JPWO2013146437A1 - 3-Decenoic acid derivatives and uses thereof - Google Patents

Abstract

A novel compound useful as a preventive / therapeutic agent for cancer is provided. According to one aspect of the present invention, there is provided a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: A in the chemical formula 1 is as defined in the specification. . Moreover, the other form of this invention is related with the pharmaceutical which contains the compound mentioned above or its pharmaceutically acceptable salt as an active ingredient as a use of the compound mentioned above. Furthermore, according to the further another form of this invention, the preventive and / or therapeutic agent of the cancer which consists of the said pharmaceutical is provided. [Selection] Figure 1

Description

  The present invention relates to 3-decenoic acid derivatives and uses thereof. Specifically, the present invention relates to a novel compound having an anticancer activity and its use as a medicine (for example, a preventive and / or therapeutic agent for cancer).

  Cancer is the disease with the highest mortality rate today, and there are three major treatments: chemotherapy, radiation therapy, and surgery. Chemotherapy includes antitumor antibiotics such as mitomycin C and actinomycin D, antimetabolites such as 5-fluorouracil and methotrexate, alkylating agents such as cyclophosphamide and nimustine, hormones such as anastrozole and ethinyl estradiol Drugs, platinum preparations such as cisplatin and oxaliplatin, and anticancer agents such as plant alkaloids such as irinotecan and etoposide are used. However, anti-cancer drugs do not act selectively on cancer cells, but also on normal cells, so patients who receive anti-cancer drugs are vomiting, loss of appetite, nausea, hair loss, There are major problems such as bone marrow suppression, liver dysfunction, renal dysfunction, cardiac dysfunction and other serious side effects that can significantly reduce the quality of life (QOL), and it has excellent anticancer activity and toxicity to normal cells. Therefore, anticancer agents with low safety and high safety are always desired.

  Conventionally, a wide variety of anticancer agents are known as described above, and anticancer agents containing unsaturated fatty acid derivatives as active ingredients have been proposed as highly safe anticancer agents (Patent Documents). 1 and Patent Document 2). Specifically, Patent Document 1 discloses an antitumor agent containing 10 trans, 12 cis-conjugated linoleic acid as an active ingredient. Patent Document 2 discloses an antitumor agent comprising a 9-trans, 11-trans-conjugated linoleic acid derivative as an active ingredient.

JP 2003-171272 A JP 2005-247754 A

  However, the effects of previously proposed unsaturated fatty acid derivatives as described above on cancer are not sufficient, and there is a demand for the creation of compounds having more potent anticancer activity.

  Accordingly, an object of the present invention is to provide a novel compound useful as a preventive / therapeutic agent for cancer.

  The present inventors have intensively studied in view of the above problems in the conventional technology. In the process, it was accidentally learned that a 3-decenoic acid derivative, which is one of unsaturated fatty acid derivatives having a specific structure, has high anticancer activity. And based on this knowledge, it came to complete this invention.

  That is, according to one aspect of the present invention, a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof is provided.

In Formula 1,
A represents —NR ¹ R ² , —OR ³ , —SR ³ , —C (R ³ ) ₃ , or —N═C (R ³ ) ₂ ;
In this case, R ¹ and R ² are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group , Aryloxy group, alkylcarbonyl group, —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, Represents an aryl group, a heteroaryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group, or an alkylcarbonyl group, or may combine with each other to form a heterocyclic ring), or —N═C (R ³ ) ₂
Here, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, or alkylcarbonyl group is a halogen atom, alkyl group, cycloalkyl group, cycloalkenyl group. , Aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, carboxy group or ester thereof, alkylcarbonyl group, arylcarbonyl group, amino group, alkylamino group, arylamino group May be substituted with a mercapto group, an alkylthio group, an arylthio group, a cyano group, a nitro group or a heterocyclic group,
Further, the alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, alkylcarbonyl group, arylcarbonyl group, alkylamino group, arylamino group, alkylthio group, arylthio group or heterocyclic group are Optionally substituted with an aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, alkoxyalkoxy group or carboxy group or ester thereof;
Alternatively, R ¹ and R ² may combine to form a heterocyclic ring,
Here, the heterocyclic ring may be substituted with a halogen atom, an alkyl group, a cycloalkyl group, an aryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group, or a carboxy group or an ester thereof,
Further, the alkyl group, cycloalkyl group, aryl group, alkoxy group or aryloxy group is substituted with an aryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, alkoxyalkoxy group or carboxy group or ester thereof. May be;
R ³ is independently of each other a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group or alkyl. Represents a carbonyl group,
The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group or alkylcarbonyl group is a halogen atom, alkyl group, cycloalkyl group, cycloalkenyl group, aryl group, Heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, carboxy group or ester thereof, alkylcarbonyl group, arylcarbonyl group, amino group, alkylamino group, arylamino group, mercapto group, May be substituted with an alkylthio group, an arylthio group, a cyano group, a nitro group or a heterocyclic group,
Further, the alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, alkylcarbonyl group, arylcarbonyl group, alkylamino group, arylamino group, alkylthio group, arylthio group or heterocyclic group are It may be substituted with an aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, alkoxyalkoxy group or carboxy group or ester thereof.

  Moreover, the other form of this invention is related with the pharmaceutical which contains the compound mentioned above or its pharmaceutically acceptable salt as an active ingredient as a use of the compound mentioned above. Furthermore, according to the further another form of this invention, the preventive and / or therapeutic agent of the cancer which consists of the said pharmaceutical is provided.

  According to the present invention, a novel compound useful as a preventive / therapeutic agent for malignant tumors is provided.

In an Example, the result of having observed with the inverted microscope (made by Olympus Corporation) the K562 cell processed with the compound (Compound 14, the compound 25, or the compound 40; concentration 10 micromol, treatment time 48 hours) concerning this invention is shown. It is a photograph. In Examples, the expression of LC3B protein in K562 cells treated with a compound according to the present invention (Compound 14, Compound 25, or Compound 40; concentration 10 μM, treatment time 48 hours) was expressed as an anti-LC3B antibody (manufactured by Cell Signaling technology). It is a photograph which shows the result confirmed by the Western blot used as a primary antibody. (A) is a result of conducting an anticancer activity confirmation test using a mouse transplanted with a cancer cell (human bladder cancer cell line NKB1) using the compound according to the present invention (Compound 24) in the Examples. It is a graph which shows. (B) is a photograph showing the results of confirming the expression of LC3B protein at the tumor site of a mouse administered with compound 24 after transplantation of cancer cells by the same Western blot as described above.

<< Definition of terms >>
In the present invention, the following terms have the following meanings unless otherwise specified.

  The “alkyl group” means a linear or branched alkyl group having 1 to 20 carbon atoms (preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms), such as a methyl group, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1 , 2-dimethylpropyl group, hexyl group, isohexyl group and the like.

  The “alkenyl group” means a linear or branched unsaturated hydrocarbon group having 2 to 20 carbon atoms (preferably 2 to 10 carbon atoms) containing one double bond. Specific examples include a vinyl group, a propenyl group, a methylpropenyl group, a butenyl group, and a methylbutenyl group.

  The “alkynyl group” means a linear or branched unsaturated hydrocarbon group having 1 to 3 carbon atoms and having 2 to 10 carbon atoms (preferably 2 to 6 carbon atoms). Specific examples include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 2-butynyl group, a pentynyl group, and a hexynyl group.

  “Cycloalkyl group” means a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms (preferably 3 to 7 carbon atoms), for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group. And is preferably a cyclopentyl group or a cyclohexyl group. The concept of “cycloalkyl group” includes a saturated bicyclo ring.

  The “cycloalkenyl group” means a cyclic unsaturated hydrocarbon group having 3 to 10 carbon atoms (preferably 3 to 7 carbon atoms) containing one double bond. Specific examples include 1-cyclopentenyl group and 1-cyclohexenyl group.

  The “aryl group” means an aromatic hydrocarbon group having 6 to 20 carbon atoms (preferably 6 to 14 carbon atoms), and examples thereof include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and the like. Is a phenyl group.

  A “heteroaryl group” is a 5 or 6 membered containing 1 to 5 carbon atoms and 1 to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur atoms. An aromatic heterocyclic group is meant. However, these rings do not contain an adjacent oxygen atom and / or sulfur atom. Specific examples of heteroaryl groups include, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, oxazolyl, thiazolyl, isoxazolyl, tetrazolyl, pyridyl, pyrazinyl Group, pyrimidyl group and the like. All positional isomers of these aromatic heterocyclic groups are conceivable (for example, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, etc.). Preferred heteroaryl groups are imidazolyl, pyrazolyl, thiazolyl, pyridyl, pyrazinyl or pyrimidyl groups.

  The “alkoxy group” means a linear or branched alkoxy group having 1 to 20 carbon atoms (preferably 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms), and includes, for example, a methoxy group, Examples include ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.

  The “aryloxy group” means a group represented by (aryl group) -O—, and examples thereof include a phenoxy group, a naphthyloxy group, an anthryloxy group, a phenanthryloxy group, and the like. Is a phenoxy group.

  The “heteroaryloxy group” means a group represented by (heteroaryl group) -O—, and examples thereof include a group corresponding to the above-described heteroaryl group.

  "Alkylcarbonyl group" means a group represented by (alkyl group) -C (= O)-, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, pivaloyl group, valeryl group, isovaleryl group An acetyl group is preferred.

  The “arylcarbonyl group” means a group represented by (aryl group) —C (═O) —, and examples thereof include a group corresponding to the above-described aryl group, specifically, a benzoyl group, Examples include 1-naphthoyl group and 2-naphthoyl group.

  “Heterocycle” is a general term for “aromatic heterocycle” and “non-aromatic heterocycle”. Among these, the “aromatic heterocycle” corresponds to the above-described heteroaryl group, for example, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine. , Pyridazine, pyrimidine, furazane, pyrazine, oxadiazole and the like. The “non-aromatic heterocycle” means a non-aromatic heterocycle having 1 to 5 carbon atoms containing 1 to 3 nitrogen atoms, oxygen atoms, and / or sulfur atoms. For example, pyrroline, Examples include pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, tetrahydropyran and the like. The “heterocyclic group” is a radical formed by removing a hydrogen atom from the above-described heterocyclic ring.

  The “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom.

  The term “hydroxy group ester” means that the hydrogen atom of the —OH group is esterified with a carboxylic acid corresponding to the alkylcarbonyl group such as the alkylcarbonyl group described above.

  The term “ester of a carboxy group” means that OH of a —C (═O) OH group is esterified with an alcohol corresponding to an alkoxy group such as the aforementioned alkoxy group.

  The “alkylamino group” is a general term for a monoalkylamino group and a dialkylamino group. The “monoalkylamino group” means an amino group to which one alkyl group described above is bonded. For example, a methylamino group, an ethylamino group, an n-propylamino group, an isopropylamino group, an n-butylamino group, An n-hexylamino group and the like can be mentioned. The “dialkylamino group” means an amino group in which two alkyl groups described above are bonded, and examples thereof include a dimethylamino group, a diethylamino group, and a di-n-propylamino group.

  “Arylamino group” means a group in which an amino group is bonded to an aryl group such as the above-described aryl group, and examples thereof include a phenylamino group, a biphenylamino group, a naphthylamino group, an anthrylamino group, and a phenanthrylamino group. Groups and the like.

  The “alkylthio group” means a group represented by (alkyl group) -S—, and examples thereof include a group corresponding to the above-described alkyl group.

  The “arylthio group” means a group represented by (aryl group) -S—, and examples thereof include a group corresponding to the aryl group described above.

≪3-Decenoic acid derivative≫
One embodiment of the present invention relates to a compound represented by the following chemical formula 1, or a pharmaceutically acceptable salt thereof (3-decenoic acid derivative).

In Chemical Formula 1, A represents —NR ¹ R ² , —OR ³ , —SR ³ , —C (R ³ ) ₃ , or —N═C (R ³ ) ₂ . Hereinafter, the preferred embodiment of the compound represented by Chemical Formula 1 will be described in more detail with respect to each of the options that the substituent A can take.

[Amide derivatives]
First, when A represents —NR ¹ R ² , the compound represented by Chemical Formula 1 is an amide derivative represented by Chemical Formula 2 below:

In Formula 2, R ¹ and R ² are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy Group, aryloxy group, alkylcarbonyl group, —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, , An aryl group, a heteroaryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group, or an alkylcarbonyl group, which may be bonded to form a heterocyclic ring, or —N═C (R ³ ₂ is represented.

The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, or alkylcarbonyl group described above as the options of R ¹ and R ² are a halogen atom, an alkyl group Cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, carboxy group or ester thereof, alkylcarbonyl group, arylcarbonyl group, amino group , An alkylamino group, an arylamino group, a mercapto group, an alkylthio group, an arylthio group, a cyano group, a nitro group, or a heterocyclic group.

In addition, the above-described alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, alkylcarbonyl group, arylcarbonyl group, alkylamino group, arylamino group as a group capable of substituting R ¹ and R ² Group, alkylthio group, arylthio group or heterocyclic group is further substituted with aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, alkoxyalkoxy group or carboxy group or ester thereof May be.

When R ¹ and / or R ² represents —N═C (R ³ ) ₂ , R ³ independently of one another is a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, An aryl group, a heteroaryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group or an alkylcarbonyl group is represented.

The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group or alkylcarbonyl group described above as options for R ³ are a halogen atom, an alkyl group, a cycloalkyl group. , Cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, carboxy group or ester thereof, alkylcarbonyl group, arylcarbonyl group, amino group, alkylamino group , Arylamino group, mercapto group, alkylthio group, arylthio group, cyano group, nitro group or heterocyclic group.

In addition, as the group capable of substituting R ³ , the above-described alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, alkylcarbonyl group, arylcarbonyl group, alkylamino group, arylamino group, alkylthio group The group, arylthio group or heterocyclic group is further substituted with an aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, alkoxyalkoxy group or carboxy group or ester thereof. Also good.

In one preferred embodiment, at least one of R ¹ and R ² may be an alkyl group that may be substituted, an alkenyl group that may be substituted, a cycloalkyl group that may be substituted, or a group that may be substituted. Represents a good aryl group, an optionally substituted heteroaryl group, —NR ⁴ R ⁵ , or —N═C (R ³ ) ₂ . In a more preferred embodiment, at least one of R ¹ and R ² is an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or —NR ^4. R ⁵ is represented. In a further preferred embodiment, R ¹ represents an unsubstituted alkyl group and R ² represents an unsubstituted cycloalkyl group.

Preferred amide derivatives when R ¹ and R ² have the above definition are selected from the group consisting of the following compounds 1 to 23.

  Among these, from the viewpoint of particularly high anticancer activity, the compound represented by Chemical Formula 1 (Chemical Formula 2) is Compound 1, Compound 2, Compound 4, Compound 7 to Compound 9, Compound 11, Compound 13, and It is preferably selected from the group consisting of Compound 14.

Alternatively, in Chemical Formula 2, R ¹ and R ² may be bonded to form a heterocyclic ring.

  Here, the heterocyclic ring may be substituted with a halogen atom, alkyl group, cycloalkyl group, aryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, carboxy group or ester thereof.

  Further, the alkyl group, cycloalkyl group, aryl group, alkoxy group or aryloxy group described above as the group capable of substituting the heterocyclic ring is an aryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group, an alkoxyalkoxy group. Alternatively, it may be further substituted with a carboxy group or an ester thereof.

  In addition, as the above-described heterocyclic ring, an azacyclooctane (azocan) ring which may be substituted, a piperidine ring which may be substituted, a piperazine ring which may be substituted, or an iminostilbene ring which may be substituted , An optionally substituted dibenzazepine ring, an optionally substituted phenothiazine ring, an optionally substituted phenoxazine ring, and an optionally substituted carbazole ring. Absent. Among them, an azacyclooctane (azocan) ring that may be substituted, a piperidine ring that may be substituted, a piperazine ring that may be substituted, an iminostilbene ring that may be substituted, A good dibenzazepine ring, an optionally substituted phenothiazine ring, and an optionally substituted phenoxazine ring are preferred.

A preferred amide derivative in the case where R ¹ and R ² are bonded to form a heterocyclic ring is selected from the group consisting of the following compounds 24 to 37.

  Among these, from the viewpoint of particularly high anticancer activity, the compound represented by Chemical Formula 1 (Chemical Formula 2) is selected from the group consisting of Compound 24 to Compound 30, Compound 32, Compound 33, and Compound 36. It is preferable.

  In addition, the compound (amide derivative) represented by Chemical Formula 2 can be produced according to a conventional method. As an example of the method for producing the compound, for example, 3-decenoic acid is reacted with thionyl chloride to synthesize a corresponding acid chloride (3-decenoic acid chloride) and a corresponding amine (including a hydrazine derivative). The method of making this react is mentioned. In addition, it may replace with acid chloride and may make it react with an amine similarly using a corresponding acid anhydride and ester. In addition, the produced target compound can be isolated using known separation and purification means such as extraction, distribution, column chromatography and the like.

[Ester derivatives]
Subsequently, when A represents —OR ³ , the compound represented by Chemical Formula 1 is an ester derivative represented by Chemical Formula 3 below:

In Chemical Formula 3, R ³ has the same definition as above. However, R ³ in Chemical Formula 3 represents preferably an optionally substituted alkyl group, an alkenyl group which may be substituted or an optionally substituted aryl group.

  Preferred ester derivatives are those selected from the group consisting of the following compounds 38 to 47.

  Among these, from the viewpoint of particularly high anticancer activity, the compound represented by Chemical Formula 1 (Chemical Formula 3) is selected from the group consisting of Compound 38, Compound 39, Compound 41, and Compound 42. It is preferable.

  In addition, the compound (ester derivative) represented by Chemical Formula 3 can be produced according to a conventional method. As an example of the method for producing the compound, for example, there is a method in which 3-decenoic acid is reacted with thionyl chloride to synthesize a corresponding acid chloride (3-decenoic acid chloride), and a corresponding alcohol is reacted. Can be mentioned. In addition, it may replace with acid chloride and may make it react with alcohol similarly using a corresponding acid anhydride and ester. In addition, the produced target compound can be isolated using known separation and purification means such as extraction, distribution, column chromatography and the like.

[Thioester derivatives]
When A represents -SR ³ , the compound represented by Chemical Formula 1 is a thioester derivative represented by Chemical Formula 4 below:

In Chemical Formula 4, R ³ has the same definition as above. However, R ³ in Chemical Formula 4 preferably represents an optionally substituted alkyl group or an optionally substituted heteroaryl group.

  Preferred thioester derivatives are those selected from the group consisting of the following compounds 48 to 50.

  Among these, from the viewpoint of particularly high anticancer activity, the compound represented by Chemical Formula 1 (Chemical Formula 4) is preferably selected from the group consisting of Compound 49 and Compound 50.

  In addition, the compound (thioester derivative) represented by Chemical Formula 4 can be produced according to a conventional method. As an example of the method for producing the compound, for example, there is a method in which 3-decenoic acid is reacted with thionyl chloride to synthesize a corresponding acid chloride (3-decenoic acid chloride) and a thiol corresponding thereto is reacted. Can be mentioned. In addition, it may replace with acid chloride and you may make it react with thiol similarly using a corresponding acid anhydride and ester. In addition, the produced target compound can be isolated using known separation and purification means such as extraction, distribution, column chromatography and the like.

[Ketone derivatives]
Further, when A represents —C (R ³ ) ₃ , the compound represented by Chemical Formula 1 is a ketone derivative represented by Chemical Formula 5 below:

In Chemical Formula 5, R ³ has the same definition as above. However, Preferably, at least 1 of R < ³ > in Chemical formula 5 contains the alkyl group which may be substituted.

  A preferred ketone derivative is represented by the following compound 51. The compound 51 is also a preferred example of the compound represented by Chemical Formula 1 in that it has high anticancer activity.

  In addition, the compound (ketone derivative) represented by Chemical Formula 5 can be produced according to a conventional method. As an example of the method for producing the compound, for example, 3-decenoic acid is reacted with thionyl chloride to synthesize the corresponding acid chloride (3-decenoic acid chloride), and the corresponding organometallic reactant (RLi, The method of making RMgX (X is a halogen atom)) react is mentioned. In addition, it may replace with an acid chloride and you may make it react with an organometallic reagent similarly using a corresponding acid anhydride and ester. In addition, the produced target compound can be isolated using known separation and purification means such as extraction, distribution, column chromatography and the like.

[Imine derivatives]
When A represents —N═C (R ³ ) ₂ , the compound represented by Chemical Formula 1 is an imine derivative represented by Chemical Formula 6 below:

In Chemical Formula 6, R ³ has the same definition as above. However, preferably, at least one of R ³ in Chemical Formula 6, comprises an aryl group which may be substituted.

  A preferred imine derivative is represented by the following compound 52. The said compound 52 is also a preferable example of the compound represented by Chemical formula 1 at the point that anticancer activity is high.

  In addition, the compound (imine derivative) represented by Chemical Formula 6 can be produced according to a conventional method. As an example of the method for producing the compound, for example, 3-decenoic acid is reacted with thionyl chloride to synthesize the corresponding acid chloride (3-decenoic acid chloride), and the corresponding ketone (in the case of Compound 52) And a method of subjecting diphenyl ketone) to a condensation reaction. In addition, about the manufactured target compound, it can isolate using well-known separation and purification means, such as extraction, distribution, and column chromatography.

  The compound represented by the above-mentioned chemical formula 1 may be the compound itself, and includes pharmaceutically acceptable salts, prodrugs and solvates of the compound as long as it is applicable. For example, a salt can be formed between an anion and a positively charged group (for example, amino group) on the compound represented by Formula 1. Suitable anions include chloride ion, bromide ion, iodide ion, sulfate ion, nitrate ion, phosphate ion, citrate ion, methanesulfonate ion, trifluoroacetate ion, acetate ion, malate ion, tosylate Ions, tartrate ions, fumarate ions, glutamate ions, glucuronic acid ions, lactate ions, glutarate ions, and maleate ions. Similarly, a salt can be formed between a cation and a negatively charged group on the compound represented by Chemical Formula 1. Suitable cations include sodium cations, potassium ions, magnesium ions, calcium ions, and ammonium cations such as tetramethylammonium ions. The compounds also include those salts containing quaternary nitrogen atoms. Examples of prodrugs include esters and other pharmaceutically acceptable derivatives, which can provide active compounds upon administration to a subject. Solvate means a complex formed between an active compound and a pharmaceutically acceptable solvent. Pharmaceutically acceptable solvents include water, ethanol, isopropanol, ethyl acetate, acetic acid and ethanolamine.

≪Use (medicine, cancer prevention and / or treatment agent) ≫
In another aspect, the present invention provides a medicament containing the above-described compound or a pharmaceutically acceptable salt (or prodrug or solvate) as an active ingredient for use of the above-described compound. In particular, according to one aspect of the present invention, a preventive and / or therapeutic agent for cancer comprising the medicament is provided. In another embodiment, a method for treating cancer is also provided. The method of treatment includes administering to a patient in need of treating a condition associated with cancer one or more effective amounts of a compound represented by Formula 1.

  Cancer is an abnormal state characterized by a class of diseases in which the cell population has the ability to autonomously grow, that is, rapidly proliferating cells and, in some cases, tumor metastasis. Examples of cancer include colorectal cancer, liver cancer, hypopharyngeal cancer, esophageal cancer, breast cancer, lung cancer, prostate cancer, stomach cancer, biliary tract cancer, spleen cancer, kidney cancer, bladder cancer, Uterine cancer, ovarian cancer, testicular cancer, thyroid cancer, pancreatic cancer, brain tumor, hematopoietic tumor (eg, acute myeloid leukemia, acute promyelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic Lymphatic leukemia, etc.). Of these, hematopoietic tumors are particularly preferred. In addition, as a mechanism by which the 3-decenoic acid derivative according to the present invention exerts anticancer activity, it is estimated that the 3-decenoic acid derivative induces autophagy in cancer cells (see below) See example).

  A patient in need of the above-described treatment may be administered simultaneously with an effective amount of one of the compounds represented by Formula 1 and one or more effective amounts of other therapeutic agents. Therapeutic agents include G-CSF, steroidal or non-steroidal anti-inflammatory drugs, chemotherapeutic drugs, anti-angiogenic drugs, COX2 inhibitors, leukotriene receptor inhibitors, prostaglandin modulators, TNF modulators and immunosuppression An agent (for example, cyclosporin A). For example, a compound of the present invention and a chemotherapeutic agent may be used in combination to treat cancer (blood cancer or solid cancer). Chemotherapeutic drugs are cancer cell growth inhibitors or cytotoxic drugs. Anti-angiogenic drugs are drugs that provide a therapeutic effect by inhibiting the angiogenic process. The term “administered simultaneously” means that two or more active agents are administered simultaneously or at different times during the treatment period. An example of co-administration includes application to a patient of a solid or liquid mixture of two or more active agents.

  One or more of the compounds represented by Formula 1 (or pharmaceutically acceptable salts, prodrugs or solvates thereof) and pharmaceutically acceptable additives (for use in the prevention and / or treatment of the above-mentioned medical conditions) Composition containing carrier, binder, excipient, diluent (eg, distilled water), pH buffer (eg, phosphate buffered saline), disintegrant, solubilizer, solubilizer, isotonic agent, etc. And the use of such compositions for the manufacture of such therapeutic agents are also encompassed within the scope of the present invention.

  Moreover, the preventive and / or therapeutic agent for cancer according to this embodiment can be administered orally or parenterally depending on the use form. For oral administration, commonly used administration forms such as powders, granules, tablets, capsules, solutions, suspensions, oils, emulsifiers and the like can be adopted. Further, as parenteral administration, a commonly used administration form, for example, a form in which the above-mentioned solution, suspension or the like is administered directly to the damaged site may be employed.

  The dose of the agent for preventing and / or treating cancer according to this embodiment can be appropriately selected according to the patient's body weight, sex, degree of disease progression, and administration method.

  EXAMPLES Hereinafter, although this invention is explained in full detail using an Example, this invention is not limited to a following example.

[Synthesis of compounds]
(Synthesis of Compound 3 (Secondary Amide Derivative))
3-Decenoic acid (17 g, 0.1 mol) (manufactured by Tokyo Chemical Industry Co., Ltd.) was heated to reflux with thionyl chloride (25 ml) (manufactured by Wako Pure Chemical Industries, Ltd.) at room temperature for 2 hours and then on a water bath for 1 hour. Excess thionyl chloride was distilled off under reduced pressure to obtain 3-decenoic acid chloride as an acid chloride.

  A tetrahydrofuran solution (20 ml) containing 1-aminopiperidine (2.1 g, 21.2 mmol) (manufactured by Tokyo Chemical Industry Co., Ltd.) in a tetrahydrofuran solution (10 ml) of the obtained 3-decenoic acid chloride (1.9 g, 10 mmol). In addition, the mixture was heated to reflux for 3 hours on a water bath. Tetrahydrofuran was distilled off under reduced pressure, and water and ethyl acetate were added and partitioned. The ethyl acetate soluble part was washed with water and then distilled off under reduced pressure. The residue was purified by silica gel chromatography (developing solvent: chloroform) to obtain 1.8 g of (E) -N- (piperidin-1-yl) dec-3-enamide (Compound 3).

(Synthesis of Compound 14 (Tertiary Amide Derivative))
N-isopropylhexylamine (705 mg, 5 mmol) (manufactured by Tokyo Chemical Industry Co., Ltd.) in a tetrahydrofuran solution (15 ml) of 3-decenoic acid chloride (0.94 g, 5 mmol) synthesized by the same method as the synthesis of compound 3 And a tetrahydrofuran solution (20 ml) containing pyridine (400 mg) was added, and the mixture was heated to reflux for 3 hours on a water bath. Tetrahydrofuran was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated and purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to give (E) -N-cyclohexyl-N-isopropyldec-3-enamide (compound 14) 1.2 g was obtained.

(Synthesis of Compound 39 (Ester Derivative))
Concentrated sulfuric acid (0.5 ml) was added to an ethanol solution (20 ml) of 3-decenoic acid chloride (1.7 g) synthesized by the same method as the synthesis of compound 3, and the mixture was heated to reflux for 3 hours in a water bath. After cooling, water was added to the reaction mixture, and the mixture was partitioned with ethyl acetate. After washing with water, ethyl acetate was distilled off. The residue was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 3: 1) to obtain 1.3 g of (E) -ethyldec-3-enoate (Compound 39).

(Synthesis of Compound 44 (Ester Derivative))
To a tetrahydrofuran solution (10 ml) of 3-decenoic acid chloride (2.0 g, 10.1 mmol) synthesized by the same method as the synthesis of compound 3, cinnamon alcohol (1.4 g, 10.1 mmol) (manufactured by Tokyo Chemical Industry Co., Ltd.) and pyridine ( A tetrahydrofuran solution (20 ml) containing 950 mg) was added, and the mixture was heated to reflux for 3 hours on a water bath. Tetrahydrofuran was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated, and purified by silica gel column chromatography (developing solvent; hexane: benzene = 2: 1) to obtain 2.5 g of (E) -cinnamyldece-3-enoate (Compound 44).

(Synthesis of Compound 48 (Thioester Derivative))
2-phenylethanethiol (1.4 g, 10.1 mmol) (manufactured by Tokyo Chemical Industry Co., Ltd.) in a tetrahydrofuran solution (10 ml) of 3-decenoic acid chloride (2.0 g, 10.1 mmol) synthesized by the same method as the synthesis of compound 3 And a tetrahydrofuran solution (20 ml) containing pyridine (950 mg) was added, and the mixture was heated to reflux for 3 hours on a water bath. Tetrahydrofuran was distilled off under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated, and purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 5: 1) to give (E) -S-phenylethyldec-3-enethioate (Compound 48) 2.6. g was obtained.

(Synthesis of compounds 1, 2, 4-13, 15-38, 40-43, 45-47, 49-52)
Compounds 1, 2, 4 to 13, 15 to 38, 40 to 43, 45 to 47, 49 to 52 are synthesized by a method similar to the synthesis of the compound described above or by partially modifying the method by a conventional method. did.

(Confirmation of physical properties and structure of product)
For some of the compounds synthesized above, physical properties (color, shape) and structure (MS, ¹ H-NMR) were confirmed. The results are shown below. In addition, it is thought that what has a desired structure is obtained also about the compound which has not confirmed that the physical property and structure were confirmed below.

[Evaluation of anticancer activity of compounds]
(Growth inhibition assay)
Using some of the compounds synthesized above as test compounds, anticancer activity was evaluated by a growth inhibition assay according to the following procedure.

As a cultured cell, human myeloid leukemia cell K562 was used. The cells were cultured in RPMI-1640 medium containing 10% FBS under conditions of 37 ^° C. and 5% CO ₂ .

Test compounds were added to K562 cells at different concentrations, and the number of viable cells after 48 hours was counted by trypan-blue staining. Based on this count result, the growth inhibitory activity of Compound 1 to Compound 52 was evaluated in three stages of +1 to +3 (+3 means that the activity is greater). The results are shown in Table 1 below. For some compounds, IC ₅₀ was calculated using dimethyl sulfoxide (DMSO), which is a solvent in which the compound was dissolved, as a control. The results are shown in Table 2 below.

As is clear from the results shown in Tables 1 and 2, the 3-decenoic acid derivative according to the present invention exhibits high cell growth inhibitory activity against K562 cells, and its IC ₅₀ value is comparable to that of existing anticancer agents. Excellent results that can be achieved.

(Microscopic observation of cell morphology)
K562 cells treated with a compound according to the present invention (compound 14, compound 24, or compound 38; concentration 10 μM, treatment time 48 hours) were observed with an inverted microscope (manufactured by Olympus Corporation). The observation results are shown in FIG. 1 together with the control observation results. As shown in FIG. 1, it was observed that the cells treated with the compound according to the present invention swelled by the compound treatment and eventually led to cell death (arrows shown in FIG. 1).

(Biochemical verification)
The present inventors have set a hypothesis that the mechanism of cell death may be due to autophagy, based on the observation results obtained by the above-described microscopic observation. For the purpose of verifying the hypothesis, the expression of LC3B protein, which is a marker protein of autophagy, was confirmed by Western blot.

  Specifically, K562 cells treated with a compound according to the present invention (compound 14, compound 24, or compound 38; concentration 10 μM, treatment time 48 hours) were recovered, and the LC3B protein was anti-LC3B antibody (manufactured by Cell Signaling technology). ) Was used as the primary antibody and Western blotting was performed using β-actin as an internal standard. The results are shown in FIG. As shown in FIG. 2, it was observed that when each compound was treated at a higher concentration (ie, dose dependent of the compound), the LC3B I band shifted to the LC3B II band. This suggests that the cell death caused by the treatment with the compound according to the present invention is due to autophagy.

(Confirmation of anticancer activity using animals transplanted with cancer cells)
Two human bladder cancer cell lines NKB1 2 × 10 ⁶ were transplanted subcutaneously into 5-week-old nude mice, and when tumors were engrafted to a certain size, 7 mice were divided into 3 groups (control group, small dose administration group, and high dose group). Divided into dose administration groups). Then, a drug solution was administered once a week into the abdominal cavity of each group of mice, and the tumor volume was measured each time. Here, soybean oil was administered as a chemical solution to the control group, and a compound obtained by emulsifying the above-mentioned compound 24 in soybean oil was administered to the small dose administration group and the high dose administration group, respectively. The dose in the small dose administration group was adjusted to 9 mg / kg body weight, and the dose in the high dose administration group was adjusted to 45 mg / kg body weight.

  The results are shown in FIG. As shown in FIG. 3 (A), the increase in tumor volume was suppressed from the 14th day in the high dose administration group, and a significant difference was seen from the control group from the 21st day. A very significant antitumor effect was observed. Here, “T” shown in FIG. 3A means transplantation, and “S” means anatomy.

  In addition, the expression of LC3B protein was confirmed also by the Western blot similar to the above-mentioned "biochemical verification" also about the tumor of each group of mice | mouths on the 42nd day. Specifically, each tumor tissue was crushed in a protein solution to recover the protein, and Western blotting was performed in the same manner as described above. The results are shown in FIG. From the results shown in FIG. 3 (B), the transition from the LC3B I band to the LC3B II band is more remarkably confirmed in the high dose administration group. The experimental results of this animal model also suggested that the cell death of cancer cells by the compound according to the present invention was due to autophagy.

Claims (19)

A compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:
Where
A represents —NR ¹ R ² , —OR ³ , —SR ³ , —C (R ³ ) ₃ , or —N═C (R ³ ) ₂ ;
In this case, R ¹ and R ² are each independently a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group , Aryloxy group, alkylcarbonyl group, —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, Represents an aryl group, a heteroaryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group, or an alkylcarbonyl group, or may combine with each other to form a heterocyclic ring), or —N═C (R ³ ) ₂
Here, the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, or alkylcarbonyl group is a halogen atom, alkyl group, cycloalkyl group, cycloalkenyl group. , Aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, carboxy group or ester thereof, alkylcarbonyl group, arylcarbonyl group, amino group, alkylamino group, arylamino group May be substituted with a mercapto group, an alkylthio group, an arylthio group, a cyano group, a nitro group or a heterocyclic group,
Further, the alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, alkylcarbonyl group, arylcarbonyl group, alkylamino group, arylamino group, alkylthio group, arylthio group or heterocyclic group are Optionally substituted with an aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, alkoxyalkoxy group or carboxy group or ester thereof;
Alternatively, R ¹ and R ² may combine to form a heterocyclic ring,
Here, the heterocyclic ring may be substituted with a halogen atom, an alkyl group, a cycloalkyl group, an aryl group, a hydroxy group or an ester thereof, an alkoxy group, an aryloxy group, or a carboxy group or an ester thereof,
Further, the alkyl group, cycloalkyl group, aryl group, alkoxy group or aryloxy group is substituted with an aryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, alkoxyalkoxy group or carboxy group or ester thereof. May be;
R ³ is independently of each other a hydrogen atom, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group or alkyl. Represents a carbonyl group,
The alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group or alkylcarbonyl group is a halogen atom, alkyl group, cycloalkyl group, cycloalkenyl group, aryl group, Heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, carboxy group or ester thereof, alkylcarbonyl group, arylcarbonyl group, amino group, alkylamino group, arylamino group, mercapto group, May be substituted with an alkylthio group, an arylthio group, a cyano group, a nitro group or a heterocyclic group,
Further, the alkyl group, cycloalkyl group, aryl group, heteroaryl group, alkoxy group, aryloxy group, alkylcarbonyl group, arylcarbonyl group, alkylamino group, arylamino group, alkylthio group, arylthio group or heterocyclic group are It may be substituted with an aryl group, heteroaryl group, hydroxy group or ester thereof, alkoxy group, aryloxy group, heteroaryloxy group, alkoxyalkoxy group or carboxy group or ester thereof. A is -NR ¹ R ^2, a compound or a pharmaceutically acceptable salt thereof according to claim 1. At least one of R ¹ and R ² is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or a substituted The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which represents a heteroaryl group which may be substituted, -NR ⁴ R ⁵ , or -N = C (R ³ ) ₂ . ^{4. At} least one of R ¹ and R ² represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or —NR ⁴ R ^5. Or a pharmaceutically acceptable salt thereof. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R ¹ represents an unsubstituted alkyl group and R ² represents an unsubstituted cycloalkyl group. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein R ¹ and R ² are bonded to form an optionally substituted heterocyclic ring.   The heterocycle may be an azacyclooctane ring that may be substituted, a piperidine ring that may be substituted, a piperazine ring that may be substituted, an iminostilbene ring that may be substituted, or an optionally substituted ring. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, which is a dibenzazepine ring, an optionally substituted phenothiazine ring, an optionally substituted phenoxazine ring, and an optionally substituted carbazole ring. A represents -OR ^3, compound or a pharmaceutically acceptable salt thereof according to claim 1. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R ³ represents an optionally substituted alkyl group, an optionally substituted alkenyl group, or an optionally substituted aryl group. A represents -SR ^3, compound or a pharmaceutically acceptable salt thereof according to claim 1. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R ³ represents an optionally substituted alkyl group or an optionally substituted heteroaryl group. A represents -C (R ^{₃₎ 3,} compound or a pharmaceutically acceptable salt thereof according to claim 1. At least one of R ^3, but includes an alkyl group which may be substituted, a compound or a pharmaceutically acceptable salt thereof according to claim 12. A represents _{^{-N = C (R 3) 2}} , the compound or salt may be a pharmaceutically acceptable according to claim 1. At least one of R ³ includes an aryl group which may be substituted, a compound or a pharmaceutically acceptable salt thereof according to claim 14. A compound according to claim 1 or a pharmaceutically acceptable salt thereof,
The compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of compounds 1 to 52. The compound is
Compound 1, Compound 2, Compound 4, Compound 7 to Compound 9, Compound 11, Compound 13, Compound 14, Compound 24 to Compound 30, Compound 32, Compound 33, Compound 36, Compound 38, Compound 39, Compound 41, Compound 42 And the compound or a pharmaceutically acceptable salt thereof according to claim 16, wherein the compound is selected from the group consisting of Compound 49 to Compound 52.   The pharmaceutical which contains the compound of any one of Claims 1-17, or its pharmaceutically acceptable salt as an active ingredient.   A preventive and / or therapeutic agent for cancer comprising the medicament according to claim 18.