JP5190892B2 - Novel 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivative, process for producing the same, and pharmaceutical composition containing the same as an active ingredient - Google Patents

Description

  The present invention relates to a novel 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivative, a process for producing the same, and a pharmaceutical composition containing the same as an active ingredient.

  Certain protein phosphatases have been shown to be involved in cell proliferation signals, and protein phosphatase inhibitors are expected as anticancer agents. In fact, RK-682, which is known as an inhibitor of the bispecific protein phosphatase, has been reported to inhibit the growth of cancer cells. However, since RK-682 has low cell membrane permeability, its effect at the cell level was low.

  RK-682 (Patent Document 1), which is known as an inhibitor of protein phosphatase, is already a known compound and has been reported to be isolated from cells or chemically synthesized (Patent Document). 2). It is also known as a bispecific protein phosphatase as an inhibitory substance mainly against VHR (Patent Document 1). In addition, various derivatives have been synthesized as optically active substances. VHR and Cdc25B are effective bispecific protein phosphatase inhibitors, and inhibitors such as CD45 and PTP-S2 are protein tyrosine phosphatase inhibitors. It has been reported (Non-Patent Document 1). However, each compound has a 3-acyltetronic acid skeleton as a chemical structure and is an acidic substance. Therefore, it is an amphiphilic compound because it has a negative charge in an aqueous solution near neutrality and also has structural characteristics derived from fatty acids. This chemical property is similar to that of a surfactant, and it was considered that there was a problem in cell membrane permeability mainly when applied to tumor cells and the like. As data showing that, the growth inhibitory activity in P388 cells was significantly reduced compared to the inhibitory activity of protein phosphatase (Non-patent Document 1).

  On the other hand, about 180 compounds are known as 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivatives (non-patent document 2 as a main report). The reported biological activities of 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivatives include herbicidal activity and antitumor activity (Non-patent Document 2). Regarding antitumor activity, 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivatives are very weak and are not described as having high activity in the paper.

Prior art documents related to the present invention include the following. In addition, there are reports on the synthesis of RK-682, synthesis of 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivatives and evaluation of their activity as herbicides (Patent Document 5).
Japanese Patent No. 2856379 Japanese Patent No. 3156006 Japanese Patent Laid-Open No. 10-45740 JP-A-10-212284 GB2237469 Synthesis of tetronic acid derivatives and phosphatase inhibitory activity, P388 cell growth inhibitory activity: Journal of Synthetic Organic Chemistry, Japan, page 1095, Mikiko Sodeoka (1 other) Synthesis and antitumor activity of 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivatives: Pharmaceutical Journal, Vol. 96, p. 536, 1976, Hideyoshi Yuki et al. (6 others)

  An object of this invention is to provide the compound which can be used as an active ingredient of an antitumor agent or a protein phosphatase inhibitor.

  The present inventors efficiently produce a 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivative when a 3-acyltetronic acid derivative represented by RK-682 is treated with an amine. I found out. Furthermore, as a result of cell proliferation inhibition tests of these derivatives and related compounds on cancer cells, they found compounds exhibiting a much stronger proliferation inhibitory activity than RK-682, and completed the present invention.

  The compound group of the present invention is a novel compound group that has not been reported in any literature. The antitumor activity of the compound group of the present invention was evaluated by a growth inhibition test of human leukemia cells HL60 cells. RK-682, which was the basis, was not found to inhibit the growth of HL60 cells in this test system. On the other hand, the 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivative of the present invention showed remarkable HL60 cell growth inhibitory activity. This activity showed a high growth inhibitory ability compared with the ability of RK-682 itself to inhibit protein phosphatase. It has also been found that the compound group of the present invention exhibits inhibitory activity against VHR, which is a bispecific protein phosphatase. Cell growth inhibitory activity and VHR inhibition do not necessarily correlate directly, but this fact suggests that other protein dephosphorylation enzymes may be inhibited to express a cell growth inhibitory effect.

  That is, the present invention includes the following inventions.

(1)
Formula (I):

[Where:
R ₁ and R ₂ , independently of each other, include hydrogen; a heteroatom selected from the group consisting of N, O and S, which may be substituted by a substituent, linear, branched or A cyclic saturated or unsaturated hydrocarbon group; an aryl group or an aralkyl group which may contain a heteroatom selected from the group consisting of N, O and S and may be substituted by a substituent; -C (= O ) —R ₅ or —S (═O) ₂ —R ₅ (R ₅ may contain a heteroatom selected from the group consisting of N, O and S, and may be substituted by a substituent, linear A saturated, unsaturated or unsaturated hydrocarbon group; or an aryl group which may contain a heteroatom selected from the group consisting of N, O and S, and may be substituted by a substituent, or An aralkyl group); or when hydrogen is replaced by a substituent May be an amino group or a hydroxyl group, provided that R ₁ and R ₂ are not hydrogen at the same time;
R ₃ is a linear, branched or cyclic saturated or unsaturated hydrocarbon which may contain a heteroatom selected from the group consisting of N, O and S, and may be substituted by a substituent A group; or an aryl group or an aralkyl group which may contain a heteroatom selected from the group consisting of N, O and S, and may be substituted with a substituent,
R ₁ and R ₂ , or R ₁ and R ₃ , together with the atoms to which they are attached, are heterogeneous selected from the group consisting of N, O and S in addition to N to which R ₁ and R ₂ are attached. May form a saturated or unsaturated aliphatic or aromatic ring, which may contain atoms and may be substituted by substituents;
In formula (I)

The bond represented by may be a single bond or a double bond; when the bond is a double bond, R ₄ is hydrogen; when the bond is a single bond, R 4 ₄ is halogen or -XY {where -X- is -O-, -S- or -NH-; -Y is hydrogen; hetero selected from the group consisting of N, O and S A linear, branched or cyclic saturated or unsaturated hydrocarbon group which may contain atoms and may be substituted by a substituent; or —C (═O) —R ₆ , —S ( = O) ₂ -R ₆ , -C (= O) -OR ₆ , -S (= O) ₂ -OR ₆ or -C (= O) -N (-H) -R ₆ (R ₆ is N, A linear, branched or cyclic saturated or unsaturated hydrocarbon group which may contain a heteroatom selected from the group consisting of O and S and may be substituted by a substituent; or N, May contain a heteroatom selected from the group consisting of O and S, depending on the substituent It is a conversion to a aryl group or an aralkyl group optionally) a is} a group represented by;
Carbon indicated by *

Is an asymmetric carbon when is a single bond, it may be an optically active substance or a racemate,
Partial structure in formula (I):

(In the formula, * ₁ and * ₂ indicate binding positions)
Is

(In the formula, * ₁ and * ₂ indicate binding positions)
Any of these may be used. ]
Or a salt or solvate thereof.

(2) In formula (I),
One of R ₁ and R ₂ is H and the other is

(In the formula, * indicates the bonding position)
A group selected from the group consisting of:
R ₃

(In the formula, * indicates a bonding position; -Ph is an unsubstituted phenyl group)
A group selected from the group consisting of:
Partial structure in formula (I):

(In the formula, * indicates the bonding position)
Is

(In the formula, * indicates the bonding position)
The compound according to claim 1, or a salt or solvate thereof, wherein the compound is a group selected from the group consisting of:

(3) In formula (I),
R ₁ and R ₂ together - (CH _{2) 4} - to form;
R ₃

(In the formula, * indicates a bonding position; -Ph is an unsubstituted phenyl group)
A group selected from the group consisting of:
Partial structure in formula (I):

(In the formula, * indicates the bonding position)
Is

(In the formula, * indicates the bonding position)
The compound or a salt or solvate thereof according to (1), which is a group selected from the group consisting of:

(4) In formula (I),
R ₁ and R ₃ together form-(CH ₂ ) _3- ;
R ₂ is H;
Partial structure in formula (I):

(In the formula, * indicates the bonding position)
Is

(In the formula, * indicates the bonding position)
The compound or a salt or solvate thereof according to (1), which is a group selected from the group consisting of:

(5) A pharmaceutical composition comprising the compound described in (1) to (4) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(6) The pharmaceutical composition according to (5), which is an antitumor agent.

(7) The pharmaceutical composition according to (5), which is a protein phosphatase inhibitor.

(8) A method for producing a compound or a salt or solvate thereof described in (1) to (4), wherein the formula:

{Wherein R ₃ is as defined in claim 1; the partial structure comprising R ′:

Is

(* Indicates a bonding position. R ₄ is as defined in claim 1)
Or a partial structure that can be converted into the partial structure in one or more stages}
And an amine NHR ₁ R ₂ (wherein R ₁ and R ₂ are as defined in claim 1) in the presence of p-toluenesulfonic acid,
formula:

A process for obtaining a compound represented by the formula:

In addition, the compound represented by the formula (I) has two tautomers in an equilibrium state.

and

Present as a mixture of

  The present invention provides a group of compounds that can be used as an active ingredient of an antitumor agent or a protein phosphatase inhibitor.

  This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2006-53742 which is the basis of the priority of the present application.

FIG. 1 shows the results of the HL60 cell growth inhibitory activity test. FIG. 2 shows the results of the HL60 cell growth inhibitory activity test.

R ₁ and R ₂ , independently of one another, represent hydrogen; a heteroatom selected from the group consisting of N, O, and S (eg, —O—, —S—, —NH—, —N═, —S (= O) _2- ) as a straight-chain, branched-chain or cyclic saturated or unsaturated, preferably C 1-20 hydrocarbon group, optionally substituted by a substituent; N, May contain a heteroatom selected from the group consisting of O and S (eg as -O-, -S-, -NH-, -N =, -S (= O) _2- ) and is substituted by a substituent An aryl group or an aralkyl group, preferably having 5 to 20 carbon atoms; —C (═O) —R ₅ or —S (═O) ₂ —R ₅ (R ₅ is composed of N, O and S) A heteroatom selected from the group (eg as —O—, —S—, —NH—, —N═, —S (═O) ₂ —), optionally substituted by a substituent, Linear, branched or cyclic saturated or unsaturated, preferably carbon A hydrocarbon group of 1 to 20; or a heteroatom selected from the group consisting of N, O and S (for example, -O-, -S-, -NH-, -N =, -S (= O) _2- ) and may be substituted by a substituent, preferably an aryl group or aralkyl group having 5 to 20 carbon atoms); or an amino group in which hydrogen may be substituted by a substituent Or a hydroxyl group, where R ₁ and R ₂ are not simultaneously hydrogen. It is preferred that at least one of R ₁ or R ₂ is hydrogen.

R ₃ may contain a heteroatom selected from the group consisting of N, O and S (eg as —O—, —S—, —NH—, —N═, —S (═O) ₂ —) A linear, branched or cyclic saturated or unsaturated, preferably C1-20 hydrocarbon group optionally substituted by a substituent; or from the group consisting of N, O and S May contain selected heteroatoms (eg as -O-, -S-, -NH-, -N =, -S (= O) _2- ) and may be substituted by substituents, preferably An aryl group or aralkyl group having 5 to 20 carbon atoms.

R ₁ and R ₂ , or R ₁ and R ₃ , together with the atoms to which they are attached, are heterogeneous selected from the group consisting of N, O and S in addition to N to which R ₁ and R ₂ are attached. Atoms may be included (eg, as —O—, —S—, —NH—, —N═, —S (═O) ₂ —), and may be substituted with substituents, preferably 4 to 4 carbon atoms 7 saturated or unsaturated aliphatic rings or aromatic rings may be formed. When R ₁ and R ₃ are combined with the atoms to which they are bonded to form a ring, R ₂ is preferably hydrogen.

In formula (I)

The bond represented by may be a single bond or a double bond. R ₄ is hydrogen when the bond is a double bond. When the bond is a single bond, R ₄ is halogen (chlorine, fluorine, bromine or iodine), or —XY {where —X— is —O—, —S— or —NH—. Yes; -Y is hydrogen; a heteroatom selected from the group consisting of N, O and S (eg, as -O-, -S-, -NH-, -N =, -S (= O) _2- ) A linear, branched or cyclic saturated or unsaturated, preferably C1-20 hydrocarbon group which may be substituted by a substituent, or -C (= O) -R ₆ , -S (= O) ₂ -R ₆ , -C (= O) -OR ₆ , -S (= O) ₂ -OR ₆ or -C (= O) -N (-H) -R ₆ (R ₆ includes a heteroatom selected from the group consisting of N, O and S (eg as -O-, -S-, -NH-, -N =, -S (= O) _2- ) A linear, branched or cyclic saturated or unsaturated, preferably C1-20 hydrocarbon group optionally substituted by a substituent; or N, O and Heteroatoms selected from the group consisting of finely S (e.g. -O -, - S -, - NH -, - N =, - S (= O) 2 - as) comprise it may, be substituted by a substituent Which is preferably an aryl group or aralkyl group having 5 to 20 carbon atoms). -Y is -C (= O) -R ₆ , -S (= O) ₂ -R ₆ , -C (= O) -OR ₆ , -S (= O) ₂ -OR ₆ or -C (= In the case of O) —N (—H) —R ₆ , —X— is preferably —O—.

Carbon indicated by *

Is an asymmetric carbon when is a single bond.

  The compound of the present invention may be optically active or racemic. When a racemate is obtained as a result of synthesis, the two optical isomers may be separated or used as a racemate without being separated. Further, as shown in the examples, when an optically pure compound is used as a starting material in the synthesis, the optically pure compound of the present invention can be obtained without performing resolution.

As the “substituent” in the present invention, halogen (chlorine, fluorine, bromine or iodine), ═O (oxo group), —NR ₁₁ R ₁₂ , —OR ₁₃ , —OC (═O) R ₁₄ , —OS ( = O) ₂ R ₁₅ , -NHC (= O) 0R _{16 and the} like, but are not limited thereto. R ₁₁ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ and R ₁₆ are, independently of one another, hydrogen; a heteroatom selected from the group consisting of N, O and S (eg, —O—, —S—, Linear, branched or cyclic saturated or unsaturated hydrocarbon groups having 1 to 20 carbon atoms, which may include (as —NH—, —N═, —S (═O) ₂ —); or N A heteroatom selected from the group consisting of, O and S (for example, as —O—, —S—, —NH—, —N═, —S (═O) ₂ —), It can be, but is not limited to, 20 aryl groups or aralkyl groups. These substituents may be further substituted with the same substituent. When R ³ is a straight-chain saturated hydrocarbon group, it is preferable that an azido group as a substituent or 6- (4,4difluoro-1,3-dimethyl-5- (4-methoxy) is substituted at the terminal. (Phenyl) -4-bora-3a, 4a-diaza-s-indacene-2-propionylamino) hexanoylamino group may be present.

In a particularly preferred embodiment of the invention, _one of R ₁ and R ₂ is H and the other is

(In the formula, * indicates the bonding position)
A group selected from the group consisting of

In a particularly preferred embodiment of the invention, R ₃ is

(In the formula, * indicates a bonding position; -Ph is an unsubstituted phenyl group)
A group selected from the group consisting of

In another preferred embodiment of the invention, R ₁ and R ₂ together form an alkylene chain (eg — (CH ₂ ) ₄ —).

In another preferred embodiment of the invention, R ₁ and R ₃ together form an alkylene chain (eg — (CH ₂ ) ₃ —). At this time, R ₂ is preferably H.

In a particularly preferred embodiment of the invention, the partial structure in formula (I):

(In the formula, * indicates the bonding position)
Is

(In the formula, * indicates the bonding position)
A group selected from the group consisting of

Among the compounds represented by formula (I), particularly preferred compounds are specifically as follows:

(In the formula, -Ph is an unsubstituted phenyl group; -Me is an unsubstituted methyl group)

And a compound represented by the formula selected from the group consisting of: In addition, the name of each compound is for convenience and does not limit the present invention. The compound containing an asymmetric carbon may be an optically active substance or a racemate.

  The compounds of the present invention can form salts. For example, when an acidic group is present, an alkali or alkaline earth metal salt such as lithium salt, sodium salt, potassium salt, magnesium salt, calcium salt; ammonium salt, methylammonium salt, dimethylammonium salt, trimethylammonium salt, etc. Ammonium salts can be formed. If basic groups are present, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, propionate, tartrate, fumarate, maleate Organic acid salts such as malate, citrate, methanesulfonate, p-toluenesulfonate, and the like can be formed. Moreover, the compound of this invention or its salt can also exist as a solvate. Solvates include those formed by absorbing moisture in the air, in addition to solvates to which the solvent used for crystal crystallization is added. Examples of the solvent include lower alcohols such as methanol and ethanol, acetone, acetonitrile, water and the like.

  Although the preferable synthesis method of the compound of this invention is outlined, the synthesis method of this invention is not limited to the following method.

In a preferred embodiment, intermediate 1: first from 4-hydroxyfuran-2 (5H) -one according to the procedure shown in the example (Scheme 1):

To prepare. Partial structure:

Is

(* Indicates a bonding position. R ₄ is as defined above)
Or a partial structure that can be converted to the partial structure in one or more stages. Examples of the group that can be converted into the partial structure in one step or multiple steps include the following formula:

(In the formula, * indicates the bonding position)
The group represented by these is mentioned. This group can be converted to a hydroxymethyl group (—CH ₂ OH, the terminal hydroxyl group corresponds to R ₄ ) by removing the protecting group. To a group having R ₄ . The conversion of the partial structure containing R ′ is preferably performed after the preparation of intermediate 3 described later.

Next, the intermediate 1 is condensed with a carboxylic acid R ₃ COOH having the desired group R ₃ (see Yoshii, E. et al. Chem. Pharm. Bull. 1986, 34, 5188-5190). 2:

To prepare.

Next, intermediate 2 is reacted with amine NHR ₁ R ₂ having the desired R ₁ and R ₂ in the presence of p-toluenesulfonic acid,
Intermediate 3:

Get.

Then, if necessary, substructure:

From

Conversion reaction to the partial structure represented by

  Intermediate 2 can also be synthesized according to the method of Sodeoka, M. et al. J. Med. Chem. 2001, 44, 3216-3222.

  The compound of the present invention is useful as an antitumor agent because it has excellent antitumor activity, and can be used as a pharmaceutical product for humans and animals, a pharmaceutical raw material, and the like.

  The antitumor agent of the present invention contains a compound represented by the formula (I) as an active ingredient. The antitumor agent of the present invention may further contain other antitumor agents and / or additives. Any other antitumor agent and additive can be used as long as they do not reduce the antitumor activity of the compound of the present invention. Examples thereof include adriamycin, cisplatin, taxol, herceptin and the like. It is done.

  When the antitumor agent of the present invention is used for the purpose of preventing or treating tumors, the subject of prevention or treatment is not particularly limited. The antitumor agent of the present invention can be used for the prevention or treatment of at least one kind of tumor such as cancer, sarcoma, benign tumor and the like. These diseases can be targeted even if they are singular, are combined, or are combined with other diseases than the above. These cancer types are not particularly limited, for example, brain tumor, nasopharyngeal cancer, tongue cancer, esophageal cancer, stomach cancer, pancreatic cancer, liver cancer, rectal cancer, colon cancer, uterine cancer, ovarian cancer, testicular cancer, osteosarcoma And at least one selected from the group consisting of leukemia. Further, not only a single cancer but also a plurality of cancers may be combined.

  The present invention also includes a step of administering an effective amount of a compound represented by formula (I) or a salt or solvate thereof to a subject animal in need of prophylaxis or treatment of a tumor, in order to prevent or treat the tumor. The present invention relates to a method for preventing or treating tumors.

  The present invention also relates to the use of a compound represented by formula (I) or a salt or solvate thereof in the manufacture of a medicament for preventing or treating a tumor.

  When a pharmaceutical composition containing a compound represented by formula (I) or a salt or solvate thereof is marketed as an antitumor agent, a package or instructions indicating that it is used for the prevention or treatment of tumors It can be attached.

  The subject to which the antitumor agent of the present invention is administered is not limited, but mammals such as humans, domestic animals (cattle, horses, etc.), pet animals (dogs, cats, etc.), laboratory animals (mouse, rats). Hamster, etc.).

  The antitumor agent of the present invention can be administered to a mammal as a pharmaceutical composition containing a pharmaceutically acceptable carrier or additive. Examples of such carriers and additives include water, pharmaceutically acceptable organic solvents, collagen, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, pectin, xanthan gum , Gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sorbitol, lactose, surfactants acceptable as pharmaceutical additives, etc. Other examples include artificial cell structures such as liposomes. The additive to be used is selected appropriately or in combination from the above according to the dosage form of the pharmaceutical composition.

  The antitumor agent of the present invention can be administered by either oral route or parenteral route.

  When the antitumor agent of the present invention is administered orally, the antitumor agent of the present invention can be formulated as a solid preparation such as a tablet, granule, powder or pill, or a liquid preparation such as a liquid or syrup. . In particular, granules and powders can be made into unit dosage forms as capsules, and in the case of liquid preparations, they may be dried products that are redissolved when used.

  Solid preparations can contain additives such as binders, excipients, lubricants, disintegrants, wetting agents and the like commonly used in preparations. The liquid preparation can contain additives such as a stabilizer, a buffering agent, a corrigent, a preservative, a fragrance, and a coloring agent that are generally used in the preparation.

  Moreover, when administering parenterally, it can be set as dosage forms, such as an injection or a suppository. For example, injections are prepared by dissolving or suspending polyalkoxyflavonoids in solutions, suspensions, emulsions, etc., and are usually provided in the form of unit dose ampoules or multi-dose containers. The injection may be a powder that is redissolved in a suitable carrier, such as sterile pyrogen-free water, when used. Examples of the injection technique include intravenous drip injection, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, and intradermal injection. These parenteral dosage forms usually contain additives such as emulsifiers and suspending agents which are generally used pharmaceutically in their compositions.

  The amount of the compound of the present invention in the antitumor agent is 1 to 5% by weight, preferably 2 to 3% by weight, based on the total weight, although it varies depending on the use, dosage form and administration route. In addition, the effective amount of the compound of the present invention varies depending on the age of the administration subject, the administration route, and the frequency of administration, and can be varied over a wide range. For example, it is 0.1 to 1000 mg per kg body weight per day, and can be administered several times a day to several weeks.

  The compound of the present invention can also be used as an active ingredient of a protein phosphatase inhibitor. The protein phosphatase inhibitor of the present invention can also be formulated in the same manner as the antitumor agent.

  In particular, the compound of the present invention has an inhibitory activity against a bispecific protein phosphatase represented by VHR (vaccinia virus-encoded phosphatase VH1-related phosphatase). Moreover, since the bispecific protein phosphatase has high homology with protein tyrosine phosphatase from the primary structure of the enzyme, the compound of the present invention is also effective for these enzymes. Moreover, it is thought that the compound of this invention has inhibitory activity also with respect to protein phosphatases other than these. Accordingly, the compounds of the present invention can be used for the prevention or treatment of diseases involving protein phosphatases. For example, since there is a report that PTP1B (protein tyrosine phosphatase 1B), which is one of protein phosphatases, is involved in insulin signal, the compound of the present invention may be used as a therapeutic agent for type 2 diabetes. . In addition, the compound of the present invention can be used as a biological research reagent for elucidation of intracellular signal transduction involving protein phosphatase.

  The present invention also provides a subject animal in need of inhibition of protein phosphatase with an effective amount of a compound represented by formula (I) or a salt or solvate thereof for inhibiting protein phosphatase. The present invention relates to a method for inhibiting protein phosphatase, comprising the step of administering to a protein.

  The present invention also relates to the use of a compound represented by formula (I) or a salt or solvate thereof in the manufacture of a protein phosphatase inhibitor.

  When a composition containing a compound represented by formula (I) or a salt or solvate thereof is sold as a protein phosphatase inhibitor, it indicates that it is used to inhibit the protein phosphatase Attached packaging or instructions.

  The present invention also relates to an amount of a compound represented by formula (I) or a salt or solvate thereof effective for preventing or treating a disease involving protein dephosphorylation enzyme, The present invention relates to a method for preventing or treating a disease involving protein dephosphorylating enzyme, comprising a step of administering to a subject animal in need of prevention or treatment of the disease.

  The present invention also relates to the use of a compound represented by formula (I) or a salt or solvate thereof in the manufacture of a medicament for preventing or treating a disease involving protein phosphatase.

  When a pharmaceutical composition containing a compound represented by formula (I) or a salt or solvate thereof is sold as a preventive or therapeutic agent for a disease involving protein dephosphorylation enzyme, Packaging or instructions indicating use for the prevention or treatment of the disease involved can be attached.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these.

In this example, a compound group represented by the formula (I) was synthesized.

(The definitions of each group and symbol are as described above).

The naming was performed as follows. If a substituent with higher priority is bound by a side chain substituent, the numbering may be different from the one below.

¹ H NMR and ¹³ C NMR spectra were measured using JEOL AL400 and AL300 manufactured by JASCO Corporation. When chloroform was used as the measurement solvent, tetramethylsilane was used as the internal standard substance. Chemical shift values are expressed in ppm. Mass spectra (FAB-MS (Pos.)) Were measured using JEOL MStation JMS-700.

  In this example, a compound having an asymmetric carbon means a racemic mixture unless otherwise specified.

First, production methods from Compound 1 to Compound 5 will be described. Compound 5 is a common intermediate for compounds with different R ₃ substituents.

Production reaction 1 → 2
Synthesis of 4- (methoxymethoxy) furan-2 (5H) -one (Compound 2) Since the 4-position hydroxyl group of 4-hydroxyfuran-2 (5H) -one (Compound 1) was protected with a methoxymethyl group, State.

  To a methylene chloride solution (50 mL) of compound 1 (5.05 g, 50.15 mmol), N, N-diisopropylethylamine (17.6 mL, 101.1 mmol) and then chloromethyl methyl ether (5.75 mL, 75.70 mmol) were added at 0 ° C. And stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane: ethyl acetate = 1: 1) to give compound 2 (8.58 g, 100%) as a pale yellow oil.

Molecular weight: 144.13
Molecular formula: C ₆ H ₈ O ₄
FAB-MS (Pos.) M / z = 145 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) 5.248 (1H, t, J = 1.2 Hz), 5.154 (2H, s), 4.656 (2H, d, J = 1.2 Hz), 3.496 (3H, s).
¹³ C-NMR (75.5 MHz, CDCl ₃ ) 176.7, 173.4, 97.0, 91.1, 67.7, 57.3.

Production reaction 2 → 3
Synthesis of 5- (hydroxymethyl) -4- (methoxymethoxy) furan-2 (5H) -one (Compound 3) A hydroxymethyl group was introduced at the 5-position, which will be described below.

  Compound 2 (620.2 mg, 4.30 mmol) was added at −78 ° C. to a tetrahydrofuran solution (25 mL) of lithium diisopropylamide (6.42 mmol) adjusted at −78 ° C. The reaction solution was stirred at -78 ° C for 1 hour and then passed through a gas of paraformaldehyde (644.9 mg, 21.48 mmol). After gradually warming to room temperature, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane: ethyl acetate = 5: 3 → 1: 1) to give compound 3 (241.0 mg, 32%) as a yellow oil. It was.

Molecular weight: 174.15
Molecular formula: C ₇ H ₁₀ O ₅
¹ H-NMR (400MHz, CDCl ₃ ) 5.284 (1H, s), 5.173 (2H, s), 4.843 (1H, t, J = 2.7 Hz), 4.064 (1H, dd, J = 12.6, 2.7 Hz), 3.829 (1H, dd, J = 12.6, 3.9 Hz), 3.491 (3H, s), 2.510 (1H, brs).

Production reaction 3 → 4
Synthesis of 5-((t-butyldiphenylsilyloxy) methyl) -4- (methoxymethoxy) furan-2 (5H) -one (Compound 4) Next, since the hydroxyl group of the hydroxymethyl group at the 5-position was protected, In the following.

  T-Butyldiphenylchlorosilane (1.34 mL, 5.15 mmol) was added to a solution of Compound 3 (731.4 mg, 4.20 mmol) and imidazole (633.7 mg, 9.31 mmol) in N, N-dimethylformamide (8 mL) at 0 ° C. . The reaction solution was stirred at room temperature under a nitrogen stream for 4.5 hours. Methanol (5 mL) was added to stop the reaction, water (5 mL) was added, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane: ethyl acetate = 15: 1 → 4: 1) to give compound 4 (1539.0 mg, 89%) as a pale yellow oil. It was.

Molecular weight: 412.55
Molecular formula: C ₂₃ H ₂₈ O ₅ Si
FAB-MS (Pos.) M / z = 413 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) 7.651 (4H, td, J = 11.6, 8.8 Hz), 7.438-7.388 (6H, m), 5.336 (1H, s), 5.142 (2H, s), 4.810 ( 1H, t, J = 2.4 Hz), 4.062 (1H, dd, J = 11.6, 2.4 Hz), 3.939 (1H, dd, J = 11.6, 2.4 Hz), 3.474 (3H, s), 1.012 (9H, s ).
¹³ C-NMR (100 MHz, CDCl ₃ ) 175.8, 172.5, 135.6, 135.3, 133.0, 132.2, 129.8, 127.7, 97.1, 92.7, 79.6, 61.6, 57.4, 26.7, 19.4.

Production reaction 4 → 5
Synthesis of 5-((t-butyldiphenylsilyloxy) methyl) furan-2,4 (3H, 5H) -dione (Compound 5) The methoxymethyl group was deprotected and will be described below.

  Bromotrimethylsilane (13.5 mL, 102.2 mmol) was added to a methylene chloride solution (25 mL) of compound 4 (2.237 g, 5.42 mmol) at −70 ° C., and the mixture was stirred at −30 ° C. for 24 hours. Saturated aqueous ammonium chloride solution was added and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (chloroform: methanol = 9: 1) to give compound 5 (1.730 g, 87%) as a white solid.

Molecular weight: 368.50
Molecular formula: C ₂₁ H ₂₄ O ₄ Si
FAB-MS (Pos.) M / z = 369 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ ) 7.650-7.611 (4H, m), 7.419-7.356 (6H, m), 4.714 (1H, m), 4.050 (1H, dd, J = 11.6, 2.7 Hz), 3.964 (1H, dd, J = 11.6, 2.9 Hz), 3.266 (1H, d, J = 15.8 Hz), 3.203 (1H, d, J = 15.8 Hz), 0.947 (9H, s).
¹³ C-NMR (75.5 MHz, acetone-d ₆ ) 178.9, 173.6, 136.35, 136.26, 133.9, 133.7, 130.9, 130.8, 130.7, 128.8, 128.6, 128.4, 128.3, 91.3, 91.2, 80.2, 80.1, 62.7, 62.6 , 26.9, 19.8.

Compounds with different R _{3 in} general formula (I) are condensed with various carboxylic acids with reference to literature (Yoshii, E. et al. Chem. Pharm. Bull. 1986, 34, 5188-5190). Can be manufactured.

As an example, production examples of compounds in which R ₃ is a C15 saturated alkyl group (compounds 5 to 8) (see schemes 2 and 3) are described below.

In addition, the compound with which R < ₁ > and R < ₂ > changed can be obtained by making various primary and secondary amines react with the compound 6 which is an intermediate of these reactions.

R _Three  =-(CH ₂ ) ₁₄ CH _Three Reaction example

Production reaction 5 → 6
Synthesis of 5-((t-butyldiphenylsilyloxy) methyl) -3-hexadecanoyl-4- hydroxyfuran -2 (5H) -one (Compound 6) Compound 5 (971.0 mg, 2.64 mmol) and triethylamine (0.4 mL, 2.87 mmol) in methylene chloride (25 mL), 4-dimethylaminopyridine (108.1 mg, 0.89 mmol), palmitic acid (742.9 mg, 2.90 mmol) and N, N'-dicyclohexylcarbodiimide (666.4 mg, 3.16 mmol) ) Was added at 0 ° C. After stirring at 0 ° C. for 1 hour, the mixture was stirred at room temperature for 30 hours. The resulting white solid was filtered and washed with chloroform. The filtrate was washed with 1M hydrochloric acid, and the aqueous layer was extracted again with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. Rough purification by silica gel chromatography (chloroform: methanol = 1: 0 → 9: 1) gave compound 6 (325.0 mg, 20%) as an orange solid.

Molecular weight: 606.91
Molecular formula: C ₃₇ H ₅₄ O ₅ Si
¹ H-NMR (400 MHz, CDCl ₃ ) 7.658-7.595 (4H, m), 7.443-7.344 (6H, m), 4.741 (t, J = 3.4 Hz), 4.626 (t, J = 2.9 Hz) (combined) 1H), 4.136-4.023 (2H, m), 2.965-2.850 (2H, m), 1.690-1.258 (26H), 0.901 (9H, s), 0.883 (3H, t, J = 8.5 Hz).

R ₁ = -CH ₂ Ph, R ₂  = H, R _Three  =-(CH ₂ ) ₁₄ CH _Three , R _Four = Example of OH production

Production reaction 6 → 7
Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (t-butyldiphenylsilyloxy) methylfuran-2,4 (3H, 5H) -dione (Compound 7) Compound 6 (350.1 mg, 0.58 mmol) P-Toluenesulfonic acid (a small amount) and benzylamine (75 μL, 0.69 mmol) were added to a toluene solution (4 mL) and stirred at 120 ° C. for 6 hours under a nitrogen stream. The reaction solution was concentrated and purified by silica gel chromatography (hexane: ethyl acetate = 15: 1 → 4: 1) to give compound 7 (250.0 mg, 62%) as a pale yellow solid.

Molecular weight: 696.04
Molecular formula: C ₄₄ H ₆₁ NO ₄ Si
¹ H-NMR (300 MHz, CDCl ₃ ) 11.393 (brs), 10.447 (brs) (1H combined), 7.694-7.637 (5H, m), 7.391-7.260 (10H, m), 4.670-4.660 (2H, m), 4.530-4.480 (1H, m), 4.110-3.980 (2H, m), 3.060-2.910 (2H, m), 1.560-1.240 (26H, m), 0.954 (9H, s), 0.880 (3H, t, J = 6.4 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ ) 197.8, 193.0, 176.2, 174.4, 173.7, 173.0, 171.4, 135.6-135.2, 133.0-132.6, 129.8-126.8, 92.8, 92.7, 91.3, 83.2, 81.2, 62.4, 62.2 46.8, 43.4, 36.6, 31.8, 29.8-29.1, 27.8, 27.7, 27.6, 27.3, 26.5, 25.7, 22.6, 19.14, 19.11, 14.0.

Production reaction 7 → 8
Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 8) Compound 7 (250.0 mg, 0.36 mmol) in tetrahydrofuran solution (7 To the reaction mixture was added tetrabutylammonium fluoride 1M tetrahydrofuran solution (500 μL) at 0 ° C., and the mixture was stirred at 0 ° C. for 7 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by silica gel chromatography (hexane: ethyl acetate = 15: 1 → 5: 1) to give compound 8 (91.0 mg, 55%) as a white solid. .

  Compound 8 can be used as a common intermediate for compounds having different R4 substituents.

Molecular weight: 457.65
Molecular formula: C ₂₈ H ₄₃ NO ₄
FAB-MS (Pos.) M / z = 458 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ ) 11.314 (brs), 10.383 (brs) (1H in total), 7.420-7.342 (3H, m), 7.278-7.243 (2H, m), 4.648 (s), 4.628 ( s) (2H combined), 4.528 (t, J = 4.0 Hz), 4.504 (t, J = 4.4 Hz) (1H combined), 3.950-3.940 (2H, m), 3.100-2.924 (2H, m) , 1.550-1.430 (4H, m), 1.295-1.247 (24H, m), 0.872 (3H, t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ ) 197.6, 193.2, 175.9, 174.9, 174.3, 171.2, 134.9, 134.8, 129.26, 129.24, 128.55, 128.52, 127.2, 127.1, 92.0, 90.5, 82.7, 80.8, 61.7, 61.5 , 47.1, 46.8, 31.9, 29.8, 29.64, 29.62, 29.19, 29.57, 29.51, 29.40, 29.36, 29.30, 29.16, 29.12, 27.9, 27.65, 27.57, 27.49, 22.6, 14.1.

Example of production of optically active derivatives from optically active RK-682

Production reaction 9 → 10
Synthesis literature for (S) -3- (1- (benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (compound 10) (Sodeoka, M. et al. J (S) -4-hydroxy-5- (hydroxymethyl) -3-palmitoylfuran-2 (5H) -one (compound 9, RK) synthesized according to the method of Med. Chem. 2001, 44, 3216-3222.) -682) was led through one step. That is, in order to obtain a hydroxymethyl form of the final product, a method for removing a hydroxymethyl group protecting group after adding an amine as in Scheme 3 and a hydroxymethyl group protecting group as shown in Scheme 4 are shown. Two methods can be used, in which the amine is added after removal of.

  P-Toluenesulfonic acid (small amount) and benzylamine (5 μL, 0.046 mmol) were added to a toluene solution (1 mL) of compound 9 (9.9 mg, 0.027 mmol), and the mixture was stirred at 110 ° C. for 2 hours under a nitrogen stream. The reaction solution was concentrated and purified by preparative chromatography (hexane: ethyl acetate = 1: 1) to give compound 10 (7.0 mg, 57%) as a white amorphous.

Molecular weight: 457.65
Molecular formula: C ₂₈ H ₄₃ NO ₄
FAB-MS (Pos.) M / z = 458 ([M + H] ⁺ ), 456
¹ H-NMR (300 MHz, CDCl ₃ )
11.314 (brs), 10.383 (brs) (1H combined), 7.420-7.342 (3H, m), 7.278-7.243 (2H, m), 4.665 (s), 4.646 (s) (2H combined), 4.528 ( t, J = 4.0 Hz), 4.504 (t, J = 4.4 Hz) (1H in total), 3.950-3.940 (2H, m), 3.100-2.924 (2H, m), 1.550-1.430 (4H, m), 1.295-1.247 (24H, m), 0.872 (3H, t, J = 6.8 Hz).

The following stereoisomers were synthesized in the same manner.

(R) -3- (1- (Benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 11)
Molecular weight: 457.65
Molecular formula: C ₂₈ H ₄₃ NO ₄
¹ H-NMR (300 MHz, CDCl ₃ )
Same as compound 10.

Using the above method, different compounds of R ₁ , R ₂ and R ₃ were synthesized. The structural formula and data of the compound are shown below. Compound 15 is a secondary amine derivative.

3- (1- (3- (N, N-dimethyl) benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (compound 12)
White amorphous molecular weight: 500.71
Molecular formula: C ₃₀ H ₄₈ N ₂ O ₄
FAB-MS (Pos.) M / z = 501 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.279 (brs), 10.370 (brs) (1H in total), 7.224 (1H, d, J = 7.50Hz), 6.834 (1H, d, J = 9.30Hz), 6.601-6.540 (2H, m), 4.589 ( s), 4.570 (s) (2H in total), 4.552-4.497 (1H, m), 3.960-3.950 (2H, m), 3.040-2.960 (2H, m), 2.966 (6H, s), 1.917-1.250 (26H, m), 0.887 (3H, t, J = 6.50Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.5, 193.2, 175.9, 174.7, 174.3, 171.3, 151.0, 135.6, 135.5, 129.98, 129.95, 114.88, 114.83, 112.4, 110.7, 110.6, 91.7, 90.3, 82.4, 80.7, 61.8, 61.7, 49.1, 47.7, 47.4, 40.4, 33.9, 31.9, 29.8, 29.66, 29.65, 29.64, 29.61, 29.56, 29.45, 29.42, 29.3, 29.22, 29.19, 27.9, 27.7, 27.6, 27.5, 25.6, 24.9, 22.7, 14.1.

3- (1- (3-hydroxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 13)
White amorphous molecular weight: 473.64
Molecular formula: C ₂₈ H ₄₃ NO ₅
FAB-MS (Pos.) M / z = 474 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.266 (brs), 10.336 (brs) (1H combined), 7.377 (1H, brs), 7.206 (1H, t, J = 8.2 Hz), 6.810 (1H, d, J = 9.6 Hz), 6.758-6.741 ( 2H, m), 4.580-4.570 (2H, m), 4.520-4.510 (1H, m), 3.960-3.950 (2H, m), 3.295 (1H, brs), 3.000-2.810 (2H, m), 1.540- 1.230 (26H, m), 0.877 (3H, t, J = 6.8 Hz).
¹³ C-NMR (100 MHz, CDCl ₃ )
197.5, 193.1, 176.2, 175.0, 174.5, 174.4, 171.6, 159.5, 136.2, 130.4, 130.3, 92.2, 83.0, 82.9, 81.1, 81.0, 61.31, 61.29, 47.0, 46.9, 46.8, 46.72, 46.68, 32.1, 32.0, 30.3, 29.9, 29.78, 29.76, 29.75, 29.72, 29.67, 29.59, 29.54, 29.49, 29.44, 29.34, 29.29, 28.07, 27.74, 22.83, 22.78, 14.28, 14.23.

3- (1- (pentylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (compound 14)
White amorphous molecular weight: 437.66
Molecular formula: C ₂₆ H ₄₇ NO ₄
FAB-MS (Pos.) M / z = 438 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.024 (brs), 10.077 (brs) (1H combined), 4.530 (t, J = 4.1 Hz), 4.493 (t, J = 4.4 Hz) (1H combined), 3.964-3.936 (2H, m), 3.458 -3.397 (2H, m), 2.900-2.840 (2H, m), 1.701-1.252 (32H, m), 0.935 (3H, t, J = 7.0 Hz), 0.876 (3H, t, J = 6.8 Hz).

3- (1- (Pyrrolidino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 15)
White amorphous molecular weight: 437.66
Molecular formula: C ₂₅ H ₄₃ NO ₄
FAB-MS (Pos.) M / z = 422 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
4.473 (1H, t, J = 4.4 Hz), 3.927 (2H, d, J = 4.0 Hz), 3.932-3.880 (2H, m), 3.773 (2H, t, J = 6.8 Hz), 3.116-3.022 (2H , m), 2.167-2.110 (2H, m), 2.093-1.980 (2H, m), 1.373-1.246 (26H, m), 0.877 (3H, t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
191.9, 174.2, 172.5, 100.5, 91.9, 85.3, 80.9, 80.8, 62.3, 62.2, 56.0, 51.3, 49.2, 33.9, 32.3, 31.9, 29.6, 29.4, 29.3, 29.2, 27.8, 25.1, 24.8, 22.7, 14.1.

3- (1- (cyclohexylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 16)
Colorless oil molecular weight: 449.67
Molecular formula: C ₂₇ H ₄₇ NO ₄
FAB-MS (Pos.) M / z = 450 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.110 (brs), 10.127 (brs) (1H in total), 4.527 (t, J = 4.2 Hz), 4.487 (t, J = 4.5 Hz) (1H in total), 3.956 (2H, m), 3.633 (1H , m), 3.018-2.845 (2H, m), 1.898-1.853 (4H, m), 1.640-1.399 (6H, m), 1.302-1.243 (26H, m), 0.882 (3H, t, J = 6.8 Hz ).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.3, 193.1, 176.1, 173.1, 172.5, 171.4, 91.2, 89.7, 80.6, 80.5, 61.7, 52.3, 52.1, 33.3, 31.9, 30.6, 30.4, 30.1, 29.9, 29.6, 29.3, 29.2, 28.4, 27.8, 27.3, 24.8, 24.0, 22.6, 14.0.

3- (1- (Cyclobutylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 17)
White amorphous molecular weight: 421.61
Molecular formula: C ₂₅ H ₄₃ NO ₄
FAB-MS (Pos.) M / z = 422 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.143 (brs), 10.187 (brs) (1H combined), 4.536-4.496 (1H, m), 4.293-4.213 (1H, m), 3.966-3.952 (2H, m), 2.945-2.813 (2H, m) , 2.485-2.396 (2H, m), 2.262-2.121 (2H, m), 1.923-1.785 (2H, m), 1.658-1.250 (26H, m), 0.881 (3H, t, J = 6.6 Hz).

3- (1- (4-Methoxybenzeneamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 18)
Milky white amorphous molecular weight: 473.64
Molecular formula: C ₂₈ H ₄₃ NO ₅
FAB-MS (Pos.) M / z = 422 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
12.322 (brs), 11.395 (brs) (1H combined), 7.129 (2H, dd, J = 3.6, 9.0 Hz), 6.964 (2H, d, J = 9.0 Hz), 4.619-4.577 (1H, m), 4.030-4.020 (2H, m), 3.857 (3H, s), 2.863-2.759 (2H, m), 1.606-1.186 (26H, m), 0.887 (3H, t, J = 7.4 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.8, 175.1, 166.7, 159.7, 128.8, 127.8, 127.2, 114.8, 61.7, 55.59, 55.52, 31.9, 31.6, 29.6, 29.3, 28.9, 27.9, 22.7, 14.1.

3- (1- (3- (2-hydroxyethoxy) ethaneamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 19)
Colorless oil molecular weight: 455.63
Molecular formula: C ₂₅ H ₄₅ NO ₆
FAB-MS (Pos.) M / z = 456 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.355 (brs), 10.422 (brs) (1H in total), 4.533 (t, J = 3.9 Hz), 4.502 (t, J = 3.9 Hz) (1H in total), 3.960-3.950 (2H, m), 3.797 -3.640 (8H, m), 3.010-2.860 (2H, m), 1.690-1.250 (26H, m), 0.878 (3H, t, J = 7.0 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.6, 174.4, 174.0, 173.9, 171.3, 138.0, 92.1, 80.8, 73.0, 68.2, 68.0, 61.8, 61.64, 61.58, 61.51, 42.8, 31.9, 29.9, 29.6, 29.4, 29.3, 29.2, 27.9, 27.6, 27.4, 22.7, 14.1.

3- (1- (2-Methylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 20)
Pale yellow oily molecular weight: 471.67
Molecular formula: C ₂₉ H ₄₅ NO ₄
FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.225 (brs), 10.288 (brs) (1H combined), 7.297-7.162 (4H, m), 4.606 (2H, d, J = 6.0 Hz), 4.537 (t, J = 4.1 Hz), 4.515 (t, J = 4.4 Hz) (1H in total), 3.960-3.950 (2H, m), 3.079-2.937 (2H, m), 2.374-2.363 (3H, s), 1.650-1.250 (26H, m), 0.879 (3H , t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.6, 193.2, 176.0, 175.9, 174.9, 174.4, 171.2, 135.9, 132.8, 131.1, 128.9, 127.9, 127.7, 127.5, 126.8, 91.9, 90.4, 82.6, 80.7, 61.7, 61.6, 45.4, 31.90, 31.85, 29.8, 29.6, 29.4, 29.3, 29.2, 28.0, 27.64, 27.58, 27.2, 22.7, 19.2, 14.1.

3- (1- (3-Methylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 21)
White amorphous molecular weight: 471.67
Molecular formula: C ₂₉ H ₄₅ NO ₄
FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ ), 471
¹ H-NMR (400 MHz, CDCl ₃ )
11.281 (brs), 10.366 (brs) (1H combined), 7.309-7.260 (1H, m), 7.177-7.159 (1H, m), 7.076-7.060 (2H, m), 4.605 (s), 4.590 (s ) (Total 2H), 4.548 (t, J = 4.1 Hz), 4.521 (t, J = 4.4 Hz) (Total 1H), 3.970-3.960 (2H, m), 3.085-2.903 (2H, m), 2.372 (3H, s), 2.093-2.050 (1H, m), 1.570-1.250 (26H, m), 0.881 (3H, t, J = 7.0 Hz).
¹³ C-NMR (100 MHz, CDCl ₃ )
197.3, 193.0, 175.7, 174.7, 174.1, 171.0, 139.1, 134.6, 134.5, 129.29, 129.26, 129.12, 129.08, 127.7, 124.2, 124.1, 91.8, 90.4, 82.4, 80.6, 61.9, 61.7, 47.3, 47.0, 32.0, 29.9, 29.78, 29.76, 29.74, 29.67, 29.55, 29.51, 29.44, 29.31, 29.28, 28.0, 27.8, 27.70, 27.65, 22.8, 21.5, 14.2.

3- (1- (4-Methylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 22)
White amorphous molecular weight: 471.67
Molecular formula: C ₂₉ H ₄₅ NO ₄
FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ ), 471
¹ H-NMR (400 MHz, CDCl ₃ )
11.268 (brs), 10.342 (brs) (total 1H), 7.251-7.134 (4H, m), 4.596 (2H, d, J = 5.8 Hz), 4.539 (t, J = 4.1 Hz), 4.514 (t, (J = 4.4 Hz) (1H combined), 3.960-3.950 (2H, m), 3.050-2.940 (2H, m), 2.361 (3H, s), 1.590-1.250 (26H, m), 0.880 (3H, t , J = 7.0 Hz).

3- (1- (3-methoxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 23)
White amorphous molecular weight: 487.67
Molecular formula: C ₂₉ H ₄₅ NO ₅
FAB-MS (Pos.) M / z = 488 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.302 (brs), 10.378 (brs) (1H combined), 7.314 (1H, td, J = 8.0, 2.7 Hz), 6.893-6.828 (2H, m), 6.800-6.780 (1H, m), 4.606 (2H , d, J = 6.0 Hz), 4.546 (t, J = 3.9 Hz), 4.519 (t, J = 4.4 Hz) (1H in total), 3.970-3.950 (2H, m), 3.815 (3H, s), 3.050-2.930 (2H, m), 1.645-1.210 (26H), 0.879 (3H, t, J = 7.0 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.6, 193.2, 175.90, 174.97, 174.4, 171.2, 160.2, 136.4, 136.2, 130.4, 119.3, 119.2, 130.4, 119.3, 119.2, 113.7, 113.2, 113.1, 92.0, 90.5, 61.8, 61.73, 61.65, 55.4, 55.35, 55.29, 47.1, 46.8, 31.9, 29.8, 29.6, 29.4, 29.3, 29.3, 27.9, 27.7, 27.5, 22.7, 14.1.

3- (1- (3-Chlorobenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 24)
White amorphous molecular weight: 487.67
Molecular formula: C ₂₉ H ₄₅ NO ₅
FAB-MS (Pos.) M / z = 488 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.317 (brs), 10.387 (brs) (1H combined), 7.350-7.340 (2H, m), 7.340-7.260 (1H, m), 7.200-7.160 (1H, m), 4.620 (2H, d, J = 5.8 Hz), 4.563 (t, J = 4.0 Hz), 4.534 (t, J = 4.0 Hz) (1H in total), 3.980-3.970 (2H, m), 3.040-2.900 (2H, m), 1.500-1.122 (26H, m), 0.881 (3H, t, J = 6.6 Hz).

3- (1- (2-Picolylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 25)
White amorphous molecular weight: 458.63
Molecular formula: C ₂₇ H ₄₂ N ₂ O ₄
FAB-MS (Pos.) M / z = 459 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.717 (brs), 10.807 (brs) (1H in total), 8.674-8.639 (1H, m), 7.755-7.716 (1H, m), 7.307-7.258 (2H, m), 4.783-4.758 (2H, m) , 4.564 (t, J = 4.1 Hz), 4.526 (t, J = 4.11Hz) (1H in total), 3.980-3.970 (2H, m), 3.127-2.934 (2H, m), 2.221 (1H, brs) , 1.657-1.249 (26H, m), 0.877 (3H, t, J = 6.8 Hz).
¹³ C-NMR (100 MHz, CDCl ₃ )
197.3, 193.1, 175.5, 174.5, 174.1, 171.1, 153.7, 153.5, 149.8, 137.1, 123.2, 121.4, 121.3, 92.1, 90.7, 82.4, 80.7, 61.9, 61.8, 48.0, 47.8, 32.0, 29.9, 29.8, 29.73, 29.66, 29.56, 29.52, 29.44, 29.35, 28.4, 28.1, 27.7, 27.6, 22.8, 14.2.

3- (1- (Cyclohexylmethylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 26)
Colorless oil molecular weight: 463.69
Molecular formula: C ₂₈ H ₄₉ NO ₄
FAB-MS (Pos.) M / z = 464 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.118 (brs), 10.163 (brs) (1H combined), 4.534 (t, J = 4.4Hz), 4.497 (t, J = 4.4 Hz) (1H combined), 3.960-3.950 (2H, m), 3.288 -3.245 (2H, m), 2.990-2.839 (2H, m), 1.798-1.031 (36H, m), 0.878 (3H, t, J = 7.2 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.5, 193.1, 176.2, 174.7, 174.1, 171.4, 91.5, 90.0, 80.6, 80.5, 61.9, 61.7, 49.6, 49.3, 38.0, 37.9, 31.9, 30.7, 29.6, 29.4, 29.3, 29.2, 27.7, 27.6, 27.3, 26.0, 25.6, 22.7, 14.15, 14.06.

3- (1- (2-Phenylethaneamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 27)
Orange oil molecular weight: 471.67
Molecular formula: C ₂₉ H ₄₅ NO ₄
FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.057 (brs), 10.130 (brs) (1H combined), 7.346-7.202 (5H, m), 4.530-4.470 (1H, m), 3.950-3.940 (2H, m), 3.699-3.671 (2H, m) , 2.990-2.964 (2H, m), 2.964-2.750 (2H, m), 1.660-1.250 (26H, m), 0.879 (3H, t, J = 6.8 Hz).
¹³ C-NMR (100 MHz, CDCl ₃ )
197.2, 192.9, 175.8, 174.6, 173.9, 171.0, 136.53, 136.51, 128.94, 128.91, 128.6, 127.3, 91.6, 90.1, 82.3, 80.6, 61.9, 61.7, 45.0, 44.8, 36.0, 36.0, 32.0, 31.0, 29.82, 29.78, 29.76, 29.74, 29.71, 29.67, 29.55, 29.51, 29.4, 29.29, 29.28, 27.72, 27.65, 27.56, 27.33, 22.8, 14.2.

3- (1- (4-Phenoxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 28)
Yellow amorphous molecular weight: 549.74
Molecular formula: C ₃₄ H ₄₇ NO ₅
FAB-MS (Pos.) M / z = 550 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.277 (brs), 10.344 (brs) (1H in total), 7.360 (2H, t, J = 7.9 Hz), 7.268-7.216 (2H, m), 7.142 (1H, t, J = 7.3 Hz), 7.034- 7.009 (4H, m), 4.624-4.604 (2H, s), 4.554-4.505 (1H, m), 3.968-3.967 (2H, m), 3.047-2.952 (2H, m), 2.385-2.383 (1H, m ), 1.779-1.259 (26H, m), 0.883 (3H, t, J = 6.4 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.6, 193.2, 175.9, 174.7, 174.1, 171.2, 157.81, 157.77, 156.50, 156.47, 129.8, 129.2, 129.1, 128.9, 128.8, 123.80, 123.77, 119.26, 119.23, 119.18, 119.17, 91.9, 90.5, 82.6, 80.8, 61.7, 61.5, 46.7, 46.4, 31.9, 29.8, 29.64, 29.61, 29.60, 29.58, 29.54, 29.43, 29.39, 29.30, 29.20, 29.17, 27.9, 27.7, 27.6, 27.5, 22.6, 14.1.

3- (1- (4-Hydroxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 29)
Colorless oil molecular weight: 473.64
Molecular formula: C ₂₈ H ₄₃ NO ₅
FAB-MS (Pos.) M / z = 474 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.157 (brs), 10.216 (brs) (1H in total), 7.650 (1H, brs), 7.084 (2H, d, J = 8.1 Hz), 6.814 (2H, d, J = 8.1 Hz), 4.524-4.523 ( 3H, m), 3.961-3.960 (2H, m), 3.100-2.890 (2H, m), 3.079 (1H, overlapped), 1.587-1.253 (26H, m), 0.879 (3H, t, J = 6.8 Hz) .
¹³ C-NMR (100 MHz, CDCl ₃ )
197.4, 193.0, 176.4, 174.5, 173.9, 171.6, 156.7, 128.7, 125.6, 125.4, 116.1, 92.0, 90.5, 83.0, 81.0, 61.4, 61.2, 47.1, 46.7, 32.0, 29.9, 29.73, 29.70, 29.65, 29.5, 29.4, 29.3, 29.2, 28.1, 27.8, 27.6, 22.7, 14.24, 14.18.

3- (1-((furan-2-yl) methylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 30)
White solid molecular weight: 447.61
Molecular formula: C ₂₆ H ₄₁ NO ₅
FAB-MS (Pos.) M / z = 448 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.217 (m), 10.280 (m) (1H combined), 7.430-7.429 (1H, m), 6.377-6.348 (2H, m), 4.634-4.612 (2H, m), 4.543 (t, J = 4.0 Hz ), 4.517 (t, J = 4.2 Hz) (1H in total), 3.967-3.966 (2H, m), 3.116-2.980 (2H, m), 2.144-2.143 (1H, m), 1.638-1.485 (4H, m), 1.400-1.263 (22H, m), 0.887 (3H, t, J = 6.7 Hz).

3- (4-Hydroxybutaneamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 31)
White amorphous molecular weight: 439.63
Molecular formula: C ₂₅ H ₄₅ NO ₅
FAB-MS (Pos.) M / z = 440 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.063 (m), 10.128 (m) (1H in total), 4.531-4.498 (1H, m), 3.960-3.950 (2H, m), 3.727 (2H, t, J = 5.9 Hz), 3.532-3.490 (2H , m), 3.021-2.870 (2H, m), 2.419 (1H, m), 1.850-1.456 (8H, m), 1.260-1.255 (22H, m), 0.879 (3H, t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.5, 193.1, 176.2, 174.7, 174.1, 171.4, 91.6, 90.1, 82.5, 80.7, 61.9, 61.8, 61.6, 43.2, 42.9, 31.9, 29.8, 29.67, 29.66, 29.64, 29.58, 29.45, 29.34, 29.32, 29.2, 27.8, 27.7, 27.6, 27.4, 26.3, 26.2, 22.7, 14.1.

3- (1- (2- (Phenylsulfonyl) ethylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 32)
Colorless amorphous molecular weight: 535.74
Molecular formula: C ₂₉ H ₄₅ NO ₆ S
FAB-MS (Pos.) M / z = 536 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.074 (m), 10.097 (m) (1H in total), 7.949-7.930 (2H, m), 7.714 (1H, t, J = 7.4 Hz), 7.615 (2H, t, J = 7.8 Hz), 4.513- 4.485 (1H, m), 3.950-3.930 (4H, m), 3.460 (2H, t, J = 6.8 Hz), 2.952-2.833 (2H, m), 2.286 (1H, brs), 1.687-1.265 (26H, m), 0.886 (3H, t, J = 6.7 Hz).
¹³ C-NMR (100 MHz, CDCl ₃ )
197.4, 192.9, 175.4, 174.7, 174.0, 170.6, 138.33, 138.30, 134.41, 134.39, 129.6, 127.84, 127.82, 92.4, 91.0, 82.7, 80.7, 61.6, 61.4, 55.09, 55.05, 37.1, 36.9, 32.0, 29.84, 29.78, 29.76, 29.75, 29.72, 29.67, 29.57, 29.53, 29.44, 29.31, 29.29, 28.0, 27.9, 27.6, 27.3, 22.8, 14.2.

The following are structural formulas and data of compounds in which R ₃ (also R ₁ and R ₂ for compound 34) was changed according to the above method.

3- (1- (Benzylamino) octylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 33)
White amorphous molecular weight: 345.43
Molecular formula: C ₂₀ H ₂₇ NO ₄
¹ H-NMR (400 MHz, CDCl ₃ ) 11.326 (m), 10.395 (m) (1H combined), 7.426-7.258 (5H, m), 4.658 (s), 4.644 (s) (2H combined), 4.544 (t, J = 4.0 Hz), 4.520 (t, J = 4.3 Hz) (1H in total), 4.001-3.914 (2H, m), 3.082-2.913 (2H, m), 2.282 (1H, brs), 1.592-1.258 (10H, m), 0.881 (3H, t, J = 7.0 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ ) 197.6, 193.2, 175.9, 174.9, 174.3, 171.2, 134.9, 134.7, 129.3, 129.2, 128.6, 128.5, 127.2, 127.1, 92.0, 90.5, 82.7, 80.8, 61.7, 61.5 , 47.1, 46.8, 31.6, 31.5, 29.7, 28.78, 28.76, 27.9, 27.63, 27.55, 27.49, 22.5, 14.0.

5- (Hydroxymethyl) -3- (pyrrolidine-2-ylidene) furan-2,4 (3H, 5H) -dione (Compound 34)
White solid molecular weight: 197.19
Molecular formula: C ₉ H ₁₁ NO ₄
FAB-MS (Pos.) M / z = 198 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
9.834 (brs), 9.081 (brs) (1H in total), 4.606 (t, J = 3.9 Hz), 4.575 (t, J = 3.9 Hz) (1H in total), 4.000-3.985 (2H, m), 3.820 -3.757 (2H, m), 3.315-3.243 (2H, m), 2.267-2.179 (2H, m), 2.104 (1H, brs).

t-Butyl 4- (benzylamino) -4- (dihydro-5- (hydroxymethyl) -2,4-dioxofuran-3 (2H) -ylidene) butyl carbamate (Compound 35)
Colorless amorphous molecular weight: 404.46
Molecular formula: C ₂₁ H ₂₈ N ₂ O ₆
FAB-MS (Pos.) M / z = 405 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.316 (brs), 10.426 (brs) (1H combined), 7.401-7.351 (3H, m), 7.291-7.272 (2H, m), 5.251, 5.165 (1H, brs), 4.669, 4.649 (2H, s) , 4.559-4.515 (1H, m), 3.968 (2H, m), 3.208-3.207 (2H, m), 3.026-2.977 (2H, m), 2.661 (1H, brs), 1.786-1.764 (2H, m) , 1.435 (9H, s).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
197.5, 193.6, 175.7, 174.0, 173.5, 171.7, 171.2, 156.2, 134.7, 134.6, 129.3, 128.61, 128.60, 127.23, 127.15, 92.2, 91.0, 82.9, 81.2, 81.1, 79.3, 61.4, 47.2, 46.9, 39.8, 28.4, 28.34, 28.31, 27.4, 25.1, 24.7.

3- (1- (Benzylamino) -2- (1H-indol-3-yl) ethylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 36)
Yellow amorphous molecular weight: 376.41
Molecular formula: C ₂₂ H ₂₀ N ₂ O ₄
FAB-MS (Pos.) M / z = 377 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.284 (m), 10.366 (m) (1H combined), 8.500, 8.419 (1H, brs), 7.551 (1H, d, J = 7.7 Hz), 7.336-7.251 (5H, m), 7.195-7.106 (2H m), 7.056-7.055 (2H, m), 4.637-4.310 (5H, m), 3.981-3.980 (2H, m), 3.068, 2.866 (1H, brs).

3- (1-Benzylamino) -8-azidooctylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (Compound 37)
White amorphous molecular weight: 400.47
Molecular formula: C ₂₁ H ₂₈ N ₄ O ₄
¹ H-NMR (300 MHz, CDCl ₃ ) 11.333 (brs), 10.406 (brs) (total 1H), 7.45-7.34; 7.29-7.26 (5H, m), 4.650 (2H, d, J = 6.2 Hz) , 4.554 (t, J = 4.0 Hz), 4.526 (t, J = 4.4 Hz) (2H in total), 3.968 (2H, br), 3.256 (2H, J = 7.0 Hz), 3.090-2.898 (2H, m ), 1.61-1.28 (10H, m).

3-((1-Benzylamino) 8- (6- (4,4difluoro-1,3-dimethyl-5- (4-methoxyphenyl) -4-bora-3a, 4a-diaza-s-indacene-2 -Propionylamino) hexanoylamino) octylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (compound 38)
Magenta oil molecular weight: 853.80
Molecular formula: C ₄₇ H ₅₈ BF ₂ N ₅ O ₇
¹ H-NMR (300 MHz, CDCl ₃ ) 11.316 (brs), 10.388 (brs) (1H combined), 7.862 (2H, d, J = 8.8 Hz), 7.43-7.33; 7.28-7.23 (5H, m) , 7.084 (1H, s), 6.964 (1H, d, J = 4.0 Hz), 6.961 (2H, d, J = 8.8 Hz), 6.534 (1H, d, J = 4.0 Hz), 6.010 (m), 5.900 (m), 5.736 (m) (2H combined), 4.615 (2H, d, J = 6.2 Hz), 4.532 (t, J = 4.0 Hz), 4.499 (t, J = 4 Hz) (1H combined) , 3.963 (2H, br), 3.847 (3H, s), 3.235-2.897 (6H, m), 2.754 (2H, t, J = 7.3 Hz), 2.523 (3H, s), 2.296 (2H, t, J = 7.3 Hz), 2.207 (3H, s), 2.114-1.975 (2H, m), 1.70-1.160 (16H, m).

Compounds of general formula (I) differing in R ₄ were derived from compounds of R ₄ = OH. Production examples in which R ₄ is a methanesulfonyl group, iodine, hydrogen (exomethylene), acetoxy group and benzoyloxy group are shown below.

R ₁  = -CH ₂ Ph, R ₂ = H, R _Three  =-(CH ₂ ) ₁₄ CH _3, R _Four = -OS (O) ₂ CH _Three  Reaction example

Production reaction 8 → 39
4- (1-Benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 39) Synthesis of Compound 8 (18.0 mg, 0.039 mmol) in tetrahydrofuran (0.3 mL) Methanesulfonyl chloride (8 μL, 0.10 mmol), triethylamine (30 μL, 0.22 mmol) and 4-dimethylaminopyridine (3.0 mg, 0.025 mmol) were added at 0 ° C. The reaction solution was stirred at room temperature for 1 hour. Water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel chromatography (hexane: ethyl acetate = 30: 1) to give compound 39 (20.0 mg, 96%) as a white solid.

Molecular weight: 535.74
Molecular formula: C ₂₉ H ₄₅ NO ₆ S
FAB-MS (Pos.) M / z = 536 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.238 (brs), 10.374 (brs) (1H combined), 7.437-7.370 (3H, m), 7.284-7.260 (2H, overlapped), 4.684-4.597 (4H, m), 4.523-4.464 (1H, m) , 3.043 (s), 3.032 (s) (3H), 3.050-2.930 (2H, m), 1.620-1.250 (26H, m), 0.879 (3H, t, J = 6.8 Hz).
¹³ C-NMR (100 MHz, CDCl ₃ )
194.3, 189.7, 175.1, 175.0, 174.5, 134.44, 134.37, 129.27, 129.25, 128.63, 128.61, 127.1, 91.5, 90.0, 79.6, 77.6, 67.9, 67.7, 47.4, 47.1, 37.8, 37.6, 32.0, 31.0, 29.9, 29.76, 29.75, 29.72, 29.69, 29.63, 29.50, 29.48, 29.42, 29.3, 28.1, 27.8, 27.70, 27.67, 22.8, 14.2.

R ₁  = -CH ₂ Ph, R ₂ = H, R _Three  =-(CH ₂ ) ₁₄ CH _3, R _Four = H reaction example

Production reaction 39 → 40
Synthesis of 3- (1- (benzylamino) hexadecylidene) -5-methylenefuran-2,4 (3H, 5H) -dione (Compound 40) Compound 39 (15.0 mg, 0.028 mmol) and 1,8-diazabicyclo [5 4.0] Undec-7-ene (21 μL, 0.15 mmol) was dissolved in toluene (1 mL) and heated with a drier for 10 seconds. Water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by preparative chromatography (hexane: ethyl acetate = 3: 2) to give compound 40 (7.0 mg, 57%) as a pale yellow solid.

Molecular weight: 439.63
Molecular formula: C ₂₈ H ₄₁ NO ₃
FAB-MS (Pos.) M / z = 440 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.474 (brs), 10.108 (brs) (1H combined), 7.427-7.342 (3H, m), 7.289-7.260 (2H, m), 5.298 (d, J = 2.0 Hz), 5.217 (d, J = 2.0 Hz) (1H combined), 4.928 (1H, d, J = 2.4 Hz), 4.683-4.654 (2H, m), 3.080-2.953 (2H, m), 1.590-1.125 (26H, m), 0.880 (3H , t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
184.5, 180.1, 175.1, 174.8, 172.0, 167.1, 152.9, 151.6, 134.74, 134.66, 129.3, 128.6, 127.1, 92.0, 91.6, 91.5, 90.3, 47.2, 47.0, 31.91, 31.87, 29.80, 29.75, 29.71, 29.65, 29.63, 29.61, 29.57, 29.51, 29.40, 29.34, 29.31, 29.2, 27.9, 27.8, 27.61, 27.58, 22.66, 22.64.

R ₁  = -CH ₂ Ph, R ₂ = H, R _Three  =-(CH ₂ ) ₁₄ CH _3, R _Four = I reaction example

Production reaction 8 → 41
Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (iodomethyl) furan-2,4 (3H, 5H) -dione (Compound 41) Compound 8 (47.7 mg, 0.10 mmol) in methylene chloride solution (1 To the reaction mixture, iodine (42.9 mg, 0.17 mmol), triphenylphosphine (42.1 mg, 0.16 mmol) and imidazole (20.0 mg, 0.29 mmol) were added and stirred at room temperature for 1.5 hours. Water was added to the reaction solution, and extracted with diethyl ether three times. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by preparative chromatography (hexane: ethyl acetate = 2.5: 1) to give compound 41 (28.0 mg, 20% compound 40, 38%). Obtained as a pale yellow solid.

Molecular weight: 567.54
Molecular formula: C ₂₈ H ₄₂ INO ₃
FAB-MS (Pos.) M / z = 568 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.267 (brs), 10.428 (brs) (1H combined), 7.440-7.341 (3H, m), 7.290-7.268 (2H, m), 4.682-4.651 (2H, m), 4.440 (t, J = 4.0 Hz ), 4.401 (t, J = 4.0 Hz) (1H in total), 3.545-3.495 (2H, m), 3.065-2.953 (2H, m), 1.601-1.260 (26H, m), 0.887 (3H, t, J = 6.6 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
196.7, 192.1, 175.3, 175.1, 174.6, 170.1, 151.7, 134.76, 134.71, 134.68, 129.33, 129.31, 128.64, 128.61, 127.12, 127.09, 91.9, 90.3, 79.8, 77.7, 47.3, 47.2, 47.0, 31.9, 29.72, 29.67, 29.66, 29.63, 29.61, 29.5, 29.40, 29.33, 29.2, 27.9, 27.7, 27.5, 22.7, 14.1, 3.1, 2.9.

R ₁  = -CH ₂ Ph, R ₂ = H, R _Three  =-(CH ₂ ) ₁₄ CH _3, R _Four = Example of Br reaction

Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (bromomethyl) furan-2,4 (3H, 5H) -dione (Compound 42) Compound 8 (29.3 mg, 0.064 mmol) in methylene chloride solution (1.5 mL) was added with carbon tetrabromide (39.5 mg, 0.12 mmol) and triphenylphosphine (18.5 mg, 0.073 mmol), and the mixture was stirred at room temperature for 22 hours. Carbon tetrabromide (20.0 mg, 0.060 mmol) and triphenylphosphine (10.0 mg, 0.039 mmol) were added, and the mixture was further stirred at room temperature for 1 hour. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated, and purified by preparative chromatography (hexane: ethyl acetate = 2: 1) to give compound 42 (21.0 mg, 63%) as a colorless oil.

Molecular weight: 520.54
Molecular formula: C ₂₈ H ₄₂ BrNO ₃
¹ H-NMR (400 MHz, CDCl ₃ )
11.246 (m), 10.398 (m) (1H combined), 7.425-7.339 (3H, m), 7.277-7.258 (2H, m), 4.714-4.641 (3H, m), 3.774-3.654 (2H, m) , 3.075-2.958 (2H, m) 1.604-1.249 (26H, m), 0.877 (3H, t, J = 7.0 Hz).
Reaction example of R ₁ = -CH ₂ Ph, R ₂ = H, R ₃ =-(CH ₂ ) ₁₄ CH _3, R ₄ = Cl

Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (chloromethyl) furan-2,4 (3H, 5H) -dione (compound 43) To compound 8 (37.7 mg, 0.082 mmol) Carbon tetrachloride (1 mL) and triphenylphosphine (45.5 mg, 0.18 mmol) were added, and the mixture was stirred at 90 ° C. for 13 hours. Ethanol (0.5 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified by preparative chromatography (hexane: ethyl acetate = 2: 1) to give compound 43 (31.0 mg, 79%) was obtained as a colorless oil.

Molecular weight: 476.09
Molecular formula: C ₂₈ H ₄₂ ClNO ₃
¹ H-NMR (400 MHz, CDCl ₃ )
11.255 (m), 10.398 (m) (1H combined), 7.410-7.361 (3H, m), 7.282-7.262 (2H, m), 4.719-4.645 (3H, m), 3.944-3.818 (2H, m) , 3.052-2.986 (2H, m), 1.601-1.252 (26H, m), 0.879 (3H, t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
(75.5 MHz) 195.7, 191.0, 175.4, 175.1, 174.4, 170.5, 134.74, 134.66, 129.31, 129.28, 128.62, 128.59, 127.1, 92.0, 90.5, 80.7, 78.7, 60.3, 47.2, 46.9, 42.8, 42.6, 31.9, 29.69, 29.65, 29.64, 29.61, 29.59, 29.52, 29.39, 29.37, 29.31, 29.17, 29.14, 27.9, 27.7, 27.53, 27.49, 22.6, 21.0, 14.2, 14.1.

R ₁  = -CH ₂ Ph, R ₂ = H, R _Three  =-(CH ₂ ) ₁₄ CH _3, R _Four = -OCOCH _Three  Reaction example

Production reaction 8 → 44
Synthesis of (4- (1- (benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl acetate (Compound 44) Compound 8 (27.9 mg, 0.061 mmol) in methylene chloride (3 mL) Were added acetic anhydride (17 μL, 0.18 mmol), pyridine (17 μL, 0.21 mmol) and 4-dimethylaminopyridine (small amount) at 0 ° C. and stirred at room temperature for 20 minutes. Ice water was added and extracted with ethyl acetate. The organic layer was washed successively with 0.5 N hydrochloric acid, water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate and concentrated. Purification by preparative TLC (hexane: ethyl acetate = 2: 1) gave Compound 44 (29.0 mg, 95%) as a white solid.

Molecular weight: 499.68
Molecular formula: C ₃₀ H ₄₅ NO ₅
FAB-MS (Pos.) M / z = 500 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.289 (brs), 10.415 (brs) (1H combined), 7.446-7.363 (3H, m), 7.286-7.268 (2H, m), 4.691-4.637 (3H, m), 4.543-4.534 (d, J = 2.6 Hz), 4.503-4.493 (d, J = 2.8 Hz) (1H combined), 4.283 (1H, td, J = 12.5, 5.5 Hz), 3.049-2.976 (2H, m), 2.041 (3H, s) , 1.579-1.257 (26H, m), 0.882 (3H, t, J = 6.8 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
196.1, 191.3, 175.6, 175.1, 174.4, 170.6, 170.4, 134.8, 134.7, 129.31, 129.29, 128.63, 128.60, 127.12, 127.10, 91.6, 90.1, 80.2, 87.1, 62.9, 62.7, 47.2, 46.9, 31.9, 29.70, 29.65, 29.63, 29.61, 29.57, 29.52, 29.39, 29.37, 29.31, 29.2, 27.8, 27.7, 27.6, 27.5, 22.6, 20.7. 14.1.

R ₁  = -CH ₂ Ph, R ₂ = H, R _Three  =-(CH ₂ ) ₁₄ CH _3, R _Four = -OCOPh reaction example

Production reaction 8 → 45
Synthesis of (4- (1- (benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl benzoate (Compound 45) Compound 8 (20.0 mg, 0.044 mmol) in methylene chloride (0.5 mL) N, N-diisopropylethylamine (16 μL, 0.092 mmol) was added. N-methylimidazole (11 μL, 0.14 mmol) and benzoyl chloride (28 μL, 0.24 mmol) were added at 0 ° C., and the mixture was stirred at room temperature for 24 hours. Ice water was added and extracted with ethyl acetate. The organic layer was washed successively with 0.5 N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate and concentrated. Purification by preparative TLC (hexane: ethyl acetate = 2: 1) gave Compound 45 (20.0 mg, 81%) as a white solid.

Molecular weight: 561.75
Molecular formula: C ₃₅ H ₄₇ NO ₅
FAB-MS (Pos.) M / z = 562 ([M + H] ⁺ )
¹ H-NMR (300 MHz, CDCl ₃ )
11.332 (brs), 10.467 (brs) (1H in total), 7.968 (2H, dd, J = 7.0, 1.5 Hz), 7.550 (1H, t, J = 7.0 Hz), 7.417-7.365 (5H, m), 7.285-7.242 (2H, m), 4.836-4.570 (3H, m), 4.685 (s), 4.665 (s) (2H in total), 3.075-2.948 (2H, m), 1.566-1.238 (26H, m) , 0.890 (3H, t, J = 6.6 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
196.2, 191.4, 175.7, 175.1, 174.5, 170.8, 165.9, 134.9, 134.8, 133.11, 133.06, 129.7, 129.63, 129.59, 129.3, 128.6, 128.29, 128.27, 127.0, 91.7, 90.2, 80.4, 78.3, 63.4, 63.1, 47.1, 46.9, 31.9, 29.8, 29.74, 29.67, 29.66, 29.63, 29.61, 29.59, 29.56, 29.54, 29.4, 29.3, 29.22, 29.17.

Using similar methods, different compounds of R ₁ , R ₂ , R ₃ and R ₄ were synthesized. The structural formula and structural data of the compound are shown below.

4- (1- (4-Phenoxy) benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 46)
Colorless oil molecular weight: 627.83
Molecular formula: C ₃₅ H ₄₉ NO ₇ S
FAB-MS (Pos.) M / z = 628 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.183 (m), 10.317 (m) (1H in total), 7.357 (2H, t, J = 7.9 Hz), 7.234 (2H, d, J = 8.0 Hz), 7.141 (1H, t, J = 7.5 Hz) , 7.023 (4H, d, J = 8.5 Hz), 4.672-4.593 (4H, m), 4.520-4.4460 (1H, m), 3.042, 3.029 (3H, s), 3.040-2.939 (2H, m), 1.594 -1.254 (26H, m), 0.878 (3H, t, J = 6.7 Hz).
¹³ C-NMR (75.5 MHz, CDCl ₃ )
194.5, 189.9, 175.14, 175.08, 174.4, 170.2, 157.95, 157.92, 156.43, 156.39, (?) 129.9, 128.9, 128.8, 128.7, 123.88, 123.86, 119.33, 119.30, 119.19, 119.18, 91.5, 90.0, 79.6, 77.6 , 67.8, 67.6, 46.8, 46.6, 37.7, 37.5, 31.9, 29.8, 29.6, 29.5, 29.4, 29.3, 29.2, 28.0, 27.7, 27.6, 14.1.

4- (1- (3- (N, N-dimethyl) benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 47)
Pale yellow oily molecular weight: 578.80
Molecular formula: C ₃₁ H ₅₀ N ₂ O ₆ S
FAB-MS (Pos.) M / z = 579 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.225 (m), 10.368 (m) (1H, m), 7.253 (1H, t, J = 7.8 Hz), 6.706 (1H, d, J = 8.6, 2.0 Hz), 6.590 (1H, d, J = 7.6 Hz), 6.555 (1H, s), 4.683-4.592 (4H, m), 4.526-4.466 (1H, m), 3.050-2.970 (2H, m), 3.047, 3.038 (3H, s), 2.977 (6H, s), 1.602-1.467 (2H, m), 1.460-1.265 (24H, m), 0.890 (3H, t, J = 6.7 Hz).

4- (1- (Benzylamino) -4-t-butoxycarbonylaminobutylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 48)
White amorphous molecular weight: 482.55
Molecular formula: C ₂₂ H ₃₀ N ₂ O ₈ S
FAB-MS (Pos.) M / z = 483 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.238 (m), 10.411 (m) (1H combined), 7.435-7.368 (3H, m), 7.287-7.261 (2H, m), 5.103, 5.027 (1H, m), 4.703-4.655 (3H, m) , 4.626 (d, J = 2.6 Hz), 4.600 (d, J = 2.6 Hz) (1H in total), 4.500 (1H, td, J = 11.3, 4.4 Hz), 3.240-3.211 (2H, m), 3.072 -2.983 (2H, m), 3.038-3.034 (3H, s), 1.799-1.756 (2H, m), 1.422, 1.437 (9H, s).

4- (1- (4-Methanesulfonyl) benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 49)
Colorless oil molecular weight: 629.83
Molecular formula: C ₃₀ H ₄₇ NO ₉ S
FAB-MS (Pos.) M / z = 630 ([M + H] ⁺ )
¹ H-NMR (400 MHz, CDCl ₃ )
11.242 (m), 10.372 (m) (Total 1H), 7.347-7.333 (4H, m), 4.692-4.656 (3H, m), 4.625, 4.595 (1H, m), 4.526-4.472 (1H, m) , 3.178 (3H, s), 3.044, 3.030 (3H, s), 3.040-2.922 (2H, m), 1.620-1.256 (26H, m), 0.880 (3H, t, J = 6.9 Hz).

4-((1-Benzylamino) 8- (6- (4,4difluoro-1,3-dimethyl-5- (4-methoxyphenyl) -4-bora-3a, 4a-diaza-s-indacene-2 Synthesis of -propionylamino) hexanoylamino) octylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (compound 50) Red purple oil Molecular weight: 931.89
Molecular formula: C ₄₈ H ₆₀ BF ₂ N ₅ O ₉ S
¹ H-NMR (300 MHz, CDCl ₃ ) 11.228 (brs), 10.368 (brs) (1H combined), 7.864 (2H, d, J = 8.4 Hz), 7.45-7.24 (5H, m), 7.090 (1H , s), 6.966 (1H, d, J = 4.4 Hz), 6.963 (2H, d, J = 8.4 Hz), 6.536 (1H, d, J = 4.4 Hz), 5.795-5.590 (2H, brm), 4.687 -4.568 (3H, m), 4.496 (dd, J = 11.4, 4 Hz), 4.472 (dd, J = 11.7, 4.4 Hz) (1H in total), 3.849 (3H, s), 3.232-3.124 (4H, m), 3.025 (3H, s), 3.02-2.91 (2H, brm), 2.761 (2H, t, J = 7.3 Hz), 2.529 (3H, s), 2.290 (2H, t, J = 7.3 Hz), 2.215 (3H, s), 2.063 (2H, q, J = 4.4 Hz), 1.620-1.160 (16H, m).

3-((1-Benzylamino) 8- (6- (4,4difluoro-1,3-dimethyl-5- (4-methoxyphenyl) -4-bora-3a, 4a-diaza-s-indacene-2 Synthesis of -propionylamino) hexanoylamino) octylidene) -5- (fluoromethyl) furan-2,4 (3H, 5H) -dione (Compound 51) Red purple oil Molecular weight: 855.79
Molecular formula: C ₄₇ H ₅₇ BF ₃ N ₅ O ₆
¹ H-NMR (300 MHz, CDCl ₃ ) 11.251 (brs), 10.410 (brs) (1H combined), 7.866 (2H, d, J = 8.8 Hz), 7.430-7.208 (5H, m), 7.088 (1H , s), 6.964 (2H, d, J = 8.8 Hz), 6.964 (1H, d, J = 4.4 Hz), 6.536 (1H, d, J = 4.4 Hz), 5.915-5.505 (2H, brm), 4.826 -4.797; 4.692-4.535 (4H, m), 3.849 (3H, s), 3.233-3.149 (4H, m), 3.20-3.10; 3.02-2.90 (2H, brm), 2.761 (2H, t, J = 7.3 Hz), 2.529 (3H, s), 2.292 (2H, t, J = 7.3 Hz), 2.214 (3H, s), 2.108-2.026 (2H, m), 1.620-1.180 (16H, m).

Synthesis of 4- (1-benzylamino) 8-azidooctylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (compound 52) White amorphous molecular weight: 478.56
Molecular formula: C ₂₂ H ₃₀ N ₄ O ₆ S
¹ H-NMR (300 MHz, CDCl ₃ ) 11.247 (brs), 10.381 (brs) (total 1H), 7.46-7.35; 7.3-7.26 (5H, m), 4.702-4.594 (4H, m), 4.537- 4.465 (1H, m), 3.259 (2H, t, J = 6.6 Hz), 3.048 (s), 3.037 (s) (1H in total), 3.060-2.900 (2H, m), 1.63-1.290 (12H, m ).

HL60 cell growth inhibitory activity The growth inhibitory activity of test compounds against human leukemia cells HL60 was evaluated using alamarBlue (trademark).

Test 1
HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) were suspended in new medium to 2x10 ⁴ cells / ml, seeded in 99.5 μl each in a 96-well plate, and cultured for 2 hours . Subsequently, DMSO (compound-free group) or DMSO solution of each compound was added in an amount of 0.5 μl, followed by further culturing for 3 days. Thereafter, 10 μl of alamarBlue (trademark) (Biosource) was added to each well as a live cell number indicator, and fluorescence [excitation immediately after addition and after standing for 2 to 3 hours in a 5% CO ₂ incubator at 37 ° C. Wavelength (Ex.): 560 nm, radiation wavelength (Em.): 590 nm] were measured with Spectra Max Gemini XS (Molecular Devices), and the fluctuation value was determined. Then, the relative value of the fluorescence fluctuation value of the compound addition group was calculated when the fluorescence fluctuation value of the compound addition group was taken as 100%. Based on this, growth inhibitory activity was determined. The results are shown in Table 1 below and FIG.

Growth inhibitory activity (%) = 100-(fluorescence fluctuation value when compound is added / fluorescence fluctuation value in group without compound) x 100

Test 2
HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) were suspended in fresh medium to 4x10 ⁴ cells / ml, seeded in 99.5 μl each in a 96-well plate, and cultured for 2 hours . Subsequently, DMSO (compound-free group) or DMSO solution of each compound was added in an amount of 0.5 μl, followed by further culturing for 3 days. Thereafter, 10 μl of alamarBlue (trademark) (Biosource) was added to each well as a live cell number indicator, and fluorescence [excitation immediately after addition and after standing for 2 to 3 hours in a 5% CO ₂ incubator at 37 ° C. Wavelength (Ex.): 560 nm, radiation wavelength (Em.): 590 nm] were measured with Spectra Max Gemini XS (Molecular Devices), and the fluctuation value was determined. Then, the relative value of the fluorescence fluctuation value of the compound addition group was calculated when the fluorescence fluctuation value of the compound addition group was taken as 100%. Based on this, growth inhibitory activity was determined. The results are shown in Table 2 below and FIG.

Growth inhibitory activity (%) = 100-(fluorescence fluctuation value when compound is added / fluorescence fluctuation value in group without compound) x 100

  From Tables 1 and 2, RK-682 shows almost no cytostatic activity even at a high concentration of 30 μM, whereas the compound developed in the present invention shows activity at 10 μM or less. It became clear that it was converted into a skeleton that can be applied. In particular, Compound 39 was found to remarkably suppress cell proliferation even at a very low concentration of 0.3 μM and to have a strong anticancer activity.

VHR inhibitory activity The inhibitory activity of the test compound against the bispecific protein phosphatase VHR (vaccinia virus-encoded phosphatase VH1-related phosphatase) was evaluated using p-nitrophenyl phosphate (pNPP).

Test 1
78 μL of VHR expressed in E. coli and diluted with enzyme reaction buffer (50 mM succinic acid, 1 mM EDTA, 150 mM NaCl, pH 6.0) is seeded in a 96-well plate, and DMSO (no compound added group) or 2 μL of each compound in DMSO was added and allowed to stand at 37 ° C. for 30 minutes. Thereafter, 120 μL of pNPP was added and allowed to stand at 37 ° C. for 30 minutes. Next, 100 μL of 0.1 M NaOH aqueous solution was added, and the absorbance (405 nm) was measured with an Ultra Microplate Reader EL808 (BIO-TEK Instruments) to determine the fluctuation value. After that, the relative value of the light absorption fluctuation value of the compound addition group when the light absorption fluctuation value of the compound addition group was taken as 100% was calculated. Based on this, VHR inhibitory activity was determined. The results are shown in Table 3 below.

Inhibition rate by test compound (%) = 100− (absorption fluctuation value at the time of compound addition / absorption fluctuation value of the compound-free group) × 100

Test 2
78 μL of VHR expressed in E. coli and diluted with enzyme reaction buffer (50 mM succinate, 1 mM EDTA, 150 mM NaCl, pH 6.0) is seeded in a 96-well plate, DMSO (no compound added group) or each 2 μL each of the compound in DMSO was added and allowed to stand at 30 ° C. for 30 minutes. Then, 120 μL of pNPP (5.0 mM) was added and left at 30 ° C. for 15 minutes. Next, 100 μL of 0.1 M NaOH aqueous solution was added, and the absorbance (405 nm) was measured with an Ultra Microplate Reader EL808 (BIO-TEK Instruments) to determine the fluctuation value. After that, the relative value of the light absorption fluctuation value of the compound addition group when the light absorption fluctuation value of the compound addition group was taken as 100% was calculated. Based on this, VHR inhibitory activity was determined. The results are shown in Table 4 below.

Inhibition rate by test compound (%) = 100− (absorption fluctuation value at the time of compound addition / absorption fluctuation value of the compound-free group) × 100

  All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims (10)

Formula (I):
[Where:
R ₁ and R ₂ are independently of each other hydrogen ; a linear , branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 20 carbon atoms ; or a group consisting of —O— and —N═ The ring may contain a heteroatom selected from: methyl, halogen, —NR ₁₁ R ₁₂ , —OR ₁₃ and —OS (═O) ₂ R ₁₅ (R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₅ Are independently of each other hydrogen; a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 20 carbon atoms; or an aryl group or aralkyl group having 5 to 20 carbon atoms) An aryl group or aralkyl group having 5 to 20 carbon atoms which may be substituted with a substituent selected from the group consisting of :
Provided that R ₁ and R ₂ are not simultaneously hydrogen;
R ₃ is —NHC (═O) 0 R ₁₆ (R ₁₆ is a linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 20 carbon atoms) and 6- (4 Substituents selected from the group consisting of 4-difluoro-1,3-dimethyl-5- (4-methoxyphenyl) -4-bora-3a, 4a-diaza-s-indacene-2-propionylamino) hexanoylamino A linear, branched or cyclic saturated or unsaturated hydrocarbon group having 1 to 20 carbon atoms , which may be substituted by: or an indolylmethyl group ,
R ₁ and R _3, which is integral with the atoms to which they are attached may form an aliphatic ring of 4 to 7 carbon atoms saturated or unsaturated;
In formula (I)
The bond represented by may be a single bond or a double bond; when the bond is a double bond, R ₄ is hydrogen; when the bond is a single bond, R 4 ₄ or are halogen, or -XY {here, -X- is -O - a and; -Y is hydrogen; Oh Rui, -C (= O) -R ₆ or -S (= O) ₂ - R ₆ (R ₆ is a linear hydrocarbon group of branched carbon atoms or a cyclic saturated or unsaturated 1 to 20; or, an aryl group or an aralkyl group having 5 to 20 carbon atoms) are } Is a group represented by
Carbon indicated by *
Is an asymmetric carbon when is a single bond, it may be an optically active substance or a racemate,
Partial structure in formula (I):
(In the formula, * ₁ and * ₂ indicate binding positions)
Is
(In the formula, * ₁ and * ₂ indicate binding positions)
Any of these may be used. ]
Or a salt or solvate thereof. In formula (I):
One of R ₁ and R ₂ is H and the other is
(In the formula, * indicates the bonding position)
A group selected from the group consisting of:
R ₃
(In the formula, * indicates a bonding position; -Ph is an unsubstituted phenyl group)
A group selected from the group consisting of:
Partial structure in formula (I):
(In the formula, * indicates the bonding position)
Is
(In the formula, * indicates the bonding position)
The compound according to claim 1, or a salt or solvate thereof, wherein the compound is a group selected from the group consisting of: In formula (I):
R ₁ and R ₃ together form-(CH ₂ ) _3- ;
R ₂ is H;
Partial structure in formula (I):
(In the formula, * indicates the bonding position)
Is
(In the formula, * indicates the bonding position)
The compound according to claim 1, or a salt or solvate thereof, wherein the compound is a group selected from the group consisting of: In formula (I):
R ₁ is benzyl; benzyl substituted with —N (CH ₃ ) ₂ , hydroxyl, methoxy, halogen, methyl, phenyloxy or methyl-S (O) ₂ —O—; pyridylmethyl; furylmethyl; pentyl; Cyclobutyl; cyclohexyl; or cyclohexylmethyl;
R ₂ is H;
R ₃ is — (CH ₂ ) ₁₄ CH ₃ ;
Partial structure in formula (I):
(In the formula, * indicates the bonding position)
Is
(In the formula, * indicates the bonding position)
The compound according to claim 1, or a salt or solvate thereof. In formula (I):
R ₁ is benzyl substituted with methyl or hydroxyl;
R ₂ is H;
R ₃ is — (CH ₂ ) ₁₄ CH ₃ ;
Partial structure in formula (I):
(In the formula, * indicates the bonding position)
Is
(In the formula, * indicates the bonding position)
The compound according to claim 1, or a salt or solvate thereof. below:
(In the formula, -Ph is an unsubstituted phenyl group; -Me is an unsubstituted methyl group; when it contains an asymmetric carbon, it may be optically active or racemic)
The compound of any one of Claims 1-5 represented by the formula selected from the group which consists of these, its salt, or a solvate. A pharmaceutical composition comprising the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The pharmaceutical composition according to claim 7 , which is an antitumor agent. The pharmaceutical composition according to claim 7 , which is a protein phosphatase inhibitor. A method for producing the compound according to any one of claims 1 to 6, or a salt or solvate thereof,
formula:
{Wherein R ₃ is as defined in claim 1; the partial structure comprising R ′:
Is
(* Indicates a bonding position. R ₄ is as defined in claim 1)
Or a partial structure that can be converted into the partial structure in one or more stages}
And an amine NHR ₁ R ₂ (wherein R ₁ and R ₂ are as defined in claim 1) in the presence of p-toluenesulfonic acid,
formula:
A process for obtaining a compound represented by the formula: