JP2006316001A - Naphthoquinone derivative compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound useful as a tyrosine phosphatase inhibitor, a tyrosine phosphatase inhibitor, a medicinal composition, a cell proliferation inhibitor, a cell-cycle progress inhibitor, an antibacterial agent, an imipenem activity promoter and a bacterial cell proliferation inhibitor containing the compound as an active component, an imipenem activity promotion method and bacterial cell proliferation inhibiting method using the compound, an activity promoting agent for the compound and an activity promoting method. <P>SOLUTION: The naphthoquinone derivative compound or its pharmacologically permissible salt has a tyrosine phosphatase inhibiting activity, cell proliferation inhibiting activity, a cell-cycle progress inhibiting activity, an antibacterial activity, an activity to promote imipenem action and bacterial cell proliferation inhibiting activity. Imipenem has an action to promote the activity of naphthoquinone derivative compounds and their pharmacologically permissible salts. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a naphthoquinone derivative compound or a pharmacologically acceptable salt thereof, and a tyrosine phosphatase inhibitor, a pharmaceutical composition, a cell growth inhibitor, a cell cycle progression inhibitor, and an antibacterial agent containing the compound as an active ingredient. The present invention relates to an imipenem activity enhancer, a bacterial growth inhibitor, a method for enhancing imipenem activity using the above-mentioned compound, a method for inhibiting bacterial growth, and an activity enhancer and a method for enhancing activity of the above-mentioned compound.

Inhibitors for tyrosine phosphatases are said to be useful for diseases caused by overexpression or activation of tyrosine phosphatases such as type 2 diabetes, obesity, tumors, and neurological diseases. It has been demanded. Conventionally, several naphthoquinone analogs are known as inhibitors for Cdc25, which is a tyrosine phosphatase (see, for example, Non-Patent Documents 1 to 4). In addition, as an inhibitor for PTP1B, which is a tyrosine phosphatase, several compounds, chlorella cell wall disrupted materials, and the like are known (see, for example, Patent Documents 1 to 5).
Bioorg. Med. Chem. Lett. 1998, 8 (18), 2507-10 J. Antibiot. 1999, 52, 256-262 Bull Chem Soc Jpn. 2004, 77, 1925-30 Bioorg. Med. Chem. Lett. 2005, 15 (1), 61-5 JP-A-11-222474 JP 2000-256330 A JP 2002-121186 A JP 2005-89322 A Japanese National Patent Publication No. 11-508919

  The present invention relates to a novel compound useful as an inhibitor of tyrosine phosphatase, and a tyrosine phosphatase inhibitor, a pharmaceutical composition, a cell growth inhibitor, a cell cycle progression inhibitor, an antibacterial agent, and an imipenem activity enhancement containing the compound as an active ingredient The present invention relates to an agent, a bacterial growth inhibitor, an imipenem activity enhancing method using the above compound, a bacterial growth inhibiting method, and an activity enhancing agent and an activity enhancing method for the above compound.

In order to solve the above-mentioned problems, the present inventors have made a naphthoquinone derivative compound represented by the following general formula (II) (wherein R ₅ is a hydrogen atom or an alkyl group, R ₆ is a hydroxyethyl group, a hydroxy group, A propyl group, a hydroxyhexyl group, an aryl alcohol group, or an alkylcarbonyl group, R ₇ is a hydrogen atom, an acyl group, or a butyldimethylsilyl group, and the R ₆ and the R ₇ do not form a ring.) As the compounds represented by the following formulas (f) to (j) (hereinafter referred to as “compound (f)”, “compound (g)”, “compound (h)”, “compound (i)”, and (Referred to as “compound (j)”) and the effect on the enzyme activity of tyrosine phosphatase was examined. As a result, it was found that the compounds represented by the compounds (f) to (j) inhibit the enzyme activity of tyrosine phosphatases such as Cdc25A phosphatase and protein tyrosine phosphatase 1B.

Moreover, the compound represented by the following formulas (k) and (l) as a naphthoquinone derivative compound (wherein R ₈ is a hydrogen atom or an acyl group) represented by the general formula (III) as described above (Hereinafter, they are referred to as “compound (k)” and “compound (l)”), respectively, and the influence on the enzyme activity of tyrosine phosphatase was examined. As a result, it was revealed that the compounds represented by the compounds (k) and (l) inhibit the enzyme activity of tyrosine phosphatases such as Cdc25A phosphatase and protein tyrosine phosphatase 1B.

Similarly, as the naphthoquinone derivative compound represented by the general formula (IV) (wherein R ₉ is a propyl group, a butyl group, a hexyl group, or an alkynyloxyalkyl group), the following formulas (m) to tyrosine phosphatase using compounds represented by (p) (hereinafter referred to as “compound (m)”, “compound (n)”, “compound (o)”, and “compound (p)”) The effect on the enzyme activity was investigated. As a result, it was revealed that the compounds represented by the compounds (m) to (p) inhibit the enzyme activity of tyrosine phosphatases such as Cdc25A phosphatase and protein tyrosine phosphatase 1B.

By the way, it is known that Cdc25A acts on Cdk2 / CyclinE and Cdk2 / CyclinA, and functions in G ₁ / S transition in cell cycle regulation. Therefore, in order to examine whether the above-mentioned compound that inhibits Cdc25A phosphatase inhibits cell cycle progression, the present inventors have investigated compounds (f) to (p) and a compound represented by the following formula (q). (Hereinafter referred to as “compound (q)”) was used to examine the effect on cell cycle progression. As a result, the compound represented by the compound (j) and (q) was found to be stopped in its progression G ₁ phase of the cell cycle.

  In addition, the present inventors examined the cell growth inhibitory activity using compounds (j) to (q) in order to examine whether the above-mentioned compound inhibits cell proliferation. As a result, it was revealed that the compound (j) and the compounds (m) to (p) have cytostatic activity.

Furthermore, the present inventors have obtained compounds represented by the following formulas (r), (s), (v), and (w) (hereinafter referred to as “compound (r)”, “compound (s)”, “Compound (v)” and “compound (w)”) have an anti-MRSA (methicillin-resistant Staphylococcus aureus) action alone, compounds (r), (s), (v), and ( w) and a compound represented by the following formula (u) (hereinafter referred to as “compound (u)”), when acting on MRSA in cooperation with imipenem, which has no effect on MRSA alone, exhibits anti-MRSA activity. Found to be enhanced.

  Thus, the present inventors have completed the present invention.

That is, the naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to the present invention is represented by the following general formula (I).

In the formula (I), when R ₃ is an aryl alcohol group or an alkylcarbonyl group, R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, R ₂ is a hydroxyl group, An acyloxy group or an alkoxyl group, and R ₄ is an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxyalkyl group, an alkoxyalkenyl group, a phenoxyalkyl group, a phenoxyalkenyl group, a carboxyalkenyl group, An alkoxycarbonylalkenyl group, an acyloxyalkenyl group, a hydroxyalkyloxiranealkyl group, an alkoxyalkyloxiranealkyl group, a dihydroxyalkyl group, a hydroxyalkoxyalkyl group, an oxirane group, or - a Jimetan 1,3-dioxane-4-alkyl group, wherein when R ₄ is alkynyloxy group or butyldimethylsilyloxy alkenyl group, R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group , An alkoxyl group, or a hydroxyalkyl group, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₃ is a hydrogen atom, a hydroxyalkyl group, a halogen atom, or an aryl alcohol group, _{When 1} is an acyloxy group, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, R ₃ is a hydrogen atom, a hydroxyalkyl group, or a halogen atom, and R ₄ is an acyl group, a hydroxyalkyl group , Hydroxyalkenyl group, carboxyl group, alkoxycarbonyl group, Alkoxyalkyl group, alkoxyalkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxiranealkyl group, alkoxyalkyloxiranealkyl group, dihydroxyalkyl group, hydroxyalkoxyalkyl group, An oxirane group or a 2-dimethane-1,3-dioxane-4-alkyl group, wherein R ₁ and R ₂ are methoxy groups and R ₄ is a hydroxybut-2-enyl group , R ₃ is a hydroxyethyl group, a hydroxypropyl group, or a hydroxyhexyl group, wherein R ₂ is a methoxy group, R ₃ is a hydrogen atom, and R ₄ is a methoxymethyl group, R ₁ is hydroxy A group, wherein, R ₁ and R ₂ is a methoxy group, when R ₃ is a hydrogen atom, hexyl oxymethyl group to R ₄ are like. In addition, it is preferable that the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention does not form a ring with R ₃ and R ₄ .

The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to the present invention is represented by the above general formulas (II) to (IV). In the formula (II), R ₅ is a hydrogen atom or an alkyl group, R ₆ is a hydroxyethyl group, a hydroxypropyl group, a hydroxyhexyl group, an aryl alcohol group, or an alkylcarbonyl group, and R ₇ is a hydrogen atom. , An acyl group, or a butyldimethylsilyl group, and the R ₆ and the R ₇ do not form a ring. In the formula (III), R ₈ is a hydrogen atom or an acyl group. In the formula (IV), R ₉ is a propyl group, a butyl group, a hexyl group, or an alkynyloxyalkyl group. The naphthoquinone derivative compound is preferably the above-mentioned compounds (a) to (q).

  The tyrosine phosphatase inhibitor according to the present invention contains the above naphthoquinone derivative compound or a pharmacologically acceptable salt thereof as an active ingredient. Examples of the tyrosine phosphatase include Cdc25A phosphatase and protein tyrosine phosphatase 1B.

  Moreover, the pharmaceutical composition which concerns on this invention contains the above-mentioned naphthoquinone derivative compound or its pharmacologically acceptable salt as an active ingredient. The pharmaceutical composition is useful for prevention or improvement of, for example, diseases caused by overexpression or activation of protein tyrosine phosphatase 1B, diseases caused by overexpression or activation of Cdc25A phosphatase, and the like. Examples of diseases caused by overexpression or activation of the protein tyrosine phosphatase 1B include, for example, type 2 diabetes, obesity, neurological diseases (eg, Alzheimer's disease, Parkinson's disease, etc.), tumors (eg, ovarian cancer, breast cancer, etc.) And myeloid leukemia. Examples of the diseases caused by overexpression or activation of the Cdc25A phosphatase include tumors.

Furthermore, the cell growth inhibitor according to the present invention contains a naphthoquinone derivative compound represented by the following general formula (V) or a pharmacologically acceptable salt thereof as an active ingredient.

In the formula (V), when R ₁₂ is an aryl alcohol group or an alkylcarbonyl group, R ₁₀ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₁₁ is a hydroxyl group, An acyloxy group or an alkoxyl group, and R ₁₃ is an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxyalkyl group, an alkoxyalkenyl group, a phenoxyalkyl group, a phenoxyalkenyl group, a carboxyalkenyl group, Alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group, alkoxyalkyloxirane alkyl group, dihydroxyalkyl group, hydroxyalkoxyalkyl group, oxirane Or 2-Jimetan a 1,3-dioxane-4-alkyl group, In formula _(V), if _{R 13} is a alkynyloxy group or butyldimethylsilyloxy alkenyl _{group, R 10} is a hydrogen atom , An alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, R ₁₁ is a hydroxyl group, an acyloxy group, or an alkoxyl group, and R ₁₂ is a hydrogen atom, a hydroxyalkyl group, a halogen atom, or an aryl alcohol group. In the formula (V), when R ₁₀ and R ₁₁ are methoxy groups and R ₁₂ is a hydroxybut-2-enyl group, R ₁₃ is a hydroxyethyl group, a hydroxypropyl group, or a hydroxyhexyl group. In the formula (V), when R ₁₀ and R ₁₁ are methoxy groups and R ₁₂ is a hydrogen atom In some cases, R ₁₃ is a hexyloxymethyl group or the like. In addition, it is preferable that the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention does not form a ring with R ₁₂ and R ₁₃ . The naphthoquinone derivative compound is preferably any of the above-mentioned compound (j) or compounds (m) to (p).

Cell cycle progression inhibitor according to the present invention is for inhibiting the progression in G ₁ phase of the cell cycle, the compound or a pharmacologically acceptable salt thereof represented by the following general formula (VI) Contains as an active ingredient.

In the formula (VI), R ₁₄ is a hydroxyalkyl group, an alkylcarbonyl group, or an aryl alcohol group, and R ₁₅ is an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxyalkyl group, an alkoxy group. Alkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxiranealkyl group, alkoxyalkyloxiranealkyl group, dihydroxyalkyl group, hydroxyalkoxyalkyl group, oxirane group, 2- A dimethane-1,3-dioxane-4-alkyl group, an alkynyloxyalkyl group, a butyldimethylsilyloxyalkenyl group, and the like. In addition, it is preferable that the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention does not form a ring with R ₁₄ and R ₁₅ . As the compound, the above-mentioned compound (j) or compound (q) is preferably used.

The naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention is characterized by being represented by the following general formula (VII) or compound (r).

In the formula (VII), R ₁₆ is a hydroxyl group or an alkoxyl group, R ₁₇ is a hydrogen atom or a halogen atom, and R ₁₈ is a hydroxyl group or an alkoxyl group. Examples of the naphthoquinone derivative compound represented by the general formula (VII) include the above-described compound (S), compound (t), compound (u) and the like.

The antibacterial agent according to the present invention comprises a naphthoquinone derivative compound represented by the following general formula (VIII) or a compound (r), a compound (v), a compound (w), or a pharmacologically acceptable salt thereof. Contains as an active ingredient.

In the formula (VIII), R ₁₉ and R ₂₀ are alkoxyl groups. Examples of the naphthoquinone derivative compound represented by the general formula (VIII) include a compound (s). The antibacterial agent according to the present invention may further contain imipenem as an active ingredient. The antibacterial agent according to the present invention contains compound (u) or a pharmacologically acceptable salt thereof and imipenem as active ingredients. The antibacterial agent according to the present invention has an antibacterial action against gram-positive bacteria such as MRSA (methicillin-resistant Staphylococcus aureus) and gram-negative bacteria.

  The imipenem activity enhancer that enhances the activity of imipenem according to the present invention is a naphthoquinone derivative compound represented by the above general formula (VII) or compound (r), compound (v), compound (w), or a drug thereof Contains a physically acceptable salt as an active ingredient. Examples of the naphthoquinone derivative compound represented by the general formula (VII) include a compound (s) and a compound (u). The activity of the imipenem is, for example, antibacterial activity against bacteria. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  Further, the bacterial growth inhibitor according to the present invention is a naphthoquinone derivative compound or compound (r), compound (v) or compound (w) represented by the above general formula (VIII), or a pharmacologically acceptable salt thereof. Salt as an active ingredient. The naphthoquinone derivative compound represented by the general formula (VIII) is, for example, the compound (s). The bacterial growth inhibitor according to the present invention may further contain imipenem as an active ingredient. The bacterial growth inhibitor according to the present invention may contain compound (u) or a pharmacologically acceptable salt thereof and imipenem as active ingredients. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  Furthermore, the pharmaceutical composition according to the present invention is a pharmaceutical composition for improving a disease caused by bacterial infection or proliferation, wherein the naphthoquinone derivative compound represented by the above general formula (VIII) or the compound (r), Compound (v), compound (w), or a pharmacologically acceptable salt thereof is contained as an active ingredient. The naphthoquinone derivative compound represented by the general formula (VIII) is, for example, the compound (s). The pharmaceutical composition according to the present invention may further contain imipenem as an active ingredient. The pharmaceutical composition according to the present invention may contain compound (u) or a pharmacologically acceptable salt thereof and imipenem as active ingredients. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  Examples of the disease caused by MRSA infection or proliferation (hereinafter sometimes referred to as “MRSA infection”) include, for example, encephalitis, pneumonia, sepsis, peritonitis, enteritis, osteomyelitis, cholangitis, cutaneous suppuration. Disease, pressure ulcer infection, MRSA-produced toxins (eg, enterotoxin, TSST-1, etc.), food poisoning, toxic shock syndrome and the like. Examples of diseases caused by infection or proliferation of Gram-positive or Gram-negative bacteria (hereinafter sometimes referred to as “infectious diseases of Gram-positive or Gram-negative bacteria”) include, for example, addiction and periodontal disease. Disease, inflammatory disease, vasculitis, type IV allergic disease, staphylococcal burn-like skin syndrome, Ritter disease, bullous impetigo in neonates, tumor, pneumonia, arthritis, meningitis, various purulent diseases, enteritis , Meningitis, bacteremia, eye infection, food poisoning, respiratory infection, otitis media, sinusitis, pharyngitis, scarlet fever, acute filamentous nephritis, rheumatic fever, impetigo, fulminant infection, tooth decay, urine It includes urinary tract infections, wound infections, biliary tract infections, and severe atopic diseases (such as atopic dermatitis) caused by bacterial infections.

  The naphthoquinone derivative compound activity enhancer according to the present invention is a naphthoquinone derivative compound represented by the above general formula (VII) or a compound (r), a compound (v), a compound (w), or a pharmacologically acceptable It is a drug that enhances the activity of the salt produced and contains imipenem as an active ingredient. Examples of the naphthoquinone derivative compound represented by the general formula (VII) include a compound (s) and a compound (u). The activity is, for example, an antibacterial activity against bacteria. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  Further, the imipenem activity enhancing method for enhancing the activity of imipenem according to the present invention, in cooperation with the imipenem, a naphthoquinone derivative compound represented by the above general formula (VII) or the compound (r), the compound (v), Alternatively, the method includes a step of allowing compound (w) or a pharmacologically acceptable salt thereof to act. Examples of the naphthoquinone derivative compound represented by the general formula (VII) include a compound (s) and a compound (u). The activity of the imipenem is, for example, antibacterial activity against bacteria. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  Further, the method for enhancing the activity of the naphthoquinone derivative compound according to the present invention includes a naphthoquinone derivative compound represented by the above general formula (VII) or a compound (r), a compound (v), a compound (w), or a pharmacological thereof A method for enhancing the activity of an acceptable salt, comprising the step of causing imipenem to act in cooperation with the naphthoquinone derivative compound. Examples of the naphthoquinone derivative compound represented by the general formula (VII) include a compound (s) and a compound (u). The activity is, for example, an antibacterial activity against bacteria. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  The method for inhibiting bacterial growth according to the present invention is a naphthoquinone derivative compound represented by the above general formula (VIII) or compound (r), compound (v), or compound (w), or a pharmacologically acceptable method thereof. A step of allowing a salt to act. The naphthoquinone derivative compound represented by the general formula (VIII) is, for example, the compound (s). The method for inhibiting bacterial growth according to the present invention may further cause imipenem to act in cooperation. In the method for inhibiting bacterial growth according to the present invention, compound (u) or a pharmacologically acceptable salt thereof and imipenem may be allowed to act in cooperation. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  A method for improving a disease caused by infection or proliferation of a bacterium according to the present invention includes a naphthoquinone derivative compound represented by the above general formula (VIII) or a compound (r), a compound (v), or a compound (w), Or a step of administering to a human or non-human vertebrate (eg, mouse, rat, etc.) so that a pharmacologically acceptable salt thereof acts. The naphthoquinone derivative compound represented by the general formula (VIII) is, for example, the compound (s). The method for improving a disease caused by bacterial infection or proliferation according to the present invention may further cause imipenem to act in cooperation. The method for ameliorating a disease caused by bacterial infection or proliferation according to the present invention may be performed by causing compound (u) or a pharmacologically acceptable salt thereof and imipenem to act in cooperation. The bacterium may be a Gram positive bacterium such as MRSA or a Gram negative bacterium.

  Examples of diseases caused by MRSA infection or proliferation include, for example, encephalitis, pneumonia, sepsis, peritonitis, enteritis, osteomyelitis, cholangitis, cutaneous abscess, pressure ulcer infection, MRSA-produced toxins (for example, enterotoxin, Food poisoning caused by TSST-1), toxic shock syndrome, etc. Examples of the diseases caused by infection or proliferation of the Gram-positive bacteria or Gram-negative bacteria include, for example, addiction, periodontal disease, inflammatory disease, vasculitis, type IV allergic disease, staphylococcal burn-like skin. Syndrome, Rittard's disease, bullous impetigo in neonates, tumor, pneumonia, arthritis, meningitis, various purulent diseases, enteritis, meningitis, bacteremia, eye infection, food poisoning, respiratory infection, otitis media, accessory Rhinitis, pharyngitis, scarlet fever, acute filiform nephritis, rheumatic fever, impetigo, fulminant infection, tooth decay, urinary tract infection, wound infection, biliary tract infection, bacterial atopic disease (atopic) Such as dermatitis).

  According to the present invention, a novel compound useful as an inhibitor of tyrosine phosphatase, and a tyrosine phosphatase inhibitor, pharmaceutical composition, cell growth inhibitor, cell cycle progression inhibitor, antibacterial agent containing the compound as an active ingredient, An imipenem activity enhancer, a bacterial growth inhibitor, an imipenem activity enhancement method using the above-described compound, a bacterial growth inhibition method, and an activity enhancer and activity enhancement method for the above-described compound can be provided. .

  Hereinafter, embodiments of the present invention completed based on the above knowledge will be described in detail with reference to examples. Unless otherwise stated in the embodiments and examples, J. Sambrook, EF Fritsch & T. Maniatis (Ed.), Molecular cloning, a laboratory manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2001); FM Ausubel, R. Brent, RE Kingston, DD Moore, JG Seidman, JA Smith, K. Struhl (Ed.), Standard Protocols in Molecular Biology, John Wiley & Sons Ltd. The method described in the protocol collection, or a modified or modified method thereof is used. In addition, when using commercially available reagent kits and measuring devices, unless otherwise explained, protocols attached to them are used.

  The objects, features, advantages, and ideas of the present invention will be apparent to those skilled in the art from the description of the present specification, and those skilled in the art can easily reproduce the present invention from the description of the present specification. it can. The embodiments and specific examples of the invention described below show preferred embodiments of the present invention and are shown for illustration or explanation, and the present invention is not limited to them. It is not limited. It will be apparent to those skilled in the art that various modifications and variations can be made based on the description of the present specification within the spirit and scope of the present invention disclosed herein.

=== Pharmacological Action of Naphthoquinone Derivative Compound According to the Present Invention ===
As described above, inhibitors of tyrosine phosphatase are used for diseases caused by overexpression or activation of tyrosine phosphatase such as type 2 diabetes, obesity, tumor, neurological disease ((Alzheimer's disease, Parkinson's disease), myeloid leukemia, etc. Therefore, the present inventors investigated whether the above-mentioned compounds (f) to (p) inhibit the enzyme activity of tyrosine phosphatase, and as a result, the compounds (f) to (( p) was found to have excellent inhibitory activity (IC ₅₀ = 10 μg / ml or less) against tyrosine phosphatases such as Cdc25A phosphatase and protein tyrosine phosphatase 1B.

  Therefore, the naphthoquinone derivative compound represented by the above general formula (I) having a structure similar to that of the above compounds (f) to (p), particularly represented by the above general formulas (II) to (IV). The naphthoquinone derivative compound is considered to have a tyrosine phosphatase inhibitory activity such as Cdc25A phosphatase and protein tyrosine phosphatase 1B. Further, pharmacologically acceptable salts of the naphthoquinone derivative compound represented by the above general formula (I) are also considered to have inhibitory activity on tyrosine phosphatases such as Cdc25A phosphatase and protein tyrosine phosphatase 1B. Therefore, the naphthoquinone derivative compound represented by the above general formula (I) or a pharmacologically acceptable salt thereof is useful as an inhibitor of tyrosine phosphatases such as Cdc25A phosphatase and protein tyrosine phosphatase 1B. It is considered useful for prevention or amelioration of diseases caused by overexpression or activation.

  Examples of the disease caused by overexpression or activation of the tyrosine phosphatase include protein tyrosine phosphatase (eg, type 2 diabetes, obesity, tumor, neurological disease (eg, Alzheimer's disease, Parkinson's disease), myeloid leukemia, etc. PTP) 1B overexpression or activation diseases, tumors and other Cdc25A phosphatase overexpression or activation diseases.

By the way, it is known that Cdc25A acts on Cdk2 / CyclinE and Cdk2 / CyclinA, and functions in G ₁ / S transition in cell cycle regulation. Therefore, the present inventors investigated the influence on the progression of the cell cycle using the compounds represented by the above-mentioned compounds (f) to (q). As a result, the compounds of the above (j) and (q) was found to have an excellent inhibitory effect on progression of the G ₁ phase of the cell cycle. From this, in order to inhibit the progression of the G ₁ phase of the cell cycle, in the naphthoquinone derivative compound represented by the above general formula (I), at least R ₁ is a methoxy group and R ₂ is a hydroxyl group. Yes, it is considered necessary that R ₃ is a group having hydroxyl or oxo. Therefore, the naphthoquinone derivative compound represented by the above general formula (VI) having a structure similar to that of the above compounds (j) and (q) and the pharmacologically acceptable salt thereof are G _{1 in} the cell cycle. It is considered useful as a cell cycle progression inhibitor that inhibits the progression of the phase.

  In addition, the present inventors examined the cell growth inhibitory activity using compounds (j) to (q) in order to examine whether the above-mentioned compound inhibits cell proliferation. As a result, it was revealed that the compound (j) and the compounds (m) to (p) have cytostatic activity. Therefore, the naphthoquinone derivative compound represented by the above general formula (V) having a structure similar to that of the above compound (j) and the compounds (m) to (p), and a pharmacologically acceptable salt thereof, It is considered useful as a cell growth inhibitor.

  Furthermore, as a result of the present inventors' extensive efforts, the compounds (r), (s), (v), and (w) alone have an anti-MRSA (methicillin-resistant Staphylococcus aureus) action, the compound (r) , (S), (u), (v), and (w) were acted on MRSA in cooperation with imipenem, and it was revealed that anti-MRSA activity was enhanced. Therefore, the naphthoquinone derivative compound represented by the above general formula (VIII), the compounds (r), (v) and (w), and pharmacologically acceptable salts thereof, and the compound (u) and Mixtures with imipenem are useful for the improvement (including prevention, suppression and treatment) of bacterial infections such as Gram-positive and Gram-negative bacteria such as MRSA, especially MRSA infections such as encephalitis, pneumonia , Sepsis, peritonitis, enteritis, osteomyelitis, cholangitis, cutaneous abscess, pressure ulcer infection, MRSA-producing toxins (eg enterotoxin, TSST-1 etc.), food poisoning, improvement of MRSA infections such as toxic shock syndrome (prevention) , Suppression, and treatment). Further, the naphthoquinone derivative compound represented by the above general formula (VIII), the compounds (r), (v), and (w), and pharmacologically acceptable salts thereof, and the compound (u) and Mixtures with imipenem can also cause infections with Gram-positive or Gram-negative bacteria, such as addiction, periodontal disease, inflammatory disease, vasculitis, type IV allergic disease, staphylococcal burn-like skin syndrome , Ritter disease, bullous impetigo in neonates, tumor, pneumonia, arthritis, meningitis, various purulent diseases, enteritis, meningitis, bacteremia, eye infection, food poisoning, respiratory infection, otitis media, sinus Inflammation, sore throat, scarlet fever, acute filiform nephritis, rheumatic fever, impetigo, fulminant infection, tooth decay, urinary tract infection, wound infection, biliary tract infection, bacterial atopic disease (atopic dermatitis, etc.) ).

  Furthermore, since the anti-MRSA action is enhanced by using the compounds (r), (s), (v), and (w) together with imipenem, the use of these compounds and imipenem is most effective in improving MRSA infection. It can be said that. Therefore, the naphthoquinone derivative compound represented by the above general formula (VII), the compounds (r), (v), and (w), and pharmacologically acceptable salts thereof are used for enhancing imipenem activity. It can be used as a drug or a pharmaceutical composition. A drug or pharmaceutical composition containing both can be used as an antibacterial agent or antibiotic, and is particularly effective against MRSA. At this time, if they are added or administered so as to act cooperatively, the dosage form of the drug or pharmaceutical composition is a single agent even if both are separately formulated. Also good. Here, “to act in cooperation” means that both are added or administered to produce a synergistic effect (for example, MRSA growth inhibitory activity). Therefore, in terms of time, both may be added or administered at the same time, or may be added or administered before and after.

=== Method for Producing Naphthoquinone Derivative Compound According to the Present Invention ===
The naphthoquinone derivative compound according to the present invention can be reacted according to the following reaction process formula, by appropriately combining the steps of the following reaction process formula and conventional methods, or by appropriately changing the substance to be used, Can be manufactured. In addition, the pharmacologically acceptable salt of the naphthoquinone derivative compound according to the present invention, that is, alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (magnesium salt, calcium salt, etc.), other metals Naphthoquinone derivative compounds containing known salts such as salts (such as aluminum salts), inorganic salts (such as hydrochlorides, ammonium salts, amines), and organic salts (such as glucosamine salts) can be produced according to a conventional method.

First, an example of a method for producing a naphthoquinone derivative compound represented by the above general formula (III) (wherein R ₈ is a hydrogen atom or an acyl group) will be described based on reaction process formula 1. In addition, R ₂₁ in the reaction process formula 1 is an acyl group.

<Step 1a: Production of compound (2)>
Compound (1) is dissolved in dimethylformamide and sodium hydride and methyl iodide are added. After stirring, a saturated aqueous ammonium chloride solution was added under ice cooling, and the reaction solution was diluted with ethyl acetate. After washing this with saturated brine, the organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure is purified by chromatography to give compound (2). it can.

<Step 2a: Production of compound (3)>
Compound (2) is dissolved in dichloromethane, and water, t-butyl alcohol and DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) are sequentially added. After stirring, the reaction solution is diluted with chloroform, and a saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound (3) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 3a: Production of compound (k)>
Compound (3) is dissolved in methanol, and aqueous sodium hydroxide solution is added. After stirring, the reaction mixture is diluted with ethyl acetate and washed with hydrochloric acid. The organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure is purified by chromatography, whereby the compound (k) can be obtained.

<Step 4a: Production of compound represented by general formula (IX)>
Carboxylic anhydride (alkanoic anhydride) and pyridine are added to compound (k) and stirred. The compound represented by the general formula (IX) can be obtained by purifying the crude product obtained by distilling off the reaction solution under reduced pressure by chromatography.

Next, an example of a method for producing the naphthoquinone derivative compound represented by the general formula (IV) will be described based on the reaction process formula 2. In addition, R ₉ in the reaction process formula 2 is a propyl group, a butyl group, a hexyl group, or an alkynyloxyalkyl group.

<Step 5a: Production of compound (4)>
Compound (1) is dissolved in dimethylformamide and potassium carbonate and methyl iodide are added. After stirring, the reaction solution is diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. Compound (4) can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 6a: Production of compound represented by general formula (X)>
Compound (4) is dissolved in dimethylformamide, and tetra n-butylammonium iodide (added as necessary), sodium hydride, and R ₉ X (X is a halogen atom) are sequentially added. After stirring, the reaction mixture is diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The compound represented by the general formula (X) can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 7a: Production of compound represented by general formula (IV)>
The compound represented by the general formula (X) is dissolved in a solvent (for example, dichloromethane, 1,4-dioxane, etc.), and water, t-butyl alcohol, and DDQ are sequentially added. After stirring, the reaction mixture is diluted with chloroform and saturated aqueous sodium hydrogen carbonate solution (15 mL) is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. The compound represented by the general formula (IV) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

Moreover, the compound represented by general formula (XVIII) is mentioned as an example of the naphthoquinone derivative compound represented by the above general formula (II), and the production method thereof will be described based on the reaction process formula 3. In the reaction process formula 3, R ₂₂ is an alkyl group, and R ₂₄ is a hydroxyethyl group, a hydroxypropyl group, a hydroxyhexyl group, or an aryl alcohol group.

<Step 8a: Production of compound (5)>
Compound (1) is dissolved in anhydrous tetrahydrofuran, and hydrobromic acid perbromide pyridine complex (Pyr · HBr ₃ ) is added. After stirring, a saturated aqueous sodium thiosulfate solution is added, and the reaction solution is diluted with ethyl acetate. This is washed with saturated saline. The organic layer is dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure is purified by chromatography to give compound (5).

<Step 9a: Production of compound (6)>
Compound (5) is dissolved in dichloromethane, and dimethyl sulfoxide, triethylamine, and sulfur trioxide pyridine complex (SO ₃ · Pyr) are sequentially added. Then, the reaction solution is diluted with chloroform, and a saturated aqueous ammonium chloride solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. Compound (6) can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 10a: Production of compound represented by general formula (XI)>
Compound (6) is dissolved in dimethylformamide and potassium carbonate and alkyl iodide are added. After stirring, the reaction is diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. The compound represented by the general formula (XI) can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 11a: Production of compound represented by general formula (XII)>
After adding dimethyl sulfoxide to sodium hydride and stirring, the reaction solution is diluted with anhydrous tetrahydrofuran. Thereafter, trimethylsulfonium iodide dissolved in dimethyl sulfoxide is added, and then a compound represented by the general formula (XI) dissolved in dimethyl sulfoxide is added and stirred. The reaction mixture is diluted with ethyl acetate and washed with saturated aqueous ammonium chloride. The compound represented by the general formula (XII) can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 12a: Production of compound represented by general formula (XIII)>
In benzene, zinc bromide is heated to reflux, and a compound represented by the general formula (XII) dissolved in benzene is added to the mixture. The reaction mixture is diluted with ethyl acetate and washed with water and saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a crude product of aldehyde.

  Dissolve ethyl diethylphosphonoacetate in anhydrous tetrahydrofuran, add sodium hydride and stir. Thereafter, aldehyde dissolved in anhydrous tetrahydrofuran is added and stirred. Saturated aqueous ammonium chloride solution is added to the reaction solution and diluted with ethyl acetate. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined and dried over anhydrous sodium sulfate. The compound represented by the general formula (XIII) can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 13a: Production of compound represented by general formula (XIV)>
The compound represented by the general formula (XIII) is dissolved in anhydrous tetrahydrofuran, and diisobutylaluminum hydride is added dropwise. Stir after the addition is complete and add hydrochloric acid. The reaction mixture is diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The compound represented by the general formula (XIV) can be obtained by dehydrating the organic layer with anhydrous sodium sulfate and purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 14a: Production of compound represented by general formula (XV)>
The compound represented by the general formula (XIV) is dissolved in dimethylformamide, imidazole and t-butyldimethylsilyl chloride are sequentially added and stirred. The reaction mixture is diluted with ethyl acetate, washed with saturated brine, and the organic layer is dried over anhydrous sodium sulfate. The compound represented by the general formula (XV) can be obtained by purifying the crude product obtained by concentrating the solvent under reduced pressure by chromatography.

<Step 15a: Production of compound represented by general formula (XVI)>
The compound represented by the general formula (XV) is dissolved in anhydrous tetrahydrofuran, and n-butyllithium (hexane solution) is added dropwise. Further, R ₂₃ CHO (R ₂₃ is a methyl group, an ethyl group, a pentyl group, or an aryl group) is added and stirred. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is diluted with ethyl acetate and washed with saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure to obtain a crude product of the compound represented by the general formula (XVI).

<Step 16a: Production of compound represented by general formula (XVII)>
A crude product of the compound represented by the general formula (XVI) is dissolved in dichloromethane, and water, t-butyl alcohol, and DDQ are sequentially added. After stirring, the reaction solution is diluted with chloroform, and a saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. The compound represented by the general formula (XVII) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 17a: Production of compound represented by general formula (XVIII)>
The compound represented by the general formula (XVII) is dissolved in anhydrous tetrahydrofuran, and tetra n-butylammonium fluoride (tetrahydrofuran solution) dissolved in acetic acid is added. After stirring, the reaction solution is diluted with ethyl acetate. Next, it is washed with water and saturated saline, and the organic layer is dehydrated with anhydrous sodium sulfate. The compound represented by the general formula (XVIII) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography. The compound (1) used in the above reaction process formulas 1 to 3 can be produced, for example, according to the method described in the literature (Bull. Chem. Soc. Jpn. 2004, 77, 1925-1930). .

Next, the compound represented by general formula (XXIV) is mentioned as an example of the naphthoquinone derivative compound represented by the above general formula (II), and the production method thereof will be described based on the reaction process formula 4. In the reaction process formula 4, R ₂₂ is an alkyl group, R ₂₅ is a hydroxyalkyl group or an aryl alcohol group, and R ₂₆ is an alkylcarbonyl group.

<Step 18a: Production of compound represented by formula (XIX)>
The compound represented by the general formula (XV) is dissolved in anhydrous tetrahydrofuran, and n-butyllithium (hexane solution) is added dropwise. Further, alkyl aldehyde or aryl aldehyde is added and stirred. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is diluted with ethyl acetate and washed with saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure to obtain a crude secondary alcohol product.

  Dissolve the secondary alcohol in anhydrous tetrahydrofuran and add tetra n-butylammonium fluoride. After stirring, the reaction solution is diluted with ethyl acetate. After washing with water and saturated brine, the organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude product is purified by chromatography and represented by the general formula (XIX). A compound can be obtained.

<Step 19a: Production of compound represented by general formula (XX)>
The compound represented by the general formula (XIX) is dissolved in dichloromethane, and pyridine and acetic anhydride are added. After the stirring, the solvent is distilled off under reduced pressure by azeotropic distillation with toluene, and the resulting residue is purified by chromatography, whereby the compound represented by the general formula (XX) can be obtained.

<Step 20a: Production of compound represented by general formula (XXI)>
The compound represented by the general formula (XX) is dissolved in dichloromethane, and water, t-butyl alcohol, and DDQ are sequentially added. After stirring, the reaction solution is diluted with chloroform, and a saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. The compound represented by the general formula (XXII) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 21a: Production of compound represented by general formula (XXI)>
Boron tribromide is dissolved in dichloromethane, and the compound represented by the general formula (XXI) dissolved in dichloromethane is added and stirred. The reaction mixture is diluted with chloroform, washed with water and saturated brine, and the organic layer is dried over anhydrous sodium sulfate. The compound represented by the general formula (XXII) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 22a: Production of compound represented by general formula (XXIII)>
The compound represented by the general formula (XXII) is dissolved in anhydrous tetrahydrofuran, and dimethyl sulfoxide and IBX (o-Iodoxylbenzoic Acid) are added. After stirring, the reaction mixture is diluted with hexane, filtered through celite, washed with a mixed solvent of hexane: ethyl acetate = 3: 1 and concentrated under reduced pressure. By purifying the obtained crude product by chromatography, a compound represented by the general formula (XXIII) can be obtained.

<Step 23a: Production of compound represented by general formula (XXIV)>
The compound represented by the general formula (XXIII) is dissolved in methanol, and potassium carbonate is added. After stirring, the reaction solution is diluted with ethyl acetate. The organic layer is dehydrated with anhydrous sodium sulfate after washing sequentially with a saturated aqueous ammonium chloride solution and saturated brine. The compound represented by the general formula (XXIV) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

Next, the compound represented by the compound (u) is given as an example of the naphthoquinone derivative compound represented by the above general formula (VII), and the production method thereof will be described based on the reaction process formula 5. In addition, R ₂₂ in the reaction process formula 5 is an alkyl group.

<Step 24a: Production of compound represented by general formula (XXV)>
Zinc bromide is heated to reflux in benzene, and a compound represented by the general formula (XII) dissolved in benzene is added to the mixture. The reaction mixture is diluted with ethyl acetate, washed with water and saturated brine, and the organic layer is dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of aldehyde.

  The obtained aldehyde is dissolved in anhydrous tetrahydrofuran, and methylmagnesium bromide (dissolved in tetrahydrofuran solution) is added dropwise. After stirring, the reaction mixture is diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with ethyl acetate. The organic layers are combined, dehydrated with anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain a crude secondary alcohol product. .

  The obtained secondary alcohol is dissolved in anhydrous tetrahydrofuran, dimethyl sulfoxide and IBX are sequentially added and stirred, and the reaction solution is diluted with hexane. The precipitate was filtered through celite, and the filtrate obtained by washing with a mixed solvent of hexane: ethyl acetate = 3: 1 was concentrated under reduced pressure, and the crude product obtained by purification by chromatography was expressed by the general formula (XXV). Can be obtained.

<Step 25a: Production of compound represented by general formula (XXVI)>
In benzene, the compound represented by the general formula (XXV), ethylene glycol, and 4-toluenesulfonic acid monohydrate are heated to reflux. The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, saturated brine, and the like, and the organic layer is dried over anhydrous sodium sulfate. The compound represented by the general formula (XXVI) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 26a: Production of compound represented by general formula (XXVII)>
The compound represented by the general formula (XXVI) is dissolved in anhydrous tetrahydrofuran, and n-butyllithium is added dropwise. Add n-butyraldehyde and stir. Saturated aqueous sodium hydrogen carbonate solution is added to the reaction mixture, and the mixture is diluted with ethyl acetate and washed with saturated brine. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure to obtain a crude secondary alcohol product.

  The resulting secondary alcohol is dissolved in benzene and 4-toluenesulfonic acid monohydrate is added. After stirring, dilute with ethyl acetate and wash with saturated aqueous sodium hydrogen carbonate solution, saturated brine and the like. The organic layer is dehydrated with anhydrous sodium sulfate, and the solvent is concentrated under reduced pressure to obtain a crude product of pyranonaphthalene.

  The obtained pyranonaphthalene is dissolved in 1,4-dioxane, and water and DDQ are sequentially added. After stirring, the reaction solution is diluted with chloroform, and a saturated aqueous sodium hydrogen carbonate solution is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. The compound represented by the general formula (XXVII) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 27a: Production of compound represented by general formula (XXVIII)>
The compound represented by the general formula (XXVII) is dissolved in methanol, and Pd / C (palladium carbon catalyst) is added. After stirring under a hydrogen stream, the precipitate is filtered through Celite and washed with methanol. A crude product obtained by concentrating the washed filtrate under reduced pressure can be purified by chromatography to obtain a compound represented by the general formula (XXVIII).

<Step 28a: Production of compound represented by general formula (XXIX)>
A compound represented by the general formula (XXVIII) is dissolved in dichloromethane, and pyridine and a hydrobromic acid perbromide pyridine complex (Pyr · HBr ₃ ) are added thereto. After stirring, the reaction solution is diluted with chloroform and hydrochloric acid is added. The organic layer is washed with saturated brine, and the aqueous layer is further washed with chloroform. The organic layers are combined and dehydrated with anhydrous sodium sulfate. The compound represented by the general formula (XXIX) can be obtained by purifying the crude product obtained by distilling off the solvent under reduced pressure by chromatography.

<Step 29a: Production of compound (u)>
A compound represented by the general formula (XXIX) and concentrated hydrochloric acid are heated to reflux in ethanol. The reaction solution is diluted with chloroform, washed with water, and the organic layer is dehydrated with anhydrous sodium sulfate. Compound (u) can be obtained by distilling off the solvent under reduced pressure.

== Pharmaceuticals and pharmaceuticals using naphthoquinone derivative compounds according to the present invention ==
The naphthoquinone derivative compound according to the present invention or a pharmacologically acceptable salt thereof and / or a composition containing imipenem as an active ingredient may be administered as a pharmaceutical to humans or non-human vertebrates, or a reagent. May be used for experiments. The pharmaceutical containing the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention as an active ingredient may be orally administered in the form of tablets, capsules, granules, powders, syrups, etc. Alternatively, it may be administered parenterally by injection into the peritoneal cavity or intravenously into a preparation such as an injection or a suppository. The pharmaceutical preparation containing the naphthoquinone derivative compound or pharmacologically acceptable salt thereof according to the present invention as an active ingredient can be prepared by using conventionally used pharmaceutical additives (for example, excipients, binders, lubricants). , Disintegrating agents, flavoring agents, solvents, stabilizers, etc.).

Hereinafter, it demonstrates in detail using an Example. In Examples, nuclear magnetic resonance spectra ( ¹ H-NMR and ¹³ C-NMR) were measured using JNM GX-400 and EX-270 (manufactured by JEOL). The infrared absorption spectrum was measured using Model A-202 (manufactured by JASCO).

  Silica gel thin layer chromatography used kieselgel 60F254 silica gel (Merck) and colored with phosphomolybdenum sulfate. Silica gel column chromatography used silica gel 60N (manufactured by Kanto Chemical). Each reaction was performed in argon unless otherwise specified.

[Example 1]
<Production of 4-benzyloxy-1,2,5-trimethoxy-7-methoxymethylnaphthalene>
8-Benzyloxy-3-hydroxymethyl-5,6-dimethoxynaphthol (compound (1) in FIG. 1; 159 mg) was dissolved in dimethylformamide (3 mL) and sodium hydride (121 mg) at 0 ° C. And methyl iodide (0.18 mL) were added. After stirring for 1.5 hours, a saturated aqueous ammonium chloride solution was added under ice cooling, and the reaction mixture was diluted with ethyl acetate (20 mL). After washing this with saturated saline (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 1: 1), and 4-benzyloxy-1,2,5-trimethoxy-7-methoxymethylnaphthalene (compound (2) in FIG. 1; 111 mg, 65%) as colorless needles. Got.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.45 (s, 3H), 3.94 (s, 6H), 3.97 (s, 3H), 4.60 (s, 2H), 5.17 (s, 2H), 6.75 (s, 1H ), 6.78 (s, 1H), 7.35 (d, 1H, J = 7.6 Hz), 7.40 (t, 2H, J = 7.6 Hz), 7.59 (d, 2H, J = 7.6 Hz), 7.65 (s, 1H ).

[Example 2]
<Production of 2,5-dimethoxy-7-methoxymethylnaphthalene-1,4-dione>
Compound (2) (78.4 mg) obtained in Example 1 was dissolved in dichloromethane (2 mL), and water (1 mL), t-butyl alcohol (1 mL) and DDQ (135 mg) were added at 0 ° C. Added sequentially. After stirring for 2 hours, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1), and 2,5-dimethoxy-7-methoxymethylnaphthalene-1,4-dione ( Compound (3) in FIG. 1; 47.1 mg, 84%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.46 (s, 3H), 3.86 (s, 3H), 4.01 (s, 3H), 4.54 (s, 2H), 6.07 (s, 1H), 7.34 (s, 1H ), 7.69 (s, 1H).

[Example 3]
<Production of 2-hydroxy-5-methoxy-7-methoxymethylnaphthalene-1,4-dione>
Compound (3) (10.8 mg) obtained in Example 2 was dissolved in methanol (4 mL), and an aqueous sodium hydroxide solution (1 M, 0.25 mL) was added at 0 ° C. After stirring at room temperature for 4 hours, the reaction mixture was diluted with ethyl acetate (30 mL). After washing with 1M hydrochloric acid (10 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 5: 1). As a result, 2-hydroxy-5-methoxy-7-methoxymethylnaphthalene-1,4-dione (compound (k) in FIG. 1; 6.9 mg, 68%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.47 (s, 3H), 4.01 (s, 3H), 4.55 (s, 2H), 6.25 (s, 1H), 7.38 (s, 1H), 7.70 (s. 1H ).

[Example 4]
<Production of 5-methoxy-7-methoxymethyl-1,4-dioxo-2-naphthyl acetate>
Acetic anhydride (0.5 mL) and pyridine (0.1 mL) were added to the compound (k) (5.4 mg) obtained in Example 3 at room temperature. After stirring for 7 hours, the reaction mixture was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-methoxy-7-methoxymethyl-1,4 -Dioxo-2-naphthyl acetate (compound (l) in FIG. 1; 3.0 mg, 49%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.37 (s, 3H), 3.46 (s, 3H), 4.02 (s, 3H), 4.56 (s, 2H), 6.64 (s, 1H), 7.37 (s, 1H ), 7.66 (s. 1H).

[Example 5]
<Production of (5-benzyloxy-4,7,8-trimethoxy-2-naphthyl) -methane-1-ol>
8-Benzyloxy-3-hydroxymethyl-5,6-dimethoxynaphthol (compound (1) in FIG. 2; 120 mg) was dissolved in dimethylformamide (3 mL), and potassium carbonate (383 mg) and Methyl iodide (0.2 mL) was added. After stirring for 10 hours, the reaction solution was diluted with ethyl acetate (25 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give (5-benzyloxy-4,7,8-trimethoxy-2-naphthyl)- Methane-1-ol (compound (4) in FIG. 2; 53.4 mg, 43%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.90 (s, 3H), 3.91 (s, 3H), 3.93 (s, 3H), 4.77 (s, 2H), 5.13 (s, 2H), 6.70 (s, 1H ), 6.72 (s, 1H), 7.34 (d, 1H, J = 7.0 Hz), 7.41 (t, 2H, J = 7.0 Hz), 7.56 (s, 1H), 7.60 (complex, 2H).

[Example 6]
<Production of 4-benzyloxy-7-hexyloxymethyl-1,2,5-trimethoxynaphthalene>
Compound (4) (8.6 mg) obtained in Example 5 was dissolved in dimethylformamide (1 mL), and tetra-n-butylammonium iodide (10 mg), sodium hydride (15 mg), 1-Bromohexane (40 μL) was added sequentially. After stirring at room temperature for 13 hours, the reaction mixture was diluted with ethyl acetate (25 mL). After washing with saturated ammonium chloride aqueous solution (15 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1). To obtain 4-benzyloxy-7-hexyloxymethyl-1,2,5-trimethoxynaphthalene (compound (7) in FIG. 2; 6.6 mg, 62%).
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.88 (t, 3H, J = 6.8 Hz), 1.27-1.42 (complex, 6H), 1.56-1.67 (complex, 2H), 3.50 (t, 2H, J = 6.5 Hz ), 3.90 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.62 (s, 2H), 5.15 (s, 2H), 6.72 (s, 1H), 6.77 (s, 1H) , 7.32-7.44 (complex, 3H), 7.55 (s. 1H), 7.58 (brs, 2H).

[Example 7]
<Production of 7-hexyloxymethyl-2,5-dimethoxynaphthalene-1,4-dione>
Compound (7) (6.6 mg) obtained in Example 6 was dissolved in dichloromethane (1 mL), and water (0.3 mL), t-butyl alcohol (0.3 mL) and DDQ (18.0 mg) were added at 0 ° C. Added sequentially. After stirring at room temperature for 1 hour, the reaction mixture was diluted with chloroform (25 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (5 mL), and the aqueous layer was further washed with chloroform (15 mL), and then the organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1), and 7-hexyloxymethyl-2,5-dimethoxynaphthalene-1,4-dione. (Compound (m) in FIG. 2; 1.3 mg, 33%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.94 (t, 3H, J = 7.0 Hz), 1.26-1.53 (complex, 6H), 1.55-1.68 (complex, 2H), 3.53 (t, 2H, J = 6.5 Hz ), 3.86 (s, 3H), 4.01 (s, 3H), 4.58 (s, 2H), 6.07 (s, 1H), 7.71 (s, 1H).

[Example 8]
<Production of 4-benzyloxy-1,2,5-trimethoxy-7- (prop-2-ynyloxymethyl) naphthalene>
Compound (4) (8.4 mg) obtained in Example 5 was dissolved in dimethylformamide (1 mL), and tetra-n-butylammonium iodide (10 mg), sodium hydride (10 mg), Propargyl bromide (70 μL) was added sequentially. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate (30 mL). After washing with a saturated aqueous ammonium chloride solution (15 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1). To obtain 4-benzyloxy-1,2,5-trimethoxy-7- (prop-2-ynyloxymethyl) naphthalene (compound (8) in FIG. 2; 7.6 mg, 82%). .
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.49 (t, 1H, J = 2.4 Hz), 3.90 (s, 3H), 3.94 (s, 3H), 3.95 (s, 3H), 4.21 (d, 2H, J = 2.4 Hz), 4.73 (s, 2H), 5.15 (s, 2H), 6.73 (s, 1H), 6.76 (s, 1H), 7.32-7.44 (complex, 3H), 7.56 (d, 2H, J = 7.0 Hz), 7.63 (s, 1H).

[Example 9]
<Production of 2,5-dimethoxy-7- (prop-2-ynyloxymethyl) naphthalene-1,4-dione>
Compound (8) (7.6 mg) obtained in Example 8 was dissolved in dichloromethane (1 mL), and water (0.3 mL), t-butyl alcohol (0.3 mL) and DDQ (19.7 mg) were added at 0 ° C. Added sequentially. After stirring at room temperature for 15 minutes, the reaction mixture was diluted with chloroform (30 mL), and saturated aqueous sodium hydrogen carbonate solution (20 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (15 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1), and 2,5-dimethoxy-7- (prop-2-ynyloxymethyl) Naphthalene-1,4-dione (compound (n) in FIG. 2; 3.2 mg, 58%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.51 (t, 1H, J = 2.4 Hz), 3.86 (s, 3H), 4.02 (s, 3H), 4.27 (d, 2H, J = 2.4 Hz), 4.70 ( s, 2H), 6.08 (s, 1H), 7.36 (s, 1H), 7.73 (s, 1H).

[Example 10]
<Production of 4-benzyloxy-1,2,5-trimethoxy-7-[(2-methylpropoxy) methyl] naphthalene>
Compound (4) (11.1 mg) obtained in Example 5 was dissolved in dimethylformamide (1 mL), and tetra-n-butylammonium iodide (10 mg), sodium hydride (10 mg), Isobutyl bromide (70 μL) was added sequentially. After stirring at room temperature for 18 hours, the reaction mixture was diluted with ethyl acetate (25 mL). After washing with a saturated aqueous ammonium chloride solution (10 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1). To give 4-benzyloxy-1,2,5-trimethoxy-7-[(2-methylpropoxy) methyl] naphthalene (compound (9) in FIG. 2; 9.2 mg, 71%).
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.94 (d, 6H, J = 6.5 Hz), 1.94 (m, 1H), 3.26 (d, 2H, J = 6.5 Hz), 3.90 (s, 3H), 3.93 ( s, 3H), 3.94 (s, 3H), 4.63 (s, 2H), 5.15 (s, 2H), 6.72 (s, 1H), 6.78 (s, 1H), 7.32-7.43 (complex, 3H), 7.55 (s, 1H), 7.59 (s, 2H).

[Example 11]
<Production of 2,5-dimethoxy-7-[(2-methylpropoxy) methyl] naphthalene-1,4-dione>
Compound (9) (9.2 mg) obtained in Example 10 was dissolved in dichloromethane (1 mL), and water (0.3 mL), t-butyl alcohol (0.3 mL) and DDQ (23.0 mg) were added at 0 ° C. Added sequentially. After stirring at room temperature for 35 minutes, the reaction mixture was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (20 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (15 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give 2,5-dimethoxy-7-[(2-methylpropoxy) methyl] naphthalene. -1,4-dione (compound (o) in FIG. 2; 2.4 mg, 35%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.96 (d, 6H, J = 4.3 Hz), 1.96 (m, 1H), 3.29 (d, 2H, J = 4.3 Hz), 3.86 (s, 3H), 3.99 ( s, 3H), 4.59 (s, 2H), 6.08 (s, 1H), 7.37 (s, 1H), 7.71 (s, 1H).

[Example 12]
<Production of 4-benzyloxy-1,2,5-trimethoxy-7-propoxymethylnaphthalene>
Compound (4) (11.3 mg) obtained in Example 5 was dissolved in dimethylformamide (1 mL), and sodium hydride (10 mg) and n-propyl iodide (100 μL) were sequentially added at 0 ° C. . After stirring at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate (30 mL). After washing with saturated ammonium chloride aqueous solution (15 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1). To obtain 4-benzyloxy-1,2,5-trimethoxy-7-propoxymethylnaphthalene (compound (10) in FIG. 2; 8.6 mg, 68%).
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.96 (t, 3H, J = 7.6 Hz), 1.58-1.73 (complex, 2H), 3.47 (t, 2H, J = 6.8 Hz), 3.90 (s, 3H), 3.93 (s, 3H), 3.95 (s, 3H), 4.63 (s, 2H), 5.15 (s, 2H), 6.72 (s, 1H), 6.78 (s, 1H), 7.32-7.43 (complex, 3H) , 7.55 (s, 1H), 7.59 (d, 2H, J = 4.9 Hz).

[Example 13]
<Production of 2,5-dimethoxy-7propoxymethylnaphthalene-1,4-dione>
The compound (10) (7.0 mg) obtained in Example 12 was dissolved in 1,4-dioxane (1 mL), and water (0.5 mL) and DDQ (15 mg) were sequentially added at 0 ° C. After stirring at room temperature for 20 minutes, the reaction mixture was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (15 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2,5-dimethoxy-7propoxymethylnaphthalene-1,4-dione (Fig. Compound (p) in 2; 4.8 mg, 76%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.98 (t, 3H, J = 7.6 Hz), 1.59-1.75 (complex, 2H), 3.50 (t, 2H, J = 6.8 Hz), 3.86 (s, 3H), 4.02 (s, 3H), 4.59 (s, 2H), 6.07 (s, 1H), 7.37 (s, 1H), 7.71 (s, 1H).

[Example 14]
<Production of 8-benzyloxy-2-bromo-3-hydroxymethyl-5,6-dimethoxynaphthol>
8-Benzyloxy-3-hydroxymethyl-5,6-dimethoxynaphthol (compound (1) in FIG. 3; 2.42 g) was dissolved in anhydrous tetrahydrofuran (50 mL) and perbromide pyridine hydrobromide at 0 ° C. Complex (Pyr · HBr ₃ ) (2.52 g) was added. After stirring for 1 hour, saturated aqueous sodium thiosulfate solution (30 mL) was added, and the reaction mixture was diluted with ethyl acetate (100 mL). This was washed with saturated brine (20 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 8- Benzyloxy-2-bromo-3-hydroxymethyl-5,6-dimethoxynaphthol (compound (5) in FIG. 3; 2.60 g, 87%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.25 (br, 1H), 3.90 (s, 3H), 3.97 (s, 3H), 4.85 (s, 2H), 5.26 (s, 2H), 6.74 (s, 1H ), 7.44-7.47 (complex, 5H), 7.65 (s, 1H), 9.99 (s, 1H).
¹³ CNMR (67.80 MHz, DMSO-d ₆ ) δ 56.7, 56.9, 60.4, 63.1, 63.8, 71.4, 97.7, 99.6, 101.4, 109.5, 128.3, 128.5, 128.7, 128.9, 135.5, 136.0, 140.1, 148.2, 149.7, 150.1.
IR (disk) 3504, 3354, 3056, 2972, 2940, 2881, 2360, 1612 cm ^-1 .
mp 165 ° C dec. (hexane-EtOAc)

[Example 15]
<Production of 5-benzyloxy-3-bromo-4-hydroxy-7,8-dimethoxynaphthalene-2-carbaldehyde>
Compound (5) (1.35 g) obtained in Example 14 was dissolved in dichloromethane (10 mL), and dimethyl sulfoxide (9 mL), triethylamine (2.7 mL), sulfur trioxide pyridine complex (SO _3. Pyr) (1.51 g) was added sequentially. After 20 minutes, the reaction mixture was diluted with chloroform (200 mL), and saturated aqueous ammonium chloride solution (50 mL) was added under ice cooling. The organic layer was washed with saturated brine (30 mL), and the aqueous layer was further washed with chloroform (100 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform) to give 5-benzyloxy-3-bromo-4-hydroxy-7,8-dimethoxynaphthalene-2 as yellow needles. Carbaldehyde (compound (6) in FIG. 3; 1.24 g, 93%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 3.92 (s, 3H), 3.97 (s, 3H), 5.27 (s, 2H), 6.85 (s, 1H), 7.44-7.47 (complex, 5H), 8.17 (s , 1H), 10.09 (s, 1H), 10.48 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 57.1, 61.5, 72.6, 99.6, 99.8, 103.1, 116.2, 116.3, 128.2, 129.1, 129.2, 131.9, 134.0, 134.3, 148.7, 150.6, 151.6, 151.7, 192.3.
IR (disk) 3303, 2950, 1703, 1606 cm ^-1 .
mp 174 ℃ dec. (hexane-EtOAc)

[Example 16]
<Production of 5-benzyloxy-3-bromo-4,7,8-trimethoxynaphthalene-2-carbaldehyde>
The compound (6) (449 mg) obtained in Example 15 was dissolved in dimethylformamide (10 mL), and potassium carbonate (463 mg) and methyl iodide (0.3 mL) were added at 0 ° C. After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate (50 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (30 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5-benzyloxy-3-bromo-4,7,8 as yellow plate crystals. -Trimethoxynaphthalene-2-carbaldehyde (compound (11) in FIG. 3; 437 mg, 94%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 3.80 (s, 3H), 3.95 (s, 3H), 3.96 (s, 3H), 5.20 (s, 2H), 6.91 (s, 1H), 7.38 (d, 1H , J = 7.2 Hz), 7.43 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 8.50 (s, 1H), 10.50 (s, 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 56.9, 61.5, 61.9, 62.0, 62.1, 72.8, 100.5, 103.3, 113.8, 119.6, 121.4, 127.7, 128.1, 128.6, 129.9, 131.5, 136.3, 138.9, 149.0, 151.0, 154.1, 192.2.
IR (disk) 2943, 2848, 1687, 1612, 1577 cm ^-1 .
mp 129-130 ° C (hexane-EtOAc)

[Example 17]
<Production of 8-benzyloxy-2-bromo-1,5,6-trimethoxy-3-oxirane-2-ylnaphthalene>
Dimethyl sulfoxide (5 mL) was added to sodium hydride (517 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with anhydrous tetrahydrofuran (50 mL). Thereafter, trimethylsulfonium iodide (2.75 g) dissolved in dimethyl sulfoxide (10 mL) was added at 0 ° C., and further 40 minutes later, compound (11) (1.89 g) dissolved in dimethyl sulfoxide (25 mL). And stirred for 45 minutes. The reaction solution was diluted with ethyl acetate (50 mL) and then washed with a saturated aqueous ammonium chloride solution (30 mL). The organic layer was dehydrated with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 8- Benzyloxy-2-bromo-1,5,6-trimethoxy-3-oxiran-2-ylnaphthalene (Compound (12) in FIG. 3; 1.77 g, 92%) was obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 2.72 (dd, 1H, J = 2.8, 6.0 Hz), 3.25 (dd, 1H, J = 4.0, 6.0 Hz), 3.78 (s, 3H), 3.89 (s, 3H ), 3.95 (s, 3H), 4.26 (dd, 1H, J = 2.8, 4.0 Hz), 5.18 (s, 2H), 6.78 (s, 1H), 7.37 (d, 1H, J = 7.2 Hz), 7.43 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.79 (s, 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 51.1, 52.9, 56.9, 61.2, 61.9, 72.6, 100.4, 100.5, 113.5, 114.4, 116.7, 127.7, 128.0, 128.5, 130.8, 136.1, 136.6, 137.3, 143.9, 148.6, 151.1, 153.2.
IR (disk) 2931, 2858, 1612, 1593, 1574 cm ^-1 .
mp 133-134 ° C (hexane-EtOAc)

[Example 18]
<Production of ethyl (2E) -4- [5-benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-enoate>
In benzene (17 mL), zinc bromide (708 mg) was heated to reflux for 40 minutes, and compound (12) (468 mg) dissolved in benzene (10 mL) was added to the mixture. After 20 minutes, the reaction solution was returned to room temperature, diluted with ethyl acetate (30 mL), and washed with water and saturated brine (20 mL each). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of aldehyde.

  Ethyl diethylphosphonoacetate (1.1 mL) was dissolved in anhydrous tetrahydrofuran (10 mL), sodium hydride (216 mg) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hr. Thereafter, an aldehyde dissolved in anhydrous tetrahydrofuran (10 mL) was added at −78 ° C., and the mixture was stirred for 25 minutes. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with ethyl acetate (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give ethyl (2E) -4- [5-benzyloxy-3-bromo-4, 7,8-trimethoxy (2-naphthyl)] but-2-enoate (compound (13) in FIG. 3; 462 mg, 85%) was obtained.

¹ HNMR (270 MHz, CDCl ₃ ) δ 1.27 (t, 3H, J = 7.0 Hz), 3.77 (s, 3H), 3.82 (d, 2H, J = 6.2 Hz), 3.90 (s, 3H), 3.95 ( s, 3H), 4.18 (q, 2H, J = 7.0 Hz), 5.18 (s, 2H), 5.81 (d, 1H, J = 16 Hz), 7.18 (dt, 1H, J = 6.2, 16 Hz), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.74 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.3, 39.5, 56.8, 60.2, 61.1, 61.8, 72.5, 100.1, 116.1, 116.3, 118.4, 122.7, 127.6, 127.9, 128.4, 130.3, 130.5, 136.4, 136.5, 136.7, 140.1, 145.7, 148.4, 151.0, 153.7, 166.2.
IR (film) 2937, 2846, 1716, 1614, 1591, 1573 cm ^-1 .

[Example 19]
<Production of (2E) -4- [5-benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol>
Compound (13) (147 mg) obtained in Example 18 was dissolved in anhydrous tetrahydrofuran (3 mL), and diisobutylaluminum hydride (1.01 M, toluene solution, 1.5 mL) was added dropwise at -78 ° C. After completion of the dropwise addition, the mixture was stirred for 35 minutes, and 4M hydrochloric acid (10 mL) was added to return to 0 ° C. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give pale yellow plate crystals (2E ) -4- [5-Benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol (compound (14) in FIG. 3; 125 mg, 93 %).

¹ HNMR (270 MHz, CDCl ₃ ) δ 1.82 (br, 1H), 3.66 (d, 2H, J = 6.2 Hz), 3.77 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.13 (q, 2H, J = 5.4 Hz), 5.17 (s, 2H), 5.75 (dt, 1H, J = 5.4, 16 Hz), 5.95 (dt, 1H, J = 6.2, 16 Hz), 6.74 (s , 1H), 7.37 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.73 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 39.6, 56.8, 61.1, 61.7, 63.4, 63.5, 72.5, 99.8, 115.8, 116.6, 117.7, 127.6, 127.8, 128.3, 129.5, 129.6, 130.5, 131.0, 131.1, 136.7, 138.5, 148.2, 151.0, 153.3.
IR (disk) 3521, 2902, 2860, 1614, 1589, 1574 cm ^-1 .
mp 104-105 ° C (hexane-EtOAc)

[Example 20]
<1-{(2E) -4- [5-Benzyloxy-3-bromo-4,7,8-trimethoxy (2-naphthyl)] but-2-enyloxy} -1,1,2,2-tetramethyl -1-Production of Silapropane>
Compound (14) (125 mg) obtained in Example 19 was dissolved in dimethylformamide (3 mL), and imidazole (180 mg) and t-butyldimethylsilyl chloride (215 mg) were sequentially added at 0 ° C. Stir for 15 minutes. The reaction mixture was diluted with ethyl acetate (15 mL), washed with saturated brine (10 mL), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by concentrating the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 1-{(2E) -4- [5-benzyloxy-3-bromo- 4,7,8-trimethoxy (2-naphthyl)] but-2-enyloxy} -1,1,2,2-tetramethyl-1-silapropane (compound (15) in FIG. 3; 149 mg, 96%) Got.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.07 (s, 6H), 0.90 (s, 9H), 3.65 (d, 2H, J = 6.8 Hz), 3.76 (s, 3H), 3.89 (s, 3H), 3.94 (s, 3H), 4.19 (q, 2H, J = 5.2 Hz), 5.18 (s, 2H), 5.67 (dt, 1H, J = 5.2, 15 Hz), 5.93 (dt, 1H, J = 6.8, 15 Hz), 6.74 (s, 1H), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.73 (s , 1H).
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ -5.0, 18.5, 25.7, 26.0, 39.6, 56.9, 61.3, 61.7, 63.7, 72.6, 99.9, 115.9, 116.8, 117.7, 127.6, 127.7, 127.9, 128.5, 130.6, 131.6 , 135.3, 136.8, 137.0, 139.0, 148.2, 151.1.
IR (film) 2931, 2894, 2854, 1614, 1591, 1576 cm ^-1 .

[Example 21]
<7-[(2E) -4- (1,1,2,2-tetramethyl-1-silapropoxy) but-2-enyl] -6-hydroxyethyl-2,5-dimethoxynaphthalene-1,4- Production of dione>
The compound (15) (65.3 mg) obtained in Example 20 was dissolved in anhydrous tetrahydrofuran (2 mL), and n-butyllithium (1.59 M, hexane solution, 0.4 mL) was added dropwise at −78 ° C. Further, acetaldehyde (1.0 mL) was added and stirred for 15 minutes. Saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction mixture, the temperature was returned to 0 ° C., diluted with ethyl acetate (30 mL), and washed with saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude product of a secondary alcohol (compound (16) in FIG. 4).

  The crude secondary alcohol product was dissolved in dichloromethane (2 mL), and water (0.2 mL), t-butyl alcohol (0.2 mL), and DDQ (40.1 mg) were sequentially added at 0 ° C. After stirring for 15 minutes, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (5 mL), and the aqueous layer was further washed with chloroform (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and 7-[(2E) -4- (1,1,2,2-tetramethyl-1-sila Propoxy) but-2-enyl] -6-hydroxyethyl-2,5-dimethoxynaphthalene-1,4-dione (compound (a) in FIG. 4; 10.5 mg, 29%) was obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.58 (d, 3H, J = 5.2 Hz), 3.54 (complex, 2H), 3.85 (s, 3H), 3.98 (s, 3H), 4.15 (d, 2H, J = 4.0 Hz), 5.18 (m, 1H), 5.55 (m, 1H), 5.77 (m, 1H), 6.08 (s, 1H), 7.78 (s , 1H).

[Example 22]
<Production of 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxyethyl-2,5-dimethoxynaphthalene-1,4-dione>
Compound (a) (10.5 mg) obtained in Example 21 was dissolved in anhydrous tetrahydrofuran (1.5 mL), and tetra-n-butylammonium fluoride (1.0 M, tetrahydrofuran dissolved in acetic acid (13 μL) at 0 ° C. Solution, 0.2 mL) was added. After stirring at room temperature for 12 hours, the reaction mixture was diluted with ethyl acetate (25 mL). After washing with water (10 mL) and saturated brine (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product on silica gel column chromatography (ethyl acetate). 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxyethyl-2,5-dimethoxynaphthalene-1,4-dione (compound (f) in FIG. 4; 7.4 mg) 95%).
¹ HNMR (400 MHz, CDCl ₃ ) δ 1.59 (d, 3H, J = 7.2 Hz), 3.55 (complex, 2H), 3.88 (s, 3H), 3.97 (s, 3H), 4.12 (d, 2H, J = 4.8 Hz), 5.18 (t, 1H, J = 7.2 Hz), 5.64 (dt, 1H, J = 6.0, 15 Hz), 5.84 (dt, 1H, J = 6.0, 15 Hz), 6.08 (s, 1H ), 7.76 (s, 1H).

[Example 23]
<7-[(2E) -4- (1,1,2,2-tetramethyl-1-silapropoxy) but-2-enyl] -6-hydroxypropyl-2,5-dimethoxynaphthalene-1,4- Production of dione>
The compound (15) (93.9 mg) obtained in Example 20 was dissolved in anhydrous tetrahydrofuran (5 mL), and n-butyllithium (1.59 M, hexane solution, 0.5 mL) was added dropwise at −78 ° C. Further, propionaldehyde (0.23 mL) was added and stirred for 15 minutes. A saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction solution, the temperature was returned to 0 ° C., diluted with ethyl acetate (40 mL), and washed with saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude secondary alcohol product (compound (17) in FIG. 5).

  The crude secondary alcohol product was dissolved in dichloromethane (2 mL), and water (0.8 mL), t-butyl alcohol (0.3 mL), and DDQ (120 mg) were sequentially added at 0 ° C. After stirring for 40 minutes, the reaction solution was diluted with chloroform (25 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (5 mL), and the aqueous layer was further washed with chloroform (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and 7-[(2E) -4- (1,1,2,2-tetramethyl-1-sila Propoxy) but-2-enyl] -6-hydroxypropyl-2,5-dimethoxynaphthalene-1,4-dione (compound (b) in FIG. 5; 24.3 mg, 33%) was obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.05 (s, 6H), 0.88 (s, 9H), 1.04 (t, 3H, J = 8.0 Hz), 1.74 (complex, 2H), 3.53 (d, 2H, J = 6.0 Hz), 3.86 (s, 3H), 3.93 (s, 3H), 4.15 (d, 2H, J = 4.0 Hz), 4.85 (m, 1H), 5.57 (dt, 1H, J = 5.2, 15 Hz ), 5.78 (dt, 1H, J = 5.2, 15 Hz), 6.06 (s, 1H), 7.77 (s, 1H).

[Example 24]
<Production of 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxypropyl-2,5-dimethoxynaphthalene-1,4-dione>
Compound (b) (24.3 mg) obtained in Example 23 was dissolved in anhydrous tetrahydrofuran (3 mL), and tetra-n-butylammonium fluoride (1.0 M, tetrahydrofuran dissolved in acetic acid (33 μL) at 0 ° C. Solution, 0.53 mL) was added. After stirring at room temperature for 11 hours, the reaction mixture was diluted with ethyl acetate (40 mL). After washing with water (15 mL) and saturated brine (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product on silica gel column chromatography (ethyl acetate). 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxypropyl-2,5-dimethoxynaphthalene-1,4-dione (compound (g) in FIG. 5; 13.1 mg 72%).
¹ HNMR (270 MHz, CDCl ₃ ) δ 1.05 (t, 3H, J = 7.2 Hz), 1.75 (complex, 2H), 3.54 (d, 2H, J = 5.4 Hz), 3.87 (s, 3H), 3.94 ( s, 3H), 4.11 (d, 2H, J = 4.8 Hz), 4.86 (m, 1H), 5.65 (dt, 1H, J = 5.4, 15 Hz), 5.83 (dt, 1H, J = 5.4, 15 Hz ), 6.07 (s, 1H), 7.76 (s, 1H).

[Example 25]
<7-[(2E) -4- (1,1,2,2-tetramethyl-1-silapropoxy) but-2-enyl] -6-hydroxyhexyl-2,5-dimethoxynaphthalene-1,4- Production of dione>
The compound (15) (93.5 mg) obtained in Example 20 was dissolved in anhydrous tetrahydrofuran (3 mL), and n-butyllithium (1.59 M, hexane solution, 0.5 mL) was added dropwise at −78 ° C. Further, n-hexylaldehyde (0.60 mL) was added and stirred for 35 minutes. A saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction solution, the temperature was returned to 0 ° C., diluted with ethyl acetate (40 mL), and washed with saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude secondary alcohol product (compound (18) in FIG. 6).

  The crude secondary alcohol product was dissolved in dichloromethane (3 mL), and water (0.5 mL), t-butyl alcohol (0.5 mL), and DDQ (112 mg) were sequentially added at 0 ° C. After stirring for 30 minutes, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (5 mL), and the aqueous layer was further washed with chloroform (15 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and 7-[(2E) -4- (1,1,2,2-tetramethyl-1-sila Propoxy) but-2-enyl] -6-hydroxyhexyl-2,5-dimethoxynaphthalene-1,4-dione (compound (c) in FIG. 6; 49.3 mg, 62%) was obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.05 (s, 6H), 0.88 (s, 9H), 0.91 (complex, 3H), 1.31 (complex, 6H), 1.63 (m, 1H), 1.92 (m, 1H ), 3.52 (d, 2H, J = 5.6 Hz), 3.86 (s, 3H), 3.93 (s, 3H), 4.13 (d, 2H, J = 4.4 Hz), 4.94 (m, 1H), 5.56 (dt , 1H, J = 4.8, 15 Hz), 5.78 (dt, 1H, J = 4.8, 15 Hz), 6.06 (s, 1H), 7.76 (s, 1H).

[Example 26]
<Production of 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxyhexyl-2,5-dimethoxynaphthalene-1,4-dione>
Compound (c) (49.3 mg) obtained in Example 25 was dissolved in anhydrous tetrahydrofuran (3 mL), and tetra-n-butylammonium fluoride (1.0 M, tetrahydrofuran dissolved in acetic acid (50 μL) at 0 ° C. Solution, 0.50 mL) was added. After stirring at room temperature for 15 hours, the reaction mixture was diluted with ethyl acetate (45 mL). After washing with water (15 mL) and saturated brine (10 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.The resulting crude product was subjected to silica gel column chromatography (ethyl acetate). 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxyhexyl-2,5-dimethoxynaphthalene-1,4-dione (compound (h) in FIG. 6; 29.0 mg) 76%).
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.88 (complex, 3H), 1.31 (complex, 5H), 1.68 (complex, 3H), 1.94 (m, 1H), 3.53 (d, 2H, J = 5.9 Hz), 3.87 (s, 3H), 3.93 (s, 3H), 4.11 (d, 2H, J = 4.3 Hz), 4.94 (m, 1H), 5.63 (dt, 1H, J = 5.4, 15 Hz), 5.82 (dt , 1H, J = 5.4, 15 Hz), 6.07 (s, 1H), 7.75 (s, 1H).

[Example 27]
<7-[(2E) -4- (1,1,2,2-tetramethyl-1-silapropoxy) but-2-enyl] -6-hydroxyphenylmethyl-2,5-dimethoxynaphthalene-1,4 -Production of dione>
The compound (15) (92.4 mg) obtained in Example 20 was dissolved in anhydrous tetrahydrofuran (2 mL), and n-butyllithium (1.59 M, hexane solution, 0.6 mL) was added dropwise at −78 ° C. Further benzaldehyde (0.60 mL) was added and stirred for 10 minutes. A saturated aqueous sodium hydrogen carbonate solution (10 mL) was added to the reaction solution, the temperature was returned to 0 ° C., diluted with ethyl acetate (45 mL), and washed with saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude secondary alcohol product (compound (19) in FIG. 7).

  The crude secondary alcohol product was dissolved in dichloromethane (4 mL), and water (1.0 mL), t-butyl alcohol (0.5 mL), and DDQ (94.9 mg) were sequentially added at 0 ° C. After stirring for 35 minutes, the reaction solution was diluted with chloroform (25 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (15 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 7-[(2E) -4- (1,1,2,2- Tetramethyl-1-silapropoxy) but-2-enyl] -6-hydroxyphenylmethyl-2,5-dimethoxynaphthalene-1,4-dione (compound (d) in FIG. 7; 30.4 mg, 25%) Obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.05 (s, 6H), 0.93 (s, 9H), 3.29 (s, 3H), 3.65 (d, 2H, J = 6.4 Hz), 3.93 (s, 3H), 3.93 (s, 3H), 4.05 (d, 1H, J = 11 Hz), 4.17 (d, 2H, J = 3.6 Hz), 5.66 (dt, 1H, J = 4.8, 15 Hz), 5.86 (dt, 1H , J = 4.8, 15 Hz), 6.12 (s, 1H), 6.20 (d, 1H, J = 11 Hz), 7.28-7.42 (complex, 5H), 7.95 (s, 1H).

[Example 28]
<Production of 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxyphenylmethyl-2,5-dimethoxynaphthalene-1,4-dione>
Compound (d) (30.4 mg) obtained in Example 27 was dissolved in anhydrous tetrahydrofuran (2 mL), and tetra-n-butylammonium fluoride (1.0 M, tetrahydrofuran dissolved in acetic acid (50 μL) at 0 ° C. Solution, 0.50 mL) was added. After stirring at room temperature for 4 hours, the reaction mixture was diluted with ethyl acetate (40 mL). After washing with water (15 mL) and saturated brine (10 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate). = 1: 3) and purified by 7-((2E) -4-hydroxybut-2-enyl) -6-hydroxyphenylmethyl-2,5-dimethoxynaphthalene-1,4-dione (in FIG. Compound (i); 14.9 mg, 63%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 3.22 (s, 3H), 3.59 (d, 2H, J = 6.0 Hz), 3.87 (s, 3H), 4.05 (d, 2H, J = 5.6 Hz), 4.09 ( d, 1H, J = 10 Hz), 4.17 (d, 2H, J = 3.6 Hz), 5.63 (dt, 1H, J = 5.6, 15 Hz), 5.80 (dt, 1H, J = 5.6, 15 Hz), 6.06 (s, 1H), 6.13 (d, 1H, J = 10 Hz), 7.22-7.34 (complex, 5H), 7.86 (s, 1H).

[Example 29]
<Production of (2E) -4- [5-benzyloxy-3-hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol>
The compound (15) (1.06 g) obtained in Example 20 was dissolved in anhydrous tetrahydrofuran (30 mL), and n-butyllithium (1.57 M, hexane solution, 3.4 mL) was added dropwise at −78 ° C. Further, n-valeraldehyde (1.0 mL) was added and stirred for 10 minutes. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction mixture, the temperature was returned to 0 ° C., diluted with ethyl acetate (30 mL), and washed with saturated brine (10 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude secondary alcohol product.

  The secondary alcohol was dissolved in anhydrous tetrahydrofuran (20 mL), and tetra n-butylammonium fluoride (1.0 M, tetrahydrofuran solution, 9.0 mL) was added at 0 ° C. After stirring at room temperature for 1.5 hours, the reaction mixture was diluted with ethyl acetate (30 mL). After washing with water (10 mL) and saturated brine (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate). = 3: 1) and purified by (2E) -4- [5-benzyloxy-3-hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-en-1-ol ( Compound (20) in FIG. 8; 693 mg, 80%) was obtained.

¹ HNMR (270 MHz, CDCl ₃ ) δ 0.92 (t, 3H, J = 6.2 Hz), 1.37-1.39 (complex, 2H), 1.63-1.80 (complex, 2H), 1.92-2.04 (complex, 2H), 3.57 (d, 2H, J = 5.4 Hz), 3.80 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H), 4.09 (d, 2H, J = 5.6 Hz), 4.99 (m, 1H) , 5.15 (d, 2H, J = 12 Hz), 5.64 (dt, 1H, J = 5.6, 15 Hz), 5.91 (dt, 1H, J = 5.4, 15 Hz), 6.73 (s, 1H), 7.36 ( d, 1H, J = 7.2 Hz), 7.41 (t, 2H, J = 7.2 Hz), 7.53 (d, 2H, J = 7.2 Hz), 7.65 (s, 1H).
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.2, 22.8, 29.2,36.6, 39.0, 50.3, 56.9, 61.1, 63.4, 64.0, 71.1, 72.9, 100.3, 113.7, 115.1, 118.2, 127.4, 127.8, 128.4, 130.7, 131.0, 131.2, 136.8, 136.9, 137.0, 147.9, 151.1, 154.8, 163.6.
IR (film) 3408, 2933, 2858, 1620, 1574 cm ^-1 .

[Example 30]
<Production of (2E) -4- [5-benzyloxy-3-hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-enyl acetate>
The compound (20) (111 mg) obtained in Example 29 was dissolved in dichloromethane (5 mL), and pyridine (36 μL) and acetic anhydride (15 μL) were added in an ice bath. After stirring at room temperature for 2 days, the solvent was distilled off under reduced pressure by azeotropic distillation with toluene, and the resulting residue was purified by silica gel column chromatography (ethyl acetate) to obtain (2E) -4- [5-benzyloxy-3 -Hydroxypentyl-4,7,8-trimethoxy (2-naphthyl)] but-2-enyl acetate (compound (21) in FIG. 8; 70.5 mg, 58%) was obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.93 (t, 3H, J = 6.8 Hz), 1.34-1.44, (complex, 4H), 1.63-1.83 (complex, 2H), 2.04 (s, 3H), 3.62 ( d, 2H, J = 6.4 Hz), 3.80 (s, 3H), 3.90 (s, 3H), 3.94 (s, 3H), 4.55 (d, 2H, J = 6.4 Hz), 5.01 (m, 1H), 5.12 (d, 1H, J = 11 Hz), 5.19 (d, 1H, J = 11 Hz), 5.61 (dt, 1H, J = 6.4, 15 Hz), 6.01 (dt, 1H, J = 6.0, 15 Hz ), 6.74 (s, 1H), 7.36 (d, 1H, J = 7.2 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.53 (d, 2H, J = 7.2 Hz), 7.66 (s, 1H )
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 14.2, 21.0, 22.7, 29.2, 36.4, 38.9, 56.9, 61.0, 63.9, 64.8, 70.9, 72.8, 100.2, 115.0, 118.3, 125.4, 127.4, 127.8, 128.2, 128.4, 130.9, 131.2, 134.2, 136.6, 136.8, 137.0, 147.9, 151.1, 154.8, 170.6.
IR (film) 3480, 2933, 2857, 1739, 1620, 1573 cm ^-1

[Example 31]
<Production of (2E) -4- [3-hydroxypentyl-4,7-dimethoxy-5,8-dioxo (2-naphthyl)] but-2-enyl acetate>
Compound (21) (60.4 mg) obtained in Example 30 was dissolved in dichloromethane (4 mL), and water (2 mL), t-butyl alcohol (2 mL), and DDQ (83.4 mg) were added at 0 ° C. Added sequentially. After stirring for 20 minutes, the reaction solution was diluted with chloroform (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate), and (2E) -4- [3-hydroxypentyl-4,7-dimethoxy-5,8-dioxo ( 2-Naphthyl)] but-2-enyl acetate (compound (v) in FIG. 8; 37.4 mg, 78%) was obtained.

¹ HNMR (400 MHz, CDCl ₃ ) δ 0.90 (t, 3H, J = 7.2 Hz), 1.28-1.37, (complex, 4H), 1.57-1.68 (complex, 2H), 2.03 (s, 3H), 3.56 ( d, 2H, J = 6.4 Hz), 3.85 (s, 3H), 3.91 (s, 3H), 4.51 (d, 2H, J = 6.0 Hz), 4.94 (m, 1H), 5.58 (dt, 1H, J = 6.4, 15 Hz), 5.88 (dt, 1H, J = 6.0, 15 Hz), 6.06 (s, 1H), 7.74 (s, 1H)
¹³ CNMR (100.40 MHz, CDCl ₃ ) δ 14.1, 20.9, 22.6, 28.8, 36.3, 37.7, 56.3, 63.4, 64.4, 70.5, 111.7, 125.1, 126.6, 126.8, 127.4, 128.4, 131.7, 132.1, 144.3, 158.7, 170.6. 179.6, 183.7.
IR (film) 3502, 2935, 1737, 1683, 1648, 1619 cm ^-1

[Example 32]
<Production of (2E) -4- [4-hydroxy-3-hydroxypentyl-7-methoxy-5,8-dioxo (2-naphthyl)] but-2-enyl acetate>
Boron tribromide (1M, dichloromethane solution, 0.22 mL) was dissolved in dichloromethane (5 mL), and compound (v) (83.2 mg) dissolved in dichloromethane (3.5 mL) was added at −78 ° C. for 25 minutes. Stir. The reaction mixture was diluted with chloroform (15 mL), washed with water and saturated brine (10 mL each), and the organic layer was dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel thin layer chromatography (hexane: ethyl acetate = 1: 2) to give (2E) -4- [4-hydroxy-3-hydroxypentyl-7. -Methoxy-5,8-dioxo (2-naphthyl)] but-2-enyl acetate (compound (w) in FIG. 8; 23.7 mg, 29%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.90 (t, 3H, J = 6.8 Hz), 1.33-1.42 (complex, 4H), 1.50-1.76 (complex, 2H), 2.05 (s, 3H), 3.50 (d , 2H, J = 5.8 Hz), 3.92 (s, 3H), 4.52 (d, 2H, J = 6.2 Hz), 4.86 (m, 1H), 5.59 (dt, 1H, J = 5.8, 15 Hz), 5.87 (dt, 1H, J = 6.2, 15 Hz), 6.07 (s, 1H), 7.48 (s, 1H), 13.11 (s, 1H)
¹³ CNMR (67.80 MHz, CDCl ₃ ) δ 14.1, 21.0, 22.7, 28.6, 36.3, 36.4, 49.2, 49.3, 56.7, 64.4, 70.6, 109.3, 121.7, 126.8, 129.0, 131.6, 138.4, 144.4, 159.5, 161.0, 190.7, 206.5.
IR (film) 3534, 2956, 1739, 1683, 1625 cm ^-1

[Example 33]
<Production of (2E) -4- (4-hydroxy-7-methoxy-5,8-dioxo-3-pentanoyl (2-naphthyl)) but-2-enyl acetate>
The compound (w) (2.6 mg) obtained in Example 32 was dissolved in anhydrous tetrahydrofuran (0.9 mL), and dimethyl sulfoxide (0.1 mL) and IBX (20.6 mg) were added at 0 ° C. After stirring at room temperature for 7 hours, the reaction solution was diluted with hexane (20 mL). The precipitate was filtered through Celite, and the filtrate obtained by washing with a mixed solvent of hexane: ethyl acetate = 3: 1 was concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1). (2E) -4- (4-hydroxy-7-methoxy-5,8-dioxo-3-pentanoyl (2-naphthyl)) but-2-enyl acetate (compound (e) in FIG. 8; 2.7 mg) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.94 (t, 3H, J = 7.3 Hz), 1.37 (complex, 2H), 1.68 (complex, 2H), 2.11 (s, 3H), 2.86 (t, 2H, J = 7.6 Hz), 3.36 (d, 2H, J = 6.2 Hz), 3.93 (s, 3H), 4.52 (d, 2H, J = 6.2 Hz), 5.62 (dt, 1H, J = 5.9, 15 Hz), 5.81 (dt, 1H, J = 5.9, 15 Hz), 6.11 (s, 1H), 7.52 (s, 1H), 12.5 (s. 1H).

[Example 34]
<Production of 7-((2E) -4-hydroxybut-2-enyl) -5-hydroxy-2-methoxy-6-pentanoylnaphthalene-1,4-dione>
The compound (e) (2.7 mg) obtained in Example 33 was dissolved in methanol (1 mL), and potassium carbonate (11.3 mg) was added at 0 ° C. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with ethyl acetate (30 mL). After washing with saturated aqueous ammonium chloride (10 mL) and saturated brine (5 mL), the organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. : Ethyl acetate = 1: 1) and purified by 7-((2E) -4-hydroxybut-2-enyl) -5-hydroxy-2-methoxy-6-pentanoylnaphthalene-1,4-dione ( The compound (j) in FIG. 8; 2.3 mg, 96%) was obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.94 (t, 3H, J = 7.3 Hz), 1.34 (complex, 2H), 1.67 (complex, 2H), 2.87 (t, 2H, J = 7.3 Hz), 3.35 ( d, 2H, J = 5.4 Hz), 3.93 (s, 3H), 4.20 (complex, 2H), 5.64-5.83 (complex, 2H), 6.11 (s, 1H), 7.53 (s, 1H), 12.5 (s .1H).

[Example 35]
<Preparation of GST-Cdc25A>
PGEX-2T-hcdc25A was prepared by incorporating cDNA of human cdc25A (hcdc25A) into pGEX-2T (Amersham Biosciences), a GST fusion protein expression vector. Each E. coli BL21 strain transformed with these plasmids was cultured at 37 ° C. until OD ₆₀₀ = 0.6 to 0.8, and 0.1 mM isopropyl-1-thio-β-D-thiogalactopyranoside (IPTG) ( GST-Cdc25A protein expression was induced by adding Stratagene). After further culturing at 37 ° C. for 4 hours, the cells were collected and solubilized solution (MT-PBS (150 mM NaCl, 20 mM Na ₂ HPO ₄ , 4 mM NaH ₂ PO ₄ ), 0.1% Triton X-100, 10 μg / mL leupeptin And suspended in 1 mM phenylmethylsulfonyl fluoride (PMSF). The suspended Escherichia coli was disrupted with an ultrasonic crusher, and then a soluble fraction was obtained by centrifugation. Glutathione agarose (SIGMA) equilibrated with MT-PBS was added to this soluble fraction, and GST-Cdc25A was adsorbed at 4 ° C. for 1 hour. Glutathione agarose was collected by centrifugation, washed 4 times with MT-PBS, and then stirred with eluate (50 mM Tris-HCl (pH 8.0), 20 mM reduced glutathione) at 4 ° C. for 1 hour to give GST-Cdc25A. Was eluted. Thereafter, the supernatant was collected by centrifugation and used as an enzyme (GST-Cdc25A) in the following examples.
In addition, PP1B (BIOMOL Research Laboratories) and PP2A (Promega) were used in the following examples as enzymes.

[Example 36]
<Phosphatase assay>
The compounds (f) to (p) obtained by the above examples, the compound (q) and the compound represented by the following formula (x) (hereinafter referred to as “compound (x)”). The inhibitory effect on phosphatase activity was investigated. In this example, as the substrate for Cdc25A, 3-O-methylfluorescein phosphate (OMFP (manufactured by SIGMA)) and 4-nitrophenyl phosphate (4-nitrophenyl phosphate; pNPP (manufactured by SIGMA)) PNPP was used as a substrate for PTP1B and PP2A.

<When pNPP is used>
Enzyme (Cdc25A, PTP1B and PP2A) 30 μl (30 μg) and each concentration of compound (compounds (f) to (q), compound (x) and Na ₃ VO ₄ (used as a phosphatase inhibitor positive control)) 1 μl The suspension was in 60 μl of assay buffer (50 mM Tris-HCl (pH 7.5)) and pre-incubated for 15 minutes at room temperature. Thereto was added 10 μl of substrate (5 mM pNPP) and reacted at 37 ° C. for 60 minutes. Thereafter, the absorbance at a wavelength of 405 nm was measured using MICRO PLATE READER (manufactured by TOSOH), and the inhibitory activity of the compound on each enzyme (Cdc25A, PTP1B, and GST-PP2A) was evaluated. The inhibition activity was evaluated by calculating the inhibition rate (%).

<When using an OMFP>
Enzyme (Cdc25A) 30 μl (15 μg) and each concentration of compound (compounds (f) to (q), compound (x) and Na ₃ VO ₄ ) 1 μl in assay buffer (50 mM Tris-HCl (pH 7.5)) 60 μl And preincubated for 15 minutes at room temperature. Thereto was added 10 μl of substrate (25 μM OMFP at a final concentration), and reacted at room temperature for 30 minutes. Thereafter, the amount of 3-O-methylfluorescein produced (excitation wavelength 355 nm, absorption wavelength 538 nm) was measured using Fluoroskan Ascent (manufactured by Labsystem), and the inhibitory activity of the compound on the enzyme (Cdc25A) was evaluated. The inhibition activity was evaluated by calculating the inhibition rate (%).

The results are shown in Table 1. In addition, each numerical value shown in Table 1 indicates the value of IC ₅₀ (μg / ml) (however, Na ₃ VO ₄ is expressed in μM).

  As shown in Table 1, compound (q) exhibits inhibitory activity against Cdc25A only when a specific substrate (pNPP) is used, and compound (x) exhibits inhibitory activity only against Cdc25A, and otherwise inhibits. No activity was found. On the other hand, it was found that the compounds (f) to (p) showed inhibitory activity only on tyrosine phosphatases (Cdc25A and PTP1B) and did not show inhibitory activity on protein phosphatase (PP2A). These facts revealed that the compounds (f) to (p) are useful as inhibitors that specifically inhibit tyrosine phosphatase.

[Example 37]
<Cell cycle analysis>
Cdc25A is a phosphatase that acts on Cdk2 / CyclinE and Cdk2 / CyclinA, and is known to be necessary for G ₁ / S transition in cell cycle regulation. Therefore, it was examined whether compounds (f) to (q) and compound (x) that inhibit Cdc25A phosphatase inhibit cell cycle progression.

NIH3T3 cells, which are 5 × 10 ⁵ mouse fibroblasts, were cultured in Dulbecco's modified Eagle medium (DMEM; 10 ml) containing 0.2% fetal bovine serum (manufactured by MOREGATE) for 2 days and synchronized with the stationary phase. Thereafter, each compound (compounds (f) to (q), compound (x) and Na ₃ VO ₄ ) dissolved in methanol is added to a final concentration of 3 μg / mL (Na ₃ VO ₄ is 10 or 100 μM). After incubation for 15 minutes, fetal bovine serum was added to a final concentration of 10%. After serum stimulation, cells cultured for 20 hours were collected and suspended in 1 ml phosphate buffer solution. As a control, the cells were cultured after adding an equal amount of methanol not containing each compound, stimulated with fetal calf serum, and then cultured for 0 hour (G0) or 20 hours (20 hours). Then, each suspended in 1 ml phosphate buffer solution was prepared. After suspension, the content of DNA stained by adding 50 μg of propidium iodide (manufactured by WAKO) was measured with a flow cytometer (EPICS ALTRA: manufactured by BECKMAN COULTER). The result is shown in FIG.

As shown in FIG. 9, the compound (j) and (q) was found to have the effect of halting the progression in G ₁ phase of the cell cycle. Therefore, the degree of inhibition of cell cycle progression at each concentration (1, 3, 10 μg / mL) was evaluated using compounds (j) and (q) by the same method as described above. As shown in FIG. 10, compound (j) and (q) is to be able to inhibit the progress of the G ₁ phase of the cell cycle at least 3 [mu] g / mL revealed.

[Example 38]
<Inhibitory effect on cell proliferation>
Next, in order to examine the inhibitory effect on the cell proliferation of the compounds (f) to (q), an MTT assay was performed using the compounds (j) to (q). To a 48-well plate, 500 μl each of NIH3T3 cell suspension (1 × 10 ⁵ cells / ml; DMEM containing 10% fetal calf serum) was added, cultured at 37 ° C. for 24 hours, and each compound dissolved in methanol ( 5 μL of a solution (0.03, 0.1, 0.3, 1, 3 mg / mL) of compound (j) to (q)) was added and cultured at 37 ° C. for 48 hours (as a control, 5 μL of methanol alone was added) What was cultured for 48 hours at 37 degreeC was prepared.). Thereafter, MTT (3- (4,5-dimethlthiazol-2-yl) -2,5-diphenyltetrazolium bromide; Sigma) solution (adjusted to 5 mg / ml with PBS ⁻ ) was added in a volume of 25 μl, and the solution was added at 37 ° C. Incubate for hours. After incubation, remove the medium, dissolve formazan precipitate (dark blue insoluble substance in which yellow water-soluble MTT is reduced by succinate dehydrogenase present in the mitochondria of cells) with 500 μl of dimethyl sulfoxide, and microplate Absorbance (measurement wavelength 570 nm, reference side 620 nm) was measured using a reader (Tosoh Corporation) to evaluate the growth inhibitory action.

The results are shown in Table 2. In addition, in order to confirm whether or not cell death was caused in the cells stimulated with each compound, the morphology of the cells was observed with a microscope.

  As shown in Table 2, compound (j) and compounds (m) to (p) have an action of inhibiting cell growth, and particularly compound (j) has an excellent action of inhibiting cell growth. It became clear that Moreover, it became clear by the morphological observation of a microscope that cell death is caused when a large amount of compound (j) or any of compounds (n) to (q) is used.

[Example 39]
<Production of 1- (5-benzyloxy-3-bromo-4,7,8-trimethoxy-2-naphthyl) acetone>
In benzene (6 mL), zinc bromide (257 mg) was heated to reflux for 30 minutes, and compound (12) (153 mg) dissolved in benzene (5 mL) was added to the mixture. After 1.5 hours, the reaction solution was returned to room temperature, diluted with ethyl acetate (35 mL), and washed with water and saturated brine (15 mL each). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of aldehyde.

  The crude product of aldehyde was dissolved in anhydrous tetrahydrofuran (5 mL), and methylmagnesium bromide (0.93 M, tetrahydrofuran solution, 2 mL) was added dropwise at −20 ° C. After stirring for 30 minutes while gradually raising the temperature, the reaction mixture was diluted with ethyl acetate (20 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (5 mL), and the aqueous layer was further washed with ethyl acetate (20 mL) .The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. A crude product of a secondary alcohol was obtained.

The crude secondary alcohol product was dissolved in anhydrous tetrahydrofuran (2.7 mL), and dimethyl sulfoxide (0.3 mL) and IBX (353 mg) were successively added at 20 ° C. After stirring at room temperature for 23 hours, the reaction solution was diluted with hexane (20 mL). The precipitate was filtered through celite, and the filtrate obtained by washing with a mixed solvent of hexane: ethyl acetate = 3: 1 was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1). Purification gave 1- (5-benzyloxy-3-bromo-4,7,8-trimethoxy-2-naphthyl) acetone (compound (22) in FIG. 11; 99.2 mg, 63%).
¹ HNMR (270 MHz, CDCl ₃ ) δ 2.25 (s, 3H), 3.77 (s, 3H), 3.90 (s, 3H), 3.95 (s, 3H), 4.03 (s, 2H), 5.18 (s, 2H ), 6.77 (s, 1H), 7.35-7.45 (complex, 3H), 7.56 (d, 2H, J = 7.0 Hz), 7.76 (s. 1H).

[Example 40]
<Production of 8-benzyloxy-2-bromo-1,5,6-trimethoxy-3- (2-methyl (1,3-dioxolan-2-yl) methyl) naphthalene>
In benzene (30 mL), compound (22) (761 mg), ethylene glycol (1.0 mL) and 4-toluenesulfonic acid monohydrate (663 mg) were heated to reflux for 4 hours. The reaction solution is allowed to return to room temperature, diluted with ethyl acetate (35 mL), washed with saturated aqueous sodium hydrogen carbonate solution (20 mL) and saturated brine (10 mL), and the organic layer is dehydrated with anhydrous sodium sulfate, and then the solvent. Was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 8-benzyloxy-2-bromo-1,5,6-trimethoxy-3- (2-Methyl (1,3-dioxolan-2-yl) methyl) naphthalene (Compound (23) in FIG. 11; 765 mg, 92%) was obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 1.43 (s, 3H), 3.37 (s, 2H), 3.78 (s, 4H), 3.90 (s, 3H), 3.95 (s, 3H), 5.18 (s, 2H ), 6.75 (s, 1H), 7.36 (d, 1H, J = 7.6 Hz), 7.42 (t, 2H, J = 7.2 Hz), 7.57 (d, 2H, J = 7.6 Hz) 7.91 (s, 1H) .

[Example 41]
<Production of 7,10-dimethoxy-3-methyl-1-propylbenzo [2,1-g] isochromene-6,9-dione>
Compound (23) (432 mg) was dissolved in anhydrous tetrahydrofuran (10 mL), and n-butyllithium (1.56 M, hexane solution, 2.8 mL) was added dropwise at -78 ° C. Further, n-butyraldehyde (1.2 mL) was added and stirred for 10 minutes. Saturated aqueous sodium hydrogen carbonate solution (15 mL) was added to the reaction solution, the temperature was returned to 0 ° C., diluted with ethyl acetate (35 mL), and washed with saturated brine (10 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude secondary alcohol product.

  The crude secondary alcohol product was dissolved in benzene (15 mL), and 4-toluenesulfonic acid monohydrate (396 mg) was added at 0 ° C. The mixture was stirred at room temperature for 10 minutes, diluted with ethyl acetate (25 mL), and washed with saturated aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (5 mL). The organic layer was dehydrated with anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to obtain a crude product of pyranonaphthalene.

  The crude product of pyranonaphthalene was dissolved in 1,4-dioxane (4 mL), and water (1 mL) and DDQ (362 mg) were sequentially added at 0 ° C. After stirring for 40 minutes, the reaction solution was diluted with chloroform (25 mL), and saturated aqueous sodium hydrogen carbonate solution (15 mL) was added. The organic layer was washed with saturated brine (10 mL), and the aqueous layer was further washed with chloroform (20 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and 7,10-dimethoxy-3-methyl-1-propylbenzo [2,1 -g] Isochromene-6,9-dione (compound (r) in FIG. 1; 75.5 mg, 27%) was obtained.

¹ HNMR (270 MHz, CDCl ₃ ) δ 0.95 (t, 3H, J = 7.0 Hz), 1.38-1.58 (complex, 3H), 1.96 (s, 3H), 2.04 (m, 1H), 3.86 (s, 3H ), 3.88 (s, 3H), 5.76 (dd, 1H, J = 3.0, 9.5 Hz), 5.66 (s, 1H), 6.03 (s, 1H), 7.47 (s. 1H).

[Example 42]
<Production of 7,10-dimethoxy-3-methyl-1-propylbenzo [2,1-g] isochroman-6,9-dione>
Compound (r) (36.2 mg) was dissolved in methanol (3 mL), and Pd / C (10 mg) was added. After stirring for 1 hour at room temperature under a hydrogen stream, the precipitate was filtered through Celite, and the filtrate obtained by washing with methanol was concentrated under reduced pressure. The crude product obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1). And purified 7,10-dimethoxy-3-methyl-1-propylbenzo [2,1-g] isochroman-6,9-dione (compound (s) in FIG. 11; 31.3 mg, 86%). Obtained.
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.88 (t, 3H, J = 7.3 Hz), 1.00 (t, 3H, J = 7.3 Hz), 1.34 (d, 2H, J = 5.9 Hz), 1.35 (d, 2H, J = 6.2 Hz), 1.20-2.05 (complex, 8H), 2.66-2.87 (complex, 4H), 3.64 (m, 1H), 3.84 (s, 3H), 3.87 (s, 3H), 3.88 (s , 6H), 4.05 (m, 1H), 5.00 (dd, 1H, J = 3.2, 9.7 Hz), 5.06 (d, 1H, J = 3.5 Hz), 6.07 (s, 2H), 7.69 (s, 1H) , 7.70 (s. 1H).

[Example 43]
<Production of 8-bromo-7,10-dimethoxy-3-methyl-1-propylbenzo [1,2-g] isochroman-6,9-dione>
The compound (s) (31.3 mg) was dissolved in dichloromethane (2 mL), and pyridine (30 μL) and hydrobromide perbromide pyridine complex (Pyr · HBr ₃ ) (42.4 mg) were added at 0 ° C. After stirring at room temperature for 4 hours, the reaction mixture was diluted with chloroform, and 1M hydrochloric acid (15 mL) was added. The organic layer was washed with saturated brine (5 mL), and the aqueous layer was further washed with chloroform (15 mL), and then the organic layers were combined and dried over anhydrous sodium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1), and 8-bromo-7,10-dimethoxy-3-methyl-1-propylbenzo [1,2-g] isochroman-6,9-dione (compound (t) in FIG. 11; 16.8 mg, 36%) and compound (s) (12.3 mg, 39%) were obtained.
¹ HNMR (400 MHz, CDCl ₃ ) δ 0.88 (t, 3H, J = 7.3 Hz), 1.00 (t, 3H, J = 7.3 Hz), 1.34 (d, 2H, J = 5.9 Hz), 1.35 (d, 2H, J = 6.2 Hz), 1.31-2.04 (complex, 8H), 2.67-2.86 (complex, 4H), 3.76 (m, 1H), 3.84 (s, 3H), 3.87 (s, 3H), 4.05 (m , 1H), 4.25 (s, 6H), 5.00 (dd, 1H, J = 3.6, 11 Hz), 5.06 (m, 1H), 7.63 (s, 1H), 7.64 (s. 1H).

[Example 44]
<Production of 8-chloro-7,10-dihydroxy-3-methyl-1-propylbenzo [1,2-g] isochroman-6,9-dione>
In ethanol (2 mL), compound (t) (3.8 mg) and concentrated hydrochloric acid (4 mL) were heated to reflux for 15 hours. The reaction solution was returned to room temperature, diluted with chloroform (40 mL), washed with water (30 mL), and the organic layer was dehydrated with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product of chloronaphthoquinone (compound (u) in FIG. 1).
¹ HNMR (270 MHz, CDCl ₃ ) δ 0.88 (t, 3H, J = 7.3 Hz), 1.00 (t, 3H, J = 7.2 Hz), 1.34 (d, 2H, J = 6.0 Hz), 1.35 (d, 2H, J = 6.1 Hz), 1.25-2.05 (complex, 8H), 2.61-2.81 (complex, 4H), 3.65 (m, 1H), 4.03 (m, 1H), 5.02 (complex, 2H), 7.43 (s , 2H), 12.4 (s. 1H), 12.6 (s, 1H).

[Example 45]
<Antimicrobial activity against MRSA and imipenem activity enhancing effect>
In this example, clinically isolated MRSA K24 strain was used as a test bacterium. The assay plate was prepared by adding 1.5% Agar (Shimizu Foods Co., Ltd.) to Mueller-Hinton Broth (DIFCO), and imipenem (Ayu Pharmaceutical Co., Ltd. An assay plate prepared by adding an infusion titer of 0.5) to a final concentration of 10 μg / mL was used. The inoculum used was an assay bacterial culture that had been cultured overnight in Mueller-Hinton Broth, prepared in the same medium to 0.5 Mc Farand (about 10 ⁸ cfu / mL). This inoculum was smeared on each plate with a sterile cotton swab according to the NCCLS method. The antibacterial activity on each plate against the test bacteria was determined by the paper disk method using a 6 mm paper disk soaked with 10 μg of a methanol solution of the test drug (compounds (r), (s), (v), and (w)). Was placed on each plate and cultured at 37 ° C. for 20 hours. Thereafter, as an index of antibacterial activity against the test bacteria, the inhibition circle diameter (diameter (mm) passing through the center of the paper disk) in the plate was measured.

The results are shown in Table 3.

  As shown in Table 3, it was revealed that the compounds (r), (s), (v), and (w) had an anti-MRSA action alone. In addition, 10 μg / mL imipenem alone has no anti-MRSA effect, but when compounds (r), (s), (u), (v), and (w) are allowed to act on the test bacteria in cooperation with imipenem. It was revealed that the anti-MRSA action is enhanced. Therefore, the compounds (r), (s), (u), (v), and (w) have an action of enhancing the activity of imipenem, or the action of imipenem to enhance the activity of these compounds. It was suggested to have

In one Example of this invention, it is a figure which shows the manufacturing process of compound (k) and (l). In one Example of this invention, it is a figure which shows the manufacturing process of compound (m)-(p). In one Example of this invention, it is a figure which shows the manufacture process of a compound (15). In one Example of this invention, it is a figure which shows the manufacture process of a compound (f). In one Example of this invention, it is a figure which shows the manufacture process of a compound (g). In one Example of this invention, it is a figure which shows the manufacture process of a compound (h). In one Example of this invention, it is a figure which shows the manufacture process of compound (i). In one Example of this invention, it is a figure which shows the manufacture process of a compound (j). In one embodiment of the present invention, it is a graph showing a result of Compound (f) ~ (q), compound (x) and Na ₃ VO ₄ was investigated the effect on cell cycle progression. In one Example of this invention, it is a figure which shows the result of having investigated the influence which the compound (compound (j) or (q)) of each density | concentration has on the progression of a cell cycle. In one Example of this invention, it is a figure which shows the manufacturing process of a compound (r), a compound (s), and a compound (u).

Claims (57)

A naphthoquinone derivative compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
(In the formula, when R ₃ is an aryl alcohol group or an alkylcarbonyl group, R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₂ is a hydroxyl group or an acyloxy group. Or R ₄ is an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxyalkyl group, an alkoxyalkenyl group, a phenoxyalkyl group, a phenoxyalkenyl group, a carboxyalkenyl group, or an alkoxycarbonyl group. An alkenyl group, an acyloxyalkenyl group, a hydroxyalkyloxiranealkyl group, an alkoxyalkyloxiranealkyl group, a dihydroxyalkyl group, a hydroxyalkoxyalkyl group, an oxirane group, or 2 A dimethane-1,3-dioxane-4-alkyl group,
In the formula, when R ₄ is an alkynyloxyalkyl group or a butyldimethylsilyloxyalkenyl group, R ₁ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₂ is a hydroxyl group. , An acyloxy group, or an alkoxyl group, and R ₃ is a hydrogen atom, a hydroxyalkyl group, a halogen atom, or an aryl alcohol group,
In the formula, when R ₁ is an acyloxy group, R ₂ is a hydroxyl group, an acyloxy group, or an alkoxyl group, R ₃ is a hydrogen atom, a hydroxyalkyl group, or a halogen atom, and R ₄ is an acyl group. , Hydroxyalkyl group, hydroxyalkenyl group, carboxyl group, alkoxycarbonyl group, alkoxyalkyl group, alkoxyalkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group An alkoxyalkyloxirane alkyl group, a dihydroxyalkyl group, a hydroxyalkoxyalkyl group, an oxirane group, or a 2-dimethane-1,3-dioxane-4-alkyl group,
In the formula, when R ₁ and R ₂ are methoxy groups and R ₄ is a hydroxybut-2-enyl group, R ₃ is a hydroxyethyl group, a hydroxypropyl group, or a hydroxyhexyl group,
In the formula, when R ₂ is a methoxy group, R ₃ is a hydrogen atom, and R ₄ is a methoxymethyl group, R ₁ is a hydroxyl group,
In the formula, when R ₁ and R ₂ are methoxy groups and R ₃ is a hydrogen atom, R ₄ is a hexyloxymethyl group,
R ₃ and R ₄ do not form a ring. ) A naphthoquinone derivative compound represented by the following general formula (II) or a pharmacologically acceptable salt thereof.
(Wherein R ₅ is a hydrogen atom or an alkyl group, R ₆ is a hydroxyethyl group, a hydroxypropyl group, a hydroxyhexyl group, an aryl alcohol group, or an alkylcarbonyl group, and R ₇ is a hydrogen atom, an acyl group, Or, it is a butyldimethylsilyl group, and the R ₆ and the R ₇ do not form a ring.) A naphthoquinone derivative compound represented by the following general formula (III) or a pharmacologically acceptable salt thereof.
(In the formula, R ₈ is a hydrogen atom or an acyl group.) A naphthoquinone derivative compound represented by the following general formula (IV) or a pharmacologically acceptable salt thereof.
(In the formula, R ₉ is a propyl group, a butyl group, a hexyl group, or an alkynyloxyalkyl group.) The naphthoquinone derivative compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein the compound is a compound represented by the following formulas (a) to (j).
The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 3, wherein the compound is a compound represented by the following formula (k) or (l).
The naphthoquinone derivative compound or a pharmacologically acceptable salt thereof according to claim 4, wherein the compound is a compound represented by the following formulas (m) to (p).
  The tyrosine phosphatase inhibitor which contains the naphthoquinone derivative compound in any one of Claims 1-7, or its pharmacologically acceptable salt as an active ingredient.   The inhibitor according to claim 8, wherein the tyrosine phosphatase is Cdc25A phosphatase or protein tyrosine phosphatase 1B.   The pharmaceutical composition which contains the naphthoquinone derivative compound in any one of Claims 1-7, or its pharmacologically acceptable salt as an active ingredient.   11. The pharmaceutical composition according to claim 10, which prevents or ameliorates a disease caused by overexpression or activation of protein tyrosine phosphatase 1B.   The pharmaceutical composition according to claim 11, wherein the disease is any disease selected from the group consisting of type 2 diabetes, obesity, neurological disease, tumor, and myeloid leukemia.   The pharmaceutical composition according to claim 10, wherein a disease caused by overexpression or activation of Cdc25A phosphatase is prevented or ameliorated.   The pharmaceutical composition according to claim 13, wherein the disease is a tumor. A cell growth inhibitor comprising as an active ingredient a compound represented by the following general formula (V) or a pharmacologically acceptable salt thereof:
(In the formula, when R ₁₂ is an aryl alcohol group or an alkylcarbonyl group, R ₁₀ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₁₁ is a hydroxyl group or an acyloxy group. Or R ₁₃ is an acyl group, hydroxyalkyl group, hydroxyalkenyl group, carboxyl group, alkoxycarbonyl group, alkoxyalkyl group, alkoxyalkenyl group, phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonyl Alkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group, alkoxyalkyloxirane alkyl group, dihydroxyalkyl group, hydroxyalkoxyalkyl group, oxirane group Or a 2-dimethane-1,3-dioxane-4-alkyl group,
In the formula, when R ₁₃ is an alkynyloxyalkyl group or a butyldimethylsilyloxyalkenyl group, R ₁₀ is a hydrogen atom, an alkyl group, a hydroxyl group, an alkoxyl group, or a hydroxyalkyl group, and R ₁₁ is a hydroxyl group. , An acyloxy group, or an alkoxyl group, and R ₁₂ is a hydrogen atom, a hydroxyalkyl group, a halogen atom, or an aryl alcohol group,
In the formula, when R ₁₀ and R ₁₁ are methoxy groups and R ₁₂ is a hydroxybut-2-enyl group, R ₁₃ is a hydroxyethyl group, a hydroxypropyl group, or a hydroxyhexyl group,
In the formula, when R ₁₀ and R ₁₁ are methoxy groups and R ₁₂ is a hydrogen atom, R ₁₃ is a hexyloxymethyl group,
R ₁₂ and R ₁₃ do not form a ring. ) The cell growth inhibitor according to claim 15, wherein the compound is a compound represented by the following formula (j) or a compound represented by any one of the following formulas (m) to (p).
A cell cycle progression inhibitor that inhibits progression in G ₁ phase of the cell cycle,
A cell cycle progression inhibitor comprising, as an active ingredient, a compound represented by the following general formula (VI) or a pharmacologically acceptable salt thereof:
(In the formula, R ₁₄ represents a hydroxyalkyl group, an alkylcarbonyl group, or an aryl alcohol group, and R ₁₅ represents an acyl group, a hydroxyalkyl group, a hydroxyalkenyl group, a carboxyl group, an alkoxycarbonyl group, an alkoxyalkyl group, or an alkoxyalkenyl group. Phenoxyalkyl group, phenoxyalkenyl group, carboxyalkenyl group, alkoxycarbonylalkenyl group, acyloxyalkenyl group, hydroxyalkyloxirane alkyl group, alkoxyalkyloxiranealkyl group, dihydroxyalkyl group, hydroxyalkoxyalkyl group, oxirane group, 2-dimethane- 1,3-dioxane-4-alkyl group, alkynyloxy group, or a butyldimethylsilyloxy alkenyl group, prior to the _{R 14} It does not constitute a cyclic between R _15.) The cell cycle progression inhibitor according to claim 17, wherein the compound is a compound represented by the following formula (j) or (q).
A naphthoquinone derivative compound represented by the following general formula (VII), a compound represented by the following formula (r) or a pharmacologically acceptable salt thereof.
(In the formula, R ₁₆ is a hydroxyl group or an alkoxyl group, R ₁₇ is a hydrogen atom or a halogen atom, and R ₁₈ is a hydroxyl group or an alkoxyl group.) The naphthoquinone derivative compound or a pharmacological thereof according to claim 19, wherein the naphthoquinone derivative compound represented by the general formula (VII) is a compound represented by the following formulas (s) to (u): Acceptable salt.
A naphthoquinone derivative compound represented by the following general formula (VIII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacologically acceptable salt thereof: Antibacterial agent contained as an active ingredient.
(In the formula, R ₁₉ and R ₂₀ are alkoxyl groups.) The antibacterial agent according to claim 21, wherein the naphthoquinone derivative compound represented by the general formula (VIII) is a compound represented by the following formula (s).
  The antibacterial agent according to claim 21 or 22, further comprising imipenem. An antibacterial agent comprising a compound represented by the following formula (u) or a pharmacologically acceptable salt thereof and imipenem as active ingredients.
  The antibacterial agent according to any one of claims 21 to 24, which has an antibacterial action against MRSA (methicillin-resistant Staphylococcus aureus). An imipenem activity enhancer that enhances the activity of imipenem,
A naphthoquinone derivative compound represented by the following general formula (VII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacologically acceptable salt thereof: An imipenem activity enhancer contained as an active ingredient.
(In the formula, R ₁₆ is a hydroxyl group or an alkoxyl group, R ₁₇ is a hydrogen atom or a halogen atom, and R ₁₈ is a hydroxyl group or an alkoxyl group.) The imipenem activity enhancer according to claim 26, wherein the naphthoquinone derivative compound represented by the general formula (VII) is a compound represented by the following formula (s) or the following formula (u).
  The imipenem activity enhancer according to claim 26 or 27, wherein the imipenem activity is antibacterial activity.   The imipenem activity enhancer according to claim 28, wherein the antibacterial activity is an antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus). A drug that inhibits bacterial growth,
A naphthoquinone derivative compound represented by the following general formula (VIII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacologically acceptable salt thereof: A drug characterized by containing as an active ingredient.
(In the formula, R ₁₉ and R ₂₀ are alkoxyl groups.) The drug according to claim 30, wherein the naphthoquinone derivative compound represented by the general formula (VIII) is a compound represented by the following formula (s).
  The drug according to claim 30 or 31, further comprising imipenem. A drug that inhibits bacterial growth,
A drug comprising a compound represented by the following formula (u) or a pharmacologically acceptable salt thereof and imipenem as active ingredients.
  The drug according to any one of claims 30 to 33, wherein the bacterium is MRSA (methicillin-resistant Staphylococcus aureus). A pharmaceutical composition for ameliorating a disease caused by bacterial infection or proliferation, comprising a naphthoquinone derivative compound represented by the following general formula (VIII), the following formula (r), the following formula (v), or the following formula ( A pharmaceutical composition comprising the compound represented by w) or a pharmacologically acceptable salt thereof as an active ingredient.
(In the formula, R ₁₉ and R ₂₀ are alkoxyl groups.) 36. The pharmaceutical composition according to claim 35, wherein the naphthoquinone derivative compound represented by the general formula (VIII) is a compound represented by the following formula (s).
  The pharmaceutical composition according to claim 35 or 36, further comprising imipenem. A pharmaceutical composition for improving a disease caused by bacterial infection or proliferation, comprising a compound represented by the following formula (u) or a pharmacologically acceptable salt thereof and imipenem as active ingredients object.
  The pharmaceutical composition according to any one of claims 35 to 38, wherein the bacterium is MRSA (methicillin-resistant Staphylococcus aureus).   The disease is one or more diseases selected from encephalitis, pneumonia, sepsis, peritonitis, enteritis, osteomyelitis, cholangitis, cutaneous abscess, pressure ulcer infection, and food poisoning caused by MRSA-produced toxins and toxic shock syndrome. 40. The pharmaceutical composition according to claim 39, wherein: A naphthoquinone derivative compound represented by the following general formula (VII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacologically acceptable salt thereof: A naphthoquinone derivative compound activity enhancer that enhances activity,
A naphthoquinone derivative compound activity enhancer containing imipenem as an active ingredient.
(In the formula, R ₁₆ is a hydroxyl group or an alkoxyl group, R ₁₇ is a hydrogen atom or a halogen atom, and R ₁₈ is a hydroxyl group or an alkoxyl group.) The naphthoquinone derivative compound activity enhancer according to claim 41, wherein the naphthoquinone derivative compound represented by the general formula (VII) is a compound represented by the following formula (s) or the following formula (u): .
  43. The naphthoquinone derivative compound activity enhancer according to claim 41 or 42, wherein the activity is antibacterial activity.   44. The naphthoquinone derivative compound activity enhancer according to claim 43, wherein the antibacterial activity is antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus). A method of enhancing imipenem activity, which enhances the activity of imipenem,
In cooperation with the imipenem, a naphthoquinone derivative compound represented by the following general formula (VII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacology thereof: A method for enhancing imipenem activity, which comprises allowing a chemically acceptable salt to act.
(In the formula, R ₁₆ is a hydroxyl group or an alkoxyl group, R ₁₇ is a hydrogen atom or a halogen atom, and R ₁₈ is a hydroxyl group or an alkoxyl group.) 46. The method for enhancing imipenem activity according to claim 45, wherein the naphthoquinone derivative compound represented by the general formula (VII) is a compound represented by the following formula (s) or the following formula (u).
  The method of enhancing imipenem activity according to claim 45 or 46, wherein the activity of the imipenem is antibacterial activity.   The method of enhancing imipenem activity according to claim 47, wherein the antibacterial activity is antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus). A naphthoquinone derivative compound represented by the following general formula (VII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacologically acceptable salt thereof: A method for enhancing activity of a naphthoquinone derivative compound that enhances activity,
A method for enhancing naphthoquinone derivative compound activity, wherein imipenem is allowed to act in cooperation with the naphthoquinone derivative compound.
(In the formula, R ₁₆ is a hydroxyl group or an alkoxyl group, R ₁₇ is a hydrogen atom or a halogen atom, and R ₁₈ is a hydroxyl group or an alkoxyl group.) The naphthoquinone derivative compound activity enhancing method according to claim 49, wherein the naphthoquinone derivative compound represented by the general formula (VII) is a compound represented by the following formula (s) or the following formula (u): .
  The method for enhancing naphthoquinone derivative compound activity according to claim 49 or 50, wherein the activity is antibacterial activity.   52. The method for enhancing naphthoquinone derivative compound activity according to claim 51, wherein the antibacterial activity is antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus). A naphthoquinone derivative compound represented by the following general formula (VIII) or a compound represented by the following formula (r), the following formula (v), or the following formula (w), or a pharmacologically acceptable salt thereof: A method for inhibiting the growth of bacteria, characterized by causing the effect to act.
(In the formula, R ₁₉ and R ₂₀ are alkoxyl groups.) 54. The method for inhibiting bacterial growth according to claim 53, wherein the naphthoquinone derivative compound represented by the general formula (VIII) is a compound represented by the following formula (s).
  55. The method for inhibiting bacterial growth according to claim 53 or 54, wherein imipenem is caused to act in cooperation. A method for inhibiting bacterial growth, comprising causing a compound represented by the following formula (u) or a pharmacologically acceptable salt thereof and imipenem to act in cooperation.
57. The method for inhibiting bacterial growth according to any one of claims 53 to 56, wherein the bacterium is MRSA (methicillin-resistant Staphylococcus aureus).