WO2012115209A1 - Inhibiteur d'époxyde hydrolase soluble - Google Patents

Inhibiteur d'époxyde hydrolase soluble Download PDF

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WO2012115209A1
WO2012115209A1 PCT/JP2012/054472 JP2012054472W WO2012115209A1 WO 2012115209 A1 WO2012115209 A1 WO 2012115209A1 JP 2012054472 W JP2012054472 W JP 2012054472W WO 2012115209 A1 WO2012115209 A1 WO 2012115209A1
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惠司 蓮見
絵里子 鈴木
哲弘 小川
新也 大竹
克和 北野
啓子 長谷川
直子 西村
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国立大学法人東京農工大学
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
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Definitions

  • the present invention relates to a soluble epoxide hydrolase inhibitor.
  • the arachidonic acid cascade is a lipid signaling cascade in which arachidonic acid is released from the lipid stores of the plasma membrane in response to various extracellular and / or intracellular signals, and is widely distributed in the living body.
  • the released arachidonic acid is converted by various oxidases into signaling lipids that play an important role in inflammation. Controlling these lipid signaling cascades remains an important strategy for many marketed drugs used to treat a number of inflammatory disorders.
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • COX1 and COX2 cyclooxygenases
  • cytochrome P450-dependent enzymes convert arachidonic acid into a series of epoxide derivatives known as epoxyeicosatrienoic acid (EET). These EETs are expressed throughout the body, and are particularly highly expressed in endothelial cells, kidneys and liver. In contrast to many end products of the prostaglandin and leukotriene pathways, which are metabolites of arachidonic acid, EET has various anti-inflammatory and anti-hypertensive properties, and is a potent vasodilator and vascular permeability mediator It is known that
  • EET has a powerful effect in vivo
  • the epoxide structure of EET is rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the less active form of dihydroxyeicosatrienoic acid (DHET) .
  • Inhibition of sEH reduces blood pressure in hypertensive animals (see, for example, Circ Res., 87 (11), 992-8 (2000), and J. Biol. Chem., 275, 40504-10 (2000)).
  • NO pro-inflammatory nitric oxide
  • cytokines cytokines
  • lipid mediators or contribute to inflammation resolution by enhancing lipoxin A4 production in vivo (see, eg, Proc. Natl. Acad. Sci. USA., 102 (28), 9772-7 (2005)).
  • SEH is an enzyme having two functions, and it has been revealed that it has a phosphatase activity in addition to a hydrolase activity that converts EET to DHET. Although there are many unclear points regarding the action of phosphatase activity, it has been suggested that it may contribute to cholesterol metabolism (see, for example, J. Biol. Chem., 283 (52), 36592-8 (2008)). .
  • low molecular weight compounds have been found to inhibit sEH and increase EET levels in connection with the above (eg, Annu. Rev. Pharmcol. Toxicol., 45, 311-33 (2005), and (See Japanese Translation of PCT International Publication No. 2010-521475).
  • Such low molecular weight compounds typically contain an adamantyl urea structure or a substituted or unsubstituted phenyl structure.
  • An object of the present invention is to provide a soluble epoxide hydrolase inhibitor capable of inhibiting the phosphatase activity of soluble epoxide hydrolase (sEH) and having excellent soluble epoxide hydrolase inhibitory activity.
  • the first aspect of the present invention is a soluble epoxide hydrolase inhibitor containing a compound represented by the following general formula (I).
  • R represents a hydrogen atom, a residue obtained by removing one amino group from an ⁇ -amino acid or amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group.
  • L represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms, and X represents a hydroxy group or a carboxy group.
  • n represents an integer of 0-2.
  • the compound represented by the general formula (I) is preferably a compound represented by the following general formula (II) or a compound represented by the general formula (III).
  • L 1 , L 2 and L 3 each independently represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms.
  • X 1 , X 2 and X 3 each independently represent a hydroxy group or a carboxy group.
  • n1, n2 and n3 each independently represents an integer of 0 to 2.
  • R 1 represents a hydrogen atom or any of the following (A) to (D).
  • A A residue obtained by removing one amino group from an ⁇ -amino acid or amino sugar.
  • B A nitrogen-containing heterocyclic group which may have at least one substituent selected from the group consisting of a phenyl group, an alkyl group having 1 to 5 carbon atoms, and a carbamoyl group.
  • (C) at least one selected from the group consisting of a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group and a group formed by removing one hydrogen atom from fluorescamine An alkyl group having 2 to 6 carbon atoms which may have a substituent.
  • (D) An aryl group that may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
  • R 2 represents a divalent linking group composed of at least one selected from the group consisting of an alkylene group having 2 to 8 carbon atoms which may have a carboxy group and a sulfur atom.
  • the ⁇ -amino acid may have at least one substituent selected from the group consisting of a natural amino acid, a D-form of a natural amino acid, or a hydroxy group, a carboxy group, and an alkyl group having 1 to 5 carbon atoms. Glycine is preferred.
  • the second aspect of the present invention is a compound represented by the following general formula (IV).
  • R 4 represents a hydrogen atom, an ⁇ -amino acid or a residue obtained by removing one amino group from an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group.
  • Y represents any one of the following chemical formulas (Y1) to (Y4). In the following chemical formula, * indicates a bonding position.
  • R 4 in the general formula (IV) is preferably a hydrogen atom.
  • the third aspect of the present invention is a therapeutic agent for inflammatory diseases comprising the soluble epoxide hydrolase inhibitor.
  • the fourth aspect of the present invention is a therapeutic agent for cancer cachexia containing the soluble epoxide hydrolase inhibitor.
  • a fifth aspect of the present invention is a method for treating cancer cachexia, comprising administering the soluble epoxide hydrolase inhibitor to a mammal in need of treatment for cancer cachexia.
  • the sixth aspect of the present invention is the use of the soluble epoxide hydrolase inhibitor as a therapeutic agent for cancer cachexia.
  • a soluble epoxide hydrolase inhibitor capable of inhibiting the phosphatase activity of a soluble epoxide hydrolase and having an excellent soluble epoxide hydrolase inhibitory activity can be provided.
  • the soluble epoxide hydrolase inhibitor of the present invention contains at least one compound represented by the following general formula (I).
  • excellent soluble epoxide hydrolase inhibitory activity hereinafter also referred to as “sEH”
  • sEH soluble epoxide hydrolase inhibitory activity
  • the compound represented by the following general formula (I) may contain one or more asymmetric carbon atoms or asymmetric centers in its structure, and may have two or more optical isomers. .
  • the present invention includes all the optical isomers and mixtures containing them in an arbitrary ratio.
  • the compound represented by the following general formula (I) may have two or more geometric isomers derived from a carbon-carbon double bond in its structure.
  • the present invention encompasses all mixtures in which each geometric isomer is contained in an arbitrary ratio.
  • R is a hydrogen atom, a residue obtained by removing one amino group from an ⁇ -amino acid or an amino sugar, a heterocyclic group which may have a substituent, or a carbon number which may have a substituent 2 8 to 8 alkyl groups or an aryl group which may have a substituent.
  • L represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms.
  • X is a substituent in the aliphatic hydrocarbon group represented by L, and represents a hydroxy group or a carboxy group.
  • n is the number of substitutions of the substituent X in L and represents an integer of 0 to 2.
  • the ⁇ -amino acid in R of the general formula (I) is not particularly limited, and may be a natural amino acid or a non-natural amino acid. Moreover, the amino acid derivative by which the substituent was introduce
  • phenylalanine or phenylglycine optionally having at least one selected from the group consisting of a natural amino acid, a D-form of a natural amino acid, or a hydroxy group, a carboxy group, and an alkyl group having 1 to 5 carbon atoms. It is more preferable that it is phenylglycine which may have a substituent.
  • Natural amino acids are not particularly limited as long as they are naturally occurring amino acids.
  • Examples include phenylalanine, homocystin, diaminopimelic acid, diaminopropionic acid, serine, leucine, phenylalanine, and tryptophan.
  • Examples of the substituent in an amino acid derivative in which a substituent is introduced into a natural amino acid include 1 hydrogen atom from nitro group, hydroxy group, arylalkyl group having 7 to 16 carbon atoms, ureido group, thioureido group, carboxy group, and fluorescamine. Groups and the like constituted by removing one. If possible, the substituent in the amino acid derivative may further have a substituent. The substituent which the substituent has is the same as the substituent in the amino acid derivative.
  • the amino sugar in R of the general formula (I) is not particularly limited as long as it is a sugar derivative having at least one amino group. Specific examples include glucosamine, galactosamine, mannosamine, neuraminic acid and the like.
  • the heterocyclic group in R of the general formula (I) is not particularly limited as long as it is a cyclic group containing a hetero atom, and may be either an aliphatic heterocyclic group or an aromatic heterocyclic group. Further, examples of the hetero atom include a nitrogen atom, an oxygen atom, and a sulfur atom.
  • a nitrogen-containing heterocyclic group containing a nitrogen atom as a hetero atom is preferable, and a heterocyclic compound selected from the group consisting of purine, pyridine, pyridazine, pyrrole, imidazole, pyrazole, and pyrazolone More preferably, it is a heterocyclic group constituted by removing one hydrogen atom from the heterocyclic group constituted by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine and pyrazolone. More preferably. Note that the position at which the hydrogen atom is removed from the heterocyclic compound is not particularly limited. Among these, it is preferable to remove from the carbon atom of the heterocyclic compound.
  • the heterocyclic group in R may have a substituent.
  • substituents in the heterocyclic group include an alkyl group having 1 to 5 carbon atoms, an aryl group having 14 or less carbon atoms, a carboxy group, a carbamoyl group, and a sulfonic acid group. Among these, at least one selected from a phenyl group and a carbamoyl group is preferable.
  • the number of substituents in the heterocyclic group is not particularly limited, but is preferably 3 or less.
  • the alkyl group having 2 to 8 carbon atoms in R of the general formula (I) may be linear, branched or cyclic. Especially, it is preferable that it is linear or branched, and it is more preferable that it is linear.
  • the number of carbon atoms is preferably 2-6.
  • the carbon number of the alkyl group does not include the carbon number of the substituent on the alkyl group.
  • the alkyl group in R may have a substituent.
  • substituent in the alkyl group include an alkyl group having 1 to 5 carbon atoms, an aryl group having 14 or less carbon atoms, an arylalkyl group having 16 or less carbon atoms, a hydroxy group, a carboxy group, a carbamoyl group, a sulfonic acid group, an amino group, Carbamoyloxy group, ureido group, thioureido group, alkyl sulfide group, alkyl disulfide group, a group constituted by removing R from the compound represented by formula (I), and constituted by removing one hydrogen atom from fluorescamine Groups and the like.
  • the number of substituents in the alkyl group is not particularly limited, but is preferably 3 or less. Moreover, the substituent in the alkyl group may further have a substituent if possible. The substituent which the substituent has is the same as the substituent in the alkyl group.
  • the aryl group in R of the general formula (I) is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and further preferably a phenyl group.
  • the aryl group in R may have a substituent.
  • substituent in the aryl group include an alkyl group having 1 to 5 carbon atoms, an aryl group having 14 or less carbon atoms, a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
  • at least one selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group is preferable.
  • the number of substituents in the aryl group is not particularly limited, but is preferably 3 or less. Moreover, the substituent in the aryl group may further have a substituent, if possible. The substituent which the substituent has is the same as the substituent in the aryl group. Furthermore, when the substituent in the aryl group is possible, the substituents may be bonded to form a cyclic structure.
  • the aliphatic hydrocarbon group having 4 to 10 carbon atoms represented by L may be linear, branched or cyclic. Moreover, the unsaturated bond may be included. Among these, an aliphatic hydrocarbon group that may contain a linear or branched unsaturated bond is preferable.
  • formula (I) the group represented by -L-X n, from the viewpoint of sEH inhibitory activity, the following formula (V), formula (Y1) ⁇ one of represented thing (Y4) preferable.
  • Z 1 and Z 2 are each independently a hydrogen atom or a hydroxy group, or together form a single bond.
  • “*” indicates a bonding position.
  • the compound represented by the general formula (I) is preferably a compound represented by the following general formula (II) or a compound represented by the general formula (III).
  • L 1 , L 2 and L 3 each independently represents an aliphatic hydrocarbon group having 4 to 10 carbon atoms.
  • the details of L 1 , L 2 and L 3 are the same as L in general formula (I), and the preferred embodiments are also the same.
  • a preferred embodiment of the group represented by -L 1- (X 1 ) n1 , -L 2- (X 2 ) n2 and -L 3- (X 3 ) n3 is represented by -LX n. Same as the group.
  • R 1 represents a hydrogen atom or any of the following (A) to (D).
  • A A residue obtained by removing one amino group from an ⁇ -amino acid or amino sugar.
  • B A nitrogen-containing heterocyclic group which may have at least one substituent selected from the group consisting of a phenyl group, an alkyl group having 1 to 5 carbon atoms, and a carbamoyl group.
  • (C) at least one selected from the group consisting of a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group and a group formed by removing one hydrogen atom from fluorescamine
  • An alkyl group having 2 to 6 carbon atoms which may have a substituent. However, the case where it has a carboxymethyl group is excluded.
  • An aryl group that may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
  • ⁇ -amino acid and amino sugar in R 1 are synonymous with the ⁇ -amino acid and amino sugar in R of general formula (I), and the preferred embodiments are also the same.
  • the nitrogen-containing heterocyclic group in R 1 is not particularly limited as long as it is a cyclic group containing at least a nitrogen atom, and may be any of a saturated heterocyclic group, an unsaturated heterocyclic group, and an aromatic heterocyclic group. Moreover, in addition to a nitrogen atom as a hetero atom, an oxygen atom, a sulfur atom, etc. may be included.
  • the nitrogen-containing heterocyclic group examples include a heterocyclic group constituted by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine, pyridazine, pyrrole, imidazole, pyrazole, and pyrazolone. Can do. Among these, a heterocyclic group constituted by removing one hydrogen atom from a heterocyclic compound selected from the group consisting of purine, pyridine, and pyrazolone is preferable. Specific examples of the nitrogen-containing heterocyclic group for R 1 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
  • the alkyl group having 2 to 6 carbon atoms in R 1 is formed by removing one hydrogen atom from a hydroxy group, a carboxy group, an amino group, a carbamoyloxy group, an arylalkyl group having 7 to 14 carbon atoms, a thioureido group, and fluorescamine. It may have at least one substituent selected from the group consisting of the above groups. These substituents may further have a substituent if possible. Examples of the substituent include the same substituents as described above. Specific examples of the alkyl group for R 1 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
  • the aryl group for R 1 is preferably an aryl group having 6 to 14 carbon atoms, more preferably an aryl group having 6 to 10 carbon atoms, and further preferably a phenyl group.
  • the aryl group in R 1 may have at least one substituent selected from the group consisting of a hydroxy group, a carboxy group, a sulfonic acid group, a carbamoyl group, and an arylcarbonyl group.
  • the number of substituents in the aryl group is not particularly limited, but is preferably 3 or less.
  • the substituent in the aryl group may further have a substituent, if possible.
  • the substituent which the substituent has is the same as the substituent in the aryl group.
  • the substituents may be bonded to each other to form a cyclic structure. Specific examples of the aryl group in R 1 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
  • R 2 represents a divalent linking group composed of at least one selected from the group consisting of an alkylene group having 2 to 8 carbon atoms which may have a carboxy group and a sulfur atom. Specific examples of the divalent linking group represented by R 2 are shown below, but the present invention is not limited thereto. In the chemical formulas below, “*” represents a bonding position.
  • the compound represented by the general formula (I) of the present invention is represented by a compound represented by the following general formula (IV).
  • Compound represented by the general formula (IV) the substituents in the general formula (I) is represented by -L-X n is characterized by having a specific structure. Thereby, the compound represented by general formula (IV) can show the more outstanding sEH inhibitory activity.
  • R 4 represents a hydrogen atom, a residue obtained by removing one amino group from an ⁇ -amino acid or an amino sugar, a heterocyclic group, an alkyl group having 2 to 8 carbon atoms, or an aryl group.
  • Y represents any one of the following chemical formulas (Y1) to (Y4). In the following chemical formula, * indicates a bonding position.
  • R 4 in the general formula (IV) are the same as those in R in the general formula (I), and preferred embodiments are also the same.
  • R 4 is preferably a hydrogen atom.
  • the compound represented by the general formula (I) may be obtained by chemical synthesis or may be obtained by purification from a culture of a filamentous fungus, for example, Stachybotrys microspora (for example, IFO30018 strain). .
  • a method for obtaining the compound represented by the general formula (I) by purification from a filamentous fungus culture for example, from a culture obtained when a predetermined organic amino compound is added to a culture solution of Stachybotrys microspora. And a method including purifying the target compound.
  • These methods can be performed by appropriately referring to, for example, JP-A-2004-224737, JP-A-2004-224738, and WO2007 / 111203.
  • the compound represented by the general formula (I) may be an enantiomer, a diastereomer, and a mixture of enantiomers or diastereomers.
  • Enantiomers, diastereomers, and mixtures of enantiomers or diastereomers may be obtained by chemical synthesis or may be obtained by purification from a filamentous fungal culture. When it is obtained by purification from a filamentous fungus culture, enantiomers corresponding to each can be obtained by using D-form or L-form of an organic amino compound added to the filamentous fungus medium.
  • the compound represented by general formula (IV) can be obtained by chemical synthesis.
  • a compound represented by the following general formula (I 0 ) (hereinafter, also referred to as “SMTP derivative”) is added to a culture solution of a microorganism selected from filamentous fungi and the like, and then hydroxylation reaction or oxidation reaction It can also be manufactured.
  • R in the following general formula (I 0 ) has the same meaning as R in the general formula (I). Note that the manufacturing method of the compound represented by formula (I 0) is the same as the compound represented by the above general formula (I).
  • the compound represented by the general formula (IV) may be an enantiomer, a diastereomer, and a mixture of enantiomers or diastereomers.
  • Enantiomers, diastereomers, and mixtures of enantiomers or diastereomers may be obtained by chemical synthesis or may be obtained by purification from a filamentous fungal culture.
  • the compound represented by the general formula (I 0 ) to be added to the filamentous fungus medium can be appropriately selected to obtain enantiomers corresponding to each. it can.
  • the compound represented by the general formula (I) can be used in a free form, a pharmaceutically acceptable salt or ester form, or a solvate form.
  • suitable inorganic or organic acids for the formation of pharmaceutically acceptable salts of compounds of general formula (I) include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or citric acid, formic acid , Fumaric acid, malic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • a compound containing an alkali metal or alkaline earth metal such as sodium, potassium, calcium, magnesium, an amine compound, or a basic amino acid is also a pharmaceutically acceptable salt of the compound represented by the general formula (I). It is suitable for.
  • an alcohol having 1 to 10 carbon atoms or a carboxylic acid having 2 to 10 carbon atoms is suitable. Is an alcohol having 1 to 4 carbon atoms or a carboxylic acid having 2 to 4 carbon atoms, and more preferably methyl alcohol, ethyl alcohol, acetic acid, or propionic acid. Water or the like is suitable for forming a pharmaceutically acceptable solvate of the compound represented by the general formula (I).
  • An sEH inhibitor comprising a compound represented by the general formula (I) can be used to treat various sEH-mediated diseases.
  • diseases that mediate sEH include hypertensive diseases, cardiovascular diseases, ischemic diseases, high cholesterol diseases, obesity, autoimmune diseases, inflammatory diseases, lung diseases, cancer cachexia, diabetes-related diseases, and the like. Can be mentioned.
  • the compound represented by the general formula (I) is used as a pharmaceutical composition for treating various diseases
  • the compound represented by the general formula (I) is a free form, a pharmaceutically acceptable salt or An ester or the like can be contained in a pharmaceutical composition in a form that is usually applicable as a medicine.
  • the pharmaceutical composition containing the compound represented by the general formula (I) can be appropriately changed in dosage form according to various administration forms.
  • oral dosage forms include tablets, capsules, powders, fine granules, granules, solutions or syrups
  • parenteral dosage forms include injections, drops, suppositories, inhalants, A patch etc. can be mentioned.
  • additives such as well-known solvents and excipients that can be used in these applications can be included.
  • the pharmaceutical composition containing the compound represented by the general formula (I) can be administered at an appropriate dose according to the age, body weight, and symptoms.
  • intravenous administration it is effective per day for an adult.
  • administration of 1 mg / kg to 25 mg / kg as an ingredient amount, or oral administration administration of 2 mg / kg to 200 mg / kg as an active ingredient amount per day for an adult is preferable, and the administration period depends on the age and symptoms. It can be arbitrarily determined depending on the situation.
  • the pharmaceutical composition containing the compound represented by the general formula (I) is used as a therapeutic agent for inflammatory diseases. That is, another aspect of the present invention is a therapeutic agent for inflammatory diseases comprising a compound represented by the general formula (I). By containing the compound represented by the general formula (I), the inflammatory reaction can be effectively suppressed and inflammatory diseases can be treated.
  • the pharmaceutical composition containing the compound represented by the general formula (I) is used as a therapeutic agent for cancer cachexia.
  • another aspect of the present invention is a therapeutic agent for cancer cachexia comprising a compound represented by the general formula (I).
  • the therapeutic agent for cancer cachexia effectively suppresses fat and skeletal muscle wasting that are characteristic symptoms of cancer cachexia by containing the compound represented by the general formula (I). be able to.
  • the effect of cancer chemotherapy can be improved by alleviating the symptoms of cancer cachexia.
  • the compound represented by the general formula (I) can be applied to a method for treating cancer cachexia. That is, another aspect of the present invention relates to cancer cachexia comprising administering a compound represented by the general formula (I) to a mammal in need of treatment for cancer cachexia in an amount necessary for treatment. This is a treatment method.
  • a method for administering the compound represented by the general formula (I) to a mammal in need of cancer cachexia the pharmaceutical composition is administered to a mammal in need of cancer cachexia. The method of doing is mentioned. Details of the pharmaceutical composition, administration method and the like are as described above.
  • the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples. Unless otherwise specified, “%” is based on mass.
  • the compound represented by the general formula (I) is also referred to as an SMTP derivative.
  • CB442 was added to 0.01 (v / v)% and sterilized by autoclaving.
  • One platinum loop from each storage slant was inoculated into a 100 mL baffle Erlenmeyer flask containing 20 mL of the same medium, and cultured with shaking at 25 ° C. and 180 rpm.
  • 5 mL of sterilized water was added per flask, and shaking culture was continued.
  • 100 ⁇ L of SMTP-0 dissolved in acetone so as to be 2.5 mg / line or 10 mg / line was added, and the culture was further continued.
  • SMTP-0a F039 from the slant medium was inoculated into a 500 mL baffled Erlenmeyer flask containing 100 mL of medium having the same composition as described above, and cultured at 25 ° C. and 180 rpm for 4 days.
  • a preculture solution was added to a 500 mL baffle Erlenmeyer flask containing 100 mL of the same medium to a final concentration of 5%, and cultured under the same conditions.
  • 1 mL of SMTP-0 dissolved in acetone was added to 100 mg / tube, and the culture was further continued for 4 days.
  • methanol was added at 200 mL / flask and the mixture was extracted by shaking for 2 hours.
  • the cells were removed by filtration under reduced pressure, and methanol contained in the supernatant was distilled off.
  • the concentrated solution was centrifuged, and the separated supernatant was extracted with ethyl acetate.
  • the obtained ethyl acetate layer was concentrated and dried, and the dried product and the precipitate were combined and dissolved in methanol.
  • SMTP-0b F388 from the slant medium was inoculated into a 500 mL baffled Erlenmeyer flask containing 100 mL of medium having the same composition as the screening, and cultured at 25 ° C. and 180 rpm for 4 days, which was used as a preculture.
  • a preculture solution was added to a 500 mL baffle Erlenmeyer flask containing 100 mL of the same medium to a final concentration of 5%, and cultured under the same conditions.
  • 1 mL of SMTP-0 dissolved in acetone was added to 100 mg / tube, and the culture was further continued for 5 days.
  • Methanol was added at 200 mL / flask at the end of the culture, and the mixture was extracted by shaking for 2 hours.
  • the cells were removed by filtration under reduced pressure, and methanol contained in the supernatant was distilled off.
  • the dried product was dissolved in methanol and insolubles were removed, and then the supernatant was subjected to reverse phase HPLC (flow rate 25 mL / min, column temperature 40 ° C.) using an ODS column (Inertsil PREP-ODS, 30 ⁇ ⁇ 250 mm; GL Science). Purified with. (A) 0.1% formic acid aqueous solution and (B) methanol are used for the moving bed, and (B) elution is performed with a linear gradient of 10 to 100% of the solvent for 30 minutes. The obtained fraction was concentrated and dried. The obtained dried product was dissolved in a mixed solution of acetonitrile and purified water, and purified again using reverse phase HPLC.
  • SMTP-0c F388 Preparation of SMTP-0c F388 from the slant medium was inoculated into a 500 mL baffled Erlenmeyer flask containing 100 mL of medium having the same composition as described above, and cultured at 25 ° C. and 180 rpm for 4 days. A preculture solution was added to a 500 mL baffle Erlenmeyer flask containing 100 mL of the same medium to a final concentration of 5%, and cultured under the same conditions. On the second day of culture, 1 mL of SMTP-0 dissolved in acetone was added to 100 mg / tube, and the culture was further continued for 5 days.
  • SMTP-0d and SMTP-0e From a slant of Stachybotrys microspora, which is an SMTP-producing bacterium, inoculated into a pre-culture medium for SMTP production, and cultured at 25 ° C. and 180 rpm for 4 days.
  • the preculture medium after this culture was inoculated at 5% (v / v) into 100 ml ⁇ 5 main culture medium for SMTP production and cultured at 25 ° C. and 180 rpm for 4 days.
  • 0.1% (w / v) NH 4 Cl was added, and further cultured under the same conditions for 8 days from the addition of NH 4 Cl.
  • 200 ml of methanol was added and blow-out was performed, followed by extraction with stirring at 180 rpm for 2 hours.
  • methanol was distilled off under reduced pressure.
  • the remaining aqueous layer and precipitate were extracted with ethyl acetate twice in the same amount and twice in the half amount.
  • the ethyl acetate layers were combined and evaporated under reduced pressure, and the pressure was reduced overnight with an oil pump to dryness.
  • the dried product was dissolved in methanol, pretreated by passing through a precolumn (LiChrolt RP-18-100 mg), and then reverse-phase HPLC (flow rate using an ODS column (Inertsil PREP-ODS, 4.6 ⁇ ⁇ 250 mm; GL Science). 25 mL / min, column temperature 40 ° C.).
  • the obtained dried product having a peak of 5 minutes was purified again using reverse phase HPLC.
  • the conditions are a column temperature of 40 ° C., a flow rate of 25 ml / min, (A) 0.1% formic acid water and (B) methanol for the moving bed, and (B) isocratic conditions of 45% solvent.
  • a peak with an elution time of 31 minutes was collected. Subsequently, it was combined with a peak at an elution time of 12 minutes in the first reverse-phase HPLC fractionation, and fractionated once again on the same reverse-phase HPLC.
  • the conditions are a column internal temperature of 40 ° C., a flow rate of 25 ml / min, (A) 0.1% formic acid water and (B) acetonitrile for the moving bed, and (B) 25% solvent isocratic conditions. A peak with an elution time of 19 minutes was collected. The isolated fractions were dried to give SMTP-0e as 18.8 mg white solid.
  • the peak with an elution time of 20 minutes in the first reverse-phase HPLC fractionation was purified using the same reverse-phase HPLC.
  • the conditions are a column temperature of 40 ° C., a flow rate of 25 ml / min, (A) 0.1% formic acid water and (B) methanol are used for the moving bed, and (B) the solvent is 60% isocratic
  • the peak with an elution time of 29 minutes was collected.
  • the isolated fraction was dried to give SMTP-0d as a 23.7 mg white solid.
  • UV spectra were measured with a model 320 spectrometer (manufactured by Hitachi High-Tech) using methanol as a solvent.
  • Infrared (IR) spectra were measured using a JIR-WINSPEC spectrometer (manufactured by JEOL), with the NaCl method for SMTP-0a, SMTP-0d and SMTP-0e, and the KBr method for SMTP-0b and SMTP-0c.
  • the MALDI-TOF-MASS (MS) spectrum was measured with a Voyager DE STR spectrometer (manufactured by Applied Biosystem) using ⁇ -cyano-4-hydroxycinnamic acid as a matrix.
  • the NMR spectrum was measured with Alpha-600 spectrometer (manufactured by JEOL) using methanol-d 4 (manufactured by Acros Organics).
  • the optical rotation was measured with model DIP-360 (manufactured by JASCO) using methanol as a solvent.
  • Tables 1 to 4 show the physicochemical properties and structural analysis results. Note that the position numbers of the atoms of each SMTP-0a, 0b, 0c, 0d, and 0e are expressed in accordance with SMTP-0 as shown below.
  • SMTP-0a has a structure having no 21-23th carbon atom and a hydroxy group at the 20th carbon atom instead.
  • UV spectrum maximum absorption was observed at 213 nm, 254 nm, and 303 nm.
  • IR spectra 3265cm -1, 2933cm -1, 1670cm -1, 1614cm -1, 1464cm -1, 1360cm -1, 1227cm -1, 1161cm -1, absorption was observed at 1078cm -1.
  • SMTP-0b had a structure in which the 19th to 23rd carbon atoms were not present, and instead the 18th carbon atom was changed to the carbonyl carbon of the carboxylic acid.
  • maximum absorption was observed at 214 nm, 255 nm, and 303 nm.
  • IR spectra 3290cm -1, 2945cm -1, 1678cm -1, 1610cm -1, 1464cm -1, 1367cm -1, 1209cm -1, 1161cm -1, absorption was observed at 1076cm -1.
  • SMTP-0c had a structure in which the 22nd carbon atom was changed to the carbonyl carbon of carboxylic acid.
  • maximum absorption was observed at 214 nm, 253 nm, and 302 nm.
  • absorption is performed at 3277 cm ⁇ 1 , 2983 cm ⁇ 1 , 2927 cm ⁇ 1 , 1689 cm ⁇ 1 , 1614 cm ⁇ 1 , 1543 cm ⁇ 1 , 1466 cm ⁇ 1 , 1358 cm ⁇ 1 , 1267 cm ⁇ 1 , 1167 cm ⁇ 1 , 1084 cm ⁇ 1 .
  • SMTP-0d had a structure having a hydroxy group at the 24th carbon atom.
  • maximum absorption was observed at 213 nm, 254 nm, and 302 nm.
  • the IR spectrum 3284cm -1, 2966cm -1, 2921cm -1, 2862cm -1, 1670cm -1, 1614cm -1, 1462cm -1, 1360cm -1, 1227cm -1, 1165cm -1, 1078cm -1, 1034cm Absorption was observed at -1 .
  • SMTP-0e has a structure in which both the 20th and 21st carbon atoms have hydroxy groups.
  • maximum absorption was observed at 213 nm, 255 nm, and 302 nm.
  • IR spectrum absorption at 3329cm -1, 2976cm -1, 2937cm -1 , 2866cm -1, 1672cm -1, 1608cm -1, 1464cm -1, 1360cm -1, 1221cm -1, 1159cm -1, 1078cm -1 was recognized.
  • Purified mouse sEH was obtained by applying mouse liver homogenate to an affinity column in which SMTP-50 was bound to Hitrap TM NHS-activated HP (GE Healthcare, UK), and 12- (3-adamantan-1-yl-ureido) -A product purified by dialysis after elution with dodecanoic acid was used.
  • sEH inhibitory activity was carried out using a 96-well black plate for fluorescence measurement in 100 ⁇ L / well of 25 mM bis-Tris-HCl (pH 7.0). Each predetermined concentration of the SMTP derivative and mouse sEH were prepared in 50 ⁇ L of buffer solution to 20 nM, and incubated at room temperature for 10 minutes. After incubation, 25 ⁇ M sEH substrate (3-phenyl-oxylany) -acetic acid cyano- (6-methoxy-naphthalen-2-yl) -methyl ester (PHOME, manufactured by Funakoshi) was added at 50 ⁇ L / well. The fluorescence intensity was measured continuously for 15 cycles every minute.
  • a substrate solution 50 ⁇ l of p-nitrophenyl phosphate solution adjusted to 5 mM was added to an assay buffer containing 0.2 mg / l bovine serum albumin and 2 mM MgCl 2, and the absorbance at 450 nm was immediately changed to 37 ° C. For 12 cycles every 10 minutes.
  • the IC 50 was 0.25 ⁇ M.
  • the phosphatase activity was evaluated using purified mouse sEH prepared in the same manner as above instead of rhsEH, and using Attophos (registered trademark, manufactured by Promega) as a substrate.
  • Evaluation of sEH inhibitory activity was carried out using 20 mM HBSS / Hepes (pH 7.4, containing 0.1 mg / ml bovine serum albumin and 1 mM MgCl 2 ) as an assay buffer, and a 96-well fluorescence black plate (# CLS3370). ).
  • a substrate solution 50 ⁇ l of p-nitrophenyl phosphate solution adjusted to 5 mM was added to an assay buffer containing 0.2 mg / l bovine serum albumin and 2 mM MgCl 2, and the absorbance at 450 nm was immediately changed to 37 ° C. For 12 cycles every 10 minutes.
  • the sEH inhibitory activity of the SMTP derivative was evaluated using HepG2 cells as follows. HepG2 cells were seeded at a concentration of 1 ⁇ 10 6 cells / ml at a concentration of 1 ⁇ 10 6 cells / ml in a 24-well plate, and cultured overnight in an incubator at 37 ° C. and 5% CO 2 to attach the HepG2 cells to the plate. After removing the supernatant, 500 ⁇ l each of the SMTP derivative prepared to the target concentration was added to RPMI-1640 medium (FBS 10%, 100 ⁇ / ml: containing penicillin, 100 ⁇ g / ml streptmycin). Incubated for 10 minutes.
  • RPMI-1640 medium FBS 10%, 100 ⁇ / ml: containing penicillin, 100 ⁇ g / ml streptmycin
  • the internal standard substance 14,15DHET-d11 14,15-dihydroeicosatrienoic acid-d11 labeled product, final concentration 200 ng / ml
  • 14,15 EET 14,15-epoxyeicosatri Enic acid, final concentration 0.3 ⁇ M
  • an SMTP derivative having the same concentration as the initial concentration was added, and incubated for 1 hour in an incubator at 37 ° C. and 5% CO 2 . After completion of the incubation, the cells were peeled off by pipetting while the plate was placed on ice, and the medium was transferred to a glass tube.
  • the SMTP derivative which is a compound represented by the general formula (I)
  • phosphatase activity inhibition is shown in addition to the conventionally known hydrolase activity inhibition activity of sEH.
  • SMTP-7 was used as the SMTP derivative which is a compound represented by the general formula (I).
  • Cancer cells Provided by RIKEN Cell Bank
  • Colon 26 was transplanted into BALB / c CrSlc subcutaneously in advance, and was extracted when the size reached about 1000 mm 3 .
  • the obtained cancer cells were suspended in PBS so that the cell concentration was 10% (w / v) to prepare a cancer cell suspension for transplantation.
  • blood albumin levels were quantified as follows on the 14th day after the start of administration.
  • the blood albumin level was quantified using Wako Pure Chemical Industries, Albumin B-Test Wako, according to the attached method. That is, 4 ⁇ l of standard bovine serum or sample plasma was added to 1 ml of albumin coloring reagent, and after sufficiently stirring, it was left at room temperature for 10 minutes. Thereafter, the absorbance was measured at a wavelength of 620 nm, and the albumin value in the sample was calculated from the standard value corresponding to the standard bovine serum.
  • SMTP-44D was used as an SMTP derivative which is a compound represented by the general formula (I), and the action of the SMTP derivative on cancer cachexia was evaluated as follows.
  • Cancer cells Colon 26 (provided by RIKEN Cell Bank) Colon 26 was cultured in a medium in which 10% FBS was added to RPMI-1640 medium in advance. The obtained cancer cells were suspended in PBS to prepare a cancer cell suspension for transplantation.
  • the blood albumin level was quantified as follows.
  • the blood albumin level was quantified using Wako Pure Chemical Industries, Albumin B-Test Wako, according to the attached method. That is, 4 ⁇ l of standard bovine serum or sample plasma was added to 1 ml of albumin coloring reagent, and after sufficiently stirring, it was left at room temperature for 10 minutes. Thereafter, the absorbance was measured at a wavelength of 620 nm, and the albumin value in the sample was calculated from the standard value corresponding to the standard bovine serum.

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Abstract

La présente invention concerne un inhibiteur d'époxyde hydrolase soluble qui comprend un composé représenté par la formule générale (I) ci-dessous. Dans la formule générale (I) : R représente un atome d'hydrogène, un résidu après retrait d'un groupe amino d'un groupe α-amino acide ou d'un aminosucre, un groupe hétérocyclique, un groupe alkyle contenant 2 à 8 atomes de carbone ou un groupe aryle ; L représente un groupe hydrocarboné aliphatique contenant 4 à 10 atomes de carbone ; X représente un groupe hydroxy ou un groupe carboxy ; et n représente un nombre entier de 0 à 2.
PCT/JP2012/054472 2011-02-24 2012-02-23 Inhibiteur d'époxyde hydrolase soluble WO2012115209A1 (fr)

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CN104418868A (zh) * 2013-08-27 2015-03-18 上海医药工业研究院 纤溶活性化合物fgfc1的分离纯化方法
JP2020070280A (ja) * 2018-11-02 2020-05-07 学校法人昭和大学 Ｓｍｔｐ一群又はｓｍｔｐ−７の製造中間体及びその化学的製造方法
WO2022171151A1 (fr) * 2021-02-10 2022-08-18 上海森辉医药有限公司 Dérivé de smtp-7 et son utilisation

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
CN104418868A (zh) * 2013-08-27 2015-03-18 上海医药工业研究院 纤溶活性化合物fgfc1的分离纯化方法
JP2020070280A (ja) * 2018-11-02 2020-05-07 学校法人昭和大学 Ｓｍｔｐ一群又はｓｍｔｐ−７の製造中間体及びその化学的製造方法
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JP7381035B2 (ja) 2018-11-02 2023-11-15 学校法人昭和大学 Ｓｍｔｐ一群又はｓｍｔｐ－７の製造中間体及びその化学的製造方法
WO2022171151A1 (fr) * 2021-02-10 2022-08-18 上海森辉医药有限公司 Dérivé de smtp-7 et son utilisation

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