Pd (PPh ₃ ) ₄ (9.1 mg, 0.00789 mmol) was added, and the system was purged with argon. Dimethyl sulfoxide (0.5 mL) was added, and degassing and argon substitution were performed three times. The mixture was stirred at 80 ° C. for 8 hours, cooled to room temperature, and water was added. The mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off and purified with an ODS column. The target compound (PTVS4) (2.3 mg) was obtained as a candy.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.01-1.10 (m, 2H), 1.22-1.37 (m, 5H), 1.41-1.54 (m, 1H), 2.37-2.51 (m, 3H), 3.74 (s, 3H), 4.10-4.16 (m, 1H), 4.385-4.43 (m, 1H), 5.58 (dd, J = 16.24, 6.17 Hz, 1H), 6.64 (dd, J = 16.11, 1.26 Hz, 1H), 7.14-7.35 (m, 6H), 7.57-7.61 (m, 1H), 7.94-7.96 (m, 1H). MS (ES ⁺ ) 436.3

(Production Example 5) Production of PTVS4 PTVS3 (20 mg, 0.0429 mmol), 1-fluoro-4-iodobenzene (14.2 mg, 0.0641 mmol), sodium carbonate (13.5 mg, 0.128 mmol), and Pd (PPh ₃ ) ₄ ( 3.4 mg, 0.00427 mmol) was added, and the system was purged with argon. Dimethyl sulfoxide (2 mL) was added, and degassing and argon substitution were performed three times. The reaction was carried out at 120 ° C. for 10 minutes under microwave irradiation. When the progress of the reaction was confirmed using LC-MS, the target compound (PTVS4) was obtained in a yield of 10%. By performing the coupling reaction under microwave irradiation, the target compound (PTVS4) could be obtained in a very short time compared to the case without microwave irradiation.

According (Production Example 6) PTVS5 and PTVS6 of manufacturing the scheme below, was prepared PTVS5 and PTVS6. The scheme will be specifically described below.

Synthesis of Compound (iii-2) A THF (10 mL) solution of compound (iii-1) (540 mg, 1.32 mmol) was cooled in an ice-water bath under a nitrogen stream. Lithium ammonium hydride (99.3 mg, 2.61 mmol) was added in three portions, and the mixture was stirred at room temperature for 3 hours. The reaction solution was cooled in an ice-water bath, and water (110 μL), a 15% aqueous sodium hydroxide solution (110 μL), and water (330 μL) were successively added dropwise. Ethyl acetate (16 mL) was added, and the mixture was filtered through Celite, dried over sodium sulfate, filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was washed with isopropyl ether / heptane = 1/1 solution (15 mL), collected by filtration and dried. The target compound (iii-2) (401 mg, 1.05 mmol) was obtained as a light brown solid in a crude yield of 79%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.09-1.12 (m, 2H), 1.36-1.41 (m, 2H), 1.62 (br.s., 1H), 2.59-2.64 (m, 1H) , 4.80 (s, 2H), 5.17 (s, 2H), 7.12-7.98 (m, 13H).

Synthesis of Compound (iii-3) Carbon tetrabromide (2.28 g, 6.87 mmol) was added to a suspension of compound (iii-2) (1.30 g, 3.41 mmol) in methylene chloride (14 mL) under a nitrogen stream. The solution was cooled in an ice-water bath, and a solution of PPh ₃ (1.79 g, 6.82 mmol) in methylene chloride (10 mL) was added dropwise. After stirring for 20 minutes in an ice-water bath, saturated aqueous sodium hydrogen carbonate (20 mL) was added dropwise, and the mixture was extracted twice with chloroform (20 mL, 10 mL). The obtained organic layers were combined, dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 50 g, developing solvent: chloroform / n-hexane = 7/1). The target compound (iii-3) (1.26 g, 2.83 mmol) was obtained as a light brown solid in a yield of 82%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.11-1.16 (m, 2H), 1.36-1.40 (m, 2H), 2.50-2.55 (m, 1H), 4.64 (s, 2H), 5.17 ( s, 2H), 7.15-7.96 (m, 13H).

2. Synthesis of Compound (iii-4) Under a nitrogen stream, Ph ₂ POEt (3.09 g, 13.4 mmol) was added to a toluene (26 mL) solution of Compound (iii-3) (1.25 g, 2.81 mmol) and stirred. Refluxed for 5 hours. After cooling to room temperature, the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was washed with isopropyl ether (30 mL), collected by filtration and dried. The target compound (iii-4) (1.52 g, 2.69 mmol) was obtained as a reddish white solid in a crude yield of 95%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.93-0.96 (m, 2H), 1.22-1.26 (m, 2H), 2.68-2.74 (m, 1H), 4.09 (d, J = 14.35 Hz, 2H), 5.15 (s, 2H), 6.68-6.70 (m, 2H), 6.91-6.93 (m, 2H), 7.13-7.16 (m, 1H), 7.21-7.58 (m, 17H), 7.94-7.96 ( m, 1H).

Synthesis of Compound (iii-5) Under a nitrogen stream, TMP (148 mg, 1.04 mmol) in THF (4 mL) was cooled in a dry ice-acetone bath and 1.6 M n-BuLi in n-hexane (1.15 mL). , 1.84 mmol) was added dropwise, and the mixture was stirred at −20 ° C. for 10 minutes. After cooling to −70 ° C. or lower, a solution of compound (iii-4) (456 mg, 806 μmol) in THF (14 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 min. At the same temperature, a solution of DIO (354 mg, 1.37 mmol) in THF (3 mL) was added dropwise, stirred for 15.5 hours while gradually warming to room temperature, saturated aqueous sodium hydrogen carbonate (6 mL) was added dropwise, and ethyl acetate (30 mL) was added. ). The obtained organic layer was washed with saturated brine (6 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 35 g, developing solvent: toluene / ethyl acetate = 15/1 → 2/3). The target compound (iii-5) (226 mg, 343 μmol) was obtained as a colorless oil in a yield of 46%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 1.01-1.12 (m, 2H), 1.25-1.35 (m, 2H), 1.38-1.41 (m, 5H), 1.46 (s, 9H), 1.48 ( s, 3H), 2.25-2.45 (m, 3H), 4.21-4.42 (m, 2H), 5.16 (s, 2H), 5.66 (dd, J = 16.24, 6.17 Hz, 1H), 6.57 (dd, J = 16.24, 1.13 Hz, 1H), 7.06-7.58 (m, 12H), 7.93-7.95 (m, 1H). MS (ES ⁺ ) 605.76

Synthesis of Compound (iii-6) Under a nitrogen stream, a solution of Compound (iii-5) (701 mg, 1.15 mmol) in methylene chloride (1 mL) was cooled in an ice-water bath, and TFA / thianisol = 10/1 (6 mL) solution. Was dripped. The mixture was stirred for 17 hours while gradually warming to room temperature. The reaction solution was added dropwise to saturated aqueous sodium bicarbonate (90 mL) cooled in an ice-water bath, and extracted three times with ethyl acetate (30 mL, 25 mL, 30 mL). The obtained organic layers were combined, washed with saturated brine (50 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 10 g, developing solvent: chloroform / ethyl acetate = 1/1 → 0/1). Compound (iii-6) (280 mg, 697 μmol) was obtained as a pale yellow amorphous solid in a yield of 60%.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 1.01-1.07 (m, 2H), 1.21-1.23 (m, 2H), 1.57-1.68 (m, 2H), 2.31-2.65 (m, 4H), 3.47 (br.s., 1H), 5.05-5.21 (m, 1H), 5.71 (dd, J = 16.24, 6.55 Hz, 1H), 6.65 (dd, J = 16.24, 1.13 Hz, 1H), 6.88-7.87 (m, 8H), 9.66 (br.s., 1H). MS (ES ⁺ ) 401.45

In a nitrogen stream of PTVS5, triethylamine (1.80 mL, 12.8 mmol) was added to a chloroform (10 mL) solution of 2-fluoroethanol (1.00 g, 15.6 mmol), cooled in an ice-water bath, and MsCl (1.00 mL, 12.8 mmol). ) Was added. After stirring at room temperature for 1 hour, the mixture was concentrated, and ethyl acetate (50 mL) and water (40 mL) were added to separate the layers. The obtained organic layer was washed successively with water (40 mL) and saturated aqueous sodium hydrogen carbonate (30 mL), dried over sodium sulfate and filtered, and then the solvent was distilled off at 40 ° C. under reduced pressure. As a colorless oil, 2-fluoroethyl methanesulfonate (1.75 g, 12.3 mmol) was obtained in a crude yield of 96%.

Under a nitrogen stream, potassium carbonate (86.6 mg, 626 μmol) and 2-fluoroethyl methanesulfonate (170 μL, 956 μmol) were sequentially added to a DMF (1.9 mL) solution of compound (iii-6) (126 mg, 314 μmol). The mixture was stirred in a 40 ° C. water bath for 21.5 hours. Ethyl acetate (4 mL) was added to the reaction mixture, washed successively with water (4 mL) and saturated brine (4 mL), dried over sodium sulfate and filtered, and the solvent was evaporated at 40 ° C. under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel: 10 g, developing solvent: toluene / ethyl acetate = 1/2 × 2 times). The target compound (PTVS5) (28.1 mg, 62.8 μmol) was obtained as a colorless oil in a yield of 20%.
¹ H NMR (400 MHz, CDCl ₃ -d) δ: 0.98-1.15 (m, 2H), 1.18-1.43 (m, 2H), 1.52-1.72 (m, 2H), 1.76-1.86 (m, 1H), 1.96 (br.s., 1H), 2.32-2.42 (m, 1H), 2.55 (ddd, J = 17.69, 4.60, 1.38 Hz, 1H), 2.70 (dd, J = 17.75, 4.91 Hz, 1H), 4.25 -4.38 (m, 2H), 4.70-4.90 (m, 2H), 5.14-5.19 (m, 1H), 5.63 (dd, J = 16.24, 6.17 Hz, 1H), 6.70 (dd, J = 16.24, 1.38 Hz , 1H), 6.98-7.08 (m, 2H), 7.12-7.20 (m, 2H), 7.29-7.34 (m, 1H), 7.37-7.46 (m, 1H), 7.57-7.61 (m, 1H), 7.91 -8.00 (m, 1H). MS (ES ⁺ ) 448.2

Synthesis of PTVS6 To a solution of PTVS5 (19.2 mg, 42.9 μmol) in ethanol (80 μL) was added 1M aqueous sodium hydroxide solution (65 μL, 65 μmol), and the mixture was stirred at room temperature for 15 minutes. Water (80 μL) was added, and the mixture was concentrated. Water (0.2 mL) and 0.1 M aqueous calcium chloride solution (236 μL, 23.6 μmol) were successively added, and the mixture was stirred at room temperature for 30 min. The precipitated solid was collected by filtration, washed with water (5 mL), and dried at 40 ° C. under reduced pressure. The target compound (PTVS6) (12.7 mg, 13.1 μmol) was obtained as a pale yellow solid in a yield of 61%.
¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 0.99-1.05 (m, 2H), 1.12-1.23 (m, 3H), 1.38-1.46 (m, 2H), 1.83-1.91 (m, 1H), 1.98-2.05 (m, 1H), 2.52-2.56 (m, 1H), 3.58-3.63 (m, 1H), 4.09-4.17 (m, 1H), 4.26-4.42 (m, 2H), 4.73-4.87 (m , 2H), 5.66 (dd, J = 16.11, 6.17 Hz, 1H), 6.48 (dd, J = 16.11, 1.38 Hz, 1H), 7.02-7.20 (m, 4H), 7.30-7.38 (m, 2H), 7.59-7.64 (m, 1H), 7.78-7.86 (m, 1H). MS (ES ⁺ ) 466.1

[Liver uptake evaluation]
PTVS6 was evaluated for liver uptake by transporters (OATP1B1, OATP1B3). As a control, the following pitavastatin calcium salt (hereinafter referred to as “pitavastatin”) was prepared.

OATP1B1 and OATP1B3 stably expressing HEK293 cells were cultured on a 12 well dish coated with collagen type I. 24 hours before the start of the experiment, the medium (DMEM (low glucose)) was replaced with a medium containing 5 mM sodium butyrate to induce transporter expression in the expression cells. 15 minutes before the start of the experiment, after removing the medium, Krebs-Henseleit buffer (KH buffer; 118 mM NaCl, 23.8 mM NaHCO ₃ , 4.8 mM KCl, 1.0 mM KH ₂ PO ₄ , 1.2 mM MgSO ₄₎ heated to 37 ° C. , 12.5 mM HEPES, 5.0 mM glucose, 1.5 mM CaCl ₂ , pH 7.4), the cells were washed twice, and preincubated with KH buffer heated to 37 ° C. Next, the KH buffer was removed, and uptake was started by placing a KH buffer containing a substrate (pitavastatin or PTVS6) (tracer condition: final 0.5 mM, excess condition: 100 mM) in the wells where the cells were seeded. After culturing at 37 ° C. for a fixed time, the KH buffer was removed, and the cells were washed three times with ice-cold KH buffer. Thereafter, 500 μL of 0.2N NaOH was added to the well to lyse the cells, and a sample neutralized with 50 μL of 2N HCl was measured by LC / MS. The result is shown in the graph of FIG.

FIG. 1 is a graph showing the time transition and saturation of pitavastatin and PTVS6 transport by the liver uptake transporter (OATP1B1, OATP1B3), where A and B are the results of pitavastatin, and C and D are the results of PTVS6. As shown in FIG. 1, under tracer conditions, uptake of both pitavastatin and PTVS6 was observed in OATP1B1 and OATP1B3-expressing HEK293 cells in a time-dependent manner (A and C: 1B1 tracer, B and D: 1B3 tracer). ). Also, its uptake was not observed in control cells (mock). From these, it was confirmed that this intracellular uptake was taken up via OATP1B1 or OATP1B3. Furthermore, as shown in FIG. 1, under excess conditions, both pitavastatin and PTVS6 have reduced uptake (A and C: 1B1 excess, B and D: 1B3 excess). It was further demonstrated that the uptake of pitavastatin and PTVS6 was via a transporter. In addition, the transport properties of PTVS6 were very similar to those of pitavastatin. Therefore, it was suggested that the transport of PTVS6 reflects the transport ability of OATP1B1 and OATP1B3.

[Body distribution experiment]
[ ¹⁸ F] PTVS2 was used to conduct biodistribution experiments in rats and mice. [ ¹⁸ F] PTVS2 (100 μCi / 100 μL / mouse) was administered by intravenous injection (tail vein) to unanesthetized 6-week-old SD rats (male). Each organ was removed 2 minutes, 5 minutes, 10 minutes, 15 minutes, 30 minutes, and 60 minutes after administration (n = 5). The radioactivity of each organ was measured, and the amount of radioactivity accumulated per organ (% dose / organ) was calculated. An example of the result is shown in FIG.

A biodistribution experiment was similarly performed (n = 5) except that mice (ddY male, 12 weeks old) were used instead of rats, and the dose of [ ¹⁸ F] PTVS2 was 20 μCi / 100 μL / animal. An example of the result is shown in Table 1 and FIG.

2 and 3 are graphs showing an example of the change with time of accumulation of [ ¹⁸ F] PTVS2 in each organ. FIG. 2 shows the results of rats and FIG. 3 shows the results of mice. As shown in FIGS. 2 and 3, it was confirmed that [ ¹⁸ F] PTVS2 was transferred to the liver immediately after administration and then transferred to the intestine and excreted in both rats and mice. In addition, migration to other organs was hardly confirmed except in the kidney.

[PET imaging]
PET imaging was performed using [ ¹⁸ F] PTVS2 under the following conditions. An example of the result is shown in FIG.
Dose: 122 μCi
6-week-old SD rat (male)
Imaging device: eXplore Vista (product name, manufactured by GE)
Imaging method: Static Scan, 1 frame every 60 seconds Construction: 2DOSEM (Dynamic OS-EM)

The images shown in FIG. 4 are all coronal images, which are images 1 minute, 4 minutes, and 20 minutes after administration in order from the left. As shown in FIG. 4, as in the results of the biodistribution experiment, it was confirmed that [ ¹⁸ F] PTVS2 quickly migrated to the liver after administration, and then migrated to the intestine to be excreted. In addition, migration to other organs was hardly confirmed except in the kidney.

As shown above, the transport properties of PTVS6 and [ ¹⁸ F] PTVS2 were very similar to those of pitavastatin. It has been reported that pitavastatin is taken up mainly by OATP1B1 in human hepatocytes. For this reason, it was suggested that PTVS6 and [ ¹⁸ F] PTVS2 can also be taken up mainly by OATP1B1 in human hepatocytes.

[Evaluation of metabolic stability]
PTVS6 was evaluated for metabolic stability by in vitro experiments using human liver microsomes. In addition, the evaluation of metabolic stability by in vitro experiments was performed in a manner according to a method already reported (Obach et al. Drug Metab Dispos 30: 831-837 (2002)).

First, prepare PTVS6, Pitavastatin and CYP3A4 substrate midazolam as substrates, each substrate (final 3 μM), human liver microsome (final 1 mg protein / mL), and 100 mM potassium containing 3.3 mM MgCl ₂ Phosphate buffer (pH 7.4) was mixed and preincubated for 5 minutes at 37 ° C. Next, NADPH, which is a driving force necessary for metabolic reaction, is added to final 1.3 mM to finally make 500 μL, and after incubation at 37 ° C., immediately after NADPH addition, 25 μL each after 2 minutes and 10 minutes. Samples were taken one by one. The obtained sample is mixed with 25 μL of Acetonitrile containing the internal standard for measurement, then the protein is removed by centrifugation, the supernatant is collected, and the residual mass in the sample is measured by LC / MS / MS did. The results are shown in the graph of FIG.

FIG. 5 is a graph showing the ratio of the substrate remaining in the sample from the start of metabolic reaction (NADPH addition) to 10 minutes later, and the vertical axis indicates the ratio of the substrate remaining in the sample with respect to the added amount. The horizontal axis indicates time. As shown in the graph of FIG. 5, midazolam, which is a CYP3A4 substrate and is known to be well metabolized in humans, has a substrate residual rate of several percent within 10 minutes from the start of metabolic reaction, as in previous reports. Decreased to. On the other hand, both PTVS6 and Pitavastatin showed almost no decrease in substrate within 10 minutes from the start of the metabolic reaction.

As shown in the graph of FIG. 5, midazolam, which is often metabolized in humans, was metabolized very rapidly even in the in vitro experimental system, and this experimental system reflects the metabolic reaction in humans. Was confirmed. In this experimental system, both PTVS6 and pitavastatin were shown to be extremely stable metabolically. Therefore, it was suggested that PTVS6 and pitavastatin have guaranteed stability as a parent compound, which is one of the ideal properties as a PET probe. Therefore, the PET probe obtained by radiolabeling PTVS6 and pitavastatin is metabolically stable, and the quantitative value of radioactivity obtained by imaging using the PET probe is mainly based on the amount of these compounds. It was suggested that it has a very ideal property that can be reflected.

Based on the above results, by performing intrahepatic kinetics using [ ¹⁸ F] PTVS2 at MD and / or clinical dose, in vivo parameters obtained using [ ¹⁸ F] PTVS2 and human gene-expressing cells, Predict the time course of the concentration of a test drug in the liver in the human body based on in vitro parameters related to transport and metabolism obtained using human frozen hepatocytes, human biliary vesicle vesicles, and / or human liver microsomes It was suggested that it would be possible to build a model. Furthermore, it was suggested that quantitative variation prediction of pharmacokinetics in the presence of genetic polymorphism and / or drug-drug interaction as an inter-individual variation factor of drug hepatic uptake / excretion process becomes possible.

Production Example 7 Production of PTVS7, PTVS5 and PTVS8 PTVS7, PTVS5 and PTVS8 were produced according to the following scheme. The scheme will be specifically described below.

Synthesis of Compound (vi-2) After adding palladium carbon (2.2 g) to a methylene chloride (20 ml) / methanol (20 ml) solution of Compound (iv-1) (2.2 g, 5.4 mmol) under an argon stream, the reaction The inside of the container was replaced with hydrogen. The mixture was vigorously stirred at room temperature for 1 hour under a hydrogen stream. After stirring, the insoluble material was removed by filtration through Hyflo Super-Cel, washed with ethyl acetate, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 4). The target compound (iv-2) (1.5 g, 87%) was obtained as a colorless solid.
¹ H-NMR (500 MHz, CDCl ₃ ) δ: 7.96 (d, J = 8.6 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.35 (br dd, J = 8.0 Hz, 7.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 3.64 (s, 3H), 2.16 (tt, J = 8.0 Hz, 4.6 Hz, 1H), 1.33 (ddd, J = 4.6 Hz, 4.6 Hz, 1.7 Hz, 1H), 1.03 (ddd, J = 6.3 Hz, 6.3 Hz, 2.9 Hz, 1H); MS (EI ⁺ , 70 eV): m / z: 319 (M ⁺ , 68), 293 (100), 260 (81), 234 (36); HRMS calcd for C ₂₀ H ₁₇ NO ₃ (M ⁺ ): 319.1208, found 319.1200.

Synthesis of Compound (vi-3) In a stream of argon, compound (iv-2) (1.5 mg, 4.7 mmol) and 2-Fluoroethyl 4-methylbenzenesulfonate (986 μl, 5.6 mmol) in N, N, -dimethylformamide (15 ml) solution. Potassium carbonate (1.3 g, 9.3 mmol) was added with stirring at room temperature, stirred at the same temperature for 10 minutes, and then stirred at 70 ° C. for 20 hours. After completion of the reaction, distilled water was added and extracted four times with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to give a pale yellow solid. As a target compound (iv-3) (1.3 g, 76%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.97 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 4.81 (dt, JF = 47.3 Hz, J = 4.1 Hz, 2H ), 4.30 (dt, JF = 27.6 Hz, J = 4.1 Hz, 2H), 3.64 (s, 3H), 2.18 (tt, J = 8.2 Hz, 4.6 Hz, 1H), 1.36 (ddd, J = 4.6 Hz, 4.6 Hz, 1.7 Hz, 1H), 1.05 (ddd, J = 6.3 Hz, 6.3 Hz, 2.9 Hz, 1H); MS (EI ⁺ , 70 eV): m / z: 365 (M +, 99), 337 (100 ), 322 (34), 306 (57), 269 (22); HRMS calcd for C ₂₂ H ₂₀ FNO ₃ (M ⁺ ): 365.1427, found 365.1424

Synthesis of Compound (vi-5) Under a stream of argon, a suspension of lithium aluminum hydride (270 mg, 98%, 7.1 mmol) in tetrahydrofuran (15 ml) was added to a suspension of compound (iv-3) (1.3 g, 3.55 mmol) in tetrahydrofuran (10.0 ml) solution was added under stirring at 0 ° C., stirred at the same temperature for 1 hour, and then stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether, and a saturated aqueous sodium sulfate solution was slowly added with stirring at 0 ° C., followed by drying over sodium sulfate. After filtration, the solvent was distilled off to obtain compound (iv-4) (1.2 g) as a crude purified product of colorless solid.

Under a stream of argon, a solution of compound (iv-4) (1.2 g) and carbon tetrabromide (2.35 g, 7.1 mmol) in methylene chloride (12 ml) in methylene chloride solution (6.0 ml) of triphenylphosphine (1.9 g, 7.1 mmol) Was added with stirring at 0 ° C., and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give a pale yellow solid. As a target compound (iv-5) (1.1 g, 76%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.95 (d, J = 8.5 Hz, 1H), 7.65-7.59 (m, 1H), 7.37-7.30 (m, 4H), 7.11 (dd, J = 8.8 Hz, 2.7 Hz, 1H), 4.84 (dt, JF = 47.3 Hz, J = 3.9 Hz, 2H), 4.71 (s, 1H), 4.63 (s, 1H), 4.34 (dt, JF = 27.8 Hz, J = 4.1 Hz, 2H), 2.52 (tt, J = 8.0 Hz, 4.0 Hz, 1H), 1.38-1.37 (m, 2H), 1.15-1.05 (m, 2H); MS (EI ⁺ , 70 eV): m / z: 399 (M ⁺ , 5.7), 355 (26), 320 (100), 273 (17), 244 (21); HRMS calcd for C ₂₁ H ₁₉ BrFNO (M ⁺ ): 399.0634, found 399.0637

Synthesis of compound (vi-6) Under a stream of argon, ethoxydiphenylphosphine (2.9 ml, 13.6 mmol) was added to a toluene (20 ml) solution of compound (iv-5) (1.1 g, 2.7 mmol) with stirring at room temperature. For 20 hours. Diethyl ether was added to the oily substance obtained by evaporating the solvent, and the precipitated crystals were washed with diethyl ether to obtain the desired compound (vi-6) (1.3 g, 91%) as colorless crystals.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.93 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.46 (qt, J = 7.0 Hz, 1.5 Hz, 1H ), 7.40-7.30 (m, 9H), 7.22 (t, J = 7.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.9 Hz, 1H), 6.73 (d , J = 8.2 Hz, 1H), 4.83 (dt, JF = 47.3 Hz, J = 4.0 Hz, 2H), 4.28 (dt, JF = 27.9 Hz, J = 4.1 Hz, 2H), 4.08 (d, J = 14.1 Hz, 1H), 2.64 (tt, J = 8.0 Hz, 4.0 Hz, 1H), 1.23-1.20 (m, 2H), 0.93-0.90 (m, 2H); MS (EI ⁺ , 70 eV): m / z : 521 (M ⁺ , 50), 396 (100), 320 (41), 280 (23), 244 (21), 201 (37); HRMS calcd for C ₃₃ H ₂₉ FNO ₂ P (M ⁺ ): 521.1920 , found 521.1927

Synthesizing PTVS7 with 2,2,6,6-tetramethylpiperidine (TMP) (212 μl, 1.2 mmol) in tetrahydrofuran (4.0 ml) with n-butyllithium (2.69 M in hexane, 2.2 mmol, 820 μl) The mixture was added dropwise with stirring at 78 ° C., stirred at the same temperature for 10 minutes, and then stirred at 0 ° C. for 1 hour. After stirring, a solution of compound (vi-6) (500 mg, 0.96 mmol) in tetrahydrofuran (15 ml) was added dropwise over 20 minutes with stirring at −78 ° C., and the mixture was stirred at the same temperature for 30 minutes. After stirring, a tetrahydrofuran solution (4.0 ml) of DIO (421 mg, 1.63 mmol) was added dropwise with stirring at −78 ° C., allowed to warm naturally, and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 7) to give a colorless amorphous product. The target compound (PTVS7) (320 mg, 59%) was obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) (major: minor = 9: 1) δ; 8.00-7.85 (m, 1H), 7.61-7.55 (m, 1H), 7.47-7.27 (m, 2H), 7.15 (dd, J = 23 Hz, 7.7 Hz, 2H), 7.04-6.96 (m, 2H), 6.55 (dd, J = 16.3 Hz, 1.1 Hz, 0.9H), 6.42 (d, = 11.4 Hz, 0.1H) , 5.64 (dd, J = 16.3 Hz, 6.0 Hz, 1H), 4.88-4.75 (m, 2H), 4.37-4.21 (m, 4H), 2.46-2.17 (m, 3H), 1.46 (s, 9H), 1.41-1.25 (m, 9H), 1.08-0.93 (m, 3H) ¹³ C-NMR (100 MHz, CDCl ₃ ) δ170.1, 160.6, 157.8, 146.7, 145.0, 137.5, 131.6, 131.2, 130.1, 129.1, 128.7, 128.5, 126.2, 125.1, 114.5, 114.1, 98.7, 82.5, 81.2, 80.5, 69.9, 67.2, 65.8, 42.6, 36.4, 29.9, 28.0 (3), 19.7, 16.0, 15.2, 10.4, 10.1; MS (EI ⁺ , 70 eV): m / z: 561 (M ⁺ , 6.7), 490 (17), 430 (36), 388 (31), 332 (100), 319 (82); HRMS calcd for C ₃₄ H ₄₀ FNO ₅ (M ⁺ ): 561.2890, found 561.2882

DIO was synthesized according to the following scheme.

First, dimethyl sulfoxide (1.64 ml, 23.0 mol) was slowly added dropwise to a solution of oxalyl chloride (813 μl, 9.6 mol) in methylene chloride (10 ml) under an argon stream at −78 ° C. with stirring at the same temperature for 30 minutes. did. After stirring, a solution of Kaneka synthon (500 mg, 1.92 mol) in methylene chloride (2.0 ml) was added dropwise with stirring at −78 ° C. and stirred for 1 hour. After stirring, Triethylamine (5.4 ml, 38.4 mol) was added dropwise and stirred for 1 hour. After completion of the reaction, the temperature was naturally raised to −25 ° C., 20% brine (6.0 ml) was added dropwise with stirring at −25 ° C., and the temperature was raised to room temperature. After washing twice with 20% brine (6.0 ml), the solvent was distilled off, isopropyl ether (12 ml) was added to the resulting pale yellow oil, celite filtration was performed, and the filtrate was dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the target compound (DIO) (448 mg, 90%) as colorless needle crystals. Obtained.

Synthesis of PTVS5 Under a stream of argon, trifluoroacetic acid (1.0 ml) was added to a solution of PTVS7 (80 mg, 0.14 mmol) in methylene chloride (2.0 ml) with stirring at 0 ° C., and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution under ice cooling, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crude product was purified by preparative thin layer chromatography (ethyl acetate: toluene = 4: 1) The target compound (PTVS5) (45 mg, 70%) was obtained as a yellow oil.

Synthesis of PTVS8 To a solution of PTVS5 (45 mg, 100 μmol) in methanol (1.0 ml) was added 2N aqueous sodium hydroxide solution (1.0 ml, 1.0 mmol), and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, purification was performed by HPLC to obtain the target compound (PTVS8) (45 mg, 100%).

Production Example 8 Production of Label Precursor Compound According to the following scheme, PTVS9, which is a label precursor compound, was produced. The scheme will be specifically described below.

Synthesis of Compound (i-3) N, N, -dimethylformamide of Compound (i-2) (2.1 g, 6.6 mmol) and (2-Bromoethoxy) -tert-butyldimethylsilane (1.7 ml, 7.9 mmol) under an argon stream 30 ml) was added potassium carbonate (1.8 g, 13.1 mmol) with stirring at room temperature, stirred at the same temperature for 10 minutes, and then stirred at 70 ° C. for 13 hours. After completion of the reaction, distilled water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to give a colorless oil. As a target compound (i-3) (2.5 g, 79%).

Synthesis of Compound (i-4) Under a stream of argon, lithium (25 mg) suspension of lithium aluminum hydride (400 mg, 98%, 10.5 mmol) was dissolved in THF (15.0) of compound (i-3) (2.5 g, 5.2 mmol). ml) solution was added under stirring at 0 ° C. and stirred at room temperature for 5 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether, and a saturated aqueous sodium sulfate solution was slowly added with stirring at 0 ° C., followed by drying over sodium sulfate. After filtration, the solvent was distilled off to obtain compound (i-4) (2.4 g) as a crude purified product of colorless solid.

Synthesis of compound (i-5) Triphenylphosphine (2.9 g, 10.9 mmol) was added to a solution of compound (i-4) (2.4 g) and carbon tetrabromide (3.6 g, 10.9 mmol) in methylene chloride (20 ml) under an argon stream. Of methylene chloride (10 ml) was added with stirring at 0 ° C., and the mixture was stirred at the same temperature for 25 minutes. After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 15) to give a pale yellow solid. As a target compound (i-5) (1.9 g, 69%).

Synthesis of compound (i-6) Under a stream of argon, ethoxydiphenylphosphine (4.1 ml, 19.9 mmol) was added to a toluene (35 ml) solution of compound (i-5) (1.9 g, 3.8 mmol) with stirring at room temperature. For 4.5 hours. Diethyl ether was added to the oily substance obtained by evaporating the solvent, and the precipitated crystals were washed with diethyl ether to obtain compound (i-6) (2.2 g, 92%) as colorless crystals.

Synthesis of Compound (i-7) Under a stream of argon, 2,2,6,6-tetramethylpiperidine (TMP) (698 μl, 4.1 mmol) in tetrahydrofuran (20 ml) in n-butyllithium (2.69 M in hexane, 7.3 mmol, 2.7 ml) was added dropwise with stirring at −78 ° C., stirred at the same temperature for 10 minutes, and then stirred at 0 ° C. for 1 hour. After stirring, a solution of compound (i-6) (4.2 g, 18.5 mmol) in tetrahydrofuran (50 ml) was added dropwise over 15 minutes with stirring at −78 ° C. After stirring at the same temperature for 45 minutes, a solution of DIO (1.4 g, 5.4 mmol) in tetrahydrofuran (15 ml) was added dropwise with stirring at −78 ° C., allowed to warm to room temperature, and then stirred for 12 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 20) to give a colorless amorphous form. The target compound (i-7) (1.0 g, 47%) was obtained as a solid.

Synthesis of Compound (i-8) Under a stream of argon, Compound (i-6) (1.0 g, 1.5 mmol) in THF (15 ml) was added with tetrabutylammonium fluoride 1.0 M tetrahydrofuran solution (1.8 ml, 1.8 mmol). The mixture was added with stirring at ° C. and stirred at room temperature for 1.5 hours. After completion of the reaction, distilled water was added to the reaction solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated to give the desired compound (i-8) (827 mg) as a colorless oil.

Synthesis of PTVS9 N-Dimethylaminopyridine (18 mg, 0.15 mmol) was added with stirring at 0 ° C., and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain the target. Compound (PTVS9) (900 mg, 85%) was obtained.

[Toxicity test]
According to a conventional method, the compound (PTVS8) obtained in Production Example 7 was administered once into the tail vein of a mouse (male, 5 weeks old). The administration dose was 174 μg / kg or 400 μg / kg. As a control, only vehicle (0.1% Tween 80-added physiological saline) was administered. As a result, the body weights of all the administration groups remained steady throughout the experimental period, and the changes caused by administration in hematological examinations, blood biochemical examinations, organ weights, pathological anatomical examinations, and histopathological examinations I was not able to admit. Moreover, local irritation (vein irritation) was not recognized.

(Production Example 11) Production of PTVS4 According to the following scheme, the target compound (PTVS4) was prepared from the compound (PTVS3) in the same manner as in Production Example 5 except that the catalyst and solvent under the

conditions

1 and 2 shown in Table 3 below were used. ) Was manufactured. The target compound (PTVS4) was produced from the compound (PTVS3) in the same manner as in Production Example 4 (Condition 3 in Table 3). The target compound (PTVS4) was prepared from the compound (PTVS3) in the same manner as in Production Example 4 except that the catalyst and solvent of Condition 4 shown in Table 3 below were used, the stirring temperature was 90 ° C., and the stirring time was 7 hours. Manufactured.

The yield of the obtained compound is shown in Table 3 below. As shown in Table 3, when PdCl ₂ (dppf) CH ₂ Cl ₂ / Pd (PPh ₃ ) ₄ was used as a catalyst, PTVS4 could be produced with the highest yield.

According to the manufacturer following scheme (Production Example 11) radiolabeled compound performs radiolabeled compound obtained in Production Example 4 (PTVS3) as a labeling precursor compound was prepared PTVS10 a radiolabeled compound. The scheme will be specifically described below.

^[18 F] 4-Fluoroiodobenzen synthesis of ^[18 F] was prepared 4-Fluoroiodobenzene according to the following scheme.

[ ¹⁸ F] KF in potassium carbonate (20 μl, 2.23 mCi) was added to a solution of Kryptofix (registered trademark) 222 (2.0 mg, 6.9 μmol) in Acetonitrile (Merck, Lot. K41266036, 50 ml, max 10 ppm H ₂ O) (300 μl). In addition, azeotropic dehydration with Acetonitrile (300 μl × 3) was performed at 120 ° C. for 15 minutes (1.963 mCi). (4-iodophenyl) diphenylsulfoniumtriflate (1.0 mg, 1.9 μmol) and Acetonitrile (100 μl) were added, and the mixture was heated at 120 ° C. for 15 minutes. After completion of the reaction, it is purified by high performance liquid chromatography (Cosmosil 5C ₁₈ -AR-II, 10x250mm, Acetonitrile: phosphate buffer = 70: 30, Flow rate = 5.0ml / min, column oven temperature = 30 ° C, manufactured by Nacalai Tesque). Acetonitrile / Phosphate buffer solution (0.695 mCi, RCY 31%) of [ ¹⁸ F] 4-Fluoroiodobenzene was obtained.

After passing through Sep-pak Plus PS-2 in the order of Acetonitrile (5.0 ml) and Milli-Q water (5.0 ml), it was diluted 30-fold with Milli-Q water [ ¹⁸ F] 4-Fluoroiodobenzene Acetonitrile / Phosphate A buffer solution (0.9 mCi) and Milli-Q water (30 ml) were passed in this order. Next, DMF (1.0 ml) was passed through, and finally the liquid through which DMF (200 μl) was passed was collected (0.275 mCi).

Synthesis of PTVS10 PTVS3 (1.0 mg, 2.1 μmol), [ ¹⁸ F] 4-Fluoroiodobenzene (300 μCi), sodium carbonate (1.0 mg, 9.4 μmol), and PdCl ₂ (dppf) CH ₂ Cl ₂ (1.0 mg, 1.2 μmol) And the inside of the system was replaced with argon. Dimethylformamide (DMF) / H ₂ O (= 90/10) (0.25 mL) was added, and degassing and argon substitution were performed three times. The reaction was performed at 120 ° C. for 20 minutes under microwave irradiation. After completion of the reaction, it was introduced into HPLC and separated and purified. The target radiolabeled compound (PTVS10) was obtained with a radiochemical yield of 12%.

By performing radiolabeling using the compound (PTVS3) which is a labeling precursor compound of the present invention, PTVS10 which is a radiolabeled compound can be produced in a short time and with a high yield.

The sample analysis method of the present invention is useful in various fields such as the medical field, clinical laboratory field, new drug development, and the like.

Claims

Formula (I)

[In the formula (I), R 11 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR 17 R 18 . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R 17 and R 18 each independently represent a C 1-2 alkyl group,
R 12 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom,
R 14 represents a hydrogen atom, a C 1-4 alkyl group, a fluorine atom, a chlorine atom, or a bromine atom,
R 15 represents a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a phenyl group,
L 1 represents — (CH 2 ) m —, —O (CH 2 ) m —, — (AO) n —, or —O (AO) n —, m represents an integer of 1 to 4, AO represents a C 2-4 oxyalkylene group, n represents an integer of 2 to 4,
X 1 represents a reactive functional group,
Y is, -CH 2 -, - CH 2 CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH 2 - indicates,
Z 1 represents —Q—CH 2 —W—CH 2 —CO 2 R 16 , a group represented by the following formula (II), or a group represented by the following formula (III), and Q and W are: Each independently represents —C (O) —, —CH (OH) —, or —CH (OR 19 ) —, R 19 independently represents a C 1-4 alkyl group, and R 16 represents hydrogen. Atom, alkyl group, NH 4 , sodium, potassium, or 1/2 calcium is shown. ]

Or a precursor thereof.
Formula (IV)

[In the formula (IV), R 11 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR 17 R 18 . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R 17 and R 18 each independently represent a C 1-2 alkyl group,
R 12 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom,
R 15 represents a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a phenyl group,
Y is, -CH 2 -, - CH 2 CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH 2 - indicates,
Z 1 represents —Q—CH 2 —W—CH 2 —CO 2 R 16 , a group represented by the following formula (II), or a group represented by the following formula (III), and Q and W are: Each independently represents —C (O) —, —CH (OH) —, or —CH (OR 19 ) —, R 19 independently represents a C 1-4 alkyl group, and R 16 represents hydrogen. Represents an atom, an alkyl group, NH 4 , sodium, potassium, or 1/2 calcium;
M represents a boronic acid ester group. ]

Or a precursor thereof.
Formula (V)

[In the formula (V), R 11 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR 17 R 18 . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R 17 and R 18 each independently represent a C 1-2 alkyl group,
R 12 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom,
R 14 represents a hydrogen atom, a C 1-4 alkyl group, a fluorine atom, a chlorine atom, or a bromine atom,
R 15 represents a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a phenyl group,
L 2 represents a bond, — (CH 2 ) m —, —O (CH 2 ) m —, — (AO) n —, or —O (AO) n —, and m is an integer of 0 to 4 AO represents a C 2-4 oxyalkylene group, n represents an integer of 2 to 4,
X 2 represents a radionuclide,
Y is, -CH 2 -, - CH 2 CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH 2 - indicates,
Z 1 represents —Q—CH 2 —W—CH 2 —CO 2 R 16 , a group represented by the following formula (II), or a group represented by the group represented by the following formula (III), Q and W each independently represent —C (O) —, —CH (OH) —, or —CH (OR 19 ) —, R 19 independently represents a C 1-4 alkyl group, R 16 represents a hydrogen atom, an alkyl group, NH 4 , sodium, potassium, or 1/2 calcium. ]

Or a salt thereof.
A method for producing the radiolabeled compound according to claim 3, comprising:
A production method comprising labeling the labeling precursor compound according to claim 1 or 2 with a labeling substance.
Formula (VI)

[In the formula (VI), R 11 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, or —NR 17 R 18 . A benzyloxy group, a fluorine atom, a chlorine atom, or a bromine atom, R 17 and R 18 each independently represent a C 1-2 alkyl group,
R 12 represents a hydrogen atom, a C 1-4 alkyl group, a C 1-3 alkoxy group, an n-butoxy group, an i-butoxy group, a sec-butoxy group, a fluorine atom, a chlorine atom, or a bromine atom,
R 15 represents a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or a phenyl group,
Y is, -CH 2 -, - CH 2 CH 2 -, - CH = CH -, - CH 2 -CH = CH-, or -CH = CH-CH 2 - indicates,
Z 1 represents —Q—CH 2 —W—CH 2 —CO 2 R 16 , a group represented by the following formula (II), or a group represented by the following formula (III), and Q and W are: Each independently represents —C (O) —, —CH (OH) —, or —CH (OR 19 ) —, R 19 independently represents a C 1-4 alkyl group, and R 16 represents hydrogen. Represents an atom, an alkyl group, NH 4 , sodium, potassium, or 1/2 calcium;
X 3 represents a sulfonate group, a halogen atom, a nitro group, or a trimethylammonium group. ]

A coupling reaction of a compound represented by the formula or a salt thereof with a boronic acid ester or diboron ester,
Formula (IV)

[In the formula (IV), R 11 , R 12 , R 15 , Y, and Z 1 are as defined in the formula (VI), and M represents a boronic ester group. ]
The manufacturing method of the compound or its salt represented by these.
An imaging method comprising detecting a radioactive signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound according to claim 3.
A method for evaluating an uptake function in an organic anion transport polypeptide (OATP), comprising detecting a radio signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound according to claim 3.
A method for observing the uptake transporter function expressed in the liver, comprising detecting a radioactive signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound according to claim 3.
A method for observing a biliary excretion transporter function, comprising detecting a radioactive signal of the radiolabeled compound from a subject previously administered with the radiolabeled compound according to claim 3.
Formula (X)

[In the formula (X), X 1 represents a mesylate group, a tosylate group, a triflate group, or a fluorine atom,
—YZ 1 represents a group represented by the following formula (II ′) or a group represented by the following formula (III ′). ]

[In the formula (III ′), R 16 represents a hydrogen atom, a physiologically hydrolyzable alkyl group, NH 4 , sodium, potassium, or 1/2 calcium. ]
Or a salt thereof.
Formula (XI)

[In the formula (XI), —YZ 1 represents a group represented by the following formula (II ′) or a group represented by the following formula (III ′). ]

[In the formula (III ′), R 16 represents a hydrogen atom, a physiologically hydrolyzable alkyl group, NH 4 , sodium, potassium, or 1/2 calcium. ]
Or a salt thereof.
Formula (XII)

[In the formula (XII), —YZ 1 represents a group represented by the following formula (II ′) or a group represented by the following formula (III ′), and —L 2 —X 2 represents 18 F] represents a fluorine atom, or —O— (CH 2 ) 2 — [ 18 F] F. ]

[In the formula (III ′), R 16 represents a hydrogen atom, a physiologically hydrolyzable alkyl group, NH 4 , sodium, potassium, or 1/2 calcium. ]
Or a salt thereof.