WO2007102368A1 - Novel 3-(1-aminoalkylidene)furan-2,4(3h,5h)-dione derivative, method for producing the same, and pharmaceutical composition containing the same as active ingredient - Google Patents

Abstract

Disclosed is a compound which can be used as an active ingredient for an antitumor agent or protein phosphatase inhibitor. Specifically disclosed is a compound represented by the formula (I) below, a salt thereof or a solvate thereof. Also specifically disclosed is a pharmaceutical composition containing such a compound, which has antitumor activity or protein phosphatase inhibitory activity.

Description

 Specification

 Novel 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) -dione derivative, production method thereof, and pharmaceutical composition containing the same as an active ingredient

 Technical field

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

 Background art

 [0002] 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 cellular level was low.

 [0003] RK-682 (Patent Document 1), which is known as an inhibitor of protein phosphatase, is a known compound and has been reported to be isolated from cells or chemically synthesized. (Patent Document 2 etc.). It is also known as a bispecific protein phosphatase mainly as an inhibitory substance against VHR (Patent Document 1). In addition, various derivatives have also been synthesized as optically active substances, and as effective bispecific protein phosphatase inhibitors, inhibition of VHR and Cdc25B, and protein tyrosine phosphatase inhibitors such as CD45 and PTP-S2 Substances have been reported (Non-Patent Document 1). However, both compounds have a 3-acyltetronic acid skeleton as a chemical structure and are acidic substances. 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 thought that there was a problem with cell membrane permeability, mainly when applied to tumor cells. As data showing this, the growth inhibitory activity in P388 cells was significantly reduced compared to the inhibitory activity of protein dephosphorylation enzymes (Non-patent Document 1).

[0004] On the other hand, about 180 compounds are known as 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) _dione derivatives. 2). Reported, R, Ru 3- (1- The biological activity of minoalkylidene) furan-2,4 (3H, 5H) _dione derivatives includes herbicidal activity and antitumor activity (Non-patent Document 2). Regarding antitumor activity, there is no description that 3-hy-aminoalkylidene) furan-2,4 (3H, 5H) _dione derivatives are highly active even in very weak papers.

 [0005] 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 herbicidal activity (Patent Document 5).

 Patent Document 1: Japanese Patent No. 2856379

 Patent Document 2: Japanese Patent No. 3156006

 Patent Document 3: Japanese Patent Laid-Open No. 10-45740

 Patent Document 4: JP-A-10-212284

 Patent Document 5: GB2237569

 Non-Patent Document 1: 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)

 Non-Patent Document 2: Synthesis and antitumor activity of 3- (1-aminoalkylidene) furan-2,4 (3H, 5H) _dione derivatives: Pharmaceutical Journal, 1976, 96-536, Hideki Yuki et al. (Other 6 Name)

 Disclosure of the invention

 Problems to be solved by the invention

[0006] An object of the present invention is to provide a compound that can be used as an active ingredient of an antitumor agent or a protein phosphatase inhibitor.

 Means for solving the problem

 [0007] The present inventors have found that 3- (1_aminoalkylidene) furan-2,4 (3H, 5H) _dione derivatives are efficient when 3-acyltetronic acid derivatives represented by RK-682 are treated with ammine. I found that it generates well. Furthermore, as a result of cell proliferation inhibition tests of these derivatives and related compounds on cancer cells, those having a much stronger proliferation inhibitory activity than RK-682 were found, and the present invention was completed.

 [0008] The compound group of the present invention is a novel compound group not reported in any literature.

The antitumor activity of the compounds of the present invention is determined by the growth inhibition test of human leukemia cells HL60 cells. And evaluated. RK-682, which was the base, did not show HL60 cell growth inhibitory activity 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 higher growth inhibitory ability than the ability of RK-682 itself to inhibit protein phosphatase. The compounds of the present invention have also been found to exhibit 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 may inhibit other protein phosphatases to produce cytostatic effects. Conceivable.

 That is, the present invention includes the following inventions.

 [0010] (1)

 Formula (I):

 [Chemical 1]

 [0011] [where

 R and R are, independently of one another, hydrogen; a hetero selected from the group consisting of N, 0 and S

1 2

 A linear, branched or cyclic saturated or unsaturated hydrocarbon group optionally substituted by a substituent which may contain atoms; a heteroatom selected from the group consisting of N, 0 and S -C (= 0) -R or -S (= 0) -R (R is selected from the group consisting of N, 0 and S). To be selected

 5 2 5 5

A linear, branched, or cyclic saturated or unsaturated hydrocarbon group optionally substituted by a substituent that may contain a tera atom; or selected from the group consisting of N, 0, and S Or an aryl group or an aralkyl group which may be substituted by a substituent which may contain a hetero atom, or an amino group or a hydroxyl group in which hydrogen may be substituted by a substituent, Where R and R are not hydrogen at the same time; R is a substituent which may contain a heteroatom selected from the group consisting of N, O and S

Three

 A linear, branched or cyclic saturated or unsaturated hydrocarbon radical which may be more substituted; or may contain a heteroatom selected from the group consisting of N, 0 and S An aryl group or an aralkyl group optionally substituted by a substituent,

 R and R, or R and R are united with the atom to which they are bonded, and R and R are bonded.

1 2 1 3 1 2 In addition to N, it may contain a heteroatom selected from the group consisting of N, 0 and S. A saturated or unsaturated aliphatic ring optionally substituted by a substituent Or may form an aromatic ring;

 In formula (I)

 [Chemical 2]

The bond represented by [0012] may be a single bond or a double bond; when the bond is a double bond, R is hydrogen; when the bond is a single bond R is a halogen

 4 4 or -X-Y {where -X- is -0-, -S- or -ΝΗ-; -Υ is hydrogen; a heteroatom selected from the group consisting of Ν, 0 and S A linear, branched or cyclic saturated or unsaturated hydrocarbon group which may be substituted by a substituent, or _C (= O) -R, -S (= 0)- R, -C (= 0) -0-R, -S (= 0) -OR or -C (= 0) _N (-H) _R (R is N,

6 2 6 6 2 6 6 6

A linear, branched or cyclic saturated or unsaturated hydrocarbon group optionally substituted by a substituent which may contain a heteroatom selected from the group consisting of ◯ and s; or A aryl group or an aralkyl group which may be substituted by a substituent which may contain a heteroatom selected from the group consisting of N, 0 and S);

 Carbon indicated by *

 [Chemical 3]

[0013] is an asymmetric carbon when is a single bond, whether optically active or racemic, Partial structure in formula (I):

 [Chemical 4]

[0014] (In the formula, * and * indicate bonding positions)

 1 2

 Is

 [Chemical 5]

 [0015] (In the formula, * and * indicate binding positions)

 1 2

 Any of these may be used. ]

A compound represented by or a salt or solvate thereof _c

 (2) In the formula (I),

 One of R and R is H and the other is

1 2

 (Wherein * represents a bonding position) is a group selected from the group consisting of:

R is * One (CH ₂ ) ₁₄ CH ₃ *-(CH ₂ ) i ₀ CH ₃ * — (CH ₂ ) ₆ CH 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):

(式中 *は結合位置を示す) [Chemical 8]

(In the formula, * indicates the bond position)

Is

[0020] (In the formula, * indicates a bonding position)

 2. The compound according to claim 1, or a salt or solvate thereof, which is a group selected from the group consisting of

(3) In the formula (I),

 R and R together form _ (CH)-;

 1 2 2 4

 R is

Three

*-(CH ₂ ) ₄ CH ₃ *-(CH ₂ ) ₁₀ CH ₃ *-(CH ₂ ) ₆ CH ₃

 [0022] (In the formula, * indicates a bonding position; -Ph is an unsubstituted phenyl group)

 A group selected from the group of forces;

 Partial structure in formula (I):

 [Chemical 11]

 *,

[0023] (* indicates a bonding position)

 Is

[Chemical 12]

 o

 *,

 And -O one S one CH,

O

[0024] (In the formula, * indicates a bonding position)

 The compound or a salt or solvate thereof according to (1), which is a group selected from the group consisting of

[0025] (4) In the formula (I),

 R and R together form _ (CH)-;

 1 3 2-3

 R is H;

 2

 Partial structure in formula (I):

[Chemical 13]

 [0026] (In the formula, * indicates a bonding position)

 Is

[Chemical 14]

 [0027] (In the formula, * indicates a bonding position)

 The compound or a salt or solvate thereof according to (1), which is a group selected from the group consisting of

 [0028] (5) A pharmaceutical composition comprising the compound described in (1) to (4) or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.

[0029] (6) The pharmaceutical composition according to (5), which is an antitumor agent.

 [0030] (7) The pharmaceutical composition according to (5), which is a protein phosphatase inhibitor.

 [0031] (8) A process for producing the compound or salt or solvate thereof described in (1) to (4), wherein

[Chemical 15]

 [0032] {wherein R is as defined in claim 1; substructure comprising R ':

 Three

[Chemical 16]

[0033] is

 [Chemical 17]

 * ,,

 Four

[0034] (* indicates a bonding position. R is as defined in claim 1)

 Four

 Or a partial structure that can be converted to the partial structure in one or more stages}

 And the amine NHR R wherein R and R are as defined in claim 1.

 1 2 1 2

 In the presence of P-toluenesulfonic acid,

 Formula:

 [Chemical 18]

[0035] The method comprising the step of obtaining a compound represented by:

[0036] The compound represented by the formula (I) has two tautomers in an equilibrium state.

[Chemical 19]

 [0038] is present as a mixture of

 The invention's effect

 [0039] 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.

[0040] This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2006-53742, which is the basis for the priority of the present application.

 Brief Description of Drawings

 [0041] FIG. 1 is a diagram showing the results of an HL60 cell growth inhibitory activity test.

 FIG. 2 is a diagram showing the results of an HL60 cell growth inhibitory activity test.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0042] R and R are, independently of one another, a hydrogen selected from the group consisting of hydrogen; N, 0 and S

 1 2

 Substituted by substituents that may contain atoms (e.g. as -0-, -S-, -NH-, -N =, -S (= 0)-)

 2

A linear, branched or cyclic saturated or unsaturated, preferably hydrocarbon group having from 20 to 20 carbon atoms; a hetero selected from the group consisting of N, 0 and S Substituted by substituents that may contain atoms (e.g. as -0-, -S-, -NH-, -N =, -S (= 0)-) Preferably an aryl group or aralkyl group having 5 to 20 carbon atoms; _C (= 0) -R

 5 or -S (= 0) -R (R is a heteroatom selected from the group consisting of N, 0 and S (e.g.

 2 5 5

 -0-, -S-, -NH-, -N =, _S (= 0)-

 2

 A linear, branched or cyclic saturated or unsaturated, preferably a hydrocarbon group having 1 to 20 carbon atoms; or a heteroatom selected from the group consisting of N, 0 and S ( For example, -〇-, -S-, -NH-, -N =, _S (= 〇)-)

 2

 Or an aryl group or an aralkyl group having 5 to 20 carbon atoms); or an amino group or a hydroxyl group in which hydrogen may be substituted by a substituent, provided that R and R is not simultaneously hydrogen. R or at least one of R is hydrogen

1 2 1 2

 It is preferable that

 [0043] R represents a heteroatom selected from the group consisting of N, 0 and S (eg, _0_, -S-, -NH

 Three

 -, -N =, -S (= O)-), which may be included or substituted by a substituent, linear,

 2

 A branched or cyclic saturated or unsaturated, preferably hydrocarbon group having 1 to 20 carbon atoms; or a heteroatom selected from the group consisting of N, 0 and S (eg -0-, -S -, -NH-, -N =, -S (= 0)-), and may be substituted by substituents, preferably

 2

 The aryl group or aralkyl group having 5 to 20 carbon atoms is preferred.

[0044] R and R, or R and R are united with the atom to which they are bonded, and R and R are bonded.

 1 2 1 3 1 2 Combine with a heteroatom selected from the group consisting of N, 0 and S (for example, -0-, -S-, -NH-, -N =, -S ( = 0) -as)) or may be substituted by a substituent,

 2

 A saturated or unsaturated aliphatic ring or aromatic ring preferably having 4 to 7 carbon atoms may be formed. R and R together with the atoms to which they are attached form a ring, R is

 1 3 2 Hydrogen is preferred.

[0045] In the formula (I)

 [Chemical 21]

The bond represented by may be a single bond or a double bond. R is hydrogen when the bond is a double bond. When the bond is a single bond, R is halogen (chlorine,

 4 4

Fluorine, bromine or iodine), or -Χ-Υ {where -X- is -〇-, -S- or -ΝΗ -Y; -Y is hydrogen; a heteroatom selected from the group consisting of N, O and S (eg as _0_, -S-, -NH-, -N =, -S (= 0)-) May be substituted by substituents

 2

 A linear, branched or cyclic, saturated or unsaturated, preferably hydrocarbon group having 1 to 20 carbon atoms; or -C (= 0) -R, -S (= 0) -R,- C (= 0) -0-R, -S (= 0) _0_R or

 6 2 6 6 2 6 is _C (= 0) -N (_H) _R (R is a heteroatom selected from the group consisting of N, O and S (eg

 6 6

 -O-, -S-, -NH-, -N =, _S (= 〇)-)

 2

 However, linear, branched or cyclic saturated or unsaturated, preferably a hydrocarbon group having 1 to 20 carbon atoms; or hetero selected from the group consisting of N, 0 and S Substituted by substituents that may contain atoms (eg as -〇-, -S-, -NH-, -N =, _S (= 〇)-)

 2

 Or an aryl group or an aralkyl group having 5 to 20 carbon atoms). -Y force C (= 0)-R, -S (= 0) -R, -C (= 0) -0-R, _S (= 0)-

6 2 6 6 2

In the case of O—R or —C (═ ◯) —N (—H) —R, —X— is preferably —O—.

 6 6

 [0047] Carbon indicated by *

 [Chemical 22]

[0048] is an asymmetric carbon when is a single bond.

 [0049] The compounds of the present invention may be optically active or racemic. When a racemic body is obtained as a result of synthesis, the two optical isomers may be separated or may be used as a racemate without being separated. In addition, as shown in the Examples, when an optically pure compound is used as a starting material in the synthesis, it is possible to obtain an optically pure compound of the present invention without performing resolution.

 As the “substituent” in the present invention, halogen (chlorine, fluorine, bromine or iodine), = 0

 (Oxo group), -NR R, _OR, _OC (= 0) R, _OS (= 0) R,-NHC (= O) 0R, etc.

 11 12 13 14 2 15 16 but not limited to these. R, R, R, R, R and R are independently of each other,

 11 12 13 14 15 16

 Hydrogen; a straight chain that may contain a heteroatom selected from the group consisting of N, O and S (eg as -0-, -S-, -NH-, -N =, _S (= 0)-) , Branched or cyclic saturated or non-cyclic

 2

A saturated hydrocarbon group having 1 to 20 carbon atoms; or selected from the group consisting of N, 0 and S Carbon atoms which may contain (e.g., -0-, -S-, -NH-, -N =, -S (= 0)-)

 2

The aryl group or aralkyl group of formula 5 to 20 can be used, but is not limited thereto. These substituents may be further substituted with the same substituent. When R ³ is a straight-chain saturated hydrocarbon group, an azido group as a substituent, 6- (4,4 difunoleo port-1, 3-dimethyl-5- (4- Methoxyphenyl) -4-bora-3a, 4a-diaza-s_indacene-2-propionylamino) hexanoylamino groups may be present.

 In a particularly preferred embodiment of the invention, one of R and R is H and the other is

 1 2

[Chemical 23]

[0052] (In the formula, * indicates a bonding position)

 A group selected from the group of forces.

[0053] In a particularly preferred embodiment of the present invention, R is [Chemical 24]

*-(CH ₂ ) i4CH ₃ * One (CH ₂ ) ₁₀ CH ₃ *-(CH ₂ )

[0054] (In the formula, * represents a bonding position; -Ph is an unsubstituted phenyl group)

 A group selected from the group of forces.

[0055] In another preferred embodiment of the present invention, R and R are combined to form an alkylene chain (for example,

 1 2

 -(CH)-).

 twenty four

 [0056] In another preferred embodiment of the present invention, R and R are combined to form an alkylene chain (for example,

 13

 -(CH)-). At this time, R is preferably H.

 2 3 2

 [0057] In a particularly preferred embodiment of the present invention, the partial structure in formula (I):

 [Chemical 25]

[0058] (In the formula, * indicates a bonding position)

 Is

[Chemical 26]

0

 And -O one S one CH,

 O

[0059] (In the formula, * indicates a bonding position)

 A group selected from the group of forces.

[0060] Among the compounds represented by the formula (I), particularly preferred compounds are specifically as follows:

[Chemical 27]

23 24 25

[0063] (wherein -Ph is an unsubstituted phenyl group; -Me is an unsubstituted methyl group)

[0064] A compound represented by a formula selected from the group consisting of: In addition, for each compound The names are for convenience and do not limit the invention. Compounds containing asymmetric carbon may be optically active or racemic.

 [0065] 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, trimethyl Ammonium salts such as ammonium salts can be formed. When basic groups are present, mineral salts such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate; acetate, propionate, tartrate, fumarate, maleate Organic acids such as malate, citrate, methanesulfonate, and P-toluenesulfonate can be formed. The compound of the present invention or a salt thereof 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, and water.

 [0066] A preferred synthesis method of the compound of the present invention will be outlined, but the synthesis method of the present invention is not limited to the following method.

[0067] In a preferred embodiment, intermediate 1 is first prepared from 4-hydroxyfuran-2 (5H) _one according to the procedure shown in the example (Scheme 1):

 [Chemical 28]

[0068] is prepared. Partial structure:

[0069] [Chemical 29]

[0069]

[Chemical 30]

(* Indicates the binding position. R is as defined above)

 Four

 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:

 [Chemical 31]

[0071] (in the formula, * indicates a bonding position)

 The group represented by these is mentioned. This group can be converted to a hydroxymethyl group (-CH OH, the terminal hydroxyl group corresponds to R) by removing the protecting group.

twenty four

 Can be further converted to other R-containing groups in one or more stages. R '

 Four

 It is preferable that the conversion of the partial structure to be included is performed after the preparation of intermediate 3 described later.

[0072] Next, intermediate 1 is condensed with a carboxylic acid R COOH having a desired group R (

 3 3

 Yoshii, E. et al. Chem. Pharm. Bull. 1986, 34, 5188-5190), intermediate 2:

 [Chemical 32]

[0073] is prepared.

[0074] Next, intermediate 2 and the amine NHR R having the desired R and R are combined with p-toluenesulfone. React in the presence of acid,

 Intermediate 3:

 [Chemical 33]

[0075] is obtained.

 [0076] Next, if necessary, the partial structure:

[Chemical 34]

 From [0077]

[Chemical 35] v_ _R4

 [0078] A conversion reaction into a partial structure represented by

 [0079] Intermediate 2 can also be synthesized according to the method of Sodeoka, M. et al. J. Med. Chem. 2001, 44, 3216-3222.

 [0080] The compound of the present invention is useful as an antitumor agent because of its excellent antitumor activity, and can be used as a human and veterinary drug, a pharmaceutical raw material, and the like.

 [0081] The antitumor agent of the present invention comprises 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 agents and additives 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. Can be mentioned.

[0082] When the antitumor agent of the present invention is used for the purpose of prevention or treatment of tumors, prevention or treatment The target of 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 illnesses can be targeted, whether they are single, concomitant, or other illnesses other than those mentioned above. Examples of these cancer types are not particularly limited: brain tumor, nasopharyngeal cancer, tongue cancer, esophageal cancer, stomach cancer, pancreas cancer, liver cancer, rectal cancer, colon cancer, uterine cancer, ovarian cancer, testicular cancer, bone And at least one selected from the group consisting of sarcoma and leukemia. Further, not only a single cancer but also a plurality of cancers may be combined.

 [0083] The present invention also provides an effective amount of a compound represented by formula (I) or a salt or solvate thereof for prevention or treatment of a tumor to a subject animal in need of prevention or treatment of the tumor. The present invention relates to a method for preventing or treating a tumor, comprising a step of administering.

 [0084] 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.

 [0085] When a pharmaceutical composition containing a compound represented by the formula (I) or a salt or solvate thereof is sold as an antitumor agent, a package indicating that it is used for prevention or treatment of tumors is used. Or it can be accompanied by instructions.

 [0086] The subject to which the antitumor agent of the present invention is administered is not limited, but mammals such as humans, domestic animals (such as horses and horses), pets (such as Inu and cats), It can be a laboratory animal (mouse, rat, hamster, etc.).

[0087] 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, carboxybule polymer, sodium alginate, water-soluble dextran, sodium carboxymethyl starch, Kuching, xanthan gum, gum arabic, casein, gelatin, agar, glycerin, propylene glycol, polyethylene glycol, petrolatum, paraffin, stearyl alcohol, stearic acid, human serum albumin, mannitol, sonolebitol, ratatoose, acceptable as a pharmaceutical additive In addition to the surfactants described above, artificial cell structures such as ribosomes can be mentioned. The additive to be used is appropriately or in combination selected from the above depending on the dosage form of the pharmaceutical composition. [0088] The antitumor agent of the present invention can be administered by either the oral route or the parenteral route.

 [0089] When the antitumor agent of the present invention is administered orally, the antitumor agent of the present invention is produced as a solid preparation such as a tablet, granule, powder, or pill, or a liquid preparation such as a liquid or syrup. It can be formulated. 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.

 [0090] The solid preparation may contain additives such as a binder, an excipient, a lubricant, a disintegrant, and a wetting agent that are generally used in the preparation. Liquid preparations can contain additives such as stabilizers, buffering agents, flavoring agents, preservatives, fragrances, and coloring agents that are commonly used in preparations.

[0091] When administered parenterally, it can be in the form of injection or 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 an appropriate carrier, for example, 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 emulsifying agents and suspending agents that are generally used pharmaceutically in their compositions.

 [0092] The amount of the compound of the present invention in the above-mentioned antitumor agent varies depending on the use, dosage form, administration route and the like, based on the total weight:! To 5 wt%, preferably 2 to 3 wt%. 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 number of administrations, and can vary widely. For example, the daily dose is 0.1 to 0.1 mg / kg body weight, and several times a day can be administered at intervals of several weeks.

 [0093] 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.

[0094] In particular, the compound of the present invention has inhibitory activity against a bispecific protein phosphatase represented by VHR (vaccinia virus-encoded phosphatase VHl-related phosphatase). To do. In addition, because of the primary structure of the enzyme, the bispecific protein phosphatase is highly homologous to the protein cysteine phosphatase, so the compounds of the present invention are also effective for these enzymes. In addition, the compounds of the present invention are considered to have inhibitory activity against other protein phosphatases. Therefore, the compounds of the present invention can be used for the prevention or treatment of diseases involving protein phosphatases. For example

PTP1B (protein tyrosine phosphatase IB), one of the protein phosphatases, has been reported to be involved in insulin signaling, so the compounds of the present invention may be used as therapeutic agents 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 dephosphorylating enzyme.

 [0095] The present invention also requires that the compound represented by the formula (I) or a salt or solvate thereof in an amount effective to inhibit protein phosphatase is used to inhibit protein phosphatase. A method for inhibiting protein dephosphorylation enzyme, comprising a step of administering to a target animal.

 [0096] The present invention also relates to the use of a compound represented by the formula (I) or a salt or solvate thereof in the production of a protein phosphatase inhibitor.

 [0097] When a composition comprising a compound represented by formula (I) or a salt or solvate thereof is marketed as a protein phosphatase inhibitor, Packaging or instructions indicating the use can be attached.

 [0098] The present invention also provides an amount of a compound represented by the 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 a disease involving an enzyme.

 [0099] 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 dephosphorylating enzyme.

[0100] A pharmaceutical composition comprising a compound represented by formula (I) or a salt or solvate thereof is When it is marketed as a prophylactic or therapeutic agent for a disease involving protein dephosphorylating enzyme, a package or instructions that indicate that it is used for the prevention or treatment of the disease involving protein dephosphorylating enzyme It can be attached.

 [0101] Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

 Example 1

 [0102] In this example, a compound group represented by the formula (I) was synthesized.

 [Chemical 36]

 [0103] (The definition of each group and symbol is as described above.)

[0104] The naming was performed as follows. If a higher-priority substituent is attached by a side-chain substituent, it may be numbered differently from below.

[Chemical 37]

5- (hydroxymethyl) furan 2, 4 (3 3- (1-(benzylamino)

 H, 5 — dione oxadecylidene)

3— (1— (Benzylamino) hexadecylidene) _5— (hydroxide

 Cymethyl) furan — 2, 4 (3H, 5H) -dione

[0105] 'Η NMR and ¹³ C NMR spectra are JEOL AL400 and AL300 manufactured by JASCO Corporation.

 It measured using. Tetramethylsilane was used as the internal standard substance when black mouth form was used as the measurement solvent. Chemical shift values are expressed in ppm. Mass spectrum (FAB-MS (Pos.))

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 substituents.

[Chemical 38] scheme

 Five

[0108] Production reaction 1 → 2

 Synthesis of 4- (methoxymethoxy) furan-2 (5H) -one (compound 2)

 The 4-position hydroxyl group of 4-hydroxyfuran-2 (5H) -one (Compound 1) is protected with a methoxymethyl group, which is described below.

 [0109] To a methylene chloride solution (50 mL) of compound 1 (5.05 g, 50.15 mmol) was added N, N_diisopropylethylamine (17.6 mL, 101.1 mmol), followed by chloromethyl methyl ether (5.75 mL, 7 5.70 mmol). The mixture was added at ° 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. .

 [0110] Molecular weight: 144.13

 Molecular formula: C H〇

 FAB-MS (Pos.) M / z = 145 ([M + H] +)

 'H-NMR (400 MHz, CDC1) 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, CDC1) 176.7, 173.4, 97.0, 91.1, 67.7, 57.3.

 [0111] 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. [0112] 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.

 [0113] Molecular weight: 174.15

 Molecular formula: C H 0

 7 10 5

 'H-NMR (400MHZ, CDCl) 5.284 (IH, s), 5.173 (2H, s), 4.843 (IH, t, J = 2.7 Hz), 4.

 Three

064 (IH, dd, J = 12.6, 2.7 Hz), 3.829 (IH, dd, J = 12.6, 3.9 Hz), 3.491 (3H, s), 2.510 (1H, brs) ₀

 [0114] 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 is protected, it will be described below.

 [0115] Compound 3 (731.4 mg, 4.20 mmol) and imidazole (633.7 mg, 9.31 mmol) in N, N-dimethylformamide solution (8 mL) were charged with t-butyldiphenylchlorosilane (1.34 mL, 5.15 mmol). I got it at ° C. The reaction solution was stirred at room temperature under a nitrogen stream for 4.5 hours. The reaction was stopped by adding methanol (5 mL), and then water (5 mL) was added and extracted with jetyl 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. Obtained.

 [0116] Molecular weight: 412.55

 Molecular formula: C H O Si

 23 28 5

 FAB-MS (Pos.) M / z = 413 ([M + H] +)

 'H-NMR (400 MHz, CDCl) 7.651 (4H, td, J = 11.6, 8.8 Hz), 7.438-7.388 (6H, m), 5

 Three

• 336 (IH, s), 5.142 (2H, s), 4.810 (IH, t, J = 2.4 Hz), 4.062 (IH, dd, J = 11.6, 2.4 Hz), 3.939 (1H, dd, J = 11.6, 2.4Hz), 3.474 (3H, s), 1.012 (9H, s).

¹³ C-NMR (100 MHz, CDC1) 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.

[0117] Production reaction 4 → 5

 Synthesis of 5-((t_Butyldiphenylsilyloxy) methyl) furan-2.4 (3H. 5H) -dione (Compound 5)

 Deprotection of the methoxymethyl group is described below.

 [0118] 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 the mixture was 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.

 [0119] Molecular weight: 368.50

 Molecular formula: C H O Si

FAB-MS (Pos.) M / z = 369 ([M + H] ⁺ )

^J H-NMR (400 MHz, CDC1) 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) 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.

 [0120] Compounds with different R in general formula (I) are described in the literature (Yoshii, E. et al. Chem. Pharm. Bull. 198

6, 34, 5188-5190), it can be produced by condensing compound 5 with various carboxylic acids.

 [0121] As an example, a production example of a compound having a saturated alkyl group with R force 5 (from compound 5 to compound

8) (See Schemes 2 and 3):

[0122] It is to be noted that compounds in which R and R are changed can be obtained by reacting compound 6 which is an intermediate of these reactions with various primary and secondary amines. [0123] R =-(CH) CH reaction example

 — 3_ 2 14 3

[Chemical 39] Scheme 2

[0124] Production reaction 5 → 6

 5-((t_Butyldiphenylsilyloxy) methyl) -3-hexadecanol _4-hydroxyfuran-2 (5H) _one

 To a methylene chloride solution (25 mL) of compound 5 (971.0 mg, 2.64 mmol) and triethylamine (0.4 mL, 2.87 mmol), 4-dimethylaminopyridine (108.1 mg, 0.89 mmol), palmitic acid (742.9 mg, 2.90 mmol) And Ν, Ν′-dicyclohexylcarbodiimide (666.4 mg, 3.16 mmol) were 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 black mouth form. The filtrate was washed with 1 M hydrochloric acid, and the aqueous layer was extracted again with acetyl acetate. The collected organic layer was dried over anhydrous sodium sulfate and concentrated. Compound 6 (325.0 mg, 20%) was obtained as an orange solid by rough purification by silica gel chromatography (black mouth form: methanol = 1: 0 → 9: 1).

 [0125] Molecular weight: 606.91

 Molecular formula: C H O Si

 37 54 5

 'H-NMR (400 MHz, CDC1) 7.658-7.595 (4H, m), 7.443—7.344 (6H, m), 4.741 (t, J =

 Three

 3.4 Hz), 4.626 (t, J = 2.9 Hz) (1H combined), 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).

 [0126] Production Example of R = — CH. Ph, R = R =-(CH) CH. R = OH

 -丄 2 2_ 3_ 2 14 3 4.

[Chemical 40] Scheme 3

[0127] Production reaction 6 → 7

 Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (t_butyldiphenylsilyloxy) methylolefuran-2.4 (3H. 5H) -dione (compound 7)

 P-Tonoleenesulfonic acid (a small amount) and benzylamine (75 μL, 0.69 mmol) were added to a toluene solution (4 mL) of Compound 6 (350.1 mg, 0.58 mmol) and heated to 120 ° C under a nitrogen stream. For 6 hours. 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. .

[0128] Molecular weight: 696.04

 Molecular formula: C H NO Si

 44 61 4

 H-NMR (300 MHz, CDCl) 11.393 (brs), 10.447 (brs) (also IH), 7.694-7.637 (

 Three

 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) 197.8, 193.0, 176.2, 174.4, 173.7, 173.0, 171.4, 135.

 Three

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. [0129] Production reaction 7 → 8

 Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2, 4 (3H. 5 H) -dione (compound 8)

 Tetrabutylammonium fluoride 1M tetrahydrofuran solution (500 zL) was added to a tetrahydrofuran solution (7 mL) of compound 7 (250.0 mg, 0.36 mmol). Calo at C, 0. The mixture was stirred at C for 7 hours. Water was added to the reaction solution and 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. It was.

 [0130] Compound 8 can be used as a common intermediate for compounds having different R4 substituents.

 [0131] Molecular weight: 457.65

 Molecular formula: C H NO

 28 43 4

FAB-MS (Pos.) M / z = 458 ([M + H] ⁺ )

 H-NMR (300MHz, CDCl) 11.314 (brs), 10.383 (brs) (also IH), 7.420-7.342 (3

 Three

 H, m), 7.278-7.243 (2H, m), 4.648 (s), 4.628 (s) (total 2H), 4.528 (t, J = 4.0 Hz), 4.504 (t, J = 4.4 Hz) (total IH), 3.950-3.940 (2H, m), 3.100-2.924 (2H, m), 1.55 0-1.430 (4H, m), 1.295-1.247 (24H, m), 0.872 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (75.5 MHz, CDCl) 197.6, 193.2, 175.9, 174.9, 174.3, 171.2, 134.9, 134.

 Three

 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.

 [0132] 't ^ notice of ffi † beef book from cochlea RK-682

 [Chemical 41]

 Scheme 4

[0133] 製造反応 9→ 10

[0133] Production reaction 9 → 10

 Synthesis of (S) -3- (1- (Benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2, 4 (3 H. 5H) -dione (Compound 10)

 (S) -4-hydroxy-5- (hydroxymethyl) -3-palmitoylfuran- synthesized according to the method of the literature (Sodeoka, M. et al. J. Med. Chem. 2001, 44, 3216-3222.) 2 (5H) -one (compound 9, RK-682) force was induced through one step. That is, in order to obtain a hydroxymethyl form of the final product, an amine is added as shown in Scheme 3 and then the hydroxymethyl group protecting group is removed, and as shown in Scheme 4, the hydroxymethyl group is protected. Two methods of adding an amine after removing the group can be used.

 [0134] To a toluene solution (1 mL) of compound 9 (9.9 mg, 0.027 mmol), p-tonoleenesulfonic acid (a small amount) and benzylamine (5 μL, 0.046 mmol) were added, and the mixture was heated to 110 ° C under a nitrogen stream. For 2 hours. 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 substance.

 [0135] Molecular weight: 457.65

 Molecular formula: C H NO

 28 43 4

FAB-MS (Pos.) M / z = 458 ([M + H] ⁺ ), 456

 JH-NMR (300 MHz, CDC1)

 Three

 11.314 (brs), 10.383 (brs) (1H in total), 7.420-7.342 (3H, m), 7.278-7.243 (2H, m), 4.665 (s), 4.646 (s) (2H in total), 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), 1.295-1.2 47 (24H, m), 0.872 (3H, t, J = 6.8 Hz).

[0136] The following stereoisomers were synthesized in the same manner.

[Chemical 42]

[0137] (R) -3- (1- (Benzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2.

 3H. 5H) -Dione (compound 11)

 Molecular weight: 457.65

 Molecular formula: C H NO

 28 43 4

 'H-NMR (300 MHz, CDC1)

 Three

 Same as compound 10.

 [0138] Different compounds of R, R and R were synthesized using the above method. Compound structure

 one two Three

 The formula and data are shown below. Compound 15 is a secondary amine derivative.

[Chemical 43]

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 H N O

 30 48 2 4

FAB-MS (Pos.) M / z = 501 ([M + H] ⁺ )

JH-NMR (300 MHz, CDC1) 11.279 (brs), 10.370 (brs) (combined IH), 7.224 (IH, 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 (IH, 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).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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, 29.2 2, 29.19, 27.9, 27.7, 27.6, 27.5, 25.6, 24.9, 22.7, 14.1.

[0141] 3- (1- (3-Hydroxybenzylamino) hexadecylidene) _5_ (hydroxymethyl) furan-2. 4 (3H. 5H) -dione (compound 13)

 White amorphous

 Molecular weight: 473.64

 Molecular formula: C H NO

 28 43 5

FAB-MS (Pos.) M / z = 474 ([M + H] ⁺ )

 JH-NMR (400 MHz, CDC1)

 Three

 11.266 (brs), 10.336 (brs) (IH), 7.377 (IH, brs), 7.206 (1H, t, J = 8.2 Hz), 6.810 (IH, d, J = 9.6 Hz), 6.758- 6.741 (2H, m), 4.580-4.570 (2H, m), 4.520-4.510 (1 H, m), 3.960-3.950 (2H, m), 3.295 (1H, brs), 3.000-2.810 (2H, m) , 1.540-1.230 (26 H, m), 0.877 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (100 MHz, CDC1)

 Three

 197.5, 193.1, 176.2, 175.0, 174.5, 174.4, 171.6, 159.5, 136.2, 130.4, 130.3, 92.2, 8 3.0, 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.

[0142] 3- (1- (pentylamino) hexadecylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5 H) -dione (compound 14)

White amorphous Molecular weight: 437.66

 Molecular formula: C H NO

FAB-MS (Pos.) M / z = 438 ([M + H] ⁺ )

 'H-NMR (400 MHz, CDC1)

 11.024 (brs), 10.077 (brs) (combined IH), 4.530 (t, J = 4.1 Hz), 4.493 (t, J = 4.4 Hz) (combined 1H), 3.964-3.936 (2H, m), 3.458 -3.397 (2H, m), 2.900-2.840 (2H, m), 1.7 01-1.252 (32H, m), 0.935 (3H, t, J = 7.0 Hz), 0.876 (3H, t, J = 6.8 Hz) .

[0143] 3- (1-(Pyrrolidino) hexadecylidene) _5-(Hydroxymethyl) furan- 2.4 (3H. 5H) _Din () 1 5)

 White amorphous

 Molecular weight: 437.66

 Molecular formula: C H NO

FAB-MS (Pos.) M / z = 422 ([M + H] ⁺ )

 JH-NMR (400 MHz, CDC1)

 4.473 (IH, 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), 1.37 3-1.246 (26H, m), 0.877 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (75.5 MHz, CDC1)

 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.

 [0144] 3- (l- (Cyclohexylamino) hexadecylidene) -5- (hydroxymethyl) furan-2, 4 (

 3H. 5H) -Dione (compound 16)

 Colorless oil

 Molecular weight: 449.67

 Molecular formula: C H NO

FAB-MS (Pos.) M / z = 450 ([M + H] ⁺ )

 'H-NMR (400 MHz, CDC1)

11.110 (brs), 10.127 (brs) (also IH), 4.527 (t, J = 4.2 Hz), 4.487 (t, J = 4.5 Hz) ( 1H), 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).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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, 3 3.3, 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.

 [0145] 3- (l- (Cyclobutylamino) hexadedecylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5H) -dione (Compound 17)

 White amorphous

 Molecular weight: 421.61

 Molecular formula: C H NO

 25 43 4

FAB-MS (Pos.) M / z = 422 ([M + H] ⁺ )

 JH-NMR (300 MHz, CDC1)

 Three

 11.143 (brs), 10.187 (brs) (IH), 4.536-4.496 (IH, m), 4.293-4.213 (IH, m), 3.966-3.952 (2H, m), 2.945-2.813 (2H, m) 2.485-2.396 (2H, m), 2.262-2.121 (2 H, m), 1.923-1.785 (2H, m), 1.658-1.250 (26H, m), 0.881 (3H, t, J = 6.6 Hz).

[0146] 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 H NO

 28 43 5

FAB-MS (Pos.) M / z = 422 ([M + H] ⁺ )

 'H-NMR (300 MHz, CDC1)

 Three

 12.322 (brs), 11.395 (brs) (collectively IH), 7.129 (2H, dd,) = 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), 2.863-2.75 9 (2H, m), 1.606-1.186 (26H, m), 0.887 (3H, t, J = 7.4 Hz).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

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.

 [0147] 3- (l- (3- (2-hydroxyethoxy) ethaneamino) hexadecylidene) -5- (hydroxymethylol) furan-2,4 (3H.5H) -dione (compound 19)

 Colorless oil

 Molecular weight: 455.63

 Molecular formula: C H NO

 25 45 6

FAB-MS (Pos.) M / z = 456 ([M + H] ⁺ )

 'H-NMR (400 MHz, CDC1)

 Three

 11.355 (brs), 10.422 (brs) (combined IH), 4.533 (t, J = 3.9 Hz), 4.502 (t, J = 3.9 Hz) (combined 1H), 3.960-3.950 (2H, m), 3.797 -3.640 (8H, m), 3.010-2.860 (2H, m), 1.6 90-1.250 (26H, m), 0.878 (3H, t, J = 7.0 Hz).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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.

 [0148] 3- (1- (2-Methylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2, 4 (3H, 5H) -dione (compound 20)

 Pale yellow oil

 Molecular weight: 471.67

 Molecular formula: C H NO

 29 45 4

FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ )

 'H-NMR (400 MHz, CDC1)

 Three

 11.225 (brs), 10.288 (brs) (also IH), 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) (also IH), 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, CDC1)

 Three

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.

 [0149] 3- (1- (3-Methylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (compound 21)

 White amorphous

 Molecular weight: 471.67

 Molecular formula: C H NO

 29 45 4

FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ ), 471

 'H-NMR (400 MHz, CDC1)

 Three

 11.281 (brs), 10.366 (brs) (collectively IH), 7.309-7.260 (IH, m), 7.177-7.159 (IH, m), 7.076-7.060 (2H, m), 4.605 (s), 4.590 (s ) (Total 2H), 4.548 (t, J = 4.1 Hz), 4.52 1 (t, J = 4.4 Hz) (Total IH), 3.970-3.960 (2H, m), 3.085-2.903 (2H, m) , 2.372 (3 H, s), 2.093-2.050 (IH, m), 1.570-1.250 (26H, m), 0.881 (3H, t, J = 7.0 Hz).

1 ³ C-NMR (100 MHz, CDC1)

 Three

 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, 2 7.70, 27.65, 22.8, 21.5, 14.2.

[0150] 3- (l- (4-Methylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2,4 (3H, 5H) -dione (compound 22)

 White amorphous

 Molecular weight: 471.67

 Molecular formula: C H NO

 29 45 4

FAB-MS (Pos.) M / z = 472 ([M + H] ⁺ ), 471

 'H-NMR (400 MHz, CDC1)

 Three

 11.268 (brs), 10.342 (brs) (also IH), 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) (also IH), 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).

[0151] 3- (1- (3-Methoxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2 4 (3H. 5H) -dione (compound 23)

 White amorphous

 Molecular weight: 487.67

 Molecular formula: C H NO

 29 45 5

 FAB-MS (Pos.) M / z = 488 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

 11.302 (brs), 10.378 (brs) (also IH), 7.314 (IH, td, J = 8.0, 2.7 Hz), 6.893—6.82 8 (2H, m), 6.800-6.780 (IH, m), 4.606 ( 2H, d, J = 6.0 Hz), 4.546 (t, J = 3.9 Hz), 4.519 (t, J = 4.4 Hz) (also IH), 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).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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, 5 5.35, 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, 1 4.1.

 [0152] 3- (l- (3-Chlorobenzylbenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2, 4

 (3H. 5H) -Dione (Compound 24)

 White amorphous

 Molecular weight: 487.67

 Molecular formula: C H NO

 29 45 5

 FAB-MS (Pos.) M / z = 488 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

 11.317 (brs), 10.387 (brs) (IH), 7.350-7.340 (2H, m), 7.340-7.260 (IH, 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) (also IH), 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).

[0153] 3- (l- (2-picolylamino) hexadecylidene) -5- (hydroxymethyl) furan-2.4 (3H.

5H) -Dione (compound 25) White amorphous

 Molecular weight: 458.63

 Molecular formula: C H N 0

 27 42 2 4

 FAB-MS (Pos.) M / z = 459 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

 11.717 (brs), 10.807 (brs) (IH), 8.674-8.639 (IH, m), 7.755-7.716 (IH, 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 (IH, brs ), 1.657 -1.249 (26H, m), 0.877 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (100 MHz, CDC1)

 Three

 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.

 [0154] 3- (l- (Cyclohexylmethylamino) hexadecylidene) -5- (hydroxymethyl) furan-2.4 (3H.5H) -dione (Compound 26)

 Colorless oil

 Molecular weight: 463.69

 Molecular formula: C H NO

 28 49 4

FAB-MS (Pos.) M / z = 464 ([M + H] ⁺ )

 'H-NMR (400 MHz, CDC1)

 Three

 11.118 (brs), 10.163 (brs) (combined IH), 4.534 (t, J = 4.4Hz), 4.497 (t, J = 4.4 Hz) (combined 1H), 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).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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, 4 9.3, 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.

[0155] 3- (1- (2-Phenylethaneamino) hexadecylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5H) -Dione (compound 27)

Orange oil

Molecular weight: 471.67

Molecular formula: C H NO

 29 45 4

 FAB-MS (Pos.) M / z = 472 ([M + H] +)

'H-NMR (400 MHz, CDC1)

 Three

 11.057 (brs), 10.130 (brs) (also IH), 7.346-7.202 (5H, m), 4.530-4.470 (IH, m), 3.950-3.940 (2H, m), 3.699-3.671 (2H, m) 2.990-2.964 (2H, m), 2.964-2.750 (2 H, m), 1.660-1.250 (26H, m), 0.879 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (100 MHz, CDC1)

 Three

 197.2, 192.9, 175.8, 174.6, 173.9, 171.0, 136.53, 136.51, 128.94, 128.91, 128.6, 1 27.3, 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 , 2 9.78, 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- (l- (4-Phenoxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5H) -dione (compound 28)

Yellow amorphous

Molecular weight: 549.74

Molecular formula: C H NO

 34 47 5

 FAB-MS (Pos.) M / z = 550 ([M + H] +)

'H-NMR (300 MHz, CDC1)

 Three

 11.277 (brs), 10.344 (brs) (IH), 7.360 (2H, t, J = 7.9 Hz), 7.268-7.216 (2H, m), 7.142 (IH, t, J = 7.3 Hz), 7.034- 7.009 (4H, m), 4.624-4.604 (2H, s), 4.554-4.50 5 (IH, m), 3.968-3.967 (2H, m), 3.047-2.952 (2H, m), 2.385-2.383 (IH, m), 1.779- 1.259 (26H, m), 0.883 (3H, t, J = 6.4 Hz).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

197.6, 193.2, 175.9, 174.7, 174.1, 171.2, 157.81, 157.77, 156.50, 156.47, 129.8, 1 29.2, 129.1, 128.9, 128.8, 123.80, 123.77, 119.26, 119.23, 119.18, 119.17, 91.9, 9 0.5, 82.6, 80.8, 61.7, 61.5, 46.7, 46.4, 31.9, 29.8, 29.64, 29.61, 29.60, 29.58, 29.5 4, 29.43, 29.39, 29.30, 29.20, 29.17, 27.9, 27.7, 27.6, 27.5, 22.6, 14.1 .

 [0157] 3- (l- (4-Hydroxybenzylamino) hexadecylidene) -5- (hydroxymethyl) furan-2.4 (3H.5H) -dione (compound 29)

 Colorless oil

 Molecular weight: 473.64

 Molecular formula: C H NO

 28 43 5

 FAB-MS (Pos.) M / z = 474 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

11.157 (brs), 10.216 (brs) (collectively IH), 7.650 (IH, 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) . 1 ³ C-NMR (100 MHz, CDC1)

 Three

 197.4, 193.0, 176.4, 174.5, 173.9, 171.6, 156.7, 128.7, 125.6, 125.4, 116.1, 92.0, 9 0.5, 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.

 [0158] 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 H NO

 26 41 5

 FAB-MS (Pos.) M / z = 448 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

 11.217 (m), 10.280 (m) (collectively IH), 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 (IH, m), 1.638- 1.485 (4H, m), 1.4 00-1.263 (22H, m), 0.887 (3H, t, J = 6.7 Hz).

[0159] 3- (4-Hydroxybutanamino) hexadecylidene) -5- (hydroxymethyl) furan- 2.4 (3 H.5H) -Dione (Compound 31)

White amorphous

Molecular weight: 439.63

Molecular formula: C H NO

 25 45 5

 FAB-MS (Pos.) M / z = 440 ([M + H] +)

'H-NMR (300 MHz, CDC1)

 Three

 11.063 (m), 10.128 (m) (also IH), 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 (IH, m),

I.850-1.456 (8H, m), 1.260-1.255 (22H, m), 0.879 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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, 4 3.2, 42.9, 31.9, 29.8, 29.67, 29.66, 29.64, 29.58, 29.45, 29.34, 29.32, 29.2 , 27.8, 2 7.7, 27.6, 27.4, 26.3, 26.2, 22.7, 14.1.

3- (l- (2- (phenylsulfonyl) ethylamino) hexadecylidene) -5- (hydroxymethyl) furan-2, 4 (3H, 5H) -dione (compound 32)

Colorless amorphous

Molecular weight: 535.74

Molecular formula: C H NO S

 29 45 6

FAB-MS (Pos.) M / z = 536 ([M + H] ⁺ )

'H-NMR (400 MHz, CDC1)

 Three

 11.074 (m), 10.097 (m) (also IH), 7.949-7.930 (2H, m), 7.714 (IH, 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 (IH, brs), 1.687-1.265 (26H, m), 0.886 (3H, t, J = 6.7 Hz).

¹³ C-NMR (100 MHz, CDC1)

 Three

197.4, 192.9, 175.4, 174.7, 174.0, 170.6, 138.33, 138.30, 134.41, 134.39, 129.6, 1 27.84, 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.

 [0161] The following is a modification of R (also R and R for compound 34) according to the method described above.

 3 1 2

 The structural formula and data of the compound.

 [Chemical 44]

[0162] 3- (1- (Benzylamino) octylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5H) _Din () 33)

 White amorphous

 Molecular weight: 345.43

 Molecular formula: C H NO

 20 27 4

 'H-NMR (400 MHz, CDCl) 11.326 (m), 10.395 (m) (1H in total), 7.426—7.258 (5H

 Three

M), 4.658 (s), 4.644 (s) (2H in total), 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), 1.592-1.25 8 (10H, m), 0.881 (3H, t, J = 7.0 Hz). C-NMR (75.5 MHz, CDC1) 197.6, 193.2, 175.9, 174.9, 174.3, 171.2, 134.9, 134.

 Three

 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.

[0163] 5- (Hydroxymethyl) _3_ (Pyrrolidine-2-ylidene) furan-2.4 (3H. 5H) -dione (chemically white solid)

 Molecular weight: 197.19

 Molecular formula: C H NO

 9 11 4

 FAB-MS (Pos.) M / z = 198 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

 9.834 (brs), 9.081 (brs) (combined IH), 4.606 (t, J = 3.9 Hz), 4.575 (t, J = 3.9 Hz) (combined 1H), 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 (IH, brs).

[0164] t-Butinole 4- (Benzylamino) -4- (dihydro-5- (hydroxymethyl) -2,4_dioxofuran-3 (2H) -ylidene) butylcarbamate (Compound 35)

 Colorless amorphous

 Molecular weight: 404.46

 Molecular formula: C H N 0

 21 28 2 6

FAB-MS (Pos.) M / z = 405 ([M + H] ⁺ )

 'H-NMR (400 MHz, CDC1)

 Three

 11.316 (brs), 10.426 (brs) (IH), 7.401-7.351 (3H, m), 7.291-7.272 (2H, m), 5.251, 5.165 (IH, brs), 4.669, 4.649 (2H, s) , 4.559-4.515 (IH, m), 3.968 (2H, m), 3.208-3.207 (2H, m), 3.026-2.977 (2H, m), 2.661 (IH, brs), 1.786-1.764 (2H, m) , 1.435 (9H, s).

¹³ C-NMR (75.5 MHz, CDC1)

 Three

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. [0165] 3- (l- (Benzylamino) -2- (1H-indole-3-yl) ethylidene) -5- (hydroxymethylol) furan-2,4 (3H.5H) -dione (compound 36)

 Yellow amorphous

 Molecular weight: 376.41

 Molecular formula: C H N O

 FAB-MS (Pos.) M / z = 377 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 11.284 (m), 10.366 (m) (collectively IH), 8.500, 8.419 (IH, brs), 7.551 (1H, d, J = 7.7 H z), 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 (IH, brs).

[0166] 3- (1-Benzylamino) -8-azidooctylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5H) -dione (Compound 37)

 White amorphous

 Molecular weight: 400.47

 Molecular formula: C H N 0

 'H-NMR (300 MHz, CDC1) 11.333 (brs), 10.406 (brs) (also IH), 7.45-7.34; 7.2

9-7.26 (5H, m), 4.650 (2H, d, J = 6.2 Hz), 4.554 (t, J = 4.0 Hz), 4.526 (t, J = 4.4 Hz) (total 2H), 3.968 (2H, br), 3.256 (2H, J = 7.0 Hz), 3.090-2.898 (2H, m), 1.61-1.28 (10H, m).

[0167] 3- ((Bok Benjiruamino) 8- (6- (4, 4 Jifuruoro _1, 3 - dimethyl _5_ (4 - Metokishifue sulfonyl) - ₄ _ bora - _{3a, 4a} _ Jiaza _ _s _ indacene - ₂ _ propionyl Amino) hexanoylamino) octylidene) -5- (hydroxymethyl) furan-2.4 (3H. 5H) -dione (compound 38) red purple oil

 Molecular weight: 853.80

 Molecular formula: C H BF N O

 'H-NMR (300 MHz, CDC1) 11.316 (brs), 10.388 (brs) (also IH), 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), 6.96 1 (2H, d, J = 8.8 Hz), 6.534 (IH, d, J = 4.0 Hz), 6.010 (m), 5.900 (m), 5.736 (m) 2H), 4.615 (2H, d, J = 6.2 Hz), 4.532 (t, J = 4.0 Hz), 4.499 (t, J = 4 Hz) (total 1H), 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) ₀

 [0168] Compounds of the general formula (I) differing in R were derived from compounds of R = OH. R force methanes

 4 4 4 Production examples in the case of a sulfonyl group, iodine, hydrogen (exomethylene), acetoxy group and a benzoyloxy group are shown below.

 [0169] R = -CH Ph, R = H. 卫 =-[CH) CH R =-OS (Q) CH reaction example

 1. '2 2 3_ 2 14 i. 4. 2 3_

 [Chemical 45]

 Scheme 5

 [0170] Production reaction 8 → 39

 4- (1-Benzylamino) hexadecylidene) -tetrahydro-3.5-dioxofuran-2-yl) methyl methanesulfonate (compound 39)

 To a tetrahydrofuran solution (0.3 mL) of compound 8 (18.0 mg, 0.039 mmol), methanesulfoninochloride (8 μL, 0.10 mmol), triethylamine (30 μL, 0.22 mmol) and 4_dimethyloleaminopyridine (3.0 mg, 0.025 mmol) was obtained 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 obtain Compound 39 (20.0 mg, 96%) as a white solid.

 [0171] Molecular weight: 535.74

 Molecular formula: C H NO S

 29 45 6

 FAB-MS (Pos.) M / z = 536 ([M + H] +)

'H-NMR (400 MHz, CDC1) 11.238 (brs), 10.374 (brs) (together IH), 7.437-7.370 (3H, m), 7.284-7.260 (2H, ov erlapped), 4.684-4.597 (4H, m), 4.523-4.464 (IH, m ), 3.043 (s), 3.032 (s) (3H), 3.0 50-2.930 (2H, m), 1.620-1.250 (26H, m), 0.879 (3H, t, J = 6.8 Hz).

1 ³ C-NMR (100 MHz, CDC1)

 Three

 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.

 [0172] Reaction example of R = -CH Ph._R = ¾ R =-(CH) CH R = H

^— 1. 2 2 3_ 2 14 S ~ 4_

 [Chemical 46] Scheme 6

 39 40

[0173] 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] unde force-7-en (21 μL, 0.15 mmol) were dissolved in toluene (1 mL) for 10 seconds. Heated with a dryer. 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.

[0174] Molecular weight: 439.63

 Molecular formula: C H NO

 28 41 3

 FAB-MS (Pos.) M / z = 440 ([M + H] +)

'H-NMR (400 MHz, CDC1) 11.474 (brs), 10.108 (brs) (also IH), 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) (combined IH), 4.928 (IH, 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, CDC1)

 Three

 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, 29.6 5, 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.

 [0175] Reaction example of R = -CH PL = H. CH =-(CH) CH R = I

 J_ 2 2 3_ 2 14 3 ~ 4_

 [Chemical 47]

[0176] Production reaction 8 → 41

 3- (1- (Benzylamino) hexadecylidene) -5- (iodomethyl) furan- 2.4 (3H. 5H) _ gin (chemical) 41)

 Add iodine (42.9 mg, 0.17 mmol), triphenylphosphine (42.1 mg, 0.16 mmol) and imidazole (20.0 mg, 0.2 9 mmol) to methylene chloride solution (1 mL) of compound 8 (47.7 mg, 0.10 mmol), Stir at room temperature for 1.5 hours. Water was added to the reaction solution and extracted three times with jetyl ether. 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%) Was obtained as a pale yellow solid.

 [0177] Molecular weight: 567.54

Molecular formula: CH INO FAB-MS (Pos.) M / z = 568 ([M + H] ⁺ )

 'H-NMR (300 MHz, CDC1)

 Three

 11.267 (brs), 10.428 (brs) (also IH), 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) (also IH), 3.54 5-3.495 (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, CDC1)

 Three

 196.7, 192.1, 175.3, 175.1, 174.6, 170.1, 151.7, 134.76, 134.71, 134.68, 129.33, 1 29.31, 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.

[0178] Reaction example of R = -CH Ph._R = ¾ R =-(CH) CH R = Br

 J_ 2 2 3_ 2 14 1_ ~ 4_

 [Chemical 48] Scheme 8

8 42

[0179] Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (bromomethyl) furan-2, 4 (3H, 5H) -dione (Compound 42)

Carbon tetrabromide (39.5 mg, 0.12 mmol) and triphenylphosphine (18.5 mg, 0.073 mmol) were added to a methylene chloride solution (1.5 mL) of compound 8 (29.3 mg, 0.064 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 extracted three 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. It was. [0180] Molecular weight: 520.54

 Molecular formula: C H BrNO

 28 42 3

 'H-NMR (400 MHz, CDC1)

 Three

 11.246 (m), 10.398 (m) (collectively IH), 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) l.604-1.249 (26H, m), 0.877 (3H, t, J = 7.0 Hz).

R = -CH Ph._R = H _L R =-(CH) CH R = CI reaction example

 1 2 2 3 2 14 4

 [Chemical 49] Scheme 9

[0181] Synthesis of 3- (1- (benzylamino) hexadecylidene) -5- (chloromethyl) furan-2, 4 (3H. 5H) _ dione (compound 43)

 Compound 8 (37.7 mg, 0.082 mmol) was charged with carbon tetrachloride (1 mL) and triphenylphosphine (4 5.5 mg, 0.18 mmol) and 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.

[0182] Molecular weight: 476.09

 Molecular formula: C H C1NO

 28 42 3

 'H-NMR (400 MHz, CDC1)

 Three

 11.255 (m), 10.398 (m) (collectively IH), 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).

1 ³ C-NMR (75.5 MHz, CDC1) (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.

[0183] R = -CH PL = H. ^ =-(CH) CH R = -OCOCH reaction example

^— 1. 2 2 3_ 2 14 3 ~ 4_ 3_

 [Chemical Formula 50] Scheme 1 0

 8 44

[0184] Production reaction 8 → 44

 Synthesis of (4- (l- (Benzenoreamino) hexadecylidene) -tetrahydro-3.5-dioxofuran-2-inole) methyl acetate (compound 44)

 Compound 8 (27.9 mg, 0.061 mmol) in methylene chloride (3 mL) at 0 ° C with acetic anhydride (17 μ μ, 0.18 mmol), pyridine (17 μ ΐ, 0.21 mmol) and 4-dimethylamino Pyridine (a small amount) was added 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.

 [0185] Molecular weight: 499.68

 Molecular formula: C H NO

 30 45 5

FAB-MS (Pos.) M / z = 500 ([M + H] ⁺ )

 'H-NMR (300 MHz, CDC1)

 Three

11.289 (brs), 10.415 (brs) (1H), 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) (total IH), 4.283 (IH, 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).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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.

[0186] Reaction example of R = -CH PL = H. 卫 =-(CH) CH R = -OCOPh

^— 1. 2 2 3_ 2 14 3 ~ 4_

 [Chemical 51] Scheme 1 1

 8 45

[0187] Production reaction 8 → 45

 Synthesis of (4- (l- (Benzenoreamino) hexadecylidene) -tetrahydro-3.5-dioxofuran-2-inole) methinole benzoate (compound 45)

N, N-diisopropylethylamine (16 _ML , 0.092 mmol) was added to a methylene chloride solution (0.5 mL) of compound 8 (20.0 mg, 0.044 mmol). 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.

 [0188] Molecular weight: 561.75

Molecular formula: CH NO FAB-MS (Pos.) M / z = 562 ([M + H] ⁺ )

'H-NMR (300 MHz, CDC1)

 Three

 11.332 (brs), 10.467 (brs) (collectively IH), 7.968 (2H, dd,) = 7.0, 1.5 Hz), 7.550 (IH, t, J = 7.0 Hz), 7.417-7.365 (5H, m), 7.285-7.242 (2H, m), 4.836-4.570 (3H, m), 4.68 5 (s), 4.665 (s) (2H in total), 3.075-2.948 (2H, m), 1.566-1.238 (26H, m ), 0.890 (3 H, t, J = 6.6 Hz).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 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, 29.5 4, 29.4, 29.3, 29.22, 29.17.

 Using a similar method, different compounds of R, R, R and R were synthesized. Compound

 1 2 3 4

The structural formula and structural data are shown below.

[Chemical 52]

4- ( l- ( 4-フエノキシ）ベンジルアミノ）へキサデシリデン） -テトラヒドロ- 3. 5-ジォキソ フラン _2_ィル）メチル メタンスルフォネート（化合物 46)

4- (l- (4-phenoxy) benzylamino) hexadecylidene) -tetrahydro-3.5-dioxofuran_2_yl) methyl methanesulfonate (compound 46)

Colorless oil

Molecular weight: 627.83

Molecular formula: C H NO S

 35 49 7

 FAB-MS (Pos.) M / z = 628 ([M + H] +)

'H-NMR (400 MHz, CDC1)

 Three

11.183 (m), 10.317 (m) (IH combined), 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 (IH, 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).

1 ³ C-NMR (75.5 MHz, CDC1)

 Three

 194.5, 189.9, 175.14, 175.08, 174.4, 170.2, 157.95, 157.92, 156.43, 156.39, (?) 12 9.9, 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.

[0191] 4- (l- (3- (N.N-Dimethyl) benzylamino) hexadecylidene) -tetrahydro-3.5-dioxofuran_2_yl) methyl methanesulfonate (Compound 47)

 Pale yellow oil

 Molecular weight: 578.80

 Molecular formula: C H N〇 S

 31 50 2 6

FAB-MS (Pos.) M / z = 579 ([M + H] ⁺ )

 JH-NMR (400 MHz, CDC1)

 Three

 11.225 (m), 10.368 (m) (IH, m), 7.253 (IH, t, J = 7.8 Hz), 6.706 (IH, d, J = 8.6, 2.0 H z), 6.590 (1H, d, J = 7.6 Hz), 6.555 (IH, 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),

I.460-1.265 (24H, m), 0.890 (3H, t, J = 6.7 Hz).

 [0192] 4- (卜 (Benzylamino) -4-t-butoxycarbonylaminobutylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 48)

 White amorphous

 Molecular weight: 482.55

 Molecular formula: C H N〇 S

 22 30 2 8

 FAB-MS (Pos.) M / z = 483 ([M + H] +)

 'H-NMR (400 MHz, CDC1)

 Three

I I.238 (m), 10.411 (m) (also IH), 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). [0193] 4- (卜 (4-Methanesulfonyl) benzylamino) hexadecylidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (Compound 49)

 Colorless oil

 Molecular weight: 629.83

 Molecular formula: C H NO S

 FAB-MS (Pos.) M / z = 630 ([M + H] +)

 'H-NMR (400 MHz, CDCl)

 11.242 (m), 10.372 (m) (collectively IH), 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), 3.04 0-2.922 (2H, m), 1.620-1.256 (26H, m), 0.880 (3H, t, J = 6.9 Hz).

[0194] 4- ((l-Benzylamino) 8_ (6 _ (4.4 Diphnoreo Mouth- 1. 3-Dimethyl _5- (4-Methoxyphenyl) _4_ Bora _3a, 4a -Diaza-s-Indacene-2_ Synthesis of propionylamino) hexanoylamino) otatidelidene) -tetrahydro-3,5-dioxofuran-2-yl) methyl methanesulfonate (compound 50)

 Magenta oil

 Molecular weight: 931.89

 Molecular formula: C H BF N 0 S

 'H-NMR (300 MHz, CDCl) 11.228 (brs), 10.368 (brs) (also IH), 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 (IH, d , J = 4.4 Hz), 5.795-5.590 (2H, brm), 4.687-4.568 (3H, m), 4.4 96 (dd, J = 11.4, 4 Hz), 4.472 (dd, J = 11.7, 4.4 Hz) ( 1H), 3.849 (3H, s), 3.2 32-3.124 (4H, m), 3.025 (3H, s), 3.02—2.91 (2H, brm), 2.761 (2H, t, J = 7.3 Hz), 2.5 29 (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) ₀

[0195] 3- ((l-Benzylamino) 8_ (6 _ (4.4 Diphnoreo Mouth-1. 3-Dimethyl _5- (4-Methoxyphenyl) _4_ Bora _3a, 4a -Diaza-s-Indacene-2_ Of propionylamino) hexanoylamino) octylidene) -5- (fluoromethyl) furan-2.4 (3H.5H) -dione (compound 51) Magenta oil

 Molecular weight: 855.79

 Molecular formula: C H BF N 0

 'H-NMR (300 MHz, CDCl) 11.251 (brs), 10.410 (brs) (1H in total), 7 · 866 (2Η, 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) ₀

[0196] Synthesis of 4- (1-benzylamino) 8-azidooctylidene) -tetrahydro-3.5-dioxofuran-2-inole) methyl methanesulfonate (Compound 52)

 White amorphous

 Molecular weight: 478.56

 Molecular formula: C H N 0 S

 'H-NMR (300 MHz, CDCl) 11.247 (brs), 10.381 (brs) (1H in total), 7.46-7.35; 7

-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), 3.060-2.900 (2H, m), 1.63-1.290 (12H, m). Example 2

[0197] HL60 cellulite growth inhibitory activity test

 The growth inhibitory activity of the compounds against human leukemia cells HL60 was evaluated using alamarBlue ™.

[0198] Exam 1

Was suspended so as to 2xl0 ⁴ cells / ml in 5% bovine fetal serum HL60 cells cultured in RPMI1640 medium containing (FCS) fresh medium, and seeded into 96-well plate at 99.5 mu 1, 2 hour incubation did. Then, DMSO (no compound added group) or DMSO solution of each compound was added at 0.5 μΐ each, and further cultured for 3 days. Then add 10 μl of a lamarBlue ™ (Biosource) as a viable cell number indicator to each well and leave it in a 5% CO incubator at 37 ° C for 2-3 hours. [Excitation wavelength (Ex.): 560 nm, Emission wavelength (E m.): 590 nm] was measured with Spectra Max Gemini XS (Molecular Devices), and the fluctuation value was obtained. Then, the relative value of the fluorescence fluctuation value of the compound-added caro group when the fluorescence fluctuation value of the compound-free group was taken as 100% was calculated. Based on this, growth inhibitory activity was determined. The results are shown in Table 1 and Figure 1 below.

[0199] Growth inhibitory activity (%) = 100-(Fluorescence fluctuation value when compound is added) Fluorescence fluctuation value of Z compound-free group) X 100

 [Table 1] Compound Drug concentration Growth inhibitory activity (%)

 No additive group 0

 RK-682 1 1

 3 2

 10 0

 30 0

 1 0 1 0

 3 6

 10 100

 2 1 1 0

 3 0

 10 98

 2 5 1 0

 3 16

 10 100

[0200] Exam 2

HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) are suspended in new medium to 4xl0 ⁴ cells / ml, then seeded at 99.5 μl each in a 96-well plate and cultured for 2 hours did. Then, DMSO (no compound added group) or DMSO solution of each compound was added at 0.5 μΐ each, and further cultured for 3 days. Then add 10 μl of a lamarBlue ™ (Biosource) as a viable cell number indicator to each well, immediately after addition and at 37 ° C with 5% CO ink.

2 Fluorescence [excitation wavelength (Ex.): 560 nm, emission wavelength (E m.): 590 nm] after standing for 2 to 3 hours in an incubator is measured with Spectra Max Gemini XS (Molecular Devices). The fluctuation value was obtained. In addition, the compound-added calorie when the fluorescence fluctuation value of the compound-free group is 100%. The relative value of the fluorescence fluctuation value of the group was calculated. Based on this, growth inhibitory activity was determined. The results are shown in Table 2 and Figure 2 below.

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

 [Table 2] Compound Drug concentration (μΜ) Growth inhibitory activity (%)

 No additive group 0

 1 3 0. 3 8

 1 12

 3 100

 3 8 0. 3 58

 1 100

 3 100

 2 5 0. 3 10

 1 9

 3 14

 10 100

 3 9 0. 3 85

 1 100

 3 100

[0202] From Tables 1 and 2, RK-682 shows almost no cytostatic activity even at a high concentration of 30 μΜ, whereas the compound developed in the present invention shows activity at 10 / M or less. From this, it was clarified that it was converted into a skeleton that can be applied to cells. Among them, compound 39 was remarkably suppressed in cell proliferation even at a very low concentration of 0.3, and was shown to have strong anticancer activity.

 Example 3

 [0203] VHR IV. Harmful activity 'cochlea test

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

[0204] Exam 1 78 mL of VHR expressed in E. coli and diluted with enzyme reaction buffer (50 mM succinic acid, 1 mM EDTA, 150 mM NaCI, pH 6.0) was seeded in a 96-well plate, and DMSO (no compound was added). (Addition group) or DMSO solution of each compound was added in increments of 2 and allowed to stand at 37 ° C for 30 minutes. Thereafter, 120 pNPP was added in increments 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. In addition, the absorbance fluctuation value of the compound-free group is 100. The relative value of the absorbance fluctuation value of the compound addition group when / was calculated 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 when compound is added / absorption fluctuation value when compound is not added) xl OO

[Table 3]

VHR inhibitory activity

 Compound Drug concentration (μ Μ) (%)

 No additive group 0

 1 0 30 68

 1 1 30 58

 1 2 30 32

 1 3 30 25

 1 4 30 32

 1 6 30 34

 1 7 30 24

 1 8 30 52

 2 1 30 62

 2 2 30 45

 2 3 30 14

 2 4 30 24

 2 6 30 33

 4 0 30 25 Exam 2

78 μL of VHR expressed in E. coli and diluted with enzyme reaction buffer (50 mM succinate, 1 mM EDTA, 150 mM NaCI, pH 6.0) is seeded in a 96-well plate at a time. The compound-free group) or DMSO solution of each compound was added in two increments and left at 30 ° C for 30 minutes. Thereafter, 120 / iL of pNPP (5.0 mM) was added at a time, and left at 30 ° C for 15 minutes. Next, 0.1 β NaOH aqueous solution was added in an amount of 100 β L, and the absorbance (405 nm) was measured with Ultra Microp late Reader EL808 (BIO-TEK Instruments) to determine the fluctuation value. Then, the relative value of the light absorption fluctuation value of the compound addition group was calculated when the light absorption fluctuation value of the compound addition group was taken as 100%. 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 when compound is added Z light absorption fluctuation value when Z compound is not added) xlOO

[Table 4]

VHR inhibitory activity

 Compound Drug concentration (M) (%)

 No additive group 0

 8 100 55

 30 28

 1 0 30 45

 2 8 100 42

 30 17

 2 9 30 5. 1

 3 0 30 15

 3 4 100 3. 3

 30 8. 8

 3 5 100 5. 1

 30 5. 8

 3 6 100 10

 30 4.3

 3 9 100 32

 30 23

 4 1 100 39

 30 18

 4 4 30 21

 4 5 30 20

 4 6 30 30

 4 7 30 17

 4 9 30 9. 2 All publications, patents and patent applications cited in this specification shall be incorporated herein by reference in their entirety.

Claims

Claim [1] Formula (I)  [Chemical 1]

[Where  R and R are, independently of one another, hydrogen; a hetero selected from the group consisting of N, 0 and S 1 2  A linear, branched or cyclic saturated or unsaturated hydrocarbon group optionally substituted by a substituent which may contain atoms; a heteroatom selected from the group consisting of N, 0 and S An aryl group or an aralkyl group which may be substituted by a substituent which may contain _C (= 0) -R or -S (= 〇) -R (R is selected from the group consisting of N, 0 and S) To be done  5 2 5 5  A linear, branched or cyclic saturated or unsaturated hydrocarbon group optionally substituted by a substituent which may contain a tera atom; or selected from the group consisting of N, 0 and S Or an aryl group or an aralkyl group which may be substituted by a substituent which may contain a hetero atom, or an amino group or a hydroxyl group in which hydrogen may be substituted by a substituent, Where R and R are not hydrogen at the same time;  1 2  R is a substituent which may contain a heteroatom selected from the group consisting of N, 0 and S Three  A linear, branched or cyclic saturated or unsaturated hydrocarbon radical which may be more substituted; or may contain a heteroatom selected from the group consisting of N, 0 and S An aryl group or an aralkyl group optionally substituted by a substituent,  R and R, or R and R are united with the atom to which they are bonded, and R and R are bonded. 1 2 1 3 1 2 Combined N may contain a heteroatom selected from the group consisting of N, 0 and S. Saturated or unsaturated aliphatic optionally substituted by a substituent May form a ring or an aromatic ring; In formula (I) [Chemical 2] The bond represented by may be a single bond or a double bond; when the bond is a double bond, R is hydrogen; when the bond is a single bond, R Is the power of being a halogen,  4 4 Or -XY {where -X- is -0-, -S- or -ΝΗ-; -Υ is hydrogen; may contain a heteroatom selected from the group consisting of Ν, 0 and S A linear, branched or cyclic saturated or unsaturated hydrocarbon group which may be substituted by a substituent; or -c (= 〇) -R, -S (= 0)-R,- C (= 0) -0-R, -S (= 0) -OR or -C (= 0) _N (-H) _R (R is N, 6 2 6 6 2 6 6 6 A linear, branched or cyclic saturated or unsaturated hydrocarbon group optionally substituted by a substituent which may contain a heteroatom selected from the group consisting of ◯ and s; or A aryl group or an aralkyl group which may be substituted by a substituent which may contain a heteroatom selected from the group consisting of N, 0 and S);  Carbon indicated by * [Chemical 3] Is an asymmetric carbon when is a single bond, it may be optically active or racemic  Partial structure in formula (I): [Chemical 4]

(In the formula, * and * indicate the bonding position)  1 2 Is  [Chemical 5]

(In the formula, * and * indicate the bonding position)  1 2 Any of these may be used. ] Or a salt or solvate thereof. In formula (I):  One of R and R is H and the other is  1 2 [Chemical 6]

(Wherein * represents a bonding position) is a group selected from the group consisting of: R is  Three  [Chemical 7] * — (CH ₂ ) ₁₄ CH ₃ *-(CH ₂ ) ₁₀ CH ₃ *-(CH ₂ ) ₆ CH 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): [Chemical 8] (In the formula, * indicates the bond position) Is [Chemical 9]

and

 (In the formula, * indicates the bond position) 2. The compound according to claim 1, or a salt or solvate thereof, which is a group selected from the group consisting of:  In formula (I):  R and R together form _ (CH)-;  1 2 2 4  R is  Three [Chemical 10] Mizuichi (CH2) i4CH3 氺 ー (CH2) ioCH; 3

Ν ₃ "and

(Wherein * represents a bonding position; -Ph is an unsubstituted phenyl group) is a group selected from the group consisting of:  Partial structure in formula (I): [Chemical 11]  , (In the formula, * indicates the bond position) Is [Chemical 12]

 (In the formula, * indicates the bond position)  2. The compound according to claim 1, or a salt or solvate thereof, which is a group selected from the group consisting of  [4] In formula (I),  R and R together form-(CH)-;  R is H;  Partial structure in formula (I): [Chemical 13]

 (In the formula, * indicates the bond position)  Is [Chemical 14]

and

(In the formula, * indicates the bond position)  2. The compound according to claim 1, or a salt or solvate thereof, which is a group selected from the group consisting of  [5] The following: [Chemical 15]

23 24 25

(Wherein -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) 2. The compound according to claim 1, which is represented by a formula selected from the group consisting of:  [6] A pharmaceutical composition comprising as an active ingredient the compound according to claims 1 to 5, or a pharmaceutically acceptable salt or solvate thereof. 7. The pharmaceutical composition according to claim 6, which is an antitumor agent.  8. The pharmaceutical composition according to claim 6, which is a protein phosphatase inhibitor.  [9] A process for producing a compound according to claims 1 to 5, or a salt or solvate thereof,  Formula:  [Chemical 16]

{Wherein R is as defined in claim 1;  Three [Chemical 17]

[Chemical 18]

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

A process for obtaining a compound represented by the formula: